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%).     

Stereoselective production of (S)-1-aralkyl- and 1-arylethanols by freshly harvested and lyophilized yeast cells

Substituted (S)-1-phenyl- 2a–h and (S)-1-benzyl-propan-2-ols 4a and b, and (S)-1-phenylethanol 6 were produced from prochiral ketones 1a–h, 3a,b and 5 by reductions with freshly harvested Zygosaccharomyces rouxii and Debaryomyces hansenii cells. The bioreductions were also performed by lyophilized cells. Comparison of the secondary alcohols from the bioreductions 2b–e,g,h and 4a and authentic (S)-alcohols (S)-2b–e,g,h and (S)-4a synthesized from enantiopure (S)-methyloxirane 7 proved the absolute configuration of the products.     

On the mechanism and diastereoselectivity of 2,3-dihydrobenzofuran formation from sulfinylbenzoquinones and 2-trimethylsilyloxyfuran

A mechanistic study of the reactions between 2-trimethylsilyloxyfuran 1 and (SS)-2-(arylsulfinyl)-1,4-benzoquinones 2a and 2b, giving rise to the diastereoselective formation of [3aS,8bS,SS]-3a,8b-dihydro-7-hydroxy-8-(arylsulfinyl)furo[3,2-b]benzofuran-2(3H)-ones 3a and 3b, is reported. The detection and ¹H NMR characterization of several precursors of 3a and 3b accounts for a Michael-type initial reaction which dictates the final diastereoselection of the process. A significant improvement of the stereoselectivity (up to 96% de) in the formation of the tert-butylsulfinyl substituted derivative 3c was achieved by using 2-(tert-butylsulfinyl)-1,4-benzoquinone 2c as the starting quinone.     

Stereoselective synthesis of imidazolidine,imidazoline and imidazole C- and N-pseudonucleosides

Methyl 2-deoxy-2-isothiocyanato-α-d-glucopyranoside 2, which exists in equilibrium with the corresponding 2,3-cyclic carbamate 1, reacts with d-glucosamine producing the pseudo-C and N-nucleoside of chiral imidazolidine-2-thione 3, in good yield and high stereoselectivity. Starting from 3, different pseudo-C- and N-nucleosides of imidazoline-2-thione 6–11, and of imidazole 12 and 13 are obtained. Conformational aspects of some of the prepared compounds are discussed.     

Lipase-mediated partial resolution of 1,2-diol and 2-alkanol derivatives: towards chiral building-blocks for pheromone synthesis

1,2-Propanediol 5, 1-chloro-2-propanol 8 and its related 2-O-acetate 9 were partially resolved by chemoenzymatic acetylation and deacetylation, in the presence of Pseudomonas fluorescens lipase (Amano P.; PFL), to (R)-(−)-1-acetoxy-2-propanol 6, (R)-(+)-2-acetoxy-1-chloropropane 9 and (R)-(−)-1-chloro-2-propanol 8, respectively. On the other hand, treatment of (2RS)-2 with vinyl acetate in ether and Chirazyme^® L-2 gave 2-O-acetyl-1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-β-d-manno-non-5-ulo-5,9-pyranose 1 and 1,3,4-trideoxy-5,6:7,8-di-O-isopropylidene-β-d-gluco-non-5-ulo-5,9-pyranose 11, respectively. Compound 10 was subsequently deacylated to 12. Both alcohols 11 and 12 were treated with Me₂CO/H⁺ to cause their rearrangement to (2S,5R,8R,9R,10S)-10-hydroxy-8,9-isopropylidenedioxy-2-methyl-1,6-dioxaspiro[4.5]decane 3 and its (2R)-epimer 4, which closely matched the skeleton of the odour bouquet minor components of Paravespula vulgaris (L.).     

Enzymatic resolution of 5-hydroxy- and 8-hydroxy-2-tetralols using immobilized lipases

(R)-2-Tetralol (R)-2a, (R)-5-hydroxy-2-tetralol (R)-2b and (R)-8-hydroxy-2-tetralol (R)-2c, which are key intermediates in the synthesis of pharmacologically active 2-aminotetralins 3, were prepared in moderate to very high enantiomeric excess (up to 99% ee) by enzymatic resolution of the corresponding racemic butyrates rac-1a, rac-1b and rac-1c, respectively, using lipases immobilized on octyl agarose. This methodology is an alternative to the microbial reduction of 2-tetralones.     

Synthesis of enantiopure C1 symmetric diphosphines and phosphino-phosphonites with ortho-phenylene backbones

Reaction of 2-(diphenylphosphino)phenylphosphonous acid tetramethyldiamide 1 with (+)-menthol, (1S,2S,3S,5R)-isopinocampheol and (1R,2R)-trans-cyclohexanediol affords enantiopure phosphino-phosphonite ligands 3–5. The X-ray structures of 1 (space group P2₁/n) and 3 (space group P2₁) have been determined. The reaction of 1 with (1R,2R,3S,5R)-(−)-pinanediol proceeds diastereoselectively to afford a novel type of enantiopure phosphino-phosphonite ligand 6 with an asymmetric substituted P atom. On reaction of (+)-cedryl alcohol with 1 the adduct 7 of the phosphonous acid 2-Ph₂PC₆H₄P(O)(H)OH 9 and its dimethylammonium salt is formed through elimination of water and subsequent hydrolysis. The structure of 7 (space group P1̄) was elucidated by X-ray structural analysis. Reduction of the chlorophosphine 8 with LiAlH₄ yields the novel primary–tertiary phosphine 10, which is a valuable starting material for the synthesis of the enantiopure C₁ symmetric bidentate phospholane ligands 11 and 12.     

Naturally-occurring acetylenic compounds and derivatives : Regio- and stereocontrolled chloroformylation of 2-(1-propynyl)thiophene and 2-phenyl-5-(1-propynyl)thiophene

2-Phenyl-5-(1-propynyl)thiophene (1), isolated from Coreopsis grandiflora, and 2-(1-propynyl)thiophene (5), an immediate precursor in the synthesis of junipal (2), were synthesized in high yield by a Pd-catalyzed reaction between propyne and 2-iodo-5-phenylthiophene (4) or 2-iodothiophene (6), respectively. Reaction of 5 with the Vilsmeier reagent derived from POCl₃ and N-methylformanilide (MFA) afforded a mixture from which it was possible to isolate (E)-3-chloro-2-methyl-3-(2-thienyl)acrolein (10) in 37.7% yield. The structure and stereochemistry of 10 was unequivocally established by X-ray diffraction of a single crystal of the 2,4-dinitrophenylhydrazone of 10. GLC analysis showed that 10 was contaminated by ca 7% with an isomer to which, on the basis of ¹H-NMR and mass spectra, the structure of (Z)-3-chloro-2-methyl-3-(2-thienyl)acrolein (11) was attributed.Contrary to what was expected from the literature, junipal (2) represented only a minor component in the reaction mixture obtained by the Vilsmeier reaction on 5.Reaction of 1 with POCl₃ and MFA afforded (44.6% yield) a (E)-3-chloro-2-methylacrolein to which the structure 15 was attributed. Compound 15 was also contaminated by ca 10% of an isomer 16, which very probably corresponded to the (Z)-stereoisomer of 15.     

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

Simple syntheses of isomers of muconaldehyde and 2-methylmuconaldehyde

Periodate oxidation of cis-1,2-dihydrocatechol (3a) affords (Z,Z)-muconaldehyde (2b), which can be readily converted (thermolysis and triethylamine catalysis, respectively) into its (E,Z)- (2c) and (E,E)-isomer (2a). Similarly, cis-1,2-dihydro-3-methylcatechol (3b) gives(Z,Z)-2-methylmuconaldehyde (2d) and thence (E,E)-2-methylmuconaldehyde (2c).     

Synthesis,spectroscopy, electrochemistry and in situ spectroelectrochemistry of partly halogenated coumarin phthalonitrile and corresponding metal-free,cobalt and zinc phthalocyanines

In this study, the preparation of novel 7-hydroxy-3-(2-chloro-4-fluorophenyl)coumarin (1), the ligand, 7-(3,4-dicyanophenoxy)-3-(2-chloro-4-fluorophenyl)coumarin (2), metal-free phthalocyanine 3 and metallophthalocyanine complexes 4 and 5 (MPcs, M = Co, Zn), β-substituted with 7-oxo-3-(2-chloro-4-fluorophenyl)coumarin functional group was achieved. By the reaction of 7-hydroxy-3-(2-chloro-4-fluorophenyl)coumarin (1) with 1,2-dicyano-4-nitrobenzen in dry DMF as the solvent in the presence of K₂CO₃ as the base, the 7-(3,4-dicyanophenoxy)-3-(2-chloro-4-fluorophenyl)coumarin (2) was synthesized. Compound 2 reacted with Co(CH₃COO)₂·4H₂O in 2-N,N-dimethylaminoethanol to furnish a novel coumarin containing cobalt(II) phthalocyanine 4. The cyclotetramerization of 2 with Zn(CH₃COO)₂·2H₂O in 2-N,N-dimethylaminoethanol gave the novel coumarin containing Zn(II)phthalocyanine 5; while tetramerization without any metal salts in 2-N,N-dimethylaminoethanol gave the metal-free phthalocyanine 3. The structures of obtained compounds were confirmed by elemental analysis, UV–Vis, IR, MALDI-TOF mass and ¹H NMR spectra. The cyclic and differential pulse voltammetry, and in situ spectroelectrochemistry of 7-oxo-3-(2-chloro-4-fuorophenyl)coumarin substituted phthalocyanines 3, 4 and 5 allowed us to identify metal- and phthalocyanine ring-based redox processes of the complexes.     

A convenient ultrasound-promoted synthesis of some new thiazole derivatives bearing a coumarin nucleus and their cytotoxic activity

Successful implementation of ultrasound irradiation for the rapid synthesis of a novel series of 3-[1-(4-substituted-5-(aryldiazenyl)thiazol-2-yl)hydrazono)ethyl]-2H-chromen-2-ones 5a-h, via reactions of 2-(1-(2-oxo-2H-chromen-3-yl)ethylidene) thiosemicarbazide (2) and the hydrazonoyl halides 3(4), was demonstrated. Also, a new series of 5-arylidene-2-(2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)hydrazinyl)thiazol-4(5H)-ones 10a-d were synthesized from reaction of 2 with chloroacetic acid and different aldehydes. Moreover, reaction of 2-cyano-N'-(1-(2-oxo-2H-chromen-3-yl)ethylidene)-acetohydrazide (12) with substituted benzaldehydes gave the respective arylidene derivatives 13a-c under the conditions employed. The structures of the synthesized compounds were assigned based on elemental analyses and spectral data. Also, the cytototoxic activities of the thiazole derivative 5a was evaluated against HaCaT cells (human keratinocytes). It was found that compound 5a possess potent cytotoxic activity.     

Lipase-mediated kinetic resolution of cis-1,2-indandiol and the Ritter reaction of its mono-acetate

Lipase-mediated kinetic resolution of cis-1,2-indandiol 5 in the presence of lipase PS was examined. Enantiomerically enriched (1S,2R)-2-acetoxy-1-indanol 6a was obtained when cis-1,2-indandiol 5 was treated with one equivalent of vinyl acetate. Treatment of 5 with two equivalents of vinyl acetate furnished a mixture of (1R,2S)-2-acetoxy-1-indanol 6a and (1R,2S)-1-acetoxy-2-indanol 6b. A route to both enantiomers of 1 was also developed by using the enantiomerically enriched mono-acetate thus obtained.     

Synthesis of syn- and anti-tricyclo [4.1.0.02,4] heptan-5-ones and related compounds

A convenient entry to both title compounds 1 and 2, as well as to cis- and trans-4-iodomethyl-bicyclo [3.1.0]-hexan-2-ones 3and 4 and to 4-methyl-bicyclo [3.1.0]-hex-3-en-2-one 5 involving base-promoted reactions of cis- and -trans-3,4-diiodomethylcyclopentanones 6 and 7 is reported, and the behaviour of 6 and 7 towards different bases. bfv40bp4761b     

Total synthesis of (+)-myxothiazols A and Z

The first synthesis of (+)-myxothiazol A 1 was achieved based on a modified Julia olefination between (3,5R)-dimethoxy-(4R)-methyl-6-oxo-(2E)-hexenamide 3, corresponding to the left side of the final molecule, and 4-(2″-benzothiazolyl)sulfonylmethyl-2′-[(1′″R),6′″-dimethylhepta-(2′″E),(4′″E)-dienyl]-2,4′-bithiazole 6, corresponding to the right side. The synthesis of (+)-myxothiazol Z 2 was also achieved based on modified Julia olefination between (3,5R)-dimethoxy-(4R)-methyl-6-oxo-(2E)-hexenoate 4, corresponding to left side of the final molecule, and (S)-sulfone 6.     

On the reaction of 3-bromo-2-nitrobenzo[b]thiophene with some ortho-substituted anilines: an analysis of the products of reaction and of their NMR and MS properties

The title reaction, carried out in DMF in the presence of triethylamine or potassium carbonate, has furnished the ‘expected’ 3-amino-2-nitrobenzo[b]thiophenes 2o together with the ‘unexpected’ 2-amino-3-nitrobenzo[b]thiophenes 3o, thus recalling the situation observed with other weak nucleophiles in the presence of non-nucleophilic bases. The effects (electronic as well as steric) of the ortho-substituent (OH, NH₂, OMe, Me, Et, F, Cl and Br) on the course of the reaction have been investigated, determining their influence on yields and product ratios (2o/3o). An analysis of ¹³C NMR and MS spectra of 2o and 3o has been carried out. Ab initio computations on 2of, 2oi, 3of and 3oi at DFT level have furnished informations on their geometry and stability in the gas phase, thus allowing to assign a role to their stability on the course of the reaction as well as on some EI-MS results.     

Pd-catalyzed asymmetric synthesis of allylic tert-butyl sulfones and sulfides: Kinetic resolution of the allylic substrate by a chiral Pd-complex

The acyclic and cyclic allylic tert-butyl sulfones 3, ent-3, 11a, 11b and 15a–c of 89–98% ee were synthesized in 40–92% yield by a Pd-catalyzed reaction of the respective allylic acetates and carbonates rac-1a, rac-1b, rac-10a, rac-10b and rac-14a–c with LiO₂St-Bu in the presence of the chiral ligands 2a, ent-2b and 12. Formation of the n-butyl sulfones 13a and 13b of 95% ee was observed. Reactions of rac-1a and 1b/ent-1b with LiO₂St-Bu in the presence of 2a and ent-2b, respectively, in THF under heterogeneous conditions were accompanied by a kinetic resolution of the allylic substrates. The faster reacting allylic substrate and the preferentially formed sulfone had the same absolute configuration. The allylic tert-butyl sulfide 17 of 92% ee was obtained in 63% yield by the Pd-catalyzed reaction of rac-1b with Me₃SiSt-Bu in the presence of ent-2b.     

Stereochemical studies-XXXIII. Saturated heterocycles-IX: Synthesis and conformations of stereoisomeric cis- and troans-tetramethylene- and pentamethylenedihydro-1,3-oxazines

By the reaction of cis- and trans-2-aminomethylcyclohexanol (1, 2), cis- and trans-2-hydroxymethyl-cyclohexylamine (3,4) and the homologous cycloheptane derivatives (5-8) with ethyl p-chlorobenzimidate (11), cis- and trans-5,6-tetramethylene- and pentamethylene-2,3,5,6-tetrahydro-4H-1,3-oxazines (12,13,16,17) and cis- and trans-4,5-tetramethylene- and pentaimethylene-4,5-dihydro-6H-1,3-oxazines (14, 15, 18, 19) were prepared. The amidine intermediate of the ring-closure reaction was isolated, and the mechanism of the acid-catalysed reaction is discussed. It follows from the ¹H NMR data that in the preferred conformations of the cis-tetramethylene-tetrahydrooxazines the methylene group of the hetero ring is equatorial and the hetero atom (O or N) axial. In contrast, the conformation equilibria of the cis pentamethylene derivatives, in accordance with earlier X-ray analysis, are shifted towards the conformer containing the methylene group in isoclinal and the hetero atom in equatorial position. The preferred conformations 12a and 14a of the tetramethylene derivatives 12 and 14 were also determined by X-ray crystal analysis.     

Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives

Efficient procedures for the synthesis of (R)-N-benzyl-2-amino-3-methoxypropionamide ((R)-3), 2-acetamido-3-methoxypropionic acid (4), and O-methylserine (5) are described beginning from (R)-Cbz-serine ((R)-7). The reactions proceeded with little or no racemization and permitted the synthesis of the potent anticonvulsant (R)-N-benzyl-2-acetamido-3-methoxypropionamide ((R)-2). The anticonvulsant activities of 2–4 were determined revealing the surprising activity of (R)-2.     

Stereochemical studies—XVII: Cyclic aminoalcohols and related compounds—IX synthesis and NMR study of stereoisomeric cis- and trans-tetramethylene- and pentamethylene-1,3-oxazine-2-ones

Isomeric tetramethylene- and pentamethylene-1,3-oxazine-2-ones (9–12 and13–16) have been synthesized, derived from cis- and trans-2-aminomethylcyclohexanol (1,2), cis- and trans-2-hydroxymethylcyclohexylamine (3,4) and from the corresponding cycloheptane analogues (5–8), respectively. The stereospecific synthesis of the aminoalcohols5–8 is described. A comparative NMR analysis of13–16 and the tetramethylene analogues (9–12) is given.