Asymmetric Synthesis of Cyclopamine, a Hedgehog (Hh) Signaling Pathway Inhibitor

Abstract

Cyclopamine is a teratogenic steroidal alkaloid, which inhibits the Hedgehog (Hh) signaling pathway by targeting the Smoothened (Smo) receptor. Suppression of Hh signaling with synthetic small molecules has been pursued as a therapeutic approach for the treatment of cancer. We report herein the asymmetric synthesis of cyclopamine based on a two-stage relay strategy. Stage-I: total synthesis of veratramine through a convergent approach, wherein a crucial photoinduced excited-state Nazarov reaction was applied to construct the basic [6–6–5–6] skeleton of C-nor-D-homo-steroid. Stage-II: conversion of veratramine to cyclopamine was achieved through a sequence of chemo-selective redox manipulations.

Synthesis of the DEF-Ring Spirocyclic Core of Cyclopamine

“…12 Quite recently, we reported a two-stage relay synthesis of cyclopamine from veratramine using a photoinduced excited-state Nazarov reaction as a key step. 9 The synthetic challenges posed by cyclopamine include the construction of a stereochemically dense C-nor-D-homo steroid skeleton and a highly substituted tetrahydrofuran ring. Our previous solution 9 involved a photo-induced excited-state Nazarov reaction and a reductive dearomatization−cyclization strategy.…”

“…The nucleophilic addition between racemic aldehyde 9 16 and amine 10 resulted in the formation of 12, which subsequently reacted with siloxyfuran 11 to produce a mixture of diastereomers (dr = 1.1:1 at C-20) in the presence of amino acid-based chiral ligand 13. Previously, our published work 9 involved aldehydes of a high enantiomeric excess. However, the aldehyde used here ( 9) is a racemic substrate.…”

“…1 belongs to a big family of Vertrum alkaloids. The biological potential and interesting structure of Vertrum alkaloids have attracted chemists to perform synthetic and biological studies. − An early synthesis of cyclopamine and jervine was achieved by Masamune and co-workers in the 1960s . Additionally, a formal synthesis of jervine was reported by Kutney in 1975 .…”

“…Our research group has been focused on the total synthesis of polycyclic alkaloids . Quite recently, we reported a two-stage relay synthesis of cyclopamine from veratramine using a photo-induced excited-state Nazarov reaction as a key step …”

“…The synthetic challenges posed by cyclopamine include the construction of a stereochemically dense C- nor -D- homo steroid skeleton and a highly substituted tetrahydrofuran ring. Our previous solution involved a photo-induced excited-state Nazarov reaction and a reductive dearomatization–cyclization strategy. In this study, in addition to the reductive dearomatization, we designed an oxidative dearomatization–spirocyclization strategy to construct the substituted furan ring.…”