The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid derivatives via thiazolones

2-Alkoxy-4-heteroarylaminomethylene-5(4H)-thiazolones 4 were converted with various nucleophiles into β-heteroarylamino-α,β-dehydro-α-amino acid derivatives 11, 14, 15, 16, 17, 18 , and 19 . Reduction of 4 with sodium borohydride in ethanol saturated with gaseous ammonia afforded the corresponding β-heteroaryl-amino substituted alanyl amides 20 . Thiazoledione derivative 7a was transformed with sodium methoxide in methanol into 1-(4,6-dimethylpyrimidinyl-2)-4-mercaptocarbonylimidazol-2(3H)-one ( 8a ).     

Synthesis and mesomorphic properties of new liquid crystalline compounds with ß-hydroxy-, ß-chloroketone and a,ß-unsaturated ketone moieties in the terminal chains

The syntheses of new liquid crystalline compounds containing β-hydroxy-, β-chloroketone and α,β-unsaturated ketone moieties are described. The key intermediate 1-(4-hydroxyphenyl)-3-hydroxyoctan-1-one was obtained by the hydrogenolysis of the heterocycle in 3-(4-hydroxyphenyl)-5-pentyl-2-isoxazoline. Dehydratation of the intermediate β-hydroxyketone led to 1-(4-hydroxyphenyl)-oct-2-en-1-one. Reaction of 1-(4-hydroxyphenyl)-3-hydroxyoctan-1-one with hydrochloric acid yielded 1-(4-hydroxyphenyl)-3-chlorooctan-1-one. The target liquid crystalline compounds were synthesized by the esterification of these phenols with corresponding acids. The relationships between the moiety type in the terminal chain and the liquid crystalline properties are discussed.     

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.     

Photochemical reactivity of α,β-unsaturated δ-lactams: Synthesis of seco-steroids. Photochemical reactions. XIII [1]

The UV. irradiation of 17 β-hydroxy-2-aza-4-androsten-3-one (1) , N-methyl-17 β-hydroxy-2-aza-4-androsten-3-one (3) , 17 β-hydroxy-4-aza-5 β-androst-1-en-3-one (2) and N-methyl-17 β-hydroxy-4-aza-5 β-androst-1-en-3-one (4) , gives rise to 1,10-seco (from 1 and 3 ) and 5, 10-seco (from 2 and 4 ) steroids.     

Synthesis of 1-tetralones by intramolecular Friedel-Crafts reaction of 4-arylbutyric acids using Lewis acid catalysts

Intramolecular Friedel-Crafts reaction of 4-arylbutyric acids efficiently proceeded in the presence of catalytic amounts of Lewis acids such as Bi(NTf₂)₃ and M(OTf)₃ (M=Bi, Ga, In and rare-earth metals) to form 1-tetralones. Chroman-4-one and thiochroman-4-one were also obtained in good yields from 3-phenoxypropionic acid and 3-phenylthiopropionic acid, respectively.     

Synthesis of (2S)-isopropyl-5-alkynylpyrimidin-2-ones: precursors of β-aminoacids

The efficient palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of (2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-one with, arylethynyl-, heteroarylethynyl-, and alkylethynyltrifluoroborate salts is reported. The standard protocol was evaluated and optimized in order to gain access to suitable precursors of enantiopure 2-substituted β-amino acids. The scope and limitations of this methodology are discussed.     

Reaction of aziridinecar☐ylic acids with thiols in aqueous solution. the formation of β-amino acid

Enantiomers of 3-methyl-2-aziridinecar☐ylic acids (1-d and 1-l) and 2-aziridinecar☐ylic acids (2-d and 2-l) reacted easily with thiophenol, cysteine and glutathione in aqueous solution or in sodium phosphate buffer solution at room temperature and gave predominantly β-amino acid derivatives with sulfur substituents at their α-position.From 1-d and thiophenol, (2S, 3R)-3-amino-2-phenylthiobutanoic acid (3-d) was produced predominantly. In order to confirm the structure, 3-d was converted to (3S, 4R)-3-phenylthio-4-methylazetidin-2-one (5) using the Ohno reaction. The configurations of 3-d and 6 were determined by X-ray diffraction and ¹³C NMR spectrum analysis, respectively. We concluded that the ring-opening reaction of unactivated aziridinecar☐yhc acids with thiols in aqueous solution occurred predominantly on C-2 of the aziridine ring with inversion of the configuration at this position. The reaction offers a good route for stereoselective synthesis of peptides or β-lactam derivatives.     

Efficient synthesis of enantiopure pyrrolizidinone amino acid

Enantiopure (3S,5R,8S)-3-[N-(Boc)amino]-1-azabicyclo[3.3.0]octan-2-one 8-carboxylic acid (1) was synthesized in nine steps and 16% overall yield from aspartate beta-aldehyde 7. Carbene-catalyzed acyloin condensation of 7, followed by acetylation and samarium iodide reduction, gave linear precursor (2S,7S)-alpha,omega-diamino-4-oxosuberate 11, which was converted to N-(Boc)aminopyrrolizidin-2-one carboxylic acid 1 by a reductive amination/lactam cyclization sequence. X-ray analysis of (3S,5R,8S)-methyl N-(Boc)aminopyrrolizidin-2-one carboxylate 21 showed that its internal backbone dihedral angles (psi = -149 degrees, phi = -49 degrees ) were in good agreement with the ideal values for a type II' beta-turn. Proton NMR experiments on N'-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamide 23 demonstrated significantly different NH chemical displacements and temperature coefficients suggestive of solvent shielded and exposed hydrogens indicative of a turn conformation. Because pyrrolizidinone amino acids can serve as conformationally rigid dipeptide surrogates, this synthesis should facilitate their application in the exploration of conformation-activity relationships of various biologically active peptides.     

Quaternary β2,2‐Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc‐Based Solid‐Phase Peptide Synthesis

β‐Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to β^2,2‐amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of β³‐ and certain β^2,3‐amino acids. Herein, we report the catalytic asymmetric synthesis of β^2,2‐amino acids and their incorporation into peptides by Fmoc‐based solid‐phase peptide synthesis (Fmoc‐SPPS). A quaternary carbon center was constructed by the palladium‐catalyzed decarboxylative allylation of 4‐substituted isoxazolidin‐5‐ones. The N?O bond in the products not only acts as a traceless protecting group for β‐amino acids but also undergoes amide formation with α‐ketoacids derived from Fmoc‐protected α‐amino acids, thus providing expeditious access to α‐β^2,2‐dipeptides ready for Fmoc‐SPPS.     

A novel conformationally restricted analogue of 3-methylaspartic acid via stereoselective methylation of chiral pyrrolidin-2-ones

Conformationally restricted analogues of β-methylaspartic acid were easily prepared starting from chiral N-protected trans-3-amino-4-methoxycarbonyl pyrrolidin-2-ones. The key step of the synthesis was the methylation reaction at C-4, proceeding with high diastereoselection syn to the protected amino group lying at C-3 of the pyrrolidin-2-one ring.     

Synthese eines steroidischen 17 β-Pyrrolinons. Partialsynthetische Versuche in der Reihe der Herzgifte. 10.Mitteilung

Synthesis of a steroidal 17 β-pyrrolinone We describe the synthesis of 4′-(3 β-hydroxy-androst-5-ene-17 β-yl)-3′-pyrrolin-2′-one (6) starting from 3β-acetoxy-21-hydroxy-pregn-5-ene-20-one (1).     

Microbiological transformation of bicyclic monoterpenes by Absidia orchidis (Vuill.) Hagem. 2. Hydroxylation of fenchone and isofenchone. 18. Section on reactions with microorganisms

(+)-Fenchone ( 3a ) was transformed to 6-exo-hydroxy-fenchone (6β-hydroxy-1, 3, 3-trimethyl-nor-bornan-2-one) ( 1a ) and to 5-exo-hydroxy-fenchone 5β-hydroxy-1, 3, 3-trimethyl-nor-bornan-2-one ( 4a ) by the mycelium of Absidia orchidis (Vuill.) Hagem. The structure of the two products was proven by a detailed analysis of the NMR. spectra of the corresponding acetyl derivatives 2a and 5a respectively, and by CrO₃-oxidation. 1a yielded the β-diketone 6a , and 4a the diketone 8a. Whereas 8a was stable to alkali 6a was cleaved to the cyclopentane carboxylic acids 7 and 9 . — Incubation of (—)-fenchone ( 3b ) yielded the enantiomeric hydroxylation products 1b and 4b in the same ratio. - (—)-Isofenchone ( 11a ) was transformed by Absidia orchidis into the two epimers 6-endo-hydroxy-isofenchone (6β-hydroxy-1, 5, 5-trimethyl-nor-bornan-2-one) ( 12a ) and 6-exo-hydroxy-isofenchone (6β-hydroxy-1, 5, 5-trimethyl-nor-bornan-2-one) ( 10a. ) CrO₃-oxidation of both 10a and 12a gave the same β-diketone 6a. - (+)-Isofenchone gave the corresponding enantiomeric hydroxy derivatives 10b and 12b on incubation with Absidia orchidis.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid and β-heteroarylamino-α-amino acid derivatives

From heteroarylaminomethyleneoxazolones 4 , obtained from N-heteroarylformamidines 2 and 2-phenyl-5-oxo-4,5-dihydro-1,3-oxazole ( 3 ), the following β-heteroarylamino-α,β-dehydro-α-amino acid derivatives were prepared: methyl 8 and ethyl esters 9 , amides 10 and 11 , hydrazides 12 , and azides 15 . By catalytic hydrogenation the compounds 4 were converted into β-heteroarylamino substituted amides 18 and β-heteroarylamino-α-amino acids 20 .     

Unusual synthesis of azines and their oxidative degradation to carboxylic acid using iodobenzene diacetate

Reaction of 3-hydrazonobutan-2-one oxime with aromatic aldehydes resulted in the formation of 1,2-bis(arylidene)hydrazine commonly referred as azine as an unexpected product, instead of expected product 3-(aryl)methylenehydrazonobutan-2-one oxime, which were subsequently oxidized to corresponding aromatic acids with an ecofriendly oxidizing agent iodobenzene diacetate. Azines and carboxylic acids were characterized by IR and NMR (¹H, ¹³C, HMBC, and HMQC) studies.     

A ceric ammonium nitrate based oxidative cleavage pathway for the asymmetric aldol adducts of oxadiazinones derived from (1R,2S)-N-p-methoxybenzylnorephedrine

An N₄-p-methoxybenzyloxadiazinone has been prepared from (1R,2S)-norephedrine through a process of reductive amination, N-nitrosation, reduction, and cyclization. The oxadiazinone was acylated and employed in the asymmetric aldol addition reaction with aromatic and aliphatic aldehydes to yield aldol adducts in isolated yields ranging from 54% to 90%. Selected aldol adducts were treated with ceric ammonium nitrate in aqueous acetonitrile to afford the desired β-hydroxycarboxylic acids through a tandem process of oxidative cleavage of the N₄-p-methoxybenzyl group and acidic hydrolysis of the N₃-acyl side chain. The β-hydroxycarboxylic acids were recovered in high diastereomeric purity as determined by 500 MHz ¹H NMR spectroscopy and the absolute configuration was confirmed by polarimetry. The chiral auxiliary unit, the 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone), was converted into its corresponding 3,6-dihydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone) through an oxidative pathway promoted by the ceric ammonium nitrate.     

Friedel-crafts cyclisation—IV: Intramolecular vs intermolecular acylation with β-aryl derivatives of propionyl chloride in aromatic substrates

Studies on the aluminium chloride-catalysed behaviour of β-phenylpropionyl, β,β-diphenylpropionyl, and β,β,β-triphenylpropionyl chlorides in anisole and some other aromatic stubstrates under standardised conditions are discussed. β,β-Diphenylpropionyl chloride gave yields of up to 27% 3-phenylindan-1-one in anisole and is one of the most easily cyclised acid chlorides so far reported. β,β,β-Triphenylpropionyl is less easily cyclised in anisole to 3,3-diphenylindan-1-one and its transformation product 2,3-diphenylind-1-one. The expected open-chain ketone is completely decomposed into products of αβ-ketonic cleavage and a subsequent redox reaction. Differences in ratios of intermolecular to intramolecular acylation (now called o/c ratios) are discussed.In benzene, β-bis-(p-chlorophenyl)propionyl chloride gave, in addition to the previously noted β-bis-(p-chlorophenyl)propiophenone (48%), the folloowing compounds: 6-chloro-3-(p-chlorophenyl)indan-1-one (4%) (the intramolecular acylation product), β-(p-chlorophenyl)-β-phenylpropiophenone (2·3%), ββ-diphenylpropiophenone (0·5%), 3-(p-chlorophenyl)-indan-1-one (5·2%). The transformation processes are discussed. Aluminium chloride-catalysed β-aryl exchange in acid chlorides is reported for the first time, but β-aryl exchange does not occur in ββ-(or 3,3-)di-aryl derivatives of indan-1-one.     

Uncommon expansion of piperidine ring into hydroazocine ring in reactions of some piperidine β-acyl derivatives with acetylenecarboxylic acids esters

Cyclohexanone condensation with formaldehyde and methylamine led to the formation of 4ahydroxy-2-methyloctahydrospiro[isoquinoline-4,1'-cyclohexan]-2'-one whose structure was established by means of X-ray diffraction (XRD) analysis. This spiro compound reacted with acetylenecarboxylic acids esters with unexpected conversion of its piperidine ring into a hexahydroazocine cycle. The uncommon expansion reaction of the β-acyl-substituted piperidine ring into a hexahydroazocine cycle is confirmed by the analogous conversion of 4-hydroxy-1-methyl-4-phenylpiperidin-3-yl(phenyl)methanone into azocine derivative at treating with methyl propiolate.     

Mimicry of peptide backbone geometry and heteroatomic side-chain functionality: synthesis of enantiopure indolizidin-2-one amino acids possessing alcohol, acid, and azide functional groups

Indolizidinone amino acids possessing various heteroatomic side chains at their 5- and 7-positions have been synthesized through modification of hydroxymethyl indolizidinone amino acids 5 and 6. Displacements of the methanesulfonates from alcohols 5 and 6 with sodium azide, as well as oxidation of alcohol 5, have been used to furnish orthogonally protected indolizidin-2-one diamino carboxylates 7 and 8, and indolizidin-2-one amino dicarboxylate 9. Both 5- and 7-hydroxymethylindolizidinone amino acids 5 and 6 were obtained from sequences commencing with the Claisen condensation of alpha-tert-butyl gamma-methyl l-N-(PhF)-L-glutamate to furnish di-tert-butyl 4-carbomethoxy-5-oxo-2,8-di-[N-(PhF)amino]azelate 10 (PhF = 9-(9-phenylfluorenyl)). Subsequent hydride reduction of 10 to an isomeric mixture of diols 12, selective protection of the primary alcohol as tert-butyldimethylsilyl ether 14 and oxidation of the secondary alcohol gave di-tert-butyl 4-tert-butyldimethylsilyloxymethyl-5-oxo-2,8-di-[N-(PhF)amino]azelate 15 as a separable diastereomeric mixture. Linear ketone 15 and alcohol 14 were then converted to the indolizidinone heterocycles by routes featuring reductive aminations, methanesulfonate displacements, and lactam cyclizations. A series of rigid scaffolds designed to mimic the conformations of dipeptides possessing serine, lysine, and glutamate residues has thus been synthesized by this new route for installing heteroatomic side-chain functional groups onto the indolizidin-2-one system.     

Synthesis and aminomethylation of some heterocyclic α-nitroxyalkyl NH acids

The recently discovered synthetic route to quaternary ammonium salts of a new series via N-aminometylation of 4,4-bis(nitroxymethyl)oxazolidin-2-one was extended to other NH acids obtained for the first time by O-nitration of known a-hydroxyalkyl derivatives of 4-methyloxazolidin-2-one, pyrrolidin-2-one, and benzimidazole. In the aminomethylation of these NH acids, dimethylamine and morpholine were used as the amine components.     

Investigation of phenanthridone and dioxotetrahydrodiazapyrene. 3. Investigation of the nitration of 5H-phenanthridin-6-one and its derivatives

The nitration of 5H-phenanthridin-6-one (I), 5H-phenanthridin-6-one-10-carboxylic (II) and 5H-phenanthridin-6-one-1-carboxylic acids (III), 4H-cyclopenta[k,l,m]-phenanthridine-5,9-dione (IV), 4H-cyclopenta[k,l,m]phenanthridine-5-one (V), 5,10-dioxo-4,5,9,10-tetrahydro-4,9-diazapyrene (VI), and 5,9-dioxo-4,5,9,10-tetrahydro-4,10-diazapyrene (VII) with nitric acid (sp. gr. 1.42–1.51) and a nitrating mixture of 0–120 °C was investigated. The orientation and sequence of incorporation of nitro groups in I-VII are determined by the presence of a phenanthridone structure in them. Mono-, di-, tri-, and tetranitro-substituted I-VII were obtained and characterized.See [l] for Communication 2.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 388–393, March, 1981.