Anionic Cyclization Approach toward Perhydrobenzofuranone:  Stereocontrolled Synthesis of the Hexahydrobenzofuran Subunit of Avermectin

Abstract

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.

Synthesis of the Polyoxygenated Cyclohexanoid Core of Bioactive Glycosides Xylosmin and Flacourtosides E and F

“…Commercial silica gel (100−200 mesh particle size) was used for column chromatography. 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 , DMSO-d 6 , and D 2 O as the solvents on a 400 or 500 MHz spectrometer at ambient temperature. The chemical shifts are expressed in a parts per million (δ) scale using tetramethylsilane (Me 4 Si) as the internal standard.…”

“…The unprotected hydroxyl group in the resulting 13 was converted into a p -nitrobenzoate (PNB) derivative, and now the cyclohexene double bond in the resulting 14 was freely accessible for executing the proposed oxyfunctionalization protocol. OsO 4 -mediated catalytic dihydroxylation in 14 was predestined to be exo -selective and smoothly led to tetracyclic cis -diol 15 , which was converted into an acetonide 16 . Now, the internally protected functionalities in 16 were liberated on exposure to Zn in MeOH–AcOH milieu to yield a PAB ( p -aminobenzoate)-protected pentaoxygenated tricycle 17 (Scheme ).…”

The Growing Synthetic Utility of the Weinreb Amide

“…Application of the same concept using heteroaryl-or aryllithium has led to the synthesis of thieno[2,3-b]thiophenes, 59 benzocyclobutenones, 60 and methylideneindanones. 61 Applications of this concept in the syntheses of (-)-brunsvigine, 62 the hexahydrobenzofuran subunit of avermectin, 63 and fused indolizinone systems 64 have been the most important and interesting contributions.…”

Biomimetic Total Synthesis of the Pentacyclic Amaryllidaceae Alkaloid Derivative Gracilamine

“…9 Accordingly, we sought to use such a process for preparing compounds related to compound 3 (Figure 1) in order to further probe the validity of the proposed biogenesis of the gracilamine framework. The preparation of a suitable C3a-arylhexahydroindole is shown in Scheme 1 and began with the conversion of the readily available 2-iodocyclohex-2-en-1-ol (5) 10 into the corresponding mesylate under the Crossland− Servis conditions. 11 The product ester reacted with sodium azide in DMF to give compound 6 (83%).…”