Macrolactonization and

The first total synthesis of erythronolide B (1) by Corey stands as an event of great historical significance in synthetic chemistry it provides a powerful illustration of the utility of Corey s methods of macrolactonization and it demonstrates, in a particularly insightful way, the value of using readily accessible six-membered ring templates for the assembly of contiguous arrays of stereo-genic centers. 

The group of Samuel Danishefsky at the Sloan-Kettering Institute for Cancer Research in New York has also been active in the synthesis of the natural epothilones and biologically active analogs. One of these syntheses also uses the olefin metathesis reaction (not shown). The synthesis in Scheme 13.51 uses an alternative approach to create the macrocycle. One of the key steps is a Suzuki coupling carried out at step H-(l,2) between a vinylborane and vinyl iodide. The macrocyclization is an aldol addition reaction at step H-4. The enolate of the acetate adds to the aldehyde, creating the C(2)-C(3) bond of the macrolactone and also establishing the stereocenter at C-3. 

S. Donadio, M. J. Staver, J. B. McAlpine, S. J. Swanson, and L. Katz, Biosynthesis of the erythromycin macrolactone and a rational approach for producing hybrid macrolides, Gene, 115 (1992) 97-103. 

Scheme 2. Macrocyclization reactions applied in epothilone total syntheses. From top to bottom ring-closing me-tathesis (RCM) macrolactonization, and C2-C3 macroaldolizalion. (TBS = tert-butyldimethylsilyl, TPS = triphe-nylsilyl, HMDS = hexamethyldisilazide).

Although Bu2SnO is a powerful catalyst for cyclization of co-hydroxy and co-amino carboxylic acids [294], treatment of co-hydroxy trifluoroethyl esters with Bu jSnOMe catalysis resulted in macrolactonization and/or diolide formation in different ratios, depending on chain lengths and reaction conditions (Scheme 12.166) [295]. In this reaction inter- and/or intramolecular transesterification occurred between trifluoroethyl esters and alkoxytrialkyltin generated by rapid exchange of the alkoxytin catalyst with the terminal alcohol. By use of this procedure as a final key step a 12-membered macrocyclic otonecine diester was obtained (Scheme 12.167) [296]. 

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. 

Efficient construction of the macrocyclic ring is essential for achievement of the total synthesis of macrolide antibiotics. Macrolactonization and intramolecular Wittig-type reaction have been frequently used so far. In recent years, olefin metathesis and Stille-type reaction for formation of C-C bonds have been efficiently applied to the construction of macrocyclic rings. 

Sections 2.2 and 2.3 focus on the detailed synthesis of the macrolactonic and southern fragments of mycolactone A/B analogs, and the assembly of all fragments will be discussed next in Section 2.4. 

Antibiotics of the streptogramin family are an association of two groups of molecules the group A components are polyunsaturated macrolactones and the group B components are peptidic macrolactones (depsipeptides). The different members of each group differ in some substituents, functional moieties or amino-acid residues (see Sects. 4.1 and 5.1). 

In 2004, Myers and Haidle reported a convergent and modular total synthesis of cytochalasin B (1088) and the [lljcytochalasan L-696,474 (1139) (742), using a late-stage macrocyclization step involving an intramolecular Horner-Wadsworth-Emmons olefination. Their strategy is applicable for the synthesis of cytochalasans of different ring sizes, as exemplified by these two total syntheses. Both macrolactone and macrocarbocyclic cytochalasans can lead back retrosyntheticaUy to the same precursors. The synthesis of the tricyclic isoindolone precursor to cytochalasin B (1088) and L-696,474 (1139) is shown in Scheme 14.1. 

Marine macrolides have numerous asymmetric centers, oxygenated function-ahties including alcohols, carbonyl groups, the tetrahydropyran moiety, di-and trisubstituted alkenes, and macrocycUc lactones. For completion of their total synthesis, efficient and stereoselective introduction of these characteristic units should be crucial. Recently, an excellent review on asymmetric synthesis of 1,3-diol, macrolactonization, and glycosidation in the syntheses of macrolides has been pubUshed by Nakata [5]. The multisubstituted tetrahydropyran moieties are often found in the marine macrohdes, and the efficient preparation of these moieties is recognized as the key reaction in their total synthesis. In this decade, efficient methods for their stereoselective construction have been developed and used in the total synthesis of marine macrolides, wherein the relative configuration of 2- and 6-substituents is pivotal. In this section, recent progress in the preparation of tetrahydropyrans is described (for a previous review on the preparation of tetrahydropyrans, see [9]). 

Recently, Shishido has achieved the third total synthesis of (+)-lasonolide A, and their synthetic strategy was based on the introduction of the side chain via Lee s protocol, the successful Yamaguchi macrolactonization, and the... 

Scheme 6.13. Solid-supported macrolactonization and simultaneous release from the resin via RCM reaction. Product 51 was further elaborated to 52.

Srihari and collaborators [88] reported the first synthesis of paecilomycin E starting from L-diethyl tartrate. As shown in Scheme 7.27, route to the fully functionalized framework of paecilomycin E is conceptually similar to the synthesis developed by Marquez group [78] for the triene precursor of LL-Z1640-2 (164, Scheme 7.18). RCM on 225 was highly efficient in generating the 14-membered macrolactone and paecilomycin E was finally obtained after global acidic deprotection. The analytical data for synthetic paecilomycin E did not match those reported for the natural... 

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