A significant obstacle to the creation of the next generation of small molecule therapeutics is the lack of general and efficient methods for accessing certain stereochemically dense structures that contain functionality important for bioactivity. This project seeks to provide simple access to a range of new functionalized small molecule building blocks based on the implementation of new reactions. The proposal focuses on new chemistry of D-keto esters and their derivatives. D-Keto acids occupy a central role in biology, for example in the biosynthesis of amino acids, but are underutilized in organic synthesis. The enantioselective reduction of racemic E-keto esters is the archetypal dynamic kinetic resolution and is performed on ton scale annually. In stark contrast, the complementary dynamic reduction of racemic D-keto esters is unknown, despite the enormous potential of this method for the creation of bioactive natural products and medicinal agents. We will develop a broad range of new transformations of racemic substrates that undergo catalyst-mediated deracemization to provide enantiomerically enriched, value-added products. Targeted product structures include D-hydroxy-E-amino acids, D,E-diamino acids, unnatural D-amino acids, and fully substituted glycolates. Access to these compounds will be enabled via new dynamic kinetic resolutions of appropriately configured racemic D-keto esters and D-hydroxy phosphonoacetates. The specific goals of this research proposal are to (i) develop dynamic kinetic resolutions (DKRs) of D-keto esters and their derivatives through the development of novel hydrogenation catalysts;(ii) implement new carbon-carbon bond constructions by using DKRs of hydroxyphosphonates;(iii) develop useful new biomimetic dynamic kinetic transaminations for the green preparation of unnatural D- amino acids.

Public Health Relevance

The reactions that are targeted in this study have the capacity to deliver functional group-rich compounds that will be immediately useful for preparation of a range of chiral small molecule building blocks. The proposal seeks to provide those in the biomedical community straightforward access to new families of molecules that will be useful for a range of applications.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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Bartlett, Samuel L; Keiter, Kimberly M; Johnson, Jeffrey S (2017) Synthesis of Complex Tertiary Glycolates by Enantioconvergent Arylation of Stereochemically Labile ?-Keto Esters. J Am Chem Soc 139:3911-3916
Bartlett, Samuel L; Johnson, Jeffrey S (2017) Synthesis of Complex Glycolates by Enantioconvergent Addition Reactions. Acc Chem Res 50:2284-2296
Horwitz, Matthew A; Zavesky, Blane P; Martinez-Alvarado, Jesus I et al. (2016) Asymmetric Organocatalytic Reductive Coupling Reactions between Benzylidene Pyruvates and Aldehydes. Org Lett 18:36-9
Goodman, C Guy; Johnson, Jeffrey S (2015) Asymmetric Synthesis of ?-Amino Amides by Catalytic Enantioconvergent 2-Aza-Cope Rearrangement. J Am Chem Soc 137:14574-7
Horwitz, Matthew A; Tanaka, Naoya; Yokosaka, Takuya et al. (2015) Enantioselective reductive multicomponent coupling reactions between isatins and aldehydes. Chem Sci 6:6086-6090
Goodman, C Guy; Walker, Morgan M; Johnson, Jeffrey S (2015) Enantioconvergent synthesis of functionalized ?-butyrolactones via (3 + 2)-annulation. J Am Chem Soc 137:122-5
Goodman, C Guy; Johnson, Jeffrey S (2014) Dynamic kinetic asymmetric cross-benzoin additions of ?-stereogenic ?-keto esters. J Am Chem Soc 136:14698-701
Corbett, Michael T; Xu, Qihai; Johnson, Jeffrey S (2014) Trisubstituted 2-trifluoromethyl pyrrolidines via catalytic asymmetric Michael addition/reductive cyclization. Org Lett 16:2362-5