Small molecule-based drugs continue to provide the foundation for developing therapeutic strategies for treating of most human illnesses. A substantial portion of drug development efforts within medicinal chemistry is, therefore, devoted to the synthesis of compounds for screening as drug candidates. Whether drug development efforts are directed toward specific bioactive targets or the synthesis of a library of selected derivatives, success in these endeavors is critically dependent on concurrent developments in organic synthesis methodology that allows the efficient and economical preparation of the targeted materials. Recognizing the synergism existing between chemistry and industrial drug development, this proposal details the development of new organic reaction methodology designed to access biologically active organic compounds efficiently and economically. Toward this goal, we will develop the reaction technology necessary to realize a general strategy for the catalytic synthesis of polypropionate-derived natural products. The composition of polyketides as repeating acetic or propionic acid units makes a modular synthesis strategy exploiting iterative installation of homologous monomer units an attractive synthesis strategy. Thus, we will develop a modular strategy for the catalytic asymmetric construction of stereochemically diverse polypropionate networks. The relevance of these reaction development activities to medicinal research and human health issues is exemplified in a de novo enantioselective total synthesis of the highly selective apoptosis regulator apoptolidin C. Heterocyclic small molecules are among the most ubiquitous features of new drug hits, important lead compounds, and commercially available pharmaceuticals. The development of a novel family of [4+2] and [2+2] cycloadditions for the asymmetric synthesis of highly substituted piperidine and 2-lactam derivatives, respectively, is inspired by the central role heterocycles play in pharmaceutical drug development efforts. Furthermore, efforts to develop catalytic asymmetric variants of these cycloadditions are intended to maximize the utility of these reactions in industrial medicinal and process chemical research.4.4.7. PROJECT NARRATIVE Small molecule-based drugs continue to provide the foundation for developing therapeutic strategies for treating of most human illnesses. A substantial portion of drug development efforts within medicinal chemistry is, therefore, devoted to the synthesis of compounds for screening as drug candidates. Based on these considerations, we will develop new reaction technologies for accelerating the synthesis of small molecule chemotherapeutic agents and that enable new strategies for target- and diversity-oriented synthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063151-06
Application #
7609119
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Schwab, John M
Project Start
2001-09-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
6
Fiscal Year
2009
Total Cost
$280,379
Indirect Cost
Name
University of Pittsburgh
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Vargo, Thomas R; Hale, James S; Nelson, Scott G (2010) Catalytic asymmetric aldol equivalents in the enantioselective synthesis of the apoptolidin C aglycone. Angew Chem Int Ed Engl 49:8678-81
Chandra, Binita; Fu, Dezhi; Nelson, Scott G (2010) Catalytic asymmetric synthesis of complex polypropionates: Lewis base catalyzed aldol equivalents in the synthesis of erythronolide B. Angew Chem Int Ed Engl 49:2591-4
Vogt, Andreas; McPherson, Peter A; Shen, Xiaoqiang et al. (2009) High-content analysis of cancer-cell-specific apoptosis and inhibition of in vivo angiogenesis by synthetic (-)-pironetin and analogs. Chem Biol Drug Des 74:358-68
Sarkar, Nihar; Banerjee, Abhisek; Nelson, Scott G (2008) [4 + 2] cycloadditions of N-alkenyl iminium ions: structurally complex heterocycles from a three-component Diels-Alder reaction sequence. J Am Chem Soc 130:9222-3
Liu, Zuosheng; Wasmuth, Andrew S; Nelson, Scott G (2006) Au(I)-catalyzed annulation of enantioenriched allenes in the enantioselective total synthesis of (-)-rhazinilam. J Am Chem Soc 128:10352-3
Gopalarathnam, Apsara; Nelson, Scott G (2006) Amphidinolide B: asymmetric synthesis of a C7-C20 synthon. Org Lett 8:7-10
Shen, Xiaoqiang; Wasmuth, Andrew S; Zhao, Junping et al. (2006) Catalytic asymmetric assembly of stereodefined propionate units: an enantioselective total synthesis of (-)-pironetin. J Am Chem Soc 128:7438-9
Nelson, Scott G; Zhu, Cheng; Shen, Xiaoqiang (2004) Catalytic asymmetric acyl halide-aldehyde cyclocondensation reactions of substituted ketenes. J Am Chem Soc 126:14-5
Zhu, Cheng; Shen, Xiaoqiang; Nelson, Scott G (2004) Cinchona alkaloid-lewis acid catalyst systems for enantioselective ketene-aldehyde cycloadditions. J Am Chem Soc 126:5352-3