Synthesis and Antimicrobial Activity of Chiral cis-Cycloheximide Isomers

Such (+)- and (?)-cis-cycloheximide isomers as isocyclohcximide (1a, 1b), α-epiisocycloheximide (2a, 2b) and neocycloheximide (3a, 3b) were synthesized by aldol condensation of (?)-(2R, 4R)- and (+)-(2S, 4S)-cis-2,4-dimethyl-1-cyclohexanone (5a, 5b). obtained by microbial resolution, with 4-(2-oxoethyl)-2,6-piperidinedione (7). The absolute configuration of the (?)-cis-ketone 5a was confirmed by chemical correlation with natural (2S, 4S, 6S, αR)-cycloheximide (4). The newly synthesized isomer, (?)-α-epiisocycloheximide (2b), showed strong antimicrobial activity against S. cerevisiae andP. oryzae close to that of natural cycloheximide (4).     

Preparation of Optically Pure cis-2,4-Dimethyl-l-cyclohexanones,the Key Intermediates in Cycloheximide Synthesis,Using Microbial Resolution

Asymmetric hydrolysis of acetate (10) of (±)-t-2,t-4-dimethyl-r-l-cyclohexanol with Bacillus subtilis var. niger gave (?)-(lS,2S,4S)-2,4-dimethyl-l-cyclohexanol (6a) and (+)-(1R,2R,4R)-acetate (10b) with high optical purities. Optically pure (?) and (+)-alcohols (6a and 6b) were prepared via corresponding 3,5-dinitrobenzoates. Oxidation of alcohols (6a and 6b) with chromic acid gave optically pure (?)-(2S,4S) and (+)-(2R,4R)-2,4-dimethyl-l-cyclohexanones (2a and 2b), respectively.     

Stereoselective Synthesis of the Optically Active Samin Type of Lignan from L-Glutamic Acid

The optically active samin type of lignan, (1R,2S,5R, 6S)-6-(2-methoxy-4,5-methylenedioxyphenyl)-3,7-dioxabicyclo[3.3.0]octan-2-ol, was stereoselectively synthesized from L-glutamic acid via (2R,3R)-2-[(1S and R)- 1-[(tert-butyldimethylsilyl)oxy]-1-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-3-[(tert-butyldiphenylsilyl)oxy]methyl-1,4-butanediol.     

Synthesis of (+)-Juvabione,a Compound with Juvenile Hormone Activity

(+)-Juvabione 1 was synthesized by employing (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one 2 as a chiral source.

(+)-Juvabione 1 shows juvenile hormone activity, and its racemate has been repeatedly synthesized.¹⁾ Optically active 1 was synthesized by Pawson et al. from (+)-limonene, ²⁾ and by Trost et al. from (+)-perillaldehyde.³⁾ However, their syntheses were not at all efficient for providing a suitable amount of optically active 1.     

Enantioselective synthesis of (R)-(+)- and (S)-(-)-higenamine and their analogues with effects on platelet aggregation and experimental animal model of disseminated intravascular coagulation

Optically active tetrahydroisoquinoline alkaloids, (R)-(+)-higenamine (1R) and (S)-(−)-higenamine (1 S), and their optically active 1-naphthylmethyl analogues (2 and 3), were synthesized by enantioselective hydrogenation of the corresponding dihydroisoquinoline intermediates 7 as a key step. The evaluation of the platelet anti-aggregation effect demonstrated clearly that the (S)-(−)-enantiomers, 1S, 2S, and 3S, had higher inhibitory potency than the corresponding (R)-(+)-antipodes, 1R, 2R, and 3R, respectively, to platelet aggregation induced by epinephrine. 1S enantiomer was superior to the corresponding 1R enantiomer in attenuating all of the disseminated intravascular coagulation (DIC) and multiple organ failure (MOF) parameters tested, while the S enantiomers 2S and 3S ameliorated some of the DIC and MOF parameters more effectively than the corresponding antipodes 2R and 3R.     

The Structure of Leucanicidin,a Novel Insecticidal Macrolide Produced by Streptomyces halstedii

( – )-Invictolide [(3R,5R,6S,1′R)-3,5-dimethyl-6-(1′-methylbutyl)-tetrahydro-2H-pyran-2-one] was synthesized in 16 steps from 2-methylpentanal.     

Synthesis of Optically Pure (1S, 4S, 5S)-2-Pinen-4-ol (cis-Verbenol) and Its Antipode,the Pheromone of Ips Bark Beetles

The enantiomers of cis-verbenol (4a and 4a′) were first synthesized in optically pure state. (1S, 4S, 5S)-2-Pinen-4-ol (4a′) was dextrorotatory in acetone or in methanol but it was levorotatory in chloroform; cis-verbenols are indistinguishable by a prefix (+) or (?). The designation of the Ips pheromone as (+)-cis-verbenol is therefore ambiguous and it should be called as (1S, 4S, 5S)-2-pinen-4-ol (4a′) or (S)-cis-verbenol.     

Stereoselective Synthesis of (2R, 3S)-2-Benzyl-2-hydroxy-3- (3,4-methylenedioxybenzyl)-γ-butyrolactone from L-(+)-Arabinose

As a model experiment for the stereoselective synthesis of optically active cis-α,β-dibenzyl-α-hydroxy-γ-butyrolactone, (2R, 3S)-2-benzyl-2-hydroxy-3-(3,4-methylenedioxybenzyl)-γ-butyrolactone (3) was stereoselectively synthesized from L-(+)-arabinose.     

Synthesis of Streptovitacin-C2 Isomers

(2R*,4S*,6S*,αS*)- and (2R,4R,6R,αS)-Streptovitacin-C₂ (STV-C₂) (1a and 1b) were synthesized by an aldol condensation of (2R*,4S*)- or (2R,4R)-2,4-dimethyl-2-trimethylsiloxy-1-cyclohexanone (15a or 15b) with 4-(2-oxoethyl)-2,6-piperidinedione (16), which was followed by desilylation of the products. The stereochemistry of the synthesized STV-C₂ isomers (1a and 1b) was elucidated by NMR. STV-C₂ isomers (1a and 1b) did not show strong antimicrobial activity against Saccharomyces cerevisiae and Pyricularia oryzae.     

Synthesis and Biological Evaluation of 1,3-Oxathiolane 5-Azapyrimidine, 6-Azapyrimidine,and Fluorosubstituted 3-Deazapyrimidine Nucleosides

Abstract

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19–24) have been synthesized by the transglycosylation of (2R,5S)-1-{2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-y1} cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B₁₆F₁₀, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.     

Enzymic Studies of the Distribution Pattern of 4-O-Methylglucuronic Acid Residues in Glucuronoxylans from Sunflower Hulls

Two epimers of methyl jasmonate were optically resolved by capillary gas chromatography, using heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin as the chiral stationary phase. In the tea volatile concentrates, both of these epimers were present as only one enantiomer, their absolute configurations being ascertained as (–)-(1R,2R)-methyl jasmonate and (+)-(1R,2S)-methyl epijasmonate.

The thermal isomerization of methyl epijamonate to methyl jasmonate was also clarified by optically resolved gas chromatography to have occurred at the asymmetric carbon of the C-2 position that is connected to the carbonyl group.     

Evaluation of enantioselectivity in lipase-catalyzed acylation of hydroxyalkylphosphine oxides

The lipase-catalyzed optical resolution of 2-, 3-, and 5-hydroxyalkyl phosphorus compounds 1 provided the corresponding optically pure diastereomers in good yields. (S_P, R)- and (R_P, S)-1 were acylated faster than (S_P, S)- and (R_P, R)-1. The stereoselectivity at the phosphorus atom changed with the flexibility of the active sites in the lipases. The stereoselectivity at the phosphorus atom was higher in the reaction of 1a than in the reaction of 1b,c. The reaction rate of -hydroxyalkylphosphine oxide 1c was faster than that of 1a, although less enantioselectivity was observed at the phosphorus atom.     

Synthesis and Field Test of a Pheromone Mimic of the Pine Sawfly (Neodiprion sertifer)

A stereochemically pure mimic of the sex pheromone components of the pine sawfly was synthesized. Acetates of (2S,3S)- and (2S,3R)-3-methylpentadecan-2-ol were prepared, and the pheromone activity of their mixture was compared with that of a true pheromone mixture of the acetates of (2S,3S,7S)- and (2S,3R,7R)-3,7-dimethylpentadecan-2-ol. Although the potency of the true pheromone system was 50 times as high as that of the pheromone mimic, the mimic could attract a sufficient number of male sawflies in the field test.     

Synthesis of the Racemate and Both Enantiomers of Massoilactone

A simple and efficient synthesis of (±)-massoilactone (1) as a key substance for the butter and milk flavor was accomplished from n-hexanal in only a few steps. Application of its racemic synthesis enabled natural (R)-(?)- and unnatural (S)-(+)-massoilactone (1a, 1b) to be synthesized by starting from commercially available (R)-(+)-1,2-epoxyheptane (5).     

Synthesis of (−)-Methyl Shikimate via Enzymatic Resolution of (1S*, 4R*, 5R*)-4-Hydroxy-6-oxabicyclo[3.2.1]oct-2-en-7-one

The synthesis of methyl (?)-shikimate [(?)-2] was achieved via lipase-catalyzed optical resolution of (1S^*,4R^*,5R^*)-4-hydroxy-6-oxabicyclo[3.2.1]oct-2-en-7-one (3). Transesterification of (±)-3 and vinyl acetate with lipase MY and subsequent hydrolysis gave optically pure (?)-3. This compound was converted to (?)-2 in two steps.     

Synthesis of Optically Active 1,4-Thiazane-3-carboxylic Acid via Optical Resolution by Preferential Crystallization of (RS)-2-Amino-3-[(2-chloroethyl)sulfanyl]propanoic Acid Hydrochloride

Optically active 1,4-thiazane-3-carboxylic acid [TCA] was synthesized from cysteine via optical resolution by preferential crystallization. The intermediate (RS)-2-amino-3-[(2-chloroethyl)sulfanyl]propanoic acid hydrochlo-ride [(RS)-ACS?HCl] was found to exist as a conglomerate based on its melting point, solubility and IR spectrum. (RS)-ACS?HCl was optically resolved by preferential crystallization to yield (R)- and (S)-ACS?HCl. (R)- and (S)-ACS?HCl thus obtained were recrystallized from a mixture of hydrochloric acid and 2-propanol, taking account of the solubility of (RS)-ACS?HCl, efficiently yielding both enantiomers in optically pure forms. (R)- and (S)-TCA were then respectively synthesized by the cyclization of (R)- and (S)-ACS?HCl in ethanol in the presence of triethylamine.     

Two New Ergosterol Derivatives from the Basidiomycete Cortinarius glaucopus

Two new sterols 1 and 2 and five known ones 3 – 7 were isolated for the first time from the fruiting bodies of Cortinarius glaucopus. Their structures were established by 1‐ and 2D‐NMR spectra and HR‐FABS‐MS. The relative configuration of 1 was firmly determined by comparison of the observed ¹H–¹H couplings and NOESY correlations, with those predicted for the computed geometries of the conformers. Calculations were performed by means of DFT with the B3LYP functional at 6‐31 + G(d,p) level of theory, in CHCl₃ as the solvent. The structures of the new ergosterol derivatives, called glaucoposterol A ( 1 ) and B ( 2 ), were thus established as (3S,5R,7R,10R,13R,17R,20S,22R,23R,24R)‐5,6‐epoxy‐3,7,23‐trihydroxystrophast‐8‐en‐14‐one and (22E,3S,5S,9S,10R,13R,17R,20R,24R)‐3,5‐dihydroxyergosta‐6,8(14),22‐trien‐15‐one, respectively. Moreover, the configuration of known strophasterol C ( 3 ) was determined as (3S,5R,6S,7R,10R,13R,17R,20S,22S,24R). Glaucoposterol A ( 1 ) and strophasterol C ( 3 ) represent the second finding in nature of steroids with the rare strophastane skeleton.     

Synthesis and characterization of pyridoxine,nicotine and nicotinamide salts of dithiophosphoric acids as antibacterial agents against resistant wound infection

The pyridine-derived biomolecules are of considerable interest in developing medicinal compounds with various specific activities. Novel ammonium salts of pyridoxine, (S)-(–)-nicotine and nicotinamide with O,O-diorganyl dithiophosphoric acids (DTPA) were synthesized and characterized. The complexation of chiral monoterpenyl DTPA, including (S)-(–)-menthyl, (R)-(+)-menthyl, (1R)-endo-(+)-fenchyl, (1S,2S,3S,5R)-(+)-isopinocampheolyl derivatives, with pyridoxine and nicotine provided effective antibacterial compounds 3a,b,e,f, and 5a,b,d,f with MIC values against Gram-positive bacteria as low as 10?µM (6?µg/mL). Two selected pyridoxine and nicotine salts based on menthyl DTPA 3a and 5a were similarly active against antibiotic-resistant bacteria from burn wounds including MRSA. The compounds had enhanced amphiphilic and hemolytic properties and effectively altered surface characteristics and matrix-secreting ability of P. aeroginosa and S. aureus. MBC/MIC ratios of 3a and 5a suggested the bactericidal mode of their action. Furthermore, the compounds exhibited moderate cytotoxicity towards human skin fibroblasts (IC₅₀?=?48.6 and 57.6?µM, respectively, 72?h), encouraging their further investigation as potential antimicrobials against skin and wound infections.     

The Synthesis of Enantiomerically Pure Pyrazolo[4,3-c]pyridine Carbarzbo C-Nucleoside

Abstract

The synthesis of (-)-3-[(1S,2S,3R,4R)-2,3-dihydroxy-4-(hydroxmethyl) cyclopentan-1-yl]-1H-pyrazolo[4,3-c]pyridme-4,6(5H,7H)-dione 3 was accomplished via enantiomerically pure carbocyclic 5-(β-D-ribofuranosyl)tetrazole 4.     

Chiral HPLC Separation,Absolute Structural Elucidation,and Determination of Stereochemical Stability of trans‐Bis[2‐(2‐pyridinyl)aminophenolato] Cyclotriphosphazene

Chiral high‐performance liquid chromatography (HPLC) separation of trans‐bis[2‐(2‐pyridyl)aminophenolato] dichlorocyclotriphosphazene 1 was achieved and the absolute configuration of (+)-1 was assigned to be S,S by single‐crystal X‐ray structural analysis. The optically pure 1,2‐diphenyl‐1,2‐ethanediolate derivatives (+)‐ 2a and (?)‐ 2b were synthesized by the reactions of (+)-1 and (-)-1 with (R,R)‐hydrobenzoin, respectively, in refluxing toluene in the presence of an excess amount of triethylamine and a catalytic amount of 4‐(dimethylamino)pyridine. The racemization of the enantiomers of 1 and the epimerization of diastereomers of 2 were not observed in refluxing toluene neither under acidic nor basic conditions. The stereochemistry of (+)-1 was confirmed by the crystal structure of (+)‐ 2a and bis[(4‐methyl‐2‐pyridyl)oxy]cyclotriphosphazene (+)-3 derived from (+)-1 . Chirality 28:556–561, 2016. © 2016 Wiley Periodicals, Inc.