The goal of this project is to develop new synthetic methods for the concise synthesis of chiral heterocyclic and carbocyclic compounds. These structures constitute the structural core of a growing number of pharmaceuticals and biologically active molecules but methods for their efficient construction and control of absolute stereochemistry remain limiting steps. We have developed new chemical transformations mediated by N-heterocyclic carbenes (NHCs) that make possible previously unrecognized strategies for the synthesis of lactams, lactones, and cyclopentanes in enantioenriched form. Importantly, these processes precede under mild reaction conditions and can be applied to the synthesis of a broad range of substitution patterns. All of these processes proceed by the catalytic generation of reactive species from alpha-functionalized aldehydes such as enals and alpha-haloaldehydes.
Specific Aims : (1) To develop concise, single-step methods for the enantioselective synthesis of disubstituted gamma-lactones, gamma-lactams, and cyclopentenes by chiral NHC-catalyzed annulations of enals. (2) To significantly expand the scope and applications of our recently developed NHC- catalyzed inverse electron demand Diels-Alder reactions that afford diverse, chiral heterocycles from simple starting materials. (3) To demonstrate the synthetic utility of chiral annulation products through chemo- and diastereoselective transformations including the concise asymmetric syntheses of (-)-chebulic acid and the neuroprotective agent (-)-clausenamide. Significance. The proposed research will provide a uniquely concise and practical entry to a wide variety of highly substituted structures with proven therapuetic potential. This work will also contribute mechanistically novel approaches to the synthesis of chiral small molecules and provide a unique, efficient synthetic strategy not readily implemented with exisiting chemical methods.

Public Health Relevance

Small organic molecules constitute the vast majority of proven therapeutic agents and new drug candidates. Recent efforts in target identification and screening have outpaced chemical methods for the synthesis of the biologically relevant heterocyclic and carbocyclic structures needed for further innovation in small molecule-based drug discovery and development. Our research offers novel, mechanistically unique, and highly efficient methods for the synthesis of these structures from simple starting materials and will contribute to ongoing efforts aimed at the discovery, understanding, and manufacture of new treatments for human diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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University of Pennsylvania
Schools of Arts and Sciences
United States
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Allen, Scott E; Hsieh, Sheng-Ying; Gutierrez, Osvaldo et al. (2014) Concerted amidation of activated esters: reaction path and origins of selectivity in the kinetic resolution of cyclic amines via N-heterocyclic carbenes and hydroxamic acid cocatalyzed acyl transfer. J Am Chem Soc 136:11783-91
Mahatthananchai, Jessada; Bode, Jeffrey W (2012) The effect of the N-mesityl group in NHC-catalyzed reactions. Chem Sci 3:192-197
Allen, Scott E; Mahatthananchai, Jessada; Bode, Jeffrey W et al. (2012) Oxyanion steering and CH-? interactions as key elements in an N-heterocyclic carbene-catalyzed [4 + 2] cycloaddition. J Am Chem Soc 134:12098-103
Mahatthananchai, Jessada; Kaeobamrung, Juthanat; Bode, Jeffrey W (2012) Chiral N-Heterocyclic Carbene Catalyzed Annulations of Enals and Ynals with Stable Enols: A Highly Enantioselective Coates-Claisen Rearrangement. ACS Catal 2:494-503
Lyngvi, Eirik; Bode, Jeffrey W; Schoenebeck, Franziska (2012) A Computational Study of the Origin of Stereoinduction in NHC-Catalyzed Annulation Reactions of *,*-Unsaturated Acyl Azoliums. Chem Sci 3:2346-2350
Chiang, Pei-Chen; Bode, Jeffrey W (2011) On the role of CO2 in NHC-catalyzed oxidation of aldehydes. Org Lett 13:2422-5
Zheng, Pinguan; Gondo, Chenaimwoyo A; Bode, Jeffrey W (2011) Late-stage diversification of chiral N-heterocyclic-carbene precatalysts for enantioselective homoenolate additions. Chem Asian J 6:614-20
Mahatthananchai, Jessada; Zheng, Pinguan; Bode, Jeffrey W (2011) ?,?-Unsaturated acyl azoliums from N-heterocyclic carbene catalyzed reactions: observation and mechanistic investigation. Angew Chem Int Ed Engl 50:1673-7
Vo, Cam-Van T; Mitchell, T Andrew; Bode, Jeffrey W (2011) Expanded substrate scope and improved reactivity of ether-forming cross-coupling reactions of organotrifluoroborates and acetals. J Am Chem Soc 133:14082-9
Kaeobamrung, Juthanat; Mahatthananchai, Jessada; Zheng, Pinguan et al. (2010) An enantioselective Claisen rearrangement catalyzed by N-heterocyclic carbenes. J Am Chem Soc 132:8810-2

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