A highly convergent total synthesis of the spiroacetal macrolide (+)-milbemycinβ1

• DOI: 10.1016/s0040-4020(01)89182-1
• Publication Date: 2002-07-25T17:44:48Z
• Authors: Steven V. Ley; Neville J. Anthony; Alan Armstrong; M.Gabriella Brasca; Trafford Clarke; David Culshaw; Christine Greck; Peter Grice; A.Brian Jones; Barry Lygo; Andrew Madin; Richard N. Sheppard; Alexandra M.Z. Sl...; David J. Williams
• Keywords: Natural product; Stereocenter; Pyran

Abstract A highly convergent synthesis of the macrolide natural product milbemycin β1 is reported. The key features of this synthesis include the introduction of the C11-C15 side chain by selective ring opening of a symmetrical 1,4-pentane bis-epoxide (3) followed by reaction with the anion derived from the 2,3-trans-dimethyl-6-phenylsulphonyl pyran (2) to afford the “northern” C11-C25 fragment (33) of milbemycin β1. Coupling of the derived C11-C25 aldehyde unit (37) with a C1-C10 southern zone fragment (5) was achieved via a novel deconjugative vinyl sulphone anion sequence to give a product containing all the carbon substituents of the natural product. Final manipulations involved macrolactonisation and subsequent introduction of the important 3,4-double bond by selenoxide syn-elimination. Methylation of the C-5 hydroxyl group was accomplished as the penultimate step with methyl iodide and silver (I) oxide under ultrasonication.