Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin-targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we report a highly stereocontrolled total synthesis (3.2 % yield) based on a convergent sequence of palladium-mediated fragment assembly and macrolactonization. Boron-mediated aldol reactions were used to configure the three key fragments 2, 5, and 6 by employing the appropriate enantiomer of the lactate-derived ketone 7.Tubulin-targetingcompoundsareperhapsthemostvalidated subset of clinically important anticancer agents, with natural products and analogues representing the mainstay for current chemotherapy, [1][2][3] recently supplemented by the approval of the antibody-maytansinoid conjugate Kadcyla (trastuzumab emtansine). [2] Leiodermatolide (1; Scheme 1) was isolated (0.001 % wet weight) by the Wright group in 2008 from the lithistid sponge Leiodermatium sp. collected by submersible off the Florida coastline. [4a] Leiodermatolide exhibits potent antiproliferative activity against a panel of human cancer cell lines (e.g. IC 50 = 3.3 nm for A549 lung adenocarcinoma cells, 5.0 nm for PANC-1 pancreatic carcinoma cells), whilst showing reduced toxicity to normal cells. This activity appears to be mediated through the disruption of tubulin dynamics to induce cell-cycle arrest in the G2/M phase and apoptosis. Although the exact mechanism of action of leiodermatolide is currently unknown, it is clearly distinct from that of other tubulin-targeting drugs. Thus, leiodermatolide could serve as a promising lead compound for the development of new anticancer agents, provided a sustainable supply can be generated by chemical synthesis. [5][6][7] From a structural perspective, leiodermatolide features a triply unsaturated 16-membered macrolactone appended at C9 with a carbamate group and at C15 with an E,E-dienyl side chain terminating in a d-lactone ring. This unique structure incorporates a total of nine stereocenters. In association with the Wright research group, [4b] we elucidated the relative configuration of leiodermatolide by using a combination of homo-and heteronuclear NMR spectroscopic analysis, molecular modeling, and computational DP4 NMR prediction. [8] The resulting assignment for the C1-C16 region was further supported by our synthesis of a macrocyclic fragment with a truncated side chain, [5] whereas an alternative stereostructure could be ruled out on the basis of synthetic studies reported earlier. [6a] The full configuration of the isolated C1-C16 and C20-C25 stereoclusters was only recently tied down Scheme 1. Retrosynthetic analysis and key fragments for the synthesis of leiodermatolide. Bz = benzoyl, PMB = para-methoxybenzyl, TBS = tert-butyldimethylsilyl, Tf = trifluoromethanesulfonyl, TMS = trimethylsilyl.
