Novel Techniques for the Synthesis and Coupling of Peptide Segments

这项研究由有机合成资助。 化学课程。 新的合成技术 天然存在的中链或长链肽正在被 开发的产品将使它们能够以数克的形式快速上市 数量用于测试目的。 基于碱敏感和溶剂敏感的新合成技术 氨基保护基团有望使 几克数量的短肽， 改善少量较长肽的合成。 用于合成100个或更多个长肽链的方法 涉及片段偶联的氨基酸单元享有 显著优于那些涉及逐步 方法。 三种方法来组装合适的 将研究以下部分：（a）FMOC/多胺溶液 技术，（B）两种聚合物（“逆梅里菲尔德”）方法 和（c）标准梅里菲尔德固相法。 在所有 新发现的FMOC的适用性的三种方法 作为快速作用的廉价偶联剂的氨基酸氟化物 代理商将进行研究。 这些试剂现在可用于 除了四种常见的氨基酸 合成 这四种化合物的合适的酰氟试剂 (Arg，Asn，Gln，His）。 以便于固体 相合成两种特殊的树脂载体， 调查：（a）叔醇树脂，应 完全抑制肽从树脂中的损失， 在脱肽阶段形成二酮哌嗪，特别是 在C-末端或倒数第二个脯氨酸或甘氨酸的情况下， (b)带有叔氨基醇官能团的树脂载体 其应当用于催化第一氨基酸的装载 从而促进完全的在线自动化合成， 第一个到最后一个氨基酸。 曾经快速的常规方法 用于合成受保护的片段， 解决方案和固相方法的节段耦合将 考察 一种实现无消旋化的新方法 涉及C-末端酰胺保护的链段偶联 将采用FM-棒或相关酰胺保护剂粘合。 选择研究这些技术应用的模型 是家蚕促前胸腺激素的19个单位的片段， PTTH-II-（1-19）.

This research is being funded by the Organic Synthesis Chemistry Program. New techniques for the synthesis of naturally occurring medium or long chain peptides are being developed which will make them rapidly available in multi-gram quantities for testing purposes. New synthetic techniques based on base- and solvent-sensitive amino-protecting groups promise to make available quickly multi-gram quantities of shorter peptides and to markedly improve the synthesis of small quantities of longer peptides. Methods for the synthesis of long peptide chains of 100 or more amino acid units which involve the coupling of segments enjoy significant advantages over those involving stepwise approaches. Three methods for assembling the appropriate segments will be studied: (a) the FMOC/Polyamine solution technique, (b) the two polymer ("inverse merrifield") approach and (c) the standard Merrifield solid phase method. In all three approaches the applicability of newly-discovered FMOC amino acid fluorides as rapid-acting, inexpensive coupling agents will be studied. Such reagents are now available for all but four of the common amino acids. Synthesis of appropriate acid fluoride reagents for these four compounds (Arg, Asn, Gln, His) will be developed. To facilitate solid phase syntheses two special resin supports will be investigated: (a) tertiary alcohol resins which should completely inhibit loss of peptide from the resin due to diketopiperazine formation at the depeptide stage, especially in the case of C-terminal or penultimate proline or glycine and (b) resin supports bearing tertiary aminoalcohol functions which should serve to catalyse loading of the first amino acid and thereby promote complete on-line automated syntheses from the first to the last amino acid. Once rapid, routine methods for the synthesis of protected segments are available, both solution and solid phase methods of segment coupling will be examined. A novel method of effecting racemization-free segment coupling involving protection of the C-terminal amide bond by FM-bar or a related amide protectant will be pursued. The model chosen to study the application of these techniques is a 19-unit segment of a silkworm prothoracicotropic hormone, PTTH-II-(1-19).