The impact of β‐azido(or 1‐piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues

The synthesis of new dermorphin analogues is described. The (R)‐alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α‐methyl‐β‐azidoalanine or α‐benzyl‐β‐azido(1‐piperidinyl)alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in rat brain using [³H]DAMGO (a μ ligand) and [³H]DELT (a δ ligand). The most active analogue in this series, Tyr‐(R)‐Ala‐(R)‐α‐benzyl‐β‐azidoAla‐Gly‐Tyr‐Pro‐Ser‐NH₂ and its epimer were analysed by ¹H and ¹³C NMR spectroscopy and restrained molecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around C^α in the α‐benzyl‐β‐azidoAla residue in position 3. The (R) configuration led to the formation of a type I β‐turn, whilst switching to the (S) configuration gave rise to an inverse β‐turn of type I′, followed by the formation of a very short β‐sheet. The selectivity of Tyr‐(R)‐Ala‐(R) and (S)‐α‐benzyl‐β‐azidoAla‐Gly‐Tyr‐Pro‐Ser‐NH₂ was shown to be very similar; nevertheless, the two analogues exhibited different conformational preferences. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.     

Biocatalytic Approach for the Synthesis of Enantiopure Acebutolol as a β1‐Selective Blocker

A new chemoenzymatic route is reported to synthesize acebutolol, a selective β₁ adrenergic receptor blocking agent in enantiopure (R and S) forms. The enzymatic kinetic resolution strategy was used to synthesize enantiopure intermediates (R)‐ and (S)‐N‐(3‐acetyl‐4‐(3‐chloro‐2‐hydroxypropoxy)phenyl)butyramide from the corresponding racemic alcohols. The results showed that out of eleven commercially available lipase preparations, two enzyme preparations (Lipase A, Candida antarctica, CLEA [CAL CLEA] and Candida rugosa lipase, 62316 [CRL 62316]) act in enantioselective manner. Under optimized conditions the enantiomeric excess of both (R)‐ and (S)‐N‐(3‐acetyl‐4‐(3‐chloro‐2‐hydroxypropoxy)phenyl)butyramide were 99.9 and 96.8%, respectively. N‐alkylation of both the (R) and (S) intermediates with isopropylamine gave enantiomerically pure (R and S)‐ acebutolol with a yield 68 and 72%, respectively. This study suggests a high yielding, easy and environmentally green approach to synthesize enantiopure acebutolol. Chirality 27:382–391, 2015. © 2015 Wiley Periodicals, Inc.     

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.     

A Simple Method for Resolution of Endo‐/Exo‐Monoesters of Trans‐Norborn‐5‐Ene‐2,3‐Dicarboxylic Acids Into Their Enantiomers

Separation of optical isomers obtainable from trans‐norborn‐5‐ene‐2,3‐dicarboxylic acid methyl and tert‐butyl monoesters was performed by crystallization of the respective salts prepared with (R)‐ and (S)‐1‐phenylethylamine. Starting from racemic endo‐monomethyl ester of trans‐norborn‐5‐ene‐2,3‐dicarboxylic acid, prepared by partial hydrolysis of the cyclopentadiene‐dimethyl fumarate adduct, the corresponding (2R,3R)‐endo‐monoester was isolated in 97% enantiomeric excess (ee) yield after seven repeated crystallizations from tetrachloromethane. Starting from exo‐mono‐tert‐butyl ester of the same acid, prepared by alcoholysis of the cyclopentadiene‐maleic anhydride adduct followed by isomerization, (2R,3R)‐exo‐monoester was isolated in >98% ee yield after four repeated crystallizations from ethanol. Crystallization of the acids from the mother liquor containing (S)‐1‐phenylethylamine yielded products with inverse stereochemical configuration. Chirality 27:151–155, 2015. © 2014 Wiley Periodicals, Inc.     

An improved synthesis of (2S, 4S)‐ and (2S, 4R)‐2‐amino‐4‐methyldecanoic acids: assignment of the stereochemistry of culicinins

An improved synthesis of (2S, 4S)‐ and (2S, 4R)‐2‐amino‐4‐methyldecanoic acids was accomplished using a glutamate derivative as starting material and Evans' asymmetric alkylation as the decisive step. The NMR data of the two diastereomers were measured and compared with those of the natural product. As a result, the stereochemistry of this novel amino acid unit in culicinins was assigned as (2S, 4R). Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

Enantioselective pharmacokinetics of (R)‐ and (S)‐ketamine after a 5‐day infusion in patients with complex regional pain syndrome

Introduction: This study determined the pharmacokinetics and pharmacodynamics of (R)‐ and (S)‐ketamine and (R)‐ and (S)‐norketamine following a 5‐day moderate dose, as a continuous (R,S)‐ketamine infusion in complex regional pain syndrome (CRPS) patients. Materials and methods: Ketamine was titrated to 10–40 mg/h and maintained for 5 days. (R)‐ and (S)‐Ketamine and (R)‐ and (S)‐norketamine pharmacokinetic and pharmacodynamic studies were performed. Blood samples were obtained on Day 1 preinfusion, and at 60–90, 120–150, 180–210, and 240–300 min after the start of the infusion, on Days 2, 3, 4, 5, and on Day 5 at 60 min after the end of infusion. The plasma concentrations of (R)‐ and (S)‐ketamine and (R)‐ and (S)‐norketamine were determined using enantioselective liquid chromatography–mass spectrometry. Results: Ketamine and norketamine levels stabilized 5 h after the start of the infusion. (R)‐Ketamine clearance was significantly lower resulting in higher steady‐state plasma concentrations than (S)‐ketamine. The first‐order elimination for (S)‐norketamine was significantly greater than that of (R)‐enantiomer. When comparing the pharmacokinetic parameters of the patients who responded to ketamine treatment with those who did not, no differences were observed in ketamine clearance and the first‐order elimination of norketamine. Conclusion: The results indicate that (R)‐ and (S)‐ketamine and (R)‐ and (S)‐norketamine plasma concentrations do not explain the antinociceptive activity of the drug in patients suffering from CRPS. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

Synthesis of enantiomers of exo‐2‐norbornyl‐N‐n‐butylcarbamate and endo‐2‐norbornyl‐N‐n‐butylcarbamate for stereoselective inhibition of acetylcholinesterase

The acetylcholinesterase inhibition by enantiomers of exo‐ and endo‐2‐norbornyl‐N‐n‐butylcarbamates shows high stereoselelectivity. For the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐exo‐2‐norbornyl‐N‐n‐butylcarbamates, the R‐enantiomer is more potent than the S‐enantiomer. But, for the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates, the S‐enantiomer is more potent than the R‐enantiomer. Optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates are synthesized from condensations of optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norborneols with n‐butyl isocyanate, respectively. Optically pure norborneols are obtained from kinetic resolutions of their racemic esters by lipase catalysis in organic solvent. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Necessary and sufficient conditions for the asymmetric synthesis of chiral amines using ω‐aminotransferases

The half reactions of ω‐aminotransferase (ω‐AT) from Vibrio fluvialis JS17 (ω‐ATVf) were carried out using purified pyridoxal 5′‐phosphate‐enzyme (PLP‐Enz) and pyridoxamine 5′‐phosphate‐enzyme (PMP‐Enz) complexes to investigate the relative activities of substrates. In the reaction generating PMP‐Enz from PLP‐Enz using L ‐alanine as an amine donor, L ‐alanine showed about 70% of the initial reaction rate of (S)‐α‐methylbenzylamine ((S)‐α‐MBA). However, in the subsequent half reaction recycling PLP‐Enz from PMP‐Enz using acetophenone as an amine acceptor, acetophenone showed nearly negligible reactivity compared to pyruvate. These results indicate that the main bottleneck in the asymmetric synthesis of (S)‐α‐MBA lies not in the amination of PLP by alanine, but in the amination of acetophenone by PMP‐Enz, where conformational restraints of the enzyme structure is likely to be the main reason for limiting the amine group transfer from PMP‐Enz to acetophenone. Based upon those half reaction experiments using the two amino acceptors of different activity, it appears that the relative activities of the two amine donors and the two acceptors involved in the ω‐AT reactions can roughly determine the asymmetric synthesis yield of the target chiral amine compound. Predicted conversion yields of several target chiral amines were calculated and compared with the experimental conversion yields. Approximately, a positive linear correlation (Pearson's correlation coefficient = 0.92) was observed between the calculated values and the experimental conversion yields. To overcome the low (S)‐α‐MBA productivity of ω‐ATVf caused by the possible disadvantageous structural constraints for acetophenone, new ω‐ATs showing higher affinity to benzene ring of acetophenone than ω‐ATVf were computationally screened using comparative modeling and protein‐ligand docking. ω‐ATs from Streptomyces avermitilis MA‐4680 (SAV2612) and Agrobacterium tumefaciens str. C58 (Atu4761) were selected, and the two screened ω‐ATs showed higher asymmetric synthesis reaction rate of (S)‐α‐MBA and lower (S)‐α‐MBA degradation reaction rate than ω‐ATVf. To verify the higher conversion yield of the variants of ω‐ATs, the reaction with 50 mM acetophenone and 50 mM alanine was performed with coupling of lactate dehydrogenase and two‐phase reaction system. SAV2612 and Atu4761 showed 70% and 59% enhanced yield in the synthesis of (S)‐α‐MBA compared to that of ω‐ATVf, respectively. Biotechnol. Bioeng. 2011;108: 253–263. © 2010 Wiley Periodicals, Inc.     

Optical Resolution and Optimization of (R,S)‐Propranolol Using Dehydroabietic Acid Via Diastereomeric Crystallization

The optical resolution of (R,S)‐propranolol by the diastereomeric crystallization method was successfully performed using dehydroabietic acid (DHAA) as the resolving agent in methanol. The three important parameters: DHAA amount, solvent (methanol) amount, and crystallization temperature of diastereomeric salts were optimized employing the response surface methodology (RSM). When maintaining a lower limit of 95% for the purity of (S)‐propranolol, the optimal resolution conditions were a DHAA/(R,S)‐propranolol molar ratio of 1.1, solvent/(R,S)‐propranolol ratio of 16.2 mL.g^‐1, and crystallization temperature of –5 °C. The desired (S)‐propranolol was prepared with 94.8% optical purity and 72.2% yield under the optimal conditions. Chirality 27:131–136, 2015. © 2014 Wiley Periodicals, Inc.     

Chiral syntheses of methyl (R)‐2‐Sulfanylcarboxylic esters and acids with optical purity determination using HPLC

Accessible chiral syntheses of 3 types of (R)‐2‐sulfanylcarboxylic esters and acids were performed: (R)‐2‐sulfanylpropanoic (thiolactic) ester (53%, 98%ee) and acid (39%, 96%ee), (R)‐2‐sulfanylsucciinic diester (59%, 96%ee), and (R)‐2‐mandelic ester (78%, 90%ee) and acid (59%, 96%ee). The present practical and robust method involves (i) clean S_N2 displacement of methanesulfonates of (S)‐2‐hydroxyesters by using commercially available AcSK with tris(2‐[2‐methoxyethoxy])ethylamine and (ii) sufficiently mild deacetylation. The optical purity was determined by the corresponding (2R,5R)‐trans‐thiazolidin‐4‐one and (2S,5R)‐cis‐thiazolidin‐4‐one derivatives based on accurate high‐performance liquid chromatography analysis with high‐resolution efficiency. Compared with the reported method utilizing AcSCs (generated from AcSH and CsCO₃), the present method has several advantages, that is, the use of odorless AcCOSK reagent, reasonable reaction velocity, isolation procedure, and accurate, reliable optical purity determination. The use of accessible AcSK has advantages because of easy‐to‐handle odorless and hygroscopic solid that can be used in a bench‐top procedure. The Ti(OiPr)₄ catalyst promoted smooth trans‐cyclo‐condensation to afford (2R,5R)‐trans‐thiazolidin‐4‐one formation of (R)‐2‐sulfanylcarboxylic esters with available N‐(benzylidene)methylamine under neutral conditions without any racemization, whereas (2S,5R)‐cis‐thiazollidin‐4‐ones were obtained via cis‐cyclo‐condensation and no catalysts. Direct high‐performance liquid chromatography analysis of methyl (R)‐mandelate was also performed; however, the resolution efficiency was inferior to that of the thaizolidin‐4‐one derivatizations.     

Synthesis of enantiopure planar chiral bis‐(para)‐pseudo‐meta‐type [2.2]paracyclophanes

A new type of planar chiral (R_p)‐ and (S_p)‐4,7,12,15‐tetrasubstituted [2.2]paracyclophanes was prepared from racemic 4,7,12,15‐tetrabromo[2.2]paracyclophane as the starting substrate. Regioselective lithiation and transformations afforded racemic bis‐(para)‐pseudo‐meta‐type [2.2]paracyclophane (4,15‐dibromo‐7,12‐dihydroxy[2.2]paracyclophane). Its optical resolution was performed by the diastereomer method using a chiral camphanoyl group as the chiral auxiliary. The diastereoisomers were readily isolated by simple silica gel column chromatography, and the successive hydrolysis afforded (R_p)‐ and (S_p)‐bis‐(para)‐pseudo‐meta‐type [2.2]paracyclophanes ((R_p)‐ and (S_p)‐4,15‐dibromo‐7,12‐dihydroxy[2.2]paracyclophanes). They can be used as pseudo‐meta‐substituted chiral building blocks.     

Enantiopure 4‐oxazolin‐2‐ones and 4‐methylene‐2‐oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles

Enantiopure 3‐((R)‐ and 3‐((S)‐1‐phenylethyl)‐4‐oxazoline‐2‐ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N‐(R)‐ or N‐(S)‐1‐phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4‐ and 5‐positions of the 4‐oxazolin‐2‐one ring through thermal and MW‐promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six‐membered carbo‐ and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4‐methylene‐2‐oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero‐Diels‐Alder cycloaddition.     

Examination of the active secondary structure of the peptide 101.10, an allosteric modulator of the interleukin‐1 receptor,by positional scanning using β‐amino γ‐lactams

The relationship between the conformation and biological activity of the peptide allosteric modulator of the interleukin‐1 receptor 101.10 (D ‐Arg‐D ‐Tyr‐D ‐Thr‐D ‐Val‐D ‐Glu‐D ‐Leu‐D ‐Ala‐NH₂) has been studied using (R)‐ and (S)‐Bgl residues. Twelve Bgl peptides were synthesized using (R)‐ and (S)‐cyclic sulfamidate reagents derived from L ‐ and D ‐aspartic acid in an optimized Fmoc‐compatible protocol for efficient lactam installment onto the supported peptide resin. Examination of these (R)‐ and (S)‐Bgl 101.10 analogs for their potential to inhibit IL‐1β‐induced thymocyte cell proliferation using a novel fluorescence assay revealed that certain analogs exhibited retained and improved potency relative to the parent peptide 101.10. In light of previous reports that Bgl residues may stabilize type II′β‐turn‐like conformations in peptides, CD spectroscopy was performed on selected compounds to identify secondary structure necessary for peptide biological activity. Results indicate that the presence of a fold about the central residues of the parent peptide may be important for activity. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

Antiproliferative Evaluation of Some 2‐[2‐(2‐Phenylethenyl)‐cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles: DFT and Molecular Docking Study

The 2‐[2‐(2‐phenylethenyl)cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles were synthesized from the reactions of 7‐benzylidenebicyclo[3.2.0]hept‐2‐en‐6‐ones with 2‐aminobenzenethiol. The antiproliferative activities of 2‐[2‐(2‐phenylethenyl)cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles were determined against C6 (rat brain tumor) and HeLa (human cervical carcinoma cells) cell lines using BrdU cell proliferation ELISA assay. Cisplatin and 5‐fluorouracil (5‐FU) were used as standards. The most active compound was 2‐{(1S,2S)‐2‐[(E)‐2‐(4‐methylphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against C6 cell lines with IC₅₀=5.89 μm value (cisplatin, IC₅₀=14.46 μm and 5‐FU, IC₅₀=76.74 μm ). Furthermore, the most active compound was 2‐{(1S,2S)‐2‐[(E)‐2‐(2‐methoxyphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against HeLa cell lines with IC₅₀=3.98 μm (cisplatin, IC₅₀=37.95 μm and 5‐FU, IC₅₀=46.32 μm ). Additionally, computational studies of related molecules were performed by using B3LYP/6‐31G+(d,p) level in the gas phase. Experimental IR and NMR data were compared with the calculated results and were found to be compatible with each other. Molecular electrostatic potential (MEP) maps of the most active 2‐{(1S,2S)‐2‐[(E)‐2‐(2‐methoxyphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against HeLa and the most active 2‐{(1S,2S)‐2‐[(E)‐2‐(4‐methylphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole against C6 were investigated, aiming to determine the region that the molecule is biologically active. Biological activities of mentioned molecules were investigated with molecular docking analyses. The appropriate target protein (PDB codes: 1 M17 for the HeLa cells and 1JQH for the C6 cells) was used for 2‐{(1S,2S)‐2‐[(E)‐2‐(2‐methoxyphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole and 2‐{(1S,2S)‐2‐[(E)‐2‐(4‐methylphenyl)ethenyl]cyclopent‐3‐en‐1‐yl}‐1,3‐benzothiazole molecules exhibiting the highest biological activity against HeLa and C6 cells in the docking studies. As a result, it was determined that these molecules are the best candidates for the anticancer drug.     

Stereoselective synthesis of fully protected (2S,4S,6S)‐2‐amino‐6‐hydroxy‐4‐methyl‐8‐oxodecanoic acid (AHMOD)

The stereocontrolled synthesis of fully protected (2S,4S,6S)‐2‐amino‐6‐hydroxy‐4‐methyl‐8‐oxodecanoic acid was accomplished using a glutamate derivative as starting material. The key steps of this stereochemical synthetic pathway involved an Evans asymmetric alkylation, a Sharpless asymmetric epoxidation, and a Grignard reaction. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

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.     

Enantioselective synthesis and antioxidant activity of 3‐(3,4‐dihydroxyphenyl)‐glyceric acid—Basic monomeric moiety of a biologically active polyether from Symphytum asperum and S. caucasicum

The racemic and enantioselective synthesis of a novel glyceric acid derivative, namely, 2,3‐dihydroxy‐3‐(3,4‐dihydroxyphenyl)‐propionic acid as well as the antioxidant activities is described. The virtually pure enantiomers, (+)‐(2R,3S)‐2,3‐dihydroxy‐3‐(3,4‐dihydroxyphenyl)‐propionic acid and (?)‐(2S,3R)‐2,3‐dihydroxy‐3‐(3,4‐dihydroxyphenyl)‐propionic acid were synthesized for the first time via Sharpless asymmetric dihydroxylation of trans‐caffeic acid derivatives using the enantiocomplementary catalysts, (DHQD)₂‐PHAL and (DHQ)₂‐PHAL. The determination of enantiomeric purity of the novel chiral glyceric acid derivatives was performed by high‐performance liquid chromatographic techniques on the stage of their alkylated precursors. The novel glyceric acid derivatives show strong antioxidant activity against hypochlorite and N,N‐diphenyl‐N‐picryl‐hydrazyl free radical. Their antioxidant activity is about 40‐fold higher than that of the corresponding natural polyether and three‐fold higher of trans‐caffeic acid itself. Chirality, 2010. © 2010 Wiley‐Liss, Inc.     

Desymmetrization of cyclic anhydrides mediated by cinchona alkaloids: Synthesis and olfactory properties of new fragrances based on (R)‐ and (S)‐2‐ethylhexanol

A series of enantiomerically pure new fragrances, derived from 2‐ethylhexanol, have been prepared and their olfactory properties evaluated. The key step of the synthesis is cinchona‐alkaloid‐catalyzed desymmetrization of cyclic meso‐anhydrides with (R)‐ and (S)‐2‐ethylhexanol and proceeded in good to excellent diastereoselectivities (92:8–98:2 dr). Enantiomerically pure alcohols were prepared by lipase‐catalyzed kinetic resolution of 2‐ethylhexanol using vinyl laurate as acyl donor. Chirality 2009. © 2009 Wiley‐Liss, Inc.     

Stereodynamics of Nitrogen Chiral Centers in aza‐β3‐Cyclodipeptides

The present work is devoted to the synthesis, conformational analysis, and stereodynamic study of aza‐β³‐cyclodipeptides. This pseudopeptidic ring shows E/Z hydrazide bond isomerism, eight‐membered ring conformation, and chirotopic nitrogen atoms, all of which are elements that are prone to modulate the ring shape. The (E,E) twist boat conformation observed in the solid state by X‐ray diffraction is also the ground conformation in solution, and emerges as the lowest in energy when using quantum chemical calculations. The relative configuration associated with ring chirality and with the two nitrogen chiral centers is governed by steric crowding and adopts the (P)S_NS_N/(M)R_NR_N combination which projects side chains in equatorial position. The nitrogen pyramidal inversion (NPI) at the two chiral centers is correlated with the ring reversal. The process is significantly hindered as was shown by VT‐NMR experiments run in C₂D₂Cl₄, which did not make it possible to determine the barrier to inversion. Finally, these findings make it conceivable to resolve enantiomers of aza‐β³‐cyclodipeptides by modulating the backbone decoration appropriately. Chirality 25:341–349, 2013. © 2013 Wiley Periodicals, Inc.     

Asymmetric Allylation of α‐Ketoester‐Derived N‐Benzoylhydrazones Promoted by Chiral Sulfoxides/N‐Oxides Lewis Bases: Highly Enantioselective Synthesis of Quaternary α‐Substituted α‐Allyl‐α‐Amino Acids

Chiral sulfoxides/N‐oxides (R)‐ 1 and (R,R)‐ 2 are effective chiral promoters in the enantioselective allylation of α‐keto ester N‐benzoylhydrazone derivatives 3a , 3b , 3c , 3d , 3e , 3f , 3g to generate the corresponding N‐benzoylhydrazine derivatives 4a , 4b , 4c , 4d , 4e , 4f , 4g , with enantiomeric excesses as high as 98%. Representative hydrazine derivatives 4a , 4b were subsequently treated with SmI₂, and the resulting amino esters 5a , 5b with LiOH to obtain quaternary α‐substituted α‐allyl α‐amino acids 6a , 6b , whose absolute configuration was assigned as (S), with fundament on chemical correlation and electronic circular dichroism (ECD) data. Chirality 25:529–540, 2013. © 2013 Wiley Periodicals, Inc.