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 .     

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 ).     

Asymmetric total synthesis of sperabillins B and D via lithium amide conjugate addition

Diastereoselective conjugate addition of homochiral lithium (R)-N-allyl-N-alpha-methylbenzylamide to methyl (2E,5E)-hepatadienoate, followed by protecting group manipulation and subsequent iodocyclocarbamation allows a concise route to the core fragment, methyl (3R,5R,6R)-3,6-diamino-5-hydroxyheptanoate, of sperabillins B and D. Differentiation between the C-3 and C-6 primary amino groups of this core amino acid was readily achieved by treatment with acetone, giving the 5,6-isopropylidene and C-3-imine protected diamine, with subsequent regioselective acylation of the C-6-nitrogen facilitating the total synthesis of sperabillin D in 10.8% overall yield, and the first asymmetric synthesis of sperabillin B in 5.8% overall yield.     

Transformations of isomeric naphthopyranones. The synthesis of substituted β-naphthyl-α,β-dehydro-α-amino acid derivatives

The opening of the pyranone ring in 2H-naphtho[1,2-b]pyran-2-one derivative (1) and 3H-naphtho[2,1-b]-pyran-3-one derivatives 8 and 20 with nucleophiles afforded 3-(naphthyl-1)- and 3-(naphthyl-2)propenoates (substituted β-naphthyl-α,β-dehydro-α-amino acid derivatives) 7, 13, 14, 15, 24 , and 35 .     

Total asymmetric synthesis of sperabillins B and D

A concise route to the core fragment of sperabillins B and D, methyl (3R,5R,6R)-3,6-diamino-5-hydroxyheptanoate, has been developed with a subsequent novel protection strategy allowing the total asymmetric synthesis of sperabillins B and D.     

Regioselective synthesis of 3-hydroxyisoxazoles and 5-isoxazolones from β-amino α,β-unsaturated esters

The regioselective synthesis of 3-hydroxyisoxazoles and 5-isoxazolones is accomplished by the reaction of β-amino α,β-unsaturated esters with hydroxylamine hydrochloride in the presence of appropriate bases. The total yield of isoxazole derivatives is sensitively influenced on the β-substituent group of the esters.     

Room-temperature polycondensation of β-amino acid derivatives. V. Synthesis of hydrophilic polyamide by the polycondensation of β-amino acid derivatives

N-(Hydroxyalkyl) β-alanine ester which was obtained from amino alcohol and acrylate yielded polyamide at room temperature in the presence of a basic catalyst. Alkali and alkali earth metal alkoxides had a strong catalytic effect on the room-temperature polycondensation of N-(hydroxyethyl)-β-alanine esters. The catalytic activity of metal alkoxides decreased in the order: Li > Na > K > Cs and Ca > Zn > Mg. Aluminum and titanium alkoxide had a weak catalytic effect, while boron (III), tin (IV), antimony (V), and tellurium (VI) alkoxides did not show any catalytic activity for the polycondensation. It was also found that solvent had an effect on the course of the polycondensation of N-(hydroxyethyl)-β-alanine esters, and the highest molecular weight polymer was formed only in methanol solution. The solid-phase polycondensation of the low molecular weight prepolymer resulted in a high molecular weight polymer with an inherent viscosity of 1.0 in the presence of a catalytic amount of phosphoric acid. The polymer obtained is hydrophilic and its moisture absorption is more than twice that of nylon 6.     

Asymmetric Mannich reactions catalyzed by cinchona alkaloid thiourea: enantioselective one-pot synthesis of novel β-amino ester derivatives

An efficient one-pot synthesis of novel β-amino ester derivatives containing a benzoxazol moiety has been developed by using cinchona alkaloid thioureas as the organocatalyst. The adducts were isolated in high enantiomeric excess and high yield.     

Room-temperature polycondensation of β-amino acid derivatives,I. Polyamide from amino alcohols and acrylates

Acrylates, such as ethyl acrylate, add with amino alcohol to form N-(hydroxyalkyl) β-alanine ester and room-temperature polycondensation follows, forming polyamide in the presence of a basic catalysts, such as alkali metal alkoxide. The reaction medium has an influence on the course of the polycondensation; that is, N-(hydroxyalkyl) polyamide is formed in methanol solution and polyamide ether in other solvents, such as tetrahydrofuran. These two courses of the room-temperature polycondensation have been studied, and the reaction mechanism is discussed in this paper.     

Transformations of N-heteroarylformamidines into derivatives of β-heteroarylamino-α,β-dehydro-α-amino acids, β-heteroarylamino-α-amino acids,and dipeptides

Transformations of N'-heteroaryl-N,N-dimethylformamidines 1 as a general method for the preparation of β-heteroarylamino-α,β-dehydro-α-amino acids, β-heteroarylamino-α-amino acid derivatives 5–9 , and dipeptides 10 , are described.     

A highly stereoselective synthesis of α,β-unsaturated oxazolines

Lithiated 2,4,4-trimethyl-2-oxazoline 2a and 2-chloromethyl-4,4-dimethyl-2-oxazoline 2b react smoothly with a number of nitrones 3 to produce α,β-unsaturated oxazolines 6 and 7 highly stereoselectively.     

Highly stereocontrolled boron-mediated synthesis of β-hydroxy-α-amino acids and dipeptides. Part 2

The chiral synthons 1(a–d) were submitted to boron-mediated asymmetric aldol condensation with acetaldehyde and benzaldehyde providing, in high diastereomeric excess (>95%), R,R-configured aldols 2(a–f) which are useful intermediates to enantiomerically pure β-hydroxy-α-amino acids.     

An efficient new enzymatic method for the preparation of β-aryl-β-amino acid enantiomers

An efficient synthesis of β-aryl-β-amino acid enantiomers has been developed via the lipase-catalysed enantioselective hydrolysis of the corresponding racemic ethyl esters in an organic solvent. High enantioselectivities (E >100) were observed when the lipase PS-catalysed reactions were performed with H₂O (0.5 equiv) in diisopropyl ether at 45 °C. The products could be easily separated and were obtained in good yields of 40%.     

A totally stereocontrolled route to N-methyl-γ-amino-β-hydroxy acids: Asymmetric synthesis of the amino acid component of hapalosin

A new approach to the synthesis of N-methyl-γ-amino-β-hydroxy acids, compounds that are essential components of several depsipeptides exhibiting highly interesting therapeutic profiles, is presented. Relevant steps in the synthetic sequence involve the totally stereoselective preparation of a protected aminoalkyl epoxide from a highly enantiopure 2,3-epoxy alcohol, efficient N-methylation and three-step conversion to the desired N-methyl amino acid. The method is exemplified by the enantioselective synthesis of (3R,4S)-4-(N-methylamino)-3-hydroxy-5-phenylpentanoic acid in two differently protected forms.     

A Reinvestigation of the α-Alkylation of 4-Monosubstituted 2-phenyloxazol-5(4H)-ones (‘azlactones’): A general entry into highly functionalized α,α-disubstituted α-amino acids

Novel, more reliable and general reaction conditions for the α-alkylation of 4-monosubstituted 2-phenyloxazol-5(4H)-ones ( = 4-monosubstituted 2-phenyl-azlactones) rac- 2 to 4,4-disubstituted 2-phenyloxazol-5(4H)-ones rac- 1 were found (Scheme 2). Thus, a whole range of highly functionalized rac- 1 were prepared in medium-to-good overall yields (40-90%, see Table). Azlactones rac- 1 are ideal precursors for the synthesis of optically pure α,α -disubstituted (R)- and (S)-α-amino acids.     

Asymmetric synthesis of protected α-fluoroglycines

Single crystal x-ray structure determination of a key fluoroiodoacetamide gives access to protected α-fluoroglycines of known absolute stereochemistry.     

Multichain copoly(α-amino acid). III. Multichain copoly(α-amino acid) prepared by the reaction of copoly(L-lysine γ-methyl-L-glutamate) with N-carboxy anhydride of β-benzyl L-aspartate

Graft copolymerization of N-carboxy anhydride of β-benzyl-L -aspartate onto copoly(L -lysine γ-methyl-L -glutamate) was carried out in N,N-dimethylformaide which contained 3 v/v% of dimethyl sulfoxide to obtain multi-N^ε-poly(β-benzyl-L -aspartyl)copoly(L -lysine γ-methyl-L gluta mate). The degree of polymerization of the branch chain attained was much influenced by the interval of the grafting sites of the copoly(L -lysine γ-methyl-L -glutamate). The solvent-induced two-step conformational transition of the multichain copoly(α-amino acid) was observed in the chloroform-dichloroacetic acid system at 25°C by the ORD technique. The stability of the α-helical conformation of the backbone polymer chain was decreased by the presence of poly(β-benzyl-L -aspartyl) branch chains that could form unstable α-helical conformations of opposite spirals.     

Polymerization of α-amino acid N-carboxy anhydride. IX. Copolymerization of α-amino acid N-carboxy anhydride in heterogeneous system

Copolymerization of NCA's was undertaken in a heterogeneous system in acetonitrile, which is not a solvent of the polypeptides. The reactivity ratio was calculated by using the Lewis-Mayo equation. Further, the conversion rate in the copolymerization and the configuration of the copolymer produced were compared with those of the copolymerization in the homogeneous system in nitrobenzene, in which the copolypeptides are swollen. The rate of copolymerization in acetonitrile was between the rates of polymerization of the individual monomers. It has been reported that the configuration of the copolymer obtained in dimethylformamide, in which the copolypeptides are swollen, is of the block type. On the other hand, many polypeptides obtained in acetonitrile, which is not a solvent of the copolypeptides, had a random configuration near to an alternating configuration.     

Uncatalyzed, anti-Michael addition of amines to β-nitroacrylates: practical, eco-friendly synthesis of β-nitro-α-amino esters

A variety of primary and secondary amines give the conjugate reaction with β-nitroacrylates, via an anti-Michael addition, without any catalyst and/or solvent, allowing good yields of β-nitro-α-amino esters.