Macrolides, preparation

Recifeiolide has been prepared from cyclononanone the generality of this approach depends mainly on the availability of the starting ketone. A full discussion on the preparation of macrolides by intramolecular cyclizations involving 7r-allyl palladium complexes has appeared, together with some preliminary notes on the application of the olefin metathesis reaction to macrolide preparation. Yields for this latter process can be as high as ca. 60% under high dilution conditions. 

The intramolecular coupling of organostannanes is applied to macrolide synthesis. In the zearalenone synthesis, no cyclization was observed between arylstannane and alkenyl iodide. However, intramolecular coupling take.s place between the alkenylstannane and aryl iodide in 706. A similar cyclization is possible by the reaction of the alkenylstannane 707 with enol triflate[579]. The coupling was applied to the preparation of the bicyclic 1,3-diene system 708[580]. 

Allylalion of the alkoxymalonitrile 231 followed by hydrolysis affords acyl cyanide, which is converted into the amide 232. Hence the reagent 231 can be used as an acyl anion equivalent[144]. Methoxy(phenylthio)acetonitrile is allylated with allylic carbonates or vinyloxiranes. After allylation. they are converted into esters or lactones. The intramolecular version using 233 has been applied to the synthesis of the macrolide 234[37]. The /i,7-unsaturated nitrile 235 is prepared by the reaction of allylic carbonate with trimethylsilyl cyanide[145]. 

This method is based on the generation of the tetraalkylammonium salt of pyrrolidorle, which acts as a base. The method is compatible with a large variety of carboxylic acids and alkylating agents. The method is effective for the preparation of macrolides. 

Use of DMF as a solvent for the oxidation of l-o1efins has been reported by Clement and Selwitz. The method requires only a catalytic amount of PdCl2 and gives satisfactory yields under mild conditions. A small amount of olefin migration product is the only noticeable contaminant in the cases reported. The procedure can be applied satisfactorily to various 1-olefins with other functional groups. This useful synthetic method for the preparation of methyl ketones has been applied extensively in the syntheses of natural products such as steroids,macrolides, dihydrojasmone, and muscone. " A comprehensive review article on the palladium-catalyzed oxidation of olefins has... 

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information on this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful list, with references, of many protected amino acids (e.g., -NH2, COOH, and side-chain-protected compounds) has been compiled/ Some general methods for the preparation of esters are provided at the beginning of this chapter conditions that are unique to a protective group are described with that group/ Some esters that have been used as protective groups are included in Reactivity Chart 6. 

The body of chemistry described above for amphotericin B (1) allowed, for the first time, the preparation of a series of novel derivatives of this polyene macrolide antibiotic and set the stage for a total synthesis of this target molecule. Below we unfold the adventure that led to the accomplishment of this goal.910... 

Figure 10.9 NeuA catalyzed preparation of a synthetic precursor to the macrolide antibiotic amphotericin B.

Using FmA catalysis and protected 4-hydroxybutanal, compound (97) has been stereoselectively prepared as a synthetic equivalent to the C-3-C-9 fragment of (-F)-aspicillin, a lichen macrolactone (Figure 10.35) [160]. Similarly, FruA mediated stereoselective addition of (25) to a suitably crafted aldehyde precursor (98) served as the key step in the synthesis of the noncarbohydrate , skipped polyol C-9-C-16 chain fragment (99) of the macrolide antibiotic pentamycin [161,162]. 

Cyclic carbonic esters were also prepared, for example, from the cardiac glycoside proscillaridine[257] (where besides CDI the benzyloxycarbonylimidazole was successfully used), ingenol, 2581 the macrolide antibiotic tylosine,[259] and an erythromycin A derivative.12601... 

The hydroxy groups in natural products like, for example, the macrolide antibiotics erythromycin, 1"1 and desmycosin, 2001 2011 as well as the 3-(hydroxymethyl)-2- or 3-cephems 2021 and derivatives of the amino sugar garamin 2031 have been converted into the carbamate function with CDI and amines. In the case of aminoglycoside antibiotics of the sisomicin series, thiocarbamates or dithiocarbamates have been prepared from alcohols or thiols using ImCSIm and amines.12041... 

A short enantioselective synthesis of (-)-(R,R)-pyrenophorin, a naturally occurring anti-fun-gal 16-membered macrolide dilactone, is prepared from (S)-5-nitropentan-2-ol via the Michael addition and Nef reaction (Scheme 4.23).162 The choice of base is important to get the E-alkene in the Michael addition, for other bases give a mixture of E and Z-alkenes. The requisite chiral (S)-5-nitropentan-2-ol is prepared by enantioselective reduction of 5-nitropentan-2-one with baker s yeast.163... 

Hesse and coworkers have used this strategy for the preparation of various macrolides.173 For example, Michael addition of 2-nitrocyclodecanone methyl vinyl ketone followed by reduction with (5)-alpine-hydride gives the nitrolactone in 72% yield. Radical denitration of the nitrolactone with Bu3SnH gives (+)-(5)-tetradecan-13-olide in 44% yield (Eq... 

Compound 17 is the so-called (+)-Prelog-Djerassi lactonic acid derived via the degradation of either methymycin or narbomycin. This compound embodies important architectural features common to a series of macrolide antibiotics and has served as a focal point for the development of a variety of new stereoselective syntheses. Another preparation of compound 17 is shown in Scheme 3-7.11 Starting from 8, by treating the boron enolate with an aldehyde, 20 can be synthesized via an asymmetric aldol reaction with the expected stereochemistry at C-2 and C-2. Treating the lithium enolate of 8 with an electrophile affords 19 with the expected stereochemistry at C-5. Note that the stereochemistries in the aldol reaction and in a-alkylation are opposite each other. The combination of 19 and 20 gives the final product 17. 

The 20-membered all-E tetraene macrolide system 58 was prepared by intramolecular cyclization of vinyl stannane 59 in the presence of tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) and triphenylarsine, as shown in equation 3354. E,E-Dienamines have been... 

Zhang, S., Huang, X., Yao, N., and Horvath, C. (2002). Preparation of monodisperse porous polymethacrylate microspheres and their application in the capillary electrochromatography of macrolide antibiotics. /. Chromatogr. A 948, 193—201. 

Clarithromycin is a macrolide antibacterial agent that should be used with caution in patients with renal impairment. The dose should be reduced if creatinine clearance is less than 30 mL/minute and the modified-release oral preparation should be avoided in this scenario. 

Cefalexin is a first-generation cephalosporin and therefore an alternative preparation would be Zinnat tablets, which contains cefuroxime, a second-generation cephalosporin. A penicillin such as Augmentin, which contains co-amoxiclav, can be an appropriate alternative since it provides a very similar spectrum of activity. Klaricid contains clarithromycin, which is a macrolide. Utinor contains norfloxacin, which is a quinolone that is effective in uncomplicated urinary-tract infections. Rocephin contains ceftriaxone, which is a third-generation cephalosporin that is available for parenteral administration only. 

Advent of ring-closing olefin metathesis reaction has influenced the synthetic strategy of pheromones very much. For example, the racemate of a macrolide pheromone such as (5Z,13S)-5-tetradecen-13-olide (29) (aggregation pheromone of the flat grain beetle, Cryptolestes pusillus) could readily be synthesized as shown in Scheme 42 [67]. Unfortunately, ( )-29 prepared by this method was a mixture of c/s, trans-isomers (Z/E=69 31). (S)-5-Hexadecanolide (27) was also synthesized by means of ring-closing olefin metathesis as shown in Scheme 43 [68]. 

A General Method for the Preparation of 9-, 10-, and 11-Membered Unsaturated Macrolides Synthesis of 8-Prop1onyl-E-5-nonenol1de... 

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluoiination of erythromycin has been studied as a strategy to insure better stability in acidic medium and/or to achieve better bioavailability. An erythromycin, fluorinated at C-8, flurithromycin, was launched several years ago. Its preparation involves an electrophilic fluorination, with CF3OF [119] or with an N-F reagent A/-fluorobenzenesulfonimide (NFSI) [120], of the 8,9-anhydroerythromy-cin-6,9-hemiacetal or of the erythronolide A (Fig. 44). 

Amphotericin is an amphoteric polyene macrolide (polyene = containing many double bonds macrolide = containing a large lactone ring of 12 or more atoms). It is nearly insoluble in water and is therefore prepared as a colloidal suspension of amphotericin and sodium desoxycholate for intravenous injection. Several new formulations have been developed in which amphotericin is packaged in a lipid-associated delivery system (Table 48-1 and Liposomal Amphotericin B). 

The reaction illustrates a typical example of the preparation of macrolides. Lactones with more than 12 members can be obtained in even better yields. For example, 15-hydroxypentadecanoic lactone (m.p. 35-37°) and 17-hydroxyheptadecanoic lactone (m.p. 40-41°) were prepared by the submitters in about 95% yield in a practically pure form, with no trace of the corresponding dilactones. 

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