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).     

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.     

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.     

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).     

Diels-alder reactions with 2-(Arylsulfinyl)-1,4-benzoquinones: effect of aryl substitution on reactivity, chemoselectivity, and pi-facial diastereoselectivity

Diels-Alder reactions of (SS)-2-(2'-methoxynaphthylsulfinyl)-1, 4-benzoquinone (1b), 2-(p-methoxyphenylsulfinyl)-1,4-benzoquinone (1c), and 2-(p-nitrophenylsulfinyl)-1,4-benzoquinone (1d) with cyclopentadiene are reported. These cycloadditions allowed the highly chemo- and stereoselective formation of both diastereoisomeric endo-adducts resulting from reaction on the unsubstituted double bond C(5)-C(6) of quinones working under thermal and Eu(fod)(3)- or BF(3).OEt(2)-catalyzed conditions. The synthesis of endo-adduct [4aS,5S,8R,8aR,SS]-9d resulting from cycloaddition on the substituted C(2)-C(3) double bond was achieved in a chemo- and diastereoselective way from quinone 1d in the presence of ZnBr(2). The reactivity and selectivity of the process proved to be dependent on the electron density of the arylsulfinyl group.     

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.     

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.     

exo-selective asymmetric Diels-Alder reaction catalyzed by diamine salts as organocatalysts

[reaction: see text] A novel binaphthyl-based diamine (R)-2 was designed and synthesized. A protonic acid-(R)-2 salt catalyst has the advantage of exhibiting unprecedented high exo selectivity in the asymmetric Diels-Alder reaction of alpha,beta-unsaturated aldehydes. For instance, the reaction between cinnamaldehyde and cyclopentadiene in the presence of 12 mol % of binaphthyl-based diamine (R)-2 and 10 mol % of p-TsOH.H(2)O in alpha,alpha,alpha-trifluorotoluene at -20 degrees C gave the corresponding exo cycloadduct with 92% ee as a major diastereomer (exo/endo = 13/1).     

Synthesis of (+/-)-bakkenolide-A and its C-7, C-10, and C-7,10 epimers by means of an intramolecular Diels-Alder reaction

(+/-)-bakkenolide-A (1) was prepared in five steps from ethyl 4-benzyloxyacetoacetate by sequential alkylations with tiglyl bromide and (Z)-5-bromo-1,3-pentadiene, followed by an intramolecular Diels-Alder reaction of (E,Z)-triene 25b as the key step. The hydrindane cycloadduct 28 was subjected to hydrogenation and spontaneous or acid-catalyzed lactonization, followed by a Witttig reaction to introduce the exocyclic methylene group of 1. The known 7-epibakkenolide-A (2) and novel 10-epi- and 7,10-diepibakkenolide-A (3 and 4, respectively) stereoisomers were obtained as minor byproducts. When (E)-5-bromo-1,3-pentadiene was used instead of the Z-isomer, the 10-epi- and 7,10-diepibakkenolides were the major products. In both cases exo cyclization was preferred over endo. An alternative approach was based on a similar intramolecular Diels-Alder cycloaddition, using dimethyl malonate instead of ethyl 4-benzyloxyacetoacetate as the starting material for the double alkylation preceding the cycloaddition step. The cycloadduct was then converted into the corresponding alpha-phenylseleno propargyl esters 16 or 22. However, attempted formation of the spiro center by a radical cyclization resulted chiefly in reductive deselenization.     

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.     

A simple and efficient approach to the synthesis of endo and exo bicyclo[6.1.0]nona-3,5-diene-9-carboxaldehyde

Monobromination of 1,5-cyclooctadiene, followed by cyclopropanation with ethyl diazoacetate, led to the formation of endo and exo ethyl 4,5-dibromobicyclo[6.1.0]nonane-9-carboxylates 3a and 3b. Bis-dehydrobromination of 3a and 3b using 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) afforded the endo and exo ethyl bicyclo[6.1.0]nona-3,5-diene-9-carboxylates 4a and 4b. Reduction of these compounds to the corresponding alcohols 5a and 5b and subsequent oxidation with pyridinium chlorochromate (PCC) resulted in the formation of the target compounds endo and exo bicyclo[6.1.0]nona-3,5-diene-9-carboxaldehydes 6a and 6b.     

A Synthesis of (+)-Oblongolide

The absolute configuration of natural oblongolide is reassigned as (3aS,5aR,7S,9aS,9bS)-3a,5a,6,7,8,9,9a,9b-octahydro-7,9b-dimethylnaphtho[1,2-c]furan-1(3H)-one 2 by a 7-stage synthesis of its enantiomer 1 from (+)-citronellol involving a regioselective reduction and an intramolecular Diels-Alder reaction (IMDA) as the key steps. (+)-Citronellol was converted into methyl (2E,4E,10E)-(S)-(+)-11-tert-butoxycarbonyl-7-methyl-undeca-2,4,10-trienoate 7 by sequential Lemieux-Johnson oxidation, Wittig reaction, pyridinium chlorochromate oxidation, and Wadsworth-Emmons-Homer alkenation. A regioselective reduction of the methoxycarbonyl group in 7 afforded tert-butyl (2.E,8E,10E)-(S)-(+)-2,6-dimethyl-12-hydroxy-dodeca-2,8,10-trienoate 8 from which (+)-oblongolide was readily obtained via an IMDA reaction.     

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.     

Asymmetric synthesis of 2-amino-3-hydroxynorbornene-2-carboxylic acid derivatives

The enantioselective synthesis of 2-amino-3-hydroxynorbornene-2-carboxylic acid derivatives (5) was studied using the Diels-Alder reaction between cyclopentadiene and different dienophiles, i.e., alkyl 5-oxo-2-phenyloxazol-4-methylenecarbonates (1) or 2-benzoylamino-3-alkoxycarbonyloxy-acrylates (12), operating with different Lewis acids and both with thermal and with ultrasound conditions. The enantioselective synthesis of the exo/endo compounds 5c,d and 5'c,d was achieved starting from the chiral menthyl acrylates 12b,c using Mg(ClO(4))(2) as the catalyst and ultrasound. The cycloadducts were obtained in very good yield, in mild conditions, in short time, and in good diastereomeric excess (exo, 80%; endo, 87%). Finally, the use of alkylidene-oxazolones or acrylates and EtAlCl(2) or Mg(ClO(4))(2) as the catalyst allowed control of the cycloaddition reaction in favor of the exo or endo products.     

Tandem ireland-claisen rearrangement ring-closing alkene metathesis in the construction of bicyclic beta-lactam carboxylic esters

4-Alkenyl-2-azetidinone systems were converted to the corresponding ethyl 2-?4-alkenyl-2-oxo-1-azetidinyl-4-pentenoates. In addition, 4-(2-propenyl-1-oxy)-, 4-(2-propenyl-1-thio)-, 4-?N-(2-propenyl)-(4-toluenesulfonyl)- and (3S, 4R)-4-(2-propenyl)-3-?(1R)-1-(tert-butyldimethylsilyloxy)ethyl-++ +azeti din-2-one were converted into beta-lactam dienes via sequential N-alkylation, Ireland-Claisen ester enolate rearrangement and esterification. Ring-closing metathesis using the Schrock ?(CF(3))(2)MeCO(2)Mo(=CHCMe(2)Ph)(=NC(6)H(3)-2,6-iso-Pr(2)) (1) or Grubbs Cl(2)(Cy(3)P)(2)Ru=CHPh (2) carbenes gave a series of ?5.2.0 and ?6.2.0 bicycles. Subsequent elaboration of the analogous (2R,7R, 8S)-tert-butyl 8-?(1R)-(tert-butyldimethylsilyloxy)ethyl-1-aza-9-oxobicyclo++ +?5.2. 0non-4-ene-2-carboxylate (15), via selenation and desilylation, gave (+)-(2S,7R,8S)-tert-butyl 8-?(1R)-hydroxyethyl-1-aza-9-oxobicyclo?5.2.0nona-2, 4-diene-2-carboxylate (18), a novel type of bicyclic beta-lactam. Diels-Alder cycloaddition further afforded tetracyclic systems exemplified by tert-butyl (1R,4S,5R,7S)-4-?(1R)-1-hydroxyethyl-3,9, 11-trioxo-10-phenyl-2,8,10,12-tetraazatetracyclo?5.5.2.0.(2, 5)0(8, 12)tetradec-13-ene-1-carboxylate (19).     

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.     

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.     

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.     

Peri- and enantioselectivity of thermal, scandium-, and [pybox/scandium]-catalyzed Diels-Alder and hetero-Diels-Alder reactions of methyl (E)-2-oxo-4-aryl-butenoates with cyclopentadiene

The cycloaddition between methyl (E)-2-oxo-4-aryl-3-butenoates (2 a-d) and cyclopentadiene, in addition to the expected normal Diels-Alder (DA) adducts endo-3 a-d and exo-4 a-d, gives the less expected endo-5 a-d products of the [4+2] hetero-Diels-Alder (HDA) reaction in which the alpha-ketoester behaves as a heterodiene. If a comparison is made between the thermal and the scandium(III) triflate-catalyzed conditions, the periselectivity changes and whereas under thermal conditions the main products are those from the DA reaction (3 a-d), in the presence of Sc(OTf)3 (OTf=triflate), the HDA products 5 a-d become largely predominant. The reactions are enantioselectively catalyzed by the scandium(III) triflate complex of (4'S,5'S)-2,6-bis[4'-(triisopropylsilyl)oxymethyl-5'-phenyl-1',3'-oxazolin-2'-yl]pyridine (1) and both the DA and the HDA products are obtained with excellent enantiomeric excess, up to >99% ee. The X-ray crystallographic structure determination of 5 c assigns it the 4R,4aS,7aR absolute configuration. The thermal retro-Claisen rearrangement of 3 c into (4R,4aS,7aR)-5 c allows the correlation of their absolute configuration, and 3 c has therefore the 2R,3R configuration. By analogy the same absolute configuration can be assigned to 3 a,b,d and 5 a,b,d, and the stereospecific thermal Claisen rearrangement of the optically active 5 a,b,d into 3 a,b,d completes the correlation between their absolute configuration. The [3,3]-sigmatropic rearrangements can be easily carried out under catalytic conditions with scandium(III) triflate, which promotes the equilibration between 3 a-d and 5 a-d, with a different degree of enantioselectivity characterizing the process starting from 3 a-d or 5 a-d. The unambiguous attributions of the configuration to the products allows us to propose a rationale of the stereochemical outcome of the catalyzed cycloaddition and to investigate the reaction mechanism of the competing DA and HDA reactions and shifts in products distribution by acid catalysis.     

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…