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

Abstract

AbstractThe 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 OCH3 (C‐11 and C‐11′). The di‐O‐methylelaiophylidene (8a), a C2‐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 C2‐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).