Efficient and Stereoselective Chiral Synthesis of Isosteric Peptides Directed toward Development of Drugs

用于药物开发的等排肽的高效立体选择性手性合成

• 批准号: 02807190
• 负责人: IBUKA Toshiro
• 金额: $ 1.02万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02807190/
• 关键词: Organocopper; Anti-S_N2'; Dipeptide; Isostere; antiーSN2^1反応; synーS_N2'反応

In recent years, increasing interest has been shown in the backbone modification of amide bonds in biologically active peptides. The major purpose in this area deals with stabilizing a given peptides toward enzymatic degradation by in vitro proteases or imparting enzyme inhibitory activity to the synthesized peptide mimic. The peptide bond in polypeptides and proteins generally assumes the trans amide bond configuration, since its cis counterpart induces unfavorable steric interactions.The(E)CH=CH bonding in peptide mimic closely resembles three-dimentional structure(bond length, bond angle, and rigidity)of the parent amide. Thus replacement of an amide bond by a(E)CH=CH bond should not signiflcantly alter the overall conformation of a peptide molecule, and hence, its biological activity, provided that the replaced amide bond is not directly involved in either the secondary or tertiary structure of the peptide or the mechanism whereby the biological response is elicited.Because it has … More been reported that alpha-carbon stereochemistry was one of the essential factors for enzyme inhibition, the synthesis of(E)-alkene dipeptide isosteres would be highly valuable. We have disclosed following points during our study on the synthesis of(E)-. dipeptide isosteres.1)Both the(E)- and(Z)-alpha, beta -unsaturated esters afford the alpha-alkylated(E)-beta, gamma -unsaturated esters in very high chemical and optical yields by treatment with alkylcyanocopper-trifluoroborane reagents under very mild conditions. The presence of a HNBoc group at the delta-position does not erert any influence on the course of the anti-S_N2' reaction.2)A simple synthsis of psi[(E)CH=CH]Gly dipeptide'Nisosteres via reduction of delta-aminated-gamma-mesyloxy-alpha, beta-unsaturated esters with alkenylcopper reagents has been developed. Reaction times of 5 - 30 min at - 78 ﾟC were sufficient for conversion of the mesylates into the isosteres.3)The absolute configuration at the alpha-alkylated carbon center in delta-oxygenated or delta-aminated beta, gamma-unsaturated esters can be determined by circular dichroism measurement with confidence. Whereas(2S)-compounds show a positive n ->PI* Cotton effect around 220 nm, (2R)-'@series of compounds exhibit a negative n ->PI* Cotton effect near 220 nm.4)The synthesized dipeptide isosteres were coupled with natural(S)-amino acids to yield a new type of peptides. Evaluation of biological activities is in progress. Less

近年来，生物活性肽中酰胺键的骨架修饰引起了人们越来越多的兴趣。这一领域的主要目的是稳定给定的肽对体外蛋白酶的酶降解或赋予合成的肽模拟物酶抑制活性。多肽和蛋白质中的肽键通常呈现反式酰胺键构型，因为其顺式对应物引起不利的空间相互作用。肽模拟物中的（E）CH=CH键与母体酰胺的三维结构（键长、键角和刚性）非常相似。因此，酰胺键被（E）CH=CH键取代不应显著改变肽分子的总体构象，并因此不应显著改变其生物活性，条件是取代的酰胺键不直接参与肽的二级或三级结构或引发生物应答的机制。 ...更多信息 由于α-碳立体化学是酶抑制的重要因素之一，因此合成（E）-烯烃二肽电子等排体具有重要的应用价值。我们在研究（E）-的合成过程中发现了以下几点。二肽电子等排体。1）通过在非常温和的条件下用烷基氰基铜-三氟硼烷试剂处理，（E）-和（Z）-α，β-不饱和酯都以非常高的化学产率和光学产率得到α-烷基化的（E）-β，γ-不饱和酯。δ-位上HNBoc基团的存在对反S_N_2 '反应的过程没有任何影响。2）通过用烯基铜试剂还原δ-胺化-γ-甲磺酰氧基-α，β-不饱和酯，建立了一种简单的合成psi[（E）CH=CH]Gly二肽'Nisosteres的方法。在-78 ° C下5 - 30 min的反应时间足以将甲磺酸酯转化为电子等排体。3）δ-氧化或δ-胺化的β，γ-不饱和酯中α-烷基化碳中心的绝对构型可以通过圆二色性测量确定。（2S）-化合物在220 nm附近显示出正的n ->PI* Cotton效应，（2 R）-系列化合物在220 nm附近显示出负的n ->PI* Cotton效应。4）合成的二肽电子等排体与天然（S）-氨基酸偶联，得到一种新型的多肽。生物活动的评价正在进行中。少

项目成果

藤井 信孝: "A Simple Synthesis of ψ[(E)CH=CH]Gly Dipeptide Isosteres via Reductive Elimination of γーOxygenatedーα,βーenoate with Alkenyl Copper Reagents." Tetrahedron Letters. 32. 4969-4972 (1991)

Nobutaka Fujii：“通过烯基铜试剂还原消除 γ-氧化-α,β-烯酸来简单合成 ψ[(E)CH=CH]Gly 二肽等排体。”32. 4969-4972 (1991)

山本 嘉則: "Higher Order Zinc Cuprate Reagents:Very Hihg 1,3ーChirality Transfer Reaction of γーMesyloxyーα,βーUnsaturated Carbonyl Derivatives" J.Org.Chem.57. (1992)

Yoshinori Yamamoto：“高阶锌铜酸盐试剂：γ-甲磺酰氧基-α,β-不饱和羰基衍生物的非常高的 1,3-手性转移反应”J.Org.Chem.57 (1992)。

井深 俊郎: "New Aspects of Organocopper Reagents:1,3ー and 1,2ーChiral Induction,Natural Product Synthesis,and Mechanism" Synlett.(1992)

Toshiro Ibuka：“有机铜试剂的新方面：1,3-和1,2-手性诱导、天然产物合成和机制”Synlett。(1992)

Toshiro Ibuka, Hiromu Habashita, Akira Otaka, Nobutaka Fujii, Yusaku Oguchi, Tadao Uyehara, and Yoshinori Yamamoto: "A Highly Stereoselective Synthesis of (E)-Alkene Dipeptide Isosteres via Organocyanocopper-Lewis Acid-Mediated Reaction." J. Org. Chem.56.

Toshiro Ibuka、Hiromu Habashita、Akira Otaka、Nobutaka Fujii、Yusaku Oguchi、Tadao Uyehara 和 Yoshinori Yamamoto：“通过有机氰铜-路易斯酸介导的反应高度立体选择性合成 (E)-烯烃二肽等排体。”

山本 嘉則: "Recent Progress of OrganocopperーLewis Acid Complex Reagents" J.Jpn.Oil Chem.Soc.39. 881-887 (1990)

Yoshinori Yamamoto：“有机铜-路易斯酸络合物试剂的最新进展”J.Jpn.Oil Chem.Soc.39（1990）。