Total synthesis of milbemycin E: resolution of the C(1)–C(10) fragment and final assembly

Abstract

The racemic hydroxycyclohexanone (±)-7, prepared by the Robinson addition of the keto ester 5 to 3-methylbut-3-enone 6, has been reduced stereoselectively to give the racemic cyclohexanediol (±)-8. This has been resolved by fractional crystallisation of the acetylmandelate esters 10 and 11. With (S)-acetyl mandelic acid 9, diastereoisomer 11 crystallises out. The required, dextrorotatory, enantiomer of the cyclohexanediol (±)-8 has been obtained by selective saponification of the mixture of the diastereoisomers 10 and 11, to give the mandelates 12 and 13, followed by crystallisation of the required diastereoisomer 12. Saponification of 12 gives the dextrorotatory enantiomer of the cyclohexanediol (+)-8 [which could alternatively have been obtained directly from the racemic diol (±)-8 using (R)-acetylmandelate ent-9]. Oxidation of the dextrorotatory diol (+)-8 gives the laevorotatory hydroxy ketone (-)-7. The 3,4-double bond has been introduced into this ketone by regioselective enol trimethylsilyl ether formation, phenylselanation and oxidative elimination, followed by reduction to give the cyclohexenediol 18. Methylation, saponification and re-esterification give the 2-furylcyclohexenoate 23, which on oxidation using singlet oxygen is converted into the hydroxybutenolide 3. The dextrorotatory diol (+)-8 has also been converted into the hydroxybutenolide 29 which lacks the 3,4-double bond. Conditions have been developed for the Wittig reactions between the hydroxybutenolides 29 and 3 and the phosphonium salt 2 to give the esters 32 and 37 after esterification using diazomethane and iodine induced isomerisation of the 10,11-double bond. Deprotection gives the hydroxy acids 33 and 39 which have been cyclised to give the macrolides 34 and 40. Selective reduction of these methyl esters gives 3,4-dihydromilbemycin E 35 and milbemycin E 1.