Stereoselective synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine from d-mannitol

A novel stereoselective synthesis of N-Boc-(2S,3S)-3-hydroxy-2-phenylpiperidine was achieved from d-mannitol involving the highly stereoselective addition of phenyl Grignard to an allyl imine (de >98%) and ring-closing metathesis (RCM) in the key steps.     

Improvement of a Stereoselective Biocatalytic Synthesis by Substrate and Enzyme Engineering: 2‐Hydroxy‐(4′‐oxocyclohexyl)acetonitrile as the Model

Even if biocatalysis is finding increasing application, it still has to gain widespread use in synthetic chemistry. Reasons for this are limitations that enzymes have with regard to substrate range, reaction scope, and insufficient selectivity with unnatural compounds. These shortcomings can be challenged by enzyme and/or substrate engineering, which are employed to alter substrate specificity and enhance the enzyme selectivity toward unnatural substrates. Herein, these two approaches are coupled to improve the hydroxynitrile lyase catalyzed synthesis of 2‐hydroxy‐(4′‐oxocyclohexyl)acetonitrile ( 4 ). The ketone functionality is masked as an enol ether, and the oxynitrilase of Hevea brasiliensis is engineered towards this masked substrate to give the product with a high optical purity and to drastically lower the amount of enzyme needed.     

Stereoselective synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one

A stereoselective synthesis of (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one is reported. The strategy utilizes an olefin cross-metathesis, syn-benzylidene acetal formation and a preferential (Z)-Wittig olefination reaction and lactonization as the key steps.     

Enantioselective synthesis of ethyl (S)-2-hydroxy-4-phenylbutyrate by recombinant diketoreductase

Recombinant diketoreductase showed excellent stereoselectivity in the double reduction of β,δ-diketo esters. To investigate the substrate specificity and to broaden the applications of this new biocatalyst, a number of ketone substrates were used to evaluate the substrate spectrum and enantioselectivity of this enzyme in the present study. Among the ketone substrates tested, only this enzyme displayed high efficiency and excellent enantioselectivity in the reduction of ethyl 2-oxo-4-phenylbutyrate to ethyl (S)-2-hydroxy-4-phenylbutyrate. After optimizing the reaction conditions, the bio-reduction of ethyl 2-oxo-4-phenylbutyrate at a substrate concentration of 0.8 M (164.8 g/L) was achieved by the recombinant diketoreductase in an aqueous-toluene biphasic system coupled with formate dehydrogenase for the regeneration of cofactor, resulting in an overall hydroxyl product yield of 88.7% (99.5% ee). This new enzymatic transformation may offer a practical method for the preparation of this important chiral building block.     

Bis(oxazoline) Lewis acid catalyzed aldol reactions of pyridine N-oxide aldehydes--synthesis of optically active 2-(1-hydroxyalkyl)pyridine derivatives: development, scope, and total synthesis of an indolizine alkaloid

A new, short, and simplified procedure for the synthesis of optically active pyridine derivatives from pro-chiral pyridine-N-oxides is presented. The catalytic and asymmetric Mukaiyama aldol reaction between ketene silyl acetals and 1-oxypyridine-2-carbaldehyde derivatives catalyzed by chiral copper(II)-bis(oxazoline) complexes gave optically active 2-(hydroxyalkyl)- and 2-(anti-1,2-dihydroxyalkyl)pyridine derivatives in good yields and diastereoselectivities, and in excellent enantioselectivities-up to 99 % enantiomeric excess. As a synthetic application of the developed method, a full account for the asymmetric total synthesis of a nonnatural indolizine alkaloid is provided.     

Enantio-complementary deracemization of (±)-2-hydroxy-4-phenylbutanoic acid and (±)-3-phenyllactic acid using lipase-catalyzed kinetic resolution combined with biocatalytic racemization

Deracemization of (±)-3-phenyllactic acid (1) and (±)-2-hydroxy-4-phenylbutanoic acid (2) was accomplished by lipase-catalysed kinetic resolution coupled to biocatalytic racemization of the non-reacting substrate enantiomers using Lactobacillus paracasei DSM 20008. Cyclic repetition of this sequence led to a single enantiomeric product from the racemate. Access to both enantiomers was achieved by switching between lipase-catalysed acyl-transfer and ester hydrolysis reactions. Both products constitute important building blocks for virus protease- and ACE-inhibitors, respectively.     

Stereoselective synthesis of fluoroalkenes via (Z)-2-fluoroalkenyliodonium salts

Stereoselective synthesis of fluoroalkenes is described. (Z)-2-Fluoro-1-alkenyl(phenyl)iodonium tetrafluoroborates (1) were synthesized stereoselectively in good yields by Michael-type addition of HF to 1-alkynyl(phenyl)iodonium tetrafluoroborates (2) with a commercially available HF reagent, hydrofluoric acid or Et₃N-3HF. Pd-catalyzed cross-coupling reactions using 1 gave (Z)-2-fluoro-1-alkene derivatives in moderate yields. The treatment of 1 with KI in the presence of a catalytic amount of CuI gave (Z)-2-fluoro-1-iodo-1-alkenes (3). Pd-catalyzed cross-coupling reactions of 3 gave better results than that of 1, and a variety of (Z)-2-fluoro-1-alkene derivatives were synthesized in good yields.     

Stereoselective synthesis of the nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid from (4S,5S)-4-formyl-5-vinyl-2-oxazolidinone

(4S,5S)-4-Formyl-5-vinyl-2-oxazolidinone (4b), which is readily obtained via a zinc-silver-mediated reductive elimination of alpha-d-lyxofuranosyl phenyl sulfone (3b), is successfully converted to the naturally occurring, nonproteinogenic amino acid (2S,3R)-3-amino-2-hydroxydecanoic acid (2). Also in this study, a facile "oxazolidinone rearrangement" reaction is uncovered during the attempted formation of the (methylthio)thiocarbonate derivative of the oxazolidinone alcohol 7.     

Preparation of dimethyl (R)- and (S)-2-(2-hydroxyphenyl)-2-hydroxyethylphosphonate derived from salicylaldehyde via resolution using (S)-methoxyphenylacetic acid (MPA)

The efficient preparation of both enantiomers of dimethyl δ,β-dihydroxyethylphosphonate 2 has been achieved from salicylaldehyde as a starting material, through the resolution of dimethyl (±)-2-(2-O-benzylphenyl)-2-hydroxyethylphosphonate 4 using (S)-methoxyphenylacetic acid (MPA). The absolute configuration was assigned by the Dale and Mosher approach using extended Newman projections and ab initio calculations.     

(S,S)-2,3-Dihydroxy-2,3-dihydrobenzoic acid: microbial access with engineered cells of Escherichia coli and application as starting material in natural-product synthesis

Cyclohexadiene-trans-5,6-diols such as (S,S)-2,3-dihydroxy-2,3-dihydrobenzoic acid (2,3-trans-CHD) have been shown to be of importance as chiral starting materials for the syntheses of bioactive substances, especially for the syntheses of carbasugars. By using methods of metabolic-pathway engineering, the Escherichia coli genes entB and entC, which encode isochorismatase and isochorismate synthase, were cloned and over-expressed in E. coli strains with a deficiency of entA, which encodes 2,3-dihydroxybenzoate synthase. A 30-fold increase in the corresponding EntB/EntC enzyme activities affects the accumulation of 2,3-trans-CHD in the cultivation medium. Although the strains did not contain deletions in chorismate-utilising pathways towards aromatic amino acids, neither chorismate nor any other metabolic intermediates were found as by-products. Fermentation of these strains in a 30 L pH-controlled stirred tank reactor showed that 2,3-trans-CHD could be obtained in concentrations of up to 4.6 g L(-1). This demonstrates that post-chorismate metabolites are accessible on a preparative scale by using techniques of metabolic-pathway engineering. Isolation and separation from fermentation salts could be performed economically in one step through anion-exchange chromatography or, alternatively, by reactive extraction. Starting from 2,3-trans-CHD as an example, we established short syntheses towards new carbasugar derivatives.     

Reactions of (1S,3S)-3-acetoxymethyl-1-(2-acetoxyvinyl)-2,2-dimethylcyclopropane with haloforms under conditions of phase-transfer catalysis

Heating of (1S,3S)-3-acetoxymethyl-1-(2-acetoxyvinyl)-2,2-dimethylcyclopropane with bromoform under phase-transfer catalysis affords dibromocyclopropane viaaddition of dibromocarbene to the double bond. In an analogous reaction with chloroform, the trichloromethyl anion adds to the double bond in the -position with respect to the acetoxy group.     

Enantioselective catalysis of the hetero-Diels-Alder reaction between Brassard's diene and aldehydes by hydrogen-bonding activation: a one-step synthesis of (S)-(+)-dihydrokawain

The first catalytic enantioselective hetero-Diels-Alder reaction between Brassard's diene and aldehydes has been achieved through hydrogen-bonding activation using TADDOL derivatives as catalysts to afford the corresponding delta-lactone derivatives in moderate-to-good yields and with high enantioselectivities (up to 91 % ee). The reactions can be carried out either under solvent-free conditions or in toluene. On the basis of the absolute configurations of the products and the hydrogen-bonding interaction pattern between TADDOL (alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolan-4,5-dimethanol) and the carbonyl group disclosed by X-ray diffraction analysis, a possible mechanism for the catalytic reaction has been proposed. To demonstrate the usefulness of the methodology, a natural product, (S)-(+)-dihydrokawain, has also been prepared in 50 % isolated yield and with 69 % enantioselectivity in one step starting from 3-phenylpropionaldehyde by using this methodology. Therefore, this catalytic system is one of the most direct approaches to the construction of delta-lactone units, which will make the methodology very attractive for the synthesis of a variety of biologically important compounds and natural products.     

新显色剂1-羟基-2-(5-NO2-2-吡啶偶氮)-8-氨基-3,6-萘二磺酸与铜显色反应的研究

探讨了新显色剂 1-羟基-2-(5-NO2-2-吡啶偶氮)-8-氨基-3,6-萘二磺酸(简称5-NO2-PAH)与铜离子显色的适宜条件及其共存离子的影响,建立了 5-NO2-PAH测定铜的新显色反应体系.在 pH 7.0～10.0 范围内,铜与试剂形成稳定的 1∶2 配合物,其最大吸收峰位于 653 nm, 表观摩尔吸光系数εCu=4.68×104 L·mol-1·cm-1,铜的浓度在 0 μg/10 mL～14 μg/10 mL 范围内遵守比尔定律.方法已用于合金中铜的测定.     

新显色剂1-羟基-2-(5-NO2-2-吡啶偶氮)-8-氨基-3,6-萘二磺酸与钯的显色反应

探讨了新显色剂1-羟基-2-(5-NO2-2-吡啶偶氮 )-8-氨基-3,6-萘二磺酸(简称5-NO2-PAH)与钯离子显色的适宜条件及其共存离子的影响,建立了5-NO2-PAH测定钯的新显色反应体系.结果表明,在pH 2.0～5.5范围内,钯与试剂形成稳定的1∶1配合物,其最大吸收峰位于712 nm, 表观摩尔吸光系数ε Pd=2.84×104 L*mol-1*cm-1,钯的浓度在0～20 μg/10 mL 范围内遵守比尔定律.方法已用于实际样品中钯的测定.     

A practical synthesis of ethyl (R)- and (S)-2-hydroxy-4-phenylbutanoate and d-homophenylalanine ethyl ester hydrochloride from l-malic acid

With the readily available l-malic acid as starting material, both enantiomers of ethyl 2-hydroxyl-4-phenylbutanoates and d-homophenylalanine ethyl ester hydrochloride were prepared conveniently in excellent optical purity and 64, 53 and 49% overall yield, respectively.     

Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Regioselective biocatalytic hydrolysis of (E,Z)-2-methyl-2-butenenitrile for production of (E)-2-methyl-2-butenoic acid

Acidovorax facilis 72W nitrilase catalyzed the regioselective hydrolysis of (E,Z)-2-methyl-2-butenenitrile, producing only (E)-2-methyl-2-butenoic acid with no detectable conversion of (Z)-2-methyl-2-butenenitrile. (E)-2-Methyl-2-butenoic acid, produced in aqueous solution as the ammonium salt, was readily separated from (Z)-2-methyl-2-butenenitrile, and isolated in high yield and purity. The combination of nitrile hydratase and amidase activities of several Comamonas testosteroni strains were also highly regioselective for the production of (E)-2-methyl-2-butenoic acid from (E,Z)-2-methyl-2-butenenitrile.