Synthetic Strategy for Macrolide Synthesis

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. 

3-diol systems are often found in the polyoxomacrolide ring. Thus, two major synthetic transformations for the construction of 1,3-diols are described in this section (1) asymmetric aldol reaction and (2) asymmetric epoxidation and epoxide ring-opening. 

The aldol reaction is a versatile method for the construction of new carbon-carbon bonds in a regio-, diastereo-, and enantioselective manner. During the last two decades, major progress toward the total synthesis of macrolide antibiotics was made as a result of the development of the stereoselective aldol reaction in acyclic systems. This section is concerned mainly with the boron-mediated aldol reaction, which is particularly effective for the efficient synthesis of P-hydroxy carbonyl compounds [2]. 

The simplest asymmetric induction involves a reaction of an achiral enolate with a chiral aldehyde. In this case, if the boron enolate geometry and facial selectivity to the aldehyde are well controlled, the stereoselective aldol reaction will proceed. For example, treatment of (Z)-boron enolate 11 with chiral aldehyde 12 effected stereoselective aldol reaction to give sy -aldol adduct 13 as a single product [3]. 

The development of catalytic asymmetric aldol reactions is being extensively studied [20]. Further progress in this field will expand the impact of these reactions on the total synthesis of natural products. 

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