Studies will be carried out on the synthesis of alkoxymethyltrifluoroborates and their utility in transition metal catalyzed coupling reactions. Both intermolecular and intramolecular versions of these reactions will be explored. Through such studies, we will gain an understanding and appreciation of these unusual reagents for the introduction of alkoxymethyl subunits into complex organic molecules, thus providing a new paradigm for the installation of this functional unit into acyclic molecules. Additionally, suitably functionalized substrates provide the opportunity for a distinctive route to oxygen heterocycles via intramolecular reactions. In a similar manner, aminomethyl- and aminoethyltrifluoroborates will be prepared, and the scope and limitations of these reagents in selective organic synthesis will be explored. Of notable interest in this particular line of research will be the development of enantiomerically pure alanine b-anion equivalents. Cyclization of appropriately ornamented analogues provides an unprecedented entry to nitrogen heterocycles that is applicable to myriad structures of biological significance. Again, the development of these reagents affords a unique approach to the construction of diverse classes of organic molecules, and the cultivation of this chemistry will thus be aggressively pursued. As a means to demonstrate the value of the developed reagents and their viability in demanding systems, several natural products have been targeted for synthesis. These include zoapatanol, alkaloid 233F, nakadomarin A, and halicyclamine A. The discovery of new Pharmaceuticals in a cost and time efficient manner requires the development of new and improved methods for their chemical synthesis. The research proposed herein addresses one aspect of this requirement. The basic science to be explored would make available several protocols that could be immediately incorporated into the pharmaceutical discovery process as well as industrial scale synthesis . Additionally, syntheses of two compounds (halicyclamine A and nakadomarin A) that exhibit selective cytoxicity against several different cell lines in preliminary tests are proposed, and these molecules could serve as lead compounds for the treatment of cancer and perhaps other afflictions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM081376-04
Application #
7902216
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Hagan, Ann A
Project Start
2007-09-07
Project End
2011-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$302,291
Indirect Cost
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Matsui, Jennifer K; Molander, Gary A (2017) Direct ?-Arylation/Heteroarylation of 2-Trifluoroboratochromanones via Photoredox/Nickel Dual Catalysis. Org Lett 19:436-439
Matsui, Jennifer K; Molander, Gary A (2017) Organocatalyzed, Photoredox Heteroarylation of 2-Trifluoroboratochromanones via C-H Functionalization. Org Lett 19:950-953
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
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
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
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
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
Noreen, Mnaza; Rasool, Nasir; El Khatib, Mirna et al. (2014) Arylation and heteroarylation of thienylsulfonamides with organotrifluoroborates. J Org Chem 79:7243-9
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
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

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