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Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules.
Acc Chem Res. 2015 Mar 17; 48(3):740-51.AC

Abstract

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: nucleophilic substitution of 3-halooxindoles, conjugate addition of boronic acids to cyclic enones, and allylic alkylation of enolates. In the first approach, malonic ester nucleophiles 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 nucleophiles to α,β-unsaturated carbonyl acceptors. We discovered that in the presence of catalytic palladium-pyridinooxazoline complex, arylboronic acids add smoothly to β-substituted cyclic enones to furnish ketones with a β-benzylic quaternary stereocenter in high yields and enantioselectivities. The reaction is compatible with a wide range of arylboronic acids, β-substituents, and ring sizes. Aside from benzylic quaternary stereocenters, a more challenging motif is a quaternary stereocenter not adjacent to an aromatic group. Such centers represent more general structures in chemical space but are more difficult to form by asymmetric catalysis. To address this greater challenge, and motivated by the greater reward, we entered the field of palladium-catalyzed asymmetric allylic alkylation of prochiral enolate nucleophiles about a decade ago. On the basis of Tsuji's work, which solved the issue of positional selectivity for unsymmetrical ketones, we discovered that the phosphinooxazoline ligand effectively rendered this reaction enantioselective. Extensive investigations since then have revealed that the reaction exhibits broad scope and accepts a range of substrate classes, each with its unique advantage in synthetic applications. A diverse array of carbonyl compounds bearing α-quaternary stereocenters are obtained in excellent yields and enantioselectivities, and more possibilities have yet to be explored. As an alternative to palladium catalysis, we also studied iridium-catalyzed asymmetric allylic alkylations that generate vicinal quaternary and tertiary stereocenters in a single transformation. Overall, these methods provide access to small molecule building blocks with a single quaternary stereocenter, can be applied to various molecular scaffolds, and tolerate a wide range of functional groups. We envision that the chemistry reported in this Account will be increasingly useful in drug discovery and design.

Authors+Show Affiliations

The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125, United States.The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125, United States.The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125, United States.The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25715056

Citation

Liu, Yiyang, et al. "Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules." Accounts of Chemical Research, vol. 48, no. 3, 2015, pp. 740-51.
Liu Y, Han SJ, Liu WB, et al. Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. Acc Chem Res. 2015;48(3):740-51.
Liu, Y., Han, S. J., Liu, W. B., & Stoltz, B. M. (2015). Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. Accounts of Chemical Research, 48(3), 740-51. https://doi.org/10.1021/ar5004658
Liu Y, et al. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc Chem Res. 2015 Mar 17;48(3):740-51. PubMed PMID: 25715056.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. AU - Liu,Yiyang, AU - Han,Seo-Jung, AU - Liu,Wen-Bo, AU - Stoltz,Brian M, Y1 - 2015/02/25/ PY - 2015/2/26/entrez PY - 2015/2/26/pubmed PY - 2015/9/22/medline SP - 740 EP - 51 JF - Accounts of chemical research JO - Acc Chem Res VL - 48 IS - 3 N2 - 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: nucleophilic substitution of 3-halooxindoles, conjugate addition of boronic acids to cyclic enones, and allylic alkylation of enolates. In the first approach, malonic ester nucleophiles 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 nucleophiles to α,β-unsaturated carbonyl acceptors. We discovered that in the presence of catalytic palladium-pyridinooxazoline complex, arylboronic acids add smoothly to β-substituted cyclic enones to furnish ketones with a β-benzylic quaternary stereocenter in high yields and enantioselectivities. The reaction is compatible with a wide range of arylboronic acids, β-substituents, and ring sizes. Aside from benzylic quaternary stereocenters, a more challenging motif is a quaternary stereocenter not adjacent to an aromatic group. Such centers represent more general structures in chemical space but are more difficult to form by asymmetric catalysis. To address this greater challenge, and motivated by the greater reward, we entered the field of palladium-catalyzed asymmetric allylic alkylation of prochiral enolate nucleophiles about a decade ago. On the basis of Tsuji's work, which solved the issue of positional selectivity for unsymmetrical ketones, we discovered that the phosphinooxazoline ligand effectively rendered this reaction enantioselective. Extensive investigations since then have revealed that the reaction exhibits broad scope and accepts a range of substrate classes, each with its unique advantage in synthetic applications. A diverse array of carbonyl compounds bearing α-quaternary stereocenters are obtained in excellent yields and enantioselectivities, and more possibilities have yet to be explored. As an alternative to palladium catalysis, we also studied iridium-catalyzed asymmetric allylic alkylations that generate vicinal quaternary and tertiary stereocenters in a single transformation. Overall, these methods provide access to small molecule building blocks with a single quaternary stereocenter, can be applied to various molecular scaffolds, and tolerate a wide range of functional groups. We envision that the chemistry reported in this Account will be increasingly useful in drug discovery and design. SN - 1520-4898 UR - https://www.unboundmedicine.com/medline/citation/25715056/Catalytic_enantioselective_construction_of_quaternary_stereocenters:_assembly_of_key_building_blocks_for_the_synthesis_of_biologically_active_molecules_ DB - PRIME DP - Unbound Medicine ER -