Cyclopropane-annelated azaoligoheterocycles by Ti-mediated intramolecular reductive cyclopropanation of cyclic amino Acid amides

Starting from pyrrole- and indole-2-carboxylic acids 5 a and 5 b, the tri- and tetracyclic N,N-dibenzylcyclopropylamines 7 a and 7 b have been synthesized in 52 and 33 % overall yield, respectively. The synthesis of the enantiopure tetracyclic diamine 10 has been achieved applying the established set of reactions to N-tert-butoxycarbonylindoline-2-carboxylic acid (8) in 46 % overall yield. The amide 15 could not be prepared in the same way starting from the N-tert-butoxycarbonylproline 11. In fact, in the allylation step the stereogenic center was deprotonated and the doubly alkylated amide 13 was formed. However, the desired intermediate 15 could be obtained from L-proline in 49 % yield performing first the N-allylation step, then the introduction of the amide function. From 15, the cyclopropane-annelated pyrrolizidine 16 was obtained in 70 % yield as a mixture of (1aS,6aS,6bR)-16 and (1aR,6aS,6bS)-16 diastereoisomers in a ratio of 1:2.9.     

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).     

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 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.     

Acid-promoted rearrangement of drimane type epoxy compounds and their application in natural product synthesis

The reactions of (±)-α-epoxy drimenol (4) and (±)-α-epoxy drimenyl cyanide (6) with acids (proton acid or Lewis acid) selectively gave the rearranged aldehyde (±)-13 and (±)-15 having the hydroindane skeleton, respectively, while the reactions of (±)-4 and (±)-6 with Dibal-H selectively afforded the allyl alcohol (±)-14 and (±)-16, respectively. The reactions of (8aR)-6 and (8aS)-6 with Dibal-H were applied for the determination of the absolute structure of natural 7β-acetoxy-ent-labda-8(17),13(14)E-dien-15-ol (18). The reaction of (±)-α-epoxy bicyclofarnesol (5) and (8aS)-5 with proton acid selectively provided the rearranged ketol (±)- and (8aS)-31 having the hydroindane skeleton, respectively. The optically active (8aS)-31 was converted to the natural (9S)-austrodoric acid (33).     

Polybrominated diphenyl ethers from Dysidea herbacea,Dysidea chlorea and Phyllospongia foliascens

The marine sponges Dysidea herbacea, D. chlorea and Phyllospongia foliascens were differentiated with difficulty in the field. D. herbacea contained 2-(2',4'-dibromophenoxy)-3,4,5-tribromophenol (1), 2-(2',4'-dibromophenoxy)-4,5,6-tribromophenol (2) and 2-(2',4'-dibromophenoxy)-3,5-dibromophenol (6). D. chlorea contained only 2-(2',4'-dibromophenoxy)-4,6-dibromophenol(3), a compound previously reported as a metabolite of D. herbacea. Phyllospongia foliascens contained 2-(3',5'-dibromo-2'-methoxy-phenoxy)-3,5-dibromoanisole (7) and a 1:2 mixture of 2-(3',5'-dibromo-2'-hydroxyphenoxy)-3,5,6-tribromophenol (8) and 2-(3',5'-dibromo-2'-hydroxyphenoxy)-3,4,5,6-tetrabromophenol (9).     

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.     

Unusual reactions of 5,5-dimethyl-2-(indenyl-2)-3-pyrazolidinone with acetylenedicarboxylates

[reaction: see text] Reaction of 5,5-dimethyl-3-pyrazolidinone (1) with 2-indanone (2) gave 5,5-dimethyl-2-(1H-indenyl-2)-3-pyrazolidinone (3) instead of the expected azomethine imine 4. Although reaction of 2-substituted 3-pyrazolidinones with acetylenedicarboxylates usually gives ring expansion products, such as 1,2-diazepines, treatment of 3 with dialkyl acetylenedicarboxylates (5, R = Me; 6 R = Et) resulted in the formation of rel-(7aR,12aS)-6,7-bis(alkoxycarbonyl)-3,4-dihydro-4,4-dimethyl-7aH-indano[1,2-b]pyrrolo[1,2-a]pyrimidin-2-ones (7, R = Me; 9, R = Et) as major products and 3,4-bis(alkoxycarbonyl)-7,7-dimethyl-2-(indenyl-2)-6,7-dihydro-2H,6H-1,2-diazepin-5-ones (8, R = Me: 10, R = Et) as minor products.     

Reaction of 3,6-diphenyl-1,2,4,5-tetrazine with cis,cis-1,5-cyclooctadiene : An attempt at preparing some dihydropyridazine derivatives

The reaction of 3,6-diphenyl-1,2,4,5-tetrazine 1 with cis,cis-cycloocta-1,5-diene 7 has been studied with a view to preparing some interesting dihydropyridazine derivatives. Refluxing a mixture of 1 with excess of 7 in benzene solution for 8hr resulted in the formation of a mixture of products consisting of 1,4-diphenyl-10a-hydroperoxy-4a, 5,6,9,10,10a-hexahydrocycloocta[d]pyridazine (8, 27%) and 2,4a,5,6,8,10a,11,12-octahydro-1,4,7,10-tetraphenyldipyridazo[4,5-a:4',5'-e]cyclooctene ( However, when the reaction of 1 with 7 was carried out in refluxing benzene for nearly 40 hr, the products formed were a 14% yield of 8, a 17% yield of 9 and a 37% yield of 1,4-diphenyl-5,6,9,10-tetrahydrocycloocta[d]pyridazine (10). Neat heating of 1 with 7 around 150° for 10 hr, on the other hand, gave a 20% yield of 9, as the only isolable product. Thermolysis of 8 around 155° gave a mixture of products consisting of 2-oxocyclooct-5-enyl phenyl ketone N-benzoylhydrazone (15,30%) and 1H-3-phenyl-4,5,8,9-tetrahydrocycloocta[d]pyrazole (16, 22%). Nickel peroxide-oxidation of the adduct 9 gave a 67% yield of 1,4,7,10-tetraphenyldipyridazo[4,5-a:4',5'-e]cyclooctene (27). Acetylation of 9, on the other hand, gave a 70% yield of 2,3,8,9-tetraacetyl-2,3,5,6,8,9,11,12-octahydro-1,4,7,10-tetraphenyldipyridazo[4,5-a:4',5'-e]cyclooctene(28).     

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...     

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.     

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.     

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.     

Asymmetric syntheses of (8R,8aS)- and (8R,8aR)-8-hydroxy-5-indolizidinones:Two promising oxygenated indolizidine building blocks

Starting from the oxygenated piperidine building block 20,two synthetic approaches to new building blocks (8R,8aS)-and (8R,8aR)-8-hydroxy-5-indolizidinones 19a/19b and 15a/15b have been developed,respectively. The first one is based on the trans-diastereoselective reductive alkylation (dr = 93:7),followed by a four-step procedure; and the second one called for the RCM reaction on the N,O-acetal derived from a vinylation,which was followed by a pyrrole formation,and a stereocontrolled cis-selective (dr = 91:...     

11H-Pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinoléines (aza-7 ellipticines) substituées sur leur position 6

6-Dialkylaminoalkylamino substituted 11H-pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinolines (7-aza ellipti-cines) were obtained by a six step synthesis starting from 2-chloro-3-nitro pyridine and 6-amino-5-methyl (and 5,8-dimethyl) isoquinoline-1-2H-ones already described. A brief survey of biological results shows that derivatives of this new heterocyclic ring system are less interesting than their 5H-pyrido(3',4':4,5]pyrrolo[2,3-g]isoquinolines (9-aza ellipticines) and pyrido[4,3-b]carbazoles (ellipticines) analogues.     

(8R,8aS)-及(8R,8aR)-8-羟基-5-吲哚里西啶酮的不对称合成:两个有用的羟基吲哚里西啶合成砌块

以3-苄氧基哌啶-2,6-二酮衍生物20为起始原料,分别合成了两类新的合成砌块(8R,8aS)-及(8R,8aR)-8-羟基-5-吲哚里西啶酮19a/19b和15a/15b.19a/19b的合成是基于反式非对映立体选择性还原烷基化反应(dr=93:7),接着经4步转化而成;而化合物15a/15b的制备则以双烯29的RCM反应为关键步骤,再经顺式立体选择性催化氢化(dr=91:9)反应完成.此外,还原化合物15a得到了(8R,8aR)-8-羟基-5-吲哚里西啶18.     

Endo-selective quenching of hexahydropyrrolo[2,3-b]indole-based N-acyliminium ions

Radical decarboxylation of L-tryptophan-derived (2S,3aR,8aS)-8-arylsulfonyl-1,2-di(methoxycarbonyl)-1,2,3,3a,8,8a-hexahydro-2H-pyrrolo[2,3-b]indoles 8 and 9 in the presence of diphenyl diselenide results in the endo-selective formation of (2R,3aR,8aS)-8-arylsulfonyl-1-methoxycarbonyl-2-phenylselenyl-1,2,3,3a,8,8a-hexahydro-2H-pyrrolo[2,3-b]indoles 10 and 11. These selenides, in conjunction with Lewis acids, serves as precursors to the corresponding N-acyl iminium ions, which undergo selective endo-face quenching by allyltributylstannane, allyltrimethylsilane, propargyltrimethylsilane, and trimethylsilylcyanide. Stereochemical assignments rest on NMR data and crystallographic studies. The endo-selective nature of these reactions is interpreted in terms of minimization of allylic strain at the transition state for nucleophilic attack on the N-acyl iminum ion.     

Synthesis of the natural enantiomers of ascochlorin,ascofuranone and ascofuranol

Three fungal metabolites with a common structural feature as prenylated phenols were synthesized in their naturally occurring and optically active forms: ascochlorin [(2'$\text{E}$,4'$\text{E}$,1'$\text{R}$,2'$\text{R}$,6'$\text{R}$)-(-)-5-chloro-2,4-dihydroxy-6-methyl-3-[5'-(1',2',6'-trimethyl-3'-oxo-cyclohexyl)-3'-methyl-2', 4'-pentadienyl] benzaldehyde], ascofuranone [(2'$\text{E}$,6'$\text{E}$,1'$\text{S}$)-(-)-5-chloro-2, 4-dihydroxy-6-methyl-3-[7'-(3',3'-dimethyl-4'-oxo-2'-oxacyclopentyl)-3',7'-dimethyl -2', 6'-heptadienyl] benzaldehyde] and ascofuranol [(2'$\text{E}$,6'$\text{E}$,1'$\text{S}$,4'$\text{S}$)-(-)-5-chloro-2,4-dihydroxy-6-methyl-3-[7'-(3', 3'-dimethyl-4'-hydroxy-2'-oxacyclopentyl)-3', 7'-dimethyl-2',6'-hepta-dienyl]benzaldehyde ]. (+)-Ascofuranone and (+)-ascofuranol were also synthesized. By the present synthesis the absolute configuration of the natural (-)-ascofuranol was established as (1'$\text{S}$,4'$\text{S}$).     

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).     

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).