Synthesis and structural characterization of a dichloro zinc complex of N,N′-bis-(2,6-dichloro-benzyl)-(R,R)-1,2-diaminocyclohexane: Application to ring opening polymerization of rac-lactide

A novel dichloro zinc complex (L¹)ZnCl₂, where L¹ is N,N′-bis-(2,6-dichloro-benzyl)-(R,R)-1,2-diaminocyclohexane, has been synthesized and characterized. The dimethyl derivatives, generated in situ from the well characterized dichloro zinc complexes (L¹)ZnCl₂ and (L²)ZnCl₂, where L² is N,N′-bis-(benzyl)-(R,R)-1,2-diaminocyclohexane, were employed as initiators for the ring opening polymerization (ROP) of rac-lactide (rac-LA). The complexes were found to be highly efficient initiators yielding the polylactide (PLA) with a narrow molecular weight distribution. The catalytic activity and heterotactic selectivity of the Zn(II) complexes were affected by the substituents on the phenyl groups of benzyl moieties in (R,R)-1,2-diaminocyclohexane. The dimethyl derivative of (L²)ZnCl₂ produced highly stereocontrolled PLA with P_r = 0.75 at −25 °C.     

Synthesis and characterization of fluorous (S)- and (R)-1-phenylethylamines that effect heat facilitated resolution of (±)-2-(8-carboxy-1-naphthylsulfinyl)benzoic acid via diastereomeric salt formation and study of their circular dichroism

Perfluoroalkyl- or nonafluoro-tert-butoxy-alkyl-substituted enantiopure amines having the structure PhCHCH₃(NR¹R²) [R¹ = H, CH₃; R² = (CH₂)₃C₈F₁₇, (CH₂)₂OC(CF₃)₃; R¹ = R² = (CH₂)₃C₈F₁₇, (CH₂)₂OC(CF₃)₃] are obtained in high yields, when (S)-(−)-1-phenylethylamine is reacted with readily accessible alkylating reagents or fluorous 2° amines (R¹ = H; R² = (CH₂)₃C₈F₁₇, (CH₂)₂OC(CF₃)₃) are methylated in a Leuckart-Wallach reaction. The solubility patterns of these novel chiral amines and their hydrochlorides are qualitatively described for a broad spectrum of solvents and the fluorous partition coefficients of the free bases are determined by GC. A novel method for the resolution of enantiomers is disclosed here, which involves the use a half-equivalent of the selected resolving agent in solvent water that displays low solubility for the crystalline diastereomeric salt(s) formed even at temperatures near to its boiling point. Compound (S)-(−)-PhCHCH₃[NH(CH₂)₃C₈F₁₇] is found to satisfy all the latter conditions and successfully used for the heat facilitated resolution of the title racemic acid. The circular dichroism (CD) spectra of six novel fluorous (S)-(−)-1-phenylethylamine derivatives are measured in ethanol, trifluoroethanol and hexafluoropropan-2-ol and discussed in detail.     

Radical mediated stereoselective synthesis of (4R,8R)-4,8-dimethyldecanal, an aggregation pheromone of Tribolium flour beetles

(4R,8R)-4,8-Dimethyldecanal, a common aggregation pheromone of Tribolium flour beetles, has been synthesized from (R)-2,3-O-isopropylideneglyceraldehyde in 11 steps and 7% overall yield. The key step in the synthesis is the highly diastereoselective chelation-controlled radical reaction of ethyl (4S,5R)-4-benzyloxy-5,6-(isopropylidenedioxy)-2-methylenehexanoate with ethyl (R)-5-iodo-3-methylpentanoate performed in the presence of 7 equiv of MgBr₂·OEt₂.     

Stereoselective synthesis of (R)-(+)-1-methoxyspirobrassinin, (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether and their enantiomers or diastereoisomers

Stereoselective synthesis of cruciferous indole phytoalexin (R)-(+)-1-methoxyspirobrassinin and its unnatural (S)-(−)-enantiomer was achieved by spirocyclization of 1-methoxybrassinin in the presence of (+)- and (−)-menthol and subsequent oxidation of the obtained menthyl ethers. Methanolysis of menthyl ethers in the presence of TFA afforded (2R,3R)-(−)-1-methoxyspirobrassinol methyl ether as well its unnatural (2S,3S)-, (2R,3S)-, and (2S,3R)-isomers.     

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura)

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of Spodoptera litura was carried out. Substrate was converted to three new terpenoids, (+)-(1R,2S)-10-hydroxyfenchol, (+)-(1R,2R,3S)-8-hydroxyfenchol and (−)-(1S,2S,6S)-6-exo-hydroxyfenchol, and one known terpenoid, (−)-(1R,2R,3R)-9-hydroxyfenchol. These structures were established by NMR, IR, specific rotation and mass spectral studies.     

Kinetics and mechanistic studies of the interaction of thiosulfate with cis-diaqua-bis[1-alkyl-2-(arylazo)imidazole]ruthenium(II) complexes

The nucleophilic substitution reaction of S₂O₃²⁻ with [Ru(HaaiR′)₂(OH₂)₂](ClO₄)₂ (1) [HaaiR′ = 1-alkyl-2-(phenylazo)imidazole] and [Ru(ClaaiR′)₂(OH₂)₂](ClO₄)₂ (2) [ClaaiR′ = 1-alkyl-2-(chlorophenylazo)imidazole] [where R′ = Me(a), Et(b) or Bz(c)] in acetonitrile–water (50% v/v) medium to yield Na₂[Ru(HaaiR′)₂(S₂O₃)₂] (3a, 3b or 3c) and Na₂[Ru(ClaaiR′)₂(S₂O₃)₂] (4a, 4b or 4c) has been studied. The products were characterized by microanalytical data and spectroscopic techniques (UV–Vis, NMR and mass spectroscopy). The reaction proceeds in two consecutive steps (A → B → C); each step follows first order kinetics with respect to each complex and S₂O₃²⁻, and the first step second order rate constant (k′₂) is greater than the second step one (k″₂). An increase in the π-acidity of the ligand increases the rate. Thermodynamic parameters, the standard enthalpy of activation (Δ^‡H⁰) and the standard entropy of activation (Δ^‡S⁰), have been calculated for both steps using the Eyring equation from variable temperature kinetic studies. The low Δ^‡H⁰ and large negative Δ^‡S⁰ values indicate an associative mode of activation for both aqua ligand substitution processes.     

Synthesis and spectroscopic characterization of enantiopure protected trans-4-amino-1-oxyl-2,2,6,6-tetramethyl piperidine-3-carboxylic acid (trans β-TOAC)

Enantiomerically pure (3R,4S) and (3S,4R) protected 4-amino-1-oxyl-2,2,6,6-tetramethylpiperidine-3-carboxylic acids were synthesized by reduction of the enamines resulting from the condensation of 3-carboxymethyl-1-oxyl-2,2,6,6-tetramethyl-4-piperidone with (R) or (S)-α-methylbenzylamine. While NaBH₃CN/CH₃COOH reduction gave predominantly a mixture of the two possible cis-diastereomers, the use of NaBH₄/(CH₃)₂CHCOOH resulted in a mixture of only one trans- and one cis-diastereomer. Removal of the chiral auxiliary from the separated diastereoisomers by hydrogenolysis and regeneration of the nitroxide radical gave the desired β-amino esters. The ESR spectrum of the (3R,4S)-enantiomer is also reported.     

Addition of tert-butylcuprate to (2S)-N-acyl-Δ-dehydroprolinates as a diastereoselective synthetic procedure for obtaining (2S,5S)-5-tert-butylproline

The synthesis of (2S,5S)-Boc-5-tert-butylproline ethyl ester via the addition of tert-butylcuprate to (2S)-N-Boc-Δ⁵-dehydroproline ethyl ester, formed from (2S)-N-Boc-5-methoxyproline ethyl ester, gives an excellent yield of 94% and a high diastereoselectivity (2S,5S):(2S,5R) 78:22. This synthesis opens up a new synthetic route to (2S,5S)-5-tert-butylproline, which is a useful, conformationally rigid, analogue of l-proline.     

Highly diastereoselective chemoenzymatic synthesis of (2′R)- and (2′S)-2′-deoxy[2′-H]guanosines

In an effort to develop an efficient synthetic method of highly diastereoselective (2′R)- and (2′S)-2′-deoxy[2′-²H]guanosines, chemoenzymatic conversion was investigated. The synthesis of (2′R > 98% de)-2′-deoxy[2′-²H]guanosine was achieved by biological transdeoxyribosylation using (2′R > 98% de)-2′-deoxy[2′-²H]uridine, 2,6-diaminopurine, and Enterobacter aerogenes AJ-11125, followed by treatment with adenosine deaminase. (2′S > 98% de)-2′-Deoxy[2′-²H]guanosine was synthesized from (2′S > 98% de)-2′-deoxy[2′-²H]uridine and 2,6-diaminopurine using thymidine phosphorylase and purine nucleoside phosphorylase instead of E. aerogenes AJ-11125.     

The enolate anions of chlorophylls a and b as ambident nucleophiles in oxidations with (−)- or (+)-(10-camphorsulfonyl)oxaziridine. Synthesis of 13(S/R)-hydroxychlorophylls a and b

The enolate anions of chlorophylls (Chl) are ambident nucleophiles that are of considerable organic chemical interest in relation to the theory of electron delocalization (aromaticity) and charge-transfer in large conjugated π-systems, as well as for their chemical reactivity. Under deaerated conditions, the (−)- and (+)-enantiomers of (10-camphorsulfonyl)oxaziridine (CSOAI) are effective oxidants for the enolate anions of Chl a and Chl b, when 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) serves as a base. In this study, the use of these sterically hindered reagents to hydroxylate Chl a and Chl b is described for the first time. The total yield of 13²(S/R)-HO-Chl a was 71 and 90% for the oxidations of Chl a with (−)-CSOAI and (+)-CSOAI, respectively. Chl b, however, behaved clearly differently from Chl a. The total yield of 13²(S/R)-HO-Chl b was 40% in the oxidation with (−)-CSOAI and 60% in the reaction with (+)-CSOAI. A competing side-reaction, which resulted in the 15²-methyl, 17³-phytyl ester of Mg-15¹(S/R)-unstable rhodin, was found to lower the yields of the desired main products. The formation of the side-products was largely avoided and the yield of 13²(S/R)-HO-Chl b was improved by increasing the volume of hexane and using phosphate buffer in the first step of the work-up. With (−)-CSOAI, a 94% diastereomeric excess (de) was achieved for 13²(R)-HO-Chl a, whereas the de for 13²(R)-HO-Chl b was 66%. With (+)-CSOAI, the de was 10% for 13²(R)-HO-Chl a and 8% for 13²(R)-HO-Chl b. The results were interpreted in terms of a nucleophilic reaction mechanism, kinetically controlled by steric hindrance, originating on the one hand in the 17-propionate phytyl ester side-chain, protruding over the isocyclic ring E of the Chl enolate ion, and on the other hand in the bulky camphorsulfonyl unit of CSOAI. Possible reasons for the different results from the Chl b oxidations as compared with those of the Chl a oxidations are discussed. Comparison of the differences in the NMR δ_C-values between 13²(S)- and 13²(R)-HO-Chl a as well as those between 13²(S)- and 13²(R)-HO-Chl b, indicated that the change of stereochemical configuration at C-13² induces only slight differences in the δ_C-values. Of special interest are the δ_C-values of C-13², which are at ca. 91 ppm for the a- and b-series diastereomers. This carbon is deshielded by ca. 25 ppm relative to the C-13² of 13²(R)-Chl a (δ_C=65.5). Owing to this, ¹³C NMR spectroscopy is a good method to distinguish the 13²-hydroxylated chlorophylls from the intact, naturally occurring chlorophylls.     

Chiral self-assembly of triorganotin complexes: Syntheses, characterization, crystal structures and antitumor activity of organotin(IV) complexes containing (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid ligands

Six new chiral triorganotin(IV) complexes, {(R₃Sn)₂[C₃H₆(COO)₂]}_n (R = Me: 1; Bu: 2), {(R₃Sn)₂[C₄H₈(COO)₂]}_n (R = Me: 3; Bu: 4), and {(R₃Sn)₂[C₂H₄O(COO)₂]}_n (R = Me: 5; Bu: 6) have been prepared by treatment of (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid, with the corresponding R₃SnCl (R = Me, Bu) and sodium ethoxide in methanol. All the complexes were characterized by elemental analysis, FT-IR, NMR (¹H, ¹³C, ¹¹⁹Sn) spectroscopy and TGA. Except for 3, all of the complexes were also characterized by X-ray crystallography. The structural analyses reveal that complexes 1 and 5 have 2D network structures in which (R)-(+)-methylsuccinic acid and l-(−)-malic acid act as tetradentate ligands coordinated to trimethyltin(IV) ions. Complexes 2 and 4 have 3D metal-organic framework structures in which the deprotoned acids serve as tetradentate ligands. Complex 6 adopts a 1D zigzag chain structure and forms a 2D supramolecular framework through intermolecular C-H?O interactions. In addition, the antitumor activities of complexes 1-6 have been studied. We also have measured the specific rotation of the chiral dicarboxylic acids and the organotin derivatives.     

Deracemisation of β-hydroxy esters using immobilised whole cells of Candida parapsilosis ATCC 7330: substrate specificity and mechanistic investigation

Deracemisation of aryl substituted β-hydroxy esters by immobilised whole cells of Candida parapsilosis ATCC 7330 gave >99% ee and up to 75% yield of their corresponding (S)-enantiomers. Mechanistic investigation of the deracemisation reaction carried out using a deuterated substrate, ethyl 3-deutero-3-hydroxy-3-phenyl propanoate revealed that while the (S)-enantiomer remains unreacted the (R)-enantiomer undergoes enantioselective oxidation to its corresponding ketoester, which on complementary enantiospecific reduction gives the (S)-enantiomer in high yield and % ee.     

Alkyl and dialkylammonium tetrafluoroborate catalyzed cis-trans isomerization of 1,3,5-trimethyl-1,3,5-triphenylcyclotrisiloxane

Alkyl and dialkylammonium tetrafluoroborate promoted cis-trans isomerization of 1,3,5-trimethyl-1,3,5-triphenylcyclotrisiloxane (1) in DMSO-d₆ were studied. The isomerization equilibrium constant K are within the range of 3.74-3.30 from 22 to 47 °C. Thermodynamic parameters of ΔH° and ΔS° for the isomerization were −0.95 kcal/mol and −0.59 cal/mol-K respectively. The isomerization rate is first order in [cis-1] and second order in [R_nNH_4−nBF₄]. Both components of R_nNH_4−n⁺ and BF₄⁻ are essential for the catalytic cis-trans isomerization. The catalytic strength follows the decreasing order of ⁺H₃N(CH₂)₆NH₃⁺>n-C₈H₁₇NH₃⁺>n-C₁₆H₃₃NH₃⁺>Me₃CNH₃⁺>PhCH₂NH₃⁺>Et₂NH₂⁺?Ph₂CHNH₃⁺, Et₃NH⁺. Inversion region was observed in the plot of ln(k_f/T) versus (1/T) with the ceiling located at around 38 °C. The positive activation enthalpy of 9 kcal/mol was estimated at 22-32 °C. The activation enthalpy turns to be slightly negative at T>38 °C.     

X-ray structure and multinuclear NMR studies of platinum(II) complexes with 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one

New dichloride platinum(II) complexes with 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO) have been synthesized and characterized by thermal analysis, infrared and ¹H, ¹³C, ¹⁵N, ¹⁹⁵Pt NMR spectroscopy. X-ray crystal structures of cis-PtCl₂(NH₃)(HmtpO) (1) and cis-PtCl₂(HmtpO)₂ · 4H₂O (2b) were determined to R = 0.0332 and R = 0.0802, respectively. In both complexes the Pt(II) ions have a square-planar geometry with two adjacent corners being occupied by two nitrogens of HmtpO molecules for 2b or NH₃ and HmtpO molecules for 1, whereas the remaining adjacent corners are occupied by two chloride anions. Spectroscopic data confirm the square planar geometry with N(3) bonded HmtpO, S-bonded dimethylsulfoxide and two trans chloride anions for trans-PtCl₂(dmso) · 4H₂O (3).     

A linear Cu-Gd-Cu-Gd complex derived from the assembly reaction of [NaCuH3L] and [Gd(thd)3(H2O)2] (H3L = meso-1,2-diphenyl-1-(2-oxybenzamido)-2-(2-oxy-3-ethoxybenzylideneamino)ethane and Hthd = 2,2,6,6-tetra-methyl-3,5-heptanedione)

A linear tetranuclear Cu^II-Gd^III-Cu^II-Gd^III complex [Cu^IIL^dpen(meso)Gd^III(thd)₂(H₂O)]₂ was synthesized from the reaction of [NaCu^IIL^dpen(meso)(DMF)] with [Gd^III(thd)₃(H₂O)₂], and the structures and magnetic properties were investigated, where H₃L^dpen(meso) = meso-1,2-diphenyl-1-(2-hydroxybenzamido)-2-(2-hydroxy-3-ethoxybenzylideneamino)ethane and Hthd = 2,2,6,6-tetramethyl-3,5-heptanedione. The Cu^II complex component [NaCu^IIL^dpen(meso)(DMF)] has a one-dimensional (1D) chain structure, in which the Na⁺ ion is coordinated by two phenoxo and an ethoxy oxygen atoms of a Cu^II complex and an amido oxygen atom of the adjacent Cu^II unit to produce the 1D structure, in which the diphenylethylenediamine moieties have the array of {(1R,2S)-Na-(1S,2R)}_1∞. The assembly reaction of the Cu^II and Gd^III components gave a linear complex with the array of Cu(1)-Gd(1)-Cu(2)-Gd(2), in which two diphenylethylenediamine moieties have the same chirality of (1R,2S)-(1R,2S) or (1S,2R)-(1S,2R). Two linear Cu(1)-Gd(1)-Cu(2)-Gd(2) units are linked by hydrogen bonds through two water molecules to give a cyclic structure with a center of symmetry. The temperature dependence of the magnetic susceptibilities and field-dependent magnetization revealed the ferromagnetic interaction between the Cu^II and Gd^III ions within the linear chain.     

Predicting the R/S absolute configuration in asymmetric bifunctional catalysis (ABC)

A predictive model for assigning the R/S absolute configuration in chiral Lewis base-dependent asymmetric bifunctional catalysis (ABC) has been developed. Chiral Lewis base (LB^∗)-dependent ABC abolishes the chiral Lewis acid (LA^∗) component as the stereochemical determining factor in asymmetric catalysis. By correlating the constant LB^∗ chirality to the facial preference for the LA^∗-bound carbonyl group for nucleophile delivery, the R/S absolute configuration of the products can be predicted a priori.     

A new titanate/(+)-(1R,2S)-cis-1-amino-2-indanol system for the asymmetric synthesis of (S)-tenatoprazole

Tenatoprazole, a substituted imidazopyridinyl derivative, is an irreversible proton pump inhibitor (PPI), which is used for the prevention and treatment of gastric acid-related diseases. A new highly efficient asymmetric oxidation using cumene hydroperoxide (CHP) as the oxidant in the presence of titanium tetraisopropoxide (Ti(OiPr)₄) and (+)-(1R,2S)-cis-1-amino-2-indanol, in a polar aprotic solvent at 0-20 °C, has been developed to prepare tenatoprazole with an enantiomeric excess of >99%, a chemoselectivity of >90% and a chemical yield of >90% from the corresponding sulfide. This procedure was successfully implemented on scales ranging from 100 mg to multiple kilograms. Detailed studies of the parameters controlling purity and yield for this reaction are presented.     

Chemomicrobial synthesis of (R)- and (S)-lavandulol

(R)- and (S)-Lavandulol are important compounds in the cosmetics industry and in pheromone research. We have developed syntheses of (R)- and (S)-lavandulol from (S)- and (R)-limonene, respectively, by microbial Baeyer-Villiger oxidation of the intermediate unsaturated hydroxy ketone. It has been found that the same strain of Acremonium roseum can be successfully used in the key step of the synthesis of both enantiomers of lavandulol.     

Synthesis of platinum-iodo-alkyl/aryl complexes in ligand-exchange reactions: Determination of the structure of Pt{(S,S)-bdpp}(X)I complexes (X = Me, I) by X-ray crystallography

Pt{(S,S)-bdpp}(R)I (bdpp = 2,4-bis(diphenylphosphino)pentane; R = Me, Ph, Bz, 2-Tioph) complexes were formed in alkyl/aryl ligand - iodide ligand-exchange reactions by reacting the corresponding Pt{(S,S)-bdpp}R₂ complexes with methyl iodide. The Pt{(S,S)-bdpp}(Me)I complex was isolated and fully characterised. The influence of the X ligand on the platinum-bdpp chelate conformation was investigated in Pt{(S,S)-bdpp}(X)I (X = I, SnCl₃, Me) complex series by means of X-ray crystallography.     

Ru-catalyzed enantioselective preparation of methyl (R)-o-chloromandelate and its application in the synthesis of (S)-Clopidogrel

The preparation of methyl (R)-o-chloromandelate via Ru-catalyzed asymmetric hydrogenation and transfer hydrogenation was investigated. With Ru-(R,R)-2,4,6-triisopropyl C₆H₂SO₂-DPEN as the catalyst and HCOOH-Et₃N azeotrope as the hydrogen donor, up to 92% ee was obtained in an optional condition. The synthesis of (S)-Clopidogrel was also studied.