Bifunctional Brønsted Base Catalyzes Direct Asymmetric Aldol Reaction of α‐Keto Amides

Abstract

The first enantioselective direct cross-aldol reaction of a-keto amides with aldehydes,m ediated by ab ifunctional ureidopeptide-based Brønsted base catalyst, is described. The appropriate combination of at ertiary amine base and an aminal, and urea hydrogen-bond donor groups in the catalyst structure promoted the exclusive generation of the a-keto amide enolate whichr eacted with either non-enolizable or enolizable aldehydes to produce highly enantioenriched polyoxygenated aldol adducts without side-products resulting from dehydration, a-keto amide self-condensation, aldehyde enolization, and isotetronic acid formation. Scheme 1. Cross-aldol reactions of 1,2-dicarbonyl compounds. BB = Brønsted base, Tf = trifluoromethanesulfonyl.

Progress in (Thio)urea‐ and Squaramide‐Based Brønsted Base Catalysts with Multiple H‐Bond Donors

“…[99] The stereoselectivity was significantly lower when the reaction was ran in the presence of catalyst C76 lacking the sulfonamide moiety. The authors proposed a plausible transition state (TS29) wherein one of the NH groups of the squaramide together with the sulfonamide NH activate [94][95][96] d) Mielgo & Palomo 2021. [97] Scheme 53.…”

“…As shown in Scheme 52, these type of catalysts performed exceedingly in several other addition reactions that involve donor substrates capable of bidentate H‐bonding to the catalyst. These include the Mannich reaction of sulfonyl acetonitriles (Scheme 52a), [94] the aldol reaction of α‐ketoamides with aldehydes (Scheme 52b) [95] and the Mannich reaction of pyridyl N ‐oxide acetates and aromatic imines (Scheme 52c) [96] . More recently it has been found that this catalyst type are also efficient for the aldol reaction of Schiff bases of glycine o‐nitroanilide and aldehydes (Scheme 52d) [97] .…”

“…Described asymmetric reactions employing multiple H-bond donating ureidopeptide-like catalysts C70-C73. a,b,c) Palomo 2014-2017 [94][95][96]. d) Mielgo & Palomo 2021 [97].…”