Jump to main content
Jump to site search

Issue 20, 2005
Previous Article Next Article

A total synthesis of milbemycin G: approaches to the C(1)–C(10)-fragment and completion of the synthesis

Author affiliations

Abstract

A synthesis of the hydroxybutenolide (−)-6 required for synthesis of α-milbemycins and the completion of a total synthesis of milbemycin G 7 is reported.

Following preliminary studies, an optimised synthesis of the hydroxybutenolide (−)-6 from the hydroxyketone 38 was developed which involved the resolution of 38 by separation of the 3-(O-chloroacetyl)-(S)-mandelates 80 and 83. Ester 80, which corresponded to the required enantiomer of the hydroxyketone 38, crystallized from the mixture of the diastereoisomeric esters 80 and 83 giving the (−)-hydroxyketone (−)-38 in an overall yield of 47% (based on racemic 38) after ethanolysis. Hydroxyketone (−)-38 was oxidised to the enolic diketone (−)-39 and phenylselenation and stereoselective reduction gave the trihydroxycyclohexyl selenide (−)-43. The regioselective introduction of the non-conjugated double-bond into the six-membered ring was then achieved by esterification of the 4-hydroxyl group using trichloroacetic acid to give the trichloroacetate (−)-69. Oxidative elimination from the trichloroacetate using tert-butyl hydroperoxide was highly regioselective and gave the endo- and exocyclic alkenes (−)-44 and (−)-46 in a ratio of 95 : 5 after ethanolysis of the trichloroacetates. Selective O-methylation of the 4-hydroxyl group via the cyclic stannylene 55 and protection of the 3-hydroxyl group as its 2-trimethylsilylethoxymethyl (SEM) ether gave the ester (−)-57. Following saponification of the ethyl ester, re-esterification using 2-trimethylsilylethanol and oxidation of the 2-trimethylsilylfuryl fragment using singlet oxygen gave the required hydroxybutenolide (−)-6.

The Wittig reaction between the phosphonium salt 2 and the hydroxybutenolide (−)-6 gave a ca. 2 : 1 mixture of the (4Z)- and (4E)-isomers of the ester 84 which on treatment with a catalytic amount of iodine was converted into the (4E)-isomer (4E)-84. Deprotection gave the seco-acid 85 but attempts to macrocyclise this were unsuccessful, the elimination product 86 being the only product isolated. The Wittig product 84 was taken through to the butenolide (2E)-91 by removal of the SEM group, cyclisation to form the butenolide ring and diene isomerization, but this could not be converted into the corresponding seco-acid 92. However, removal of the SEM group from the seco-acid 85 gave the trihydroxy-acid 93 which was cyclized under modified Yamaguchi conditions to give the macrolide 94 together with a small amount of the macrocyclic butenolide 95. Reduction of this mixture using diisobutylaluminium hydride gave (6R)-6-hydroxymilbemycin E 96 which was converted to milbemycin G 7 by cyclisation of the primary chloride 97. The synthetic milbemycin G 7 was identical to a sample prepared by methylation of a commercial sample of milbemycin D 98, 7-O-methylmilbemycin G 99 being a side-product of this methylation.

Graphical abstract: A total synthesis of milbemycin G: approaches to the C(1)–C(10)-fragment and completion of the synthesis

Back to tab navigation

Supplementary files

Publication details

The article was received on 22 Jun 2005, accepted on 08 Aug 2005 and first published on 14 Sep 2005


Article type: Paper
DOI: 10.1039/B508675B
Org. Biomol. Chem., 2005,3, 3654-3677

  •   Request permissions

    A total synthesis of milbemycin G: approaches to the C(1)–C(10)-fragment and completion of the synthesis

    S. Bailey, M. Helliwell, A. Teerawutgulrag and E. J. Thomas, Org. Biomol. Chem., 2005, 3, 3654
    DOI: 10.1039/B508675B

Search articles by author

Spotlight

Advertisements