Streamlined syntheses of (-)-dictyostatin, 16-desmethyl-25,26-dihydrodictyostatin, and 6-epi-16-desmethyl-25,26-dihydrodictyostatin.
The dictyostatins are a promising class of potential anti-cancer drugs because they are powerful microtubule-stabilizing agents, but the complexity of their chemical structures is a severe impediment to their further development. On the basis of both synthetic and medicinal chemistry analyses, 16-desmethyl-25,26-dihydrodictyostatin and its C6 epimer were chosen as potentially potent yet accessible dictyostatin analogues, 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 analogues and the natural product. All of the syntheses are streamlined because of their high convergency. The work provided several new analogues of dictyostatin, including a truncated macrolactone and a C10 E-alkene, which were 400- and 50-fold less active than (-)-dictyostatin, respectively. In contrast, the targeted 16-desmethyl-25,26-dihydrodictyostatin analogues retained almost complete activity in preliminary biological assays.
Zhu
Wei
W
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Jiménez
María
M
Jung
Won-Hyuk
WH
Camarco
Daniel P
DP
Balachandran
Raghavan
R
Vogt
Andreas
A
Day
Billy W
BW
Curran
Dennis P
DP
D002244:Carbon / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004951:Esterification; D006801:Humans; D007783:Lactones / Q000737:chemistry; D008094:Lithium / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C552383:6-epi-16-desmethyl-25,26-dihydrodictyostatin; D007783:Lactones; D018942:Macrolides; C470814:dictyostatin; D002244:Carbon; D008094:Lithium