Organoboron chemistry is increasingly important in large-scale production as well as laboratory-scale synthesis of pharmaceuticals due to the widespread use of boronic acid derivatives in transition metal- catalyzed C-C coupling. In particular, palladium or nickel catalyzed Suzuki-Miyaura coupling of boronic acids is revolutionizing the way that experimental drugs are made due to its excellent catalyst efficiency and compatibility with numerous heterocyclic environments of medicinal interest. The proposed studies will access synthetically important boronates using new procedures for boron activation. The emphasis is on conversion of simple Lewis base-borane complexes into versatile borane and boronic acid derivatives. A variety of heterocyclic boronic acid environments will be prepared using directed hydroboration methodology, and palladium catalyzed coupling chemistry of these intermediates will be confirmed under recently developed conditions for boronic acids that contain a secondary C-B bond. Specific applications of amine directed hydroboration will study stereocontrol and the synthesis of a pyrrolidine subunit common to the HIV1 inhibitor batzelladine F and batzelladine K. Newly developed N-directed ionic hydrogenations of amine and phosphite boranes will be used to control relative and absolute stereochemistry, and to explore applications to dihydroretinoid synthesis. The new amine borane activation methods also allow intramolecular and intermolecular electrophilic borylation of heterocyclic substrates. This technique will be applied to substrates where alternative methods are not suitable and the interface between mechanism and synthesis will be studied to improve the reactivity of boron reagents and to develop related organoaluminum reagents.

Public Health Relevance

Relevance Access to new organoboron environments is important because boronic acid coupling technology is revolutionizing large-scale as well as lab-scale synthesis of pharmaceuticals and experimental drugs. Boronic acids are also of interest as biologically active agents, and as carbohydrate sensors. Heterocyclic substrates are common building blocks for pharmaceuticals, and the derived organoboron structures are among the most useful tools for heterocycle assembly and functionalization.

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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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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Prokofjevs, Aleksandrs (2015) Thermal Dehydrogenation of Base-Stabilized B2H5(+) Complexes and Its Role in C-H Borylation. Angew Chem Int Ed Engl 54:13401-5
Miller, Daniel K (2013) Facile conversion of chromane-6-triflate to chromane-6-alanines under Palladium conditions. Tetrahedron Lett 54:811-813
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Prokofjevs, Aleksandrs; Vedejs, Edwin (2011) N-Directed aliphatic C-H borylation using borenium cation equivalents. J Am Chem Soc 133:20056-9
Prokofjevs, Aleksandrs; Kampf, Jeff W; Vedejs, Edwin (2011) A boronium ion with exceptional electrophilicity. Angew Chem Int Ed Engl 50:2098-101

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