The overall goal of this program of research is to develop new tactics and strategies to synthesize alkaloid natural products and other biologically-active nitrogen containing compounds. Within this context a number of specific objectives have been established, and these may be divided into methodological studies and the total syntheses of biologically active alkaloids and related compounds. On the methodological front, the principal goals are to: (1) examine cycloaddition reactions, especially Diels-Alder reactions involving heterodienes or vinylogous imides, to construct heterocyclic structural subunits found in alkaloids; (2) investigate ring-closing metathesis as a method for forming unsaturated nitrogen heterocycles; (3) expand the scope and synthetic utility of vinylogous Mannich reactions that involve inter- and intramolecular reactions of iminium salts with nucleophilic partners, especially oxygenated furans; and (4) explore 1,2-metallate rearrangements as a novel entry to unsaturated nitrogen compounds. In the arena of total synthesis, the PI is to: (1) apply intramolecular hetero Diels-Alder reactions in tandem with biomimetic chemistry to synthesize complex indole alkaloids of the Strychnos, Ajmaline, and Sarpagine families including the glycine receptor antagonist strychnine, condylocarpine, polyneuridine, quebrachidine and the anesthetic agent akuammidine; (2) complete a convergent asymmetric synthesis of the anticancer agent manzamine A using a strategy that features an intramolecular (4+2) cycloaddition of a vinylogous imide and ring-closing metathesis reactions; and (3) develop a general approach to alkaloids containing butyrolactone and piperidine subunits exploiting novel vinylogous Mannich additions as key constructions and demonstrate the broader efficacy of this strategy by applying it to concise syntheses of Stemona alkaloids including the insecticidal and antitussive agent croomine and the related alkaloid stemoamide, the neuroactive Ergot alkaloid methyl lysergate, the sodium channel activator pumiliotoxin 251 D, and the angiotensin converting enzyme inhibitor A58365A. It is intended to prepare reasonable quantities of the targeted compounds and selected intermediates for submission to C. P. Starks, Inc., Eli Lilly, Merck and Abbott Laboratories for biological evaluation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of Texas Austin
Schools of Arts and Sciences
United States
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Martin, Stephen F (2017) Natural Products and Their Mimics as Targets of Opportunity for Discovery. J Org Chem 82:10757-10794
Cheng, Bo; Sunderhaus, James D; Martin, Stephen F (2015) Applications of Ring Closing Metathesis. Total Synthesis of (±)-Pseudotabersonine. Tetrahedron 71:7323-7331
Bian, Zhiguo; Marvin, Christopher C; Pettersson, Martin et al. (2014) Enantioselective total syntheses of citrinadins A and B. Stereochemical revision of their assigned structures. J Am Chem Soc 136:14184-92
Granger, Brett A; Jewett, Ivan T; Butler, Jeffrey D et al. (2014) Concise total synthesis of (±)-actinophyllic acid. Tetrahedron 70:4094-4104
Hethcox, J Caleb; Shanahan, Charles S; Martin, Stephen F (2013) Total synthesis of (-)-dihydroprotolichesterenic acid via diastereoselective conjugate addition to chiral fumarates. Tetrahedron Lett 54:2074-2076
Granger, Brett A; Jewett, Ivan T; Butler, Jeffrey D et al. (2013) Synthesis of (±)-actinophyllic acid and analogs: applications of cascade reactions and diverted total synthesis. J Am Chem Soc 135:12984-6
Fu, Tsung-Hao; McElroy, William T; Shamszad, Mariam et al. (2013) Studies toward welwitindolinones: formal syntheses of N-methylwelwitindolinone C isothiocyanate and related natural products. Tetrahedron 69:5588-5603
Bian, Zhiguo; Marvin, Christopher C; Martin, Stephen F (2013) Enantioselective total synthesis of (-)-citrinadin A and revision of its stereochemical structure. J Am Chem Soc 135:10886-9
Shanahan, Charles S; Fang, Chao; Paull, Daniel H et al. (2013) Asymmetric Formal Total Synthesis of the Stemofoline Alkaloids: The Evolution, Development and Application of a Catalytic Dipolar Cycloaddition Cascade. Tetrahedron 69:7592-7607
Granger, Brett A; Wang, Zhiqian; Kaneda, Kyosuke et al. (2013) Multicomponent assembly processes for the synthesis of diverse yohimbine and corynanthe alkaloid analogues. ACS Comb Sci 15:379-86

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