Convergent Total Synthesis of (-)-Cyclopamine

被引：21

作者：

Sofiadis, Manolis ^{[1
]}

Xu, Dongmin ^{[1
]}

Rodriguez, Anthony J. ^{[1
]}

Nissl, Benedikt ^{[1
]}

Clementson, Sebastian ^{[2
]}

Petersen, Nadia Nasser ^{[2
]}

Baran, Phil S. ^{[1
]}

机构：

[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

[2] LEO Pharm AS, Res & Early Dev, DK-2750 Ballerup, Denmark

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2023年 / 145卷 / 40期

基金：

欧盟地平线“2020”;

关键词：

VERATRUM ALKALOID SERIES; CONSTRUCTION; CYCLOPAMINE; ALKYLATION; DESIGN; CORE; DERIVATIVES; INHIBITORS; JERVINE;

D O I：

10.1021/jacs.3c09085

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

A concise and enantioselective total synthesis of the Veratrum alkaloid cyclopamine is disclosed. This highly convergent synthesis with a 16-step longest linear sequence (LLS) was enabled by a de novo synthesis of the trans-6,5-heterobicycle via a strain-inducing halocyclization process, a key Tsuji-Trost cyclization to construct the fully substituted, spirocyclic THF motif with exquisite diastereocontrol, and a late-stage ring-closing metathesis (RCM) reaction to forge the central tetrasubstituted olefin.

引用

页码：21760 / 21765

页数：6

共 52 条

[1] Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926 [J].

Austad, Brian C. ;

Hague, Andrew B. ;

White, Priscilla ;

Peluso, Stephane ;

Nair, Somarajan J. ;

Depew, Kristopher M. ;

Grogan, Michael J. ;

Charette, Andre B. ;

Yu, Lin-Chen ;

Lory, Caroline D. ;

Grenier, Louis ;

Lescarbeau, Andre ;

Lane, Benjamin S. ;

Lombardy, Richard ;

Behnke, Mark L. ;

Koney, Nii ;

Porter, James R. ;

Campbell, Matthew J. ;

Shaffer, Jeanne ;

Xiong, Jimin ;

Helble, Joseph C. ;

Foley, Michael A. ;

Adams, Julian ;

Castro, Alfredo C. ;

Tremblay, Martin R. .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2016, 20 (04) :786-798

[2] (BDP)CuH: A "hot" Stryker's reagent for use in achiral conjugate reductions [J].

Baker, Benjamin A. ;

Bokovic, Zarko V. ;

Lipshutz, Bruce H. .

ORGANIC LETTERS, 2008, 10 (02) :289-292

[3] A TOTAL SYNTHESIS OF C-NOR D-HOMOSTEROIDS OF THE A-]B-]C-]D-TYPE, INVOLVING A REDUCTIVE ALKYLATION STEP FOR CONSTRUCTION OF THE D-RING [J].

BROWN, E ;

LEBRETON, J .

TETRAHEDRON LETTERS, 1986, 27 (23) :2595-2598

[4] Enantioselective Total Synthesis of (+)-Heilonine [J].

Cassaidy, Kyle J. ;

Rawal, Viresh H. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2021, 143 (40) :16394-16400

[5] I only have eye for ewe: the discovery of cyclopamine and development of Hedgehog pathway-targeting drugs [J].

Chen, James K. .

NATURAL PRODUCT REPORTS, 2016, 33 (05) :595-601

[6] N-heterocyclic carbene and phosphine ruthenium indenylidene precatalysts: A comparative study in Olefin metathesis [J].

Clavier, Herve ;

Nolan, Steven P. .

CHEMISTRY-A EUROPEAN JOURNAL, 2007, 13 (28) :8029-8036

[7] Teratogen-mediated inhibition of target tissue response to Shh signaling [J].

Cooper, MK ;

Porter, JA ;

Young, KE ;

Beachy, PA .

SCIENCE, 1998, 280 (5369) :1603-1607

[8] Review: Veratrum californicum Alkaloids [J].

Dirks, Madison L. ;

Seale, Jared T. ;

Collins, Joseph M. ;

McDougal, Owen M. .

MOLECULES, 2021, 26 (19)

[9] Total Synthesis of the Tremorgenic Indole Diterpene Paspalinine [J].

Enomoto, Masaru ;

Morita, Akira ;

Kuwahara, Shigefumi .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2012, 51 (51) :12833-12836

[10] Aiming for the Ideal Synthesis [J].

Gaich, Tanja ;

Baran, Phil S. .

JOURNAL OF ORGANIC CHEMISTRY, 2010, 75 (14) :4657-4673

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