- Lipase activity of Lecitase Ultra: characterization and applications in enantioselective reactions
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The general properties of Lecitase Ultra, a phospholipase manufactured and marketed by Novozymes, Denmark, have been studied after purification by ultrafiltration. The enzyme has a molecular mass of 35 KD, pH-optimum of 8.5, and appears to possess a single active site which exhibits both the lipase and phospholipase activities that increase in the presence of Ca2+ and Mg2+ ions. The enzyme is inhibited by heavy metal ions and surfactants, and does not accept p-nitrophenyl acetate and glycerol triacetate. Substrates, such as glycerol tributyrate and p-nitrophenyl palmitate, esters of N-acetyl-α-amino acids and α-hydroxy acids are readily accepted. Amino acids with aliphatic residues, such as alanine, isoleucine, and methionine, are hydrolyzed with high enantioselectivity for the l-enantiomer (E >100), but amino acids with aromatic residues such as phenylalanine and phenylglycine, and esters of α-hydroxy acids are hydrolyzed with low enantioselectivity (E = 1-5). Immobilization of the enzyme in a gelatin matrix (gelozyme) leads to a marginal improvement in the enantioselectivity for these substrates. However, a dramatic improvement in enantioselectivity is observed for ethyl 2-hydroxy-4-oxo-4-phenylbutyrate (E value increases from 4.5 to 19.5 with S-selectivity). Similarly, glycidate esters, such as ethyl trans-(±)-3-phenyl glycidate and methyl trans-(±)-3-(4-methoxyphenyl) glycidate, are selectively hydrolyzed with a remarkable selectivity towards the (2S,3R)-enantiomer providing unreacted (2R,3S)-glycidate esters (ee >99%, conversion 52-55%) by the immobilized enzyme.
- Mishra, Mithilesh Kumar,Kumaraguru, Thenkrishnan,Sheelu, Gurrala,Fadnavis, Nitin W.
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- A novel synthesis of a key intermediate for diltiazem
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A practical synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2a, a key intermediate for diltiazem (3), was described. Treatment of methyl (E)-4-methoxycinnamate (E)-1a with chiral dioxirane, generated in situ from a catalytic amount of an 11-membered C2-symmetric binaphthyl ketone 7a, provided (-)-2a in 78% ee and 89% yield. The crude mixture of (-)-2a and 7a was efficiently separated by the use of novel equipment performing continuous dissolution and crystallization to furnish the optically pure (-)-2a (>99% ee) and recovery of 7a in 64 and 88% yields, respectively.
- Seki, Masahiko,Furutani, Toshiyuki,Imashiro, Ritsuo,Kuroda, Tooru,Yamanaka, Takeshi,Harada, Naoyuki,Arakawa, Hiroaki,Kusama, Mari,Hashiyama, Tomiki
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- Asymmetric synthesis of methyl (2R,3S)-3-(4-methoxyphenyl) glycidate, a key intermediate of diltiazem, via Mukaiyama aldol reaction
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Methyl (2R,3S)-3-(4-methoxyphenyl) glycidate, a key intermediate of diltiazem, was synthesized in good yield with high enantioselectivity based on chiral oxazaborolidine-mediated Mukaiyama aldol reaction of p-anisaldehyde with α,α-dichloro silyl ketene acetal (up to 96% ee), followed by reduction and cyclization.
- Imashiro, Ritsuo,Kuroda, Tooru
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- Asymmetric reduction of 2-chloro-3-oxo-ester into enantiomerically high pure diltiazem precursor by a Candida ketoreductase
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Methyl (2R,3S)-3-(4-methoxyphenyl)glycidate [(2R,3S)-MPGM] is an advanced chiral synthon for the synthesis of the cardiovascular drug diltiazem. It can be easily accessed by cyclizing the reduction products of methyl 2-chloro-3-(4-methoxyphenyl)-3-oxo-propanoate (1a). Herein, we report an identified carbonyl reductase (CpKR) from Candida parapsilosis that displayed an excellent stereoselectivity toward the keto substituent at the C3-position of the 2-chloro-3-oxo-ester 1a. The engineered Escherichia coli cells harboring CpKR gene were directly applied for the asymmetric reduction of keto ester 1a with a space-time yield of 46 g L?1 d?1, which represents the highest productivity in bio-reduction of 1a reported so far. The isolated chiral alcohol products were then applied to the chemical synthesis of (2R,3S)-MPGM in 99% ee and a total yield of 76% in the two-step chemo-enzymatic reactions, which far exceeded the maximum theoretical yield (50%) of the existing industrial process based on a lipase-catalyzed resolution of racemic MPGM. This work provides a promising eco-friendly and cost-effective route toward industrial synthesis of pharmaceutically relevant diltiazem.
- Chen, Cheng,Chen, Qi,Ni, Guo-Wei,Pan, Jiang,Xu, Jian-He,Xuan, Yang
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- Asymmetric reduction of aromatic ketones. II. An enantioselective synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate
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Asymmetric reduction of some 3-keto esters (6, 8, and 11) to 3-hydroxy esters (7, 9, and 12) with various chiral reducing agents was investigated. The products (9 and 12) were converted to methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (2R,3S-3), a key intermediate in the practical enantioselective synthesis of diltiazem (1).
- Matsuki,Sobukawa,Kawai,Inoue,Takeda
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- Bioresolution production of (2R,3S)-Ethyl-3-phenylglycidate for chemoenzymatic synthesis of the taxol C-13 side chain by galactomyces geotrichum ZJUTZQ200, a new epoxide-hydrolase-producing strain
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A newly isolated Galactomyces geotrichum ZJUTZQ200 strain containing an epoxide hydrolase was used to resolve racemic ethyl 3-phenylglycidate (rac-EPG) for producing (2R,3S)-ethyl-3-phenylglycidate ((2R,3S)-EPG). G. geotrichum ZJUTZQ200 was verified to be able to afford high enantioselectivity in whole cell catalyzed synthesis of this chiral phenylglycidate synthon. After the optimization of the enzymatic production and bioresolution conditions, (2R,3S)-EPG was afforded with high enantioselectivity (e.e.S > 99%, E > 49) after a 8 h reaction. The co-solvents, pH buffer solutions and substrate/cell ratio were found to have significant influences on the bioresolution properties of G. geotrichum ZJUTZQ200. Based on the bioresolution product (2R,3S)-EPG, taxol's side chain ethyl (2R,3S)-3-benzoylamino-2-hydroxy- 3-phenylpropionate was successfully synthesized by a chemoenzymatic route with high enantioselectivity (e.e.S > 95%).
- Wei, Chun,Ling, Jinlong,Shen, Honglei,Zhu, Qing
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p. 8067 - 8079
(2014/07/08)
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- Sc(OTf)3-catalyzed diastereoselective Friedel-Crafts reactions of arenes and hetarenes with 3-phenylglycidates
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Five different para-substituted 3-phenylglycidates (3-phenyloxirane-2- carboxylates) were prepared and subjected to reactions with arenes and hetarenes under Lewis acid catalysis. Sc(OTf)3 was found to effectively (5 mol%) promote a Friedel-Crafts reaction in nitromethane as the solvent. The reaction was shown to proceed stereoconvergently, which makes the intermediacy of a benzylic cation likely. The diastereoselectivities varied depending on the choice of the nucleophile and 3-arylglycidate. Best results were obtained with tert-butyl 3-anisylglycidate, which delivered the respective products with high syn-preference in diastereomeric ratios (d.r.) between 82:18 and >95:5. The observed selectivity can be explained by a model, according to which the intermediate benzylic cations adopt a preferred conformation, which allows for diastereoface-differentiation by the adjacent stereogenic center.
- Wilcke, David,Bach, Thorsten
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supporting information; experimental part
p. 6498 - 6503
(2012/09/08)
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- An unusual (R)-selective epoxide hydrolase with high activity for facile preparation of enantiopure glycidyl ethers
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A novel epoxide hydrolase (BMEH) with unusual (R)-enantioselectivity and very high activity was cloned from Bacillus megaterium ECU1001. Highest enantioselectivities (E>200) were achieved in the bioresolution of ortho-substituted phenyl glycidyl ethers and para-nitrostyrene oxide. Worthy of note is that the substrate structure remarkably affected the enantioselectivities of the enzyme, as a reversed (S)-enantiopreference was unexpectedly observed for the ortho-nitrophenyl glycidyl ether. As a proof-of-concept, five enantiopure epoxides (>99% ee) were obtained in high yields, and a gram-scale preparation of (S)-ortho-methylphenyl glycidyl ether was then successfully performed within a few hours, indicating that BMEH is an attractive biocatalyst for the efficient preparation of optically active epoxides. Copyright
- Zhao, Jing,Chu, Yan-Yan,Li, Ai-Tao,Ju, Xin,Kong, Xu-Dong,Pan, Jiang,Tang, Yun,Xu, Jian-He
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experimental part
p. 1510 - 1518
(2011/08/03)
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- Asymmetric epoxidation of cinnamic acid derivatives by in situ generated dioxiranes of chloroacetones: Scope and limitations
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Efficient epoxidation of chiral cinnamic acid derivatives has been achieved by in situ generated dioxiranes of chloroacetones with moderate to good diastereoselectivity (dr up to 90:10) in high yields. Reactivity of cinnamic acid derivatives containing different chiral auxiliaries versus chloroacetones-monochloroacetone 3 (MCA), 1,1-dichloroacetone 4 (DCA) and 1,1,1-trichloroacetone 5 (TCA) and Oxone loading was studied. Both Oxone loading and reaction time reduce with an increase of chlorine atoms in the acetone. The use of 1.1 equiv of TCA was found to be effective for the epoxidation of cinnamate substrates and enhances the reaction up to 4-10-fold compared to acetone and that also decreases the Oxone loading. This method provided methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for the synthesis of diltiazem hydrochloride, with >99% of enantiomeric purity.
- Hajra, Saumen,Bhowmick, Manishabrata
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experimental part
p. 2223 - 2229
(2010/11/04)
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- Arabinose-derived ketones as catalysts for asymmetric epoxidation of alkenes
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Readily available arabinose-derived ketones, containing a tunable butane-2,3-diacetal as the steric blocker, displayed increasing enantioselectivity (up to 90% ee) with the size of the acetal alkyl group in catalytic asymmetric epoxidation of trans-disubstituted and trisubstituted alkenes. The stereochemical communication between our ketone catalysts and the alkene substrates is mainly due to steric effect, and electronic effect involving π-π interaction between phenyl groups of substrate and of catalyst did not appear to be operative in our system.
- Shing, Tony K. M.,Leung, Gulice Y. C.,Luk, To
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p. 7279 - 7289
(2007/10/03)
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- Chemoenzymatic approach to optically active phenylglycidates: Resolution of bromo- and iodohydrins
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Enantiomerically enriched phenylglycidates, precursors of the taxol C-13 phenylisoserine side chain and diltiazem, were prepared by kinetic resolution of anti-2-bromo-3-hydroxy- and anti-3-hydroxy-2-iodophenylpropanoates to provide enantioriched (2R,3R)- and (2S,3S)-halohydrins. The bulkiness and inflexibility of bromo and iodo groups in halohydrins have made them inaccessible to the active site of most of the lipases utilized for the hydrolysis of their acyloxy derivatives. In a set of 22 hydrolases screened herein, including native as well as commercial enzymes, only Aspergillus niger (Lipase AS, AMANO) could catalyze the hydrolysis with high enantioselectivity (E = 176). The resolved halohydrins easily underwent transformation to the corresponding (2S,3R)- and (2R,3S)-phenylglycidates.
- Anand, Naveen,Kapoor, Munish,Koul, Surrinder,Taneja, Subhash C.,Sharma, Rattan L.,Qazi, Ghulam N.
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p. 3131 - 3138
(2007/10/03)
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- A catalytic asymmetric synthesis of chiral glycidic acid derivatives through chiral dioxirane-mediated catalytic asymmetric epoxidation of cinnamic acid derivatives
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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 C2-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.
- Imashiro, Ritsuo,Seki, Masahiko
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p. 4216 - 4226
(2007/10/03)
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- Effect of α-fluorination on asymmetric epoxidation of trans-olefins using α-fluorinated cyclohexanone dioxiranes
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Epoxidations of trans-β-methylstyrene, trans-stilbene and trans-methyl p-methoxycinnamate using chiral dioxiranes derived from both enantiopure diastereomers of α-fluoro cyclohexanones, (2 S, 5 R )-3a-6a and (2 R,5 R)-3e-6e are studied and compared. From ab initio calculations at the HF/6-31G* level of conformational inter-conversion for (2 S,5 R)-D5a and (2 R,5 R)-D5e dioxiranes it was found that, due to the α-fluorine atom, conformer K1 is more stable in the case of (2 S, 5 R)-D5a while conformer K2 is more stable in the case of (2 R, 5 R)-D5e. However, in both cases, the more stable conformers, K1 and K2, undergo rapid inter-conversion. Therefore, based on slow epoxidation reactions and rapid ring inversion of six-membered ring dioxiranes the Curtin-Hammett principle holds. Conformation K2 with axial fluorine having been found to be more reactive, the inversion of configuration observed for the epoxides obtained with ketones 3e-6e (compared with ketones 3a-6a) could be rationalized from competitive reactions of K2 and K1 conformations leading to simultaneous production of both (-) and (+) epoxides in the case of ketones 3e-6e.
- Solladié-Cavallo, Arlette,Jierry, Lo?c,Norouzi-Arasi, Hassan,Tahmassebi, Daryush
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p. 1371 - 1377
(2007/10/03)
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- Cyclohexanones derived from dihydrocarvone as precursor of chiral dioxiranes for epoxidation of olefins
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New ketones having an axial α-fluorine atom and substituents other than fluorine at C8, derived from commercially available (+)-dihydrocarvone, have been prepared and used for epoxidations of trans stilbene, trans methyl p-methoxy cinnamate, trans cinnamyl alcohol and derivatives. It was found that replacement of the H at C8 by a substituent containing an oxygen atom increases the enantioselectivities in all cases. It was also shown that protic substituents (hydroxyl groups) provide a decrease in enantioselectivity in the case of cinnamates probably because of H-bonding dioxirane-substrate. It is noted that the absolute configurations of the various epoxides obtained hold with the usual model involving a spiro-approach on the dioxirane conformation C1 having the α-fluorine axial. Moreover, sub-stoichiometric amounts (0.3 equiv) of ketone can be used in all cases as these ketones do not undergo Baeyer-Villiger oxidation and are recovered. Graphical abstract.
- Solladié-Cavallo, Arlette,Jierry, Lo?c,Lupattelli, Paolo,Bovicelli, Paolo,Antonioletti, Roberto
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p. 11375 - 11381
(2007/10/03)
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- Stereoselective Synthesis of Diltiazem via Dynamic Kinetic Resolution
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An efficient synthesis of diltiazem has been developed using dynamic kinetic resolution (DKR) as a key step. The methyl (2S,3S)-2-chloro-3-hydroxy-3- (4-methoxyphenyl)propionate was synthesized from a racemic mixture of α-chloro-β-keto ester, with high anti diastereoselectivity (92%) and enantioselectivity (95%), based on an asymmetric hydrogenation reaction with a chiral ruthenium(II) catalyst, simply prepared by mixing Ru(cod)(2-methylallyl) 2 with the atropisomeric ligand (S)-MeO-BIPHEP. By treatment of this α-chloro-β-hydroxy ester with a base, the corresponding trans methyl glycidate, a key intermediate of diltiazem, was easily obtained.
- Mordant, Celine,De Andrade, Cristina Cano,Touati, Ridha,Ratovelomanana-Vidal, Virginie,Hassine, Bechir Ben,Genet, Jean-Pierre
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p. 2405 - 2409
(2007/10/03)
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- Highly enantioselective Mukaiyama aldol reaction of αα-dichloro ketene silyl acetal: An efficient synthesis of a key intermediate for diltiazem
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An efficient synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), has been developed on the basis of the highly enantioselective Mukaiyama aldol reaction of p-anisaldehyde (4a) with αα-dichloro ketene silyl acetal 5. Thus, the reaction using a stoichiometric amount of chiral oxazaborolidinone catalyst 12a proceeded to excellent yield (83%) and high enantioselectivity (96% ee), together with the chiral ligand 13a in nearly quantitative recovery. The reaction using a substoichiometric amount of 12e (20 mol%) also proceeded to excellent yield (88%), with somewhat lower enantioselectivity (77% ee). The aldol product 3a thus obtained was easily converted to (-)-2 in excellent yield (80%) and high optical purity (>99% ee). The highly enantioselective Mukaiyama aldol reaction with 5 catalyzed by 12a proved to be applicable to various aldehydes. An efficient preparation of 5 from inexpensive starting materials was also described.
- Imashiro, Ritsuo,Kuroda, Tooru
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p. 974 - 979
(2007/10/03)
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- Catalytic asymmetric epoxidation of α,β-unsaturated carboxylic acid imidazolides and amides by lanthanide-BINOL complexes
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Highly enantioselective catalytic asymmetric epoxidation of α,β-unsaturated carboxylic acid imidazolides and simple amides was developed. In the presence of 5-10mol% of lanthanide-BINOL complexes, the reaction proceeded smoothly with high substrate generality. In particular, in the cases of α,β-unsaturated amides, there was nearly perfect enantioselectivity (>99% ee). The corresponding epoxides were successfully transformed into many types of useful chiral compounds such as α,β-epoxy esters, α,β-epoxy amides, α,β-epoxy aldehydes, α,β-epoxy β-keto ester, and α- and β-hydroxy carbonyl compounds. B3LYP density functional studies were performed to predict substrate reactivity.
- Ohshima, Takashi,Nemoto, Tetsuhiro,Tosaki, Shin-Ya,Kakei, Hiroyuki,Gnanadesikan, Vijay,Shibasaki, Masakatsu
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p. 10485 - 10497
(2007/10/03)
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- Process for the preparation of intermediates useful for the synthesis for benzothiazepines
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A process for the preparation of the compounds of formula (wherein R has the meanings reported in the specification) by enzymatic transesterification of enantiomeric mixtures is described.These compounds are intermediates useful in the synthesis of Diltiazem.
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Page column 5
(2008/06/13)
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- A practical procedure for the large-scale preparation of methyl (2R,3S)-3-(4-methoxyphenyl) glycidate, a key intermediate for diltiazem
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A practical synthesis of methyl (2R,3S)-3-(4- methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), was developed. Treatment of methyl (E)-4-methoxycinnamate 3 with chiral dioxirane, generated from chiral ketone 4, provided (-)-2 in 77% ee and 89% yield. The crude mixture of (-)-2 and 4 was efficiently separated by the use of novel and simple equipment performing a lipase-catalyzed transesterification and a continuous dissolution and crystallization to furnish the optically pure (-)-2 and recovery of 4 in 74% and 91% yield, respectively.
- Furutani, Toshiyuki,Imashiro, Ritsuo,Hatsuda, Masanori,Seki, Masahiko
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p. 4599 - 4601
(2007/10/03)
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- Enzymatic Kinetic Resolution of Methyl 3-Phenylglycidate by Transesterification with Amino Alcohols
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Kinetic resolution of racemic methyl trans-3-(4-methoxyphenyl)glycidate, a key intermediate for the synthesis of the well-known drug diltiazem hydrochloride, has been accomplished by transesterification reactions with suitable amino alcohols catalyzed by Novozym 435 in organic solvents.
- Cantele, Francesca,Restelli, Angelo,Riva, Sergio,Tentorio, Dario,Villa, Marco
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p. 721 - 725
(2007/10/03)
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- Asymmetric epoxidation of trans-olefins via chiral dioxiranes: A possible contribution of axial approaches in the case of tri- and tetrasubstituted α-fluoro cyclohexanones
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During the asymmetric epoxidation of stilbene and methyl p-methoxycinnamate with chiral dioxiranes (derived from 2,2′,5-tri- and 2,2′,5,5′-tetrasubstituted cyclohexanones with an axial fluorine at C2) a 26 to 30percent increase in ee was observed upon desymmetrization of the axial face of the dioxirane (through disubstitution at C5 or introduction of a fluorine on the equatorial iPr-substituent located at C5), which suggests a contribution of the axial approach of the olefin to the dioxirane (in addition to the main equatorial approach). The two ketones 5a and 6a, which do not undergo Baeyer-Villiger oxidation, can be used in substoichiometric amounts and are fully recovered after the reactions, provide epoxides in high yield (75-90percent) and high (95:5) to satisfying (83:17 to 87:13) enantiomeric ratios.
- Solladie?-Cavallo, Arlette,Boue?rat, Lae?titia,Jierry, Loi?c
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p. 4557 - 4560
(2007/10/03)
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- Process for preparing an optically active phenylglycidyl acid derivative
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The invention relates to a process for preparing an optically active trans-compound having formula (1), in which R represents a phenyl group, whether or not substituted, preferably p-methoxyphenyl, and A is derived from an optically active compound, in which an aldehyde having formula (2), in which R is as defined above, is, in the presence of a base, brought into contact with an optically active acetyl compound having formula (3), in which X represents a leaving group and in which A is derived from an amino alcohol, preferably a beta -amino alcohol having a rigid structure. Particularly good results were obtained when use was made of a compound having formula (3), in which A is derived from an amino indanol compound having formula (4), in which R1 and R2 represent a (hetero)alkyl or (hetero)aryl group, whether or not substituted, having 1-10 C atoms, or R1 and R2 constitute an aromatic or aliphatic ring together with the N atom to which they are bound, in particular in which R1 and R2 each independently of one another represent methyl, ethyl, isopropyl, n-propyl, n-butyl, allyl, benzyl or tosyl.
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- Enantioselective Darzens reaction: Asymmetric synthesis of trans-glycidic esters mediated by chiral lithium amides
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Enantioselective and diastereoselective Darzens reaction mediated by chiral lithium amides was achieved between tert-butyl chloroacetate and aromatic aldehydes to give the corresponding trans-glycidic esters in up to 84% enantiomeric excess.
- Takahashi,Muraoka,Capo,Koga
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p. 1821 - 1823
(2007/10/03)
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- A new enantioselective synthesis of glycidates via dynamic kinetic resolution of racemic 2-chloro-3-keto esters using chiral Ru (II) complexes
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2-chloro-3-keto esters were quantitatively hydrogenated to syn and anti 2-chloro-3-hydroxyester by asymmetric hydrogenation with chiral ruthenium (II) catalysts prepared in-situ from (COD)Ru(2-methylallyl)2 in presence of atropisomeric ligands such as MeO-Biphep and Binap, giving enantioselectivity up to 99%, 2-chloro-3-hydroxy esters were treated with different bases to give (E)-and (Z)-2,3-epoxyalkanoates in 65-90% yields with 84-97% ee.
- Genet, Jean-Pierre,Cano De Andrade,Ratovelomanana-Vidal
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p. 2063 - 2066
(2007/10/02)
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- Enantioselective Catalytic Epoxidation of Cinnamate Esters
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A broad study of the (salen)Mn(III)-catalyzed asymmetric epoxidation of cis-cinnamate esters reveals that the steric properties of the ester group have a profound influence on enantioselectivity in the epoxidation reaction, with bulkier esters affording highest ee's.The sensitivity of the reaction selectivity to the steric properties of the cis-alkene are consistent with a "skewed" side-on approach of olefin to the metal -oxo.The electronic properties of the substrate arene ring substituents do not correlate with epoxidation ee, but instead with the cis/trans partitioning of product formation.Evidence is provided for a non-polar inter mediate in a stepwise oxygen-atom-transfer mechanism.The presence of pyridine N-oxide derivatives has a significant effect on catalysts rates and total turnovers, but negligible influence on the stereoselectivity of epoxidation.A mechanistic basis for the role of these additives is proposed.The synthetic applicability of the cinnamate epoxidation methodology is illustrated in the highly enantioslective synthesis of diltiazem.
- Jacobsen, Eric N.,Deng, Li,Furukawa, Yoshiro,Martinez, Luis E.
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p. 4323 - 4334
(2007/10/02)
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- A new enantioselective synthesis of (2R,3S)-3-(4-methoxyphenyl)glycidic ester via the enzymatic hydrolysis of erythro-N-acetyl-β-(4- methoxyphenyl)serine
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Enantioselective synthesis of (2R,3S)-3-(4-methoxyphenyl)glycidic ester ((2R,3S)-1) via the enzymatic hydrolysis of erythro-N-acetyl-β-(4- methoxyphenyl)serine (9) was investigated. Treatment of the obtained α- amino acid (-)-10 with NaNO2-KBr-dilute H2SO4, esterification, and subsequent oxiran-ring closure of the halohydrin gave the target compound (2R,3S)-1 with high enantiomeric excess (94% ee).
- Inoue,Matsuki,Oh-Ishi
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p. 1521 - 1523
(2007/10/02)
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- Racemic epoxyester resolution through enantioselective enzymatic hydrolysis
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Resolution of racemic trans-epoxyester in order to get the (-)(2R,3S)-enantiomer, a useful intermediate in the synthesis of a coronarian vasodilatator, has been achieved through enantioselective hydrolysis by hydrolases.
- Laffitte, J A,Gancet, C,Soccol, C
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- Process for preparing 2-halogeno-3-hydroxy-3-phenyl-propionic acid ester compounds
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Disclosed is a process for preparing 2-halogeno-3-hydroxy-3-phenylpropionic acid ester compounds represented by the formula (I): STR1 wherein Ring A is a phenyl group which may be substituted, R1 is an ester residue, and X is a halogen atom, which comprises permitting an enzyme having the ability of stereoselectively reducing oxo group to hydroxy group to act on 2-halogeno-3-oxo-3-phenylpropionic acid ester compounds represented by the formula (II): STR2 wherein Ring A, R1 and X have the same meanings as defined above.
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- Reactions of Methyl threo-2-Acetoxy-3-chloro-3-(4-methoxyphenyl)propanoate and Methyl cis-2,3-Epoxy-3-(4-methoxyphenyl)propanoate with 3,5-Dimethoxyphenol: Potential Routes to Flavan-3-ols
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Attempted syntheses of flavan-3-ols by reaction of either methyl threo-2-acetoxy-3-chloro-3-(4-methoxyphenyl)propanoate (3) or methyl cis-2,3-epoxy-3-(4-methoxyphenyl)propanoate (14) with 3,5-dimethoxyphenol failed to give the required aryl ethers.Products usually were derived from C-alkylation of the electron-rich phenol although reaction of the chloro acetate (3) with the phenoxide ion gave the furanone (5).The single-crystal X-ray structures of methyl 4-hydroxy-3-(4-methoxyphenyl)-2-(4-methoxyphenylmethyl)-5-oxo-2,5-dihydrofuran-2-carboxylate and cis-3-hydroxy-5,7-dimethoxy-4-(4-methoxyphenyl)-3,4-dihydro-2H-1-benzopyran-2-one have been determined.
- Brown, Roger. F. C.,Jackson, W. Roy,McCarthy, Tom D.,Fallon, Gary D.
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p. 1833 - 1843
(2007/10/02)
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- Facile synthesis of (2R,3S)-3-(4-methoxyphenyl)glycidic esters via optical resolution of the unisolated labile free acid
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(,3S)-3-(4-Methoxyphenyl)glycidic esters were efficiently synthesized by the optical resolution of the racemic acid and esterification of the optically active acid thus obtained, in the form of its alkali metal salt.
- Yamamoto,Hayashi,Masaki,Nohira
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p. 403 - 406
(2007/10/02)
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- Method for preparing optically active 3-phenylglycidic acid esters
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There is disclosed a method for preparing an optically active 3-phenylglycidic acid ester compound, which comprises permitting an enzyme having the ability of stereoselectively hydrolyzing an ester bond to act on a racemic 3-phenylglycidic acid ester which may be unsubstituted or substituted on the phenyl group, thereby stereoselectively hydrolyzing one of the optically active isomers and then separating and collecting the antipode from the reaction mixture.
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- REACTION OF 4-SUBSTITUTED BENZALDEHYDES AND ACETOPHENONES WITH CHLOROACETONITRILE
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Under conditions of phase-transfer catalysis or in homogeneous solution of potassium tert-butoxide the title compounds give stereoisomeric mixtures of substituted 2,3-epoxy nitriles III and IV.Alkaline hydrolysis of epoxy nitriles IV afforded the corresponding 2-arylpropanals in low yields.On treatment with methanol and potassium carbonate, epoxy nitriles III and IV were converted into epoxy esters in good yields.
- Svoboda, Jiri,Kocfeldova, Zuzana,Palecek, Jaroslav
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p. 822 - 832
(2007/10/02)
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- Reaction of 3-Phenylglycidic Esters. Part 1. Stereoselective Opening of the Oxirane Ring of trans-3-Phenylglycidic Esters with 2-nitrothiophenols and the Effects of Various Catalysts Thereon
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In the reaction of 2-nitrothiophenol (2) with trans-3-phenylglycidic esters carrying various substituents on the benzene ring, both reactivity and stereoselectivity of the oxirane ring-opening of the glycidates were markedly influenced by the electronic nature of the substituents.The presence of electron-donating groups was favourable for both reactivity and the preferential formation of cis-opening products, while the reverse was true for electron-withdrawing groups.As a result of our investigation on the catalytic effect of various Lewis acids in the reaction of the 4-methoxy derivative (1) with (2), tin compounds were found to be effective catalysts for cis-opening and readily produced the threo-nitro ester (3a), a key intermediate for the synthesis of diltiazem (5).Isolation of the crystalline complex (adduct A) from the reaction of (2) with SnCl4 and its efficient catalytic activity similar to that of SnCl4 suggest that the transition state involves co-ordination of tin derivatives both with (2) and the epoxy oxygen of (1) to cause highly specific cis-opening.
- Hashiyama, Tomiki,Inoue, Hirozumi,Konda, Mikihiko,Takeda, Mikio
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p. 1725 - 1732
(2007/10/02)
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