Stereochemical Aspects in the Asymmetric Michael Addition of Chiral Imines to Substituted Electrophilic Alkenes

Abstract

The Michael-type addition of chiral imines, derived from racemic alpha-substituted cyclanones and optically active 1-phenylethylamine, to electrophilic alkenes, in neutral conditions, constitutes one of the most efficient methods for the stereocontrolled construction of quaternary carbon centers. In order to create an additional stereogenic center at the alpha- or beta-position to the quaternary one, the behavior of a variety of alpha- and beta-substituted alkenyl acceptors was examined. In general, these additions are highly regioselective, the alkylation taking place predominantly, if not exclusively, at the more substituted alpha-side of the imine function; however, in some cases (electrophilic alkenes 28 and 49), significant amounts (10-15%) of regioisomeric adducts were obtained. With the exception of methyl propiolate 52, a remarkable control of the absolute configuration of the adducts were always observed with these Michael acceptors. According to the general rule we have previously proposed, the alkylation process takes place preferentially on the less hindered pi-face of the more substituted secondary enamine, in tautomeric equilibrium with the starting imine. An excellent diastereocontrol was always obtained by using the present alpha- and beta-substituted alkenes. These stereochemical outcomes can be interpreted by invoking that the reaction proceeds through a compact approach of the reactants, the hydrogen atom at the nitrogen center of the enamine being transferred to the alpha-vinylic carbon atom of the acceptor, concertedly with the creation of the C-C bond. In this respect the "endo-approach" 58, in which the electron-withdrawing group of the acceptor faced to the nitrogen atom of the enamine (case of acceptors 10, methyl methacrylate, 24, 28, 43, 47, and 49) largely prevails over the "exo-approach" 59 (case of acceptor 38). This predominant "endo-preference" can be reasonably interpreted in terms of a cooperative effect between steric and stereoelectronic factors.

Highly enantioselective synthesis of α-methylene-δ-valerolactones by an asymmetric Michael reaction

“…The absolute configuration at the quaternary stereogenic center in adducts 4 and 16 is fully consistent with the transition-state model proposed for asymmetric Michael addition of chiral imines to electron-deficient alkenes 17 and with the results of our earlier studies. 2 The alkylation occurs preferentially on the less hindered p-face at the more substituted secondary enamine, in tautomeric equilibrium with the starting imine, anti-to the phenyl group.…”

Asymmetric synthesis of glutamate derivatives

“…[22][23][24] The energy difference is in favour of the Reapproach in which the benzyl group of 6b is pushed away from the methyl acrylate face approach. Consequently, using a benzyl enaminoester does not disturb the asymmetric Michael mechanism.…”

A comparative study of high pressure versus other activation modes in the asymmetric Michael reaction of chiral imines

“…Consequently, activation may be required for their condensation with chiral imines. Methyl methacrylate 28 polymerizes in the presence of basic imine 8 prior to the expected Michael reaction under both D (85 C, 7 days, [24]) or HP activation [25]. Under drastic conditions (24 days at 85 C) and with excess methyl methacrylate 28, imine (1 0 S)-8 leads to an 83:17 mixture of the expected adduct 29 (de ¼ 98%, ee ¼ 93%) and its regioisomers 30 in 69% combined yield (re ¼ 66%) (Sch.…”

“…In the intermolecular version of the reaction, and except in the case of a few reactive acceptors [24,32], b-substituted electrophilic alkenes such as alkyl crotonates are inert under standard conditions. For example, methyl crotonate 52 does not react with imine (1 0 R)-8 even at 120 C (D1) [25].…”

“…7). The remarkably complete stereocontrol, due to the concerted nature of the mechanism, originates from a syn endo approach 38 of the two reactants [24]. It should be mentioned that methyl methacrylate 28 polymerizes in the presence of enaminoester 14 prior to the expected Michael reaction under HP activation [25].…”