Scope and applications of second generation palladium-catalyzed cycloalkenylation. Stereoselective total syntheses of isoiridomyrmecin, isodihydronepetalactone, and α-skytanthine

Functionalized bicyclo[3.2.1]octanes, -oxabicyclo-[4.3.0]nonanes, 3-azabicyclo[3.3.0]octanes, and 3-azabicyclo[4.3.0]nonanes were easily synthesized via a second generation palladium-catalyzed cycloalkenylation. Isoiridomyrmecin and isodihydronepetalactone, both of which feature a 3-oxabicyclo[4.3.0]nonane subunit, were stereoselectively synthesized via a second generation palladium-catalyzed cycloalkenylation as the key step. α-Skytanthine, a typical 3-azabicyclo[4.3.0]nonane alkaloid, was also constructed using the same catalytic cyclization protocol.     

Tungsten(0)- and rhenium(I)-catalyzed tandem cyclization of acetylenic dienol silyl ethers based on geminal carbo-functionalization of alkynes

Tungsten(0)- and rhenium(I)-catalyzed reactions of acetylenic dienol silyl ethers based on the concept of geminal carbo-functionalization of alkynes are reported. Treatment of 3-siloxy-1,3-diene-7-ynes with catalytic amounts of [W(CO)(6)] or [ReCl(CO)(5)] under photoirradiation conditions gives synthetically useful bicyclo[3.3.0]octane derivatives in good yields. Extremely high catalytic activity is noted for the rhenium(I) complex. The reaction has been extended to substrates containing a nitrogen atom in their tethers. In this case, two kinds of synthetically useful heterocyclic compounds-the 2-azabicyclo[3.3.0]octane derivatives 9 and the monocyclic dihydropyrroles 10, with allenyl substituents-are obtained, and selective preparation of either product can be achieved through the use of an appropriate combination of the nitrogen substituent and the type of the rhenium(I) catalyst. The 2-azabicyclo[3.3.0]octane derivatives 9 are obtained selectively by carrying out treatment of N-Ns derivatives in the presence of [ReCl(CO)(4)(PPh(3))], whereas the dihydropyrrole derivatives 10 are obtained by treatment of N-Mbs derivatives with [ReCl(CO)(5)]/AgSbF(6) . Finally, we have applied this geminal carbo-functionalization to one-carbon-elongated substrates containing N-Ts moieties in their tethers. Selective 5-exo cyclization is achieved in the presence of gold(I) or rhenium(I) catalysts, whereas 6-endo cyclization is observed on use of [W(CO)(6)].     

Exploiting the regioselectivity of pyroglutamate alkylations for the synthesis of 6-azabicyclo[3.2.1]octanes and 4-azabicyclo[3.3.0]octanes

Depending on the N-protecting group of pyroglutamates, the reactivity can be directed to the formation of 6-azabicyclo[3.2.1]octanes or 4-azabicyclo[3.3.0]octanes, which are conformationally restricted glutamate analogues.     

Alkaloid synthesis using 2nd generation palladium-catalyzed cycloalkenylation. Diastereoselective total synthesis of α-skytanthine

An efficient approach to the synthesis of 3-azabicyclo[3.3.0]octanes and 3-azabicyclo[4.3.0]nonanes by 2nd generation palladium-catalyzed cycloalkenylation is described. Additionally, this reaction is used for the diastereoselective total synthesis of (±)-α-skytanthine.     

Mass spectral fragmentation of (S,S)-2-substituted 4,4-diphenyl-3,1-oxazabicyclo[3.3.0]octanes: ring contraction of pyrrolidine and 1,3-oxazolidine in mass spectrometry

The mass spectral behaviour of (S,S)-2-substituted 4,4-diphenyl-3,1-oxazabicyclo[3.3.0]octanes has been studied with the aid of mass-analyzed ion kinetic energy spectrometry and accurate mass measurements under fast atom bombardment (FAB) and electron impact (EI) ionization conditions. Under FAB ionization, all compounds show a tendency to form protonated aldehyde or benzophenone ions and to form protonated 1-azabicyclo[3.1.0]hexane ions, which can further lose an ethylene or cyclopropane from the pyrrolidine ring to produce protonated 1-azabicyclo[1.1.0]butane ions and 3H-azirine ions, respectively. Under EI ionization, a similar fragmentation to that under FAB ionization was observed. The title compounds also show a tendency to yield oxirane ions and oxirenium ions by loss of pyrrolidine and pyrrolidine plus H. Ring contractions of 1,3-oxazolidine by loss of an aldehyde or ketone and of pyrrolidine by loss of an ethylene or cyclopropane were observed under both FAB and EI ionization conditions.     

W(CO)5(L)-catalyzed tandem intramolecular cyclopropanation/cope rearrangement for the stereoselective construction of bicyclo[5.3.0]decane framework

Utilizing the biscarbene character of electrophilically activated alkynes, a novel tandem intramolecular cyclopropanation/Cope rearrangement of 3-siloxy-1,3,9-trien-7-ynes catalyzed by W(CO)5(L) for the stereoselective construction of bicyclo[5.3.0]decane framework is achieved. When 3-siloxy-1,3,9-trien-7-ynes were treated with a catalytic amount of W(CO)6 under photoirradiation, bicyclo[5.3.0]decanes were obtained in good yield stereoselectively. In this reaction, the Cope rearrangement of the divinylcyclopropane intermediates, generated by the intramolecular cyclopropanation of 3-siloxy-1,3,9-trien-7-ynes based on the W(CO)5(L)-catalyzed electrophilic activation of alkynes, occurs to give synthetically useful functionalized bicyclo[5.3.0]decane derivatives stereoselectively.     

W(CO)5(L)-catalyzed formal cope rearrangement of allenyl silyl enol ethers

[reaction: see text] On treatment of 5-siloxyhexa-1,2,5-trienes with a catalytic amount of W(CO)(6) under photoirradiation, formal Cope rearrangement proceeded to give 2-siloxyhex-1-en-5-ynes in good yield. The electrophilic activation of the allenyl moiety by W(CO)(5) triggers the intramolecular attack of the silyl enol ether in a 6-endo manner to produce a cyclohexenyl tungsten species. Carbon-carbon bond cleavage occurs by electron donation from the anionic W(CO)(5) into the silyloxonium moiety to afford the products with regeneration of the W(CO)(5)(L).     

Synthesis of 1-azabicyclo[3.3.0]octane derivatives and their effects as piracetam-like nootropics

A useful pharmaceutical intermediate, 5-nitromethyl-1-azabicyclo[3.3.0]octane (1), was prepared in one step from 1,7-dichloro-4-heptanone (4) under mild conditions. Catalytic hydrogenation of 1 over Raney Ni in the presence of sodium hydroxide afforded 5-aminomethyl-1-azabicyclo[3.3.0]octane (2) in high yield. Piracetam analogues 20-23, which were pyrrolidine derivatives involving a 1-azabicyclo[3.3.0]octane ring, were synthesized. Pharmacological tests showed that N-[(1-azabicyclo[3.3.0]octan-5-yl)methyl]-2-oxo-1-pyrrolidineacetamid e (20) improves cerebral function.     

W(CO)5-amine catalyzed exo- and endo-selective cyclizations of omega-alkynyl silyl enol ethers: a highly useful method for the construction of polycyclic compounds

[reaction: see text] A highly useful method for the construction of polycyclic compounds based on the amine-controlled exo- and endo-selective cyclizations of omega-alkynyl silyl enol ethers catalyzed by W(CO)5L is reported. When bis-alkynyl silyl enol ethers were treated with a catalytic amount of W(CO)6, DABCO, and water under photoirradiation, synthetically useful tricyclic ketones were obtained in good yield.     

Simple construction of bicyclo[4.3.0]nonane,bicyclo[3.3.0]octane,and related benzo derivatives by palladium-catalyzed cycloalkenylation

[reaction: see text] Bicyclo[4.3.0]nonanes (hydrindanes) and bicyclo[3.3.0]octanes (octahydropentalenes) are easily synthesized by palladium-catalyzed cycloalkenylations. Additionally, benzo-fused bicyclo[3.3.0]octanes are prepared for the first time through intramolecular coupling between silyl enol ethers and aromatic rings in the presence of catalytic palladium acetate.     

Synthesis of (1-azabicyclo[3.3.0]octanyl)methyl-substituted aromatic heterocycles and their muscarinic activity.

In our development of drugs effective against Alzheimer's disease, we have researched a series of aromatic compounds having a characteristic cyclic amine, 1-azabicyclo[3.3.0]octane ring. In this report, we describe synthesis of a series of aromatic heterocycles with the 1-azabicyclo[3.3.0]octane ring and their pharmacological evaluation. 3-Amino-5-(1-azabicyclo[3.3.0]octan-5-yl)methyl-1,2,4-oxadiazole (2b) showed the highest M1 selectivity.     

Cycloaddition between electron-deficient pi-systems, photochemical and radical-induced reactions: a novel, general, and stereoselective route to polyfunctionalized bridged bicyclo[2.2.2]octanes, bicyclo[3.3.0]octanes, bicyclo[4.2.0]octanes, and tricyclo[4.3.1.0(3,7)]decanes

A novel, general, and stereoselective route to functionalized bridged bicyclo[2.2.2]octanes, bicyclo[3.3.0]octanes, bicyclo[4.2.0]octanes, and tricyclo[4.3.1.0(3,7)]decanes has been described. Various functionalized and substituted bicyclo[2.2.2]octanes endowed with a beta,gamma-enone chromophore were synthesized via cycloaddition of in situ generated cyclohexa-2,4-dienones with electron-deficient 2pi partners and manipulation of the resulting adducts. Triplet sensitized irradiation of bridged bicyclooctenones led to synthesis of bicyclo[3.3.0]octanoids, whereas the direct irradiation furnished bicyclo[4.2.0]octanes in stereoselective fashion as a result of modulation of reactivity in excited states. Further, manipulation of the adducts led to appropriately appended and functionalized bicyclo[2.2.2]octanes that upon radical induced cyclization provided an efficient and stereoselective route to the tricyclo[4.3.1.0(3,7)]decane (isotwistane) framework of pupukeananes.     

W(CO)5(L)-catalyzed endo-selective cyclization of allenyl silyl enol ethers: an efficient method for the cyclopentene annulation onto alpha,beta-unsaturated ketones

[reaction: see text] Indium-mediated allenylation of alpha,beta-unsaturated ketones in the presence of tert-butyldimethylsilyl triflate and dimethyl sulfide gives 6-siloxy-1,2,5-trienes, which undergo W(CO)(5)(L)-catalyzed 5-endo cyclization to give the corresponding cyclopentene derivatives in good yield. Furthermore, this novel W(CO)(5)(L)-catalyzed cyclization of allenyl silyl enol ethers proceeds in a 6-endo manner when 5-siloxy-1,2,5-trienes are employed as a substrate. In these reactions, effective electrophilic activation of allenyl compounds for attack by silyl enol ethers is achieved using a catalytic amount of W(CO)(6).     

Preparation of hydrido(vinylidene)ruthenium(II) complexes and a one-pot synthesis of Grubbs-type ruthenium carbenes

Treatment of the hydrido(dihydrogen) compound [RuHCl(H2)(PCy3)2] 1 with alkynes RC[triple bond, length as m-dash]CH (R=H, Ph) afforded the hydrido(vinylidene) complexes [RuHCl(=C=CHR)(PCy3)2] 2, 3 which react with HCl or [HPCy3]Cl to give the corresponding Grubbs-type ruthenium carbenes [RuCl2(=CHCH2R)(PCy3)2] 4, 5. The reaction of 2 (R=H) with DCl, or D2O in the presence of chloride sources, led to the formation of [RuCl2(=CHCH2D)(PCy3)2] 4-d1. Based on these observations, a one-pot synthesis of compounds 4 and 5 was developed using RuCl3.3H2O as the starting material. The hydrido(vinylidene) derivative 2 reacted with CF3CO2H and HCN at low temperatures to yield the carbene complexes [RuCl(X)(=CHCH3)(PCy3)2] 6, 7, of which 7 (X=CN) was characterized crystallographically. Salt metathesis of 2 with CF3CO2K and KI led to the formation of [RuH(X)(=C=CH2)(PCy3)2] 8, 9. The bis(trifluoracetato) and the diiodo compounds [RuX2(=CHCH3)(PCy3)2] 10, 11 as well as the new phosphine P(thp)3 12 (thp=4-tetrahydropyranyl) and the corresponding complex [RuCl2(=CHCH3){P(thp)3}2] 14 were also prepared. The catalytic activity of the ruthenium carbenes 4-7, 10, 11 and 14 in the olefin cross-metathesis of cyclopentene and allyl alcohol was investigated.     

Rh(I)-catalyzed Pauson-Khand reaction of 1-phenylsulfonyl-1,2-octadien-7-yne derivatives

The Rh(I)-catalyzed PKR of 1-phenylsulfonyl-1,2-octadien-7-ynes and their aza derivatives exclusively produced the corresponding 9-phenylsulfonylbicyclo[4.3.0]nona-1,6-dien-8-ones and no 4-(phenylsulfonylmethylidene)bicyclo[3.3.0]oct-1-en-3-ones could be detected. Thus, the ring-closing pattern was found to be the same as those of the previously reported 3-phenylsulfonyl-1,2-octadien-7-yne derivatives. However, the formation of 4-(phenylsulfonylmethylidene)-7-oxabicyclo[3.3.0]oct-1-en-3-ones was observed as a minor product when the 5-oxa congeners were used. In addition, a larger ring-sized product, 10-phenylsulfonyl-5-azabicyclo[5.3.0]deca-1,7-dien-9-one derivative, was obtained from the 6-aza derivative of 1-phenylsulfonyl-1,2-nonadien-8-yne.     

Novel synthesis of 3-azabicyclo[3.1.0]hexanes by unusual palladium(0)-catalyzed cyclopropanation of allenenes

Novel stereoselective synthesis of 3-azabicyclo[3.1.0]hexanes from allenenes is presented. Treatment of N-protected 4-alkyl-4-(N-allyl)amino allenes with allyl carbonate and a catalytic amount of Pd(2)(dba)(3).CHCl(3) in MeCN leads to stereoselective formation of the 3-azabicyclo[3.1.0]hexane framework in moderate to good yields. [reaction: see text]     

5-Perfluoroalkyl bicyclic amide acetals

A new route to a novel class of bicyclic amide acetals, 5-perfluoroalkyl-4,6-dioxa-1-azabicyclo [3.3.0] octanes, is described. These compounds are prepared by the acid catalyzed dehydration of N,N-bis-(2-hydroxyethyl)-perfluoroalkylamides and are characterized by their lack of reactivity with a variety of electrophiles and nucleophiles relative to the very reactive 5-alkyl bicyclic amide acetals.     

Synthesis of fluorinated 2,6-heptanediones and 2-oxa-6- azabicyclo[2.2.2]octanes from 1,4-dihydropyridines

Electrophilic fluorination of Hantzsch-type 1,4-dihydropyridines with Selectfluor^® led to the formation of new fluorinated 2,6-heptanediones - dialkyl 2,4-diacetyl-2,4-difluoro-3-phenylpentanedioates. Novel 2,6-heptanedione derivatives in reaction with hydrazine hydrate easily form 6-amino-4,7-difluoro-3-hydroxy-1,3-dimethyl-5-oxo-8-phenyl-2-oxa-6-azabicyclo[2.2.2]octanes instead of the corresponding diazepine derivatives. The obtained 2-оxa-6-azabicyclo[2,2,2]octanes are thermally stable at the temperatures below 50°С. At higher temperatures rearrangement of 2-oxa-6-azabicyclo[2,2,2]octanes offers new fluorine-containing pyrazolinone derivatives - alkyl esters of 2-fluoro-2-((4-fluoro-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)-3-oxobutanoates.     

Reactions of Substituted 2,3,7-Triazabicyclo[3.3.0]oct-3-ene-4-carboxylic Acid Esters with Halogens

Substituted 2,3,7-triazabicyclo[3.3.0]oct-3-ene-4-carboxylic acid esters react with chlorine and bromine to give the corresponding 4-halo-2,3,7-triazabicyclo[3.3.0]oct-2-ene-4-carboxylates. Heating of the latter to 120°C under reduced pressure leads to elimination of nitrogen molecule and formation of 6-halo-3-azabicyclo[3.1.0]hexane-6-carboxylates.     

Chromium- and tungsten-triggered valence isomerism of cis-1-acyl-2-ethynylcyclopropanes via [3,3]sigmatropy of (2-acylcyclopropyl)vinylidene-metal intermediates.

The reaction of cis vicinal acetylethynylcyclopropanes 1 with a catalytic amount of M(CO)5(THF) (M = Cr or W) in the presence of Et3N at room temperature gave ortho-substituted phenols 7 in good yields as valence isomerized products. In the absence of Et3N the reactions did not work at all. The reaction of a cyclopropane having an ester or an amide instead of an acetyl moiety with M(CO)5(THF) did not take place, whereas an ethynylvinylcyclopropane gave a mixture of 1- and 2-substituted 1,3,5-cycloheptatrienes. These valence isomerization reactions are assumed to proceed via the formation of vinylidene-metal intermediates 2 from terminal alkynyl moieties followed by [3,3]sigmatropy of 2 to give seven-membered carbene complexes 3.