Enantioselective total synthesis of (+)-amphidinolide t1.
An enantioselective first total syntheis of amphidinolide T1 (1) is described. Amphidinolide T1 (1), a 19-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent and involves the assembly of C1-C10 segment 2 and C11-C21 segment 3 by an oxocarbenium ion-mediated alkylation and Yamaguchi macrolactonization sequence. The synthesis of fragment 2 involves an efficient cross metathesis and hydrogenation sequence between the terminal olefins of 5 and 6 to form the C4-C5 carbon-carbon bond. Enol ether 4 is designed to be the surrogate of fragment 3 where the sensitive C16-exo-methylene and the C13-hydroxyl group were protected as the bromoether derivative during the Lewis acid-catalyzed alkylation process. Both stereocenters in fragment 5 as well as the C2 and C3 stereocenters in fragment 4 are accessed by a highly diastereoselective ester-derived titanium enolate-mediated syn-aldol reaction. The bromoether derivative 24 was unraveled at the final stage of the synthesis, providing (+)-amphidinolide T1.
Ghosh
Arun K
AK
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA. arunghos@uic.edu
Liu
Chunfeng
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis*; D004141:Dinoflagellida / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis*; D018942:Macrolides; D013237:Stereoisomerism; D000097442:Amphidinolides
D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007783:Lactones; D018942:Macrolides; C414522:amphidinolide T; D000097442:Amphidinolides