Stereochemistry of the D and L copolymerization of valine N-carboxyanhydride

In the D and L copolymerization of valine N-carboxyanhydride (NCA) with various D /L ratios initiated by n-butylamine, the stereoselection of monomer NCA by the growing polymer chains, which take a β-like conformation, does not take place. This result is in remarkable contrast to that in the D and L copolymerization of alanine NCA and of γ-benzyl glutamate NCA where the growing α-helical polymer chains participate in the stereoselection of the monomer antipodes.     

Polymerization of optical isomers of phenylalanine N-carboxyanhydride by poly(N-methylalanine) diethylamide

In the polymerization of phenylalanine N-carboxyanhydride (NCA) using poly(N-methyl-L -or DL -alanine) diethylamide as initiator, the polymerization rate was L -NCA ? D -NCA > DL -NCA. This is a new type of selective polymerization and indicates the incompleteness of earlier investigations to study the asymmetrically selective polymerization without D -NCA. Neither secondary structure nor optical activity of the polymeric initiator is a reason for the selectivity. Hence the cause for the selectivity was sought in the properties of the NCA's in solution. However, the selectivity was not observed in the polymerization initiated by poly(L -phenylalanine) dimethylamide. The importance of the initiator being a secondary amine type was suggested. The experimental results are discussed on the basis of these considerations.     

Polymerization of N-carboxyanhydrides of various α-amino acids using secondary amines as initiator

In the polymerizations of alanine, γ-ethyl glutamate, and leucine N-carboxyanhydrides (NCA's) initiated by tertiary amines and some secondary amines such as N-methyl-L -alanine dialkylamide, a stereoselectivity was observed: the polymerization rates of L - and D -NCA's were identical to each other and larger than that of DL -NCA. However, this selectivity was not observed in the polymerizations of valine and isoleucine NCA's initiated by N-methyl-L -alanine dialkylamide. The stereoselective polymerizations of valine and isoleucine NCA's were induced only with tetriary amines such as tri-n-butylamine. N-Methyl-L -alanine di-alkylamide has been shown to initiate the polymerization of usual α-amino acid NCA according to the activated-NCA mechanism, but it initiated the polymerizations of valine and isoleucine NCA's according to the primary amine-type mechanism. This is because in the latter NCA's the N–H group is masked by the adjacent C^β-branched alkyl substituent against the approach of the secondary amine. Poly(DL -alanine)s produced in the stereoselective polymerization had higher viscosities and were more stereoblock-like than those produced without the stereoselectivity. These experimental results indicate that the stereoselective polymerization is possible only when the polymerization proceeds through the activated-NCA mechanism.     

Polymerization of optical isomers of phenylalanine N-carboxyanhydride by various secondary amines

In the polymerization of phenylalanine NCA initiated by some secondary amines, the two enatimorphs of phenylalanine NCA were polymerized with the same rate, which was almost twice as high, as that found for the racemic mixture. This stereoselectivity was observed only when the polymerization was initiated by secondary amines which are sterically crowded and reluctant to undergo a nucleophilic addition to NCA. Poly(DL -phenylalanine) produced in the stereoselective polymerization had a higher molecular weight than that produced in nonstereoselective polymerization. These findings point to the possibility that the stereoselectivity arises only in those polymerizations which are propagated by the activated monomers and not in the propagation involving the terminal amine of the growing polymer. A possible mechanism for the stereoselective polymerization is proposed and examined.     

Polymerization of amino acid derivatives by polymer catalysts. V. Polymerization of DL-β-phenylalanine N-carboxyanhydride by several poly(N-alkylamino acid) diethylamides

The polymerization of DL -β-phenylalanine N-carboxyanhydride (NCA) initiated by poly(N-benzylglycine)diethylamide (DEA) and poly(N-methyl-DL -alanine)DEA has been investigated. As previously reported, polysarcosine DEA, poly-N-ethylglycine DEA, and poly-N-n-propylglycine DEA showed marked accelerations in the polymerization of DL -β-phenylalanine NCA as compared with the polymerization initiated by low molecular weight, amines having similar base strength. However, this phenomenon (the chain effect) was not observed with the two polymer catalysts studied in the present investigation With poly-N-methyl-DL -alanine DEA, adsorption of DL -β-phenylalanine NCA onto the polymer chain takes place, though not so effectively as with other polypeptides, so the absence of chain effect was ascribed to a reduced flexibility of the polymer chain. With poly(N-benzylglycine)DEA, the reactivity of terminal base group was found to be much lower than that of other polymer catalysts. However, the absence of the chain effect would be attributed to the rigidity of polymer chain of poly-N-benzylglycine DEA due to the bulkiness of the N-benzyl group.     

Polymerization of L- and DL-phenylalanine N-carboxyanhydride by poly(N-methyl-L-alanine)

Polymerizations of L - and DL -phenylalanine N-carboxyanhydride in nitrobenzene by poly (N-methyl-L -alanine) of varying degrees of polymerization (n = 1–30) were investigated. Poly(N-methyl-L -alanine) was prepared by the polymerization of N-methyl-L -alanine NCA with N-methyl-L -alanine diethylamide and the degree of polymerization was controlled by the molar ratio [NCA]/[Catalyst] + 1. This polymer was shown to be an asymmetrically selective catalyst which polymerized L -phenylalanine NCA at a faster rate than DL -phenylalanine NCA. With increasing degree of polymerization the stability of the secondary structure of poly(N-methyl-L -alanine) increased. This was confirmed by circular dichroism spectra. However, the degree of asymmetric selection did not increase as the stability of the secondary structure of poly(N-methyl-L -alanine) increased. These findings indicate that the interaction of a growing polypeptide in an ordered structure with NCA molecules prior to the reaction does not lead to an asymmetric selection, and that the mechanism of the asymmetric selection by poly(N-methyl-L -alanine) should be different from those proposed so far.     

Enantiomer selection in the addition reaction of optically active 3-methyl-5-substituted hydantoins to N-[(S)-α-methylbenzyl]glycine N-Carboxyanhydride: Model Reaction for the Stereoselective Polymerization of α-amino acid N-carboxyanhydride

In order to investigate the contribution from the chiral penultimate unit to the enantiomer selection in the activated N-carboxyanhydride (NCA) polymerizations, the addition reaction to N-[(S)-methylbenzyl]glycine NCA of various α-amino acid hydantoins activated by the tertiary amines was investigated in different solvents. The reactions of activated Ala, Val, and Phe hydantoins were stereoselective and suggested the participation of the penultimate unit in the enantiomer selection of the activated NCA type of polymerization. The degree of enantiomer selection was not well correlated with the structure of hydantoins. Taking into account the dipole repulsion and the orbital overlapping between the reaction species, the transition-state model was proposed, which gave a good explanation of the selectivity for (R)-hydantoin in PhNO₂ and CH₃CN and the selectivity for (S)-hydantoin in AcNMe₂ and HCONMe₂. In these two types of solvents the orientation of the methylbenzyl group with respect to the NCA ring is so different that the direction of the approach of the activated hydantoin to the NCA is different. This difference leads to the inversion of enantiomer selection in amide solvents and in others. Cationic species derived from tertiary amines and the chiral amide compound were found to affect the enantiomer selection in the model reaction. The implications of these findings with regard to enantiomer selection in the activated NCA type of polymerization are discussed.     

Polymerization of DL-phenylalanine NCA initiated by copolymer of sarcosine and DL-phenylalanine

Polymerizations of DL -phenylalanine NCA by block copolymers of sarcosine and DL -phenylalanine, designated by (Phe)_m(Sar)n and capable of reaction at the phenylalanyl terminal, were investigated in nitrobenzene solution at 25°C. With increasing n for constant m (m = 0, 1, 2, and 5), the polymerization rate greatly increased. Previously the acceleration of the initiation reaction in the polymerization of DL -phenylalanine NCA by polysarcosine (m = 0) was reported. The present results showing the acceleration by the copolymers of sarcosine and DL -phenylalanine indicate the presence of the polymer effect in the propagation reaction as well. However, the polymer effect was most marked with polysarcosine (m = 0), and decreased with increasing m. The same polymerizations by sequential copolymers composed of ten sarcosine units and two DL -phenylalanine units were also investigated. Again with these copolymer catalysts the polymerization rate was larger than that by monomeric amines. But the polymer effect decreased sharply when the phenylalanine units take positions near the terminal amine group of the copolymer catalyst. These two deteriorating effects of the phenylalanine unit have been interpreted in terms of the decrease of the flexibility of polymer chain, caused possibly by an intramolecular hydrogen bond of the phenylalanine unit.     

Contribution from the chirality of the growing chain to the enantiomer selectivity in activated-NCA polymerization of α-amino acid N-carboxyanhydride

As a model compound for the growing chain in the activated-NCA type of polymerization of α-amino acid N-carboxyanhydride (NCA), 3-[ω-acetylglycyl-poly(α-amino acid) acyl]-α-amino acid NCA (called the prepolymer) having various degrees of polymerization (DPs) was synthesized by the polymerization of Phe, Val, Glu(OEt), and Asp(OBzl) NCA in the presence of AcGly NCA by the tertiary amine. Activated (S)-Phe, Val, Glu(OEt), and Asp(OBzl) NCA were added to the terminal cyclic group of the corresponding (S)- or (R)- prepolymer, and the enantiomer selectivity in the reaction was investigated. With prepolymers having DPs ranging from 1 to 15, the addition reaction always took place preferentially between species having the same configuration, and the degree of the enantiomer selection increased with increasing DP of the prepolymer. With prepolymers having DP = 1 and 2, we found contributions from the chiral terminal unit and the chiral penultimate unit to the enantiomer selection, respectively. Prepolymer having DP = 5 was shown to take a β-type conformation, which led to higher enantiomer selection; and prepolymers having DP = 10 and 15 were shown to take an α-helix conformation, which led to much higher enantiomer selection than did the β-type conformation. In the present investigation the mechanisms of terminal-unit control, penultimate-unit control and conformational control of the enantiomer selection in the activated-NCA type of polymerization were clearly observed.     

Asymmetric selection in the copolymerization of N-carboxyl-L- and D-alanine anhydride

The copolymerization of N-carboxy-L - and D -alanine anhydride with methanol as initiator was carried out. The enantiomer excess in the starting monomer mixture is preferentially incorporated into polymer chains, demonstrating asymmetric selection during the D - and L -copolymerization. The mechanism of asymmetric-selective polymerization of α-amino acid NCA is discussed in terms of the stereoregulation by molecular asymmetry of the growing polymer chain.     

Stereoselectivity in the nucleophilic addition-type polymerization of α-amino acid N-caboxyanhydride initiated by diastereomeric dipeptide amines

In order to investigate the effect of the chiral penultimate unit on the stereoselection of α-amino acid N-carboxyanhydride (NCA) by the terminal unit of a growing chain in the nucleophilic addition-type polymerization, the diastereomers of dipeptide amines, H-(R)-Phe-(S)-Phe-Mo and H-(S)-Phe-(S)-Phe-Mo, in which Mo represents a morpholine residue, were synthesized, and the stereoselectivity in their nucleophilic addition reactions to NCA was investigated and compared with that of a monopeptide amine H-(S)-Phe-OEt. In the reaction with Phe NCA in nitrobenzene, either of the dipeptide amines reacted preferentially with an enantiomer of NCAs having a configuration opposite to the N-terminal unit of the dipeptide amine. The preference of enantiomeric NCA and the extent of stereoselectivity were nearly the same as those found with H-(S)-PheOEt. The opposite-enantiomer selectivity of the dipeptide amines was also observed in the reaction with N-MePhe NCA, and the extent of stereoselectivity was found to increase very much in the reaction of H-(R)-PHe-(S)-Phe-Mo compared with that of H-(S)-Phe-OEt. Therefore, the enhancement of the stereoselectivity of the N-terminal unit by the penultimate unit was shown experimentally. On the other hand, the stereoselectivity of H-(S)-Phe-(S)-Phe-Mo was not very different from that of H-(S)-Phe-OEt. These results were obtained either in nitrobenze or in m-dimethoxybenzene. H-(S)-Phe-(S)-Phe-OEt tends to aggregate by an intermolecular hydrogen bond in aqueous and tetrahydrofuran solutions. Its pK_a value and nucleophilicity towards NCA were much lower than H-(R)-Phe-(S)-Phe-Mo, which was free from the aggregation under similar conditions. These experimental results suggest that the major product in the polymerization of (RS)-Phe NCA by amine should be an alternating copolymer. However, this prediction was not verified experimentally, and the important contributions from the aggregation and the molecular weight distribution of growing chains were suggested.     

Effect of degree of polymerization and steric configuration of poly(2-vinylpyridine) as catalyst in the polymerization of phenylalanine NCA

Despite its being weaker base poly(2-vinylpyridine) polymerized DL -β-phenylalanine NCA at a much faster rate than pyridine and α-picoline. Poly(2-vinylpyridine) adsorbs NCA by hydrogen bonding with the cooperation of a few pyridine groups. This results in a high local concentration of NCA. The syndiotactic configuration of pyridine group seemed to be least suitable for the cooperative hydrogen bonding. Adsorbed NCA is activated to form an “activated” NCA which in turn reacts with an NCA adsorbed on the same polymer chain. Since the polymer chain is flexible, this intramolecular reaction takes place frequently, resulting in the acceleration of polymerization. The intramolecular reaction along the polymer chain is dependent on the degree of polymerization of polymer catalyst. A suitable model was proposed for the intramolecular reaction to explain the effect of degree of polymerization.     

Circular dichroism studies on the polymerization of N-carboxy alpha-amino acid anhydride

The D and L copolymerizations of N-carboxy γ-benzyl glutamate anhydride (NCA) were carried out in a homogeneous solution with various D /L ratios, initiated by either n-butylamine or sodium methoxide, and were followed directly by circular dichroism (CD) to observe the behavior of the secondary structure of growing polymer molecules. In the n-butylamine system, the difference of the helical content between the righthanded and the lefthanded (Δα-helix) gradually increased as the polymerization proceeded, while in the sodium methoxide system, the Δα-helix had a tendency to decrease during the later stages of the polymerization. These results suggest a difference of the power of stereo-selection of monomer antipodes by the growing chain end between these systems, the stereoselectivity by the growing chain end in the sodium methoxide system being higher than that in the n-butylamine system.     

Polymerization of amino acid derivatives by polymer catalysts. I. Polymerization by poly-2-vinylpyridine

Polymerizations of D ,L -β-phenylalanine, p-nitro-D ,L -β- phenylalanine, and o,p-dinitro-D ,L -β-phenylalanine NCA's were carried out with the use of α-picoline or poly-2-vinyl-pyridine as initiator. Polymerizations induced by the polymer catalyst were always faster than those with α-picoline in the same base concentrations. Furthermore, the polymer effect was more marked when the number of nitro groups in the NCA's increased. It was considered that the polymer catalyst interacts with the NCA's primarily by hydrogen bonding and increases the effective concentration of NCA along the chain. The increase of the NCA concentration in the vicinity of the polymer catalyst wits also achieved through charge-transfer complexes between nitrophenyl groups in the NCA's and pyridine groups in the polymer catalyst. As the polymer chain is flexible, a collision between an adsorbed NCA and a pyridine unit in the same polymer chain is favored, thus increasing the polymerization rate.     

Enantiomer selection in the reaction of N-methyl-α-amino acid N-carboxyanhydride and 3-methyl-5-substituted hydantoin: A model reaction for the stereoselective polymerization of α-amino acid N-carboxyanhydride

The addition reaction to N-methyl-(S)-alanine or N-methyl-(S)-phenylalanine N-car-boxyanhydride (NCA) of 3-methyl-5-substituted hydantoin (HDT) catalyzed by a tertiary amine was investigated as a model reaction for the propagation reaction of NCA according to the activated-NCA mechanism. Several activated HDTs having the (S)-configuration of the asymmetric carbon atom were found to react more rapidly than their activated enantiomers. This experimental result indicates that the enantiomer selection by terminal-unit control takes place in the propagation reaction according to the activated-NCA mechanism in which an activated NCA is added to a terminal acylated NCA ring of the growing chain. The enantiomer excess of the HDT recovered from the reaction mixture of N-methyl-(S)-phenylalanine NCA and racemic HDTs activated by a tertiary amine was determined. The extent of the enantiomer selection in the polymerization was found to be 3–10 times as large as that in the model reaction. From these results, it was concluded that the chirality of the penultimate unit, as well as that of the terminal NCA ring, plays an important role in determining the enantiomer selection in the NCA polymerization.     

Stereoselective synthesis and characterization of new enantiomerically pure phosphoric acids

Starting from (R)‐6,6′‐dimethyldiphenyl‐2,2′‐dicarboxylic acid, a novel class of enantiomerically pure cyclic dialkyl phosphates was synthesized and properly characterized. The absolute configuration was determined by 2D NOESY experiments. The catalytic behavior of the new chiral Bronsted acids was investigated in the stereoselective addition of a silyl keteneacetal to aldimines. The Mannich‐type reaction was promoted in up to 94% yields and enantioselectivities up to 55%. On the basis of preliminary molecular mechanic calculations, a model of stereoselection was also proposed to explain the sense of the enantioselectivity observed in the reaction. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Effects of temperature on the polymerization of γ-ethyl DL-glutamate N-carboxy anhydride in DMF initiated by tri-n-propylamine

Polymerization of γ-ethyl DL -glutamate N-carboxy anhydride (NCA) in DMF has been carried out at various temperatures and with the use of tri-n-propylamine as the initiator. It was found that on decreasing the polymerization temperature the reaction rate is lowered but the molecular weight and the helix content of the final polymer are enhanced. An overall activation energy of ～4 kcal/mole has been found for the polymerization process. Preliminary experiments carried out on the polymerization of γ-benzyl D -glutamate NCA in DMF and with tri-n-propylamine as the initiator showed a strong depressing effect of the CO₂ evolved during the polymerization, both on the reaction rate and on the molecular weight of the polymer. All data are interpreted in terms of the Bamford-Swarc mechanism.     

The beta conformation of polypeptides of valine, isoleucine, and threonine in solution and solid-state: optical and infrared studies.

Water-soluble polypeptides of L -valyl and L -isoleucyl residues flanked with DL -lysyl blocks [poly(DL Lys · HCl)_x–poly(L Val)_y–poly(DL Lys · HCl)_x, poly(DL Lys · HCl)_x–poly-(L Ile)_y–poly(DL Lys · HCl)_x] and homopoly(L -threonine) were prepared. The β conformation of these polymers in water, as well as in aqueous methanol, was confirmed by infrared spectroscopy and circular dichroism studies. The optical properties of these valyl and isoleucyl polypeptides were quite different from those of previously reported synthetic homopolypeptides in the β structure. Their differences could be explained by the presence of a “single extended β chain” without either intra- or interchain association.     

Exciton coupling effects and conformational change of perhexyloligosilanes with optically active methyl(1-naphthyl)phenylsilyl terminals

Perhexyloligosilanes (R,R)-(+)-MeNpPhSi*(Hex(2)Si)(n)Si*PhNpMe (n = 2; (R,R)-(+)-4a, n = 4; (R,R)-(+)-6a, n = 6; (R,R)-(+)-8a) with chiral methyl(1-naphthyl)phenylsilyl terminals were synthesized and characterized. The absorption wavelengths lambda(max) by (1)L(a,Ph) transition of phenyl chromophore conjugated with oligosilane units in (R,R)-(+)-4a - (R,R)-(+)-8a show bathochromic shift of about 3-4 nm compared with those of the alpha,omega-phenyl substituted perhexyloligosilanes Ph(Hex(2)Si)(m)Ph (m = 4; 4b, m = 6; 6b, m = 8; 8b) having the same silicon chain length. Longer chain length induces the separated lambda(max) of (1)L(a,Ph) from (1)B(b,Np) of naphthyl chromophore with positive exciton chiralities. In (R,R)-(+)-8a, although the extremum wavelengths lambda(ext) of exciton coupling between (1)B(b,Np) and (1)L(a,Ph) are separated by about 80 nm, the compound retains the positive exciton chirality, which provides definite information on the absolute configuration of terminal chiral silicon atoms. Bulky terminal substituents and lowering the temperature affect the conformation of the main chain, inducing extended silicon backbone structure.     

X-Ray studies on crystalline complexes involving amino acids and peptides. XVII. Chirality and molecular aggregation: The crystal structures of DL-arginine DL-glutamate monohydrate and DL-arginine DL-aspartate

DL -Arginine DL -glutamate monohydrate and DL -arginine DL -aspartate, the first DL -DL amino acid–amino acid complexes to be prepared and x-ray analyzed, crystallize in the space group P1 with a = 5.139(2), b = 10.620(1), c = 14.473(2) Å, α = 101.34(1)°, β = 94.08(2)°, γ = 91.38(2)° and a = 5.402(3), b = 9.933(3), c = 13.881(2) Å, α = 99.24(2)°, β = 99.73(3)°, γ = 97.28(3)°, respectively. The structures were solved using counter data and refined to R values of 0.050 and 0.077 for 1827 and 1739 observed reflections, respectively. The basic element of aggregation in both structures is an infinite chain made up of pairs of molecules. Each pair, consisting of a L - and a D -isomer, is stabilized by two centrosymmetrically or nearly centrosymmetrically related hydrogen bonds involving the α-amino and the α-carboxylate groups. Adjacent pairs in the chain are then connected by specific guanidyl–carboxylate interactions. The infinite chains are interconnected through hydrogen bonds to form molecular sheets. The sheets are then stacked along the shortest cell translation. The interactions between sheets involve two head-to-tail sequences in the glutamate complex and one such sequence in the aspartate complex. However, unlike in the corresponding LL and DL complexes, head-to-tail sequences are not the central feature of molecular aggregation in the DL -DL complexes. Indeed, fundamental differences exist among the aggregation patterns in the LL , the LD , and the DL -DL complexes.