Eugenius Butkus

Synthesis and chiroptical properties of enantiopure tricyclo[4.3.0.03,8]nonane-4,5-dione (twistbrendanedione)

Abstract The synthesis of chiral tricyclo[4.3.0.0 3,8 ]nonane-4,5-dione was accomplished starting from enantiomerically pure (+)-(1 S ,5 S )-bicyclo[3.3.1]nonane-2,6-dione 1 . Ring contraction of the latter with thallium(III) nitrate proceeded with high stereoselectivity giving exclusively methyl (+)-(1 S ,4 S )-(+)- exo , exo -bicyclo[2.2.1]heptan-2,5-dicarboxylate 2 . Inversion of the configuration of this diester to the required di- endo derivative was realized via the following reaction sequence. Bromination of the corresponding acid dichloroanhydride and subsequent reduction with zinc in acetic acid gave a diastereoisomeric mixture of esters, from which the endo , endo -ester 5 was isolated by column chromatography. Acyloin condensation of the latter with trimethylchlorosilane in toluene led to intramolecular ring closure, and subsequent oxidation of the enol silyl ether 7 in situ gave tricyclo[4.3.0.0 3,8 ]nonane-4,5-dione 8 . The chiroptical properties of this cage molecule were studied by electronic and vibrational circular dichroism spectroscopy. The (1 R ,3 R ,6 R ,8 R ) absolute configuration of the title structure was also unambiguously proved.

1H NMR spectroscopic study of the interaction between cyclodextrins and bicyclo[3.3.1]nonanes

The formation and structure of inclusion complexes of 2,6- and 2,9-substituted bicyclo[3.3.1]nonanes withα- andβ-cyclodextrin (CD) has been investigated by high-resolution1H NMR spectroscopy.α- andβ-CD were found to form 1:1 inclusion complexes and the binding constants were estimated from titration studies. 2D ROESY experiments provided insight into the structure of the complexes.

Stereochemical studies of bicyclo[5.3.1]undecane-8,11-dione. Conformational analysis, enantiomer separation, CD-spectroscopy and enolization

Abstract The stereochemical properties of the title compound have been examined by various methods. Dynamic NMR spectroscopy shows the existance of two conformers or sets of conformational families separated by a barrier of 8.2±0.4 kcal/mol. At low temperatures only one conformer was appreciably populated. Chromatographic enantiomer enrichment was performed on a microcrystalline triacetylcellulose column and the circular dichroism (CD) spectrum was recorded. The conformational space was explored by MM3 calculations giving six conformers within 2 kcal/mol. The high energy barrier observed by DNMR was assigned a chair-boat inversion of the eight-membered ring. The CD spectrum of the conformational mixture given by the MM-computations was calculated by the method developed by Schellman, giving information about the absolute configuration of the first eluted enantiomer, and about the conformational mixture in solution. Formation of enol esters under equilibrium conditions gave 83% of the bridgehead enol ester.

Synthesis of Diastereomeric Bicyclo[3.3.1]nonane Dibenzoyl Esters and Study of Their Chiroptical Properties

A synthesis of diastereomeric bicyclic dibenzoyl esters derived from enantiomerically pure (1S,5S)-bicyclo[3.3.1]nonane-2,6-dione was accomplished. Molecules containing two benzoyl chromophores with different configuration in the bicyclic framework were obtained. Chiroptical properties of the synthesized enantiomerically pure molecules were studied. Diastereomeric esters exhibited exciton couplets in the circular dichroism (CD) spectra because of transannular interaction between non-conjugated benzoate chromophores. The conformational effects and solvent impact on the exciton coupling were examined by CD spectroscopy. Theoretical computation of the CD spectra of diastereomers correctly reproduced the sign of the exciton couplets in the studied molecules, however, no major solvent dielectric constant influence and conformational effects per se on the exciton coupling was observed.

Synthesis of enantiomerically pure (+)-(1S, 2R, 5S, 6R)-endo, endo-2,6-diaminobicyclo[3.3.1]nonane

Abstract Enantiospecific synthesis of enantiomerically pure (+)-(1S,2R, 5S,6R)-endo,endo-2,6-diaminobicyclo[3.3.1]nonane was accomplished via a reaction sequence including stereospecific synthesis of the corresponding dinitro compound and the subsequent reduction of the latter with LiAlH4. The title diamine was also obtained in a direct reduction of the corresponding dioxime with sodium in ethanol with high stereoselectivity.

Intramolecular ring closure via ether bond in reaction of α,α′-halogeno bicyclo[3.3.1]nonanediones under basic conditions

The stereoselectivity of halogenation of bicyclo[3.3.1]nonan-2-one 1 and bicyclo[3.3.1]nonane-2,6-dione 2 with molecular bromine and chlorine was studied. The transformation of α-bromo- and chloro-bicyclo[3.3.1]nonanones 3–5 under Favorskii reaction conditions was studied. The reaction of α,α′-dihalogeno diones in the presence of sodium methoxide, ethoxide, propoxide and potassium cyanide led to the intramolecular ring closure via C–O bond formation giving the highly functionalized chiral 2-oxatricyclo[4.3.1.03,8]decane (2-oxaprotoadamantane) structure. Enantiomers of this cage structure were resolved by chiral GLC. The intramolecular ring closure pathway involving the intermediate alkoxybicyclo[3.3.1]nonanolate structure was proposed.

Stereochemistry of the reduction of bicyclo[3.3.1]nonane-2,9-dione by complex hydrides

Bicyclo[3.3.1]nonane-2,9-dione (1) has been reduced by sodium borohydride, lithium aluminium hydride and sodium cyanoborohydride. The regio- and diastereo-selectivity, as well as the product distribution of the four possible diastereoisomeric diols and four possible hydroxy ketones has been determined by a combination of GC and NMR spectroscopy. The first reduction step showed low regioselectivity between the two carbonyl groups but essentially total diastereoselectivity at reduction of either the 2- or the 9-carbonyl group. The 9-(catechol)acetal, which is regioselectively formed, gives an entry to the only diol which is not obtained in direct reduction of 1. Benzoate or p-bromobenzoate esters were subjected to chiral chromatographic resolution on triacetylcellulose and CD spectroscopy gave information on the diastereochemistry as well as on the absolute configuration. Conformational preferences were established by molecular mechanics computations. The chair–chair conformation was calculated to be the most stable form of all the studied compounds except 1, for which a chair–boat conformation is preferred. Transition structures for all possible lithium hydride additions to 1 were analysed by MNDO and ab initio methods.

Stereoselective Baeyer–Villiger oxidation of some bridged bicyclic diketones

The regioselectivity of the Baeyer–Villiger oxidation of bicyclo[3.3.1]nonane and bicyclo[2.2.2]octane ketones 1–7 with carbonyl groups located at different positions and bearing other substituents in the bicyclic ring is studied. The impact of the formation of the tetrahedral intermediate and the ring-bond migratory aptitude are considered as major factors governing the reactions regioselectivity. The distortion from sp2-hybridization of the valence angle of the C-9 carbonyl group is found to be considerably greater than that at the C-2 carbonyl in bicyclo[3.3.1]nonane-2,9-dione structures according to semiempirical calculations. Highly regioselective oxygen insertion leading to the functionalized oxabicyclic keto lactones is accounted for by kinetic and stereoelectronic factors.

Chromatographic enantiomer separation and absolute configuration of spiro[benzo-1,3-dioxole-2,9′-bicyclo[3.3.1]nonan]-2′-one and the corresponding diastereomeric hydroxy acetals

The enantiomers of spiro[benzo-1,3-dioxole-2,9′-bicyclo[3.3.1]nonan]-2′-one 2 and the corresponding diastereomeric exo-2′- and endo-2′-hydroxy acetals 3a,b obtained from this monoacetal were resolved by HPLC on a swollen microcrystalline triacetylcellulose column. The absolute configuration of the enantiomers of 2 and 3a,b was assigned based on the signs of the Cotton effect and employing the octant rules for the carbonyl and the aromatic chromophores. The low intensity of the band at 290 nm in the CD spectrum of monoacetal 2 was accounted for by the interaction of the carbonyl and aromatic chromophores.

Formation of 2-oxatricyclo[4.3.1.03,8]decanes in intramolecular cyclization of α-halobicyclo[3.3.1]nonanones

Transformations of α-chloro- and α-bromobicyclo[3.3.1]nonanones under conditions of the Favorskii reaction were studied. The interaction of dihalodiketones with MeONa gives 2-oxatricyclo[4.3.1.03.8]decane (oxaprotoadamantane) derivatives as a result of intramolecular cyclization, whereas 3-bromobicyclononanone undergoes only nucleophilic substitution of bromine.