Asymmetric synthesis of anti-homopropargylic alcohols from aldehydes and chiral sulfonimidoyl substituted bis(allyl)titanium complexes through generation and elimination of novel chiral alkylidenecarbene (dimethylamino)sulfoxonium ylides

A new method for the asymmetric synthesis of anti-configured homopropargylic alcohols 1 is described, which features the addition of chiral sulfonimidoyl substituted bis(allyl)titanium complexes 3 to aldehydes, the methylation of sulfonimidoyl substituted homoallylic alcohols 2 at the N-atom, and the elimination of alkenyl (dimethylamino)sulfoxonium salts 7 with LiN(H)tBu. The reaction of isopropyl, cyclohexyl, and methyl substituted allylic titanium complexes 3a-c with benzaldehyde, p-bromobenzaldehyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde, (E)-3-phenylpropenal, and phenylpropynal afforded with high regio- and diastereoselectivities the anti-configured sulfonimidoyl substituted homoallylic alcohols 2a-j, respectively. Only one allylic unit of the titanium complexes 3a-c was transferred in the case of unsaturated aldehydes, and the starting allylic sulfoximines 2a-g were recovered in approximately 50% yield. The methylation of the silyl protected alkenyl sulfoximines 6a-j with Me(3)OBF(4) gave in practically quantitative yields the (dimethylamino)sulfoxonium salts 7a-j, respectively. Salts 7a-e, 7g, 7h, and 7j delivered upon treatment with 2 equiv of LiN(H)tBu the enantio- and diastereomerically pure saturated and unsaturated alkynes 9a-e, 9g, 9h, and 9j, respectively, in high yields. Besides the alkynes the sulfinamide 8 (96% ee) was isolated. Aminosulfoxonium salts 9f and 9i, which carry a CC triple bond, also suffered an elimination under these conditions but did not yield the corresponding diynes. Elimination of salts 7a-e, 7g, 7h, and 7j proceeds most likely through deprotonation at the alpha-position with formation of the novel alkylidenecarbene aminosulfoxonium ylides 19a-e, 19g, 19h, and 19j, respectively. The ylides 19a-e, 19g, 19h, and 19j presumably eliminate sulfinamide 8 with generation of the chiral nonracemic (beta-siloxyalkylidene)carbenes 20a-e, 20g, 20h, and 20j, which suffer a 1,2-H-shift with formation of alkynes 9. Support for the formation of the putative alkylidenecarbenes 20 as intermediates comes from the elimination of the beta-methyl substituted aminosulfoxonium salt 24, which delivered the enantio- and diastereomerically pure 2,3-dihydrofuran derivative 28 upon treatment with LiN(H)tBu in high yield. Here, the putative (beta-siloxyalkylidene)carbene 26 suffers a 1,5-O,Si bond insertion rather than a 1,2-Me shift. Methylation of the alkenyl sulfoximine 6a at the alpha-position with formation of 13 was achieved through deprotonation of the former with formation of the alpha-lithioalkenyl sulfoximine 11a and its treatment MeI. Reaction of the alpha-methylated alkenyl aminosulfoxonium salt 14a with LiNiPr(2) at low temperatures gave the enantio- and diastereomerically pure anti-configured homoallenylic alcohol derivative 15, while reaction of the salt with LiNiPr(2) or LiN(H)tBu at higher temperatures afforded the enantio- and diastereomerically pure nonterminal homopropargylic alcohol derivative 17. Deprotonation of the alkenyl (dimethylamino)sulfoxonium salts 7a and 7b with nBuLi afforded the novel alkylidenecarbene aminosulfoxonium ylides 19a and 19b, respectively, which upon treatment with MeI yielded the methylated aminosulfoxonium salts 14a and 14b, respectively.     

Direct synthesis of esters and amides from unprotected hydroxyaromatic and -aliphatic carboxylic acids

A facile method for the activation of hydroxy-substituted carboxylic acids using benzotriazole chemistry without prior protection of the hydroxy substituents is presented. The N-acylbenzotriazole intermediates 2a-g, 6a-d, and 9a-c have been used for high-yielding synthesis of both aliphatic (3a-l) and aromatic (7a-h, 10a-f) hydroxy carboxamides. High yields of aromatic hydroxy esters 12a-h and 13a-i were obtained using either neat alcohols in neutral microwave conditions or nucleophilic alkoxides and the intermediate N-(arylacyl)benzotriazoles. Moderate yields were obtained in the case of aliphatic hydroxy esters 11a,b and thiolesters 11e-g from the intermediates 2a-c.     

Reaction of lumichrome or 2-thiolumichrome with alkylamines

The reaction of lumichrome ( 2 ) with alkyl (or allyl)amines such as n-butylamine, n-hexylamine and allylamine gave 2,3-disubstituted 6,7-dimethylquinoxalines 4a-d, 5a-d, 6a-d, 7a-d and 8a-d . Similar reaction of 2-thiolumichrome ( 3 ) with alkyl (or allyl)amines gave 2,3-disubstituted 6,7-dimethylquinoxalines 6a-c, 9a-c and 10a-c , 2-alkyl (or allyl)amino-6,7-dimethyl-3,4-dihydrobenzo[g]pteridine-4-ones 11a-c and 2,4-dialkyl (or allyl)amino-6,7-dimethylbenzo[g]pteridines 12a-c .     

Functionalized chiral vinyl aminosulfoxonium salts: asymmetric synthesis and application to the synthesis of enantiopure unsaturated prolines, beta,gamma-dehydro amino acids, and cyclopentanoid keto aminosulfoxonium ylides

Methylation of the enantiopure functionalized vinyl sulfoximines 5a-e and 14a-d followed by a F- ion or DBU-mediated isomerization of the vinyl aminosulfoxonium salts 7a-e and 15a-d, respectively, gave the allyl aminosulfoxonium salts 10a-e and 17a-d, respectively. A concomitant intramolecular substitution of the aminosulfoxonium group of 10a-e and 17a-d by the amino group afforded the unsaturated prolines 8a-e and 18a-d, respectively. The starting vinyl sulfoximines are accessible through a highly selective and stereo-complementary aminoalkylation of the corresponding sulfonimidoyl-substituted mono- and bis(allyl)titanium complexes with the imino ester 4. The vinyl aminosulfoxonium salts 34, 7a-d, and E-15c experienced upon treatment with the Cl- ion a migratory substitution with formation of the delta-chloro-beta,gamma-dehydro amino acids 36, E/Z-37a-d, and 38, respectively. A migratory substitution of the hydroxy-substituted vinyl aminosulfoxonium salts 46a and 46b furnished the delta-chloro allyl alcohols E/Z-48a and E-48b, respectively. A facile one-pot conversion of the vinyl sulfoximines 31b, 5c and 45a to the allyl chlorides 36, E/Z-37c and E/Z-48a, respectively, was achieved upon treatment with a chloroformiate. A tandem cyclization of the vinyl aminosulfoxonium salts 7b, Al-7b and 57 with LiN(H)tBu yielded the cyclopentanoid keto aminosulfoxonium ylides 54, Al-54, 59, 60 and 61, respectively. The structure of the tricyclic keto aminosulfoxonium ylide Al-54 has been determined by X-ray crystal structure analysis. Ab initio calculations and a NBO analysis of the tricyclic keto aminosulfoxonium ylide XXIII show a polar structure stabilized by electrostatic interactions between the ylidic C atom and both the carbonyl C atom and the S atom.     

Photochemical deconjugation of chiral 3-methyl-2-butenoates derived from carbohydrate-based alcohols: the influence of the sugar backbone on the facial diastereoselectivity

The photodeconjugation of the alpha-(4-trimethylsilyl-3-butynyl)-substituted senecio acid esters 7 was studied. Chiral alcohols ROH (9) were employed as auxiliaries to control the facial diastereoselectivity of the protonation step. The conversion of the four sugar alcohols diacetone-D-glucofuranose, diacetone-D-allofuranose, diacetone-D-gulofuranose, and diacetone-D-fructopyranose (9a-d) to the esters 7 was achieved in four steps employing 4-iodo-1-trimethylsilylbut-1-yne (3) as the alkylating agent (27-45% yield overall). Their photodeconjugation gave the corresponding beta,gamma-unsaturated (R)-esters 14a-d with moderate to excellent diastereomeric excess. The best results were achieved with diacetone-D-glucofuranose and diacetone-D-fructopyranose as the auxiliary (>95% de). To achieve the synthesis of the target compound 1 which has the (S)-configuration, the deconjugation was conducted with the diacetone-L-fructopyranose (ent-9d) derived ester ent-7d. L-Fructose (20) was prepared from L-sorbose (15) in a modified procedure that allowed for the isolation of intermediates. The 2-fold inversion of configuration worked nicely, and the fructofuranose 19 was obtained in 19% yield from L-sorbose. The conversion of L-fructose to the ester ent-7d was conducted in full analogy to the synthesis of its enantiomer 7d. Deconjugation of ester ent-7d yielded the product 2d (70% yield), which was reduced to the alcohol 1 (85% yield).     

Microwave Irradiated Reactions of N-Phenacylpyridinium Chloride with Aromatic Aldehydes and Ketones

Pyridinium cations show a great variety of synthetic applications,due to the aromatic character of the pyridine heterocycle, to its basicity, and the electron-attracting influence of the nitrogen atom1-3. N-phenacylpyridium bromide in the presence of base…     

Synthesis and Chemistry of 4-Aroyl-3-oxo- and 3-Chloropyridazine Derivatives

4H,5H-6-Phenyl (1a) and 6-p-phenoxyphenyl (1b) pyridazin-3(2H)-ones were reacted with aromatic aldehydes to give 4-arylmethylpyridazm-3(2H)-ones (2a-g), Oxidation of (2a-g) with various oxidising agents (selenium dioxide in ethanol or chromium trioxide in acetic acid) gave 4-aroyl-6-arylpyridazin-3(2H)-ones (3a-g). Chlorination of (3a-g) with phosphorous oxychloride afforded 4-aroyl-6-aryl-3-chloropyridazine (4a-g). 1H-3-Aryl-5-phenylpyrazolo[3,4-c]pyridazines (5a-d) were obtained by heating (4a-d) with excess hydrazine hydrate. Hydroxyamination of (3e-g) with iydroxylamine gave aryl-4(6-p-phenoxyphenyl-2,3-dihydro-3-oxo)pyridazinyl oxime (6a-c). Silylation of oximes (6b & 6c) gave (7a & 7b) as acyclic compound instead of the expected seven - membered - ring compound (8).     

Syntheses, structure, and reactivity of chiral titanium compounds: procatalysts for olefin polymerization

Titanium complexes with chelating alkoxo ligands have been synthesised with the aim to investigate titanium active centres in catalytic ethylene polymerisation. The titanium complexes cis-[TiCl2(eta2-maltolato)2] (1, 89%), and cis-[TiCl2(eta2-guaiacolato)2] (2, 80%) were prepared by direct reaction of TiCl4 with maltol and guaiacol in toluene. The addition of maltol to [Ti(OiPr)4] in THF results in the formation of species [Ti(OiPr)2(maltolato)2] (3, 82%). The titanium compound cis-[Ti(OEt)2(eta2-maltolato)2] (4, 74%) was obtained by the transesterification reaction of species 3 with CH3CO2Et. When compound 4 is dissolved in THF a dinuclear species [Ti2(mu-OEt)2(OEt)4-(eta2-maltolato)2] (5, 45%) is formed. Reaction of [Ti(OiPr)4] with crude guaiacol in THF yields a solid, which after recrystallisation from acetonitrile gives [Ti4(mu-O)4(eta2-guaiacolato)] x 4CH3CN (6, 55%). In contrast, reaction of TiCl4 with crude guaiacol in tetrahydrofuran affords [Ti2(mu-O)Cl2(eta2-guaiacolato)4] (7, 82%). Crystallographic and electrochemical analyses of these complexes demonstrate that maltolato and guaiacolato ligands can be used as a valuable alternative for the cyclopentadienyl ring. These complexes have been shown to be active catalysts upon combination with the appropriate activator.     

Studies on penem and carbapenem. I. Syntheses and oral absorption of ester-type prodrugs of sodium (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-c arboxylat e

Acyloxyalkyl esters (2a-d), alkyloxycarbonyloxyalkyl esters (2e-g) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (2h) of (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3- carboxylic acid (1) were synthesized. Enhanced oral absorption was observed in mice reflecting increased lipophilicity, compared with the parent 1 itself. Among them, the ester 2h showed a prolonged plasma level and a large area under the blood concentration-time curve (AUC) in rats. These ester-type prodrugs of penem 1 in phosphate buffer (pH 6.86) were much more stable than those of cephalosporins which easily degraded via isomerization to delta 2 cephalosporins.     

Mononucleating bis(beta-diketonate) ligands and their titanium(IV) complexes

Novel bis(beta-diketones) linked by 2,2'-biphenyldiyl, 2,2'-tolandiyl, and 2,2'-bis(methylene)biphenyl moieties have been prepared. All are metalated readily by titanium(IV) isopropoxide, but the nature of the complexes formed depends on the linker structure. The biphenyl-bridged ligand gives only traces of a mononuclear complex, which is thermodynamically unstable with respect to oligomerization. The tolan-bridged ligand does form mononuclear complexes, but only as a mixture of geometric isomers. In contrast, the substituted 2,2'-bis-(2,4-dioxobutyl)biphenyl ligands, R2BobH2 (R = tBu, p-Tol), react with Ti(OiPr)4 to give, initially, a mixture of monomer and oligomers, which is converted quantitatively to monomer upon heating in the presence of excess Ti(OiPr)4. Only a single relative configuration of the biphenyl and bis(chelate) titanium moieties, established by crystallography of (tBu2Bob)Ti(O-2,6-iPr2C6H3)2 to be the (R)-/(S)- diastereomer, is observed. The kinetic and thermodynamic robustness of the (R2Bob)Ti framework is confirmed by reactions with Lewis acids. For example, (Tol2Bob)Ti(OiPr)2 reacts with trimethylsilyl triflate or triflic acid to substitute one or both of the isopropoxide groups with triflates without any redistribution or loss of the diketonate ligands. Cationic complexes can be prepared by abstraction of triflate from (Tol2Bob)Ti(OiPr)(OTf) with Na[B(C6H3(CF3)2)4]. For example, in the presence of diethyl ether, the crystallographically characterized [(Tol2Bob)Ti(OiPr)(OEt2)][B(C6H3(CF3)2)4], containing a rapidly dissociating ether ligand, is formed.     

Asymmetric peroxidation of prochiral allylic and benzylic compounds with tert-butyl hydroperoxide and chiral bisoxazoline–copper complexes

The first enantioselective peroxidation of prochiral allylic and benzylic C-H compounds by the use of chiral bisoxazoline-copper(I) complexes, generated in situ from the ligands 3 and 4a-d, and t-BuOOH as oxidant is reported. Cyclohexene 1, cyclopentene 5, -angelica lactone 7, allylbenzene 9 and 2-phenylbutane 11 were converted into the optically active allylic and benzylic tert-butyl peroxides 2, 6, 8, 10a and 12 in good yields and ee values of 4-20%. Oxidations of 1-substituted 1-cyclohexenes 13a-c led to mixtures of regioisomeric peroxides 16a-c, 17a-c and 18a-c with different regio- and enantioselectivities, depending on the 1-substituent and the ligand used. The highest ee values (up to 84%) were observed for (S)-3-tert-butylperoxy-1-methyl-1-cyclohexene 17a.     

Synthesis and characterization of some new C2 symmetric chiral bisamide ligands derived from chiral Feist's acid

The hemilabile chiral C2 symmetrical bidentate substituted amide ligands (1R,2R)-5(a-d) and (1S,2S)-6(a-d) were synthesized in quantitative yield from (1R,2R)-(+)-3-methylenecyclo-propane-1,2-dicarboxylic acid (1R,2R)-3 and (1S,2S)-(-)-3-methylene-cyclopropane-1,2-dicarboxylic acid (1S,2S)-3, in two steps, respectively. The chiral Feist's acids (1R,2R)-3 and (1S,2S)-3 were obtained in good isomeric purity by resolution of trans-(±)-3-methylene-cyclopropane-1,2-dicarboxylic acid from an 8:2 mixture of tert-butanol and water, using (R)-(+)-α-methylbenzyl amine as a chiral reagent. This process is reproducible on a large scale. All these new synthesized chiral ligands were characterized by 1H-NMR, 13C-NMR, IR, and mass spectrometry, as well as elemental analysis and their specific rotations were measured. These new classes of C2 symmetric chiral bisamide ligands could be of special interest in asymmetric transformations.     

Syntheses of optically active tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones and hexahydroimidazo[1,2-a]pyridin-2(3H)-ones

The reactions of (2S)-2-amino-2-substituted-N-(4-nitrophenyl)acetamides 16a-c, succindialdehyde (13), and benzotriazole afforded enantiopure (3S,5R,7aR)-5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a-c, which were converted by sodium borohydride into (3S,7aR)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 18a-c. Chiral (2S)-2-amino-2-substituted-N-(4-methylphenyl)acetamides 12a-d, easily prepared in two steps from N-Boc-alpha-amino acids 10a-d, similarly reacted with glutaraldehyde (20) and benzotriazole to generate 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 21a-d, which were converted by sodium borohydride directly into optically active 3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a-d.     

Syntheses, characterizations, and single-crystal X-ray structures of soluble titanium alkoxide phosphonates

Reactions of Ti(OiPr)4 with different phosphonic acids RPO3H2 (R = Ph, 4-CNPh, Me, tBu) in organic solvents have been investigated. In the presence of small amounts of water, the new molecular titanium oxide alkoxide phosphonates [Ti4(mu 3-O)(OiPr)5(mu-OiPr)3(RPO3)3].DMSO [R = Ph (1), Me (2), tBu (3), 4-CNPh (4)] were isolated. The single-crystal X-ray structure analyses of 1 and 2 revealed hexacoordinated titanium atoms and a connectivity of (111) for each phosphonate. Under rigorous exclusion of water, the reaction of Ti(OiPr)4 with tert-butylphosphonic acid in toluene gave the titanium phosphonate tetramer [Ti(OiPr)2(tBuPO3)]4 (5). A single-crystal X-ray structure analysis of 5 revealed a 5 + 1 coordination of the titanium atoms as a result of the (112) connectivity of each phosphonate; such a coordination mode has never been reported for a titanium phosphate, phosphonate, or phosphinate. Compounds 1-5 were characterized by FT-IR, 31P MAS NMR, and solution multinuclear NMR (1H, 13C(1H,) 31P(1H)) spectroscopies. 13C CP MAS NMR experiments were carried out on arylphosphonates 1 and 4. Solution NMR experiments were also used to investigate the exchange reaction between 1 and 2 and the conversion of 5 to [Ti4(mu 3-O)(OiPr)5(mu-OiPr)3(tBuPO3)3].iPrOH by partial hydrolysis in the presence of Ti(OiPr)4. The phosphonate clusters 1-5 are soluble in organic solvents and are likely intermediates in the sol-gel processing of inorganic-organic hybrids based on titanium oxide and phosphonate groups that we are currently developing.     

A catalytic asymmetric synthesis of chiral glycidic acid derivatives through chiral dioxirane-mediated catalytic asymmetric epoxidation of cinnamic acid derivatives

A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a catalytic amount (5 mol %) of an 11-membered C(2)-symmetric binaphthyl ketone (R)-7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates and those of the lactone moieties in the binaphthyl dioxirane.     

Electroreductive intramolecular coupling of chiral alpha-imino esters: stereoselective synthesis of mixed ketals of cis-2,4-disubstituted azetidine-3-ones

The electroreduction of chiral aromatic alpha-imino esters prepared from (S)-alpha-amino acids, such as (S)-valine, (S)-leucine, and (S)-phenylalanine, in the presence of chlorotrimethylsilane and triethylamine afforded four-membered cyclized products, mixed ketals of cis-2,4-disubstituted azetidine-3-ones, stereospecifically (>99% de, 85-99% ee). The best result of the electroreductive cyclization was obtained using Bu(4)NClO(4) as a supporting electrolyte and a Pt cathode. The absolute stereochemistry of the obtained single stereoisomers was confirmed to be 2R,3R,4S by X-ray crystallography. Calculations for the transition states of the cyclization support the stereospecific formation of the (2R,3R,4S)-isomers.     

Reactivity of p-phenyl substituted β-enamino compounds using k-10/ultrasound. I. synthesis of pyrazoles and pyrazolinones

The reactivity of the β-enamino ketones, 3-amino-1-(p-phenyl-substituted)-2-buten-1-ones 1a-d and β-enamino esters. Ethyl-3-amino-3-(p-phenyl-substituted)-2-propenoates 5a-d were evaluated by systematic studies of the reactions with hydrazine and methylhydrazine by reactions with solid support K-10/ultrasound and homogeneous media (reflux in ethanol or dichloromethane) yielding pyrazole rings 2a-d , N-methylpyrazoles 3a-d, 4a-d and N-methylpyrazolinones 6a-c and 7a-c . The regiochemistry of the cyclization showed dependence of the reaction conditions employed as well as the substituent in the aromatic ring.     

Stereoselective synthesis of optically active bicyclic beta-lactam carboxylic acids that target pilus biogenesis in pathogenic bacteria

Optically active bicyclic beta-lactams were synthesized, starting from 2-H-delta 2-thiazolines and Meldrum's acid derivatives. Several methods to accomplish an ester hydrolysis without damaging the beta-lactam framework were investigated. A rapid CsOH saponification of the beta-lactam methyl esters was developed and protonation of the Cs-carboxylates by Amberlite (IR-120 H+) afforded a series of bicyclic beta-lactam carboxylic acids. Moreover, a convenient method for the synthesis of 2-H-delta 2-thiazolinecarboxylic acid methyl ester 2 was developed. Bicyclic beta-lactam carboxylic acids 7a-g and aldehydes 4a-d were screened for their affinity to the bacterial periplasmic chaperone PapD using a surface plasmon resonance technique. beta-Lactams substituted with large acyl substitutents showed better binding to the chaperone than the native C-terminal peptide PapG 8, demonstrating that bicyclic beta-lactams constitute a new class of potential bacterial chaperone inhibitors.     

Structural requirements in chiral diphosphine-rhodium complexes—XI: Asymmetric homogeneous hydrogenation of z-α-acylaminocinnamic acids and esters with (1s, 2s)-trans-1,2-bis(diphenylphosphinomethyl) cyclohexane/rhodium(i) complexes

Z-α-acylaminocinnamate esters were hydrogenated with neutral rhodium(I) complexes containing (1S, 2S)-trans-1,2-bis(diphenylphosphinomethyl)cyclohexane. Increasing the steric bulk of the alcohol moiety of the ester function results in increased enantioface differentiation in favor of the re-si prochiral face to yield an excess of the S-amino acid derivatives. In the series of N-acetylphenylalanine ester products (resulting from hydrogenation of Z-α-acetamidocinnamate esters) the optical purity increased from 1% ee-(R) [Me]; 20% ee-(S) [Et]; 47% ee-(S) [i-Pr]; to 58% ee-(S) [t-Bu]. Increasing the steric bulk of the acyl function (NHCOR, where R is an alkyl moiety) favors the reduction of the si-re prochiral face [in the methyl ester substrates] to yield an excess of the R-amino acid derivatives. In the series of N-acylphenylalanine methyl ester products (resulting from hydrogenation of Z-methyl α-acylaminocinnamates) the optical purity increased from 1% ee-(R) [Me]; 13% ee-(R) [i-Pr]; to 15% ee-(R) [t-Bu and 1-adamantyl]. The α-formamido and α-benzamido substrates gave hydrogenation products having 22% ee-(R) [H] and 35% ee-(R) [Ph]. In the corresponding free acids, increasing the steric bulk of the acyl function (NHCOR, where R is an alkyl moiety) results in almost no change in the optical purity of the reduction products. In the series of N-acylphenyl-alanine products (resulting from hydrogenation of Z-α-acylaminocinnamic acids) the optical purity was 35% ee-(S) [Me]; 31% ee-(S) [i-Pr]; 33% ee-(S) [t-Bu]; and 35% ee-(S) [1-adamantyl]. The α-benzamido substrate gave a hydrogenation product having 8% ee-(S).     

5-氟尿嘧啶N1-甲酰基氨基酸、短肽的合成及抗肿瘤活性

5-氟尿嘧啶N¹-甲酰氯分别与Gly、Val、Leu、Ile、Phe、Asp和Glu的苄酯反应,制备了7种5-氟尿嘧啶-N¹-甲酰基氨基酸苄酯。氢解后得到了相应的5-氟尿嘧啶N¹-甲酰氨基酸。将其进一步与氨基酸甲酯或二肽甲酯缩合,制备了5-氟尿嘧啶N¹-甲酰基二肽甲酯和三肽甲酯。5-氟尿嘧啶-N¹-甲酰基二肽甲酯也可采用5-氟尿嘧啶-N¹-甲酰氯与二肽甲酯直接反应制备。