Total Synthesis of Methynolide

Yamaguchi s methynolide synthesis is based on the coupling of the C1-C7 (13) and Cg-Cii (14) segments, both of which are prepared from the resolved compounds, and the macrolactonization using the mixed anhydride prepared by use of 2,4,6-trichlorobenzoyl chloride and dimethylaminopyridine (Yamaguchi method). 

Yonemitsu s methynolide synthesis is based on the coupling of the Cj-Cg (28) and C9-C11 (30) segments, both derived from o-glucose. 

The known diol 18 derived from the ketone 17 was converted into the olelin 19 or 20, each of which was submitted to a stereoselective hydroboration to give 

Similarly, Yonemitsu s group synthesized Masamune s seco-acid 8 (SBu = OH) by using the p-methoxybenzylidene protecting group. 

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This methodology was utilized effectively by Inanaga and coworkers in the total synthesis of methynolide.96 Using the silver acetylide in this case allowed for the mild introduction of the acetylenic moiety, avoiding the use of strong base in the presence of the base sensitive ynone product (Scheme 1.36). 

Ditrich, K., Bube, T., Sttirmer, R., and Hoffmann, R.W., Total synthesis of mycinolide V, the aglycone of a macrolide antibiotic of the mycinamycin series, Angew. Chem., Int. Ed. Engl., 25, 1028, 1986. Hoffmann, R.W., and Ditrich, K., Total synthesis of mycinolide V, Liebigs Ann. Chem., 23, 1990. Ditrich, K., Total synthesis of methynolide. Liebigs Ann. Chem., 789, 1990. 

Masamune et al. [42] developed the macrolactonization of to-hydroxy r-butyl thioester with Hg(OCOCp3)2 in MeCN at room temperature, and this method accomplished the first total synthesis of methynolide [1]. They further developed an alternative method using a phosphoric acid mixed anhydride, which was apphed to the synthesis of narbonolide [43] and tylonolide [44]. 

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

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

Since such reactivity has recently been reviewed,8 only a few examples are reported here. Acyl halides or epoxides can be alkynylated with preformed silver acetylides. Such processes have been applied to the total synthesis of the antibiotic macrolide (+ )-methynolide,96 and in the total synthesis of the antitumor agent FR901464 isolated from a Pseudomonas species (Scheme 10.62).97... 

The additional presence of a 3-methoxy substituent on the benzyl group confers greater stability on the intermediate cation, and consequently oxidation of DMPM ethers by DDQ is even more facile. Yonemitsu and cowoikers have used this differential reactivity of substituted benzyl ethers to great effect in the total synthesis of the macrolide antibiotics methynolide, tylonolide, (95)-9-dihydroerythro-nolide and pikronolide. The pikronolide synthesis provides an excellent example of the selective, sequential deprotection of DMPM, MPM and benzyl ether protecting groups (Scheme 7). 

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). 

Nitronate esters have been used for the same purpose of C=S to C=0 conversion, and the procedure was notably applied in a (+)-methynolide total synthesis [518]. 

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