Synthesis of (+)-uniflorine a: a structural reassignment and a configurational assignment

The total synthesis of (+)-uniflorine A has allowed for the structural reassignment and the configurational assignment of the alkaloid (-)-uniflorine A from a 1,2,6,7,8-pentahydroxyindolizidine structure to (-)-(1 R,2 R,3 R,6 R,7 S,7a R)-1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine (6- epi-casuarine).     

A convenient preparation of (1R,2S,7S,8R)-3,5-diaza-2,7-dimethyl-1,8-diphenyloctan-1,8-diol and its enantiomer

The synthesis of (1R,2S,7S,8R)-3,5-diaza-2,7-dimethyl-1,8-diphenyloctan-1,8-diol 6 and its enantiomer 7 are described utilising (-)-(1R,2S)- or (+)-(1S,2R)-norephedrine, respectively.     

Total synthesis of optically active lycopladine A by utilizing diastereoselective protection of carbonyl group in a 1,3-cyclohexanedione derivative

We successfully synthesized two enantiomers of bicyclic enones, (7R,7aR)- and (7S,7aS)-9, from the hemiacetal 2a, which we first synthesized from the symmetrical diketone 1a via diastereoselective carbon-oxygen bond formation between one of the carbonyl groups and the chiral alcohol on the C2 side chain in a 2,2-disubstituted 1,3-cycloalkanedione derivative. We also report the total synthesis of natural (+)-lycopladine A [(+)-6] from (7R,7aR)-9 and the formal synthesis of unnatural (-)-lycopladine A [(-)-6] from (7S,7aS)-9.     

Heterotricyclodecane VIII. (−)-(1S, 3R, 6R, 8R)-2, 7-Dioxaisotwistan und (−)-(1R, 3R, 6R, 8R)-2, 7-Dioxa-twistan; Synthese und Bestimmung der absoluten Konfiguration

A synthesis and the determination of the absolute configuration of (?)-(1S, 3R′ 6R, 8R)-2, 7-dioxa-isotwistane ( 13 ) and (?)-(1R, 3R, 6R, 8R)-2, 7-dioxa-twistane ( 14 ) is described. The results for 14 are compared with those for carboeyclic (+)-twistane ( 2 ) of known chirality.     

Stereoselective synthesis of c3-c12 dihydropyran portion of antitumor laulimalide using copper-catalyzed oxonium ylide formation-[2,3] shift

Copper-catalyzed oxonium ylide formation-[2,3] shift of (5S,7R)-5-allyloxy-1-diazo-8-(p-methoxybenzyloxy)-7-methyl-2-octanone (3) proceeded in tetrahydrofuran-dichloromethane (4 : 1) under reflux with an excellent stereoselectivity (97 : 3) to give (2R,6S)-2-allyl-6-[(2R)-3-(p-methoxybenzyloxy)-2-methylpropyl]-3-dihydropyranone (2) as a major isomer in 82% yield. The resultant pyranone (2) was converted to the key intermediate (1) of the Mulzer's laulimalide synthesis and its derivatives (14, 15).     

Lipase-catalyzed asymmetric synthesis of desprenyl-carquinostatin A and descycloavandulyl-lavanduquinocin

An asymmetric synthesis of the core carbazole structure, 6-desprenyl-carquinostatin 3 and 6-descycloavandulyl-lavanduquinocin 3, toward a total synthesis of carquinostatin A (1) and lavanduquinocin (2), has been established. Lipase QLM (Meito) catalyzed enantioselective acetylation of the racemic alcohol 6 gave the (-)-acetate 7 and the (+)-alcohol 6 with high enantioselectivity. The absolute stereochemistry of the (-)- and (+)-alcohol 6 have been determined to be R- and S-configurations, respectively, by the advanced Mosher method. In the same manner, the (-)-acetate 13 and the (+)-alcohol 12 have been obtained from the racemic alcohol 12. The (R)-(-)-acetate 13, derived from the (R)-(-)-acetate 7, was the same as the (-)-acetate 13, which has been determined to be (R)-configuration. Oxidation of the (R)-(-)-acetate 13 followed by hydrolysis afforded (R)-(-)-6-desprenyl-carquinostatin [and (R)-(-)-6-descycloavandulyl-lavanduquinocin] 3. In addition, oxidation of the (S)-(+)-alcohol 12 provided (S)-(+)-3, which is the enantiomer of 6-desprenyl-carquinostatin A (R)-(-)-3.     

Stereoselective syntheses of 1,4-dideoxy-1,4-imino-octitols and novel tetrahydroxyindolizidines

A new route for the preparation of four new indolizidines, (1R,2S,6S,7S,8aS)- and (1R,2S,6R,7R,8aS)-1,2,6,7-tetrahydroxyindolizidine (30 and 32) and (1S,2R,7S,8S,8aR)- and (1S,2R,7R,8R,8aR)-1,2,7,8-tetrahydroxyindolizidine (44 and 46), is reported. The synthesis is based on Knoevenagel homologation of the readily available enantiomerically pure pyrrolidin-carbaldehydes 13 and 37followed by asymmetric dihydroxylation of the subsequent alkenyl pyrrolidines and cyclization of the corresponding imino-octitols. The new indolizidines and their precursors (imino-octitols 20, 25, 26) and indolizidinones 28a and 28b have been tested for inhibitory activities toward 26 glycosidases. The enzymatic inhibition of trans-7-hydroxy-d-(-)-swainsonine (44) toward alpha-mannosidases is similar to that described for trans-7-hydroxy-l-(+)-swainsonine (11b) toward naringinase (alpha-l-rhamnosidase from Penicillium decumbens).     

Synthesis and bioassay of all four stereoisomers of (2E,4E)-4,6,10,12-tetramethyl-2,4-tridecadien-7-one, the assignment of the absolute configuration of the sex pheromone of Matsucoccus matsumurae Japanese pine bast scale

A facile enantioselective synthesis of all four stereoisomers of (2E,4E)-4,6,10,12-tetramethyl-2,4-tridecadien-7-one (1) is described. The stereochemistry at 6-C and 10-C of 1 was constructed by using optically active citronellal as starting material and by the asymmetric crotylic metal reaction. In the bioassay and field tests, only la, i.e. (6R,10R)-1 was active. The other three isomers 1b (6S,10R), 1c (6R,10S) and 1d (6S,10S) were inactive. Therefore, the naturally occurring pheromone was assigned as (6K,10R)-1.     

Tobacco chemistry. 65. Two new 7,8-epoxycembranoids from tobacco

Two new diterpenoids have been isolated from tobacco. They have been identified as the (1S,2E,4S,6R,7R,8R,11E)- and (1S,2E,4S,6R,7S,8S,11E)-7,8-epoxy-2,11-cembradiene-4,6-diols 1 and 2 by synthesis and X-ray analysis. The conformation about the 5,6 bond in some 7,8-epoxycembranoids is discussed, as is the biogenesis of the two new compounds.     

5-Demethoxyfumagillol, a potent angiogenesis inhibitor isolated from Aspergillus fumigatus

A novel angiogenesis inhibitor, 5-demethoxyfumagillol (1), was obtained by isolation, purification and saponification of cultured broth of Aspergillus fumigatus. The structure was assigned as (3R,4R,6R)-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2,5]octan-6-ol (1) by spectroscopic analysis and confirmed by independent synthesis from fumagillol (3). In addition, 6-O-(chloroacetylcarbamoyl)-5-demethoxyfumagillol (7) showed a potential anti-angiogenic activity in CAPE cells in vitro.     

Enantioselective Total Synthesis of Four Styrylpyrone Derivatives

The first enantioselective total synthesis of 5-acetoxygoniothalamin 1 and 5-acetoxyisogoniothalamin oxide 2 was achieved through the Sharpless kinetic resolution of recemic secondary 2-furylmethanol 5 and the Mitsunobu reaction. At the same time we developed a short synthetic route for 6R-( )-goniothalamin 3 and (6R,7R,8R)-( )-goniothalamin oxide 4. And according to this route the configuration of 5-acetoxygoniothalamin 1 was confirmed as (5S,6S).     

Enantioselective synthesis of (2-pyridyl)alanines via catalytic hydrogenation and application to the synthesis of L-azatyrosine

[reaction: see text] A novel method for the synthesis of (2-pyridyl)alanines 2a-b was developed by converting (2-pyridyl)dehydroamino acid derivatives 1a-b to the corresponding N-oxides 3a-b followed by asymmetric hydrogenation using (R,R)-[Rh(Et-DUPHOS)(COD)]BF(4) [(R,R)-6] catalyst and subsequent N-oxide reduction in 80-83% ee. This methodology was applied to the total synthesis of L-azatyrosine [(+)-12], an antitumor antibiotic, starting from (5-benzyloxy)-2-pyridylmethanol (7), in >96% enantiomeric purity.     

Synthesis of 1-[6-Fluoro-(2S)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2- ethanediol and 1-[6-Fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]- (1R)-1,2-ethanediol

Benzopyran compounds possess diverse pharmacological properties such as β-blockade, anticonvulsant and antimicrobial.[1,2] Our interest has been focused on the synthesis of 1-[6-Fluoro-2S]-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol (6) and 1-[6-fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol (7) which are particularly convenient precursor to (S,R,R,R)-NE (8). 8 containing four asymmetrical carbon atoms was reported to be the most active isomer.[3] Chandrasekhar[4] has reported on the synthesis of 8. The key step to synthesize this compound is to obtain the chiral chromanone 6 and 7. 6 was accomplished in 8 steps by the Clasien rearrangement and a one-pot Sharpless asymmetric epoxidation, but the compound 7 was accomplished in 10 steps. Johannes[5] used Zr-catalytic kinetic resolution of allylic ethers and Mo-catalyzed chromene formation to synthesize 8 in 14 steps. However both of the methods request many synthetic steps and expensive reagents.     

Synthesis of d- and l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5-hydroxymethylproline and tripeptides containing them

Enantiomerically pure (-)-(1R,4R,5R,6S)- and (+)-(1S,4S,5S,6R)-7-(tert-butoxycarbonyl)-5,6-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]hept-2-one ((-)-3 and (+)-3) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrrole and 2-bromo-1-(p-toluenesulfonyl)acetylene, including the Alexakis optical resolution of ketone (+/-)-3 via formation of cyclic aminals with (1R,2R)-diphenylethylenediamine. Compounds (-)-3 and (+)-3 were converted into d- and l-2,3-trans-3,4-cis-4,5-trans-N-(tert-butoxycarbonyl)-5-hydroxymethyl-3,4-isopropylidenedioxyprolines (-)-4 and (+)-4, respectively. Applying the Boc and Fmoc strategies of peptide synthesis, these compounds were used to construct two tripeptides containing the d- or l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5-hydroxymethylproline.     

Optically active cyclohexene derivative as a new antisepsis agent: an efficient synthesis of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242)

Two new synthetic methods were established for the efficient synthesis of optically active cyclohexene antisepsis agent, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-1: TAK-242)]. The first method involved recrystallization from methanol of the diastereomeric mixture (6RS,1'R)-7, obtained by esterification of carboxylic acid 3 with (S)-1-(4-nitrophenyl)ethanol [(S)-5)] to give the desired isomer (6R,1'R)-7 with 99% de in 32% yield. Subsequent catalytic hydrogenolysis and esterification gave (R)-1 with >99% ee. The second method employed enantioselective hydrolysis of acetoxymethyl ester 9a (prepared by alkylation of 3 with bromomethyl acetate) with Lipase PS-D to give the eutomeric enantiomer (R)-9a with excellent enantioselectivity (>99% ee) and high yield (48%). The desired (R)-1 was then obtained by transesterification with ethanol in the presence of concentrated sulfuric acid without loss of ee. Of these, the procedure employing enzymatic kinetic resolution using Lipase PS-D is the more efficient and practical preparation of (R)-1.     

Preparation of perhydroisoquinolines via the intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates: a formal synthesis of (+/-)-reserpine

The intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates provides an efficient method for the synthesis of cis-fused hexahydroisoquinolones. As a demonstration of the stereochemical control offered by this cycloaddition, two approaches to the construction of the DE rings of reserpine are reported. In the second entry, N-((4-(trimethylsilyl)ethoxymethoxy)methyl-6-benzyloxy-3Z,5E-hexadienoyl)-1-aza-2-ethoxy-1,3-butadiene (40) undergoes cycloaddition to produce as the major product (4aS,7R,8aS)-7-benzyloxy-5-((2-trimethylsilyl)ethoxymethoxy)methyl-3,4,4a,7,8,8a-hexahydroisoquinol-3-one (41). Cycloadduct 41 is then stereospecifically elaborated to (4aS,5S,6R,7R,8aR)-6-methoxy-5-methoxycarbonyl-7-(3,4,5-trimethoxy)benzoyldecahydroisoquinoline-2-carboxylic acid methyl ester (3), a key intermediate previously transformed to reserpine.     

阿莫西林杂质L的化学合成

阿莫西林是一种最常用的β-内酰胺抗生素,作为基本医疗系统中最重要药物之一被世界卫生组织基本药物标准清单收录。其杂质L,即:(2S,5R,6R)-6-((2S,5R,6R)-6-((R)-2-氨基-2-(4-羟基苯基)乙酰氨基)-3,3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-甲酰胺)-3,3-二甲基-7-氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-甲酸(6-APA amoxicillin amide),由于含量少难以获取成为影响产品质量的因素之一,因此,我们以6-氨基青霉素烷酸和阿莫西林三水合物为原料,分别通过3步和1步转化为相应的中间体化合物3和6,并使用酰胺缩合试剂六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)以76%的收率实现了化合物3和6的脱水缩合,得到的关键中间体化合物7在Pd/C催化条件下一步脱除苄基及两个苄氧羰基保护基,首次通过化学方法合成了β-内酰胺化合物阿莫西林杂质L,反应使用简单易得的原料,温和的反应条件,无需复杂的分离纯化处理,对以阿莫西林为代表的β-内酰胺类抗生素的过敏研究以及新型β-内酰胺抗生素的开发和作用机制研究等有着参考和借鉴意义。     

Enzyme-purification and catalytic transformations in a microstructured PASSflow reactor using a new tyrosine-based Ni-NTA linker system attached to a polyvinylpyrrolidinone-based matrix

The synthesis of a Ni-nitrilotriacetic acid (Ni-NTA) attached via a new tyrosine-based linker matrix on monolithic crosslinked poly(vinyl benzyl chloride)/poly(vinylpyrrolidinone) is described. This matrix is incorporated inside a microstructured PASSflow reactor which was used for automatic purification and immobilisation of His(6)-tagged proteins. These could be used as stable and highly active biocatalysts for the synthesis of (R)-benzoin (6), (R)-2-hydroxy-1-phenylpropan-1-one (7) and 6-O-acetyl-D-glucal (17) in a flow-through mode.     

Design and synthesis of a conformationally restricted trans peptide isostere based on the bioactive conformations of saquinavir and nelfinavir

The design and synthesis of a new peptide isostere which contains a trans alkene core is described. The key step involves a Wadsworth-Emmons reaction between chiral aldehyde (2S)-9a and chiral phosphonate 7 under base-sensitive conditions to give a chiral enone (2R)-24a which was reduced to afford the desired trans alkene isosteres (2R,5R)-6a and (2R,5S)-6b (Scheme 6). A potential application of this isostere in the synthesis of HIV protease inhibitors is also discussed.     

Studies on the Synthesis of (2R,4′R,8′R)-α-Tocopherol Alternative Syntheses of 2-Chroman-acetic Acid Intermediates

As an extension of previous studies on the total synthesis of (2R,4′R,8′R)-α-tocopherol ( 1 ) [1] [2], (S)-(?)-2-(6-benzyloxy-2,5,7,8-tetramethylchroman)acetic acid ( 6 ), a pivotal intermediate, possessing the absolute configuration required for construction of 1 was prepared by optical resolution of the racemic modification 11 . the latter substance was obtained by two routes, one emanating from the hydroxy acetal 7 [1] and the other based upon the Lewis acid mediated cycloaddition of trimethylhydroquinone to rac.-3-hydroxy-3-methylpent-4-en-l-yl acetate ( 16 ) giving rac. ethyl 2-(6-hydroxy-2,5,7,8-tetramethyl-chroman)acetate ( 12 ).