Selection of enantioselective acyl transfer catalysts from a pooled peptide library through a fluorescence-based activity assay: An approach to kinetic resolution of secondary alcohols of broad structural scope
Selection of enantioselective acyl transfer catalysts from a pooled peptide library through a fluorescence-based activity assay: An approach to kinetic resolution of secondary alcohols of broad structural scope
复制标题
DOI：
10.1021/ja0108584
复制
发表时间：
2001-07-11
影响因子：
15
通讯作者：
Miller, SJ
中科院分区：
文献类型：
--
作者：
Copeland, GT;Miller, SJ
采用荧光标记的拆分和池肽库的测定已被应用于发现一类新的用于仲醇的动力学拆分的八肽催化剂。在固相合成珠上合成高度多样化的基于肽的催化剂的文库，使得每个单独的珠与（i）均匀负载的pH敏感性荧光团和（i）独特的基于肽的催化剂共官能化。然后筛选文库在使用（+/-）-仲-苯基乙醇作为底物和乙酸酐作为酰化剂的酰化反应中的活性。从最具活性的催化剂中，鉴定出先导肽（4），其在均相条件下再合成和评价时提供8.2的选择性因子（k（rel））。合成“定向”第二代分裂和汇集肽文库，使得文库中的新肽序列偏向前导结构。在单珠测定中筛选第二代文库的随机样品，其揭示了几种新的基于肽的催化剂，其在动力学分辨率中提供改进的选择性。肽催化剂13证明对于仲苯基乙醇（k（rel）= 20）以及宽底物范围（k（rel）= 4至> 50）的八种其它仲醇的动力学拆分是有效的。
An assay employing a fluorescently labeled split and pool peptide library has been applied to the discovery of a new class of octapeptide catalysts for the kinetic resolution of secondary alcohols. A highly diverse library of peptide-based catalysts was synthesized on solid-phase synthesis beads such that each individual bead was co-functionalized with (i) a uniform loading of a pH-sensitive fluorophore and () a unique peptide-based catalyst. The library was then screened for activity in acylation reactions employing (+/-)-sec-phenylethanol as the substrate and acetic anhydride as the acylation agent. From the most active catalysts, a lead peptide (4) was identified that provides a selectivity-factor (k(rel)) of 8.2 upon resynthesis and evaluation under homogeneous conditions. A "directed" second-generation split and pool peptide library was synthesized such that the new peptide sequences in the library were biased toward the lead structure. Random samples of the second generation library were screened in single bead assays that revealed several new peptide-based catalysts that afford improved selectivities in kinetic resolutions. Peptide catalyst 13 proves effective for the kinetic resolution of sec-phenylethanol (k(rel) = 20), as well as eight other secondary alcohols of a broad substrate scope (k(rel) = 4 to > 50).