First total syntheses of aeruginosin 298-A and aeruginosin 298-B, based on a stereocontrolled route to the new amino acid 6-hydroxyoctahydroindole-2-carboxylic acid

The first total syntheses of aeruginosin 298-A (1) and aeruginosin 298-B (3) are described. The syntheses of the alternative putative structures 2 and 4 were also accomplished. The key common strategic element is the stereo-controlled synthesis of (2S,3aS,6R,7aS)-6-hydroxyoctahydroindole-2-carboxylic acid (L-Choi, 5) from L-tyrosine. The synthesis of this new bicyclic alpha-amino acid, which is the core of aeruginosins, involves Birch reduction of O-methyl-L-tyrosine (6) and aminocyclization of the resulting dihydroanisole 7 in acid medium, followed by N-benzylation to give the diastereoisomers 12 and 13. Upon acid treatment with HCl-MeOH, the last two produce an equilibrium mixture in which the endo isomer 13 significantly predominates. Hydrogenation of 13 in the presence of (Boc)2O gives 16, which on reduction with LS-Selectride furnishes the alcohol 22, a protected L-Choi. Successive couplings of 22 with D-leucine, protected (R)-(4-hydroxyphenyl)lactic acid, and L-arginine fragments, followed by reduction to the argininol level and a deprotection end step complete the synthetic sequence to produce aeruginosin 298-A (1). Spectral comparison showed that peptide 2, with the structure previously proposed for aeruginosin 298-A, was different from the natural product. However, synthetic 1 was found to be identical to the isolated natural sample of aeruginosin 298-A. These results unequivocally establish that the absolute stereochemistry of aeruginosin 298-A, formerly assigned incorrectly, is D-Hpla-D-Leu-L-Choi-L-Argol, as shown by structure 1. Aeruginosin 298-B was also synthesized and shown to be a mixture of rotamers of D-Hpla-D-Leu-L-ChoiNH2 (3), rather than an epimeric mixture of 3 and the L-Leu-incorporating 4.     

Liquid chromatography-electrospray ionization mass spectrometry study of the flavonoids of the roots of Astragalus mongholicus and A. membranaceus

High-performance liquid chromatography-electrospray ionization mass spectrometry has been applied to analyze the flavonoids of Huangqi, the roots of Astragalus mongholicus and A. membranaceus. Eight flavonoids were identified as calycosin-7-O-beta-D-glucoside, calycosin-7-O-beta-D-glucoside-6"-O-malonate (2), ononin, (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan-3-O-bet a-D-glucoside, calycosin, (3R)-7,2'-dihydroxy-3',4'-dimethoxyisoflavan-7-O-beta-D-glucoside, formononetin-7-O-beta-D-glucoside-6"-O-malonate and formononetin by direct comparison with the isolated standards from Huangqi. The existence of (6aR,11aR)-3-hydroxy-9,10-dimethoxypterocarpan, (3R)-7,2'-dihydroxy-3',4'-dimethoxyisoflavan, astrapterocarpanglucoside-6'-O-malonate and astraisoflavanglucoside-6'-O-malonate was detected. This is the first report of flavonoid glycoside malonates in these two Astragalus species, and malonate 2 is a structurally completely identified new compound.     

First Total Synthesis of Hyacinthacine A6 from the Protected Derivative of Polyhydroxylated Pyrrolidine

（1S、2R、3R、5R、7aR）-1,2-Dihydroxy-3-hydroxy methyl-5-methylpyrrolizidine（hyacinthacine A6, I） was synthesized by Wittig＇s methodology via the reaction of aldehyde 6, prepared from the partially protected derivative of polyhydroxylated pyrrolidine, with appropriated ylides, followed by cyclization through the intemal reductive amination process of the resulting a,B-unsaturated ketone 7, and total deprotection.     

Enantiospecific synthesis of polhydroxylated indolizidines related to castanospermine: 1 (6R,7S,8aR)-6,7-dihydroxyindolizidine and (6R,7R,8S,8aR)-6,7,8-trihydroxyindolizidine.

Enantiospecific syntheses of (6R,7S,8aR)-6,7-dihydroxy-indolizidine (3) and (6R,7R,8S,8aR)-6,7,8-trihydroxy-indolizidine (4) from methyl 2-azido-4,6-O-benzylidene-2-deoxy-α-D-altropyranoside (7) are reported. The two synthetic indolizidines (3) and (4) have been tested against a wide range of enzymes.     

Total synthesis of (+)-hatomarubigin B.

The first total synthesis of (+)-hatomarubigin 3 is described. The tetra-O-acetyl diborate promoted Diels-Alder reaction of 5-hydroxy-8-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyloxy)-1,4-naphthoquinone 8 and (E, 1R*,5R*)-3-(2'-methoxyvinyl)cyclohex-2-enol (+/-)-7 gave a mixture of four cycloadducts from which (1S,3S,6S,6aR,12aR,12bS)-1,8-dihydroxy-6-dimethoxy-1-hydroxy-3-methyl-11-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyloxy)-1,2,3,4,6,6a,12a,12b-octahydrobenz[a]anthracene-7,12-dione 12 was isolated in 51% yield. Selective methylation and acetylation of 12 gave (1S,3S,6S,6aR,12aR,12bS)-1-acetoxy-6,8-dimethoxy-3-methyl-11-(2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyloxy)-1,2,3,4,6,6a,12a,12b-octahydrobenz[a]anthracene-7,12-dione 10a. Sequential aromatization, photooxidation and hydrolysis of the glucosyl unit gave (+)-3 (98% ee) in an 8% overall yield from 8.     

Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans

The N-phenethyl analogues of (1R*,4aR*,9aS*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol and 8-ol and (1R*,4aR*,9aR*)-2-phenethyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2.3-c]pyridin-6-ol and 8-ol, the ortho- (43) and para-hydroxy e- (20), and f-oxide-bridged 5-phenylmorphans (53 and 26) were prepared in racemic and enantiomerically pure forms from a common precursor, the quaternary salt 12. Optical resolutions were accomplished by salt formation with suitable enantiomerically pure chiral acids or by preparative HPLC on a chiral support. The N-phenethyl (-)- para-e enantiomer (1S,4aS,9aR-(-)-20) was found to be a mu-opioid agonist with morphine-like antinociceptive activity in a mouse assay. In contrast, the N-phenethyl (-)-ortho-f enantiomer (1R,4aR,9aR-(-)-53) had good affinity for the mu-opioid receptor (K(i) = 7 nM) and was found to be a mu-antagonist both in the [(35)S]GTP-gamma-S assay and in vivo. The molecular structures of these rigid enantiomers were energy minimized with density functional theory at the level B3LYP/6-31G* level, and then overlaid on a known potent mu-agonist. This superposition study suggests that the agonist activity of the oxide-bridged 5-phenylmorphans can be attributed to formation of a seven membered ring that is hypothesized to facilitate a proton transfer from the protonated nitrogen to a proton acceptor in the mu-opioid receptor.     

Formation of the Dinitro-3H-pyrazole Derivative of Cycloartemisiaketone Oxime

(3aR*,6aR*)-3,3,5,5-Tetramethyl-3a,6a-dinitro-3a,6a-dihydro-3H-cyclopentano[c]pyrazol-2-oxide was formed by reaction of cycloartemisiaketone oxime [4,4-dimethyl-2-(1-methylethylidene)cyclopentanone oxime] with AcOH and NaNO₂ in CHCl₃ solution. The structure was solved by x-ray structure analysis.     

Preparation of carbocyclic S-adenosylazamethionine accompanied by a practical synthesis of (-)-aristeromycin

For the preparation of a carbocyclic nitrogen analogue of S-adenosylmethionine (carba-AdoazaMet, 4), a practical synthesis of (-)-aristeromycin (7) has been developed using variations of literature procedures. This approach called for a stereospecific synthesis of (3aR,6aR)-2,2-dimethyl-3a,6a-dihydrocyclopenta[1,3]dioxol-4-one ((4R, 5R)-4,5-O-isopropylidene-2-cyclopentenone) (8), which was achieved by modifying reported procedures from D-(-)-ribose.     

Enantiospecific synthesis of (6R,7S,8aR)-dihydroxyindolizidine and (6R,7R,8S,8aR)-trihydroxyindolizidine from D-glucose.

Enantiospecific syntheses of (6R,7S,8aR)-dihydroxyindolizidine (1) and (6R,7R,8S,8aR)-trihydroxyindolizidine (2) from readily available methyl 2-azido-4,6-O-benzylidene-2-deoxy-α-D-altropyranoside (5) are described.     

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.     

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

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

替格瑞洛的合成工艺改进

以2-丙硫基-4,6-二氢-5-氨基嘧啶和2-{［(3aR,4S,6R,6aS)-6-氨基-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇L-酒石酸盐为原料,经C-N偶联,亲核取代和环合反应制得2-{［(3aR,4S,6R,6aS)-6-(7-氯-5-丙硫基-3H-［1,2,3］三唑［4,5-d］嘧啶-3-基)-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇(4); 4与(1R,2S)-2-(3,4-二氟苯基)环丙胺D-扁桃酸盐经亲核取代反应后酸解脱除丙酮叉保护基合成替格瑞洛,总收率58.7%,纯度99.2%,其结构经¹H NMR, MS(ESI)和XRD确证。     

Synthesis of （3aS,6aR）- 1,3-Dibenzyl-tetrahydro- 1H-thieno[3,4-d]-imidazole-2（3H）-one-4-ylidenepentanoic Acid and Characterization of Its Crystal

1 INTRODUCTION The title compound, (3aS,6aR)-1.3-dibenzyl- tetrahydro-1H-thieno[3,4-d]-imidazole-2(3H)-one- 4-ylidenepentanoic acid 3, is a key intermediate for the synthesis of d-biotin 1 (VITH, Fig. 1) which has been widely used not only as a pharmaceu…     

Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para-f oxide-bridged phenylmorphan isomers

In an attempt to obtain the para-f isomer, rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol, via mesylation of an intermediate 9[small alpha]-hydroxyphenylmorphan, we obtained, instead, a rearranged chloro compound with a 5-membered nitrogen ring, 7-chloro-3a-(2,5-dimethoxyphenyl)-1-methyl-octahydroindole. This indole underwent a second rearrangement to give us the desired para-f isomer. The structures of the intermediate indole and the final product were unequivocally established by X-ray crystallography. A resynthesis of the known rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-8-ol, the ortho-f isomer, was achieved using the reaction conditions for the para-f isomer, as well as under Mitsunobu reaction conditions where, unusually, the oxide-bridge ring in the 5-phenylmorphan was closed to obtain the desired product. The synthesis of the para-f isomer adds an additional compound to those oxide-bridged phenylmorphans that were initially visualized and synthesized; the establishment of the structure and configuration of 8 of the theoretically possible 12 racemates has now been achieved. The X-ray crystallographic structure analysis of the para-f isomer provides essential data that will be needed to establish the configuration of a ligand necessary to interact with an opioid receptor.     

Microwave‐Assisted Synthesis of Novel Spiro Phosphonyl Thiazolo Pyrazole Glycosides as Potential Nematicidal Agents

A series of novel dimethyl 7‐((3aR,5S,6S,6aR)‐6‐((1‐(4‐chlorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐2,2‐dimethyltetrahydrofuro[2,3‐d][1,3]dioxol‐5‐yl)‐4‐(4‐fluorophenyl)‐9‐oxo‐8‐phenyl‐6‐thia‐1,2,8‐triazaspiro[4.4]non‐2‐en‐3‐ylphosphonate 2a – g were synthesized by the reaction of chalcone derivatives of 2‐((3aR,5S,6S,6aR)‐6‐((1‐(4‐chlorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methoxy)‐2,2‐dimethyltetrahydrofuro[2,3‐d][1,3]dioxol‐5‐yl)‐3‐phenylthiazolidin‐4‐one 1 with Bestmann–Ohira reagent. The chemical structures of newly synthesized compounds were elucidated by IR, NMR, MS, and elemental analysis. The compounds 2a – g were evaluated for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans; compounds 2b , 2c , 2g , and 2f showed appreciable nematicidal activity.     

Total synthesis of aeruginosin 298-A analogs containing ring oxygenated variants of 2-carboxy-6-hydroxyoctahydroindole

Aeruginosins are a family of naturally occurring oligopeptides sharing a common perhydroindole-2-carboxylic acid (l-Choi) core structure. Many aeruginosins exhibit inhibitory activity against serine proteases including thrombin. Aeruginosin 298-A is a tetrapeptide containing the l-Choi core structure and three other unusual amino acids or their derivatives; it is a thrombin and trypsin inhibitor. As part of our effort in finding effective thrombin inhibitors from natural product analogs and to understand the influence of the rigid bicyclic amino acid to the thrombin inhibition activities, we synthesized two aeruginosin 298-A analogs in which the l-Choi is replaced with ring oxygenated perhydroindole-2-carboxylic acids. The Choi variants are enantiomers synthesized from d- and l-glucose, respectively. The preparation of the aeruginosin 298-A analogs containing the ring oxygenated Choi variants and their inhibition activities toward thrombin and trypsin are reported.     

Synthesis,Crystal Structure and Insecticidal Activities of(4aR,7aS)-6-Benzyl-1-((R)-2-(2-chlorophenyl)-4,5-dihydrothiazole-4-carbonyl)hexahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

The title compound(4aR,7aS)-6-benzyl-1-((R)-2-(2-chlorophenyl)-4,5-dihydrothiazole-4-carbonyl)-hexahydro-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione(C24H22ClN3O3S)w...     

Efficient synthesis of (-)-gamma-lycorane alkaloid by two Bu3SnH-mediated radical cyclisations

An asymmetric induction using (S)-1-arylethylamine-based chiral auxiliary and two Bu(3)SnH-mediated radical cyclisations have been developed for a total synthesis of (-)-gamma-lycorane (1). The first cyclisation proceeded in 5-endo-trig manner with moderate diastereoselectivtiy to give (3aR,7aR)-octahydroindol-2-one 6b as the major product using alpha-iodo-N-(6-oxocyclohexen-1-yl)-N-[(S)-1-phenylethyl] acetamide (5b). In the second cyclisation, the radical precursor 8 was used as substrate to construct the optically active lycorane skeleton 15 which was reduced using LiAlH4 into (-)-gamma-lycorane (1).     

Determination and identification of isoflavonoids in Radix astragali by matrix solid-phase dispersion extraction and high-performance liquid chromatography with photodiode array and mass spectrometric detection

The isoflavonoids in Radix astragali were determined and identified by HPLC-photodiode array detection-MS after extraction employing matrix solid-phase dispersion (MSPD). As a new sample preparation method for R. astragali, the MSPD procedure was optimized, validated and compared with conventional methods including ultrasonic and Soxhlet extraction. The amounts of two major components in this herb, formononetin (6) and ononin (2), were determined based on their authentic standards. Four major isoflavonoids, formononetin (6), ononin (2), calycosin (5) and its glycoside (1), and three minor isoflavonoids, (6aR,11aR)-3-hydroxy-9, 10-dimethoxypterocarpan (7), its glycoside (3), and (3R)-7,2'-dihydroxy-3',4'-dimethoxyisoflavone-7-O-beta-D-glycoside (4), were identified based on their characteristic two-band UV spectra and [M + H], [aglycone + H]+ and [A1 + H]+ ions, etc. The combined MSPD and HPLC-DAD-MS method was suitable for quantitative and qualitative determination of the isoflavonoids in R. astragali.     

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).