Enantioselective Total Synthesis of (−)‐Deoxoapodine

Abstract

The first enantioselective total synthesis of (−)-deoxoapodine is described. Our synthesis of this hexacyclic aspidosperma alkaloid includes an efficient molybdenum-catalyzed enantioselective ring-closing metathesis reaction for desymmetrization of an advanced intermediate that introduces the C5-quaternary stereocenter. After C21-oxygenation, the pentacyclic core was accessed via an electrophilic C19-amide activation and transannular spirocyclization. A biogenetically inspired dehydrative C6-etherification reaction proved highly effective to secure the F-ring and the fourth contiguous stereocenter of (−)-deoxoapodine with complete stereochemical control.

Amide activation: an emerging tool for chemoselective synthesis

“…Indoles (such as 93, 95, 100 and 103), core structures of a large number of naturally occurring alkaloids, have moreover found extensive application in total synthesis (Scheme 17b-d). [67][68][69][70][71] Nucleophilic alkenes and alkynes have also been shown to be suitable moieties for intramolecular trapping of activated amides, foremost in such cases where intramolecular [2+2]cycloaddition is precluded for reasons of steric hindrance or ring-strain. Several efficient applications of silyl enol ethers (such as 109, 111 and 114) 64,72 in synthetic methodologies and natural product synthesis [73][74][75] have been reported in recent years, including the syntheses of tashiromine (113) and pervilleine B Scheme 14 Wang's indole synthesis employing EDA.…”

Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization

“…Later, this concept has been exploited for the asymmetric synthesis of a range of Aspidosperma ‐type natural products (Scheme ). For this, either chiral pool starting material, biocatalytic kinetic resolution or enantioselective ring‐closing metathesis (RCM) mediated desymmetrization was employed to access enantioenriched lactam 162 as starting material.…”

Total Syntheses of Dihydroindole Aspidosperma Alkaloids: Reductive Interrupted Fischer Indolization Followed by Redox Diversification

“…Despite their (bio)synthetic and biological potential, this subset of natural products has received relatively less attention in stereoselective synthetic programs. 6 …”