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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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Walk, Jordan T; Buchan, Zachary A; Montgomery, John (2015) Sugar Silanes: Versatile Reagents for Stereocontrolled Glycosylation via Intramolecular Aglycone Delivery. Chem Sci 6:3448-3453
Wang, Hengbin; Negretti, Solymar; Knauff, Allison R et al. (2015) Exo-selective reductive macrocyclization of ynals. Org Lett 17:1493-6
Jackson, Evan P; Montgomery, John (2015) Regiocontrol in catalytic reductive couplings through alterations of silane rate dependence. J Am Chem Soc 137:958-63
Jackson, Evan P; Malik, Hasnain A; Sormunen, Grant J et al. (2015) Mechanistic Basis for Regioselection and Regiodivergence in Nickel-Catalyzed Reductive Couplings. Acc Chem Res 48:1736-45
Haynes 2nd, M Taylor; Liu, Peng; Baxter, Ryan D et al. (2014) Dimer involvement and origin of crossover in nickel-catalyzed aldehyde-alkyne reductive couplings. J Am Chem Soc 136:17495-504
Miller, Zachary D; Montgomery, John (2014) Regioselective allene hydroarylation via one-pot allene hydrosilylation/Pd-catalyzed cross-coupling. Org Lett 16:5486-9
Miller, Zachary D; Li, Wei; Belderrain, Tomás R et al. (2013) Regioselective allene hydrosilylation catalyzed by N-heterocyclic carbene complexes of nickel and palladium. J Am Chem Soc 135:15282-5
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
Lage, Marta L; Bader, Scott J; Sa-Ei, Kanicha et al. (2013) Chemoselective hydrosilylation of hydroxyketones. Tetrahedron 69:5609-5613
Shareef, Abdur-Rafay; Sherman, David H; Montgomery, John (2012) Nickel-Catalyzed Regiodivergent Approach to Macrolide Motifs. Chem Sci 3:892-895

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