One of the main objectives of this research program is the development of general strategies for the syntheses of natural products, especially alkaloids, that exhibit biological activity. An important feature common to the various synthetic approaches outlined herein is the pivotal role played by an intramolecular Diels-Alder reaction to assemble the essential elements of the molecular architecture. In each of these [4+2] cycloadditions, a heteroatom such as nitrogen and/or oxygen is present in the dienic moiety or in the chain linking the diene with the dienophile so that fused nitrogen and oxygen heterocyclic systems are accessible. Other functionality may be incorporated on the trienic backbone to facilitate refunctionalization as required to complete the total syntheses. In some instances, the subsequent transformations of the initial cycloadducts into the targets will be patterned after the known biosynthetic pathways. Where possible the feasibility of executing an asymmetric synthesis will be examined. The natural products which shall be considered the primary synthetic targets of these investigations include: dendrobine, a novel sesquiterpenoid alkaloid having antipyretic and hypotensive activity; morphine, a potent analgesic agent; yohimbine, an alleged aphrodisiac, together with related alkaloids as 19-dehydro-Beta-yohimbine; the heteroyohimbine alkaloid ajmalicine, a useful therapeutic agent for treatment of certain cardiovascular diseases; the secoyohimbine alkaloid geissoschizzine, an important biosynthetic precursor of numerous indole alkaloids; the Strychnos alkaloids stemmadenine, akuammicine, condylocarpine, and strychnine; the Ajmaline and Sarpagine alkaloids quebrachidine and akuammidine; the iridoid monoterpenes loganin and secologanin, which are important biosynthetic precursors of the indole alkaloids and the iridoids, together with the related monoterpenoid alkaloid bakankoside; and lysergic acid, whose derivatives exhibit a fascinating spectrum of pharmocodynamic actions. Selected synthetic intermediates will be screened for biological activity by The Upjohn Company, McNeil Laboratories, Chevron, and Shell Development Laboratories.

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National Institute of General Medical Sciences (NIGMS)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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University of Texas Austin
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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
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
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

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