Rapid and reliable access to synthetically-derived chemical structures plays an essential role in many aspects of biomedical research. While advances in complex molecule synthesis have illustrated that a remarkable range of structures can be prepared, the underlying difficulties of potential synthetic approaches often prevent interesting chemical structures from being selected for study. The underlying objective of this proposal is to provide fundamentally new entries to (i) simple chemical substructures that serve as subunits or precursors of many bioactive natural products and other complex structures, and (ii) complex carbohydrate- containing structures of the type that are well known to modulate the bioactivity of chemical entities, but that are often exceptionally challenging to prepare efficiently by existing methods. The first specific aim focuses on developing a mechanistically-driven approach for discovery of highly regioselective and enantioselective reductive coupling procedures. The expected impact of solving challenges in the regio- and enantioselective reductive union of aldehydes and alkynes will be the creation of a process that becomes widely adopted by synthetic chemists. This outcome will be broadly significant since allylic alcohols are an integral feature in many bioactive compounds and serve as versatile building blocks for a wide range of complexity-building and diastereoselective or enantioselective transformations. Furthermore, developing a fundamental understanding of the origin of regiocontrol in the catalytic operation will facilitate related advances in many other reactions that require regioselectivity in a catalytic insertion process. The second specific aim focuses on development of a suite of orthogonal catalytic processes for chemoselective glycosylation of complex molecules. The expected impact of our efforts to develop chemical methods for site-selective glycosylation will be that the speed, efficiency, and selectivity with which complex glycosylated structures may be obtained will be significantly improved. This outcome will allow the rapid preparation of either a specific target molecule or small collections of unnatural or natural product-derived glycosylated structures to examine as medicinal chemistry leads or probe molecules for biochemical studies. The approach represents a merger of two distinct fields: catalytic reductive coupling technology and carbohydrate chemistry, which have not previously been examined synergistically. This unique perspective allows examination of strategies that cannot be addressed by conventional approaches. The improved entries to biomedically important structures made possible by this research will enable their biological function and therapeutic potential to be more efficiently studied.

Public Health Relevance

The goal of this research is to develop new methods for the preparation of compounds of biomedical significance. Improvements in the speed, efficiency, selectivity, and cost of introducing structural subunits that impact the biological properties and function of complex structures will be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057014-17
Application #
8516046
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
1998-01-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
17
Fiscal Year
2013
Total Cost
$285,642
Indirect Cost
$92,642
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Miller, Zachary D; Montgomery, John (2014) Regioselective allene hydroarylation via one-pot allene hydrosilylation/Pd-catalyzed cross-coupling. Org Lett 16:5486-9
Partridge, Katherine M; Bader, Scott J; Buchan, Zachary A et al. (2013) A streamlined strategy for aglycone assembly and glycosylation. Angew Chem Int Ed Engl 52:13647-50
Miller, Zachary D; Li, Wei; Belderrain, Tomas R et al. (2013) Regioselective allene hydrosilylation catalyzed by N-heterocyclic carbene complexes of nickel and palladium. J Am Chem Soc 135:15282-5
Lage, Marta L; Bader, Scott J; Sa-Ei, Kanicha et al. (2013) Chemoselective hydrosilylation of hydroxyketones. Tetrahedron 69:5609-5613
Baxter, Ryan D; Montgomery, John (2011) Mechanistic study of nickel-catalyzed ynal reductive cyclizations through kinetic analysis. J Am Chem Soc 133:5728-31
Liu, Peng; Montgomery, John; Houk, K N (2011) Ligand steric contours to understand the effects of N-heterocyclic carbene ligands on the reversal of regioselectivity in Ni-catalyzed reductive couplings of alkynes and aldehydes. J Am Chem Soc 133:6956-9
ElDouhaibi, Ahmad S; Kassab, Refaie M; Song, Minsoo et al. (2011) Nickel-catalyzed cyclizations of enoates and chiral allenes: an approach to domoic acid. Chemistry 17:6326-9
Malik, Hasnain A; Sormunen, Grant J; Montgomery, John (2010) A general strategy for regiocontrol in nickel-catalyzed reductive couplings of aldehydes and alkynes. J Am Chem Soc 132:6304-5
Li, Shengying; Chaulagain, Mani Raj; Knauff, Allison R et al. (2009) Selective oxidation of carbolide C-H bonds by an engineered macrolide P450 mono-oxygenase. Proc Natl Acad Sci U S A 106:18463-8
Sa-Ei, Kanicha; Montgomery, John (2009) Diastereoselective Nickel-Catalyzed Reductive Couplings of Aminoaldehydes and Alkynylsilanes: Application to the Synthesis of D-erythro-Sphingosine. Tetrahedron 65:6707-6711

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