Synthesis of (1R,cis,αS)-cypermethrine via lipase catalyzed kinetic resolution of racemic m-phenoxybenzaldehyde cyanohydrin acetate

A technical scale preparation of optically active (1R,cis,αS)-cypermethrine 4 from racemic m-phenoxybenzaldehyde cyanohydrin acetate (RS)-1 and (1R,cis)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (1R,cis)-3 is described. Key steps of the new procedure are a lipase catalyzed enantioselective transesterification of (RS)-1 with n-butanol and direct acylation of the mixture of (R)-1 and (S)-cyanohydrin (S)-2 with (1R,cis)-3 to give enantiomerically pure (1R,cis,αS)-4. The unchanged (R)-1 is removed from (1R,cis,αS)-4 by distillation, and is racemized with triethylamine to give (RS)-1 which is returned to the process. The total yield of (1R,cis,αS)-4 referred to (RS)-1 is 80%.     

Aminomethinylierung H-aktiver verbindungen in der reihe analgetischer wirkstoffe

Electrophilic attack of the active methylene group in 3-methyl-1-phenyl-5-pyrazolone (2) by s-triazine (1) leads to aminomethinylation of 2 with formation of 3-methyl-1-phenyl-4-aminomethylene-5-pyrazolone (4). Subsequent interaction of 4 with 2 explains the formation of 4,4′-methenyl-bis-[3-methyl-1-phenyl-5-pyrazolone (5). 1-Phenyl-3,5-pyrazolidinedione (6) reacts analogously with 1 forming 1-phenyl-4-aminomethylene-3,5-pyrazolidinedione (7). N,N′-Bis-indanyl-formamidine (9) results from the interaction of 2-amino-indane (8) with 1.     

Organische schwefelverbindungen—VI : Thiaxanthonsynthese durch photoumlagerung von diaryl-α-ketosulfiden (thiolestern), eine neue lichtinduzierte aromatische substitutionsreaktion

4′-Tolyl-2-methylsulfono-thio-benzoate (1) undergoes a new type of photorearrangement to give 2-methyl-thiaxanthone (4). The isomeric 3-methylsulfono-thio-benzoate (2) suffers cleavage of the S-benzoyl bond, giving rise to the corresponding thiyl and benzoyl radicals. The resulting radicals form bis-4′-tolyl disulfide (5) by dimerization and 3-methylsulfono-benzaldehyde (6) by hydrogen abstraction respectively. No thia-photo-Fries products are formed by the photolysis of 1 and 2. In contrast to 1 4′-tolyl-2-methylsulfono-benzoate (3) displays the normal photo-Fries reaction and affords the benzophenone derivative 8. A mechanism for the photorearrangement of thiol ester 1 into thiaxanthone derivative 4 is discussed.     

Novel thiosemicarbazone derivatives containing benzimidazole moiety: Green synthesis and anti-malarial activity

A series of (E)-2-[5-chloro-1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (7a–7t) and (E)-2-[1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (8a–8t) were prepared via the synthesis of 1-(substituted-1H-benzimidazol-2-yl) ethanol (3a–3b) which was synthesized by the condensation of substituted o-phenylenediamine (2a–2b) with dl-lactic acid (1) followed by oxidation with sodium hypochlorite in mild acidic condition to form the corresponding ketones 4a–4b. Final compounds were formed by condensation of 4a–4b with different thiosemicarbazides 6a–6t. A total of 40 compounds were synthesized and characterized by FT-IR, ¹H NMR, ¹³C NMR, Mass spectral technique and elemental analysis, in addition they were evaluated for anti-malarial properties. Among the compounds tested 7o, 7p, 7q, 7r, 7s, 8e and 8h exhibited good antimalarial activity in vitro.     

Resolution of 1-phenyl-2-(p-tolyl)ethylamine via diastereomeric salt formation

(S)-1-Phenyl-2-(p-tolyl)ethylamine (S)-1, used for the industrial scale resolution of chrysanthemic acids, was obtained via resolution of the racemate with the hemiphthalate of (S)-isopropylidene glycerol (R)-2. The maximum experimental efficiency [69% yield and >99% e.e. of (S)-1] was achieved by a simple precipitation of (S)-1·(R)-2 from the solution of the 1:1 diastereomeric salt mixture in 93/7 isopropanol/water at saturation of the more soluble (R)-1·(R)-2 salt. Such an experimental efficiency was consistent with 0.79 maximum theoretical resolvability, derived from the solubilities of the two diastereomeric salts, and with DSC data, which indicated that the (S)-1·(R)-2/(R)-1·(R)-2 system is a binary mixture exhibiting an eutectic with composition approximately corresponding to a 0.2 molar ratio of (S)-1·(R)-2.     

Reactions of β-substituted amines-IV: Kinetics and stereochemistry of the thermal to (r) 3-chloro-1-ethylpiperidine,and the stereo-chemical course of their reactions with nucleophiles

The rate of the thermal rearrangement of (S) 2 chloromethyl-1-ethylpyrrolidine [(S)-1a] to (R)-3-chloro-1-ethylpiperidine [(R) 2a] has been examined at three temperatures in benzene by PMR and polarimetry. The rearrangement was shown to be completely stereospecific and to obey a simple first order rate law. The calculated E_a ΔH3 and ΔS3 were 22 ± 2 $\text{kcal}\text{mole}$ (25°), 21 ± 2.5 $\text{kcal}\text{mole}$ (25°) and - 10 ± 2 e.u. (0°K) respectively. The effect of solvents having differing dielectric constants was also studied. A transition state 9'a and an ion pair intermediate 3a are suggested for the rearrangement. The stereochemical course of the reactions of (S)-1a, (R)-2a and (S)-2a with hydroxide and methoxide ions have been shown to be 100% stereospecific with an uncertainty of about 1%. The absolute configurations of all optically active reactants and products [(S)- and (R)-4a, (S)-4b (R)- and (S)-5a, (R)-5b, (S,S')-6a, (S,R')-7a and (R,R')-8a] were established by chemical correlations with known compounds or by ORD and chemical inference. The ring opening of both the primary and secondary aziridinium ion positions of 1-azonia-1-ethylbicyclo [3.1.0]hexane [(S)-3a] by nucleophiles proceeds entirely by S_N2 processes. The conversion of (R)-1-ethyl-3-hydroxypiperidine [(R)-5a] to (S)-2a. HCl with thionyl chloride in chloroform proceeds by inversion with 4.8% racemization, whereas the thermal rearrangement of (S)-1a to (R)-2a occurs with complete retention of absolute configuration.     

Studies on AI-77s,microbial products with gastroprotective activity. Structures and the chemical nature of AI-77s

The structures and the chemical nature of a novel gastroprotective substance AI-77-B (1) and its analogues AI-77-C (2), D (3), F (4) and G (5), which are produced by Bacillus pumilus AI-77, are described. The structure of 1 was confirmed to be 6-[[1(S)-(3(S), 4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-4(S),5(S)-dihydroxy-6-oxo-3(S)-aminohexanoic acid by X-ray in combination with chemical studies and the structures of 2, 3, 4 and 5 were determined by chemical syntheses from 1 and spectral analyses.     

Kinetic resolution of racemic secondary aliphatic allylic alcohols in lipase-catalyzed transesterification

Different lipases were screened as biocatalysts in the kinetic resolution process of (±)-hept-1-en-3-ol 1, (±)-5-methylhex-1-en-3-ol 2, (±)-6-methylhept-2-en-4-ol 3, (±)-6,6-dimethylhept-2-en-4-ol 4, and 1-phenylbut-3-en-2-ol 5 by enantioselective transesterification. The acylation of (±)-1 and (±)-2 catalyzed by Novozym 435 (Candida antarctica) was very effective and proceeded with good enantioselectivity. After 4–8 h of reactions the esters formed and the alcohols, which remained were obtained with high enantiomeric excess with 97–100% ee and 91–100% ee, respectively. The lipase Amano PS (Burkholderia cepacia) was the best catalyst in the asymmetric transesterification of (±)-5 affording the (R)-alcohol with 90–95% ee and the (S)-ester with 98–100% ee. Low enantioselectivities were observed in the cases of lipase-catalyzed acylation of (±)-3 and (±)-4.     

Conformational study of α-arylethylamides of (−)-camphanic acid

The absolute conformation and configuration of diastereomeric amides (4A,B–6A,B) of (1S,3R)-camphanic acid (lactone of 1-hydroxy-2,2,3-trimethylcyclopentan-1,3-dicarboxylic acid, (−)-camphanic acid 9) with α-arylethylamines 1–3 are deduced from ¹H NMR data and MM2 calculations. The α-arylethyl group in diastereomers A and B adopt nearly opposite absolute conformations, stabilized by hydrogen bonding in the syn-oriented O–C(1)–C(6)–N–H unit, and repulsive interaction between the 1′C–Me group and the amide CO group. The absolute configuration (1′S) is assigned to the 4A–6A diastereomers, and the (1′R)-configuration to the 4B–6B diastereomers; this assignment is confirmed by the preparation of 4A and 5A from enantiomerically pure (1′S)-α-arylethylamines 1 and 2, respectively. These results also enabled the assignment of pro-R (H_R) and pro-S (H_S) protons in the benzyl derivative 7.     

A new group of isoquinoline alkaloids : The secoberbines

The new isoquinoline alkaloid (?)-peshawarine (1) has been isolated from Hypecoum parviflorum Kar. & Kir. (Papaveraceae). Its synthesis in the racemic form from coptisine (6b) involves a novel approach to cyclic hemiacetals in which the key step is the transformation of the aldehyde (±)-aobamine (10b) into the hemiacetal 12b using ethyl chloroformate. (±)-Corydalisol (11b) and (±)-canadaline (10a) have also been synthesized for the first time. The absolute configuration of (?)-1 was determined by chemical correlation with (+)-rhoeagenine methiodide (20). The chirality of the alkaloid (+)-canadaline (10a) has also been established by analogy to (+)-corydalisol (11b). (?)-Peshawarine (1), (+)-canadaline (10a), (+)-corydalisol (11b), and aobamine (10b), as well as hypecorine (22) and hypecorinine (23), are members of a new group of isoquinoline alkaloids, the secoberbines.     

Kinetic resolution of 1-(benzofuran-2-yl)ethanols by lipase-catalyzed enantiomer selective reactions

Kinetic resolution of racemic 1-(benzofuran-2-yl)ethanols rac-1a–d was performed by lipase-catalyzed enantiomer selective acylation (E≫100) yielding (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d and (1S)-1-(benzofuran-2-yl)ethanols (S)-1a–d in highly enantiopure form. The degree of enantiomer selectivity for enzymatic alcoholysis/hydrolysis processes starting from racemic 1-acetoxy-1-(benzofuran-2-yl)ethane rac-2 was also tested under various conditions including supercritical CO₂ medium. Racemization-free lipase-catalyzed ethanolysis of the (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d yielded almost quantitatively the enantiopure (1R)-1-(benzofuran-2-yl)ethanols (R)-1a–d.     

Biosynthesis of tylophorine and tylophorinine

Administration of 3,4-dihydroxyphenyl[2-¹⁴C] alanine to young Tylophora asthmatica plants revealed that ring B and carbon atoms C₉ and C₇ of tylophorine and tylophorinine are derived from dopa. Tracer experiments with 6,7-diphenylhexahydroindolizines (1–7) and (26) demonstrated that compound 1 is efficiently and specifically incorporated into tylophorine (13) and tylophorinine (16). Compounds (3), (4) and (26) were not metabolized by the plants to form (13) and (16) whereas (5) and (6) were utilized to yield (13) and (16). Compound (2) was very poorly converted into (13) and (16) and thus is not on the major biosynthetic pathway of (13) and (16).     

Transformations of enaminones. A simple one-pot synthesis of imidazolone derivatives

Ethyl (5-benzoyl-2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1-yl)carbamates 7 were prepared by the Michael addition of diethyl azodicarboxylate (3) to (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2) followed by substitution of the dimethylamino group with primary amines 5a–n to afford a mixture of (E) and (Z) diethyl 1-(1-(substituted)amino)-3-oxo-3-phenylprop-1-en-2-yl)hydrazine-1,2-dicarboxylates (6a–n), followed by cyclization to give final products 7a–n. The intermediate 6i was isolated and characterized and transformed into 7i. All imidazolones 7a–n were synthesized in one pot reaction sequences with individual reactions being very clean.     

The stereochemistry of pipitzols and perezols

The stereochemistry of α-pipitzol (1a) has been established by transformation to cedrene (4) and by single crystal X-ray diffraction of α-pipitzol benzoate (1b). The stereochemistries of the related cedranolides β-pipitzol (2a), α-(1c), β-(2c) and γ-perezol (1d) are assigned from their respective ORD curves.     

A C2-symmetric analogue of dppf: synthesis and structures of the indenyl-diphosphine complex 1,3-(Ph2PSe)2(C9H6) and the racemic and meso isomers of the heterobimetallic complex Mo(CO)4(1-PPh2-η-C9H6)2Fe

The preparation, isolation and characterisation of 1,3-bis(diphenylphosphino)indene (1) from indene and chlorodiphenylphosphine is described. The reaction of 1 with selenium gives the diselenide adduct 1,3-bis(diphenylselenophosphino)indene (2) which was characterised crystallographically. Deprotonation of 1 and treatment with ferrous chloride gives the unstable tetraphosphine complex bis(1,3-bis(diphenylphosphino)indenyl)iron(II) (3). Complex 3 decomposes to the diphosphine complex bis(1-diphenylphosphinoindenyl)iron(II) (4) via replacement of one diphenylphosphine substituent per indenyl ligand by a hydrogen atom. Complex 4 was also prepared by treatment of two equivalents of 1-diphenylphosphinoindenide with ferrous chloride. The heterobimetallic complex tetracarbonyl(bis(1-diphenylphosphinoindenyl)iron(II))molybdenum(0) (5) was also prepared and crystal structures of both the meso (5a) and C₂-symmetric racemic (5b) isomers are reported.     

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.     

Synthesis, characterization, DNA binding and cleavage studies of chiral Ru(II) salen complexes

Interaction of chiral Ru(II) salen complexes (S)-1 and (R)-1 with Calf Thymus DNA (CT-DNA) was studied by absorption spectroscopy, competitive binding study, viscosity measurements, CD measurements, thermal denaturation study and cleavage studies by agarose gel electrophoresis. The DNA binding affinity of (S)-1 (6.25 × 10³ M⁻¹) was found to be greater than (R)-1 (3.0 × 10³ M⁻¹). The antimicrobial studies of these complexes on five different gram (+)/(−) bacteria and three different fungal organisms showed selective inhibition of the growth of gram (+) bacteria and were not affective against gram (−) and fungal organisms. Further, the (S)-1 enantiomer inhibited the growth of organisms to a greater extent as compared to (R)-1 enantiomer.     

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.     

Bromination of 3-phenylindoles

Brominations of 3-phenylindole (1a) and its 1-methyl-(1b) and 1-acetyl-(1c) derivatives with NBS in AcOH and CCl₄ have been carried out. In AcOH 1 gave 2-bromo derivatives (2) in high yields and the relative reactivity was found to be NH > NMe ? NAc by competitive reactions. In boiling CCl₄1a and 1b gave 2 but bromination of 1c did not proceed. Bromination of 1a with 2 moles of NBS in AcOH gave 2,6-(major) and 2,5-dibromides (8 and 9). Reaction of 2a with thiourea gave 19. Selective reduction of the bromine atom at the 2-position in 2,6-dibromide (10) was achieved by Zn3CuNaOH, and irradiation of 8 in EtOH-alkali reduced 2,6-dibromide to 1a.     

Synthesis of decalin type chiral synthons based on enzymatic functionalisation and their application to the synthesis of (−)-ambrox and (+)-zonarol

Stereoselective syntheses of (−)-ambrox 2 and (+)-zonarol 3 were achieved based on the enzymatic syntheses of (8aS)- and (8aR)-decalin-type 1,3-diols 1, respectively. Non-racemic intermediates such as (8aS)-1 and (8aR)-1 were obtained based on the enantioselective hydrolyses of the phenolic acetal derivative (±)-7 by acylase I.