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

furaquinocins是一类对HeLa S3和B16黑色素瘤细胞具有细胞毒性但无抗菌活性的新型抗生素。这些化合物由聚酮衍生的萘醌和类异戊二烯侧链组成的独特杂化结构给合成带来了新的挑战，包括(1)对C-2、C-3（季）和C-10三个连续立体中心的立体控制，(2)选择性构建密集功能化的萘醌，以及(3)建立立体拥挤的芳-类异戊二烯杂化结构。以钴络合炔为迁移基的旋光性环氧醇的1,2-重排影响了三个连续立体中心中的两个的立体控制结构，包括一个季手性中心。在钴配位后，所得到的同丙基醇中的炔有效地作为C2单元，通过电环苯并反应构建了萘呋喃骨架。第三个手性中心是通过邻于第四手性中心的硫酰基立体选择性甲基化而形成的。以所得环氧化物为共同中间体，聚合合成呋喃醌醌D、呋喃醌醌A、呋喃醌醌B和呋喃醌醌H。生物活性测试表明，部分合成中间体具有与天然呋喃醌相当的强杀细胞活性，这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.