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.     

Solvent effect in the stereoselective polymerization of α-amino acid N-carboxyanhydride and some considerations on the mechanism of stereoregulation

In the Polymerization of phenylalanine N-carboxyanhydride (NCA) in No₂Oh initiated by MeNHBzl, L -,D -, and DL -NCA As were polymerized at the same rate, and no stereoselectivity was observed. When the same experiment was carried out in HCONEt₂, however, L - and D -NCA were both polymerized at a rate which was about twice as large as that of DL -NCA. In this case, the polymerization is stereoselective, ascribable to a preferable reaction between the optical enantiomorphs of the terminal residue of the growing chain and the NCA of the same chirality. On the other hand, the polymerization initiated by SarNMe₂ and MeNH(CH₂)₂CONMe₂ were stereoselective in NO₂Ph and HCONEt₂, but they were not stereoselective in m-(MeO)₂Ph. These findings indicate that the polymerizations initiated by a strong base in highly dipolar solvents are stereoselective. Apparently, the reaction between a chiral, cyclic terminal of growing chain and a chiral, cyclic activated NCA in the activated-NCA mechanism is highly stereoselective. In addition, from a kinetic investigation on on the copolymerization between L - and D -NCAs, the penultimate chiral centers were also suggested to contribute to the stereoselection. Stereoselection by the α-helical conformation of the growing chain and by a chiral, linear terminal amine have been considered so far, and the contribution from the present type of stereoselection must have been overlooked.     

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.     

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.     

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.     

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. 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.     

Block copolymerization of α-amino acid N-carboxyanhydride initiated by vinyl polymers having a terminal amino group and the characterization of the block copolymers

Poly(methyl methacrylate) and polystyrene having terminal amino groups were synthesized by the radical polymerization of those monomers in the presence of 2-mercaptoethylammonium chloride as a chain-transfer agent. By the terminal group analysis and the molecular weight determination of the polymers, 0.5–1.3 amino groups were found in a chain of poly(methyl methacrylate) and 0.5–2.5 amino groups in a chain of polystyrene. Using these polymers having a terminal amino group as an initiator, the block polymerization of α-amino acid N-carboxyanhydride (NCA) was carried out. In the polymerizations of Glu(OBzl) NCA and Lys(Z) NCA by the poly(methyl methacrylate) initiator, the terminal amino group underwent a nucleophilic addition reaction to NCA and initiated the polymerization, yielding A-B-type block copolymers in a high yield. The same was observed in the polymerizations of Gly(OBzl) NCA and Lys(Z) NCA by the polystyrene initiator. By eliminating the protecting groups of the side chains of the polypeptide segment, the block copolymers poly(methyl methacrylate)-poly(Glu), poly(methyl methacrylate)-poly(Lys), polystyrene-poly(Glu) and polystyrene-poly(Lys) were synthesized with little side reactions. The side chain amino groups of poly(Lys) segment in the poly(methyl methacrylate)-poly(Lys) block copolymers were sulphonated or stearoylated successfully.     

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.     

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.     

Stereoselective coupling of hemigossypol to form (+)-gossypol in moco cotton is mediated by a dirigent protein

The terpenoid gossypol, a secondary metabolite found in the cotton plant, is synthesized by a free radical dimerization of hemigossypol. Gossypol exists as an atropisomeric mixture because of restricted rotation around the central binaphthyl bond. The dimerization of hemigossypol is regiospecific in cotton. In the case of some moco cotton, the dimerization also exhibits a high level of stereoselectivity. The mechanism that controls this stereoselective dimerization is poorly understood. In this paper, we demonstrate that a dirigent protein controls this stereoselective dimerization process. A partially purified protein preparation from cotton flower petals, which by itself is unable to convert hemigossypol to gossypol, converts hemigossypol with a 30% atropisomeric excess into (+)-gossypol when combined with an exogenous laccase, which by itself produces racemic gossypol.     

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.     

Synthesis of rhodamine 6G-based compounds for the ATRP synthesis of fluorescently labeled biocompatible polymers

Facile derivatization of rhodamine 6G in the 2' position by direct reaction with secondary amines is reported. If the secondary amine contains a hydroxy group, the hydroxyl-functional intermediate can be readily esterified to give either fluorescent initiators for atom transfer radical polymerization (ATRP) or a fluorescent methacrylic comonomer. In contrast to rhodamine dyes functionalized using primary amines, which are only fluorescent at low pH, these compounds are highly fluorescent at physiological pH. These new compounds were subsequently used to prepare a range of fluorescently labeled biocompatible polymers based on the biomimetic monomer, 2-(methacryloyloxy)ethyl phosphorylcholine (MPC), for biomedical studies.     

Enantiomer selection in the nucleophilic addition reaction of optically active amines to α-amino acid N-carboxyanhydrides

The enantiomer selection in the nucleophilic addition reaction of optically active amines such as α-amino acid esters to phenylalanine and $\text{N-}\text{methylphenylalanine}\text{N-}\text{carboxyanhydride}$ in $\text{m-}\text{dimethoxybenzene}$ as a solvent has been investigated. Stereoselectivity between the amines and the $\text{N-}\text{carboxyanhydrides}$ was found to change markedly according to the reaction conditions. This experimental finding is in contrast to the idea hitherto accepted that in the nucleophilic addition-type polymerization of α-amino acid $\text{N-}\text{carboxyanhydride}$ the growing chain end reacts preferentially with one of the enantiomorphic $\text{N-}\text{carboxyanhydrides}$ having the same configuration, and indicates the importance of the investigation of stereoselectivity in the $\text{N-}\text{carboxyanhydride}$ polymerization using suitable model reactions. Most $\text{(S)-α-}\text{amino}$ acid esters reacted preferentially with $\text{(R)-}\text{phenylalanine}\text{N-}\text{carboxyanhydride}$, and this type of stereoselectivity increased with the $\text{N-}\text{methylation}$ of $\text{N-}\text{carboxyanhydride}$ and with increasing bulkiness of the C^α substituent of α-amino acid esters (alanine < norleucine < leucine < valine). The relationship observed between the stereoselectivity and the structures of amines and $\text{N-}\text{carboxyanhydrides}$ was explained satisfactorily in terms of the transition state model in which the interaction of $\text{N-}\text{carboxyanhydride}$ nitrogen and α-amino acid ester carbonyl as well as the interaction of $\text{N-}\text{carboxyanhydride}$ carbonyl and α-amino acid ester nitrogen was taken into account. $\text{(S)-}\text{Proline}$ ethyl ester did not show enantiomer selectivity toward phenylalanine $\text{N-}\text{carboxyanhydride}$, but reacted preferentially with $\text{(S)-(N)-}\text{methylphenylalanine}\text{N-}\text{carboxyanhydride}$. for the reaction of proline ester with $\text{N-}\text{carboxyanhydride}$ a transition-state model was proposed, which was different from the transition state model proposed for other α-amino acid esters. Some experiments were carried out to examine the transition-state models proposed. The implications of the present investigation in stereoselectivity in the nucleophilic addition-type polymerization of $\text{N-}\text{carboxyanhydride}$ hitherto reported are discussed.     

Phenethylamines in brain and liver of rats with experimentally induced phenylketonuria-like characteristics

1. Phenethylamines were extracted from brain and liver of rats with phenylketonuria-like characteristics produced in vivo by inhibition of phenylalanine hydroxylase (EC 1.14.3.1) with p-chlorophenylalanine, with or without phenylalanine administration. To protect amines against oxidation by monoamine oxidase, pargyline was also administered. 2. beta-Phenethylamine was the major compound found in brain and liver. beta-Phenethanolamine and octopamine were also present, in lesser amounts, and the concentrations of these three amines paralleled blood phenylalanine concentrations. By comparison, tissues from control animals had only very low concentrations of these amines. 3. Small amounts of normetadrenaline, m-tyramine and 3-methoxytyramine were also found. 4. The inhibitors used, p-chlorophenylalanine and pargyline, gave rise to p-chlorophenethylamine and benzylamine respectively, the first via decarboxylation, the second probably by breakdown during extraction. 5. Distribution of phenethylamines in different brain regions and in subcellular fractions of rat brain cells was also investigated. The content of phenethylamine was highest in the striatum. 6. These findings are discussed in the light of changes occurring in human patients with uncontrolled phenylketonuria.     

Understanding lipase stereoselectivity

Microorganisms or isolated enzymes can be applied as catalysts to create highly regio- and stereoselective conversions under mild conditions. Lipases (EC 3.1.1.3, triacylglycerol lipase) are lipid-hydrolysing enzymes, which are increasingly used in stereoselective reactions. Their industrial importance arises from the fact that they act on a variety of substrates promoting a broad range of biocatalytic reactions. Lipase stereoselectivity is exploited for the production of single enantiomers instead of racemic mixtures and will become more important in the pharmaceutical and agrochemical industry because, in most cases only one of the two enantiomers has the desired activity, whereas no activity or even undesirable side effects reside in the other enantiomer. Enantiomer differentiation is due to the various diastereomeric interactions that occur between the enantiomers and the active site of the enzyme. The stereospecificity of a lipase depends largely on the structure of the substrate, interaction at the active site and on the reaction conditions. Stereoselectivity involves a wide range of factors such as differentiation of enantiotopes, differentiation of enantiomers, type of substrate, biochemical interaction of the substrate with the enzyme, steric interaction of the substrates, competition between two different substrates, nature and availability of the active site for stereoselective action, presence of water and nature of solvents based on polarity and supercritical state. This article reviews factors responsible for lipase stereoselectivity.     

L-Phe end-capped poly(L-lactide) as macroinitiator for the synthesis of poly(L-lactide)-B-poly(L-lysine) block copolymer

A poly(L-lactide)-b-poly(Nepsilon-(Z)-L-lysine) (PLLA-b-PZLys) block copolymer was synthesized through the ring-opening polymerization of Nepsilon-(Z)-lysine-N-carboxyanhydride using L-Phe-terminated PLLA as a macroinitiator. The L-Phe-terminated PLLA was prepared through a novel three-step process. First, the hydroxyl-terminated PLLA was synthesized through the ring-opening polymerization of L-lactide initiated by n-butanol under the existence of tin(II) ethylhexanoate. Subsequently, the complete capping of the hydroxyl end group of PLLA with BOC-L-Phe was achieved by using a mixed anhydride of BOC-L-Phe under the catalysis of 4-(1-pyrrolidinyl) pyridine. Finally, the free amino end group was obtained by removal of the t-butoxycarbonyl group through trifluoroacetic acid treatment under anhydrous condition. All these treatments were conducted under mild conditions, thus avoiding the breakdown of the PLLA backbone. Poly(L-lactide)-b-poly(L-lysine) block copolymer was produced after deprotection treatment of PLLA-b-PZLys. The structure of the block copolymer was confirmed by 1H NMR, IR, and GPC. Adjustment of the ratio of the NCA monomer to the macroinitiator could control the chain length of the PLys block.     

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.