Aminolysis of α-hydroxy acid esters with α-amino acid salts; first step in the synthesis of optically active 2,5-morpholinediones

A process for preparing optically active 2,5-morpholinediones 1 is described starting from optically active α-amino acids and optically active α-hydroxy esters. The process involves three steps: In the first step the sodium salt of an α-amino acid is condensed with an α-hydroxy ester to yield an optically active N-(α-hydroxy acyl)-α-amino acid 4 . In the second step the hydroxy acid obtained is subjected to esterification with ethanol. In the third step the N-(α-hydroxy acyl)-α-amino acid ethyl ester 5 is subjected to cyclization with an acidic catalyst. For some examples the cyclization was also performed directly from the hydroxy acid 4 . Morpholinediones 1 are useful as precursors for the preparation of poly(depsipeptides) 2 and copolymers containing depsipeptide repeating units.     

Polymerization reaction with diphenylphosphoryl azide. Preparation of poly(α-amino acid)s by direct polycondensation of α-amino acids

Polypeptides can be prepared by stirring an amino acid solution in the presence of diphenylphosphoryl azide (DPPA) and an adequate tertiary amine. Generally, 1,3 mol of DPPA and 2,3 mol of triethylamine per mol of amino acid gave the best result. Polymerization of various amino acids (Gly, Ala, Leu, Phe, Met, Glu(OBzl), Glu(OMe), Cys(Bzl), Ser(Bzl), His(Bzl), Lys(Z), Arg(Tos), Arg(NO₂), Arg(Mts), etc.; cf. Tab. 2) in dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, pyridine, etc. gave the corresponding polypeptides with molecular weights as estimated from their intrinsic viscosities between 3 000 and 16 000, in reasonable yields. The purity of the resulting polypeptides was confirmed by IR, elemental analysis and optical rotation measurements of their acid total hydrolysates.     

Copolymerization of N-carboxy-α-amino acid anhydrides by organometallic compounds

During thermal degradation of poly(vinyl chloride) in a nitrogen atmosphere polyene sequences of different lengths are formed by dehydrochlorination. The distribution of the sequence lengths in the polymer is approximated by analysis of the electron spectra, and the spectroscopically determined polyene content is compared with the amount of hydrogen chloride split off. With increasing temperature, as well as with increasing time of degradation, the distribution of the polyene sequence lengths shifts towards shorter sequences. In contrast to degraded poly(vinyl chloride) powder, degraded poly(vinyl chloride) foils exhibit a marked shift towards longer sequences. Vinylisobutyl ether as comonomer unit in the polymer chains effects a considerable shift of the sequence lengths distribution towards shorter polyene sequences. The spectroscopically determined polyene content agrees with the amount of liberated hydrogen chloride only a t very low conversions while with increasing dehydrochlorination a growing polyene deficit is found. Therefore, it is to be concluded that polyene sequences are consumed by consecutive reactions in which primarily the longer polyene sequences are involved. A further conclusion that may be drawn from these experiments is that the formation of long polyene sequences takes place very rapidly once the initial step of dehydrochlorination has occurred at a labile site. Apart from the above mentioned consecutive reactions, only the number, not the average length, of the polyene sequences changes substantially with increasing time of degradation.     

Conformation and gas permeability of poly(α-amino acid) membranes

The permeability of some poly(?-amino acid) (PAA) membranes like such of poly(N,δ-carbobenzoxy-L -lysine) (PCBL), poly(N,δ-carbobenzoxy-L -ornithine) (PCBO) as well as of copolymers of L -lysine and carbobenzoxy-L -lysine to oxygen and carbon dioxide were determined at different water content especially with regard to their use for artificial lungs. The conformations of these polymer membranes were studied by means of IR-spectra and X-ray diffraction. The results on the diffusion coefficient obtained for PCBL and PCBO were analysed in terms of Eyring's theory. They suggest that the microvoids in the interstices between the α-helices, assumed on the basis of X-ray analyses, play an important role, especially below the glass transition temperature T_g of the side-chains. This seems also to contribute partly to the diffusion of gas through the membrane even above T_g and results in an abnormally high “apparent activation energy” of diffusion in the wet state below T_g. It was found that the permeability of the membrane of partially decarbobenzoxylated PCBL for oxygen in a certain temperature range is higher than that for carbon dioxide. This has never been observed for any other synthetic polymer, because usually carbon dioxide has a higher solubility in these materials than oxygen. In the case of the partially decarbobenzoxylated PCBL membranes, however, the diffusion coefficient of carbon dioxide, and therefore the permeation of this gas, decreases much more than that of oxygen with increasing decarbobenzoxylation accompanied by the formation of β-structure and concomitantly the formation of intermolecular hydrogen bonds. Obviously, this phenomenon may be responsible for the permselectivity of these membranes for oxygen compared with carbon dioxide.     

Vinyl polymerization by metal complexes. VI. On the initiation mechanism of vinyl polymerization by the α-amino acid ester/copper(II) system

Polymerization of acrylonitrile and methyl methacrylate was studied in the presence of an α-amino acid ester and copper(II) ion in dimethyl sulfoxide solution. The initiation mechanism of the polymerization by the α-amino acid ester/copper(II) system was refered to the complex forming properties of the system, confirmed by spectroscopic measurements. The polymerization of both monomers was influenced by the kind of the α-alkyl group of the α-amino acid esters, but it was not affected by the kind of the ester groups. The carboxylic group of the esters was found to affect only the polymerization of methyl methacrylate. Based on the results, the character of the free radicals was discussed.     

Polymerization of β-propiolactones by nickel carboxylate/tributylphosphine complexes

The kinetics of polymerization of β-lactones — β-propiolactone, α-ethyl-α-phenyl- and α-benzyl-α-ethyl-β-propiolactone — was investigated using nickel carboxylate/phosphine complexes as initiators. The apparent rate constants of initiation and propagation, k_i and k_p, were calculated assuming first order kinetics. The variations of k_i values with monomer concentration suggest that the mechanism is more complex, with a reaction order which is not as admitted for calculation. The infrared study has shown that the polymerization initiated by the complex is of zwitterionic type, and the kinetic curves indicate that the nickel carboxylate participates in the reaction.     

Optically active polyamides with regular structural sequences prepared froni α-amino acid

Optically active polyamides with regular structural sequences have been prepared from L-lysine and adipic acid. A novel optically active symmetrical diamine, N.N'-bis(L-5-amino-5-carboxyl-amyl)adipamide, was obtained by treating L-lysine with adipyl chloride in the presence of copper(II) ions. The interfacial polycondensation of this diamine with adipyl chloride afforded a regular polymer, while the polycondensation of L-lysine with adipyl chloride gave an irregular polymer of the same analytical composition. The melting points, optical rotations and the optical rotatory dispersions of these polymers were investigated.     

Copolymerization of N-carboxy-α-amino acid anhydride with propylene oxide

The copolymerization of N-carboxy-L(+)-alanine anhydride (L(+)-alanine NCA) with DL-propylene oxide was examined using diethylzinc or triethylaluminum as catalysts. Analytical data, IR and NMR-spectra indicate that dioxane soluble copolymers contain various kinds of linkage such as amide, ester, ether, and urethane in their polymer chains. Optical rotatory dispersion curves of the copolymers measured in benzene or chloroform were analyzed in terms of the one term DRUDE equation and of the MOFFITT-YANG equation. The copolymerization of L(-)-β-phenylallanine NCA with DL-propylene oxide was also examined. The sign of the optical rotation of the copolymer prepared with diethylzinc catalyst was opposite to that of the copolymer prepared with triethylaluminum.     

Coordination polymers of β-hydroxy-γ-amino schiff bases

Ligands 3a–d (N,N-disubstituted 2,2′-dihydroxy-3,3′-[1,4-phenylenebis(methylenenitrilo)]-dipropaneamines) for the preparation of the coordination polymers of Ag(I), Cu(II), Zn(II), and Ti(IV) were synthesized by condensation of terephthalaldehyde ( 2 ) with the N,N-substituted 2-hydroxy-1,3-propanediamines ( 1a–d ). The copper and zinc coordination polymers were found to be compatible with polyethylene. Their blends could be processed by injection molding or extrusion. The thermal stability of the polymers was found to increase in the order Cu- <Ag- <Ti- <Zn-derivatives. The electronic, IR, and ESR spectra of the copper coordination compounds were measured and the mechanism of formation of the coordination polymers is discussed. The polymers were found to be semi-conductive, their electric resistivity being in the range of 10³ ? Ω·cm. The temperature dependence of the conductivity yielded activation energies in the range of 26 ?106 kJ·mol^?1. Both electronic and ionic conductance may contribute to the semiconductive properties of these coordination polymers.     

Asymmetric synthesis catalyzed by poly(α-amino acid)s with a tertiary amino end group

Poly(α-amino acid)s having a 2-(dimethylamino)ethylamido group at the carboxyl end were synthesized, and their catalytic activity in the asymmetric addition of 1-dodecanethiol to isopropenyl methyl ketone was examined. By using monomeric derivatives, an optical yield of 11–31% was obtained, while polymeric catalysts gave much lower optical yield. The role of the conformation of the polymer catalysts is discussed.     

Polymerization of methyl methacrylate in the presence of poly(α-amino acid)s

The polymerization of methyl methacrylate (MMA) was studied in the presence of poly(α-amino acid)s, water, and copper(II) ion. It was found that the polymerization behaviour depends very much on the conformation of the poly(α-amino acid) in the system. If the poly(α-amino acid) had the α-helix conformation, the polymerization of MMA did not occur. This is supposed to be due to the stability of the intramolecular hydrogen bond in the α-helix, which is too high to form a chelate complex between the copper ion and the polypeptide together with the MMA monomer and water. When the same polypeptides took a random coil conformation, however, the polymerization occurred, although to a small extent. Furthermore, when the polypeptide with the β-conformation was used, the polymerization of MMA occured to a higher extent than in the case of the polypeptide with the random coil conformation. Therefore, it was concluded that the delocalization of electrons in the copper ion to the neighbouring atoms plays an important rǒle in the initiation of the polymerization of MMA. It was also found that the size of the nonpolar side chain of the initiating polypeptides affects the polymerization of MMA. Since this polymerization is carried out in water, the hydrophobic bonds between the nonpolar side chain of the polypeptide and the MMA monomer may also play an important rǒle.     

Synthesis of poly(α-malic acid) and its hydrolysis behavior in vitro

Biodegradable poly(α-malic acid) ( 7 ) was synthesized by means of ring-opening homopolymerization of malide dibenzyl ester ( 5 ), which is a cyclic dimer of β-benzyl malate. In order to obtain a high-molecular-weight biodegradable lactic acid type polyester having pendent modifiable groups, ring-opening copolymerization of malide dibenzyl ester with L -dilactide was applied to give poly(α-malic acid-co-lactic acid) ( 10 ). It was found from the results of hydrolysis of poly(α-malic acid) that the main-chain ester bonds were cleaved randomly and slowly in vitro.     

The production of 3aα-H-4α-(3′-propionic acid)-5α-hydroxy-7aβ-methylhexahydro-1-indanone-δ-lactone by Nocardia restricta mutants

Two mutants of Nocardia restricta breakdown androst-4-ene-3,17-dione into 3aα-H-4α-(3′-propionic acid)-5α-hydroxy-7aβ-methylhexahydro-l-indanone-δ-lactone. The metabolic intermediates formed are very different in each mutant. One uses certain aromatic compounds very slowly. A degradation pathway for steroids by Nocardia restricta has been proposed.     

Enantioselective hydro-oligomerization (protio- or deuterio-) of α-olefins

The enantioselective protio(deuterio)oligomerization of propene, 1-pentene and 4-methyl-1-pentene was carried out with the diastereomerically pure catalyst precursor (?)-(R)-ethylenebis [1–3a,7a-η-(4,5,6,7-tetrahydro-1-indenyl)]zirconium (S)-1,1′-bis-2-naphtholate ( 3 ) and/or with (?)-(R)-ethylene [1–3a,7a-η-bis(4,5,6,7-tetrahydro-1-indenyl]dimethylzirconium ( 1 ) in the presence of methylalumoxanes. The enantioselectivity of both reactions which take place (deuteration and oligomerization) is from fair to high and essentially independent of the catalyst precursor. In the hydrooligomerization the enantioface of the olefinic monomer which prevailingly reacts is from a geometric point of view the same for all three substrates. In the case of 1-pentene and 4-methyl-1-pentene the enantioface prevailing embedded in the oligomers is opposite to that prevailingly deuterated. The significance of the growing chain for enantioface selection during stereospecific polymerization is thus emphasized.     

Comparative analysis of αβ and γδ T cell activation by Mycobacterium tuberculosis and isopentenyl pyrophosphate

Phosphorylated nonpeptide compounds have recently been identified as potent mycobacteria-derived ligands for human Vγ9/Vδ2-expressing γδ T cells. Crude mycobacterial extracts also contain protein antigens which stimulate CD4 αβ T cells to produce growth factors that are used by γδ T cells for clonal expansion. We have investigated the dynamics in vitro of expansion of CD4 T cells and Vγ9 cells in cultures of peripheral blood mononuclear cells stimulated with synthetic isopentenyl pyrophosphate (IPP) in the absence or presence of additional stimuli. The results indicated that following stimulation with IPP, γδ T cells express CD25 and CD69 antigens, but fail to proliferate unless growth factors are provided exogenously or endogenously through activation of CD4 T cells by additional stimuli such as tetanus toxoid, alloantigen, or superantigens. Furthermore, the presence of antigen presenting cells are required for expansion of γδ T cells. In response to IPP stimulation, purified CD4 T cells neither express CD25 or CD69, nor do they proliferate even in the presence of exogenous IL-2. Apart from IL-2, IL-15 and, less efficiently, IL-4, IL-7, and IL-12 can contribute to cellular expansion of IPP-reactive Vγ9 cells. Together, the results demonstrate that peripheral blood γδ T cells proliferate in response to IPP only if CD4 T cells are simultaneously activated by an additional stimulus. This mechanism provides a tight control of the reactivity of γδ T cells towards phosphorylated nonpeptide antigens.     

Enzyme-analogue built polymers, 25. Synthesis of macroporous copolymers from α-amino acid based vinyl compounds

The suitability of a variety of newly prepared polymerizable a-amino acid derivatives for the preparation of template-imprinted polymers was investigated. The polymerizable binding sites were attached to the α-amino acid template via azomethine, carboxylic ester or boronic ester linkages. Macroporous polymers containing these monomers were prepared. The extent to which the templates could be split off from the polymer, the degree of racemization of the a-amino acids during polymerization and cleavage as well as the degree of rebinding to the polymers were studied.     

13C NMR sequence analysis, 15. Copolymerization of alanine-NCA with other α-amino acid NCAs

Alanine-N-carboxylic acid anhydride (Ala-NCA) was copolymerized with glycine-NCA, phenylalanine-NCA, valine-NCA, leucine-NCA, and sarcosine-NCA in various solvents and with various catalysts; 22,6 MHz ¹³C NMR spectra and 90 MHz ¹H NMR spectra of the resulting copolypeptides were measured in trifluoroacetic acid and from the signal intensities the rate of incorporation was estimated. The copolypeptides poly(Ala/Gly) and poly(Ala/Phe) contained both monomeric units in an almost equal concentration, while the low reactivity of Val-NCA and Leu-NCA resulted in a lower concentration of these residues compared with Ala in poly(Ala/Val) and poly(Ala/Leu). The ¹³C NMR spectra of poly(Ala/Gly) exhibit four CO-signals which could be assigned by comparison with the corresponding homopolypeptides and with the sequence polypeptides (Ala-Ala-Gly-Gly)_n, and (Ala-Gly-Gly)_n. From the intensities of these CO-signals the average length of the homogeneous blocks was calculated. Both block lengths and rate of incorporation proved to be almost independent of solvent, catalyst, and reaction temperature. Poly(Ala/Phe) and poly(Ala/Sar) show also four CO-signals, but poly(Ala/Val) only two and poly(Ala/Leu) one. The number and shape of the CO-signals allow one to decide whether random copolypeptides were obtained or not.