Kazutaka Shibatomi

Highly enantioselective chlorination of β-keto esters and subsequent S(N)2 displacement of tertiary chlorides: a flexible method for the construction of quaternary stereogenic centers.

Highly enantioselective chlorination of β-oxo esters and subsequent stereospecific substitution of tertiary chlorides are described. Enantioselective chlorination of β-keto esters and malonates was performed using a chiral Lewis acid catalyst prepared from Cu(OTf)(2) and the newly developed spirooxazoline ligand 2 to yield the desired α-chlorinated products with high enantioselectivity (up to 98% ee). Nucleophilic substitution of the resulting chlorides proceeded smoothly to afford a variety of chiral molecules such as α-amino, α-alkylthio, and α-fluoro esters, without loss of enantiopurity. The results of X-ray crystallographic analysis proved that Walden inversion occurs at the chlorinated tertiary carbon center. These results supported the fact that the substitution proceeds via an S(N)2 mechanism.

Stereoselective Synthesis of α,α-Chlorofluoro Carbonyl Compounds Leading to the Construction of Fluorinated Chiral Quaternary Carbon Centers

The preparation of fluorine-containing organic molecules has attracted considerable attention in the field of pharmaceutical and agricultural chemistry.[1] One of the most challenging synthetic operations used to access these molecules is the stereoselective construction of a fluorinated chiral carbon center.[2] Various stereoselective electrophilic fluorination reagents have been developed for this purpose.[3] Following a study by Hintermann and Togni,[4a] efficient catalytic asymmetric fluorination reactions of β-ketoesters have been reported.[4b, e] Organocatalytic enantioselective α-fluorination reactions of aldehydes have also been successfully realized.[5] Although the field of asymmetric α-fluorination is progressing steadily, a flexible route for the stereoselective construction of fluorinated quaternary carbon centers is still required. We propose the synthesis of optically active α,α-chlorofluoro carbonyl compounds, which can be stereoselectively converted into various chiral molecules with a fluorinated quaternary carbon by nucleophilic substitution (Scheme 1). Surprisingly little attention has been given to the synthesis of optically active α,α-chlorofluoro carbonyl compounds[6] or their selective transformation.[7] Herein, we disclose the first enantioselective synthesis of α,α-chlorofluoro carbonyl compounds from simple aldehydes or ketones, and their subsequent transformation into a variety of optically active molecules in which the fluorinated quaternary carbon center is adjacent to the carbonyl group.

Enantioselective gem-chlorofluorination of active methylene compounds using a chiral spiro oxazoline ligand.

Highly enantioselective gem-chlorofluorination of active methylene compounds was carried out by using a copper(II) complex of a chiral spiro pyridyl monooxazoline ligand. This reaction yielded α-chloro-α-fluoro-β-keto esters and α-chloro-α-fluoro-β-keto phosphonates with up to 92% ee. The resulting dihalo β-keto ester was converted into various α-fluoro-α-heteroatom-substituted carbonyl compounds via nucleophilic substitution without loss of optical purity. A fully protected β-amino acid with a gem-chlorofluoromethylene function was also synthesized.

Asymmetric Inter‐ and Intramolecular Cyclopropanation Reactions Catalyzed by a Reusable Macroporous‐Polymer‐Supported Chiral Ruthenium(II)/Phenyloxazoline Complex

relatively low to moderate yields have so far been achieved.After an extensive literature survey, we concluded that all ofthe previously reported PSCCs depended on the polymeri-zation of a monomeric chiral ligand or the grafting of a chiralligand onto a polymeric support and subsequent complex-ation with a metal.

Stereoselective Construction of Halogenated Quaternary Stereogenic Centers via Catalytic Asymmetric Diels−Alder Reaction

Highly enantioselective Diels-Alder reactions of alpha-halo-alpha,beta-unsaturated ketones with Lewis acid-activated chiral oxazaborolidine 1 are described. The reaction with alpha-fluoroenones provided the corresponding cyclohexane derivatives having a fluorinated quaternary stereogenic center with up to 99% de and 94% ee. The reaction with alpha-bromo cyclic enones provided the corresponding bromo bicyclic adducts with up to 99% de and 95% ee. A brominated cis-fused bicyclic adduct derived from 2-bromocyclopenten-1-one and Danes diene was converted to the trans-fused bicyclic system via reductive alkylation with the bulky aluminum reagent aluminum tris(2,6-diphenylphenoxide) (ATPH). With this process, formal syntheses of (+)-estrone and norgestrel have been demonstrated.

Highly Enantioselective Synthesis of Cyclopropylamine Derivatives via Ru(II)-Pheox-Catalyzed Direct Asymmetric Cyclopropanation of Vinylcarbamates

The Ru(II)-Pheox-catalyzed asymmetric cyclopropanation of vinylcarbamates with diazoesters resulted in the corresponding cyclopropylamine derivatives in high yield and excellent diastereoselectivity (up to 96:4) and enantioselectivity (up to 99% ee).

Highly Stereoselective Cyclopropanation of α,β‐Unsaturated Carbonyl Compounds with Methyl (Diazoacetoxy)acetate Catalyzed by a Chiral Ruthenium(II) Complex

Transition-metal-catalyzed asymmetric cyclopropanation of olefins with diazoacetates is a highly useful synthetic transformation for the construction of optically active cyclopropane frameworks, which are important structures because of their appearance in a wide variety of biologically active molecules. Therefore, during the past two decades, various catalytic systems have been developed for the highly diastereoand enantioselective cyclopropanation reactions. In particular, good stereocontrolled syntheses of cyclopropane derivatives have been achieved using copper, rhodium, ruthenium, and recently cobalt as catalysts. However, despite these considerable advances, only a few catalytic systems can catalyze the asymmetric cyclopropanation of electron-deficient olefins, such as a,b-unsaturated carbonyl compounds. Because of the electrophilic nature of the metal–carbene intermediate obtained by the reaction of metal complexes and diazoacetate, electron-rich olefins are generally preferred as reactants (Scheme 1).

New homochiral phosphine ligands having a hexahydro-1H-pyrrolo[1,2-c]imidazolone backbone: preparation and use for palladium-catalyzed asymmetric alkylation of cycloalkenyl carbonates

New chiral ligands having a pyrrolo[1,2-c]imidazolone backbone were prepared by condensation of anilides of homochiral cyclic amino acids with 2-(diphenylphosphino)benzaldehyde. Of these ligands, (3R,9aS)-(3-(2-diphenylphosphino)phenyl-2-phenyl)tetrahydro-1H-imidazo[1,5-a]indole-1-one was found to be effective for palladium-catalyzed asymmetric allylic alkylation of cycloalkenyl carbonates with dimethyl malonate to give the corresponding dimethyl cycloalkenylmalonates with e.e. of up to 89%.

Highly Stereoselective Synthesis of Cyclopropylphosphonates Catalyzed by Chiral Ru(II)-Pheox Complex

Ru(II)-Pheox-catalyzed asymmetric cyclopropanation of diethyl diazomethylphosphonate with alkenes, including α,β-unsaturated carbonyl compounds, afforded the corresponding optically active cyclopropylphosphonates in high yields and with excellent diastereoselectivity (up to 99:1) and enantioselectivity (up to 99% ee).

Lewis Acid Catalyzed Benzylic Bromination

The Lewis acid catalyzed bromination of aromatic side chains was achieved efficiently by using 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) as the bromination reagent under mild conditions. Zirconium(IV) chloride showed the highest catalytic activity for this benzylic bromination. It was revealed that the present Lewis acid catalysis proceeds by the radical-generation pathway. In contrast, Brønsted acids promoted aromatic-ring bromination without any benzylic bromination. Monobromination of tetramethylsilane was also demonstrated with zirconium(IV) chloride and DBDMH to provide the desired product in good yield.