(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸的合成

以(R)-(+)-α-甲基苄胺为原料,依次经缩合,Diels-Alder反应,还原,Cbz-保护和水解反应,合成了抗丙肝新药HCV NS3/4A蛋白酶拟肽类抑制剂的重要中间体——(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸,总收率66%,其结构经1H NMR和ESI-MS确证。     

A novel synthetic approach to very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via tert-butyl trans-[(4S)-Methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate as a key intermediate

This contribution describes a novel synthetic approach to very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1) via tert-butyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate. The synthesis, which includes n-Bu?NSO?H that catalyzed basic etherification of 12 and iodine-mediated cyclization to provide the 2,4-disubstituted pyrrolidine frame of 2b, is designed to utilize trans-4-hydroxycyclohexanecarboxylic acid (9) as a commercially available starting material.     

Synthesis of trimethyl (2S,3R)- and (2R,3R)-[2-2H1]-homocitrates and dimethyl (2S,3R)- and (2R,3R)-[2-2H1]-homocitrate lactones-an assay for the stereochemical outcome of the reaction catalysed both by homocitrate synthase and by the Nif-V protein

Trimethyl (3R)-homocitrate 17, trimethyl (2S,3R)-[2-2H1]-homocitrate 17a and (2R,3R)-[2-2H1]-homocitrate 17b, as well as dimethyl (3R)-homocitrate lactone 18, (2S,3R)-[2-2H1]-homocitric lactone 18a and (2R,3R)-[2-2H1]-homocitric lactone 18b have been synthesised. D-quinic acid 12 was used as the source of the (3R)-centre in the unlabelled target compounds 17 and 18. (2)-Shikimic acid 19 and the (2)-[2-2H]-shikimic acid derivative 32 respectively were used in the synthesis of the labelled compounds. In the latter syntheses, Sharpless directed epoxidation of the olefin in the 5-deoxy ester diols 23 and 35 ensured a reaction from the same face as the allylic and homoallylic alcohols, and the reduction of the protected epoxides 25 and 37 ensured that the label was introduced in a stereoselective manner. The 1H NMR spectra of the labelled products present an assay for the stereochemistry of the biological reactions catalysed by homocitrate synthase and by the protein from the nifV gene.     

Synthesis of (2S,3R)-[3',3',3'-2H3]-valine and (2S,3S)-4-fluorovaline

A new synthesis of (2S,3R)-[3',3',3'-2H3]-valine has been completed and (2S,3S)-4-fluorovaline has been synthesised for the first time. Both compounds have been prepared by routes involving stereoselective addition to the (S)-pyroglutamate derivative and are available for studies in several areas of bio-organic chemistry.     

Improved preparation of (1S,3’R,4’S,5’S,6’R)-5-chloro-6-[(4-ethylphenyl)methyl]-3’,4’,5’,6’-tetrahydro-6’-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2’-[2H]pyran]-3’,4’,5’-triol

A convenient approach for the preparation of(1S,3’R.4’S,5’S,6’R)-5-chloro-6-[(4-ethylphenyl)methyl]- 3’,4’,5’,6’-tetrahydro-6’-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2’-[2H]pyran]-3’,4’,5’-triol is developed. The targeted compound was synthesized from 2-bromo-4-methylbenzoic acid in nine steps and the isomers of undesired ortho-products were avoided during the preparation.     

Synthesis of 1-[6-Fluoro-(2S)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2- ethanediol and 1-[6-Fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]- (1R)-1,2-ethanediol

Benzopyran compounds possess diverse pharmacological properties such as β-blockade, anticonvulsant and antimicrobial.[1,2] Our interest has been focused on the synthesis of 1-[6-Fluoro-2S]-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol (6) and 1-[6-fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol (7) which are particularly convenient precursor to (S,R,R,R)-NE (8). 8 containing four asymmetrical carbon atoms was reported to be the most active isomer.[3] Chandrasekhar[4] has reported on the synthesis of 8. The key step to synthesize this compound is to obtain the chiral chromanone 6 and 7. 6 was accomplished in 8 steps by the Clasien rearrangement and a one-pot Sharpless asymmetric epoxidation, but the compound 7 was accomplished in 10 steps. Johannes[5] used Zr-catalytic kinetic resolution of allylic ethers and Mo-catalyzed chromene formation to synthesize 8 in 14 steps. However both of the methods request many synthetic steps and expensive reagents.     

1-(3,5-二甲基苯基)-1-[(1S,4S)-1,7,7-三甲基双环[2.2.1]庚烷-2-基]肼的合成工艺改进

以3,5-二甲基苯胺和2-莰酮为起始原料,在微波促进下,经缩合反应制得N-(3,5-二甲基苯基)-1-(1S,4S)-1,7,7-三甲基二环[2.2.1]庚烷-2-亚胺(1);1经硼氢化钠还原后再与羟胺-O-磺酸经胺化反应合成了1-(3,5-二甲基苯基)-1-[(1S,4S)-1,7,7-三甲基双环[2.2.1]庚烷-2-基]肼,总收率70.4%,其结构经1H NMR和ESI-MS确证。     

Cluster oxalate complexes [M3(mu3-Q)(mu2-Q2)3(C2O4)3]2- and [Mo3(mu3-Q)(mu2-Q)3(C2O4)3(H2O)3]2- (M = Mo, W; Q = S, Se): mechanochemical synthesis and crystal structure

Mechanochemical reaction of cluster coordination polymers 1infinity[M3Q7Br4] (M = Mo, W; Q = S, Se) with solid K2C2O4 leads to cluster core excision with the formation of anionic complexes [M3Q7(C2O4)3]2-. Extraction of the reaction mixture with water followed by crystallization gives crystalline K2[M3Q7(C2O4)3].0.5KBr.nH2O (M = Mo, Q = S, n = 3 (1); M = Mo, Q = Se, n = 4 (2); M = W, Q = S, n = 5 (3)). Cs2[Mo3S7(C2O4)3].0.5CsCl.3.5H2O (4) and (Et4N)1.5H0.5K{[Mo3S7(C2O4)3]Br}.2H2O (5) were also prepared. Close Q...Br contacts result in the formation of ionic triples {[M3Q7(C2O4)3](2)Br}5- in 1-4 and the 1:1 adduct {[Mo3S7(C2O4)3]Br}3- in 5. Treatment of 1 or 2 with PPh(3) leads to chalcogen abstraction with the formation of [Mo3(mu3-Q)(mu2-Q)3(C2O4)3(H2O)3]2-, isolated as (Ph4P)2[Mo3(mu3-S)(mu2-S)3(C2O4)3(H2O)3].11H2O (6) and (Ph4P2[Mo3(mu3-Se)(mu2-Se)3(C2O4)3(H2O)3].8.5H2O.0.5C2H5OH (7). All compounds were characterized by X-ray structure analysis. IR, Raman, electronic, and 77Se NMR spectra are also reported. Thermal decomposition of 1-3 was studied by thermogravimetry.     

Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4- triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]- 3(2H,4H)-1,2,4-triazolone and its analogs

A new route for the synthesis of the optically active antifungal azole TAK-187, 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4 - triazolone, was established. The key synthetic intermediate, 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8), was prepared starting from the esters (11a, b) of (S)-lactic acid in a stereocontrolled manner. This optically active propiophenone derivative 8 was converted to the one carbon-elongated (1R,2S)-diol 7, which was then reacted with 1H-1,2,4-triazole to yield TAK-187. This newly developed route was applied to the synthesis of the analogs (25a, b--28a, b) containing an imidazolone or imidazolidinone nucleus.     

A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via reductive etherification

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.     

Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide).

The enantiomers of 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid [(+/-)-1, rebamipide, OPC-12759], a new antiulcer agent that enhances mucosal resistance, were synthesized from optically active alpha-amino acid derivatives of 2(1H)-quinolinone. The key intermediates, alpha-amino acid derivatives, were prepared by asymmetric synthesis and optical resolution. The (+)-1 was about 1.7 times as potent as the (-)-isomer in antiulcer activity against ethanol-induced gastric ulcers.     

First characterization of the ammine-ammonium complex [(NH4(NH3)4)2(mu-NH3)2]2+ in the crystal structure of [NH4(NH3)4][B(C6H5)4].NH3 and the [NH4(NH3)4]+ complex in [NH4(NH3)4][Ca(NH3)7]As3S6.2NH3 and [NH4(NH3)4][Ba(NH3)8]As3S6.NH3

The compound [NH4(NH3)4][B(C6H5)4].NH3 (1) was prepared by the reaction of NaB(C(6)H(5))(4) with a proton-charged ion-exchange resin in liquid ammonia. [NH(4)(NH(3))(4)][Ca(NH(3))(7)]As(3)S(6).2NH(3) (2) and [NH4(NH3)4][Ba(NH3)8]As3S6.NH3 (3) were synthesized by reduction of As(4)S(4) with Ca and Ba in liquid ammonia. All ammoniates were characterized by low-temperature single-crystal X-ray structure analysis. They were found to contain the ammine-ammonium complex with the maximal possible number of coordinating ammonia molecules, the [NH4(NH3)4]+ ion. 1 contains a special dimer, the [(NH4(NH3)4)2(mu-NH3)2]2+ ion, which is formed by two[NH4(NH3)4]+ ions linked by two ammonia molecules. The H(3)N-H...N hydrogen bonds in all three compounds range from 1.82 to 2.20 A (DHA = Donor-H...Acceptor angles: 156-178 degrees). In 2 and 3, additional H(2)N-H...S bonds to the thioanions are observed, ranging between 2.49 and 3.00 A (DHA angles: 120-175 degrees). Two parallel phenyl rings of the [B(C(6)H(5))(4)](-) anion in 1 form a pi...pi hydrogen bond (C...C distance, 3.38 A; DHA angles, 82 degrees), leading to a dimeric [B(C6H5)4]2(2-) ion.     

Solvent- and temperature-controlled in situ ligand reactions mediated by Cu(II) and 3'-[(E)-{[(1S,2S)-2-aminocyclohexyl]imino}methyl]-4'-hydroxy-4-biphenylcarboxlic acid

Three new compounds, CuL, CuL', and Cu(2)O(2)L'(2) (H(2)L = 3'-[(E)-{[(1S,2S)-2-aminocyclohexyl]imino}methyl]-4'-hydroxy-4-biphenylcarboxlic acid, H(2)L' = 3'-[(E)-{[(1S,2S)-2-aminocyclohexyl]imino}methyl]-4'-hydroxy-5'-nitro-4-biphenylcarboxlic acid, H(2)L' = 3'-(N,N-dimethylamino methyl)-4'-hydroxy-4-biphenylcarboxlic acid), were selectively synthesized through a controlled in situ ligand reaction system mediated by copper(II) nitrate and H(2)L. Selective nitration was achieved by using different solvent mixtures under relatively mild conditions, and an interesting and economical reductive amination system in DMF/EtOH/H(2) O was also found. All crystal structures were determined by single-crystal X-ray diffraction analysis. Both CuL and CuL' display chiral 1D chain structures, whereas Cu(2)O(2)L'(2) possesses a structure with 13×16?? channels and a free volume of 41.4?%. The possible mechanisms involved in this in situ ligand-controlled reaction system are discussed in detail.     

Synthesis and structure of nickel-containing cuboidal clusters derived from [W3Se4(H2O)9]4+. Site-differentiated substitution at the nickel site in the series [W3NiQ4(H2O)10]4+ (Q = S, Se)

New Ni-containing heterometallic cuboidal cluster aqua complex [W3(NiCl)Se4(H2O)9]3+, the missing link in the family of the M3NiQ4 clusters (M = Mo, W; Q = S, Se), has been prepared by the reaction of [W3Se4(H2O)9]4+ with Ni in 2 M HCl. Single crystals of edge-linked double-cuboidal cluster [{W3NiSe4(H2O)9}2](pts)8.18H2O (pts = p-toluenesulfonate) were grown from the solution of the aqua complex in 3 M Hpts, and their structures were determined. The Ni site in the clusters [W3(NiCl)Q4(H2O)9]3+ selectively coordinates typical pi-acceptor ligands such as CO, olefins, acetylenes, phosphines, arsines, or SnCl3-. This allows stabilization by coordination of such elusive species as HP(OH)2 and As(OH)3. The stability constants for coordination of HP(OH)2, As(OH)3, and SnCl3- were determined. The Se for S substitution increases the stability by 1-2 orders of magnitude. Supramolecular adducts with cucurbit[6]uril (Cuc), [W3(Ni(HP(OH)2))Q4(H2O)9]Cl4.Cuc.11H2O and [W3(NiAs(OH)3)S4(H2O)8Cl]Cl3.Cuc.13H2O, were isolated and structurally characterized.     

Mononuclear [NiII(L)(P-(o-C6H4S)2(o-C6H4SH))]0/1- (L = thiolate, selenolate, PPh3, and Cl) complexes with intramolecular [Ni...S...H...S]/[Ni...H...S] interactions modulated by the coordinated ligand L: relevance to the [NiFe] hydrogenases

The shift of the IR nu(S)(-)(H) frequency to lower wavenumbers for the series of complexes [Ni(II)(L)(P-(o-C6H4S)2(o-C6H4SH))]0/1- (L = PPh3 (1), Cl (6), Se-p-C6H4-Cl (5), S-C4H3S (7), SePh (4)) indicates that a trend of increasing electronic donation of the L ligands coordinated to the Ni(II) center promotes intramolecular [Ni-S...H-S] interactions. Compared to the Ni...S(H) distance, in the range of 3.609-3.802 A in complexes 1 and 4-7, the Ni...S(CH3) distances of 2.540 and 2.914 A observed in the [Ni(II)(PPh3)(P(o-C6H4S)2(o-C6H4-SCH3))] complexes (8a and 8b, two conformational isomers with the chemical shift of the thioether methyl group at delta 1.820 (-60 degrees C) and 2.109 ppm (60 degrees C) (C4D8O)) and the Ni...S(CH3) distances of 3.258 and 3.229 A found in the [Ni(II)(L)(P(o-C6H4S)2(o-C6H4-SCH3))]1- complexes (L = SPh (9), SePh (10)) also support the idea that the pendant thiol protons of the Ni(II)-thiol complexes 1/4-7 were attracted by both the sulfur of thiolate and the nickel. The increased basicity (electronic density) of the nickel center regulated by the monodentate ligand attracted the proton of the pendant thiol effectively and caused the weaker S...H bond. In addition, the pendant thiol interaction modes in the solid state (complexes 1a and 1b, Scheme 1) may be controlled by the solvent of crystallization. Compared to complex 1a, the stronger intramolecular [Ni-S...H-S] interaction (or a combination of [Ni-S...H-S]/[Ni...H-S] interactions) found in complexes 4-7 led to the weaker S-H bond strength and accelerated the oxidation (by O2) of complexes 4-7 to produce the [Ni(Y)(L)(P(o-C6H4S)3)]1- (L = Se-p-C6H4-Cl (11), SePh (12), S-C4H3S (13)) complexes.     

Synthesis and structure of asymmetric zirconium-substituted silicotungstates, [Zr6O2(OH)4(H2O)3(beta-SiW10O37)3]14- and [Zr4O2(OH)2(H2O)4(beta-SiW10O37)2]10-

The reaction of ZrCl4 with [gamma-SiW10O36]8- in a potassium acetate buffer results in two different products depending on the reactant ratios. The trimeric species [Zr6O2(OH)4(H2O)3(beta-SiW10O37)3]14- (1) consists of three beta23-SiW10O37 units linked by an unprecedented Zr6O2(OH)4(H2O)3 cluster with C1 point group symmetry. The dimeric species [Zr4O2(OH)2(H2O)4(beta-SiW10O37)2]10- (2) consists of beta22- and beta12-SiW10O37 units sandwiching a Zr4O2(OH)2(H2O)4 cluster, which also has C1 symmetry. Polyanion 1 contains more zirconium centers than any other polyoxometalate known to date.     

Synthesis and Crystal Structure of 2-(4''-Methylphenoxy)-5,8,9-trimethyl-3-phenyl Thieno[3'',2'':5,6]pyrido[4,3-d]pyrimidin-4-(3H)-one Hydrochloride

The title compound 2-(4′-methylphenoxy)-5,8,9-trimethyl-3-phenyl thieno[3′,2′:5,6]pyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (C26H23Cl4N3O2S, Mr = 583.33) has been deter- mined by single-crystal X-ray diffraction. The crystal belongs to monoclinic, space group P21/c with a = 14.8442(11), b = 11.5131(8), c = 17.2010(13) (A), β = 113.7250(10)o, V = 2691.3(3) (A)3, Z = 4, Dc = 1.440 g/cm3, S = 1.094, μ = 0.547 mm-1, F(000) = 1200, the final R = 0.0571 and wR = 0.1458. X-ray analysis reveals that the title compound combines with a molecule of dichloromethane by an intramolecular hydrogen bond. The thienopyridine ring is almost coplanar, and the dihedral angle between the thiophene plane and the pyridine plane is 0.6o.     

Monocarbaborane anion chemistry. An interesting encapsulation of the Pd2I2(P(C6H(4)-4-Me)3)4]2+ cation by a pair of [PhCB9H4I(C6H4Me)4]- anions

Reaction of the [1-Ph-closo-1-CB9H(4)-6,7,8,9,10-I5]- anion with 4-MeC6H4MgBr in the presence of [PdCl2(PPh3)2] gives the [Pd2I2(P(C6H(4)-4-Me)3)4]2+ salt of the [1-Ph-closo-1-CB9H(4)-10-I-6,7,8,9-(C6H(4)-4-Me)4]- anion, which exhibits an unusual neutral supramolecular assembly in the solid state, in which the dipalladium dication is encapsulated by two four-armed 'tetrapus' anionic units; the anion also has potentialities for four-fold dendrimer construction.     

(S)-2-((S)-2-(4-(3-[18F]fluoropropyl)benzamido)-3-phenylpropanamido)pentanedioic acid labeled with 18F

As degradation product of Antineoplaston A10 in vivo, phenylacetyl glutamine showed antitumor activities. According to literatures, we designed and radiosynthesized a phenylacetyl glutamine derivative, which was achieved under a mild reaction condition. Evaluations in vitro and in vivo were performed on tumor bearing mice. Excitingly, the radiochemical purity of (S)-2-((S)-2-(4-(3-fluoropropyl)benzamido)-3-phenylpropanamido)pentanedioic acid ([¹⁸F]FBPPA) was 98%, and besides the best radiochemical yield was up to 46%. T/Bl (Tumor/Blood) and T/M (Tumor/Muscle) ratios of [¹⁸F]FBPPA at 60 min post injection were 2.33 and 3.51. Meanwhile, it showed satisfied stability in vitro and in vivo, compared with 2-[¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG). Although [¹⁸F]FBPPA deserved further studies to make optimizations on its structure, the results revealed it might become a potential PET imaging agent for detecting tumors.     

[(CH_3)_4N]_2Na[Mo_2O(S_2)_3S_5]·H_2O的合成和晶体结构

标题晶体属斜方晶系,空间群Pbn2_1,a=9.086(2),b=13.439(3),c=22.858(11),V=2791,Z=4,Dc=1.927g/cm~3。在CAD—4衍射仪上收集强度数据,采用直接法和Fourier技术解出结构,并用全矩降最小二乘法修正。对于1180个独立衍射最终偏离因子0.067。结构中的阴离子与其同系物[(CH_3)_4-N]_2K(Mo_2O(S_2)_3(NO)_2]·H_2O中的阴离子配位情况相似。只是结构中的Mo—S与Mo—O键长有差异。这种差异在两者的红外光谱上有着相应的表现。