Orbital control of stereochemistry in acid-catalysed addition reactions of endo -tricyclo[3.2.1.02,4]0ct-6-ene

The reaction of endo-tricyclo[3.2.1.0^2,4]oct-6-ene 1 with methanol in the presence of catalytic amounts of toluene-p-sulphonic acid has been shown to give 2-exo- and endo-methoxybicyclo[3.2.1]oct-3-ene (2c) and (2d) and 2-endo-methoxybicyclo[3.2.1]oct-6-ene (13). The formation of 2-exo- methoxybicyclo[3.2.1]oct-3-ene (2c), the major product of reaction, has been probed by deuterium labelling experiments and a series of 6-exo-7-exo- dideuterobicyclo[3.2.1]oct-3-enes synthesised for ²H, ¹H and ¹³C NMR spectral analysis in order unambiguously to determine the stereochemistry of proton attack on endo-tricyclo[3.2.1 0^2,4]oct-6-ene (1). The formation of 2-exo-methoxybicyclo[3.2.1]oct-3-ene (2c) has been determined to involve corner protonation of the cyclopropyl moiety and skeletal rearrangement to an allylic cation with a small but measurable memory effect     

The Reaction of Dihalocarbenes with Quadricyclane

The reactions of difluoro-, dichloro- and dibromocarbene with quadricyclane ( 2 ) were examined. In all cases, conversions were low (4–15%), but three distinct reaction courses were observed: cleavage, 1,2-addition, and 1,4-addition. Difluorocarbene gave mainly 6-endo-(2,2-difluorovinyl)-cis-bicyclo[3.1.0]hex-2-ene ( 8 ; 52–89% relative yield), together with minor amounts of exo-3,3-difluorotricyclo[3.2.1.0^2,4]oct-6-ene (7; 13–17%), and 4,4-difluorotetracyclo[3.3.0.0^2,8.0^3,6]octane ( 5 ; 2–4%). Dichlorocarbene gave analogous products, but in relative yields of 35 ( 17 ), 51 ( 11 ), and 12% ( 16 ). The product 11 of 1,2-endo addition underwent further rearrangement to its allylic derivative 12 . A small amount of 1,2-endo addition also occurred (2% of 14 / 15 ). Dibromocarbene gave predominantly products derived from rearrangement of the 1,2-exo (61% of 20 / 21 ) and 1,2-endo adducts (10% of 23 / 24 ). In addition, a significant amount of 4,4-dibromotetracyclo[3.3.0.0^2,8.0^3,6]octane ( 25 ; 21%) was formed. The cleavage product, 6-endo-(2,2-dibromovinyl)-cis-bicyclo[3.1.0]hex-2-ene ( 26 ) was also observed (7%). The yields and product compositions were compared to those obtained from norbornadiene ( 1 ) and found to be entirely different (Table 1), for example no cleavage occurred with difluorocarbene.     

Azabrendanes IV. Synthesis and characterization of N-(alkyl- and benzylsulfonyl)-exo-2-hydroxy-4-azatricyclo[4.2.1.0]nonanes

exo- and endo-5-Aminomethylbicyclo[2.2.1]hept-2-enes have been obtained from stereoisomeric exo- and endo-5-cyanobicyclo[2.2.1]hept-2-enes and the corresponding sulfonamides were obtained through reaction of amines with methyl-, n-propyl-, n-butyl-, benzyl-, and cyclohexylsulfonyl chlorides. From the stereoisomeric sulfonamides with peroxy acids, various products were obtained: exo-sulfonamides were transformed into epoxy derivatives, and, in contrast, most of the endo-stereoisomers underwent heterocyclization resulting in substituted exo-2-hydroxy-4-azatricyclo[4.2.1.0^3,7]nonanes. The type of the products obtained did not depend on the type of peroxy acid used (peroxyacetic, peroxyphthalic, and m-chloroperoxybenzoic one). In contrast to other endo-sulfonamides, N-(cyclohexylsulfonyl)-endo-5-aminomethylbicyclo[2.2.1]hept-2-ene in reaction with peroxyacetic acid did not undergo heterocyclization, probably, due to steric factors. The structure and stereochemical homogeneity of the sulfonamides and the structure of the products of their oxidation with peroxy acids were confirmed by spectroscopic methods. The molecular structure of N-(cyclohexylsulfonyl)-endo-5-aminomethyl-exo-2,3-epoxybicyclo[2.2.1]heptane was determined by X-ray diffraction analysis. The mechanism of the intramolecular heterocyclization reaction of N-substituted endo-5-aminomethyl-exo-2,3-epoxybicyclo[2.2.1]heptanes was studied at the BHandHLYP/6-31G(d) level of theory.     

Stereoselective Synthesis of 2,4,6-Trimethylcyclohex-4-ene-1,3-diol Derivatives and of polypropionate fragments with four contiguous stereogenic centers

The Diels-Alder adduct (±)- 3 of 2,4-dimethylfuran and 1-cyanovinyl acetate was converted stereoselectively into benzyl 6-(4-chlorophenylsulfonyl)-1,3-exo,5-trimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl ( 26 ) and -2-endo-yl ether ( 36 ). Addition of LiAlH₄ to the latter led to the 3-O-benzyl derivatives 28 and 37 of (1RS,2SR,3SR,6SR)- and (1RS,2SR,3RS,6SR)-5-(4-chlorophenylsulfonyl)-2,4,6-trimethylcyclohex-4-ene-1,3-diol, respectively. Methylenation of 6-exo-(4-chlorophenylthio)-1-methyl-5-methylidene-7-oxabicyclo[2.2.1]heptan-2-one ( 16 ), obtained by reaction of (±)- 3 with 4-Cl-C₆H₄SCl and saponification gave, 6-exo-(4-chlorophenylthio)-1-methyl-3,5-dimethylidene-7-oxabicyclo [2.2.1]heptan-2-one ( 43 ), the reduction of which with K-Selectride afforded 6-exo-(4-chlorophenylthio)-1,3-endo-dimethyl-5-methylidene-7-oxabicyclo[2.2.1]heptan-2-endo-ol ( 44 ). The 3-O-benzyl derivative 48 of (1RS,2RS,3RS,6SR)-5-(4-chlorophenylsulfonyl)- 2,4,6-trimethylcyclohex-4-ene-1,3-diol was derived from 44 via based-induced oxa-ring opening of benzyl 6-endo-(4-chlorophenylsulfonyl)-1,3-endo-5-endo-trimethyl-7-oxabicyclo[2.2.1]hept-2-endo-yl ether ( 49 ). Benzylation of 28 , followed by reductive desulfonylation and oxidative cleavage of the cyclohexene moiety afforded (2RS,3SR,4RS,5RS)-3,5-bis(benzyloxy)-2,4-dimethyl-6-oxoheptanal ( 32 ).     

The predictable behaviour of cations deriving from endo-4-chlorotetracyclo[3.3.0.0.2,8O.3,6]octane.

Silver cation-initiated ionization of the title compound in aqueous dioxane gives the exo and endo-tetracyclo[3.3.0.0.^2,8O.^4,6]octane-3-ols (35 and 65%). Thermal isomerization in chloroform gives the exo and endo isomers of 4-chlorobicyclo[3.2.1]octa-2,6-dienes (3.5 and 1.5%) and 6-chlorotricyclo[3.2.1.0.^2,7]oct-3-ene (90 and 5%). The behaviour of the cations involved is compatible with MINDO/3 calculations.     

Synthesis of novel thienonorbornylpurine derivatives

The synthesis and antiviral evaluation of 6-amino- and 6-chloro-9-(exo-bicyclo[2.2.1]hept-2yl)-9H-purine derivatives with thiophene and tetrahydrothiophenes annelated to a norbornane moiety are described. The key step in the synthesis of derivatives with the symmetrically annelated thiophene was the Mitsunobu reaction of endo-4-thiatricyclo[5.2.1.0^2,6]deca-2,5-dien-8-ol with 6-chloropurine. The key alcohol was obtained by DDQ mediated aromatization of the corresponding tetrahydro derivatives, which were used for the preparation of the target tetrahydrothieno analogs. The key intermediate for the synthesis of derivatives with the asymmetrically annelated thiophene was 8-exo-azido-3-thiatricyclo[5.2.1.0^2,6]deca-2(6),4-diene, which was prepared from 5-exo-azido[2.2.1]heptan-2-one by aldol condensation with O-ethyl S-(2-oxoethyl) carbonodithioate, deprotection and cyclization. The target compounds were obtained by the construction of the purine base on an amine, which was obtained by LAH reduction of the key azide. The synthesized compounds were evaluated for antiviral and cytostatic activity.     

Synthesis and chemistry of tricyclic cyclopropene-tricyclo[3.2.2.0]nona-2(4),6-diene

The 1,2-bridged tricyclic cyclopropene, tricyclo[3.2.2.0^2,4]nona-2(4),6-diene (1), has been synthesized by the elimination of 2-bromo-4-chlorotricyclo[3.2.2.0^2,4]-non-6-ene (5). Cyclopropene 1 will undergo different isomerizations in ether solution and in neat conditions. Compound 1 rearranged to an anti-Bredt compound 4 via diradical mechanism in ether and tricyclic compound 6 via vinyl carbene mechanism in neat conditions. Compound 1 can be trapped with DPIBF at different temperatures yielding different results: the exo-endo adduct 2 (exo-addition from the view of the cyclopropene and endo-addition from the view of bicyclo[2.2.2]octene) is a sole product at 0°C by slowly addition of methyllithium, and the exo-endo adduct 2, endo-endo adduct 9, anti-Bredt adduct 3, and styrene 8 are isolated at ether refluxing temperature. Styrene 8 is proposed to be formed from endo-endo adduct 9 by diradical mechanism. The chemistry of exo-endo adduct 2 and endo-endo adduct 9 is as well studied. The exo-endo adduct 2 undergoes hydration in trifluoroacetic acid to generate 1,3-cis-diol 11 followed by eliminations of water and formaldehyde to give naphthalene 12. The endo-endo adduct 9 reacts with water in tetrahydrofuran-containing silica gel to yield 1,4-cis-diol 10. Both 9 and 10 react with trifluoroacetic acid to form trans-3-hydroxy trifluoroacetate 13. Compound 13 will undergo hydrolysis and isomerization to generate 1,3-cis-diol 11 in trifluoroacetic acid.     

Mass spectrometry in stereochemical problems. 6 — The case of mono and di-substituted norbornanes

The mass spectrometric behaviour of pairs of stereoisomeric mono- and di-substituted norbornanes, namely bicyclo[2.2.1]heptane-2-endo- and -exo-carboxylic acid, methyl bicyclo[2.2.1]heptane-2-endo- and -exo-carboxylate, 2-exo-acetamidobicyclo[2.2.1]heptane-2-endo- and 2-endo-acetamidobicyclo[2.2.1]heptane-2-exo-carboxylic acid and methyl 2-exo-acetamidobicyclo[2.2.1]heptane-2-endo- and 2-endo-acetamido-bicyclo[2.2.1]heptane-2-exo-carboxylate was studied in detail with particular emphasis on characterization of the stereoisomers. The fragmentation patterns, studied with the aid of mass-analysed ion kinetic energy spectrometry, were supported by semi-empirical MO–SFC calculations, performed using the AM1 method included in the AMPAC program.     

Synthesis of 7-sulfonyl-substituted norpinan-6-ones and -thiones from 1-bromotricyclo[4.1.0.0<Superscript>2,7</Superscript>]heptane

1-Bromotricyclo[4.1.0.0^2,7]heptane reacted with benzene- and methanesulfonyl thiocyanates in benzene at 20°C via anti addition to the central C¹–C⁷ bicyclobutane bond with formation of 6-endo-bromo-6-exo-thiocyanato-7-syn-(R-sulfonyl)bicyclo[3.1.1]heptanes. Treatment of the benzenesulfonyl thiocyanate adduct with potassium tert-butoxide in THF at 20°C gave 7-endo-(benzenesulfonyl)norpinan-6-one, whereas the reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene in methylene chloride afforded 7-exo-(benzenesulfonyl)-norpinane-6-thione which was converted into 7-exo-(benzenesulfonyl)norpinan-6-one by alkaline hydrolysis.     

Ring currents that survive bond alternation in constrained 8π and 6π monocycles

Current density maps are computed at the ipsocentric CTOCD-DZ/6-31G^**//RHF/6-31G^** level for angle-constrained planar 1,3,5,7-cyclooctatetraenes (COT) and benzene. Constraint of α(CCH) angles to 90° in D_4h COT (3b) leads to endo-4 and exo-4 valence isomers. The exo structure, with CH bonds perpendicular to long sides of the octagon, is lower in energy by 202 kJ/mol and has stronger bond alternation (ΔR 0.265 Å). However, endo-4, exo-4 and COT 3b at its best planar geometry all sustain intense paratropic ring currents, attributed to the rotational character of the HOMO–LUMO transition, and consistent, mutatis mutandis, with the diatropic current in D_3h benzene 5.     

The fragmentation of exo-5-norbornenyl-2-oxychlorocarbene: stereochemistry and mechanism

The fragmentation of (S)-exo-5-norbornenyl-2-oxychlorocarbene (3) affords (S)-exo-5-norbornenyl-2-chloride (4), (R)-endo-5-norbornenyl-2-chloride (5), and (S)-3-nortricyclyl chloride (6) with varying degrees of enantiomeric excess. A weighted blend of S_Ni fragmentation and escape to norbornenyl/nortricyclyl ion pairs rationalizes the stereochemical results.     

Evaluation of lipase from Candida rugosa in the resolution of endo-(±)-1,8,9,10,11,11-hexachloropentacyclo[6.2.1.13,6.02,7.05,9]dodecan-4-alcohol

endo-(±)-1,8,9,10,11,11-Hexachloropentacyclo[6.2.1.1^3,6.0^2,7.0^5,9]dodecan-4-ol (±)-7 and exo-(±)-1,8,9,10,11,11-hexachloropentacyclo[6.2.1.1^3,6.0^2,7.0^5,9]dodecan-4-ol (±)-4 have been prepared and the enantiomeric enrichment capacity of the lipase from Candida rugosa in the transesterification with vinyl acetate of these compounds was evaluated. It was verified that the lipase recognize only the alcohol (±)-7, producing endo-(+)-1,8,9,10,11,11-hexachloropentacyclo[6.2.1.1^3,6.0^2,7.0^5,9]dodecan-4-yl acetate (+)-8 with ee >95% and conversion of 44% as the only product.     

Reduction of 6/7-substituted 3-phenyltrop-3-en-2-ones: stereoselectivity and conformational analysis of the products

Reduction of 6/7-carboethoxy-3-phenyltrop-3-en-2-ones with H₂/Pd/C and NaBH₄ was studied in order to find a stereoselective route to the corresponding 3-phenyltropan-2-ones and 2α/2β-hydroxy-3-phenyltropanes. The 6/7-exo-carboethoxy-3-phenyltrop-3-en-2-ones were selectively reduced by Pd/C to 3β-phenyltropan-2-ones and 2α-hydroxy-3β-phenyltropanes. The corresponding 2β-hydroxy-3β-phenyl analogues were synthesized using NaBH₄, with a yield of 40%. Reduction of 6-endo-carboethoxy-3-phenyltrop-3-en-2-one yielded several products. The corresponding 7-endo-substituted analogue was selectively reduced with both Pd/C and NaBH₄ to 7-endo-carboethoxy-3β-phenyltropin-2-one. Analysis of stereochemically important ¹H NMR spectroscopy parameters was performed for all the products and used for conformational analysis in solution. X-ray analysis was performed for selected compounds.     

Cage-like amines in the synthesis and oxidation of camphor-10-sulfonic acid amides

Reactions of bicyclo[2.2.1]hept-5-en-exo- and -endo-2-ylmethanamines, exo-5,6-epoxybicyclo-[2.2.1]hept-exo-2-ylmethanamine, 1-(bicyclo[2.2.1]hept-2-yl)ethanamine, and 1-(1-adamantyl)ethanamine with camphor-10-sulfonyl chloride in chloroform in the presence of triethylamine gave the corresponding sulfonamides having two cage-like fragments. Stereoisomeric N-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)camphor-10-sulfonamides were oxidized with peroxyphthalic acid generated in situ from phthalic anhydride and 50% hydrogen peroxide. The exo stereoisomer was thus converted into the corresponding 5,6-epoxy derivative, while the endo isomer gave rise to 4-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethyl)-4-azatricyclo[4.2.1.0^3,7]-nonan-exo-2-ol (substituted azabrendane). The structure of the synthesized camphor-10-sulfonamides was confirmed by IR and ¹H and ¹³C NMR spectra with the use of homo- (COSY) and heteronuclear ¹H-¹³C correlation techniques (HMQC, HMBC). Heterocyclization of sulfonamides of the norbornene series was also simulated by quantum-chemical calculations at the PM3 and BHandHLYP/6-31G(d) levels of theory.     

Reaction of N-substituted <Emphasis Type="Italic">exo</Emphasis>-2-hydroxy-5-oxo-4-oxatricyclo[4.2.1.0<Superscript>3,7</Superscript>]nonane-<Emphasis Type="Italic">endo</Emphasis>-9-carboxamides with acetic acid

Acylation of N-substituted exo-2-hydroxy-5-oxo-4-oxatricyclo[4.2.1.0^3,7]nonane-endo-9-carboxamides on heating in boiling glacial acetic acid gave the corresponding trans-diacetoxy imides of the norbornane series. The effect of the reaction time on the product composition was studied in the reaction with exo-2-hydroxy-N-(4-methylphenyl)-5-oxo-4-oxatricyclo[4.2.1.0^3,7]nonane-endo-9-carboxamide. The structure of the resulting norbornane-2,3-dicarboximides was confirmed by IR, ¹H NMR, and mass spectra, and the structure of N-(2,5-dimethylphenyl)-exo-2,endo-3-diacetoxybicyclo[2.2.1]heptan-endo-5,endo-6-dicarboximide was additionally proved by X-ray analysis.     

Reductive Radical Cyclisations of Bromo Acetals and (Bromomethyl)silyl Ethers of Terpenoid Alcohols

The tin hydride promoted and the reductive vitamin B₁₂ catalysed radical cyclisation of mixed 2-bromo-acetaldehyde acetals and of (2-bromomethyl)dimethylsilyl ethers of allylic terpenoid alcohols has been investigated: 3-oxadeca-5,9-dien-l-yl radicals undergo 5-‘exo’ cyclisation to oxolanes (Scheme 4), 3-oxa-2-siladeca-5,9-dien-1-yl radicals sequential 6-‘endo’→5-‘exo’ tandem cyclisation to cis-3-oxa-4-silabicyclo[4.3.0]nonanes (Scheme 5), and 3-oxa-2-silatetradeca-5,9,13-trien-l-yl radicals sequential 6-‘endo’→6-‘endo’→5-‘exo’ triple cyclisation to trans-transoid-trans- 12-oxa-11-silatricyclo[7.4.0.0^2,6] tridecanes (Scheme 6).     

Photoinduced Double Addition of Acetylene to 3-Oxocyclopent-1-ene-1-carbonitrile or 3-oxocyclopent-1-enyl acetate leading to 2,3-dihydro-1H-inden-1-one and other rearranged products

UV Irradiation of 3-oxocyclopent-1-enyl acetate ( 17 ) and acetylene in MeCN at 0° gives, besides the product of normal enone-alkyne [2 + 2] cycloaddition (cis-4-oxobicyclo[3.2.0] hept-6-en-1-yl acetate, 18 ) and its product of oxa-di-π-methane rearrangement (5-oxotricyclo[4.1.0.0^2,7]hept-2-yl acetate, 19 ), unexpected products of further addition of a molar equivalent of acetylene. These are indanone ( = 2,3-dihydro-1H-inden-1-one, 16 ), in 21% yield, cis-1-cisoid-1,2-cis-2- ( 20 ) and cis-1-transoid-1,2-cis-2-7-oxotricyclo[4.3.0.0^2,5]non-3-en-1-yl acetate ( 21 ), 4-oxo-7-‘exo’-vinyltricyclo[3.2.0.0^2,6]hept-2-yl acetate ( 22 ), cis-4-oxo-6-‘endo’- ( 23 ) and cis-4-oxo-6-‘exo’-vinylbicyclo[3.2.0]hept-1-yl acetate ( 24 ), and cis-4-oxo-7-‘exo’-vinylbicyclo[3.2.0]hept-1-yl acetate ( 25 ). At least in part, indanone must be formed via intermediates 20 and 21 . In fact, on heating a 9:1 mixture 20/21 , indanone is obtained quantitatively. With 3-oxocyclopent-1-ene-1-carbonitrile ( 15 ) in place of 17 , indanone is formed in lower (8%) yield besides much tars.     

Sterical Hindrances as a Driving Force of Skeleton Rearrangements of Fenchone and Its Oxime in Ritter Reaction

Fenchone (1,3,3-trimethylbicyclo[2.2.1]heptan-2-one) in reaction with acetonitrile in the presence of sulfuric acid (Ritter reaction) due to steric hindrances preventing geminal addition of two nucleophile molecules gives rise to a mixture of 1,2-exo-diacetamido-6-endo,7,7-trimethylbicyclo[2.2.1]heptane, 2-endo6-exo-diacetamido-3,3,6-trimethylbicyclo[2.2.1]heptane, and 2-exo,6-exo-diacetamido-1,3,3-tri- methylbicyclo[2.2.1]heptane in the ratio of 6:4:1. Fenchone oxime under condition of this reaction affords a mixture of stereoisomeric cis- and trans-acetamido-1-methyl-3-(-cyanoisopropyl)cyclopentanes in 2:3 ratio.     

Unusual pathway of the tantalum-catalyzed carboalumination reaction of alkenes with triethylaluminum

Carboalumination of 1-alkenes (1-hexene, 1-octene, 1-decene) with Et₃Al in the presence of catalytic amounts of TaCl₅ results in a mixture of 2-(R-substituted)- and 3-(R-substituted)-n-butylaluminums (1:1 ratio) in total yields of 75–85%. The TaCl₅-catalyzed reaction of bicyclo[2.2.1]hept-2-ene, endo-tricyclo[5.2.1.0^2,6]deca-3,8-diene, and (exo/endo)-5-methylbicyclo[2.1.1]hept-2-ene with Et₃Al leads to the formation of diethyl[2-exo-(2′-norbornylethyl)]aluminums in high yields. DFT calculations confirm the thermodynamic preference of the final exo product. The multistep reaction mechanisms for the formation of the resultant organoaluminums through tantalacyclopentanes as key intermediates are also discussed.     

(+)-Camphor-derived amino alcohols as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehydes

1,7,7-Trimethyl-3-(pyrid-2-ylmethyl)bicyclo[2.2.1]heptan-2-ol 4 and its 2-phenyl, 2-methyl and 2-butyl analogs 5–7 were synthesized, characterized and used as ligands for the addition of diethylzinc to benzaldehydes. Best results were attained with 5 mol% of amino alcohol trans-4 (2-exo,3-endo), in hexane/toluene at rt. Thus, (1S)-1-phenylpropanol was obtained in 96% yield and 89% e.e. An increase of the size of the 2-substituent had a dramatic effect on enantioselectivity and yield.