The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Oxford Antibiotic Group, The Oxford Science Park, Magdalen Centre, Oxford OX4 4GA, UK.
Org Biomol Chem. 2023 May 17;21(19):4061-4071. doi: 10.1039/d3ob00376k.
A general route which provides direct access to substituted bicyclic tetramates, making use of Dieckmann cyclisation of oxazolidine derivatives derived from -phenylserines, is reported. Of interest is the high level of diastereoselectivity observed for the -acylation reaction of oxazolidines and the complete chemoselectivity of their ring closure in the Dieckmann cyclisation. Significantly, the sense of the chemoselectivity is different to earlier reported -phenylserine systems, showing the importance of steric bulk around the bicyclic ring system. The derived C7-carboxamidotetramates, but not C7-acyl systems, exhibited potent antibacterial activity against MRSA, with the most active compounds exhibiting well-defined physicochemical and structure-activity properties. This work clearly demonstrates that densely functionalised tetramates are both readily available and may exhibit high levels of antibacterial activity.
报道了一种直接合成取代双环四氢叶酸的一般方法，该方法利用来源于-phenylserines 的恶唑烷衍生物的Dieckmann 环化反应。值得注意的是，恶唑烷的酰化反应具有很高的非对映选择性，并且它们在 Dieckmann 环化中的闭环反应具有完全的化学选择性。重要的是，这种化学选择性的意义与早期报道的-phenylserine 体系不同，表明双环体系周围的空间位阻很重要。衍生的 C7-羧酰胺四氢叶酸，但不是 C7-酰基系统，表现出对 MRSA 的强大的抗菌活性，最有效的化合物表现出明确的物理化学和结构活性特性。这项工作清楚地表明，高度官能化的四氢叶酸不仅易于获得，而且可能具有很高的抗菌活性。
