Direct and enantioselective α-allylation of ketones via singly occupied molecular orbital (SOMO) catalysis

Abstract

The first enantioselective organocatalytic α-allylation of cyclic ketones has been accomplished via singly occupied molecular orbital catalysis. Geometrically constrained radical cations, forged from the one-electron oxidation of transiently generated enamines, readily undergo allylic alkylation with a variety of commercially available allyl silanes. A reasonable latitude in both the ketone and allyl silane components is readily accommodated in this new transformation. Moreover, three new oxidatively stable imidazolidinone catalysts have been developed that allow cyclic ketones to successfully participate in this transformation. The new catalyst platform has also been exploited in the first catalytic enantioselective α-enolation and α-carbooxidation of ketones.asymmetric synthesis | organocatalysis T he enantioselective catalytic α-alkylation of simple ketones remains a fundamental goal in chemical synthesis (1-4). Seminal work from Doyle and Jacobsen (5), Trost and co-workers (6-8), Stoltz and co-workers (9, 10), Braun and co-workers (11,12), and Hartwig and co-workers (13, 14) has introduced valuable previously undescribed technologies for (i) the enantioselective alkylation of preformed or in situ generated metal enolates (5,6,(11)(12)(13)(14)(15)(16)(17) and (ii) the asymmetric and decarboxylative conversion of allyl keto carbonates to α-allylated ketones (7-10). With these key advances in place, a goal now for asymmetric catalysis has become the direct α-allylation of simple ketone substrates (18,19), an elusive yet potentially powerful bond construction (Scheme 1).Recently, we questioned whether the catalytic principles of singly occupied molecular orbital (SOMO) activation (20) might be translated to ketonic systems, thereby providing an unreported mechanism for direct and enantioselective α-carbonyl alkylation. Despite the superficial similarities between aldehydes and ketones, these carbonyl families exhibit largely different steric and electronic properties with respect to catalyst interactions. As a consequence, the translation of enantioselective activation modes between these carbonyl subclasses is often difficult (if not unattainable in many cases) (21,22). Herein, we describe the invention of a previously undisclosed family of organocatalysts that enable cyclic ketones to successfully function within the SOMO-activation platform while being chemically robust to oxidative reagents. Moreover, we document the introduction of a previously undescribed catalytic α-ketone alkylation reaction that is immediately amenable to asymmetric induction. Enantioselective SOMO CatalysisOver the last decade, the field of enantioselective synthesis has witnessed tremendous progress in the successful implementation of small organic molecules as asymmetric catalysts. In particular, two modes of carbonyl activation by chiral secondary amines have led to the discovery of a large number of previously undescribed reactions (Scheme 2): (i) Iminium catalysis (23), wherein lowest unoccupied molecular orbital (LUMO) lowering a...

Direct Enantioselective α‐Allylation of Unfunctionalized Cyclic Ketones with Alkynes through Pd‐Amine Cooperative Catalysis

“…A significant advancement in this challenging endeavor was reported by the MacMillan group, who applied the concept of SOMO catalysis to direct enantioselective α‐allylation of unfunctionalized cyclic ketones (Scheme a) . In this transformation, allylsilanes were employed as the reagent.…”

“…As ignificant advancement in this challenging endeavor was reported by the MacMillan group, who applied the concept of SOMO catalysis to direct enantioselective a-allylation of unfunctionalizedc yclic ketones (Scheme1a). [11] In this transformation, allylsilanes were employed as the reagent. In addition, the Melchiorre group also successfully developed an enantioselective a-alkylation of unfunctionalized cyclic ketones using electron-deficient benzyl bromides or a-bromok etones under photo-organocatalysis.…”

Direkte asymmetrische Alkylierung von Ketonen: noch immer ein unerreichtes Ziel

“…[39] Dabei katalysierte ein Tr ifluorbenzylcinchonidiniumbromid die Umsetzung mit Allyl-, Propargyl-und Benzylhalogeniden als Alkylierungsmitteln (Schema 18 a). [41] Mit dieser Methode wurden ausgezeichnete Enantioselektivitäten erzielt, allerdings war die Anwendbarkeit auf cyclische und heterocyclische Ketone und auf Allylsilane als Alkylierungsmittel begrenzt. [40] MacMillan et al berichteten 2010 über das erste Beispiel unter Verwendung der SOMO-Organokatalyse (SOMO = singly occupied molecular orbital;S chema 19).…”

Organocatalysis

“…17 The group have introduced a method for direct and enantioselective α-allylation of ketones using SOMO catalysis (Schemes 17 and 18). 18 In conjuction with MacMillan, Houk and co-workers have investigated the nature of the intermediates involved in organo-SOMO catalysis of α-arylation of aldehydes. 19 This was due to the fact that both the MacMillan group 20 and Nicolaou group 21 have reported the intramolecular α-arylation of aldehydes, where cyclization of a enamine radical was shown to react ortho to the methoxy group (as in Scheme 19), but 1,3,4-substituted aldehydes were shown to have a different reaction profile, preferring to cyclize to afford para arylated products.…”