Total synthesis of (-)-apratoxin A, 34-epimer, and its oxazoline analogue.
A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18-step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent beta-hydroxyl group at the C35-position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization of all individual transformations. In the synthesis of 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid (Dtena), the three reagent-controlled asymmetric reactions enables us to introduce four chiral carbon centers in a dihydroxylated fatty acid moiety. Formation of the hindered ester and sterically-unfavorable N-methylamide bonds were successfully demonstrated. The thiazoline in apratoxin A was constructed by Tf(2)O and Ph(3)PO-mediated dehydrative cyclization, and final macrocyclization was achieved between N-methylisoleucine and proline residues. Moreover, an oxazoline analogue and a C34 epimer of apratoxin A have also been elaborated in a similar approach. This synthetic route would enable assembly of other analogues differing in stereocenters of Dtena and their amino acids.
Numajiri
Yoshitaka
Y
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan.
Takahashi
Takashi
T
Doi
Takayuki
T
D002384:Catalysis; D003500:Cyclization; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D012211:Rhenium / Q000737:chemistry; D013237:Stereoisomerism
D047630:Depsipeptides; D010080:Oxazoles; C442201:apratoxin A; D012211:Rhenium