Design, Synthesis, and Evaluation of Irciniastatin Analogues: Simplification of the Tetrahydropyran Core and the C(11) Substituents

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• 作者：Qi Liu ; Chihui An ; Karen TenDyke ; Hongsheng Cheng ; Young Yongchun Shen ; Adam T. Hoye ; Amos B. Smith III
• 刊名：Journal of Organic Chemistry
• 出版年：2016
• 出版时间：March 4, 2016
• 年：2016
• 卷：81
• 期：5
• 页码：1930-1942
• 全文大小：657K
• ISSN：1520-6904

文摘

The design, synthesis, and biological evaluation of irciniastatin A (1) analogues, achieved by removal of three synthetically challenging structural units, as well as by functional group manipulation of the C(11) substituent of both irciniastatins A and B (1 and 2), has been achieved. To this end, we first designed a convergent synthetic route toward the diminutive analogue (+)-C(8)-desmethoxy-C(11)-deoxy-C(12)-didesmethylirciniastatin (6). Key transformations include an acid-catalyzed 6-exo-tet pyran cyclization, a chiral Lewis acid mediated aldol reaction, and a facile amide union. The absolute configuration of 6 was confirmed via spectroscopic analysis (CD spectrum, HSQC, COSY, and ROESY NMR experiments). Structure–activity relationship (SAR) studies of 6 demonstrate that the absence of the three native structural units permits access to analogues possessing cytotoxic activity in the nanomolar range. Second, manipulation of the C(11) position, employing late-stage synthetic intermediates from our irciniastatin syntheses, provides an additional five analogues (7–11). Biological evaluation of these analogues indicates a high functional group tolerance at position C(11).