手性桃潜蛾性信息素的新合成路线

桃潜蛾(peach leafminer moth;Lyonetiaclerkella,L.)属鳞翅目潜蛾科,在日本和我国辽东半岛等各地果园中危害极大。因化蛹后的     

Microbial enantioselective ester hydrolysis for the preparation of optically active 4,1-benzoxazepine-3-acetic acid derivatives as squalene synthase inhibitors

Microbial enantioselective ester hydrolysis for the preparation of optically active (3R,5S)-(-)-5-phenyl-4,1-benzoxazepine-3-acetic acid derivatives as potent squalene synthase inhibitors was investigated. Pseudomonas diminuta and Pseudomonas taetrolens hydrolyzed the racemic ethyl ester of the 5-(2-chlorophenyl) analogue to yield the (-)-carboxylic acid with excellent enantiomeric excess (>99% ee). We found that the (-)-enantiomer was an active inhibitor. Bulkiness of the ester moiety did not affect the enantioselectivity but did affect reactivity. The racemic ethyl ester of the 5-(2-methoxyphenyl) analogue, 5-(2,3-dimethoxyphenyl) analogue and 5-(2,4-dimethoxyphenyl) analogue were also hydrolyzed with Pseudomonas taetrolens to afford enantiomerically pure (-)-carboxylic acids in large scale. As another route to (3R,5S)-(-)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid [(-)-1c], the earlier intermediate (-)-2-amino-5-chloro-alpha-(2,3-dimethoxyphenyl)benzyl alcohol [(-)-12] was successfully obtained by asymmetric hydrolysis of (+/-)-5-chloro-alpha-(2,3-dimethoxyphenyl)-2-pivaloylaminobenzyl acetate with Pseudomonas sp. S-13 with >99% ee in kilogram scale followed by alkaline treatment. The product (-)-12 was converted to (-)-1c without racemization.     

Lipase-catalyzed kinetic resolution on solid-phase via a "capture and release" strategy

The lipase-catalyzed kinetic resolution of (R/S)-3-phenylbutyric acid 2 using solid-supported cyclohexane-1,3-dione (CHD) 6 is described. In each case the predominant enantiomer observed, after cleavage from the resin, was (R)-(-)-3-phenylbutyric acid (R)-2 (ee > 99%) rather than the expected (S)-enantiomer of 2. This observation is in contrast to the fact that Chromobacterium viscosum lipase shows high enantiospecificity for the (S)-enantiomer in the corresponding solution-phase hydrolysis reactions. The (R)-acyl group was subsequently released from the resin by NaOH hydrolysis, and the yield of the reaction could be improved by triple acylation of the resin.     

Syntheses of PDE3A inhibitor ORG9935 and determination of the absolute stereochemistries of its enantiomers by X-ray crystallography

Two synthetic methods were developed for the synthesis of PDE3A inhibitor ORG9935. The first one proceeds in six steps and 34% overall yield and the second one in five steps and an overall yield of 69% starting from commercially available starting material 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid (6). The enantiomers of ORG9935 were separated by chiral column chromatography and the absolute stereochemistry of the (+)-enantiomer, ORG20865 was determined by X-ray crystallography to possess the (S)-configuration. The (?)-enantiomer, ORG20864, was therefore assigned the (R)-stereochemistry. The biologically less active (+)-isomer ORG20865 was converted to racemic ORG9935 under basic conditions, which then can be separated again into the enantiomers. The crystal structure of ORG20865 is notable for having the highest Z′ for any known pharmaceutical substance.     

Palladium-catalyzed enantioselective 1,3-rearrangement of racemic allylic sulfinates: asymmetric synthesis of allylic sulfones and kinetic resolution of an allylic sulfinate

Described is an asymmetric synthesis of cyclic and acyclic allylic S-aryl and S-alkyl sulfones through a highly selective palladium(0)-catalyzed 1,3-rearrangement of racemic allylic sulfinates. Treatment of racemic cyclic and acyclic allylic S-tolyl- and S-tert-butylsulfinates with Pd(2)(dba)(3).CHCl(3) as precatalyst and N,N'-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphosphino)benzamide] as ligand for the palladium atom afforded the corresponding isomeric allylic S-tolyl and S-tert-butyl sulfones of 93-99% ee in 82-96% yield. The rearrangement of the allylic sulfinates most likely proceeds in an intermolecular fashion via formation of a cationic pi-allylpalladium complex and the sulfinate ion. The racemic allylic sulfinates were obtained from the corresponding racemic alcohols and racemic tolylsulfinyl chloride and racemic tert-butylsulfinyl chloride, respectively, in high yields. Rearrangement of the racemic tert-butylsulfinic acid 2-cyclooct-1-enyl ester with Pd(2)(dba)(3).CHCl(3) and the bisphosphane was accompanied by a highly selective kinetic resolution of the substrate and gave at 50% conversion the (R)-configured sulfinate as mixture of the S(S) and R(S) diastereomers of 92% ee and 85% ee and the (S)-configured 3-tert-butylsulfonyl cyclooctene sulfone 15a with 98% ee in almost quantitative yields.     

Preparation of optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolution

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1), (2RS,3SR)-2-benzoylamino-3-hydroxy-3-phenylpropanoic acid [(2RS,3SR)-2] was first optically resolved using (1S,2S)- and (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol as the resolving agents to afford (2R,3S)- and (2S,3R)-2 in yields of 73% and 66%, based on half of the starting amount of (2RS,3SR)-2. Next, the racemic structures of ammonium and some organic ammonium salts of (2RS,3SR)-2 were examined based on melting point, solubility, and infrared spectrum, with the aim of optical resolution by preferential crystallization. The benzylammonium salt of (2RS,3SR)-2 was suggested to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization of the racemic salt afforded the (2R,3S)- and (2S,3R)-salts with optical purities of 90-97%. The (2R,3S)- and (2S,3R)-2 obtained from the purified salts were hydrolyzed by reflux in hydrochloric acid to give (2R,3S)- and (2S,3R)-1.     

Access to Wieland-Miescher ketone in an enantiomerically pure form by a kinetic resolution with yeast-mediated reduction

Both enantiomers of Wieland-Miescher ketone [3,4,8, 8a-tetrahydro-8a-methyl-1,6(2H,7H)-naphthalenedione], in a highly enantiomerically enriched form, became readily available by a newly developed kinetic resolution with yeast-mediated reduction. From a screening of yeast strains, Torulaspora delbrueckii IFO 10921 was selected. The collected cells of this strain, obtained by an incubation in a glucose medium, smoothly reduced only the isolated carbonyl group of the (S)-enantiomer, while the (R)-enantiomer remained intact. Starting from both enantiomers ( approximately 70% ee) prepared by an established proline-mediated asymmetric Robinson annulation, the reduction with T. delbrueckii gave the (R)-enantiomer (98% ee) and the corresponding alcohol (4aS,5S)-4,4a, 5,6,7,8-hexahydro-5-hydroxy-4a-methyl-2(3H)-naphthalenone (94% ee, 94% de) in preparative scale in nearly quantitative yields. An approach for the asymmetric synthesis of the Wieland-Miescher ketone was also successful. 2-Methyl-2-(3-oxobutyl)-1,3-cyclohexanedione, the prochiral precursor, was reduced with this strain to give a cyclic acetal form of (2S, 3S)-3-hydroxy-2-methyl-2-(3-oxobutyl)cyclohexanone, in a stereomerically pure form.     

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.     

Enantioselective synthesis of (-)-terpestacin and (-)-fusaproliferin: clarification of optical rotational measurements and absolute configurational assignments establishes a homochiral structural series

An enantioselective synthesis of the syncytium formation inhibitor (-)-terpestacin (1, 19 steps, 5.8% yield from the allylation product of (R,R)-pseudoephedrine propionamide, 3) and the fungal metabolite (-)-fusaproliferin (2, 21 steps, 5.3% yield from 3) in their natural configurations is described. The route employs a series of stereoselective enolate alkylation reactions to establish the initial stereogenic center, set the quaternary carbon configuration, close the 15-membered ring, and introduce the side-chain residue with proper stereocontrol. Careful analysis of our synthetic materials alongside natural samples has revealed that several errors were made in the earlier measurements of optical rotation or in the absolute stereochemical assignments of these natural products. Clarifying all discrepancies, we show here that natural terpestacin (1) is levorotatory, not dextrorotatory as originally described, but was correctly assigned as the (1S,11S,15R,23S)-enantiomer. Fusaproliferin (2) is levorotatory, as reported, but is in fact the (1S,11S,15R,23S)-enantiomer and not the antipodal configuration originally assigned.     

Enantioselective oxidation of O-methyl-N-hydroxylamines using monoamine oxidase N as catalyst

Enantioselective oxidation of racemic O-methyl-N-hydroxycyclohexylethylamine, using a variant of monoamine oxidase N (MAO-N) from Aspergillus niger, yields unreacted (R)-enantiomer (e.e. = 99%) together with the oxime exclusively in the (E)-configuration.     

(R)-tert-Butoxycarbonylamino-fluorenylmethoxycarbonyl-glycine from (S)-benzyloxycarbonyl-serine or from papain resolution of the corresponding amide or methyl ester

The enantiospecific synthesis of (R)-Boc-(Fmoc)-aminoglycine 7 was achieved. (S)-Cbz-serine 1 was reacted with diphenylphosphoryl azide in the presence of triethylamine to yield cyclic (S) carbamate 2. The ring nitrogen of 2 was protected with a Boc group (3). The cyclic carbamate of 3 was hydrolyzed with benzyltrimethylammonium hydroxide to yield the (R)-enantiomer of alcohol 4. The oxidation of 4 with pyridinium dichromate yielded the enantiomerically pure (97% ee) (R)-Boc-(Cbz)-aminoglycine 5, which was converted to 7 with retention of optical purity. Similarly, starting from (S)-Boc-serine 9, cyclic (S) carbamate 10 was obtained. The ring nitrogen of 10 was protected with a Cbz group (11) with retention of configuration. The cyclic carbamate of 11 was base hydrolyzed to yield 12, the (S)-enantiomer alcohol. Independently, Boc-(Fmoc)-aminoglycine amide 13 and Boc-(Fmoc)-aminoglycine methyl ester 14 were resolved using papain. The stereochemistry of the isolated acid was determined to be (R) by coelution on HPLC of its derivative with Marfey's reagent and that of an authentic sample (7) obtained by enantiospecific synthesis.     

Chiral separation of enantiomeric 1,2-diamines using molecular imprinting method and selectivity enhancement by addition of achiral primary amines into eluents.

The imprinted polymers based on a transient complex formation between methacrylic acid and template molecules were prepared by using methacrylic acid and ethylene dimethacrylate as a cross-linking agent. The template molecules used were (R,R)-cyclohexanediamine (1), (S,S)-1,2-diphenylethylenediamine (2) and (S)-1,1'-binaphthyl-2,2'-diamine (3). Another group of templates were those in which the amino group of these templates had been substituted by the hydroxy group: (R,R)-1,2-cyclohexanediol (4) and (S,S)-hydrobenzoin (5). Racemic 2 was separated by the polymer prepared with template 2 (P2) and that with template 1 (P1). Template 2 is larger than template 1 in steric bulkiness, but P1 was effective for the enantiomer separation of racemic 2. P1 was not effective for the separation of racemic 4. Enantioselectivity observed in racemic 2 in P2 was higher than that in racemic 1 in P1. P2 has no definite predetermined shape for solute 1, but it was capable of separating racemic 1. This separation should be thus ascribed to the orientation of at least two carbonyl groups reflecting the conformation of template 2 in P2 cavity. Racemic 5, having the same configuration of the two bulky phenyl groups as that of solute 2, was separated in P2. When the primary amines such as propylamine, cyclohexylamine and 1-adamantanamine were added into the acetic acid-methanol mixtures as eluents, both enantioselectivity and retentivity for racemic 2 were enhanced along with the remarkable peak tailing.     

苯磺酸贝他斯汀的合成新方法

探索了一条合成苯磺酸贝他斯汀的新路线。以2-吡啶甲酸、氯苯为原料，经过9步反应合成苯磺酸贝他斯汀，其中关键消旋中间体(4-氯苯基)(2-吡啶基)甲氧基哌啶，经过D-DBTA拆分，可得到光活性(S)-(4-氯苯基)(2-吡啶基)甲氧基哌啶(>99% ee)。同时，(R)-(4-氯苯基)(2-吡啶基)甲氧基哌啶经过消旋化后再次拆分得到(S)-构型产物。该合成方法反应条件温和，具有工业化生产前景。最终产物结构由¹H NMR， ¹³C NMR和HR-MS(ESI)确证。      

Optical resolution by preferential crystallization of (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid and its use in synthesizing optically active 2-amino-2-methyl-3-phenylpropanoic acid

To synthesize optically active 2-amino-2-methyl-3-phenylpropanoic acid (1), (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid [(RS)-2] was first optically resolved using cinchonidine as a resolving agent to yield optically pure (S)- and (R)-2 in yields of about 70%, based on half of the starting amount of (RS)-2. Next, the racemic structure of (RS)-2 was examined based on melting point, solubility, IR spectrum, and binary and ternary phase diagrams, with the aim of optical resolution by preferential crystallization of (RS)-2. Results indicated that the (RS)-2 exists as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization yielded (S)- and (R)-2 with optical purities of about 90%, which were fully purified by recrystallization. After O-tosylation of (S)- and (R)-2, reduction by zinc powder and sodium iodide gave (R)- and (S)-1, respectively.     

Chiral HPLC Separation of Rosiglitazone and its Main Metabolites and Studies on Their Racemization

Rosiglitazone (RSG) is marketed as a racemic mixture although the antidiabetic activity is essentially related to the (S)-enantiomer. The chiral center has an adjacent carbonyl group; therefore, the (R)-enantiomer could be transformed to the (S)-enantiomer or vice versa by keto-enolic tautomerism. The literature indicates that this racemization is slow enough to allow the evaluation of the properties of the isolated enantiomers. However, there is no information about the enantioselective kinetic disposition and metabolism of RSG. Additionally, there are no studies on the racemization of its metabolites. Considering these facts, a chiral HPLC method was developed and used for the first time to study the racemization of RSG and its main metabolites. Different conditions, including those used to evaluate the in vitro enantioselective metabolism, were employed. The simultaneous chiral separation of RSG and metabolites was achieved on a Chiralcel OJ-H column by employing methanol/ethanol (90:10, v/v) as mobile phase. The racemization studies showed that the half-life of RSG decreased more than 30 times when the temperature increased from 4 to 37 °C. It was also observed that the half-life of RSG changed from approximately 20 h at pH 3.5 to approximately 2 h at pH 7.4. The same profile was observed for its metabolites. Organic solvents and UV light did not present influence on the racemization process. In addition, a Complete Factorial Design was conducted to evaluate the influence of some parameters that can be changed during an in vitro metabolism study. The results obtained showed that the racemization occurs under in vitro metabolism conditions.     

Dynamic kinetic resolution of racemic gamma-aryl-delta-oxoesters. Enantioselective synthesis of 3-arylpiperidines

Cyclodehydration of racemic gamma-aryl-delta-oxoesters with (R)- or (S)-phenylglycinol stereoselectively affords bicyclic delta-lactams, in a process that involves a dynamic kinetic resolution. Subsequent reduction of these lactams leads to enantiopure 3-arylpiperidines. Starting from racemic aldehyde esters, this short sequence has been applied to the synthesis of (R)-3-phenylpiperidine and the antipsychotic drug (-)-3-PPP (an (S)-3-arylpiperidine), whereas starting from racemic ketone esters enantiopure cis-2-alkyl-3-arylpiperidines are prepared.     

Fluorescent high-performance liquid chromatographic analysis of vigabatrin enantiomers after derivatizing with naproxen acyl chloride

Vigabatrin is widely used as an anticonvulsant in the treatment of seizures. Vigabatrin is usually supplied as racemate in formulation, but only the (S)-(+)-enantiomer of vigabatrin is pharmacologically active. A simple and sensitive liquid chromatographic method is described for the separation and quantification of vigabatrin enantiomers. The method is based on derivatizing racemic vigabatrin with a fluorescent chiral reagent (naproxen acyl chloride). The resulting diastereomeric derivatives are highly responsive to a fluorimetric detector (lambda(ex)=230 nm, lambda(em)=350 nm). The lower quantitation limit of the method is attainable at 25 nM for (S)-(+)-vigabatrin or (R)-(-)-vigabatrin with a detection limit of about 2.5 nM (S/N=3 with 10 microl injected). Application of the method to the analysis of vigabatrin in serum of dosed patients proved feasible.     

Resolution and absolute stereochemistry of 6,7-dimethoxy-4-phenyl- 1,2,3,4-tetrahydroisoquinoline. The crystal structure of the R-hydrochloride salt form.

Stereospecific multistep synthesis and resolution of 6,7-dimethoxy-4- phenyl-1,2,3,4-tetrahydroisoquinoline (3) has been achieved from its racemic base. The absolute configurations of the optical antipodes converted into their hydrochloride salt forms have been determined by X-ray diffractometric analysis, thus permitting assignment of the antipodes as the (+)-(4R)-3 and (-)-(4S)-3 enantiomers. The crystal structures of the two enantiomers are related as mirror images and only the (4R)-3.HCl form has been fully determined by three-dimensional X-ray diffraction. In the solid state, the carbon atoms of the two methoxy groups deviate slightly from the benzene-ring plane and the chirally oriented phenyl substituent is almost perpendicularly tilted out of conjugation with the isoquinoline system. Examination of the enantiomers in several biochemical tests for 5-HT, NE and DA uptake inhibition-activity revealed an exclusive preference for the (4S)-enantiomer. These results are in accord with previous suggestions that the S-configurational state of the 4-phenyl substituent is important for biological activity.     

erythro-1-Naphthyl-1-(2-piperidyl)methanol: synthesis,resolution, NMR relative configuration,and VCD absolute configuration

The erythro isomer of 1-naphthyl-1-(2-piperidyl)methanol 4, an efficient chiral modifier for asymmetric heterogeneous hydrogenation, was obtained as the major isomer (95%) in two steps while the threo isomer can be obtained as the major isomer (67%) in three steps. erythro-4 and threo-4 were resolved on a CHIRALCEL OD-RH column. It has been shown by VCD that the diastereomer determined as the erythro by NMR was indeed the erythro and that the first eluted (-)-enantiomer on CHIRALCEL OD-R or -RH columns has the (1R,2S) configuration. The VCD studies identify the presence of at least five conformers in CDCl(3) solution. Moreover, this (-)-(1R,2S) absolute configuration found by VCD is consistent with the expected stereo-outcome of catalytic hydrogenation of pyruvate into lactate, which supported the (+)-(1S,2R) assignment.     

Crystallization-induced chiral inversion as the key step for synthesis of (S)-2-acetylthio-3-phenylpropanoic acid from l-phenylalanine

[reaction: see text] A novel crystallization-induced chiral inversion of (S)-2-bromo-3-phenylpropanoic acid to its (R)-enantiomer with excellent enantiomeric excess (96-99%) is achieved. Optically pure (S)-2-acetylthio-3-phenylpropanoic acid can be prepared in good yield from inexpensive and commercially available l-phenylalanine via diazotization/bromination, chiral inversion, and thioacetate substitution reactions.