Synthesis of β-heteroaryl propionates via trapping of carbocations with π-nucleophiles

Abstract

A variety of heterocyclic alcohols and acetates were coupled with silyl ketene acetals and other π-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide an array of substituted β-heteroaryl propionates, including those with contiguous quaternary centers, as well as vinylogs thereof. This reaction also proceeds with high diastereoselectivity when the π-nucleophile bears a chiral auxiliary.

Studies toward welwitindolinones: formal syntheses of N-methylwelwitindolinone C isothiocyanate and related natural products

“…It is also noteworthy that this experiment served as the basis for developing a general method for preparing β-heteroaryl carbonyl compounds by trapping carbocations with different π-nucleophiles. 14,15 …”

“…This novel process involves a variant of a vinylogous Mannich reaction in which a benzylic-type carbocation is trapped by a π-nucleophile, and this discovery was subsequently extended to a more general entry to the synthesis of β-heteroaryl carbonyl compounds. 14 We also extended the scope of cyclizations via allylic alkylations to include γ-acyloxyenones, and we developed an improved method for enolate arylations of carbonyl compounds.…”

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

“…The Fischer indole synthesis [8,[20][21][22][41][42][43] is ac lassic tandem reaction that involves the condensation of an N-arylhydrazine 38 with an aldehyde/ketone 39 (Scheme 4A). This initial reaction gives an arylhydrazone intermediate (41), which tautomerizes to undergo a [ 3,3]-sigmatropic rearrangement before af inal cyclization-aromatization sequence to give an indole product (40). The Fischer indole synthesis has found extensive use in both natural product synthesis and medicinal chemistry,i n-cluding the synthesis of clinically used antiemetic agent ondansetron (4).…”

Concise total synthesis of (±)-actinophyllic acid

“…18 Indeed, we had developed this reaction into a general method to couple stabilized carbocations derived from heteroaromatic carbinols with various π-nucleophiles to deliver β-heteroaryl propionates as exemplified by the preparation of 10 by the TMSOTf-promoted reaction of 8 and 9 (Equation 1). 19 …”