The overarching objective of this research program is to invent and develop efficient chemical synthesis methods that allow complex polyfunctional molecules to be prepared as single enantiomers in practical fashion. We target structural motifs that are commonly found in molecules of biomedical relevance, yet are difficult, or impossible, to prepare with existing chemical methods. One emphasis of the proposed research is the development of practical chemistry for the asymmetric synthesis of two heterocyclic motifs that are found in numerous biologically active natural products, epidithiodioxopiperazines and tertiary carbinyl heterocyclic amines. The proposed studies will also continue our development of versatile methods for constructing complex polyfunctional molecules containing quaternary carbon stereocenters. The new chemical synthesis methods we develop will be evaluated in the context of the enantioselective total synthesis of structurally complex, biologically active alkaloids, for which no chemical synthesis entry exists. Our total synthesis targets include (a) alkaloids that contain an epidithiodioxopiperazine ring fused to a cyclotryptamine fragment, such as bionectin A, gliocladine A, leptosin D, and verticillin A, (b) the kapakahine alkaloids A and F, and (c) communensin A. We will collaborate in studies to confirm and evaluate the antimalarial properties of kapakahine alkaloids and in broad phenotypic screening of the novel structures prepared in this program of research. In the long term, the availability of the new organic synthesis methods that are developed in this research will facilitate discovery and production of improved drugs for treating medical disorders.

Public Health Relevance

The aim of the proposed research is to develop new chemical transformations that allow biologically active organic molecules to be prepared from inexpensive starting materials by chemical synthesis. This new chemistry will be of value in the discovery and production of new medicines, as well as in molecular-level studies of life processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030859-28
Application #
8019114
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
1982-08-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
28
Fiscal Year
2011
Total Cost
$350,966
Indirect Cost
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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
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
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
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; 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
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
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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