Natural products which contain chiral alpha-branched amine substructures, and their unnatural analogs available only through synthesis, are critically important for medical research. For example, tubulysins are newly discovered anticancer agents with unusual chemical structures and extraordinary potency, and therefore represent a new lead in the search for novel experimental synthetic drugs for chemotherapy. In the specific aims proposed, amine-containing natural products will be synthesized as the first tests of newly developed asymmetric carbon-carbon bond construction methodology in complex molecule synthesis. Novel asymmetric free radical addition, tandem cyclization, hybrid radical-ionic annulation, and allylsilane addition reactions of chiral hydrazones will be used. Synthesis targets include tubulysins (picomolar antimitotic agents), dysiherbaine (non-NMDA glutamate receptor agonist), azasugars (glycosidase inhibitors), quinine (antimalarial agent), and lasubine II (subunit of bioactive quinolizidines). Success in the proposed program has potential to increase overall efficiency in syntheses of medicinally important compounds, a broad and general contribution to the science of organic chemistry which provides critical enabling technology for health sciences research. The projects also provide excellent training to prepare new researchers for productive careers in health-related fields. In the long term, these endeavors will advance the art and science of synthetic organic chemistry toward the ideal of efficiency, a long-term goal which remains mostly inaccessible in syntheses of complex natural products.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067187-02
Application #
6622970
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2002-05-01
Project End
2007-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$265,125
Indirect Cost
Name
University of Vermont & St Agric College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Friestad, Gregory K; Banerjee, Koushik; MariƩ, Jean-Charles et al. (2016) Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog. J Antibiot (Tokyo) 69:294-8
Friestad, Gregory K (2014) Control of asymmetry in the radical addition approach to chiral amine synthesis. Top Curr Chem 343:1-32
Friestad, Gregory K (2012) Radical additions to chiral hydrazones: stereoselectivity and functional group compatibility. Top Curr Chem 320:61-91
Friestad, Gregory K; Ji, An; Baltrusaitis, Jonas et al. (2012) Scope of stereoselective Mn-mediated radical addition to chiral hydrazones and application in a formal synthesis of quinine. J Org Chem 77:3159-80
Friestad, Gregory K; Ji, An; Korapala, Chandra Sekhar et al. (2011) Intermolecular radical addition to N-acylhydrazones as a stereocontrol strategy for alkaloid synthesis: formal synthesis of quinine. Org Biomol Chem 9:4039-43
Friestad, Gregory K; Mathies, Alex K (2007) Effects of alpha-Alkoxy Substitution and Conformational Constraints on 6-exo Radical Cyclizations of Hydrazones via Reversible Thiyl and Stannyl Additions. Tetrahedron 63:9373-9381
Korapala, Chandra Sekhar; Qin, Jun; Friestad, Gregory K (2007) Quinine synthesis studies: a radical-ionic annulation via Mn-mediated addition to chiral N-acylhydrazones. Org Lett 9:4243-6
Friestad, Gregory K; Korapala, Chandra Sekhar; Ding, Hui (2006) Dual activation in asymmetric allylsilane addition to chiral N-acylhydrazones: method development, mechanistic studies, and elaboration of homoallylic amine adducts. J Org Chem 71:281-9
Friestad, Gregory K; Marie, Jean-Charles; Deveau, Amy M (2004) Stereoselective Mn-mediated coupling of functionalized iodides and hydrazones: a synthetic entry to the tubulysin gamma-amino acids. Org Lett 6:3249-52
Ding, Hui; Friestad, Gregory K (2004) Trifluoroacetyl-activated nitrogen-nitrogen bond cleavage of hydrazines by samarium(II) iodide. Org Lett 6:637-40