Elena V. Sergeeva

Regioselective Fries Rearrangement and Friedel−Crafts Acylation as Efficient Routes to Novel Enantiomerically Enriched ortho-Acylhydroxy[2.2]paracyclophanes

Two useful approaches to ortho-acylhydroxy[2.2]paracyclophanes, starting from 4-hydroxy[2.2]paracyclophane, have been developed. TiCl4-catalyzed Fries rearrangement and direct acylation occur regioselectively (to the ortho position with respect to the hydroxy group), leading to 4-acetyl-5-hydroxy[2.2]paracyclophane (3) and 4-benzoyl-5-hydroxy[2.2]paracyclophane (4) in high to excellent chemical yields. For compound 4, an X-ray investigation has been performed. ortho-Acylhydroxy[2.2]paracyclophanes 3 and 4 have been obtained in enantiomerically enriched forms (ee 92−99%) and the absolute configurations of their enantiomers have been determined.

Novel chiral tridentate Schiff base ligands of the [2.2]paracyclophane series: synthesis and application

The first example of the efficient application of chiral tridentate N,O-[2.2]paracyclophane ligands of the imino type for enantioselective diethylzinc addition to aliphatic and aromatic aldehydes is presented. The enantiomeric excess of the resulted secondary alcohols is up to 93% e.e.

Synthesis, resolution and absolute configuration determination of (S)- and (R)-4-formyl-5-hydroxy [2.2]paracyclophane and its application in the asymmetric synthesis of α-amino acids

Racemic (R,S)-4-formyl-5-hydroxy[2.2]paracyclophane (FHPC) was resolved into enantiomers via its Schiffs base with (S)- and (R)-α-phenylethylamine (α-PEAM) and its absolute configuration was determined by an X-ray diffraction structural study. Scalemic FHPC or its derivatives can be used as chiral auxiliaries for the asymmetric synthesis of β-hydroxy-α-amino acids and α-methylphenylalanine with ees ranging mostly from 45 to 98%.

Symmetrically tetrasubstituted [2.2]paracyclophanes: their systematization and regioselective synthesis of several types of bis-bifunctional derivatives by double electrophilic substitution.

The possible number of chiral and achiral tetrasubstituted [2.2]paracyclophanes possessing different types of symmetry (C(2), C(i), C(s), C(2v), C(2h)) is evaluated and a unified independent trivial naming descriptor system is introduced. The reactivity and regioselectivity of the electrophilic substitution of the chiral pseudo-meta- and achiral pseudo-para-disubstituted [2.2]paracyclophanes are investigated in an approach suggested to be general for the synthesis of bis-bifunctional [2.2]paracyclophanes. The mono- and diacylation of chiral pseudo-meta-dihydroxy[2.2]paracyclophane 14 with acetylchloride occur ortho-regioselectively to produce tri- 22, 23 and symmetrically 21 tetrasubstituted acyl derivatives. The same reaction with benzoylchloride is neither regio-, nor chemoselective, and gives rise to a mixture of ortho-/para-, mono-/diacylated compounds 27-31. The double acylation of pseudo-meta-dimethoxy[2.2]paracyclophane 18 is completely para-regioselective. Electrophilic substitution of pseudo-meta-bis(methoxycarbonyl)[2.2]paracyclophane 20 regioselectively generates the pseudo-gem-substitution pattern. Formylation of this substrate produces the monocarbonyl derivatives 35 only, whereas the Fe-catalyzed bromination may be directed towards mono- 36 or disubstitution 37 products chemoselectively by varying the reactions conditions. The diacylation and dibromination reactions of the respective achiral diphenol 12 and bis(methoxycarbonyl) 40 derivatives of the pseudo-para-structure retain regioselectivities which are characteristic for their pseudo-meta-regioisomers. Imino ligands 26, 25, and 39, which were obtained from monoacyl- 22 and diacyldihydroxy[2.2]paracyclophanes 21, 38, are tested as chiral ligands in stereoselective Et(2)Zn addition to benzaldehyde producing 1-phenylpropanol with ee values up to 76 %.

Resolution and Novel Reactions of 4-Hydroxy[2.2]paracyclophane

The resolution of racemic 4-hydroxy[2.2]paracyclophane (1) by fractional crystallization of the diastereomeric esters 3 with (1S)-(−)-camphanic acid and the determination of the absolute configurations of (R)- and (S)-4-hydroxy[2.2]paracyclophanes by X-ray diffraction have been carried out. The Friedel−Crafts oxaloylation of 1 with AlCl3 was found to occur with formation of both ortho- and para-hydroxy[2.2]paracyclophanylglyoxylic acids, whereas in the presence of TiCl4, quantitative formation of 2,3-dioxo-2,3-dihydrofurano[4,5-d][2.2]paracyclophane (8) as a product of an unusual cooperative C- and O-acylation was observed. Replacement of the OH group in the substrate for OCH3 (compound 18) changes the regioselectivity of the oxaloylation, which now occurs with formation of a para-substituted α-diketone 19. A novel technique for the synthesis of 4-formyl-5-hydroxy[2.2]paracyclophane (FHPC, 15) involving stereoselective reduction of 8 followed by oxidative cleavage of the intermediate diol 14 is also presented.

An improved synthesis of (S)-(+)- and (R)-(−)-[2.2]paracyclophane-4-carboxylic acid

Abstract Treatment of 4-bromo[2.2]paracyclophane with n-butyllithium followed by CO2 produced [2.2]paracyclophane-4-carboxylic acid, 1. Both enantiomeric forms [63% of (+)-(S)-1 and 48% of (−)-(R)-1] were obtained by resolution via the corresponding diastereomeric α-(p-nitrophenylethylammonium salts.

New chiral β-diketones based on [2.2]paracyclophane

Abstract Two chiral β-diketones, 1,3-bis[( S )-(4-[2.2]paracyclophanyl)]propane-1,3-dione (BPPD) and [1-( S )-(4-[2.2]paracyclophanyl)-3-phenyl]propane-1,3-dione (PPPD), were synthesized by acylation of ( S )-4-acetyl[2.2]paracyclophane with methyl esters from the corresponding carboxylic acids. 4-Acetyl[2.2]paracyclophane was synthesized in a quantitative yield by the reaction of [2.2]paracyclophane-4-carboxylic acid with methyllithium.

Asymmetric synthesis of (R,S)- and (R,R)-4-hydroxy-5-(α-substituted)-hydroxymethyl[2.2]paracyclophane and derivatives by stereoselective addition to (R)-4-hydroxy-5-formyl[2.2]paracyclophane and derivatives

Abstract Highly diastereoselective nucleophilic addition reactions of organometallic reagents to formyl[2.2]paracyclophane derivatives which were ortho-substituted by hydroxy-, alkoxy- and trimethylsilyloxy-groups are reported. The absolute configuration of the newly formed secondary alcohols is assigned on the basis of the X-ray diffraction study as well as chemical correlation. The magnitude of the asymmetric induction and even the sense of chirality of the forming asymmetric carbon atoms of the alcohols depended on the nature of the ortho-substituents.

Synthesis of (2.2)paracyclophane-pseudo-ortho-dicarboxylic acid

An efficient three-step synthesis of [2.2]paracyclophane-pseudo-ortho-dicarboxylic acid by dibromination of [2.2]paracyclophane, thermal isomerization of the resultingpseudopara-dibromide topseudo-ortho-isomer, followed by lithiation/carboxylation was developed. The possibility of preparation of two other novelpseudo-ortho-disubstituted carbonyl derivatives, 4-carboxy-12-(1-oxopenthyl)-[2.2]paracyclophane and di(4-carboxy[2.2]paracyclophanyl-12)ketone, was demonstrated when an excess of lithiation reagent (4 or 10 eq.) was used in the final step.

First stereoselective pinacol coupling in the [2.2]paracyclophane series

The planar chiral N-arylimines of [2.2]paracyclophane undergo stereoselective pinacol coupling under the action of the Zn/Cu couple in the presence of p-TosOH, thus forming N-aryl substituted 1,2-diamines. The stereoselective formation of the asymmetric centers is governed by the planar chiral [2.2]paracyclophanyl moiety.