Enantioselective hydrogenation accounts for over half the chiral drugs produced industrially, withstanding physical or enzymatic resolution. Whereas conventional hydrogenation involves C-H bond formation, our research breaks dogma by establishing hydrogenation as a method for C-C bond formation. In the prior funding period, we demonstrated that hydrogenation could be used to couple diverse p-unsaturated reactants to carbonyl compounds and imines, constituting a byproduct-free alternative to stoichiometrically preformed organometallics in a range of classical C=X (X = O, NR) addition processes. In the proposed funding period, we seek to continue these first systematic efforts to exploit catalytic hydrogenation in C-C couplings beyond hydroformylation.
Over 50% of the world's top-selling drugs are single enantiomers and it is estimated that 80% of all drugs currently entering development are chiral and will be marketed as single-enantiomer entities. In 1994, the chiral drug market grossed over "45.2 billion US dollars worldwide, which corresponds to an increase of 27% in a single year!" In 1999, the chiral drug market topped 100 billion US dollars in sales. In 2002, world-wide sales of single enantiomer drugs reached more than 159 billion US dollars. Notably, enantioselective hydrogenation accounts for over half the chiral drugs produced industrially, withstanding physical or enzymatic resolution. The enormous impact of hydrogenation vis-?-vis chiral drugs portends an equally powerful approach to reductive C-C bond formations mediated by hydrogen. However, since the discovery of alkene hydroformylation and the parent Fischer-Tropsch reaction, processes restricted to the use of carbon monoxide, the field of hydrogenative coupling has lain fallow. In this proposal, we report the first systematic efforts to exploit hydrogenation in C-C couplings beyond hydroformylation. Our efforts have led to the development of a broad new family "hydrogenative C-C couplings" - byproduct-free alternatives to stoichiometrically preformed organometallics in an ever-increasing range classical C=X (X = O, NR) addition processes.
|Shin, Inji; Wang, Gang; Krische, Michael J (2014) Catalyst-directed diastereo- and site-selectivity in successive nucleophilic and electrophilic allylations of chiral 1,3-diols: protecting-group-free synthesis of substituted pyrans. Chemistry 20:13382-9|
|Kasun, Zachary A; Geary, Laina M; Krische, Michael J (2014) Ring expansion of cyclic 1,2-diols to form medium sized rings via ruthenium catalyzed transfer hydrogenative [4+2] cycloaddition. Chem Commun (Camb) 50:7545-7|
|Feng, Jiajie; Garza, Victoria J; Krische, Michael J (2014) Redox-triggered C-C coupling of alcohols and vinyl epoxides: diastereo- and enantioselective formation of all-carbon quaternary centers via tert-(hydroxy)-prenylation. J Am Chem Soc 136:8911-4|
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|Sam, Brannon; Montgomery, T Patrick; Krische, Michael J (2013) Ruthenium catalyzed reductive coupling of paraformaldehyde to trifluoromethyl allenes: CF3-bearing all-carbon quaternary centers. Org Lett 15:3790-3|
|Schmitt, Daniel C; Lee, Jungyong; Dechert-Schmitt, Anne-Marie R et al. (2013) Ruthenium catalyzed hydroaminoalkylation of isoprene via transfer hydrogenation: byproduct-free prenylation of hydantoins. Chem Commun (Camb) 49:6096-8|
|McInturff, Emma L; Mowat, Jeffrey; Waldeck, Andrew R et al. (2013) Ruthenium-catalyzed hydrohydroxyalkylation of acrylates with diols and ?-hydroxycarbonyl compounds to form spiro- and ?-methylene-?-butyrolactones. J Am Chem Soc 135:17230-5|
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