An asymmetric synthesis of carboxylic acid derivatives,including lactic acid and α-amino acid derivatives,from optically active 1-chlorovinyl p-tolyl sulfoxides and ester lithium enolates with creation of chirality at the α-position

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones or methyl formate and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent (alkyl, alkoxy, or dibenzylamino group) at the α-position with high 1,4-chiral induction from the sulfur chiral center. The adducts were converted to optically active esters, lactic acid, and α-amino acid derivatives having a chiral center at the α-position. When this addition reaction was carried out with an ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolate, a new method for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the α-position from the one chiral source, (R)-(−)-chloromethyl p-tolyl sulfoxide, was achieved.     

Synthesis of 3-substituted 2-cyclohexenones through umpoled functionalization

A new protocol to obtain 3-substituted 2-cyclohexenones, was developed by reversing the chemical reactivity of 2-cyclohexenone. One-pot synthesis of 3-substituted 2-cyclohexenones can be achieved by treatment of 3-phenylthiosilyl enol ether with a mixture of t-BuLi/HMPA that allows hydrogen-selective exchange in presence of reactive electrophiles such as aldehydes, ketones and alkyl halides. This affords the corresponding product in moderate overall yield, after silyl enol ether cleavage and concomitant thiophenol elimination initiated with TBAF.     

Base-induced transformations of ortho-nitrobenzylketones: intramolecular displacement of nitro group versus nitro-nitrite rearrangement

Reactions of 4-bromo-5-nitrophthalonitrile (BNPN) with enolates of alkyl 4-R-2,4-dioxobutanoates gave alkyl 3-acyl-5,6-dicyanobenzofuran-2-carboxylates, 4-(2-R-2-oxoethyl)-5-nitrophthalonitriles, or 3-acyl-1,2-benzoxazole-5,6-dicarbonitriles. With a base, 4-(2-R-2-oxoethyl)-5-nitrophthalonitriles either undergo nitro-nitrite rearrangement resulting in 3-acyl-1,2-benzoxazole-5,6-dicarbonitriles or yield 2-R-benzofuran-5,6-dicarbonitriles with a nitro group displacement.     

Reaction of N-substituted 2-oxochromen-3-carboxamides with bromoderivatives of zinc enolates prepared from alkyl 2,2-dialkyl-4,4-dibromo-3-oxoalkanoates and zinc

Zinc enolates obtained from ethyl 2,2-dialkyl-4,4-dibromo-3-oxobutanoates and zinc react with N-substituted 2-oxochromen-3-carboxamides forming ethyl 3-{1a-(R³-carbamoyl)-2-oxo-1a,7b-dihydrocyclopropa[c]chromen-1-yl}-2,2-dialkyl-3-oxopropanoate isomer with a Z-position of methine hydrogens. Zinc enolates prepared from alkyl 2,2-dialkyl-4,4-dibromo-3-oxopentanoates and-hexanoates and zinc react with N-substituted 2-oxochromen-3-carboxamides to give rise to esters of 3-{1-alkyl-1a-(R³-carbamoyl)-2-oxo-1a,7b-dihydrocyclopropa-[c]chromen-1-yl}-2,2-dialkyl-3-oxopropanoic acid as isomers with the E-position of the methine proton and the alkyl substituent. The reaction carried out in the presence of small quantities of THF and HMPA leads to the formation of 9c-alkyl-2-R³-9b,9c-dihydro-5-oxa-2-azacyclopenta[2,3]-cyclopropa[1,2-a]naphthalene-1,3,4-triones. Zinc enolates from alkyl 2,2-dialkyl-4,4-dibromo-3-oxopentanoates and-hexanoates and zinc with the secondary amides of 2-oxochromen-3-carboxylic acid form alkyl 3-{2-oxo-1a-(piperidinocarbonyl)-and 3-{6-R¹-1a-(morpholinocarbonyl)-2-oxo-1a,7b-dihydrocyclopropa[c]chromen-1-yl}-2,2-R²,R²-3-oxopropanoates as single geometrical isomers.     

Asymmetric chemoenzymatic synthesis of N-acetyl-α-amino esters based on lipase-catalyzed kinetic resolutions through interesterification reactions

Several phenylalanine analogs have been synthesized through a four-step route starting from easily available ethyl acetamidocyanoacetate. In a first reaction, and making use of phase transfer catalysts, this compound reacted with several alkyl halides, being benzyltributylammonium chloride identified as the best one for the production of a series of quaternary amino acids in moderate to excellent yields (52–95%). Then, the corresponding N-acetyl-phenylalanine methyl and allyl ester derivatives were obtained through acidic hydrolysis, esterification, and N-acetylation. Rhizomucor miehei lipase was found as a versatile enzyme for the resolution of these amino esters, finding the best results through interesterification reactions with butyl butyrate in acetonitrile. A great influence in the stereoselectivity was found depending on the chemical structure of the compound, achieving for the non- or para-substituted in the phenyl ring excellent stereoselectivities, being moderate for the meta-nitro derivative, while the ortho-nitro amino ester did not react.     

Synthesis of bicyclic dipeptide mimetics for the cholecystokinin and opioid receptors

The cholecystokinin C-terminal octapeptide analogue H-Asp-Tyr-D-Phe-Gly-Trp-(N-Me)-Nle-Asp-Phe-NH₂ (SNF 9007) is a potent and selective ligand for both the CCK-B and δ-opioid receptors. To constrain the peptide into the biologically active conformation(s), bicyclic dipeptide mimetics for Nle-Gly and homoPhe-Gly were designed and synthesized from β-substituted aspartic acids. Alkylation of L-aspartic acid using lithium bis(trimethylsilyl)amide (LHMDS) in the presence of hexamethylphosphoramide (HMPA) gave β-substituted aspartic acids, with the major product being the (2S,3R) isomer. Additional isomers of Nle-Gly bicyclic dipeptide mimetic were obtained via the Kazmaier-Claisen rearrangement reaction. The stereochemistries of the bicyclic dipeptide mimetics were assigned by X-ray and NMR.     

Phase-transfer catalyzed asymmetric arylacetate alkylation

Phenethyl arylacetates are alkylated under phase-transfer conditions with cinchona catalysts with alkyl halides in high yield with excellent enantioselectivity (84-99% ee) following recrystallization. Cinchonidine (CD) derived catalyst gave the (R)-product and cinchonine (CN) catalyst produced the (S)-product. The phenethyl (PE) ester group is removed, using ammonium formate and catalytic Pd/C, to give alkylated carboxylic acid products in high selectivity. The utility of the approach is demonstrated by a direct synthesis of (S)-naproxen^™.     

Stereoselective synthesis of 2-(α-hydroxyalkyl)benzimidazoles

Lithiated oxazolo[3,4-a]benzimidazole 4 reacted with various alkyl halides to give oxazolo[3,4-a]benzimidazoles 5a–d in good yields as single diastereoisomers. (R)-Benzimidazol-2-yl carbinols 6a–d were obtained upon hydrolysis under acidic conditions of 1H,3H-oxazolo[3,4-a]benzimidazole derivatives.     

PTC and organic bases–LiCl assisted alkylation of imidazolidinone–glycine iminic derivatives for the asymmetric synthesis of α-amino acids

Iminic derivatives of (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one and glycine 4 have been highly diastereoselectively alkylated with activated alkyl halides or electrophilic olefins either under PTC conditions or in the presence of the strong organic bases DBU or BEMP at −20°C in the presence of LiCl. Hydrolysis of the alkylated imino imides gave (S)-α-amino acids with recovery of the imidazolidinone chiral auxiliary.     

A crystallization-induced asymmetric transformation to prepare (R)-4-chlorophenylalanine methyl ester

A second order asymmetric transformation of racemic 4-chlorophenylalanine methyl ester was achieved via salt formation with (2S,3S)-(−)-tartaric acid in the presence of salicylaldehyde to afford the desired (R)-enantiomer of 4-chlorophenylalanine methyl ester in good yield and high enantiomeric purity.     

Enantioselective synthesis of Fmoc-l-3-(2-benzothienyl)alanine (2-BtAla) via diastereoselective alkylation of a glycine equivalent

Stereoselective alkylation of the anion derived from (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with 2-chloromethylbenzothiophene afforded the corresponding trans-monosubstituted product, (2S,5R)-2-((1-benzo[b]thiophen-2-yl)methyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihyropyrazine in 88% yield. Hydrolysis of the alkylated product using 40% TFA/H₂O at 0?°C and subsequent protection of the α-amino functional group with Fmoc-OSu afforded Fmoc-l-3-(2-benzothienyl)alanine methyl ester in 88% yield. Hydrolysis of the methyl ester with aqueous LiOH gave Fmoc-l-3-(2-benzothienyl)alanine in 62% overall yield.     

Synthesis, characterization and thermal properties of small R2R2NX-type quaternary ammonium halides

Twenty-one R₂R^′₂N⁺X⁻ -type (R=methyl or ethyl, R^′=alkyl, X=Br or I) quaternary ammonium (QA) halides have been prepared by using a novel one-pot synthetic route in which a formamide (dimethyl-, diethylformamide, etc.) is treated with alkyl halide in the presence of sodium or potassium carbonate. The formation of QA halides was verified with ¹H-NMR, ¹³C-NMR, MS and elemental analysis. The crystal structures of four QA halides (two bromide and two iodide) were determined using X-ray single crystal diffraction, and the powder diffraction method was used to study the structural similarities between the single crystal and microcrystalline bulk material. The thermal properties of all compounds were studied using TG/DTA and DSC methods. The smallest compounds decomposed during or before melting. The decreasing trend of melting points was observed when the alkyl chain length was increased. The liquid ranges of 120-180 °C were observed for compounds with 5-6 carbon atoms in the alkyl chain. The low melting points and wide liquid ranges suggest potential applicability of these compounds for example as ionic liquids precursors.     

New approach to the enantiomerically pure 1,2,3-trihydroxypropylphosphonates

The replacement of 2,3-O-cyclohexylidene-d-glyceraldehyde with (2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde (Ley’s aldehyde) has led to significant improvements in the isolation of both diastereoisomers of the respective 2,3-O-BDA 1,2,3-trihydroxypropylphosphonates. The triethylamine-catalysed addition of dialkyl phosphites and lithium diethyl phosphonate gave the products in moderate (ca. 1:2) diastereoselectivity while the application of diethyl trimethylsilyl phosphite afforded a 1:9 mixture of diethyl (R)- and (S)-hydroxy-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]methylphosphonates.     

Highly diastereoselective aldol additions to five-ring N,O-acetals

Highly diastereoselective aldol additions of pure (2R,4S)-2-tert-butyloxazolidinone-3,4-dicarboxylic acid 3-tert-butyl ester 4-methyl ester 1 are reported. While achiral carbonyl compounds lead to mixtures of diastereomers, the double stereodifferentiation of chiral aldehydes gave a single product isomer. The relative and absolute configurations of the aldol products were assigned by NOESY.     

The synthesis, N-alkylation and epimerisation study of a phthaloyl derived thiazolidine

The synthesis of the phthaloyl protected thiazolidine, N-phthaloyl-methyl-2(R)-thiazolidine-4(R)-methyl ester, 2, and a study of its susceptibility to epimerise in a range of solvents, using ¹H NMR spectroscopy, are described. Compound 2 was further reacted to yield the thiazole amino acid derivative, 3, and an N-alkylated thiazolidine derivative, 6, as a single diastereoisomer. The N-alkylation of 2, using mild bases, resulted in the formation of a mixture of diastereoisomers of 2 (2R,4R) and (2S,4R). Successful cleavage of the methyl ester and the phthaloyl protecting groups was achieved, giving rise to the formation of the two heterocyclic building blocks, 4 and 5.     

A convenient method for the preparation of chiral phosphonoacetamides and their Horner–Wadsworth–Emmons reaction

Chiral phosphonoacetamides bearing (S)-(α-methylbenzyl)benzylamine, (S,S)-bis(α-methylbenzyl)amine, l-phenylglycine methyl ester and l-phenylglycinol were easily prepared in good yield by means of the Michaelis–Arbuzov reaction of chiral bromoacetamides obtained in quantitative yield, with trimethyl phosphite, which under Horner–Wadsworth–Emmons conditions with several aryl and alkyl aldehydes under Masamune–Roush procedure using LiCl and DBU in THF or toluene gave the corresponding chiral α,β-unsaturated amides. The present procedure is a convenient and efficient methodology for the preparation of phosphonoacetamides and chiral α,β-unsaturated amides in high E-selectivity.     

A novel method for asymmetric synthesis of both enantiomers of α-substituted carboxylic acid derivatives from optically active 1-chlorovinyl p-tolyl sulfoxides and lithium ester enolates with 1,4-chiral induction from the sulfur chiral center

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent at the α-position with high 1,4-chiral induction from the sulfur chiral center in high yields. The adducts were converted to optically active esters and carboxylic acids having a chiral center at the α-position. When this addition reaction was carried out with the ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolates, a new method for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the α-position from the one chiral source, (R)-(−)-chloromethyl p-tolyl sulfoxide, was realized.     

A synthesis of optically active α-quaternary α-amino acids and esters by assembling three components, ketones, (R)-chloromethyl p-tolyl sulfoxide, and sodium azide, via sulfinyloxiranes

Treatment of lithium α-sulfinyl carbanion of chloromethyl p-tolyl sulfoxides with ketones at low temperature afforded adducts in almost quantitative yields, which were exposed to t-BuOK to give sulfinyloxiranes in high yields. The sulfinyloxirane was reacted with benzylamine to give α-amino aldehyde, which was oxidized with iodine in methanol to afford α-amino carboxylic ester in moderate yield. The sulfinyloxiranes were treated with sodium azide to afford α-azido aldehydes in good yields. Oxidation with NaClO₂ followed by catalytic hydrogenation of the azido group of the α-azido aldehydes gave α-quaternary α-amino acids in good overall yields. The oxidation of the azido aldehydes with iodine in methanol in the presence of KOH followed by the catalytic hydrogenation resulted in α-quaternary α-amino acid methyl esters in good yields. When these reactions were carried out starting from unsymmetrical ketones and optically pure (R)-chloromethyl p-tolyl sulfoxide, a new method for a synthesis of optically active α-quaternary α-amino acids and esters in good overall yields was realized.     

Highly efficient double enantioselection by lipase-catalyzed transesterification of (R,S)-carboxylic acid vinyl esters with (RS)-1-phenylethanol

Transesterification of the title compounds using lipase B from Candida antarctica in toluene afforded the corresponding esters in good to excellent diastereomeric excess. (R)-2-Phenylpropionic acid-(R)-1-phenethyl ester 4 was isolated in 45% yield and 64% de after 2.5 h, whereas (R)-2-phenylbutyric acid-(R)-1-phenethyl ester 5 was obtained in 40% yield and 56% de after 35 h. A single recrystallization from n-hexane gave 4 with 98% de. In all reactions CAL-B showed excellent enantioselectivity (E >100) toward (RS)-1-phenylethanol and moderate enantioselectivity (E∼10) toward both carboxylic acid vinyl esters.     

Fluorinated stannanes : Part 2. The stereospecific synthesis of fluorinated stannanes via a Barbier-type reaction between fluorinated halides and tributyltin chloride mediated by zinc or cadmium

Fluorinated stannanes are valuable synthons in synthetic organofluorine chemistry. Fluorinated vinyl, alkyl and aryl halides reacted efficiently with tri-n-butyltin chloride in the presence of zinc or cadmium to yield the corresponding stannanes in good yields. In some cases, yield of the stannanes showed a dramatic improvement over the transmetalation method. In all other cases, comparable yields were obtained.