Intramolecular [2+2] cycloaddition of homoallylketenes to bicyclo[2.1.1]hexan-5-ones

Intramolecular [2+2] cycloaddition of γ,δ-unsaturated ketenes derived from hex-5-enoyl chloride derivatives gave bicyclo[2.1.1]hexan-5-ones with complete regioselectivity.     

Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2-Oxabicyclo[2.1.1]hexanes

Synthesis of bicyclic scaffolds has attracted tremendous attention because they are playing an important role as saturated bioisosteres of benzenoids in modern drug discovery. Here, we report a BF₃-catalyzed [2π+2σ] cycloaddition of aldehydes with bicyclo[1.1.0]butanes (BCBs) to access polysubstituted 2-oxabicyclo[2.1.1]hexanes. A new kind of BCB containing an acyl pyrazole group was invented, which not only significantly facilitates the reactions, but can also serve as a handle for diverse downstream transformations. Furthermore, aryl and vinyl epoxides can also be utilized as substrates which undergo cycloaddition with BCBs after in situ rearrangement to aldehydes. We anticipate that our results will promote access to challenging sp³-rich bicyclic frameworks and the exploration of BCB-based cycloaddition chemistry.     

Saturated Bioisosteres of ortho-Substituted Benzenes

Saturated bioisosteres of ortho-disubstituted benzenes (bicyclo[2.1.1]hexanes) were synthesized, characterized and validated. These cores were incorporated into the bioactive compounds Valsartan, Boskalid and Fluxapyroxad instead of the benzene ring. The saturated analogues showed a similar level of antifungal activity compared to that of Boskalid and Fluxapyroxad.     

Enantioselective synthesis of bicyclo[6.1.0]nonane-9-carboxylic acids via Me2AlOTf-promoted intramolecular Friedel-Crafts alkylation of arenes with the gamma-lactone moiety of 3-oxabicyclo[3.1.0]hexan-2-ones

A strategy to rapidly assemble enantiomerically pure bicyclo[6.1.0]nonane-9-carboxylic acids via Me2AlOTf-promoted intramolecular Friedel-Crafts alkylation of tethered pi-nucleophiles with the gamma-lactone moiety of 3-oxabicyclo[3.1.0]hexan-2-ones is described. The approach begins with the enantioselective synthesis of 3-oxabicyclo[3.1.0]hexan-2-ones bearing a tethered pi-nucleophile at the 6-position by intramolecular Rh(II)-catalyzed cyclopropanation of allylic diazoacetates, prepared from the corresponding (Z)-allylic alcohols. Me2AlOTf-induced intramolecular Friedel-Crafts cyclization provides medium-sized carbocycles and heterocycles in high yields without requiring high-dilution or slow substrate addition techniques. The scope and limitations of this synthetic methodology are presented.     

Photochemical Studies on Bicyclo[2.1.1]hexyl Derivatives: Chemical Behavior and Asymmetric Induction

The photochemical behavior of bicyclo[2.1.1]hexyl derivatives was investigated by irradiation with a 450 W medium‐pressure mercury lamp in acetonitrile solution. The irradiation of methyl bicyclo[2.1.1]hexane‐5‐carbonylbenzoate ( 1a ) led to both Norrish type II cyclization and cleavage products with a molar ratio of 1:2.2, whereas the irradiation of methyl 5‐methylbicyclo[2.1.1]hexane‐5‐carbonylbenzoate ( 1b ) afforded the only Norrish/Yang photocyclization compound as the sole product. Such results were illustrated by several geometric parameters for Norrish/Yang photoreaction as ?₁, ?₄ and β obtained from the crystal structures. Furthermore, asymmetric photochemical studies using ionic chiral auxiliary technique were also conducted in the solid state.     

Water‐Soluble Non‐Classical Benzene Mimetics

A new generation of saturated benzene mimetics, 2‐oxabicyclo[2.1.1]hexanes, was developed. These compounds were designed as analogues of bicyclo[1.1.1]pentane with an improved water solubility. Crystallographic analysis of 2‐oxabicyclo[2.1.1]hexanes revealed that they occupy a novel chemical space, but, at the same time, resemble the motif of meta‐disubstituted benzenes.     

Water-Soluble Non-Classical Benzene Mimetics

A new generation of saturated benzene mimetics, 2-oxabicyclo[2.1.1]hexanes, was developed. These compounds were designed as analogues of bicyclo[1.1.1]pentane with an improved water solubility. Crystallographic analysis of 2-oxabicyclo[2.1.1]hexanes revealed that they occupy a novel chemical space, but, at the same time, resemble the motif of meta-disubstituted benzenes.     

13C-NMR-spektren von bicyclo[n.1.0]alkenen

The ¹³C-NMR spectra of some bicyclo[3.1.0]hex-3-en-2-ols and of some bicyclo[3.1.0]hex-3-en-2-ones are described. The bond parameters of bicyclo[3.1.0]hex-3-en-2-one are derived from a structure determination of endo-6-methoxy-1,3,6-triphenylbicyclo[3.1.0]hex-3-en-2-one. The electron density is calculated by the EHT method, and correlated with the ¹³C NMR shifts. For comparison the ¹³C NMR spectrum of a bicyclo[4.1.0]hepta-1,5-dione derivative is analysed. The influence of a cyclopropane system attached to a five-membered and to a six-membered ring is elucidated. Whereas the five-membered ring shows conjugation between the carbonyl group and the cyclopropane system, the same effect is not observed in the six-membered ring analogue. This is explained by the highly rigid structure of the five-membered ring.     

Unusual carbon shielding effects of cyclopropanes and double bonds in strained bicyclo[3.1.0]hexanes and cyclopentenes

Carbon-13 shieldings and one-bond ¹³C? H coupling constants of bicyclo[2.1.1]hexane, bicyclo[2.1.1]hex-2-ene, tricyclo[3.1.1.0^2,4]heptane and benzvalene are presented and compared to the data of related compounds. If a bicyclo[3.1.0]hexane system is part of a rigid skeleton, the cyclopropane ring exerts specific γ substituent effects of two kinds. In the case of the bicyclohexane boat form an upfield shift of the C-3 signal is observed and in the case of the chair form a downfield shift of 15–20 ppm. Compared to the corresponding cyclopentanes the double bond in strained cyclopentenes causes downfield shifts of the C-4 absorption. This effect increases with increasing strain, reaching a 45.9 ppm maximum in benzvalene. Hence it is the only known bicyclo[1.1.0]butane having a reversed order of carbon shieldings. The downfield shifts are explained by means of simple orbital interaction schemes.     

Synthesis of Bicyclo[1.1.1]pentane Bioisosteres of Internal Alkynes and para‐Disubstituted Benzenes from [1.1.1]Propellane

We report a general preparation of arylated bicyclo[1.1.1]pentanes through the opening of [1.1.1]propellane with various arylmagnesium halides. After transmetalation with ZnCl₂ and Negishi cross‐coupling with aryl and heteroaryl halides, bis‐arylated bicyclo[1.1.1]pentanes are obtained. These bis‐arylated bicyclo[1.1.1]pentanes may be considered as bioisosteres of internal alkynes. Bioisosteres of tazarotene and the metabotropic glutamate receptor 5 (mGluR5) antagonist 2‐methyl‐6‐(phenylethynyl)pyridine were prepared and their physicochemical properties were evaluated.     

Intramolecular cyclopropanation of unsaturated terminal epoxides and chlorohydrins

Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-beta-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.     

The Synthesis of 5,6-Disubstituted Bicyclo[2.1.1]hexenes and 3,5-Disubstituted Tricyclo[2.2.0.02,6]hexanes

There are relatively few methods for synthesizing bicyclo[2.1.1]-hexenes and tricyclo[2.2.0.0^2,6]hexanes.¹ However, now that benzvalene (I), the highly strained structural isomer of benzene has become a readily available compound,² it is possible to prepare disubstituted compounds like II and III in a straightforward fashion.     

Photorearrangement of 4,4-Dimethylcyclohex-2-enones with Alkyl or Fluoro Substituents at C(5) and C(6): In Search of the Mechanism

The photorearrangement of cyclohex-2-enones 4a-h to bicyclo[3.1.0]hexan-2-ones 5 and cyclopent-2-enones 6 (λ = 350 nm, MeCN) was investigated. Both the quantum yield (Φ_?4 = 0.004– 0.024) and the product ratio ( 5/6 = 65:35–31:69) vary only over a rather small range, indicating the rearrangement to be relatively insensitive to substituents on C(5) or C(6). Compounds 4b, 4c , and 4g with just one alkyl group at either C(6) or C(5) rearrange selectively to the diastereoisomer 5 with alkyl group and three-membered ring in trans-configuration, while 6-fluorocyclohex-2-enones 4d and 4f afford mixtures of diastereoisomeric bicyclohexanones. Mechanistic conclusions regarding an intermediate trimethylene biradical are presented.     

Synthesis of cyclopropane-fused α-chlorolactones utilizing the nucleophilicity of cyclopropylmagnesium carbenoids

A novel method for the synthesis of cyclopropane-fused α-chloro-γ-lactones was developed utilizing the nucleophilicity of cyclopropylmagnesium carbenoids. Cyclopropylmagnesium carbenoids were generated from i-PrMgCl and 1-chlorocyclopropyl p-tolyl sulfoxides with a [(phenoxycarbonyl)oxy]methyl group at the 2-position of the cyclopropane ring. The resulting cyclopropylmagnesium carbenoids reacted with an intramolecular carbonate unit to give 1-chloro-3-oxabicyclo[3.1.0]hexan-2-ones in moderate to good yields. The asymmetric synthesis of 1-chloro-3-oxabicyclo[3.1.0]hexan-2-one was achieved using optically active dichloromethyl p-tolyl sulfoxide as a starting material.     

Samarium(II) iodide-induced tandem reductive coupling-Dieckmann condensation reaction: one-step synthesis of bicyclic oxacyclopentanecarboxylate from bis-α,β-unsaturated esters

The tandem cyclization of bis-α,β-unsaturated esters with SmI₂-Sm-THF in the presence of catalytic amount of methanol was found to stereoselectively provide bicyclo[4.3.0]nonan-8-ones and bicyclo[3.3.0]octan-3-ones.     

Eine Synthese methylierter Epoxyhydroazulenone durch intramolekulare [4 + 3]-Cycloaddition einer aus 1,1-Dichloro-6-(3-methylfur-2-yl)hexan-2-on erzeugten Oxyallyl-Zwischenstufe

A synthesis of Methylated Epoxyhydroazulenones by Intramolecular [4 + 3] Cycloaddition of an Oxyallyl Intermediate, Generated from 1,1-Dichloro-6-(3-methyl-2-furyl)hexan-2-one (Z)-3-Methylpent-2-en-4-yn-1-ol ( 7 ) was transformed to 2-(4-chlorobutyl)-3-methylfuran ( 4b ) and 2-(but-3-enyl)-3-methylfuran ( 10a ) by C-alkylation and 5-exo-dig cyclization. The Grignard derivative formed from 4b gave 1,1-dichloro-6-(3-methylfur-2-yl)hexan-2-onc ( 1b ) on reaction with dichloroacetyl chloride. This dichloromethyl ketone undergoes a base-induced cyclization to form diastereoisomeric 7-chloro-1,2,3,6,7,8a-hexahydro-4-methyl-8H-3a,6-epoxyazulen-8-ones ( 3bα and 3bβ ) by way of an intramolecular [4+3] cycloaddition of an oxyallyl intermediate 2b. By dechlorination and hydrogenation of 3bβ , the tricyclic hydroepoxyazulenones 18 and 19 have been synthesized.     

The Non-planarity of the Bicyclo[2.2.1]hept-2-ene Double bond. Crystal Structures of Bicyclo[2.2.2]oct-2-ene,Bicyclo[2.2.1]hept-2-ene,and Bicyclo[2.1.1]hex-2-ene Systems

The crystal structures of (1R,4R,5S,8S)-9,10-dimethylidentricyclo[6.2.1.0^2,7]undec2(7)-ene-4,5-dicarboxylic anhydride ( 3 ), (1R,4R,5S,8S)11-isopropylidene-9,10-dimethylidenetricyclo[6.2.1.m^2,7]undec-2(7)-ene-4,5-dicarboxylic anhydride ( 6 ), (1R,4R,5S8S)-9,10-dimethylidenetricyclo[6.2.2.0^2,7]dodec-2(7)-ene-4,5-dicarboxylic anhydride ( 9 ), (1R4R5S8S)-TRICYCLO[6.2.2.0^2,7]dodeca-2(7), 9-diene-4,5-dicarboxylic anhydride ( 12 ) and (4R,5S)-tricyclo[6.1.1.0^2.7]dec-2(7)-ene-4,5-dicarboxylic acid ( 16 ) were established by X-ray diffraction. The alkyl substituents onto the endocyclic bicyclo[2.2.1]hept-2-ene double bond deviate from the C(1), C(2), C(3), C(4), plane by 13.5°4 in 3 and by 13.9° in 6 , leaning toward the endo-face. No such out-of-plane deformations were observed with the bicyclo[2.2.2]oct-2-ene derivatives 9 and 12 . The exocyclic s-cis-butadiene moieties in 3, 6 and 9 do not deviate significantly from planarity. The deviation from planarity of the double bond n bicyclo[2.2.1]hept-2-ene derivatives and planarity in bicyclo[2.2.2]oct-2-ene analogues is shown to be general by analysis of all known structures in the Cambridge Crystallographic Data File. The non-planarity of the bicyclo[2.2.1]hept-2-ene double bond cannot be attributed only to bond-angle deformations which would favour rehybridizatoin of the olefinic C-atoms since the double bond in the more strained bicyclo[2.1.1]hex-2-ene drivative 16 deviates from planarity by less than 4°.     

Alkene epoxidation catalyzed by bicyclo[3.2.1]octan-3-ones: effects of structural modifications on catalyst efficiency and epoxidation enantioselectivity

Several 2-substituted bicyclo[3.2.1]octan-3-ones are prepared and have been tested as catalysts for alkene epoxidation by Oxone^®.     

A novel synthesis of bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones through [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with ring expansion

Treatment of [chloro(p-tolylsulfinyl)methylidene]cyclobutanes, which were synthesized from cyclobutanones and chloromethyl p-tolyl sulfoxide in three steps in high overall yields, with excess cyanomethyllithium gave enaminonitriles in high yields. Heating of these enaminonitriles with H₃PO₄ in acetic acid gave 2-cyanobicyclo[3.3.0]oct-1-en-3-ones in good yield. On the other hand, treatment of the [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with cyanomethyllithium followed by lithium carbanion of the homologues of acetonitrile afforded enaminonitriles having a substituent at the 3-position. Heating of the enaminonitriles with H₃PO₄ in acetic acid gave 2-substituted bicyclo[3.3.0]oct-1-en-3-ones in good to high yields. This method offers a novel and versatile procedure for synthesis of 2-substituted bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones in good overall yields.     

NMR isotope shifts in the 2-methyl-2-bicyclo[2.1.1]hexyl cation and related systems

NMR isotope shifts at ¹³C nuclei due to deuteriation in the 2-methyl-2-bicyclo[2.1.1]hexyl cation are reported. Comparisons are made to the 2-methyl-2-bicyclo[2.2.1]heptyl and 2-methyl-2-bicyclo[2.2.2]octyl cations, and also to neutral molecules containing the bicyclo[2.1.1]hexyl framework. The combination of isotope effects with temperature dependence of ¹³C chemical shifts allows predictions of the shapes of the energy surfaces along the bending coordinate corresponding to bridging in these cations.