Separation of palonosetron stereoisomers by electrokinetic chromatography using sodium cholate as chiral selector: Comparison of separation modes and elucidation of migration orders

Based on sodium cholate as chiral selector, four stereoisomers of palonosetron hydrochloride, i.e. PALO (3aS, 2S), PALO (3aR, 2R), PALO (3aS, 2R), and PALO (3aR, 2S), have been separated by five EKC modes, i.e. MEKC, solvent‐modified MEKC, cosurfactant‐modified MEKC, MEEKC, and MEEKC without cosurfactant. The performances of different modes were compared. The migration order and its change with experimental conditions were elucidated. In every mode studied, the migration orders in each enantiomeric pair were (3aS, 2S), (3aR, 2R) and (3aS, 2R), (3aR, 2S), respectively, determined by the selectivity of chiral selector (chromatographic mechanism). Enantiomeric pair (3aS, 2S), (3aR, 2R) was eluted before enantiomeric pair (3aS, 2R), (3aR, 2S) due to mobility difference (electrophoretic mechanism). For the separation between (3aR, 2R) and (3aS, 2R), the second enantiomer of the first pair and the first enantiomer of the second pair, two mechanisms gave opposite migration orders according to the measured selectivity and mobility data. Therefore, three different migration orders were observed at different conditions, depending on the relative strength of two effects.     

Chemoenzymatic synthesis of (+)-alpha-polypodatetraene and methyl (5R,10R,13R)-labda-8-en-15-oate

The reported enzymatic resolution products {acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal} (8aS)-5 (>99% ee)] and [(1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-4 (98% ee) were converted to (+)-alpha-polypodatetraene (1) and methyl (5R,10R,13R)-labda-8-en-15-oate (2), respectively. For the synthesis of (5R,10R,13R)-2, chiral isoprene congener (3S)-26 corresponding to the right part of 2 was synthesized based on the lipase-assisted resolution of (+/-)-2-methyl-3- (p-methoxyphenyl)propanol (17).     

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.     

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.     

Enantioselective synthesis of piperidine,indolizidine, and quinolizidine alkaloids from a phenylglycinol-derived delta-lactam

Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (1), or its enantiomer, the enantioselective synthesis of 2-alkylpiperidines and cis- and trans-2,6-dialkylpiperidines is reported. The potential of this approach is illustrated by the synthesis of the piperidine alkaloids (R)-coniine, (2R,6S)-dihydropinidine, (2R,6R)-lupetidine, and (2R,6R)-solenopsin A, the indolizidine alkaloids (5R,8aR)-indolizidine 167B and (3R,5S,8aS)-monomorine I, and the nonnatural base (4R,9aS)-4-methylquinolizidine.     

Putative Diels-Alder-Catalyzed Cyclization during the Biosynthesis of Lovastatin

A Diels-Alder cyclization proposed to occur during polyketide synthase assembly of the bicyclic core of lovastatin (1) (mevinolin) by Aspergillus terreus MF 4845 was examined via the synthesis of the N-acetylcysteamine (NAC) thioester of [2,11-(13)C(2)]-(E,E,E)-(R)-6-methyldodecatri-2,8,10-enoate (5a). In vitro Diels-Alder cyclization of the corresponding unlabeled NAC ester 5b, ethyl ester 18b, and acid 20b yielded two analogous diastereomers in each case, under either thermal or Lewis acid-catalyzed conditions. The reaction of thioester 5 proceeds readily at 22 degrees C in aqueous media. For 18b, one product is trans-fused ethyl (1R,2R,4aS, 6R,8aR)-1,2,4a,5,6,7,8,8a-octahydro-2,6-dimethylnaphthalene-1-carboxylate (30) (endo product), and the other is cis-fused ethyl (1R,2S,4aR,6R,8aR)-1,2,4a,5,6,7,8,8a-octahydro-2,6-dimethylnaphthalene-1-carboxylate (31) (exo product). Isomer 21 with stereochemistry analogous to 4a,5-dihydromonacolin L (2), a precursor of 1, was made by transformation of a tricyclic lactone, (1S,2S,4aR,6S,8S,8aS)-1-(ethoxycarbonyl)-1,2,4a,5,6,7,8,8a-octahydro-2-methyl-6,8-naphthalenecarbolactone (22) using reduction and Barton deoxygenation. Comparison of 21 with 30 and 31 confirmed the structural assignments and showed that the nonenzymatic 4 + 2 cyclizations of 5, 18, and 20 proceed via chairlike exo and endo transition states with the methyl substituent pseudoequatorial. The proposed biosynthetic Diels-Alder leading to lovastatin (1) would require an endo conformation with the methyl substituent pseudoaxial. Intact incorporation of the labeled hexaketide triene 5a into 1 was not achieved because of rapid degradation by A. terreus cells.     

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.     

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).     

Atropisomeric properties of the dibenzo[b,d]azepin-6-one nucleus

Dibenzo[b,d]azepin-6-ones (2a,b) were separated by chiral HPLC into the aR- and aS-atropisomers with high stereochemical stability, and methylation at C7 of 2a stereoselectively gave the (aR*,7R*) isomer (4a), which converted to the thermodynamically stable (aS*,7R*) atropisomer (5a) after heating.     

Total syntheses of (+)-chloropuupehenone and (+)-chloropuupehenol and their analogues and evaluation of their bioactivities

Tetracyclic pyrans (+)-chloropuupehenone (1) and (+)-chloropuupehenol (5) and its C8-R-isomer (+)-3 were synthesized via a one-pot condensation of 1-chloro-2-lithio-3,5,6-tris(tert-butyldimethylsilyloxy)benzene (8) with (4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethylnaphthalene-1-carboxaldehyde (7). The major condensation product, (4aS,6aR,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (4), after desilylation provided tetracyclic pyran (+)-(4aS,6aR,12bS)-2H-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene-9,10-diol (3). At a dosage of 42 mg/rat over 8 h, pyran diol 3 inhibited the intestinal absorption of cholesterol by 71% in rats. Tetracyclic pyran 4 was also converted to o-quinone 28, which inhibited cholesteryl ester transfer protein (CETP) activity and L1210 leukemic cell viability with IC(50) values of 31 and 2.4 microM, respectively. Diol (+)-5 inhibited CETP activity with an IC(50) value of 16 microM. The minor condensation product, (4aS,6aS,12bS)-2H-9,10-bis(tert-butyldimethylsilyloxy)-11-chloro-1,3,4,4a,5,6,6a,12b-octahydro-4,4,6a,12b-tetramethyl-benzo[a]xanthene (6), was transformed into (+)-5 and (+)-1. A stepwise stereoselective synthesis of (+)-1 was also developed utilizing an oxyselenylation ring-closure reaction. The synthetic sequence also produced four biologically active naturally occurring drimanic sesquiterpenes, (+)-drimane-8alpha,11-diol (34), (-)-drimenol (38), (+)-albicanol (39), and (-)-albicanal (31) as intermediates.     

A spiro[chroman-3,7'-isochromene]-4,6'(8'H)-dione from the Cordyceps-colonizing fungus Fimetariella sp

Fimetarone A (1), a metabolite with the new spiro[chroman-3,7'-isochromene]-4,6'(8'H)-dione skeleton, was isolated from cultures of the Cordyceps-colonizing fungus Fimetariella sp. Compound 1 was a 1:1 atropdiastereomeric mixture in NMR data, and aS,9S and aR,9R enantiomers were found and confirmed by X-ray crystallography. Compound 1 could be derived from the hypothetical precursors 3,4,5-trihydroxy-2-(2-methylene-3,5-dioxohexanoyl)benzoic acid (5) and lapidosin (6).     

含四氢噻吩类生物素杂质的合成

d-生物素(d-Biotin)又称维生素H、辅酶R,其已广泛应用于医药、家禽、家畜的营养和饲料添加剂方面[1-4].目前比较权威的质量标准是欧洲药典[5],其在美国药典[6]的基础上提出了5个有关物质(杂质A,B,C,D,E)的TLC控制.     

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…     

Three-component synthesis of polysubstituted homoproline analogs

Tetrasubstituted pyrrolidines representing analogs of homoproline were synthesized by three-component condensation of aryl(heteroaryl)aldehydes, asparagine and N-methylmaleimide (NMM). Compounds with (1S*, 3R*, 3aS*, 6aR*)-configuration at the corresponding carbon positions of the bicyclic pyrrolidine ring could be isolated ona preparative scale.     

Enantioselective [6pi]-photocyclization reaction of an acrylanilide mediated by a chiral host. Interplay between enantioselective ring closure and enantioselective protonation

The [6pi]-photocyclization of the anilides 1a and 5 was studied in the absence and in the presence of the enantiomerically pure chiral lactam 4. The relative configuration of the products was unambiguously established by single-crystal X-ray crystallography and by NMR spectroscopy. A significant enantiomeric excess was observed upon reaction of compound 1a to its photocyclization products at -55 degrees C employing lactam 4 as a chiral complexing agent in toluene as the solvent (66% yield). The trans product ent-3a was obtained in 57% ee, and the minor diastereoisomer (trans/cis = 73/27), cis product ent-2a, was obtained in 30% ee. DFT calculations were conducted modeling the complexation of intermediates 8 and ent-8 to host 4. In agreement with steric arguments concerning the conrotatory ring closure of 1a, the formation of ent-8 is favored leading to the more stable complex 4.ent-8 as compared to 4.8. Whereas the enantioselectivity in the photocyclization to trans compound ent-3a increased upon reduction in the reaction temperature, the enantiomeric excess in the formation of cis compound ent-2a went through a maximum at -15 degrees C (45% ee) and decreased at lower temperatures. Deuteration experiments conducted with the pentadeuterated analogue of 1a, d(5)-1a, revealed that the protonation of the intermediates 8 and ent-8 is influenced by chiral amide 4. In the formation of ent-3a/3a, both the enantioselective ring closure and the enantioselective protonation by amide 4 favor the observed (6aS,10aS)-configuration of the major enantiomer ent-3a. In the formation of ent-2a/2a, the enantioselective ring closure (and the subsequent diastereoselective protonation) favors the (6aR,10aS)-configuration that is found in compound 2a. Contrary to that, the enantioselective protonation by amide 4 shows a preference for ent-2a with the (6aS,10aR)-configuration.     

A convergent approach to the marine natural product eleutherobin: synthesis of key intermediates and attempts to produce the basic skeleton

Synthesis of (1R,5R,6R)-2-(6-hydroxymethyl-5-isopropyl-2-methylcyclohex-2-enyl)-N- methoxy-N-methylacetamide 8 from R-(-)-phellandrene in six steps, and (3aR*,4S*,6R*,6aS*)- (6-hydroxymethyl-4-methoxy-2,2,6-trimethyltetrahydrofuro[3,4-d][1,3]dioxol- 4-yl)acetic acid methyl ester 17 from tetrabromoacetone and 2-methoxy-5-methylfuran in six steps, provided two key fragments which have been combined to produce intermediates for attempted construction of the basic skeleton of eleutherobin.     

A general enantioselective approach to jasmonoid fragrances: synthesis of (+)-(1R,2S)-methyl dihydrojasmonate and (+)-(1R,2S)-magnolione

Methyl dihydrojasmonate 1 and magnolione 3 are of both academic and industrial interest. In this paper, we describe a flexible, high-yielding route to diastereomerically pure (+)-cis-(1R,2S)-methyl dihydrojasmonate 1 and the first synthesis of (+)-cis-(1R,2S)-magnolione 3, both with enantiomeric excesses up to 93%. The two syntheses diverged from the same advanced intermediate 5, readily available from the enantioenriched hydroxymethyl delta-lactone (-)-(3aS,4S,6aR)-6. The olfactory properties of (1R,2S)-1 and (1R,2S)-3 are reported.     

Asymmetric Synthesis of Octahydrobenzofuran Core Structure with Three Contiguous Stereogenic Centers and Development of the Absolute Configurations

Cyclization of enantiopure (S/R)-1 with halogen-reagent-constructed enantiopure octahydrobenzofuran core structure with contiguous three stereogenic centers of both enantiomers (SRR and RSS). The absolute configurations of all compounds have been established from x-ray analysis of the single crystal of (3aS,7aR,7R)-3. The chiral initiation in diastereoselective mode of 5-exo ring closure across C?C bond of pendant cyclohexene moiety has been proposed.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Resolution, enantiomerization kinetics, and chiroptical properties of 7,7'-dihydroxy-8,8'-biquinolyl

(+/-)-7,7'-Dihydroxy-8,8'-biquinolyl (6) was resolved into its enantiomorphic atropisomers via reverse phase (C18) chromatographic separation of epimeric bismenthyl carbonates, (-)-lk-9 and (+)-ul-9, derived from 6 and (+)-menthyl chloroformate. The faster eluting diastereoisomer, (-)-lk-9, was revealed to possess an (aS)-configurated biaryl axis by X-ray crystallographic analysis. Saponification of the separated bismenthyl carbonates gave enantioenriched samples of biquinolyl 6, and absolute stereochemical configurations were assigned to the two optical isomers as (-)-(aS)-6 and (+)-(aR)-6 by correlation with their respective progenitors, (-)-lk-9 and (+)-ul-9. First-order rate constants for the enantiomerization of 6 in water were obtained over the temperature range 316-366 K, and activation parameters were determined as DeltaH(++) = 34.0 kcal mol(-1) and DeltaS(++) = 18.7 cal mol(-1) K(-1) by Eyring plot analysis. A low level (AM1) computational study of the rotational dynamics of 6 showed excellent agreement with kinetic experimental data and suggested that enantiomerization occurs preferentially via a syn pathway. In common with (-)-(aS)-1,1'-bi-2-naphthol (BINOL), (-)-(aS)-6 showed positive exciton chirality in its electronic circular dichroism (CD) spectrum and gave a characteristic couplet composed of a positive maximum Cotton effect at 250 nm and a negative minimum at 234 nm (Delta Delta epsilon = +40 M(-1) cm(-1) at 64% ee).     

Nine constituents including six xanthone-related compounds isolated from two ascomycetes, Gelasinospora santi-florii and Emericella quadrilineata, found in a screening study focused on immunomodulatory activity

Five metabolites tentatively called GS-1 (1)-5 (5) from Gelasinospora santi-florii, and four tentatively called EQ-4 (6), EQ-6 (7)-8 (9) together with 1-4 from Emericella quadrilineata have been isolated in a screening study on immunomodulatory fungal constituents. Among these nine metabolites, EQ-7 and 8 have been unknown. This time, the structures of GS-4 which has previously been isolated, EQ-7, and -8 have been determined to be (4R,4aS,9aR)-1,9a-dihydronidulalin A (4), (4S,4aR,9aR)-4a-carbomethoxy-1,4,4a,9a-tetrahydro-4,8-dihydroxy-6-methylxanthone (8), and 9-hydroxymicroperfuranone (9), respectively, and the six other metabolites have been identified. On bioassay, a dihydroxanthone, nidulalin A (1), a hexaketide, sordarial (5), and a xanthone, pinselin (7) have displayed significant immunosuppressive activities. The structure-activity relationships of these constituents have also been discussed.