Exploiting the ring strain in bicyclo[2.2.1]heptane systems for the stereoselective preparation of highly functionalized cyclopentene, dihydrofuran, pyrroline, and pyrrolidine scaffolds

The high strain of bicyclic systems drives retro-condensation reactions on bridgehead substituted bicyclo[2.2.1]hept-2-enes giving rise to orthogonally functionalized cyclopentene, 2,5-dihydrofuran, and 3-pyrroline scaffolds. Retro-Dieckman reactions were easily carried out on 3-tosyl-(7-carba/7-oxa/7-aza)bicyclo[2.2.1]hept-5-en-2-ones. Retro-aldol reactions of N-Boc-3-tosyl-7-azabicyclo[2.2.1]hept-5-en-2-ol and functionalized N-Boc-3-tosyl-7-azabicyclo[2.2.1]heptan-2-ols yield functionalized pyrrolidine scaffolds stereoselectively. The same reaction does not work with corresponding norbornene and 7-oxanorbornene derivatives.     

Substituent effects on the regioselectivity of the baeyer-villiger oxidation of 7-oxabicyclo[2.2.1]heptan-2-ones

New 3-oxy substituted and 3,6-dioxydisubstituted 7-oxabicyclo[2.2.1]heptan-2-ones have been prepared. The regioselectivity of their Baeyer-Villiger oxidation has been determined and compared with that of other 7-oxabicyclo[2.2.1]heptan-2-one derivatives. If the substituent at C(3-exo) is an O-acyl or another group less electron-releasing, the bridgehead C(1) migration is favoured, leading to 2,8-dioxabicyclo[3.2.1]octan-3-ones. When the substituent at C(3) is a MeO or (tBu)Me₂SiO group, the Baeyer-Villiger oxidation leads to 3,8-dioxabicyclo[3.2.1]octan-2-ones due to preferred C(3) migration. The latter regioselectivity is higher for 3-endo-MeO than for 3-exo-MeO substituted ketones and it can be enhanced by remote oxy substituents at the C(6-endo) position.     

Stereoselective additions to the exocyclic CC bond of some α-alkylidene-(+)-camphor derivatives

Stereoselective additions to the exocyclic CC double bond of some (1R,3E,4S)-3-alkylidene-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and (1R,4E,5S)-4-alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones were studied. All additions took place predominantly from the less hindered endo-face of the methylidene compounds to give the corresponding exo-adducts as the major isomers. Thus, catalytic hydrogenations afforded the α-alkylated (1R,3R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and (1R,4R,5R)-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones in 28–100% de. Similarly, 1,3-dipolar cycloadditions of 2,4,6-trisubstituted benzonitrile oxides gave the corresponding spiro cycloadducts in 66–100% de. The structures were determined by 2D NMR techniques, NOESY spectroscopy and X–ray diffraction.     

Synthesis of Bicyclo[2.2.1]heptan-2-ones by thermal cyclization of 3-allylcyclopentanones

Pyrolysis of 3-allylcyclopentanones affords $\text{endo}$-6-substituted bicyclo[2.2.1]heptan-2-ones.     

5,5,6-Trimethylbicyclo[2.2.1]heptan-2-one in the Synthesis of Carbocyclic Analogs of Prostaglandin Endoperoxides

1,3-Dipolar cycloaddition of nitrile oxides to 5,5,6-trimethyl-exo-2-ethynylbicyclo[2.2.1]heptan-endo-2-ol yields the corresponding 2-(isoxazol-5-yl) derivatives. Opening of the isoxazole ring in the latter gives rise to prostanoid precursors with partially built up or completed side chain. 5,5,6-Trimethyl-3-methylenebicyclo[2.2.1]heptan-2-one reacts with nitromethane in the presence of tetramethylguanidine to afford 5,5,6-trimethyl-exo-3-(2-nitroethyl)bicyclo[2.2.1]heptan-2-one which can be converted into the corresponding nitrile oxide by the action of phenyl isocyanate in benzene in the presence of triethylamine as catalyst. 1,3-Dipolar cycloaddition of the nitrile oxide to ethyl 4-pentynoate yields 3-exo-[5-(2-ethoxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one. Treatment of the latter with hydroxyl amine leads to formation of the corresponding Z-oxime whose reaction with n-hexyl bromide results in transalkylation of the ester group to afford 3-exo-[5-(2-hexyloxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one oxime.     

Reductions of (1R,3R,4R)-3-([1,2,4]triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and their analogues

Reductions of (1R,3R,4R)-3-([1,2,4]triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and their lactone analogues, prepared from (1R)-(+)-camphor, were studied. Catalytic hydrogenation selectively led to partial saturation of the [1,2,4]triazolo[4,3-x]azine residue, while in reactions with borane–methylsulfide coordination of borane to the 1-position of [1,2,4]triazolo[4,3-x]azine system took place. On the other hand, activation of the carbonyl group in (1R,3R,4R)-3-([1,2,4]triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones with boron trifluoride etherate followed by reaction with borane–methylsulfide furnished the corresponding isoborneols, stereoselectively. The structures of all representative compounds were confirmed by X-ray diffraction.     

Synthesis of spiro[bicyclo[2.2.1]heptane-2,2′-furan]-3-amines via stereoselective cycloadditions of trimethylenemethane to (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones

Stereoselective [3+2] cycloadditions of trimethylenemethane (TMM) to the exocyclic CO and CN double bonds of (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones gave the corresponding spiro[bicyclo[2.2.1]heptane-2,2′-furan] and spiro[bicyclo[2.2.1]heptane-3,2′-pyrrolidine] derivatives. Further stereoselective reductions of the CN or CO bond in these cycloadducts furnished new chiral amines, diamines, and a new aminoalcohol. All cycloadditions and reductions of the CN double bonds took place from the less hindered endo-face of the (1S,3EZ,4R)-3-arylimino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones, exclusively, thus giving the corresponding products in 100% de. The structures were determined by NMR, NOESY spectroscopy, and by X-ray diffraction.     

Synthesis of Bicyclic Isocyanates and Bioisosteric 1,3-Disubstituted Ureas as Soluble Epoxide Hydrolase Inhibitors

Russian Journal of Organic Chemistry - (1S)-1-Isocyanato-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one and 2-isocyanatobicyclo[2.2.1]-hept-5-ene were prepared by the Curtius rearragement reaction...     

Radical deoxygenation of 3-azatricyclo[2.2.1.0]heptan-5-ols to 2-azabicyclo[2.2.1]hept-5-enes and 1,2-dihydropyridines

Additions of alkyl or aryl Grignard reagents, or pyridin-3-yl-lithiums or lithium alkoxides, to exo-5,6-epoxy-7-(tert-butoxycarbonyl)-2-tosyl-7-azabicyclo[2.2.1]hept-2-ene lead to 7-substituted-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols. Radical deoxygenations of 7-alkyl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 7-alkyl-4-tosyl-2-azabicyclo[2.2.1]hept-5-enes, whereas 7-aryl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 2-(arylmethyl)-5-tosyl-1,2-dihydropyridines.     

The Quantum Yield of Singlet Oxygen in Thermal Degradation of Alcohol Hydrotrioxides

The yield of singlet oxygen (¹О₂) in the decomposition of a number of hydrotrioxides of alcohols (cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, cyclooctanol, L-menthol, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol, 1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol, heptan-4-ol, propanol-2, and 1-cyclopropylethanol) has been determined using the IR chemiluminescence technique. It has been shown that cyclopentanol, 1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol and 1-cyclopropylethanol hydrotrioxides are efficient sources of singlet oxygen; the yield of ¹О₂ reaches up to 58%.     

2-Chlorobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2-chlorobicyclo[2.2.1]heptane-2-carboxamide as precursors of bicyclo[2.2.1]hept-5-en-2-one and bicyclo[2.2.1]heptan-2-one: resolution,absolute configuration and hydrogen-bonding properties

The absolute configuration of bicyclo[2.2.1]heptan-2-one has not been correlated with a crystal structure of a chemical precursor. The only chemical correlation available had an ambiguity, which could have reversed the assignment. Herein, we report the resolution of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide on a cellulose triacetate column and the crystal structures of the enantiomerically pure and racemic α-chloroamide. We found the absolute configuration (1R,2R,4R) for the (+)-enantiomer of the α-chloroamide. This compound was converted to (+)-bicyclo[2.2.1]hept-5-ene-2-one by base hydrolysis, and the 5,6-unsaturated compounds converted to the saturated congeners. This is the first unambiguous experimental determination of the absolute configuration of bicyclo[2.2.1]heptan-2-one and of bicyclo[2.2.1]hept-5-ene-2-one. The three crystal structures of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide reported herein reveal H-bonded dimers, with two distinct orientations of the bicyclic portion relative to the carboxamide dimer. In the racemic crystal, each dimer is composed of two enantiomers, and the bicyclic portions have their bridge carbon atom (C-7) on opposite sides of the H-bonded carboxamide dimer moiety. In the enantiomerically pure crystals, the major dimer had both C-7 atoms on the same side of the carboxamide dimer moiety while the minor dimer had the C-7 atoms on opposite sides. The dimers are present in solution, and can be easily monitored.     

Synthesis and stereochemical assignment of exo- and endo-7-methyl-7-azabicyclo[2.2.1]heptan-2-ol

[formula: see text] The syntheses of both exo and endo stereoisomers of 7-methyl-7-azabicyclo[2.2.1]heptan-2-ol were achieved in straightforward fashion. Alternatively, the intramolecular cyclization of syn-4-N-methylaminocyclohexane 1,2-epoxide was found to give exo-7-methyl-7-azabicyclo-[2.2.1]heptan-2-ol as the sole product. The stereochemistry of the exo isomer was unequivocally confirmed by X-ray crystallography.     

对映体纯1-甲基-7-氧杂双环[2.2.1]庚烷-2-酮的制备

1-甲基 - 7-氧杂双环 [2 .2 .1 ]庚烷 - 2 -酮 ( 1 )是萜类天然产物全合成中的重要中间体 ,能被广泛地应用于多种桉烷 ( Eudesmane)、沉香呋喃 ( Agarofuran)和降胡萝卜素 ( Norcarotenoids)等倍半萜天然产物的全合成[1,2 ] .我们以对映体纯化合物 1为原料 ,实现这类天然产物的不对称全合成 [3～ 6 ] .消旋的化合物 (± ) - 1可以 2 -甲基呋喃和 2 -氯丙烯腈为原料 ,经 3步反应得到 [2 ] .但对映体纯化合物 1的制备尚未见报道 .本文用化学拆分方法 ,成功地制备了对映体纯的 ( + ) - 1和 ( - ) - 1 ,并确定了其绝对构型 .1　结果与讨论为减…     

1-(3,5-二甲基苯基)-1-[(1S,4S)-1,7,7-三甲基双环[2.2.1]庚烷-2-基]肼的合成工艺改进

以3,5-二甲基苯胺和2-莰酮为起始原料,在微波促进下,经缩合反应制得N-(3,5-二甲基苯基)-1-(1S,4S)-1,7,7-三甲基二环[2.2.1]庚烷-2-亚胺(1);1经硼氢化钠还原后再与羟胺-O-磺酸经胺化反应合成了1-(3,5-二甲基苯基)-1-[(1S,4S)-1,7,7-三甲基双环[2.2.1]庚烷-2-基]肼,总收率70.4%,其结构经1H NMR和ESI-MS确证。     

Chemical transformations of 3-aminopyrrolidin-2-ones of the norbornane and cyclopropane series

3-Aminopyrrolidin-2-ones containing a fused norbornane or spirocyclopropane fragment react with benzaldehyde to give azomethines, which can be transformed into N-substituted 3-aminopyrrolidin-2-ones by reduction with sodium borohydride. Diazotization of amino-pyrrolidinones with NaNO₂ in acetic acid results in the elimination of molecular nitrogen and in the formation of acetoxy or unsaturated derivatives (through stabilization of intermediate carbocations). 6-Methylidene4-azaspiro[2.4]heptan-5-one obtained by diazotization of 6-amino-6-methyl-4-azaspiro[2.4]heptan-5-one easily reacts with diazomethane, diazocyclo-propane, and benzonitrile oxide to yield heterocyclic spiranes by means of 1,3-dipolar cycloaddition.     

Synthesis of 1-p-Methoxyphenyl and 1-p-Methoxyphenyl-4-methylbicyclo-[2.2.1]heptan-7-one. The Oxidation of 7-Hydroxy-1-p-methoxyphenyl-4-methylbicyclo[2.2.1]heptan-7-carboxylic Acid with Lead Tetraacetate

A simple synthetic route to 1-p-methoxyphenyl and 1-p-methoxyphenyl-4-methylbicyclo [2.2.1]heptan-7-one 6b,a has been developed through benzilic acid rearrangement of the bicyclo[2.2.1]octandiones 2b,a. The oxidation of 7-hydroxy-1-p-methoxyphenyl-4-methylbicyclo[2.2.1]heptan-7-carboxylic acid 3a with lead tetraacetate gives the carbolactone 7a which is also formed by the reaction of the ketone 6a with m-chloroperbenzoic acid.     

The Homoconjugated Electron-Releasing Carbonyl Group of 1-Methylbicyclo[2.2.1]hept-5-en-2-one. Regioselective syntheses of 5-chloro- and 6-chloro-1-methylbicyclo[2.2.1]hept-5-en-2-one

Syntheses of (±)-2-exo-cyano-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate ( 1 ) and of (±)-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 2 ) are reported. The additon of PhSeCl to 1 afforded (±)-5-endo-chloro-2-exo-cyano-1-methyl-6-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]hept-2-endo-yl acetate ( 6 ), whereas 2 added to PhSeCl with the opposite regioselectivity giving (±)-6-endo-chloro-1-methyl-5-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]heptan-2-one ( 7 ). These adducts were converted into 5-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 9 ) and 6-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 10 ), respectively.     

Synthesis of (+)-1,3:2,5-dianhydroviburnitol ((+)-(1R,2R,3S,5R,6S)-4,7-dioxatricyclo[3.2.1.03,6]octan-2-ol)

Epoxidation of (?)-(1R,2R,4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((?)-5) followed by saponification afforded (+)-(1R,4R,5R,6R)-5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ((+)-7). Reduction of (+)-7 with diisobutylaluminium hydride (DIBAH) gave (+)-1,3:2,5-dianhydroviburnitol ( = (+)-(1R,2R,3S,4R,6S)-4,7-dioxatricyclo[3.2.1.0^3,6]octan-2-ol; (+)-3). Hydride reductions of (±)-7 were less exo-face selective than reductions of bicyclo[2.2.1]heptan-2-one and its derivatives with NaBH₄, AlH₃, and LiAlH₄ probably because of smaller steric hindrance to endo-face hydride attack when C(5) and C(6) of the bicyclo-[2.2.1]heptan-2-one are part of an exo oxirane ring.     

Synthesis and aminolysis of N-(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)-N-(oxiran-2-ylmethyl)(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide

A new N-(oxiran-2-ylmethyl) (glycidyl) derivative has been obtained by reaction of N-(bicyclo-[2.2.1]hept-5-en-endo-2-ylmethyl)(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide with epichlorohydrin. Its epoxidation and aminolysis have been studied, and the regioselectivity of these transformations has been determined by IR and ¹H NMR spectroscopy and mass spectrometry.     

The octant rule. XIV. synthesis and circular dichroism of α-exo and endo-deuteriobicyclo[3.2.1]octan-3-one and 6,6-dimethybicyclo[3.1.1]heptan-3-one

(1R,5S)-2S-Deuteriobicyclo[3.2.1]octan-3-one ($\text{1}$) and (1R,5S)-2R-Deuteriobicyclo[3.2.1]octan-3-one ($\text{2}$), prepared by diazomethane ring enlargement of (1S,4R)-2(exo)-deuteriobicyclo-[2.2.1] heptan-2-one and (1S,4R)-2(endo)-deuteriobicyclo[2.2.1]heptan-2-one respectively, both gave (?) n-π^* circular dichroism (CD) Cotton effects, Δε^max₂₉₄ = ?0.05 and Δε^max₂₉₄=?0.1, respectively, in hydrocarbon solvent. (1S,5R)-2S-Deuterio-6,6-diaethylbicyclo[3.1.1] heptan-3-one ($\text{3}$) and (1S,5R)-2R-deuterio-6,6-dimethylbicyclo[3.1.1] heptan-3-one ($\text{4}$), prepared from (-) myrtenal, both exhibited extraordinary vibrational fine structure for the n-π^* CD transitions observed in hydrocarbon solvent and oppositely?signed CEs, Δε^max₂₈₂=?0.01 and Δε^max₂₇₉=+0.01 respectively in CF₃CH₂OH solvent.