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

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).