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.     

Structure of amauromine,a new hypotensive vasodilator produced by amauroascus sp.

The structure of amauromine, a novel alkaloid with potent vasodilating activity was determined chemically and spectroscopically to be (5aS, 7aS, 8aR, 13aS, 15aS, 16aR)-8a, 16a-bis-(1,l-dimethyl-2-propenyl)-5a, 8,8a,13,13a,15a,16,16a-octahydropyrazino [1',2':1, 5;4', 5':1',5']dipyrrolo[2,3-b:2',3'-b']- diindole-7, 15(5H,7aH)-dione.     

Compounds with bridgehead nitrogen: 46—The 1H NMR spectra and stereochemistry of derivatives of 1,3,3a,4,5,6,6a,11a-octahydroindolo[3,2,1-ij][3, 1]benzoxazine

The ¹H NMR parameters of the NCH₂O protons of the reduced pyrrolo[1,2-c][1,3]oxazine moiety in rel-(3aS,6aS,11aS)-1,3,3a,4,5,6,6a,11a-octahydro-6a-methylindolo[3,2,ij][3, 1]benzoxazine and in the alkaloid rosibiline indicate a trans ring fusion for the grouping. The O-inside cis-fused moiety is present in the related rel-(3aR,6aS,11aS)-octahydro-6a-methylindolo[3,2,1-ij][3, 1]benzoxazine and in Wieland–Gumlich glycol formal.     

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.     

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.     

Origin of stereoselectivity in a chiral N-heterocyclic carbene-catalyzed desymmetrization of substituted cyclohexyl 1,3-diketones

The mechanism and stereoselectivity in a chiral N-heterocyclic carbene-catalyzed desymmetrization of a 1,3-diketone is established by using density functional theory computations. The Breslow intermediate formation is identified to involve Hunig's base-assisted proton transfer. The relative energies of stereoselectivity-determining intramolecular aldol cyclization transition states reveal that in the most preferred mode the re-face of enolate adds to the si-face of carbonyl leading to a tricyclic lactone with a configuration (2aS,4aS,8'S) in excellent agreement with previous experimental reports.     

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.     

Novel chiral bisoxazoline ligands with a biphenyl backbone: preparation, complexation, and application in asymmetric catalytic reactions

Novel C(2)-symmetric chiral bisoxazoline ligands 1 were easily prepared from enantiomerically pure 2-amino alcohols and achiral 2, 2'-biphenyldicarboxylic acid via the corresponding amide and mesylate as intermediates. Since these ligands bear only two ortho-substituents on the biphenyl backbone, the biphenyl axis is not fixed, and the two diastereomers of these ligands exist in equilibrium in solution. Interestingly, when the ligands 1 were coordinated with a metal ion, only one of the two possible diastereomer complexes, an (S,aS,S)-complex, can be formed depending on the combination of the ligand and the metal ion. Thus, copper(I) afforded only the (S,aS,S)-complexes with all ligands 1, while zinc(II), palladium(II), and silver(I) afforded the (S,aS, S)-complexes as the sole product only with 1b, which has a bulky tert-butyl group on the oxazoline ring, and a mixture of the two diastereomer complexes with 1a,c,d. The copper(I)-catalyzed asymmetric cyclopropanation of styrene with diazoacetate proceeded successfully with these ligands and good to excellent enantioselectivities were afforded.     

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.     

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).     

Characteristic features of reduction with i-Bu2AlH of products of ring opening with (?)-α-methylbenzylamine of (3aS,4R,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-epoxy-2-benzofuran-1,3-dione

A special procedure of synthesis was developed for amidoaminals of atypical topology through a reduction with i-Bu₂AlH of primary products of thermodynamical opening of (3aS,4R,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-epoxy-2-benzofuran-1,3-dione at treating with (−)-α-methylbenzylamine. Characteristic spectral criteria are described for assignment of diastereomeric compounds; possible routes of reaction stages are considered.     

(+)-Africanal,a new lignan of the aryltetrahydronaphthalene class

The absolute configuration (1R,2R,3R,3aS) and structural relationships of africanal, a novel lignan from Olea africana, are defined.     

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 nucleoside analogues bearing the five naturally occurring nucleic acid bases built on a 2-oxabicylo[3.1.0]hexane scaffold

Hitherto unknown nucleoside analogues incorporating the five naturally occurring nucleic acid bases built on a 2-oxabicyclo[3.1.0]hexane template were synthesized. The synthesis of these new conformationally restricted nucleoside analogues involved the preparation of a suitable sugar precursor bearing the 2-oxabicyclo[3.1.0]hexane scaffold. This sugar was readily obtained from [(3aS,6aS)-2,2-dimethyl-3a,6a-dihydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzyl ether (4) following a Simons-Smith-type cyclopropanation reaction. Finally, glycosylation reactions and deprotection provided the nucleoside analogues. Using nucleoside 14 bearing thymine base as a model, we found that the conformation of such nucleoside analogue was restricted toward a (0)T(1) conformation.     

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.     

Mercuric triflate-catalyzed tandem cyclization leading to polycarbocycles

[reaction: see text] We developed Hg(OTf)2-catalyzed cyclization of (E)-1,3-dimethoxy-5-(4-methyl-3-nonen-7-ynyl)benzene leading to the formation of (4aS,10aS)-3,4,4a,9,10,10a-hexahydro-5,7-dimethoxy-1,4a-dimethylphenanthrene in 98% yield with up to 100 catalytic turnovers. This is the first mercuric salt-catalyzed biomimetic tandem cyclization.     

Total synthesis of (+)-trans-195A

[reaction: see text] The first enantioselective synthesis of (+)-trans-195A is described. The structure has been constructed by ring-rearrangement metathesis (RRM) and zirconium-mediated Negishi-coupling, used for the first time to prepare 6,6-membered heterocycles, as key steps. By comparison of the synthesized material with the isolated natural product, the absolute configuration of natural trans-195A was determined to be (2R,4aS,5R,8aS)-(-).     

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.     

Inhibition of (+)-aristolochene synthase with iminium salts resembling eudesmane cation

Trigonal iminium halides of (4aS,7S)-1,4a-dimethyl- and (4aS,7S)-4a-methyl-7-(prop-1-en-2-yl)-2,3,4,4a,5,6,7,8-octahydroquinolinium ions, aimed to mimic transition states associated with the aristolochene synthase-catalyzed cyclization of (-)-germacrene A to eudesmane cation, were evaluated under standard kinetic steady-state conditions. In the presence of inorganic diphosphate, these analogues were shown to competitively inhibit the enzyme, suggesting a stabilizing role for the diphosphate leaving group in this apparently endothermic transformation.     

Synthesis of 1.3 Dioxans Related with Ambergris

An improved preparation of the odoriferous acetal (4aR, 6aS, 10aS, 10bR)-4a,7,7,10a-tetramethylper-hydronaphtho[2, 1-d] [1, 3] dioxin (4) and related products are described. The synthesis of 4 is accomplished in six steps, starting with the readily available sesquiterpene (-)-drimenol (5) (overall yield 19.1%).