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. 2020 Mar 25;142(12):5870-5875.
doi: 10.1021/jacs.0c01324. Epub 2020 Mar 16.

Convergent Catalytic Asymmetric Synthesis of Esters of Chiral Dialkyl Carbinols

Ze-Peng Yang  1 , Gregory C Fu  1
Affiliations

Convergent Catalytic Asymmetric Synthesis of Esters of Chiral Dialkyl Carbinols

Ze-Peng Yang et al. J Am Chem Soc. .

Abstract

Because chiral dialkyl carbinols, as well as their derived esters, are significant as intermediates and end points in fields such as organic, pharmaceutical, and biological chemistry, the development of efficient approaches to their asymmetric synthesis is an important endeavor. In this report, we describe a method for the direct catalytic enantioselective synthesis of such esters, beginning with an alkyl halide (derived from an aldehyde and an acyl bromide), an olefin, and a hydrosilane, catalyzed by nickel, an earth-abundant metal. The method is versatile, tolerating substituents that vary in size and that bear a range of functional groups. We further describe a four-component variant of this process, wherein the alkyl halide is generated in situ, thus obviating the need to isolate either an alkyl electrophile or an alkylmetal, while still effecting an alkyl-alkyl coupling. Finally, we apply our convergent method to the efficient catalytic enantioselective synthesis of three esters that are bioactive themselves or that have been utilized in the synthesis of bioactive compounds.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
(A) Examples of bioactive compounds that include a chiral dialkyl carbinol, free or acylated. (B) Approaches to metal-catalyzed enantioconvergent alkyl–alkyl couplings of racemic electrophiles. (C) This study.
Figure 2.
Figure 2.
Catalytic asymmetric synthesis of an ester of a chiral dialkyl carbinol. (A) Effect of reaction parameters. (B) Comparison with the corresponding Negishi and Suzuki reactions.
Figure 3.
Figure 3.
Catalytic asymmetric synthesis of esters of chiral dialkyl carbinols: Scope. All data are the average of two experiments. Unless otherwise noted, couplings were conducted on a 0.8-mmol scale. a In place of the standard conditions, 2.0 equivalents of (EtO)3SiH and 2.0 equivalents of K3PO4•H2O were used, with i-Pr2O as the solvent. b In place of the standard conditions, a balloonful of propylene was used. c In place of the standard conditions, 5.0 equiv of 1-butene (b.p. 21 °C) was used. d In place of the standard conditions, 2.0 equiv of the olefin was used.
Figure 4.
Figure 4.
Catalytic asymmetric four-component couplings. (A) Initial examples. (B) Preparation of intermediates used in the synthesis of paleic acid and (R)-dodecanolide. (C) One-step syntheses of (S)-heptadecan-7-yl propionate, a component of a sex pheromone for the lichen moth. All data are the average of two experiments.
See this image and copyright information in PMC

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