Abstract
Homologation of readily available α‐boryl pyrrolidines with metal carbenoids is especially challenging even when good leaving groups (Cl−) are employed. By performing a solvent switch from Et2O to CHCl3, efficient 1,2‐metalate rearrangement of the intermediate boronate occurs with both halide and ester leaving groups. The methodology was used in the total synthesis of the Stemona alkaloid (−)‐stemaphylline in just 11 steps (longest linear sequence), with high stereocontrol (>20:1 d.r.) and 11 % overall yield. The synthesis also features a late‐stage lithiation–borylation reaction with a tertiary amine containing carbenoid.
Highlights
Homologation of readily available a-boryl pyrrolidines with metal carbenoids is especially challenging even when good leaving groups (ClÀ) are employed
The methodology was used in the total synthesis of the Stemona alkaloid (À)-stemaphylline in just 11 steps, with high stereocontrol (> 20:1 d.r.) and 11 % overall yield
Homologation through lithiation–borylation has emerged as a powerful tool for the assembly of multiple stereogenic centers with high stereocontrol (Scheme 1 A),[1] and the method has been applied in total synthesis, for acyclic polyketide-type natural products.[2]
Summary
Homologation of readily available a-boryl pyrrolidines with metal carbenoids is especially challenging even when good leaving groups (ClÀ) are employed. The use of a-amino boronic esters in homologation reactions is notoriously troublesome, as documented by Matteson[8] and Whiting[9] (Scheme 2 A).[10] The N-Boc/N-Ac pyrrolidine ring is a reluctant migrating group, even with exceptionally good leaving groups (ClÀ), leading to unwanted side-reactions and low conversions.
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