Catalytic and Stereoselective C-C-Heteroatom Bond Forming Reactions

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Project Summary Organic molecules containing chiral α-substituted amines and ethers can be applied to the synthesis of countless medicinally relevant molecules. These valuable compounds have been prepared by routes wherein the carbon-based stereogenic center is introduced using “indirect” diastereo- or enantioselective methods that require the preparation of intermediates that contain α-substituted leaving groups (e.g., ZnI, halides, triflate, trichloroacetimidates, phosphates); such approaches lead to lengthy and somewhat inefficient pathways that increase the time required to secure the desired molecules, substantially increasing the cost of preparing compounds that are important to human healthcare. There are also the issues of selectivity and substrate scope: not only must high enantioselectivity and diastereoselectivity be achieved through the use of readily accessible and cost-effective catalysts, expansion in the scope of compatible substrate is imperative. Particularly challenging are schemes that lead to chiral α-substituted amines and ethers through enantio-, diastereo- and regioselective activation of otherwise unreactive α- amino or α-ethereal C–H bonds. We will develop catalytic processes that combine an assortment of nucleophiles (enolates, Breslow intermediates, enamines, (hetero)arenes, and allyl silanes, amines and alcohols), and amines or ethers to generate - in a single operation - a diastereomically pure and highly enantiomerically enriched product. The resulting compounds will contain one or two stereogenic centers. Some will carry α- or β-amino carbonyl units as well as α-(hetero)aryl, α-allyl amino units that are indispensable building blocks in biologically active molecules. Others will carry α-acyl, β-carbonyl, α-(hetero)aryl, α-amino, α-alkoxy ether moieties. Various chiral α-substituted amine and ether compounds will thus become readily accessible; preparation of these entities would otherwise require several operations that can at times proceed with moderate selectivity. Chiral organoborane catalysts and Lewis acid co-catalysts will be used to promote the proposed transformations. We will utilize the above strategies to design pathways that are significantly more efficient than those previously disclosed. We will develop catalytic processes that can be applied for the late stage functionalization of biologically important amine and ether molecules. Among the medicinally relevant molecules that will be subjected to the late stage functionalization are Cymbalta, Sensipar, Methylphenidate, Metoprolol, Vyvanse and OxyContin, as well as various deoxy sugar molecules.