Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany.
Chemistry. 2009 Nov 16;15(45):12310-9. doi: 10.1002/chem.200901817.
An expeditious total synthesis of the highly cytotoxic F-ATPase inhibitor cruentaren A (1) is described based on a ring-closing alkyne metathesis (RCAM) reaction for the formation of the macrocylic ring. Other key transformations comprise a C-acylation of the benzyl lithium reagent derived from orsellinic acid ester 9 with Weinreb amide 7, a CBS reduction of the resulting ketone 10, and a Soderquist propargylation of aldehyde 21 with allenylborane (S)-27 to set the C-15 chiral center of the required alcohol fragment 25. The RCAM precursor 33 was assembled by acylation of 25 with acid fluoride 32, since more conventional methods for ester bond formation were unproductive. Moreover, the choice of the protecting groups, in particular for the secondary alcohol at C-9, which is prone to engage in translactonization, turned out to be critical; a relatively stable TBDPS ether had to be chosen for this site, which was removed in the final step of the synthesis with aqueous HF since other fluoride sources met with failure. The successful synthetic route was then expanded beyond the natural product, bringing a series of analogues into reach that feature incremental but deep-seated structural modifications. Three of these fully synthetic compounds turned out to be as or even more cytotoxic than cruentaren A itself against L-929 mouse fibroblast cells, reaching IC(50) values as low as 0.7 ng mL(-1).
基于环 closing 炔烃复分解反应 (RCAM) 构建大环，描述了具有强细胞毒性的 F-ATPase 抑制剂 cruentaren A（1）的快速全合成。其他关键转化包括：用 Weinreb 酰胺 7 对来源于 Orsellinic 酸酯 9 的苄基锂试剂进行 C-酰化，所得酮 10 的 CBS 还原，以及烯丙基硼烷 (S)-27 对醛 21 的 Soderquist 炔基化，以构建所需醇片段 25 的 C-15 手性中心。RCAM 前体 33 通过 25 与氟化物 32 的酰化反应组装，因为酯键形成的更常规方法没有效果。此外，保护基的选择至关重要，特别是对于易发生转酯化的 C-9 仲醇；必须选择相对稳定的 TBDPS 醚作为该位点的保护基，因为在合成的最后一步中，使用 HF 水溶液将其去除，因为其他氟化物源失败了。然后，成功的合成路线扩展到天然产物之外，使一系列具有增量但深层次结构修饰的类似物成为可能。这三个完全合成的化合物对 L-929 小鼠成纤维细胞的细胞毒性与 cruentaren A 本身一样甚至更强，IC（50）值低至 0.7ngmL（-1）。
