Ti-mediated addition of diethylzinc to benzaldehyde. The effect of chiral additives

In the presence of a chiral tridentate bissulfonamide, the titanium-mediated addition of diethylzinc to benzaldehyde gave alkylated products ranging from the (R)-enantiomer, formed with an e.e. of 26%, to the (S)-enantiomer, formed in 72% e.e. The enantioselectivity was also affected by the presence of additional chiral mono- and bidentate ligands, with the reactions proceeding via complexes containing the chiral sulfonamide and the additive. The addition of (1R,2R)-1,2-diphenyl-1,2-ethanediamine and (1S,2S)-1,2-diphenyl-1,2-ethanediamine gave the (S)-product with e.e. of 49% and the (R)-product with 16% e.e., respectively, whereas without additives the (R)-product was obtained in 26% e.e. In the presence of (1R,2R)-1,2-diphenyl-1,2-ethanediamine only (i.e. without the chiral sulfonamide), the (S)-product formed with a 3% e.e.     

Preparation of halohydrin β-blocker precursors using yeast-catalysed reduction

The preparation of halohydrin β-blocker precursors using yeast-catalysed reduction of α-haloketones was performed. The influence in the yield and e.e. of several process variables was analysed. The (S)-enantioselectivity observed with Saccharomyces cerevisiae can be changed to (R)-enantioselectivity using methyl vinyl ketone as selective inhibitor (25 mM). Using resting fresh cells better yields and e.e.s are observed than using growing cells. Yarrowia lipolytica 1240 resting cells gave 87% yield of (S)-1-chloro-3(1-naphthyloxy)propan-2-ol (99% e.e.). Pichia mexicana 11105 resting cells gave 85% yield of (R)-1-chloro-3(1-naphthyloxy)propan-2-ol (precursor of propranolol) (95% e.e). The reduction process is applied to other α-haloketones, a lower e.e. being obtained the closer the size of the ketone substituents.     

Resolution of C2-symmetric 2,3-diphenylbutane-1,4-diol and purification of diastereomeric 1,4-diphenylbutane-1,4-diol using (S)-proline and boric acid

Racemic 2,3-diphenylbutane-1,4-diol (±)-1 is resolved to obtain the corresponding (R,R)-isomer in 98% e.e. through reaction with (S)-proline and boric acid. Partially resolved (R,R)-(−)-1 and (S,S)-(+)-1 have been enriched to obtain samples of 95 and 97% e.e. through reaction with (S)-proline and boric acid. Diastereomeric 1,4-diphenylbutane-1,4-diol 2 has been purified to obtain the (R,R)-isomer in 98% e.e. using (S)-proline and boric acid.     

Microwave-mediated ruthenium-catalyzed asymmetric hydrogen transfer

Ru-catalyzed hydrogen transfer from propan-2-ol to acetophenone under microwave conditions using monotosylated (R,R)-diphenylethylenediamine as the chiral source afforded (R)-1-phenylethanol in >90% yield and 82% e.e. within 9 min, while use of ephedrine or norephedrine gave the same compound in high yield with 70 and 46% e.e., respectively. t-Butylphenylketone was reduced to (R)-2,2-dimethyl-1-phenyl-1-propanol under the same conditions in close to quantitative yield, although with low enantioselectivity.     

Preparation of optically active N-benzyl-3-hydroxypyrrolidine by enzymatic hydroxylation

Hydroxylation of N-benzylpyrrolidine 2 with Pseudomonas oleovorans GPo1 afforded 62% of (R)-N-benzyl-3-hydroxypyrrolidine 3 in 52% e.e. This reaction was catalyzed by the alkane hydroxylase system in this strain, which was demonstrated by hydroxylation of 2 with Escherichia coli GEc137 (pGEc47), a recombinant strain that carries the genes for the alkane hydroxylase system of P. oleovorans GPo1. In a set of 70 alkane-degrading microorganisms, 12 were found to catalyze the biotransformation of 2 into 3 by screening with a microtiter plate technique. Hydroxylation of 2 with isolates HXN-1100 and HXN-200 gave 67% of (R)-3 in 70% e.e. and 62% of (S)-3 in 53% e.e., respectively.     

Preparation of the enantiomers of 1-phenylethan-1,2-diol. Regio- and enantioselectivity of acylase I and Candida antarctica lipases A and B

Acylase I and Candida antarctica lipases A (CAL-A) and B (CAL-B) were evaluated for the preparation of the enantiomers of 1-phenylethan-1,2-diol. In the presence of CAL-B, the sequential one-pot methanolysis of the diacetate in acetonitrile allowed the preparation of (S)-diol (e.e. 97%) and (R)-1-acetoxy-1-phenylethanol (e.e. 94%). Base-catalyzed methanolysis of the monoacetate resulted in the corresponding (R)-diol. When one of the diol enantiomers was subjected to Mitsunobu esterification, inversion of configuration occurred, allowing transformation of the initially racemic mixture to one enantiomer. Acylase I-catalysis led to the chemo- and enantioselective formation of (S)-1-acetoxy-1-phenylethanol (e.e. 97%) in the presence of the primary hydroxyl function through acetylation of the secondary hydroxyl group. The low chemical yield (ca. 25%) was due to the moderate enzymatic regioselectivity. CAL-A behaved in a similar way to acylase I.     

Highly enantioselective hetero Diels–Alder reactions of N-sulfinyl dienophiles promoted by copper(II)- and zinc(II)-chiral bis(oxazoline) complexes

Hetero Diels–Alder reactions of 1,3-cyclohexadiene with N-sulfinyl dienophiles 1a or 1b, promoted by Cu(II)- or Zn(II)-chiral bis(oxazoline) complexes, afforded endo adducts in high yields (up to 85%) and enantiomeric excess (e.e. of up to >98%) under stoichiometric conditions. With 10 mol% loading of the Zn(II) catalyst up to 75% e.e. was obtained for the endo adduct (endo:exo=10:1, total yield 68%).     

Chemoenzymatic preparation of (2S,3S)- and (2R,3R)-2,3-butanediols and their esters from mixtures of d,l- and meso-diols

An efficient method of preparing the pure enantiomers of 2,3-butanediol from commercially available mixtures of the d,l- and meso-isomers was developed. It furnished (2S,3S)-2,3-butanediol with >99% e.e. and a >99.5/0.5 diastereomeric ratio and (2R,3R)-2,3-butanediol in 95% e.e. and >95/<5 diastereomeric ratio.     

The synthesis of 1-hydroxy phosphonates of high enantiomeric excess using sequential asymmetric reactions: titanium alkoxide-catalyzed PC bond formation and kinetic resolution

Titanium alkoxide-catalyzed asymmetric phosphonylation of aldehydes yields hydroxy phosphonates in moderate to good enantiomeric excess (e.e.s ∼70%). The hydroxy phosphonates were acetylated and the acetates were subjected to enzyme-catalyzed kinetic resolution. The non-racemic acetates 2 (predominantly (R)-enantiomer) were hydrolyzed with an (R)-enantiomer-selective lipase, resulting predominantly in the hydrolysis of the (R)-isomer (at 85% conversion) to give the alcohols 3 with high e.e. Alternatively, hydrolysis of the minor enantiomeric (S)-acetate to approximately 20% conversion left the enriched (R)-configured acetate with improved e.e. (>90%). The moderate enantioselectivities obtained in the catalytic PC bond formation are enhanced during the enzymatic hydrolysis. Furthermore, availability of the non-racemic phosphonates permits the use of less selective enzymes, resulting in higher yields in comparison with the standard resolution of racemic materials.     

Asymmetric allenylation of aliphatic aldehydes catalyzed by a chiral formamide

(S,S)-N,N-Bis(α-methylbenzyl)formamide in combination with HMPA catalyzes the allenylation of aliphatic aldehydes with propargyltrichlorosilane with good enantioselectivity (up to 95% e.e.).     

Linkages of volatile fatty acids and polyhexamethylene guanidine stress during sludge fermentation: Metagenomic insights of microbial metabolic traits and adaptation

The massive use of polyhexamethylene guanidine (PHMG), as a typical bactericidal agent, raised environmental concerns to the public. This work comprehensively revealed the hormesis effects of PHMG occurred in waste activated sludge (WAS) on the generation of volatile fatty acids (VFAs) during anaerobic fermentation. The low level of PHMG (100 mg/g TSS) significantly promoted the VFAs generation (1283 mg COD/L, compared with 337 mg COD/L in the control) via synchronously facilitating the solubilization, hydrolysis, and acidification steps but inhibiting methanogenesis. Metagenomic analysis showed that the functional anaerobe (i.e., Bacteroides, Macellibacteroide and Parabacteroide) and corresponding genetic expressions responsible for extracellular hydrolysis (i.e., clpP), membrane transport (i.e., ffh and gspF), intracellular substrates metabolism (i.e., ald and paaF) and VFAs biosynthesis (i.e., ACACA and FASN) were enhanced in the optimal presence of PHMG. Moreover, the anaerobic species could respond and adapt to low PHMG stimuli via quorum sensing (i.e., cqsA, rpfC and rpfG), and thus maintain the high microbial metabolic activities. However, they were unable to tolerate the toxicity of excessive PHMG, resulting in the extremely low VFAs production. This work enlightened the effects of emerging pollutants on WAS fermentation at the genetic levels, and provided guidance on the WAS treatment and resource recovery.     

A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole via resolution

(±)-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with O,O′-di-p-toluoyl l-(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline β₃-agonist) in 99.5% e.e. and 36% overall yield. The unwanted enantiomer (S)-1 (61.9% e.e.; recovered in 57% yield from the crystallization filtrate) can be reused in another round of resolution after its enantiomeric purity is lowered to 3.7% by Raney Co treatment under a hydrogen atmosphere.     

Synthesis of novel P-ketimine bidentate ferrocenyl ligands with central and planar chirality and comparsion in the catalytic activity between P-ketimine and P-aldimine

A series of novel ferrocenylphosphine-ketimine ligands 6 were prepared by reaction of (R,S_p)-PPFNH₂-R or (S,S_p)-PPFNH₂ with a variety of m-substituted acetophenones. A different catalytic activity was observed between ferrocenylphosphine-ketimine ligands and corresponding aldimine ligands. The efficiency and diastereomeric impact of these ferrocenylphosphine-ketimine ligands in Pd-catalyzed asymmetric allylic alkylation were first investigated, and higher enantioselectivity of over 98% e.e. with 95% yield was obtained by the use of ferrocenylphosphine-ketimine ligands. However, in Rh-catalyzed asymmetric hydrosilylation of aryl ketones, only 42% e.e. was obtained by the use of ferrocenylphosphine-ketimine ligands compared to 90% e.e. with the use of aldimine ligands.     

Investigation of the importance of nitrogen substituents in a N–P chiral ligand for enantioselective allylic alkylation

The synthesis of three chiral chelate nitrogen–phosphorus (S)-valine derived ligands with the potential for stereogenic nitrogen donation is described. In palladium catalysed allylic substitution reactions the ligands induced varying enantioselectivities ranging from 92% e.e. of the (R)-enantiomer to 83% e.e. of the (S)-enantiomer. Structural and spectroscopic investigations into the origin of this effect were conducted, but were inconclusive. However, the importance of the consideration of N-substituents in such systems is highlighted.     

A convenient synthesis of (1S,2R)-1,2-indene oxide and trans-(1S,2S)-2-bromo-1-indanol via oxazaborolidine-catalyzed borane reduction

A facile synthesis of (1S,2R)-indene oxide with >99% e.e. and (1S,2S)-trans-2-bromo-1-indanol with 87% e.e. has been established by employing CBS-oxazaborolidine-catalyzed asymmetric borane reduction of 2-p-toluenesulfonyloxy-1-indanone using N-ethyl-N-isopropylaniline–borane complex as the borane carrier.     

A pilot-scale synthesis of (1R)-trans-2-(2,3-dihydro-4-benzofuranyl)cyclopropanecarboxylic acid: a practical application of asymmetric cyclopropanation using a styrene as a limiting reagent

Asymmetric cyclopropanation of styrene 1 (as the limiting reagent) was demonstrated using excess ethyl diazoacetate and catalytic Ru(ip-Pybox). Selective hydrolysis of the resulting 90:10 trans:cis mixture of cyclopropane 4 generated cyclopropyl acid 2 as a 96:4 trans:cis mixture with 84% e.e. for the trans-cyclopropane. Further purification and enantiomeric enrichment was achieved by diastereoselective crystallization with (+)-dehydroabeitylamine to afford the (R,R)-isomer with ≥99.9% e.e in 60–65 M% yield starting from styrene 1.     

Efficient resolution of prostereogenic arylaliphatic ketones using a recombinant alcohol dehydrogenase from Pseudomonas fluorescens

A broad range of arylaliphatic ketones is efficiently reduced to the corresponding optically active (R)-alcohols by a recombinant alcohol dehydrogenase from Pseudomonas fluorescens (PFADH) produced by overexpression in Escherichia coli. PFADH shows high activity and stereoselectivity in the reduction of acetophenone and various derivatives (45–99% e.e.), as well as in the reduction of 3-oxobutyric acid methyl ester (>99% e.e.). The highest activity was observed between 10 and 20°C. The cofactor NADH can be efficiently recycled by the addition of 10–20% (v/v) of iso-propanol.     

Enantioselective synthesis of (S)-α-methylphenylalanine using (S)-BINOLAMs as new phase-transfer catalysts

A series of (S)-bis(aminomethyl)binaphthols [(S)-BINOLAMs] 4 have been prepared and used as catalysts in the enantioselective C-alkylation reaction of the aldimine Schiff bases of alanine esters 5 under solid–liquid phase-transfer catalysis (PTC) conditions employing NaOH as base in toluene at room temperature. (S)-3,3′-Bis[(diethylamino)methyl]-2,2′-dihydroxy-1,1′-binaphthalene 4a gave the best e.e.s. (S)-α-Methylphenylalanine 7 was isolated, after hydrolysis of the iminoester, in 85% yield with an e.e. of 68%.     

Andersen chemistry with an α,β-unsaturated sulfinyl chloride: synthesis and Grignard reactions of homochiral cholesteryl (R)S-(E)-t-butylethenesulfinate

(−)-Cholesteryl (R)_S-(E)-t-butylethenesulfinate 2 was prepared in enantiopure form through the reaction of (E)-t-butylethenesulfinyl chloride and (−)-cholesterol in the presence of quinine (ca. 36% yield). Diastereomerically enriched versions of (S)-2 were prepared with d.e.s up to 75%. Grignard substitution reactions of 2 proceed with high stereospecificity to provide a new access to enantiomerically enriched (E)-2-t-butylethenylaralkyl sulfoxides in good yield and excellent e.e.     

Polymorphisms of COTL1 gene identified by proteomic approach and their association with autoimmune disorders

To select candidate genes, we attempted to comparative analysis of protein levels between rheumatoid arthritis (RA) patients and healthy controls by two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption ionization mass spectrometry (MALDI-TOF-MS). We identified 17 proteins that showed up- or down-regulated spots in RA patients. We found that coactosin-like1 (COTL1) were highly expressed in RA patients compared with healthy controls. We performed a case-control study to determine whether the COTL1 gene polymorphisms were associated with RA and systemic lupus erythematosus (SLE). The genotype frequency of c.-1124G>T and the allelic frequency of c.484G>A in RA patients, and the genotype frequency of c.484G>A in SLE patients were significantly different from healthy controls (P = 0.009, 0.027, and 0.025, respectively). We also investigated the correlation with the levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibody in RA patients, and anti-nuclear antibodies (ANA) in SLE patients. The c.484G>A polymorphism in RA patients has significant association with the levels of anti-CCP antibody (P = 0.03). Our findings demonstrated that c.-1124G>T and c.484G>A polymorphisms of the COTL1 gene might be associated with the genetic susceptibility of autoimmune disorders.