Synthesis and glutamate-agonistic activity of (S)-2-amino-3-(2,5-dihydro-5-oxo-3-isoxazolyl)-propanoic acid derivatives.

(S)-2-Amino-3-(2,5-dihydro-5-oxo-3-isoxazolyl)propanoic acid, (3a) and its analogs (3b--h) were prepared and evaluated for glutamate receptor-agonistic and antifungal activities. Several (S)- and (R)-2-amino-3-isoxazolylpropanoic acid derivatives (3a--d) were synthesized starting with (S)- and (R)-N-tert-butoxycarbonyaspartic acid alpha-methyl esters (4, n = 1) by means of Masamune's chain extension reaction followed by isoxazolone formation with hydroxylamine and subsequent deprotection reactions. Furthermore, (S)- and (R)-N-tert-butoxycarbonylglutamic acid alpha-methyl esters (4, n = 2) were converted to (S)- and (R)-2-amino-4-isoxazolylbutyric acid derivatives (3e-h) via the same sequence of reactions.     

The pKa and pH dependence of the formation of nitroxide radicals from some drug substances with an aliphatic secondary amino group by oxidation with hydrogen peroxide. An Electron Spin Resonance (ESR) Study

The pKa and pH dependence of the formation of nitroxide radicals from the following drugs that contain an aliphatic secondary amino group, by oxidation with hydrogen peroxide, have been studied by ESR spectroscopy: Ephedrine, (1R,2S)-1-phenyl-2-methyl-aminopropanol, timolol, (S)-1-(tert-butyl-amino)-3-[(4-morpholino-1,2,3-thiadiazol-3-yl)ox y]-2- propanol, metoprolol, 1-[4-(2-methoxyethyl)phenoxy]-3-[(1-methylethyl)amino]-2-propanol and terodiline, N-tert-butyl-3,3-diphenyl-1-methylpropylamine. Radicals were formed from the non-ionized base only. Therefore, the pKa value of the amine and the pH of the reaction mixture is of crucial importance for the yield of nitroxide radical. At 37 degrees C the pKa values of 1-3 are about 9.2, and of 4 about 9.6, which means that 1.5% of 1-3, and 0.6% of 4, are present in the reactive base form at the physiological pH of 7.4. Horse-radish peroxidase was found both to enhance radical production and to decrease the life-time of the radicals formed in the reaction with hydrogen peroxide.     

Synthesis and biological activity of (S)-2-amino-3-(2,5-dihydro-5-oxo-4-isoxazolyl)propanoic acid (TAN-950 A) derivatives.

(S)-2-Amino-3-(2,5-dihydro-5-oxo-4-isoxazolyl)propanoic acid (TAN-950 A (1)) is a novel amino acid antibiotic which shows a high affinity for glutamate receptors of the central nervous system. To improve the affinity for glutamate receptors, the structure-activity relationships of TAN-950 A derivatives 6a--o, 15a--o were investigated. Optically active TAN-950 A analogs 15a--h were synthesized starting with methyl (S)- and (R)-N-Boc-pyroglutamate (8) via acylation at the C-4 position followed by isoxazolone formation with hydroxylamine and subsequent deprotection reactions. The lactam 16, prepared from (RS)-aminoadipic acid, and dimethyl esters 19 of (R)- and (S)-aspartic acid were converted to (RS)-3-methyl-homo-TAN-950 A (15i) and optically active nor-TAN-950 A derivatives 15j--o, respectively, utilizing a similar sequence of reactions. Most of TAN-950 A derivatives 6a--o, 15a--o showed an affinity for glutamate receptors. The 3-alkyl derivatives 15b, d--g, especially, showed a high affinity for the quisqualate subtype-receptor and had a strong activating effect on the hippocampal neurons (glutamate agonistic activity). The (R)-enantiomer 15a of TAN-950 A had increased selectivity for the N-methyl-D-aspartate (NMDA) subtype-receptor. This selectivity was further enhanced by removal of the methylene group in the amino acid moiety of 15a. The most potent and selective NMDA agonistic activity was observed with (R)-3-methyl-nor-TAN-950 A (15m).     

Highly enantioselective conjugate addition of nitroalkanes to alkylidenemalonates using efficient phase-transfer catalysis of N-spiro chiral ammonium bromides

Highly enantioselective conjugate addition of nitroalkanes to alkylidenemalonates has been accomplished for the first time by the utilization of efficient phase-transfer catalysis of N-spiro C2-symmetric chiral quaternary ammonium bromide 1. For instance, simple mixing of nitropropane (2, R1 = Et), diisopropyl benzylidienemalonate (3, R2 = Ph), Cs2CO3 (1 equiv), and (S,S)-1 (1 mol %) in toluene at 0 degrees C for 2.5 h gave rise to the desired conjugate addition product 4 (R1 = Et, R2 = Ph) quantitatively (anti/syn = 86:14) with 97% ee (anti isomer). The applicability of this procedure has been demonstrated with other representative alkylidenemalonates and nitroalkanes. Since 4 can be readily transformed into the corresponding gamma-amino acid hydrochloride 5 without loss of diastereo- and enantioselectivity, the present method provides a new and practical access to various optically active gamma-amino acid derivatives.     

Stereocontrolled synthesis of cis-dibenzoquinolizine chlorofumarates: curare-like agents of ultrashort duration

The quaternizations of dibenzoquinolizines 9 and 14 with 3-halo-1-propanols are highly cis-selective (94-100% cis), results consistent with the N-methylation of O-methylcapaurine (7b), but in contrast to the proposed trans-stereochemistry of dibenzo[a,h]quinolizine methiodide 10 and the analogous quaternizations of 1-benzyl- and 1-phenylisoquinoline congeners 5b and 5c. In this report, we describe stereoselective preparation of the unique cis-dibenzoquinolizinium propanols 15 and 16and their transformation into bis- and mixed-onium chlorofumarates 19, 20ab, and 26. Dibenzo[a,g]quinolizinium propanol 15 was prepared enantioselectively in three steps from dihydroisoquinoline 11. Asymmetric transfer hydrogenation of 11 in the presence of triethylamine/formic acid and Noyori's chiral ruthenium catalyst 12 produced R-(-)-5',8-dimethoxynorlaudanosine (13) in 98% yield and 87% ee. Pictet-Spengler cyclization of 13 in formalin/formic acid afforded the dibenzo[a,g]quinolizine 14 in 65% yield. Quaternization of 14 with 3-chloro-1-propanol under Finkelstein conditions generated cis-dibenzoquinolizinium propanol 15 in 85% yield with >94% cis-selectivity. The cis-dibenzo[a,h]quinolizinium propanol 16 was obtained as a single stereoisomer by reaction of the known tetramethoxyquinolizine 9 with neat 3-iodo-1-propanol. Bis-onium chlorofumarates 18 and 19 and the mixed-onium derivative 20ab were prepared by a pool synthesis procedure from (1R)-trans-6a, 16, and chlorofumaryl chloride (17). Mixed-onium alpha-chlorofumarate 26 was synthesized from (1S)-trans-6d, 15 and (+/-)-trans-2,3-dichlorosuccinic anhydride (22), employing a recently disclosed chlorofumarate mixed-diester synthesis. The title compounds (19, 20ab, and 26) displayed curare-like effects of ultrashort duration in rhesus monkeys.     

Preparation of optically active (2RS,3SR)-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolutions by replacing and preferential crystallization

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by replacing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1.HCl] was examined based on the melting point, solubility, and infrared spectrum. (2RS,3SR)-1.HCl was indicated to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. When, in optical resolution by replacing crystallization, L-phenylalanine methyl ester hydrochloride (L-2) was used as the optically active co-solute, (2R,3S)-1.HCl was preferentially crystallized from the supersaturated racemic solution; the use of D-2 as the co-solute afforded (2S,3R)-1.HCl with an optical purity of 95%. In addition, optical resolution by preferential crystallization was successfully achieved to give successively (2R,3S)- and (2S,3R)-1.HCl with optical purities of 90-92%. The (2R,3S)- and (2S,3R)-1.HCl purified by recrystallization from 1-propanol were treated with triethylamine in methanol to give optically pure (2R,3S)- and (2S,3R)-1.     

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.     

One-electron versus two-electron mechanisms in the oxidative addition reactions of chloroalkanes to amido-bridged rhodium complexes

The compound syn-[{Rh(mu-NH{p-tolyl})(CNtBu)(2)}(2)] (1) oxidatively adds C--Cl bonds of alkyl chlorides (RCl) and dichloromethane to each metal centre to give the cationic complexes syn-[{Rh(mu-NH{p-tolyl})(eta(1)-R)(CNtBu)(2)}(2)(mu-Cl)]Cl and anti-[{Rh(mu-NH{p-tolyl})Cl(CNtBu)(2)}(2)(mu-CH(2))]. Reaction of 1 with the chiral alkyl chloride (-)-(S)-ClCH(Me)CO(2)Me (R*Cl) gave [{Rh(mu-NH{p-tolyl})(eta(1)-R*)(CNtBu)(2)}(2)(mu-Cl)]Cl ([3]Cl) as an equimolecular mixture of the meso form (R,S)-[3]Cl-C(s) and one enantiomer of the chiral form [3]Cl-C(2). This reaction, which takes place in two steps, was modeled step-by-step by reacting the mixed-ligand complex syn-[(cod)Rh(mu-NH{p-tolyl})(2)Rh(CNtBu)(2)] (4) with R*Cl, as a replica of the first step, to give [(cod)Rh(mu-NH{p-tolyl})(2)RhCl(eta(1)-R*)(CNtBu)(2)] (5) with racemization of the chiral carbon. Further treatment of 5 with CNtBu to give the intermediate [(CNtBu)(2)Rh(mu-NH{p-tolyl})(2)RhCl(eta(1)-R*)(CNtBu)(2)], followed by reaction with R*Cl reproduced the regioselectivity of the second step to give (R,S)-[3]Cl-C(s) and [3]Cl-C(2) in a 1:1 molar ratio. Support for an S(N)2 type of reaction with inversion of the configuration in the second step was obtained from a similar sequence of reactions of 4 with ClCH(2)CO(2)Me first, then with CNtBu, and finally with R*Cl to give [(CNtBu)(2)(eta(1)-CH(2)R)Rh(mu-NH{p-tolyl})(2)(mu-Cl)Rh(eta(1)-R*)(CNtBu)(2)]Cl (R = CO(2)Me, [7]Cl) as a single enantiomer with the R configuration at the chiral carbon. The reactions of 1 with (+)-(S)-XCH(2)CH(CH(3))CH(2)CH(3) (X = Br, I) gave the related complexes [{Rh(mu-NH{p-tolyl})(eta(1)-CH(2)CH(CH(3))CH(2)CH(3))(CNtBu)(2)}(2)(mu-X)]X, probably by following an S(N)2 profile in both steps.     

Novel malonamide derivatives as alpha v beta 3 antagonists. Syntheses and evaluation of 3-(3-indolin-1-yl-3-oxopropanoyl)aminopropanoic acids on vitronectin interaction with alpha v beta 3.

In attempt to find novel integrin alphavbeta3 antagonists, we selected SC65811 and its guanidine analogue (1) as lead compounds. Modification of the glycine part of SC65811 led to a new series of malonamide derivatives that exhibited alphavbeta3 inhibitory activity. Among them, (R,S)-3-[3-[6-(3-benzylureido)indolin-1-yl]-3-oxopropanoylamino]-3- (pyridin-3-yl)propanoic acid (43a) showed not only potent activity with an IC50 value of 3.0 nM but also good selectivity for alphavbeta3 relative to alphaIIbbeta3, alpha5beta1, and alphavbeta5 with IC50 values of 19,000, 11,000, and 14 nM, respectively. Furthermore, optimization of 43a led to the most potent alphavbeta3 antagonist, (R,S)-3-(3-[6-[(4,5-dihydro-1H-imidazol-2-yl)amino]indolin-1-yl]-3-oxopropanoylamino)-3-(quinolin-3-yl)propanoic acid (431) with an IC50 value of 0.42 nM. The synthesis and the structure-activity relationships of these malonamide derivatives are presented.     

Preparation of Optically Pure p-[(1-Hydroxy-2,2,2-trifluoro)ethyl]benzoic Acid

The preparation of optically pure p-[(1-hydroxy 2,2,2-trifluoro)ethyl]benzoic acid via the enzymatic resolution is described.     

Dehydropolymerization of arylsilanes catalyzed by a novel silylmolybdenum complex

A complex [MoH3(Si(Ph)[Ph2PCH2CH2P(Ph)C6H4-o]2)] (1) can act as single-component catalyst for dehydrogenative polymerization of ArSiH2R (Ar = Ph, p-tolyl, o-tolyl; R = H, Me) to (ArSiR)n: p- and o- tolylsilane produced the polymers of respectable molecular weights (Mw of 17300 and 6700 respectively) and polymerization of secondary silane, methylphenylsilane, gave a substantial molecular weight (Mw of 1750).     

Development of new synthetic methods with aryl 1-chlorovinyl sulfoxides

Aryl 1-chlorovinyl sulfoxides were easily synthesized from ketones and aldehydes with aryl chloromethyl sulfoxide in three-steps with high overall yields. Low-temperature treatment of the aryl 1-chlorovinyl sulfoxides with alkyllithium or a Grignard reagent gave alkylidene carbenoids via a sulfoxide-metal exchange reaction. From the alkylidene carbenoids, acetylenic compounds, tetra-substituted olefins, and allenes were synthesized. Enolization of alpha-chloro alpha-sulfinyl ketones, which were synthesized from methyl esters and chloromethyl phenyl sulfoxide, is another method for the generation of aryl 1-chloroalkyl sulfoxides. Treatment of 1-chlorovinyl phenyl sulfoxides so generated with t-BuLi followed by some nucleophiles having an acidic hydrogen gave one-carbon elongated carboxylic acids and their derivatives. Conjugate addition of some carbanions with 1-chlorovinyl p-tolyl sulfoxides was found to have taken place. For example, reaction of 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium gave high yields of cyclic enaminonitriles. Acidic treatment of the enaminonitriles afforded good yields of 4,4-disubstituted 2-cyclopentenones. By using unsymmetrical ketones and optically pure chloromethyl p-tolyl sulfoxide, this procedure suggests a good method for an asymmetric synthesis of optically pure 4,4-disubstituted 2-cyclopentenones. This method achieved an asymmetric total synthesis of (+)-alpha-cuparenone starting from methyl 4-methylphenyl ketone and (R)-(-)-chloromethyl p-tolyl sulfoxide. A novel synthesis of 2,4,4-trisubstituted 2-cyclopentenones is also successful using cyanomethyllithium and its homologues. Conjugate addition of the lithium enolate of tert-butyl acetate and its homologues gave high yields of the adduct, 3,3-disubstituted esters. Synthesis of various kinds of carboxylic acids and their derivatives and lactones was realized from the adducts.     

手性3,5-二甲基-2-芳基-2-吗啉醇盐酸盐的合成及其晶体结构

以(S)-2-氨基丙醇为手性源与α-溴-3-氯苯丙酮反应, (R)-2-氨基丙醇为手性源与6-甲氧基-2-(2-溴丙酰基)萘反应, 分别合成了手性纯化合物(2R,3R,5S)-3,5-二甲基-2-(3-氯苯基)-2-吗啉醇盐酸盐(4a)和(2S,3S,5R)-3,5-二甲基-2-(6-甲氧基-2-萘基)-2-吗啉醇盐酸盐(4b), 利用X射线单晶衍射仪测定了两化合物的晶体结构和两化合物的空间结构, 并初步分析两化合物空间结构, 化合物4a晶体属正交晶系, 空间群为P2₁2₁2, 晶胞参数为: a＝0.8718(2) nm, b＝0.7883(2) nm, c＝2.0247(6) nm, Z＝4, V＝1.3915(7) nm³, D_c＝1.328 g/cm³, F(000)＝584, R₁＝0.0399, wR₂＝0.0797, S＝1.042. 化合物4b晶体属正交晶系, 空间群为P2₁2₁2₁, 晶胞参数为: a＝0.71035 (9) nm, b＝0.77703(10) nm, c＝2.9820(4) nm, Z＝4, V＝1.6318(4) nm³, D_c＝1.318 g/cm³, F(000)＝688, R₁＝0.0520, wR₂＝0.1108, S＝0.994.     

A spiro[chroman-3,7'-isochromene]-4,6'(8'H)-dione from the Cordyceps-colonizing fungus Fimetariella sp

Fimetarone A (1), a metabolite with the new spiro[chroman-3,7'-isochromene]-4,6'(8'H)-dione skeleton, was isolated from cultures of the Cordyceps-colonizing fungus Fimetariella sp. Compound 1 was a 1:1 atropdiastereomeric mixture in NMR data, and aS,9S and aR,9R enantiomers were found and confirmed by X-ray crystallography. Compound 1 could be derived from the hypothetical precursors 3,4,5-trihydroxy-2-(2-methylene-3,5-dioxohexanoyl)benzoic acid (5) and lapidosin (6).     

Synthesis and Crystal Structure of (1S)-1,1'-Bis{[N-ethyl-N-(1-methylethyl)-amino]-carbonyl}-2-(hydroxydiphenylmethyl)-ferrocene

The title complex, (1S)-1,1'-bis{[N-ethyl-N-(1-methylethyl)-amino]carbonyl}-2- (hydroxyldiphenylmethyl)-ferrocene ([Fe(C24H22NO2)(C11H16NO)]2·H2O, Mr = 1207.13), was synthesized via (-)-Sparteine-mediated enantioselective directed ortho-lithiation of 1,1'-bis{[N- ethyl-N-(1-methylethyl)-amino]carbonyl}-2-(hydroxydiphenylmethyl)-ferrocene. The structure of the title compound was determined by X-ray single-crystal diffraction. The crystal belongs to the orthorhombic system, space group P212121, with a = 10.26...     

Practical synthesis of optically active styrene oxides via reductive transformation of 2-chloroacetophenones with chiral rhodium catalysts

[reaction: see text] A practical method for the synthesis of optically active styrene oxides has been developed via formation of optically active 2-chloro-1-phenylethanols generated by reductive transformation of ring-substituted 2-chloroacetophenones. The optically active alcohols with up to 98% ee are obtainable from the asymmetric reduction of acetophenones with an S/C = 1000-5000 with a formic acid triethylamine mixture containing a well-defined chiral Rh complex, CpRhCl[(R,R)-Tsdpen].     

抗体酶催化Oxy-Cope重排反应的研究

经七步反应合成了Oxy-Cope重排反应的过渡态类似物-2-对羧丙氧基苯基环己醇(3),并以此为半抗原联接载体蛋白BSA制成抗原后免疫动物,从动物血清中分离纯化得到多克隆抗体。在200mmol/L的MES(4-吗啉乙磺酸)和200mmol/L的NaCl缓冲液中(pH=6.0),底物和抗体的摩尔比为100:1及37℃条件下,该抗体能催化3-对甲氧苯基-4-羟基-1,5-已二烯(1)重排生成6-对甲氧苯基-5-烯-已醛(2),ν~m~a~x=15μmol/L·min,K~M=1025μmol/L,K~c~a~t~.=10min^-^1.     

R(-)四氢噻唑-2-硫酮-4-羧酸对D,L-氨基酸酯拆分的研究

以新手性拆分试剂R(-)四氢噻唑-2-硫酮-4-羧酸[简称R(-)TTCA]对D,L-氨基酸酯进行手性拆分,分别得到(R)TTCA氨基酸酯盐1a_1f([α]_D²⁰＝-30.40°～-42.70°)及光学活性氨基酸酯2a-2f,其光学纯度为35.4%～75.8%.由1a_1f在碱存在下分解出2a-2f的对映体3a-3f,光学纯度为39.50%～69.10%.用半经验的量子化学PM3方法研究了氨基的碱性、中间产物铵盐生成热和稳定性.     

New optically active organotin compounds for heterogeneous bimetallic catalysis

Chiral tin(IV) derivatives with two or three chiral centers adjacent to the metal (−)-Ment₂SnMe₂, (−)-Ment₂SnPh₂, (−)-Ment₃ SnCl, (−)-Ment₃SnH; (−)-Ment = (1R, 2S, 5R)-1-chloro-5-methyl-2-isopropylcyclohexane, R₂Sn[CH(Me)(n-Hex)]₂ (R = Bu or Ph) have been prepared either by the coupling of methylmagnesium chloride with tin halides or by the reaction of lithium stannates with optically active (2-octyl)tosylate. The stereospecificity of both processes was remarkably high, leading to new optically pure organotin reagents which have been fully characterized.     

Highly stereoselective iodolactonization of 4,5-allenoic acids--an efficient synthesis of 5-(1'-iodo-1'(Z)-alkenyl)-4,5-dihydro-2(3H)-furanones

In this paper, it is reported that the efficient iodolactonization of 4,5-allenoic acid with I2 in cyclohexane in the presence or absence of K2CO3 afforded 5-(1'-iodo-1'(Z)-alkenyl)-4,5-dihydro-2(3H)-furanones highly stereoselectively. However, the reaction of axially optically active 4,5-allenoic acids (R)-(-)-5 a and (R)-(-)-5 b with I2 afforded the corresponding products with a serious loss of chirality. This problem was solved by conducting the iodolactonization with N-iodosuccinimide in CH2Cl2 in the presence of Cs2CO3; however, the Z/E selectivity is somewhat lower. The pure optically active Z products were prepared by subsequent kinetic resolution with Sonogashira coupling. The reaction of the substrates with a substituent at the 3-position of the starting 4,5-allenoic acids afforded the trans-4,5-disubstituted gamma-butyrolactones as the only products. The reaction of the 4,5-allenoic acids (S)-(+)-1 l, (R)-(-)-1 l, and (S)-(+)-1 m with a center chirality at the 3-position afforded the trans products with very high enantiopurity and up to 98:2 Z/E selectivity regardless of the axial chirality of the allene moiety.