Functional analysis of an aspartate-based epoxidation catalyst with amide-to-alkene peptidomimetic catalyst analogues
Functional analysis of an aspartate-based epoxidation catalyst with amide-to-alkene peptidomimetic catalyst analogues
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DOI：
10.1002/anie.200802223
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Miller, Scott J.
中科院分区：
文献类型：
--
作者：
Jakobsche, Charles E.;Peris, Gorka;Miller, Scott J.
含环氧化合物的天然产物的生物合成为“环氧酶”的研究提供了强有力的刺激。同样，这些过程激发了一代专注于通过各种机制介导选择性环氧化的小分子催化剂的科学。[ii]对于天然存在的环氧化酶，o原子转移的机制基础通常与类黄酮辅助因子、含有血红素基团的P450酶或导致逐步形成环的氯过氧化物酶的化学作用有关。[iii]在考虑已知的环氧化物形成的生物合成装置时，我们对基于蛋白质中可用的官能团的o -原子转移- 1的替代模式感到好奇，但在环氧化物的生物合成中可能没有很好的记录。特别是，我们推测并最近表明，含天冬氨酸的肽（例如，1；图1a）可能在侧链羧酸和相应的过氧化物（例如，2）之间穿梭，形成一个催化循环，使天冬氨酸衍生的催化剂发生不对称环氧化反应。这种方法与Julia-Colonna环氧化是正交的，这是一种基于亲核机制的互补肽基环氧化。[iv]事实上，如图1b所示，这种新的亲电环氧化催化循环介导了3等底物的不对称环氧化反应，从而得到4等产物的ee含量高达92%。在这个催化系统中有许多机械问题。到目前为止，我们已经确定了一些有关方面。例如，我们观察到非催化循环中间体，包括催化活性低的二酰基过氧化物(6)。[vi]我们还表明，这些非催化循环中间体可以通过亲核试剂如DMAP或DMAP- n -氧化物的作用重新插入到生产途径中(7)。另一方面，立体化学信息传递的基础并没有立即明确。事实上，无论催化剂是酶还是小分子，对手性催化剂的立体化学作用模式的高精度描述是不对称催化学科的一个关键前沿。有了这个背景资料，我们开始了对催化剂作用方式的详细研究。
The biosynthesis of natural products that contain epoxides represents a powerful stimulus for the study of “epoxidase” enzymes.[i] Likewise, these processes have inspired a generation of science focused on small molecule catalysts that mediate selective epoxidations through a variety of mechanisms.[ii] With respect to the naturally occurring epoxidases, the mechanistic basis of O-atom transfer is often associated with the chemistry of either flavinoid cofactors, P450 enzymes containing a heme group, or chloroperoxidases that lead to stepwise ring formation.[iii] In thinking about the known biosynthetic apparatus for epoxide formation, we became curious about an alternative mode for O-atom transfer–one based on functional groups available in proteins, but perhaps not well-documented in the biosynthesis of epoxides. In particular, we speculated and recently showed that asparticacid-containing peptides (eg, 1; Figure 1a) might shuttle between the side-chain carboxylic acid and the corresponding peracid (eg, 2) creating a catalytic cycle competent for asymmetric epoxidation with turnover of the aspartate-derived catalyst. Such an approach is orthogonal to the Julia-Colonna epoxidation, a complementary peptide-based epoxidation based on a nucleophilic mechanism.[iv] Indeed, as shown in Figure 1b, this new electrophilic epoxidation catalytic cycle mediates the asymmetric epoxidation of substrates like 3 to give products like 4 with up to 92% ee.[v]Mechanistic questions abound in this catalytic system. To date, we have identified a number of relevant aspects. For example, we observed off-catalytic cycle intermediates, including catalytically inactive diacyl peroxides (6).[vi] We also showed that these off-cycle intermediates could be reinserted into the productive pathway through the action of nucleophiles such as DMAP or DMAP-N-oxide (7). On the other hand, the basis of stereochemical information transfer was not immediately clear. Indeed, the high precision delineation of the stereochemical mode of action of chiral catalysts is a critical frontier in the discipline of asymmetric catalysis, whether the catalysts are enzymes or small molecules. With this back-drop, we began a detailed study of the mode of action for catalyst 5.