A highly enantioselective chemoenzymatic synthesis of syn-3-amino-2-hydroxy esters: key intermediates for taxol side chain and phenylnorstatine

Starting from the bromination of α-ketoesters to obtain 3-bromo-2-oxoalkanoates and bioreduction with Saccharomyces cerevisiae entrapped in calcium alginate pellets with double gel layers, syn-(2R,3S)-β-bromo-α-hydroxy esters were obtained regioselectively in high yields and high ee. These chiral bromohydrins were cyclized to epoxides that were transformed into oxazolidines and finally opened by acidic hydrolysis to give syn-(2S,3S)-β-amino-α-hydroxy esters in high overall yields and high ee. The enantiomeric excesses of all the intermediates were maintained during the reaction sequence.     

Enantiodiscrimination of racemic electrophiles by diketopiperazine enolates: asymmetric synthesis of methyl 2-amino-3-aryl-butanoates and 3-methyl-aspartates

Enolates of (S)-N,N′-bis-(p-methoxybenzyl)-3-iso-propylpiperazine-2,5-dione exhibit high levels of enantiodiscrimination in alkylations with (RS)-1-aryl-1-bromoethanes and (RS)-2-bromoesters, affording substituted diketopiperazines containing two new stereogenic centres in high de. Deprotection and hydrolysis of the resultant substituted diketopiperazines provides a route to the asymmetric synthesis of homochiral methyl 2-amino-3-aryl-butanoates and 3-methyl-aspartates in high de and ee.     

Synthesis, including asymmetric synthesis, of 1-substituted cyclopentenes from cyclobutanones with one-carbon ring-expansion by 1,2-carbon-carbon insertion of magnesium carbenoids

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were derived from cyclobutanones and chloromethyl p-tolyl sulfoxide, with lithium enolate of tert-butyl carboxylates, amides, lithium α-sulfonyl carbanions, and lithium α-carbanion of acetonitrile gave adducts in high to quantitative yields. The adducts were treated with Grignard regents, such as i-PrMgCl and EtMgCl in toluene to afford 1-substituted cyclopentenes in good to high yields with one-carbon ring-expansion via 1,2-carbon-carbon (1,2-CC) insertion reaction of the generated magnesium carbenoid intermediates. The magnesium carbenoid 1,2-CC insertion was found to be highly stereospecific. When optically pure chloromethyl p-tolyl sulfoxide was used in this procedure, optically active 1-substituted cyclopentenes were obtained in high optical purity.     

Stereoselective synthesis of N-protected pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and γ-(N-Boc-amino) alkenes with aryl bromides

The stereoselective synthesis of N-acyl- and N-Boc-protected pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and γ-(N-Boc-amino) alkenes with aryl bromides is described. These reactions effect formation of two bonds in a single operation and proceed with generally high levels of diastereoselectivity. In contrast to previously described reactions of γ-(N-arylamino) alkenes, these transformations proceed in high yield and high regioselectivity with both electron-rich and electron-deficient aryl bromides as well as vinyl bromide substrates.     

A new synthesis, including asymmetric synthesis, of alkylidenecyclopropanes by 1,2-CC insertion of cyclobutylmagnesium carbenoides as the key reaction

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters gave adducts in high yields. The adducts were converted to 1-chlorocyclobutyl p-tolyl sulfoxides in four steps in high overall yields. Treatment of the 1-chlorocyclobutyl p-tolyl sulfoxides with cyclopentylmagnesium chloride in THF at −40 °C resulted in the formation of cyclobutylmagnesium carbenoids. The magnesium carbenoid 1,2-CC insertion reaction took place smoothly from the cyclobutylmagnesium carbenoids to afford alkylidenecyclopropanes in good to high yields. An asymmetric synthesis of optically active alkylidenecyclopropane was successfully achieved starting from optically active 1-chlorovinyl p-tolyl sulfoxide.     

Asymmetric synthesis of β-substituted Baylis-Hillman products via lithium amide conjugate addition

A three-step protocol for the asymmetric synthesis of a range of β-substituted Baylis-Hillman products has been developed. This procedure involves the diastereoselective conjugate addition of lithium (R)-N-methyl-N-(α-methylbenzyl)amide to an α,β-unsaturated ester to generate an N-protected β-amino ester in high de. Subsequent asymmetric aldol reaction via deprotonation with LDA, transmetallation with B(OMe)₃ and addition of an aldehyde gives a range of syn-aldol products in moderate to high de. Purification of the syn-aldol products to homogeneity followed by tandem N-oxidation and Cope elimination gives the desired β-substituted Baylis-Hillman products in good yield and high de and ee.     

Greener synthesis using hydrogen peroxide in ethyl acetate of alicyclic ring-fused benzimidazoles and anti-tumour benzimidazolequinones

Environmentally-friendly and cost effective hydrogen peroxide in ethyl acetate was used to prepare in high yields pyrrolo[1,2-a]benzimidazoles from commercial o-(pyrrolidin-1-yl)anilines without the requirement for organic-aqueous extraction and chromatography. Six, seven and eight membered ring-fused analogues were similarly obtained in high yields with methanesulfonic acid required for the pyrido[1,2-a]benzimidazole. Anti-tumour benzimidazolequinone derivatives were obtained in high yield via the cyclization of 3,6-dimethoxy-2-(cycloamino)anilines.     

L-tert-Leucine derived urea-ammonium salts: Efficient bifunctional phase transfer catalysts for highly diastereo- and enantioselective aza-Henry reaction of isatin-derived N-Boc ketimines with α-aryl nitromethanes

An efficient way of aza-Henry reaction between isatin-derived N-Boc ketimines and α-aryl nitromethanes catalyzed by bifunctional phase transfer catalysts with a quaternary ammonium center derived from L-tert-Leucine has been developed. A series of 3-substituted 3-amino-oxindoles were constructed by this catalytic protocol in excellent yields (90–99%), with high enantioselectivities (83–95%) and diastereoselectivities (79:21–97:3). The asymmetric aza-Henry reaction of N-Boc amidosulfones and α-aryl nitromethanes were also investigated and gave the corresponding products in high to excellent yields (72–97%) with high enantioselectivities (up to 99%) and diastereoselectivities (up to >99:1).     

Highly stereoselective direct aldol reactions catalyzed by (S)-NOBIN-l-prolinamide

(S)-NOBIN-l-prolinamide was employed as organocatalyst in the direct aldol reactions of different ketones and aromatic aldehydes using dioxane as solvent and in the presence of water as additive. Acetone led to the aldol products in up to 93% ee, while cyclic ketones furnished the anti-aldols in moderate to high yield, excellent diastereoselectivity (up to >99/<1 anti/syn ratio) and high ee (up to 95%).     

Stereoselective synthesis of CF3-substituted trans- and cis-enediynes via carbocupration or hydrostannation reactions of CF3-containing diyne

CF₃-containing diyne, readily prepared from (Z)-2,3,3,3-tetrafluoro-1-iodoprop-1-ene in two steps, was smoothly subjected to carbocupration reaction with various organocuprates, followed by treatment of the resultant carbocupration adducts with iodine, the corresponding vinyl iodides being formed in good yields in a cis-addition manner. Thus obtained iodide could be successfully converted into CF₃-substituted trans-enediynes in high yields. Also, hydrostannation reaction of the diyne proceeded well in a trans-addition manner to give the corresponding vinylstannane in high yield. The vinylstannane was also found to be effectively convertible to CF₃-substituted cis-enediynes in high yields.     

Highly diastereoselective boron and titanium mediated aldol reactions of a mannitol derived 2,3-butanediacetal ethyl ketone

A mannitol derived 2,3-butanediacetal ethyl ketone displays high levels of diastereoselectivity in boron and titanium mediated aldol reactions with a range of aliphatic and aromatic aldehydes to afford syn aldol products in high yield. The stereochemical outcome of the reaction was determined using J-value analysis, NMR analysis of O-acetylmandelate derivatives and X-ray crystallography.     

(+)-syn-Benzotriborneol: the first functionalised enantiopure C3-symmetric benzocyclotrimer

Copper(I) thiophencarboxylate readily and effectively cyclotrimerises protected 5-bromo-6-trimethylstannylborn-5-en-2-ols, leading to oxygen-functionalised benzocyclotrimers. The remarkably high syn to anti ratio is driven by relative displacement of the halide and metal on the alkene moiety and depends on the steric hindrance of the protecting group of the hydroxy function. The less hindered methyl derivative affords exclusively syn-benzocyclotrimer. The readily removable methoxymethyl derivative gives enantiopure syn-tribenzoborneol in high yields.     

P′CP′-Pincer palladium complex-catalyzed allylation of N,N-dimethylsulfamoyl-protected aldimines

The P′CP′-pincer palladium complex-catalyzed allylation of N,N-dimethylsulfamoyl-protected aldimines with allyl(tributyl)stannane is investigated for the preparation of N-homoallylic sulfamides. The desired N,N-dimethylsulfamoyl-protected products are obtained in moderate to high yields in DMF under very mild conditions and a high yielding and convenient deprotection of the N,N-dimethylsulfamoyl group is also demonstrated.     

Ag/ThioClickFerrophos catalyzed highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides with alkenes

A silver(I)/ThioClickFerrophos complex catalyzed the endo selective asymmetric 1,3-dipolar cycloaddition reaction of methyl N-benzylideneglycinate (the source of azomethine ylides) with α,β-unsaturated esters and maleimides to give the endo-2,4,5- and 2,3,4,5-substituted pyrrolidines in good yields with high enantioselectivities (up to 99% ee). The complex also effectively catalyzed the endo selective reactions with β-nitrostyrene to give the 4-nitropyrrolidine in a high enantioselectivity.     

A synthesis of bicyclo[n.1.0]alkanes having tert-butyl carboxylate or acetamide moiety via the intramolecular 1,3-CH insertion of magnesium carbenoids

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from various cyclic ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters or N,N-dimethylacetamide gave adducts in high yields. The adducts were treated with ether solution of isopropylmagnesium chloride in dry toluene to give bicyclo[n.1.0]alkane derivatives having tert-butyl carboxylate or acetamide moiety on the bridgehead carbon in high to quantitative yields via magnesium carbenoid 1,3-CH insertion reaction. The 1,3-CH insertion reaction proved to be regioselective and stereospecific. The reaction mechanism and origin of the selectivity and specificity are discussed.     

Chemometric Approach to Prediction of Antibacterial Agent Production by Streptomyces hygroscopicus

The nutritional requirements for antimicrobial agent production using Streptomyces hygroscopicus were analyzed in shake flask experiments. Antimicrobial activity was tested against Staphylococcus aureus and Bacillus cereus. The mathematical models have been generated with relative high complexity in order to give an adequate fit to the data. All the results suggest a high dependence of produced antimicrobial agent quantities on the amount of carbon, nitrogen, and phosphorus in cultivation medium. The statistical results of the generated models reflect the high predictive ability. The derived models were validated using leave-one-out cross-validation technique, and from statistical point of view, they have significantly high values of the cross-validation parameters.     

Silver-catalyzed cascade reaction of o-aminoaryl compounds with alkynes: an aniline mediated synthesis of 2-substituted quinolines

An efficient silver-catalyzed, aniline mediated cascade hydroamination/cycloaddition of o-aminoaryl compounds including o-aminoaryl aldehydes, o-aminoaryl ketones with alkynes for the synthesis of 2- or 2,4-substituted quinolines is reported. The reactions proceed with high regioselectivity to afford mono- or disubstituted quinoline derivatives in good to high yields using AgOTf as the catalyst in the air.     

A new synthesis of amides and γ-lactones based on the conjugate addition of lithium enolate of amides to 1-chlorovinyl p-tolyl sulfoxides

Reaction of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from chloromethyl p-tolyl sulfoxide and ketones or aldehydes, with lithium enolate of N,N-dimethylacetamide gave the adducts in good to quantitative yields. The adducts were converted to several kinds of amides in high overall yields. Treatment of the adducts with trifluoroacetic anhydride in the presence of NaI resulted in the formation of γ-tolylsulfanylated γ-lactones in high yields. The scope and limitations of this method and the mechanism of the reactions are also discussed. These procedures offer a new and effective method for the synthesis of amides and γ-lactones having substituents on the β-carbon from N,N-dimethylacetamide with carbon elongation.     

Comparison of linseed (Linum usitatissimum L.) genotypes with respect to the content of polyunsaturated fatty acids

The aim of our work was to characterize linseed (Linum usitatissimum L.) genotypes divided into groups with high and low content of alpha-linolenic acid (ALA). Out of 32 linseed genotypes, 68.75 % represented high alpha-linolenic genotypes and 31.25 % were genotypes with low ALA content. Proportional representation of fatty acids was realized according to the norm (Czech Office for Standards, Metrology and Testing, 1994). Oil content was analyzed according to the internal methodology of Agritec Ltd., based on the norm (Czech Office for Standards, Metrology and Testing, 2011). The content of total fat ranged from 36.22 % to 46.35 %, that of ALA from 1.10 % to 65.20 %, and that of linoleic acid (LA) from 11.10 % to 75.00 % in the analyzed seed samples within all groups. The genotypes were divided also according to the seed color and a linear correlation between all three parameters within these groups was observed. Negative linear dependence was confirmed between parameters; ALA and LA content in the groups: high ALA brown seed (p < 0.0001; correlation coefficient (r) = ?0.70), and high ALA yellow seed (p < 0.001; r = ?0.36). Also, positive linear dependence between the total fat and the LA content in the groups: low ALA brown seed (p < 0.001; r = 0.34); low ALA yellow seed (p < 0.0001; r = 0.62), was found.     

Growth Inhibition of Thermotolerant Yeast,Kluyveromyces marxianus,in Hydrolysates from Cassava Pulp

In this study, we report the inhibition of Kluyveromyces marxianus TISTR5925 growth and ethanol fermentation in the presence of furan derivatives and weak acids (acetic acid and lactic acid) at high temperatures. Cassava pulp, obtained as the waste from starch processing, was collected from 14 starch factories located in several provinces of Thailand. At a high temperature (42 °C), the cassava pulp hydrolysate from some starch factories strongly inhibited growth and ethanol production of both K. marxianus (strain TISTR5925) and Saccharomyces cerevisiae (strain K3). HPLC detected high levels of lactic acid and acetic acid in the hydrolysates, suggesting that these weak acids impaired the growth of K. marxianus at high temperature. We isolated Trp-requiring mutants that had reduced tolerance to acetic acid compared to the wild-type. This sensitivity to acetic acid was suppressed by supplementation of the medium with tryptophan.