The objectives of this ongoing proposed research are to make creative contributions to the synthesis of complex naturally occurring substances possessing clinically significant biological activity. This grant will continue to develop new stereoselective reactions and the application of this methodology to the asymmetric synthesis of complex polyketide antibiotics and antineoplastic agents. The synthesis targets will include amphinidinol 3, aflastatin 3, (+) peloruside A, salvinorin A, phorbol, and the tetracycline family of antibiotics. An important new approach in the synthesis of polycyclic structures from acyclic precursors has been illustrated in the design of salvinorin A, phorbol, and tetracycline. All of these syntheses begin with bond constructions that are stereochemically regulated by acyclic stereocontrol. The carbon framework is then assembled by a series of intramolecular, transannular processes from medium-ring macrocycles. Along with polynucleotides, peptides, and polysaccharides, polyketides represent the fourth broad family of naturally occurring materials that are assembled from common subunits. In extending the comparison with peptide synthesis, polyketide assembly through complex aldol bond constructions is a far greater challenge that the analogous peptide fragment assembly analogy since up to two new stereocenters are created during the fragment coupling event. Our long term objective in this grant has been the development of all of the methodology to assemble polyketide-derived natural products. This objective includes the development of chiral enolate methodology, the study of remote stereocenters on carbonyl and enolate pi-face selectivities, and the development of predictive models for double stereodifferentiating aldol addition reactions. The goal is to improve reaction design predictability. The polyketide targets are amphidinol A, aflastatin 3, peloruside, and salvinorin A. Chemical synthesis provides the capacity to produce chemotherapeutic agents, and chemical reactions are the irreplaceable tools of the medicinal chemist engaged in the drug discovery process. Advances in chemical reaction technology reduce the interval between the conception of the chemical entity as a potential drug candidate and its synthesis for subsequent biological evaluation. As a consequence, organic synthesis is a critical discipline that continues to have an important impact on the fields of both medicine and biology. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM081546-01
Application #
7300781
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
Project Start
2007-07-05
Project End
2011-05-31
Budget Start
2007-07-05
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$409,310
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Kwan, Eugene E; Scheerer, Jonathan R; Evans, David A (2013) The stereochemical course of intramolecular Michael reactions. J Org Chem 78:175-203
Catino, Arthur J; Sherlock, Alexandra; Shieh, Peyton et al. (2013) Approach to the tricyclic core of the tigliane-daphnane diterpenes. Concerning the utility of transannular aldol additions. Org Lett 15:3330-3
Bonazzi, Simone; Cheng, Bichu; Wzorek, Joseph S et al. (2013) Total synthesis of (-)-nakadomarin A. J Am Chem Soc 135:9338-41
Wzorek, Joseph S; Knopfel, Thomas F; Sapountzis, Ioannis et al. (2012) A macrocyclic approach to tetracycline natural products. Investigation of transannular alkylations and Michael additions. Org Lett 14:5840-3
Kwan, Eugene E; Evans, David A (2010) Intermolecular Michael reactions: a computational investigation. Org Lett 12:5124-7
Evans, David A; Welch, Dennie S; Speed, Alexander W H et al. (2009) An aldol-based synthesis of (+)-peloruside a, a potent microtubule stabilizing agent. J Am Chem Soc 131:3840-1