This research program focuses on the development of new synthetic strategies for the total synthesis of biologically active complex alkaloid natural products. Within each total synthesis goal lies the implicit aim of discovering and exploiting new reactions that push the boundaries of chemical synthesis innovation. In this context, new strategies for the total synthesis of several guanidine-containing complex alkaloids will be explored. These classes of targets include the family of anti-HIV/immunomodulating batzelladine alkaloids, the family of anticancer and ion-channel disrupting crambescidin alkaloids, the potent cytotoxin cylindrospermopsin, and the powerful immunosuppressant palau'amine. All of these natural products exhibit significant yet distinct biological responses, yet they are all structurally characterized by at least one guanidine moiety embedded within a complex polycyclic architecture, a synthetic challenge that will be addressed by investigating novel annulation strategies and reactions for nitrogen-heterocycle synthesis. These proposed goals will involve investigation diastereoselective [4+2]-annulation of vinyl carbodiimides with chiral imine and imidate derivatives for dihydropyrimidine and pyrimidine synthesis, as well as other convergent cycloaddition strategies for the construction of fully substituted all-cis cyclopentanes. Successful synthesis of these target molecules will not only lay the foundation of efficient and practical strategies for complex alkaloid synthesis, but also provide access to complex natural products of biological interest and therapeutic potential in a variety of health areas, including small molecule cytotoxic/anticancer, antiviral, and immunomodulating agents, as well as unique heterocyclic constructs that specifically disrupt ion channel function. PROJECT NARRATIVE This research program focuses on the development of new synthetic strategies for the total synthesis of biologically active complex guanidine alkaloid natural products. Successful synthesis of these target molecules will not only lay the foundation of efficient and practical strategies for complex molecule synthesis, but also provide access to natural products of biological interest and therapeutic potential in a variety of health areas, including small molecule cytotoxic/anticancer, antiviral, and immunomodulating agents, as well as unique heterocyclic constructs that specifically disrupt ion channel function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067659-09
Application #
7924605
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Hagan, Ann A
Project Start
2003-04-10
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
9
Fiscal Year
2010
Total Cost
$383,555
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Pla, Daniel; Tan, Derek S; Gin, David Y (2014) 5-(Methylthio)tetrazoles as Versatile Synthons in the Stereoselective Synthesis of Polycyclic Pyrazolines via Photoinduced Intramolecular Nitrile Imine-Alkene 1,3-Dipolar Cycloaddition. Chem Sci 5:2407-2415
Shi, Yuan; Wilmot, Jeremy T; Nordstrøm, Lars Ulrik et al. (2013) Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine. J Am Chem Soc 135:14313-20
Huh, Jun R; Leung, Monica W L; Huang, Pengxiang et al. (2011) Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing ROR?t activity. Nature 472:486-90
Perl, Nicholas R; Ide, Nathan D; Prajapati, Sudeep et al. (2010) Annulation of thioimidates and vinyl carbodiimides to prepare 2-aminopyrimidines, competent nucleophiles for intramolecular alkyne hydroamination. Synthesis of (-)-crambidine. J Am Chem Soc 132:1802-3
Peese, Kevin M; Gin, David Y (2008) Asymmetric synthetic access to the hetisine alkaloids: total synthesis of (+)-nominine. Chemistry 14:1654-65
Eckelbarger, Joseph D; Wilmot, Jeremy T; Epperson, Matthew T et al. (2008) Synthesis of antiproliferative Cephalotaxus esters and their evaluation against several human hematopoietic and solid tumor cell lines: uncovering differential susceptibilities to multidrug resistance. Chemistry 14:4293-306
Carra, Ryan J; Epperson, Matthew T; Gin, David Y (2008) Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids. Tetrahedron 64:3629-3641
Bultman, Michael S; Ma, Jun; Gin, David Y (2008) Synthetic access to the chlorocyclopentane cores of the proposed original and revised structures of palau'amine. Angew Chem Int Ed Engl 47:6821-4
Arnold, Michael A; Day, Kenneth A; Duron, Sergio G et al. (2006) Total synthesis of (+)-batzelladine A and (-)-batzelladine D via [4 + 2]-annulation of vinyl carbodiimides with N-alkyl imines. J Am Chem Soc 128:13255-60
Eckelbarger, Joseph D; Wilmot, Jeremy T; Gin, David Y (2006) Strain-release rearrangement of N-vinyl-2-arylaziridines. Total synthesis of the anti-leukemia alkaloid (-)-deoxyharringtonine. J Am Chem Soc 128:10370-1

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