Optically Active Methacrylic Polymers Bearing in the Side Chain the (S)-3-Hydroxypyrrolidinyl Group Linked to trans-bisazoaromatic Chromophore: Synthesis and Characterization

The synthesis by radical homopolymerization of a novel optically active methacrylic polymer containing a side-chain chiral moiety linked to a photochromic bisazoaromatic chromophore has been carried out starting from the related monomer (S)-3-methacryloyloxy-1-[4′-phenylazo-(4-azobenzene)]-pyrrolidine [(S)- MPAAP ]. The polymeric derivate has been fully characterized and its spectroscopic properties compared to those of the monomer and of the corresponding homopolymer bearing only one azoaromatic chromophore in the side chain. The optical activity displayed by the bisazo polymer is discussed in terms of extent of chiral conformation assumed by the macromolecules as a consequence of dipole-dipole interactions between the bisazoaromatic chromophores.     

Synthesis, chiroptical properties and photoinduced linear birefringence of the homopolymer of (R)-3-methacryloyloxy-1-(4′-cyano-4-azobenzene)pyrrolidine and of the copolymers with the enantiomeric monomer

We have investigated a new optically active photochromic homopolymer poly[(R)-3-methacryloyloxy-1-(4′-cyano-4-azobenzene)pyrrolidine] containing in the side-chain a chiral group of one prevailing configuration linked to a trans-azoaromatic system. As expected it exhibits in solution homogeneous conformations with a prevailing chirality induced by dipole-dipole interactions between side-chain chromophores. Copolymers with the enantiomeric monomer (S)-3-methacryloyloxy-1-(4′-cyano-4-azobenzene)pyrrolidine have also been prepared in order to evaluate the effect on the photoinduced optical properties of side-chain chiral groups of opposite configuration in various ratios. The possibility of producing reversible photomodulation of linear birefringence without any significant degradation of these materials seems to be promising for their use in optical data storage.     

Herstellung enantiomerenreiner cis- oder trans-konfigurierter 2-(tert-Butyl)-3-methylimidazolidin-4-one aus den Aminosäuren (S)-Alanin, (S)-Phenylalanin, (R)-Phenylglycin, (S)-Methionin und (S)-Valin

Preparation of the Enantiomerically Pure cis- and trans-Configurated 2-(tert-Butyl)-3-methylimidazolidin-4-ones from the Amino Acids (S)-Alanine, (S)-Phenylalanine, (R)-Phenylglycine, (S)-Methionine, and (S)-Valine In contrast to α-hydroxy and α-mercapto carboxylic acids, simple α-amino acids do not form acetal-type derivatives ( 2 , X = NH) with pivalaldehyde. For the generation of amino-acid-derived chiral, nonracemic enolates (cf. 3 ), and hence, for the α-alkylation of amino acids without racemization and without an external chiral auxiliary, the imidazolidinones 12–14 were prepared diastereoselectively. To this end, the methyl or ethyl esters of amino-acid hydrochlorides were first converted to N-methylamides of amino acids which in turn were condensed with pivalaldehyde to give (neopentylidenamino)amides ( 11 ). These Schiff bases could be cyclized either to trans-or to cis-imidazolidinones ( 12, 14 and 13 , respectively), which were obtained in enantiomerically pure form after recrystallization. The enantiomeric purities were confirmed by HPLC with chiral stationary phases or by ¹H-NMR spectroscopy in the presence of chiral shift reagents. The configurations (cis, trans) were assigned by NOE measurements on 300- or 360-MHz ¹H-NMR spectrometers.     

An Unexpected Asymmetric Reduction of 4-(1-Nitro-2-oxocyclododecyl)butan-2-one. Determination of the absolute configuration of (‒)-15-hexadecanolide

Reduction of the carbonyl group in the side chain of 4-(1-nitro-2-oxocyclododecyl)butan-2-one ( 3 ) with organoboron complexes are influenced by the chiral center, in 4-position with respect to the carbonyl C-atom, to which the NO₂ group is attached, a rare type for an asymmetric reduction. Independent of the (R)- or (S)-configuration of the Alpine-Hydride, (+)- 3 is reduced only to the (15S)-nitrolactone (+)- 5 and, after subsequent transformations, to (+)-(-S)-15-hexadecanolide ((+)- 1 ), enantiomer of the naturally occurring (?)- 1 .     

Synthesis of(+)-(2S, 6S)-trans-α-Irone and of(-)-(2S, 6S)-trans-γ-Irone

A 3:1 mixture of (+)-(2S, 6S)-trans-α-irone ((+)-1) and (?)-(2S, 6S)-trans-γ-irone (?)-2) has been synthesized with ca. 70% e. e. by the ene reaction of (?)-(S)-3 and but-3-yn-2-one.     

Asymmetric anionic polymerization of (2-fluorophenyl)(4-fluorophenyl)(2-pyridyl)methyl methacrylate leading to a helical polymer

A novel racemic methacrylate, (2-fluorophenyl)(4-fluorophenyl)(2-pyridyl)-methyl methacrylate¹ (2F4F2PyMA), was synthesized and polymerized with chiral complexes of N,N′-diphenylethylenediamine monolithium amide (DPEDA-Li) with (−)-sparteine (Sp), (2S, 3S)-(+)-2,3-dimethoxy-1,4-bis(dimethylamino)butane (DDB), and (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (PMP) in toluene at −78°C. The monomer showed higher resistance against methanolysis compared with triphenylmethyl methacrylate (TrMA) and several other analogues. In the asymmetric anionic polymerization of 2F4F2PyMA, PMP was found to be a more effective chiral ligand than DDB and Sp and gave quantitatively an optically active polymer with nearly perfect isotacticity. Enantiomer selection was observed in the polymerization of racemic 2F4F2PyMA with the chiral lithium complexes. Chiral recognition ability of the optically active poly(2F4F2PyMA) was examined by an enantioselective adsorption experiment. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 2013–2019, 1998     

Proof of the Absolute Configuration of (−)-(S)-2-Hydroxy-β-ionone by correlation with ursolic acid and with (−)-trans-verbenol

(?)-(S)-2-Hydroxy-β-ionone ( 33 ), (+)-(2 S, 6 S)-2-hydroxy-α-ionone ( 34 ), and their acetates 35 and 36 have been synthesized from (+)-(S)-6-methylbicyclo [4.3.0]-non-1-ene-3, 7-dione ( 3 ). The key intermediate (+)-(1 R, 3 S, 6 S)-2, 2, 6-trimethyl-7-oxobicyclo [4.3.0]non-3-yl acetate ( 7 ) was correlated with a degradation product of the pentacyclic triterpene ursolic acid ( 16 ). Compound 33 was also synthesized by an alternative route starting from (?)-trans-verbenol ( 42 ).     

An efficient synthesis of (R)- and (S)-8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene

Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as a potent inhibitor of phosphoinositide 3-kinase (PI3K). In order to investigate the effects of its two enantiomers on tumor cell lines, we designed a novel synthesis for (R)-S14161 and (S)-S14161 using a chemical resolution and derivation strategy. The readily available 3-(tert-butyldimethylsilyloxy)-salicylaldehyde underwent a tandem oxa-Michael–Henry reaction with trans-4-fluoro-β-nitrostyrene in the presence of a catalytic amount of l-proline and triethylamine to give the 3-nitro-2H-chromene. Upon removal of the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-3-nitro-2H-chromene was achieved via diastereomeric ester formation using (S)-(+)-α-methoxyphenylacetic acid as the derivatizing agent, followed by aminolysis. Finally, the ethyl ether formation of each enantiomer furnished (R)-S14161 and (S)-S14161 in enantiomerically pure forms. The absolute configurations of these chiral molecules were determined by a circular dichroism method. The two enantiomers showed no marked differences in inhibition of growth of human myeloma LP1 and OPM-2 cells.     

Neue Synthese von (−)-(R)-Cembren A,Synthese von (+)-(R)-Cembrenen und (+)-(S)-Cembren

Novel Synthesis of (?)-(R)-Cembrene A, Synthesis of (+)-(R)-Cembrenene and (+)-(S)-Cembrene A novel synthesis of (?)-(R)-cembrene A ((?)- 3 ) was developed using the Sharpless epoxidation for the introduction of the chiral center. Furthermore, the synthesis of (+)-(R)-cembrenene ((+)- 4 ) showed that this cembranoid must have the (R)-configuration and not, as previously reported, the (S)-configuration. Selective hydrogenation of (+)- 4 afforded (+)-(S)-cenibrene ((+)- 5 ).     

Effect of lateral substituents on the mesomorphic properties of side-chain liquid crystalline polysiloxanes containing 4-[(S)-2-methyl-1-butoxy]phenyl 4-(alkenyloxy)benzoate side groups

The synthesis of side-chain liquid crystalline polysiloxanes containing either 4-[(S)-2-methyl-1-butoxy]phenyl 4-(alkenyloxy)benzoate or laterally fluoro-, chloro-, bromo-, and methoxy-substituted 4-[(S)-2-methyl-1-butoxy]phenyl 4-(alkenyloxy)benzoate mesogenic side groups is presented. The mesomorphic properties of the synthesized polymers have been characterized by optical polarizing microscopy, differential scanning calorimetry, and X-ray diffraction measurements. The effects of spacer length and lateral substituent on the mesomorphic properties of the obtained polymers are examined. The five polymers which contain three methylene units in the spacers show no mesophase, while the five polymers which contain eleven methylene units in the spacer display smectic mesomorphism. Among the other fifteen polymers which contain respectively four, five, or six methylene units in the spacers, those with small fluoro and chloro substituents reveal respectively an S_A phase, while those with bulky bromo and methoxy substituents show no liquid crystalline behavior. The experimental results demonstrate that introducing a bulky lateral substituent into the mesogenic core of a polymer depresses the tendency to form a mesophase. Furthermore, the technique of thermally stimulated current has been used to study the dipolar relaxation mechanisms in a side-chain liquid crystalline polysiloxane. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 2793–2800, 1997     

Photochemische Umsetzung von optisch aktiven 2-(1′-Methylallyl)anilinen mit Methanol

Photochemical Reaction of Optically Active 2-(1′-Methylallyl)anilines with Methanol It is shown that (?)-(S)-2-(1′-methylallyl)aniline ((?)-(S)- 4 ) on irradiation in methanol yields (?)-(2S, 3R)-2, 3-dimethylindoline ((?)-trans- 8 ), (?)-(1′R, 2′R)-2-(2′-methoxy-1′-methylpropyl)aniline ((?)-erythro- 9 ) as well as racemic (1′RS, 2′SR)-2-(2′-methoxy-1′-methylpropyl) aniline ((±)-threo- 9 ) in 27.1, 36.4 and 15.7% yield, respectively (see Scheme 3). By deamination and chemical correlation with (+)-(2R, 3R)-3-phenyl-2-butanol ((+)-erythro- 13 ; see Scheme 4) it was found that (?)-erythro- 9 has the same absolute configuration and optical purity as the starting material (?)-(S)- 4 . Comparable results are obtained when (?)-(S)-N-methyl-2-(1′-methylallyl)aniline ((?)-(S)- 7 ) is irradiated in methanol, i.e. the optically active indoline (+)-trans- 10 and the methanol addition product (?)-erythro- 11 along with its racemic threo-isomer are formed (cf. Scheme 3). These findings demonstrate that the methanol addition products arise from stereospecific, methanol-induced ring opening of intermediate, chiral trans, -(→(?)-erythro-compounds) and achiral cis-spiro [2.5]octa-4,6-dien-8-imines (→(±)-threo-compounds; see Schemes 1 and 2).     

Stereospecific syntheses of all four stereoisomers of 4-fluoroglutamic acid

(+)- -threo-4-Fluoroglutamic acid [(+)-(2S, 4S)-fluoroglutamic acid] has been synthesizedstarting with the natural (−)-4-trans-hydroxy- -proline. Its acetylation at nitrogen followedby esterification with diazomethane afforded methyl 1-acetyl-trans-4-hydroxy- -prolinatewhich was converted to methyl 1-acetyl-cis-4-fluoro- -prolinate by means of diethylaminosulfurtrifluoride (DAST) or 2-chloro-1,1,2-trifluorotriethylamine. The mixture wasoxidized by ruthenium tetroxide to methyl 1-acetyl-cis-4-fluoro- -pyrrolidin-5-one-2-carboxylate,whose acid hydrolysis yielded the title compound. A similar sequence of reactionsconverted cis-4-hydroxy- -proline to (−)- -erythro-4-fluoroglutamic acid [(−)(2R, 4S)-fluoroglutamic acid]. (−)- -threo-4-Fluoroglutamic acid [(−)-(2R, 4R)-floroglutamicacid] was prepared analogously from trans-4-hydroxy- -proline, obtained from its diastereomerby inversion of configuration at carbon 4 of the pyrrolidine ring using thediethyl azodicarboxylate-triphenylphosphine procedure. cis-4-Hydroxy- -proline, necessaryfor the synthesis of (+)- -erythro-4-fluoroglutamic acid [(+)-(2S, 4R)-fluoroglutamicacid], was prepared from trans-4-hydroxy- -proline by benzyloxycarbonylation at thenitrogen, oxidation of the 1-benzyloxycarbonyl-trans-4-hydroxy- -proline to 1-benzyloxy-carbonyl-4-oxo- -proline, its reduction to 1-benzyloxycarbonyl-cis-4-hydroxy- -proline anddeprotection of the latter at the nitrogen. (−)-cis-4-Fluoro- -proline and (+)-trans-4-fluoro- -proline were isolated after the hydrolysis of incompletely oxidized methyl 1-acetyl-cis-4-fluoro- -prolinate and methyl 1-acetyl-trans-4-fluoro- -prolinate, respectively.     

Über die Stereospezifität der α-Alkylierung von β-Hydroxycarbonsäureestern. Vorläufige Mitteilung

About the Stereospecific α-Alkylation of β-Hydroxyesters It was found, that dianions derived from β-hydroxyesters with lithium diisopropylamide (LDA) at ?50 to ?20° were alkylated stereospecifically (Scheme 1). The stereospecificity was 95–98%, the threo-compound (threo -2, -3 and -4) being the main product. This was proved for threo -2 and -3 by preparing the β-lactones 7 and 8 , respectively, which were pyrolyzed to trans-1, 4-hexadiene (9) and trans-1-phenyl-2-butene (10) , respectively (Scheme 2). Moreover, the acid threo -6 from threo -3 was converted by dimethylformamide-dimethylacetal to cis-1-phenyl-2-butene (11) (s. footnote 6). The alkylation of α-monosubstituted β-hydroxyesters also turned out to be stereospecific. Reduction of 16 and 18 with actively fermenting yeast furnished (+) -17 and (+) -2. respectively (Scheme 4), which were each mixtures of the (2R, 3S)- and the (2S, 3S)-isomers. Alkylation of (+) -17 with allyl bromide yielded after chromatography (2S, 3S) -19 and of (+) -2 with methyl iodide (2R, 3S) -19 , the oxidation of which finally gave (S)-(?) -20 and (R)-(+) -20 , respectively.     

Absolute Conformation and Configuration of (2S, 3S)-3-Acetoxy-5-(dimethylaminoethyl)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one Chloride (Dilthiazem Hydrochloride)

Resolution of racemic cis-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl) propionic acid ( 2 ) via the cinchonidine salt 3 , and brucine salt 4 , isolation of the calcium salts (+)- and (?)- 5 , as well as their cyclization to enantiomeric 1,5-benzothiazepines (+)- and (?)- 1 , are described. X-Ray single-crystal analysis reveals (2S, 3S) absolute configuration of (+)- 1 on the basis of tentative comparison of CD data with those for the 1,4-benzodiazepine derivative (+)- 8 of known absolute configuration.     

Circular Dichroism of Tricarbonyl(diene)iron Complexes. The Octant Rule Applied to Ketones Perturbed by Remote Fe(CO)3 Groups. Crystal Structure of (±)-Tricarbonyl[(1RS,4RS,5RS,6SR)-C5,6,C-η-(5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octanone)]iron

The preparation and the CD spectra of optically pure (+)-trans-μ-[(1R,4S,5S,6R,7R,8S)-C,5,6,C -η : C,7,8,C-η-(5,6,7,8-tetramethylidene-2-bicyclo [2.2.2]octanone)]bis(tricarbonyliron) ((+)- 7 ) and (+)-tricarbonyl[(1S,4S,5S,6R)-C-5,6,C-η-(5,6,7,8,-tetramethylidene-2-bicyclo[2.2.2]octanone)]iron ((+)- 8 ), and of its 3-deuterated derivatives (+)-trans-μ-[(1R,3R,4S,5S,6R,7R,8S)-C,5,6,C-η : C,7,8,C-η-5,6,7,8-tetramethylidene(3-D)-2-bicyclo[2.2.2]-(octanone)]bis(tricarbonyliron) ((+)- 11 ) and (+)-tricarbonyl[(1S,3R,4S,5S,6R)-C-5,6,C- η-(5,6,7,8-tetramethylidene(3-D)-2-bicyclo[2.2.2]octanone)]iron ((+)- 12 ) are reported. The chirality in (+)- 7 and (+)- 8 is due to the Fe(CO)₃ moieties uniquely. The signs of the Cotton effects observed for (+)- 7 and (+)- 8 obey the octant rule (ketone n→π*_CO transition). Optically pure (?)-3R-5,6,7,8-tetramethylidene(3-D)-2-bicyclo[2.2.2]octanone ((?)- 10 ) was prepared. Its CD spectrum showed an ‘anti-octant’ behaviour for the ketone n→π*_CO transition of the deuterium substituent. The CD spectra of the alcoholic derivatives (?)-trans-μ-[(1R,2R,4S, 5S,6R,7R,8S)-C,5,6,C-η : C,7,8,C- η-(5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octanol)]bis(tricarbonyliron) ((?)- 2 ) and (?)-tricarbonyl- [(1S,2R,4S,5S,6R)- C,5,6,C- η-(5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octanol)]iron ((?)- 3 ) and of the 3-denterated derivatives (?)- 5 and (?)- 6 are also reported. The CD spectra of the complexes (?)- 2 , (?)- 3 , (+)- 7 , and (+)- 8 were solvent and temperature dependent. The ‘endo’-configuration of the Fe(CO)₃ moiety in (±)- 8 was established by single-crystal X-ray diffraction.     

First synthesis of enantiomerically pure (1S,2S)- and (1R,2R)-1,2-diaminocyclobutanecarboxylic acid–ornithine derivative–, from racemic 2-aminocyclobutanone

An easy and efficient one-pot reaction from readily available 2-(N-Cbz) aminocyclobutanone selectively gave, by means of an asymmetric Strecker synthesis in the presence of a chiral benzylic amine, the thermodynamic 1,2-diamino nitriles. Basic hydrolysis, cleavage of the benzylic group and acidic hydrolysis of the resulting trans-1,2-diaminocyclobutanecarbonitrile gave, in a four-step sequence from the ketone, (1S,2S)- or (1R,2R)-1,2-diaminocyclobutanecarboxylic acid, ornithine derivatives. The absolute configuration has been established by X-ray analysis of the corresponding trans-diamino amide.     

Synthesis of (1R,4R,7S)- and (1S,4S,7S)-2-(4-tolylsulfonyl)-5-phenyl-methyl-7-methyl-2,5-diazabicyclo[2.2.1]heptanes via regioselective opening of 3,4-epoxy-d-proline with lithium dimethyl cuprate

The synthesis of (1S,4S,7S)- and (1R,4R,7S)-2-(4-tolylsulfonyl>5-phenylmethyl-7-rnethyl-2,5-diazabicyclo-[2.2.1]heptanes ( 20 ) and ( 22 ) from trans 4-hydroxy-L-proline is described.     

Synthesis and Circular Dichroism of Optically Pure (±)-(1S,2S,5S)-5-Methoxy-3,4,6,7-tetramethylidenebicyclo[3.2.1]oct-2-yl Derivatives. Baker's Yeast Reduction of 4-Methoxy-5,6,7,8-tetramethylidenebicyclo[2.2.2]octan-2-one

Baker's yeast reduction of 4-methoxy-5,6,7,8-tetramethylidenebicyclo[2.2.2]octan-2-one ( 11 ) under fermenting conditions afforded (?)-(1S,2S,4R)-4-methoxy-5,6,7,8-tetramethylidenebicyclo[2.2.2]octan-2-ol ((?)- 13 ) in 60% yield with an e.e. > 99.5%. Its methanesulfonate (?)- 14 was hydrolyzed and rearranged with high stereo-selectivity into (+)-(1S,2S,5S)-5-methoxy-3,4,6,7-tetramethylidenebicyclo[3.2.1]octan-2-ol ((+)- 15 ). The absolute configuration of (?)- 13 was deduced from the CD spectrum of its 4-(dimethylamino)benzoate ((+)- 22 ) applying the chiral exciton-coupling method. The CD spectrum of (+)- 15 and of its (tert-butyl)dimethylsilyl ether ((+)- 23 ) showed exciton-split type of Cotton effects attributed to through-space interactions between the s-gauche-buta-diene and s-cis-butadiene chromophores of these systems.     

An efficient and stereoselective synthesis of (3S,4R)-(−)-trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine

An asymmetric conjugate addition reaction between a chiral α,β-unsaturated amido ester and ethyl-N-methylmalonamide has been used as a key step in the synthesis of (3S,4R)-(−)-trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine, a key intermediate for (−)-paroxetine.     

New Chiral Diamines of the Dioxolane Series: (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(diphenylaminomethyl)- 1,3-dioxolane and (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(methyl- aminomethyl)-1,3-dioxolane

The reaction of sodium diphenylamide with 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane gave (+)-(4S,5S)-2,2-dimethyl-4,5-bis(diphenylaminomethyl)-1,3-dioxolane, which was brought into complex formation with cobalt chloride. Treatment of 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane with sodium N-methylanilide resulted in cleavage of the SÄO bond in the p-toluenesulfonate moiety with formation of N-methyl-N-phenyl-p-toluenesulfonamide and 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane disodium salt. Diethyl (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate reacted with methylamine to give the corresponding dicarboxamide which was reduced with lithium aluminum hydride to (4S,5S)-2,2-dimethyl-4,5-bis(methylaminomethyl)-1,3-dioxolane having chiral carbon and nitrogen atoms.