Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using … · Mukaiyama Michael addition,...

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J. L. Freeman et al. AccountSyn lett

SYNLETT0 9 3 6 - 5 2 1 4 1 4 3 7 - 2 0 9 6© Georg Thieme Verlag Stuttgart · New York2020, 31, 657–671accounten

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Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder ReactionsJared L. Freemana 0000-0002-5448-5010 Freda F. Lia Daniel P. Furkert*a,b 0000-0001-6286-9105 Margaret A. Brimble*a,b 0000-0002-7086-4096

a School of Chemical Sciences, the University of Auckland, 23 Symonds Street, Auckland 1010, New [email protected]@auckland.ac.nz

b Maurice Wilkins Center for Molecular Biodiscovery, the University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand

HN

O O

HO

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Me

N

O

OH

O

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H

HO

O

O

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H O O

O

HON

H

O

O OH

H

N

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OR

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Received: 13.12.2019Accepted after revision: 17.01.2020Published online: 13.02.2019DOI: 10.1055/s-0039-1691593; Art ID: st-2019-a0673-a

Abstract Cyclic imine marine toxins have attracted considerable at-tention from the synthetic community in the past two decades due totheir unique chemical structures and clinically relevant biological activi-ties. This review presents recent efforts of our group in the develop-ment of various strategies to efficiently construct the common spirocy-clic imine fragments of the cyclic imine toxins. In particular, the use of,-unsaturated N-acyl iminium ion dienophiles in Diels–Alder reactionsare highlighted, whereby direct access to spirocyclic imine motifs wasobtained and important mechanistic details were discovered. Alterna-tive approaches to spirocyclic imine systems involving hydroaminationof amino alkynes are also summarized. One such approach led to seren-dipitous access to N-vinyl amide products, while our most recentlyreported approach involving an intermolecular Diels–Alder/cross-coupling sequence using novel 2-bromo-1,3-butadienes to access 5,6-spirocyclic imines is also discussed. Additionally, the development of anovel method to construct another challenging motif present in theportimines is also introduced.1 Introduction2 Strategies towards the Spirocyclic Imine Fragment of Cyclic Imine

Toxins2.1 Diels–Alder Cycloadditions of ,-Unsaturated N-Acyl Iminium

Dienophiles2.2 Early Studies Using in situ-Generated Iminium Ion Dienophiles2.3 Use of More Stable Iminium Ion Dienophiles for Diels–Alder Reac-

tions2.4 Other Notable Strategies towards Spirocyclic Imines2.5 Recent Efforts towards the 5,6-Spirocyclic Imine Marine Toxin

Portimine A2.6 Construction of Another Challenging Motif of Portimine A3 Conclusion and Future Perspectives

Key words spiroimines, Diels-Alder reaction, N-acyl iminium ions,Mukaiyama Michael addition, iminium dienophiles

1 Introduction

Oceanic microalgae can proliferate to concentrations ofup to millions of cells per liter under favorable conditions,forming ‘algal blooms’ which are often visible as patches ofred or brown on the ocean surface.1 Often, the species ofmicroalgae involved produce toxins which accumulate inthe tissues of feeding shellfish and can then pass on to hu-mans when they are ingested. Harmful algal blooms are re-sponsible for the death of wildlife and human illness andare therefore considered an increasing global health con-cern.2

The toxins produced by marine dinoflagellates oftendisplay unique biological activities, rendering them poten-tial pharmacological candidates. In particular, cyclic iminetoxins have garnered particular interest from the syntheticcommunity due to their synthetic complexity and potentactivity. Named after their common structural motif (shad-ed in blue, Figure 1), these toxins can be further classifiedby the size of the cyclic imine ring, with either 7,6-spirocy-clic systems (as in the spirolides, e.g. spirolide A (1), pinna-toxins, and pteriatoxins) or 6,6-spirocyclic systems (as ingymnodimine A (2) and recently isolated kabirimine (3)3)being the most common.4 Portimine A (4), isolated in 2013,is an example of a cyclic imine toxin bearing a 5,6-spirocy-clic imine system. Reviews regarding the classification andbiological evaluation of these toxins are numerous.5,6 Inparticular, the toxicity displayed by the pinnatoxins,7,8 pte-riatoxins,9 and spirolides10 stem from their ability to acti-vate Ca2+ channels, while gymnodimine and members ofthe spirolide family have demonstrated affinity for nicotinicacetylcholine (nACh) receptors.11 Meanwhile, portimine A(4) displays high in vitro cytotoxicity and promotes apopto-sis via caspase-3 activation in P388 leukemia cells.12,13

© 2020. Thieme. All rights reserved. Synlett 2020, 31, 657–671Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

http://orcid.org/0000-0002-5448-5010

http://orcid.org/0000-0001-6286-9105

http://orcid.org/0000-0002-7086-4096

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The spirocyclic imine motif is postulated to be an im-portant component of the active pharmacophore of thesetoxins, since spirolides E and F (derivatives of spirolide A (1)possessing a hydrolyzed keto amine motif)14 and a spirocy-clic amine analogue of gymnodimine15 all lacked biologicalactivity. Work by Romo and co-workers suggests that the

cyclic imine component acts as a masked enamine, and themechanism of action may involve reaction of this latent nu-cleophile.16 Therefore, there is immense value in these spi-rocyclic imine fragments as pharmacological probes, andconvenient synthetic access to these systems is highlysought after.

ited.

Biographical sketches

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Jared L. Freeman completed
his PhD in 2019 from the Uni-versity of Auckland under thesupervision of DistinguishedProfessor Dame MargaretBrimble and Dr. Daniel Furkert.

His PhD focused on the synthe-sis of an antibiotic macrocyclicnatural product. He is currentlyundertaking a postdoctoralresearch position at Bayer AG inFrankfurt am Main, Germany,

where his research interests cur-rently include the synthesis ofnovel herbicides to address theissue of highly resistant weeds.

Freda F. Li received her PhD in2017 from the University ofAuckland in New Zealand underthe supervision of DistinguishedProfessor Dame MargaretBrimble. She is currently a post-

doctoral research fellow inDame Brimble’s research groupat the University of Auckland.Her research interests includethe synthesis of bioactive het-erocycles, cell-imaging fluoro-

phores, and anticancer peptidenatural products. Her currentresearch focuses on synthesesof spirocyclic imine natural toxinand related bioactive frag-ments.

Dr. Daniel Furkert is a seniorresearch fellow at The Universityof Auckland, leading ProfessorBrimble’s natural product syn-thesis and medicinal chemistrygroup in the School of ChemicalSciences. After undergraduateand doctoral degrees at The

University of Auckland, he car-ried out postdoctoral fellow-ships in the synthesis ofazaspiracid at Oregon State Uni-versity (USA) and the medicinalchemistry of novel opioid recep-tor ligands at the University ofBath (UK). He returned to New

Zealand take up his current rolein 2010, where his current inter-ests include asymmetric synthe-sis and medicinal chemistryapplications of natural prod-ucts, novel chemical reactivity,and drug discovery.

Dame Margaret Brimble isDirector of Medicinal Chemistryand a Distinguished Professor atthe University of Aucklandwhere her research focuses onthe synthesis of bioactive natu-ral products and peptide chem-istry. She has published over500 papers and named as an in-ventor on more than 50 pat-ents. She was inducted into the

American Chemical Society Me-dicinal Chemistry Division Hallof Fame in 2019 and was elect-ed a Fellow of the Royal Society(London) and awarded the RSCSosnovsky Award in CancerTherapy in 2018. She won the2012 RSNZ Rutherford,MacDiarmid, and Hector Med-als. She is past president ofIUPAC Organic and Biomolecu-

lar Division III and an associateeditor for Organic Letters. Shediscovered the first drug ‘trof-inetide’ to treat Rett syndromethat is in phase III clinical trialswith Neuren Pharmaceuticals(http://www.neurenpharma.com)and co-founded the companySapVax to develop self-adju-vanting cancer vaccines(https://sapvaxllc.com).

© 2020. Thieme. All rights reserved. Synlett 2020, 31, 657–671

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Figure 1 Representative examples of spirocyclic imine toxins

The synthesis of key members of this class of com-pounds has been the focus of a number of reviews,17,18 andin recent times, a renewed interest has emerged, with fiveseparate reports of synthetic strategies to access spirocyclicimine systems of the cyclic imine toxins since 2017.19–23

Since the early 2000s, our group has remained interested inthis unique structural motif and have previously publisheda review on selected synthetic efforts towards the spirocy-clic imine unit of the spirolides prior to 2011.24 Syntheticapproaches detailed in that particular review include inter-molecular Diels–Alder strategies,25,26 alkylation–cyclizationapproaches27–29 and an asymmetric Birch reductive alkyla-tion.30 Importantly, those approaches often involved target-ing spirocyclic lactam fragments as precursors to spirocy-clic imines. This review represents our recent efforts in thedevelopment of synthetic approaches towards cyclic iminetoxins, which focus on providing direct access to spirocyclicimine fragments using N-acyl iminium chemistry, with ser-endipitous discoveries and new methodology developedalong the way. Key relevant work from other researchgroups will also be described where appropriate.

2 Strategies towards the Spirocyclic Imine Fragment of Cyclic Imine Toxins

2.1 Diels–Alder Cycloadditions of ,-Unsaturated N-Acyl Iminium Dienophiles

The spirocyclic imine fragments of cyclic imine toxinsare largely purported to arise from intramolecular Diels–Alder cycloaddition reactions.31 Indeed, this reflects the mostconvergent method for synthesizing the spirocyclic iminemotif, given the ability to forge the precise stereochemicalconfiguration of both the quaternary carbon center and theadjacent tertiary center in a single step. This factor justifiesthe prevalence of Diels–Alder strategies in reported synthe-

ses of spirocyclic imine fragments by groups includingRomo,32 Murai,33 Nakamura,34 and White.35,36 These methodsoften involved the use of -exo-methylene lactam/lactonedienophiles, which ultimately afforded spirolactam/lactonering systems and required further elaboration to the desiredspirocyclic imine motif.

Alternatively, direct access to a spirocyclic imine couldbe achieved via a Diels–Alder reaction of an ,-unsaturat-ed iminium ion dienophile. From 2005 to 2007, intramolec-ular Diels–Alder approaches to gymnodimine A (2) andsymbioimine involving ,-unsaturated iminium ions werereported by Kishi,37 Snider,38 and Thomson.39 In particular,both Snider and Thompson groups utilized a highly reactiveN-acyl iminium dienophile which was generated in situfrom Lewis acid activation of a stable N-acyl enecarbamateprecursor. Intermolecular variants of the Diels–Alder reac-tion, however, were relatively unexplored prior to our initialinvestigations of N-acyl iminium ion chemistry in 2008.40

Reaction of an exocyclic ,-unsaturated N-acyl iminiumion 5 with an appropriate diene 6 could provide convenientaccess to spirocyclic imine fragment 7 similar to thosefound in the cyclic imine toxins (Scheme 1). It was rational-ized that in situ iminium ion generation could occurthrough - or -elimination of a nucleofuge from cyclic car-bamates 8 and 9, respectively, and a scalable synthesis ofstable iminium ion precursors was the focus of our initialinvestigations.

Scheme 1 Possible pathways for in situ generation of ,-unsaturated N-acyl iminium ion 5 and its use in Diels–Alder reactions

2.2 Early Studies Using in situ-Generated Iminium Ion Dienophiles

Our first-generation synthetic approach to iminium ionprecursors 10a and 10b (Scheme 2, A), reported in 2008 in-volved base treatment of the corresponding six- or seven-membered N-CBz lactam 11a and 11b, followed by alkyla-tion of the amide enolates with Eschenmoser’s salt andHofmann elimination.40 Reduction of the -methylenatedlactams 12a and 12b with DIBAL-H/TMSCl and quenchingwith MeOH at low temperature afforded N,O-acetals 10aand 10b as iminium ion precursors, likely proceeding via

gymnodimine A (2)

portimine A (4)

spirolide A Δ2,3 (1)

HN

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OH

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OH

O

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H

H

HO

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O

N

HO

H O O

O

HO

N

H

O

O OH

H

kabirimine (3)

NO

OR

R1O

NO

OR

NO

OR

R1O

R2

n

NO

OR

n

OR1

α-elimination

γ-elimination

nn

R2

Diels–Alder

5

67

8n = 1, 2

9n = 1, 2

R1 = H, Me, Et


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iminium intermediates 13a and 13b. The modest overallyield of this sequence warranted investigation of an alter-native second-generation route to the six-membered imini-um precursor 10a. Later in 2009 it was discovered that anelectrochemical oxidation of N-protected piperidine 14could be employed to access hemiaminal 15 in greater yield(92% brsm) than conventional chemical oxidation methods(Scheme 2, B).41 Pihko organocatalytic methylenation af-forded ring-opened ,-unsaturated aldehyde 16, and sub-sequent treatment with catalytic amount of Sc(OTf)3 inMeOH afforded enecarbamate 17 as an iminium ion precur-sor. Despite likely proceeding through identical iminiumion intermediate 13a, it is noteworthy that 17 was formedunder thermodynamic conditions, while kinetic conditions(i.e., DIBAL-H, –78 °C) afforded its constitutional isomer10a. This reaction sequence was then further modified in athird-generation approach to iminium ion precursor 18while bypassing unstable aldehyde intermediates of theprevious generation synthesis (Scheme 2, C).41 Iminium ionprecursor 18 was synthesized in a much improved yieldthrough anodic -oxidation of N-protected piperidine 19,followed by NH4Cl-mediated elimination and microwave-promoted organocatalytic alkylation.

The reactivity of six-membered iminium precursors 17and 18 was evaluated in a series of nucleophile trapping ex-periments, whereby reactive iminium ions 13a and 20 were

generated in the presence of a catalytic amount of Sc(OTf)3,then quenched with various nucleophiles (Scheme 3). Thecorresponding alkylated products 21 and 22 were affordedin high yields for various nucleophiles such as indole and si-lyl enol ethers.

Scheme 3 Nucleophile trapping with six-membered N-acyl iminium ions 13a and 2041

Use of iminium precursors 10a, 10b, and 17 in Diels–Alder reactions to access spirocyclic systems was also report-ed in our 2008 study.40 Both six- and seven-memberedN-carboalkoxy-N,O-acetals 10a and 10b were reacted withdiene 23 following iminium ion generation using BF3·OEt2

Scheme 2 Our first- (A), second- (B), and third-generation (C) syntheses of N-acyl iminium ion precursors 10, 17, and 1840,41

Sc(OTf)3MeOH

3.1 Faraday/molMeCN/H2O (6:1)Et4NOTs, 3 °C

14 15

92% (brsm)

pyrrolidinepropionic acid

formalin

32%(2 steps)

B) 2nd Generation Synthesis (2009)

pyrrolidinepropionic acid

formalinmicrowave 130 °C

2.2 Faraday/molMeOH

Et4NOTs, 5 °C

18

92%

NH4Cl, Δ

52%

C) 3rd Generation Synthesis (2009)

1) LiHMDS, THF, –78 °C, Eschenmoser's salt2) MeI, CH2Cl2, rt

11a n = 111b n = 2

NO

OBn

12a n = 112b n = 2

O

DIBAL-H TMSCl–78 °C

10a n = 1, 11% (3 steps)10b n = 2, 20% (3 steps)

A) 1st Generation Synthesis (2008)

95%

19

17

nNO

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O

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NO

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O

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16

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OMe

NO

OBn

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likely iminium intermediates

thenMeOH

13a n = 113b n = 2

NO

OMe

NO

OMe

MeO

NO

OMeNO

OMe

OMe

29% (3 steps)

45% (3 steps)

17 R = Bn18 R = Me

Sc(OTf)3 CH2Cl2

0 °C

ScX4

HN O

OTMS

OTMS

nucleophile

21 R = Bn, 75–96%22 R = Me, 65–92%

nucleophile

13a R = Bn 20 R = Me

NO

OR

OMe

NO

OR

NO

OR

Nu

OTMS

EtO

ON


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to deliver tricyclic N,O-acetals 24a and 24b in good yields withhigh endo selectivity, although simple dienes such as iso-prene failed to react with the generated six- or seven-mem-bered iminium ions (Scheme 4). Meanwhile, enecarbamate17 reacted similarly using diene 25 to afford tricycle 26,suggesting that the reaction proceeds through in situ gener-ation of an identical iminium ion species. These tricyclic ad-ducts likely formed through Diels–Alder cycloaddition,in situ PMB ether deprotection, and intramolecular N,O-ac-etal formation through trapping of the resulting iminiumintermediate. The precise order of these events, however,was unclear, as was the impact of intramolecular O-alkyla-tion on the stereochemical outcome of the reaction. Typi-cally, cyclic -exo-methylene dienophiles provide exo ad-ducts, due to a combination of steric and electronic factorsassociated with the s-cis dienophile configuration.42,43 Theexclusive formation of endo adducts in our study was con-firmed on the basis of 2D NOESY NMR analysis, which wasrationalized to be due to favorable secondary orbital over-lap between the diene and the s-trans-configured iminiumdienophile.

These investigations demonstrated that in situ genera-tion of iminium ions in the presence of functionalizeddienes could be a promising method for accessing spirocy-clic systems resembling those of cyclic imine toxins. In par-ticular, preventing N,O-acetal formation would be requiredin order to further elaborate the generated fragments to-wards the natural products. In addition, the moderate reac-tion yields could be attributed to instability of the iminiumion prior to cycloaddition.

2.3 Use of More Stable Iminium Ion Dienophiles for Diels–Alder Reactions

Following these studies, in 2011, advances in intermo-lecular Diels–Alder reactions of iminium ions were report-ed by Evans and co-workers (Scheme 5).44 Remarkably, sev-

en- and six-membered NH-,-unsaturated iminium salts27 and 28 were found to be isolable and stable to flash col-umn chromatography. Iminium ions 27 and 28 were used inDiels–Alder reactions with simple dienes 29, with spirocy-clic adducts 30 and 31 afforded in excellent yields and highendo selectivities (>90:10) due to LUMO-lowering activa-tion of the iminium dienophiles. The dienophilic counteri-on (X–) was found to have a significant effect on the rateand diastereoselectivity of the reaction, with the noncoor-dinating hexafluoroantimonate (SbF6

–) counterion resultingin substantial reaction-rate acceleration. Importantly, imine-functionalization in the form of a methyl and n-butylsubstituents appeared important for the hydrolytic stabilityof the iminium ions.

Scheme 5 Iminium ion Diels–Alder cycloadditions by Evans et al.44

Evans’ work therefore prompted a redesign of our imini-um ion dienophile scaffold to incorporate a methyl substit-uent at the imine center (Scheme 6, A), which would serve

Scheme 4 Use of 10a, 10b, and 17 in iminium ion activated Diels–Alder cycloadditions40

NO

OBn

OMe

OH

23 BF3•OEt2 (20 mol%)

CH2Cl2, –78 °C

25Sc(OTf)3 (3.5 mol%)

CH2Cl2, 0 °C

60%

17

25

[4+2]PMB

removal

H

HO

OBn

N

O

OBn

H

HO

OBn

N

O

26

PMBO

N

OOBn

BnO

NO

OBn

10a n = 110b n = 2

MeO

24a n = 1, 53% 24b n = 2, 78%

H

O

OBn

N

OBn

PMBO

nn

23

n

n

OPMB

BnO

NH

X

R3

R1

R2

XHN

MeCN (0.1 M)rt to 40 °C 2–24 h

R2

R3 R1

94–98% yieldendo/exo 77:23–90:10

H N

X

27

28

MeCN (0.1 M)rt to 60 °C 15–24 h

H N

R3

R2

X

30

R1 = Me, Ph, CH2OBnR2 = H, MeR3 = H, Me

X = TFA, OTf, OTs, (PhO)2PO2, ClO4, SbF6

91–98% yieldendo/exo 92:8–94:6

29

29

29

31

R1


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to improve the hydrolytic stability of the resultant iminiumion while also providing a synthetic handle for naturalproduct elaboration through methodology previously re-ported by our group.45 Such a substituent at the -positionwould also render the iminium center less susceptible tonucleophilic attack, prohibiting the previously observed in-tramolecular N,O-acetal formation. As an exo-Diels–Alderreaction was required to establish the natural C6–C7 rela-tive stereochemical configuration, we postulated that in-creasing steric bulk of the dienophile through bulky pro-tecting groups on both the diene and iminium dienophilecomponents could direct Diels–Alder cycloaddition throughan exo transition state (Scheme 6, B). An electron-with-drawing N-Boc protecting group would serve to enhancethe reactivity of the resultant iminium ion, while also prov-ing easy to remove and reveal the desired spirocyclic iminemotif. Additionally, the isolation of portimine A (4, Figure 1)in 2013,12 which possesses a 5,6-spirocyclic imine system,

presented itself as an additional application for this chemis-try through accessing an analogous five-membered imini-um ion, which was previously unexplored.

As a result, we reported our progress regarding the syn-thesis and reactivity of more stable six- and five-membered,-unsaturated N-acyl iminium ions in 201646 and 2019,47

respectively. Robust syntheses of bench-stable six- and five-membered iminum ion precursors 32 and 33 were estab-lished in these studies (Scheme 7). Alkylation of iodides 34and 35 using ethyl acetoacetate proceeded smoothly to af-ford -keto esters 36 and 37. Direct cyclization of -keto es-ter 36 to form six-membered cyclic enecarbamate 38proved problematic; however, it was found that N-Bocdeprotection, cyclization, and subsequent amine reprotec-tion were required to give stable six-membered cyclic ene-carbamate ester 38 in high overall yield. Comparatively, di-rect cyclization of the analogous two-carbon-chain com-pound 37 to form cyclic five-membered enecarbamate 39

Scheme 6 Our revised iminium ion scaffold and proposed outcome of their use in Diels–Alder reactions

previous iminium ion design

our revised iminium ion design

NO

OBn

NO

OtBu

synthetic handlefor fragment elaboration

bulky electron- withdrawing

N-protecting group

improved hydrolytic stability

n

n

exo [4+2]

desiredstereochemistry

undesiredstereochemistry

endo [4+2]

n = 1, 2n = 0, 1

n66

BzOH

OSiR3

NBoc

n

77BzO

H

OSiR3

NBoc

n

A) B)

N

O

tBuO

R3SiO

BzO

NO

OtBu

OSiR3

OBz

n6

7

Scheme 7 Synthesis of six- and five-membered N-Boc cyclic enecarbamates 32 and 33 as stable iminium ion precursors46,47

BocHN

O

OEt

O

NBoc

CO2Et

NBoc

OH

stable for storage

NHBoc

NBoc

OMe

I

N

CO2Et

BocO

OEt

O

BocHN

O

I K2CO3DMF/acetone

NHBoc

83%(3 steps)

>20 g scale

DIBAL-HCH2Cl2

NBoc

NBoc

NaH, MeITHF

90% 85%

6-membered iminium ion precursor

5-membered iminium ion precursor

O

OEt

94%

1) TFA, CH2Cl22) aq NaHCO33) Boc2O, NaH DMAP, NEt3, THF

OH OMe

34 36 38 40 32

O

K2CO3DMF/acetone

O

OEt

aq 1 M HClworkup

73%

DIBAL-HCH2Cl2

NaH, MeITHF

72%(2 steps)

35 37 39 41 33

stable for storagestable for storage

stable for storage


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was successful, with facile cyclization of 37 occurringduring the acidic workup following alkylation. DIBAL-H-mediated reduction of the ester motif of both 38 and 39provided allylic alcohols 40 and 41 which were initially in-vestigated as potential iminium precursors. However, insta-bility and low reactivity led us to favoring methylation ofalcohols 40 and 41, delivering both methyl ethers 32 and 33as convenient precursors of N-acyl iminium ions, whichalso proved stable long-term. Our newly developed routeproved robust on gram-scale and overcame synthetic diffi-culties of previously reported methods, proceeding throughstable intermediates (e.g., 38 and 39) suitable for long-termstorage if required.

Use of precursors 32 and 33 to prepare the correspond-ing ,-unsaturated N-acyl iminium ion dienophile 42 inthe presence of the Lewis acid, which can then react with arange of silyloxy E/Z-dienes in the Diels–Alder reaction,were therefore investigated (Scheme 8). It was rationalizedthat a Z-diene configuration could also provide adducts 43bearing the desired stereochemical orientation through aconcerted cycloaddition via an endo reactivity mode.

Scheme 8 Proposed outcome of Diels–Alder reactions of iminium ion 42 with E- or Z-silyloxy dienes

To probe the reactivity of six-membered N-acyl imini-um ions as dienophiles in Diels–Alder reactions, an initialreaction involved the generation of the iminium ion dieno-phile from precursor 32 using BF3·OEt2 prior to reactionwith silyloxydiene (E)-44 to provide adduct 45 as a singlediastereomer in 34% yield (Scheme 9, A). Use of an excessamount of triethylamine was required to convert iminiumadduct intermediate 46 into the observed enamine adduct45. Interestingly, unpublished results from our group in-volved an analogous reaction using Z-diene (Z)-44 with six-membered iminium precursor 32 which afforded the sameadduct diastereomer 45 in 27% yield. This appeared to cor-

roborate a similar observation reported by Romo and co-workers in 2000, whereby Diels–Alder reaction of a six-membered -exo-methyl lactam resulted in a single adductdiastereomer obtained, irrespective of the diene configura-tion.48 In their case, they reasoned that a formal Diels–Alderreaction, proceeding stepwise via sequential Michael addi-tions was in fact occurring, and it was conceivable that asimilar process was occurring in our reaction. Further in-vestigation of diene protecting groups revealed that re-placement of benzyl with a benzoyl group on the primaryalcohol of the diene [(E)-47 and (E)-48] improved the yieldof the cycloaddition products 49 and 50 significantly(Scheme 9, B). Stereochemical elucidation was enabledthrough hydrolytic ring opening of the N-heterocycle 50, af-fording keto amine 51 which displayed a plausible through-space correlation between the C-6 acetyl substituent andH-1 in a 2D ROESY spectrum. This correlation correspondedto the desired natural configuration, which would havearisen from a formal exo cycloaddition. More recently, un-published results from these ongoing studies within ourgroup involved iminium Diels–Alder reactions using N-Tsenecarbamate precursor 52 which could be readily pre-pared through an analogous reaction sequence to previous-ly reported N-Boc enecarbamate precursor 32 (Scheme 9,C). The desired iminium Diels–Alder reaction proceededsmoothly, however, stereochemical elucidation of adduct 53through 2D NMR experiments proved ambiguous. Silylgroup removal using TBAF provided crystalline ketone 54,which possessed formal endo configuration as determinedby X-ray crystallography. At this stage, whether or not therewas a stereochemical discrepancy between the Diels–Alderreaction products of N-Boc and N-Ts iminium ions is yet tobe confirmed unambiguously, and further work will be re-quired to determine the factors controlling the stereochem-ical outcome of this reaction.

The discrepancy between the reactivity of five- and six-membered iminium ions was noted when investigating theDiels–Alder reaction with diene (E/Z)-48 in our 2019study,47 with the N-protecting group also playing a majorrole (Scheme 10). The Diels–Alder reaction of five-mem-bered N-Boc enecarbamate 33 with diene (E/Z)-48 was ini-tially attempted using conditions previously optimized forsix-membered 32 (Scheme 10, A). Extensive decompositionwas observed, and subsequent investigation of an extensiverange of reaction conditions failed to afford more than atrace amount of bicyclic adduct 55. It was soon realized thatthe five-membered N-Boc acyl iminium ion was unstable,and modification of the N-acyl substituent appeared as apromising method to modulate the reactivity of the result-ing iminium ion. N-CBz and N-Ts enecarbamates 56 and 57were therefore synthesized using similar sequences tothose used to prepare 33. In the case of N-CBz enecarba-mate 56, the desired bicyclic adduct 58 was afforded in a20% yield, and a 2D NOESY experiment revealed a through-space correlation between H-3 and H-6, suggesting the for-

N

OMe

NLewisacid

BocBoc

R1O

OR2endo [4+2]

NBoc

4232

exo [4+2]

N

H

R2O OR1

Boc

N

OR1

OR2

Boc

desired stereochemistryOR1

R2O

OR1

OR2

E-diene

Z-diene

43


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mation of an endo-cycloaddition adduct. Meanwhile, ananalogous reaction using N-Ts enecarbamate 57 providedthe expected bicyclic adduct 59 in 5% yield, alongside a ma-jor quantity (64%) of enone 60, which likely forms throughMukaiyama–Michael addition of diene 48 to the five-mem-bered N-Ts iminium ion 61 (Scheme 10, B). This marked thefirst instance that such an intermediate had been detectedand isolated throughout our extensive investigation of reac-tive iminium ions. It was expected that enone 60 could un-dergo intramolecular cyclization to afford bicyclic adduct62, and this was indeed the case, with exposure of 60 toSc(OTf)3 facilitating cyclization to afford adduct 62 as a sin-gle diastereomer (Scheme 10, C). The configuration of 62was determined to be the formal endo-cycloaddition prod-uct through X-ray crystallography, and 62 could be furtherelaborated to natural product like fragment 63, albeit withnon-natural C5–C6 configuration. The isolation of enone 60and its ability to cyclize to bicyclic compound 62 appearedto suggest that the iminium Diels–Alder reactions were in

fact proceeding through a stepwise mechanism involvinginitial Mukaiyama–Michael addition of diene (E/Z)-48 toiminium ion 61, followed by Lewis acid mediated intramo-lecular cyclization. In support of this conclusion, the sameadduct diastereomer was obtained irrespective of the dienegeometry employed in the reaction, with use of a mixtureof dienes (E)-48 and (Z)-48 affording the same, single dia-stereomer 62.

N-Acyl iminium ions are well established as versatile in-termediates for the synthesis of nitrogen-containing com-pounds, and their chemistry remains a promising area ofresearch, particularly towards complex alkaloid synthesis,with extensive reviews regarding this field have been re-ported.49,50 Taken together, these findings appeared tostrongly suggest that the originally hypothesized concertedDiels–Alder cycloadditions of ,-unsaturated N-acyl imini-um ions may in fact proceed through a stepwise mecha-nism. Despite providing adducts bearing non-natural rela-tive stereochemical configuration, we demonstrated easy

Scheme 9 Studies of 32 and 52 as precursors of six-membered iminium ion dienophiles in Diels–Alder reactions

B)

N

H

BzO

Ts

O

N

OMe

52

Ts N

H

BzO

Ts

OTBS

TBAF CH2Cl2–78 °C

41%

BF3•OEt2 then NEt3 (10 equiv)

CH2Cl2, –78 °C

63%*

*determined by 1H NMR internal standard

BF3•OEt2 then NEt3 (10 equiv)

CH2Cl2, –78 °C

N

H

BzO OR1

Boc

49 R1 = TIPS, 80%50 R1 = TBS, 60%single diastereomer

1 M HClTHF

O

H

BzO OTBS

NHBoc

36% with 50

66

11

H

BocHN

O OTBS

OBz

apparent ROESYcorrelation

A)

proposed structure of exo-adduct based on 2D NMR

analysis

N

OMe

N

H

H

BnO OTIPS

BF3•OEt2then NEt3 (10 equiv)

CH2Cl2, –78 °C

32 46

NEt3Boc

Boc N

H

BnO OTIPS

34% (with (E)-44)27% (with (Z)-44)

single diastereomer

45

Boc

C)

OBn

OTIPS

OBz

OR

(E)-47 R = TIPS(E)-48 R = TBS

(E/Z)-44

(E)-48

51

32

53 54

ORTEP of formal endo-adduct

16


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access to highly reactive iminium ions from stable precur-sors and their use in a highly convergent approach to accessspirocyclic systems. Additionally, the ability to access inter-mediate enone 60 in the recent study (Scheme 10) offersthe possibility for asymmetric control of the subsequent cy-clization step, which is an ongoing area of investigation byour group.

2.4 Other Notable Strategies towards Spirocyclic Imines

Although Diels–Alder cycloadditions were utilized asthe most efficient strategy to construct the spirocyclicimine fragments, other synthetic methods, developed byour group and others, have been utilized to construct thespirocyclic ring systems of members of the spirolides,26

gymnodimine,51 and, more recently, portimines.21 As an al-ternative, indirect approach to forge spirocyclic imine frag-ments, these methods often involve construction of the

‘lower’ cyclohexene ring bearing the required stereochem-istry at the quaternary center, with tethered side chains in-stalled to later form the nitrogen-containing ‘upper’ ring.

In 2005, Zakarian and co-workers reported a syntheticapproach to the spirocyclic imine ring system of the pinna-toxins, whereby dihydropyran 64 underwent a cascade sig-matropic rearrangement to afford chiral ketone 65, thusconstructing the chiral quaternary center present in thepinnatoxins (Scheme 11, A). Subsequent elaboration of ke-tone 65 to azide 66 was followed by an aza-Wittig reaction,which facilitated cyclization of the seven-membered iminering of 67.52 In 2010, our research group reported the syn-thesis of the spirocyclic imine fragment of members of thespirolides, whereby the cyclic imine formation was alsoachieved using a late-stage aza-Wittig cyclization (Scheme11, B). The synthesis involved a microwave-assisted Diels–Alder cycloaddition between Danishefsky’s diene (68) and,-unsaturated ester 69, affording cyclohexenone 70 in65% yield as a mixture of three diastereomers (5:2:1). Fol-lowing successful formation of the ‘lower’ ring, subsequenttransformations of the desired (S,S)-adduct 70 to keto-azide

Scheme 10 Studies of 33, 56, and 57 as precursors of five-membered iminium ion dienophiles in Diels–Alder reactions

62

55 R = Boc, trace58 R = Cbz, 20%59 R = Ts, 5%

nOeN 33

66

H

BzO

Hb HaR

OTBS

RN

OTBS

OBz

(E/Z)-48

TsN

O

OBz

33 R = Boc56 R = Cbz57 R = Ts

Sc(OTf)3,MeCN, rt

MeO

Sc(OTf)3, (10 mol%),

MeCN, –20 °C

+

60 64%

44%

N

BzOO

NEt3

Ts

A)

C)

NTs

BzO

63

42%

N

N

BzOOTBS

60

desilylation

N

BzOO

intramolecular cyclization

NTs

BzOH

O

OTBSBzO

N

55

66

BzOO

N

BzO OTBS

intramolecular cyclization

NEt3

NEt359

TsTs

Ts

Ts

TsB)

desilylation

61

X-raystructure

60

62

(E/Z)-48

2 steps485

6


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71 was followed by an aza-Wittig cyclization reaction, af-fording spirocyclic imine 72 possessing the same relativestereochemistry as members of the spirolide family.26

Scheme 11 Use of aza-Wittig reaction to construct spirocyclic imine fragments26

The Guillou group has reported several synthetic ap-proaches to the 6,6-spirocyclic imine motif of the gymnodi-mine family since 2011.51,53 Their most recent work in 2014hinged on a palladium-catalyzed decarboxylative allylationreaction of 73 to forge the required quaternary stereocenterin high yield and enantioselectivity (Scheme 12). This wasfollowed by a microwave-assisted alkene isomerization toafford azidoalkene 74 which subsequently underwent a[3+2] cycloaddition to afford spirocyclic imine 75 in moder-ate yield. Importantly, 6,6-spirocyclic imine 75 incorporatesthe requisite functional handles to be further elaborated toa viable spirocyclic imine intermediate for the synthesis ofthe gymnodimines.

Scheme 12 Synthesis of 6,6-spirocyclic imine 75 by Guillou et al.51

Also in 2011, our research group reported a new ap-proach to model spirocyclic imines which relied on quater-nary center construction via an alkylation reaction, fol-lowed by a gold-catalyzed intramolecular hydroaminationreaction to construct the cyclic imine system (Scheme13).54 This mild chemical transformation appeared ideallysuited for late-stage construction of spirocyclic imine mo-tifs. Alkylation of methyl cyclohexanecarboxylate (76) usingalkyl iodides 77a–c afforded the corresponding alkylatedadducts 78a–c which were subsequently functionalized toafford amino alkynes 79a–c in good overall yield. With ami-no alkynes 79a–c in hand, a large range of cyclization con-ditions were trialed, culminating in successful hydroamina-tion of amines 79a and 79b through reaction withAu(PPh3)SbF6 and triethylamine at high temperature, gen-erating spirocyclic imines 80a and 80b in good yield. How-ever, hydroamination proved unsuccessful for amine 79c,with complex mixtures generated instead, thus this ap-proach was not feasible for accessing 7,6-spirocyclic iminefragments (e.g., 80c).

Scheme 13 Intramolecular hydroamination towards spirocyclic imine fragments by Brimble et al.54

The proposed structure of upenamide (81) contains a6,6-spirocyclic imine derived fragment (Scheme 14). In2013, Taylor and co-workers reported a 19-step linear se-quence from commercially available meso-anhydride 82 for

A) Zakarian et al. (2005)

N3 O

PMBO

OAc

OO

PMBO

OAcN

OO

PMe3 toluene110 °C

51%

B) Brimble et al. (2010)

OO

CO2Et

OTBSTMSO

OMe

69

68

70

7172

9 steps

microwave 150 °C neat, 48 h

65%dr 5:2:1

PMe3 toluene

reflux

61%

O

OO

PvO

PMBO

SO

91%

75%4 steps

(EtO)3P s-collidine

diethylene glycol monomethyl ether

150 °C

H

N

OO

(S)(S)

(S)(S)

H

O

OO

N3

H

EtO2C

OO

O

(S)(S)

(S)(S) OTBS

PvOO

PMBO

OH

OO

33

3

3

64 65

6667

O

SPh

N

O

SPh

N3

O

SPh

N3

O

O

1) Pd2(pmdba)3 (2.5 mol%), A, toluene, 50 °C, 71%, 88% ee2) Pd(PhCN)2Cl2 (10 mol%), toluene, microwave 60 °C, 78%

toluene microwave 160 °C

35%PPh2 N

O

tBuA

73 74

75

N

n

Au(PPh3)SbF6 (5 mol%)NEt3, MeCN, 95 °C

n

IOPMB

n

O

MeONH2

n

77a n = 177b n = 277c n = 3

LHMDS, THF –78 °C to rt

78a n = 1, 81%78b n = 2, 83%78c n = 3, 89%

7 steps

79a n = 179b n = 279c n = 3

OMeO

76

80a n = 1, 91%80b n = 2, 80%80c n = 3, unsuccessful

OPMB


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the synthesis of 6,6-spirocyclic imine 83 as a key fragmentof upenamide (81, Scheme 14).55 To this end, 82 was con-verted into syn-methyl ester 84 over 7 steps in 55% yield.The subsequent construction of the spirocyclic imine ringsystem involved a base-mediated alkylation of cyclohexene84 with iodoazide 85, Staudinger reduction of azide 86, andlactam formation from amine ester 87 afforded bicycliccompound 88, which was eventually elaborated to spirocy-clic imine 83.

In particular, the alkylation of cyclohexyl methyl ester84 using iodoazide 85 reported by Taylor and co-workersappeared relevant for our own investigations as a means tostreamline our previously reported synthesis of spirocyclicimine ring systems through the direct alkylation of ester 76with iodoazides 85 and 89 (Scheme 15, A). Indeed, alkyla-tion of 76 using iodide 85 provided the desired alkylatedadduct 90 in high yield. Interestingly, the analogous reac-tion using iodoazide 89 failed to deliver the expected al-kylated adduct 91, instead affording ,-unsaturated N-vi-nyl amide 92. Following this observation, our study ex-panded the substrate scope to confirm this unexpectedresult and soon realized this reaction to be a remarkableand direct synthesis of industrially important ,-unsatu-rated N-vinyl amides 93 from esters 94 and N-vinyl amides95 from aldehydes 96 (Scheme 15, B). The reaction mostlikely proceeds through the in situ formation of an N-vinylazide 97, which undergoes facile azide–enolate [3+2] cyclo-addition, followed by rearrangement and nitrogen extru-sion (Scheme 15, C). This work was published in 201756 andremains an ongoing area of research within our group, us-ing differentially substituted iodoazides and their reactionwith aldehydes and esters to construct unique N-vinyl am-ide building blocks.

2.5 Recent Efforts towards the 5,6-Spirocyclic Imine Marine Toxin Portimine A

Among the cyclic imine marine toxin family, portimineA (4) represents the smallest member (5,6-spirocyclicimine) identified to date with a unique biological profile. Itexhibits high in vitro cytotoxic activity (P388 cells, EC50 =2.7 nM), yet low in vivo toxicity, setting it apart from therest of cyclic imine toxin families which exhibit less specifictoxicity.57 In 2019, Fujiwara and co-workers reported thefirst synthetic study towards portimine A (4, Scheme 16), inwhich the synthesis of the cyclohexene fragment 98 of thenatural toxin was achieved in 6.5% overall yield over 16steps. The sequence involved the construction of the tertia-ry center of 99 through conjugate addition of vinylmagne-sium bromide to ,-unsaturated ketone 100, followed bydiastereoselective dihydroxylation of the vinyl group andacetal formation to provide acetal 101. Installation of thediene moiety through a Grignard addition–dehydration se-quence afforded diene 102, which was subsequently elabo-rated to provide racemic cyclohexene fragment 98.21

Meanwhile, the most recent study from our group in2019 has demonstrated 2-bromo-1,3-butadiene systems(e.g., 103, Scheme 17) as highly effective substrates for tan-dem Diels–Alder–transition-metal cross-coupling reactionsequences.58 Intermolecular cycloaddition of 2-bromodiene103 with a variety of activated dienophiles was shown toproceed in generally high yield, with good to excellent endodiastereoselectivity. The resulting vinyl bromide cycload-ducts 104 readily underwent subsequent Stille and Suzukicross-couplings under standard conditions to provide ac-cess to novel substituted cyclohexene products 105. Of par-ticular importance to this review is our application of thisstudy to successfully assemble the spirocyclic imine motif106 of portimine A (4), whereby the Diels–Alder reaction ofdiene 103 and enal dienophile 107 was used to forge the

Scheme 14 Synthesis of the spirocyclic imine fragment 83 of upenamide (81) by Taylor et al.55

O

MeO

OBn

O

MeO

OBn

N3

O

MeO

OBn

NH2

HN

O

BnO

KHMDS THF, –78 °C then 85, rt

PPh3, H2O THF, reflux

N

71%

OTIPS

I8%

84 86

83

I N3

85

N

O

O

OH

O

NH

H

upenamide (81)

O

O7 steps

55%

9 steps

O

82 87

88

3 steps


668


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Scheme 15 Unexpected formation of N-vinyl amide 92 and related study by Brimble and Furkert et al.56

O

MeOLHMDS, THF –78 °C to rt

OMeO

76NH

OO

MeO

91not observed

N3

N3

IN3

I N3

85

LHMDS, THF –78 °C to rt

89

9076%

85%

92

R1 = alkyl, PhR2 = H, alkyl

O

R2N N

N

H

[3+2]

O

R2

N3

97

O

R2 N N

N

MeO

O

R2

OMeR1

R1

H – N2

– MeOH

89

– N2

hydride shift

H

[3+2]

KOtBu 89, CH2Cl2

LHMDS89, THF

A)

B)O

R2

OMeR1

O

R2

R1

O

R2

NH

R1

O

R2

NH

R1H

4 examples29–87% yield

5 examples54–85% yield

94 96

R1 = alkyl, PhR2 = H, alkyl

93 95

C)

R1

93

95

–78 °C to rt 0 °C to rt

R1

O

MeO

OMeO

NH

OO

MeON3

N3

IN3

I N3

O

R2N N

N

H

O

R2

N3

O

R2 N N

N

MeO

O

R2

OMeR1

R1

H

H

O

R2

OMeR1

O

R2

R1

O

R2

NH

R1

O

R2

NH

R1H

R1

R1

Scheme 16 Synthesis of the cyclohexene fragment 98 of portimine A (4) by Fujiwara et al.21

O

iBu-O

O OTIPS

O

iBu-O

O OTIPS

inseparable

O

iBu-O

O OTIPS

HO

O

iBu-O

O OH

HO

O

CuI, Me2S, THF–78 °C, then 100

–78 °C

94%dr 1:1

MgBr

2 steps

3 steps

98 102

10199100

(R)(R)

(S)(S)

iBu-O

O

HHO

HO

NHOBn

36%dr 4:1

61%

O OEt

portimine A (4)

(R)(R)N

(S)(S)

O

OH

O

O

H

H

HO

5 steps

87%

5 steps

36%


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cyclohexene quaternary center. Adduct 108 then under-went Seyferth–Gilbert homologation, N-phthalimidedeprotection, and gold-catalyzed hydroamination, employ-ing conditions previously developed by our group,54 to af-ford bicyclic imine 109. Subsequent Stille coupling success-fully installed a vinyl substituent to construct bicyclic frag-ment 106 resembling the 5,6-spirocyclic imine system ofportimine A (4), albeit with non-natural (R,R)-relative ste-reochemical configuration. Future efforts will focus on un-derstanding factors governing the diastereoselectivity ofDiels–Alder reactions using 2-bromo-1,3-butadienes, andmethods to reverse the inherent endo selectivity and favoradducts bearing the same stereochemical configurationseen in the cyclic imine toxins.

2.6 Construction of Another Challenging Motif of Portimine A

While the spirocyclic imine fragments of cyclic iminetoxins command particular attention from synthetic chem-ists, each toxin of the family also bears a complexpolyketide motif, representing another formidable synthet-ic task. At the time of Fujiwara and co-workers’ synthesis ofthe cyclohexene fragment of portimine A (4), the polyketide

portion of the natural product remained a challenging tar-get, with the syn-1,3-dihydroxyketone motif in particular(shaded in blue of 4, Scheme 18), identified by our group asan important synthetic issue to address before a total syn-thesis could be realized. The syn-dihydroxyketones are em-bedded in a wide range of biologically active natural prod-ucts, however, development of stereoselective syntheticmethods to assemble these structures has proven a chal-lenging task. In 2019, we reported our development of ahighly stereoselective synthesis of syn-dihydroxyketonemotifs 110 from readily available propargylic alcohols 111(Scheme 18).59 The reaction sequence involved regioselec-tive cyclization of propargylic alcohols 111 with incorpora-tion of triketone 112 to give enol dioxolanes 113 that thenunderwent highly diastereoselective epoxidation to givespiroepoxide intermediates 114. Hydrolysis or acetolysis ofthe spiroepoxides 114 then cleanly afforded syn-dihy-droxyketones 110 or the corresponding monoacetylated di-hydroxyketones 115 as single diastereomers. This method-ology also included a telescoped one-pot protocol with noloss of overall yield or diastereoselectivity comparing to thethree-step sequence, with wide scope for application in thestereoselective synthesis of complex molecular architec-tures.

3 Conclusion and Future Perspectives

Taken together, this review details multiple syntheticinvestigations by our research group towards cyclic iminetoxins. In particular, iminium chemistry has been investi-gated and has proved to be an efficient method for directaccess to spirocyclic imine fragments, albeit bearing non-natural relative stereochemical configuration. In parallel,we also investigated alternative approaches to spirocyclicimine fragments, including alkylation–hydroamination se-quences and Diels–Alder–hydroamination sequences. Alongthe way, an efficient method to synthesize N-vinyl amidebuilding blocks was serendipitously discovered, and recent-ly, a novel approach to access the challenging 1,3-syn-dihy-droxyketone motif present in many bioactive natural prod-ucts, including portimines, was established.

Recent years have seen a resurgence in interest in thespirocyclic imine fragment of cyclic imine toxins, with mul-tiple new reports since 2017 validating the importance ofthese structural motifs. Diels–Alder approaches appear themost efficient means of accessing spirocyclic imine frag-ments, with the iminium Diels–Alder reaction in particularproviding rapid access to spirocyclic imine systems. Furtherwork is required to investigate the factors governing thestereochemical outcome of iminium Diels–Alder reactions,since the means with which to precisely control this willenable access to adducts bearing the natural stereochemicalconfiguration.Scheme 17 Use of 2-bromodiene 103 in Diels–Alder cycloadditions to

access 5,6-spirocyclic imine 106 by Brimble and Furkert et al.58

+

BrBzO

ONPhth

NPhth

O

108X-ray structure

TiCl4, CH2Cl20 °C

109

OBz

N

Br

106

(R)(R)

(R)(R)

OBz

N

88%>19:1 endo/exo

103

107

1) H2NNH2·H2O, MeOH, reflux 2) Au(PPh3)Cl, AgSbF6, NEt3, MeCN, 95 °C

vinyl tributylstannanePd2(dba)3, CsF

[tBu3PH]BF4 DMF, 100 °C

86%(2 steps)

68%

O

POMe

OMe

H

N

N B

B, NaHMDS, THF–78 °C

87%

BrBzO

NPhth

Br Br

BzO

EWG

Lewis acid

Pd cat.

R2MXn

R2

BzO

EWGR1 R1

BzO

EWG

7 examples, 24–91% yieldup to >19:1 endo/exo

R1

103 104 105


670


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References

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Scheme 18 Diastereoselective synthesis of syn-1,3-dihydroxyketone motifs 110 by Furkert and Brimble et al.59

dimethyl dioxirane (DMDO)

acetone, –20 °C to rt

O O

O

AgNO3, DBUMeCN0 °C to rt, 18 h

portimine A (4)

N

O

OH

O

O

H

H

HO 5,6-spiroimine

syn-1,3-dihydroxyketone

R2

OH

R1

O

OR3 one-potprocess

aq 1 M TFA acetone (1:10), 0 °C or AcOH, rt, 18 h

110 R3 = H115 R3 = Ac

syn

R2

OH

R1

R1

OO

R2 R1

OO

OH

H

R2

O O O O

111 R1 = alkyl, aryl R2 = alkyl, aryl

113

75–95% yield 75–95% yieldup to >20:1 dr

114

12 examples65–86% yield, up to >20:1 dr

112


671


Thi

s do

cum

ent w

as d

ownl

oade

d fo

r pe

rson

al u

se o

nly.

Una

utho

rized

dis

trib

utio

n is

str

ictly

pro

hibi

ted.

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