Search

A synthetic approach to the eastern part of spiramycin, an important antibiotic compound, is described. Introduction of the side chain was first envisaged through a Hoppe aldehyde allylation. This reaction was carried outbetween an optically pure aldehyde 32 and a (′)-γ-alkoxy allyltitanium(IV) species derived from a primary γ-alkoxy allyl (diisopropyl)carbamate. Under kinetic resolution conditions, the anti-Cram compound 35 was obtained in an 80:20 mixture, with the Cram isomer 34, in 81% yield. Employing the optically pure (S)-γ-alkoxy allyl (diisopropyl)carbamate 36, the corresponding (R)-γ-alkoxy allyltitanium (R)-'Ti'-III was generated under n-BuLi.TMEDA/Ti(Oi-Pr) 4 conditions, that reacted with aldehyde 32 in double stereodifferentiation to deliver the expected Cram compound 40 in 80% yield (95% de). This latter corresponded to the C1-C7 fragment of spiramycin.

An efficient access to optically active (R)- or (S)-γ-alkoxy allyltitanium(IV) intermediates, in aldehyde allylation reactions, is described. Enantiomeric γ-alkoxy secondary allyl carbamates (R)- and (S)-14 were first prepared. Determination of their enantiomeric excess was realised on the corresponding deuterated isotopic derivatives by NMR in chiral liquid media. Subsequent aldehyde allylation reaction with propanal performed under Hoppe n-BuLi.(-)-sparteine/Ti(Oi-Pr) 4 or n-BuLi.TMEDA/Ti(Oi-Pr) 4 conditions, led to both enantiomeric homoallylic alcohols 15 or ent-15 in 90% yield, 100% ed and 80% ee.

The synthesis of the S1-N10 nine-membered lactone core 28 of ent-griseoviridin is reported. Starting from cystine derivative 25, encompassing a terminal ynoate, treatment under Zn/ AcOH conditions led to the formation of lactone 28 in 12% yield. Therefore, the lactone moiety of ent-griseoviridin is obtained in 10.7% overall yield for two steps. An access to the corresponding 5-epi-griseoviridin lactone 29 is also described.