CuH-Catalyzed Enantioselective Ketone Allylation with 1,3-Dienes: Scope, Mechanism, and Applications.
ABSTRACT: Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of the product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process. Finally, this method was applied to the preparation of an important drug, ( R)-procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.
Project description:Chiral ruthenium(II) complexes modified by Josiphos ligands catalyze the reaction of alkynes with primary alcohols to form homoallylic alcohols with excellent control of regio-, diastereo-, and enantioselectivity. These processes represent the first examples of enantioselective carbonyl allylation using alkynes as allylmetal equivalents.
Project description:Catalytic chemo- and enantioselective generation of tertiary benzylic copper complexes from Cu-B(pin) (pin = pinacolato) additions to 1,1-disubstituted alkenes followed by <i>in situ</i> reactions with ketones and carboxylic acid phenol esters to construct multifunctional alkylboron compounds that contain quaternary stereogenic centers is presented. The method is distinguished by the unprecedented reaction mode of tertiary benzylic Cu complexes, allowing reaction with a wide range of carbonyl electrophiles in good yields and with high chemo-, site-, diastereo- and enantioselectivity. The catalytic protocol was performed with easily accessible chiral ligands and copper salts at ambient temperature. Functionalization of multifunctional alkylboron products provides useful building blocks that are otherwise difficult to access.
Project description:A copper-catalyzed, chemoselective hydrometalation process enables the use of simple allenes as allylmetal nucleophile surrogates in imine allylation reactions. By modulating the nitrogen-protecting group, either highly branched- or linear-selective addition can be achieved from the same allene. Both reactions exhibit excellent diastereoselectivity and broad functional-group tolerance. Preliminary results indicate that good enantioselectivity can also be achieved in the linear-selective reaction. Finally, a mechanistic model for the regiodivergence is proposed on the basis of density functional theory calculations.
Project description:The first enantioselective carbonyl crotylations through direct use of alkynes as chiral allylmetal equivalents are described. Chiral ruthenium(II) complexes modified by Josiphos (SL-J009-1) catalyze the C-C coupling of TIPS-protected propargyl ether 1a with primary alcohols 2a-2o to form products of carbonyl siloxy-crotylation 3a-3o, which upon silyl deprotection-reduction deliver 1,4-diols 5a-5o with excellent control of regio-, anti-diastereo-, and enantioselectivity. Structurally related propargyl ethers 1b and 1c bearing ethyl- and phenyl-substituents engage in diastereo- and enantioselective coupling, as illustrated in the formation of adducts 5p and 5q, respectively. Selective mono-tosylation of diols 5a, 5c, 5e, 5f, 5k, and 5m is accompanied by spontaneous cyclization to deliver the trans-2,3-disubstituted furans 6a, 6c, 6e, 6f, 6k, and 6m, respectively. Primary alcohols 2a, 2l, and 2p were converted to the siloxy-crotylation products 3a, 3l, and 3p, which upon silyl deprotection-lactol oxidation were transformed to the trans-4,5-disubstituted ?-butyrolactones 7a, 7l, and 7p. The formation of 7p represents a total synthesis of (+)-trans-whisky lactone. Unlike closely related ruthenium catalyzed alkyne-alcohol C-C couplings, deuterium labeling studies provide clear evidence of a novel 1,2-hydride shift mechanism that converts metal-bound alkynes to ?-allyls in the absence of intervening allenes.
Project description:We report a method for the highly enantioselective CuH-catalyzed allylation of ketones that employs terminal allenes as allylmetal surrogates. Ketones and allenes bearing diverse and sensitive functional groups are efficiently coupled with high stereoselectivity and exclusive branched regioselectivity. In stoichiometric experiments, each elementary step of the proposed hydrocupration-addition-metathesis mechanism can be followed by NMR spectroscopy.
Project description:A new method for the enantioselective synthesis of hexahydro-1H-benz[f]indoles is described. This copper-catalyzed enantioselective intramolecular alkene carboamination process can install vicinal tertiary and quaternary carbon stereocenters with high levels of diastereo- and enantioselectivity. The C-C bond-forming component of the reaction constitutes a C-H functionalization and no electronic activation of the aryl ring that undergoes addition is required. A known 5-HT(1A) receptor antagonist was synthesized efficiently using this method.
Project description:The catalytic asymmetric methylation of fluoroalkylated pyruvates is shown with dimethylzinc as a methylating reagent in the presence of a copper catalyst bearing a chiral phosphine ligand. This is the first catalytic asymmetric methylation to synthesize various ?-fluoroalkylated tertiary alcohols with CF<sub>3</sub>, CF<sub>2</sub>H, CF<sub>2</sub>Br, and <i>n</i>-C <i><sub>n</sub></i> F<sub>2</sub><i><sub>n</sub></i><sub>+1</sub> (<i>n</i> = 2, 3, 8) groups in good-to-high yields and enantioselectivities. Axial backbones and substituents on phosphorus atoms of chiral phosphine ligands critically influence the enantioselectivity. Moreover, the methylation of simple perfluoroalkylated ketones is found to be facilitated by only chiral phosphines without copper.
Project description:Tri- and tetrasubstituted allenylboronic acids were prepared via a new versatile copper-catalyzed methodology. The densely functionalized allenylboronic acids readily undergo propargylboration reactions with ketones and imines without any additives. Catalytic asymmetric propargylborylation of ketones is demonstrated with high stereoselectivity allowing for the synthesis of highly enantioenriched tertiary homopropargyl alcohols. The reaction is suitable for kinetic resolution of racemic allenylboronic acids affording alkynes with adjacent quaternary stereocenters.
Project description:The asymmetric alkylation of acyclic ketones is a longstanding challenge in organic synthesis. Reported herein are diastereoselective and enantioselective allylic substitutions with acyclic ?-alkoxy ketones catalyzed by a metallacyclic iridium complex to form products with contiguous stereogenic centers derived from the nucleophile and electrophile. These reactions occur between allyl methyl carbonates and unstabilized copper(I) enolates generated in?situ from acyclic ?-alkoxy ketones. The resulting products can be readily converted into enantioenriched tertiary alcohols and tetrahydrofuran derivatives without erosion of enantiomeric purity.
Project description: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 ?-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.