γ-peptides forming more stable secondary structures than α-peptides:: Synthesis and helical NMR-solution structure of the γ-hexapeptide analog of H-(Val-Ala-Leu)2-OH
γ-peptides forming more stable secondary structures than α-peptides:: Synthesis and helical NMR-solution structure of the γ-hexapeptide analog of H-(Val-Ala-Leu)2-OH
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DOI：
10.1002/hlca.19980810514
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发表时间：
1998-01-01
影响因子：
1.8
通讯作者：
Seebach, D
中科院分区：
文献类型：
--
作者：
Hintermann, T;Gademann, K;Seebach, D
为了与相应的α -和β -六肽H-(Val-Ala-Leu)(2)- oh (a)和H-(β - hval - β - hala - β - hleu)(2)- oh (B)进行比较，我们现在用同手性相似的(S)-4-氨基丁酸、(R)-4-氨基-5-甲基己酸和(R)-4-氨基-6-甲基庚酸合成了相应的γ -六肽1。前驱体的制备可以采用双Arndt-Eistert同源法（方案1和方案2）对受保护氨基酸boc -缬氨酸- oh、Boc-Ala-OH和Poe-Leu-OH进行双Arndt-Eistert同源，也可以采用相应醛的烯烃化/加氢方法（方案3）制备。传统的肽偶联方法（EDC/HOBt）提供了-六肽1（通过中间的-二肽和-三肽衍生物9-11）。对（D-5）吡啶和CD3OH溶液（COSY， TOCSY， HSQC， HMBC， ROESY）的核磁共振测量结果分析表明，γ -六肽1采用右旋螺旋结构(（P)-2.6(1)螺旋，约5埃螺距，含14元氢键环），这与相应的β肽B的左旋螺旋结构(（M)-3(1)螺旋，5埃螺距，14元氢键环）和我们熟悉的右旋、所谓的α -肽的α -螺旋(（P)3.6(1)螺旋5.4埃，节距，13元环）。像螺旋感觉一样，螺旋偶极子在从α - (N +- > C)到β - (C +- > N)到γ肽（N +- > C）时反转。天然α -肽与类似的β -肽和γ -肽之间令人惊讶的区别是，螺旋稳定性随着残基的同源性而增加。
For a comparison with the corresponding alpha- and beta-hexapeptides H-(Val-Ala-Leu)(2)-OH (A) and H-(beta-HVal-beta-HAla-beta-HLeu)(2)-OH (B), we have now prepared the corresponding gamma-hexapeptide 1 built from the homochirally similar (S)-4-aminobutanoic acid, (R)-4-amino-5-methylhexanoic acid, and (R)-4-amino-6-methylheptancic acid. The precursors were prepared either by double Arndt-Eistert homologation of the protected amino acids Boc-Val-OH, Boc-Ala-OH, and Poe-Leu-OH (Schemes 1 and 2), or by the superior route involving olefination/hydrogenation of the corresponding aldehydes (Boc-valinal, Boc-alaninal, and Boc-leucinal; Scheme 3). Conventional peptide-coupling methodology (EDC/HOBt) furnished the gamma-hexapeptide 1 (through the intermediate gamma-di- and gamma-tripeptide derivatives 9-11). Analysis of NMR measurements in (D-5)pyridine and CD3OH solution (COSY, TOCSY, HSQC, HMBC, ROESY) reveals that the gamma-hexapeptide 1 adopts a right-handed helical structure ((P)-2.6(1) helix of ca. 5-Angstrom pitch, containing 14-membered H-bonded rings) which is to be compared with the left-handed helix of the corresponding beta-peptide B ((M)-3(1) helix of 5-Angstrom pitch, 14-membered H-bonded rings) and with the familiar right-handed, so-called alpha-helix of alpha-peptides ((P)3.6(1) helix of 5.4-Angstrom, pitch, 13-membered rings). Like the helix sense, the helix dipole reverses when going from alpha- (N +--> C) to beta- (C +--> N) to gamma-peptides (N +--> C). The surprising difference between the natural alpha-, and the analogous beta- and gamma-peptides is that the helix stability increases upon homologation of the residues.