The objective of this research program is to develop efficient chemical methods for the preparation of complex organic molecules. Our ultimate goal is to develop sufficiently versatile and efficient synthesis tools so that any desired molecule can be synthesized in a practical manner. If the aims of this application are achieved, biomedical researchers will have new tools for preparing and modifying the structure of stereochemically complex, polycyclic organic molecules. In the long term, the availability of the new organic synthesis methodology we are developing will facilitate discovered and production of improved chemical agents for treating medical disorders. The major focus of this project are two classes of pharmacologically significant molecules whose chemical synthesis is beyond the capability of existing methods: complex cardenolides and polyindoline alkaloids.
Specific aims for the project are: (1) Develop methodology for enantioselective synthesis of polyindoline alkaloids; specific targets include- the octaazadodecacyclic alkaloids psycholeine and quadrigemine, which are structurally novel stimulants of growth hormone (GH) release; the trispyrroloindoline alkaloid hodgkinsine; representative chiral 3a- bispyrroloindoline; and more complex, fungal-derived 3-a bispyrroloindoline alkaloids which display a variety of pharmacological activities including anti-cancer and antagonism of substance P, neurokinin 1 and cholecystokinin type B receptors. (2) Prepare the powerful Na+/K+-ATPase-inhibitor ouabain; if analogs or stereoisomers of ouabain are confirmed to be endogenous regulators of this enzyme expand our cardenolide program to prepare these agents as well. (3) Invent/develop new ways to control relative and absolute stereochemistry in constructing vicinal quaternary carbon centers. (4) Further develop our bis-cyclization route to morphine. (5) Collaborate in pharmacological evaluation of our synthesis targets and selected analogs. The proposed studies are founded on recent discoveries in our laboratories on controlling stereochemistry in the synthesis of vicinal quaternary carbon centers and the unique utility of intra molecular Heck reactions to fashion sterically congested carbon-carbon bonds.

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 California Irvine
Schools of Arts and Sciences
United States
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Büschleb, Martin; Dorich, Stéphane; Hanessian, Stephen et al. (2016) Synthetic Strategies toward Natural Products Containing Contiguous Stereogenic Quaternary Carbon Atoms. Angew Chem Int Ed Engl 55:4156-86
Canham, Stephen M; Hafensteiner, Benjamin D; Lebsack, Alec D et al. (2015) Stereocontrolled enantioselective total synthesis of the [2+2] quadrigemine alkaloids. Tetrahedron 71:6424-6436
Baumann, Marcus; Dieskau, André P; Loertscher, Brad M et al. (2015) Tricyclic Analogues of Epidithiodioxopiperazine Alkaloids with Promising In Vitro and In Vivo Antitumor Activity. Chem Sci 6:4451-4457
Quasdorf, Kyle W; Overman, Larry E (2014) Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516:181-91
Jabri, Salman Y; Overman, Larry E (2013) Enantioselective total syntheses of plectosphaeroic acids B and C. J Org Chem 78:8766-88
DeLorbe, John E; Horne, David; Jove, Richard et al. (2013) General approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors: enantioselective total syntheses of (+)- and (-)-gliocladine C, (+)-leptosin D, (+)-T988C, (+)-bionectin A, and (+)-gliocladin A. J Am Chem Soc 135:4117-28
Jabri, Salman Y; Overman, Larry E (2013) Enantioselective total synthesis of plectosphaeroic acid B. J Am Chem Soc 135:4231-4
Cannon, Jeffrey S; Overman, Larry E (2012) Is there no end to the total syntheses of strychnine? Lessons learned in strategy and tactics in total synthesis. Angew Chem Int Ed Engl 51:4288-311
Cannon, Jeffrey S; Frederich, James H; Overman, Larry E (2012) Palladacyclic imidazoline-naphthalene complexes: synthesis and catalytic performance in Pd(II)-catalyzed enantioselective reactions of allylic trichloroacetimidates. J Org Chem 77:1939-51
DeLorbe, John E; Jabri, Salman Y; Mennen, Steven M et al. (2011) Enantioselective total synthesis of (+)-gliocladine C: convergent construction of cyclotryptamine-fused polyoxopiperazines and a general approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors. J Am Chem Soc 133:6549-52

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