Broad Spectrum Enolate Equivalent for Catalytic Chemo-, Diastereo-, and Enantioselective Addition to N-Boc Imines

Abstract

Alkynyl ketones are attractive but challenging nucleophiles in enolate chemistry. Their susceptibility to other reactions such as Michael additions and the difficulty of controlling the enolate geometry make them difficult substrates. Mannich-type reactions, which previously have not been reported using N-carbamoyl-imines with simple ketone enolates became our objective. In this report, we describe the first direct catalytic Mannich-type reaction between various ynones and N-Boc imines, whose stereocontrol presumably derives from catalyst control of enolate geometry. This method produces α-substituted β-amino ynones with excellent chemo-, diastereo- and enantioselectivity. The products can be readily transformed into a broad range of molecular scaffolds upon further one-step transformations, demonstrating the utility of ynones as masked synthetic equivalents for a variety of unsymmetrically substituted acyclic ketones. In particular, alkynyl alkyl ketones resolve the longstanding problem of the inability to use the enolates of unsymmetrical dialkyl ketones lacking α-branching for regio- and stereoselective reactions.

Dinuclear Metal‐ProPhenol Catalysts: Development and Synthetic Applications

“…The Zn‐ProPhenol catalyst was also found to be effective with less activated pronucleophiles. In 2015, the Trost group disclosed the use of alkynyl ketones 129 to react with a broad range of aromatic, α,β‐unsaturated, and aliphatic N ‐Boc imines 124 b (Scheme ) . Ynones are attractive yet challenging nucleophiles due to their intrinsic susceptibility to Michael additions and the difficulty of controlling the enolate geometry.…”

“…In 2015, the Trost group disclosed the use of alkynyl ketones 129 to react with a broad range of aromatic, a,b-unsaturated, and aliphatic N-Boc imines 124 b (Scheme 30). [61] Ynones are attractive yet challenging nucleophiles due to their intrinsic susceptibility to Michael additions and the difficulty of controlling the enolate geometry. Nonetheless, this method produces bamino ynones 130 with excellent chemo-, diastereo-and enantioselectivity.…”

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

“…Der Zn‐ProPhenol‐Katalysator erwies sich auch gegenüber weniger aktivierten Pronukleophilen als reaktionsfreudig. Im Jahr 2015 berichtete die Trost‐Gruppe über die Reaktion von Alkinylketonen 129 mit einer Vielfalt an aromatischen, α,β‐ungesättigten und aliphatischen N ‐Boc‐Iminen 124 b (Schema ) . Inone sind attraktive, aber aufgrund ihrer intrinsischen Anfälligkeit für Michael‐Additionen und der Schwierigkeit, die Enolat‐Struktur zu kontrollieren, zugleich problematische Nukleophile.…”

Enantioselective Addition of Alkynyl Ketones to Nitroolefins Assisted by Brønsted Base/H‐Bonding Catalysis

“…[4] In addition, usefulm ethods would require exquisite control of the intervening ketone enolateg eometrya sw ell as the stereochemistryo fthe subsequent CÀCb ond forming reaction. Somed irect asymmetric aldol [5] and Mannich [6] reactions of enolizable ynones acting as donor componentsp romoted by bifunctional metal catalysts [5a-e, 6] or enamine activation [5f-h] are known. In some instances, the enamine activation approach cannot stop at the acyclic addition adduct which undergoes intramolecularc ycli-zation, [7] hence exemplifying the tendency of a,b-ynones to act as Michael acceptors.…”