Efficient syntheses of 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, two potent new microtubule-stabilizing agents

Abstract

SummaryThe dictyostatins are powerful microtubule-stabilizing agents that have shown antiproliferative activity against a variety of human cancer cell lines. Two highly active analogs of dictyostatin, 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, were prepared by a new streamlined total synthesis route. Three complete carbon fragments were prepared to achieve maximum convergency. These were coupled by a Horner–Wadsworth–Emmons reaction sequence and an esterification. A late stage Nozaki–Hiyama–Kishi reaction was then used to form the 22-membered macrolide. The stereoselectivity of this reaction depended on the configurations of the nearby stereocenter at C6.

Recent advances in microtubule-stabilizing agents

“…At the same year, Phillips and coworkers designed a convergent synthesis approach to achieve the total synthesis of (-)-dictyostatin in 26 steps, and their synthesis offered a novel synthetic strategy of the complex polyketide with cis-trans isomerisms via a (silyloxy)enyne cyclizations reaction [90]. role for the further synthesis researches [91][92]. In 2013, Stephen et al accomplished the total synthesis of dictyostatin via three fragment syntheses, and the most advantage of their strategy is that they used an unrivalled step-economy route with one-pot procedures at several points, and each of the three fragments was prepared by commercial reagents just in 4 or 5 steps, which further promoted the synthesis efficiency of dictyostatin [93].…”

Role of the Nozaki–Hiyama–Takai–Kishi Reaction in the Synthesis of Natural Products

“…Some other relevant molecules that have been accessed following this NHTK cyclization methodology to reach a 2-en-ol macrocycle are calystegines B 2 and B 3 , cochliomycins A and B, 3,6-dihydroxydec-4-enolides, analogs of dictyostatin, modiolide A, the spirotetracyclic carbon core of mangicols, and aspinolide B (Figure ). …”

Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities

“…50 This increased convergency made this, at the time, the shortest synthesis of dictyostatin with 36–40 total steps. 50 This same group later 51 presented a streamlined total synthesis of 2 analogues of dictyostatin; 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin. These syntheses were based on 3 complete carbon fragments coupled by Horner-Wadsworth-Emmons reaction sequences and an esterification.…”

“…These syntheses were based on 3 complete carbon fragments coupled by Horner-Wadsworth-Emmons reaction sequences and an esterication. 51 These reactions produced dictyostatin in 7-8% yield with the synthesis of each fragment taking 10 steps or less, with 10 additional steps to couple the fragments. These new analogues retained the low nanomolar potency of dictyostatin, and are effective in paclitaxel and epothilone-resistant cells lines with mutations in the taxane binding site or that express Pgp.…”