(+)‐11,11′‐Di‐<i>O</i>‐methylelaiophylidene – preparation from elaiophylin and total synthesis from (<i>R</i>)‐3‐hydroxybutyrate and (<i>S</i>)‐malate

Abstract

Abstract The macrodiolide antibiotic elaiophylin ( 6 , Scheme 1) is converted into an aglycone 8a by acid‐catalysed cleavage of the deoxyfucoses in methanol, with replacement of two lactol OH‐groups by OCH 3 (C‐11 and C‐11′). The di‐ O ‐methylelaiophylidene ( 8a ), a C 2 ‐symmetrical macrodiolide with 2 × 11 stereogenic units, was synthesised from ( R )‐3‐hydroxy‐butanoate (from the biopolymer PHB) and ( S )‐malic ester, using diastereoselective steps for the generation of the other stereogenic units. The key intermediates (Scheme 2) are the macrocyclic dialdehyde 10 (cf. 26 , 27 ; 2 × 5 stereogenic units) and the silyl‐protected dihydroxy ketone derivative 11 (cf. 34, 35 ; 3 stereogenic units). These two intermediates almost statistically were subjected to aldol coupling with relative topicity ul , using the Z ‐boron enolate of the ketone, to give the two C 2 ‐symmetrical and the asymmetric aldol ( 40a, b, c ), one of which furnished the aglycone 8a upon acid‐catalysed methanolysis (Fig. 1 and 2, NMR spectra). The diastereoselective key steps, by which three of the six new asymmetric carbon atoms are created, are α‐alkylations of β‐hydroxy ester or lactone alkoxide‐enolates (malic acid → 12 and 15 → 16 in the dialdehyde synthesis, hydroxybutanoic acid → 29 in the ketone preparation).