Highly enantioselective introduction of bis(alkoxycarbonyl)methyl group into the 2-position of piperidine skeleton

Copper ion catalyzed carbon–carbon bond forming reaction of N-acyliminium ions with diaryl malonates was achieved with high enantioselectivity. The key intermediates in the method were 2-methoxy-3,4-didehydropiperidines, which were easily prepared through electrochemical oxidation of 1-(p-methoxybenzoyl)piperidine in methanol followed by the conversion of the oxidation product to didehydropiperidine derivative, which was subjected to a chiral Cu(II) catalyzed coupling reaction with diaryl malonates affording diaryl 2-piperidylmalonates. The maximum % ee (ee, enantiomeric excess) was 97% when di-p-chlorophenyl malonate was used as a nucleophile.     

Metal/linked-BINOL complexes: Applications in direct catalytic asymmetric Mannich-type reactions

Development of metal/linked-BINOL complexes and their applications in direct catalytic asymmetric Mannich-type reactions of hydroxyketones are reviewed. A Et₂Zn/linked-BINOL complex was effective for diastereo- and enantioselective synthesis of β-amino alcohols. By choosing the proper protective groups on the imine nitrogen, either anti- or syn-β-amino alcohol was obtained in excellent enantioselectivity (up to >99.5% ee) using the same zinc catalysis. Y{N(SiMe₃)₂}₃/linked-BINOL complex was effective for various hydroxyketones, affording syn-β-amino alcohols with high enantioselectivity (up to 98% ee). To broaden the nucleophile scope to carboxylic acid derivatives, N-acylpyrrole was utilized as an ester equivalent donor. In(O-iPr)₃/linked-BINOL complex was effective for generating an In-enolate from N-acylpyrrole in situ, giving Mannich adducts with high enantioselectivity (up to 98% ee).     

Enantioselective fluoride ring opening of aziridines enabled by cooperative Lewis acid catalysis

The enantioselective ring opening of aziridines using a latent source of HF is described. A combination of two Lewis acids, (salen)Co and an achiral Ti(IV) cocatalyst, provided optimal reactivity and enantioselectivity for the trans β-fluoroamine product. The use of a chelating aziridine protecting group was crucial. Acyclic and cyclic meso N-picolinamide aziridines underwent fluoride ring opening in up to 84% ee, and the kinetic resolution of a piperidine-derived aziridine was performed with k_rel=6.6. The picolinamide group may be readily removed without epimerization of the fluoroamine. Preliminary studies revealed a bimetallic mechanism wherein the chiral (salen)Co catalyst delivers the nucleophile and the Ti(IV) cocatalyst activates the aziridine.     

Asymmetric Mukaiyama aldol reaction of nonactivated ketones catalyzed by allo-threonine-derived oxazaborolidinone

Asymmetric Mukaiyama aldol reaction of nonactivated ketones is realized for the first time by using an oxazaborolidinone catalyst derived from O-benzoyl-N-tosyl-allo-threonine. By employing a dimethylsilyl ketene S,O-acetal as a nucleophile, a variety of acetophenone derivatives afford the corresponding tertiary beta-hydroxy carbonyl compounds with high enantioselectivity up to 98% ee.     

Palladium-catalyzed asymmetric tandem allylic substitution using chiral 2-(phosphinophenyl)pyridine ligand

Palladium-catalyzed asymmetric tandem allylic substitution of (Z)-1,4-diacyloxy- and (Z)-1,4-bis(alkoxycarbonyloxy)-2-butene (2a-c) using 2-(phosphinophenyl)pyridine 1 as chiral ligand provided optically active six-membered 2-vinyl-1,4-diheterocyclic compounds with good to high enantioselectivity. For example, the reactions with catechol, 2-(benzylamino)phenol, or 1,2-bis(benzylamino)ethane as a nucleophile gave 2-vinyl-1,4-benzodioxane (71% ee), 4-benzyl-2-vinyl-1,4-benzoxazine (86% ee), and 1,4-dibenzyl-2-vinylpiperazine (86% ee), respectively.     

A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions

A novel chiral 1,2-diaminocyclohexane derivative, (1R,2R)-N¹-n-pentyl, N¹-benzyl-1,2-cyclohexanediamine, was designed, synthesized and applied as a catalyst in a number of aldol reactions between ketones and aryl aldehydes. Reactions between acetone and aryl aldehydes gave aldol products with moderate to good yields and with excellent enantioselectivity (up to yield 85%, ee 98%), while reactions between cyclohexanone and aryl aldehydes provided anti-β-hydroxyketone products with excellent yields, diastereoselectivity and with enantioselectivity (up to 82% yield, anti/syn ratio 99:1, ee 99%). The aldol reactions between acetone and isatins were investigated, which afforded excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-isomers of convolutamydine A were obtained with 95% yield and 96% ee, and 95% yield and 94% ee, respectively.     

Enantioselective aza-Friedel–Crafts reaction catalyzed by a water inclusion complex of O,O′-diacyl tartaric acid

The efficiency of an O,O′-diacyl tartaric acid derivative as a chiral Brønsted acid catalyst was investigated in the enantioselective Friedel–Crafts reaction of indoles with an α-imino ester. The inclusion of water in the O,O′-di-p-toluoyl-d-tartaric acid catalyst is crucial for obtaining the enantioselectivity, and under optimal conditions the corresponding Friedel–Crafts product was obtained with an enantioselectivity of up to 88% ee.     

Catalytic enantioselective alkenylation and phenylation of trifluoromethyl ketones

Catalytic enantioselective alkenylation and phenylation of trifluoromethyl ketones are described. High enantioselectivity (up to 84% ee) was produced in an alkenylation of aryl trifluoromethyl ketones using a CuF-DTBM-SEGPHOS complex as the catalyst (5-10 mol %) and alkenylsilanes as the nucleophile. This is the first example of catalytic enantioselective alkenylation of trifluoromethyl ketones. The products are versatile chiral building blocks, which contain a trifluoromethyl-substituted tertiary alcohol moiety.     

Malonate-type bis(oxazoline) ligands with sp hybridized bridge carbon: synthesis and application in Friedel-Crafts alkylation and allylic alkylation

A series of simple and new C₂-symmetric diphenylmethylidene malonate-type bis(oxazoline) ligands were synthesized and applied to the Friedel-Crafts reaction and allylic alkylation. The Cu(II) complex of ligand 4b bearing the benzyl group afforded good to excellent enantioselectivity for the F-C adducts (up to >99% ee) between indole and alkylidene malonate, and the palladium complex of ligand 4c bearing the phenyl group afforded excellent enantioselectivity (up to 94% ee) for the allylic alkylation product.     

Aminolytic kinetic resolution of trans epoxides for the simultaneous production of chiral trans β-amino alcohols in the presence of chiral Cr(III) salen complex using an ionic liquid as a green reaction media

Chiral Cr(III) salen complex 1 having t-Bu substituents at 3,3′ and 5,5′-positions was used as a catalyst for the highly enantioselective aminolytic kinetic resolution (AKR) of racemic trans epoxides with different anilines as nucleophile in the presence of different ionic liquids at rt. Excellent yields (>98%) of anti β-aminoalcohols with high enantioselectivity (ee >99%) was achieved in 4 h when [bmim]PF₆ was used as the ionic liquid. The present ionic liquid mediated AKR process is recyclable (up to six cycles with no loss in performance) and is five times quicker than the homogeneous process utilizing conventional organic solvents.     

Chiral 1,2-diaminocyclohexane as organocatalyst for enantioselective aldol reaction

A simple and commercially available chiral 1,2-diaminocyclohexane as catalyst, hexanedioic acid as co-catalyst could efficiently catalyze the asymmetric aldol reaction in MeOH-H₂O. Cyclic ketones as aldol substrates gave the anti-β-hydroxyketone products with moderate to good yields, diastereoselectivity and enantioselectivity (up to 78% yield, >20:1 anti/syn, 94% ee). Hydroxyacetone as aldol substrate afforded the syn-α, β-dihydroxyketones as major products in up to 85% yield with good enantioselectivity (up to >20:1 syn/anti, 93% ee).     

Cymantrene-based iminodiamidophosphites: the first phosphite-type ligands with planar chirality

Optically active phosphite-type ligands with planar chirality have been synthesized for the first time. The new cymantrene-based P,N-iminodiamidophosphites demonstrated high enantioselectivity in the Pd-catalyzed allylic substitution of 1,3-diphenylallyl acetate with dimethyl malonate (up to 94% ee), pyrrolidine (up to 78% ee) and sodium para-toluene sulfinate (up to 84% ee).     

Synthesis of enantiopure β-amino alcohols via AKR/ARO of epoxides using recyclable macrocyclic Cr(III) salen complexes

A series of chiral macrocyclic Cr(III) salen complexes 1-8 were synthesized and characterized. These complexes were found to be highly active, regio-, diastereo-, and enantioselective catalysts in aminolytic kinetic resolution (AKR) of racemic trans-epoxides as well as asymmetric ring opening (ARO) of prochiral meso-epoxides with various anilines as nucleophiles at room temperature in 18-24 h. Excellent yields (>99% with respect to the nucleophile) with high enantioselectivity (ee, >99%) of chiral anti-β-amino alcohols was achieved with concomitant recovery of corresponding epoxides in high ee (up to >99%). The complex 1 also catalyzed the ARO of meso-epoxides to provide corresponding syn-β-amino alcohols in high yield (99%) and ee (up to 91%). Due to built-in basic sites in the catalyst, no external base (as an additive) was required to promote AKR and ARO reactions. The catalyst 1 was conveniently recycled several times with retention of its performance. The AKR of trans-stilbene oxide with aniline was successfully demonstrated at relatively higher scale (10 mmol) using the catalyst 1.     

Catalytic enantioselective allylation of ketoimines

A general catalytic allylation of simple ketoimines was developed using 1 mol % of CuF.3PPh(3) as catalyst, 1.5 mol % of La(O(i)Pr)(3) as the cocatalyst, and stable and nontoxic allylboronic acid pinacol ester as the nucleophile. This reaction constituted a good template for developing the first catalytic enantioselective allylation of ketoimines. In this case, using LiO(i)Pr as the cocatalyst produced higher enantioselectivity and reactivity than La(O(i)Pr)(3). Thus, using the CuF-cyclopentyl-DuPHOS complex (10 mol %) and LiO(i)Pr (30 mol %) in the presence of (t)BuOH (1 equiv) produced high enantioselectivity up to 93% ee from a range of aromatic ketoimines. Mechanistic studies indicated that LiO(i)Pr accelerates the reaction by increasing the concentration of an active nucleophile, allylcopper.     

Asymmetric synthesis of activated cyclopropanes catalyzed by cinchonidine as a chiral Brønsted base

Cinchonidine catalyzed the cyclopropanation reaction between chloromethyl ketones and β-substituted methylidenemalononitriles to give trans-cyclopropanes with enantioselectivity up to 82% ee. Experimental evidence suggests that cinchonidine functions as a chiral Brønsted base catalyst in the reaction and hydrogen bonding is essential for inducing high enantioselectivity.     

Dimethylsilyl ketene acetal as a nucleophile in asymmetric Michael reaction: enhanced enantioselectivity in oxazaborolidinone-catalyzed reaction

[reaction: see text] Dimethylsilanyl [Me2Si(H)] ketene S,O-acetal 6b is an effective nucleophile that retards the undesirable Si+-catalyzed racemic pathway in the oxazaborolidinone-catalyzed asymmetric Michael reaction. Through the further suppression of the Si+-catalyzed pathway by carrying out the reaction in the presence of 2,6-diisopropylphenol and t-BuOMe as additives, enantioselectivity up to 98% ee could be achieved for a variety of acyclic enones.     

Catalytic enantioselective allylboration of ketones

The first example of catalytic enantioselective allylboration and crotylboration of simple ketones is described. High enantioselectivity (up to 93% ee) was obtained using 3 mol % CuF-iPr-DuPHOS as a chiral catalyst and 4.5 mol % La(OiPr)3 as a cocatalyst. Mechanistic studies strongly suggested that the active nucleophile of the present reaction is an allylcopper, and that La(OiPr)3 facilitates the generation of an active allylcopper from the allylboronate, without affecting the transition-state structure of the ketone allylation step.     

N-Salicyl-β-aminoalcohols as a new class of ligand for catalytic asymmetric Strecker reactions

An enantioselective Strecker synthesis employing novel chiral titanium complex catalysts derived from structurally simple chiral N-salicyl-β-amino alcohols is described. Reactions of N-benzylidenebenzylamine with trimethylsilyl cyanide in the presence of the catalyst (10 mol%) gave the corresponding α-aminonitrile in good to excellent yields, along with relatively high enantioselectivity (up to 86% ee). Similar reactions with various imines derived from aromatic aldehydes resulted in moderate to good enantioselectivity (44-81% ee).     

Reductive aldol cyclizations of unsaturated thioester derivatives of 1,3-cyclopentanedione catalyzed by chiral copper hydrides

The first study on the asymmetric reductive aldol reactions of enethioate derivatives of 1,3-cyclopentanedione showed that 5 mol % of TANIAPHOS (SL-T001-1), and Cu(OAc)₂·H₂O, together with phenylsilane as the stoichiometric reductant, generated the best yields and enantioselectivities of β-hydroxythioester products. With S-benzyl keto-enethioate as substrate, the bicyclo[4.3.0] hydroxythioester product was obtained only as the all-cis diastereomer, in good yield (84%) and enantioselectivity (up to 90% ee). With the related indanedione enethioate derivatives, the reductive aldol cyclization could attain up to 96% ee. These results demonstrate that enethioates have a significantly different reactivity and selectivity profile compared to enoate derivatives in the copper-catalyzed reductive aldol cyclization.     

Asymmetric synthesis of chiral glutaric acid derivatives via Rh-catalyzed enantioselective hydrogenation

The first Rh-catalyzed enantioselective hydrogenation of dimethyl 2-methyleneglutarate and its derivatives has been reported. For the hydrogenation of dimethyl 2-methyleneglutarate with a chiral ferrocene-based monodentate phosphoramidite ligand (FAPhos), good enantioselectivity (over 90% ee) with full conversions was achieved. In contrast, the hydrogenation of substrates bearing an aryl substituent at a methylene moiety proved to be more difficult, in which the best enantioselectivity of up to 81% ee was obtained by the use of a P-stereogenic BoPhoz-type ligand.