Difficult Macrocyclizations:  New Strategies for Synthesizing Highly Strained Cyclic Tetrapeptides

Meutermans, Wim; Bourne, Gregory T.; Golding, Simon W.; Horton, Douglas A.; Campitelli, Marc Ronald; Craik, David J.; Scanlon, M.J.; Smythe, Mark L.

doi:10.1021/ol034907o

Cited by 83 publications

(82 citation statements)

References 27 publications

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“…以环(丙-酪-精-苯丙) [14] 为模型化合物, 我们首先合成四肽酰肼 H-Cys-Tyr-Arg-Phe-NHNH 2 (1a), 再利用已优化出的条件进行环化测试 [18] (图 3). 实验表明, 浓度为 1.0 mmol/L 的未经纯化的四肽酰肼 1a (ESI found .…”

Section: 四肽酰肼环化反应的发现unclassified

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Synthesis of Cyclic Tetrapeptides via Ligation of Peptide Hydrazides

Tang¹,

Zheng²,

Yang³

et al. 2012

Acta Chim. Sinica

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Naturally occurring or man-made cyclic tetrapeptides have unique rigid skeletons and therefore, represent an interesting class of candidate bioactive molecules in drug discovery. However, efficient chemical synthesis of cyclic tetrapeptides often presents a difficult problem due to the large strain involved in this category of target compounds. To overcome this problem we describe in the present study the use of peptide hydrazides for the preparation of highly strained 12-membered all-L cyclic tetrapeptides. The new synthetic route starts with the easy Fmoc solid phase synthesis of a linear N-Cys-tetrapeptide hydrazide precursor. Upon quick activation by NaNO 2 at pH 3 and -10 ℃ for 20 min followed by treatment with a pH 7 buffer containing an external thiol (4-mercaptophenylacetic acid, 40 equiv.) at room temperature, the N-Cys-tetrapeptide hydrazide precursor is converted in situ to an N-Cys-tetrapeptide thioester. This thioester undergoes a fast intramolecular thioester exchange reaction to generate a 13-membered thiolactone intermediate. Then an S-to-N acyl shift is expected to take place to create an amide bond, which affords the desired cyclic tetrapeptide in a modest overall yield (ca. 40%). Finally, desulfurization of the cyclic peptide product can be carried out to produce the target cyclic tetrapeptide that does not contain any Cys residue. Through detailed 1 H, 13 C, and TOSCY NMR and HPLC analyses, it is found that the new method for tetrapeptide synthesis can be carried out at relatively high substrate concentrations (0.8-1.0 mmol/L) without causing the formation of much cyclic octapeptide byproduct. Our test also showed that the reaction can generate the desired cyclic tetrapeptide in an epimerization free manner. By using the new method we have successfully prepared several cyclic tetrapeptides including cyclo(Ala-Leu-Ala-Leu), cyclo(Ala-His-Gly-Trp), and cyclo(Ala-Val-Gly-Ile) in 18%-25% overall yields. We expect that our method of cyclic tetrapeptide synthesis may find applications in the development of cyclic peptide libraries for bioactivity screening.

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Section: 四肽酰肼环化反应的发现unclassified

“…实验表明, 浓度为 1.0 mmol/L 的未经纯化的四肽酰肼 1a (ESI found . 谱图结果与文献报道一致 [14] . 同时, 以八肽酰肼为原料合成 2c, 得到环八肽 2c' cyclo(Ala-Tyr-Arg-Phe-Ala-Tyr-Arg-Phe)…”

Section: 四肽酰肼环化反应的发现unclassified

Synthesis of Cyclic Tetrapeptides via Ligation of Peptide Hydrazides

Tang¹,

Zheng²,

Yang³

et al. 2012

Acta Chim. Sinica

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“…35,36 The observation of such conformational equilibria underscores the general principle that any constraining elements in peptide design, and not only those pertaining to cyclization, can nonetheless impart a degree of flexibility that does not readily reveal itself in averaged NMR data. For example, a previous study investigated the solution structure of a pentapeptide that was purportedly constrained in an ahelical form by metal complexation.…”

Section: Conformations Of Stevastelin C3 Analogs 973mentioning

confidence: 99%

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

Jogalekar

2010

Biopolymers

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The stevastelins are depsipeptide natural products that show valuable immunomodulatory and phosphatase inhibitory activity. A previous report described the synthesis, conformational analysis, and biological activity of modified diastereomeric C3 analogs (1) of these molecules and deduced a single dominant conformational scaffold for each of the six benzylated stevastelin diastereomers in solution. In this study, we report a combined computational and experimental approach (NAMFIS) of these analogs based on geometric variables from the NMR data and extensive conformational searching that suggests a more subtle and complex distribution of conformations in solution. Although the results indicate some conformations to be similar to those previously proposed, they include novel motifs not observed earlier such as gamma turns. In addition, the NAMFIS analysis confirms dramatic changes in conformations accompanying a chirality change at the C3 center and also establishes the conformational homogeneity of the D-serine diastereomers. The NAMFIS analysis thus suggests the use of D-serine as a possible constraining element in peptide design and derives a set of experimental solution conformers that could shed light on the bioactive conformation of the stevastelins. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 968-976, 2010.

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“…Recently developed approaches to the head-to-tail cyclization of a native peptide sequence include the use of native chemical ligation, [12] a-ketoacid-hydroxylamine amide ligation, [13] traceless Staudinger ligation, [14] Ugi peptide ligation, [15] auxiliary-based ring contraction approaches, [16] and the use of traceless turn-inducers. [9,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Traceless Turn-Inducers to Facilitate Peptide Cyclization…”

Section: Introductionmentioning

confidence: 99%

“…[32] This was attributed to a lowering of the energy barrier for trans-cis isomerization of the amide bonds and first exploited by Cavelier et al [9] who introduced removable tert-butyloxycarbonyl (Boc) protecting groups onto the main chain nitrogen atoms of a linear peptide sequence, thereby providing, after cyclization, a cyclic peptide that was not accessible by direct methods (Scheme 1). Subsequently, a variety of removable turn-inducers have been employed for peptide cyclization, including 2,4-dimethoxybenzyl (Dmb) protecting groups, [17] 2-hydroxy-6-nitrobenzyl substituents, [18] dehydrophenylalanine, [19] and pseudoprolines. [20][21][22][23][24][25][26][27][28][29][30][31] A related approach, which uses a removable tether to bring the N-and C-termini of a cyclic peptide into close proximity has also been reported.…”

Section: Introductionmentioning

confidence: 99%

The Pseudoproline Approach to Peptide Cyclization

Jolliffe¹

2018

Aust. J. Chem.

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The development of efficient methods for the synthesis of cyclic peptides is of interest because of the many potential applications of this class of molecule. Pseudoprolines are derived from serine, threonine, and cysteine and can be used as traceless turn-inducers to facilitate the cyclization of a wide range of linear peptide precursors. The incorporation of a pseudoproline into the peptide to be cyclized generally results in a cyclization reaction that proceeds more quickly and with higher yield than that of an analogous sequence without the pseudoproline. Installation of a pseudoproline at the C-terminal position of a linear peptide sequence has also been shown to eliminate any epimerization of this residue during the reaction. Following pseudoproline-mediated cyclization, these turn-inducers can be removed on treatment with acid in a similar manner to other protecting groups to provide the native peptide sequence, and in the case of cysteine-derived pseudoprolines, the resulting cysteine can be readily converted into alanine through desulfurization. These traceless turninducers have been successfully used in the synthesis of cyclic peptides containing either serine, threonine, cysteine or alanine residues.

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Difficult Macrocyclizations: New Strategies for Synthesizing Highly Strained Cyclic Tetrapeptides

Cited by 83 publications

References 27 publications

Synthesis of Cyclic Tetrapeptides via Ligation of Peptide Hydrazides

Synthesis of Cyclic Tetrapeptides via Ligation of Peptide Hydrazides

Conformations of stevastelin C3 analogs: Computational deconvolution of NMR data reveals conformational heterogeneity and novel motifs

The Pseudoproline Approach to Peptide Cyclization

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