Ogrel A, Bloemhoff W, Lugtenburg J, Raap J
Leiden Institute of Chemistry, Leiden University, The Netherlands.
J Pept Sci. 1997 May-Jun;3(3):193-208. doi: 10.1002/(sici)1099-1387(199705)3:3<193::aid-psc101>3.0.co;2-6.
For the first time the total synthesis of the peptaibol zervamicin IIB is described. Synthesis of this peptaibol was achieved by the Fmoc/tert-butyl strategy in solution using a fragment condensation approach. Three fragments of zervamicin IIB were obtained by stepwise elongation with Fmoc amino acids using BOP as a coupling reagent. For the introduction of the highly sterically hindered alpha-aminoisobutyric acid residues BOP/DMAP activation was applied. The fmoc group was removed by reaction with 0.1 M NaOH in dioxane/methanol/water (30/9/1, v/v/v). Peptide fragments were coupled by means of a new coupling reagent, CF3-PyBOP. Using the strategy developed, zervamicin IIB and two analogues specifically deuterium-labelled at different positions of the glutamine-11 residue have been synthesized in 40% overall yield based on the isotopically labelled amino acid and with 98 +/- 2% of isotope enrichment. FAB mass spectroscopy, 600 MHz 1H-NMR spectroscopy and high-performance liquid chromatography provided convincing evidence that the synthetic products, zervamicin IIB and its deuterium-labelled analogues, fully correspond to the naturally occurring zervamicin IIB.
首次描述了肽抗生素泽尔瓦霉素IIB的全合成。该肽抗生素的合成通过溶液中的Fmoc/叔丁基策略采用片段缩合方法实现。使用BOP作为偶联试剂，通过用Fmoc氨基酸逐步延长获得了泽尔瓦霉素IIB的三个片段。为了引入空间位阻较大的α-氨基异丁酸残基，采用了BOP/DMAP活化方法。通过与0.1 M NaOH在二氧六环/甲醇/水（30/9/1，v/v/v）中反应去除Fmoc基团。肽片段通过一种新的偶联试剂CF3-PyBOP进行偶联。基于同位素标记的氨基酸，采用所开发的策略，以40%的总收率合成了泽尔瓦霉素IIB以及在谷氨酰胺-11残基的不同位置特异性氘标记的两种类似物，同位素富集率为98±2%。快原子轰击质谱、600 MHz 1H-NMR光谱和高效液相色谱提供了令人信服的证据，表明合成产物泽尔瓦霉素IIB及其氘标记类似物与天然存在的泽尔瓦霉素IIB完全一致。
