Scalable Total Synthesis of (-)-Vinigroly ( ) g

Reporter: Bo WuChecker: Yang ZhaoD 2019/04/01Date: 2019/04/01

Yu X ; Luo TYu, X.; Luo, T. J. Am. Chem. Soc. 2019, 141, 3440.

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ContentsContents

1 Introduction

2 Total Synthesis of Vinigrol

3 Scalable Total Synthesis of (-)-Vinigrol

4 Summaryy

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CV of ProfCV of Prof. . TuopingTuoping LuoLuo

Background:g2001-2005 B.S., Peking University2005-2011 Ph.D., Harvard University2011-2013 Postdoc H3 Biomedicine Inc2011-2013 Postdoc, H3 Biomedicine Inc.2013-Now Principal Investigator, Peking University

Provisional Principal Investigator, Peking University-Tsinghua University

Research Interests:Exploring and applying novel chemical reactions with the goal to advance synthetic organic chemistry and chemical biologysynthetic organic chemistry and chemical biologyDiscovering innovative approaches to address the demanding medical needs of human beings

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IntroductionIntroduction

Isolated from a fungal strain Virgaria nigra F-5408 in 1987;Exhibiting potent antihypertensive and platelet aggregation-g p yp p gg ginhibiting properties; an antagonist for tumor necrosis factor α;The 6-6-8 tricyclic ring system with the axial four-carbon tether b id i th d l d t d i d li Ei ht tibridging the densely decorated cis-decalin core. Eight contiguous stereogenic centers.

H hi t T t l J O Ch 1987 52 5292

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Hashimoto, T. et al. J. Org. Chem. 1987, 52, 5292.

RetrosyntheticRetrosynthetic AnalysisAnalysis

MeMe

MeMe

MeMe

ShapiroMe

MeDipolarMeOH

H

H

HO

OH

MeOH

H

H

H

OH

OH

Shapiroreaction MeO

H

H

H

MeDipolarcylcoaddition

17Me OHMe OH

Vinigrol (1) 11H

Grobfragmentation

MeM

OMs

fragmentation

MeOH

OTBSO

Diels-AlderMe

OH

H

H

H

MeMe

MeOR

H

IMDA

TBSOMe

MeMeO+

Diels Aldercycloaddition

B P S t l J A Ch S 2009 131 17066

10'HH

8Me

3 4

5

Baran, P. S. et al. J. Am. Chem. Soc. 2009, 131, 17066.

Synthesis of Compound 9Synthesis of Compound 9

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Baran, P. S. et al. Angew. Chem. Int. Ed. 2008, 47, 3054.

Synthesis of Compound 13Synthesis of Compound 13

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GrobGrob FragmentationFragmentation

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Synthesis of Compound 17Synthesis of Compound 17

Me Me

OHH

Me

H H

Me

H1) NaH, CS2, MeI, 88%

2) o-DCB, 180 oC, 96%

Xanthate formation LiAlH4

MeH

ONBr

13

MeH

ONBr

14

Chugaev elimination

H

Me

HH

Me

H

1) HCO2HCDMT

2) COCl2Et N

1) OsO4NMO

MeMe

OHH

Me

Me

Me

HOH

H2NMe

Me

HOH

Me

Et3N

81%56%

Saegusa

3) Bu3SnHAIBN

NMO2) NaOCl

OH

H

H

HO

Me OH

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H2N

16

e

17

Saegusadeamination

sequence

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XanthateXanthate Formation and Formation and ChugaevChugaev EliminationElimination

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Saegusa Deamination Saegusa Deamination SquenceSquence

Saegusa, T. et al. J. Am. Chem. Soc. 1968, 90, 4182.

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Synthesis of Synthesis of VinigrolVinigrol

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Shapiro ReactionShapiro Reaction

Shapiro, R. H. et al. J. Am. Chem. Soc. 1967, 89, 5734.

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RetrosyntheticRetrosynthetic AnalysisAnalysis

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Luo, T. et al. J. Am. Chem. Soc. 2019, 141, 3440.

Synthesis of Compound (Synthesis of Compound (--))--77

Mehta, G. et al. Indian J. Chem. Sect B 1998, 37B, 201.

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Synthesis of Compound (+)Synthesis of Compound (+)--1212

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Synthesis of Compound (+)Synthesis of Compound (+)--1717

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ZweifelZweifel OlefinationOlefination

Zweifel, G. et al. J. Am. Chem. Soc. 1967, 89, 3652.

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Synthesis of Compound (Synthesis of Compound (--))--2020

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Synthesis of (Synthesis of (--))--VinigrolVinigrol

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Burgess DehydrationBurgess Dehydration

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SummarySummary

Baran's Group in 2009Me

MOMe

OH

H

H

H

Me

OH

OTBS

TBSOMe

O

MeO+

G f STotal synthesis, 23 steps, 2.7% overall yield

HMe OH

Vinigrol

TBSOMe

Luo's Group in 2019

Grob fragmentation, Diels-Alder cycloaddition, dipolar cycloaddition, Shapiro reaction

MeMe Me

MeOH

OH

Me

Me H

Me

Me

Anionic oxy Cope rearrangement hydroboration Zweifel olefination transannular DAScalable total synthesis, 20 steps, 1.4% overall yield, 605 mg

OHMeOH

H

(-)-Vinigrol

Me

(S)-(-)-Limonene

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Anionic oxy-Cope rearrangement, hydroboration, Zweifel olefination, transannular DA

The First The First ParagraphParagraph

First isolated from a fungal strain in Japan by Hashimoto and co-workers, vinigrol (1, Figure 1) occupies a special position in naturalproduct small molecules. Among the structurally diverse terpenoids,product small molecules. Among the structurally diverse terpenoids,vinigrol is the only one that is characterized by the 6−6−8 tricyclic ringsystem with the axial four-carbon tether bridging the denselyd t d i d li Thi t l d t di l t tdecorated cis-decalin core. This natural product displays potentantihypertensive and platelet aggregation-inhibiting properties andhas been reported as an antagonist for tumor necrosis factor α (TNF-α), which intrigues us the most.

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The Last The Last ParagraphParagraph

In summary, we have developed a concise and scalable synthesisto accomplish ( ) inigrol Each step of this ro te has been optimi edto accomplish (−)-vinigrol. Each step of this route has been optimizedand validated on a gram-scale reaction whereas all the reagentsshown in Scheme 1 were commercially available. But the syntheticapproach is not without flaw. Even if the efficiency of our approach interms of the overall steps is high (20 steps from S-limonene), theoverall yield (1 4%) is lower than that of Baran’s for racemic vinigroloverall yield (1.4%) is lower than that of Baran s for racemic vinigrol(2.7%). If (+)-vinigrol is required, (R)-(+)-limonene would be needed.Nonetheless, our new strategy enabled the execution of carefullyorchestrated transformations to construct such a strained frameworkand uniquely substituted stereogenic centers without the use ofprotecting groups. Investigation of the biological activities of (−)-protecting groups. Investigation of the biological activities of ( )vinigrol is ongoing, which will be reported in due course together withthe evolution of our synthetic strategies.

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AcknowledgementAcknowledgement

ThanksThanksThanks Thanks for your attentionfor your attentionfor your attentionfor your attention

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HydroborationHydroboration with (+)with (+)--IpcBHIpcBH22

Renaud, P. et al. Angew. Chem. Int. Ed. 2017, 56, 10858.

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