The primary objective of this research program is to continue to develop a combination of novel synthetic methods and new strategies for the synthesis of bioactive heterocycles and alkaloid natural products. Emphasis will be placed upon producing and refining methodology having potentially broad applicability which will be of practical value to both organic and medicinal chemists involved in synthesis of bioactive compounds. In addition, studies will be conducted on target oriented total syntheses of a number of structurally unique and complex nitrogen-containing natural products. Goals involve completing ongoing enantioselective total syntheses of the cytotoxic Lycopodium alkaloid (+)-lyconadin A and the cytotoxic marine alkaloid (-)- haouamine A, which are currently well advanced. Enantioselective total syntheses of the structurally unique cytotoxic marine natural products perophoramidine and the communesins will also be completed using asymmetric intramolecular Heck reactions or tandem Heck reactions/carbonylations as key strategic steps. Studies will be conducted on the use of intramolecular Michael additions of vinylnitroso compounds in enantioselective total syntheses of the core of the stemofoline alkaloids, as well as the unique indole alkaloid actinophyllic acid, a potent inhibitor of the enzyme carboxypeptidase U. Intermolecular conjugate additions of carbon nucleophiles to vinylnitroso compounds will constitute key steps in total syntheses of the vallesamine class of indole alkaloids including (Z)-vallesamine, angustilobine A and angustilodine. New synthetic methodology involving inter- and intramolecular conjugate additions to vinylnitroso compounds will be explored in order to generate quaternary carbon centers as well as spirocycles bearing quaternary centers. Finally, methodology will be investigated for effecting catalytic enantioselective conjugate additions of vinylnitroso compounds.

Public Health Relevance

The primary objective of this research program is to develop a combination of novel synthetic methods and new strategies for the synthesis of bioactive heterocycles and alkaloid natural products. Emphasis will be placed upon producing and refining methodology having potentially broad applicability which will be of practical value to both organic and medicinal chemists involved in synthesis of chemotherapeutic agents and other bioactive compounds. In addition, studies will be conducted on total synthesis of a number of structurally unique and complex nitrogen-containing natural products.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
High Priority, Short Term Project Award (R56)
Project #
9R56GM087733-26A1
Application #
7885895
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
Project Start
2009-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2011-07-31
Support Year
26
Fiscal Year
2009
Total Cost
$317,449
Indirect Cost
Name
Pennsylvania State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Feng, Yiqing; Majireck, Max M; Weinreb, Steven M (2014) Total syntheses of the monoterpene indole alkaloids (±)-alstilobanine A and E and (±)-angustilodine. J Org Chem 79:7-24
Feng, Yiqing; Majireck, Max M; Weinreb, Steven M (2012) Total synthesis of the unusual monoterpenoid indole alkaloid (±)-alstilobanine A. Angew Chem Int Ed Engl 51:12846-9
Sengupta, Ritobroto; Witek, Jason A; Weinreb, Steven M (2011) Stereochemical investigation of conjugate additions of carbon- and heteronucleophiles to ring-substituted nitrosocyclohexenes. Tetrahedron 67:8229-8234
Sacher, Joshua R; Weinreb, Steven M (2011) Exploratory studies towards a total synthesis of the unusual bridged tetracyclic Lycopodium alkaloid lycopladine H. Tetrahedron 67:10203-10207
Kumar, Praveen; Li, Puhui; Korboukh, Ilia et al. (2011) Further studies of intramolecular Michael reactions of nitrosoalkenes for construction of functionalized bridged ring systems. J Org Chem 76:2094-101
Witek, Jason A; Weinreb, Steven M (2011) Investigation of the stereochemistry of intermolecular conjugate additions of nucleophiles to acyclic nitrosoalkenes. Org Lett 13:1258-60
Seo, Jae Hong; Liu, Peng; Weinreb, Steven M (2010) Evolution of a strategy for total synthesis of the marine fungal alkaloid (+/-)-communesin F. J Org Chem 75:2667-80
Li, Puhui; Majireck, Max M; Witek, Jason A et al. (2010) Efficient methodology for alkylation of vinylnitroso compounds with carbon nucleophiles. Tetrahedron Lett 51:2032-2035
Majireck, Max M; Witek, Jason A; Weinreb, Steven M (2010) An expedient reductive method for conversion of ketoximes to the corresponding carbonyl compounds. Tetrahedron Lett 51:3555-3557