Disparate Catalytic Scaffolds for Atroposelective Cyclodehydration

Catalysts
that control stereochemistry are prized tools in chemical
synthesis. When an effective catalyst is found, it is often explored
for other types of reactions, frequently under the auspices of different
mechanisms. As successes mount, a unique catalyst scaffold may become
viewed as “privileged”. However, the mechanistic hallmarks
of privileged catalysts are not easily enumerated or readily generalized
to genuinely different classes of reactions or substrates. We explored
the concept of scaffold uniqueness with two catalyst types for an
unusual atropisomer-selective cyclodehydration: (a) C2-symmetric chiral phosphoric acids and (b) phosphothreonine-embedded,
peptidic phosphoric acids. Pragmatically, both catalyst scaffolds
proved fertile for enantioselective/atroposelective cyclodehydrations.
Mechanistic studies revealed that the determinants of often equivalent
and high atroposelectivity are different for the two catalyst classes.
A data-descriptive classification of these asymmetric catalysts reveals
an increasingly broad set of catalyst chemotypes, operating with different
mechanistic features, that creates new opportunities for broad and
complementary application of catalyst scaffolds in diverse substrate
space.

能够调控立体化学的催化剂，是化学合成领域中备受珍视的工具。当开发出高效催化剂后，研究人员通常会依托不同的反应机理，探索其在其他类型反应中的应用。随着研究成果不断积累，独特的催化剂骨架（scaffold）可能会被视为"优势（privileged）催化剂骨架"。然而，优势催化剂的标志性机理特征难以被系统归纳，也无法便捷地推广至真正不同类别的反应或底物。
本研究针对一种罕见的阻旋选择性环脱水反应（atropisomer-selective cyclodehydration），选取两类催化剂展开研究，以探究骨架独特性的相关概念：(a) C2对称手性磷酸（C2-symmetric chiral phosphoric acids）；(b) 嵌入磷酸苏氨酸的肽基磷酸（phosphothreonine-embedded peptidic phosphoric acids）。
实际应用中，两类催化剂骨架均能有效实现对映选择性/阻旋选择性环脱水反应。
机理研究表明，尽管两类催化剂均可实现近乎同等水平的高阻旋选择性，但其选择性的决定因素却存在显著差异。
对这类不对称催化剂进行数据驱动的分类后发现，其所涵盖的催化剂化学型（chemotype）愈发广泛，且各自具备独特的机理特征，这为催化剂骨架在多样底物空间（substrate space）中的广谱互补应用创造了全新机遇。