The overarching objective of this research is to develop new synthetic organic methodology that will provide efficient ways to prepare structurally-complex biomedically-relevant molecular scaffolds from simple starting materials. Polycyclic nitrogen containing heterocycles and medium or large ring systems are structural motifs that are ubiquitous in medicines and biologically active compounds. However, these structural motifs can be challenging to prepare, which can limit their use in biomedical studies. New methods to prepare these motifs would benefit biomedical research by providing synthetic routes to important compounds. Our proposed research is based on our recent discovery of a novel ring fragmentation that provides tethered aldehyde ynone products in high yield. Our central hypothesis is that this ring fragmentation will provide us with a unique and efficient way to prepare both polycyclic nitrogen containing heterocycles and medium or large ring systems. These synthetic methods will be directly applicable to the synthesis of biologically active natural products and we propose to prepare several natural products over the course of this grant period.
The specific aims for this proposal are to study the fragmentation of fused bicyclic ?-silyloxy-?-hydroxy-?-diazo carbonyl compounds in which the ring fusion bond breaks as a way to prepare medium and large sized cyclic ynones and cyclic ynoates. To apply the ring fragmentation of fused bicyclic ?-diazo esters to the synthesis of (-)-phoracantholide I, (-)-diplodialide C, and the kinase inhibitor resorcylic macrolide L-783,277. To further develop the use of tethered aldehyde ynoate fragmentation products as substrates for intramolecular 1,3-dipolar cycloaddition reactions in order to prepare polycyclic 2,5-dihydropyrroles. To apply the ring fragmentation / 1,3-dipolar cycloaddition sequence to concise syntheses of the aeruginosin alkaloid core (choi), (-)-mesembrine, demissidine and (+)-aspidospermine.

Public Health Relevance

The overarching objective of this research is to develop new synthetic organic methodology to efficiently prepare structurally-complex biomedically-relevant molecular scaffolds from simple starting materials. Advances in biomedical research depend to a great extent on chemists'abilities to prepare structurally-complex molecules and our research will provide new tools to efficiently prepare polycyclic heterocycles and macrocycles, which in turn will facilitate the use of these compounds in biomedical research and could lead to the discovery of new and improved medicinal agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM092870-04
Application #
8444688
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2010-04-15
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$258,804
Indirect Cost
$86,841
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
Jabre, Nitinkumar D; Watanabe, Teruki; Brewer, Matthias (2014) Formal and total synthesis of (±)-cycloclavine. Tetrahedron Lett 56:197-199
Bayir, Ali; Brewer, Matthias (2014) Fragmentation of bicyclic ?-silyloxy-?-hydroxy-?-diazolactones as an approach to ynolides. J Org Chem 79:6037-46
Zhang, Zhe; Giampa, Geoffrey M; Draghici, Cristian et al. (2013) Synthesis of demissidine by a ring fragmentation 1,3-dipolar cycloaddition approach. Org Lett 15:2100-3
Tsvetkov, Nikolay P; Bayir, Ali; Schneider, Samuel et al. (2012) A ring fragmentation approach to medium-sized cyclic 2-alkynones. Org Lett 14:264-7