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. 2018 Feb 14;140(6):1998-2001.
doi: 10.1021/jacs.7b12185. Epub 2018 Feb 5.

Biomimetic Desymmetrization of a Carboxylic Acid

Matthew T Knowe  1 , Michael W Danneman  1 , Sarah Sun  1 , Maren Pink  2 , Jeffrey N Johnston  1
Affiliations

Biomimetic Desymmetrization of a Carboxylic Acid

Matthew T Knowe et al. J Am Chem Soc. .

Abstract

The enantioselective desymmetrization of carboxylic acids by chiral Brønsted base catalysis is reported, leading to bridged bicyclic lactones with up to 94% ee. Crystallographic analysis of a substrate-catalyst complex suggests an origin of stereocontrol, reminiscent of functional Brønsted bases in biological settings, and enabled reaction optimization. The products contain an all-carbon quaternary stereocenter and can be derivatized to functionalized cyclopentanes.

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Conflict of interest statement

Funding Sources

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Hydrogen Bond-Driven Activation A) double hydrogen bond donation to one oxygen, and Brønsted base activation of the other, leading to enhancement of an oxygen’s nucleophilicity in dethiobiotin synthetase; B) model for simultaneous electrophile and carboxylic acid activation by a chiral phosphoric acid (proposed); C) carboxyl oxygen desymmetrization using an array of three hydrogen bonds (proposed). *For Etter graph set nomenclature see ref. .
Figure 2
Figure 2
Prior approaches to alkene functionalization (I, II) and this approach (III) requiring simultaneous control of nucleophilic carboxyl oxygen and carbon-CO2H bond conformation by a chiral base (*B:).
Figure 3
Figure 3
Key features of the X-ray cocrystal structure of 1a·(R,R)-3a
Scheme 1
Scheme 1
Conversions of Lactone 2aa
See this image and copyright information in PMC

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