Evolution of the total syntheses of ustiloxin natural products and their analogues.
Ustiloxins A-F are antimitotic heterodetic cyclopeptides containing a 13-membered cyclic core structure with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. The first total synthesis of ustiloxin D was achieved in 31 linear steps using an S(N)Ar reaction. An NOE study of this synthetic product showed that ustiloxin D existed as a single atropisomer. Subsequently, highly concise and convergent syntheses of ustiloxins D and F were developed by utilizing a newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achieve a better macrolactamization strategy. Ustiloxins D, F, and eight analogues (14-MeO-ustiloxin D, four analogues with different amino acid residues at the C-6 position, and three (9R,10S)-epi-ustiloxin analogues) were prepared via the second-generation route. Evaluation of these compounds as inhibitors of tubulin polymerization demonstrated that variation at the C-6 position is tolerated to a certain extent. In contrast, the S configuration of the C-9 methylamino group and a free phenolic hydroxyl group are essential for inhibition of tubulin polymerization.
Li
Pixu
P
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, USA.
Evans
Cory D
CD
Wu
Yongzhong
Y
Cao
Bin
B
Hamel
Ernest
E
Joullié
Madeleine M
MM
D007536:Isomerism; D008958:Models, Molecular; D009183:Mycotoxins / Q000138:chemical synthesis*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D050257:Tubulin Modulators / Q000138:chemical synthesis*
D009183:Mycotoxins; D010456:Peptides, Cyclic; D050257:Tubulin Modulators; C089079:ustiloxin D