Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States.
J Am Chem Soc. 2023 Mar 1;145(8):4828-4852. doi: 10.1021/jacs.2c13889. Epub 2023 Feb 17.
Here, we report our detailed efforts toward the synthesis of phainanoids, a novel class of dammarane-type triterpenoids with potent immunosuppressive activities and unique structural features. Systematic model studies have been carried out, and efficient approaches have been established to construct the benzofuranone-based 4,5-spirocycle, the D/E/F tricyclic core, the [4.3.1] propellane, and the 5,5-oxaspirolactone moieties. The asymmetric synthesis of (+)-phainanoid A has been achieved through kinetic resolution of the tricyclic core followed by diastereoselective installation of the A/B/C and G/H rings and fragment coupling with the enantioenriched I/J rings. In addition, novel estrone-derived phainanoid analogues have been prepared. The immunosuppressive and cell survival assays revealed that (+)-phainanoid A and some of its synthetic analogues can specifically inhibit stimulation-induced lymphocyte proliferation but not cell survival at their effective concentrations. Preliminary structure-activity relationship information has been obtained, which could inspire future design of immunosuppressive phainanoid analogues.
在这里，我们报告了我们在合成菲烷类化合物方面的详细工作，菲烷类化合物是一类具有强效免疫抑制活性和独特结构特征的新型达玛烷型三萜类化合物。我们进行了系统的模型研究，并建立了有效的方法来构建基于苯并呋喃酮的 4,5-螺环、D/E/F 三环核心、[4.3.1]丙烷和 5,5-氧杂螺内酯部分。通过对三环核心进行动力学拆分，然后对 A/B/C 和 G/H 环进行非对映选择性安装，并与手性富集的 I/J 环进行片段偶联，实现了 (+)-菲烷 A 的不对称合成。此外，还制备了新型雌酮衍生的菲烷类似物。免疫抑制和细胞存活实验表明，(+)-菲烷 A 及其一些合成类似物可以特异性抑制刺激诱导的淋巴细胞增殖，但在有效浓度下不会抑制细胞存活。初步的结构-活性关系信息已经获得，这可能为设计具有免疫抑制活性的菲烷类似物提供启示。
