Demethoxycarbonylation and oxidation of 13(S/R)-hydroxy-chlorophyll a to 13-demethoxycarbonyl-13-oxo-chlorophyll a and Mg-purpurin-18 phytyl ester

The conversion of 13²(S/R)-hydroxy-chlorophyll (Chl) a to 13²-demethoxycarbonyl-13²-oxo-Chl a in a yield of 40%, utilizing a simple pyrolysis technique, is described. About 10% of the phytyl ester of Mg-purpurin-18 was formed as a side product. The completely assigned ¹H and ¹³C NMR spectra are presented for 13²-demethoxycarbonyl-13²-oxo-Chl a and a likely mechanism for its formation is proposed. A slight extension of this mechanism also explains the formation of the Mg-purpurin-18 side product. The proposed mechanism has several features comparable with those previously suggested for the allomerization of 13²(R/S)-Chl a. Attempts to apply the same pyrolysis method to prepare 13²-demethoxycarbonyl-13²-oxo-Chl b from 13²(S/R)-hydroxy-Chl b were unsuccessful.     

Electronic structure of the enolate anion of chlorophyll b

The enolate anion of chlorophyll b (Chl b) has been synthesized under deoxygenated conditions and its electronic structure characterized for the first time by ¹H NMR and electronic absorption spectroscopy. The formation of the enolate anion caused a marked perturbation to the 18 π-electron [18]diazaannulene aromatic pathway of Chl b. This perturbation appeared as noticeable upfield shifts, exceeding 1 ppm, for the meso-CH protons of the Chl b enolate anion. Nevertheless, the enolate anion remained diatropic, maintaining aromaticity in its delocalized macrocycle.     

C13-Methylation of methyl pheophorbide a and stereoselective preparation of methyl (13R)-methylpyropheophorbide a

The (13²R)-methoxycarbonyl group of methyl pheophorbide a, one of the chlorophyll-a derivatives, was converted to a methyl group through methylation at the C13² position followed by removal of the methoxycarbonyl group. The methylation of the C13² carboanion gave a 4:1 mixture of methyl 13²-methyl-pheophorbide a and its 13²-epimer. The successive pyrolysis of the major methylated product afforded methyl (13²R)-methyl-pyropheophorbide a with a small amount of its (13²S)-epimer. The substitution effects at the C13² position including stereochemistry were discussed on the basis of 1D/2D NMR, UV–vis absorption, and circular dichroism spectroscopic analyses as well as molecular modeling simulation.     

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.     

Synthesis of (2S,3R)- and (2S,3S)-[3-H1]-proline via highly stereoselective hydrolysis of a silyl enol ether

A straightforward synthesis of (2S)-[3,3-²H₂]-proline 1c and (2S,3R)- and (2S,3S)-[3-²H₁]-proline, 1b and 1a, respectively, has been devised. The key step of the route to the latter compounds involves highly stereoselective hydrolysis of the silyl enol ethers 3 and 3a, respectively, with protonation (deuteriation) from the re-face of the silyl enol ether.     

Assignment of the relative and absolute configurations of acyclic secondary 1,2-diols

The NMR profiles (¹³C-δ, ¹H-δ, ¹H(OH)-δ, and ³J_H,H) of syn- and anti-diols—3a,b in achiral solvents were found to be very similar to each other. Contrarily, their Δδ (Δδ=δ_(R,R)-2−δ_(S,S)-2) behaviors in chiral bidentate NMR solvent (R,R)- and (S,S)-BMBA-p-Me (2) were found to be significantly different. On the basis of this NMR characteristic, a method has been developed to predict both the relative and absolute configurations of acyclic secondary 1,2-diols.     

Hydridic reactivity of W(CO)(H)(NO)(PMe3)3 - Dihydrogen bonding and H2 formation with protic donors

The hydridic reactivity of the complex W(CO)(H)(NO)(PMe₃)₃ (1) was investigated applying a variety of protic donors. Formation of organyloxide complexes W(CO)(NO)(PMe₃)₃(OR) (R = C₆H₅ (2), 3,4,5-Me₃C₆H₂ (3), CF₃CH₂ (4), C₆H₅CH₂ (5), Me (6) and iPr (7)) and H₂ evolution was observed. The reactions of 1 accelerated with increasing acidity of the protic donor: Me₂CHOH (pK_a = 17) < MeOH (pK_a = 15.5) < C₆H₅CH₂OH (pK_a = 15) < CF₃CH₂OH (pK_a = 12.4) < C₆H₂Me₃OH (pK_a = 10.6) < C₆H₅OH (pK_a = 10).Regioselective hydrogen bonding of 1 was probed with two of the protic donors furnishing equilibrium formation of the dihydrogen bonded complexes ROH···HW(CO)(NO)(PMe₃)₃ (R = 3,4,5-Me₃C₆H_2,3a and iPr, 7a) and the O_NO hydrogen bonded species ROH···ONW(CO)(H)(PMe₃)₃ (R = C₆H₂Me_3,3b and iPr, 7b) which were studied in hexane and d₈-toluene solutions using variable temperature IR and NMR spectroscopy. Quantitative IR experiments at low temperatures using 3,4,5-trimethylphenol (TMP) confirmed the two types of competitive equilibria: dihydrogen bonding to give 3a (ΔH₁ = −5.8 ± 0.4 kcal/mol and ΔS₁ = −15.3 ± 1.4 e.u.) and hydrogen bonding to give 3b (ΔH₂ = −2.8 ± 0.1 kcal/mol and ΔS₂ = −5.8 ± 0.3 e.u.). Additional data for the hydrogen bonded complexes 3a,b and 7a,b were determined via NMR titrations in d₈-toluene from the equilibrium constants K_(Δδ) and K_(ΔR1) measuring either changes in the chemical shifts of H_W(_Δδ) or the excess relaxation rates of H_W (ΔR₁) (3a,b: ΔH_(Δδ) = −0.8 ± 0.1 kcal/mol; ΔS_(Δδ) = −1.4 ± 0.3 e.u. and ΔH_(ΔR1) = −5.8 ± 0.4 kcal/mol; ΔS_(ΔR1) = −22.9 ± 1.9 e.u) (7a,b: ΔH_(Δδ) = −2.3 ± 0.2 kcal/mol; ΔS_(Δδ) = −11.7 ± 0.9 e.u. and ΔH_(ΔR1) = −2.9 ± 0.2 kcal/mol; ΔS_(ΔR1) = −14.6 ± 1.0 e.u). Dihydrogen bonding distances of 1.9 Å and 2.1 Å were derived for 3a and 7a from the NMR excess relaxation rate measurements of H_W in d₈-toluene. An X-ray diffraction study was carried out on compound 2.     

Hydrothermal synthesis, thermal, structural, spectroscopic and magnetic studies of the Mn5−xCox(HPO4)2(PO4)2(H2O)4 (x=1.25, 2, 2.5 and 3) finite solid solution

The Mn_5−xCo_x(HPO₄)₂(PO₄)₂(H₂O)₄ (x=1.25, 2, 2.5, 3) finite solid solution has been synthesized by mild hydrothermal conditions under autogeneous pressure. The phases crystallize in the C2/c space group with Z=4, belonging to the monoclinic system. The unit-cell parameters obtained from single crystal X-ray diffraction are: a=17.525(1), b=9.0535(6), c=9.4517(7) Å, β=96.633(5) ° being R1=0.0436, wR2=0.0454 for Mn75Co25; a=17.444(2), b=9.0093(9), c=9.400(1) Å, β=96.76(1) ° being R1=0.0381, wR2=0.0490 for Mn60Co40; a=17.433(2), b=8.9989(9), c=9.405(1) Å, β=96.662(9) ° being R1=0.0438, wR2=0.0515 for Mn50Co50 and a=17.4257(9), b=8.9869(5), c=9.3935(5) Å, β=96.685(4) ° being R1=0.0296, wR2=0.0460 for Mn40Co60. The structure consists of a three dimensional network formed by octahedral pentameric entities (Mn,Co)₅O₁₆(H₂O)₆ sharing vertices with the (PO₄)³⁻ and (HPO₄)²⁻ tetrahedra. The limit of thermal stability of these compounds is, approximately, 165 °C, near to this mean temperature the phases loose their water content in two successive steps. IR spectra show the characteristic bands of the water molecules and the phosphate and hydrogen-phosphate oxoanions. The diffuse reflectance spectra are consistent with the presence of MO₆ octahedra environments in slightly distorted octahedral geometry, except for the M(3)O₆ octahedron which presents a remarkable distortion and so a higher Dq parameter. The mean value for the Dq and B-Racah parameter for the M(1),(2)O₆ octahedra is 685 and 850 cm⁻¹, respectively. These parameters for the most distorted M(3)O₆ polyhedron are 825 and 880 cm⁻¹, respectively. The four phases exhibit antiferromagnetic couplings as the major magnetic interactions. However, a small spin canting phenomenon is observed at low temperatures for the two phases with major content in the anisotropic-Co(II) cation.     

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.     

Synthesis of trimethyl (2S,3R)- and (2R,3R)-[2-H1]-homocitrates and the corresponding dimethyl ester lactones—towards elucidating the stereochemistry of the reaction catalysed by homocitrate synthase and by the Nif-V protein

Trimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitrates, 10b and 10c respectively, and dimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitric lactones, 11b and 11c respectively, have been synthesised from shikimic acid and [2-²H]-shikimic acid by a route which defines the stereochemistry of the two chiral centres in each compound. The NMR spectra of these products will enable the stereochemistry of the biological reaction catalysed by homocitrate synthase and by the protein from the nifV gene to be elucidated.     

Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from d-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by intramolecular reductive amination of amino-aldehyde.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Asymmetric synthesis of the marine alkaloid (−)-(S)-nakinadine C

The first asymmetric synthesis of the marine alkaloid (−)-(S)-nakinadine C is described. This synthesis employs the conjugate addition of lithium dibenzylamide to an N-α-phenylacryloyl SuperQuat derivative followed by diastereoselective protonation of the intermediate enolate using 2-pyridone as the key step to introduce the stereochemistry. (−)-(S)-Nakinadine C was isolated in 13% yield over 9 steps from commercially available atropic acid, 98:2 dr [(Z):(E) ratio] and >99% ee.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.     

Solid-state structure determination and solution-state NMR characterization of the (2R,4R)/(2S,4S)- and (2R,4S)/(2S,4R)-diastereomers of the agricultural fungicide propiconazole,the (2R,4S)/(2S,4R)-symmetrical triazole constitutional isomer,and a ditriazole analogue

Single-crystal X-ray diffraction analysis was used to determine the structure of a racemic diastereomer of the agricultural fungicide propiconazole [1-(2-(2,4-dichlorophenyl)-4-n-propyl-1,3-dioxolane-2-yl-methyl)-1-H-1,2,4-triazole] and of two by-products (a symmetrical 1,3,4-triazole racemic-constitutional isomer and a propiconazole ditriazole analogue). All three crystalline racemic-diastereomers had (2R,4S)/(2S,4R)-stereochemistry in which then-propyl group was observed in atrans-to-phenyl disposition. Propiconazole (2R,4S)/(2S,4R)-diastereomer gives crystals belonging to the monoclinic space group P2₁,/a, and, at 293 K,a=8.1192(3),b=18.9769(6),c=10.7137(4) å,Β=99.765(3)?,V=1626.8(1) å³, Z=4,R(F)=0.060, andR _w(F)=0.058. The constitutional isomer by-product (2R,4S)/(2S,4R)-1-(2-(2,4-dichlorophenyl)-4-n-pro-pyl-1,3-dioxolane-2-yl-methyl)-1-H-1,3,4-triazole gives crystals belonging to the monoclinic space group P2₁/n, and, at 293 K,a=11.1763(6),b=10.7716(4),c=14.5804(8) å,Β=107.445(4)?,V=1674.6(1) å³, Z=4,R(F)=0.043, andR _w(F)=0.043. The ditriazole byproduct (2R,4S)/(2S,4R)-1-(2-(2-chloro-4-(1,2,4-triazole-1-yl)phenyl)-4-n-propyl-1,3-dioxolane-2-yl-methyl)-1-H-1,2,4-triazole gives crystals belonging to the triclinic space groupP¯ 1, and, at 193 K,a=5.3329(8),b=8.3738(7),c=20.240(2) å, α=84.213(6)?,Β=87.20(1)?,γ=86.23(1)?,V=896.5(2) å³, Z=2,R(F)=0.046, andR _w(F)=0.051. The presence of both propiconazole (2R.4S)- and (2S,4R)-enantiomers enables the formation of a crystalline racemic modification, while the diastereomeric propiconazole (2R,4R)- and (2S,4S)-enantiomers are viscous oils. In the absence of its enantiomorphic partner, the propiconazole (2R,4S)- or (2S,4R)-enantiomers remain as viscous oils rather than form chiral crystals.     

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.     

Stereoselective synthesis of (E)-N,N-diethyl-3-(imidazo[1,2-a]pyrid-2-yl)-2-(phenylsulfonyl)propenamide

The title compound, gem-amidovinylsulfone 3, was synthesized stereoselectively by aldolic condensation of N,N-diethylphenylsulfonylacetamide 1 on imidazo[1,2-a]pyridine-2-carbaldehyde 2 adding Et₃N at the end. The X-ray crystal structure of 3 [C₂₀H₂₁N₃O₃S: M_r=383.5, monoclinic, P2₁, a=8.191(4) Å, b=21.132(2) Å, c=11.752(1) Å, β=96.40(2)°, V=2022(1) Å³, Z=4 (two molecules per asymmetric unit), D_calc=1.260 g cm⁻³, λ(Mo Kα)=0.71073 Å, μ=0.184 mm⁻¹, F(000)=808, T=293(2)K, R=0.059 for 5105 observed reflections with I≥2σ(I)] was determined, and confirmed the (E) configuration.     

Synthesis of (S)-, (R)-, and (rac)-2-amino-3,3-bis(4-fluorophenyl)propanoic acids and an evaluation of the DPP IV inhibitory activity of Denagliptin diastereomers

The non-proteinogenic amino acid (2S)-2-amino-3,3-bis(4-fluorophenyl)propanoic acid [(S)-1] is a key intermediate required for the synthesis of Denagliptin (2a). Denagliptin is a dipeptidyl peptidase IV (DPP IV) inhibitor that is being developed for the treatment of type-2 diabetes mellitus. A diastereoselective, cost-efficient synthetic procedure for (S)-1 was developed by alkylating a Ni(II) glycine equivalent derived from (S)-2-[(N-benzylprolyl) amino] benzophenone [(S)-BPB]. The alkylated product was then decomposed to isolate the target amino acid (S)-1 (ee >99%) and ligand (S)-BPB, which can be reused in subsequent reactions. The enantiomer (R)-1 and racemate (rac)-1 were synthesized from their corresponding Ni(II) glycine equivalents. Denagliptin diastereomers (2), derived from the key intermediates (S)-1, (R)-1, and (rac)-1 were synthesized, and their dipeptidyl peptidase IV inhibitory activities were investigated. These findings are important in the design and synthesis of DPP IV inhibitors.     

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.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.