Development of viable synthetic route to the furaquinocins and its application to creating new antitumor agents

呋喃喹菌素是一类对HeLa S3和B16黑色素瘤细胞显示细胞毒性活性但没有抗菌活性的新型抗生素，开发了一种有效且灵活的合成路线。这些化合物由于其独特的由聚酮衍生的萘醌和类异戊二烯侧链组成的杂合结构而提出了新的合成挑战，包括（1）在C-2，C-3（季）和C-10，（2）选择性构建密集官能化的萘醌，以及（3）空间拥挤的芳香族-类异戊二烯杂化结构的建立。三个相邻的立体异构中心中的两个（包括一个四级手性中心）的立体控制构建受到1，2-重排的光学活性环氧醇武装与钴络合炔作为迁移基团。所得高炔丙醇中的炔经钴的脱配位后，有效地作为C2单元通过电环苯并环化来构建萘并呋喃骨架。第三个手性中心是通过与季手性中心相邻的醛的立体选择性亚甲基化，通过硫叶立德构建的。以环氧化物为通用中间体，实现了呋喃喹辛D、呋喃喹辛A、呋喃喹辛B和呋喃喹辛H的聚合全合成，生物活性测试结果表明，部分合成中间体具有与天然呋喃喹辛相当的杀细胞活性，为设计新的合成抗肿瘤药物提供了有价值的信息。

An efficient and flexible synthetic route to the furaquinocins, a new class of antibiotics which show cytotoxic activity against HeLa S3 and B16 melanoma cells but no antimicrobial activity, was developed. These compounds pose new synthetic challenges due to their unique hybrid structure composed of the polyketide-derived naphthoquinone and the isoprenoid side chain, including (1) stereocontrol of three contiguous stereogenic centers at C-2, C-3 (quaternary), and C-10, (2) selective construction of the densely functionalized naphthoquinone, and (3) establishment of the sterically congested aromatic-isoprenoid hybrid structure.Stereocontrolled construction of two of the three contiguous stereogenic centers, including a quaternary chiral center, was effected by the 1,2-rearrangement of optically active epoxy alcohol armed with the cobalt-complexed alkyne as the migrating group. The alkyne in the resulting homopropargyl alcohol, after decoordination of the cobalt, effectively worked as the C2 unit for constructing the naphthofuran skeleton by an electrocyclic benzannulation. The third chiral center was constructed by stereoselective methylenation of the aldehyde, adjacent to the quaternary chiral center, by a sulfur ylide. Through the resulting epoxide as the common intermediate, total syntheses of furaquinocin D, furaquinocin A, furaquinocin B, and furaquinocin H were achieved in a convergent manner.Biological activity test revealed that some of the synthetic intermediates exhibit potent cyctocidal activities comparable to natural furaquinocins, which provides a valuable information for designing new synthetic antitumor agents.