A Stereodivergent Synthesis of All Stereoisomers of Centrolobine: Control of Selectivity by a Protecting‐Group Manipulation

Abstract

All stereoisomers of the natural product centrolobine are selectively synthesized, by starting from a common precursor. Key steps are an enantioselective allylation with enantiomerically pure allylsilanes, a tandem ring-closing metathesis-isomerization reaction, and a Heck reaction by using an arene diazonium salt. By choosing appropriate conditions for the final deprotection step, either the cis-configured centrolobines or their epimers are selectively obtained.

Ru‐ and Pd‐Catalysed Synthesis of 2‐Arylfurans by One‐Flask Heck Arylation/Oxidation

“…Again, Heck coupling products of electron-rich arenediazonium salts (Entries 15,16,20) were smoothly oxidized to the corresponding furans 15ca, 15cb and 15cd with 1.2 equiv. of chloranil, whereas larger amounts of the oxidant were required for 15cc and 15ce (Entries 17-19 and 21-22).…”

“…To overcome these drawbacks we sought an alternative route not based on furan cross-coupling reactions. Inspired by recent research in our group directed towards the synthesis of centrolobines [16] and related diarylheptanoids [17] through Heck coupling reactions of dihydropyrans and arenediazonium salts, [18] we decided to investigate the feasibility of a synthesis as outlined in Scheme 1. Scheme 1.…”

Mizoroki–Heck Reactions with 4‐Phenoldiazonium Salts

“…[27,28] The reaction is highly trans-diastereoselective and occurs without undesired double bond migration reactions, enabling a stereodivergent synthesis of all stereoisomers of the natural product centrolobine. [29] With a view towards the synthesis of the closely related bisphenol natural product de-O-methylcentrolobine, we synthesized the benzyl-protected diazonium salt 1b with the intention to remove the benzyl protecting group after the Pd-catalyzed transformation by hydrogenation. 1b and a number of other O-alkylated derivatives were obtained via a one-flask deacetylation-diazotation sequence from paracetamol and other substituted acetanilides.…”

Chemoselective Reduction and Alkylation of Carbonyl Functions Using Phosphonium Salts as an <i>in Situ</i> Protecting Groups

“…[36][37][38] Asymmetric syntheses of centrolobine have been reported by several groups, but they involve multiple steps and/or give low yields. [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] Our synthetic route is summarized in Chart 7. This enantioselective synthesis was accomplished in five steps from commercially available cyclopentene 3; the overall yield was 75%, which is the highest total yield reported for the asymmetric synthesis of (+)-centrolobine.…”