Divergent Stereoselectivity in Phosphothreonine (pThr)-Catalyzed Reductive Aminations of 3‑Amidocyclohexanones

Phosphothreonine (pThr)-embedded
peptide catalysts are found to
mediate the reductive amination of 3-amidocyclohexanones with divergent
selectivity. The choice of peptide sequence can be used to alter the
diastereoselectivity to favor either the cis-product
or trans-product, which are obtained in up to 93:7
er. NMR studies and DFT calculations are reported and indicate that
both pathways rely on secondary interactions between substrate and
catalyst to achieve selectivity. Furthermore, catalysts appear to
accomplish a parallel kinetic resolution of the substrates. The facility
for phosphopeptides to tune reactivity and access multiple products
in reductive aminations may translate to the diversification of complex
substrates, such as natural products, at numerous reactive sites.

本研究发现，嵌入磷酸化苏氨酸（phosphothreonine, pThr）的肽催化剂可介导3-酰胺基环己酮的还原胺化反应，且展现出差异化的选择性。通过调整肽序列，可改变反应的非对映选择性，使其偏向生成顺式产物或反式产物，两类产物的比例最高可达93:7 er。本研究通过核磁共振（Nuclear Magnetic Resonance, NMR）实验与密度泛函理论（Density Functional Theory, DFT）计算证实，两条反应路径均依赖底物与催化剂之间的次级相互作用以实现选择性调控。此外，该类催化剂可实现底物的平行动力学拆分。磷酸肽在还原胺化反应中调控反应活性、生成多种产物的能力，有望实现复杂底物（如天然产物）在多个活性位点的多样化修饰。