Enantioselective, Palladium-Catalyzed Conjugate Additions of Arylboronic Acids to Form Bis-benzylic Quaternary Stereocenters.

We report enantioselective, palladium-catalyzed conjugate additions of arylboronic acids to β-aryl, β,β-disubstituted enones to generate ketones containing bis-benzylic quaternary stereocenters. A catalyst generated from palladium trifluoroacetate and (S)-4-tert-butyl-2-(2-pyridyl)oxazoline ligand ((S)-t-BuPyOx) promotes conjugate additions of a wide range of arylboronic acids to a variety of β-aryl, β,β-disubstituted enones. Iterative addition of the arylboronic acid to minimize undesired protodeboronation pathways leads to efficient formation of the corresponding ketones containing bis-benzylic quaternary stereocenters in up to 92% yield and up to 93% enantioselectivity.

[1]  B. Stoltz,et al.  Preparation of (S)-tert-ButylPyOx and Palladium-catalyzed Asymmetric Conjugate Addition of Arylboronic Acids. , 2016, Organic syntheses; an annual publication of satisfactory methods for the preparation of organic chemicals.

[2]  C. Ottmann,et al.  Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation. , 2016, Journal of medicinal chemistry.

[3]  B. Stoltz,et al.  Synthesis of diverse β-quaternary ketones via palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enones. , 2015, Tetrahedron.

[4]  B. Stoltz,et al.  Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Cyclic Electrophiles. , 2015, Organic process research & development.

[5]  R. Zeeland,et al.  Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β,β-Disubstituted Enones in Aqueous Media: Formation of Bis-benzylic and ortho-Substituted Benzylic Quaternary Centers , 2015 .

[6]  B. Stoltz,et al.  Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. , 2015, Accounts of chemical research.

[7]  K. Houk,et al.  Mechanistic analysis of an asymmetric palladium-catalyzed conjugate addition of arylboronic acids to β-substituted cyclic enones , 2015, Chemical science.

[8]  R. Gainetdinov,et al.  Further Insights Into the Pharmacology of the Human Trace Amine‐Associated Receptors: Discovery of Novel Ligands for TAAR1 by a Virtual Screening Approach , 2014, Chemical biology & drug design.

[9]  A. Minnaard,et al.  Enantioselective palladium catalyzed conjugate additions of ortho-substituted arylboronic acids to β,β-disubstituted cyclic enones: total synthesis of herbertenediol, enokipodin A and enokipodin B. , 2014, Organic & biomolecular chemistry.

[10]  Susanta Banerjee,et al.  Effect of introduction of cardo cyclohexylidene moiety on gas transport properties of fluorinated poly(arylene ether)s , 2014 .

[11]  Chun-Young Lee,et al.  Protodeboronation of ortho- and para-phenol boronic acids and application to ortho and meta functionalization of phenols using boronic acids as blocking and directing groups. , 2013, The Journal of organic chemistry.

[12]  K. Houk,et al.  Mechanism and enantioselectivity in palladium-catalyzed conjugate addition of arylboronic acids to β-substituted cyclic enones: insights from computation and experiment. , 2013, Journal of the American Chemical Society.

[13]  A. Hoveyda,et al.  Enantioselective synthesis of quaternary carbon stereogenic centers through copper-catalyzed conjugate additions of aryl- and alkylaluminum reagents to acyclic trisubstituted enones. , 2013, Angewandte Chemie.

[14]  C. Butts,et al.  Diastereodivergent synthesis of trisubstituted alkenes through protodeboronation of allylic boronic esters: application to the synthesis of the Californian red scale beetle pheromone. , 2012, Angewandte Chemie.

[15]  M. Lutz,et al.  Palladium-Catalyzed Asymmetric Quaternary Stereocenter Formation , 2012, Synfacts.

[16]  B. Stoltz,et al.  Palladium-catalyzed asymmetric conjugate addition of arylboronic acids to five-, six-, and seven-membered β-substituted cyclic enones: enantioselective construction of all-carbon quaternary stereocenters. , 2011, Journal of the American Chemical Society.

[17]  V. Aggarwal,et al.  Protodeboronation of tertiary boronic esters: asymmetric synthesis of tertiary alkyl stereogenic centers. , 2010, Journal of the American Chemical Society.

[18]  A. Alexakis,et al.  Metal-catalyzed asymmetric conjugate addition reaction: formation of quaternary stereocenters. , 2010, Chemical communications.

[19]  A. Alexakis,et al.  Formation of quaternary chiral centers by N-heterocyclic carbene-Cu-catalyzed asymmetric conjugate addition reactions with Grignard reagents on trisubstituted cyclic enones. , 2010, Chemistry.

[20]  S. Snyder,et al.  Total syntheses of dalesconol A and B. , 2010, Angewandte Chemie.

[21]  R. Shintani,et al.  Chiral tetrafluorobenzobarrelenes as effective ligands for rhodium-catalyzed asymmetric 1,4-addition of arylboroxines to beta,beta-disubstituted alpha,beta-unsaturated ketones. , 2010, Angewandte Chemie.

[22]  M. Burke,et al.  General method for synthesis of 2-heterocyclic N-methyliminodiacetic acid boronates. , 2010, Organic letters.

[23]  F. Glorius,et al.  Olefin-oxazolines (OlefOx): highly modular, easily tunable ligands for asymmetric catalysis. , 2010, Angewandte Chemie.

[24]  R. Shintani,et al.  Sodium tetraarylborates as effective nucleophiles in rhodium/diene-catalyzed 1,4-addition to beta,beta-disubstituted alpha,beta-unsaturated ketones: catalytic asymmetric construction of quaternary carbon stereocenters. , 2009, Journal of the American Chemical Society.

[25]  M. Burke,et al.  A general solution for unstable boronic acids: slow-release cross-coupling from air-stable MIDA boronates. , 2009, Journal of the American Chemical Society.

[26]  Michal M. Achmatowicz,et al.  Practical synthesis of a p38 MAP kinase inhibitor. , 2009, The Journal of organic chemistry.

[27]  A. Alexakis,et al.  Copper-catalyzed asymmetric conjugate addition of aryl aluminum reagents to trisubstituted enones: construction of aryl-substituted quaternary centers. , 2008, Angewandte Chemie.

[28]  A. Hoveyda,et al.  Enantioselective synthesis of all-carbon quaternary stereogenic centers by catalytic asymmetric conjugate additions of alkyl and aryl aluminum reagents to five-, six-, and seven-membered-ring beta-substituted cyclic enones. , 2008, Angewandte Chemie.

[29]  R. Harvey,et al.  Efficient syntheses of C(8)-aryl adducts of adenine and guanine formed by reaction of radical cation metabolites of carcinogenic polycyclic aromatic hydrocarbons with DNA. , 2007, The Journal of organic chemistry.

[30]  A. Hoveyda,et al.  All-carbon quaternary stereogenic centers by enantioselective cu-catalyzed conjugate additions promoted by a chiral N-heterocyclic carbene. , 2007, Angewandte Chemie.

[31]  A. Alexakis,et al.  Copper-catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted enones. Construction of all-carbon quaternary chiral centers. , 2006, Journal of the American Chemical Society.

[32]  A. Hird,et al.  A practical method for enantioselective synthesis of all-carbon quaternary stereogenic centers through NHC-Cu-catalyzed conjugate additions of alkyl- and arylzinc reagents to beta-substituted cyclic enones. , 2006, Journal of the American Chemical Society.

[33]  E. Nesterov,et al.  An experimental and theoretical study of the type C enone rearrangement: mechanistic and exploratory organic photochemistry. , 2003, Journal of the American Chemical Society.

[34]  K. Tsubaki,et al.  Asymmetric synthesis and determination of the absolute configuration of FK584, an agent for the treatment of overactive detrusor. , 2000, Chemical & pharmaceutical bulletin.

[35]  D. L. Larson,et al.  Synthesis of 7-arylmorphinans. Probing the "address" requirements for selectivity at opioid delta receptors. , 1998, Journal of medicinal chemistry.

[36]  M. Beckett,et al.  Protodeboronation of arylboronic acids and triarylboroxines in Bu20/THF , 1993 .

[37]  H. Kuivila,et al.  Electrophilic Displacement Reactions. X. General Acid Catalysis in the Protodeboronation of Areneboronic Acids1-3 , 1961 .

[38]  H. Kuivila,et al.  Electrophilic Displacement Reactions. XII. Substituent Effects in the Protodeboronation of Areneboronic Acids1-3 , 1961 .

[39]  F. Challenger,et al.  CCLXXX.—Studies of the boron–carbon linkage. Part I. The oxidation and nitration of phenylboric acid , 1930 .