NOVEL REAGENTS AND CATALYSTS FOR CHIRAL PHARMACEUTICALS

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Description (Adapted from Application): The project goals are directed toward the invention and development of novel, chiral, main-group organometallic reagents and catalysts for applications to the asymmetric synthesis of pharmaceuticals and natural products. The research focuses upon the chemistry of boron and silicon, which are generally both environmentally friendly and exhibit low toxicity. These structurally sound metalloidal systems provide defined stereochemical features, which can be utilized effectively in the synthetic and analytical operations commonly employed in the chemistry used in the health industry. Specific aims of the project include: (1) The design, synthesis, and evaluation of new types of chiral axazaborolanes and related catalysts for the borane-based catalytic asymmetric reduction of prochiral ketones. Constructed by a novel, intramolecular nitrogen-employing beta-azidoalkyl borinate esters and boranes, they have potential pharmaceutical applications (i.e., Prozac, D1 antagonists, beta-agonists, prostaglandins, thromboxane A2) by analogy to those of Corey's CBS catalysts, including the synthesis of anti-hypertensive drugs. Alternative catalysts based upon B-chiral borohydrides derived from diborons are also proposed. (2) Complementary to the above, new chiral potassium borohydride reagents are proposed, based upon the 10-trimethylsilyl-9-borabicyclo[3.3.2]decane ring system, which contain a B-chiral borohydride in a rigid system, a potentially versatile system for the asymmetric reduction of many ketone types. (3) Preliminary data also supports the feasibility of generating a wide variety of potassium aminoborohydrides through the simple reaction of aminoboranes with activated potassium hydride, a process which appears amenable to the synthesis of chiral potassium aminoborohydrides, systems which will also be examined as novel asymmetric reduction catalysts. (4) A new 11B-NMR protocol has been discovered which will be further developed as a highly effective, direct analysis of organoborane mixtures. Its utility in pharmaceutical applications has already been successful, providing a clear picture of the diastereomeric composition of the organoboranes employed in a drug synthesis, a finding that could have far-reaching significance for borane-based asymmetric processes. (5) Such technology has been utilized to prepare a new chiral silane derivatizing agent, which will be examined as a more versatile protocol than the Mosher ester method. (6) A new simple silane-based method for carboxylate protection will be applied to amino acids for potential applications to peptide and asymmetric synthesis.