Asymmetric synthesis of α,β-substituted β-aminoalkanamides and stereochemical determination

Highly enantiomerically enriched β-aminoalkanamides 12 and β-phenylaminoalkanamides 13 have been prepared by the addition reaction of α-lithiated 2-alkyl-2-oxazolines 9-Li, derived from optically active oxazolines 9, to N-cumyl nitrones 2. The relative stereochemistry of alkanamides 5 and 6 has been established by 1D-NOESY experiments carried out on the related pyrimidinones 7, whereas the absolute configuration of alkanamides 12 and 13 has been confirmed by an X-ray analysis.     

Highly stereoselective synthesis of β,γ-disubstituted and α,β,γ-trisubstituted butyrolactones

β,γ-Disubstituted butyrolactones were produced effectively and steroeselectively from arsonium ylides generated in situ and substituted olefins. The transformation could be realized in one-pot or in two steps, which depended on the electronic properties of the olefins. With the adjustment of the solvent and in the presence of EtOH, α,β,γ-trisubstituted butyrolactones were also obtained in high yield from arsonium ylides and substituted olefins.     

RCM/PCC oxidation strategy for synthesis of functionalized cyclic α,β-unsaturated lactones: synthesis of (+)-triacetoxygoniotriol and its diastereomers

A novel methodology leading to the synthesis of (+)-triacetoxygoniotriol 2 from d-glucose is described. Construction of the core six-membered α,β-unsaturated lactone moiety involved ring closing metathesis (RCM) followed by a PCC oxidation. Later exploiting the pseudo-symmetry of d-glucose three other diastereomers of triacetoxygoniotriol were synthesized using the developed methodology.     

Reversed-phase high performance liquid chromatographic separation of diastereomers of β-amino alcohols and microwave assisted synthesis of Marfey's reagent,its chiral variants and diastereomers

Ten chiral derivatizing reagents (CDRs) were synthesized by replacing the l-Ala–NH₂ moiety in Marfey's reagent (MR) by seven l-amino acid amides and three l-amino acids employing microwave irradiation (MW) and were characterized. Ten racemic amino alcohols were derivatized with these CDRs under MW. The diastereomers were separated on a reversed-phase C₁₈ column using binary mixtures of acetonitrile with aqueous trifluoroacetic acid (TFA) and triethylammonium phosphate buffer (TEAP). In general, amino acid variants of MR provided better separation of diastereomers in comparison to amino acid amide variants. The method was also found successful for the separation of 20 diastereomers from a mixture.     

Total synthesis of anthrasteroids—I : Formylation of certain cyclic α,β- and β,γ-unsaturated ketones

As part of a study concerning the total synthesis of certain anthraequilenine, anthraestrone and diaza-anthraestrane derivatives, the synthesis and structure proof of the key intermediate trans-1β-hydroxy-8β-methyl-4,5-(3′-hydroxy-methylene-4′-oxo-2′,3′,4′,5′-tetrahydrobenzo) hydrindane (VI) is described. The preparation of this system involves a base catalyzed formylation of a cyclic β,γ-unsaturated ketone. The course and the selectivity of this acylation reaction is examined in more detail with the bicyclic model compounds Δ⁹⁽¹⁰⁾-octalone-2 and Δ¹⁽⁹⁾-octalone-2.     

Electrochemical reduction of dehydroamino acids: synthesis and photophysical properties of β,β-diarylalanines

Several β,β-disubstituted dehydroalanines were prepared from β,β-dibromo or β-bromo, β-substituted dehydroalanines and aryl boronic acids using a Suzuki-Miyaura cross-coupling reaction. The electrochemical behaviour of these compounds was studied by cyclic voltammetry. All compounds studied showed similar reduction potentials and these were similar to the peak potential of the methyl ester of N-tert-butoxycarbonyl dehydrophenylalanine. Thus, the presence of a second aryl moiety in the dehydroalanine scaffold does not significantly change the reduction potential.Controlled potential electrolyses were performed at the cathodic peak potential in the presence of triethylammonium chloride as proton donor. The only products isolated in good to high yields were the corresponding β,β-diarylalanines. This reaction was also carried out using a dipeptide containing a β,β-diaryldehydroalanine to give a 1:1 diastereomeric mixture of the reduction product.The photophysical properties of two of the β,β-diaryldehydroalanines and of the corresponding β,β-diarylalanines were studied in three solvents of different polarity. The β,β-diaryldehydroalanines show low fluorescent quantum yields (Φ_F<9%) due to the conjugation of the aromatic moieties with the α,β-double bond and with the carbonyl group, which favours the non-radiative deactivation pathways. The absence of conjugation in the reduction products leads to a significant increase in the fluorescence quantum yields. These results show that the β,β-disubstituted alanines could be used as fluorescent markers.     

A general route for the synthesis of β,β-difluorocarboxylic acids

A new method for the preparation of β,β-difluoro- (and other gem-difluoro) acids has been developed. It is based on the fact that 3-oxocarboxylic esters are easy to make and convert to the corresponding dithiane derivatives. These dithianes reacted with BrF₃, a commercial, but rarely used reagent in organic chemistry, under very mild conditions to form the corresponding difluoroesters, which in turn could be quantitatively hydrolyzed to the free gem-difluoroacids.     

α-Bromo-β,γ-unsaturated ketenes for the synthesis of α-benzylamino-β,γ-unsaturated acids

The synthesis of α-benzylamino-β,γ-unsaturated acids has been developed starting from α-bromo-α,β-unsaturated chlorides. Via treatment of the acyl chlorides with (R)-pantolactone in the presence of TEA, the in situ formation of the deconjugated ketenes and their direct transformation into chiral esters was performed. The substitution of bromine with benzylamine, followed by acid hydrolysis, allowed to us obtain enantiomerically enriched α-benzylamino-β,γ-unsaturated acids.     

Stereoselective synthesis of unsymmetrical β,β-diarylacrylates by a Heck-Matsuda reaction: versatile building blocks for asymmetric synthesis of β,β-diphenylpropanoates, 3-aryl-indole, and 4-aryl-3,4-dihydro-quinolin-2-one and formal synthesis of (-)-indatraline

β,β-Disubstituted α,β-unsaturated esters may serve as valuable derivatives for the preparation of other highly functionalized systems found in many natural products and marketed drugs. The stereoselective synthesis of unsymmetrical β,β-diarylacrylate compounds possessing two similar aromatic groups remains a substantial challenge. A simple and convenient stereoselective protocol for the preparation of β,β-disubstituted acrylates via a Heck-Matsuda reaction is reported. Good to high yields were accomplished by a "ligand-free" Pd-catalyzed arylation reaction of cinnamate esters with arenediazonium tetrafluoroborates. Both electron-deficient and electron-rich arenediazonium salts could be employed as arylating reagents, and cinnamate esters were generally more reactive when substituted with an electron-donating group. The overall methodology is highly stereoselective, and this attribute was taken advantage of in the asymmetric Cu-catalyzed 1,4 reduction reaction to provide β,β-diarylpropanoates in high enantioselectivities. The synthesis of a 3-aryl indole and a chiral 4-aryl-2-quinolone from β,β-diarylacrylates was achieved by cyclization in the presence of a diphosphine ligated CuH catalyst. A convenient route for the asymmetric formal synthesis of the psychoactive compound (-)-Indatraline is also presented.     

Development of methods for the synthesis of libraries of substituted maleimides and α,β-unsaturated-γ-butyrolactams

Synthetic methods for the preparation of maleimide and α,β-unsaturated-γ-butyrolactam compound collections are described. These routes take advantage of Pd cross-coupling and conjugate addition/elimination reactions to permit the facile production of bisaryl-maleimides, anilinoaryl-maleimides, and bisanilino-maleimides while allowing control over the synthesis of symmetrical or nonsymmetrical derivatives. Similarly, the chemistry developed allows for the generation of bisaryl substituted α,β-unsaturated-γ-butyrolactams. The scope and limitations of the approaches are presented.     

The chemistry of α,β-ditosyloxyketones: new and convenient route for the synthesis of 1,4,5-trisubstituted pyrazoles from α,β-chalcone ditosylates

The reaction of α,β-chalcone ditosylates with various reagents such as phenylhydrazine hydrochloride, semicarbazide hydrochloride and thiosemicarbazide in suitable conditions leads to 1,2-aryl shift, thereby providing a novel route for the synthesis of 1,4,5-trisubstituted pyrazoles.     

Phosphonic acids and esters–XVIII : Preparation of β,γ-unsaturated phosphonates by the stobbe condensation with diethyl β-carbethoxyethylphosphonate; stereochemical dependencies of homoallylic 31P1H spin-spin coupling constants

The base catalyzed condensation of the title compound (4) with benzaldehyde and a variety of ketones follows a normal Stobbe course yielding β,γ-unsaturated phosphonates, i.e. ethyl hydrogen β-carbethoxy-γ-substituted allylphosphonates (5). Despite the unsymmetrical nature of 4, condensation is specific at the position adjacent to the carbethoxy function; neither the isomeric α,β-unsaturated phosphonates nor the dephosphonated (Wittig) products, β,γ-unsaturated carboxylates, are observed. The specificity presumably reflects the greater stabilization afforded an α-anion by a carbonyl function than by a dialkoxyphosphono function. Condensations with unsymmetrical carbonyl components (acetophenone, benzaldehyde) yield mixtures of cis- and trans-5 in a nonstereoselective manner. Gross structures and stereochemical relationships were assigned on the basis of PMR spectroscopy. In 5 derived from acetophenone and acetone, a long-range (five bond) ³¹P¹H coupling is observed. Based upon studies of these and model compounds (dimethyl γ,γ-dimethylallylphosphonate), it was shown that the transoid ⁵J_PH is of larger magnitude than the corresponding coupling involving cisoid geometry.     

Efficient synthesis of an optically pure β-bromo-β,β-difluoroalanine derivative,a general precursor for β,β-difluoroamino acids

A highly efficient enantioselective preparation of a β-bromo-β,β-difluoroalanine derivative, a promising general precursor for optically active β,β-difluoroamino acids, is described. Alkylation of the hydroxypinanone glycinate Schiff base 2a with CF₂Br₂ resulted in the production of undesired dehydrobrominated product 4a promoted by the lithium alkoxide moiety on the hydroxypinanone chiral auxiliary. Dehydrobromination was prevented by protection of the hydroxyl group on the chiral auxiliary. Utilization of TMSOTf resulted in production of (S,S,S,S)-3b as the sole diastereomer without dehydrobromination. Further transformations of (S,S,S,S)-3b to other optically active β,β-difluoroamino acids were demonstrated.     

β-Acetyl-β-nitrostyrenes: Structure and use for synthesis of heteryl-containing structures

¹H, IR, and electronic absorption spectroscopy and X-ray diffraction analysis were used to establish that 1-acetyl-1-nitro-2-phenyl-and 2-(p-methoxyphenyl)ethenes have Z configuration, and their 2-(p-N,Ndimethylaminophenyl)-substituted analog exists in chloroform-d ³ as a mixture of Z and E isomers. The reactions of gem-acetylnitroethenes with N-methylpyrrole were shown to involve alkylation at the C²-reaction center of the heterocycle. The reactions of these nitroalkenes with hydrazine form pyrazoles and azines, with acetylhydrazine, the corresponding hydrazones (via transalkenylation), and with sodium azide, acetylsubstituted 1,2,3-triazoles.     

Rh(I)-catalyzed [5+1] cycloaddition of vinylcyclopropanes and CO for the synthesis of α,β- and β,γ-cyclohexenones

A cationic Rh(I)-catalyzed [5 + 1] cycloaddition of vinylcyclopropanes and CO has been developed, affording either β,γ-cyclohexenones as major products or α,β-cyclohexenones exclusively, under different reaction conditions.     

Heterocyclization of β,γ-dichloro ketones as a method for the synthesis of furan derivatives

Dichloro ketones obtained from acyl chlorides and allyl or -methylallyl chloride undergo spontaneous cyclization to give 2-alkyl- and 2,4-dialkylfurans when they are heated; the intermediates in the case of 2,3-dichloropropene split out a molecule of hydrogen chloride to give 3,4-dichloro-2-butenones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 313–319, March, 1992.     

Asymmetric synthesis of β,β-difluoroamino acids via cross-coupling and Strecker reactions

β,β-Difluoroamino acids were synthesized from commercially available ethyl bromodifluoroacetate using cross-coupling and Strecker reactions as key steps. The coupling reaction of aryl iodides with ethyl bromodifluoroacetate gave the corresponding coupling products, which were transformed to 2-difluoromethyl-1,3-oxazolidines in two steps. Boron trifluoride etherate promoted Strecker reaction of 2-difluoromethyl-1,3-oxazolidines gave α-amino nitriles in good yields and diastereoselectivities. After removal of chiral auxiliary and hydrolysis of the nitrile group, β,β-difluorophenylalanine was obtained with 73% ee. Partial racemization occurred during the hydrolysis of nitrile group.