The goal of the research proposed is to facilitate the construction of organic molecules by developing new reagents and subsequently exploiting the novel reactivity patterns of those reagents. Herein are described protocols for novel syntheses of organoboron compounds that will increase the productivity and efficiency of chemists in the synthesis of organic molecules. The development of tetrahydroxydiborane [(HO)2B-B(OH)2] and its commercial synthetic precursor, (Me2N)2B-B(NMe2)2, will reduce dependency on the wholly inefficient bis(pinacoloato)diboron (B2pin2). Proposed are unique, more cost effective, and environmentally sound procedures for the synthesis of boronic acids and diverse derivatives. Most importantly, new vistas for chemical reactivity will be developed. As a result of the studies described, novel methods for the introduction of boron into organic molecules will be realized;processes that are far more sustainable than previous methods. Direct access to boronic acids will make these protocols more versatile in two important ways: 1) Sequential reactions that require reactive but unstable boronic acids can be carried out without a tedious and inefficient hydrolysis procedure, thus permitting rapid and more sustainable access to high value-added products. Not only would this address significant efficiencies inherent to the multi-step protocol generally employed, but it would also extend synthetic methods both to novel organoborons as well as those boronic acids that are prone to significant degradation by protodeboronation during routine handling. 2) A variety of more useful and robust organotrifluoroborates can be directly synthesized without the wasteful hydrolysis methods required with protocols employing pinacolboronates. Novel approaches to organoborons that take advantage of boryl anion-like reactivity patterns of bisbora compounds and avoid expensive transition metal catalysts represent another centerpiece of the described research. These protocols will enable the formation of novel organoboron reagents in a direct approach. Importantly, these useful new reagents will be employed in unprecedented bond-forming reactions, including the engagement of nucleophilic umpolung reagents, polyfluoroalkyltrifluoroborates, and ?-trifluoroborato- substituted nitrogen- and oxygen heterocycles that will provide solutions to long-standing challenges in organic synthesis. Using the novel methods developed, a number of unique 2? alkylating reagents, including amino alkylating and alkoxy alkylating agents, will be synthesized in enantiopure form, and protocols for their cross-coupling, based on secondary interactions with embedded functional groups, will be developed. These distinctive reagents will allow unprecedented bond constructions and insertion of stereocenters with complete stereochemical fidelity into organic substrates via cross-coupling.

Public Health Relevance

Pharmaceutical drug discovery, development, and manufacture depend heavily on chemical reactions known as Suzuki cross-couplings. Current methods for the synthesis of the molecular building blocks used in these reactions are inherently inefficient, and many of the chemical reagents themselves are intrinsically unstable and limited in terms of structural diversity. The proposed research outlines unique ways to access existing building blocks more efficiently, as well as allowing access to novel reagents that hold promise in increasing molecular diversity in drug discovery efforts.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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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 Pennsylvania
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Amani, Javad; Molander, Gary A (2015) Toward Efficient Nucleophilic Azaborine Building Blocks for the Synthesis of B-N Naphthyl (Hetero)arylmethane Isosteres. Org Lett 17:3624-7
Rizwan, Komal; Karakaya, Idris; Heitz, Drew et al. (2015) Copper-mediated N-Arylation of Methyl 2-Aminothiophene-3-carboxylate with Organoboron Reagents. Tetrahedron Lett 56:6839-6842
Molander, Gary A; Trice, Sarah L J; Tschaen, Brittany (2015) A modified procedure for the palladium catalyzed borylation/Suzuki-Miyaura cross-coupling of aryl and heteroaryl halides utilizing bis-boronic acid. Tetrahedron 71:5758-5764
Primer, David N; Karakaya, Idris; Tellis, John C et al. (2015) Single-electron transmetalation: an enabling technology for secondary alkylboron cross-coupling. J Am Chem Soc 137:2195-8
Gutierrez, Osvaldo; Tellis, John C; Primer, David N et al. (2015) Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. J Am Chem Soc 137:4896-9
Tellis, John C; Primer, David N; Molander, Gary A (2014) Dual catalysis. Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysis. Science 345:433-6
Molander, Gary A; Amani, Javad; Wisniewski, Steven R (2014) Accessing 2-(hetero)arylmethyl-, -allyl-, and -propargyl-2,1-borazaronaphthalenes: palladium-catalyzed cross-couplings of 2-(chloromethyl)-2,1-borazaronaphthalenes. Org Lett 16:6024-7
Molander, Gary A; Wisniewski, Steven R (2014) Accessing 2,1-borazaronaphthols: self-arylation of 1-alkyl-2-aryl-3-bromo-2,1-borazaronaphthalenes. J Org Chem 79:8339-47
Wisniewski, Steven R; Guenther, Courtney L; Argintaru, O Andreea et al. (2014) A convergent, modular approach to functionalized 2,1-borazaronaphthalenes from 2-aminostyrenes and potassium organotrifluoroborates. J Org Chem 79:365-78
El Khatib, Mirna; Molander, Gary A (2014) Copper(II)-mediated O-arylation of protected serines and threonines. Org Lett 16:4944-7

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