The proposed research will focus on a broad set of aims that center around the development and application of the nickel-catalyzed, silane-promoted reductive coupling of aldehydes and alkynes to generate allylic alcohols. Allylic alcohols are a common structural motif in many biologically and medicinally important compounds as well as versatile precursors for a broad array of organic reactions and catalytic processes. Fundamental studies will focus on understanding the mechanism and scope of this novel coupling process, and on developing new regioselective, diastereoselective, and enantioselective variants. An important aim of the proposed project period is the development of a new procedure for the direct assembly of a glycosylated macrocycle from a simple acyclic ynal, which will significantly simplify the preparation of carbohydrate- functionalized macrocycles. Applications in synthesis of natural and unnatural macrolides will be an important focus of the research plan. Naturally occurring macrolides make up a large family of biologically active macrocyclic natural products, and many members of this group possess carbohydrate appendages that greatly impact the molecular recognition events that are key in their biological activity. The antibiotic activities of members of this class are widely documented and clinically important, and many other modes of biological activity have been documented for this class of compounds. The structures specifically targeted include aigialomycin D, amphidinolide W, and 7-O-(alpha-glucosyl)-2,3-dihydrocineromycin B, and novel nickel-catalyzed reactions will be used as key steps in each of the syntheses. In addition to developing approaches to several macrolide natural products, our proposed method for assembly of glycosylated macrocycles will be used to access novel structures that will examined by the research group of David Sherman as substrates for cytochrome P450-catalyzed oxidations. This collaborative research will elucidate the substrate scope in cytochrome P450 oxidations and may lead to new compounds with potential as therapeutic agents.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
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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
Lage, Marta L; Bader, Scott J; Sa-Ei, Kanicha et al. (2013) Chemoselective hydrosilylation of hydroxyketones. Tetrahedron 69:5609-5613
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
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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