Total Synthesis of (−)‐FR182877 through Tandem IMDA–IMHDA Reactions and Stereoselective Transition‐Metal‐Mediated Transformations

Abstract

A research group at the Fujisawa (now, Astellas) Pharmaceutical Company isolated (À)-FR182877 [1a-d] and its congener, (À)-FR182876 [1e] , from Streptomyces sp. no. 9885. (À)-FR182877 binds and stabilizes microtubules, exhibiting potent cytotoxic activity toward a number of human cancer cell lines with a potency comparable to that of Taxol.[1] The in vivo assay of (À)-FR182877 using mouse models revealed its promising antitumor activity, [1c] suggesting its potency as a lead compound for chemotherapeutic agents. (À)-FR182877 features a unique hexacyclic structure with twelve contiguous stereogenic centers and a reactive "push-pull" alkene [1c] distorted by the ethylene bridge. Its remarkable biological profile and unprecedented structural features has made (À)-FR182877 an attractive compound for total synthesis [2][3][4][5] as well as chemical biology studies. [6] The groups led by Sorensen [2] and Evans [3] have independently reported elegant asymmetric total syntheses of (À)-FR182877 through closely related strategies, involving consecutive transannular cycloadditions. Our interests in the total synthesis of this complex architecture and the recently disclosed unique mode of action of this compound [6c] have prompted us to report herein an alternate synthetic approach to (À)-FR182877.The stereoselective syntheses of the AB-ring and the CD-ring moieties were accomplished by the intramolecular Diels-Alder (IMDA) reaction and the intramolecular heteroDiels-Alder (IMHDA) reaction, [4c,d] respectively. We surmised that these cycloadditions could be sequential; that is, the one-pot tandem IMDA-IMHDA reaction of the acyclic substrate 2 (Scheme 1) could provide the tetracyclic comScheme 1. Synthesis of 6 by the tandem IMDA-IMHDA reaction: a) TESCl, imidazole, CH 2 Cl 2 , RT, 30 min; b) K 2 CO 3 , MeOH, RT, 30 min, 75 % (2 steps); c) MnO 2 , toluene, 80 8C, 2 d, 28 %; d) PPTS (cat.), MeOH, RT, 1.5 h, 82 %; e) Dess-Martin periodinane, NaHCO 3 , CH 2 Cl 2 , RT, 30 min, 89 %; f) BH 3 ·THF, THF, À20 8C, 30 min, 75 %, (24:1 d.r.); g) TBSOTf, Et 3 N, CH 2 Cl 2 , RT, 2 h, 94 %. PPTS = pyridinium p-toluenesulfonate, TBS = tert-butyldimethylsilyl, TES = triethylsilyl, Tf = trifluoromethanesulfonyl, TIPS = triisopropylsilyl.

Recent advances in microtubule-stabilizing agents

“…They formed the AB ring moiety of FR182877 via a diastereoselective IMDA reaction [74] and constituted the CD ring moiety of FR182877 via highly diastereoselective intramolecular hetero-Diels-Alder (IMHDA) reaction [75][76]. Two years later, they reported an asymmetric total synthesis of (-)-FR182877 via a sequence of IMDA-IMHDA reactions and stereoselective transformations mediated by palladium and iridium [77]. Then in 2012, this group accomplished the compound corresponded exactly to the DEF-ring moiety of (-)-FR182877 through an inverse-electron-demand IMHDA [78].…”