Diastereoselective Substrate-Controlled Transition-Metal-Cata ...DOI: 10.1055/s-0035-1560811; Art...

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J. Wencel-Delord, F. Colobert AccountSyn lett

SYNLETT0 9 3 6 - 5 2 1 4 1 4 3 7 - 2 0 9 6© Georg Thieme Verlag Stuttgart · New York2015, 26, 2644–2658account

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Diastereoselective Substrate-Controlled Transition-Metal-Cata-lyzed C–H Activation: An Old Solution to a Modern Synthetic Chal-lengeJoanna Wencel-Delord* Françoise Colobert*

Laboratoire de Chimie Moléculaire (UMR CNRS 7509), Université de Strasbourg, ECPM, 25 Rue Becquerel, 67087 Strasbourg, [email protected]@unistra.fr

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Received: 18.08.2015Accepted after revision: 09.10.2015Published online: 11.11.2015DOI: 10.1055/s-0035-1560811; Art ID: st-2015-a0647-a

Abstract The synthesis of chiral compounds by means of asymmetricC–H activation is an appealing modern strategy for the straightforwardconversion of simple and nonfunctionalized substrates into high-value-added stereogenic molecules. For several years, considerable attentionhas been focused on the design of enantioselective transformations in-volving the use of chiral ligands as sources of chirality. In addition, acomplementary strategy based on direct functionalization of substratesbearing a chiral element has recently demonstrated its potential. Suchdiastereoselective transformations can be achieved by incorporating achiral auxiliary into a directing group (DG). Alternatively, direct func-tionalization of chiral-pool molecules, such as α-amino acids, provides avaluable synthetic route to novel non-natural amino acid derivatives.The aim of this account is to highlight major achievements in diastereo-selective C–H activation. Particular attention will be paid to the contri-butions of our group in this emerging field.1 Introduction2 Directing Group Controlled Diastereoselective C–H Activation3 Substrate-Controlled Diastereoselective C–H Activation4 Conclusions

Key words direct functionalization, asymmetric synthesis, bond acti-vation, diastereoselectivity, chiral auxiliary, directing group

1 Introduction

The growing level of environmental awareness has a di-rect impact on scientific research. Consequently, organicchemists face critical challenges, such as the design ofmore-ecoreliable transformations that permit the rapidconstruction of complex molecular scaffolds from availablefeedstocks. To meet these challenges, the scientific commu-nity has, since the beginning of this century, made signifi-cant efforts to develop reactions that allow the direct func-tionalization of ubiquitous C–H bonds to form desirablefunctional groups. Consequently, numerous innovative cat-

alytic systems have been designed for the conversion of la-tent C–H bonds into a wide variety of carbon–carbon andcarbon–heteroatom linkages.1 Moreover, advancements inthe field of C–H activation continue to stimulate chemiststo reconsider standard retrosynthetic disconnections,thereby allowing more-straightforward syntheses of high-value-added complex organic molecules in fewer steps.2

Chirality is an intriguing feature of numerous naturalproducts, and its importance is universally recognized. Inparticular, the use of small three-dimensional molecules asbiologically active moieties has recently emerged as apromising solution in medicinal chemistry.3–4 Furthermore,axial chirality is a key feature of several natural productsand chiral ligands essential for homogeneous catalysis.5 Forthese reasons, the stereoselective synthesis of optically ac-tive skeletons is a challenging and appealing research tar-get.

Despite the growing importance of the field of C–Hbond activation, its applications in building up chiral mole-cules have been underestimated for quite a long time.6 In-deed, because studies have concentrated primarily on di-rect functionalizations of aromatic C–H bonds, opportuni-ties for accessing stereogenic scaffolds have been limited.Also, the high reaction temperatures and the widespreaduse of strongly acidic and/or oxidative conditions appear tobe incompatible with a use of chiral ligands and with effi-cient stereoinduction. In 2005, however, Yu and co-workersdemonstrated that chiral compounds can be generated bydirect functionalization of C–H bonds, provided that a chi-ral directing group is embedded within a substrate and co-ordinates the metal catalyst to permit the formation of astereogenic metallacyclic intermediate in the key C–Hbond-cleavage step.7 Despite the importance of this seminalwork, stereoselective C–H activation remained a niche topicuntil about 2010, when interest in asymmetric direct func-tionalization was revived. At this time, the development of

© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2644–2658

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enantioselective transformations became clearly favored.Consequently, several classes of stereogenic ligands com-patible with C–H activation reactions have been designed;among these ligands, chiral monoprotected amino acid de-rivatives are arguably the most prominent. The superiorityof enantioselective transformations, which involve the useof a chiral ligand, over diastereoselective reactions, forwhich a stereogenic auxiliary is installed directly on a sub-strate, is widely recognized, because only a catalyticamount of the chiral source is required in the former case.8If, however, the preparation of the chiral ligand requires amultistep, laborious, and difficult synthesis, this argumentis no longer valid. This is even more true since a chiral aux-iliary installed on a substrate can be readily obtained from acheap and abundant chiral pool. In the context of asymmet-ric transition-metal-catalyzed C–H activation, there areseveral additional key points that favor the diastereoselec-tive approach. Because of problems associated with regi-oselectivity and reactivity, C–H activation reactions fre-quently involve the use of substrates that bear a prein-stalled coordinating DG. Consequently, if a chiral DG (DG*)can be embedded straightforwardly and can be easily re-moved after the C–H activation event, no additional step isrequired in comparison to analogous nonasymmetric C–H transformations. Moreover, the installation of a stereo-genic element directly on a substrate ensures that the chiralsource is near the metal atom in the key metallacyclic inter-mediate, thereby maximizing the chances of efficient chiralinduction. Moreover, in such cases, only two coordinationsites of the metal catalyst (M) are occupied (one DG*–M

bond and one C–M bond), thereby preserving the additionalfree coordination sites required to coordinate a couplingpartner. In contrast, in enantioselective transformations, ametal catalyst is significantly more encumbered as a resultof coordination to a nonchiral DG of the substrate, forma-tion of a C–M bond, and complexation of an externalmonodentate or bidentate ligand. Consequently, the coordi-nation of a second coupling partner might be compromised.Finally, the use of a DG* opens the possibility of accessingrather general catalytic systems, compatible with severaldifferent coupling reactions, because a single stereogenicmetallacyclic intermediate can react smoothly with variouscoupling partners.

Accordingly, following the pioneering work of Yu, sever-al research efforts have recently focused on the develop-ment of substrate-controlled stereoselective C–H activationreactions. Not only have novel monocoordinating chiralauxiliaries been successfully employed as stereogenic DGs,but also innovative bidentate asymmetric DGs have beendevised. Furthermore, significant efforts have been devotedto the construction of non-natural α-amino acids throughdiastereoselective C–H activation. Since 2013, we too havebeen actively involved in this expanding field, and our re-search interest is concerned mainly with the synthesis ofaxially chiral compounds. In this account, therefore, we willdiscuss the use of diastereoselective C–H activation reac-tions as a complementary approach to enantioselective C–Hfunctionalizations. Two distinct strategies are discussed:DG-controlled diastereoselective C–H activation, and sub-strate-controlled transformations. In addition, we would

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Biographical Sketches

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Joanna Wencel-Delord was
educated in chemistry at theÉcole Nationale Supérieure deChimie de Rennes, France, andgained her Ph.D. in 2010 fromthe University of Rennes 1,France (Dr. C. Crévisy and Dr. M.Mauduit). After postdoctoral

studies with Professor F. Gloriusat the Westfälische Wilhelms-Universität Münster (Germany)and a position as a temporaryassistant professor (ATER) at theUniversity of Strasbourg (Profes-sor P. Compain), in 2013 shejoined CNRS as an associate re-

searcher in the group of Profes-sor F. Colobert (University ofStrasbourg, France). Her re-search focuses on transition-metal-catalyzed asymmetricC–H activation.

Françoise Colobert received aPh.D. in organic chemistry in1985 from the University Pierreet Marie Curie (Paris), workingwith Professor Jean-Pierre Genêtin the field of asymmetric catal-ysis. After a postdoctoral posi-tion in molecular biology in the

group of Professor Jules Hoff-man (Nobel Prize, Strasbourg),she became an assistant profes-sor in the group of ProfessorGuy Solladié, and was appointedfull professor of organic chemis-try in 2001. Currently, she is di-rector of the molecular

chemistry department of theChemistry Engineering HighSchool of the University ofStrasbourg. Her current re-search concerns asymmetricC–H functionalization and thesynthesis of biologically activemolecules.


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like to draw the reader’s attention to various mechanisticstrategies pertaining to these asymmetric transformations.Indeed, a stereogenic center can be generated either by adesymmetrization reaction, in which a prochiral substitu-ent (such as a methyl or phenyl group) is functionalized[Figure 1(A)] or by selective C–H cleavage of a stereotopichydrogen atom [Figure 1(B)]. Alternatively, a chiral carboncenter can be constructed through the use of a prochiralcoupling partner [Figure 1(C)]. Finally, diastereoselective di-rect functionalization is also an appealing route to axiallychiral compounds [Figure 1(D)].

Figure 1 Strategies for diastereoselective C–H activation

2 Directing Group-Controlled Diastereose-lective C–H Activation

At the beginning of this century, although the stoichio-metric activation of inert C–H bonds by metals such as pal-ladium, iridium, rhodium, or ruthenium to give isolablemetallacyclic intermediates was well established, the fieldof transition-metal-catalyzed C–H activation was in its in-fancy. At that time, most direct functionalization reactionsinvolved aromatic substrates and, generally, high reactiontemperatures were required to ensure acceptable efficien-cies. In this context, the seminal work of Yu on asymmetricC–H activation represented a real breakthrough.7 Yu andco-workers surmised that the oxazoline moiety might beused as an efficient σ-chelating DG that would facilitate theassembly of a pretransition state for cyclometallationthrough a square-planar complex. This assumption was ini-tially confirmed by conducting a palladium-mediated stoi-chiometric iodination of an aliphatic pivalic acid substrateto give a monoiodinated product in a high (80%) yield. Inparallel, a trinuclear palladacyclic intermediate was isolat-ed, unambiguously demonstrating the favored formation ofa geometrically well-defined metallacyclic intermediate.

Subsequently, a related catalytic transformation wassuccessfully achieved by using a (diacetoxyiodo)benzene–diiodine mixture as an iodine source and a precursor for thegeneration in situ of iodine monoacetate, required to regen-erate the palladium(II) acetate catalyst at the end of the cat-alytic cycle. Accordingly, catalytic and diastereoselective di-rect C(sp3)–H functionalization could be performed undersurprisingly mild conditions (Scheme 1). The substitution

pattern of the oxazoline DG was found to have a marked ef-fect on both the reactivity and stereoselectivity of the tar-get transformation.9 When small substituents were intro-duced at the 4-position of oxazoline 1a, direct iodinationwas sluggish and no stereoinduction was observed. Intrigu-ingly, high reactivity and an improved level of diastereose-lectivity were achieved when a bulky tert-butyl group waspresent at the 4-position of the oxazoline DG in 1d. Thesubstitution pattern of the substrate also had a major im-pact on the diastereoselectivity of this transformation, as abulky group at the α-position was required to reach highchiral induction in products 2g and 2h. Accordingly, the de-sired halogenated products could be obtained with diaste-reoselectivities of up to 86% when a noncyclic substrate wasused. Furthermore, the asymmetric functionalization of thecyclopropane scaffold 1i could also be performed withcomplete diastereoselectivity.

Scheme 1 Diastereoselective oxazoline-directed iodination

Interestingly, direct functionalization of cyclopropanesby means of enantioselective C–H activation remained un-explored until the beginning of this decade. In 2011, Yuused monoprotected amino acid ligands to achieve a palla-dium-catalyzed alkylation and arylation of cyclopropanesbearing a weakly coordinating amide DG. In this case, orga-noboron coupling partners were used as the arylatingagents.10 Recently, the same research group discovered that(cyclopropylmethyl)amines are also attractive substrates

MeR2

O

NR1

H Pd(OAc)2 (10 mol%)PhI(OAc)2 (1 equiv)

I2 (1 equiv)

CH2Cl2, 24–50 °CMe

R2O

NR1

I

Impact of R1

MeEt

O

NR1

I

2a: R1 = Me, 20% yield, 0% de2b: R1 = CH2OTBS, 38% yield, 6% de2c: R1 = i-Pr, 15% yield, 0% de2d: R1 = t-Bu, 92% yield, 25% de

Impact of R2

Me

O

Nt-Bu

I

Me

O

Nt-Bu

I

2e: 60% yield, 35% de 2f: 45% yield, 55% de

MeTBSO

O

Nt-Bu

I

2g: 62% yield, 86% de

Met-Bu

O

Nt-Bu

I

2h: 83% yield, 82% de

Cl TBSO

Me

O

Nt-Bu

2i: 65% yield, 98% deI

Pd

Pd

OO R

OR

OO

O

O

O Pd

R

R

CH2

N

Ot-Bu

Met-Bu

H

N

O

t-Bu

CH2

Me

H t-Bu

Key trinuclear Palladacyclic intermediate

anti-orientation of the two bulky substituents

1 2


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for palladium/chiral amino acid catalyzed direct arylationswith iodoarenes.11 An intramolecular palladium(0)-cata-lyzed enantioselective direct functionalization of cyclopro-pane skeletons has been investigated by Cramer and co-workers.12

In-depth mechanistic investigations, involving the char-acterization of key intermediates and computational stud-ies, provided a rationale for the stereoselectivity of thetransformation (Scheme 2).13 When the prochiral substrate1h, bearing tert-butyl groups on the oxazoline DG and inthe α-position, is treated with palladium(II) acetate, stereo-selective C–H activation occurs at a monomeric palladiumcenter, affording one isomer of the trinuclear palladium(II)complex (isomeric ratio 91:9) almost exclusively. Indeed,because of steric repulsion between the two bulky substit-uents, the palladacyclic intermediate in which these twogroups are orientated in anti-positions at both termini ofthe trinuclear complex is favored, producing a highly dia-stereoselective outcome for the catalytic transformation.Importantly, the lack of reactivity of substrates bearing aless sterically demanding oxazoline DG (for example, onebearing an isopropyl substituent) can be attributed to thehigh stability of the bis(oxazoline)palladium(II) acetatecomplex and to a concomitant increase in the overall acti-vation barrier. In contrast, a larger steric hindrance on theoxazoline DG results in destabilization of the correspondingbis(oxazoline)palladium(II) acetate, thereby enhancing itsconversion into the catalytically active monomeric (oxazo-line)palladium(II) acetate intermediate.

Scheme 2 Mechanistic studies on the diastereoselective oxazoline-di-rected functionalization

Another key aspect of this seminal work is the recycla-ble character of the catalytic system; palladium(II) iodide,generated through reductive elimination of the iodinated

compound, precipitates from the solvent, and can be recov-ered by centrifugation and reused directly in a new catalyt-ic system without any significant change in the efficiency ofthe reaction.

A few months later, the same research group expandedthe potential of the chiral oxazoline-directed stereoselec-tive C–H activation by performing an acetoxylation reaction(Scheme 3).14 The catalytic system based on palladium(II)acetate catalyst in combination with lauroyl peroxide as astoichiometric oxidant and acetic anhydride (used as a cru-cial promoter of the oxidative addition of the peroxide tothe palladacyclic intermediate), enabled mild and diastereo-selective oxidation of prochiral aliphatic substrates bearingthe same, highly sterically demanding, chiral oxazoline DG.The functionalization occurs selectively and the stereoin-duction is strongly influenced by the steric environmentaround the two prochiral methyl groups of a starting mate-rial. Consequently, the enantioenriched acetoxylated prod-ucts 3 could be isolated in yields of 38–73% and diastereo-meric excesses of 18–82%.

Scheme 3 Diastereoselective oxazoline-directed acetoxylation

At the same time as Yu and co-workers were examiningpalladium-catalyzed oxazoline-directed iodination and ace-toxylation, the group of Bergman and Ellman astutely useda chiral imine as a potent DG* (Scheme 4).15 When design-ing a new synthetic route to (+)-lithospermic acid, the re-searchers surmised that chiral 2,3-dihydrobenzofuran coresmight be accessible by means of an intramolecular asym-metric Fujiwara–Moritani reaction. Although initial at-tempts at enantioselective transformations using a rhodi-um(I) catalyst in combination with chiral ligands failed,synthetically useful levels of diastereoselectivity were ob-served when a chiral imine was used as both the DG andthe chiral auxiliary. The stereogenic benzylic amines turnedout to be appealing precursors for imine DGs*, but the mostselective transformation was achieved by using an (–)-ami-noindane-derived substrate. Under the optimized reactionconditions, benzofuran 5, a key precursor of (+)-lithosper-

O N

t-Bu

Ht-Bu

MeMe

Pd3(OAc)6

Me

Met-Bu

H

t-BuN

O

PdO

O

AcOCH2

Met-BuH

t-BuN

O

PdO

O

AcO

H

‡

Pd

Pd

OO R

OR

OO

O

O

O Pd

R

R

CH2

N

Ot-Bu

Met-Bu

H

N

O

t-Bu

CH2

Me

H t-BuI2

O N

t-Bu

Ht-Bu

MeCH2

I

91:9 dr

R = CF3 isolable complex characterized by X-ray

computed transition stateminimal steric hindrance between two t-Bu groups

stereoselective C–H activation occuring at a monomeric Pd center

2 2

2

2

R = Me

1h

2h

MeR

O

Nt-Bu

HPd(OAc)2 (5 mol%),

lauroyl peroxide (2 equiv)

Ac2O, 50 °CMe

R2O

Nt-Bu

OAc

MeEt

O

Nt-Bu

OAc

Me

O

Nt-Bu

OAc

3b: 66% yield, 38% de

MeTBSO

O

Nt-Bu

OAc

3d: 43% yield, 62% de

Met-Bu

O

Nt-Bu

OAc

3e: 49% yield, 82% de

Cl

3a: 67% yield, 18% de

Me

O

Nt-Bu

OAc

3c: 73% yield, 24% de

MeO2C

1 3


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mic acid, could be obtained in 88% yield and 73% de bymeans of diastereoselective rhodium(I)-catalyzed C–Hfunctionalization.

Scheme 4 Rhodium(I)-catalyzed diastereoselective oxidative Heck re-action

Intriguingly, after the appearance of these seminal pub-lications on diastereoselective C–H activation in the middleof the last decade, this research field remained overlookedfor several years. In 2012, Ferreira proposed a complemen-tary strategy to achieve regio- and stereoselective C–H acti-vation.16 Contrary to the standard directing-group strategy,in which a DG is directly embedded within the substrate,this approach involved the use of a specific chiral molecularframework bearing an additional nonstereogenic coordi-nating moiety. This molecular framework should be easy toinstall on a C–H activation substrate and might be readilyremovable after the functionalization step. In pursuit of thisidea, the researchers selected aldehydes as the C–H activa-tion substrates and a chiral proline derivative as a molecu-lar platform (Scheme 5). The acetalization reaction deliv-ered aminal products containing a pyridine DG. Such finelydesigned substrates were tested in a direct acetoxylation re-action. The isopropyl-derived substrate 6a underwent theexpected C–O coupling reaction, although a large loading ofpalladium(II) diacetate catalyst (50 mol%) was required. Im-portantly, chirality transfer occurred correctly during thistransformation, as the acetoxylated product was formedwith nearly complete selectivity. It is noteworthy that the

efficiency of this transformation was improved by the in-corporation of conformational flexibility, for example, byintroducing a CH2 linker between the pyridine DG and theaminal moiety in 6b. Consequently, both the catalyst load-ing and the reaction temperature could be decreased.

In 2013, our research group initiated a new researchproject on diastereoselective C–H activation, with particu-lar attention to the design of novel chiral DGs. Our laborato-ry has a longstanding experience in sulfoxide chemistry.17,18

In particular, in the first decade of the 21th century, we dis-covered that the atropodiastereoselective Suzuki–Miyauracoupling can be performed by using iodoarenes bearing achiral sulfoxide substituent in the ortho-position as cou-pling partners.19 We speculated that a stereogenic sulfox-ide-coordinated palladacyclic intermediate might be gener-ated through oxidative addition and, consequently, chiralinformation might be efficiently transferred either throughstereoselective transmetallation or reductive elimination.The possible generation of such chiral sulfoxide-coordinat-ed palladacyclic species encouraged us to investigate thepotential of our chiral auxiliary in the context of palladium-catalyzed C–H activation. Additionally, as enantiopure sulf-oxides are readily available on a large scale from inexpen-sive starting materials, and because they can be straightfor-wardly removed through sulfoxide–lithium exchange fol-lowed by electrophilic trapping, these chiral auxiliariesappear to be particularly appealing.

Our initial efforts involved an atroposelective function-alization of biaryl scaffolds bearing the chiral sulfoxideDG.20 We were soon able to devise a catalytic system thatpermitted direct olefination of the sulfoxides 8 (Scheme 6).The use of palladium(II) acetate as a catalyst in combinationwith a large excess of silver acetate as an oxidant (6 equiv)in dichloroethane at 80 °C gave the functionalized atropiso-meric products 9 (Scheme 6). Unfortunately, rather moder-ate results were obtained in terms of both stereoselectivityand efficiency (dr 64.5:35.5 to 91:9). Importantly, total at-roposelection could be achieved by using the trisubstitutedbiaryl substrate 8h, but the desired product was isolated inonly a modest 40% yield.

Although both the efficiency and stereoselectivity ofthis transformation were moderate, this pioneering workdemonstrated that the sulfoxide moiety could be used asboth a chiral auxiliary and a DG. In a continuation of ourstudies, we discovered a related acetoxylation reaction(Scheme 7).21 The use of acetic acid as a cosolvent in a pres-ence of a catalytic amount of palladium(II) acetate as a cata-lyst and ammonium persulfate as an oxidant permitted se-lective oxidation to give the corresponding atropo-enrichedacetate-substituted biaryls 10. Surprisingly, 1,1,1,3,3,3-hexafluoropropan-2-ol turned out to be the optimal medi-um for this reaction, allowing direct functionalization tooccur at room temperature. This acetoxylation reaction isalso extremely robust; no precautions to avoid air or mois-

H N

OMe

O Ar

MeO2C

[RhCl(coe)2]2 (10 mol%)FcPCy2 (30 mol%)

OAr

H NCO2Me

588% yield, 73% de

4Ar = 3,4-(OMe)2C6H3

PhMe, 75 °C, 20 h

OMe

coe = cyclooctene

Scheme 5 Diastereoselective acetoxylation by an approach involving a chiral molecular scaffold and a remote DG

NN

N

O

Ph

cond. Acond. B

NN

N

O

Ph

OAc

R

O

n n

6b: n = 1cond. B:

Pd(OAc)2 (10 mol%)PhI(OAc)2 (1.5 equiv)

AcOH/Ac2O, 55 °C 43% yield, 10:1 dr

6a: n = 0cond. A:

Pd(OAc)2 (50 mol%)PhI(OAc)2 (1.8 equiv)

AcOH/Ac2O, 85 °C66% yield, > 10:1 dr

NH

NN

RPh

R = i-Pr

N

O

NHPh

N

O

stereogenic molecular scaffold bearing a remote

DG

Concept:

"C–H activation substrate"

chiral framework

achiral DG

6 7


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ture are required, and the addition of a small amount of wa-ter is even beneficial. Under the optimized reaction condi-tions, a large panel of variously substituted biaryl sulfoxides8 underwent the atroposelective acetoxylation with re-markable efficiency and stereoselectivity. Both electron-do-nating and electron-withdrawing substituents could be in-stalled at either the 2′-position or the 6-position, and thecorresponding C–O coupling products 10 were isolated in75–95% yield and 91:9 to > 98:2 diastereoselectivity. Thetrisubstituted biaryl sulfoxides 8j–n could also be success-fully used in this coupling reaction; the acetoxylation ofsubstrate 8j bearing two unbulky substituents (fluoro andmethoxy, respectively), in addition to the sulfoxide DG,around the biaryl axis delivered the corresponding atropo-pure product 10j in 88% yield. In contrast, increasing thesteric demand around the biaryl axis turned out to be detri-mental either to efficiency (10m–n) or diastereoselectivity(10k–l) of the transformation.

The majority of our biaryl sulfoxide substrates (R1 ≠ H)are axially chiral molecules, atropisomerically stable atroom temperature, that were used as mixtures of two atrop-isomers (typically, the NMR spectra of these substratesclearly indicated the presence of a mixture of two atropodi-astereomers in 1:1.1 to 1:1.6 ratio). Our direct functional-

ization reaction allows their conversion at room tempera-ture into highly atropo-enriched compounds, generally iso-lated in excellent yields. These results clearly suggest thatthis transformation might occur either through a dynamickinetic asymmetric transformation or through dynamic ki-netic resolution.22 Indeed, if the steric hindrance around thebiaryl axis is high enough to prevent atropo-epimerization(rotation around the biaryl axis) of the substrate (rotationbarrier > 22 kcal·mol–1), the two atropisomers should reactwith palladium(II) acetate to generate the correspondingatropostereogenic palladacyclic intermediates. As the sterichindrance of such an intermediate is reduced when pallada-tion occurs on the opposite side to the 4-tolyl substituent ofthe sulfoxide moiety, the disfavored palladacycle undergoesrapid atropo-epimerization. We surmise that this rotationaround the Ar–Ar bond is possible as a result of the forma-tion of a pallada-bridged cyclic species that might increasethe angle between the two aromatic units, thereby lower-ing the rotation barrier in this intermediate compared withthat in the corresponding substrate.23 The rate of this atro-po-epimerization is expected to be significantly faster thanthe reductive elimination from the disfavored metallacyclicintermediate, thereby permitting excellent stereocontrolthroughout the reaction (Scheme 8).

Scheme 6 Atropodiastereoselective sulfoxide-directed oxidative Heck reaction

SO

4-TolH

+ CO2MeR1

R2

(2 equiv)

9a: 87% yield; 82:18 dr

9d: 30% yield; 74:26 dr

9c: 86% yield; 76:24 dr9b: 87% yield; 64.5:35.5 dr

Pd(OAc)2 (10 mol%)AgOAc (6 equiv)DCE, 80 °C, 6 h

S4-Tol

O

MeCO2Me

S4-Tol

O

MeOCO2Me

S4-Tol

O

CO2Me

S4-Tol

O

F3CCO2Me

S4-Tol

O

ClCO2Me

S4-Tol

O

CO2Me

R1

R2

9e: 43% yield; 71:29 dr

S4-Tol

O

MeOCO2Me

MeO

9h: 40% yield; > 98:2 dr

S4-Tol

O

CO2Me

MeO

9f: 56% yield; 83:17 dr

S4-Tol

O

CO2Me

F3C

9g: 36% yield; 91:9 dr

8 9

Scheme 7 Atropodiastereoselective sulfoxide-directed acetoxylation. The dr was determined by 1H NMR analysis of the crude mixture.a Yield and dr after recrystallization.

R1

R1

S

H

Pd(OAc)2 (10 mol%)(NH4)2S2O8 (2 equiv)

H2O, (2 equiv)

AcOH–HFIP (1:1)25 °C

4-Tol

OS

4-Tol

O

OAcR1R2 R2

S4-Tol

O

OAc

S4-Tol

O

10c: 95% yield; 98:2 dr (38 h)

OAc

10a: R1 = Me, 96% yield; > 98:2 dr (16 h)10b: R1 = OMe, 87% yield; 91:9 dr (36 h, 15 °C) [78% yield; > 98:2 dr]a

10e: R1 = Cl, 87% yield; 92:8 dr (36 h) [77% yield; > 98:2 dr]a 10d: R1 = CF3, 79% yield; 95:5 dr (60 h) [72% yield; > 98:2 dr]a

10i: R1 = CO2Et, 82% yield; 95:5 dr (48 h)

S4-Tol

OR2

OAc

10g: R2 = CF3, 89% yield; 98:2 dr (38 h)10f: R2 = OMe, 75% yield; >98:2 dr (20 h)

S4-Tol

O

OAcR1

MeO

S4-Tol

O

OAcMe

ClS4-Tol

O

OAcF

ClS4-Tol

OMeO

OAc

10l: 98% yield; 66:34 dr (38 h)

10m: 59% yield; > 98:2 dr (80 h)

10n: 56% yield; > 98:2 dr (42 h)

HFIP = (F3C)2CHOH

10j: R1 = F, 88% yield; >98:2 dr (90 h)10k: R1 = Me, 79% yield; 91:9 dr (38 h) [67% yield; > 98:2 dr]a

8 10


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Scheme 8 Dynamic kinetic asymmetric transformation mechanism of the sulfoxide-directed atroposelective acetoxylation

Alternatively, if the substituents around the biaryl axisare less sterically demanding (small R1 and R2 = H, as, forexample, in 8a), slow atropo-epimerization of the startingmaterial over a prolonged time cannot be excluded. Conse-quently, the excellent atroposelection of this acetoxylationreaction might result from both dynamic kinetic resolution(epimerization of the starting material) and dynamic kinet-ic asymmetric transformation (epimerization of the pallada-cyclic intermediate) (Scheme 9).

Finally, if a bulky substituent is introduced in the orthoposition of the aromatic ring bearing the DG [as, for exam-ple, in 8m or 8n (R2 = Cl)], the acetoxylated product is iso-lated in an atropopure form, but in moderate yield. In addi-tion, the unreacted starting material could be recoveredfrom the reaction mixture, also as a single diastereomer. Ac-cordingly, a simple kinetic resolution occurs in this case.The increase in steric hindrance either disfavors metallationof one atropisomer or it prevents the epimerization of themetallacyclic intermediate. Consequently, the stericallyless-congested metallacyclic intermediate is functionalizedin a stereoretentive manner, yielding a single diastereomerof the coupling product (Scheme 10).

In pursuing our study, we were delighted to discoverthat this original diastereoselective sulfoxide-directed C–Hprotocol can also be efficiently used to construct halogenat-ed atropopure products 11 (Scheme 11). A slight modifica-tion of the reaction conditions, i.e., by replacement of theammonium persulfate oxidant with N-iodosuccinimidepermitted extremely mild and selective iodination of biarylsulfoxide substrates. This reaction is highly efficient and at-roposelective for a large panel of substrates. As with the

acetoxylation reaction, this direct halogenation is believedto involve a comparable dynamic kinetic asymmetric trans-formation /dynamic kinetic resolution mechanism.

Finally, the truly synthetically useful character of thisdiastereoselective C–H functionalization was evidenced bya post-modification of the atropo-pure acetoxylated prod-uct. The sulfoxide auxiliary could be straightforwardly re-

S4-Tol

OMeO

F HS

4-Tol

OMeO

F Pd

8j-A

#

OAc

S4-Tol

OMeO

F OAc

AcOH

k3A

Int-8j-A

10j-A (SaS)

Pd(OAc)2

k1A

S4-Tol

O

HF

MeOPd(OAc)2

S4-Tol

O

PdF

MeO

#

OAc

k1B S

4-Tol

OMeO

F OAc

AcOH

k3B

Int-8j-B steric hindrance

S4-Tol

OMeO

FPd

#

OAc

k2B

k2A

8j-B

- favoured rotation around Ar–Ar axis of Int-8j-B - k3

A >> k3B: selective formation

of 10j-A

88% yield, > 98:2 dr

10j-B

Scheme 9 Dynamic kinetic asymmetric transformation/dynamic kinet-ic resolution mechanism of the sulfoxide-directed atroposelective ace-toxylation

S4-Tol

O

Me HS

4-Tol

O

Me Pd

8a-A

#

OAc

S4-Tol

O

Me OAc

AcOH

k3A

Int-8a-A

10a-A (SaR)

Pd(OAc)2

k1A

S4-Tol

O

HMe

Pd(OAc)2

S4-Tol

O

PdMe

#

OAc

k1B S

4-Tol

O

Me OAc

AcOH

k3B

Int-8a-B steric hindrance

S4-Tol

O

MePd

#

OAc

k2B

k2A

8a-B

- atropo-epimerization of the starting material and/or palladacyclic intermediate- k3

A >> k3B: selective formation

of 10a-A

96% yield, > 98:2 dr

10a-B

B


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moved in the presence of a lithium base to give an aryllithi-um intermediate that is configurationally stable at low tem-perature and can subsequently undergo electrophilictrapping without any loss of axial purity.

In 2015, Yang et al. reported a closely related diastereo-selective C–H activation/dynamic kinetic resolution proto-col for the synthesis of the axially chiral phosphates 14(Scheme 12).24 The researchers used a chiral menthyl-sub-stituted P(O)R1R2-DG to control the atroposelective out-come of the C–H activation event. (Notably, in the case ofthe olefination reaction, amino acid ligands were added tothe reaction mixture). Accordingly, an oxidative Heck reac-tion, acetoxylation, and iodination of the biaryl precursors13 were achieved with excellent stereoinduction. However,the efficiency of this transformation was rather moderate(yields 31–73%), and harsh reaction conditions (100 °C)were required. These results suggest that epimerization ofthe starting material and/or palladacyclic intermediates isless efficient compared with the related sulfoxide-directedprotocol.

Concurrently with our work on atropodiastereoselectiveC–H functionalization, You described a related enantiose-lective transformation.25 In this protocol, 1-(1-naphthyl)-benzo[h]isoquinoline (15) was used as a biaryl substrate,and asymmetric oxidative olefination was achieved by us-ing a chiral (η5-cyclopentadienyl)rhodium-derived catalyst(Scheme 13). Although the axially chiral compound 16 wasdelivered with good enantioselectivity (up to 86%) by usingonly a catalytic amount of the chiral inductor, this transfor-

mation is limited to rather specific isoquinoline derivatives;consequently, it cannot be used as a general strategy tobuild up highly substituted atropo-pure skeletons.

Asymmetric transformations involving activation ofC(sp2)–H bonds are relatively rare, as only specific skeletonscontaining either axial or planar chirality can be targeted.In contrast, the stereoselective functionalization of C(sp3)–H bonds is clearly more appealing, as an almost unlimitedpanel of stereogenic carbon moieties can be prepared inthis manner from simple, nonfunctionalized substrates.However, the activation of aliphatic C–H bonds is generallymuch more challenging. A major advance in C(sp3)–H acti-vation was achieved when Daugulis and co-workers discov-ered that bidentate DGs are particularly suitable for en-hancing the direct insertion of a metal catalyst into such la-tent bonds.26 Inspired by this seminal work, severalresearch groups have devised catalytic systems that benefitfrom bicoordinating N,N- and N,S-DGs to permit activationof both primary and secondary C(sp3)–H bonds.27 Surpris-ingly, no design of stereogenic bidentate DGs was reporteduntil 2015. The first example of a diastereoselective C(sp3)–H activation by such an approach was reported by Shi andco-workers,28 who speculated that the oxazoline group

Scheme 10 Kinetic resolution mechanism of the sulfoxide-directed at-roposelective acetoxylation

S4-Tol

OCl

F H

S4-Tol

OCl

F Pd

8m-A

#

OAc

S4-Tol

OCl

F OAc

59% yield, > 98:2 dr

AcOH

k3A

Int-8m-A10m-A (SaR)

Pd(OAc)2

k1A

S4-Tol

O

HF

Cl

Pd(OAc)2

S4-Tol

O

PdF

Cl

#

OAc

k1B S

4-Tol

OCl

F OAc

AcOH

k3B

Int-8m-Bsteric

hindrance

S4-Tol

OCl

FPd

#

OAc

k2B

k2A

8m-B

- increased steric congestion: disfavored palladation of 8m-B or impossible epimerization of Int-8m-B- selective functionalization of 8m-A- 8m-B recovered unreacted

recovered unreacted SM40% yield; > 98:2 dr

10m-A

Scheme 11 Atropodiastereoselective sulfoxide-directed halogenation. The dr was determined by 1H NMR analysis of the crude mixture.a Yield and dr after recrystallization.

R1

R1

S

H

Pd(OAc)2 (10 mol%)NXS (1.3 equiv)

AcOH–HFIP (1:1)25 °C

4-Tol

OS

4-Tol

O

IR1R2 R2

S4-Tol

O

I

S4-Tol

O

11c: 90% yield; 96:4 dr (18 h)[80% yield, > 98:2 dr]a

I

11a: R1 = Me, 98% yield; > 98:2 dr (9 h)11b: R1 = OMe, 96% yield; 96:4 dr (5 d)11e: R1 = Cl, 83% yield; 91:9 dr (60 h) [75% yield; > 98:2 dr]a

11d: R1 = CF3, 86% yield; 93:7 dr (5 d) [75% yield; 97:3 dr]a

11i: R1 = CO2Et, 94% yield; 92:8 dr (5 d)

S4-Tol

OR2

I

11g: R2 = CF3, 98% yield; 97:3 dr (31 h); [87% yield; 98:2 dr]a

11f: R2 = OMe, 90% yield; 98:2 dr (20 h)

S4-Tol

O

IF

MeO S4-Tol

O

IMe

MeO

11j: 93% yield; > 98:2 dr (44 h)

11k: 97% yield; 81:19 dr (7 d)[67% yield; 97:3 dr]a

S4-Tol

O

IMe

ClS4-Tol

OMeO

I

11l: 98% yield; 63:37 dr (38 h)[59% yield; > 98:2 dr]a

11n: 48% yield; > 98:2 dr (7 d)

Me

S4-Tol

O

Br

12: 82% yield; 93:7 dr (36 h)[65% yield; > 98:2]a

8 11–12


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might be applied as a surrogate for the pyridine or quino-line moieties generally used as key coordinating functional-ities of bidentate DGs. The choice of an oxazoline core pres-ents some additional advantages, such as the opportunityto include chiral elements in the DG, straightforward syn-thesis of the DG from the corresponding amino alcohols,and possible cleavage of the DG after the C–H activationevent. Initial efforts provided evidence that the α-amino-oxazoline moiety can indeed be used as a potent DG for pal-ladium-catalyzed arylations of aliphatic substrates. Subse-quently, an asymmetric version of this transformation wasstudied by using enantiopure oxazolines as a source of chi-rality (Scheme 14). Disappointingly, under the previouslyoptimized reaction conditions, mediocre diastereoselectivi-ty was observed when the isopropyl-substituted oxazoline17a was used as a chiral auxiliary (59:41 dr). This ineffi-cient chirality transfer was attributed to the large distancebetween the stereogenic element and the reactive site. Ele-gant chirality enhancement was achieved in the presence ofa sterically demanding sodium pivalate additive. It is be-

lieved that the pivalate anion participates in C–H activationevent through a concerted metalation-deprotonation path-way, and subsequently influences the chirality of the oxazo-line ring, thereby forming a chirality relay. Under such mod-ified reaction conditions, arylation occurred with signifi-cantly better diastereoselectivity (83:17 dr). Furtherimprovement was achieved by installing a benzylic substit-uent on the oxazoline ring 17b, thereby affording the func-tionalized product 18b in 90:10 dr and 59% yield. Unfortu-nately, such encouraging chirality transfer could only be ob-served when C–H activation occurred at a benzylic position.

Scheme 14 Chiral bidentate DG for a diastereoselective arylation

Only few weeks later, Hong and co-workers reported an-other example of a stereogenic bidentate DG, in which theyastutely employed an amino acid motif as a remote coordi-nation site (Scheme 15).29 Currently, monoprotected aminoacids are arguably the most potent and general chiral li-gands for use in the context of the Pd-catalyzed asymmetricC–H activation.1c The initially designed valine-derived DGembedded in the cyclopropane substrate turned out to bean inefficient promoter of the palladium-catalyzed aryla-tion. Intriguingly, the introduction of the aminomethyl mo-tif on the valine core enhanced the desired transformation,and the arylated product was isolated in moderate 26%

Scheme 12 Atropodiastereoselective phosphate-directed C–H func-tionalization

Me

R1

P

H

cond. Acond. Bcond. C

O-(–)-Men

OP

O-(–)-Men

O

FGR1R2 R2

PO-(–)-Men

O14a: R = CO2Et, 73% yield; > 95:5 dr 14b: R = CO2-t-Bu, 53% yield; > 95:5 dr 14c: R = SO2Ph, 31% yield; > 95:5 dr 14d: R = P(O)(OEt)2, 62% yield; > 95:5 dr 14e: R = CHO, 27% yield; > 95:5 dr

Ph Ph

R

Ph Ph

PO-(–)-Men

O

CO2Et

Ph

14f: 42% yield; > 95:5 dr

Me

PO-(–)-Men

O

OAc

Ph

14g: 46% yield; > 95:5 dr

Me

PO-(–)-Men

O

I

Ph

14h: 54% yield; > 95:5 dr

cond. C : Pd(TFA)2 (10 mol%) NIS (1.5 equiv) AcOH/TFE, 100 °C, 16 h

cond. A : CH2=CHR, Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%), Cu(OAc)2 (20 mol%), Ag2CO3 (1 equiv), TFE, 100 °C

cond. B : Pd(OAc)2 (10 mol%) PhI(OAc)2 (3 equiv) TFE, 100 °C, 16 h

13 14

(–)-Men = (–)-menthylAc-Gly-OH = N-acetylglycineTFE = F3CCH2OH

Scheme 13 Atropo-enantiostereoselective C–H activation

N+ Ar

Rhcat (5 mol%)(BzO)2 (5 mol%)

Cu(OAc)2 (20 mol%)Ag2CO3 (1 equiv)

MeOH, 80 °C

N

Ar

16: Ar = 2-naphthyl 94% yield; 80% ee

OMe

OMe

Rh

15

R1

H O

NH

N

O

R2

+

Pd(OPiv)2 (10 mol%)Ag2CO3 (1.5 equiv)

(BnO)2PO2H (1 equiv)NaOPiv (2.0 equiv)

HFIP–DMSO (9:1)90 °C, 12 h

R1

O

NH

N

O

R2

O

NH

N

O

i-Pr

OMe

18a:73% yield, 59:41 dr (without NaOPiv)

56% yield, 83:17 dr

O

NH

N

O

R

18b: R = OMe; 59% yield, 90:10 dr18c: R = Br; 66% yield, 88:12 dr

Me

O

NH

N

O

18d: 80% yield, 64:36 dr

O

N

N

O

R2HR1

HPd

OO

relay of chirality

Ar-I

Ar

proposed key intermediate

17 18


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yield, but with encouraging diastereoselectivity (8.5:1 dr).Further investigations revealed that an NH2-terminal motifon the DG was crucial to ensure acceptable reactivity andthat the increased steric bulk enhanced the selectivity ofthe overall transformation. Under the optimized reactionconditions, diastereoselective arylation of the cyclopropanederivatives 19 occurred smoothly at 100 °C with a range ofboth electron-rich and electron-deficient aromatics, yield-ing the desired products 20 in 28–78% yield and a diaste-reomeric ratio of 5.7:1 to 71.5:1. It is noteworthy that thechiral induction during this transformation is rate depen-dent and is generally improved when higher conversionsare achieved. Indeed, a second arylation of the functional-ized products follows the kinetic resolution scenario; andthe second arylation of the minor isomer of the monoary-lated product is favored. As far as the mechanism is con-cerned, this arylation is believed to occur through an initialDG-assisted palladation to give two diastereomeric metalla-cyclic intermediates in equilibrium; this is followed by anoxidative addition of aryl iodides to generate palladium(IV)species, and a final reductive elimination. Because C–Hcleavage of the two diastereotopic protons of the cyclopro-pane core appears to be relatively fast, the oxidative addi-tion is assumed to be the stereoselective step.

3 Substrate-Controlled Diastereoselective C–H Activation

A complementary approach to diastereoselective C–Hactivation involves the use of chiral pool-derived startingmaterials bearing nonstereogenic DGs. In this context, di-rect functionalization of α-amino acids is particularly ap-pealing, as it paves the way to synthesis of structurally di-verse nonnatural amino acids that might be difficult to pre-pare by other synthetic routes. A pioneering effort in thisfield was reported in 2006 by Corey and co-workers,30 who

installed a bicoordinating DG on the carboxylate function ofleucine and protected the amino moiety with a phthaloylgroup (Scheme 16). The initial studies revealed that 8-ami-noquinoline was the most potent DG and that under theoptimized reaction conditions, β-acetoxylation of 21 oc-curred smoothly at 80 °C, delivering the desired compoundin 60% yield and with excellent trans-stereoselectivity(20:1). It is noteworthy that chiral induction is believed toresult from the preferential formation of a trans-palladacy-cle as a key intermediate. Accordingly, the diastereoselectiv-ity of this transformation is strongly influenced by sterichindrance at the α-position. In addition, related N2-phtha-loyl-N1-quinolin-8-ylleucinamides (21) can also be used assubstrates for this direct arylation, thereby providing a se-ries of β-arylated leucine skeletons.

Scheme 16 Acetoxylation of α-amino acid derivatives

In 2010, this seminal work inspired Chen to utilize asimilar stereoselective direct arylation as a key step in a to-tal synthesis of celogentin C.31 They hypothesized that thestrategy developed by Corey might provide a suitable ap-proach for constructing a Leu–Trp linkage. In an attempt toreach this goal, they initially studied the stereoselectiveC–H coupling of N2-phthaloyl-N1-quinolin-8-ylleucinamide(21a) and 6-iodo-1-tosyl-1H-indole, which gave the desiredproduct in 80% yield when palladium(II) acetate was usedas a catalyst with silver acetate as an additive in tert-butylalcohol at 110 °C. Importantly, the functionalized iodotryp-tophan 23 is also a potent coupling partner in this reaction,allowing generation of the key intermediate 24 as sole di-

Scheme 15 Diastereoselective arylation of the cyclopropane deriva-tives

NH

O R

O

NH2

+ Ar-I

Pd(OAc)2 (10 mol%)K2CO3 (2 equiv)

t-Amyl-OH, 100 °C

H

NH

O R

O

NH2

Ar

NH

O i-Pr

O

NH2

Ph

20a: 71% yield; 8.6:1 dr

NH

O Ph

O

NH2

Ph

20b: 56% yield; 3.2:1 dr

NH

O t-Bu

O

NH2

Ph

20c: 49% yield; 13.7:1 dr

NH

O s-Bu

O

NH2

Ph

20d: 70% yield; 10.2:1 dr

NH

O s-Bu

O

NH2

Ar

20e: Ar = 4-MeC6H4, 63% yield; 16.5:1 dr20f: Ar = 4-PhC6H4, 68% yield; 10.9:1 dr20g: Ar = 3,5-Cl2C6H3, 41% yield; 71.5:1 dr20h: Ar = 4-F3CC6H4, 52% yield; 20.4:1 dr20i: Ar = 4-MeCOC6H4, 34% yield; 6.3:1 dr20j: Ar = 3-Tol, 59% yield; 21.0:1 dr20k: Ar = 2-ClC6H4, 67% yield; 5.7:1 dr

19 20

PhthNNH

O

NR H

Pd(OAc)2 (20 mol%)Oxone (5 equiv)Ac2O (10 equiv)

Mn(OAc)2 (1.2 equiv)

MeNO2, 80 °C, 22 h

PhthNNH

O

NR OAc

22a: R = i-Pr, 60% yield, 15:1 dr22b: R = Ph, 63% yield, > 50:122c: R = Me, 51% yield, 5:1 dr22d: R = Et, 56% yield, 8:1 dr

H H

H21

Scheme 17 Application of the stereoselective arylation of leucine de-rivative for total synthesis of a macrocyclic peptide

PhthNNH

O

NH

Pd(OAc)2 (20 mol%)AgOAc (1.5 equiv)

t-BuOH, 110 °C, 36 h

PhthNNH

O

N

NTs

I

CO2-t-BuBocHN

+

TsNNHBoc

t-BuO2C

21a(2 equiv)

23(1 equiv)

85% yield, > 50:1 dr

24key intermediate of celogentin C


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astereomer an in excellent 85% yield on a four-gram scale,unlocking the door to an original synthesis of the targetedmacrocyclic peptide (Scheme 17).

Since these initial reports, the scientific community hasfocused significant efforts on developing other diastereose-lective functionalizations of α-amino acids. A general aryla-tion protocol was reported by Tran and Daugulis in 2012.32

An 8-aminoquinoline DG and a phthalimide protectinggroup on the amino moiety were once again selected as thefavored activating moieties for the aliphatic substrates(Scheme 18). When an aryl iodide was used as the couplingpartner in combination with palladium(II) acetate as cata-lyst, silver acetate as base, and toluene as solvent, the de-sired asymmetric functionalization took place at 60 °C, per-mitting isolation of the corresponding nonnatural aminoacids 25 in excellent yields (77–95%) and good diastereose-lectivities (13:1 to >50:1). As previously, anti-diastereo-mers were generated. Deuteration experiments suggestedthat the key palladacyclic intermediate has a trans-arrange-ment of the phthaloyl moiety and the R group of the aminoacid precursor; consequently, C–H activation is the stereo-determining step.

An interesting synthetic application of this stereoselec-tive C(sp3)–H functionalization in preparing α-amino-β-lactams was reported by Shi and co-workers.33 They hy-pothesized that by using the alanine derivate 26 as a start-ing material, β-arylation of the methyl group and subse-quent intramolecular C–N coupling should deliver the com-mon α-amino-β-lactam structural motifs. However, thedevelopment of this two-step reaction presents two majordifficulties. First, in the initial C(sp3)–H arylation step, se-lective monofunctionalization rather than diarylation is re-quired. Secondly, the catalytic system needs to be suffi-ciently reactive to enhance palladation of the methyleneC(sp3)–H bond and the subsequent intramolecular amida-tion. The choice of the DG installed on the alanine precursorwas therefore crucial, and a 2-pyridin-2-ylisopropyl (PIP)moiety turned out to be the optimal choice (Scheme 19).Rewardingly, arylation of 26 occurred in good yields and ex-cellent monoselectivity. Furthermore, when the newly gen-erated chiral substrates reacted with the palladium(II) ace-tate catalyst, a stereodiscriminating palladation of the ben-zylic methylene C(sp3)–H bond occurred. The final C–Ncoupling was promoted by a carefully selected oxidant (amixture of sodium periodate and acetic anhydride) that fa-cilitated palladium(II)/palladium(IV) oxidation, thereby ex-pediting stereoretentive reductive elimination. Under opti-mized condition, this sequential methyl arylation/diastere-oselective CH2 amidation permitted a straightforward andhighly efficient synthesis of a large panel of α-amino β-lact-ams 28 from a simple chiral pool.

In attempts to expand the synthetic utility of this directand diastereoselective functionalization of amino acid scaf-folds, several research groups endeavored to design a cata-lytic system that would permit related C(sp3)–C(sp3) cou-plings. The challenging character of the stereoselective al-kylation reactions stems from the difficulty in performingoxidative addition of alkyl halides, which are rather elec-tron rich, and the sluggish alkyl–alkyl reductive elimina-tion, which can be outcompeted by undesired side-reac-tions. The research groups of Shi34 and Chen35 simultane-Scheme 18 Stereoselective arylation of α-amino acids

PhthNNH

O

NR H

Pd(OAc)2 (5–11 mol%)AgOAc (2.5 equiv)

PhMe, 60 °C, 72–96 h

PhthNNH

O

NR

+ Ar-I

Ar(5 equiv)

R = Ph 91% yield, 24:1 dr 95% yield, > 50:1 drR = (CH2)3NPhth 85% yield, 16:1 dr 80% yield, 13:1 drR = i-Pr 77% yield, > 50:1 dr 80% yield, 24:1 dr

Ar = 4-OMeC6H4 Ar = 2-thienyl

PhthN N

O

NPh

Pd

H

H

Ltrans arrangement

21 25

Scheme 19 α-Amino-β-lactam synthesis by a sequential arylation/stereoselective intramolecular amidation

PhthNNH

O

NH H

Pd(OAc)2 (10 mol%)CuF2 (1.5 equiv)DMPU (5 equiv)acetone, 100 °C

Ar-I, 1.5 equiv

PIP

PhthNNH

O

Ar H

PIP

Pd(OAc)2 (10 mol%)NaIO3 (2 equiv)Ac2O (10 equiv)

MeCN, 70 °C

N

O

PIP

PththN

Ar

N

O

PIP

PththN

28a: 86% yield, 20:1 dr

N

O

PIP

PththN

28b: 61% yield, 20:1 dr

MeO

N

O

PIP

PththN

28c: 64% yield, > 30:1 dr

O2N

MeO

N

O

PIP

PththN

28d: 65% yield, 17:1 dr

S

N

O

PIP

PththN

28e: 46% yield, > 30:1 dr

AcN

26 27 28

PIP = 2-pyridin-2-ylisopropyl


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ously and independently discovered that the key to successin this ambitious transformation involved the use of adibenzyl hydrogen phosphate ligand. Dibenzyl hydrogenphosphate is believed to enhance the solubility of the silvercarbonate base, thereby increasing concentration of silvercations in the medium. In addition, dibenzyl hydrogenphosphate also facilitated both oxidative addition and re-ductive elimination events (by coordination to the palladi-um species), as well as subsequent protonolysis (release ofthe alkylated product), thereby ensuring optimal turnoverof the catalytic system. Accordingly, stereoselective alkyla-tion of the secondary C(sp3)–H bonds at β- or γ-positionswith activated alkyl halides (iodo- or bromoacetate esters)delivered the aliphatic nonnatural α-amino acids with ex-cellent control of the trans-configuration (Scheme 20). It isnoteworthy that the key trans-palladacyclic intermediatehas been isolated and characterized by X-ray analysis, cor-roborating the stereodiscriminant nature of the C–H activa-tion step.32

A further major advance in such diastereoselective al-kylation was disclosed by Chen and Shi in 2014.36 An inten-sive optimization study revealed that nonactivated alkylhalides could also be efficiently coupled with the aminoacid derivatives when a sulfonamide ligand (4-chloroben-zenesulfonamide) and sodium cyanate base were added tothe reaction mixture. The particular efficiency of this sul-fonamide ligand can be attributed to its labile character.This permits its decoordination from the key palladacycleto provide a vacant coordination site (essential for oxidativeaddition of the alkyl iodide to generate a palladium(IV) spe-cies) and its subsequent recoordination with the palladi-um(IV) species to facilitate C(alkyl)–C(alkyl) reductiveelimination. This optimized protocol is highly tolerant to abroad range of simple alkyl iodides, permitting expedientsynthesis of β,β-heterodialkyl- and β-alkyl-β-aryl-α-aminoacids by sequential methyl C(sp3)–H and stereoselectivemethylene C(sp3)–H functionalizations (Scheme 21).

A complementary approach to diastereoselective func-tionalization of α-amino acid scaffolds was reported by Yuand co-workers.37 They surmised that a monoprotected DGinstalled on an aliphatic scaffold might efficiently promotea C–H activation event if an additional ligand was present inthe reaction mixture. Notably, such ligand-controlled func-tionalizations might permit sequential one-pot difunction-alizations of alanine scaffolds. The polyfluorinated aromaticsecondary amide 32 was selected as a weakly coordinating,powerful and general DG. An initial study identified 2-pico-line as the best ligand for the arylation of primary C(sp3)–Hbonds, and under such conditions various beta-arylaminoacids could be prepared in high yields. Further investiga-tions revealed that for activation of the secondary C(sp3)–Hbonds, 2-substituted quinoline ligands stood out as promis-ing promoters, and the most efficient catalytic system wasobtained by using tricyclic 2,5-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]quinoline (Scheme 22). Under the optimizedreaction conditions, the required methylene C–H activationproceeded smoothly and with total stereoselectivity. Bothelectron-rich and electron-deficient aromatic iodides couldbe used as coupling partners. Finally, the feasibility of thetargeted ligand-controlled C(sp3)–H arylation was demon-

Scheme 20 Diastereoselective direct alkylation of α-amino acids

PhthNNH

O

NR1 H

Pd(OAc)2 (10 mol%)(BnO)2PO2H (30 mol%)

Ag2CO3 (0.8 equiv)

DCE–t-BuOH, 90 °C

PhthNNH

O

NR

+

1.5 equiv

PhthN N

O

NPd

H

H

MeCN

CO2R2X

CO2R2

PhthNNH

O

N

CO2R2

29a: R2 = Me, 87% yield, > 50:1 dr29b: R2 = Et, 56% yield, > 50:1 dr

PhthNNH

O

NPh

CO2R2

29c: R2 = Et, 85% yield, > 50:1 dr29d: R2 = Bn, 91% yield, > 50:1 dr

PhthNNH

O

Ni-Pr

CO2R2

29e: R2 = Et, 77% yield, > 50:1 dr

palladacycle characterized by X-ray analysis

21 29

Scheme 21 Sequential C(sp3)–H functionalizations of α-amino acids

PhthNNH

O

H H

Pd(OAc)2 (10 mol%)(BnO)2PO2H (30 mol%)

Ag2CO3 (0.8 equiv)

R1-I (1.5 equiv)DCE–t-BuOH, 50 °C

Pd(OAc)2 (10 mol%)Ag2CO3 (1.5 equiv)4-Cl-C6H4SO2NH2,

(0.3 equiv)

R2-I (2 equiv)NaOCN (2 equiv)

1,4-dioxane, 80 °C

PhthNNH

O

R1 R2

PhthNNH

O

31a: 57% yield (2 steps), 9:1 dr

N N

NPhthN

Ph

PhthNNH

O

31b: 42% yield (2 steps), 8:1 dr

NPh

CO2Me2

4

PhthNNH

O

Ar

31c: 80% yield (2 steps), > 30:1 dr

NPh

Ar = 4-F-C6H4

30 31


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strated by performing sequential one-pot arylations. It isnoteworthy that the configuration of the newly generatedstereogenic center can be altered simply by switching theorder of the two arylation events. In addition, in-depth the-oretical studies were undertaken to elucidate the mecha-nism of this transformation and to determine the key fac-tors that govern the stereoselectivity of the overall transfor-mation.38

Scheme 22 Ligand-controlled C(sp3)–H arylation

One year later, the same research group reported an im-proved catalytic system.39 Although the previously usedpolyfluorinated secondary amide DG is very efficient forvarious C–H activation reactions, its simpler congener, theN-methoxyamide (CONHOMe) motif, has appealing advan-tages in terms of its installation and removal. Moreover, itappears to be more appropriate for large-scale applications.Consequently, Yu and co-workers reinvestigated both pri-mary and secondary arylations of the amino acid scaffoldsby using the new N-methoxyamide as a simplified DG. Thedesired reactivity was achieved by using the same 2-pico-line ligand, but with modifications to the reaction medium.1,1,1,3,3,3-Hexafluoropropan-2-ol proved to be the solventof choice, as it prevented decomposition of the starting ma-terial. Importantly, the scope of this arylation reactioncould be enlarged to include the use of heteroaromatic io-dides as coupling partners. With respect to the second ary-lation of the methylene moiety, an extensive optimizationstudy identified 2,6-lutidine as the optimal ligand andshowed that addition of sodium dihydrogen phosphatemonohydrate was crucial to achieving maximal reactivity.Consequently, one-pot heterodiarylation of the alanine de-rivative 34 gave structurally diverse diastereomericallypure β,β-heterodialkyl amino acids 35 in synthetically use-

ful yields (Scheme 23). The synthetic potential of this pro-tocol was illustrated by applying this sequential asymmet-ric C(sp3)–H functionalization to construct BOX and PyBOXligands.

Scheme 23 Reoptimized catalytic system for the ligand-controlled het-erodiarylation of alanine substrates

Recently, the ligand-promoted N-(trifluorophenyl)am-ide-directed C(sp3)–H activation of α-amino acids was alsoapplied to prepare nonnatural fluorinated scaffolds.40 Se-lectfluor was selected as the fluorine source. The additionof an N-heterocyclic ligand was essential to promote thistransformation, and an optimization study revealed that5,7-dimethylquinoline clearly outperformed other pyri-dine- and quinoline-derived additives. Consequently, thetargeted C–F coupling could be performed efficiently and ina totally diastereocontrolled manner. Importantly, a relatedasymmetric fluorination using Selectfluor as fluorinesource was also achieved by using a bicoordinating 2-(pyri-din-2-yl)isopropyl-derived DG.41

4 Conclusions

Despite significant advances achieved over the last 5years, a chirality transfer in the C–H activation field still re-mains a great scientific challenge. Apart from enantioselec-tive transformations involving the use of finely adjustedenantiopure ligands, a complementary approach based ondiastereoselective transformations has gathered the inter-est of the scientific community. Indeed, as the chiral sourceis directly embedded within a substrate, a highly efficientcontrol of the chiral environment of a metallacyclic inter-mediate may be reasonably expected. However, to be syn-thetically useful, the use of an inexpensive chiral auxiliary

PhthNNHArF

O

H H

Pd(TFA)2 (10 mol%)L1 (20 mol%)

Ag2CO3 (1.5 equiv)TFA (20 mol%)

Ar1-I (1.5 equiv)DCE, 100 °C

N O

Me

Me

Pd(TFA)2 (10 mol%)L2 (20 mol%)

Ag2CO3 (2 equiv)TFA (20 mol%)

Ar2-I (3 equiv)DCE, 100 °C

PhthNNHArF

O

Ar1 Ar2

NMe

L1 L2

PhthNNHArF

O

Me OMe

33a: 68% yield, 19:1 dr

PhthNNHArF

O

MeO2C

33b: 65% yield, > 20:1 dr

OMe

PhthNNHArF

O

33c: 59% yield, > 20:1 dr

Me

Me OMe

32 33

ArF = 4-CF3-C6F4

PhthNNHOMe

O

H H

Pd(OAc)2 (10 mol%)L1 (20 mol%)

AgOAc (2 equiv)

Ar1-I (1.2 equiv)HFIP, 75 °C

Pd(OAc)2 (10 mol%)L3 (20 mol%)

AgOAc (2 equiv)NaH2PO4⋅H2O (3 equiv)

Ar2-I (3 equiv)100 °C

PhthNNHOMe

O

Ar1 Ar2

NMe

L1

PhthNNHOMe

O

Me CF3

35a: 48% yield, > 20:1 dr

PhthNNHOMe

O

Me

35b: 67% yield, > 20:1 dr

Me

PhthNNHOMe

O

35c: 51% yield, > 20:1 dr

Me

Me

NMe

L3

Me

Me

Me

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that is easy to install and remove after the functionalizationevent is crucial. Accordingly, in a majority of the herein dis-cussed examples an efficient removal of a DG could indeedbe achieved without loss of the optical purity (Figure 2). Asan illustration, Yu’s oxazoline DG can be hydrolyzed to givethe corresponding carboxylic acid, the imine chiral DG* canbe converted into the corresponding aldehyde. The sulfox-ide is a truly traceless DG as it can be removed via lithiumexchange followed by an electrophilic trapping thus en-abling synthesis of the optically pure axially chiral com-pounds. Also any epimerization is observed when the bico-ordinating, amide-based DGs* are cleaved. In addition, DGinstalled on amino acid scaffolds can also be hydrolyzed togive the corresponding carboxylic acid derivatives.

Besides, the C–H activation established itself as a reli-able tool to build up chiral, unnatural α–amino acids. Pres-ence of a stereogenic element on such scaffolds accountsfor the stereocontrolled metallation event allowing forma-tion of the sterically less hindered trans-palladacyclic inter-mediate and subsequent stereoretentive functionalization.

Accordingly, the diastereoselective C–H activation canbe reasonably considered as a complementary strategy tothe enantioselective transformations and in the near future

significant advances in this field may be expected. In par-ticular design of original stereogenic DG could catch the in-creasing attention of the scientific community.

Acknowledgment

We thank the Centre National de la Recherche Scientifique (CNRS),the Ministere de l’Education Nationale et de la Recherche (France),CiFRC of Strasbourg, and the Agence Nationale de la Recherche (ANR),France for financial support.

References

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Figure 2 Removal of DGs

MePh

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OAr

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> 98% ee21

NH

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PhthNNH

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PhthNOMe

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86% ee32

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Diastereoselective C–H activation product

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