Methynolide synthesis

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 compounds 26 and 30 were also used for his methynolide synthesis. The aldehyde derived from 26 reacted with crotyltributylstannane to give stereoselectively 121, which was selectively protected to the alcohol 122. This alcohol was transformed into the ketophosphonate carboxylic acid 123. Yamaguchi esterification of 30 with 123 gave the corresponding ester, which was cyclized by Nicolaou method to give the 14-membered enone 124. Selective deprotection of the DMPM group with DDQ followed by Swem s oxidation... 

Conversion of Thioketones to Ketones. Thioketones generated by a Norrish-type photofragmentation of a sulfenyl acetophenone are trapped in situ by [3 + 2] dipolar cycloaddition with a silyl nitronate (eq 10). Fluoride treatment of the resulting heterocycle produces the ketone. This transformation is compatible with a variety of functional groups and has been used as part of a synthetic manipulation in which an a-acyl cyclic thioether is converted stereoselectively, with ring enlargement, to a ketolactone (methynolide 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). 

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]. 

If the acyl moiety is sensitive to acid and base the imidazolide method for synthesis of (acylmethylidene)phosphoranes is the method of choice, as shown by the following example, which represents a step on the way to the antibiotic methynolide ... 

The overall sequence occurs under nearly neutral conditions at room temperature and was shown to be an efficient tool for an oxidative desulfurization step required in sulfur-mediated synthesis of complex molecules such as methynolide and cytochalasin [253]. 

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]. 

F. J. Lopez-Herrera, F. Sarabia-Garcia, M. S. Pino-Gonzalez, and J. F. Garcia-Aranda, A new synthesis of 2-C-methyl-D-ribono-1,4-lactone and the C-9/C-13 fragment of methynolide, J. Carbohydr. Chem., 13 (1994) 767-775. 

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). 

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). 

Lactonization. Esters and lactones can be prepared using a trichlorobenzoic mixed anhydride, prepared by reaction of an acid with trichlorobenzoyl chloride. Thus the anhydride reacts with an alcohol in the presence of 4-dimethylamino-pyridine to form an ester in yields usually >90%. The same method can be used for lactonization. Nine- to thirteen-membered rings can be prepared in 35-65% yield. This method was used for synthesis of methynolide (6), a macrolide antibiotic, from a sequence shown in equation (I). 

The foregoing methods have been successfully applied to the synthesis of carbocyclic cytochalasans and the macrolide methynolide (191 equation 22). Iterative ring expansion of the five- and eight-mem-bered ring sulfonium salts (187) and (189) leads to the 11-membered ring sulfur heterocycle (190). Sulfonium salt (189) is a 1 1 mixture of stereoisomers that gives (190) with 16 1 selectivity in 76% yield. 

The formation of mixed anhydrides, which in some cases may be isolated, is an established method. For instance, racemic zearalenone (352) has been obtained by treating the seco-acid (351) with trifluo-roacetic anhydride (equation 126). Similarly, antimycin A3 has been prepared. A more modem procedure makes use of Yamaguchi s 2,4,6-benzoyl chloride esterification. For example, a synthesis of methynolide is based on the lactonization of the alkynic seco-acid (353) to (354 equation 127). 

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]. 

In an earlier ehapter in this series (Volume 1, Chapter 13) written twenty years go, one of us compared the exercise of a complex synthesis to a tortuous journey "that continually asserts the unpredictability of travel through all but the most familiar terrain." And that was a chapter describing a synthesis of the Prelog-Djerassi lactone Onward travel to methynolide, the simplest of all the macrolide aglycons, seemed like a daunting task for its time. It is a measure of the distance synthetic organic chemistry has come in the past two decades that we can now plan and execute routes to the most complex macrolide structures found in nature, albeit with a blueprint that usually requires many steps and at a level of overall efficiency that removes practical value from the sequence in most... 

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