POLYPEPTIDES .17. A STUDY OF THE KINETICS OF THE PRIMARY AMINE-INITIATED POLYMERIZATION OF N-CARBOXY-ANHYDRIDES WITH SPECIAL REFERENCE TO CONFIGURATIONAL AND STEREOCHEMICAL EFFECTS
POLYPEPTIDES .17. A STUDY OF THE KINETICS OF THE PRIMARY AMINE-INITIATED POLYMERIZATION OF N-CARBOXY-ANHYDRIDES WITH SPECIAL REFERENCE TO CONFIGURATIONAL AND STEREOCHEMICAL EFFECTS
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DOI：
10.1021/ja01572a004
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发表时间：
1957-01-01
影响因子：
15
通讯作者：
DOTY, P
中科院分区：
文献类型：
--
作者：
LUNDBERG, RD;DOTY, P
伯胺引发L-戊二酸苄酯的N-羧酸酐在多种溶剂中的聚合反应，在相对快速的引发后，以两个连续的速率进行。第二增长步骤的速率常数比第一增长步骤的速率常数大至少5倍，因此，首先达到较快增长条件的那些增长链随后快速增长，并且通过降低酸酐浓度，降低尚未达到快速增长条件的链的增长速率。这就是先前观察到的非常宽的分子量分布的起源。在二氧六环中，当平均链长达到约8个残基时，发生从慢增长速率到快增长速率的转变。由于这一链长位于范围（7至13），这已被分配到临界长度的稳定的螺旋构型在这种溶剂中，它出现的传播常数的变化的原因是构型转变。结果表明，N-羧基酸酐中极少量的HCl污染可显著降低第二增长常数，并在一定限度内阻止其出现。确定了两个替代终止步骤，它们的组合作用将平均聚合度限制在约500。在二甲基甲酰胺中，只观察到一个单一的速率常数，所得多肽的分子量分布比二氧六环的情况大大降低。因此，具有窄泊松分子量分布的低分子量多肽的制备似乎是可能的。N-羧基酸酐的外消旋和D，L-混合物的聚合速率的研究显示相对于纯L-酸酐的聚合速率的显著降低。虽然增长的链是非螺旋的，但降低小于2倍，因此根据链的偏好来解释，以添加对应于其末端残基的异构体。后来，当增长链已经达到螺旋构型时，速率的降低大于2倍，这表明位于末端后面的残基所施加的偏好。当旋光度以及CO，进化被用来跟踪L-，dl-和oN-羧酸酐与预形成的L-多肽（螺旋构型）的聚合反应时，发现起始螺旋的螺旋方向倾向于继续。在D-酸酐的情况下，在大约四个残基加入后，螺旋义的逆转发生;在DL-酸酐的情况下，逆转发生得较晚，大概是由于顺序上偶然加入四个D-残基的结果。2-7如果引发相对于增长不慢，并且不发生副反应，则链增长应该以几乎均匀的速率进行，产生分子量的泊松分布。最近，终止步骤已被证实83，并已分析了这将导致的分子量分布的加宽。811因此，假定聚合反应是通过所示的机理发生的。本研究的目的是确定由N-羧酸酐生成聚--L-谷氨酸苄酯在多大程度上遵循这一动力学规律。选择这种特殊的氨基酸残基是因为它是天然存在的氨基酸的少数前体之一，其酸酐和多肽都可溶于液体。
The primary amine-initiated polymerizationof N-carboxy-anhydride of-benzyl-L-glutarnate in a number of solvents is shown to proceed at two successive rates following a relatively rapid initiation. The rate constant for the second propagation step is at least five times larger than that for the first and as a consequence those growing chains that first achieve the con-dition for the faster propagation then grow rapidly and, by lowering the anhydride concentration, reduce the rate of growth of the chains that have not attained the condition for fast growth. This is the origin of the very broad molecular weight distributions previously observed. In dioxane the transition from the slow to thefast propagation rate occurs when the average chain length has reached approximately 8 residues. Since this chain length lies in the range (7 to 13) which has been assigned to the critical length for stabilization ofthe-helical configuration in this solvent it appears that the cause of the change in propagation constants is the configurational transition. It is shown that very minor HC1 contamination of the N-carboxy-anbydride can substantially lower the second propagation constant and in the limit prevent its appearance alto-gether. Two alternativetermination steps are identified and their combined effect limits the average degree of polymerization to about 500. In dimethylformamide only a single rate constant isobserved and the molecular weight distribution of the resulting polypeptides is greatly reduced over that of the dioxane case. Thus the preparation of low molecular weight polypeptides having the narrow Poisson distribution of molecular weights appears possible. Investigation of the rate of polymerization of racemic and D, L-mixtures of N-carboxy-anhydride shows a pronounced lowering of the propagation rate relative to that of the pure L-anhydride. While the growing chain is non-helical the lowering is less than a factor of two and is thereby accounted for in terms of a preference of the chain to add the isomer corresponding to its terminal residue. Later, w hen the growing chain has reached the helical configuration, the lowering of the rate is greater than a factor of two and this indicates a preference exerted by residues lying behind the terminal one. When optical rotation as well as CO, evolution is used to follow polymerizations of L-, dl- and oN-carboxy-anhydrides with preformed L-polypeptide (helical configuration) it is found that the screw sense of the initiating helix tends to be continued. In the D-anhydride case, the reversal of the helix sense occurs after about four residues have added; in the DL-anhydride case, reversal occurs later presumably as a result of the occasional addition of four D-residues in sequence.The polymerization of N-carboxy-a-amino acid anhydrides has been generally thought to proceed by a repetitive, stepwise addition of the peptide units with the simultaneous expulsion of carbon di-oxide. 2-7 If initiation is not slow relative to propagation andside reactions do not occur, chain growth should proceed at a nearly uniform rate producing a Poisson distribution of molecular weights. Recently a termination step has been suggested83 and the broadening of the molecular weight distribution which this would bring about has been analyzed. 811 Thus the polymerization is presumed to occur by the mechanism shown. The purpose of this investigation has been to de-termine to what extent the formation of poly--benzyl-L-glutamate from its N-carboxy-anhydride follows this kinetic scheme. This particular amino acid residue was chosen because it is one of the few precursors of naturally occurring amino acidswhose anhydride and polypeptide are both soluble in liquids …