Erythronolide approach

A stereoselective osmylation approach was applied to the synthesis of C(l)—C(7) and C(7)—C(13) subunits of erythronolide A41. A key synthon of the erythronolide A seco acid, 30, was prepared in an enantiomerically pure form by utilizing a stereoselective osmylation of the chiral hydroxy (Z, )-diene ester 31 and subsequent hydrogenation of the resulting butenolide 32 (equation 24). 

Examples are the synthesis of prostaglandin F2 and erythronolide A (8) from D-glucose, by Stork [20] and Hanessian [19] and their coworkers, respectively, whose retrosynthetic pathways are shown in Schemes 9.9 and 9.10. For more details concerning this strategy, known as "the chiron approach", see the book by Hanessian [19]. 

Deoxyerythronolide B (105) is a 14-membered lactone with 10 asymmetric centers arrayed on the framework of the macrocyclic ring. This compound, produced by the mutant strain Steptomyces erytheus, is the common biosynthetic precursor of erythronolide A and B. A rather novel approach to this compound... 

Owing to the complexity of the erythronolides, the problems involved in a synthetic approach seemed at one time insurmountable. The late R. B. Woodward once wrote, Erythromycin, with all of our advantages, looks at present hopelessly complex, particularly in view of its plethora of asymmetric centers. Yet Woodward s group completed a remarkable synthesis of erythromycin B after his death. 

Because of the intricacies associated with construction of the erythronolide framework, this group of macrolides served as the yardstick for accomplishment in this area, and as such has attracted considerable.attention. Consequently, we would like to develop, for the benefit of the reader, several other synthetic approaches that have been described (some of which are still under investigation). Although not total syntheses in the strictest sense, all of the efforts presented here have made substantial progress toward the elaboration of the stereochemistry of this complex system. We have by necessity exercised editorial judgment as to which among a number of ongoing efforts have been included in this chapter. Additionally, several other unpublished routes have recently been reviewed. ... 

Stork had also recognized the symmetry element present in the erythronolide A skeleton. The Stork approach is outlined in Scheme 2.18. Cyclopentadiene was converted into the optically pure (lS,2S)-(4-)-2-methyl-3-cyclopenten-l-ol (196) utilizing literature procedures. Stereoselective syn epoxidation followed by oxidation and base treatment afforded an alcohol which was silylated to give 197 in 71% overall yield. As expected, the y-silyloxy group induced the addition... 

A unique approach to the stereochemical complexities of erythronolide A was developed by Deslongchamps as outlined in Scheme 2,19. The methyl ester of erythronolide A seco acid (212) was dehydrated to form the cyclic ketal 213. A multistep oxidation of the side chain then gave aldehyde 214 which, when condensed with the zirconium enolate of methyl propionate, afforded a 10 1 ratio of aldol diastereomers, the major being 213. Furthermore, aldehyde 214 could easily be converted into the y-lactone 215. 

Another concise approach to the erythronolide ring system was developed by Chamberlin and co-workers, as described in Scheme 2.20. Like Woodward... 

Note the preferential reaction at the anomeric hydroxyl. The method is also effective for the protection of primary and secondary alcohols. A modification of this approach which uses f-Bu0C02CH2CH=CH2as the allyl source selectivity monoalkylates a tertiary hydroxyl in the erythronolide derivative. 

Martin, S.F., Lee, W.-C., Pacofsky, G.J. et a(. (1994) Strategies for macrolide synthesis. A concise approach to protected seco-acids of erythronolides A and B. Journal of the American Chemical Society, 116, 4674-4688. 

Another successful approach for blocking the intramolecular decomposition illustrated in Fig. 2 involved inhibition of the dehydration step leading to the anhydrohemiketal by replacement of the C-8 proton of erythromycin with fluorine. Preparation of flurithromycin (8-fluoroerythromycin, see Fig. 4) has been achieved by both chemical and biochemical methods. Addition of 8(S)-8-fluoroerythronolide A to a mutant strain of Streptomyces erythreus blocked in biosynthesis of its endogenous lactone (erythronolide) yielded the desired fluorinated erythromycin [40]. This technique of mutasynthesis has been further employed for the production of other fluorinated derivatives of erythromycin [40, 41]. Fluorination of different 8,9-anhydro-6,9-hemiketal derivatives of erythromycin by chemical means with reagents such as trifluoromethyl hypo-fluorite or perchloryl fluoride (with subsequent reduction of the N-oxide) has also been reported [42, 43]. 

A novel and ingenious approach to the stereochemically frightening macrolide erythronolide A (M, Scheme 15) is being pursued by Hannes-siAN, Rancourt and Guindon. The approach is based on the recognition of hidden symmetry in the molecule (33) a conception which enables... 

We realized that a linear synthesis is generally less efficient than a convergent one. Therefore a number of convergent variants of the above synthetic plan were considered and tested. These efforts were discontinued when it was found that these convergent approaches to erythronolide could theoretically be only marginally more (and in practice less) efficient than the linear synthesis described below. 

Although macrolides are of contemporary interest, the first major steps toward successful macrolide syntheses were reported in the 1970 s. Thus, for historical reasons, we will look at two approaches to the classical target erythromycin A and its aglycone, erythronolide-A. 

Carreira has demonstrated that the hydroxy-directed nitrile oxide cycloaddition reaction is a general synthetic approach to polyketide fragments, with the intermediate isoxazolines functioning as latent, masked aldol adducts [65], The 1,3-dipolar cycloadditions have been shown to tolerate a large variety of alcohol substrates, including aliphatic allylic, homoallylic, and cyclic allylic alcohols [65-67], A demonstration of the versatility of the approach was reported in the synthesis of erythronolide A (58, Scheme 18.12) [67], This synthetic effort took advantage of two sequential hydroxy-directed nitrile oxide cycloadditions to provide fragments 55 and 57, both of which were obtained with excellent yields and diastereoselectivity (dr2 98 2). 

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