Catalytic Enantioselective Addition of an Allyl Group to Ketones Containing a Tri-, a Di-, or a Monohalomethyl Moiety. Stereochemical Control Based on Distinctive Electronic and Steric Attributes of C-Cl, C-Br, and C-F Bonds.

We disclose the results of an investigation designed to generate insight regarding the differences in the electronic and steric attributes of C-F, C-Cl, and C-Br bonds. Mechanistic insight has been gleaned by analysis of variations in enantioselectivity, regarding the ability of electrostatic contact between a halomethyl moiety and a catalyst's ammonium group as opposed to factors lowering steric repulsion and/or dipole minimization. In the process, catalytic and enantioselective methods have been developed for transforming a wide range of trihalomethyl (halogen = Cl or Br), dihalomethyl, or monohalomethyl (halogen = F, Cl, or Br) ketones to the corresponding tertiary homoallylic alcohols. By exploiting electrostatic attraction between a halomethyl moiety and the catalyst's ammonium moiety and steric factors, high enantioselectivity was attained in many instances. Reactions can be performed with 0.5-5.0 mol % of an in situ generated boryl-ammonium catalyst, affording products in 42-99% yield and up to >99:1 enantiomeric ratio. Not only are there no existing protocols for accessing the great majority of the resulting products enantioselectively but also in some cases there are hardly any instances of a catalytic enantioselective addition of a carbon-based nucleophile (e.g., one enzyme-catalyzed aldol addition involving trichloromethyl ketones, and none with dichloromethyl, tribromomethyl, or dibromomethyl ketones). The approach is scalable and offers an expeditious route to the enantioselective synthesis of versatile and otherwise difficult to access aldehydes that bear an α-halo-substituted quaternary carbon stereogenic center as well as an assortment of 2,2-disubstituted epoxides that contain an easily modifiable alkene. Tertiary homoallylic alcohols containing a triazole and a halomethyl moiety, structural units relevant to drug development, may also be accessed efficiently with exceptional enantioselectivity.

[1]  P. Bobál,et al.  Bianthryl-based organocatalysts for the asymmetric Henry reaction of fluoroketones. , 2019, Organic & biomolecular chemistry.

[2]  A. Chan,et al.  Chiral Phosphoric-Acid-Catalyzed Regioselective and Enantioselective C7-Friedel-Crafts Alkylation of 4-Aminoindoles with Trifluoromethyl Ketones. , 2019, Organic letters.

[3]  Zhiyong Jiang,et al.  Catalytic Enantioselective Addition of Prochiral Radicals to Vinylpyridines. , 2019, Journal of the American Chemical Society.

[4]  N. Kumagai,et al.  Direct Catalytic Asymmetric Aldol Reaction of α-Alkoxyamides to α-Fluorinated Ketones. , 2019, Angewandte Chemie.

[5]  S. Buchwald,et al.  Enantioselective Allylation Using Allene, a Petroleum Cracking Byproduct. , 2019, Journal of the American Chemical Society.

[6]  L. Yin,et al.  Asymmetric Borylative Propargylation of Ketones Catalyzed by a Copper(I) Complex. , 2019, Organic letters.

[7]  R. Fernández,et al.  Asymmetric Organocatalytic Synthesis of Fluorinated β-Hydroxy Diazenes , 2018, European Journal of Organic Chemistry.

[8]  P. Espinet,et al.  Highly enantioselective addition of dimethylzinc to fluorinated alkyl ketones, and the mechanism behind it. , 2018, Chemical communications.

[9]  K. Sugita,et al.  Enantioselective, Protecting-Group-Free Total Synthesis of Boscartin F. , 2018, Organic letters.

[10]  N. Kumagai,et al.  Heterogeneous Heterobimetallic Catalysis Enabling Expeditious Access to CF3-Containing vic-Amino Alcohols. , 2018, Organic Letters.

[11]  Qi Zhang,et al.  Correction to Asymmetric Construction of Fluoroalkyl Tertiary Alcohols through a Three-Component Reaction of (Bpin)2, 1,3-Enynes, and Fluoroalkyl Ketones Catalyzed by a Copper(I) Complex. , 2018, Organic Letters.

[12]  N. Zanatta,et al.  4-Trichloroacetyl-1,2,3-triazoles: A versatile building block for rapid assessment of carbohydrazides and rufinamide derivatives , 2017 .

[13]  A. Hoveyda,et al.  Practical, Broadly Applicable, α-Selective, Z-Selective, Diastereoselective, and Enantioselective Addition of Allylboron Compounds to Mono-, Di-, Tri-, and Polyfluoroalkyl Ketones. , 2017, Journal of the American Chemical Society.

[14]  Jing Zhao,et al.  Design, synthesis, and in vitro evaluation of novel antifungal triazoles. , 2017, Bioorganic & medicinal chemistry letters.

[15]  Haizhu Sun,et al.  Rational design and synthesis of cationic Ir(III) complexes with triazolate cyclometalated and ancillary ligands for multi-color tuning , 2017 .

[16]  Virender Singh,et al.  Medicinal attributes of 1,2,3-triazoles: Current developments. , 2017, Bioorganic chemistry.

[17]  E. Meggers,et al.  Octahedral Ruthenium Complex with Exclusive Metal-Centered Chirality for Highly Effective Asymmetric Catalysis. , 2017, Journal of the American Chemical Society.

[18]  K. Szabó,et al.  Recent Advances in the Preparation and Application of Allylboron Species in Organic Synthesis. , 2017, Journal of the American Chemical Society.

[19]  Jun-Ichi Ito,et al.  Enantioselective Direct Alkynylation of Ketones Catalyzed by Chiral CCN Pincer RhIII Complexes. , 2016, Chemistry.

[20]  Fanke Meng,et al.  Catalytic Enantioselective Conjugate Additions of (pin)B-Substituted Allylcopper Compounds Generated in situ from Butadiene or Isoprene. , 2016, Angewandte Chemie.

[21]  A. Hoveyda,et al.  Practical and Broadly Applicable Catalytic Enantioselective Additions of Allyl-B(pin) Compounds to Ketones and α-Ketoesters. , 2016, Angewandte Chemie.

[22]  A. Hoveyda,et al.  Catalytic enantioselective addition of organoboron reagents to fluoroketones controlled by electrostatic interactions , 2016, Nature Chemistry.

[23]  A. Hoveyda,et al.  Lewis Acid Catalyzed Borotropic Shifts in the Design of Diastereo- and Enantioselective γ-Additions of Allylboron Moieties to Aldimines. , 2016, Angewandte Chemie.

[24]  C. Vanderwal,et al.  Stereoselective Halogenation in Natural Product Synthesis. , 2016, Angewandte Chemie.

[25]  C. Wolf,et al.  Efficient Access to Multifunctional Trifluoromethyl Alcohols through Base-Free Catalytic Asymmetric C-C Bond Formation with Terminal Ynamides. , 2016, Angewandte Chemie.

[26]  K. Mikami,et al.  Catalytic Asymmetric Synthesis of Tertiary Alcohols and Oxetenes Bearing a Difluoromethyl Group. , 2015, Organic letters.

[27]  M. D. Hill,et al.  Applications of Fluorine in Medicinal Chemistry. , 2015, Journal of medicinal chemistry.

[28]  Yi Zhou,et al.  Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8 , 2015, J. Chem. Inf. Model..

[29]  K. Higashiyama,et al.  Bisoxazoline-Catalyzed Asymmetric Nucleophilic Addition of Diethyl Zinc to Fluorinated Alkyl Ketones: Enantiofacial Control by Changing the Bisoxazoline Substituent , 2015 .

[30]  Marcos A. P. Martins,et al.  New solventless and metal-free synthesis of the antiepileptic drug 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide (Rufinamide) and analogues , 2015 .

[31]  D. O'Hagan,et al.  Successful fluorine-containing herbicide agrochemicals , 2014 .

[32]  N. Zanatta,et al.  Organoallylaluminum Reagents Promote Easy Access to Trihalomethyl Triazolyl Homoallylic Alcohols Analogous to Rufinamide. , 2014 .

[33]  U. Kragl,et al.  Synthesis of Aliphatic and α-Halogenated Ketone Cyanohydrins with the Hydroxynitrile Lyase from Manihot esculenta. , 2014 .

[34]  R. Hosseinzadeh,et al.  Efficient Synthesis and Antibacterial Activities of Some Novel 1,2,3‐Triazoles Prepared from Propargylic Alcohols and Benzyl Azides , 2014 .

[35]  Daniel Oehlrich,et al.  The evolution of amidine-based brain penetrant BACE1 inhibitors. , 2014, Bioorganic & medicinal chemistry letters.

[36]  N. Zanatta,et al.  Organoallylaluminum reagents promote easy access to trihalomethyl triazolyl homoallylic alcohols analogous to rufinamide , 2014 .

[37]  U. Kragl,et al.  Synthesis of Aliphatic and α‐Halogenated Ketone Cyanohydrins with the Hydroxynitrile Lyase from Manihot esculenta , 2014 .

[38]  N. Kumagai,et al.  An enantioselective synthesis of the key intermediate for triazole antifungal agents; application to the catalytic asymmetric synthesis of efinaconazole (Jublia). , 2014, The Journal of organic chemistry.

[39]  Hong Liu,et al.  Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011). , 2014, Chemical reviews.

[40]  N. Zanatta,et al.  Synthesis of 1H-1,2,3-triazoles—Rufinamide analogs by 1,3-dipolar cycloaddition and eletrocyclization reactions of trifluoroacetyl enolethers under thermal solventless conditions , 2013 .

[41]  M. E. Harris,et al.  Trichloromethyl ketones: asymmetric transfer hydrogenation and subsequent Jocic-type reactions with amines. , 2013, Chemical communications.

[42]  Fanke Meng,et al.  Cu-catalyzed chemoselective preparation of 2-(pinacolato)boron-substituted allylcopper complexes and their in situ site-, diastereo-, and enantioselective additions to aldehydes and ketones. , 2013, Angewandte Chemie.

[43]  Scott E. Harpstrite,et al.  A new nucleoside analogue with potent activity against mutant sr39 herpes simplex virus-1 (HSV-1) thymidine kinase (TK). , 2012, Organic letters.

[44]  Matthew S Sigman,et al.  Multidimensional steric parameters in the analysis of asymmetric catalytic reactions. , 2012, Nature chemistry.

[45]  Sébastien Ladouceur,et al.  One-Pot Click Synthesis of 1N-Alkyl-4-aryl-1,2,3-triazoles from Protected Arylalkynes and Alkyl Bromides. , 2012 .

[46]  E. Carreira,et al.  Recent Advances in the Total Synthesis of Chlorosulfolipids (Eur. J. Org. Chem. 9/2012) , 2012 .

[47]  I. Davies,et al.  Convergent, Fit-For-Purpose, Kilogram-Scale Synthesis of a 5-Lipoxygenase Inhibitor , 2012 .

[48]  S. Matsunaga,et al.  Enantioselective Synthesis of 2,2-Disubstituted Terminal Epoxides via Catalytic Asymmetric Corey-Chaykovsky Epoxidation of Ketones , 2012, Molecules.

[49]  Vijay T. Ahuja,et al.  An Efficient, Direct Bis-ortho-chlorination of 4-(Difluoromethoxy)aniline and Its Application to the Synthesis of BMS-665053, a Potent and Selective Pyrazinone-Containing Corticotropin-Releasing Factor-1 Receptor Antagonist , 2012 .

[50]  Y Wang,et al.  Recent researches in triazole compounds as medicinal drugs. , 2012, Current medicinal chemistry.

[51]  Sébastien Ladouceur,et al.  One-Pot Click Synthesis of 1N-Alkyl-4-aryl-1,2,3-triazoles from Protected Arylalkynesand Alkyl Bromides , 2011 .

[52]  V. Pore,et al.  Click chemistry: 1,2,3-triazoles as pharmacophores. , 2011, Chemistry, an Asian journal.

[53]  M. Yus,et al.  Catalytic enantioselective allylation of carbonyl compounds and imines. , 2011, Chemical reviews.

[54]  R. Yazaki,et al.  Asymmetric synthesis of isothiazoles through Cu catalysis: direct catalytic asymmetric conjugate addition of allyl cyanide to α,β-unsaturated thioamides. , 2011, Angewandte Chemie.

[55]  Lili Lin,et al.  Catalytic asymmetric conjugate allylation of coumarins. , 2011, Organic letters.

[56]  P. Metrangolo,et al.  Organic fluorine compounds: a great opportunity for enhanced materials properties. , 2011, Chemical Society reviews.

[57]  Wenqin Zhang,et al.  Catalytic enantioselective alkynylation of trifluoromethyl ketones: pronounced metal fluoride effects and implications of zinc-to-titanium transmetallation. , 2011, Angewandte Chemie.

[58]  Y. Funahashi,et al.  N-(heteroarenesulfonyl)prolinamides-catalyzed aldol reaction between acetone and aryl trihalomethyl ketones. , 2011, Organic letters.

[59]  P. Cozzi,et al.  Copper-promoted enantioselective Reformatsky-type reaction with ketones , 2010 .

[60]  Shuangliu Zhou,et al.  Highly Enantioselective 3‐Furylation of Ketones Using (3‐Furyl)titanium Nucleophile. , 2010 .

[61]  Songlin Zhang,et al.  A Facile Synthesis of Two Series of Multifunctional Carbon Compounds from α,α-Dihalo Ketones Using Allylsamarium Bromide. , 2010 .

[62]  Shuangliu Zhou,et al.  Highly enantioselective 3-furylation of ketones using (3-furyl)titanium nucleophile. , 2010, Organic letters.

[63]  B. G. Davis,et al.  Accessible sugars as asymmetric olefin epoxidation organocatalysts: glucosaminide ketones in the synthesis of terminal epoxides. , 2009, Organic & biomolecular chemistry.

[64]  M. Zhang,et al.  Multi-product classes obtained from allylation of alpha-halo ketones with allylzinc bromide. , 2009, Chemistry.

[65]  Songlin Zhang,et al.  A Facile Synthesis of Two Seriesof Multifunctional Carbon Compounds from α,α-DihaloKetones Using Allylsamarium Bromide , 2009 .

[66]  トーマス クライン,et al.  dpp-iv inhibitors for use in the treatment of Nafld , 2009 .

[67]  A. Fu,et al.  A perfect double role of CF3 groups in activating substrates and stabilizing adducts: the chiral Brønsted acid-catalyzed direct arylation of trifluoromethyl ketones. , 2009, Chemical communications.

[68]  Kuo-Hui Wu,et al.  Highly enantioselective arylation of aldehydes and ketones using AlArEt(2)(THF) as aryl sources. , 2009, The Journal of organic chemistry.

[69]  Songlin Zhang,et al.  A Facile One‐Pot Synthesis of α‐Halo‐α‐allyl‐aldehydes from α,α‐Dihaloketones Using Allylsamarium Bromide and DMF. , 2008 .

[70]  Yian Shi,et al.  Asymmetric epoxidation of 1,1-disubstituted terminal olefins by chiral dioxirane via a planar-like transition state. , 2008, The Journal of organic chemistry.

[71]  S. Matsunaga,et al.  Catalytic asymmetric synthesis of 2,2-disubstituted terminal epoxides via dimethyloxosulfonium methylide addition to ketones. , 2008, Journal of the American Chemical Society.

[72]  M. Snapper,et al.  Catalytic enantioselective Hosomi-Sakurai conjugate allylation of cyclic unsaturated ketoesters. , 2008, Angewandte Chemie.

[73]  Songlin Zhang,et al.  A Facile One-Pot Synthesis of α-Halo-α-allyl-aldehydes from α,α-Dihaloketones Using Allylsamarium Bromide and DMF , 2008 .

[74]  J. Morken,et al.  Asymmetric Ni-catalyzed conjugate allylation of activated enones. , 2008, Journal of the American Chemical Society.

[75]  Philip Taynton,et al.  Asymmetric indium-mediated Barbier-type allylation reactions with ketones to form homoallylic alcohol products , 2008 .

[76]  E. Jacobsen,et al.  Cooperative catalysis by tertiary amino-thioureas: mechanism and basis for enantioselectivity of ketone cyanosilylation. , 2007, Journal of the American Chemical Society.

[77]  M. Kanai,et al.  Copper(I) alkoxide-catalyzed alkynylation of trifluoromethyl ketones. , 2007, Organic letters.

[78]  Kuo-Hui Wu,et al.  Highly enantioselective aryl additions of [AlAr3(thf)] to ketones catalyzed by a titanium(IV) catalyst of (S)-binol. , 2007, Angewandte Chemie.

[79]  P. Ramachandran,et al.  The influence of fluorine on the asymmetric reduction of fluoromethyl ketones , 2007 .

[80]  Ching-Yao Chang,et al.  Asymmetric zinc-Reformatsky reaction of Evans chiral imide with acetophenones and its application to the stereoselective synthesis of triazole antifungal agents , 2007 .

[81]  M. Yus,et al.  First catalytic enantioselective synthesis of the cocaine abuse therapeutic agent (S)-(+)-1-(4-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazin-1-yl)-2-phenyl-2-propanol , 2007 .

[82]  M. Sigman,et al.  Design and synthesis of modular oxazoline ligands for the enantioselective chromium-catalyzed addition of allyl bromide to ketones. , 2007, Journal of the American Chemical Society.

[83]  S. Schaus,et al.  Asymmetric allylboration of ketones catalyzed by chiral diols. , 2006, Journal of the American Chemical Society.

[84]  M. Yus,et al.  trans-1-Sulfonylamino-2-isoborneolsulfonylaminocyclohexane derivatives: excellent chiral ligands for the catalytic enantioselective addition of organozinc reagents to ketones. , 2006, Chemistry.

[85]  Masato Suzuki,et al.  Catalytic enantioselective synthesis of key intermediates for triazole antifungal agents. , 2005, Organic letters.

[86]  Q. Xia,et al.  Advances in homogeneous and heterogeneous catalytic asymmetric epoxidation. , 2005, Chemical reviews.

[87]  P. Cozzi,et al.  BINOL catalyzed enantioselective addition of titanium phenylacetylide to aromatic ketones. , 2004, Chemical communications.

[88]  A. Khosropour,et al.  Zn/CeCl3.7H2O-TBPB: A new and 'green' promoter system for rapid and regioselective thiolyzation of 1,2-epoxides with aryl disulfides , 2004 .

[89]  M. Iwata,et al.  Stereospecific Construction of Chiral Quaternary α-Oxygenated Aldehydes from Chiral Secondary Alcohol Derivatives , 2004 .

[90]  P. Walsh,et al.  Highly enantioselective catalytic phenylation of ketones with a constrained geometry titanium catalyst. , 2003, Organic letters.

[91]  M. Iwata,et al.  Stereospecific Construction of Chiral Quaternary Carbon Compounds from Chiral Secondary Alcohol Derivatives , 2003 .

[92]  J. Yadav,et al.  Cerium(III) chloride promoted highly regioselective ring opening of epoxides and aziridines using NaN(3) in acetonitrile: a facile synthesis of 1,2-azidoalcohols and 1,2-azidoamines. , 2002, Organic letters.

[93]  J. Yadav,et al.  Highly Regioselective Ring Opening of Epoxides and Aziridines Using Cerium(III) Chloride. , 2001 .

[94]  T. Loh,et al.  An enantioselective indium-mediated allylation reaction of aldehydes and ketones in dichloromethane , 1999 .

[95]  M. Wills,et al.  A Novel Phosphinamide Catalyst for the Asymmetric Reduction of Ketones by Borane. , 1998, The Journal of organic chemistry.

[96]  A. Dexter,et al.  Highly Enantioselective Epoxidation of 1,1-Disubstituted Alkenes Catalyzed by Chloroperoxidase , 1995 .

[97]  S. Didomenico,et al.  The enantioselective synthesis of the potent dopamine D1 agonist (1R,3S)-3-(1'-adamantyl)-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran (A77636) , 1992 .

[98]  E. Corey,et al.  A general, catalytic, and enantioselective synthesis of .alpha.-amino acids , 1992 .

[99]  E. Corey,et al.  Remarkably effective and simple syntheses of enantiomerically pure secondary carbinols from achiral ketones , 1991 .

[100]  E. Corey,et al.  A CATALYTIC ENANTIOSELECTIVE SYNTHESIS OF DENOPAMINE, A USEFUL DRUG FOR CONGESTIVE HEART FAILURE , 1991 .

[101]  E. Meltzer,et al.  A dose-ranging study of fluticasone propionate aqueous nasal spray for seasonal allergic rhinitis assessed by symptoms, rhinomanometry, and nasal cytology. , 1990, The Journal of allergy and clinical immunology.

[102]  Scott R. Wilson,et al.  Enantioselective Epoxidation of Unfunctionalized Olefins Catalyzed by (salen)Manganese Complexes , 1990 .

[103]  E. Corey,et al.  A stable and easily prepared catalyst for the enantioselective reduction of ketones. Applications to multistep syntheses , 1987 .

[104]  E. Corey,et al.  Highly enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines. Mechanism and synthetic implications , 1987 .

[105]  A. Sjoerdsma,et al.  Late-stage African trypanosomiasis and eflornithine. , 1986, Annals of internal medicine.

[106]  J. Domagala,et al.  Synthesis and stereochemistry of ethyl (E)-3-methyl-3-phenylglycidate and (E)- and (Z)-1,3-diphenyl-2-buten-1-one oxide , 1979 .