Quaternary Carbon Synthesis via Lewis Base Reductive Aldol: Mechanistic Calculations and Application towards isopalhinine A Core Synthesis

[摘要] To synthesize palhinine alkaloids, a quaternary reductive aldol reaction was used togenerate rapid stereochemical complexity from simple building blocks. This approach, which canalso be used for diterpene synthesis, couples an asymmetric Diels Alder adduct with a N-containingaldehyde fragment while also generating an alcohol stereocenter. In subsequent steps,this intermediate is hydrogenated and isomerized into a cage-like structure through protectinggroup manipulation. This core has the prospective to be elaborated into the natural productisopalhinine A.In particular, the reductive aldol reaction was examined with a variety of substrates andcatalysts, experimentally and computationally. The electron-rich tris(4-methoxyphenyl)phosphine oxide was used as a Lewis base catalyst capable of promoting bothreduction and aldol. This catalyst was effective for a variety of substrates including lactones,lactams, and morpholine amides, which were coupled with aldehydes to generate quaternaryaldol fragments. For several examples, a mixture of diastereomers is generated, and thisstereochemistry was verified by X-ray crystallography.To model this reaction, DFT, Zstruct, and GSM were used to study the mechanisms ofreduction, catalyst placement, and aldol for a variety of substrates and catalysts. Interestingly, itwas found that reduction results in a trigonal bipyramidal Si complex with both catalyst andsubstrate equatorial, approximately 120° apart. According to DFT, axial catalyst and equatorialsubstrate placement, separated by approximately 90°, is the most stable conformation. However,for the aldol step, both ligands are axial, separated by approximately 180° to accommodate theincoming aldehyde partner. These isomers could interconvert through a Berry mechanism or by astepwise dissociation and re-coordination. These DFT and TS structures set the stage for the goalof developing stronger and more selective Lewis base catalysts.

[发布机构] University of Michigan

[效力级别] isopalhinine A

[关键词] quaternary reductive aldol;isopalhinine A;Lewis base catalysis;heterocycles;automated reaction discovery;Birch reduction;Chemistry;Science;Chemistry