Asymmetric Organocatalysis at the Service of Medicinal...

Review ArticleAsymmetric Organocatalysis at the Serviceof Medicinal Chemistry

Alfredo Ricci

Department of Industrial Chemistry ldquoToso Montanarirdquo School of Science University of Bologna V Risorgimento 440136 Bologna Italy

Correspondence should be addressed to Alfredo Ricci alfredomarcoricciuniboit

Received 4 December 2013 Accepted 30 December 2013 Published 11 March 2014

Academic Editors J M Campagne G Li J C Menendez and L Wang

Copyright copy 2014 Alfredo RicciThis is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The application of the most representative and up-to-date examples of homogeneous asymmetric organocatalysis to the synthesisof molecules of interest in medicinal chemistry is reported The use of different types of organocatalysts operative via noncovalentand covalent interactions is critically reviewed and the possibility of running some of these reactions on large or industrial scale isdescribed A comparison between the organo- and metal-catalysed methodologies is offered in several cases thus highlighting themerits and drawbacks of these two complementary approaches to the obtainment of very popular on market drugs or of relatedkey scaffolds

1 Introduction

Over the past ten years the field of enantioselective organ-ocatalysis has had a significant impact on chemical synthesis[1 2] Currently asymmetric organocatalysis is recognized[3] as an independent synthetic tool besides asymmetricmetallic catalysis and enzymatic catalysis for the synthesisof chiral organic molecules Multiple advantages comparedwith the other two catalytic domains are the reasons for therapid growth and acceptance of organocatalysis In generalorganocatalysts are air- and moisture-stable and thus inert-equipments such as vacuum lines or glove boxes are notnecessary They are easy to handle even on large scale andrelatively less toxic compared to transition metals Moreoverfrequently the reactions are conducted undermild conditionsand high concentrations thus avoiding the use of largeamounts of solvents and minimizing waste

The organocatalysts can be classified by means of theirinteractionswith the substrate or ldquomode of actionrdquo as covalentor noncovalent catalysts (Figure 1)

In covalent organocatalysis a new covalent bond betweenthe catalysts and the substrate is formed as in the case ofaminocatalysis [4] and carbenes [5] leading to a strong inter-action between the substrate and the reagent in the reaction

In the case of noncovalent interactions between the substrateand the catalyst the activation of the substrate occurs viaweak binding exemplified by hydrogen bonding [6] or ionicinteraction as in the case of phase transfer catalysis [7]

The field of asymmetric organocatalysis has enjoyedphenomenal growth in the past 15 years [8ndash10] and duringthe ldquogolden agerdquo [11] of organocatalysis many researchersfrom academia and chemical industry were involved in thisfield with most efforts focused on the development of novelorganocatalysts new reactivities and asymmetric method-ologies Moreover current developments in the field of thesynthesis of structurally complex andor polyfunctionalizedmolecules indicate that chemists have adopted the funda-mental principles of biosynthesis as synthetic strategic keyelements for their synthetic approaches [12] Among thesecascade reactions [13 14] employing a single catalyst capableof promoting each single step have gained in the recent yearsan important role in the efficient and rapid generation ofmolecules with complex architectures generally correlatedwith specificity of action and potentially useful biologicalproperties [15] Organocatalysts turn out to be particularlyfavourable when used in catalytic cascade reactions becausethey allow distinct modes of activation which can often becombined [16 17]

Hindawi Publishing CorporationISRN Organic ChemistryVolume 2014 Article ID 531695 29 pageshttpdxdoiorg1011552014531695

2 ISRN Organic Chemistry

ldquoSynzymesrdquosimple molecules which mimic enzyme functions

Organocatalysis

Noncovalent organocatalysis Covalent organocatalysisnew covalent bond formationweak interactions

AminesHydrogen bonds

Ionic interactionsCarbenes

OP

O O

O H

R

R

NH

NH

S

NH

NH OTMS

PhPh

NH

NO

N

HOH

NN F

F

FF

F

F3C

CF3

N+

BF4minus

+N

NMe2

Brminus

CO2H

Figure 1 General classification of the activation mode of several representative classes of molecules in organocatalysis

Despite their great development the application oforganocatalyticmethodologies to the synthesis of active com-pounds in medicinal chemistry in the past years has rarelybeen reported However in most recent years organocat-alytic methodologies for the synthesis of enantioenrichedmolecules for medicinal chemistry purposes have been gain-ing momentum being particularly attractive for the prepara-tion of compounds that do not tolerate metal contaminationIn academia several groups have made a remarkable effortto show the great applicability of organocatalysts to the totalsynthesis of bioactive natural products [18] and of drugs[19] most of them currently available in the market such asoseltamivir warfarin paroxetine baclofen and maravirocThese efforts mainly focused on the removal of barriersfor scale-up by addressing issues such as catalyst loadingproduct inhibition substrate scope and bulk availability ofdesigner catalysts which have drawn the attention of the com-panies [20 21] that have begun to incorporate organocatalysisas a synthetic tool in some industrial scale processes [22 23]

In this review some of the most recent representativeapplications of asymmetric organocatalysis to medicinalchemistry will be highlighted Not only the access to marketavailable drugs but also the access to drug candidates tomedicinal scaffolds and to promising new compoundswhosebiological profile has not yet been fully explored will bereviewed In some cases a comparison between organo-and metal-catalysed methodologies aimed at the obtainmentof the same medicinal targets will be reported and a few

interesting industrial examples of the use of organocatalysisin medicinal chemistry taken from the literature will bediscussed as well

2 Discussion

21 Noncovalent Organocatalysis

211 Hydrogen Bonding Catalysis This ubiquitous interac-tion is one of the central forces in Nature As an individualhydrogen bonds are feeble and quite easy to break Howeverwhen acting together they become much stronger and leaneach otherThis phenomenon is called ldquocooperativityrdquo (1 + 1 ismore than 2) Some of themany vital functions that hydrogenbonds fulfil in biological systems are shown in Figure 2

The simultaneous donation of two hydrogen bonds leadsto a highly successful strategy for electrophilic activationincreased strength and directionality relative to single hydro-gen bonds Therefore asymmetric catalysis via noncovalentbond interactions such as hydrogen bonding turns out to bea powerful synthetic strategy

Original achievements regarding bis-hydrogen bondcomplexes have been reported through the years It is worthnoting that this two-point binding is a powerful strategy bothinmetal-centered catalysis and in organocatalysis as shown inFigure 3

However whereas coordination to a chiral Lewis acidimposes limitations upon substrate structure any Lewis

ISRN Organic Chemistry 3

Organization andbase pairing of DNA and RNA

Maintenance of the form and thefunction of most biological systems

Secondary and tertiarystructure of proteins

Catalytic cycle ofvarious enzymes

Figure 2 Some of the vital functions that hydrogen bonds fulfil inbiological systems

O OH H O

OO

Kellyrsquos bisphenol

N NH H

Etterrsquos urea

HO

H

HO

H

Jorgensenrsquoshydration model

N

O

N

O

Cu

O O

N NH H

X

Y

O

Me3C CMe3

Figure 3 Original achievements regarding bis-hydrogen-bondedcomplexes

base is in principle capable of engaging bifurcated hydrogenbonds so that this catalytic strategy has potential as ageneral paradigm for synthesis Thiourea catalysts designedby Sigman and Jacobsen [24] and Corey and Grogan [25]as well as minimal peptides introduced by Davie et al [26]appeared together with many others during the last decadethey all fall into this class of catalysts These structuresare highly modular and can be readily modified and finelytuned Many organocatalysts have been recognized to bereminiscent of natural enzymes in their mode of actionand substrate interactionactivation [27] Their use in severalbioinspired methodologies has led to envisaging efficientsynthetic routes leading among the others to the obtainmentof target compounds of interest in medicinal chemistry

In the biosynthesis of fatty acids and polyketides theactive site of polyketide synthase (PKS) clearly highlights thekey role displayed by hydrogen bonds (Scheme 1) [28]

The possibility of mimicking the hydrogen bond inter-actions of PKSrsquos with a simple organic molecule (ldquohunt forsmallest enzymesrdquo according to Schreiner) has been shown

feasible by using double hydrogen bond-based organocata-lysts The potential of this strategy has been appreciated bysynthetic chemists for many years and has been widely usedin asymmetric catalysis [29]

The application of the enantioselective decarboxylativereaction of malonic half thioesters (MAHTs) to the synthesisof medicinal targets is exemplified by the synthesis of GABAreceptor antagonists 3 and 4 using I and II as the organocata-lysts (Scheme 2) The 120574-nitrothioesters 1 and 2 easily achiev-able through these organocatalytic approaches occurringunder mild conditions and tolerating both moisture andair are versatile building blocks for further modificationsAmong them the formation of 120574-butyrolactams by reductionof the nitro group followed by intramolecular cyclizationleads to intermediates en route to the antidepressant (R)-Rolipram [30] 3 and to gram scale synthesis and transforma-tion to (S)-baclofensdotHCl 4 a GABA receptor antagonist usedin the treatment of spasticity [31]

Several enantioselective syntheses of GABA receptorshave been reported based on the use of a metalligand assem-bly as the catalyst system So far (Scheme 3) the Rh(acac)-catalyzed asymmetric 14-additions of arylboronic acids to 4-aminobut-23-enoic acid derivatives led to (minus)-(R)-baclofenent-4 and to (minus)-(R)-rolipram 3 in high yields and excellentenantioselectivities [32]However the use of inert atmosphere(argon) and the to some extent difficult purification byflash chromatography prevent this methodology to be easilyapplied on large scale

An alternative metal-catalysed system [33] in whichthe potential for scale-up is clear is shown in Scheme 4and appears highly competitive with the organocatalysedapproach The chiral Lewis acid-catalyzed Michael additionof diethyl malonate to fully elaborated nitrostyrene 5 allowsthe nitroester 6 that upon reduction and saponification leadsto the target compound 3 Both enantiomers of rolipram 3can be accessed in a total of six steps and at 10 gram scale withexcellent overall yields of 76 and without chromatography

The use of magnesium is preferable to many other metalcatalysts since toxicity issues are avoided The dependenceon solvents such as chloroform does however raise in thismethod toxicological and environmental issues

The range of applications of bioinspired decarboxylativereactions is witnessed by the very recent [34] hydrogen-bonddirected enantioselective decarboxylative Mannich reactionof keto acids with ketimines Under the action of saccharide-derived amino thioureas as chiral catalysts (III) this reactionthat can be run on a gram scale without any detriment on thereaction outcome leads to the expected trifluoromethylated34-dihydro-quinazolin-2(1H)-one rings in very high yieldsand up to 99 ee The potential application of this decar-boxylativeMannich reaction in the domain of pharmaceuticsis demonstrated in a new and efficient and shortcut synthesisof the anti-HIV drug DPC083 7 shown in Scheme 5 Hereinthe crucial role of the hydrogen bond interactions in buildinga complex rigid architecture responsible for the high stereos-electivity is highlighted

Hydrogen bond-based organocatalysis also plays a pri-mary role in the synthesis of low molecular weight drug can-didates The aza-Henry reaction (nitro-Mannich reaction)


NHN H

As nO

NH

H

HisS

Cys

S

O

O

O

CoA

cisthis

asn

RNO

S O

O

R

N

N

H

NO

H

H

Chiralspacer R

S

O RO(minus)O(minus)

(minus)O (+)

(+)

(+)

R998400

NO2

Scheme 1 Activation of MAHT in the active of PKA synthase and in the chiral core of the organocatalyst

X

Y

+

NH

O

NH

OO

3-(R)-rolipram

NH

OCl

4-(S)-baclofenHCl

X = HY = Cl

X = OBnY = OMe

67 yield97 ee

S

O

OBn

Up to 97 yieldand 90 ee

82 yield 90 ee5 gr scale

S

O

Cl1

2

S

MeO

MeO

MeOMeO

MeO

O

OH

O

NNH

N

O

H

OMe

OMe

OMe

N

NNH

N

NH

OO

Cat II

Cat II 5 mol Cat I 20 mol

Cat I

Cl

HO

CF3

CF3

CF3

NO2

NO2

NO2

CF3

Raney-NiH2

H3PO4 64

NH2HCl

HO2C

Scheme 2 Synthesis of GABA receptors via hydrogen bonds directed organocatalysis mimicry of polyketide synthase

BINAP base+

(R)-baclofen ent 4

Up to 96 yield

OH

Cl

O

80 overall yield89 ee

OOMe

OMeOMe

NHO

(R)-rolipram 357 overall yield84 ee

OO

DioxaneH2O

Rh(acac)(C2H4)2R2R1N

R2R1N

R4R4

R3

R3

2M NaOH MeOH rt

TFA CH2Cl2 rt 2h

12h HCl Et2O rt 24h

(+)H3NCl(minus)

B(OH)2

Et3N toluene rfx 20h

Scheme 3 Metal-catalysed synthesis of GABA receptors


CHOHO

MeOMeO

MeO

MeO

Ligand (55 mol)

NMM (6 mol)mol sieves rt

95 yield on 10 g scale 96 ee

NHNH O

NaOH TsOH

OMe

O

EtO

O

(R)-rolipram

Ligand

92 three steps

56

3

N

OO

N

EtO

O

OEt

O

OC4H9

NO2

NO2

OC4

4

H9

OC4H9

EtO2C

Ra-NiH2

H3PO

CO2Et

C4H9O

Mg(OTf)2 (5mol)

Scheme 4 Scalable metal-catalysed synthesis of both enantiomers of rolipram

N

N N

NH

O

O

N

NH

PMBPMB

PMB

PMB

PMB

O

OHN

NH

O

N

NH

O

+Cat 10 mol+

MeOH RT (2) TFA anisole

(Z)-DPC 08326 96 ee

(E)-DPC 08353 96 ee

O

N

NO

Cl

Cl

Cl Cl

Cl

Cl

OOAc

AcO

OAc

OAcN N

S

H H

N

H

Ar

O

OH

7

IIIO

OH

OF3C

F3C

F3C

F3C

CF3

CF3

(minus)O

(+)

R998400

NaBH4

(1) 220ndash230∘CHMPA

THF minus20∘C 48h

Scheme 5 Hydrogen-bonding assembly between organocatalyst ketimine and 120573-ketoacid in the preparation of the anti-HIV drug DPC 083

was used by Xu and coworkers [35] for the short asymmet-ric synthesis of the chiral piperidine derivative CP-999948 (Scheme 6) The previous asymmetric syntheses of thispotent neurokin-1 receptor antagonist were mainly basedon the use of metal complexes as catalysts but sufferedfrom several drawbacks for example low overall yield andenantioselectivity or a lengthy synthetic route Notably theorganocatalysed Takemotorsquos synthesis proceeded in five stepswithout the need to separate the diastereomeric intermediatesthat were cyclized as a mixture The catalyst employed wasa chiral thiourea IV which served as an activator of boththe nitroalkane and imine reactants The transition state isrelatively complex and is dominated by hydrogen-bondinginteractions

The simultaneous donation of two hydrogen bonds hasalso proven to be a highly successful strategy for electrophilicactivation in enzymes with an ldquooxyanion holerdquo having apostulated role in the stabilization of many high-energytetrahedral intermediates [36] It appears that living systemsdiscovered and made use of these interactions in the ubiq-uitous useful ring-forming Diels-Alder reaction eons agofor the construction of complex natural products so thatthe prospect of discovering a Diels-Alderase mimic wouldbe especially exciting Following this concept and inspiredby the antibody 13G5-catalyzed Diels-Alder cycloadditionof acrylamide with a carbamate (Scheme 7) taking placevia a cooperative multiple hydrogen bond coordination toboth diene and dienophile [37] a catalytic asymmetric


H MeO

HN

HN

Ph

Ph

PhMeO

MeO

Boc

Boc

Ph

PhNH

HN

OMe

++

(i) TFA

80

80

75

Epimerization andreduction

Cat IV 10 mol

83 ee

95 ee

cistrans 191

Reductive amination of

HN

S

HN

Cat IV8 (minus)-CP-99 994

NBoc

F3C

F3C

NMe2

NO2

NO2

NH2

NO2

NO2

CH2Cl2 minus20∘C

(ii) K2CO3

o-MeOC6H4CHO

NH

NH

Scheme 6 Organocatalytic synthesis of CP-99994 8 a neurokinin-1 receptor agonist

O

NH

R

H ONN

N NH H

57-His

HO

O

Asp-102O

NR

O

Ser-195

NN

Gly-193Gly-193 Ser-195Ser-195

Ser-195

N NH H

57-His

HO

O

Asp-102 (+)

H

HOxyanion hole

Serine protease

HN

O

O Ar

O

Antibody 13G5pH 74

+

95 ee 49 1 dr

N

O O Ar

HOO H

L36-Tyr

O

N

Asn-91L

H H

O

O Asp-50H

N(CH3)2

N(CH3)2

H2O 37∘C

(minus)

(minus)

(minus)

(minus)

NHCO2CH2Ar

CON(CH3)2

R998400

R998400

Scheme 7 Occurrence of the oxyanion hole in enzymatic processes

cycloaddition of 3-vinylindoles with activated dienophileshas been recently reportedThe synthetic elaboration of vinylindole derivatives via cycloaddition appears highly promisingin that it leads (Figure 4) to fused poly-heterocyclic ringsystems otherwise not easily accessible like carbazoles andpyridocarbazoles with antibiotic and antitumor activities

A scenario in which a suitable bifunctional acid-baseorganic catalyst (V) coordinates through H-bond interac-tions both diene and dienophile leading (Scheme 8) to ahighly organized transition state has been designed [38]delivering in very high yields and excellent enantioselectiv-ities a wide range of indolines and tetracarbazoles common

scaffolds in a variety of biologically active and pharmacolog-ically important alkaloids [39ndash41] The synthetic potential ofthe cycloadducts is exemplified by the access to indoline 9to tetrahydrocarbazole 10 with potent activity against humanpapillomaviruses [42] and to a precursor [43] of tubifolidine11 a Strychnos alkaloid previously prepared using a nine-stepsynthesis (Scheme 9)

The combination of hydrogen bond-based organocatal-ysis and cascade reactions or one-pot processes in thesynthesis of therapeutics is powerful and can be illustratedby the synthesis of the alkaloid (minus)-epibatidine developedby the Takemotorsquos group and based on an enantioselective


CycloadditionsSynthetic elaboration ofvinyl indole derivatives

Het

NH

R

Ph

Natural product from algae

NH

OMeOMe

Antibiotic action

Carbazoles

NH

R

Antitumoral action

N

Me

Me

MeMeMe

NH

NMe

Pyridocarbazoles

R1

R2O

R3

Figure 4 Biological activity of ring-fused indoles

N

N

N

NN

S

H

O

X HH

N

N

O

O

R

X

O

O

R-N

[4 + 2]

X = Boc Ts or Me racemic mixturesX = H high enantioselectivities

Lewis base activationincrease in the HOMO energyof the diene

Broensted acid activationlowering in the LUMOenergy of the dienophile

N

N

NH N

H

S

H

O

Cat V

CF3

CF3

CF3

CF3

lowast

lowastlowast

Scheme 8 Bifunctional activation in the Diels-Alder reaction of 3-vinylindoles

double Michael addition [44] The bifunctional thiourea-based organocatalyst IV catalysed the first Michael additionof the 120574120575-unsaturated 120573-ketoester 12 to the nitroalkene 13and on addition of KOH the newly formed nitroalkanecyclized to form the polysubstituted cyclohexene 14 in ahigh yield and 75 ee (Scheme 10) The total synthesisof (minus)-epibatidine 15 was achieved in further seven stepsfrom 14 Though due to its high toxicity (200 times morepotent than morphine) and lacking of selectivity on nicotinicreceptors (minus)-epibatidine cannot be considered a lead forpharmaceutical development it has already opened the routeto a wide series of more selective and promising derivatives

Other laboratory scale syntheses based on the useof thiourea-derived bifunctional organocatalysts have beenreported leading to targets of interest in medicinal chem-istry Among them a further highly enantioselective (99ee) synthesis of (R)-rolipram and of (3S-4R)-paroxetine(see Section 221) has been accessed through the use ofa combined thiourea-cinchona catalyst [45] using a highly

enantioselective Michael addition of malonate nucleophilesas key steps An indanol-thiourea organocatalyst resulted onthe other hand very effectively in one of the first enantiose-lective Friedel-Crafts alkylations of indole with nitroalkenesleading after a synthetic elaboration of the alkylation productsto the synthesis of 1234-tetrahydro-120573-carbolines [46] withanti-inflammatory and anti-arrhythmic activities

212 Phase Transfer Catalysis Phase transfer catalysis (PTC)has long been recognized as a versatile catalytic methodologyfor organic synthesis in both industry and academia Itfeatures operational simplicity typically mild reaction condi-tions inexpensive and environmentally benign reagents andsolvents and relatively cheap catalysts that can be found inreasonable abundance [47] Moreover it has proven particu-larly viable for large- and industrial-scale applications Chiralphase transfer catalysis has seen an explosive growth in thepast couple of decades [48ndash50] and is still one of the hottestresearch areas in asymmetric noncovalent organocatalysis


N NPh

O

O

H

HHN NPh

O

O

H

H N NPh

O

O

H

HHO

N

O

OH

H

HCl 9

quant97 ee

97 ee

88 yield95 5 dr

HCl 5 M TFA

(ii) Acetone CNDEAD Ph3P(iii) HClMeOH

93 eeN

H

N

H

H

Tubifolidine 11

Indoline 10tetra-H-carbazole 9

(ent)

68 yield 94 ee

N

RH

HH

H

Reference [43]

CF3

CO2Me

(i) LiAlH4

H2 PdC

Scheme 9 Synthetic elaborations of the vinylindole cycloadducts

N

Cl

Cl

Cl

Cl

Cl

MeO

MeO

O

O O

O

MeO

O O

N

N

O

O

NOH

OH

HN

H

N 3 steps

4 steps

+

Cat IV 10 mol

85

Cascade sequence

75 ee

(minus)-epibatidine

NH

NH

S

Cat IV

12

15

1413

NO2

NO2

NO2

NO2

NMe2

CF3

lowastlowastlowast

F3C

Toluene 0∘C

KOH EtOH 0∘C

Scheme 10 Organocatalyzed cascade synthesis of (minus)-epibatidine 15

[51 52] The development through the years of various typesof chiral phase transfer catalysts relying on the moleculardesign of both natural product-derived and purely syntheticquaternary ammonium salts delivered [53 54] not onlyhigher reactivity and stereoselectivity but also new syntheticopportunities [55] So far a wide variety of highly enan-tioselective transformations catalyzed mainly by cinchonaalkaloids or binaphthyl-derived quaternary ammonium saltshave been introduced and applied to the asymmetric syn-thesis of biologically active compounds including a numberof pharmaceuticals Furthermore pharmaceutical companies

have demonstrated the viability of asymmetric phase transferreactions in the large-scale preparation of drugs

Interestingly the first landmark example in the domainof chiral phase transfer organocatalysis was developed byMerck as early as in 1984 for the synthesis of a uricosuricdrug (+)-indacrinone (MK-0197) In thiswork [56] the highlyenantioselective alkylation of compound 16 was achievedusing the cinchona alkaloid derivative V (obtained by N-alkylation of the quinuclidine core) NaOH as a base andMeCl as the alkylating agent (Scheme 11) Using this approachintermediate 17 used for the synthesis of the indacrinone


OCl Cl

O

Ph PhPh

C l Me MeO

O

O

HO

MeCl

50 aq NaOH

60 overall

95 yield92 ee

(+)-indacrinone

N

Cat V

Cat V

OH

N

O

OHClCl

H

10 mol17 1816

MeOMeO

MeO

C l C l

20∘C 18h

CF3CF3

N(+)

N(+)Br(minus)

Br(minus)

Scheme 11 Phase transfer catalysed synthesis of (+)-indacrinone 18

O

MeO

MeO

O O

HOOC-O

O

N

OH

NHH

H

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

(+)

Cat VI

Cat 55 mol

Toluene RT 15 h

O

+

92 yield 100 g scale40 ee

19

20 21

(minus)

Scheme 12 Synthesis of a drug candidate for treatment of brain edema via PTC catalysis

18 could be accessed in high yield and enantiomeric purityon a pilot plant scale (sim75Kg) the cost of producing thisenantiomer is significantly lower than the cost of producingthe same molecule by a resolution process

Studies on the origin of the stereoselectivity substantiatedthe hypothesis of a tight ion pair transition state where theenolate anion and the cationic catalyst were held close to eachother through 120587-interactions

Almost in the same period scientists fromMerck demon-strated that cinchona derivatives such as VI could catalysethe Michael addition of ketone 19 with methyl vinyl ketone(MVK) under mild conditions and crucially at large scale[57] (Scheme 12) to give 20

The ultimate goal of this study was the synthesis of drugcandidate 21 (and analogues) for the treatment of brainedema and traumatic head injuries [58] This reaction wascarried out under various conditions and the operationallysimple liquidsolid system gave excellent isolated yields at100 g scale albeit with modest levels of enantioselectivityThese early examples showed the potential power of theasymmetric PTC reactions for industrial-oriented synthesis

The learning generated in the previous examples wasof great benefits for further developments of chiral phasetransfer organocatalysis An impressive use of the use ofquaternary salts of cinchona alkaloids in phase transfercatalysis for the pilot scale production of drug candidatesis shown in the development at Merck Sharp amp Dohme ofthe asymmetric synthesis of an estrogen receptor 120573-selectiveagonist [59] (Scheme 13) The base-catalysed Michael addi-tion of the enolate of indanone 22 to MVK in the presenceof a (+)-cinchonine-derived quaternary ammonium phasetransfer catalyst VII gives diketone 23 in enantioenrichedform Robinson annulation then follows with construction ofthe cyclohexenone ring of tetrahydrofluorenone 24 that uponcyclization gives rise to the expected target 25 Overall thechemistry developed has been used to prepare gt6 kg of thedrug candidate in 18 overall yields and with gt99 ee The2-naphtylmethylcinchoninium bromide catalyst VII selectedon the basis of the 50 ee in the Michael addition stepand on the bulk commercial availability of the required 2-naphtylmethyl bromide and the agitation rate were param-eters critical to the success of this reaction


O

O

NaOH tolueneCat VII (8 mol)

O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R

Cat VIIR = 2-naphtylmethyl

252423

22

N(+)

Br(minus)

Scheme 13 Pilot-scale synthesis of an estrogen receptor-120573

O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR

Cl BaclofenCat VIII 54 yield97 ee (S)

94 ee (R)

91 ee (S)

89 ee (R)Cat ent-VIII 66 yield

(S)-(+)-4 HCl(R)-(minus)-4 HCl

N

NHO HOH

H

N

N

H

H

Cat ent-VIIICat VIII

+

26R

CF3CF3 (+)(+)Br(minus)

Cl(minus)

Br(minus)

F3CF3C

NO2

NO2

CH3-NO2 O2NO2N(+)H3N

Cat VIII R = 4-ClC6H4

Cat ent-VIII R = 4-ClC6H4

87ndash89100∘C

K2CO3 (5 equiv)

87ndash89

Scheme 14 Laboratory-scale synthesis of both the enantiomers of baclofen 4

In another more recent example the capability of chiralphase transfer catalysis based on quaternary ammoniumsalts VIII and ent-VIII-derived from cinchona alkaloids toinduce highly enantioselective CndashC bond forming reactionshas been disclosed in the conjugate addition of nitroalkanesto 4-nitro-5-stirylisoxazoles a valuable synthetic alternativeto cinnamic esters [60] (Scheme 14) The transformation ofthe Michael adducts 26 into 120574-nitro acids could be easilyperformed and the subsequent Raney-Ni reduction gave thehydrochlorides of the GABA receptors (S)- and (R)-baclofen4 thus outlining a short organocatalysed route alternativewith respect to that outlined in Scheme 1

The accessibility of both the enantiomers in goodyields and excellent enantioselectivities the wide reactionscope and the easy availability and the use of inexpensiveorganocatalysts outline major assets of this organocatalysedmethodology

213 Lewis and Broslashnsted Base Catalysis Nucleophilic cat-alysts have had a wide role in the development of newsynthetic methods [61] In particular the cinchona alkaloids

catalyse many useful processes with high enantioselectivities[62] They can be used as bases to deprotonate substrateswith relatively acidic protons such as malonates forming acontact pair between the resulting anion and the protonatedamine This interaction leads to a chiral environment aroundthe anion and permits enantioselective reactions with elec-trophiles (Figure 5)

Since the seminal publication by Hiemstra and Wynberg[63] there have been different applications of this method-ology with significantly improved catalysts [64] Importantin many of these processes is the ability to control theformation of quaternary centers with high enantiomericexcess [65] The robustness and the easy availability of thecommercially available cinchona derivatives attracted in thelast decades increasing interest of both the academic andapplied research Inmedicinal chemistry relevant targets suchas anticancer and antiparasitic agents were approached byusing this methodology

In the past 10 years the number of chiral nonracemicpharmaceuticals on the market was consistently increasingand many new single enantiomer drugs were produced to


NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)

Figure 5 Cinchona alkaloids catalysis through chiral contact ion pair

Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)

Yields 67ndash94dr 75 25ndash98 2ee 80ndash99

N Ts Ts+

292827 SEtSEt

N

TMSO N

H

R = i-Pr i-Bu R = aryl heteroaryl

Et2O 20∘C 16h R1

1

R1

R2

R2

2

Scheme 15 Synthesis of anticancer thiazolone derivatives by organocatalytic aza-Mannich reaction

offer enhanced therapy and reduced toxicity Organocatalysisemerged to be an effective way to reach this goal A seriesof chiral 2-ethylthio-thiazolone derivatives 29 have beenprepared (Scheme 15) by a straightforward enantioselectiveaza-Mannich addition of thiazolones 27 to N-tosylimines 28catalyzed by a simple cinchona alkaloid (IX) as the chiralbase with a 20mol of catalyst loading using diethyl ether assolvent [66]The derivatives bearing a quaternary center wereobtained in good yields and in general with high diastereo-and enantioselectivities All the compounds evaluated infive human cell cancer lines using MTT essay caused adose-dependent growth inhibitory effect on all the testedcancer lines This study provides a foundation for furtherdevelopments of new single enantiomer anticancer drugs

Malaria is one of the most important diseases of thethird world and the efficacy of the available drugs is limitedby emerging resistance In 2011 in an extensive effort tofind unique chemotypes for the treatment of malaria ithas been found that dihydropyrimidinone-derived guanidinederivatives were the most promising [67] These guanidineanalogs 34 were synthesized in a multistep synthesis withcommercially available and inexpensive (+)-cinchonine Xand (minus)-cinchonidine XI promoting the key organocatalyticstep (Scheme 16)

In this step the diketone derivative 30 was deproto-nated by the nitrogen of the chiral base (cinchonine orcinchonidine) which attacks the imine formed in situ startingfrom 31 to give the corresponding intermediates 32 inhigh enantiomeric excesses These were then cyclised into

dihydropyrimidinones 33 Being the two organocatalystspseudoenantiomers both enantiomers of dihydropyrimidi-nones could be synthesized Further treatment of 33 withLawesson reagent followed by sulphur alkylation and itssubstitution with different anilines led to a library of 96guanidine derivatives 34

Another quite impressive example of how simple andunmodified cinchona alkaloids can be used for the syn-thesis of medicinally important scaffolds is provided bythe synthesis of (minus)-uperzine A 37 currently being testedin clinical trials as a promising drug for the treatment ofAlzheimer disease [68] This reaction that can be consideredas the first application of cascade reaction to the synthesisof targets in medicinal and natural product chemistry datesback to 1998 when the field of organocatalysis was just at itsinfancy Huperzine-A containing a challenging bridged tri-cyclic core was obtained via a simple Michaelaldol cascadereaction sequence between a120573-ketoester 35 andmethacrolein(Scheme 17) The commercially available and inexpensiveorganocatalyst (minus)-cinchonidine (XI) acts as a bifunctionalorganocatalyst As a base it deprotonates 35 forming a chiralion pair but the secondary alcohol function of the catalystsimultaneously activates amethacroleinmolecule by forminga distinct hydrogen bond and incorporating it into the ioniccomplexTheMichael reaction as the first step of the cascadereaction is thus initiated followed by intramolecular aldolcondensation The tricyclic core 36 of (minus)-huperzine A wasformed with an overall yield of 60 and 64 enantiomericexcess (ee) The completion of the total synthesis starting


HNXO O

O O

N H

O X

SHNN

+ Catalyst

Lawessonrsquosreagent

Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine

(minus)-cinchonidine

Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O

Scheme 16 Synthesis of a library of dihydropyrimidinones 34 anti-malarial derivatives by a cinchona alkaloid-driven key organocatalyticstep

N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps

(minus)-Huperzine A45

AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O

Intermediate ionic complex(minus)-cinchonidine XI

minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120

∘C 24hDCM 10d minus10∘C

Scheme 17 Preparation of (minus)-huperzine A by means ofan organocatalysed Michaelaldol cascade reaction sequence

from 36 required 5 further steps It is worth noting that thesynthesis of ent-37 could be achieved in the sameway startingfrom cinchonine Though to some extent disappointing forthe modest enantioselectivity this procedure outlines a rapidone-pot entry to molecular complexity by using a simplemetal-free commercially available and inexpensive air- andmoisture-stable organocatalyst

214 Broslashnsted Acid Catalysis Recently chiral Broslashnsted acidshave found widespread application in organocatalysis [6970] For instance in one of the most relevant processes theaction of a Hantzsch ester a biomimetic source of hydridecombines with that of chiral phosphoric acid as the catalystThis can be considered as a metal-free simple H(+)-H(+)cascade reaction and has become a favourite application to

the enantioselective reduction of nitrogen-containing hete-rocycles like pyridines or quinolines to the correspondingtetrahydroquinolines and tetrahydropyridines [71 72] Thisapproach gives access to a variety of highly enantioenrichedheterocycles that are privileged structures in natural productsand drugs

The preparation of fluoroquinolones reported by Ruepingand coworkers [73] outlines the application of the transferhydrogenation process to the synthesis of building blocksthat have been utilized to complete the metal-free synthesisof drugs like (R)-flumequine (43) or (R)-levofloxacin (44)that display antibacterial activity towards a broad spectrumofbacteria [74 75] The readily available fluorinated quinoline37 and benzoxazine 38 were reduced in the presence ofHantzsch esters 39 or 40 with only 1mol of the stericallydemanding chiral phosphoric acid XII as catalyst to give


N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43

(R)-Levofloxacine 44

37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h

Scheme 18 Enantioselective transfer hydrogenation for the preparation of tricyclic fluoroquinolone antibacterial agents 43 and 44

N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46

(i) CH2O AcOH(ii) NaBH4

1mol cat XIV PhH 60∘C

Scheme 19 Synthesis of (+)-galipinine via binolphosphoric acid-catalyzed enantioselective cascade reduction

the corresponding hydrogenated compounds 41 and 42in very good yields and with excellent enantioselectivities(Scheme 18)

The synthesis of the two targets 43 and 44 was thenaccomplished in three more steps

Moreover through the use of only 1mol of the binaph-thol phosphate catalysts XIV a stepwise hydride transferfrom the Hantzsch ester 45 to quinoline 46 afforded [76] thecorresponding tetrahydroquinoline 47 in excellent yields andenantioselectivities (Scheme 19) Mechanistically it has beenassumed that this enantioselective cascade hydrogenationoccurs in two cycles involving iminium ion an enamine

species respectively A reductive N-methylation concludes aconcise synthesis of (+)-galipinine 48 showing antimalarialactivity on Plasmodium Falciparum for the chloroquine-resistant strains

Another remarkable and to some extent different useof a chiral phosphoric acid in the synthesis of a drugcandidate is represented by the one-pot acid-catalyzed three-component condensation of an aldehyde 49 a thiourea 50and a 120573-ketoester 51 in an asymmetric Biginelli reaction togive the chiral 34-dihydropyrimidin-2-one derivatives 54[77] These scaffolds are privileged structures that dependingon the substitution pattern exhibits a variety of important


O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation

Yield up to 86Up to 97 ee

10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO

R1 = Ar AlkR2 = AlkR3 = Alk

Scheme 20 Enantioselective chiral Broslashnsted acid-catalyzed three-component Biginelli reaction

pharmacological properties like the inhibition of HepatitisB virus replication Here the chiral phosphoric acid XVcatalyzes the Biginelli reaction by forming a chiral N-acyliminium phosphate ion pair 52 to which enantioselectiveaddition of 120573-ketoesters 51 occurs to generate optically active54 via the enantioenriched intermediate 53 (Scheme 20)

An asymmetric variant with an ytterbium-based catalystfor this Biginelli reaction was reported earlier [78] but thediscovery of a metal-free synthesis by using Broslashnsted acidXV which avoided contamination of the product with tracesof metal resulted in an important advancement The phos-phoric acid-based catalyst matched or even improved thelevel of conversion and stereoselectivity of the correspondingLewis acid-catalyzed reaction while maintaining the samesubstrate scope

22 Covalent Organocatalysis The area of amine-organoca-talysed reactions is clearly dominated by secondary aminesdue to the versatility of possible combination of enamine(EN) and iminium (IM) activation However the primaryamino function as a part of a chiral scaffold could beengaged as well in a number of synthetically appealingorganocatalysed reactions Several reviews on amino catalysishave recently appeared [79 80]

221 Secondary Amine Organocatalysis via Enamines andIminium Ions The reaction that alerted the scientific com-munity to the potential of organocatalysis was a proline-catalysed intramolecular aldol reaction reported almostsimultaneously by two groups during the early 1970s [81 82]It was not until List et al published a related intermolecularprocess [83] that secondary amine catalysis via enamineinspired by Naturersquos aldolase enzymes became en vogue inthe domain of organocatalysed reactions Since this reportthere have been many subsequent publications of catalytic

reactions via enamines Proline-catalysed Mannich reactions[84] dihydroxylations [85] cross aldolizations [86] andaminations [87 88] have held persistent interest in the areaof asymmetric catalysis

Mechanistically this enamine catalysis might be betterdescribed as a bifunctional catalysis because the amine-containing catalyst (proline) typically interacts with a ketonesubstrate to form an enamine intermediate but simul-taneously engages with an electrophilic reaction partnerthrough either hydrogen bonding or electrostatic interaction(Scheme 21)

The capacity of chiral amines to function as enantioselec-tive LUMO-lowering catalysts for a range of transformationsthat had traditionally employed Lewis acids has also beenextensively used in organocatalysis This strategy termediminium activation was founded on the mechanistic pos-tulate that the reversible formation of iminium ions from120572120573-unsaturated aldehydes and chiral amines might emulatethe equilibrium dynamics and 120587-orbital electronics that areinherent to Lewis acid catalysts thereby providing a platformfor designing organocatalytic processes (Scheme 22)Thefirstgeneration catalyst to fulfil criteria such as efficient andeasily reversible iminium ion formation discrimination ofthe olefin 120587-face and easy preparation was imidazolidinoneXVI that in 2001 evolved in the more efficient imidazo-lidinone catalyst XVII (second generation) With its tailor-made family of imidazolidinone catalysts iminium catalysishas been successfully applied to a broad range of chemicaltransformations including cycloadditions [89 90] conjugateadditions [91ndash93] hydrogenations [94] and cascade reac-tions [95]The operational simplicity of these processes madethem attractive alternatives to Lewis acid catalysis

A number of drugs currently on the market have beenapproached with the enamine-iminium-based organocatal-ysis taking advantage by the simplicity of these inexpensiveorganocatalyst and by their high efficiency


HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=

Scheme 21 Mechanism for the proline-catalysed intermolecular aldol reaction

N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe

I-generation II-generation

O + Lewis acid (LA) OLA

O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX

Scheme 22 Iminium activation through LUMO lowering

The case of warfarin is a very good example of theexceeding utility of organocatalytic methodologies in theassembly of relatively simple yet highly relevant moleculesand many iminium-based organocatalysed processes havebeen designed for this aimWarfarin is a vitamin K analogueinhibiting vitamin K epoxide reductase Its sodium saltcommercialised mainly under the trade names Coumadinand Marevan is one of the most widely prescribed anti-coagulants Warfarin has been administered as a racematefor over fifty years however its two enantiomers displayremarkably different pharmacological and pharmacokineticprofiles Even if the S isomer shows higher activity it ismetabolised more rapidly than its less active R counterpart

[96] Thus production of both (R)- and (S)-warfarin inenantiopure form might be of importance for a tailoredpatient treatment [97]

An obvious synthetic approach to warfarin is repre-sented by the Michael addition of 4-hydroxycoumarin tobenzylideneacetone a reaction which is well posited foriminium ion catalysis through enone activation Such anapproach appears superior and more straightforward com-pared to the few reported catalytic asymmetric methodsbased on organometallic chemistry which rely on more tor-tuous oxidation-reduction sequences with protecting groupsusage [98 99] Accordingly the feasibility of the organocat-alytic strategy leading directly to warfarin has been well


Table 1 Catalytic asymmetric approaches to warfarin through iminium ion catalysis

O O+

OCatalyst

cocatalystconditions

O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H

Entry Catalyst Cocatalyst Conditions Yield () ee () Ref1 XVIII (10mol) mdash CH2Cl2 RT 150 h 96 82 (R) [100 101]2 XIX (10mol) AcOH (10 equiv) THF RT 24 h 99 92 (R) [102]3 XX (5mol) LiClO4 (5mol) AcOH (10 equiv) 14-dioxane RT 24 h 61 92 (R) [103]4 ent-XX (2mol) BzOH (4mol) H2O RT 12 h 78rarr 50a 70 rarrgt99a (S) [104]5 XXI (10mol) Caproic acid (10 equiv) THF RT 36 h 96 91 (S) [105]6 XXII (10mol) 4-MeBzOH (20mol) Toluene RT 72 h 99 94 (R) [106]7 XXIII (20mol) mdash THFDMSO 4 1 RT 48 h 99 42b [107]8 XXIV (20mol) TFA (40mol) CH2Cl2 0

∘C 96 h 88 96 (S) [108]9 XXV (10mol) Succinic acid (10mol) n-BuOHH2O 40

∘C 12 h 97 83 (R) [109]10 XXVI (20mol) AcOH (1 equiv) THF RT 24 h 76 81b [110]aIsolated by precipitation from the reaction mixture bAbsolute configuration not reported

demonstrated with the large number of reports well wit-nessing its success and appeal A survey of the variousorganocatalysts engaged in this synthesis and of the relatedresults is shown in Table 1

The first approach to enantioenriched warfarin throughiminium ion catalysis disclosed in 2003 involved [100]the employment of the phenylenediamine-derived catalystXVIII and provided after prolonged reaction time the targetcompound in good yield and moderate enantioselectivitywhich could be improved to gt99 by a simple crystalli-sation (Table 1 entry 1) It was also mentioned [101] thatthe reaction could be performed on a kg scale by employ-ing a related catalyst structure recoverable after reactioncompletion The approach is the same as the commercialsynthesis of Coumadin in a retrosynthetic sense but cruciallythe presence of imidazolidine catalysts XVIII affords anenantioselective reaction whilst the commercial synthesis

is racemic A few years later it was discovered that theputative catalyst XVIII was undergoing a hydrolysis underthe reaction conditions delivering the corresponding freephenylenediamine which was the actual catalytic species ofthe Michael addition On this basis the results obtained inthis transformation could be improved [102] by employing arelated diamine XIX in combination with a large amount ofan acidic cocatalyst (acetic acid entry 2) Subsequent effortswith simple primary diamine catalysts were directed [103]at improving the practical applicability of this reaction andincluded the discovery that the catalyst loading of phenylene-diamine XX could be lowered by exploiting a combinationof Lewis (lithium perchlorate) and Broslashnsted (acetic acid)acid cocatalysts in the reaction (entry 3) and that water asreactionmedium under ultrasound activation [104] provideda fast protocol allowing the isolation of warfarin in essen-tially enantiopure form by simple filtration of the reaction


N

O

OH

O

+

Figure 6 Reaction between coumarin and iminium ion in aconcerted pathway

mixture (entry 4) Variations in the phenylenediamine motifby functionalization of one of the amines have also beenreported and include the monoamine XXI generated in situby acidic hydrolysis from a corresponding diimine [105] andthe monophosphonamide XXII [106]

Both of these catalysts employed in combination withcarboxylic acids provide the product warfarin in excellentenantioselectivity (entries 5 and 6) A different diaminenamely 12-cyclohexanediamine was employed for thepreparation of catalyst XXIII bearing a lithium sulfate func-tionality on one of the amines which however led [107]to rather poor results (entry 7) The lithium based catalystXXIII was designed to exploit the mild Lewis acidity oflithium for the intramolecular activation of the imine formedbetween the catalyst and the Michael acceptor Interestinglycomputational studies showed that a related reaction (withcyclohexenone as Michael acceptor) follows an ene-typeconcerted pathway with simultaneous CndashC bond formationand proton transfer between the hydroxyl coumarin andthe iminium ion activated olefin of the Michael acceptor(Figure 6)

A structurally distinct primary amine catalyst XXIVderived from a Cinchona alkaloid was also successfullyapplied in this reaction [108] with very good results atrelatively high catalyst loadings (entry 8) Highlighting thehigh interest that this specific transformation has surgedin the academic community a recent publication reportedthe search for a more readily available catalytic systemconsidering that the preparation of the phenylenediaminecores of catalysts XVIIIndashXXII is rather troublesome andthat the synthesis of the Cinchona derivative XXIV presentsconsiderable safety issues (it is prepared through aMitsunobureaction which employs hazardous azides) To that purposethe focus was set [109] on amino acid as starting materialsresulting in the disclosure of the diphenyl phenylglycinolXXV as a moderately efficient and easily available catalystfor the obtainment of warfarin in enantioenriched form(entry 9) The same report highlighted the better perfor-mances of primary amine compared to secondary amines inthis reaction reporting also the poor performances in thistransformation of other popular secondary amine catalystssuch as proline or a MacMillan imidazolidinone However itwas more recently demonstrated [110] that also a secondaryamine the dimeric proline-derived catalyst XXV could beapplied in this Michael addition reaction with fairly goodresults (entry 10)

Simple iminium ion catalysed reactions have also beeninserted into more complex multistep reaction sequencessome of them herein are discussed in detail leading tomedicinally relevant compounds In this context the exampleof Telcagepant is significant as an iminium ion catalysedreaction was selected as the key step for the establishmentof the stereochemistry in an industrial-scale preparationof this molecule Telcagepant [111] is an antagonist of thecalcitonin gene-related neuropeptide and was consideredhighly promising for the treatment of migraine avoiding con-comitant cardiovascular problems often generated by otherantimigraine agents Telcagepant can be retrosyntheticallydisconnected between a chiral 2-amino-5-aryl caprolactamand a 4-aminopiperidine units assembled with concomitanturea formation (Scheme 23)

A first-generation multi-kg (gt500) process [112] relyingon a dynamic kinetic resolution of the enantiomers throughcrystallisation showcased several pitfalls in the preparationof the chiral caprolactam thus calling for alternative syn-thetic strategies to this unit To this end an organocatalyticapproach namely an iminium ion catalysed conjugate addi-tion of nitromethane to a proper cinnamaldehyde [113] wasjudged as more promising than other asymmetric prepa-rations based on transition metal catalysed reactions suchas ruthenium-catalysed hydrogenation [114] and rhodiumbased Hayashi-Miyaura addition [115] Although previouslyreported with related substrates [116 117] the organocat-alytic step required a careful optimisation for its large scaleimplementation as the formation of several by-productswas observed under the reported conditions In particularto avoid the formation of acetals the usual alcoholic sol-vents were replaced with a THFwater solvent mixture Theemployment of a carefully tailored additive mixture com-posed by boric and pivaloyl acid proved also to be necessaryto achieve an acceptable reaction rate while minimisingby-products formation A final amelioration involved theemployment of the crude mixture of the in situ silylateddiphenylprolinol XXVII as catalyst [118 119] thus avoidingits purification Finally the reaction could be performed on apilot plant (gt100 kg) affording the desired Michael adduct 56in 73 assay yield and 95 enantiomeric excess (Scheme 24)

Obviously both the preparation of the starting aldehydeand the subsequent reaction steps leading to the caprolac-tam had also to be carefully optimised for the large scalesynthesis The first part of the overall sequence is depictedin Scheme 25 and involves the preparation of an allylicalcohol from difluorobenzene through lithiation quenchingwith acrolein acid promoted rearrangement and TEMPOcatalysed oxidation to give the substrate 55 to be submittedto the organocatalytic step The aldehyde product 56 wasnot isolated but treated directly in a Doebner-Knoevenageltype reaction with an in situ generated acetamido malonicacid (not isolated due to safety issues) in the presence ofpyrrolidineThis decarboxylative Knoevenagel-type reactioneven if required extensive optimisation was preferred overmore established Wittig protocols based on atom economyreasoning The resulting acid 57 was isolated and upgradedto gt99 ee as a tributyl ammonium salt 58 obtained in animpressive 48 overall yield starting from difluorobenzene


NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2

Scheme 23 Retrosynthetic disconnection of Telcagepant

FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2

NO2t-BuCO2H (5mol)B(OH)3(50mol)

Scheme 24 Organocatalysed Michael addition

Hydrogenation of this enamide intermediate (57) withconcomitant nitro group reduction proved to be very chal-lenging due to the unwanted formation of desfluoro prod-ucts which could not be present in more than tiny (02)amounts for the successful employment of this synthesis fortelcagepant production After several attempts (Scheme 26)the hydrogenation reduction showed the desired featureswhen performed on the acid in the presence of lithium saltsin isopropanol under acidic conditions conditions whichalso promoted esterification of the carboxylate Trifluoroethylalkylation with a triflate gave the N-alkylated compound 59whose ester was hydrolysed to the carboxylic acid

Cyclisation involved the employment of a mixed anhy-dride possible for the decreased nucleophilicity of the tri-fluoroethyl nitrogen and was followed by a base promoteddynamic crystallisation process in aqueous NaOHDMSOmixture which allowed the isolation of the 2-acetamidocaprolactam 60 in 73 overall yield from the enamideAcidic hydrolysis of the acetamide gave the amine 61 whichwas engaged in urea formation by treatment with carbonyldiimidazole and the corresponding piperidine Deproto-nation of the benzamide hydrogen in ethanol furnishedthe potassium salt of telcagepant 62 as an ethanol solvatewith gt998 purity and gt999 ee This environmentallyresponsible synthesis contains all of the elements required foramanufacturing process and prepares telcagepant 62with thehigh quality required for pharmaceutical use

The key role played by proline-derived organocatalysts inmedicinal chemistry is also witnessed by the recent synthesisof maraviroc Human immunodeficiency virus (HIV) is apandemic that was first recognized in 1981 In 2008 HIVcaused the death of 2 million people due to the acquiredimmune deficiency syndrome (AIDS) Due to high medical

need the exciting prospect of a new class of drugs for HIVled to the rapid development of the academic and industrialresearch in this field Maraviroc (UK-427857) (69) is achemokine receptor 5 (CCR-5) receptor antagonist that iscurrently developed at Pfizer for the treatment of HIV Arobust plant-suitable synthesis of 69was urgently required tomanufacture larger quantities and the process research [120121] of a commercialisable route has been recently developed

The chiral 120573-amino aldehyde 65 a key intermediate insynthesis of 68 was produced in the industrial process inan 83 overall yield in a multistep sequence in which theenantioenriched 120573-amino ester 64 was obtained by tartaricacid resolution of the racemic counterpart Moreover theresolution of the 120573-amino ester was only moderately efficientwith two recrystallisations required to achieve the desiredenantiomeric excess of gt95 (Scheme 27 route a)

An interesting perspective for introducing improvementsin this process is offered by organocatalysis In a recent paper[122] the Cordova group has proposed the asymmetric syn-thesis of maraviroc and its analogues via an organocatalysedhighly enantioselective synthesis of the key chiral 120573-aminoaldehyde 66 fragment The assembly of 66 occurs via a two-step protocol involving catalytic enantioselective tandem aza-Michael hemiacetal formation between hydroxylamine andenal followed by NndashO cleavage (Scheme 27 route b)

The use of (S)-diphenylprolinol silyl ether XXVII as thecatalyst appears to be very helpful in providing the 120573-aminoaldehydes 66 in yields up to 75 and remarkably good(92ndash95) enantioselectivities Moreover the tolerance of theorganocatalysed reaction to awide range of protecting groupsat nitrogen opens the route to structural diversity leadingto different analogues of maraviroc of potential interest forscouting new medicinal targets


FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH

TEMPO (1 mol)NaOCl NaBr F

F CHO

CHO

Organocatalyticstep

FF

86 7395 ee

Pyrrolidine (35 mol)

DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane

ZE gt 99 1ZE 94 6ee gt 99

9391

95

48 overall yieldfrom difluorobenzene

5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2

NaO2C CO2Na CO2HH2SO4

HO2C

DMA 15∘C

THF minus55∘C

K2HPO4 MTBE(iii) H2SO4

Scheme 25 Large scale preparation of 58

FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH

73 overall yieldfrom the enamide

(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F

(ii) Piperidine(iii) KOt-Bu EtOH

HN N NHO

NO

NF

FN

ON

OH

Telcagepant potassium saltEtOH solvategt998 puritygt999 ee

626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+

(i) CDI Et3NTHF 60∘C

(i) CF3CH2OTfEt3N 50ndash60∘C

H2SO4 (25 equiv)H2 (50ndash100 psig)

35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C

Scheme 26 Second part of the synthesis of Telcagepant

CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield

Up to 75 yield and 95 ee

64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2

R = Cbz Boc C6H11-CO C6F2H9-COR1

R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me

Scheme 27 Resolution-based (route a) and organocatalysed (route b) asymmetric synthesis of 120573-amino aldehydes


NN

NN

F F

Ph

O NH

Maraviroc (UK-427 857)69

Figure 7 The structure of maraviroc (69)

Following the organocatalysed methodology maraviroc69 (Figure 7) could be obtained (3 steps) by reaction of 120573-amino aldehyde 67 and tropane 68 in 53 overall yieldwith 80 ee and (3 steps) 45 overall yield with 92ee by varying the reaction conditions (Scheme 28) It isalso worth noting that the reaction presented herein can bescaled up Thus the multigram-scale reaction between cin-namic aldehyde (314 g) and Cbz-protected hydroxylaminein the presence of 7mol of (S)-proline-derived catalystgave the corresponding 5-hydroxyoxazolidinone precursorof the of 120573-amino aldehyde 67 in 91 yield (65 g) and 99ee

Iminium ion organocatalysis appears to be key step inthe synthesis of the antidepressants (minus)-paroxetine (72)This molecule originally marketed by GlaxoSmithKline asSeroxat a blockbuster selective serotonin reuptake inhibitorfor the treatment of depression and anxiety related disor-ders has previously been focused on enzymatic asymmetricdesymmetrization [123 124] chiral auxiliary-assisted [125] orasymmetric deprotonation reactions [126] In the previousmethodologies the total synthesis of this chiral compoundconsisted of approximately 12ndash14 steps A novel approachbased on organocatalysis employing a chiral proline-derivedcatalyst led to a number of brief (formal) syntheses of paroxe-tine Using simple building blocks like fluorocinnamaldehyde70 and malonate derivative 71 with the silylated prolinolXXVII as the organocatalyst Michael reaction was shown(Scheme 29 route a) to proceed in good yields and stereos-electivity [127] to afford the target product 72 in a three-stepsequence A previous report [128] leading to (minus)-paroxetinein six steps overall and based on organocatalyst XVIII hadalso shown the possibility of performing a potentially scalableMichael addition (Scheme 29 route b)

In both cases the nature of the solvent was highlightedas a key parameter and polar-protic solvents were requiredWhereas the latter example utilised a muchmore industriallyfriendly solvent (ethanol versus trifluoroethanol) the reac-tion timeswere greater running formultiple days Regardlessthe potential step saving in these routes is significant takinginto account that current industrial syntheses are typically 10ndash15 steps Moreover the simplicity of the chemistry involvedmakes these organocatalysed processes suitable candidates orfurther scale-up activities

The spirocyclic motif is featured in a number of naturalproducts as well as medicinally relevant compounds [129ndash131] The stereocontrolled construction of the spirocyclicindole core of high interest for the synthesis of biologicallyactive compounds poses a challenging synthetic problemmainly in connection with the installation of the spiro-quaternary stereocenter Only a few asymmetric transfor-mations based on cycloaddition processes [132ndash134] or onthe intramolecular Heck reaction [135 136] have provensuccessful for achieving this goal The asymmetric cascadeorganocatalysis exploiting the ability of chiral amines tocombine twomodes of activation of carbonyl compounds viaiminium and enamine catalysis into one mechanistic schemeallows the direct one-step synthesis of complex spirocyclicoxindoles having multiple stereocenters

Among them the synthesis of spirooxindole 77 recentlypatented by Hoffmann-La Roche [137] a specific and potentinhibitor of MDM2-p53 interaction and innovative target forthe discovery of anticancer agents [138] has been recentlyreported [139] which highlights the potential of organocas-cades in building complex structures of interest in medicinalchemistry (Scheme 30) In the one-pot double organocascadecompound 73 would first act as aMichael acceptor intercept-ing the nucleophilic diamine intermediate 75 generated bycondensation of the catalyst XXIX with the 120572120573-unsaturatedketone 74 The resulting Michael addition product 76 wouldthen selectively engage itself in an intramolecular iminiumcatalysed conjugate addition to afford the spirooxindole 77The target product could be obtained with 99 de and eeafter a single crystallization

Influenza viruses pose a serious threat to world publichealth Two of the drugs currently used to treat influenzapatients are (minus)-oseltamivir phosphate (Tamiflu) [140] andzanamivir (Relenza) [141] Enamine catalysed transforma-tions were exploited in the realisation of synthetic sequencesleading to (minus)-oseltamivir The phosphate salt of thismolecule commercialised as Tamiflu is a neuraminidaseinhibitor useful as antiviral agent for the treatment andthe prevention of influenza infections Due to its specificbiological action (minus)-oseltamivir is considered to be verygeneral against all types of influenza viruses including theavian H5N1 which has a mortality rate close to 50 Inthe mid-2010s fear for a potentially disastrous pandemicspread of a mutation of this virus amongst humans hasprompted several nations to plan the accumulation ofmassivestocks of this drug The production of this molecule is beingbased on a multistep synthesis employing shikimic acid asstarting material Both the variable availability of naturalshikimic acid and the relative length of the synthesis putgreat pressure on industrialists and academics to develop veryquickly alternative synthetic routes in order to satisfy theexponentially increasing requests [142] Asymmetric catalysiswas considered a very attractive method as it would notrely heavily on natural chiral sources Accordingly severalsyntheses based on enantioselective Lewis acid catalysis havebeen reported [143] starting already from 2006 [144 145]Enamine catalysis was later appreciated as a useful alternativeand was consequently applied as the key stereodeterminingstep in a few syntheses of (minus)-oseltamivir Interestingly many


HNN

NNF F

Ph

Ph

O NHHN

OHO

O

+ p-TsOH Maraviroc (UK-427 857)+ i iiiiiiv ii

Conditions i ii = 78 80 ee3 steps 53 overall yield

Conditions ii iv = 78 92 ee3 steps 45 overall yield

67

68

69

CHO

Conditions i = 20mol catalyst XXVII CHCl3 4∘C 18hii = MO(CO)6 CH3CNH2O (9 1) rfx 2hiv = 20mol (S)-proline catalyst toluene minus40∘C 120hiii = TsOH NaBH(OAc)3 rt 15h

Scheme 28 Silylated prolinol-catalysed enantioselective synthesis of Maraviroc

EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF

Ar = 35 minus(CF3)2Ph

Scheme 29 Formal syntheses of (minus)-paroxetine via organocatalysis

of the reported protocols went beyond the study of thesimple reaction steps but increased the overall efficiency bycombining many of the steps in a one pot fashion

Essentially two complementary organocatalyticstrategies to (minus)-oseltamivir have been developed bothbased on the addition of an 120572-alkoxy aldehyde (pentan-3-yloxyacetaldehyde) to a nitroalkene The first approachdisclosed in 2009 [146] involved the addition of thisaldehyde to a 2-ester substituted nitroalkene catalysed bya silyl-protected D-prolinol derivative This constituted thefirst reaction of a nine-step synthesis leading to the targetcompound (minus)-oseltamivir in which all steps were carefullyoptimised and designed for their combination in one-potsequences The whole sequence could be in fact carried outin only three one-pot operations which soon after [147] werereduced to two in the second generation synthesis depictedin Scheme 31 The synthesis starts with the mentionedorganocatalytic reaction The nitroaldehyde product 78generated with high enantioselectivity reacts then with

a vinyl phosphonate in the presence of a base giving anitro-Michael Horner-Wadsworth-Emmons sequentialreaction which however leads to a mixture of differentproducts 79 andashc Solvent evaporation followed by stirringthe basic mixture in ethanol triggers retroaldol eliminationprocesses followed by olefination rendering very nicely asingle cyclohexene product 80 which upon treatment witha thiophenol gives a cyclic five-substituted cyclohexane 81featuring the desired stereochemistry isolated in overall 56yield over the three stepsThe introduction of the thiophenolis necessary to control the relative configuration at the 120572-nitro chiral centre through equilibration This intermediate(81) is converted into the target (minus)-oseltamivir 84 througha six-step one-pot sequence starting with tert-butyl estercleavage with trifluoroacetic acid leading to an acid which isconverted first in a chloride and then in an acylazide 82

This azide undergoes a Curtius rearrangement withconcomitant acetylation which serves to install the desiredacetamide functionality (83) Nitro group reduction with


O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe

HCat XXIX+ Cat XXIX 20 mol

MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O

IntramolecularMichael addition

Michael addition

70 yield45 1 dr84 ee

74

7773

7576

NH2

o-FC6H4CO2H (30mol)Toluene 1M 40

∘ 72h

Ominus

+

Scheme 30 Tandem double Michael addition via enamine-iminium activation sequence toward spirocyclic oxindole

OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S

56 yield over the three one pot steps

(i) TFA tolueneRT 4 h thenevaporation

RT 30 min thenevaporation

toluene RT 20 min OS

O

RT 48 h thenevaporation

AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O

81 yield over the six one-pot steps

+

OOH

O

+

Evaporationthen EtOH RT

10 min O

78 79 a

79 c

79 b

80 81

82 83 (minus)-oseltamivir 84

XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N

t-BuO2Ct-BuO2Ct-BuO2C

t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)

(ii) (COCl)2 toluene

(iii) TMSN3 pyridineAcOH Ac2O

Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C

NH3 0∘C 10min(ii) K2CO3 RT 9h

Scheme 31 Two-pot organocatalysed synthesis of (minus)-oseltamivir 84


OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O

28 yield on gram scale

O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir

HCO2H (30mol)ClC6H5 20∘C 15h

EtOH 70∘C


OSiPh2Me

Scheme 32 Scalable organocatalysed short synthesis of (minus)-oseltamivir 84

zinc ammonia bubbling and elimination of the stereodirect-ing thiophenol through a retro-Michael addition finally leadsto the target oseltamivir product 84 It is worth noting thatthe metal-based reagents employed in this synthesis containeither alkali-metal ions or nontoxic Zn Thus this procedureis suitable for large-scale preparation

A second approach to this target molecule throughorganocatalysis aimed at avoiding the hazardous azide addi-tion and Curtius rearrangement steps by introducing theamide functionality already at the beginning of the synthesisTo this end the readily available 2-Z-acetamido nitroethene85 was engaged in an enamine catalysed reaction withthe same aldehyde previously employed By this approachdisclosed in 2010 [148] the target oseltamivir 84 couldbe obtained after a few more steps based on the previoussynthesis Due to its importance this organocatalytic reactionand the subsequent steps were then the subject of thoroughstudies directed at their generalisation [149 150] and carefuloptimisation [151] which culminated very recently in thedisclosure of a synthesis of oseltamivir proceeding in one-potfrom the aldehyde and this nitroalkene [152] Compared tothe previous sequence reported in Scheme 31 this synthesis(Scheme 32) not only obviates the need of introducing theacetamide functionality with azide chemistry but also avoidsevaporation steps and the usage of toxic chlorinated solventsallowing the obtainment of oseltamivir even on gram scalewith a remarkable 28 yield over the five steps without anyintermediate work-up or isolation

In the same year a nine-step synthesis of (minus)-oseltamivirhas been proposed [153] in which a novel barium-catalysedasymmetric Diels-Alder-type reaction gives access to thecyclohexene framework of Tamiflu in the key enantioselec-tive reaction path with a Pd-catalysed allylic occurring in thefollowing steps of the synthetic sequence Though of relevant

interest for employing a nontoxicmetal and for being effectiveat 60 g scale the advantage of this synthesis with respect to theorganocatalysed methodology is to some extent diminishedby the need of isolating all the intermediates and by the useof a potentially explosive reagent such as diphenyl phosphorylazide

3 Concluding Remarks

Featuring aspects of medicinal chemistry are the strongreliability of the processes the use of cheap and commercialcatalysts and short synthetic sequences Moreover bothenantiomers of the catalysts should be easily available inorder to obtain both enantiomers of the products andallow analysing them from a biological viewpoint As hereinhighlighted enantioselective organocatalysis plays nowadaysamajor role alongsidemetal-catalysed processes in chemicalsynthesis because together these complementary disciplineshave revolutionized the way the synthesis is carried out Apoint that should not be underestimated is the attractive-ness of the operational simplicity of organocatalytic reac-tions rigorous exclusion of oxygen and moisture is usuallynot required and potential toxic metal contamination isavoidedThe success and the usefulness of the organocatalyticapproach are well demonstrated by the several examples inwhich different organocatalytic strategies involving variousactivation modes andor catalyst structures have been suc-cessfully applied to the same target compound as hereinexemplified in the case of baclofen or rolipram

The application of organocatalysis to the synthesis ofmolecules of interest in various fields including medicinalchemistry is however still facing problems such as therelatively high catalyst loading the long reaction time andalso the difficult recyclability of the organocatalyst To give a


partial solution significant advances have been reported inrecent times describing polymer supported organic catalystseasily recovered after the reaction has taken place by filtration[154ndash156] In contrast with immobilised metal complexes(via solid-supported bound ligand) leaching problems aremuch less critical when using organocatalysts immobilisedby covalent bonding to the solid support Even if costsconsiderations as well as decrease of catalyst activity andselectivity are issues not fully solved yet several remarkableexamples have been reported which show great promise forfuture development

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The author expresses the warmest thanks to Dr LucaBernardi for his precious suggestions and reading of thepaper

References

[1] P I Dalko and LMoisan ldquoIn the golden age of organocatalysisrdquoAngewandte Chemie International Edition vol 43 no 39 pp5138ndash5175 2004

[2] B List ldquoThe ying and yang of asymmetric aminocatalysisrdquoChemical Communications pp 819ndash824 2006

[3] B List ldquoOrganocatalysis a complementary catalysis strategyadvances organic synthesisrdquo Advanced Synthesis amp Catalysisvol 346 no 9-10 p 1021 2004

[4] M Nielsen D Worgull T Zwifel B Gschwend S Bertelsenand K A Jorgensen ldquoMechanisms in aminocatalysisrdquoChemicalCommunications vol 47 no 2 pp 632ndash649 2011

[5] A Grossmann and D Enders ldquoN-heterocyclic carbene cat-alyzed domino reactionsrdquo Angewandte Chemie InternationalEdition vol 51 no 2 pp 314ndash325 2012

[6] P M Pihko Hydrogen Bonding in Organic Synthesis Wiley-VCH Weinheim Germany 2009

[7] K Maruoka Asymmetric Phase Transfer Catalysis Wiley-VCHWeinheim Germany 2008

[8] E N Jacobsen and D W C McMillan ldquoOrganocatalysisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 48 pp 20618ndash20619 2010

[9] DW C McMillan ldquoCommentary the advent and developmentof organocatalysisrdquo Nature vol 455 pp 304ndash308 2008

[10] B List ldquoBiocatalysis and organocatalysis asymmetric synthesisinspired by naturerdquo in Asymmetric Synthesis The EssentialsM Christmann and S Brase Eds pp 161ndash165 Wiley-VCHWeinheim Germany 2007


[12] T Newhouse P S Baran and RW Hoffmann ldquoThe economiesof synthesisrdquo Chemical Society Reviews vol 38 no 11 pp 3010ndash3021 2009

[13] D Enders M R M Huttl C Grondal and G Raabe ldquoControlof four stereocentres in a triple cascade organocatalytic reac-tionrdquo Nature vol 441 no 7095 pp 861ndash863 2006

[14] A Carlone S Cabrera M Marigo and K A Joslashrgensen ldquoAnew approach for an organocatalytic multicomponent dominoasymmetric reactionrdquo Angewandte Chemie International Edi-tion vol 46 no 7 pp 1101ndash1104 2007

[15] M Eichelbaum B Testa and A Somogyi Eds StereochemicalAspects of Drug Action and Disposition Spriger HeidelbergGermany 2003

[16] K C Nicolau D J Edmonds and P G Bulger ldquoCascadereactions in total synthesisrdquo Angewandte Chemie InternationalEdition vol 45 no 43 pp 7134ndash7186 2006

[17] C Grondal M Jeanty and D Enders ldquoOrganocatalytic cascadereactions as a new tool in total synthesisrdquoNature Chemistry vol2 no 3 pp 167ndash178 2010

[18] R M de Figueiredo and M Christman ldquoOrganocatalyticsynthesis of drugs and bioactive natural productsrdquo EuropeanJournal of Organic Chemistry no 16 pp 2575ndash2600 2007

[19] J Aleman and S Cabrera ldquoApplications of asymmetricorganocatalysis in medicinal chemistryrdquo Chemical SocietyReviews vol 42 no 2 pp 774ndash793 2013

[20] H U Blaser and E SchmidtAsymmetric Catalysis on IndustrialScale Challenges Approaches and Solutions Wiley-VCHWein-heim Germany 2004

[21] H Groger ldquoAsymmetric organocatalysis on a technical scalecurrent status and future challengesrdquo Organocatalysis vol20072 pp 227ndash258 2008

[22] C A Busacca D R Fandrick J J Song and C H SenanayakeldquoThe growing impact of catalysis in the pharmaceutical indus-tryrdquo Advanced Synthesis and Catalysis vol 353 no 11-12 pp1825ndash1864 2011

[23] G P Howell ldquoAsymmetric and diastereoselective conjugateaddition reactions CndashC bond formation at large scalerdquoOrganicProcess Research amp Development vol 16 no 7 pp 1258ndash12722012

[24] M S Sigman and E N Jacobsen ldquoSchiff base catalysts for theasymmetric strecker reaction identified and optimized fromparallel synthetic librariesrdquo Journal of the American ChemicalSociety vol 120 no 19 pp 4901ndash4902 1998

[25] E J Corey and M J Grogan ldquoEnantioselective synthesis of120572-amino nitriles from N-benzhydryl imines and HCN with achiral bicyclic guanidine as catalystrdquo Organic Letters vol 1 no1 pp 157ndash160 1999

[26] E A C Davie S MMennen Y Xu and S J Miller ldquoAsymmet-ric catalysis mediated by synthetic peptidesrdquo Chemical Reviewsvol 107 no 12 pp 5759ndash5812 2007

[27] L Bernardi M Fochi M Comes Franchini and A RiccildquoBioinspired organocatalytic asymmetric reactionsrdquo Organicand Biomolecular Chemistry vol 10 no 15 pp 2911ndash2922 2012

[28] M M Benning T Haller J A Gerlt and H M HoldenldquoNew reactions in the crotonase superfamily structure ofmethylmalonyl CoA decarboxylase from Escherichia colirdquoBiochemistry vol 39 no 16 pp 4630ndash4639 2000

[29] S Nakamura ldquoCatalytic enantioselective decarboxylative reac-tions using organocatalystsrdquo Organic amp Biomolecular Chem-istry vol 12 pp 394ndash405 2014

[30] J Lubkoll and H Wennemers ldquoMimicry of polyketidesynthases-enantioselective 14-addition reactions of malonicacid half-thioesters to nitroolefinsrdquo Angewandte ChemieInternational Edition vol 46 no 36 pp 6841ndash6844 2007


[31] H Y Bae S Some J Y - Kim et al ldquoOrganocatalytic enantios-elective Michael-addition of malonic acid half-thioesters to 120573-nitroolefins from mimicry of polyketide synthases to scalablesynthesis of 120574-amino acidsrdquoAdvanced Synthesis ampCatalysis vol353 no 17 pp 3196ndash3202 2011

[32] J Becht O Meyer and G Helmchen ldquoEnantioselective synthe-ses of (-)-(R)-rolipram (-)-(R)-baclofen and other GABA ana-logues via rhodium-catalyzed conjugate addition of arylboronicacidsrdquo Synthesis no 18 pp 2805ndash2810 2003

[33] DM Barnes S JWittenberger J Zhang et al ldquoDevelopment ofa catalytic enantioselective conjugate addition of 13-dicarbonylcompounds to nitroalkenes for the synthesis of endothelin-Aantagonist ABT-546 Scope mechanism and further applica-tion to the synthesis of the antidepressant rolipramrdquo Journal ofthe American Chemical Society vol 124 no 44 pp 13097ndash131052002

[34] H N Yuan S Wang J Nie W Meng Q Yao and J AMa ldquoHydrogen-bond-directed enantioselective decarboxyla-tive mannich reaction of 120573-ketoacids with ketimines applica-tion to the synthesis of anti-HIV drug DPC 083rdquo AngewandteChemie International Edition vol 52 no 14 pp 3869ndash38732013

[35] X Xu T Furukawa T Okino H Miyabe and Y TakemotoldquoBifunctional-thiourea-catalyzed diastereo- And enantioselec-tive Aza-Henry reactionrdquoChemistry vol 12 no 2 pp 466ndash4762005

[36] Y Zhang J Kua and J A McCammon ldquoRole of the catalytictriad and oxyanion hole in acetylcholinesterase catalysis anab initio QMMM studyrdquo Journal of the American ChemicalSociety vol 124 no 35 pp 10572ndash10577 2002

[37] J T Yli-Kauhaluoma J A Ashley L C Lo Chih-Hung LTucker M M Wolfe and K D Janda ldquoAnti-metalloceneantibodies a new approach to enantioselective catalysis of thediels-alder reactionrdquo Journal of the American Chemical Societyvol 117 no 27 pp 7041ndash7047 1995

[38] C Gioia A Hauville L Bernardi F Fini and A RiccildquoOrganocatalytic asymmetric diels-Alder reactions of 3-vinylindolesrdquo Angewandte Chemie International Edition vol47 no 48 pp 9236ndash9239 2008

[39] M HesseAlkaloids Nature Curse or BlessingWiley-VCH NewYork NY USA 2002

[40] J E Saxton ldquoRecent progress in the chemistry of the monoter-penoid indole alkaloidsrdquoNatural Product Reports vol 14 no 6pp 559ndash590 1997

[41] G Abbiati V Canevari D Facoetti and E Rossi ldquoDiels-alderreactions of 2-vinylindoles with open-chain C=C dienophilesrdquoEuropean Journal of Organic Chemistry vol 2007 no 3 pp 517ndash525 2007

[42] K S Gunmudsson P R Sebahar L DrsquoAurora Richardson et alldquoSubstituted tetrahydrocarbazoles with potent activity againsthuman papillomavirusesrdquo Bioorganic amp Medicinal ChemistryLetters vol 19 no 13 pp 3489ndash3492 2009

[43] S Shimizu K Ohori T Arai H Sasai and M ShibasakildquoA catalytic asymmetric synthesis of tubifolidinerdquo Journal ofOrganic Chemistry vol 63 no 21 pp 7547ndash7551 1998

[44] Y Hoashi T Yabuta and Y Takemoto ldquoBifunctional thiourea-catalyzed enantioselective double Michael reaction of 120574120575-unsaturated120573-ketoester to nitroalkene asymmetric synthesis of(-)-epibatidinerdquo Tetrahedron Letters vol 45 no 50 pp 9185ndash9188 2004

[45] P S Haynes P A Stupple and D J Dixon ldquoOrganocatalyticasymmetric total synthesis of (R)-rolipram and formal synthesis

of (3S4R)-paroxetinerdquo Organic Letters vol 10 no 7 pp 1389ndash1391 2008

[46] R P Herrera V Sgarzani L Bernardi and A Ricci ldquoCat-alytic enantioselective Friedel-Crafts alkylation of indoles withnitroalkenes by using a simple thiourea organocatalystrdquo Ange-wandte Chemie International Edition vol 44 no 40 pp 6576ndash6579 2005

[47] K Maruoka ldquoPractical aspects of recent asymmetric phase-transfer catalysisrdquoOrganic Process ResearchampDevelopment vol12 no 4 pp 679ndash697 2008

[48] T Shioiri ldquoChiral phase transfer catalysisrdquo in Handbook ofPhase Transfer Catalysis Y Sasson and R Nuemann Edschapter 14 pp 462ndash479 Blackie Academic amp ProfessionalLondon UK 1997

[49] A Nelson ldquoAsymmetric phase-transfer catalysisrdquo AngewandteChemie International Edition vol 38 no 11 pp 1583ndash1585 1999

[50] K Maruoka and T Ooi ldquoEnantioselective amino acid synthesisby chiral phase-transfer catalysisrdquo Chemical Reviews vol 103no 8 pp 3013ndash3028 2003

[51] M J OrsquoDonnell ldquoThe enantioselective synthesis of 120572-aminoacids by phase-transfer catalysis with achiral schiff base estersrdquoAccounts of Chemical Research vol 37 no 8 pp 506ndash517 2004

[52] B Lygo and B I Andrews ldquoAsymmetric phase-transfer catalysisutilizing chiral quaternary ammonium salts asymmetric alky-lation of glycine iminesrdquo Accounts of Chemical Research vol 37no 8 pp 518ndash525 2004

[53] S Shirakawa and K Maruoka in Catalytic Asymmetric Synthe-sis I Ojima Ed chapter 2C p 95 Wiley Hoboken NJ USA3rd edition 2010

[54] K Maruoka ldquoHighly practical amino acid and alkaloid syn-thesis using designer chiral phase transfer catalysts as high-performance organocatalystsrdquoThe Chemical Record vol 10 no5 pp 254ndash259 2010

[55] S Shirakawa and K Maruoka ldquoRecent developments in asym-metric phase-transfer reactionsrdquo Angewandte Chemie Interna-tional Edition vol 52 no 16 pp 4312ndash4348 2013

[56] UHDolling P Davis and E J J Grabowski ldquoEfficient catalyticasymmetric alkylations 1 Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysisrdquo Journal of theAmerican Chemical Society vol 106 no 2 pp 446ndash447 1984

[57] R S E Conn A V Lovell S Karaday and L M WeinstockldquoChiral Michael addition methyl vinyl ketone addition cat-alyzed by Cinchona alkaloid derivativesrdquo Journal of OrganicChemistry vol 51 no 24 pp 4710ndash4711 1986

[58] E J Cragoe Jr O W Woltersdorf Jr N P Gould et al ldquoAgentsfor the treatment of brain edema 2 [(2399a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alkanoic acids andsome of their analoguesrdquo Journal of Medicinal Chemistry vol29 no 5 pp 825ndash841 1986

[59] J P ScottM SAshwoodKM J Brands et al ldquoDevelopment ofa phase transfer catalyzed asymmetric synthesis for an estrogenreceptor beta selective agonistrdquo Organic Process Research andDevelopment vol 12 no 4 pp 723ndash730 2008

[60] A Baschieri L Bernardi A Ricci S Suresh and M F AAdamo ldquoCatalytic asymmetric conjugate addition of nitroalka-nes to 4-nitro5-styrylisoxazolesrdquo Angewandte Chemie Interna-tional Edition vol 48 no 49 pp 9342ndash9345 2009

[61] S France D J Guerin S JMiller and T Letchka ldquoNucleophilicchiral amines as catalysts in asymmetric synthesisrdquo ChemicalReviews vol 103 no 8 pp 2985ndash3012 2003


[62] T Marcelli and H Hiemstra ldquoCinchona alkaloids in asymmet-ric organocatalysisrdquo Synthesis no 8 Article ID E26109SS pp1229ndash1279 2010

[63] H Hiemstra and H Wynberg ldquoAddition of aromatic thiols toconjugated cycloalkenones catalyzed by chiral beta-hydroxyamines A mechanistic study of homogeneous catalytic asym-metric synthesis rdquo Journal of the American Chemical Society vol103 no 2 pp 417ndash430 1981

[64] M Bella and K A Joslashrgensen ldquoOrganocatalytic enantioselectiveconjugate addition to alkynonesrdquo Journal of the AmericanChemical Society vol 126 no 18 pp 5672ndash5673 2004

[65] H Li Y Wang L Tang et al ldquoStereocontrolled creation ofadjacent quaternary and tertiary stereocenters by a catalyticconjugate additionrdquo Angewandte Chemie International Editionvol 44 no 1 pp 105ndash108 2004

[66] X D Liu L J Deng H J Song H Z Jia and R Wang ldquoAsym-metric Aza-Mannich addition synthesis of modified chiral2-(Ethylthio)-thiazolone derivatives with anticancer potencyrdquoOrganic Letters vol 13 no 6 pp 1494ndash1497 2011

[67] L E Brown K C Cheng W Wei et al ldquoDiscovery of newantimalarial chemotypes through chemical methodology andlibrary developmentrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 108 no 17 pp 6775ndash6780 2011

[68] S Kaneko T Yoshino T Katoh and S Terashima ldquoSyntheticstudies of huperzine A and its fluorinated analogues 1 Novelasymmetric syntheses of an enantiomeric pair of huperzine ArdquoTetrahedron vol 54 no 21 pp 5471ndash5484 1998

[69] T Akiyama J Itoh K Yokota andK Fuchibe ldquoEnantioselectivemannich-type reaction catalyzed by a chiral Broslashnsted acidrdquoAngewandte Chemie International Edition vol 43 no 12 pp1566ndash1568 2004

[70] D Uraguchi and M Terada ldquoChiral Broslashnsted acid-catalyzeddirect mannich reactions via electrophilic activationrdquo Journalof the American Chemical Society vol 126 no 17 pp 5356ndash53572004

[71] S Hoffmann A M Seyad and B List ldquoA powerful Broslashnstedacid catalyst for the organocatalytic asymmetric transfer hydro-genation of iminesrdquo Angewandte Chemie International Editionvol 44 no 45 pp 7424ndash7427 2005

[72] M Rueping J Dufour and F R Schoepke ldquoAdvances incatalytic metal-free reductions from bio-inspired concepts toapplications in the organocatalytic synthesis of pharmaceuticalsand natural productsrdquoGreen Chemistry vol 13 no 5 pp 1084ndash1105 2011

[73] M Rueping M Stoeckel E Sugiono and T TheissmannldquoAsymmetric metal-free synthesis of fluoroquinolones byorganocatalytic hydrogenationrdquo Tetrahedron vol 66 no 33 pp6565ndash6568 2010

[74] I Hayakawa S Atarashi S YokohamaM Imamura K SakanoandM Furukawa ldquoSynthesis and antibacterial activities of opti-cally active ofloxacinrdquo Antimicrobial Agents and Chemotherapyvol 29 no 1 pp 163ndash164 1986

[75] D Seiyaku ldquoThe s-(-) isomer of 78-difluoro-23-dihydro-3-methyl-4H-14-benzoxazine can be utilized in the synthesis ofthe optically active form of Ofloxacin known as LevofloxacinLevofloxacin is 8 to 128 times more active than Ofloxacindepending upon the bacteria testedrdquo Drugs Future vol 17 no7 pp 559ndash563 1992

[76] M Rueping A P Antonchick and T Theissmann ldquoA highlyenantioselective Broslashnsted acid catalyzed cascade reaction

organocatalytic transfer hydrogenation of quinolines and theirapplication in the synthesis of alkaloidsrdquo Angewandte ChemieInternational Edition vol 45 no 22 pp 3683ndash3686 2006

[77] X Chen X Xu H Liu L Cun and L Gong ldquoHighlyenantioselective organocatalytic Biginelli reactionrdquo Journal oftheAmericanChemical Society vol 128 no 46 pp 14802ndash148032006

[78] Y Huang F Yang and C Zhu ldquoHighly enantioseletive biginellireaction using a new chiral ytterbium catalyst asymmetricsynthesis of dihydropyrimidinesrdquo Journal of the AmericanChemical Society vol 127 no 47 pp 16386ndash16387 2005

[79] P Melchiorre M Marigo A Carlone and G Bartoli ldquoAsym-metric aminocatalysis-gold rush in organic chemistryrdquo Ange-wandte Chemie International Edition vol 47 no 33 pp 6138ndash6171 2008

[80] C F Barbas III ldquoOrganocatalysis lost modern chemistryancient chemistry and an unseen biosynthetic apparatusrdquoAngewandte Chemie International Edition vol 47 no 1 pp 42ndash47 2008

[81] Z G Hajos and D R Parrish ldquoAsymmetric synthesis of bicyclicintermediates of natural product chemistryrdquo Journal of OrganicChemistry vol 39 no 12 pp 1615ndash1621 1974

[82] U Eder G Sauer and R Wiechert ldquoNew type of asymmetriccyclization to optically active steroid CD partial structuresrdquoAngewandte Chemie International Edition in English vol 10 no7 pp 496ndash497 1971

[83] B List R A Lerner and C F Barbas III ldquoProline-catalyzeddirect asymmetric aldol reactionsrdquo Journal of the AmericanChemical Society vol 122 no 10 pp 2395ndash2396 2000

[84] W Notz F Tanaka and C F Barbas III ldquoEnamine-basedorganocatalysis with proline and diamines the development ofdirect catalytic asymmetric aldol mannich Michael and diels-alder reactionsrdquo Accounts of Chemical Research vol 37 no 8pp 580ndash591 2004

[85] W Notz and B List ldquoCatalytic asymmetric synthesis of anti-12-diolsrdquo Journal of the American Chemical Society vol 122 no 30pp 9336ndash7387 2000

[86] A B Northrup and D W C MacMillan ldquoThe first direct andenantioselective cross-aldol reaction of aldehydesrdquo Journal ofthe American Chemical Society vol 124 no 24 pp 6798ndash67992002

[87] B List ldquoDirect catalytic asymmetric 120572-amination of aldehydesrdquoJournal of the American Chemical Society vol 124 no 20 pp5656ndash5657 2002

[88] NKumaragurubaran K JuhlW ZhuangA Boslashgevig andKAJoslashrgensen ldquoDirect l-proline-catalyzed asymmetric120572-aminationof ketonesrdquo Journal of the American Chemical Society vol 124no 22 pp 6254ndash6255 2002

[89] A B Northrup and D W C MacMillan ldquoThe first generalenantioselective catalyticDiels-Alder reactionwith simple (120572120573-unsaturated ketonesrdquo Journal of the American Chemical Societyvol 124 no 11 pp 2458ndash2460 2002

[90] R M Wilson W S Jen and D W C MacMillan ldquoEnantios-elective organocatalytic intramolecular Diels-Alder reactionsThe asymmetric synthesis of solanapyrone Drdquo Journal of theAmericanChemical Society vol 127 no 33 pp 11616ndash11617 2005

[91] J F Austin and D W C MacMillan ldquoEnantioselectiveorganocatalytic indole alkylations Design of a new and highlyeffective chiral amine for iminium catalysisrdquo Journal of theAmerican Chemical Society vol 124 no 7 pp 1172ndash1173 2002


[92] N A Paras and D W C MacMillan ldquoThe enantioselectiveorganocatalytic 14-addition of electron-rich benzenes to 120572120573-unsaturated aldehydesrdquo Journal of the American ChemicalSociety vol 124 no 27 pp 7894ndash7895 2002

[93] S P Brown N C Goodwin and D W C MacMillan ldquoThefirst enantioselective organocatalyticMukaiyama-Michael reac-tion a direct method for the synthesis of enantioenriched120574-butenolide architecturerdquo Journal of the American ChemicalSociety vol 125 no 5 pp 1192ndash1194 2003

[94] S G Ouellet J B Tuttle and D W C MacMillan ldquoEnan-tioselective organocatalytic hydride reductionrdquo Journal of theAmerican Chemical Society vol 127 no 1 pp 32ndash33 2005

[95] J F Austin S G Kim C J Sinz W J Xiao and D WC MacMillan ldquoEnantioselective organocatalytic constructionof pyrroloindolines by a cascade addition-cyclization strategysynthesis of (-)-flustramine Brdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 101 no15 pp 5482ndash5487 2004

[96] H P Rang MM Dale J M Ritter and P Gardner Pharmacol-ogy Churchill Livingstone Philadelphia Pa USA 4th edition2001

[97] H J Bardsley and A K Daly ldquoThe therapeutic use of r-warfarinas anticoagulantrdquo Patent Cooperation Treaty InternationalApplication WO 0043003 2000

[98] A Robinson and H Y Li ldquoThe first practical asymmetricsynthesis of R and S-Warfarinrdquo Tetrahedron Letters vol 37 no46 pp 8321ndash8324 1996

[99] Y Tsuchiya Y Hamashima and M Sodeoka ldquoA new entry toPdndashH chemistry catalytic asymmetric conjugate reduction ofenones with EtOH and a highly enantioselective synthesis ofwarfarinrdquo Organic Letters vol 8 no 21 pp 4851ndash4854 2006

[100] N Halland T Hansen and K A Joslashrgensen ldquoOrganocatalyticasymmetric Michael reaction of cyclic 13-dicarbonyl com-pounds and 120572 120573-unsaturated ketones-a highly atom-economiccatalytic one-step formation of optically active warfarin antico-agulantrdquo Angewandte Chemie International Edition vol 42 no40 pp 4955ndash4957 2003

[101] NHalland K A Joslashrgensen andTHansen Patent CooperationTreaty International Application WO 03050105 9 413 2003

[102] H Kim C Yen P Preston and J Chin ldquoSubstrate-directedstereoselectivity in vicinal diamine-catalyzed synthesis of war-farinrdquo Organic Letters vol 8 no 23 pp 5239ndash5242 2006

[103] H Yang L Li K Jiang J Jiang G Lai and L Xu ldquoHighly enan-tioselective synthesis of warfarin and its analogs by means ofcooperative LiClO4DPEN-catalyzed Michael reaction enan-tioselectivity enhancement and mechanismrdquo Tetrahedron vol66 no 51 pp 9708ndash9713 2010

[104] M Rogozinska A Adamkiewicz and J Mlynarsky ldquoEfficientldquoonwaterrdquo organocatalytic protocol for the synthesis of opticallypure warfarin anticoagulantrdquoGreen Chemistry vol 13 no 5 pp1155ndash1157 2011

[105] X Zhu A Lin Y Shi J Guo C Zhu and Y Cheng ldquoEnantios-elective synthesis of polycyclic coumarin derivatives catalyzedby an in situ formed primary amine-imine catalystrdquo OrganicLetters vol 13 no 16 pp 4382ndash4385 2011

[106] J Dong and D M Du ldquoHighly enantioselective synthesisof warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalystsrdquoOrganic amp BiomolecularChemistry vol 10 no 40 pp 8125ndash8131 2012

[107] M Leven J M Neudorfl and B Goldfuss ldquoMetal-mediatedaminocatalysis provides mild conditions enantioselective

Michael addition mediated by primary amino catalysts andalkali-metal ionsrdquo Beilstein Journal of Organic Chemistry vol9 pp 155ndash165 2013

[108] J W Xie L Yue W Chen et al ldquoHighly enantioselectiveMichael addition of cyclic 13-dicarbonyl compounds to 120572120573-unsaturated ketonesrdquo Organic Letters vol 9 no 3 pp 413ndash4152007

[109] T E Kristensen K Vestli F K Hansen and T Hansen ldquoNewphenylglycine-derived primary amine organocatalysts for thepreparation of optically active warfarinrdquo European Journal ofOrganic Chemistry vol 2009 no 30 pp 5185ndash5191 2009

[110] Z H Dong L J Wang X H Chen X H Liu L L Lin andXM Feng ldquoOrganocatalytic enantioselectiveMichael additionof 4-hydroxycoumarin to 120572 120573-unsaturated ketones a simplesynthesis of warfarinrdquo European Journal of Organic Chemistryno 30 pp 5192ndash5197 2009

[111] D V Paone A W Shaw D N Nguyen et al ldquoPotentorally bioavailable calcitonin gene-related peptide receptorantagonists for the treatment of migraine discoveryof N-(3R6S)-6-(23- difluorophenyl)-2-oxo-1-(222-trifluoroethyl)azepan-3-yl-4-(2-oxo-2 3-dihydro-1H-imidazo[45-b]pyridin-1-yl)piperidine-1-carboxamide (MK-0974)rdquo Journal of Medicinal Chemistry vol 50 no 23 pp5564ndash5567 2007

[112] M Palucki I Davies D Steinhuebel and J Rosen PatentCooperation Treaty International Application WO20071205892007

[113] F Xu M Zacuto N Yoshikawa et al ldquoAsymmetric synthesisof telcagepant a CGRP receptor antagonist for the treatmentof migrainerdquo Journal of Organic Chemistry vol 75 no 22 pp7829ndash7841 2010

[114] D P Steinhuebel S W Krska A Alorati et al ldquoAsymmetrichydrogenation of protected allylic aminesrdquoOrganic Letters vol12 no 18 pp 4201ndash4203 2010

[115] C S Burgey D V Paone A W Shaw et al ldquoSynthe-sis of the (3R6S)-3-amino-6-(23-difluorophenyl)azepan-2-oneof telcagepant (MK-0974) a calcitonin gene-related peptidereceptor antagonist for the treatment of migraine headacherdquoOrganic Letters vol 10 no 15 pp 3235ndash3238 2008

[116] H Gotoh H Ishikawa and Y Hayashi ldquoDiphenylprolinolsilyl ether as catalyst of an asymmetric catalytic and directMichael reaction of nitroalkanes with 120572120573-unsaturated aldehy-desrdquo Organic Letters vol 9 no 25 pp 5307ndash5309 2007

[117] Y Wang P Li X Liang T Y Zhang and J Ye ldquoAn efficientenantioselective method for asymmetric Michael addition ofnitroalkanes to 120572120573-unsaturated aldehydesrdquo Chemical Commu-nications no 10 pp 1232ndash1234 2008

[118] Y Hayashi H Gotoh T Hayashi and M Shoji ldquoDiphenylpro-linol silyl ethers as efficient organocatalysts for the asymmetricMichael reaction of aldehydes and nitroalkenesrdquo AngewandteChemie International Edition vol 44 no 27 pp 4212ndash42152005

[119] M Marigo T C Wabnitz D Fielenbach and K A JoslashrgensenldquoEnantioselective organocatalyzed sulfenylation of aldehydesrdquoAngewandte Chemie International Edition vol 44 no 5 pp794ndash797 2005

[120] J Ahman M Birch S J Haycock-Lewandowski J Long andAWilder ldquoProcess research and scale-up of a commercialisableroute tomaraviroc (UK-427857) a CCR-5 receptor antagonistrdquoOrganic Process ResearchampDevelopment vol 12 no 6 pp 1104ndash1113 2008


[121] S J Haycock-Lewandowski A Wilder and J Ahman ldquoDevel-opment of a bulk enabling route to maraviroc (UK-427857)a CCR-5 receptor antagonistrdquo Organic Process Research ampDevelopment vol 12 no 6 pp 1094ndash1103 2008

[122] G-L Zhao S Lin AKorotvicka LDeianaMKullberg andACordova ldquoAsymmetric synthesis of maraviroc (UK-427857)rdquoAdvanced Synthesis amp Catalysis vol 352 no 13 pp 2291ndash22982010

[123] M S Yu I Lantos Z Peng J Yu and T Cacchio ldquoAsymmetricsynthesis of (-)-paroxetine using PLE hydrolysisrdquo TetrahedronLetters vol 41 no 30 pp 5647ndash5651 2000

[124] J M Palomo G Fernandez-Lorente C Mateo R Fernandez-Lafuente and J M Grison ldquoEnzymatic resolution of (plusmn)-trans-4-(41015840-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylatean intermediate in the synthesis of (minus)-ParoxetinerdquoTetrahedronvol 13 no 21 pp 2375ndash2361 2002

[125] M Amat J Bosch J Hidalgo et al ldquoSynthesis of enantiopuretrans-34-disubstituted piperidines An enantiodivergent syn-thesis of (+)- and (-)-paroxetinerdquo Journal of Organic Chemistryvol 65 no 10 pp 3074ndash3084 2000

[126] T A Johnson D O Jang W Slafer M D Curtius andP Beak ldquoAsymmetric carbon-carbon bond formations inconjugate additions of lithiated N-Boc allylic and benzylicamines to nitroalkenes enantioselective synthesis of substi-tuted piperidines pyrrolidines and pyrimidinonesrdquo Journal ofthe American Chemical Society vol 124 no 39 pp 11689ndash116982002

[127] G Valero J Schimer I Cisarova J Vesely A Moyano andR Rios ldquoHighly enantioselective organocatalytic synthesis ofpiperidines Formal synthesis of (-)-Paroxetinerdquo TetrahedronLetters vol 50 no 17 pp 1943ndash1946 2009

[128] S Brandau A Landa J Franzen M Marigo and K AJorgensen ldquoOrganocatalytic conjugate addition of malonates to120572 120573-unsaturated aldehydes asymmetric formal synthesis of (-)-paroxetine chiral lactams and lactonesrdquo Angewandte ChemieInternational Edition vol 45 no 26 pp 4305ndash4309 2006

[129] C Lagisetti A Pourpak Q Jiang et al ldquoAntitumor compoundsbased on a natural product consensus pharmacophorerdquo Journalof Medicinal Chemistry vol 51 no 19 pp 6220ndash6224 2008

[130] X Jiang YCao YWang L Liu F Shen andRWang ldquoAuniqueapproach to the concise synthesis of highly optically activespirooxazolines and the discovery of a more potent oxindole-type phytoalexin analoguerdquo Journal of the American ChemicalSociety vol 132 no 43 pp 15328ndash15333 2010

[131] S Kotha A C Deb K Lahiri and E Manivannan ldquoSelectedsynthetic strategies to spirocyclicsrdquo Synthesis no 2 pp 165ndash1932009

[132] E J Corey ldquoCatalytic enantioselective diels-alder reactionsmethods mechanistic fundamentals pathways and applica-tionsrdquo Angewandte Chemie International Edition vol 114 pp1724ndash1741 2002

[133] P R Sebahar and R M Williams ldquoThe asymmetric totalsynthesis of (+)- and (-)-spirotryprostatin Brdquo Journal of theAmerican Chemical Society vol 122 no 23 pp 5666ndash56672000

[134] B M Trost N Cramer and S M Silverman ldquoEnantioselectiveconstruction of spirocyclic oxindolic cyclopentanesby palladium-catalyzed trimethylenemethane-[3+2]-cycloadditionrdquo Journal of the American Chemical Societyvol 129 no 41 pp 12396ndash12397 2007

[135] A B Dounay and L E Overman ldquoThe asymmetric intramolec-ular heck reaction in natural product total synthesisrdquo ChemicalReviews vol 103 no 8 pp 2945ndash2963 2003

[136] A Madin C J OrsquoDonnell T Oh D W Old L E Overmanand M J Sharp ldquoUse of the intramolecular heck reaction forforming congested quaternary carbon stereocenters Stereocon-trolled total synthesis of (plusmn)-gelseminerdquo Journal of the AmericanChemical Society vol 127 no 51 pp 18054ndash18065 2005

[137] J J Liu and Z Zhang Patent Cooperation Treaty InternationalApplication WO 2008055812 2008

[138] P Chene ldquoInhibiting the p53-MDM2 interaction an importanttarget for cancer therapyrdquo Nature Reviews Cancer vol 3 pp102ndash109 2003

[139] G Bencivenni L Wu A Mazzanti et al ldquoTargeting structuraland stereochemical complexity by organocascade catalysisconstruction of spirocyclic oxindoles having multiple stereo-centersrdquo Angewandte Chemie International Edition vol 48 no39 pp 7200ndash7203 2009

[140] C U Kim W Lew M A Williams et al ldquoInfluenza neu-raminidase inhibitors possessing a novel hydrophobic interac-tion in the enzyme active site design synthesis and structuralanalysis of carbocyclic sialic acid analogues with potent anti-influenza activityrdquo Journal of the American Chemical Societyvol 119 no 4 pp 681ndash690 1997

[141] M Von Itzstein W-Y Wu G B Kok et al ldquoRational design ofpotent sialidase-based inhibitors of influenza virus replicationrdquoNature vol 363 no 6428 pp 418ndash423 1993

[142] V Farina and J D Brown ldquoTamiflu the supply problemrdquoAngewandte Chemie International Edition vol 45 no 44 pp7330ndash7334 2006

[143] M Shibasaki andM Kanai ldquoSynthetic strategies for oseltamivirphosphaterdquo European Journal of Organic Chemistry vol 2008no 11 pp 1839ndash1850 2008

[144] Y Y Yeung S Hong and E J Corey ldquoA short enantioselectivepathway for the synthesis of the anti-influenza neuramidaseinhibitor oseltamivir from 13-butadiene and acrylic acidrdquoJournal of the American Chemical Society vol 128 no 19 pp6310ndash6311 2006

[145] Y Fukuta T Mita N Fukuda M Kanai and M ShibasakildquoDe novo synthesis of tamiflu via a catalytic asymmetricring-opening of meso-aziridines with TMSN3rdquo Journal of theAmerican Chemical Society vol 128 no 19 pp 6312ndash6313 2006

[146] H Ishikawa T Suzuki andYHayashi ldquoHigh-yielding synthesisof the anti-influenza neuramidase inhibitor (-)-oseltamivir bythree ldquoone-potrdquo operationsrdquo Angewandte Chemie InternationalEdition vol 48 no 7 pp 1304ndash1307 2009

[147] H Ishikawa T Suzuki H Orita T Uchimaru and Y HayashildquoHigh-yielding synthesis of the anti-influenza neuraminidaseinhibitor (-)-oseltamivir by two ldquoone-potrdquo sequencesrdquo Chem-istry vol 16 no 42 pp 12616ndash12626 2010

[148] S Zhu S Yu Y Wang and D Ma ldquoOrganocatalytic Michaeladdition of aldehydes to protected 2-amino-1-nitroethenes thepractical syntheses of oseltamivir (Tamiflu) and substituted 3-aminopyrrolidinesrdquo Angewandte Chemie International Editionvol 49 no 27 pp 4656ndash4660 2010

[149] J Rehak M Hutrsquoka A Latika et al ldquoThiol-free synthesisof oseltamivir and its analogues via organocatalytic Michaeladditions of oxyacetaldehydes to 2-acylaminonitroalkenesrdquoSynthesis vol 44 pp 2424ndash2430 2012

[150] J Weng Y B Li R B Wang and G Lu ldquoOrganocatalyticMichael reaction of nitroenamine derivatives with aldehydes


short and efficient esymmetric eynthesis of (-)-oseltamivirrdquoChemCatChem vol 4 no 7 pp 1007ndash1012 2012

[151] VHajzer A Latika J Durmis andR Sebesta ldquoEnantioselectiveMichael addition of the 2-(1-ethylpropoxy)acetaldehyde to N-[(1Z)-2-nitroethenyl]acetamide-optimization of the key step inthe organocatalytic oseltamivir synthesisrdquo Helvetica ChimicaActa vol 95 no 12 pp 2421ndash2428 2012

[152] TMuakaiyamaH IshikawaHKoshino andYHayashi ldquoOne-pot synthesis of (-)-oseltamivir and mechanistic insights intothe organocatalyzed Michael reactionrdquo Chemistry vol 19 no52 pp 17789ndash17800 2013

[153] K Yamatsugu L Yin S Kamijo Y Kimura M Kanai andM Shibasaki ldquoA synthesis of tamiflu by using a barium-catalyzed asymmetric diels-alder-type reactionrdquo AngewandteChemie International Edition vol 48 no 6 pp 1070ndash1076 2009

[154] F Cozzi ldquoImmobilization of organic catalysts when why andhowrdquo Advanced Synthesis amp Catalysis vol 348 no 12-13 pp1367ndash1390 2006

[155] T E Christensen and T Hansen ldquoPolymer-supported chiralorganocatalysts synthetic strategies for the road towards afford-able polymeric immobilizationrdquo European Journal of OrganicChemistry vol 17 pp 3179ndash3204 2010

[156] A L W Demuynck L Peng F De-Clippel J Vanderleyden PA Jacobs and B F Sels ldquoSolid acids as heterogeneous supportfor primary amino acid-derived diamines in direct asymmetricaldol reactionsrdquo Advanced Synthesis and Catalysis vol 353 no5 pp 725ndash732 2011

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


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International Journal of


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Advances in

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Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

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Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International


CatalystsJournal of

ElectrochemistryInternational Journal of



ldquoSynzymesrdquosimple molecules which mimic enzyme functions

Organocatalysis

Noncovalent organocatalysis Covalent organocatalysisnew covalent bond formationweak interactions

AminesHydrogen bonds

Ionic interactionsCarbenes

OP

O O

O H

R

R

NH

NH

S

NH

NH OTMS

PhPh

NH

NO

N

HOH

NN F

F

FF

F

F3C

CF3

N+

BF4minus

+N

NMe2

Brminus

CO2H

Figure 1 General classification of the activation mode of several representative classes of molecules in organocatalysis

Despite their great development the application oforganocatalyticmethodologies to the synthesis of active com-pounds in medicinal chemistry in the past years has rarelybeen reported However in most recent years organocat-alytic methodologies for the synthesis of enantioenrichedmolecules for medicinal chemistry purposes have been gain-ing momentum being particularly attractive for the prepara-tion of compounds that do not tolerate metal contaminationIn academia several groups have made a remarkable effortto show the great applicability of organocatalysts to the totalsynthesis of bioactive natural products [18] and of drugs[19] most of them currently available in the market such asoseltamivir warfarin paroxetine baclofen and maravirocThese efforts mainly focused on the removal of barriersfor scale-up by addressing issues such as catalyst loadingproduct inhibition substrate scope and bulk availability ofdesigner catalysts which have drawn the attention of the com-panies [20 21] that have begun to incorporate organocatalysisas a synthetic tool in some industrial scale processes [22 23]

In this review some of the most recent representativeapplications of asymmetric organocatalysis to medicinalchemistry will be highlighted Not only the access to marketavailable drugs but also the access to drug candidates tomedicinal scaffolds and to promising new compoundswhosebiological profile has not yet been fully explored will bereviewed In some cases a comparison between organo-and metal-catalysed methodologies aimed at the obtainmentof the same medicinal targets will be reported and a few

interesting industrial examples of the use of organocatalysisin medicinal chemistry taken from the literature will bediscussed as well

2 Discussion

21 Noncovalent Organocatalysis

211 Hydrogen Bonding Catalysis This ubiquitous interac-tion is one of the central forces in Nature As an individualhydrogen bonds are feeble and quite easy to break Howeverwhen acting together they become much stronger and leaneach otherThis phenomenon is called ldquocooperativityrdquo (1 + 1 ismore than 2) Some of themany vital functions that hydrogenbonds fulfil in biological systems are shown in Figure 2

The simultaneous donation of two hydrogen bonds leadsto a highly successful strategy for electrophilic activationincreased strength and directionality relative to single hydro-gen bonds Therefore asymmetric catalysis via noncovalentbond interactions such as hydrogen bonding turns out to bea powerful synthetic strategy

Original achievements regarding bis-hydrogen bondcomplexes have been reported through the years It is worthnoting that this two-point binding is a powerful strategy bothinmetal-centered catalysis and in organocatalysis as shown inFigure 3

However whereas coordination to a chiral Lewis acidimposes limitations upon substrate structure any Lewis







O OH H O

OO


N NH H

Etterrsquos urea

HO

H

HO

H


N

O

N

O

Cu

O O

N NH H

X

Y

O

Me3C CMe3













NHN H

As nO

NH

H

HisS

Cys

S

O

O

O

CoA

cisthis

asn

RNO

S O

O

R

N

N

H

NO

H

H

Chiralspacer R

S

O RO(minus)O(minus)

(minus)O (+)

(+)

(+)

R998400

NO2


X

Y

+

NH

O

NH

OO

3-(R)-rolipram

NH

OCl

4-(S)-baclofenHCl

X = HY = Cl

X = OBnY = OMe

67 yield97 ee

S

O

OBn



S

O

Cl1

2

S

MeO

MeO

MeOMeO

MeO

O

OH

O

NNH

N

O

H

OMe

OMe

OMe

N

NNH

N

NH

OO

Cat II


Cat I

Cl

HO

CF3

CF3

CF3

NO2

NO2

NO2

CF3

Raney-NiH2

H3PO4 64

NH2HCl

HO2C


BINAP base+

(R)-baclofen ent 4

Up to 96 yield

OH

Cl

O


OOMe

OMeOMe

NHO


OO

DioxaneH2O


R2R1N

R4R4

R3

R3

2M NaOH MeOH rt

TFA CH2Cl2 rt 2h

12h HCl Et2O rt 24h

(+)H3NCl(minus)

B(OH)2




CHOHO

MeOMeO

MeO

MeO

Ligand (55 mol)



NHNH O

NaOH TsOH

OMe

O

EtO

O

(R)-rolipram

Ligand

92 three steps

56

3

N

OO

N

EtO

O

OEt

O

OC4H9

NO2

NO2

OC4

4

H9

OC4H9

EtO2C

Ra-NiH2

H3PO

CO2Et

C4H9O

Mg(OTf)2 (5mol)


N

N N

NH

O

O

N

NH

PMBPMB

PMB

PMB

PMB

O

OHN

NH

O

N

NH

O

+Cat 10 mol+


(Z)-DPC 08326 96 ee

(E)-DPC 08353 96 ee

O

N

NO

Cl

Cl

Cl Cl

Cl

Cl

OOAc

AcO

OAc

OAcN N

S

H H

N

H

Ar

O

OH

7

IIIO

OH

OF3C

F3C

F3C

F3C

CF3

CF3

(minus)O

(+)

R998400

NaBH4


THF minus20∘C 48h





H MeO

HN

HN

Ph

Ph

PhMeO

MeO

Boc

Boc

Ph

PhNH

HN

OMe

++

(i) TFA

80

80

75


Cat IV 10 mol

83 ee

95 ee

cistrans 191


HN

S

HN


NBoc

F3C

F3C

NMe2

NO2

NO2

NH2

NO2

NO2

CH2Cl2 minus20∘C

(ii) K2CO3

o-MeOC6H4CHO

NH

NH


O

NH

R

H ONN

N NH H

57-His

HO

O

Asp-102O

NR

O

Ser-195

NN


Ser-195

N NH H

57-His

HO

O

Asp-102 (+)

H

HOxyanion hole

Serine protease

HN

O

O Ar

O

Antibody 13G5pH 74

+

95 ee 49 1 dr

N

O O Ar

HOO H

L36-Tyr

O

N

Asn-91L

H H

O

O Asp-50H

N(CH3)2

N(CH3)2

H2O 37∘C

(minus)

(minus)

(minus)

(minus)

NHCO2CH2Ar

CON(CH3)2

R998400

R998400








Het

NH

R

Ph


NH

OMeOMe

Antibiotic action

Carbazoles

NH

R

Antitumoral action

N

Me

Me

MeMeMe

NH

NMe

Pyridocarbazoles

R1

R2O

R3


N

N

N

NN

S

H

O

X HH

N

N

O

O

R

X

O

O

R-N

[4 + 2]




N

N

NH N

H

S

H

O

Cat V

CF3

CF3

CF3

CF3

lowast

lowastlowast







N NPh

O

O

H

HHN NPh

O

O

H

H N NPh

O

O

H

HHO

N

O

OH

H

HCl 9

quant97 ee

97 ee

88 yield95 5 dr

HCl 5 M TFA


93 eeN

H

N

H

H

Tubifolidine 11


(ent)

68 yield 94 ee

N

RH

HH

H

Reference [43]

CF3

CO2Me

(i) LiAlH4

H2 PdC


N

Cl

Cl

Cl

Cl

Cl

MeO

MeO

O

O O

O

MeO

O O

N

N

O

O

NOH

OH

HN

H

N 3 steps

4 steps

+

Cat IV 10 mol

85

Cascade sequence

75 ee

(minus)-epibatidine

NH

NH

S

Cat IV

12

15

1413

NO2

NO2

NO2

NO2

NMe2

CF3

lowastlowastlowast

F3C

Toluene 0∘C

KOH EtOH 0∘C






OCl Cl

O

Ph PhPh

C l Me MeO

O

O

HO

MeCl

50 aq NaOH

60 overall

95 yield92 ee

(+)-indacrinone

N

Cat V

Cat V

OH

N

O

OHClCl

H

10 mol17 1816

MeOMeO

MeO

C l C l

20∘C 18h

CF3CF3

N(+)

N(+)Br(minus)

Br(minus)


O

MeO

MeO

O O

HOOC-O

O

N

OH

NHH

H

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

(+)

Cat VI

Cat 55 mol

Toluene RT 15 h

O

+


19

20 21

(minus)








O

O


O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R


252423

22

N(+)

Br(minus)


O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR


94 ee (R)

91 ee (S)



N

NHO HOH

H

N

N

H

H


+

26R


Cl(minus)

Br(minus)

F3CF3C

NO2

NO2




87ndash89100∘C

K2CO3 (5 equiv)

87ndash89









NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of









O OH H O

OO


N NH H

Etterrsquos urea

HO

H

HO

H


N

O

N

O

Cu

O O

N NH H

X

Y

O

Me3C CMe3













NHN H

As nO

NH

H

HisS

Cys

S

O

O

O

CoA

cisthis

asn

RNO

S O

O

R

N

N

H

NO

H

H

Chiralspacer R

S

O RO(minus)O(minus)

(minus)O (+)

(+)

(+)

R998400

NO2


X

Y

+

NH

O

NH

OO

3-(R)-rolipram

NH

OCl

4-(S)-baclofenHCl

X = HY = Cl

X = OBnY = OMe

67 yield97 ee

S

O

OBn



S

O

Cl1

2

S

MeO

MeO

MeOMeO

MeO

O

OH

O

NNH

N

O

H

OMe

OMe

OMe

N

NNH

N

NH

OO

Cat II


Cat I

Cl

HO

CF3

CF3

CF3

NO2

NO2

NO2

CF3

Raney-NiH2

H3PO4 64

NH2HCl

HO2C


BINAP base+

(R)-baclofen ent 4

Up to 96 yield

OH

Cl

O


OOMe

OMeOMe

NHO


OO

DioxaneH2O


R2R1N

R4R4

R3

R3

2M NaOH MeOH rt

TFA CH2Cl2 rt 2h

12h HCl Et2O rt 24h

(+)H3NCl(minus)

B(OH)2




CHOHO

MeOMeO

MeO

MeO

Ligand (55 mol)



NHNH O

NaOH TsOH

OMe

O

EtO

O

(R)-rolipram

Ligand

92 three steps

56

3

N

OO

N

EtO

O

OEt

O

OC4H9

NO2

NO2

OC4

4

H9

OC4H9

EtO2C

Ra-NiH2

H3PO

CO2Et

C4H9O

Mg(OTf)2 (5mol)


N

N N

NH

O

O

N

NH

PMBPMB

PMB

PMB

PMB

O

OHN

NH

O

N

NH

O

+Cat 10 mol+


(Z)-DPC 08326 96 ee

(E)-DPC 08353 96 ee

O

N

NO

Cl

Cl

Cl Cl

Cl

Cl

OOAc

AcO

OAc

OAcN N

S

H H

N

H

Ar

O

OH

7

IIIO

OH

OF3C

F3C

F3C

F3C

CF3

CF3

(minus)O

(+)

R998400

NaBH4


THF minus20∘C 48h





H MeO

HN

HN

Ph

Ph

PhMeO

MeO

Boc

Boc

Ph

PhNH

HN

OMe

++

(i) TFA

80

80

75


Cat IV 10 mol

83 ee

95 ee

cistrans 191


HN

S

HN


NBoc

F3C

F3C

NMe2

NO2

NO2

NH2

NO2

NO2

CH2Cl2 minus20∘C

(ii) K2CO3

o-MeOC6H4CHO

NH

NH


O

NH

R

H ONN

N NH H

57-His

HO

O

Asp-102O

NR

O

Ser-195

NN


Ser-195

N NH H

57-His

HO

O

Asp-102 (+)

H

HOxyanion hole

Serine protease

HN

O

O Ar

O

Antibody 13G5pH 74

+

95 ee 49 1 dr

N

O O Ar

HOO H

L36-Tyr

O

N

Asn-91L

H H

O

O Asp-50H

N(CH3)2

N(CH3)2

H2O 37∘C

(minus)

(minus)

(minus)

(minus)

NHCO2CH2Ar

CON(CH3)2

R998400

R998400








Het

NH

R

Ph


NH

OMeOMe

Antibiotic action

Carbazoles

NH

R

Antitumoral action

N

Me

Me

MeMeMe

NH

NMe

Pyridocarbazoles

R1

R2O

R3


N

N

N

NN

S

H

O

X HH

N

N

O

O

R

X

O

O

R-N

[4 + 2]




N

N

NH N

H

S

H

O

Cat V

CF3

CF3

CF3

CF3

lowast

lowastlowast







N NPh

O

O

H

HHN NPh

O

O

H

H N NPh

O

O

H

HHO

N

O

OH

H

HCl 9

quant97 ee

97 ee

88 yield95 5 dr

HCl 5 M TFA


93 eeN

H

N

H

H

Tubifolidine 11


(ent)

68 yield 94 ee

N

RH

HH

H

Reference [43]

CF3

CO2Me

(i) LiAlH4

H2 PdC


N

Cl

Cl

Cl

Cl

Cl

MeO

MeO

O

O O

O

MeO

O O

N

N

O

O

NOH

OH

HN

H

N 3 steps

4 steps

+

Cat IV 10 mol

85

Cascade sequence

75 ee

(minus)-epibatidine

NH

NH

S

Cat IV

12

15

1413

NO2

NO2

NO2

NO2

NMe2

CF3

lowastlowastlowast

F3C

Toluene 0∘C

KOH EtOH 0∘C






OCl Cl

O

Ph PhPh

C l Me MeO

O

O

HO

MeCl

50 aq NaOH

60 overall

95 yield92 ee

(+)-indacrinone

N

Cat V

Cat V

OH

N

O

OHClCl

H

10 mol17 1816

MeOMeO

MeO

C l C l

20∘C 18h

CF3CF3

N(+)

N(+)Br(minus)

Br(minus)


O

MeO

MeO

O O

HOOC-O

O

N

OH

NHH

H

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

(+)

Cat VI

Cat 55 mol

Toluene RT 15 h

O

+


19

20 21

(minus)








O

O


O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R


252423

22

N(+)

Br(minus)


O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR


94 ee (R)

91 ee (S)



N

NHO HOH

H

N

N

H

H


+

26R


Cl(minus)

Br(minus)

F3CF3C

NO2

NO2




87ndash89100∘C

K2CO3 (5 equiv)

87ndash89









NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




NHN H

As nO

NH

H

HisS

Cys

S

O

O

O

CoA

cisthis

asn

RNO

S O

O

R

N

N

H

NO

H

H

Chiralspacer R

S

O RO(minus)O(minus)

(minus)O (+)

(+)

(+)

R998400

NO2


X

Y

+

NH

O

NH

OO

3-(R)-rolipram

NH

OCl

4-(S)-baclofenHCl

X = HY = Cl

X = OBnY = OMe

67 yield97 ee

S

O

OBn



S

O

Cl1

2

S

MeO

MeO

MeOMeO

MeO

O

OH

O

NNH

N

O

H

OMe

OMe

OMe

N

NNH

N

NH

OO

Cat II


Cat I

Cl

HO

CF3

CF3

CF3

NO2

NO2

NO2

CF3

Raney-NiH2

H3PO4 64

NH2HCl

HO2C


BINAP base+

(R)-baclofen ent 4

Up to 96 yield

OH

Cl

O


OOMe

OMeOMe

NHO


OO

DioxaneH2O


R2R1N

R4R4

R3

R3

2M NaOH MeOH rt

TFA CH2Cl2 rt 2h

12h HCl Et2O rt 24h

(+)H3NCl(minus)

B(OH)2




CHOHO

MeOMeO

MeO

MeO

Ligand (55 mol)



NHNH O

NaOH TsOH

OMe

O

EtO

O

(R)-rolipram

Ligand

92 three steps

56

3

N

OO

N

EtO

O

OEt

O

OC4H9

NO2

NO2

OC4

4

H9

OC4H9

EtO2C

Ra-NiH2

H3PO

CO2Et

C4H9O

Mg(OTf)2 (5mol)


N

N N

NH

O

O

N

NH

PMBPMB

PMB

PMB

PMB

O

OHN

NH

O

N

NH

O

+Cat 10 mol+


(Z)-DPC 08326 96 ee

(E)-DPC 08353 96 ee

O

N

NO

Cl

Cl

Cl Cl

Cl

Cl

OOAc

AcO

OAc

OAcN N

S

H H

N

H

Ar

O

OH

7

IIIO

OH

OF3C

F3C

F3C

F3C

CF3

CF3

(minus)O

(+)

R998400

NaBH4


THF minus20∘C 48h





H MeO

HN

HN

Ph

Ph

PhMeO

MeO

Boc

Boc

Ph

PhNH

HN

OMe

++

(i) TFA

80

80

75


Cat IV 10 mol

83 ee

95 ee

cistrans 191


HN

S

HN


NBoc

F3C

F3C

NMe2

NO2

NO2

NH2

NO2

NO2

CH2Cl2 minus20∘C

(ii) K2CO3

o-MeOC6H4CHO

NH

NH


O

NH

R

H ONN

N NH H

57-His

HO

O

Asp-102O

NR

O

Ser-195

NN


Ser-195

N NH H

57-His

HO

O

Asp-102 (+)

H

HOxyanion hole

Serine protease

HN

O

O Ar

O

Antibody 13G5pH 74

+

95 ee 49 1 dr

N

O O Ar

HOO H

L36-Tyr

O

N

Asn-91L

H H

O

O Asp-50H

N(CH3)2

N(CH3)2

H2O 37∘C

(minus)

(minus)

(minus)

(minus)

NHCO2CH2Ar

CON(CH3)2

R998400

R998400








Het

NH

R

Ph


NH

OMeOMe

Antibiotic action

Carbazoles

NH

R

Antitumoral action

N

Me

Me

MeMeMe

NH

NMe

Pyridocarbazoles

R1

R2O

R3


N

N

N

NN

S

H

O

X HH

N

N

O

O

R

X

O

O

R-N

[4 + 2]




N

N

NH N

H

S

H

O

Cat V

CF3

CF3

CF3

CF3

lowast

lowastlowast







N NPh

O

O

H

HHN NPh

O

O

H

H N NPh

O

O

H

HHO

N

O

OH

H

HCl 9

quant97 ee

97 ee

88 yield95 5 dr

HCl 5 M TFA


93 eeN

H

N

H

H

Tubifolidine 11


(ent)

68 yield 94 ee

N

RH

HH

H

Reference [43]

CF3

CO2Me

(i) LiAlH4

H2 PdC


N

Cl

Cl

Cl

Cl

Cl

MeO

MeO

O

O O

O

MeO

O O

N

N

O

O

NOH

OH

HN

H

N 3 steps

4 steps

+

Cat IV 10 mol

85

Cascade sequence

75 ee

(minus)-epibatidine

NH

NH

S

Cat IV

12

15

1413

NO2

NO2

NO2

NO2

NMe2

CF3

lowastlowastlowast

F3C

Toluene 0∘C

KOH EtOH 0∘C






OCl Cl

O

Ph PhPh

C l Me MeO

O

O

HO

MeCl

50 aq NaOH

60 overall

95 yield92 ee

(+)-indacrinone

N

Cat V

Cat V

OH

N

O

OHClCl

H

10 mol17 1816

MeOMeO

MeO

C l C l

20∘C 18h

CF3CF3

N(+)

N(+)Br(minus)

Br(minus)


O

MeO

MeO

O O

HOOC-O

O

N

OH

NHH

H

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

(+)

Cat VI

Cat 55 mol

Toluene RT 15 h

O

+


19

20 21

(minus)








O

O


O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R


252423

22

N(+)

Br(minus)


O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR


94 ee (R)

91 ee (S)



N

NHO HOH

H

N

N

H

H


+

26R


Cl(minus)

Br(minus)

F3CF3C

NO2

NO2




87ndash89100∘C

K2CO3 (5 equiv)

87ndash89









NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




CHOHO

MeOMeO

MeO

MeO

Ligand (55 mol)



NHNH O

NaOH TsOH

OMe

O

EtO

O

(R)-rolipram

Ligand

92 three steps

56

3

N

OO

N

EtO

O

OEt

O

OC4H9

NO2

NO2

OC4

4

H9

OC4H9

EtO2C

Ra-NiH2

H3PO

CO2Et

C4H9O

Mg(OTf)2 (5mol)


N

N N

NH

O

O

N

NH

PMBPMB

PMB

PMB

PMB

O

OHN

NH

O

N

NH

O

+Cat 10 mol+


(Z)-DPC 08326 96 ee

(E)-DPC 08353 96 ee

O

N

NO

Cl

Cl

Cl Cl

Cl

Cl

OOAc

AcO

OAc

OAcN N

S

H H

N

H

Ar

O

OH

7

IIIO

OH

OF3C

F3C

F3C

F3C

CF3

CF3

(minus)O

(+)

R998400

NaBH4


THF minus20∘C 48h





H MeO

HN

HN

Ph

Ph

PhMeO

MeO

Boc

Boc

Ph

PhNH

HN

OMe

++

(i) TFA

80

80

75


Cat IV 10 mol

83 ee

95 ee

cistrans 191


HN

S

HN


NBoc

F3C

F3C

NMe2

NO2

NO2

NH2

NO2

NO2

CH2Cl2 minus20∘C

(ii) K2CO3

o-MeOC6H4CHO

NH

NH


O

NH

R

H ONN

N NH H

57-His

HO

O

Asp-102O

NR

O

Ser-195

NN


Ser-195

N NH H

57-His

HO

O

Asp-102 (+)

H

HOxyanion hole

Serine protease

HN

O

O Ar

O

Antibody 13G5pH 74

+

95 ee 49 1 dr

N

O O Ar

HOO H

L36-Tyr

O

N

Asn-91L

H H

O

O Asp-50H

N(CH3)2

N(CH3)2

H2O 37∘C

(minus)

(minus)

(minus)

(minus)

NHCO2CH2Ar

CON(CH3)2

R998400

R998400








Het

NH

R

Ph


NH

OMeOMe

Antibiotic action

Carbazoles

NH

R

Antitumoral action

N

Me

Me

MeMeMe

NH

NMe

Pyridocarbazoles

R1

R2O

R3


N

N

N

NN

S

H

O

X HH

N

N

O

O

R

X

O

O

R-N

[4 + 2]




N

N

NH N

H

S

H

O

Cat V

CF3

CF3

CF3

CF3

lowast

lowastlowast







N NPh

O

O

H

HHN NPh

O

O

H

H N NPh

O

O

H

HHO

N

O

OH

H

HCl 9

quant97 ee

97 ee

88 yield95 5 dr

HCl 5 M TFA


93 eeN

H

N

H

H

Tubifolidine 11


(ent)

68 yield 94 ee

N

RH

HH

H

Reference [43]

CF3

CO2Me

(i) LiAlH4

H2 PdC


N

Cl

Cl

Cl

Cl

Cl

MeO

MeO

O

O O

O

MeO

O O

N

N

O

O

NOH

OH

HN

H

N 3 steps

4 steps

+

Cat IV 10 mol

85

Cascade sequence

75 ee

(minus)-epibatidine

NH

NH

S

Cat IV

12

15

1413

NO2

NO2

NO2

NO2

NMe2

CF3

lowastlowastlowast

F3C

Toluene 0∘C

KOH EtOH 0∘C






OCl Cl

O

Ph PhPh

C l Me MeO

O

O

HO

MeCl

50 aq NaOH

60 overall

95 yield92 ee

(+)-indacrinone

N

Cat V

Cat V

OH

N

O

OHClCl

H

10 mol17 1816

MeOMeO

MeO

C l C l

20∘C 18h

CF3CF3

N(+)

N(+)Br(minus)

Br(minus)


O

MeO

MeO

O O

HOOC-O

O

N

OH

NHH

H

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

(+)

Cat VI

Cat 55 mol

Toluene RT 15 h

O

+


19

20 21

(minus)








O

O


O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R


252423

22

N(+)

Br(minus)


O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR


94 ee (R)

91 ee (S)



N

NHO HOH

H

N

N

H

H


+

26R


Cl(minus)

Br(minus)

F3CF3C

NO2

NO2




87ndash89100∘C

K2CO3 (5 equiv)

87ndash89









NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




H MeO

HN

HN

Ph

Ph

PhMeO

MeO

Boc

Boc

Ph

PhNH

HN

OMe

++

(i) TFA

80

80

75


Cat IV 10 mol

83 ee

95 ee

cistrans 191


HN

S

HN


NBoc

F3C

F3C

NMe2

NO2

NO2

NH2

NO2

NO2

CH2Cl2 minus20∘C

(ii) K2CO3

o-MeOC6H4CHO

NH

NH


O

NH

R

H ONN

N NH H

57-His

HO

O

Asp-102O

NR

O

Ser-195

NN


Ser-195

N NH H

57-His

HO

O

Asp-102 (+)

H

HOxyanion hole

Serine protease

HN

O

O Ar

O

Antibody 13G5pH 74

+

95 ee 49 1 dr

N

O O Ar

HOO H

L36-Tyr

O

N

Asn-91L

H H

O

O Asp-50H

N(CH3)2

N(CH3)2

H2O 37∘C

(minus)

(minus)

(minus)

(minus)

NHCO2CH2Ar

CON(CH3)2

R998400

R998400








Het

NH

R

Ph


NH

OMeOMe

Antibiotic action

Carbazoles

NH

R

Antitumoral action

N

Me

Me

MeMeMe

NH

NMe

Pyridocarbazoles

R1

R2O

R3


N

N

N

NN

S

H

O

X HH

N

N

O

O

R

X

O

O

R-N

[4 + 2]




N

N

NH N

H

S

H

O

Cat V

CF3

CF3

CF3

CF3

lowast

lowastlowast







N NPh

O

O

H

HHN NPh

O

O

H

H N NPh

O

O

H

HHO

N

O

OH

H

HCl 9

quant97 ee

97 ee

88 yield95 5 dr

HCl 5 M TFA


93 eeN

H

N

H

H

Tubifolidine 11


(ent)

68 yield 94 ee

N

RH

HH

H

Reference [43]

CF3

CO2Me

(i) LiAlH4

H2 PdC


N

Cl

Cl

Cl

Cl

Cl

MeO

MeO

O

O O

O

MeO

O O

N

N

O

O

NOH

OH

HN

H

N 3 steps

4 steps

+

Cat IV 10 mol

85

Cascade sequence

75 ee

(minus)-epibatidine

NH

NH

S

Cat IV

12

15

1413

NO2

NO2

NO2

NO2

NMe2

CF3

lowastlowastlowast

F3C

Toluene 0∘C

KOH EtOH 0∘C






OCl Cl

O

Ph PhPh

C l Me MeO

O

O

HO

MeCl

50 aq NaOH

60 overall

95 yield92 ee

(+)-indacrinone

N

Cat V

Cat V

OH

N

O

OHClCl

H

10 mol17 1816

MeOMeO

MeO

C l C l

20∘C 18h

CF3CF3

N(+)

N(+)Br(minus)

Br(minus)


O

MeO

MeO

O O

HOOC-O

O

N

OH

NHH

H

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

(+)

Cat VI

Cat 55 mol

Toluene RT 15 h

O

+


19

20 21

(minus)








O

O


O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R


252423

22

N(+)

Br(minus)


O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR


94 ee (R)

91 ee (S)



N

NHO HOH

H

N

N

H

H


+

26R


Cl(minus)

Br(minus)

F3CF3C

NO2

NO2




87ndash89100∘C

K2CO3 (5 equiv)

87ndash89









NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of





Het

NH

R

Ph


NH

OMeOMe

Antibiotic action

Carbazoles

NH

R

Antitumoral action

N

Me

Me

MeMeMe

NH

NMe

Pyridocarbazoles

R1

R2O

R3


N

N

N

NN

S

H

O

X HH

N

N

O

O

R

X

O

O

R-N

[4 + 2]




N

N

NH N

H

S

H

O

Cat V

CF3

CF3

CF3

CF3

lowast

lowastlowast







N NPh

O

O

H

HHN NPh

O

O

H

H N NPh

O

O

H

HHO

N

O

OH

H

HCl 9

quant97 ee

97 ee

88 yield95 5 dr

HCl 5 M TFA


93 eeN

H

N

H

H

Tubifolidine 11


(ent)

68 yield 94 ee

N

RH

HH

H

Reference [43]

CF3

CO2Me

(i) LiAlH4

H2 PdC


N

Cl

Cl

Cl

Cl

Cl

MeO

MeO

O

O O

O

MeO

O O

N

N

O

O

NOH

OH

HN

H

N 3 steps

4 steps

+

Cat IV 10 mol

85

Cascade sequence

75 ee

(minus)-epibatidine

NH

NH

S

Cat IV

12

15

1413

NO2

NO2

NO2

NO2

NMe2

CF3

lowastlowastlowast

F3C

Toluene 0∘C

KOH EtOH 0∘C






OCl Cl

O

Ph PhPh

C l Me MeO

O

O

HO

MeCl

50 aq NaOH

60 overall

95 yield92 ee

(+)-indacrinone

N

Cat V

Cat V

OH

N

O

OHClCl

H

10 mol17 1816

MeOMeO

MeO

C l C l

20∘C 18h

CF3CF3

N(+)

N(+)Br(minus)

Br(minus)


O

MeO

MeO

O O

HOOC-O

O

N

OH

NHH

H

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

(+)

Cat VI

Cat 55 mol

Toluene RT 15 h

O

+


19

20 21

(minus)








O

O


O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R


252423

22

N(+)

Br(minus)


O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR


94 ee (R)

91 ee (S)



N

NHO HOH

H

N

N

H

H


+

26R


Cl(minus)

Br(minus)

F3CF3C

NO2

NO2




87ndash89100∘C

K2CO3 (5 equiv)

87ndash89









NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




N NPh

O

O

H

HHN NPh

O

O

H

H N NPh

O

O

H

HHO

N

O

OH

H

HCl 9

quant97 ee

97 ee

88 yield95 5 dr

HCl 5 M TFA


93 eeN

H

N

H

H

Tubifolidine 11


(ent)

68 yield 94 ee

N

RH

HH

H

Reference [43]

CF3

CO2Me

(i) LiAlH4

H2 PdC


N

Cl

Cl

Cl

Cl

Cl

MeO

MeO

O

O O

O

MeO

O O

N

N

O

O

NOH

OH

HN

H

N 3 steps

4 steps

+

Cat IV 10 mol

85

Cascade sequence

75 ee

(minus)-epibatidine

NH

NH

S

Cat IV

12

15

1413

NO2

NO2

NO2

NO2

NMe2

CF3

lowastlowastlowast

F3C

Toluene 0∘C

KOH EtOH 0∘C






OCl Cl

O

Ph PhPh

C l Me MeO

O

O

HO

MeCl

50 aq NaOH

60 overall

95 yield92 ee

(+)-indacrinone

N

Cat V

Cat V

OH

N

O

OHClCl

H

10 mol17 1816

MeOMeO

MeO

C l C l

20∘C 18h

CF3CF3

N(+)

N(+)Br(minus)

Br(minus)


O

MeO

MeO

O O

HOOC-O

O

N

OH

NHH

H

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

(+)

Cat VI

Cat 55 mol

Toluene RT 15 h

O

+


19

20 21

(minus)








O

O


O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R


252423

22

N(+)

Br(minus)


O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR


94 ee (R)

91 ee (S)



N

NHO HOH

H

N

N

H

H


+

26R


Cl(minus)

Br(minus)

F3CF3C

NO2

NO2




87ndash89100∘C

K2CO3 (5 equiv)

87ndash89









NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




OCl Cl

O

Ph PhPh

C l Me MeO

O

O

HO

MeCl

50 aq NaOH

60 overall

95 yield92 ee

(+)-indacrinone

N

Cat V

Cat V

OH

N

O

OHClCl

H

10 mol17 1816

MeOMeO

MeO

C l C l

20∘C 18h

CF3CF3

N(+)

N(+)Br(minus)

Br(minus)


O

MeO

MeO

O O

HOOC-O

O

N

OH

NHH

H

Cl

Cl

Cl

Cl

Cl Cl

Cl

Cl

Cl

(+)

Cat VI

Cat 55 mol

Toluene RT 15 h

O

+


19

20 21

(minus)








O

O


O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R


252423

22

N(+)

Br(minus)


O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR


94 ee (R)

91 ee (S)



N

NHO HOH

H

N

N

H

H


+

26R


Cl(minus)

Br(minus)

F3CF3C

NO2

NO2




87ndash89100∘C

K2CO3 (5 equiv)

87ndash89









NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




O

O


O

HO

HO

OPh

OPh O

+MeO

Cl

O

HOCl

OCl

Cl

Cl

NOH

OH

R


252423

22

N(+)

Br(minus)


O N

Cat (10 mol)

toluene RT 48 h O N

R

NaOH THF

COOH COOHR


94 ee (R)

91 ee (S)



N

NHO HOH

H

N

N

H

H


+

26R


Cl(minus)

Br(minus)

F3CF3C

NO2

NO2




87ndash89100∘C

K2CO3 (5 equiv)

87ndash89









NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




NH

H

N

NH

H

N

OMeOMe

ORORO

AB

ElectrophileR1

R2

(+)


Cat IX

N

S

O

NS

O

NH

Cat IX (20 mol)


N Ts Ts+

292827 SEtSEt

N

TMSO N

H


Et2O 20∘C 16h R1

1

R1

R2

R2

2








HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




HNXO O

O O

N H

O X

SHNN

+ Catalyst


Toluenereflux

(i) MeI

(96 compounds)

N

NHO

HO

H

H

H

NH

H

H

(+)-cinchonine


Cat X

Cat XI

Cat

34

3032

33

31

R2

R2

R1

R1

R1

R3R3

R4

R3

R2OC

R2OC

(ii) NH2R5

OR2C

SO2Ar

NHR5

N Cat

NN

R1

R4

R3

OH

NN

R1

R4

R3

O


N

CHO

NHO

HO O

N

O

N

OMeOMeOMe

OMe

OMe

+5 steps


AcONa AcOH

7764 ee

N

NH

OH

N

NHHO

HO

N

OMe

O

O


minus+


36

37

35NH2CO2Me

CO2Me

CO2Me120








N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




N

F

NH

F

N

OF

NH

OFF

OO

OHP

O

Cat XIII

NH

H H

OEt

OEt

EtO

EtO

Et Et

t-But-Bu

O O

NH

H HO O

12 equivCat 1 mol

24 equivCat 1 mol

79 yield 96 ee

67 yield 93 ee

N

O

F

(R)-Flumequine 43


37 41

40

4238

39

O

N

F

COOH

COOH

O

N

N

SiPh3

SiPh3

CH2Cl2 RT 48h

PhH 60∘C 14h


N

O

O

NH

H H

OEtEtO

Me Me

O O

NH

O

O

N

O

O

Me

OO P

O

OH

Cat XIV

94

Galipinine 48

95

91 ee47

45

46










O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




O O

X

+ N

X

H

P

O

O H+ O

O

HN

X

Condensation


10 mol

OO

OHP

O

Cat XV

Cat XV

X = O S

52

51

535049

54

O

NH

NH

O

R3O2C

H2N R1

R1

R1

OR3

OR3R2

R1 R2

R2

NH2

NH2 CH2Cl2 25∘C

lowast

lowast

ROlowastRO












HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




HN HO

OR

O

N HO

HOHO

HO

HO

HO

HOOH OH

OH

RCHO

N HO

O

N HO

NO

O

R H

O H

N HO

O

R

N HO

R

R2

R2

R2

R2

R2

R2

R2 R2

R1

R1

R1

R1

R1R1

R1R1

H2O

H2O

+

+

minus

minus

=|=


N

NH

O Me

MeMe

Me

Me

Me

Ph Ph

N

NH

OMe



O + NR

R

X

XVI XVII

120575

120575

minus

minus+

+

R2N middot HX







O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of





O O+

OCatalyst


O O

O

NH

HN

Ph

Ph

Ph Ph

Ph

PhPh

Ph

Ph

Ph

Ph

Ph

Ph

XVIII

N

MeO

NH

XXIV

XIX

NNH H

OO

HNNH

XXVI

XX XXII

Warfarin

N

XXI

N

NH

O

BrBr

Br

Br

XXIII

OH

OH

OHOH

XXV

NH2

NH2

NH2

NH2

NH2NH2

NH2

NH2

H2NSO3Li

NHP(O)Ph2

lowast

CO2H








N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




N

O

OH

O

+









NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




NO

NF

FN

ON

NH

NHOH

Telcagepant

NO

FF HN N

O

+

F3C F3C

NH2


FF CHO CHO

+

(6 equiv)

Cat (5 mol)

aq THF

NH

OH

PhPh

TMSClimidazole

NH

OTMS

PhPh

Cat XXVII

FF

73 assay yield95 ee

55 56CH3NO2











FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




FF

(i) n-BuLi

(ii) Acrolein

THFwater

FF

OH


F CHO

CHO

Organocatalyticstep

FF

86 7395 ee


DMA

FF

NHAc

NHAc NHAc

NHAc

FF

i-PrOAcHeptane


9391

95


5758

55

56

NO2NO2 NO2

CO2Hn-Bu3NH+

n-Bu3N

COminus2


HO2C

DMA 15∘C

THF minus55∘C



FF

LiCl (03 equiv)

i-PrOHF

F (ii) NaOH

FF

HN

95

83

95

95

DMAP (5 mol)

NO

FF NHAc

NHAc

NHAc NHAc NHAc

NO

FF

aq DMSONaOH


(i) HCl aq i-PrOH

(ii) HCl MTBEN

OF

F


HN N NHO

NO

NF

FN

ON

OH


626160

5957

NO2 NH2CF3

CO2H

F3C

F3C F3C F3C

CO2i-Pr CO2i-Pr

95∘C Clminus

NH3+




35ndash50∘C

Pd(OH)2C

t-BuCOCl Et3N

NminusK+

middotEtOH

i-PrOAc 35∘C


CHO

CHO CHO

CHOHOOC COOH

+

+

(route a)

(route b)

83 overall yield


64 65

66

NHBoc NHBocCO2Me

RHN

OHNH

PhPh

OTMS NOR OH NH

P

NH2


R1R1

R1

= Ph p-Br-Ph napht

Mo(CO)6

CO2Me



NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




NN

NN

F F

Ph

O NH










HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




HNN

NNF F

Ph

Ph

O NHHN

OHO

O




67

68

69

CHO



EtO

EtOH

NH

Ph

Ph Ph

O O

F

O

HN OHO

F

N O

Ph

Ph

F

OH

N O

F

O

OO

F

O

HO

N O

F

+

(minus)-paroxetine

+Route a

Route b

72 86 ee

76

84 90 ee

10 mol cat XXVIII

Cat XXVIII

20 mol cat XXVII

rfx

72

70

71

NH

ArAr

OTMS

BnO2C

CF3CH2OH

CO2Bn

CO2BnCO2Bn

CO2R

CO2Bn

BH3 THF rt

LiAlH4 THF








O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




O

NH

O

Et

Et

Et

Cl

Cl

Cl

ClCl

N

N

OMe


MDM2-p53

NH

O

NH

NH

Et

O

NH

NCl

O Ar

Ar

Ar

HCat

Cat

+ Cat

O


Michael addition


74

7773

7576

NH2


∘ 72h

Ominus

+


OH

O

+

NH

PhPh

OTMS

1 mol

toluene RT 6 hO

O

syn anti 78 197 ee

PO

EtOEtO

O

p-TolSHO

S





O


AcHN

OS

(i) Zn TMSCl

2 h then

AcHN

O


+

OOH

O

+


10 min O

78 79 a

79 c

79 b

80 81


XXVII

NO2

NO2NO2NO2

NO2

N3

NO2

NO2NO2

NH2

CO2Et

CO2Et

CO2EtCO2Et

CO2Et

CO2Et CO2Et CO2Et

CO2EtCO2Et

P(O)(OEt)2

P(O)(OEt)2

O2N


t-BuO2C t-BuO2C

t-BuO2C

t-BuO2C

ClCH2CO2H (20mol)



Cs2CO3

0∘C to RT 4h

minus15∘C 36h

EtOH 70∘C




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of




OH

O

+

NH

PhPh

O

AcHN

AcHNAcHN

AcHN

O

P

O

then EtOH 1 h

10 mol

OS

(i) Zn TMSCl

2 h then

O


O

NHAc

XXVII

85

84

EtO

EtOCO2Et

CO2EtCO2Et

CO2EtCs2CO3

0∘C 3 h

NO2NO2

NO2

NH2

NO2

p-TolSHminus15

∘C 36h

(minus)-oseltamivir


EtOH 70∘C


OSiPh2Me













Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of







Acknowledgments


References















































































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of



















































































































































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry




CatalystsJournal of



Asymmetric Organocatalysis at the Service of Medicinal...

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