Total Synthesis of Selected Macrolides

The total synthesis of FK506 has been completed by the Merck group [121] in 1989, by Schreiber et al. [122] in 1990, and by Ireland et al. [123] in 1996. In addition, Danishefsky etal. [124], Gu and Sih [125], and Smith et al. [126] have each completed formal total synthesis. The synthetic strategy of each group is outlined in Fig. 5. The order of bond connection of significant segments for the synthesis of the target molecule is described by number and reaction names. The several 

218a R = Me 218b R = Cl 218c R = allyl 218d R = OMPM 218e R = OMe 

The first total synthesis by the Merck group was accomplished via coupling of the C10-C19 and C20-C34 segments, attachment of (5 )-pipecolic acid to the C26 hydroxyl group, aldol addition of glycolate derivatives to the CIO aldehyde, and final macrolactamization (Fig. 5). 

The Schreiber group has fiuther carried out structural and mechanistic studies combined with chemistry and biology [128]. The solution structure of FK506 and rapamycin binding protein (FKBP) has been determined by NMR and the structure of FKBP, complexed with FK506, has also been determined by X-ray crystallography. 

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In Section II, the synthetic strategies for macrolide synthesis are introduced and focus in particular on asymmetric synthesis of 1,3-diol, synthetic methodology for macrolactone, and glycosidation. In Section III, the total synthesis of selected macrolide antibiotics is introduced FK506 (tacrolimus 1), rapamycin (sirolimus 2), avermectins (3), altohyrtins (spongistatins 4), and epothilones (5) (Fig. 1). Several other synthesized macrolides are also illustrated. 

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