benzofurans and avermectin

Although known for over a quarter of a century, the oxidative radical cyclisation route to spiroketals has found limited use in natural product synthesis in comparison to classical approaches. Its successful application in this field of research forms the subject of this perspective.

Topics: Anthelmintics; Anti-Bacterial Agents; Antineoplastic Agents; Benzofurans; Biological Products; Bridged-Ring Compounds; Ciguatoxins; Cyclization; Ethers; Ethers, Cyclic; Furans; Hydrogen; Ivermectin; Marine Toxins; Molecular Structure; Oxazoles; Oxidation-Reduction; Phenazines; Phosphoprotein Phosphatases; Pyrans; Spiro Compounds

In the present study a family of macrocyclic and acyclic analogues as well as seco-analogues of avermectins were prepared from commercial Ivermectin (IVM) and their antileishmanial activity assayed against axenic promastigote and intracellular amastigote forms of Leishmania amazonensis. Contrarily to the filaricidal activity, the leishmanicidal potentiality of avermectin analogues does not appear to depend on the integrity of the non-conjugated Delta(3,4)-hexahydrobenzofuran moiety. Conjugated Delta(2,3)-IVM or its corresponding conjugated secoester show higher anti-leishmania activity than the parent compound. Surprisingly, the diglycosylated northern sub-unit exhibits the same anti-amastigote potentiality as the southern hexahydrobenzofuran. As expected for compounds derived from the widely used Ivermectin antibiotic, little toxicity has been noticed for most of the novel analogues prepared.

Topics: Animals; Benzofurans; Disaccharides; Ivermectin; Leishmania mexicana; Macrophages; Mice; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanocidal Agents

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.

Topics: Anions; Anthelmintics; Benzofurans; Ivermectin; Molecular Structure; Spectrum Analysis

Three products resulting from free-radical-induced oxidation of the oxahydrindene portion of 22,23-dihydroavermectin B1a (H2B1a) are 5-oxo-H2B1a, 8a-oxo-H2B1a, and 5,8a-bisoxo-H2B1a. The last of these compounds has not been reported previously.

Topics: Benzofurans; Chemistry, Pharmaceutical; Drug Stability; Free Radicals; Ivermectin; Oxidation-Reduction; Peroxides; tert-Butylhydroperoxide