Macrolides, formation

Total syntheses have been reported by E.J. Corey (1978B, 1979). We outline only the stereoselective synthesis of a protected fragment (A) which contains carbon atoms 1—9. This fragment was combined with fragment (B) by a Grignard reaction and cyclized by one of the methods typical for macrolide formation (see p. 146). 

Elaboration of triol 88b to bryostatin 7 requires chemoselective hydrolysis of the Cl methyl ester in the presence of the C7 and C20 acetates, macrolide formation, installation of the C13 and C21 methyl enoates, and, finally, global deprotection. The sequencing of these transformations is critical, as attempts to introduce the C21 methyl enoate to form the fully functionalized C-ring pyran in advance of macrolide formation resulted in lactonization onto the C23 hydroxyl. In the event, trimethyltin hydroxide promoted hydrolysis [73] of the Cl carboxylate of triol 88b, and subsequent trie thy lsilylation of the C3 and C26 hydroxyls each occurs in a selective fashion, thus providing the seco-acid 89. Yamaguchi macrolacto-nization [39] proceeds uneventfully to provide the macrolide 67 in 66 % yield (Scheme 5.14). 

The macrolide systems described above are produced by formation of an intramolecular ester or amide linkage, utilizing appropriate functionalities in the growing polyketide chain. Macrolide formation does not always occur, and similar acetate-propionate precursors might also be expected to yield molecules which are essentially linear in nature. Good examples of such molecules... 

The intramolecular version of vinyl-vinyl coupling has been less often applied, but the potential shonld be clear from one example of macrolide formation. This example also demonstrates the use of formic acid as an in situ reducing agent and the high reactivity of vinyl iodides 25 °C is an unusually low temperature for the Heck reaction (equation 18). ... 

Oxyselenation ofalkeues, - Treatment of olefins with 1 or 2, water, and an acid catalyst (e.g., p-TsOH) in CH2CI2 affords j3-hydroxy selenides in excellent yield. Unsaturated carboxylic acids, phenols, alcohols, thioacetates, and urethanes react with 1 or 2 and an acid catalyst ( —78- 25°) to afford products of oxidative cyclization. These reagents are superior to benzeneselenenyl halides for selenium-induced ring closures. This reaction is also useful for synthesis of 14- and 16-membered lactones. Benzeneselenenyl halides and benzeneselenenic acid do not promote macrolide formation under similar conditions. 

Conversion to benzoate ester 96, obtained by conversion of 94 into the corresponding acid chloride 95 followed by addition of alcohol 91, then set the stage for macrolide formation. This cyclization was effected by deprotonation and intramolecular alkylation at the benzylic position in 41% yield. Desulfurization and concomitant reduction of the olefin then provided 0-methyl lasiodiplodin (97) in 68% yield. Although Tsuji was readily able to construct the six-membered ring at the proper oxidation level, the symmetry implicit in this strategy precluded the required differentiation of the phenolic hydroxyl groups. 

However, the main emphasis in this area recently with respect to the development of new methodology has been on macrolide formation by C-C rather than C-0 coupling. Intramolecular displacement of a methylthio-group by an allyl-stannane function, initiated by dimethyl(methylthio)sulphonium fluoroborate (DMTSF), under high dilution conditions (O.OlM) has been used to prepare... 

Dipyridyl disulfide and related compounds have also been used as a method for macrolide formation the addition of thio-philic metal cations and/or pyridine derivatives has been found to assist this process. This oxidation-reduction condensation, using 2,2 -dipyridyl disulfide, constitutes an excellent strategy for the solid-phase synthesis of peptides. This method does not affect amino acids sensitive to oxidation, proceeds under mild conditions without the requirement of basic or acid catalysts, and has the advantages of minimizing both racemization of carboxyl component and side-reactions of certain amino acids. Furthermore, it has been successfully applied to phosphorylation reactions, such as the synthesis of coenzyme A, oligothymidilates, and nucleotide cyclic phosphates, and nucleotides from G ,2 -cyclouridine. ... 

The prevalence of diols in synthetic planning and in natural sources (e.g., in carbohydrates, macrolides, and nucleosides) has led to the development of a number of protective groups of varying stability to a substantial array of reagents. Dioxolanes and dioxanes are the most common protective groups for diols. The ease of formation follows the order H0CH2C(CHc,)2CH20H > H0(CH2)20H > H0(CH2)30H. 

Oxazol-5(4//)-ones as intermediates in the formation of macrolides, cyclodep-sipeptides, and cyclopeptides 99JHC1539. 

Radical cyclization to macrolides.111 Cyclization of iodoalkyl acrylates (1) by reaction with Bu3SnH (1 equiv.) in the presence of AIBN is useful for formation of macrolides (2) containing 11 or more members. Similar cyclization of iodoalkyl fumarates (3) results in two macrolides with the endo-product predominating except when n is 16 or higher. Tertiary iodides undergo this free radical cyclization more... 

Zotarolimus (53 Endeavor stent) Sirolimus (33) Macrolide antibiotic Semi-synthetic NP Microbial Cardiovascular surgery Inhibits cell proliferation, preventing scar tissue formation and minimizes restenosis in angioplasty patients 467 74... 

Shimagaki et al. reported the synthesis of the C11-C16 fragment of the penta-mycin based in the stereoselechve C—C bond formation reaction catalyzed by FBPA [45]. Pentamycin is a polyene macrolide antibiotic, whose configurations at C15 and C14 would correspond to those of the C3 and C4 posihons of an aldol constructed from addihon of DHAP-derived from FBP by use of FBPA and TIM-to the corresponding aldehyde catalyzed by FBPA (Scheme 4.19). 

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