Anionic cyclization approach toward perhydrobenzofuranone: stereocontrolled synthesis of the hexahydrobenzofuran subunit of avermectin.
A facile anionic cyclization approach toward stereocontrolled synthesis of the hexahydrobenzofuran subunit 3 of avermectin is described. As a model study, treatment of iodo compound 7 with n-BuLi at -100 degrees C effected metal-halogen exchange and subsequent anionic cyclization to afford perhydrobenzofuranone 8. For the total synthesis of subunit 3, compound 9 was dihydroxylated to give diol 10. Protection of the hydroxyl groups of diol 10 gave compound 11. Ketone 11 was then converted into the required enone 12 using Saegusa's protocol. On iodination followed by Luche reduction, enone 12 yielded alpha-iodo allylic alcohol 14, which on alkylation afforded ether 15. Conversion of the ester unit of 15 into a Weinreb amide group followed by anionic cyclization gave enone 17. 1,4-Addition of (MeOCH(2))(2)CuCNLi(2) to enone 17 followed by cleavage of the acetal unit afforded ketone 19. Preferential acetylation of the secondary alcoholic function of 19 afforded compound 20. The stereochemistry of 20 is confirmed by single-crystal X-ray analysis. Elimination of HOAc from 20 gave the crucial olefin 21. Hydrolysis of the acetate unit of 21 followed by protection of the resulting alcoholic function yielded tert-butyldimethylsilyl ether 23. Introduction of a hydroxyl group at the ring junction of 23, using Davis's procedure, finally afforded the hexahydrobenzofuran subunit 3.
Sha
Chin-Kang
CK
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, Republic of China. cksha@chem.nthu.edu.tw
Huang
Shih-Jung
SJ
Zhan
Zhuang-Ping
ZP
D000838:Anions; D000871:Anthelmintics / Q000138:chemical synthesis* / Q000737:chemistry; D001572:Benzofurans / Q000737:chemistry*; D007559:Ivermectin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D013057:Spectrum Analysis
D000838:Anions; D000871:Anthelmintics; D001572:Benzofurans; D007559:Ivermectin; C019264:avermectin; C105430:benzofuran