Synthesis of Enantiomerically Pure 2,2,3,4,5-Pentasubstituted Pyrrolidines by Phenylsulfanyl Migration

Abstract

[reaction: see text] Enantiomerically pure 2,2,3,4,5-pentasubstituted pyrrolidines can be prepared, in high overall yield, from alpha,beta-unsaturated esters. Asymmetry is introduced via a Michael addition, and additional stereogenic centers are introduced by an aldol reaction. A novel stereospecific ring-forming reaction, proceeding via a thiiranium (episulfonium) ion, yields pyrrolidines from beta-hydroxy sulfides. In this manner, 2,2,3,4,5-pentasubstituted pyrrolidines, containing three contiguous stereogenic centers around the ring, can be prepared in 44% overall yield from ethyl crotonate.

Theoretical studies on the methylsulfenyl chloride addition to propene

“…Usually the nucleophilic halide attacks the substituted C-1 carbon atom of the thiiranium intermediate to give M-adducts, whereas propene, iso-butylene, and other nonconjugated olefins give aM-adducts of the halide attack on the C-2 carbon atom [13][14][15][16][17][18]. This experimental observation was explained as resultant competition between a steric and electronic effects [13][14][15][16][17][18][19][20][21][22][23][24].…”

“…From the kinetic SCHEME 1 Addition reaction of methylsulfenyl chloride to propene. and spectroscopic experimental data [13][14][15][16][17][18][19][20][21][22][23][24], the formation of the thiiranium intermediate is known as the rate-determining step for this reaction. At low temperatures, this reaction goes under a kinetic control.…”

“…At low temperatures, this reaction goes under a kinetic control. Obtained adducts of the kinetically controlled reaction undergo further rearrangement to the thermodynamically stable products [13][14][15][16][17][18][19][20][21][22][23][24].…”

“…Usually the nucleophilic halide attacks the substituted C-1 carbon atom of the thiiranium intermediate to give M-adducts, whereas propene, iso-butylene, and other nonconjugated olefins give aM-adducts of the halide attack on the C-2 carbon atom [13][14][15][16][17][18]. This experimental observation was explained as resultant competition between a steric and electronic effects [13][14][15][16][17][18][19][20][21][22][23][24]. The electronic effect contends that the π electron density on the C-2 carbon atom of the thiiranium intermediate increases with the conjugation effect between the double bond and the substituent; subsequently, chloride attacks the less negative carbon atom C-1 forming M product.…”

“…The electronic effect contends that the π electron density on the C-2 carbon atom of the thiiranium intermediate increases with the conjugation effect between the double bond and the substituent; subsequently, chloride attacks the less negative carbon atom C-1 forming M product. While, if the substituent is aliphatic, the addition occurs conversely as mentioned above forming the aM product, and the steric factor between the chloride and the substituent was introduced to explain the resulting orientation of the adducts [13][14][15][16][17][18][19][20][21][22][23][24].…”