Graduate Student, University of Utah
My research is applying transition metal catalysis to construct asymmetric remote stereocentres
A molecule in which a carbon atom is connected to four different substituents is considered to be chiral and can exist in two different configurations (R or S), which are non-superimposable mirror images of each other and has a distinct 3D orientation in space. In fact, 3D orientation of molecules can have significant biological effects which perhaps has led the DNA strands to exist specifically in a right hand screw orientation and protein building blocks such as amino acids to be chiral. Moreover, drug-protein interaction is an important example of how chirality in molecules can have a momentous impact on human lives. Asymmetric catalysis enables construction of such molecules in an enantioselective and stereospecific manner, thus permitting installation of sterocentres in a more defined manner. Most organic transformations rely on the close proximity of different functional groups to impart high level of enantio-control at a site adjacent to the functional group. However, installation of chiral centres more remote from a functional group remains an ongoing synthetic challenge. To address such limiations, we have developed a unique redox-relay Heck reaction, which enables formation of stereocentres remote from a carbonyl functional group. This strategy utilizes a transition metal palladium catalyst with a chiral ligand to generate an organometallic species in situ, which can react with disubstituted or trisubstituted alkenols via a Heck type reaction. The palladium alkyl intermediate thus generated relays the unsaturation of the alkene via iterative β-hydride elimination and migratory insertion processes to form carbonyl products functionalized at remote positions. This strategy has been utilized to install aryl and alkenyl groups in high enantioselectivity to form tertiary and quaternary stereocentres. The resulting chiral building blocks have unique structural features and can be derivatized towards complex molecule synthesis effectively.
Abstract: Small molecules that contain all-carbon quaternary stereocentres-carbon atoms bonded to four distinct carbon substituents-are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted β-, γ-, δ-, ε- or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.
Pub.: 11 Apr '14, Pinned: 31 Jul '17