Nitrile biotransformations for highly enantioselective synthesis of oxiranecarboxamides with tertiary and quaternary stereocenters; efficient chemoenzymatic approaches to enantiopure alpha-methylated serine and isoserine derivatives

[reaction: see text] Biotransformations of a number of differently substituted and configured oxiranecarbonitriles using Rhodococcus sp. AJ270, a microbial whole-cell catalyst that contains nitrile hydratase/amidase, were studied. While almost all trans-configured 3-aryl-2-methyloxiranecarbonitriles and 2,3-dimethyl-3-phenyloxiranecarbonitrile were efficiently hydrated by the action of the less enantioselective nitrile hydratase, the amidase exhibited excellent 2S,3R-enantioselectivity against 2-methyl-3-(para-substituted-phenyl)oxiranecarboxamides. Under very mild conditions, biotransformations of nitriles provided an efficient and practical synthesis of 2R,3S-(-)-3-aryl-2-methyloxiranecarboxamides, electrophilic epoxides with tertiary and quaternary stereocenters, in excellent yield with enantiomeric excess greater than 99.5%. The synthetic applications of the resulting enantiomerically pure epoxides were demonstrated by convenient and straightforward syntheses of polyfunctionalized chiral molecules possessing a quaternary stereocenter such as R-(+)-2-hydroxy-2-methyl-3-phenylpropionic acid, 2R,3R-(-)-3-amino-2-hydroxy-2-methyl-3-phenylpropionic acid, and 2S,3S-(+)-2-amino-3-hydroxy-2-methyl-3-phenylpropionic acid, employing the regio- and stereospecific epoxide ring opening reactions of 2R,3S-(-)-2-methyl-3-phenyloxiranecarboxamide as the key steps.     

Regioselective intramolecular ring closure of 2-amino-6-bromo-2,6-dideoxyhexono-1,4-lactones to 5- or 6-membered iminuronic acid analogues: synthesis of 1-deoxymannojirimycin and 2,5-dideoxy-2,5-imino-D-glucitol

1-Deoxymannojirimycin (8c) was synthesised from 2-amino-6-bromo-2,6-dideoxy-D-mannono-1,4-lactone (7) by intramolecular direct displacement of the C-6 bromine employing non-aqueous base treatment followed by reduction of the intermediate methyl ester. Likewise, using aqueous base at pH 12, ring closure took place by 5-exo attack on the 5,6-epoxide leading to 2,5-dideoxy-2,5-imino-L-gulonic acid (9b), which was reduced to 2,5-dideoxy-2,5-imino-D-glucitol (9b). The method was further applied to 2-amino-6-bromo-2,6-dideoxy-D-galacto- as well as D-talo-1,4-lactones (14 and 15). However, only the corresponding six-membered ring 1,5-iminuronic acid mimetics, namely (2R,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-galactonic acid, 16) and (2S,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-talonic acid, 17), were obtained. The corresponding enantiomers, L-galacto- as well as L-talo-2-amino-6-bromo-2,6-dideoxy-1,4-lactones ent-14 and ent-15, reacted accordingly to give the D-galacto- and L-altro-1,5-iminuronic acid mimetics, (2S,3S,4R,5S)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-L-galactonic acid, ent-16) and (2R,3S,4R,5S)-3,4,5-trihydroxypipecolic acids (2,6-dideoxy-2,6-imino-L-talonic acid, ent-17), respectively.     

Synthesis of polymers bearing pendant norbornadiene moieties by addition reaction of poly(glycidyl methacrylate-co-methyl methacrylate)s with 2,5-norbornadiene-2-carboxylic acids

Polymers bearing photoresponsive norbornadiene (NBD) moieties were synthesized by the addition reaction of poly(glycidyl methacrylate-co-methyl methacrylate)s containing pendant epoxide groups with 3-phenyl-2,5-norbornadiene-2-carboxylic acid (PNBC), 3-[(phenyl)carbamoyl]-2,5-norbornadiene-2-carboxylic acid 3-[(4-acetylphenyl) carbamoyl]-2,5-norbornadiene-2-carboxylic acid (APCND), and 3-[(4-methoxyphenyl)carbamoyl]-2,5-norbornadiene-2-carboxylic acid using tetrabutylammonium bromide as a catalyst in DMF. The polymers bearing pendant PNBC or APCND moieties have higher photochemical reactivity in the film state than the polymers bearing pendant PCND or MPCND moieties. Although the pendant quadricyclane (QC) group produced by the photoirradiation of the PNBC moiety in these polymers has excellent storage stability in the film state, without catalyst at room temperature, the QC group in the polymer film with the catalyst reverts gradually to the NBD moiety at room temperature. © 1993 John Wiley & Sons, Inc.     

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.     

Enzymatic resolution, desymmetrization, and dynamic kinetic asymmetric transformation of 1,3-cycloalkanediols

An efficient desymmetrization of cis-1,3-cyclohexanediol to (1S,3R)-3-(acetoxy)-1-cyclohexanol ((R,S)-2a) was performed via Candida antarctica lipase B (CALB)-catalyzed transesterification, in high yield (up to 93%) and excellent enantioselectivity (ee's up to >99.5%). (R,R)-Diacetate ((R,R)-3a) was obtained in a DYKAT process at room temperature from (1S,3R)-3-acetoxy-1-cyclohexanol ((R,S)-2a), in a high trans/cis ratio (91:9) and in excellent enantioselectivity of >99%. Metal- and enzyme-catalyzed dynamic transformation of cis/trans-1,3-cyclohexanediol using PS-C gave a high diastereoselectivity for cis-diacetate (cis/trans = 97:3). The (1R,3S)-3-acetoxy-1-cyclohexanol (ent-(R,S)-2a) was obtained from cis-diacetate by CALB-catalyzed hydrolysis in an excellent yield (97%) and selectivity (>99% ee). By deuterium labeling it was shown that intramolecular acyl migration does not occur in the transformation of cis-monoacetate to the cis-diacetate.     

Synthesis and photochemical properties of solar energy storage-exchange polymers containing pendant norbornadiene moieties

New photoresponsive polymers 1–4 containing pendant norbornadiene (NBD) moieties with N,N-disubstituted amide groups were synthesized with 97, 98, 92, and 94% conversions by the substitution reaction of poly (p-chloromethyl) styrene] with potassium salts of 3piperidyloxo-2,5-NBD-2-carboxylic acid, 3-(NN-dipropylcarbamoyl) -2,5-NBD-2-carboxylic acid, 3-(N-methyl-N-phenylcarbamoyl)-2,5-NBD-2-carboxylic acid, and 3-(N,N-dipheylcarbmoyl)-2,5-NBD-2-carboxylic acid, respectively, using tetrabutylammonium bromide as a phase transfer catalyst for all. Polymers 1–4 with N,N-disubstituted amide groups on the NBD moieties were sensitized by adding appropriate photosensitizers such as Michler's ketone and 4- (N,N-dimethylamino) benzophenone in the film state, although the reactivities of the polymers without photosensitizer were lower than that of our previously reported polymer 5 containing pendant 3- (N-phenylcarbamoyl) -2,5-NBD-2-carboxylate moiety. It was also found that the photo-irradiated retaining polymers 1–4 containing the corresponding QC moieties can be stored about 80–86 kJ/mol of their thermal energy. © 1994 John Wiley & Sons, Inc.     

Synthesis of (3S,5R)-carbapenam-3-carboxylic acid and its role in carbapenem biosynthesis and the stereoinversion problem

(5R)-Carbapenem-3-carboxylic acid is the simplest structurally among the naturally occurring carbapenem beta-lactam antibiotics. It is the produced from (3S,5S)-carbapenam-3-carboxylic acid utilizing a remarkable stereoinversion/desaturation process by CarC (carbapenem synthase), an alpha-ketoglutarate dependent non-heme iron oxygenase. In this communication, we demonstrate for the first time that the epimeric (3S,5R)-carbapenam-3-carboxylic acid is an intermediate in the overall catalytic cycle to the carbapenem antibiotic. The role of alpha-ketoglutarate in the stereoinversion and desaturation processes is also examined.     

An unusual beta-vinyl effect leading to high efficiency and enantioselectivity of the amidase, nitrile biotransformations for the preparation of enantiopure 3-arylpent-4-enoic acids and amides and their applications in synthesis

Biotransformations of 3-arylpent-4-enenitriles catalyzed by Rhodococcus erythropolis AJ270, a nitrile hydratase/amidase-containing microbial whole-cell catalyst were studied, and an unusual beta-vinyl effect of the substrate on the biocatalytic efficiency and enantioselectivity of the amidase was observed. While 3-arylpent-4-enenitriles and 3-phenylpentanenitrile were efficiently hydrated by the action of the less R-enantioselective nitrile hydratase, the amidase showed greater activity and higher enantioselectivity against 3-arylpent-4-enoic acid amides than 3-arylpentanoic acid amides. Under very mild conditions, nitrile biotransformations provided an efficient synthesis of highly enantiopure (R)-3-arylpent-4-enoic acids and (S)-3-arylpent-4-enoic acid amides, and their applications were demonstrated by the synthesis of chiral gamma-amino acid, 2-pyrrolidinone, and 2-azepinone derivatives.     

Three new diterpenes and the biological activity of different extracts of Jasonia montana

Three new diterpenes, namely jasonin-a (1), jasonin-b (2), and jasonin-c (3) were isolated from the aerial parts of Jasonia montana (Asteraceae). Their structures were elucidated on the basis of spectral data as [(1E)-2-((2S)-1,2,5-trimethylbicyclo[3.2.l]octan-8-yl)vinyl] benzene-3-carboxylic acid (1), [3-((2S, 5S)-1,2, 5-trimethylcycloheptanyl)propyl]benzene-3-carboxylic acid (2), and [(1E)-3-((7R)-1,7-dimethy-4-methylenecycloheptanyl)prop-1-enyl] benzene-3-carboxylic acid (3). In addition, the previously reported 5,7,3'-trihydroxy-3,6,4'-trimethoxy flavone designated as centaureidin (4), was also isolated and characterized from this source. The different extracts of the plant were also screened for hypoglycemic, antidiabetic, and antimicrobial activities, wherein the petroleum ether and ethanolic extracts exhibited hypoglycemic and antidiabetic activity, and the petroleum ether and chloroform extracts showed antimicrobial activity.     

Development of a 6-hydroxychroman-based derivatization reagent: application to the analysis of 5-hydroxytryptamine and catecholamines by using high-performance liquid chromatography with electrochemical detection

We developed a novel derivatization reagent, (2R)-2,5-dioxopyrrolidin-1-yl-2,5,7,8-tetramethyl-6-(tetrahydro-2H-pyran-2-yloxy)chroman-2-carboxylate (NPCA), for electrochemical (EC) detection in HPLC. NPCA was synthesized from (R)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (alpha-CA), which exhibits intense EC response. NPCA successfully yielded alpha-CA derivatives of primary amines by a two-step derivatization procedure. Following pre-column derivatization with NPCA, a simultaneous determination of alpha-CA derivatives of neuroactive monoamines [dopamine (DA), epinephrine, and 5-hydroxytryptamine (5-HT)], their monoamine oxidase metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole-3-acetic acid) and their catechol-O-methyltransferase metabolites [3-methoxytyramine (3-MT) and normetanephrine (NMN)] was completely achieved using our HPLC-EC method. Using an HPLC equipped with coulometric electrode-array detection system, the resultant alpha-CA derivatives of NMN, 5-HT, DA and 3-MT showed intense EC responses, that were approximately 1.3, 1.4, 1.1 and 1.4-fold higher than the corresponding native forms, respectively. The detection limits were in the range of approximately 16-60 fmol on column (signal-to-noise ratio 3). The proposed HPLC method was applied to determine 5-HIAA, HVA, alpha-CA-5-HT and alpha-CA-DA in rat urine. As a consequence, these analytes were successfully determined with satisfactory precisions.     

Carbapenem biosynthesis: confirmation of stereochemical assignments and the role of CarC in the ring stereoinversion process from L-proline

(5R)-Carbapen-2-em-3-carboxylic acid is the simplest structurally among the naturally occurring carbapenem beta-lactam antibiotics. It co-occurs with two saturated (3S,5S)- and (3S,5R)-carbapenam carboxylic acids. Confusion persists in the literature about the signs of rotation and absolute configurations of these compounds that is resolved in this paper. (3S,5S)-Carbapenam carboxylic acid was prepared from L-pyroglutamic acid to unambiguously establish its absolute configuration as identical to the natural product isolated from Serratia marcescens and from overexpression of the biosynthetic genes carAB in Escherichia coli. L-Proline labeled with deuterium or tritium at the diastereotopic C-5 methylene loci was shown to incorporate one label at the bridgehead of (3S,5S)-carbapenam carboxylic acid, but not into the "inverted" (3S,5R)-carbapenam carboxylic acid or the final carbapenem product. CarC, the third enzyme of the biosynthetic pathway required to synthesize the carbapenem, was demonstrated in cell-free studies to be dependent on alpha-ketoglutarate and ascorbate in keeping with weak sequence identities with other non-heme iron, alpha-ketoglutarate-dependent oxygenases. CarC mediated the stereoinversion of synthetic (3S,5S)-carbapenam carboxylic acid to the (5R)-carbapenem as judged by bioassay. These findings suggest that L-proline is desaturated to pyrroline-5-carboxylic acid prior to uptake into the biosynthetic pathway. The loss of the bridgehead hydrogen from the (3S,5S)-carbapenam during the ring inversion process to form the epimeric (3S,5R)-carbapenam and desaturation to the (5R)-carbapenem are proposed to be coupled by CarC to the reduction of dioxygen to drive the formation of these higher energy products, an unprecedented reaction for this enzyme class.     

Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).     

The development of scalemic multidentate niobium complexes as catalysts for the highly stereoselective ring opening of meso-epoxides and meso-aziridines

The discovery and development of a new Lewis acid system based on a complex formed from niobium(V) methoxide and (R)-3,3'-bis(2-hydroxy-3-isopropylbenzyl)-1,1'-binaphthalene-2,2'-diol, a novel tetradentate BINOL derivative, is presented. The system was shown to be extremely effective in promoting the desymmetrative ring opening of linear and cyclic meso-epoxides using anilines as nucelophiles, delivering the corresponding (R,R) anti-amino alcohols in good to excellent yields (up to quantitative) and excellent enantioselectivity (up to 96% ee). Furthermore, the catalyst system displays a remarkable sensitivity to steric bulk at the beta-carbon of the epoxide, selectively facilitating ring opening of smaller epoxides in the presence of more sterically hindered epoxides. This property was confirmed by a series of competition reactions using a mixture of meso-2-butene oxide and another aliphatic meso-epoxide, with the result that the former, less encumbered epoxide reacted preferentially with up to 98% chemical selectivity. While it was found to be most convenient to conduct the reactions with 10 mol % catalyst loading at 0.16 M, at higher overall concentration the reaction still proceeded efficiently with as little as 0.25 mol % catalyst to give the desired products with no significant reduction in yields or enantioselectivities. In addition, the current catalyst system was also found to mediate the asymmetric ring opening of nonsymmetrical cis-2-alkene oxides with anilines to give preferentially the corresponding (2R,3R)-2-amino-3-ols arising from ring opening at the methyl terminus, in excellent yields (up to quantitative) and good to excellent regio- and enantioselectivities (up to 18:1 and >99% ee, respectively). Intriguingly, it was discovered that the same catalyst system also promoted the ring-opening desymmetrization of aziridines with aniline nucleophiles to give the corresponding (S,S) vicinal diamines in good to excellent yields and enantioselectivity (up to 95% and 84% ee [>99% ee following a single recrystallization]). Catalyst systems that promote closely related reactions with opposite stereochemical outcomes in high selectivity such as the current niobium system are extremely unusual. To the best of our knowledge, this report constitutes not only the first example of the catalytic desymmetrization of both meso-epoxides and meso-aziridines but also a rare example of such complementary stereoselectivity in a catalytic reaction.     

2-Acyl-tetrahydroisoquinoline-3-carboxylic acids: lead compounds with triple actions, peroxisome proliferator-activated receptor α/γ agonist and protein-tyrosine phosphatase 1B inhibitory activities

2-Acyl-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2,4-Hexadienoyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14) showed peroxisome proliferator-activated receptor γ (PPARγ) and PPARα agonist activities and protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activities. PPARγ agonist activity of 14 was comparable to that of rosiglitazone, and PTP-1B inhibitory activity was about 10-fold weaker than that of ertiprotafib, a PTP-1B inhibitor. Compound 14 showed high oral absorption in rats and potent hypoglycemic effects in KK-A(y) mice. In conclusion, 14 would be an excellent lead compound for a new type of anti-diabetic drug with triple actions.     

A novel C(2)-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester as a promising chiral building block for piperidine-related alkaloids

C(2)-symmetric 2,6-diallylpiperidine 1-carboxylic acid methyl ester (5) was examined via the double asymmetric allylboration of glutaraldehyde followed by aminocyclization and carbamation as a promising chiral building block for piperidine-related alkaloids, which were synthesized by the desymmetrization of 5 using intramolecular iodocarbamation as a key step. [reaction: see text]     

Two- and three dimensional combinatorial chemistry from multicomponent Grignard reagents

The conjugate addition of five component Grignard reagents to methyl ecgonidine was used to create libraries of 3-substituted tropanes. By variation in the reagent combination in 10 such 5-membered sublibraries, a library of 25 compounds was made in a two-dimensional format. Screening of this library led to identification of two new potent monoamine transporter ligands that were subsequently synthesized. The most potent compound in this library was (1R,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester, which inhibited dopamine transporter (hDAT) binding and reuptake with a K(i) of 26 and 20 nM, respectively. The conjugate addition to a 5-membered library of methyl ecgonidine analogues with variation of nitrogen substituent was also carried out and used to create 15 sublibraries of 25 compounds, which displayed 125 compounds in a three-dimensional format. From this 3D library, several potent dopamine transport inhibitors were likewise identified and synthesized. The most potent hDAT inhibitor discovered was (1R,2S,3S,5S)-3-(3,4-dimethylphenyl)-8-pentyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester. The study also showed that 3-alkyltropanes were poor inhibitors of monoamine transporters.     

酶催化拆分制备手性2-氯-1-(2,4-二氟苯基)乙醇及 光学活性抗真菌药物的合成

用Pseudomonas stutzeri脂肪酶催化转酯化反应动力学拆分外消旋体法制备高对映体纯的手性2-氯-1-(2,4-二氟苯基)乙醇, 得到95.8% ee值的(R)-异构体和94.5% ee值的(S)-异构体, 以此手性醇为关键中间体合成了4种具有抗真菌活性的光学活性化合物α-氯代苄氧基-β-(1-咪唑基)-2,4-二氟乙苯硝酸盐. 纸片扩散法测试体外抗真菌活性结果表明, 对各种念珠菌(Candida species) (R)-5a和(R)-5b具有与氟康唑相当的抗菌活性, 特别是对氟康唑耐药的烟曲霉菌(Aspergillus fumigatus), 5a, 5b及其两种光学活性异构体均有优异的抗菌活性, 而且(R)-异构体的活性明显高于(S)-异构体和外消旋体.     

Synthesis of two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids

[structures: see text] Two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids, 6-hydroxy-3-methyl-8-(phenylethyl)-2,5-dihydro-1-benzoxepin-9-carboxylic acid (radulanin E) (1) and 9-hydroxy-3-methyl-2,5-dihydro-1-benzoxepin-7-carboxylic acid (2), were synthesized using Stille coupling followed by Mitsunobu cyclization.     

New, efficient synthesis of oseltamivir phosphate (Tamiflu) via enzymatic desymmetrization of a meso-1,3-cyclohexanedicarboxylic acid diester

A new, enantioselective synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate 1 (Tamiflu) and its enantiomer ent-1 starting from cheap, commercially available 2,6-dimethoxyphenol 10 is described. The main features of this approach comprise the cis-hydrogenation of 5-(1-ethyl-propoxy)-4,6-dimethoxy-isophthalic acid diethyl ester (6a) and the desymmetrization of the resultant all-cis meso-diesters 7a and 7b, respectively. Enzymatic hydrolysis of the meso-diester 7b with pig liver esterase afforded the (S)-monoacid 8b, which was converted into cyclohexenol 17 via a Curtius degradation and a base-catalyzed decarboxylative elimination of the Boc-protected oxazolidinone 14. Introduction of the second amino function via S(N)2 substitution of the corresponding triflate 18 with NaN3 followed by azide reduction, N-acetylation, and Boc-deprotection gave oseltamivir phosphate 1 in a total of 10 steps and an overall yield of approximately 30%. The enantiomer ent-1 was similarly obtained via an enzymatic desymmetrization of meso-diester 7a with Aspergillus oryzae lipase, providing the (R)-monoacid ent-8a.     

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.