A method for synthesis of bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones with one-carbon ring expansion and its application to a formal synthesis of racemic 1-desoxyhypnophilin

A method for synthesis of 2-cyanobicyclo[3.3.0]oct-1-en-3-ones and 2-substituted bicyclo[3.3.0]oct-1-en-3-ones was developed by assembly of three components, cyclobutanones, chloromethyl p-tolyl sulfoxide, and nitriles, with one-carbon ring expansion of the cyclobutane ring. As an application of this method, a formal synthesis of 1-desoxyhypnophilin in racemic form was performed starting from 3,3-di(phenylthiomethyl)cyclobutanone.     

Alkoxide-Accelerated [1,3] Sigmatropic Shift of Bicyclo[3.2.1]oct-6-en-2-ols to 8-endo-Hydroxybicyclo[3.3.0]oct-2-en-4-ones

Bicyclo[3.2.1]oct-6-en-2-ols 6 are shown to undergo [1,3] sigmatropic shift to afford 8-endo-hydroxy-bicyclo[3.3.0]oct-2-en-4-ones 8 under the influence of potassium hydride.     

Rearrangements initiated by trimethylsilyl iodide: ready deoxygenative rearrangement of bicyclo[4.2.0]octane-2,5-diones to bicyclo[3.3.0]oct-1(5)-en-2-ones

Reaction of bicyclo[4.2.0]octane-2,5-diones with trimethylsilyl iodide gave bicyclo[3.3.0]oct-1(5)-en-2-ones by a clean reductive rearrangement in good yields, providing a simple and effecient synthetic method for the enones.     

A Stereoselective Preparation of 1,2,7-Triazabicyclo[3.3.0]oct-2-enes

5-(Alkylamino)methyl-2-pyrazolines react with ketones or aldehydes to give 1,2,7-triazabicyclo-[3.3.0]oct-2-enes in high yields. The reaction gives only one diastereomer with various aldehydes, except for CH₃CHO.     

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.     

Synthesis of bicyclo[2.2.2]oct-5-en-2-ones via a tandem intermolecular Michael addition intramolecular aldol process (a bridged Robinson annulation)

A novel one-pot synthesis of the several bicyclo[2.2.2]oct-5-en-2-ones 19 has been developed in which a cyclic or acyclic ketone 18 is reacted with a cyclic enone 6 in the presence of strong acid to give the bicyclic enone product 19. Alternatively, the intermediate diketone 21 can be prepared separately and subjected to the reaction conditions to give the bicyclic enones 19 in good yields.     

A simple organocobalt mediated synthesis of substituted 3-oxabicyclo[3.3.0]oct-6-en-7-ones

A range of substituted propargyl alcohols form ethers with allyl bromide in good yields; conversion of these ethers to the alkyne hexacarbonyl dicobalt complexes using Co₂(CO)₈, followed by intramolecular cyclisation gives substituted 3-oxabicyclo[3.3.0]oct-6-en-7-ones (4a–4e) in fair to moderate yields.     

A new synthesis, including asymmetric synthesis, of spiro[4.n]alkenones from three components: cyclic ketones, chloromethyl p-tolyl sulfoxide, and acetonitrile; and a formal total synthesis of racemic acorone

1-Chlorovinyl p-tolyl sulfoxides were synthesized from several kinds of cyclic ketones and chloromethyl p-tolyl sulfoxide in good yields. Treatment of the 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium at −78°C to room temperature gave spirocyclic enaminonitriles in high yields. Acidic treatment of the enaminonitriles afforded spiro[4.n]alkenones in good yields. By using an unsymmetrical cyclic ketone, α-tetralone, and optically active chloromethyl p-tolyl sulfoxide, this procedure afforded enantiomerically pure spiro[4.5]decenone in good yield with excellent asymmetric induction from the sulfoxide chiral center. By using this method a formal total synthesis of a racemic spirocyclic sesquiterpene, acorone, was realized.     

Double Michael Additions of Lithium Enolate of 1,4-Dioxaspiro[4.5]dec-6-en-8-One to Acrylates

Double Michael additions of lithium enolaie of 1,4-dioxaspiro[4.5]dec-6-en-8-one to four acrylates afforded bicyclo[2.2.2]octan-2-ones with high regio- and stereoselectivities in moderate yields.     

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.     

Simple NMR method for assigning relative stereochemistry of bridged bicyclo[3.n.1]-2-enes and tricyclo[7.n.1.0]-2-enes

The stereochemistry of syn and anti-forms of bridged bicyclo[3.n.1]-2-ene, tricyclo[7.n.1.0]-2-ene (n=1-3) and bicyclo[4.3.1]dec-7-ene derivatives can be assigned from the ¹³C chemical shift difference of the double bond. Both syn-9-R-bicyclo[3.3.1]non-2-enes and syn-13-R-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes have a large shielding difference between sp² carbons, while the corresponding anti-forms have a smaller one. In contrast, 8-R-bicyclo[3.2.1]oct-2-enes and 12-R-tricyclo[7.2.1.0^2,7]dodec-2(7)-enes have an inverse correlation. The reason of this specificity is the influence of the γ-gauche effect on the chemical shift of C(2) atom. The GIAO theory has been applied to investigate the ¹³C chemical shifts. The conformational equilibrium in the formamide group of 13-formylamino-tricyclo[7.3.1.0^2,7]tridec-2(7)-enes has been studied.     

A practical route to both enantiomers of bicyclo[3.3.0]oct-2-en-7-one and their use for the synthesis of key trisubstituted cyclopentanes

We describe new methodology for the synthesis of both enantiomers of 7,7-dichlorobicyclo[3.2.0]hep-2-en-6-one and conversion of these compounds into stereochemically defined bicyclo[3.3.0]oct-2-en-7-ones and thence trisubstituted cyclopentanes. These are key intermediates for the synthesis of prostanoids, brefeldin and other cyclopentane-containing natural products.     

Lewis acid catalyzed reactions of donor-acceptor cyclopropanes with 1- and 2-pyrazolines: formation of substituted 2-pyrazolines and 1,2-diazabicyclo[3.3.0]octanes

The reaction of 2-substituted cyclopropane-1,1-dicarboxylates with 1- and 2-pyrazolines is efficiently catalyzed by scandium or ytterbium triflates to give N-substituted 2-pyrazolines or 1,2-diazabicyclo[3.3.0]octanes. The reactions of 2-pyrazolines give diazabicyclooctanes as the major products. In contrast, the reactions starting from 1-pyrazolines predominantly give N-substituted 2-pyrazolines, which become the major compounds obtained if an equimolar amount of GaCl₃ is used. A possible reaction mechanism is suggested.     

Retro-Diels-Alder reaction using bicyclo[2.2.2]octatriene-fused pyrrole during porphyrin synthesis

Porphyrin synthesis using 4,7-etheno-4,7-dihydro-2H-isoindole and tripyrranedicarbaldehyde gave a porphyrin derivative bearing no bicyclo[2.2.2]octatriene moiety as well as the targeted bicyclo[2.2.2]octatriene-fused porphyrin.     

Rearrangement approach to the formal displacement of the bridgehead methoxyl group of bicyclo[3.2.2]non-6-en-2-ones with alkyl alkenyl and aryl groups

A preferential trasformation of the C₂ -substituted 1-methoxybicyclo[3.2.2]non-6-en-2-ols, derived from 1-methoxybicyclo[3.2.2]non-6-en-2-ones, into the C₁-substituted bicyclo[3.2.2]non-6-en-2-ones was accomplished by utilizing TsOH in toluene (85°C) or boiling benzene.     

Consecutive reaction of 1-chlorovinyl p-tolyl sulfoxides with [chloro(p-tolylsulfinyl)methyl]lithium leading to the formation of multi-functionalized methylenecyclopropanes

The reaction of 1-chlorovinyl p-tolyl sulfoxides with excess [chloro(p-tolylsulfinyl)methyl]lithium gave methylenecyclopropanes consisting of a chloro(p-tolylsulfinyl)methylene moiety and a (p-tolylsulfinyl)cyclopropylidene moiety. Treating the methylenecyclopropanes with butyllithium resulted in the formation of conjugated enynes.     

A versatile synthesis, including asymmetric synthesis, of bicyclo[n.1.0]alkanes from cyclic ketones via the magnesium carbenoid 1,3-CH insertion as a key reaction

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from various cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps, in high yields, with lithium enolate of tert-butyl acetate or its homologues gave the adducts in quantitative yields. The adducts were treated with isopropylmagnesium chloride in ether in dry toluene as the reaction solvent to afford bicyclo[n.1.0]alkanes in high to quantitative yields via magnesium carbenoid 1,3-CH insertion. When this method was carried out starting from unsymmetrical cyclic ketones and (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of bicyclo[n.1.0]alkane was realized.     

Synthesis and rearrangement of [1,1′-bicyclobutyl]-1-ols and spiro[3.4]octan-5-ols: a general access to bicyclo[3.3.0]octenes (hexahydropentalenes)

Several new Grignard reagents based on substituted cyclobutanes have been generated and added to cyclobutanones to yield mono- to trimethylated [1,1′-bicyclobutyl]-1-ols. Mono- to trimethylated spiro[3.4]octan-5-ols have been prepared from the parent ketone via alkylation and/or addition reactions. Upon treatment with acid, all [1,1′-bicyclobutyl]-1-ols and spiro[3.4]octan-5-ols rearrange to yield a single bicyclo[3.3.0]octene.     

The Synthesis and Chemistry of 8-Substituted Bicyclo[5.1.0]oct-1(8)-ene

8-Bromobicyclo[5.1.0]oct-1(8)-cne (7), an intermediate for the preparation of 8-substituted bicyclo[5.1.0]oct-1(8)-enes, was synthesized by denomination of 1,8,8-tribromobicyclo[5.1.0]octane (6). Compound 7 underwent bromo-lithium exchange followed by nucleophilic substitution reactions to generate bicyclo[5.1.0]oct-1(8)-ene (5), 8-methylbicyclo[5.1.0]oct-1(8)-ene (10), and 8-trimethylsilylbicyclo[5.1.0]oct-1(8)-ene (11). The bicyclic cyclopropenes 7, 5, 10, and 11 reacted with cyclopentadiene to form adducts 12, 13, 14, and 15, respectively. All of these Diels-Alder adducts are endo-exo isomers (endo-addition from the view of the cyclopropene and exo-addition from the view of the cyclooctene).     

Bifunctional pyridyl alcohols with the bicyclo[3.3.0]octane scaffold in the asymmetric addition of diethylzinc to aldehydes

Some new pyridyl alcohols with the cis-bicyclo[3.3.0]octane scaffold were synthesized and used as chiral ligands for the enantioselective addition of diethylzinc to aldehydes. Ligands 4 were found to be far superior to the C₂-symmetric ligands 2 in terms of enantioselectivities. Quantitative yields and enantiomeric excesses of up to 92% were obtained when the ligand 4 was used. The carbonyl function in 4 proved to be beneficial for the high enantioselectivities in the addition of diethylzinc to aldehydes. Conversion of the carbonyl group into oxime or oxime ether group led to a sort of more active ligands, which catalyzed the same reaction with rate acceleration.