Macrolides

In Che last filteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R. B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

Erythromycins from Streptomyces erythreus strains are probably the structurally most complex of the best selling drugs. Erythromycin A costs only about 5 DM per gram. The two principal erythromycins A and B differ only with respect to hydroxylation at C-12. 

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). 

Synthesis of (A) started with the combination of 2,4,6-trimethylphenol and allyl bromide to give the or/Ao-allyl dienone. Acid-catalyzed rearrangement and oxidative hydroboration yielded the dienone with a propanol group in pore-position. Oxidation of the alcohol and bromolactonization (see p. 273) followed. Bromine and the lactone ring were trans in the product as expected (see p. 273). Treatment with aqueous potassium hydroxide gave the epoxy acid, which formed a crystalline salt with (R)-l-(a-naphthyDethylamine. This was recrystallized to constant rotation. 

The 9—15 fragment was prepared by a similar route Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i e, at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde 

The term macrolide was introduced to denote the class of substances produced by Streptomyces species containing a macrocydic lactone ring (27). 

Saccharide CAS Registry Number Molecular formula Structure number 

Kirk-Othmer Encyclopedia of Chemical Technology (4th Edition) 

The few macrolides having 12-membered rings are listed in Table 2. Methymycin (12, R = OH, R = H), isolated from culture broths of a Streptomyces species (29), was the first macrolide structure 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 macrolide 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). 

Figu re 8.6 Tylosin derivatives obtained by combining gene inactivation, gene expression and feeding experiments. 

Methymycin (4) and neomethymycin (5) are 12-membered macrolides produced by Streptomyces venezudae-3L strain that also produces the 14-membered 

The DesVll desosaminyl transferase naturally transfers D-desosamine to both 12- and 14-membered macrolactones, which is an example of inherent flexibility towards the acceptor aglycone. This unusual property of DesVll has been exploited to generate novel macrolide derivatives that differ in size of the macrolactone ring and in their oxygenation/reduction state. A Streptomyces lividans strain in which the genes involved in the biosynthesis and transfer of D-desosamine were 

The naturally occurring cryptand aplasmomycin (190) is one of a unique family of ionophore antibiotics, and several syntheses of the total structure, half structure and various abbreviated segments have been published. White et al. have now described a new approach to (190) which features a novel ring contraction based on the rearrangement of a-(acyloxy) acetates originally described by Chan et al. Thus, the key intermediate (191) was treated successively with lithium diisopropylamide and trimethylsilyl triflate leading to (192) which was ultimately converted to aplasmomycin. In Corey s recent 

Gerlach has used a rather different approach in a synthesis of curvularin (107) in which the final ring closure is achieved by an intramolecular Friedel-Crafts 

Utimoto, K. Uchida, M. Yamaya, and H. Nozaki, Tetrahedron Letters, 1977, 3641. 

Corey et al have reported some modifications to their previously published synthesis of brefeldin A (111), and a group led by Crabbe has developed an alternative approach to the key a -hydroxy-acid used in Corey s synthesis. Another synthesis of (111) has also been recorded.  

Corey s group have also reported a total synthesis of (-l-)-enterobactin (112), a bacterial iron transport agent the three lactone bonds were all formed using Corey s substituted imidazoylthioester method.  

Seebach, B. Seuring, H.-O. Kalinowski, W. Lubosch, and B. Renger, Angew. Ghent. Internal. Edn., 1977,16, 264. 

Carbomycin, also called magnamycin, was isolated in 1952 from filtrates of Strep-tomyces halstedii. One year later, the same antibiotic was isolated from S. hygroscop-icus and, in 1959, also from Streptomyces albiraticuli [336-338]. The structure of carbomycin was proposed some years later but was not correct, and it was revised to 

THREE-MEMBERED HETEROCYCLIC RINGS AND THEIR FUSED DERIVATIVES 

335 in 1965 [339, 340], Many years later, studies aimed at setting chemical and biochemical conditions to increase the biosynthesis of carbomycin by S. halstedii were performed, and it was observed that higher yields of the antibiotic were obtained by cultivating S. halstedii in the presence of 40-45 mg/kg of copper ions [341, 342], 

El and ESI MS, H, and 2D NMR spectroscopy and on comparison of the NMR data with those of chalcomycin, was determined to be 337 and named chalcomycin B. The latter showed antibacterial activity very close to that of 336 [354], 

Erythromycin, from the actinomycete Saccharo-polyspora (formerly Streptomyces) erythraea, is the first member of this family of antibiotics to be marketed and successfully used clinically to treat infections in humans. It has an antimicrobial spectrum at least as wide as the penicillins, and interestingly, from our perspective, it is often used as a replacement for patients allergic to that group of drags. Besides erythromycin, other members of the macrolide family of antibiotics that are clinically useful include azithromycin, clarithromycin, dirithromycin, roxithromycin, telithromycin (these six are approved by the FDA), oleandomycin, and spiramycin. Clarithromycin, dirithromycin, and roxithromycin and the azalide azithromycin are more recent members of the group and can be regarded as newer generation macrolide antibiotics. 

Chanically, the macrolide antibiotics comprise a laige cyclic lactone ring slnicture with one or more molecules of the unusual sugars, L-cladinose and D-desosamine, attached by glycosidic linkage. The lactone ring structure may be from 12- to 16-membered—clarithromycin, dirithromycin, 

Several synthesis of the Prelog-Djerassi lactone elevate the compound almost to the position of cis-jasmone in terms of its popularity as a synthetic target. Full details of the Danishefsky route to ( )-quadrone have appeared as well as a report of a concurrent synthesis. A new method for the preparation of 5-lactones involving the reaction of a y,5-unsaturated aldehyde with NaOH followed by oxidation has been applied to the synthesis of ( )-pentaleno-lactone. The first total synthesis of (+)-compactin has been reported.  

An 5n2 displacement of a caesium carboxylate on a remote mesylate group is used in an effective synthesis of / -zearaIenone. This compound has also been prepared by carbon-carbon bond formation using the displacement of a tosylate group by a protected cyanohydrin carbanion. The intramolecular coupling of a terminal vinyl iodide with an enone catalysed by PdCl2(CH3CN)2 has been used as a route to an unsaturated 16-membered macrolide.  

Notegen, M. Tori, and C. Tamm, Helv. Chim. Acta, 1981, 64, 316. 

Hirata, H. Sueoka, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1981,22,2679. 

The intramolecular cyclization of a stabilized phosphonate carbanion onto an aldehyde has proved to be an effective method for the synthesis of brefeldin polyene macrolides, and in a formal synthesis of carbomycin Pyrenophorin has been synthesized using a pent-3-enoic acid d reagent two other routes to the racemic compound have also appeared. Macrocyclic polyether macrolides have been prepared by cyclization, and by ozonolysis of a furan crown-ether compound. 

A closely related set of conditions for the direct lactonization of to-hydroxyacids in good yield by treatment with l-methyl-2-chloropyridinium iodide and triethy-lamine has been reported.Masamune s lactonization procedure [Mercury(ii) methanesulphonate and disodium hydrogen phosphate with benzenethioesters of oj-hydroxyacids] has been utilized in a partial synthesis of the aglycone of the complex macrolide tylosin. 

One of the little mysteries of 1976 presents itself in a method for the lactonization of co-hydroxyacids [H0(CH2) C02H] which involves refluxing a dilute solution of the acid in 1,2-dichloroethane for 7 days in the presence of BF3 etherate and insoluble polystyrene beads The mechanism is unclear, yet both of the latter 

Full details of the total synthesis of ( )-pyrenophorin (107) have been published. The final cyclization was affected using di-imidazoyl-l-yl ketone as lactonizing reagent. The synthesis also features the use of the 2-(tolyl-/7-sulphonyl) ethyl protecting group for carboxylic acids selective removal of this group in the presence of other esters is easily achieved (DBN 25 °C). 

Further syntheses of simple macrolides from various peroxides have been reported low yields have been obtained from cyclic trimeric peroxides and by thermolysis of 3-benzosuberone dioxide the latter paper also contains a summary of earlier work on these fascinating reactions. 

A stereoselective total synthesis of the poly-ether macroHde nonactin has been published with full experimental details. 

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A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

The cyclization reactions discussed here either involve the intramolecular reaction of a donor group D with an acceptor group A or a cyclizing dimerization of two molecules with two terminal acceptors and two donors. A polymerization reaction will always compete with cyclization. For macrolides see p. 146 and p. 319 — 329. 

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]. 

Intramolecular 1,4-addition is useful for macrolide synthesis. An unusual molecule of punctaporonin B (272) has been synthesized by this 1,4-addition of 271(160]. Cyclization to form the seventeen-membered ring macrolide 273 was carried out at 0.1-0.5 vi concentration[161. The choice of ligands seems to be important in the macrocyclization. The 26-membered ring model 274 for a synthesis of the ring system of tetrin A was obtained in 92% yield by using triisopropyl phosphite as a ligand[162]. 

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