Methymycin, total synthesis

The few macrolides having 12-membered rings are Hsted in Table 2. Methymycin (12, R = OH, R = H), isolated from culture broths of a Streptomjces species (29), was the first macroHde stmcture elucidated (30). It is comprised of the aglycone methynolide (13, R = OH, R = H) and the aminosugar desosamine (1, R = OH, R = H) (31,32). Methymycin was also the first conventional macroHde made by total synthesis (33). 

Neomethymycin (12, R = H, R = OH), an isomer co-produced with methymycin, is the product of hydroxylation at C-12 rather than C-10 of the lactone (34,35). The corresponding aglycone, neomethynoHde (13, R = H, R = OH), was isolated with methynolide from broths of S. vene elae (36). The stereochemistry of 12(R)- for neomethynoHde was estabHshed by total synthesis (37). YC-17 (12, R = R = H), also found in broths of S. vene elae is a possible precursor of methymycin and neomethymycin. The hydroxyl groups at C-12 and C-10 are probably added as late steps in the biosynthesis (38). 

In the total synthesis of the macrolide antibiotic methymycin 49), Masamune and coworkers [28] developed a new macrolactonization method which makes use of the electrophilicity of Hg(II) toward bivalent sulfur. It involves the S -f-butyl thiolester 44 of the hydroxy acid 41 and employs mercuric trifluoroacetate as an activating agent. The required S -r-butyl thiolester 44 can be prepared in high... 

This lactonization procedure was used by Masamune et al. in a total synthesis of methynolide (6), the aglycone of the macrolide antibiotic methymycin. 

Mercuric trifluoroacetate [Hg(OCOCF3)2] is an effective reagent for the cyclization of hydroxy thio-esters. 5 This cyclization procedure was used by Masamune et al. for the conversion of 225 to 227 (in 90% yield) in a synthesis of zearalenone dimethyl ether. Masamune developed this procedure to complete the total synthesis of methymycin, where one step involved treatment of a thioester with mercuric salts. 2,96 Mercury(II) has an affinity for bivalent sulfur and it binds the thioester unit as well as the terminal hydroxyl... 

When a stone is thrown into a pond, several waves are produced in succession, gradually spreading until they finally cover the whole pond. The stone in macrolide synthesis was the news that R.B. Woodward had started the total synthesis of erythromcyin A in 1973. Some waves are represented by Masamune s methymycin synthesis in 1975, Corey s erythronolide synthesis in 1978 and Tatsuta s carbomycin and tylosin syntheses in 1977 and 1981. One of the biggest waves is Woodward s erythromycin synthesis in 1981. 

Total syntheses of the following antibiotics and/or their aglycones are dealt with methymycin, erythromycin, pikromycin, oleandomycin, ingramycin (albo-cycline), carbomycin B, leucomycin A3 (josamycin), tylosin, mycinamicins, rosaramicin, A26771B and elaiophylin (azalomycin B). Since the total synthesis of the macrolide-like immunosuppressant FK-506 has been recently reported, it is also reviewed here. Today, erythromycin A, oleandomycin, leucomycin A3 (josamycin), tylosin and mycinamicin II are clinically important antibiotics. 

J.1.1 The First Total Synthesis of Methymycin Masamune, 1975 (Scheme 1) 4,5 ]... 

A review on the total synthesis of macrolide antibiotics includes discussion of chiral routes to the aglycones from carbohydrates. Hethynolide (27), the aglycone of methymycin, has been prepared from the hydroxy-aldehyde (28) and the acid (29) by esterification followed by intramolecular Wadsworth-Emmons reaction (Scheme 5) ... 

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