Diastereoselective synthesis of (2S)-2-[(R)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one

Double asymmetric induction in Michael reactions has been studied. Enantioselective alkylation of a cyclic ketone (1-indanone) with α-phenyl-nor-gramine was carried out. The relative configuration of (2S^∗)-2-[(R^∗)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one was established by X-ray diffraction. The relative configuration of (R^∗,R^∗,S^∗)- and (S^∗,R^∗,S^∗)-2-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-ols was established by ¹H NMR studies.     

Enantioselective synthesis of phosphonate analogues of (R)- and (S)-homoserine

The enantioselective synthesis of (R)- and (S)-1-amino-3-hydroxypropylphosphonic acid, the phosphonate analogues of (S)- and (R)-homoserine, has been accomplished in four steps and good overall yield starting from diethyl (3R,5R)- or (3S,5S)-5-(hydroxymethyl)-2-[(S)-1-phenylethyl]isoxazolidinyl-3-phosphonate, respectively.     

An improved synthesis of (1R,3S)-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid

An improved synthesis of (1R,3S)-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid from 3-aminobenzoic acid is described utilising milder and more selective conditions. Both a classical salt resolution and an enzymatic approach have been shown to give the desired compound in high selectivity.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

A convenient and new approach to the synthesis of ω-heterocyclic amino acids from carboxy lactams through ring-chain-transformation. Part 2: Synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid

Making use of amide activation, a convenient and short path synthesis of optically pure ω-heterocyclic-β-amino acids has been achieved from (1R,3R)- and (1R,3S)-5-oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl ester. The key step of the synthesis involves a regiospecific ring-chain-transformation of the enaminones when subjected to 1,2-binucleophilic attacks. The method is illustrated by the synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid.     

Simultaneous enzymatic synthesis of (S)-3-fluoroalanine and (R)-3-fluorolactic acid

A coupled enzymatic system for the simultaneous synthesis of (S)-3-fluoroalanine (1a) and (R)-3-fluorolactic acid (3) with l-alanine dehydrogenase (l-AlaDH) from Bacillus subtilis and rabbit muscle l-lactate dehydrogenase (l-LDH) using rac-1 and NAD⁺ is described. Analysis of isolated products of the laboratory preparative scale process revealed 1a in 60% yield and 88% ee and 3 in 80% yield and over 99% ee. The compounds 1a and 3 represent chiral building blocks for the synthesis of several products with pharmacological activity.     

Homochiral (R)- and (S)-1-heteroaryl- and 1-aryl-2-propanols via microbial redox

Preparation of various heteroaryl propanols 2a–g and of the corresponding propanones 3a–g as starting materials for microbial redox is described. The kinetic resolution of the racemic propanols 2a–g is obtained via oxidation with Pseudomonas paucimobilis and Bacillus stearothermophilus [(R)-alcohols, ee 74–100%]. Similar results are achieved with 3-(2-hydroxypropyl)trifluoromethylbenzene 7 (44%, ee 100% of the (R)-alcohol 6). The reduction of the propanones 3a–d and 3g with baker's yeast and other fungi gives the (S)-alcohols (ee 100%). The pure (S)-alcohols are also obtained by reduction of 1-[3-(trifluoromethyl)phenyl]-2-propanone 7. 1-[(4,4-Dimethyl)-2-(Δ²)oxazolinyl]-2-propanone 3e and 1[2-(Δ²)-thiazolinyl)-2-propanone 3f are not reduced. The heterocyclic rings of (S)-5-(2-hydroxypropyl)-3-methylisoxazole 2d and of (S)-2-(2-hydroxypropyl)-4-methylthiazole 2g are deblocked to the homochiral enamino ketone 8 (78%) and to the protected β-hydroxy aldehyde 9 (73%), respectively. The (R)-3-(2-hydroxypropyl)trifluoromethylbenzene 6 is transfomed into the homochiral precursor of (S)-fenfluramine 10 (overall yield 65%).     

Synthesis and analytical properties of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid

2-Methoxy-2-(9-phenanthryl)propionic acid was synthesized as a novel chiral resolving agent. The absolute configuration of (+)-2-methoxy-2-(9-phenanthryl)propionic acid was determined to be S by using X-ray structural analysis of the (1R,2S,5R)-menthyl ester. In the crystal, the methoxyl and carbonyl groups of the ester are in a syn-periplanar position. The syn-periplanar conformations of (1R,2S,5R)-menthyl esters were also observed by the NMR analyses in CDCl₃. The utility of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid was exemplified by the resolution of (±)-3-octanol.     

Resolution of (±)-[2.2]paracyclophane-4,12-dicarboxylic acid

The resolution of (±)-[2.2]paracyclophane-4,12-dicarboxylic acid (±)-1 has been realized through the diastereomeric esters of (1S)-hydroxymethyl-4,7,7-trimethyl-2-oxabicyclo-[2.2.1]heptan-3-one, simply separated by flash chromatography and hydrolyzed with ^tBuOK/H₂O. (R)-(−)-1 and (S)-(+)-1 were obtained in high enantiomeric excesses (>97%) while the determinations of the absolute configurations of (R)-1 and (S)-1 were carried out by X-ray diffraction.     

Stereoselective synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-dione hydrochlorides: bicyclic glutamic acid derivatives

Asymmetric synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-diones has been achieved. The underlying second generation asymmetric synthesis proceeds via a Strecker reaction with commercially available (R)-1-phenylethylamine (1-PEA) as chiral auxiliary, TMSCN as cyanide source and racemic ethyl 2-(2-oxocyclohex-1-yl)ethanoate. A ring closure addition-elimination reaction between an amide nitrogen and the ester functionality leads to the 1-amino-3-azabicyclo[4.4.0]decan-2,4-diones. The absolute configurations of the title compounds have been assigned based on detailed NMR-spectroscopic analysis and X-ray data.     

Operationally convenient asymmetric synthesis of (S)- and (R)-3-amino-4,4,4-trifluorobutanoic acid: Part II. Enantioselective biomimetic transamination of 4,4,4-trifluoro-3-oxo-N-[(R)-1-phenylethyl]butanamide

An asymmetric synthesis of (S)- and (R)-3-amino-4,4,4-trifluorobutanoic acid via DBU-catalyzed asymmetric 1,3-proton shift transfer reaction of (Z)-3-[(R)-1-phenylethylamino]-4,4,4-trifluoro-N-[(R)-1-phenylethyl]but-2-enamide has been developed. The intermediate Schiff base (S,R′)-9 was found to be relatively configurationally stable under the highly basic reaction conditions allowing preparation of the target amino acid in high chemical yield and enantioselectivity. This method was demonstrated to be practical for large (>25 g) scale synthesis of the target β-amino acid.     

An efficient approach to the synthesis of enantiomerically pure trans-1-amino-2-(hydroxymethyl)cyclopropanephosphonic acids

The synthesis of (1R,2S)- and (1S,2R)-1-amino-2-(hydroxymethyl)cyclopropanephosphonic acids was accomplished using different strategies. The (1R,2S)-stereoisomer could be efficiently obtained by the cyclopropanation of ethyl diethoxyphosphorylacetate with the cyclic sulfate derived from (S)-3-benzyloxy-1,2-propandiol as a key step. The (1S,2R)-stereoisomer was synthesized from a readily available (1S,5R)-3-oxabicyclo[3.1.0]hexan-2-on-1-phosphonate.     

Prostaglandin chemistry—V : Synthesis of new prostaglandin synthons; 4(R)-(+)- and 4(S)-(−)-t-butyldimethylsiloxycyclopent-2-en-1-one

Optically active prostaglandin intermediates, 4(R)-(+)- and 4(S)-(?)-hydroxycyclopent-2-en-1-one derivatives, were synthesized from 3(R),5(R)-diacetoxycyclopent-1-ene, 3(R)-acetoxy-5(R)-hydroxycyclopent-1-ene and 3(S),5(S)-dihydroxycyclopent-1-ene obtained by microbiological hydrolysis of 3,5-diacetoxycyclopent-1-ene. The absolute configurations of all these compounds were determined by the exciton chirality method and the induced CD method. The optical purities were determined by NMR measurements of the diastereomeric esters of a versatile optically pure acid, (+)-α-methoxy-α-trifluoromethylphenylacetic acid.     

Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained as O-ethyl or O,O-diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonates, when (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate or its 3-O-trityl derivative were used as starting materials, respectively. The intramolecular Williamson cyclisations of diethyl (1S,2R)- and (1R,2S)-1-benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates led to diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, respectively, with the concomitant formation of diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phosphonate. From diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, enantiomerically pure diethyl (1S,2S)- and (1R,2S)-1,2-dihydroxypropylphosphonates were obtained by catalytic hydrogenation, while diethyl (1S,2S)- and (1R,2S)-3-acetamido-1,2-dihydroxypropylphosphonates were produced after epoxide ring opening with dibenzylamine, acetylation and hydrogenolysis.     

Reaction of azulene with 1,2-bis[4-(dimethylamino)phenyl]-1,2-ethanediol in a mixed solvent of methanol and acetonitrile in the presence of hydrochloric acid: a facile one-pot synthesis and properties of new triarylethylenes possessing an azulen-1-yl group

Reaction of azulene (1) with 1,2-bis[4-(dimethylamino)phenyl]-1,2-ethanediol (2) in a mixed solvent of methanol and acetonitrile in the presence of 36% hydrochloric acid at 60 °C for 3 h gives 2-(azulen-1-yl)-1,1-bis[4-(dimethylamino)phenyl]ethylene (3) (8% yield), 1-(azulen-1-yl)-(E)-1,2-bis[4-(dimethylamino)phenyl]ethylene (4) (28% yield), and 1,3-bis{2,2-bis[4-(dimethylamino)phenyl]ethenyl}azulene (5) (9% yield). Besides the above products, this reaction affords 1,1-di(azulen-1-yl)-2,2-bis[4-(dimethylamino)phenyl]ethane (6) (15% yield), a meso form (1R,2S)-1,2-di(azulen-1-yl)-1,2-bis[4-(dimethylamino)phenyl]ethane (7) (6% yield), and the two enantiomeric forms (1R,2R)- and (1S,2S)-1,2-di(azulen-1-yl)-1,2-bis[4-(dimethylamino)phenyl]ethanes (8) (6% yield). Furthermore, addition reaction of 3 with 1 under the same reaction conditions as the above provides 6, in 46% yield, which upon oxidation with DDQ (=2,3-dichloro-5,6-dicyano-1,4-benzoquinone) in dichloromethane at 25 °C for 24 h yields 1,1-di(azulen-1-yl)-2,2-bis[4-(dimethylamino)phenyl]ethylene (9) in 48% yield. Interestingly, reaction of 1,1-bis[4-(dimethylamino)phenyl]-2-(3-guaiazulenyl)ethylene (11) with 1 in a mixed solvent of methanol and acetonitrile in the presence of 36% hydrochloric acid at 60 °C for 3 h gives guaiazulene (10) and 3, owing to the replacement of a guaiazulen-3-yl group by an azulen-1-yl group, in 91 and 46% yields together with 5 (19% yield) and 6 (13% yield). Similarly, reactions of 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene (12) and 1,1-bis{4-[2-(dimethylamino)ethoxy]phenyl}-2-(3-guaiazulenyl)ethylene (13) with 1 under the same reaction conditions as the above provide 10, 2-(azulen-1-yl)-1,1-bis(4-methoxyphenyl)ethylene (16), and 1,3-bis[2,2-bis(4-methoxyphenyl)ethenyl]azulene (17) (93, 34, and 19% yields) from 12 and 10 and 2-(azulen-1-yl)-1,1-bis{4-[2-(dimethylamino)ethoxy]phenyl}ethylene (18) (97 and 58% yields) from 13.     

Approaches to (R)- and (S)-1′-(1-aminoethyl)ferrocene-1-carboxylic acid derivatives

Lipase-catalyzed esterification of (±)-methyl 1′-(1-hydroxyethyl)ferrocene-1-carboxylate 4 afforded its (R)-acetate (−)-5 (ee = 99%) and (S)-(+)-4 (ee = 90%). Stereoretentive azidation/amination/acetylation of (R)-(−)-5 gave (R)-(+)-methyl 1′-(1-acetamidoethyl)ferrocene-1-carboxylate (R)-3 (ee = 98%). In a similar manner (S)-(+)-4 was converted into (S)-(−)-3 (ee = 84%). Both enantiomers of 3 were obtained in high chemical yields without a loss of enantiomeric purity. The title compounds can be coupled with natural amino acids and peptides on both C- and N-termini.     

Enantioselective Deprotonation of Cyclohexene Oxide to (R)-2-Cyclohexen-1-ol

The reaction of cyclohexene oxide with homochiral lithium amides, prepared from (S)-phenylglycine and (S)-valine has been studied and (R)-2-cyclohexen-1-ol 3 was prepared in a maximum of 72% ee. The optical purity was determined by ¹H NMR measurement of the α-methoxy-α-(trifluoromethyl)phenyl acetic acid (MTPA) derivative of the corresponding alcohol.     

On the easy oxidation of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid to its disulfide dimer

The physical and spectroscopic data of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid are reviewed and the synthesis of (R)-di-[2-(N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid disulfide is described. The product resulting from the conjugate addition of the dithioacid to 2(5H)-furanone is also characterised.     

Steric consequence of the diastereoselective addition of chiral lithium 2-(1-dimethylaminoethyl)phenyl cuprates to some enones

Conjugate addition of the mixed chiral species lithium [(S)-2-(1-dimethylaminoethyl)phenyl](2-thienyl)cuprate to (E)-4-phenyl-3-buten-2-one, 2-cyclohexenone or to 2-cyclopentenone proceeds with high diastereoselectivity. The first two enones gave crystalline adducts directly, while the non-crystalline cyclopentenone adduct was converted into a crystalline methiodide. The crystal structures of the compounds have been determined from single-crystal X-ray diffractometer data in order to reveal the configurations at the new chiral centres. In all three cases the configuration at the new asymmetric centre is S. (S,S)-4-[2-(1-Dimethylaminoethyl)phenyl]-4-phenyl-2-butenone, C₂₀H₂₅NO, crystallizes in space group P2₁ with a 7.604(2), b 9.398(5), c 12.290(6) Å, β 92.30(3)° and Z = 2. Full-matrix least-squares refinement of 273 structural parameters gave R = 0.066 for 1015 observed independent reflections. (S,S)-3-[2-(1-Dimethylaminoethyl)phenyl]-2-cyclohexanone, C₁₆H₂₃NO crystallizes in space group P2₁2₁2₁ with a 12.499(4), b 6.645(3), c 17.568(7) Å and Z = 4. Full-matrix least-squares refinement of 142 structural parameters gave R = 0.068 for 1507 observed independent reflections. (S,S)-1-[2-(3-Oxocyclopentyl)phenyl]ethyltrimethylammonium iodide, C₁₆H₂₄NOI, crystallizes in space group P4₁, with a 10.569(3), c 30.895(7) Å and Z = 8; there are thus two crystallographically independent cations in the asymmetric unit. Full-matrix least-squares refinement of 342 structural parameters gave R = 0.054 for 2119 observed independent reflections.The (S,S)-configuration observed in these adducts indicates that the conjugate addition gives the least crowded lithium enolate as the major product.     

Efficient synthesis of the cyclopentanone fragrances (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone and Magnolione

This paper describes the selective syntheses of two cis-isomer-enriched cyclopentanone fragrances: (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone (four steps, 62% overall yield, 67% cis) and Magnolione^® (five steps, 60% overall yield, 55% cis). In addition, the asymmetric synthesis of (3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one as well as (3a′R,7a′S)-5′-methyl-2′,3′,3a′,4′,7′,7a′-hexahydrospiro[[1,3]dioxolane-2,1′-indene] has been realized by an efficient kinetic resolution, which enables the selective synthesis of the 2S,3R-isomer-enriched 3 and 4.