Photochemistry of bicyclo[2.2.2]oct-7-ene-2,5-diones and the corresponding 5-hydroxyimino and 5-methylene derivatives

Synthesis and photochemistry of several title compounds 1-3 containing multiple chromophoric systems are described. The Diels-Alder reactions of 2,6,6-trimethylcyclohexa-2,4-dienone (5) with acetylenes 6a-d provided the adducts 7a-d, which upon hydrolysis furnished the desired bicyclo[2.2.2]octenediones 1a-d. Oximes 2a-d were prepared from diones 1a-d by treatment with hydroxylamine hydrochloride in pyridine. 5-Methylenebicyclo[2.2.2]oct-7-en-2-ones 3a-d were obtained via chemoselective Wittig reaction of the corresponding diones 1a-d. Bicyclo[2.2.2]octenediones 1a-c underwent chemoselective oxa-di-pi-methane rearrangement under sensitized conditions and suffered formal ketene extrusion upon direct irradiation. Direct irradiation of 1d afforded 11d via formal ketene extrusion but under sensitization it remained unchanged. Oximes 2a-d suffered ketene extrusion upon direct irradiation and E/Z isomerization under sensitized conditions. On the other hand, 5-methylenebicyclo[2.2.2]oct-7-en-2-ones 3a-d generally underwent 1,3-acyl shift. The plausible courses of all these photochemical processes are discussed.     

Characterization of metabolites of a NK1 receptor antagonist, CJ-11,972, in human liver microsomes and recombinant human CYP isoforms by liquid chromatography/tandem mass spectrometry

The in vitro metabolism of CJ-11,972, (2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl)-(5-tert-butyl-2-methoxybenzyl)amine, an NK1 receptor antagonist, was studied in human liver microsomes and recombinant human CYP isoforms. Liquid chromatography/mass spectrometry (LC/MS) and tandem mass spectrometry (LC/MS/MS) coupled to radioactive detection were used to detect and identify the metabolites. CJ-11,972 was extensively metabolized in human liver microsomes and recombinant human CYP 3A4/3A5 isoforms. A total of fourteen metabolites were identified by a combination of various MS techniques. The major metabolic pathways were due to oxidation of the tert-butyl moiety to form an alcohol (M6) and/or O-demethylation of the anisole moiety. The alcohol metabolite M6 was further oxidized to the corresponding aldehyde (M7) and carboxylic acid (M4). Two unusual metabolites (M13, M17), formed by C-demethylation of the tert-butyl group, were identified as 2-{3-[(2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-ylamino)methyl]-4-methoxyphenyl}propan-2-ol and (2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl)-(5-isopropenyl-2-methoxybenzyl)amine. A plausible mechanism for C-demethylation may involve oxidation of M6 to form an aldehyde metabolite (M7), followed by cytochrome P450-mediated deformylation leaving an unstable carbon-centered radical, which would quickly form either the alcohol metabolite M13 and the olefin metabolite M17.     

Nitroxydes—LXIII : Oxydation de nitroxydes isoquinuclidiniques par l'oxyde d'argent humide. Preparation de nitroxydes aza-6 bicyclo[3.2.1]octeniques

Moist silver oxide oxidation of three isoquinuclidinic nitroxide ketones is described. 1,3,3-Trimethyl-2-azabicyclo[2.2.2]octane-5-one-2-oxyl 3, and 1,3,3,7-anti-tetramethyl-2-azabicyclo[2.2.2]octane-5-one-2-oxyl 4 lead to 6-aza-bicyclo[3.2.1]oct-3-ene-2-one-7-oxyl derivatives 6, 7, and 1,3,3,7-syn-tetramethyl-2-aza-bicyclo[2,2.2]octane-5-one-2-oxyl 5 to 8-substituted p-menthenones.     

Synthesis and transformations of di-endo-3-aminobicyclo-[2.2.2]oct-5-ene-2-carboxylic acid derivatives

all-endo-3-amino-5-hydroxybicyclo[2.2.2]octane-2-carboxylic acid (13) and all-endo-5-amino-6-(hydroxymethyl)bicyclo[2.2.2]octan-2-ol (10) were prepared via dihydro-1,3-oxazine or g-lactone intermediates by the stereoselective functionalization of an N-protected derivative of endo-3-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acid (2). Ring closure of b-amino ester 4 resulted in tricyclic pyrimidinones 15 and 16. The structures, stereochemistry and relative configurations of the synthesized compounds were determined by IR and NMR.     

Interaction between Exocyclic s-cis-Butadiene and Homoconjugated Functions. Preparation and Diels-Alder Reactivity of Remotely Substituted 2,3-Dimethylidenebicyclo[2.2.2]octanes

The preparations of 5,6-dimethylidene-2exo-bicyclo[2.2.2]octanol ( 8 ), its endo isomer 9 , 5,6-dimethylidene-2-bicyclo[2.2.2]octanone ( 10 ) and 2 exo, 3 exo-epoxy-5,6dimethylidenebicyclo[2.2.2]octane ( 11 ) are described. The kinetics of their cycloaddition to tetracyanoethylene has been measured in toluene at 25° together with those of 2,3-dimethylidenebicyclo[2.2.2]octane ( 7 ) and 5,6-dimethylidenebicyclo[2.2.2]oct-2-ene (12). The effects of remote substitution on the Diels-Alder reactivity of 2,3-dimethyl idenebicyclo[2.2.2]octanes are compared with those observed in the 2,3-dimethylidenenorbornane series ( 1–6 ).     

Regioselective additions of electrophiles to olefins remotely perturbed. The carbonyl group as a homoconjugated electron donating substituent.

Electrophiles attack preferentially at the C(5) position of 2-norborn-5-enone and 2-bicyclo[2.2.2]oct-5-enone whereas the C(6) position is preferred for 2-chloronorborn-5-ene-2-carbonitriles and 2-chlorobicyclo[2.2.2]oct-5-ene-2-carbonitriles.     

Diels-alder reaction of 2-chloro-2-nitrosopropane with 1,3-cyclohexadiene

3-(2-Chloropropyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-ene and 2-oxa-3-azabicyclo[2.2.2]oct-5-ene hydrochloride have been prepared by cycloaddition of 2-chloro-2-nitrosopropane to 1,3-cyclohexadiene and their structure determined by nmr, using a ¹H nmr shift reagent.     

Cycloaddition of cyclohexa-2,4-dienones with electron deficient 2 pi partners: a novel and stereoselective route to functionalized bicyclo[2.2.2]octenones

A novel route to functionalised bicyclo[2.2.2]octenones via pi 4s + pi 2s cycloaddition of cyclohexa-2,4-dienones with electron deficient 2 pi partners, and crystal structure of 1,7-dimethyl-5-hydroxy-5-chloromethyl-2-carboethoxy bicyclo[2.2.2]oct-7-ene-6-one, is reported.     

Base-promoted acyloin rearrangement of 1,8-di-tert-butyldimethylsilyloxybicyclo[2.2.2]oct-5-en-2-ones

Treatment of 1,8-di-tert-butyldimethylsilyloxybicyclo[2.2.2]oct-5-en-2-ones having an electron-withdrawing group such as a nitro, formyl, cyano, and imido group at C-7 with a strong base (potassium hydride, or potassium bistrimethylsilylamide, etc.), resulted in an acyloin rearrangement reaction accompanied by retention of two silyloxy groups to afford 1,8-disilyloxybicyclo[3.2.1]oct-3-en-2-ones.     

Neighboring group participation in the additions of iodonium and bromonium ions to N-alkoxycarbonyl-2-azabicyclo[2.2.n]alk-5-enes (n = 1,2)

Additions of iodonium-X reagents to N-alkoxycarbonyl-2-azabicyclo[2.2.1]hept-5-enes and the homologous 2-azabicyclo[2.2.2]oct-5-enes have been found to mirror the outcomes of additions of bromonium-X reagents. Only rearranged products were observed for reactions of either of these halonium ion reagents with the azabicylo[2.2.1]hept-5-enes. For the azabicyclo[2.2.2]oct-5-enes, nitrogen participation in addition of IOH or BrOH was dependent on the N-alkoxycarbonyl group. With larger N-Boc, N-Cbz, or N-Troc protecting groups, unrearranged 5-anti-hydroxy-6-syn-I(or Br)-2-azabicyclo[2.2.2]octanes were formed by nucleophilic attack at C(5) on syn-halonium ions. The structure of N-methyl-8-anti-bromo-4-anti-hydroxy-2-azabicyclo[3.2.1]octane has been reassigned by X-ray analysis.     

Synthesis and Crystal Structure of 5-Amino-4-cyano-8-isobutyl-7-isopropyl-6-thiocarbamoyl-2-azabicyclo[2.2.2]oct-5-en-3-thione

5-Amino-4-cyano-8-isobutyl-7-isopropyl-6-thiocarbamoyl-2-azabicyclo[2.2.2]oct-5-en-3-thione was synthesized by the condensation of isovaleryl aldehyde with cyanothioacetamide. The structure of the product was established by X-ray crystallography.     

Face Selectivity of the Diels-Alder Additions of 2-Substituted 5,6-bis((E)-chloromethylidene)bicyclo[2.2.2]octanes

The preparation of 5,6-bis((E)-chlorommethylidene)bicyclo[2.2.2]oct-2-ene ( 13 ), 2,3-bis((E)-chloromethyl idene)-5exo,6exo- and -5endo,6endo-epoxybicyclo[2.2.2] octane ( 14 and 15 ), 5,6-bis((E)-chloromethylidene)-2exo- and -2endo-bicyclo[2.2.2] octanol ( 16 and 17 ) and 5,6-bis((E)-chloromethylidene)-2-bicyclo[2.2.2]octanone ( 18 ) are described. The face selectivity (endo-face vs. exo-face attack onto the exo-cyclic diene) of their cycloadditions to tetracyanoethylene has been determined in benzene at 20°. It is 78/22, 80/20, 60/40, 68/32, 3/97 and 30/70 for 13 , 14 , 15 , 16 , 17 and 18 , respectively.     

Scalable synthesis of enantiomerically pure bicyclo[2.2.2]octadiene ligands

An operationally simple and scalable synthesis of enantiomerically pure bicyclo[2.2.2]octadiene (bod*) ligands relying on an organocatalytic one-pot Michael addition-aldol reaction with cheap 2-cyclohexenone and phenylacetaldehyde is presented. The crystalline bicyclic product 4a (6-hydroxy-5-phenylbicyclo[2.2.2]octan-2-one) is transformed into phenylbicyclo[2.2.2]oct-5-en-2-one 2, a versatile starting material for the 2-step synthesis of both symmetrical, such as Hayashi's Ph-bod* ligand, as well as novel unsymmetrical chiral dienes.     

Cycloaddition between electron deficient partners: an efficient regio- and stereoselective synthesis of functionalised bicyclo[2.2.2]octenones. A tandem alkylation, stereochemical inversion and aldol condensation

A novel one step regio- and stereoselective synthesis of functionalised bicyclo[2.2.2]octenones from readily available aromatic precursors is described. The methodology involved in situ generation of reactive spiroepoxycyclohexadienones and π^4s+π^2s cycloaddition with methyl vinyl ketone. Study on π-facial alkylation that led to the formation of homobrendane derivatives as a result of stereochemical inversion and aldol condensation in tandem, is also presented. The crystal structure of 6-acetyl-1-methoxy-bicyclo[2.2.2]oct-7-en-2-one-spiro[3,2′]oxirane and 3-methoxy-4,6,9-trimethyltricyclo[4.3.1.0^3,7]decan-8-en-5-one-spiro[2,2′]oxirane is also reported.     

Novel bicyclo[2.2.2]octanyl-1,4-benzodiazepinones. Their syntheses and rearrangement to bicyclooct-2-enylbenzimidazoles

The synthesis of the novel bicyclo[2.2.2]octanyl[1,4]benzodiazepinone ring system (IV) and its facile acid catalysed rearrangement to the corresponding bicyclo[2.2.2]oct-2-enylbenzirnid-azole system (IX) is described.     

Benzomorphan related compounds. XII 2,5-Methanothieno[3,2-g]quinolines as rigid bridged thienomorphans

The preparation of a 1,2,3,4,4a,5,9,9a-octahydro-2,5-methanothieno[3,2-g]quinoline, which can be considered as a rigid thieno[3,2-f]morphan system due to an additional two-atoms bridge between the 3 and 9 positions of the morphan nucleus, is described. The synthetic route involved the acidic cyclization of a 3-(2-thenyl)-2-azabicyclo[2.2.2]oct-7-ene, obtained by the Diels-Alder reaction between 1,3,4-trimethyl-2-(2-thenyl)-1,2-dihydropyridine and ethyl acrylate.     

Synthesis and Claisen rearrangement of bridged bicyclic enol ethers of relevance to the course of ketene s-cis-diene cycloaddition

The synthesis is described of a range of 3-alkylidene-2-oxabicyclo[2.2.1]hept-5-ene and 3-alkylidene-2-oxabicyclo[2.2.2]oct-5-ene derivatives; Claisen rearrangement of these substrates either thermally or in the presence of an added Lewis acid results in the formation of bicyclic cyclobutanones with generally good conversions. These reactions may be performed in hydroxylic solvents, supporting a largely non-dissociative pathway for the rearrangement.     

Synthesis and total 1H- and 13C-NMR assignment of cephem derivatives for use in ADEPT approaches

We report the synthesis and total NMR characterization of 5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-[[[(4'-nitrophenoxy)carbonyl]oxy]-methyl]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (5), a new cephalosporin derivative. This compound can be used as the carrier of a wide range of drugs containing an amino group. The preparation of the intermediate product, 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (6), as well as the synthesis of the antimalarial primaquine prodrug 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]- 5-dioxide (7) are also described, together with their total (1)H- and (13)C-NMR assignments.     

Spherical shape complementarity as an overriding motif in the molecular recognition of noncharged organic guests by p-sulfonatocalix[4]arene: complexation of bicyclic azoalkanes

[reaction: see text] The complexation of p-sulfonatocalix[4]arene (CX4) with 2,3-diazabicyclo[2.2.1]hept-2-ene (1), 2,3-diazabicyclo[2.2.2]oct-2-ene (2), 2,3-diazabicyclo[3.2.2]non-2-ene (3), 1-methyl-4-isopropyl-2,3-diazabicyclo[2.2.2]oct-2-ene (4), and 1-phenyl-2,3-diazabicyclo[2.2.2]oct-2-ene (5) was studied in D2O at pD 7.4 by 1H NMR spectroscopy. The formation of deep inclusion complexes was indicated by large upfield 1H NMR shifts of the guest protons (up to 2.6 ppm), which were also used to assign, in combination with 2D ROESY spectra, a preferential inclusion of the isopropyl group of 4 and a dominant inclusion of the azo bicyclic residue for 5. The bicyclic azoalkanes 1-3 showed exceptionally high binding constants on the order of 1000 M(-1), 1-2 orders of magnitude larger than for previously investigated noncharged organic guest molecules. The strong binding was attributed to the spherical shape complementarity between the guest and the conical cavity offered by CX4. Interestingly, although the derivatives 4 and 5 are more hydrophobic, they showed a 2-3 times weaker binding, which was again attributed to the deviation from spherical shape in these bridgehead-substituted derivatives. The preferential inclusion of the hydrophilic but spherical bicyclic residue of 5 rather than the hydrophobic aromatic phenyl group provides a unique observation in aqueous host-guest chemistry and corroborates the pronounced spherical shape affinity of CX4.     

β-Cleavage of Potassium Bicyclo[2.2.2]oct-5-en-2-olates. Stereoselective synthesis of (±)-trichodiene

The transformations of 12 bicyclo[2.2.2]oct-5-en-2-ols ( V or VI ) to 3-(cyclohex-3-enyl)-2-alkanones ( III or IV ), via β-cleavage of their potassium alkoxides in HMPA, has been investigated (cf. Table 1). As an illustration of this synthetic methodology, a stereoselective synthesis of (±)-trichodiene ((±)- 1 ) is described which involves the β-cleavage of the tricyclic potassium alkoxides 46a and 47a to cyclopentanone 4 (cf. Scheme 7).