The purpose of this application is to delve into amino acid problems to which poor or less effective methodologies exist. This proposal describes plans to further develop the utility of the glycine templates developed in our laboratory for the asymmetric synthesis of complex, densely functionalized amino acids and derivatives in optically pure form. The specific targets that have been selected for the upcoming grant cycle have been chosen by the following criteria: (1) the synthetic targets all contain beta-substitution (in some cases, beta,gamma-polysubstitution) in the amino acid side chain; (2) the synthetic targets are biomedically interesting and important; and (3) methodologies to access these types of substances are, in general, lacking in the literature. During the coming grant period, plans are described to develop new synthetic methodologies necessary to achieve the asymmetric total synthesis of the following natural products: (1) nitrone dipolar cycloaddition reactions as applied to the asymmetric total synthesis of cylindrospermopsin; (2) development of novel intramolecular azomethine ylid dipolar cycloaddition reactions for application to the asymmetric total synthesis of palau'amine; (3) diastereoselective aldol and lactone functionalization methods for application to a short, asymmetric total synthesis of quinine featuring a facially selective intramolecular SN2' cyclization reaction; (4) utilization of novel diastereoselective azomethine ylide dipolar cycloaddition strategies for a concise, asymmetric total synthesis of nakadomarin A and the manzamine alkaloids; (5) manipulation of a facially selective intramolecular SN2' cyclization reaction for the asymmetric total synthesis of spiroquinazoline and alantrypinone. A shorter-term goal will be devoted to completion of the asymmetric total synthesis of the proteasome inhibitors TMC-95A/B and synthetic analogs. In each area (except the quinine project), biological studies of synthetic analogs of the biologically active natural products will be undertaken. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068011-02
Application #
6836552
Study Section
Special Emphasis Panel (ZRG1-SSS-B (01))
Program Officer
Schwab, John M
Project Start
2004-01-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$227,137
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Pearson, Aaron D; Williams, Robert M (2014) Synthetic studies towards Zetekitoxin AB: preparation of 4,5-epi-11-hydroxy-saxitoxinol. Tetrahedron 70:7942-7949
Pan, Guojun; Williams, Robert M (2014) Efficient Synthesis of the Cyclopentanone Fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione. Tetrahedron 70:276-279
Welch, Timothy R; Williams, Robert M (2013) Studies on the Biosynthesis of Chetomin: Enantiospecific Synthesis of a Putative, Late-Stage Biosynthetic Intermediate. Tetrahedron 69:770-773
Rafferty, Ryan J; Williams, Robert M (2012) FORMAL SYNTHESIS OF HAPALINDOLE O AND SYNTHETIC EFFORTS TOWARDS HAPALINDOLE K AND AMBIGUINE A. Heterocycles 86:219-231
Schuber, Paul T; Williams, Robert M (2012) SYNTHETIC STUDIES ON MPC1001: A DIPOLAR CYCLOADDITION APPROACH TO THE PYRROLIDINE RING SYSTEM. Heterocycles 84:1193-1207
Rafferty, Ryan J; Williams, Robert M (2012) Total synthesis of hapalindoles J and U. J Org Chem 77:519-24
Schuber Jr, Paul T; Williams, Robert M (2012) Synthetic Studies Towards MPC1001: Preparation of a ?-hydroxyl-Tyrosine Derivative. Tetrahedron Lett 53:380-382
Pan, Guojun; Williams, Robert M (2012) Unified total syntheses of fawcettimine class alkaloids: fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B. J Org Chem 77:4801-11
Williams, Robert M (2011) Natural products synthesis: enabling tools to penetrate Nature's secrets of biogenesis and biomechanism. J Org Chem 76:4221-59
Rafferty, Ryan J; Williams, Robert M (2011) Synthetic Studies on the Ambiguine Family of Alkaloids: Construction of the ABCD Ring System. Tetrahedron Lett 52:2037-2040

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