Macrolide antibiotic intermediate

The well known valerolactone (115), commonly described as the Prelog-Djerassi lactone, has attracted the attention of many synthetic chemists over the years and another synthesis of this important macrolide antibiotic intermediate has appeared (Scheme 13). The synthesis involves the Hg -induced cycliz-ation of the aldehyde (114) to control the stereochemistry at C(2) and C(3). This was followed by demercuration with sodium trithiocarbonate in methanol at -60 C, hydrolysis, and oxidation to give the lactone (115) and its epimer in a 3.5 1 ratio. Demercuration with sodium borohydride followed by hydrolysis and oxidation gave almost complete inversion. 

One of the most famous examples of intramolecular attack of oxygen on the nitriUnm ion intermediate was observed in the Beckmann rearrangement of Erythromycin oxime derivatives and was used in the discovery and synthesis of the commercial macrolide antibiotic Azithromycin 464. In fact, the Beckmann rearrangement of Erythromycin A 9( )-oxime 460 produced only small amounts (5%) of the expected amide 463, along with two isomeric imino ethers (461 and 462) in a fair yield (38 and 43%) (equation 198). 

Oxidation reactions can produce hydroxylation on the aromatic rings, such as in the case of the steroids and thiabendazole, or on the aliphatic carbon chain such as in the case of pentobarbitone. They can also cause epoxidation, which leads to normally unstable intermediates that can be hydrolyzed by epoxide hydrolase to dihydrodiols. In addition, they can produce oxidative dealkylation at the alpha carbons of the alkyl groups attached to a nitrogen, sulfur, or oxygen atom of the drug molecule, as in the case of the macrolide antibiotics and trimethoprim. Moreover, they can induce oxidation of sulfur atoms to the corresponding sulfox-... 

The malonate adduct (186c) has been used62 as an intermediate for the preparation of molecules corresponding to substructures of the macrolide antibiotics tylosin (193) and carbomycin B (194 Scheme 32). Decomplexation of (186c), followed by decarboxylation and ester hydrolysis, gives the carboxylic acid... 

At the start of the analysis when you have done no more than recognise the FGs and note special features (such as rings) or easy disconnections, note also the number of chiral centres and their relationship to each other. The Prelog-Djerassi lactone 1 is an important intermediate in the synthesis of macrolide antibiotics.1 It has a six-membered lactone ring and a separate carboxylic acid. More to the point, it has four chiral centres la. Three (1-3) are adjacent and one (5) separate. We might say that the three adjacent centres should be easy to control because they are next to each other but that we might have trouble with C-5. Another way to look at it is to say that the three round the six-membered ring (2, 3 and 5) should be easy to control, as the... 

Pershing L, Franklin MR. Cytochrome P-450 metabolic-intermediate complex formation and induction by macrolide antibiotics a new class of agents. Xenobiotica 1982 12 687-699. 

Since ketene is probably the intermediate of the Wolff rearrangement, the choice of solvents dictates the nature of the product. Indeed, water gave carboxylic acids, whereas alcohols or amines led to esters and amides, respectively. These combinations have been applied to the synthesis of more complex molecules. For example, the total synthesis of carbonolide B, a 16-membered macrolide antibiotic, relied on Amdt-Eistert homologation. In this sequence, a protected furanuronic acid was transformed to the corresponding a-diazoketone, which was then converted to its homologous carboxylic ester. The reaction was achieved using catalytic amounts of silver benzoate and excess of triethylamine in methanol (Scheme 3.4).11... 

The second example [Scheme 2.126] shows how a latent carboxyl function was released from the a-hydroxyoxazoline by /V-methylation to give an iminium salt that was then hydrolysed to an advanced intermediate in a synthesis of the macrolide antibiotic Nargenicin.257... 

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). 

Aside from alkylcuprates, alternate methods for the introduction of a second methyl group via olefination reactions have been proposed, as shown below. An illustrative example of this strategy will be given in conjunction with synthetic approaches to the Prelog-Djerassi lactone [46,47], a degradation product of the macrolide antibiotic methymycin and a key intermediate on the way to polypropionate products. 

Nicolaou, K.C., Pavia, M.K.. and Seitz, S.P., Carbohydrates in organic synthesis. Synthesis of 16-membered-ring macrolide antibiotics. Part 5. Total synthesis of 0-mycinosyltylonolide. Syntliesis of key intermediates, J. Am. ( hem.. Soc., 104, 2027, 1982. 

In a separate, elegant use of 165, Rychnovsky and coworkers have carried out a diastereoselective addition of methyl acetate-derived silyl ketene acetal to aldehyde 174 to afford adduct 175 in high diastereomeric purity (Scheme 15) [102]. Hydroxy ester 175 was subsequently employed as an intermediate in the total synthesis of the polyene macrolide antibiotic Roflamycoin. This work highlights a novel application of the chiral catalyst system in reagent-controlled coupling of chiral functionahzed substrates which by themselves display only mod-... 

At the start of the analysis when you have done no more than recognise the FGs and note special features or easy disconnections, note also the number of chiral centres and their position. The Prelog-Djerassi lactone (1) is an important intermediate in the synthesis of macrolide antibiotics. It has a lactone ring, a carboxylic acid, and four chiral centres—three adjacent C2-C4) and one (C6) separate. 

A Merck group was interested in the introduction of a basic amino group into the avermectin molecule [228]. This should change its physical properties, make it more polar, and result in a different tissue distribution. In addition, most of the anti-bacterially active macrolide antibiotics contain an aminosugar. After suitable protection and deprotection, reductive amination of a 4"-oxo intermediate gave the 4"-amino-4"-deoxy analogue as the major reaction product (Scheme 19). Since they also had observed better activity in the southern armyworm assay for certain monosaccharides, they prepared their 4 -amino derivatives as well as the... 

Franklin, M.R. (1991). Cytochrome P450 metabolic intermediate complexes from macrolide antibiotics and related compounds. Meth. Enzymol. 206, 559-573. 

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