Acyloin Research Articles

Silica-Catalysed and Highly Stereoselective Convergent and Nonconvergent Rearrangements of Menthone Enol Acetate Epoxides: Easy Access to the Four α-Hydroxymenthone Stereoisomers

During a program dedicated to the biocatalytic access of structurally useful α-hydroxy ketones, we made the unexpected observation that epoxy enol acetates derived from (+)- and (–)-menthone stereoselectively rearranged on exposure to silica through a diastereoselective process, providing easy access to the complete set of α-hydroxymenthone stereoisomers. The absolute configurations of the four stereoisomers were unambiguously established by IR-VCD and X-ray diffraction, thus clarifying some literature discrepancy. Two of the four stereoisomers could also be obtained through astereoconvergent process, thus avoiding the inherent 50 % yield limitations of such diastereoselective reactions. A solvent-free version allowing an extremely rapid reaction (< 2 h) is also described. Finally, the observed diastereoselection was investigated by DFT calculations.

Enhancement of the reduction efficiency of soluble starch for platinum nanoparticles synthesis

In this work, the efficiency of soluble starch as a reducing and a stabilizing agent in the synthesis of platinum nanoparticles under acidic–alkaline treatment is systematically studied. The degraded intermediates with reducing potential (i.e., small molecules containing aldehyde and α-hydroxy ketone moieties) are concomitantly generated when the alkaline concentration is greater than 0.025M. The in situ generated species could completely reduce platinum ions (20mM) and sufficiently stabilize the obtained platinum nanoparticles (5mM) of uniform particle size (2–4nm). The reduction is efficient and rapid as a complete conversion is achieved within 5min. In a stronger alkaline condition, the platinum nanoparticles tend to aggregate and form a bigger domain because extensive degradation generates small starch fragments with less stabilization efficiency. This observation suggests that starch is a promising green material which could be chemically treated and transformed to a powerful reducing agent and stabilizer for the synthesis of metal nanoparticles.

CaO-catalyzed Aerobic Oxidation of α-Hydroxy Ketones: Application to One-pot Synthesis of Quinoxaline Derivatives

Abstract The aerobic oxidation of α-hydroxy ketones into α-diketones catalyzed by CaO is compared with the same reaction catalyzed by other metal oxides. The catalytic activities of the various metal oxides were proportional to their surface basicities. The direct conversion of α-hydroxy ketones into quinoxalines via CaO-catalyzed aerobic oxidation followed by in situ reaction with 1,2-diaminoaromatics is also achieved. Various types of quinoxalines were synthesized in the presence of the CaO catalyst and molecular oxygen. It was also found that the CaO catalyst was reusable without any loss of its catalytic activity.

Asymmetric α-hydroxy ketone synthesis by direct ketone oxidation using a bimetallic palladium(II) complex

The oxidation of ketones by a chiral bimetallic palladium(II) complex in the presence of CuCl2 in THF–water solvents gave an enantioselective synthesis of α-hydroxyketones in catalytic oxidation utilizing an atmosphere of oxygen. The ee’s ranged from 61% to 92%. The reaction was accelerated by addition of strong acid that presumably increases the rate of enolization.

A stereospecific pathway for the introduction of deuterium on the brassinosteroid skeleton by reductive dechlorination of chlorocarbonates

A new and efficient procedure for the preparation of brassinosteroids labeled with hydrogen isotopes was developed. A four-step reaction sequence started with the selective oxidation of a 2,3-diol group to an α-hydroxy ketone, which was converted stereospecifically into a chlorocarbonate by reaction with triphosgene. A subsequent Pd-catalyzed reductive dechlorination with deuterium gas yielded deuterium-labeled brassinosteroid 2,3-carbonates. The reaction sequence was completed by base-catalyzed hydrolysis of the cyclic carbonate.

Diarylpentanoids from Diplomorpha canescens and Diplomorpha ganpi

Two new α-hydroxy ketone type diarylpentanoids, diplomorphanone A, 2(S)-hydroxy-1-(4-hydroxyphenyl)-5-phenyl-1-pentanone (1) and diplomorphanone B, 2(R)-hydroxy-1,5-diphenyl-1-pentanone (2) were isolated from aerial parts of Diplomorpha canescens (Meisn.) C.A. Meyer and roots of Diplomorpha ganpi (Sieb. et Zucc.) Nakai, respectively. Nine known compounds including diarylpentanoids (3–6), phenylpropanoid derivatives (7–9), (+)-afzelechin (10) and apiosylskimmin (11) were also isolated for the first time from D. ganpi. Structures of these compounds were elucidated on the basis of spectroscopic data.

α-Hydroxy ketones as useful templates in asymmetric reactions

Approaching the Nature's efficiency in controlling both reactivity and stereoselectivity of organic reactions by means of a catalyst species remains a formidable challenge for chemists to face. Despite impressive advances in the design of novel catalysts and activation modes, current catalytic and asymmetric methodologies rarely meet desirable standards of robustness, substrate scope, and selectivity altogether. One trick to improve catalyst behaviour is to identify adequate substrate template-catalyst combinations so that optimum performance of the reaction system could be achieved. During the last couple of years α-hydroxy ketones, and most particularly α'-hydroxy enones, have emerged as useful templates with applications in a number of metal-catalyzed as well as organocatalyzed C-C and C-X bond-forming stereoselective reactions. The first review of these accomplishments is presented here along with a brief historical introduction.

CuO/CNTs-catalyzed heterogeneous process: a convenient strategy to prepare furan derivatives from electron-deficient alkynes and α-hydroxy ketones

As heterogeneous catalysts and nanoparticle support materials, CNTs have attracted great interest in organic chemistry. This paper reports facile CuO/CNTs-catalyzed cyclization to form furan derivatives from electron-deficient alkynes and α-hydroxy ketones. It represents a facile synthetic route, and the eco-friendly catalyst can be easily separated by filtration and reused.

Self-assembled monolayer coated gold-nanoparticle catalyzed aerobic oxidation of α-hydroxy ketones in water: an efficient one-pot synthesis of quinoxaline derivatives

For the first time, 4-aminothiophenol self-assembled monolayer-coated gold-nanoparticles (Au-NPs) which catalyze the aerobic oxidation of aryl substituted α-hydroxy ketones to aryl 1,2-diketones are reported. In addition, a one-pot synthesis of quinoxalines has been successfully achieved via in situ oxidation of α-hydroxy ketones and subsequent condensation with aryl 1,2-diamines in water. This method offers the potential for simple self-assembled monolayer-coated Au-NPs to exhibit catalytic activity for the aerobic oxidation reaction in a green and efficient manner.

Stability, activity, and selectivity of benzaldehyde lyase in supercritical fluids

Benzaldehyde lyase is a versatile catalyst for the organic synthesis of enantiopure α-hydroxy ketones. In view of poor solubility and stability of many substrates and products and the prospect of downstream processing, supercritical fluids are explored as an alternative solvent in view of residual stability, activity, and selectivity. Four supercritical fluids were investigated: carbon dioxide, fluoroform, ethane, and sulphur hexafluoride. Water activity and enzyme preparation (pH of lyophilisation) showed to be the main influence parameters. Activity increased with increasing water activity but stability decreased. Furthermore, non-carbon dioxide supercritical fluids give better results in view of stability, activity, and enantioselectivity. Suprisingly, the enantioselectivity is heavily influenced by the reaction from almost racemic in sulphur hexafluoride with up to 90% enantiomeric excess.

Microbial Oxidation of 1,2-Diols Bearing a Substituent with an Oxyfunctional Group: Preparation of Optically Active 1,2-Diols and &amp;#945;-Hydroxy Ketones

The preparation of optically active 1,2-diols bearing a substituent with a benzyloxy group at the terminus has been achieved by microbial enantioselective oxidation of the racemic compounds. In the screening test, Ochrobactrum sp. MU2293 was selected as the best strain to perform the enantioselective oxidation of (±)-4-benzyloxybutane-1,2-diol to give the corresponding 4-benzyloxy-1-hydroxybutan-2-one and the remaining (R)-diol with a high ee. This microbial oxidation was applicable to other substrates bearing a substituent with a different carbon number. On the other hand, Bacillus sp. MU2289 catalyzed the oxidation of the 1,2-diols to afford the corresponding α-hydroxy ketones and the (S)-diols as the remaining substrates with the opposite absolute configuration Keywords: Bacteria, enantioselective oxidation, enzymatic reaction, hydroxy ketones, microorganisms, optically active 1,2-diols, alkoxy groups, dihydroxylation, phosphate, benzyloxy

Small molecule probes of the receptor binding site in the Vibrio cholerae CAI-1 quorum sensing circuit

Based on modification of separate structural features of the Vibrio cholerae quorum sensing signal, (S)-3-hydroxytridecan-4-one (CAI-1), three focused compound libraries have been synthesized and evaluated for biological activity. Modifications to the acyl tail and α-hydroxy ketone typically provided agonists with activities correlated to tail length and conservative changes to the hydroxy ketone. Among the molecules identified within this collection of agonists is Am-CAI-1 (B11), which is among the most potent agonists reported to date with an EC50 of 0.21μM. Modifications to the ethyl side chain delivered molecules with both agonist and antagonist activity, including m-OH-Ph-CAI-1 (C13) which is the most potent antagonist reported to date with an IC50 of 36μM. The molecules described in this manuscript are anticipated to serve as valuable tools in the study of quorum sensing in Vibrio cholerae and provide new leads in the development of an antivirulence therapy against this human pathogen.

Direct Spectrophotometric Assay for Benzaldehyde Lyase Activity

Benzaldehyde lyase from Pseudomonas fluorescens Biovar I. (BAL, EC 4.1.2.38) is a versatile catalyst for the organic synthesis of chiral α-hydroxy ketones. To allow fast assessment of enzyme activity, a direct spectrophotometric assay is desirable. Here, a new robust and easy-to-handle assay based on UV absorption is presented. The assay developed is based on the ligation of the α-hydroxy ketone (R)-2,2′-furoin from 2-furaldehyde. A robust assay with direct monitoring of the product is facilitated with a convenient concentration working range minimising experimental associated with low concentrations.

An Efficient Synthesis of a Cyclopentannulated Pyrrolidine Derivative

A racemic cyclopentannulated pyrrolidine derivative was synthesized utilizing ruthenium oxidation and borane reduction as the key steps. Ruthenium oxidation reaction of the 1,2-dibromoalkene moiety in an N-Boc-protected tetrabromonorbornyl derivative afforded a tricyclic α-hydroxy ketone, which on alkaline hydrogen peroxide cleavage furnished a bicyclic lactam in excellent yield. Borane reduction of the N-Boc-protected bicyclic lactam gave an unexpected product as a single diastereomer resulting from the reduction of not only the lactam and ester moieties but also the ketal to the corresponding methyl ether. A plausible mechanism involving an oxocarbenium ion is discussed.

Synthesis of 2‐Keto‐anti‐1,3‐diols by Chemoselective Tandem Oxidation of 2‐B(pin)‐Substituted Allylic Alcohols

A new role for vinyl boronates: Vinyl boronate esters are well known as synthons for ketones and for their ability to participate in cross-coupling reactions. A tandem oxidation is introduced to convert 2-B(pin)-substituted allylic alcohols into 2-keto-anti-1,3-diols with high diastereoselectivity. Under these reaction conditions, the vinyl boronate ester is now a synthon for α-hydroxy ketones.

Highly diastereoselective chelation-controlled additions to α-silyloxy ketones.

The polar Felkin-Anh, Cornforth-Evans, and Cram-chelation models predict that the addition of organometallic reagents to silyl-protected α-hydroxy ketones proceeds via a nonchelation pathway to give anti-diol addition products. This prediction has held true for the vast majority of additions reported in the literature, and few methods for chelation-controlled additions of organometallic reagents to silyl-protected α-hydroxy ketones have been introduced. Herein, we present a general and highly diastereoselective method for the addition of dialkylzincs and (E)-di-, (E)-tri-, and (Z)-disubstituted vinylzinc reagents to α-silyloxy ketones using alkyl zinc halide Lewis acids, RZnX, to give chelation-controlled products (dr ≥18:1). The compatibility of organozinc reagents with other functional groups makes this method potentially very useful in complex molecule synthesis.

Chiral Zn-catalyzed aerobic oxidative kinetic resolution of α-hydroxy ketones

The aerobic oxidative kinetic resolution of racemic α-hydroxy ketones was accomplished using a chiral Zn–quinine complex as the catalyst in the presence of molecular oxygen. The resulting optimized reaction conditions were applied to resolute different types of racemic α-hydroxy ketones and a maximum of 9.2 selectivity ( s) was obtained with 88% ee for the recovered α-hydroxy ketone.

Oxidovanadium(V)-Catalyzed Kinetic Resolution of α-Hydroxy Ketones

Oxidovanadium complexes have previously been used for the oxidation and kinetic resolution of sulfides and sulfoxides, respectively. In 2005, Toste and co-workers demonstrated an efficient kinetic resolution of α-hydroxy acid derivatives catalyzed by an oxidovanadium complex (A. T. Radosevich, C. Musich, F. D. Toste J. Am. Chem. Soc. 2005, 127, 1090). The authors report a study of the vanadium-catalyzed kinetic resolution of α-hydroxy ketones. During this study several ligands are examined and various substituted benzoin adducts are investigated under optimized conditions, expanding the scope of vanadium-catalyzed kinetic resolutions.

Synthesis of (+)- and (-)-Fluvastatin

Fluvastatin is an HMG-CoA reductase inhibitor marketed as a racemate. The key step in the synthesis depicted was the enantio­selective addition of diketene E to the aldehyde C mediated by the enantiopure Schiff base D and ­titanium isopropoxide. The stoichiometric version of the reaction shown gave the α-hydroxy ketone H in 78% yield (er = 96:4), whereas 10 mol% of (S)-D delivered H in 70% yield (er = 87:13).

17,20-Lyase inhibitors. Part 4: Design, synthesis and structure–activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors

A novel series of naphthylmethylimidazole derivatives and related compounds have been investigated as selective 17,20-lyase inhibitors. Optimization of the substituent at the 6-position on the naphthalene ring was performed to yield a methylcarbamoyl derivative, which exhibited potent inhibitory activity against human 17,20-lyase and promising selectivity (>200-fold) for 17,20-lyase over CYP3A4. Further modifications of the methylcarbamoyl derivative led to the discovery of the corresponding tricyclic compound, which showed highly potent activity against human 17,20-lyase (IC50 19nM) and good selectivity (>1000-fold) for inhibition of 17,20-lyase over CYP3A4. Additional biological evaluation revealed that the tricyclic compound had potent in vivo efficacy in monkeys and favorable pharmacokinetic profiles when administered in rats. Asymmetric synthesis of the selective tricyclic inhibitor was also achieved using a chiral α-hydroxy ketone.