Direct Asymmetric Alkylation of Ketones: Still Unconquered

Abstract

The alkylation of ketones is taught at basic undergraduate level. In many cases this transformation leads to the formation of a new stereogenic center. However, the apparent simplicity of the transformation is belied by a number of problems. So much so, that a general method for the direct asymmetric alkylation of ketones remains an unmet target. Despite the advancement of organocatalysis and transition-metal catalysis, neither field has provided an adequate solution. Indeed, even use of an efficient and general stoichiometric chiral reagent has yet to be reported. Herein we describe the state-of-the-art in terms of direct alkylation reactions of some carbonyl groups. We outline the limited progress that has been made with ketones, and potential routes towards ultimately achieving a widely applicable methodology for the asymmetric alkylation of ketones.

Highly Versatile β-C(sp3)–H Iodination of Ketones Using a Practical Auxiliary

“…Again, the quaternary centers in these products cannot be formed using enolate alkylation, which prefers the even more acidic and less hindered α -positions. 1 Although halogens at β - or more distal positions should be tolerated as we can obtain di-iodination products from C(sp 3 )–H iodination of mono-iodination products, the halogenated substrates are not compatible with oxime condensation step due to the nucleophilicity of alkoxyamine. Finally, a variety of functional groups at the α -position, including nitriles, esters, TBS-protected hydroxyl, alkenyl, and alkynyl groups, were tolerated ( 2l–r ), exhibiting significantly broader substrate scope than previously reported oxime-directed C(sp 3 )–H functionalizations.…”

“…As shown in Table 2, a variety of alkyl substituted ketones were β -iodinated in good-to-excellent yields ( 2a–d ). Note that the quaternary centers in products 2a–c and 2e–h are inaccessible via classic enolate alkylation methods as alkylation of the α -methyl group is kinetically favored; 1 all of these products were formed in good-to-excellent yields. The bicyclic natural product Fenchone was iodinated with excellent mono-selectivity despite the presence of three α -methyl groups ( 2d ).…”

Photochemical Asymmetric Nickel‐Catalyzed Acyl Cross‐Coupling

“…[19] This required the preparation of racemic DHP radical precursors bearing both 167 m]at108 8Cfor 48 hona0.1 mmol scale using 2equiv of 1a and 1equiv of lutidine as base under illumination by asingle high-power(HP) LED (l max = 405 nm) with an irradiance of 75 mWcm À2 . [19] This required the preparation of racemic DHP radical precursors bearing both 167 m]at108 8Cfor 48 hona0.1 mmol scale using 2equiv of 1a and 1equiv of lutidine as base under illumination by asingle high-power(HP) LED (l max = 405 nm) with an irradiance of 75 mWcm À2 .…”

Synthese α‐chiraler Ketone und chiraler Alkane durch eine radikalisch/ionische Kreuzungsreaktion von Vinyl‐Bor‐At‐Komplexen

“…Obwohl in den letzten Jahrzehnten viele Vorschriften fürA uxiliar-kontrollierte asymmetrische Enolatreaktionen entwickelt wurden, [9] ist die direkte asymmetrische Alkylierung von Ketonen noch immer hçchst anspruchsvoll [10] und erfordert meistens die Gegenwart eines Übergangsmetallkatalysators. Dieses chirale Strukturmotiv ist in Naturstoffen weit verbreitet, wodurch die Entwicklung neuartiger Syntheserouten zur Herstellung a,a-disubstituierter Ketone große Bedeutung erfährt.…”