Methymycin synthesis

In Masamune s methymycin synthesis [28b], the S-r-butyl thioester 47 upon treatment with 2 equiv of mercuric trifluoroacetate in acetonitrile solution (0.01 M) at room temperature for 1 h afforded the lactone 48 in up to 30% yield (Scheme 15). 

The cycloadduct (75d) has been utilized for the synthesis of nonactic acid (116) and lilac alcohol (119) via (118). The Prelog-Djerassi lactone (117), a pivotal intermediate in Masamune s methymycin synthesis, has been prepared tom the key compound (75e) (Scheme 21)J ... 

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. 

Masamune s methymycin synthesis is based on the coupling of the racemic Cj-Cg segment 4 with the optically pure Cg-C segment 7, and the introduction of the sugar moiety 10. 

As we predicted in last year s Report, the Sharpless chiral epoxidation procedure for allylic alcohols is beginning to make its impact with the synthesis of several important synthetic intermediates and natural products. We highlight here just one application to the synthesis of a key building block (2) for methymycin synthesis. This epoxide was produced in 79% yield and in >95% e.e. (Scheme 4). Owing to the water solubility of (2) modified work-up conditions were also developed and discussed. This enantioselective epoxidation method has been applied to produce a remarkably high kinetic resolution procedure for... 

The validity of the propionate rule of Birch et al. (i960) for methymycin synthesis was demonstrated by assuming that the Cg unit, represented by the carbon atoms C-7 and C-8, was derived from an acetate precursor. An alternate suggestion by Bentley (I962) was that even the Cg unit might have come from a propionate unit whose methyl group was oxidized and subsequently decarboxy-... 

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). 

As a model study for this methodology, Evans and Bartroli carried out the synthesis of (+)-Prelog-Djerassi Lactonic acid 47 [14b] [27], which is a degradation product of either methymycin or narbomycin [28] and has some of the important structural features present in macrolide antibiotics. 

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... 

The first part of the synthesis gives an intermediate that had been used in the synthesis of the antibiotic methymycin. In practice the Wittig was carried out on the epoxy-aldehyde and treatment of the last intermediate with aqueous acid gave the target molecule. 

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) ... 

Bicyclo[5,3,0]dec-l(7)-en-2-one was obtained by anodic oxidation of bicyclo-[4,4,0]decane-l,6-diol in methanol containing tetraethylammonium p-toluenesul-phonate. The dicarboxylic acid (68), used in the synthesis of methymycin, was obtained by oxidative cleavage of 8-formylbicyclo[4,2,l]nona-2,4-dien-7-one. Autooxidation of (-t-)-car-3-ene in the presence or absence of cobalt stearate gave a complex mixture of products including eucarvone (up to 11.5 %) and 3,6,6-trimethylcyclohepta-2,4-dienone (up to 48 %). 3-Methylene-4-cholestene gave a 40% yield of 3,3-diazido-A-homochoIest-5-ene when treated with Pb(OAc)4 (N3) . ... 

Sharpless and co-workers have utilized their recently discovered method for epoxidation of olehnic alcohols in a highly enantioselective manner to prepare the chiral epoxy-alcohols (5), (6), and (7), key intermediates for the synthesis of methymycin, erythromycin, and leukotriene C-1, respectively. The first stages in these reactions were described last year but the work-up procedures have now been modified to avoid problems with water-soluble products. 

Scheme 1.8 De novo synthesis of a methymycin monosaccharide iibrary.

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