Organic molecules containing an alkene, a carbon-based stereogenic center and a C-B bond can be applied to the synthesis of countless medicinally relevant molecules. These valuable fragments are typically prepared by routes wherein each functional unit (or units) is introduced separately through linear sequences; 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 is also the issue of selectivity: not only must high enantioselectivity be achieved through the use of readily accessible and cost-effective catalysts, control of alkene stereochemistry is imperative. Particularly challenging are schemes that lead to trisubstituted olefins with high E or Z selectivity. We will develop catalytic processes that combine a commercially available diboron reagent, an easily accessible unsaturated hydrocarbon (an allene, an enyne, a diene, an alkene or an alkyne), and an allylic phosphate or a,-unsaturated carbonyl 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 either carry an E trisubstuted alkene, or a trisubstituted alkenylboron unit that can be converted to E or Z trisubstituted olefin with three C-based substituents. Others will carry a 1,1-disubstituted alkenylboron moiety, a primary alkylboron group, or a boron-substituted tertiary carbon stereogenic center. Certain products will contain a terminal alkene, a trisubstituted allene formed enantioselectively or an internal alkyne. Various multi-functional organoboron compounds will thus become accessible; preparation of these entities would otherwise require several operations that can at times proceed with moderate selectivity. Catalysts will be prepared in situ from inexpensive Cu salts and readily accessible chiral NHCs or mostly commercially available bis-phosphine ligands. We will utilize the above strategies to design pathways that are significantly more efficient than those previously disclosed. We will develop catalytic processes, based on which synthetic schemes can be devised, that will allow access to gram quantities of complex molecules. Among the medicinally relevant molecules the synthesis of which will be pursued are acalycixeniolide K, with anti-leukemic and anti-HIV activities, a naturally occurring antibiotic pentalenolactone methyl ester, anti-parasitic inhibitor nafuredin, anti-obesity drug taranabant and anti-fungal agent natural product ambruticin.
Our ability to prepare various medicinally active agents in a cost-effective, reliable, efficient and selective manner is most critical to advances in human health care. The proposed research will lead afford unique, inexpensive and highly potent multicomponent transformations that afford otherwise difficult-to-access and valuable poly-functional fragments that can be used in expeditious preparation of numerous complex organic molecules that are of significance to human health care.
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