Strategies for the Synthesis and Use of β-Stereogenic α-Keto Esters

Steward, Kimberly Michelle

Strategies for the Synthesis and Use of β-Stereogenic α-Keto Esters Public Deposited

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March 21, 2019

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Steward, Kimberly Michelle
- Affiliation: College of Arts and Sciences, Department of Chemistry

Abstract

I. Extant Methods for the Preparation of α-Keto Esters An overview of the synthetic methods to prepare α-keto esters is presented, with a particular focus on strategies to incorporate a stereocenter at the β-position. II.Catalytic Nucleophilic Glyoxylation of Aldehydes The synthesis of β-silyloxy α-keto esters via a cyanide catalyzed benzoin-type reaction with silyl glyoxylates and aldehydes is described. Critical to the success of the reaction was identifying Yb(OiPr)?3? and acetone cyanohydrin as a mild source of cyanide to prevent isomerization of the products to the corresponding α-silyloxy β-keto esters. Several secondary transformations add to the utility to the α-keto ester products. Of the methods available to prepare β-hydroxy α-keto acid derivatives, this method provides the most direct route and displays the broadest substrate scope. III.Asymmetric Synthesis of α-Keto Esters via Cu(II)-Catalyzed Aerobic Deacylation of Acetoacetate Alkylation Products A simple and efficient method for the preparation of β-stereogenic α-keto esters is described using a copper(II)-catalyzed aerobic deacylation of substituted acetoacetate esters. The substrates for the title process arise from catalytic, enantioselective conjugate addition and alkylation reactions of acetoacetate esters. The mild conditions do not induce racemization of the incipient enolizable α-keto ester. The reaction is tolerant of a number esters, certain ketones, ketals and nitro groups and establishes synthetic equivalency between acetoacetate esters and the glyoxylate anion synthon. IV.Dynamic Kinetic Resolution of α-Keto Esters via Asymmetric Transfer Hydrogenation The development of the first highly selective dynamic kinetic resolution of β-stereogenic α-keto esters via asymmetric transfer hydrogenation using a newly designed (arene)Ru(monosulfonamide) catalyst is described. For substrates incorporating a diester at the γ-postion, spontaneous lactonization of the nascent α-hydroxyl group onto the pendant ester occurs to provide trisubstituted γ-butyrolactones with complete diastereocontrol. Extension of this method to β-substituted α,δ-diketo esters results in chemoselective dynamic reduction of the α-keto ester providing highly enriched δ-keto α-hydroxy esters.

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