This program has as its goal the synthesis of structurally and biologically interesting natural products through creative application of asymmetric catalytic methodologies. Targets of varying structural and stereochemical complexity are selected to both illustrate and challenge recently discovered methods for enantioselective synthesis, and to inspire development of new catalytic reactions. Bipinnatin I (1) is a recently discovered member of the cembrane diterpenoids and a promising cytotoxic agent. This target has a densely functionalized 14-membered carbocyclic structure, and presents an outstanding platform for the application of new synthetic methodologies. We propose to apply novel butenolide methodology and inverse demand hetero-Diels Alder chemistry, along with more established asymmetric epoxidation reactions to introduce the majority of the stereocenters present in 1. Completion of the synthesis will rely on substrate-directed diastereoselective transformations for the efficient generation of the remaining stereocenters, including the key macrocyclization event. Of the nine stereocenters in the anti-cancer agent peloruside A (2), we plan to introduce four through innovative ring-openings of enantiopure terminal epoxides. All but one of the remaining stereocenters will then be established by extending known catalytic, enantioselective methods to catalyst-controlled diastereoselective contexts. Colombiasin (3) and elisapterosin B are complex tetracyclic marine natural products incorporating two contiguous all carbon-stereogenic centers. We propose concise syntheses through application of asymmetric catalytic reactions discovered specifically for these targets to generate bicyclic quinone intermediates, followed by late stage intramolecular cycloaddition reactions. We propose to accomplish the first asymmetric catalytic synthesis of quinine (4), taking advantage of recently discovered asymmetric Michael addition and epoxidation methodologies to access this classic target in a concise and selective manner.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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Harvard University
Schools of Arts and Sciences
United States
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Rajapaksa, Naomi S; McGowan, Meredeth A; Rienzo, Matthew et al. (2013) Enantioselective total synthesis of (+)-reserpine. Org Lett 15:706-9
McGowan, Meredeth A; Stevenson, Christian P; Schiffler, Matthew A et al. (2010) An enantioselective total synthesis of (+)-peloruside A. Angew Chem Int Ed Engl 49:6147-50
Groll, Michael; Balskus, Emily P; Jacobsen, Eric N (2008) Structural analysis of spiro beta-lactone proteasome inhibitors. J Am Chem Soc 130:14981-3
Grachan, Melissa L; Tudge, Matthew T; Jacobsen, Eric N (2008) Enantioselective catalytic carbonyl-ene cyclization reactions. Angew Chem Int Ed Engl 47:1469-72
Mergott, Dustin J; Zuend, Stephan J; Jacobsen, Eric N (2008) Catalytic asymmetric total synthesis of (+)-yohimbine. Org Lett 10:745-8
Balskus, Emily P; Jacobsen, Eric N (2007) Asymmetric catalysis of the transannular Diels-Alder reaction. Science 317:1736-40
Balskus, Emily P; Jacobsen, Eric N (2006) Alpha,beta-unsaturated beta-silyl imide substrates for catalytic, enantioselective conjugate additions: a total synthesis of (+)-lactacystin and the discovery of a new proteasome inhibitor. J Am Chem Soc 128:6810-2
Boezio, Alessandro A; Jarvo, Elizabeth R; Lawrence, Brian M et al. (2005) Efficient total syntheses of (-)-colombiasin A and (-)-elisapterosin B: application of the Cr-catalyzed asymmetric quinone Diels-Alder reaction. Angew Chem Int Ed Engl 44:6046-50
Jarvo, Elizabeth R; Lawrence, Brian M; Jacobsen, Eric N (2005) Highly enantio- and regioselective quinone Diels-Alder reactions catalyzed by a tridentate [(Schiff Base)Cr(III)] complex. Angew Chem Int Ed Engl 44:6043-6
Raheem, Izzat T; Goodman, Steven N; Jacobsen, Eric N (2004) Catalytic asymmetric total syntheses of quinine and quinidine. J Am Chem Soc 126:706-7

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