Stereo- and regioselective synthesis of β-amino-β-tetrazolylvinylphosphonates

Addition of 5-substituted tetrazoles to dimethyl [(N,N-diisopropylamino)ethynyl]phosphonate proceeds regio- and stereoselectively to yield (Z)-[2-diisopropylamino-2-(tetrazolyl)vinyl]phosphonic acid dimethyl esters. The Z-configuration of the products was confirmed by ¹Н NMR spectroscopy and single-crystal X-ray diffraction. The reactions occur via nucleophilic attack of tetrazole involving predominantly the N-1 atom of the tetrazole ring.     

Efficient, enantioselective synthesis of a β,β-disubstituted carboxylic acid by Ru-XylPhanePhos-catalyzed asymmetric hydrogenation

Enantioselective preparation of a key α_vβ₃ integrin antagonist intermediate was accomplished via catalytic asymmetric hydrogenation of the corresponding β,β-disubstituted α,β-unsaturated carboxylic acid bearing a 3-quinolinyl moiety. The successful application of a Ru-(R)-XylPhanePhos catalyst to this type of substrate is unprecedented. In situ NMR experiments of pre-catalyst formation/activation by CH₃CO₂H, and reaction parameter modification, revealed that [Ru(COD)(CF₃CO₂)₂]₂/(R)-XylPhanePhos is a highly active and efficient catalytic system.     

Stereoselective synthesis of 3,4,5,6-tetrahydroxycyclohexyl β-amino acid derivatives

Stereoselective syntheses of racemic (1S,2R,3R,4R,5S,6R)- and (1S,2R,3R,4S,5S,6R)-3,4,5,6-tetrahydroxy derivatives of 2-aminocyclohexanecarboxylic acid have been achieved by a stereospecific Diels-Alder reaction between furan and maleic anhydride, a Curtius rearrangement and hydroxylation reactions.     

Cyclopropanation of 1,2-dibromoethylphosphonate: a synthesis of β-aminocyclopropylphosphonic acid and derivatives

Diethyl (1,2-dibromoethyl)phosphonate was found to undergo cyclopropanation with nitromethane in good yield. The resulting trans β-nitrocyclopropylphosphonate was converted to the trans N-protected aminocyclopropylphosphonate through a reduction–protection sequence. Subsequent hydrolysis gave the free β-aminocyclopropylphosphonic acid without any formation of ring-opening byproduct. Cyclopropanation of 1,2-dibromoethylphosphonates with nitroalkanes and their reduction are also discussed.     

N-glycyl-β-glycopyranosylamines, derivatives of mono- and disaccharides, and their use for the preparation of carboxylic acid glycoconjugates

A convenient preparative procedure was developed for the synthesis ofN-glycyl-β-glycopyranosylamines, derivatives of monosaccharides (d-galactose,d-mannose,l-fucose, andN-acetyl-d-glucosamine) and disaccharides (lactose, melibiose, cellobiose, and maltose). These compounds were demonstrated to be useful for the preparation of glycoconjugates of biologically active compounds containing the carboxy group (nicotinic, orotic, kynurenic, and indoleacetic acids). Synthetic pathways were developed for conversions ofN-glycyl-β-glycopyranosylamines into derivatives containing the carboxy group with the use of malonic andl-tartaric acid derivatives. Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1461–1466, August, 2000.     

Diastereoselective synthesis of β-amino ketone and acid derivatives by palladium-catalyzed conjugate addition

The first diastereoselective synthesis of β-amino ketone and β-amino acid derivatives by palladium-catalyzed conjugate addition of arylboronic acids to chiral β-enamino ketones and β-enamino esters is reported. The catalytic system employing (S)-4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary in water under an air atmosphere provides β-amino ketone and β-amino acid derivatives in high yields with excellent diastereoselectivity.     

Synthesis of α-chiral-β,γ-unsaturated carboxylic acid derivatives using chiral auxiliaries

We report an efficient and reliable method for the synthesis of α-chiral-β,γ-unsaturated carboxylic acid derivatives using chiral auxiliaries and vinylacetic acid. Two well-established chiral auxiliaries ((S,S)-pseudoephedrine and (R)-benzyl-oxazolidinone) were chosen to test the merits of this method. Six different electrophiles were examined in the diastereoselective alkylation with both auxiliaries. The pseudoephedrine auxiliary provided isolated yields between 61 and 85% and diastereomeric ratios all greater than 96:4. Employing the same reactions as with the pseudoephedrine derivative, the corresponding oxazolidinone auxiliary provided isolated yields between 0 and 80% with diastereomeric ratios from 80:20 to 93:7.     

Stereoselective synthesis of α-hydroxy-β-amino acid derivatives from β-hydroxy-γ,δ-unsaturated sulfilimine

The first report on the use of N-sulfinyl benzylcarbamate for the preparation of N-Cbz sulfilimine from the corresponding sulfoxide is reported. The sulfilimine moiety is utilized as an intramolecular nucleophile for the regio- and stereoselective heterofunctionalization of an alkene to furnish a bromo carbamate which is used as a key advanced intermediate in the synthesis of representative α-hydroxy-β-amino acid derivatives.     

New β-amino-α-trifluoromethyl alcohols and their exploration in the synthesis of trifluoromethylated imidazole derivatives

Racemic and enantiomerically pure β-amino-α-trifluoromethyl alcohols were obtained via sequential nucleophilic trifluoromethylation of selected α-imino ketones, derived from arylglyoxals, and subsequent removal of the MeO or Ph(Me)CH substituent, respectively, located at the N-atom. The obtained products, containing a primary amino group, were used for the synthesis of imidazole N-oxides bearing a trifluoromethyl group as a part of the N(1)-alkyl chain. Imidazole N-oxides with an electron-withdrawing ester group at C(4) underwent spontaneous isomerization under the reaction conditions, and the corresponding imidazol-2-ones derivatives were isolated as final products.     

Efficient chemoenzymatic synthesis of enantiomerically pure β-heterocyclic amino acid derivatives

Enantiomerically pure (S)-pyrazolyl alanine and its derivatives are nonproteinogenic amino acids with antidiabetic activity. A short and effective enantioselective synthesis of these compounds is described, using a kinetic resolution by an acylase from Aspergillus sp.     

Chiral phosphoric acid catalyzed enantioselective synthesis of β-amino-α,α-difluoro carbonyl compounds

A biphenol-based chiral phosphoric acid bearing a 9-anthryl group at each of the 3,3'-positions catalyzed the asymmetric Mannich-type reaction of N-Boc imine with difluoroenol silyl ethers in the presence of MS3A in THF to afford β-amino-α,α-difluoroketones in good yields and with excellent enantioselectivities. Optically pure 3,3-difluoroazetidin-2-one was readily synthesized from the Mannich-adduct.     

A versatile and selective chemo-enzymatic synthesis of β-protected aspartic and γ-protected glutamic acid derivatives

Two versatile, high yielding, and efficient chemo-enzymatic methods for the synthesis of β-protected Asp and γ-protected Glu derivatives using Alcalase are described. The first method is based on the α-selective enzymatic hydrolysis of symmetrical aspartyl and glutamyl diesters. The second method involving mixed diesters comprises a three-step protocol using (i) α-selective enzymatic methyl-esterification, (ii) chemical β-esterification, and finally (iii) α-selective enzymatic methyl ester hydrolysis. The yields of the purified β- and γ-esters range from 77% to 91%.     

Synthesis and characterization of novel β-amino acid derivatives

In the work discussed in this paper, novel β-amino acid derivatives were prepared by Michael addition between 3-substituted-2-propenic acid and hydrazine hydrate. The optimum reaction conditions were determined by analyzing the effects of the ratio of the starting materials, temperature, and reaction time. The conclusions were: reaction temperature 80 °C, reaction time 8 h, n (3-substituted-2-propenic acid)/n (hydrazine hydrate) = 1:15. Products were characterized by measurement of melting point, elemental analysis, and IR and ¹H NMR spectroscopy.     

Microwave-assisted synthesis of 6-amino-β-cyclodextrins

A general microwave-assisted procedure for the synthesis of 6-amino-β-cyclodextrins is reported. Mono-tosyl-β-cyclodextrin was used as the starting material in a one-pot route employing a solvent-free microwave-assisted reaction with a liquid amine. Shorter reaction times were observed for the formation of 6-amino-β-cyclodextrins using this novel microwave approach compared to the thermal procedure.     

Efficient synthesis of β-halogeno protected l-alanines and their β-phosphonium derivatives

Ring opening of oxazolines, prepared from l-serinates, with trimethylsilyl halides (TMSX) led to β-halogeno-N-benzoyl-α-amino esters in good to excellent yields. Quaternization of triphenylphosphine by the β-bromo or -iodo amino esters gave the corresponding β-phosphonium salts in overall yields of up to 93% and with e.e. >96%. Hydrolysis of the ester function afforded the phosphonium salt bearing an N-benzoyl-α-amino acid substituent, with partial racemization. However, the reaction of the TMSX with the carboxylic salt, prepared by saponification of the starting oxazoline ester, furnished the corresponding β-halogeno-N-benzoyl-α-amino acids in 70–95% yields. Quaternization of triphenylphosphine by the bromo or iodo derivatives led to the phosphonium salts bearing a free acid function in 95% yield, without racemization. The efficiency of this synthesis was demonstrated by the preparation of these phosphonium salts in excellent overall yields, by a one-pot procedure starting from the oxazoline.     

Reaction of aspartic acid derivatives with Grignard reagents—synthesis of γ,γ-disubstituted α- and β-amino-butyrolactones

A series of γ,γ-dimethyl and γ,γ-diphenyl substituted α- and β-amino-butyrolactones have been prepared in enantiomerically pure form using l-aspartic acid as a chiral building block. For the final Grignard reaction the difference in chemical reactivity between the carboxyl groups of aspartic acid was increased or inverted by preparing the corresponding semiesters, diesters and anhydrides. The resulting hydroxyacids and hydroxyesters lactonised in most cases during work up. Thus, (2S)-2-ethoxycarbonylamino-succinic acid-4-methylester 1 reacted with methylmagnesium iodide to form (3S)-3-ethoxycarbonylamino-5,5-dimethyl-tetrahydrofuran-2-one 2b. Two interesting side products were obtained and were found to result from attack at the C-1 carboxylic acid rather than the C-4 carboxylic ester group leading to (3S)-3-ethoxycarbonylamino-4-oxo-pentanoic acid methylester 3 and (4S)-4-ethoxycarbonylamino-5,5-dimethyl-tetrahydrofuran-2-one 5a.     

Iron-catalyzed, highly regioselective synthesis of α-aryl carboxylic acids from styrene derivatives and CO2

The iron-catalyzed hydrocarboxylation of aryl alkenes has been developed using a highly active bench-stable iron(II) precatalyst to give α-aryl carboxylic acids in excellent yields and with near-perfect regioselectivity. Using just 1 mol % FeCl(2), bis(imino)pyridine 6 (1 mol %), CO(2) (atmospheric pressure), and a hydride source (EtMgBr, 1.2 equiv), a range of sterically and electronically differentiated aryl alkenes were transformed to the corresponding α-aryl carboxylic acids (up to 96% isolated yield). The catalyst was found to be equally active with a loading of 0.1 mol %. Preliminary mechanistic investigations show that an iron-catalyzed hydrometalation is followed by transmetalation and reaction with the electrophile (CO(2)).     

Efficient preparation of β-hydroxy aspartic acid and its derivatives

We reported an efficient and practical synthetic route to various properly-protected erythreo-β-OH-Asp compounds, which are key β-branched a-amino acid units in coralmycin A and other peptide natural products.     

Asymmetric synthesis of aminocyclooctenecarbonitriles: Cyclooctene β-lactam and hydroxyaminocyclooctene carboxylic precursors

Enantiopure β-aminocyclooctenenitriles, as precursors of β-amino acids and β-lactams, were synthesized from a readily available chloroalkene nitrile and (S)-methylbenzylamine via a straightforward substitution reaction and purified by crystallization. Acidic hydrolysis of the nitrile groups to their corresponding amides followed by DCC assisted carbonyl group activation gave novel α,β-unsaturated lactams. The treatment of 3-bromo-8-chlorocyclooctenecarbonitrile with (S)-methylbenzylamine furnished a diastereomeric mixture of bromoaminocyclooctenecarbonitriles via an S_N2′ pathway rather than bromide substitution via an S_N2 pathway. The diastereomeric mixture of bromoaminocyclooctanecarbonitriles provided two novel aziridines upon heating. TFA catalyzed aziridine ring opening gave γ-hydroxyl-β-aminocyclooctenecarbonitriles and γ-amino-β-hydroxycyclooctenecarbonitriles.