Improved synthesis of trans-4-alkylcyclohexane carboxylic acids

Several stereomerically pure amino acid derivatives containing the N-terminal trans-4-alkylcyclohexanoyl fragment were obtained. Hydrogenation of 4-alkylbenzoic acids in the presence of a special Ru-Ni/C catalytic system and isomerization of the resulting mixture of trans- and cis-isomers of 4-alkylcyclohexanecarboxylic acids were used as the key steps. The stereomeric configuration of all compounds was confirmed by ¹H NMR spectroscopy. The compounds obtained possess a broad biological activity potential and are useful intermediates in the synthesis of stereomerically pure modified peptides.     

Synthesis of a constrained tricyclic scaffold based on trans-4-hydroxy-l-proline

Drug discovery research has taken advantage of peptidomimetic chemistry in order to achieve new leads possessing structural and functional characteristics of bioactive peptides together with enhanced metabolic resistance towards proteases. Herein is reported the synthesis of a tricyclic peptidomimetic scaffold derived from the combination of trans-4-hydroxy-l-proline and tartaric acid derivatives by means of amidation and acid trans-acetalisation reactions. Further manipulations of the hydroxylic function on the pyrrolidine ring gave access to a new set of amino acid scaffolds possessing high rigidity and a fixed arrangement of the functional groups.     

Synthesis and nonlinear optical properties of new symmetrically substituted stilbenes

Three new chromophores and trans-4-(N-(ethyl 4″-nitrobenzoate)-N-ethyl amino)-4′-(dimethyl amino) stilbene (DMANHAS) have been synthesized and whose chemical structures have been characterized by ¹H NMR, IR, and elemental analyses. Linear absorption, single-photon-induced fluorescence and two-photon-induced fluorescence are experimentally studied. Trans-4-(N-2-hydroxyethyl-N-ethyl amino)-4′-(dimethyl amino)stilbene (DMAHAS) and trans-4-(N-2-hydroxyethyl-N-ethyl amino)-4′-(diethyl amino)stilbene (DEAHAS) have effective two-photon absorption cross-sections of σ₂=0.91×10⁻⁴⁶ cm⁴ s/photon and σ₂=1.19×10⁻⁴⁶ cm⁴ s/photon at 532 nm by using an open aperture Z-scan technique, respectively. When pumped with 800 nm laser irradiation, DMAHAS and DEAHAS indicate strong two-photon-induced blue fluorescence of 436 and 440 nm, respectively, while trans-4-(N-(ethyl 4″-nitrobenzoate)-N-ethyl amino)-4′-(diethyl amino) stilbene (DEANHAS) and DMANHAS exhibit no fluorescence.     

A novel conformationally restricted analogue of 3-methylaspartic acid via stereoselective methylation of chiral pyrrolidin-2-ones

Conformationally restricted analogues of β-methylaspartic acid were easily prepared starting from chiral N-protected trans-3-amino-4-methoxycarbonyl pyrrolidin-2-ones. The key step of the synthesis was the methylation reaction at C-4, proceeding with high diastereoselection syn to the protected amino group lying at C-3 of the pyrrolidin-2-one ring.     

Synthesis of enantiomerically pure cis- and trans-cyclopentane analogues of phenylalanine

For the first time, all stereoisomers of 1-amino-2-phenylcyclopentanecarboxylic acid—c₅Phe—have been synthesised. A Strecker reaction on 2-phenylcyclopentanone and further transformations of each amino nitrile into the amino acid provides cis-c₅Phe and trans-c₅Phe with high efficiency. A divergent synthetic route was then developed to obtain the target compounds cis- and trans-c₅Phe in their racemic form. The preparation of the final enantiomerically pure amino acids and their corresponding N-protected derivatives was also achieved by HPLC resolution of one of the intermediates using a cellulose-derived chiral stationary phase. The relative stereochemistry of each amino acid and its precursors have been unambiguously assigned.     

The conversion of pentoses to 3,4-dihydroxyprolines

The synthesis of two naturally-occurring isomers of 3,4-dihydroxyproline is reported. l-2,3-cis-3,4-trans-3,4-Dihydroxyproline was synthesized from l-arabinose in 10 steps and 31% overall yield. The same series of reactions was employed to convert l-xylose to l-2,3-trans-3,4-trans-3,4-dihydroxyproline. Orthogonally protected versions of these amino acids were produced on gram scale, en route to the free amino acids, and these will serve as versatile intermediates in peptide synthesis. This synthetic strategy involved Nα-Fmoc protection and protection of the C3 and C4 secondary alcohols as methoxyethoxymethyl (MEM) ethers.     

Synthesis of Tetrahydrothiophene 1,1-Dioxides Fused to Oxazolidin-2-one and Morpholin-2-one Fragments

While developing methods of synthesis of sulfolanes fused through the C³–C⁴ bond to oxazolidin-2- one and morpholin-2-one fragments, the reactivity of cis- and trans-isomeric amino alcohols of the sulfolane series toward a number of cyclizing agents was studied. The cis isomers reacted with dimethyl acetylenedicarboxylate and triphosgene to afford the corresponding morpholin-2-ones and oxazolidin-2-ones, whereas the trans isomers gave rise to open-chain aminofumarates and urea derivatives, respectively. The reactions of both cis- and trans-amino alcohols with oxalic acid derivatives (diethyl oxalate, oxalyl chloride) led to the formation of exclusively acyclic mono- and/or diamides.     

Separation of 5-Lipoxygenase Metabolites Using Cyclodextrin-Modified Microemulsion Electrokinetic Chromatography and Head Column Field-Amplified Sample Stacking

A cyclodextrin-modified microemulsion electrokinetic chromatography method employing head column field-amplified sample stacking was developed for the analysis of arachidonic acid metabolites of the lipoxygenase pathways. The influence of the concentration of boric acid, the surfactant sodium dodecyl sulfate, the co-surfactant 1-butanol and the oil phase octane as well as the pH of the background electrolyte, the separation voltage and the separation temperature was studied. The optimized microemulsion consisting of 20 mM boric acid buffer, pH 9.0, 3.0 % (m/v) sodium dodecyl sulfate, 0.5 % (v/v) octane, 5.0 % (v/v) 1-butanol and 15 mM α-cyclodextrin enabled the separation of 20-hydroxy-leukotriene B₄, leukotriene B₄, 6-trans-leukotriene B₄, 6-trans-12-epi-leukotriene B₄, 5(S)-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid, 12(S)-hydroxy-5,8,14-cis-10-trans-eicosatetraenoic acid, 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid as well as the internal standard prostaglandin B₁ in <10 min employing a separation voltage of 17.5 kV at a temperature of 23 °C. A matrix peak from solid-phase extraction sample workup co-migrated with 5(S)-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid affecting peak integration. The addition of 5 % (v/v) 2-propanol to the microemulsion resulted in the separation of this eicosatetraenoic acid and the matrix components at the expense of analysis time and peak resolution between the diastereomers 6-trans-leukotriene B₄ and 6-trans-12-epi-leukotriene B₄. In summary, the MEEKC method appeared to be especially suitable for the more polar arachidonic acid metabolites.     

A facile synthesis of 3-aryl pyroglutamic acid. Facile synthesis of baclofen and chlorpheg

A facile synthesis of 3-aryl pyroglutamic acids via stepwise [3+2] annulation and desulfonated hydrolysis is reported. Base-induced coupling/cyclization reactions of α-sulfonylacetamide with various β-functional groups of (Z)-2-bromoacrylates yielded three contiguous chiral centers on the polysubstituted pyroglutamates system with trans-trans orientation in a one-pot synthesis. This facile strategy was used to synthesize amino acid derivatives baclofen and chlorpheg.     

The synthesis and photochemical properties of amphiphilic phenylazonaphthalenes

Three novel amphiphilic phenylazonaphthalenes, namely, 6-(4-(4-octylphenylazo)naphthoxy)hexanoic acid, 6-(4-(4-dodecylphenylazo)naphthoxy)hexanoic acid, 6-(4-(4-hexadecylphenylazo)naphthoxy)hexanoic acid, were synthesized by diazo coupling, etherification and hydrolysis reactions successively. The kinetic studies of the trans–cis isomerization indicated that about 95% of the trans isomers of these compounds in chloroform solutions were transformed to cis isomers under the irradiation of near-ultraviolet light (380±30 nm) observed from UV–Vis spectra. In the dark condition, the cis isomers could reversibly convert to trans isomers following the first-order kinetics at the rates of 4.9×10^-4, 5.7×10^-4, 7.7×10^-4 S^-1, respectively.     

Synthesis of trans-vaccenic acid and cis-9-trans-11-conjugated linoleic acid

The preparation of the monounsaturated fatty acid, trans-vaccenic acid 4 (TVA), using both Wittig and one-pot Julia-Kocieński olefination protocol, was achieved in good yield. Similarly a Wittig approach was employed for the stereoselective synthesis of cis-9-trans-11-conjugated linoleic acid 2 from trans-2-nonenal and (8-carboxyoctyl)triphenylphosphonium bromide 12.     

Asymmetric Diels–Alder reaction using a new chiral β-nitroacrylate for enantiopure trans-β-norbornane amino acid preparation

The main nitronorbornene adduct derived from the asymmetric Diels–Alder reaction of (S)-benzyl-4-(3-(3-nitroacryloyloxy)-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (S)-1 and cyclopentadiene was isolated and transformed to afford the enantiopure bicyclic β-amino acid (1S,2R,3R,4R)-trans-β-norbornane amino acid 9. The enantiomer (1R,2S,3S,4S)-9 could be obtained by the same synthetic route by using the chiral auxiliary (R)-1.     

A new access to 3,5-disubstituted piperazinones via Pd(0)-catalyzed amination

An original synthetic route toward 3,5-disubstituted piperazinones has been developed. The method relies upon a 6-exo intramolecular process between a sulfonylated nitrogen atom of amino acid derivation and an η³-allyl-palladium moiety. This cyclization process generates the two possible (cis and trans) diastereoisomers whose ratio depends on the amino acid employed. The bulkier the amino acid residue, the higher the observed cis:trans ratio. Convincing evidence for reversible intramolecular addition of the nitrogen nucleophile to the η³-allyl-palladium complex is put forward.     

Synthesis of optically active α-benzyl paraconic acids and their esters and assignment of their absolute configuration

The cis- and trans-4-benzylparaconic acids and their ethyl esters were synthesized with high enantiomeric excess by hydrolysis of the corresponding diastereomeric lactonic esters using α-chymotrypsin. Thus, at low conversion values, cis- and trans-4-benzyl-5-oxo-3-tetrahydrofurancarboxylic acids were separately isolated with 99% ee and 92% ee, respectively. Both ethyl ester diastereomers were also obtained in enantiopure form. The absolute configuration of the trans-lactonic acid was assigned by ¹H NMR analysis of its ester derivatives with both enantiomers of 1-(9-anthryl)-2,2,2-trifluoroethanol, while that of the cis-lactonic acid was assigned by means of X-ray analysis of a crystalline derivative. The circular dichroism curves of the products obtained are also reported.     

Revised structure and synthesis of piperolein acids,guineensine and wisanine from Piper guineense

The structures of piperolein acids guineensine and wisanine have been confirmed by synthesis, UV irradiation of trans piperolein B acid ester gave the cis-isomer reported in the literature as the trans-isomer. The trans-2, trans-4 ethylenic bonds in guineensine and wisanine were introduced by reacting piperolein B aldehyde and 2-methoxy piperonal with the appropriate Wittig or Reformatsky reagent.     

A facile approach to trans-4,5-pyrrolidine lactam and application in the synthesis of nemonapride and streptopyrrolidine

An efficient approach to trans-4-hydroxylpyrrolidine lactams 1 starting from amino acid is described. The utility of this method has been demonstrated in the synthesis of antipsychotic nemonapride 3 and antiangiogenic streptopyrrolidine 4. Compared four synthetic stereoisomers of natural streptopyrrolidine 4 in term of spectroscopic and physical data, the absolute structure of the natural product was proposed as (4S,5S)-configuration.     

Synthesis of new β- and γ-benzyloxy-S-glutamic acid derivatives and evaluation of their activity as inhibitors of excitatory amino acid transporters

An efficient stereoselective preparation of the two enantiomerically pure diasteroisomers of γ-benzyloxy-S-glutamic acid was performed using trans-4-hydroxy-l-proline as a source of chirality, while the erythro and threo isomers of β-benzyloxy-S-glutamic acid were prepared starting from (R)-Garner's aldehyde. All new derivatives were tested for their inhibitory activity against excitatory amino acid transporters in a rat synaptosomal preparation and their IC₅₀ values were compared to that of TBOA, a one carbon lower homologue commonly used as the reference blocker of glutamate transporters.     

Solvent dependent photo-isomerization of 4-dimethylaminoazobenzene carboxylic acid

We have observed reversible trans–cis photo-isomerization behaviors of 4-dimethylaminoazobenzene carboxylic acid (4DAzC) in ethyl acetate by alternating irradiations at 370 and 430 nm. The photo-isomerization from trans- to cis-isomer was found to be strongly solvent dependent and not to occur efficiently in water and ethanol. Also photo-isomerization from cis- to trans-isomer was occurred upon 370 nm illumination or via thermal relaxation. The activation energy for the thermal isomerization from cis to trans-isomer was estimated to be 49.2 kJ/mol in ethyl acetate from the temperature-dependent kinetic absorption measurements.     

Stereoselective synthesis and Lewis acid mediated functionalization of novel 3-methylthio-β-lactams

A proficient etiquette for the stereoselective synthesis of novel 3-methylthio-β-lactams and their Lewis acid mediated functionalization is described. Treatment of 2-methylthioethanoic acid and appropriate imines in the Staudinger reaction leads to the stereocontrolled synthesis of novel trans-3-methylthio-β-lactams in excellent yields. cis-3-Chloro-3-methylthio-β-lactams, obtained from stereoselective chlorination of trans-3-methylthio-β-lactams using N-chlorosuccinimide (NCS) and AIBN, were subjected to Lewis acid (TiCl₄ or SnCl₄) mediated functionalization using various active aromatic, heterocyclic and aliphatic compounds (nucleophiles). This reaction provides an easy access to novel, stereoselective cis-3-monosubstituted-3-methylthio-β-lactams, which further undergo smooth desulfurization with Raney-nickel to afford C-3 cis- and trans-monosubstituted-β-lactams. The cis or trans configuration of the hydrogen/chloro/nucleophile substituent at C-3 was assigned with respect to C4–H.     

New synthetic methods : Volumes 4,5 and 6, Verlag Chemie,Weinheim/New York 1979; Volume 4, viii + 266 pages; Volume 5, viii + 270 pages; Volume 6, viii + 274 pages; DM 68 each.

trans-β-Phenylethenylboronic acid, trans-β-p-methylphenylethenylboronic acid and trans-β-p-methoxyphenylethenylboronic acid on treatment with catalytic amounts of palladium chloride in presence of excess of lithium chloride and triethylamine give the corresponding (E, E)-1,4-diaryl-1,3-butadienes in virtually quantitative yield.