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Review
. 2017 Aug 1;56(32):9278-9290.
doi: 10.1002/anie.201703079. Epub 2017 Jun 27.

Direct Asymmetric Alkylation of Ketones: Still Unconquered

Rafael Cano  1   2 , Armen Zakarian  3 , Gerard P McGlacken  1   2
Affiliations
Review

Direct Asymmetric Alkylation of Ketones: Still Unconquered

Rafael Cano et al. Angew Chem Int Ed Engl. .

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.

Keywords: asymmetric; ketones; organocatalysis; transition-metal catalysis; α-alkylation.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Unreported direct α-alkylation of ketones.
Figure 2
Figure 2
Complications associated with the asymmetric alkylation of ketones. a) Geometry of enolate; b) Electrophile orbital approach.
Figure 3.
Figure 3.
Discrimination of axial protons by chiral lithium bases.
Figure 4.
Figure 4.
Role of (1 R)-(+)-camphor at the sequential preparation of α- alkylated ketones.
Figure 5.
Figure 5.
Proposed model for asymmetric induction of rhodium-catalyzed allylic alkylation of acyclic α-alkoxy aryl ketones.
Figure 6.
Figure 6.
Proposed model for asymmetric α-allylation of ketones with allylic alcohols.
Scheme 1.
Scheme 1.
Chiral amines used and the asymmetric α-alkylation of cyclic ketones.
Scheme 2.
Scheme 2.
Alkylation of ketones derived from (1 R)-(+)-camphor.
Scheme 3.
Scheme 3.
SAMP/RAMP methodology applied to the a-alkylation of ketones.
Scheme 4.
Scheme 4.
Coltart’s chiral N-amino cyclic carbamate hydrazones methodology.
Scheme 5.
Scheme 5.
Asymmetric α-alkylation of dimethylhydrazones using sparteine as chiral ligand.
Scheme 6.
Scheme 6.
Enantioselective Tsuji allylation reported by Stoltz.
Scheme 7.
Scheme 7.
a) Allylic alkylation of ketones through allyl enol carbonates. b) Decarboxylative allylation of β-ketoesters.
Scheme 8.
Scheme 8.
Pd-catalyzed asymmetric alkylation of ketone enolates.
Scheme 9.
Scheme 9.
Enantioselective alkylation of tributyltin enolates.
Scheme 10.
Scheme 10.
Enantioselective allylic allylation of acylsilanes.
Scheme 11.
Scheme 11.
Palladium-catalyzed enolate alkylation cascade.
Scheme 12.
Scheme 12.
a) Iridium-catalyzed allylic alkylation of β-ketoesters, b) Palladium-catalyzed enantioselective allylic allylation of (trimethylsilyl)- ethyl ester protected enolates.
Scheme 13.
Scheme 13.
Rhodium-catalyzed enantioselective allylic alkylation of acyclic α-alkoxy aryl ketones.
Scheme 14.
Scheme 14.
a) Iridium-catalyzed enantio- and diastereoselective allylation of cyclic ketone enolates, b) iridium-catalyzed enantio- and diastereoselective allylation of a-alkoxy ketones.
Scheme 15.
Scheme 15.
Asymmetric α-allylation of ketones with CO2 and allylic alcohol.
Scheme 16.
Scheme 16.
Ir/Zn dual catalysis for α-allylation of α-hydroxyketones.
Scheme 17.
Scheme 17.
Ru/Pd dual catalysis for a route to 3-allyl-3-aryl oxindoles.
Scheme 18.
Scheme 18.
a) Asymmetric phase-transfer-catalyzed glycolate alkylation; b) Asymmetric phase-transfer-catalyzed alkylation of isoflavones.
Scheme 19.
Scheme 19.
Asymmetric α-alkylation of cyclic ketones via (SOMO) catalysis.
Scheme 20.
Scheme 20.
a) Asymmetric Michael addition of α-substituted cyclo- pentanones to nitroolefins. b) Thiourea-catalyzed enantioselective synthesis of a,α-substituted cyclic ketones. c) Primary amine-catalyzed enantioselective synthesis of a,α-substituted cyclic ketones.
Scheme 21.
Scheme 21.
Asymmetric α-alkylation of cyclic ketones using N-benzylic sulfonamides.
Scheme 22.
Scheme 22.
Asymmetric α-alkylation of ketones by chiral phosphoric acids.
Scheme 23.
Scheme 23.
a) Chiral phosphoric acid-catalyzed addition of cyclic ke tones to enones, b) Asymmetric a-alkylation of a-substituted cyclic ketones with allenamides.
Scheme 24.
Scheme 24.
Phase-transfer catalyzed α-alkylation of 2-arylcyclohexa- nones.
Scheme 25.
Scheme 25.
Asymmetric α-alkylation of β-tetralones and other related cyclic ketones.
Scheme 26.
Scheme 26.
a) Photo-organocatalyzed a-alkylation of cyclic ketones by a chiral primary amine. b) a) Photo-organocatalyzed enantioselective perfluoroalkylation of β-ketoesters.
Scheme 27.
Scheme 27.
α-Photoalkylation of β-ketocarbonyls by primary amine and Ru(bpy)3Cl2 catalysis.
Scheme 28.
Scheme 28.
Enantioselective α-photoalkylation with diazo compounds.
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