Asymmetric 1,6‐Conjugate Addition of para‐Quinone Methides for the Synthesis of Chiral β,β‐Diaryl‐α‐Hydroxy Ketones

Abstract

A direct asymmetric 1,6-conjugated addition of a-hydroxy ketone to para-quinone methides has been developed. It is an efficient approach to the synthesis of chiral b,b-diaryl-a-hydroxy ketones. The reaction runs smoothly in the presence of ZnEt 2 and nonracemic bis(diarylhydroxymethylpyrrolidinylmethyl)phenols (ProPhenols), and the desired products are obtained in good yields (up to 88%) and with high stereoselectivity (up to > 99% ee and up to > 99:1 dr). This reaction also can be run on a gram scale without impacting its enantioselectivity.

Dinuclear Metal‐ProPhenol Catalysts: Development and Synthetic Applications

“…Besides 1,4‐additions, the Zn‐ProPhenol catalyst was also found to facilitate 1,6‐addition of α‐hydroxyacetophenones 17 a to p ‐quinone methides 185 (Scheme ) . Using catalyst derived from ligand L‐1 i , a variety of chiral β,β‐diaryl‐α‐hydroxyketones 186 were obtained in high yield, diastereo‐, and enantioselectivity (up to >99:1 dr, 99 % ee ).…”

“…Besides 1,4-additions, the Zn-ProPhenol catalyst was also found to facilitate 1,6-addition of a-hydroxyacetophenones 17 a to p-quinone methides 185 (Scheme 47). [87] Using catalyst derived from ligand L-1 i, a variety of chiral b,b-diaryl-ahydroxyketones 186 were obtained in high yield, diastereo-, and enantioselectivity (up to > 99:1 dr, 99 % ee). The scope of the reaction highlights the importance of the tert-butyl groups to achieve high diastereoselectivity which can subsequently be removed upon treatment with AlCl 3 .…”

Recent Advances in the Catalytic Enantioselective Reactions of para‐Quinone Methides

“…Very recently,H ua, Wang, and Gao established ad irect asymmetric 1,6-conjugated addition of a-hydroxy ketones 88 to p-QMs 87 (Scheme 28). [33] The reactionp roceeded smoothly in the presence of aZ nEt 2 /ProPhenols complex, and chiral b,bdiaryl-a-hydroxyk etones 89 were obtained in good yields with high stereoselectivities. In their proposed catalytic cycle, ZnEt 2 reactedw ith ligand L6 to form ad inuclear ZnÀProPhenol complex, which activated and spatially arranged the p-QM and ahydroxy ketonef or the formal intramolecular Michael addition reaction.…”

“…Very recently, Hua, Wang, and Gao established a direct asymmetric 1,6‐conjugated addition of α‐hydroxy ketones 88 to p ‐QMs 87 (Scheme ) . The reaction proceeded smoothly in the presence of a ZnEt 2 /ProPhenols complex, and chiral β,β‐diaryl‐α‐hydroxy ketones 89 were obtained in good yields with high stereoselectivities.…”

Zweikernige Metall‐ProPhenol‐Katalysatoren: Entwicklung und Anwendungen in der Synthese

“…Neben 1,4‐Additionen vermag der Zn‐ProPhenol‐Katalysator auch die 1,6‐Addition von α‐Hydroxyacetophenonen 17 a an p ‐Chinonmethide 185 zu vermitteln (Schema ) . Mit dem L‐1 i ‐modifizierten Zn‐Katalysator wurden diverse chirale β,β‐Diaryl‐α‐hydroxyketone 186 mit hoher Ausbeute, Diastereo‐ und Enantioselektivität erhalten (bis zu >99:1 dr, 99 % ee ).…”