Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules
- Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules
- 한서정; Yiyang Liu; Wen-Bo Liu; Brian M. Stoltz
- Issue Date
- Accounts of chemical research
- VOL 48, NO 3-751
- CONSPECTUS: The ever-present demand for drugs with better efficacy and fewer side effects continually motivates scientists to explore the vast chemical space. Traditionally, medicinal chemists have focused much attention on achiral or so-called "flat" molecules. More recently, attention has shifted toward molecules with stereogenic centers since their three-dimensional structures represent a much larger fraction of the chemical space and have a number of superior properties compared with flat aromatic compounds. Quaternary stereocenters, in particular, add greatly to the three-dimensionality and novelty of the molecule. Nevertheless, synthetic challenges in building quaternary stereocenters have largely prevented their implementation in drug discovery. The lack of effective and broadly general methods for enantioselective formation of quaternary stereocenters in simple molecular scaffolds has prompted us to investigate new chemistry and develop innovative tools and solutions.
In this Account, we describe three approaches to constructing quaternary stereocenters: nudeophilic substitution of 3-halooxindoles, conjugate addition of boronic acids to cyclic enones, and allylic alkylation of enolates. In the first approach, malonic ester nudeophiles attack electrophilic 3-halooxindoles, mediated by a copper(II)-bisoxazoline catalyst. A variety of oxindoles containing a benzylic quaternary stereocenter can be accessed through this method. However, it is only applicable to the specialized 3,3-disubstituted oxindole system. To access benzylic quaternary stereocenters in a more general context, we turned our attention to the enantioselective conjugate addition of carbon nudeophiles to alpha,beta-unsaturated carbonyl acceptors. We discovered that in the presence of catalytic palladium-pyridinooxazoline complex, arylboronic acids add smoothly to beta-substituted cyclic enones to furnish ketones with a beta-benzylic quaternary
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