The overall goal of this proposed program of research is the development of new tactics and strategies for the synthesis of alkaloid natural products and biologically active nitrogen containing compounds. Within this general context, a number of specific objectives have been established, and these may be divided into methodological studies and efforts directed toward the total syntheses of biologically active, nitrogen-containing natural products. On the methodological front, the principal goals are to: (1) develop new methods for the stereoselective synthesis of functionalized dienes; (2) explore further the utilization of cycloaddition reactions, especially Diels-Alder reactions involving heterodienes or vinylogous imides, for the construction of heterocyclic structural subunits found in alkaloids; and (3) expand the scope and synthetic utility of the inter- and intramolecular reactions of iminium salts with electron-rich nucleophilic partners, especially oxygenated furans. In the arena of total synthesis, we will: (1) continue development of intramolecular hetero Diels-Alder reactions in tandem with biomimetic chemistry for the syntheses of alkaloids of Strychnos, Ajmaline, and Sarpagine families including condylocarpine, akuammicine, strychnine, polyneuridine, quebrachidine and akuammidine; (2) exploit a novel and recently discovered sequence that entails nucleophilic addition to a 3,4-dihydrocarboline iminium salt followed by skeletal reorganization as a key step for the syntheses of indole alkaloids of the Aspidosperma (e.g., vindorosine) and perhaps Strychnos families; (3) design a convergent approach to manzamine A, a complex cytotoxic alkaloid, using a strategy that features an unusual intramolecular [4+2] cycloaddition of a vinylogous imide; and (4) develop a potentially general approach to alkaloids containing butyrolactone subunits using a novel condensation of oxygenated furans with iminium salts and demonstrate the efficacy of such methodology by its application to concise syntheses of the polycyclic Stemona alkaloid croomine and the Ergot alkaloids rugulovasines A and B and lysergic acid. Finally, we intend to prepare reasonable quantities of the targeted compounds and selected intermediates for submission to C. P. Starks, Inc., Eli Lilly, DuPont, Merck and Abbott Laboratories for biological evaluation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM025439-12A2
Application #
3273020
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1979-01-01
Project End
1996-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
12
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
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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