Streamlined Syntheses of (−)-Dictyostatin, 16-Desmethyl-25,26-dihydrodictyostatin, and 6-epi-16-Desmethyl-25,26-dihydrodictyostatin

Abstract

The dictyostatins are a promising class of potential anticancer drugs because they are powerful microtubule stabilizing agents, but the complexity of their chemical structures is a severe impediment to their further development. Based on both synthetic and medicinal chemistry analyses, 25,26-dihydro-16-desmethyldictyostatin and its C6 epimer were chosen as potentially potent yet accessible dictyostatin analogs, and three new syntheses were developed. A relatively classical synthesis involving vinyllithium addition and macrocyclization gave way to a newer and more practical approach based on esterification and ring-closing metathesis reaction. Finally, aspects of these two approaches were combined to provide a third new synthesis based on esterification and Nozaki-Hiyama-Kishi reaction. This was used to prepare the target dihydro analogs and the natural product. All of the syntheses are streamlined because of their high convergence. The work provided several new analogs of dictyostatin including a truncated macrolactone and a C10 E-alkene, which were 400-fold and 50-fold less active than (−)-dictyostatin. In contrast, the targeted 25,26-dihydro-16-desmethyldictyostatin analogs retained almost complete activity in preliminary biological assays.

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

“…Curran and colleagues were the first to synthesize dictyostatin from 3 fragments followed only by fragment couplings. 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.…”

Update 1 of: Macrolactonizations in the Total Synthesis of Natural Products

“…The synthesis of dictyostatin analogues exemplifies the difficulties inherent in the natural product synthesis. 551 RCM efforts toward the construction of the C10−C11 double bond led either to a truncated 16-membered macrolactone or the desired final product but with a (10E)-configured double bond. Better results were obtained by forming the C4−C5 double bond by ring-closing metathesis, thus avoiding side-products.…”

8.18 Reduction of CåC and CåC by Noncatalytic Chemical Methods

“…37 A reagent that has attracted some synthetic usage for the reduction of ynones to enones has been the mixture of diisobutylaluminum hydride and hexamethylphosphoric triamide. 38 Alkynes have been reduced to Z-alkenes by the Stryker reagent, [(Ph 3 P)CuH] 6 , with distinct reactivity trends observed. Terminal alkynes are seen to react fastest, being reduced at room temperature, whereas internal alkynes require elevated temperatures.…”