Bioreductive synthesis of perfluorinated chiral alcohols

Perfluorinated chiral alcohols are interesting building blocks for pharmaceuticals and agrochemicals. Different chiral (R)- and (S)-configured perfluorinated alcohols were produced by asymmetric reduction of the corresponding ketones. Commercially available alcohol dehydrogenases were used as catalyst in combination with different cofactor regenerating systems. High selectivities of >99% were observed in most cases. The results also demonstrate the influence of the CF₃ group on reactivity and enantioselectivity of alcohol dehydrogenases.     

Lipase-catalyzed kinetic resolution of aryltrimethylsilyl chiral alcohols

Lipase-catalyzed kinetic resolution of aryltrimethylsilyl chiral alcohols through a transesterification reaction was studied. The optimal conditions found for the kinetic resolution of m- and p-aryltrimethylsilyl chiral alcohols, led to excellent results, high conversions (c = 50%), high enantiomeric ratios (E > 200) and enantiomeric excesses for the remaining (S)-alcohol and (R)-acetylated product (>99%). However, kinetic resolution of o-aryltrimethylsilyl chiral alcohols did not occur under the same conditions applied to the other isomers.     

Enantioselective alkynylation of aromatic aldehydes catalyzed by new chiral amino alcohol-based ligands

A series of binaphthyl-derived amino alcohols were synthesized and used as catalytic ligands in the asymmetric alkynylation of aromatic aldehydes in the presence of a dialkylzinc reagent. The alkynylation of a variety of aromatic aldehydes gave the corresponding chiral propargylic alcohols in 61–93% e.e.     

Preparative access to medicinal chemistry related chiral alcohols using carbonyl reductase technology

Libraries of highly enantioenriched secondary alcohols in both enantiomeric forms were synthesised by enzymatic reduction of their parent ketones using selectAZyme? carbonyl reductase (CRED) technology. Commercially available CREDs were able to reduce a range of substrate classes efficiently and with very high enantioselectivity. Matching substrate classes to small subsets of CREDs enabled the fast development of preparative bioreductions and the rapid generation of 100–1500 mg samples of chiral alcohols in typically >95% ee and the majority in ?99.0% ee. The conditions for small scale synthesis were then scaled up to 0.5 kg to deliver one of the chiral alcohols, (S)-1-(4-bromophenyl)-2-chloroethanol, in 99.8% ee and 91% isolated yield.     

Diastereoselective allylation of planar chiral substituted ferrocenecarboxaldehyde: an efficient entry to chiral ferrocenyl ligands

2,2′-Disubstituted ferrocenecarboxaldehydes are subjected to zinc-mediated allylation to form homoallylic ferrocenyl alcohols. The effects of ortho-substituted functional groups on facial selectivities of planar chiral aldehydes were studied and it was found that the corresponding homoallylic alcohols were obtained as single diastereomers in excellent yields.     

Enantiomeric impurities in chiral synthons,catalysts, and auxiliaries: Part 3

The enantiomeric excess of chiral reagents used in asymmetric syntheses directly affects the reaction selectivity and product purity. In this work, 84 of the more recently available chiral compounds were evaluated to determine their actual enantiomeric composition. These compounds are widely used in asymmetric syntheses as chiral synthons, catalysts, and auxiliaries. These include chiral alcohols, amines, amino alcohols, amides, carboxylic acids, epoxides, esters, ketones, and oxolanes among other classes of compounds. All enantiomeric test results were categorized within five impurity levels (i.e., <0.01%, 0.01–0.1%, 0.1–1%, 1–10%, and >10%). The majority of the reagents tested were determined to have enantiomeric impurities over 0.01%, and two of them were found to contain enantiomeric impurities exceeding the 10% level. The most effective enantioselective analysis method was a GC approach using a Chiraldex GTA chiral stationary phase (CSP). This method worked exceedingly well with chiral amines and alcohols.     

Asymmetric reductions using the chiral boronic ester TarB-H: a practical and inexpensive procedure for synthesizing chiral alcohols

Chiral alcohols are prepared in high enantiomeric excesses using an inexpensive and easily synthesized tartaric acid derived boronic ester (TarB-H) with sodium borohydride. The phenylboronic acid could be recovered quantitatively using a simple extraction with sodium hydroxide and diethyl ether. The optimized TarB-H system was used to reduce aromatic and aliphatic ketones in an open flask to chiral alcohols with enantiomeric excesses up to 99%.     

Screening of chiral ferrocenyl amino alcohols as ligands for ruthenium-catalysed transfer hydrogenation of ketones

A variety of ferrocenyl amino alcohols possessing central chirality have been screened as ligands for ruthenium(II)-catalysed transfer hydrogenation of acetophenone using 2-propanol in the presence of KOH as the hydrogen source. Enantiomerically enriched 1-phenylethanol was obtained in high yield and 70% e.e. using ligand 9. This ligand was employed in the asymmetric reduction of different arylalkyl ketones and the corresponding alcohols were obtained in up to 80% e.e. A comparison of the catalytic properties of ferrocenyl amino alcohols and their phenyl analogues is discussed briefly.     

One-pot synthesis and resolution of chiral allylic alcohols

Substituted α,β-unsaturated ketones were selectively reduced to the corresponding allylic alcohols under mild reaction conditions. The allylic alcohols thus obtained were kinetically resolved by lipase catalyzed transesterification in the same pot to afford chiral allylic alcohols in excellent enantioselectivity. Various lipases were screened for this one-pot transesterification of allylic alcohols. Effects of different solvent have also been studied under these conditions. Pseudomonas cepacia lipase immobilized on ceramic particles (PS-C) and on diatomaceous earth (PS-D) catalyzes this transesterification in diisopropyl ether in a highly efficient manner.     

CBS法合成光学活性二茂铁基醇

以非天然氨基酸合成的手性β-氨基醇(4a～4c)为催化剂，用于不对称硼烷还原反应来合成光学活性的二茂铁基醇(1a～1e)，对映体过量值高达96%。     

Enantioselective fluorescence sensing of chiral alpha-amino alcohols

1,8-Bis(3-tert-butyl-9-acridyl)naphthalene N, N'-dioxide, 1, has been synthesized in five steps from 3-tert-butylaniline and 2-chlorobenzoic acid in 29% overall yield. This C 2-symmetric ligand forms a highly fluorescent scandium complex that can be used for enantioselective sensing of chiral amino alcohols. A fluorescence ligand displacement assay that allows accurate measurements of both the total amount and the enantiomeric excess of several amino alcohols at micromolar concentrations is reported.     

Kinetic resolution of racemic secondary alcohols catalyzed by chiral diaminodiphosphine-Ir(I) complexes

Chiral diaminodiphosphine-Ir(I) complexes were found to efficiently catalyze enantioselective oxidation of racemic secondary alcohols in acetone. In the presence of base, oxidative kinetic resolution of the alcohols proceeded smoothly with excellent enantioselectivity (up to 98% ee) under mild conditions. [reaction: see text].     

Synthesis of quinazoline based chiral ligands and application in the enantioselective addition of phenylacetylene to aldehydes

Five novel 4-phenylquinazolinols were synthesised in three steps. Their application as ligands in the titanium tetraisopropoxide promoted catalytic enantioselective addition of phenylacetylene to a variety of aldehydes gave propargylic alcohols. Under the optimised reaction conditions, the best enantioselectivity was obtained using l-lactic acid derived 4-phenylquinazolinol and apart from the cyclohexylcarbaldehyde derivative, 16 propargylic alcohols were then synthesised in moderate to excellent enantiomeric excess from 53% to 97%.     

Diastereoselective reduction of a chiral N-Boc-protected delta-amino-alpha,beta-unsaturated gamma-keto ester Phe-Gly dipeptidomimetic

The readily available N-Boc-protected delta-amino alpha,beta-unsaturated gamma-keto ester 1 was diastereoselectively reduced to the corresponding alcohols 2 and 3, using boron- and aluminum-based reducing reagents. Reduction reactions were successful and resulted in anti/syn ratios of alcohols of >95:5 (80% yield), using LiAlH(O-t-Bu)(3) in EtOH at -78 degrees C under chelation control, and 5:95 (98% yield), using NB-Enantride in THF at -78 degrees C under Felkin-Anh control.     

Second generation levoglucosenone-derived chiral auxiliaries. Scope and application in asymmetric Diels-Alder reactions

Chiral alcohols were designed and easily prepared from levoglucosenone, a biomass-derived valuable synthon. These alcohols were tested as chiral auxiliaries in asymmetric Diels-Alder reactions between the corresponding acrylates with acyclic and cyclic dienes. The regio, stereo, and facial selectivity varied from very good to excellent, depending upon the benzylic substitution of the auxiliary and the diene employed. As a consequence, after removal of the auxiliary, the resulting carboxylic acid derivatives were obtained in 72-99% ee.     

Highly stereoselective Saucy-Marbet rearrangement using chiral ynamides. Synthesis of highly substituted chiral homoallenyl alcohols

[reaction: see text] A highly stereoselective Saucy-Marbet rearrangement using chiral ynamides and propargyl alcohols is described here. This rearrangement can be catalyzed by para-nitrobenzenesulfonic acid leading to high diastereoselectivities for a range of different chiral propargyl alcohols and ynamides in a stereochemically intriguing matched, mismatched, or indifferent manner. This provides an excellent entry to highly substituted chiral homoallenyl alcohols.     

New chiral amino alcohol ligands derived from 1-phenylethylamine for efficient Ru-catalyzed asymmetric transfer hydrogenation

A series of chiral amino alcohols have been prepared from cheap and readily available (S)-1-phenylethylamine through a one-step transformation. The ability of these newly developed amino alcohols as chiral ligands was evaluated in the Ru-catalyzed asymmetric transfer hydrogenation of aromatic alkyl ketones, providing chiral secondary alcohols with good to excellent conversions (71-100%) and moderate to good enantioselectivities (67-95% ee). The results also showed that the structure of these amino alcohols has a significant influence on the conversion and enantioselectivity.     

Enantioselective synthesis of butadien-2-ylcarbinols via (silylmethyl)allenic alcohols from chromium-catalyzed additions to aldehydes utilizing chiral carbazole ligands

The synthesis of chiral, nonracemic butadienylcarbinols by employing intermediate (trimethylsilyl)methylallenic alcohols is described. Allenic alcohols are obtained by treatment of aldehydes with (4-bromobut-2-ynyl)trimethylsilane in the presence of a catalytic amount of CrCl₃ or CrCl₂. Several new tridentate bis(oxazolinyl)carbazole ligands were synthesized and evaluated as the source of chirality. The synthesis of chiral allenic alcohols can be achieved in good yields (58-88%) and enantioselectivities (55-78% ee). Allenic alcohols may be treated with TBAF or 2 M HCl to provide the desired dienes in 43-86% yields. Alternatively, the (trimethylsilyl)methyl allenic alcohols afford iodobutadienyl carbinols when treated with N-iodosuccinimide.     

Kinetic resolution of racemic alcohols with chiral carboxylic acids and dicyclohexylcarbodiimide

The DCC-esterification method has been used to kinetically resolve racemic mixtures of alcohols. With simple chiral carboxylic acids, such as O-aryl lactic acids, in the presence of various basic catalysts, mixtures of the enantiomerically enriched alcohols (e.e. <50%) and the corresponding esters (d.e.<70%) have been obtained.     

Synthesis of new chiral hydroxy oxazolines and their use in the catalytic asymmetric phenyl transfer to aldehydes

Starting either from benzoylformic acid or ethyl oxamate and enantiopure β-amino alcohols, several chiral α-hydroxy oxazolines have been prepared by short synthetic routes. Subsequently, they have been employed in the catalytic asymmetric phenyl transfer to various aldehydes, using a mixture of triphenylborane and diethylzinc as the phenyl source. The corresponding secondary alcohols were obtained with good enantioselectivities (up to 81% ee) and up to 92% yield.