Enantioselective Synthesis of Quaternary Carbon Stereogenic Centers through the Primary Amine‐Catalyzed Michael Addition Reaction of α‐Substituted Cyclic Ketones at High Pressure

Abstract

The enantioselective Michael addition reaction of α‐substituted cyclic ketones with acrylates was efficiently promoted by a primary amine chiral catalyst under high‐pressure conditions (1.0 GPa) in tetrahydrofuran. This method was highly successful for the construction of an all‐carbon‐substituted quaternary‐carbon stereogenic center at the α‐position of cyclic ketones in high enantiomeric excess, and could be conveniently applied to the formal synthesis of (+)‐aspidospermidine.

α‐Branched Ketone Dienolates: Base‐Catalysed Generation and Regio‐ and Enantioselective Addition Reactions

“…At 90 °C, product 11 A was formed (72 % yield), albeit with very low (15 % ee ) selectivity, indicating that the amine catalyst probably acted as a base rather than by forming an enamine. This latter observation suggests that the enamine pathway is marginal with sterically congested ketones such as 10 A , in line with previous observations by Carter and Kotsuki, who showed that amine catalysis is impractical for branched ketones with α‐substituents larger than methyl or ethyl.…”

Direct Asymmetric Alkylation of Ketones: Still Unconquered

“…The asymmetric alkylation of cyclohexanones through an asymmetric Pfau–dQAngelo reaction was accomplished by the use of thiourea- and primary amine-based systems by Carter (Scheme 20b) and Kotsuki (Scheme 20c) independently. [43] However, only cyclic substrates were reported.…”

Straightforward access to densely substituted chiral succinimides through enantioselective organocatalyzed Michael addition of α-alkyl-cyclic ketones to maleimides

“…Pure samples were isolated for analysis purposes. The electronic nature of the R groups of maleimide, from donor (entries 2-5) to attractor (entries [6][7][8][9][10][11][12] as well as that of their respective larger or smaller sizes did not significantly influence products distribution in these reactions, giving good yields (58-71%), good to excellent diastereoselectivities (67/33 to 98/2) and enantioselectivities for compounds 15 (75-98% ee). We propose the following mechanism (Scheme 2) to explain the influence of a co-acid on the reaction process.…”

“…10 A catalytic version was disclosed by Carter et al 11 involving acrylates as Michael acceptors and a thiourea-based dual organocatalytic pathway promoting enamine/Brønsted acid activations. Kotsuki et al later reported 12 the enantioselective Michael addition of -alkyl cyclic ketones to acrylates promoted by (S)-1phenylethylamine 1 under high pressure conditions. The formation of small amounts (<5%) of undesired tertiary regioisomers (TCCs) was noticed (Scheme 1, a).…”