Catalytic enantioselective epoxidation with arabinose-derived uloses containing tunable steric sensors

Readily available arabinose-derived 4-uloses, containing a tunable butane-2,3-diacetal as the steric sensor, displayed increasing enantioselectivity (up to 93% ee) with the size of the acetal alkyl group in catalytic asymmetric epoxidation of trans-disubstituted and trisubstituted alkenes.     

New mannose-derived ketones as organocatalysts for enantioselective dioxirane-mediated epoxidation of arylalkenes. Part 3: Chiral ketones from sugars

New d-arabino-hexopyranosid-3-uloses were synthesized by a simple method from mannopyranoside derivatives. The common skeleton possesses a tunable alkoxy group as steric sensor on carbon 2 of the sugar. The new ketones were employed in the dioxirane-mediated epoxidation of a range of trans- and trisubstituted arylalkenes giving enantiomeric excesses from low to good (30-90%). The effect of the size of the steric sensor on the enantioselectivity was also studied. The least bulky group (methoxy group) enhanced the stereoselectivity (up to 90% ee toward triphenylethylene).     

Enabling highly (R)-enantioselective epoxidation of styrene by engineering unique non-natural P450 peroxygenases

Unlike the excellent (S)-enantioselective epoxidation of styrene performed by natural styrene monooxygenases (ee > 99%), the (R)-enantioselective epoxidation of styrene has not yet achieved a comparable efficiency using natural or engineered oxidative enzymes. This report describes the H₂O₂-dependent (R)-enantioselective epoxidation of unfunctionalized styrene and its derivatives by site-mutated variants of a unique non-natural P450BM3 peroxygenase, working in tandem with a dual-functional small molecule (DFSM). The observed (R)-enantiomeric excess (ee) of styrene epoxidation is up to 99% with a turnover number (TON) of 918 by the best enantioselective mutant F87A/T268I/L181Q, while the best active mutant F87A/T268I/V78A/A184L (with 98% ee) gave a catalytic TON of 4350, representing the best activity of a P450 peroxygenase towards styrene epoxidation to date. Following this approach, a set of styrene derivatives, such as o-, m-, p-chlorostyrenes and fluorostyrenes, could also be epoxidized with modest to very good TONs (362–3480) and high (R)-enantioselectivities (95–99% ee). The semi-preparative scale synthesis of (R)-styrene oxide performed at 0 °C with high conversion, maintaining enantioselectivity, and moderate isolated yields, further suggests the potential application of the current P450 enzymatic system in styrene epoxidation. This study indicates that the synergistic use of protein engineering and an exogenous DFSM constitutes an efficient strategy to control the enantioselectivity of styrene epoxidation, thus substantially expanding the chemical scope of P450 enzymes as useful bio-oxidative catalysts.

H₂O₂-dependent epoxidation of unfunctionalized styrenes is achieved with high (R)-enantioselectivity and moderate to excellent TONs by combining site-mutated variants of cytochrome P450BM3 monooxygenase and a dual-functional small molecule (DFSM).     

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).     

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.     

Catalytic asymmetric 1,4-addition reactions using alpha,beta-unsaturated N-acylpyrroles as highly reactive monodentate alpha,beta-unsaturated ester surrogates

Synthesis and application of alpha,beta-unsaturated N-acylpyrroles as highly reactive, monodentate ester surrogates in the catalytic asymmetric epoxidation and Michael reactions are described. alpha,beta-Unsaturated N-acylpyrroles with various functional groups were synthesized by the Wittig reaction using ylide 2. A Sm(O-i-Pr)(3)/H(8)-BINOL complex was the most effective catalyst for the epoxidation to afford pyrrolyl epoxides in up to 100% yield and >99% ee. Catalyst loading was successfully reduced to as little as 0.02 mol % (substrate/catalyst = 5000). The high turnover frequency and high volumetric productivity of the present reaction are also noteworthy. In addition, a sequential Wittig olefination-catalytic asymmetric epoxidation reaction was developed, providing efficient one-pot access to optically active epoxides from various aldehydes in high yield and ee (96-->99%). In a direct catalytic asymmetric Michael reaction of hydroxyketone promoted by the Et(2)Zn/linked-BINOL complex, Michael adducts were obtained in good yield (74-97%), dr (69/31-95/5), and ee (73-95%). This represents the first direct catalytic asymmetric Michael reaction of unmodified ketone to an alpha,beta-unsaturated carboxylic acid derivative. The properties of alpha,beta-unsaturated N-acylpyrrole are also discussed. Finally, the utility of the N-acylpyrrole unit for further transformations is demonstrated.     

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).     

Effective asymmetric epoxidation of styrenes by chiral dioxirane

High enantioselectivity (80-92% enantiomeric excess (ee)) has been obtained for the epoxidation of various styrenes using an easily prepared ketone (4) catalyst.     

Synthesis of cinchonidinium salts containing sulfonamide functionalities and their catalytic activity in asymmetric alkylation reactions

Various kinds of 4-(bromomethyl)benzenesulfonamides were prepared as quaternization reagent of cinchonidine. Cinchonidinium salts obtained from the quaternization of cinchonidine with 4-(bromomethyl)benzenesulfonamide showed highly enantioselective catalytic activity in the asymmetric benzylation of N-(diphenylmethylene)glycine tert-butyl ester. The corresponding phenylalanine derivative was obtained in high yield with a high level of enantioselectivity, up to 98% ee.     

Asymmetric epoxidation of cis-alkenes with arabinose-derived ketones: enantioselective synthesis of the side chain of Taxol

The ee values of asymmetric epoxidation of cis-ethyl cinnamate 15 with arabinose-derived ketones as catalyst and Oxone^® as the terminal oxidant were found to increase inversely with the size of the catalyst acetal blocking group. Ketone catalyst 2, with the least bulky methoxy acetal group, displayed the best enantioselectivity and afforded ethyl (2R,3R)-3-phenylglycidate 16 in 68% ee. Epoxide 16 was readily converted into a protected side chain of Taxol^® in five steps with an overall yield of 89%. The enantioselectivity of the epoxidation of other cis-alkenes was moderate to poor.     

Organocatalytic stereoselective epoxidation of trisubstituted acrylonitriles

The first diastereospecific and enantioselective epoxidation of trans-2-aroyl-3-arylacrylonitriles by means of the commercially available diaryl L-prolinol/tert-butyl hydroperoxide system has been developed. These diversely functionalized epoxides were obtained in excellent yield (up to 99%), complete diastereoselectivity for the trans-isomer, and good enantioselectivity (up to 84% ee). Highly enantioenriched epoxides can be easily obtained after a single crystallization (ee > 90%).     

Titanium Salalen Catalyzed Enantioselective Benzylic Hydroxylation

The titanium complex of the cis-1,2-diaminocyclohexane (cis-DACH) derived Berkessel-salalen ligand is a highly efficient and enantioselective catalyst for the asymmetric epoxidation of terminal olefins with hydrogen peroxide (“Berkessel-Katsuki catalyst”). We herein report that this epoxidation catalyst also effects the highly enantioselective hydroxylation of benzylic C−H bonds with hydrogen peroxide. Mechanism-based ligand optimization identified a novel nitro-salalen Ti-catalyst of the highest efficiency ever reported for asymmetric catalytic benzylic hydroxylation, with enantioselectivities of up to 98 % ee, while overoxidation to ketone is marginal. The novel nitro-salalen Ti-catalyst also shows enhanced epoxidation efficiency, as evidenced by e.g. the conversion of 1-decene to its epoxide in 90 % yield with 94 % ee, at a catalyst loading of 0.1 mol-% only.     

Molecular basis for enantioselectivity of lipase from Chromobacterium viscosum toward the diesters of 2,3-dihydro-3-(4'-hydroxyphenyl)-1,1,3-trimethyl-1H-inden-5-ol

2,3-Dihydro-3-(4'-hydroxyphenyl)-1,1,3-trimethyl-1H-inden-5-ol, 1, is a chiral bisphenol useful for preparation of polymers. Previous screening of commercial hydrolases identified lipase from Chromobacterium viscosum (CVL) as a highly regio- and enantioselective catalyst for hydrolysis of diesters of 1. The regioselectivity was > or =30:1 favoring the ester at the 5-position, while the enantioselectivity varied with acyl chain length, showing the highest enantioselectivity (E = 48 +/- 20 S) for the dibutanoate ester. In this paper, we use a combination of nonsymmetrical diesters and computer modeling to identify that the remote ester group controls the enantioselectivity. First, we prepared nonsymmetrical diesters of (+/-)-1 using another regioselective, but nonenantioselective, reaction. Lipase from Candida rugosa (CRL) showed the opposite regioselectivity (>30:1), allowing removal of the ester at the 4'-position (the remote ester in the CVL-catalyzed reaction). Regioselective hydrolysis of (+/-)-1-dibutanoate (150 g) gave (+/-)-1-5-dibutanoate (89 g, 71% yield). Acylation gave nonsymmetrical diesters that varied at the 4'-position. With no ester at the 4'-position, CVL showed no enantioselectivity, while hindered esters (3,3-dimethylbutanoate) reacted 20 times more slowly, but retained enantioselectivity (E = 22). These results indicate that the remote ester group can control the enantioselectivity. Computer modeling confirmed these results and provided molecular details. A model of a phosphonate transition state analogue fit easily in the active site of the open conformation of CVL. A large hydrophobic pocket tilts to one side above the catalytic machinery. The tilt permits the remote ester at the 4'-position of only the (S)-enantiomer to bind in this pocket. The butanoate ester fits and fills this pocket and shows high enantioselectivity. Both smaller and larger ester groups show low enantioselectivity because small ester groups cannot fill this pocket, while longer ester groups extend beyond the pocket. An improved large-scale resolution of 1-dibutanoate with CVL gave (R)-(+)-1-dibutanoate (269 g, 47% yield, 92% ee) and (S)-(-)-1-4'-monobutanoate (245 g, 52% yield, 89% ee). Methanolysis yielded (R)-(+)-1 (169 g, 40% overall yield, >97% ee) and (S)-(-)-1 (122 g, 36% overall yield, >96% ee).     

Catalytic asymmetric epoxidation of α,β-unsaturated N-acylpyrroles as monodentate and activated ester equivalent acceptors

Catalytic asymmetric epoxidation of α,β-unsaturated N-acylpyrroles as monodentate and activated ester equivalent acceptors is described. A Sm(O-i-Pr)₃/(R)-H₈-BINOL complex promoted the epoxidation reaction to afford products in high yield (up to quant) and high enantiomeric excess (up to >99.5% ee). Reaction proceeded smoothly using cumene hydroperoxide (CMHP) with low explosive hazard, and completed within 0.2-0.5 h with 5 mol % catalyst. Catalyst loading was successfully reduced to as little as 0.02 mol %. The N-acylpyrrole properties as well as efficient synthesis of α,β-unsaturated N-acylpyrroles are also described.     

Bicyclo[3.2.1]octanone catalysts for asymmetric alkene epoxidation: the effect of disubstitution

A series of 2-fluoro-8-oxabicyclo[3.2.1]octan-3-ones are prepared and tested as catalysts for alkene epoxidation with Oxone^®. These catalysts provide trans-stilbene oxide with up to 83% ee, but the highest ee value is obtained with the monofluorinated ketone 2: both 2,2- and 2,4-disubstituted catalysts afford epoxide of lower ee.     

Stereoselective chemoenzymatic synthesis of sitophilate: a natural pheromone

The aggregation pheromone of the granary weevil Sitophilus granarius, (2S,3R)-1-ethylpropyl 3-hydroxy-2-methylpentanoate, has been synthesized in 63% total isolated yield and high chemical and enantiomeric purity (98% de, >99% ee) from readily available methyl 3-oxopentanoate. A stereoselective ketone reduction followed by an ester hydrolysis, were the two key steps of the synthesis and were both performed by commercially available enzymes.     

Chiral epoxides via borane reduction of 2-haloketones catalyzed by spiroborate ester: application to the synthesis of optically pure 1,2-hydroxy ethers and 1,2-azido alcohols

An enantioselective borane-mediated reduction of a variety of 2-haloketones with 10% spiroaminoborate ester 1 as catalyst is described. By a simple basic workup of 2-halohydrins, optically active epoxides are obtained in high yield and with excellent enantiopurity (up to 99% ee). Ring-opening of oxiranes with phenoxides or sodium azide is investigated under different reaction conditions affording nonracemic 1,2-hydroxy ethers and 1,2-azido alcohols with excellent enantioselectivity (99% ee) and in good to high chemical yield.     

Highly enantioselective CH oxidation of vic-Diols with Shi's oxazolidinone dioxiranes

[reaction: see text] Through an analogical study of the transition states of CH oxidation and asymmetric epoxidation of terminal alkenes, the first dioxirane-mediated catalytic highly enantioselective CH oxidation method was realized with Shi's oxazolidinone ketone derivatives. Very good enantioselectivity (up to 92% ee) may be obtained for both asymmetrization of meso vic-diols and kinetic resolution of racemic vic-diols.     

"Achiral" benzophenone ligand for highly enantioselective Ru catalysts in ketone hydrogenation

[reaction: see text] The chirality of an "achiral" benzophenone-based complex can be controlled. The benzophenone-based complex thus controlled affords high enantioselectivity in the catalytic asymmetric ketone hydrogenation (up to 99% ee, >99% yield).     

Catalytic asymmetric epoxidation of alkenes with arabinose-derived ketones containing a cyclohexane-1,2-diacetal

The effect of diol blocking groups, cyclohexane-1,2-diacetal verses butane-1,2-diacetal, on the asymmetric epoxidation of trans- and cis-alkenes by arabinose-derived ketones is reported. The ketone catalysts with a cyclohexane-1,2-acetal display similar asymmetric induction as those catalysts with a butane-1,2-diacetal in most cases. For (E)-1-benzyloxy-4-hexene, the ee of the enantioselective epoxidation has reached 61% with the cyclohexane-1,2-dineopentyl acetal ketone catalyst.