Synthesis,chromatographic resolution and chiroptical properties of carboxyibuprofen stereoisomers: Major metabolites of ibuprofen in man

The chromatographic resolution of the four stereoisomers of carboxyibuprofen, a major metabolite of ibuprofen in man, was achieved using a Chiralpak AD chiral stationary phase (CSP) (J.T. Baker, Milton, Keynes, UK). The elution order of the stereoisomers was determined to be 2′S,2R; 2′R,2R; 2′R,2S; 2′S,2S by a combination of stereoselective synthesis of diastereoisomeric mixtures and analysis of the two diastereoisomers isolated from human urine following the administration of (S)-ibuprofen. The individual stereoisomers were isolated by semipreparative chiral phase chromatography and characterized by circular dichroism spectroscopy. Chirality 9:75–87, 1997. © 1997 Wiley-Liss, Inc.     

Synthesis and Antimicrobial Activity of Optically Active trans-Cycloheximide Isomers

Optically active tiraras-cycloheximide isomers such as cycloheximide [(2S,4S,6R,αR)-form (1)], naramycin B[(25,4S,6RαR)-form(4)], and new stereoisomers (2S,4S,6S,αS)-form (8) and (2S,4S,6R,αS)-from (9) were synthesized by an aldol condensation of trans-2,4-dimethyl-l-cyclohexanone (5b), with 4-(2-oxoethyl)-2,6-piperidinedione(6). The antimicrobial activity of trans- cycloheximide isomers (1, 4, 8, and 9) was examined against S. cerevisiae and P. oryzae. The stereoisomers 1 and 4 exhibited marked antimicrobial activity against both microorganisms as compared with their C- α-epimers 8 and 9.     

Synthesis and evaluation of in vivo anti‐hypothermic effect of all stereoisomers of the thyrotropin‐releasing hormone mimetic: Rovatirelin Hydrate

We discovered the orally active thyrotropin‐releasing hormone (TRH) mimetic: (4S,5S)‐5‐methyl‐N‐{(2S)‐1‐[(2R)‐2‐methylpyrrolidin‐1‐yl]‐1‐oxo‐3‐(1,3‐thiazol‐4‐yl)propan‐2‐yl}‐2‐oxo‐1,3‐oxazolidine‐4‐carboxamide 1 (rovatirelin). The central nervous system (CNS) effect of rovatirelin after intravenous (iv) administration is 100‐fold higher than that of TRH. As 1 has four asymmetric carbons in its molecule, there are 16 stereoisomers. We synthesized and evaluated the anti‐hypothermic effect of all stereoisomers of 1 , which has the (4S),(5S),(2S),(2R) configuration from the N‐terminus to the C‐terminus, in order to clarify the structure?activity relationship (SAR) of stereoisomers. The (4R),(5R),(2R),(2S)‐isomer 16 did not show any anti‐hypothermic effect. Only the (4S),(5S),(2S),(2S)‐isomer 10 , which has the (2S)‐2‐methylpyrrolidine moiety at the C‐terminus showed the anti‐hypothermic effect similar to 1 . Stereoisomers, which have the (5R) configuration of the oxazolidinone at the N‐terminus and the (2R) configuration at the middle‐part, showed a much lower anti‐hypothermic effect than that of 1 . On the other hand, stereoisomers, which have the (4R) configuration of the oxazolidinone at the N‐terminus or the (2S) configuration of the C‐terminus, have little influence on the anti‐hypothermic effect.     

Enantioselective Degradation of (2RS, 3RS)‐Paclobutrazol in Rat Liver Microsomes

Paclobutrazol, with two stereogenic centers, but gives only (2R, 3R) and (2S, 3S)‐enantiomers because of steric‐hindrance effects, is an important plant growth regulator in agriculture and horticulture. Enantioselective degradation of paclobutrazol was investigated in rat liver microsomes in vitro. The degradation kinetics and the enantiomer fraction were determined using a Lux Cellulose‐1 chiral column on a reverse‐phase liquid chromatography–tandem mass spectrometry system. The t_1/2 of (2R, 3R)‐paclobutrazol is 18.60 min, while the t_1/2 of (2S, 3S)‐paclobutrazol is 10.93 min. Such consequences clearly indicated that the degradation of paclobutrazol in rat liver microsomes was stereoselective and the degradation rate of (2S, 3S)‐paclobutrazol was much faster than (2R, 3R)‐paclobutrazol. In addition, significant differences between the two enantiomers were also observed in enzyme kinetic parameters. The V_max of (2S, 3S)‐paclobutrazol was more than 2‐fold of (2R, 3R)‐paclobutrazol and the Cl_int of (2S, 3S)‐paclobutrazol was higher than that of (2R, 3R)‐paclobutrazol after incubation in rat liver microsomes. These results may have potential implications for better environmental and ecological risk assessment for paclobutrazol. Chirality 27:344–348, 2015. © 2015 Wiley Periodicals, Inc.     

Isolation and identification of sapotexanthin 5,6-epoxide and 5,8-epoxide from red mamey (Pouteria sapota)

Two new carotenoids, sapotexanthin 5,6-epoxide and sapotexanthin 5,8-epoxide, have been isolated from the ripe fruits of red mamey (Pouteria sapota). Sapotexanthin 5,6-epoxide was also prepared by partial synthesis via epoxidation of sapotexanthin, and the (5R,6S) and (5S,6R) stereoisomers were identified by high-performance liquid chromatography–electronic circular dichroism (HPLC-ECD) analysis. Spectroscopic data of the natural and semisynthetic derivatives obtained by acid-catalyzed rearrangement of cryptocapsin 5,8-epoxide stereoisomers were compared for structural elucidation.     

Enantioselective induction of cyclophosphamide metabolism by phenytoin

The objective of this study was to investigate the effect of phenytoin (PHE) on cyclophosphamide (CP) disposition. CP was administered to 6 adult patients in a preparative regimen for bone marrow transplantation consisting of busulfan and CP. Three of the patients received PHE and the other 3 “control” patients received diazepam (DZP) as anti‐epileptic prophylactic treatment. Plasma samples were collected at intervals up to 24 h after CP administration. The plasma concentrations of (R)‐ and (S)‐CP and their respective N‐dechloroethylated metabolites, (R)‐ and (S)‐DCE‐CP were simultaneously fitted using an enantiospecific 2‐compartment pharmacokinetic (PK) model with Bayesian control estimation. DZP had no significant effect on the metabolism of CP and any of its PK parameters. PHE, however, increased significantly the formation of (S)‐DCE‐CP while having no effect on the formation of (R)‐DCE‐CP. These results suggest that different enzymes are responsible for the formation of (S)‐DCE‐CP from (S)‐CP and (R)‐DCE‐CP from (R)‐CP. Additionally, assuming that PHE does not affect the passive renal elimination of (R)‐ and (S)‐CP, this analysis suggests that the clearance of both (R)‐ and (S)‐CP to 4‐hydroxy‐CP (the activation pathway) is increased by PHE. Chirality 11:569–574, 1999. © 1999 Wiley‐Liss, Inc.     

Synthesis of Optically Active β-Amino-γ-butyrolactone Derivatives from Aspartic Acid

(3S, 4R)-3-Methoxycarbonylamino-4-phenyl-4-butanolide (4a) was prepared from l-aspartic acid by stereoselective reduction of ethyl (*S)-3-methoxycarbonylamino-4-oxo-4-phenylbutyrate (3a).     

The stereoselective sulfate conjugation of 4'-methoxyfenoterol stereoisomers by sulfotransferase enzymes

The presystemic sulfate conjugation of the stereoisomers of 4′‐methoxyfenoterol, (R,R′)‐MF, (S,S′)‐MF, (R,S′)‐MF, and (S,R′)‐MF, was investigated using commercially available human intestinal S9 fractions, a mixture of sulfotransferase (SULT) enzymes. The results indicate that the sulfation was stereospecific and that an S‐configuration at the β‐OH carbon of the MF molecule enhanced the maximal formation rates with (S,R′)‐MF (S,S′)‐MF (R,S′)‐MF ≈ (R,R′)‐MF, and competition studies demonstrated that (S,R′)‐MF is an effective inhibitor of (R,R′)‐MF sulfation (IC₅₀ = 60 μM). In addition, the results from a cDNA‐expressed human SULT isoform screen indicated that SULT1A1, SULT1A3, and SULT1E1 can mediate the sulfation of all four MF stereoisomers. Previously published molecular models of SULT1A3 and SULT1A1 were used in docking simulations of the MF stereoisomers using Molegro Virtual Docker. The models of the MF‐SULT1A3 and MF‐SULT1A1 complexes indicate that each of the two chiral centers of MF molecule plays a role in the observed relative stabilities. The observed stereoselectivity is the result of multiple hydrogen bonding interactions and induced conformational changes within the substrate–enzyme complex. In conclusion, the results suggest that a formulation developed from a mixture of (R,R′)‐MF and (S,R′)‐MF may increase the oral bioavailability of (R,R′)‐MF. Chirality 24:796–803, 2012. © 2012 Wiley Periodicals, Inc. ¹      

Synthesis of stereoisomers of antithrombotic nipecotamides

The stereoisomers of α,α′-bis[3-(N,N-diethylcarbamoyl)-piperidino]-p-xylene ( 1 ) were synthesized. Rac ethyl nipecotate was resolved by diastereomeric (-)-D - and (+)-L-tartrate salt formation. The enantiomeric esters were hydrolyzed to the corresponding nipecotic acids, which were then converted into t-BOC derivatives. Treatment of the latter with diethylamine/isobutyl chloroformate and removal of the t-BOC protecting group afforded (R)- and (S)-N,N-diethylnipecotamides. Condensation of the latter with α,α′-dibromo-p-xylene gave (R,R)- and (S,S)- 1 . The meso-diastereomer was obtained by stereospecific synthesis in addition to our earlier procedure involving fractional crystallization of the diastereomeric mixture obtained by synthesis. The latter was resolved earlier into 1A , 1B , and 1C using chiral high-performance liquid chromatography (HPLC). Based on the stereospecific synthesis now achieved, 1A and 1B are assigned the configurations, (R,R) and (S,S) respectively, and 1C is assigned the meso configuration. The (R,S) structure of the latter is also confirmed by X-ray crystallography. © 1995 Wiley-Liss, Inc.     

Chemistry,physiological properties,and microbial production of hydroxycitric acid

The tropical plants Garcinia cambogia and Hibiscus subdariffa produce hydroxycitric acid (HCA), of which the absolute configurations are (2S,3S) and (2S,3R), respectively. (2S,3S)-HCA is an inhibitor of ATP-citrate lyase, which is involved in fatty acid synthesis. (2S,3R)-HCA inhibits pancreatic α-amylase and intestinal α-glucosidase, leading to a reduction in carbohydrate metabolism. In this study, we review current knowledge on the structure, biological occurrence, and physiological properties of HCA. The availability of HCA is limited by the restricted habitat of its source plants and the difficulty of stereoselective organic synthesis. Hence, in our recent study, thousands of microbial strains were screened and finally two bacterial strains were, for the first time, found to produce trace amounts of HCA. The HCA variants produced were the Hibiscus-type (2S,3R) enantiomer. Subsequent genome shuffling rapidly generated a mutant population with improved HCA yield relative to the parent strain of bacteria. These bacteria are a potential alternative source of natural HCA.     

Syntheses of all eight stereoisomers of conidendrin

ABSTRACT

All eight stereoisomers of conidendrin were synthesized from (1 R,2 S,3 S)-1-(4-benzyloxy-3-methoxyphenyl)-3-(4-benzyloxy-3-methoxybenzyl)-2- hydroxymethyl-1,4-butanediol ((+)-4) and its enantiomer with high optical purity. The configurations at 4-positions of the conidendrin stereoisomers were constructed by intramolecular Friedel-Crafts reaction of protected 4. After conversion to tetrahydronaphthalene intermediate 7a, the 2- and 3-position of tetrahydronaphthalene structure 7a were converted to 3a- and 9a-position of (+)-α-conidendrin (3a), respectively. By the epimerization process of 2- or 3-position of 7a, the other diastereomers were obtained. All enantiomers were also synthesized from (?)-4.     

Absolute configuration of norcoronatine

Norcoronamic acid was established as having the absolute stereochemistry (1S,2S)-2-methyl-1-aminocyclopropane-1-carboxylic acid by comparison of its properties with synthetic preparations of the (1R,2R), (1R,2S) and (1S,2R) stereoisomers.     

Synthesis of (4aR, 10aS)-(—)-8-Methoxy-1,1,4a-trimethyl-2-oxo-1,2,3,4,4a,9,10,10a-octahydrophenanthrene,an Optically Active Intermediate for the Synthesis of Diterpenes

(4aR,10aS)-(—)-8-Methoxy-1,1,4a-trimethyl-2-oxo-1,2,3,4,4a,9,10,10a-octahydrophenanthrene, a useful intermediate for the synthesis of optically active diterpenes, was synthesized from (S)-3-hydroxy-2,2-dimethylcyclohexanone.     

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.     

Constitutional Studies on the Mucilage of “Yamanoimo,” Dioscorea batatas Decne,forma Tsukune

All four stereoisomers of 10,14-dimethyloctadec-1-ene, a sex pheromone component of the apple leafminer (Lyonetia prunifoliella: Lepidoptera), were synthesized starting from (R)- and (S)-propylene oxide by applying stereospecific inversion of chiral secondary tosylates as a key step. Field evaluation showed that male moths of the Japanese population were selectively attracted by the (10S,14S)-isomer and that the activity was not inhibited by the enantiomer.     

Novel antioxidant agents deriving from molecular combinations of vitamins C and E analogues: 3,4-dihydroxy-5(R)-[2(R,S)-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2(R,S)-yl-methyl)-[1,3]dioxolan-4(S)-yl]-5H-furan-2-one and 3-O-octadecyl derivatives

Molecular combinations of two antioxidants (i.e., ascorbic acid and the pharmacophore of α-tocopherol), namely the 2,3-dihydroxy-2,3-enono-1,4-lactone and the chromane residues, have been designed and tested for their radical scavenging activities. When evaluated for their capability to inhibit malondialdehyde (MDA) production in rat liver microsomal membranes, the 3,4-dihydroxy-5R-2(R,S)-(6-hydroxy-2,5,7,8-tetramethylchroman-2(R,S)yl-methyl)-1,3]dioxolan-4S-yl]-5H-furan-2-one (11a–d), exhibited an interesting activity. In particular the 5R,2R,2R,4S and 5R,2R,2S,4S isomers (11c,d) displayed a potent antioxidant effect compared to the respective synthetic α-tocopherol analogue (5) and natural α-tocopherol or ascorbic acid, used alone or in combination. Moreover, the mixture of stereoisomers 11a–d also proved to be effective in preventing damage induced by reperfusion on isolated rabbit heart, in particular at the higher concentration of 300 μM. In view of these results our study represents a new approach to potential therapeutic agents for applications in pathological events in which a free radical damage is involved. Design, synthesis and preliminary biological activity are discussed.     

Stereoselective Formation and Metabolism of 20(S)‐Protopanaxadiol Ocotillol Type Epimers in Vivo and in Vitro

(20S,24S)‐epoxy‐dammarane‐3,12,25‐triol (24S‐epimer) and (20S,24R)‐epoxy‐ dammarane‐3,12,25‐triol (24R‐epimer), a pair of ocotillol type epimers, were identified as the main metabolites of 20(S)‐protopanaxadiol (PPD). The aim of this study was to systematically investigate the formation and metabolism of this pair of epimers in vivo and in vitro and to elucidate the isoforms of cytochrome P450 enzymes responsible for the stereoselective metabolism of both epimers. The result showed that 24S‐epimer was a more predominant ingredient in rat plasma after oral administration of PPD with higher area under the curve (AUC) values. Both the enzyme kinetic evaluations of the formation and elimination of 24S‐epimer and 24R‐epimer in rat liver microsomes (RLM) and human liver microsomes (HLM) indicated that 24S‐epimer had a higher formation rate and a lower oxygenation metabolism rate than 24R‐epimer, and the stereoselective differences were more obvious in HLM than in RLM. The chemical inhibition and recombinant human P450 isoforms assay showed that CYP3A4 was the predominant isoform responsible for the further metabolism of 24R‐epimer in HLM. The biliary excretion ratio of the 24S‐epimer glucuronide was more than 28‐fold higher than that of 24R‐epimer glucuronide after intravenous administration to rats, which also indicated 24S‐epimer was more preferential to be metabolized as the glucuronide conjugate than 24R‐epimer. Chirality 27:170–176, 2015. © 2014 Wiley Periodicals, Inc.     

Stereochemical and structural effects of (2R,6R)-hydroxynorketamine on the mitochondrial metabolome in PC-12 cells

Background

Impairment in mitochondrial biogenesis and function plays a key role in depression and anxiety, both of which being associated with changes in fatty acid and phospholipid metabolism. The antidepressant effects of (R,S)-ketamine have been linked to its conversion into (2S,6S;2R,6R)-hydroxynorketamine (HNK); however, the connection between structure and stereochemistry of ketamine and HNK in the mitochondrial homeostatic response has not yet been fully elucidated at a metabolic level.

Stereoselective Synthesis of erythro-Serricornin, (4R, 6R, 7S)-, and (4S, 6R, 7S)-4,6-Dimethyl-7-hydroxynonan-3-one,Stereoisomers of the Sex Pheromone of Cigarette Beetle

A stereoselective synthesis of erythro-serricornin [(4RS,6R,7S)-4,6-dimethyl-7-hydroxynonan-3-one] was completed starting from l-(+)-tartaric acid. The relative configuration of C(6)-methyl and C(7)-hydroxyl groups in naturally occurring serricornin was threo.     

Stereoselective Synthesis of 1- and 2-O-α-d-Cellotriosyl-3-deoxy-2(R)- and 2(S)-glycerols Related to Rhynchosporoside

The stereoselective synthesis of 1- and 2-O-α-d-cellotriosyl-3-deoxy-2(R)- and 2(S)-glycerols, which determined the structure of rhynchosporoside produced by Rhynchosporium secalis, and their phytotoxicity toward the host plant (Hordeum vulgare) are described in detail.