Natural products erythronolide

This chapter has introduced the asymmetric synthesis of several types of natural products erythronolide A, 6-deoxyerythronolide, rifamycin S, prostaglandins and baccatin III, the polycyclic part of taxol, as well as the taxol side chain. The... 

Natural product total syntheses are particularly valuable when they are attended by the development of general utility methods of synthesis. In some instances, the successful completion of a natural product total synthesis requires the development and application of a new synthetic method. The total synthesis of erythronolide B by Corey et al. is one of these instances. The double activation macro-lactonization method was a fruitful innovation that was introduced in response to the challenge presented by the macrocyclic structures of the erythromycins. Several other methods to achieve the same objective, and numerous applications followed. 

A stereoselective total synthesis of erythronolide A, using two Mg/z-mediated cycloadditions of nitrile oxides has been described. Of broader significance, the strategy not only facilitates the synthesis of specific polyketide targets (i.e., natural products) but also opens up new possibilities for the preparation of nonnatural analogs (482). 

The metal derivatives of alkynes can be added to carbonyl electrophiles as in the following examples. The first (we have reminded you of the mechanism for this) is the initial step of an important synthesis of the antibiotic, erythronolide A, and the second is the penultimate step of a synthesis of the widespread natural product, farnesol. 

Hikota, M., Tone, H., Horita, K., Yonemitsu, O. Chiral synthesis of polyketide-derived natural products. 31. Stereoselective synthesis of erythronolide A by extremely efficient lactonization based on conformational adjustment and high activation of seco-acid. Tetrahedron 1990, 46, 4613 628. 

As an application in natural product synthesis, the C -Cg macrolide subunit of ery-thronolide B aglycon is prepared by stereoselective cnolatc Claisen rearrangement of diox-anone 1 to dihydropyran 2533. Dihydropyran 2 is further transformed to give an intermediate in the synthesis of erythronolide B aglycon. 

Figure 5.8. Natural products synthesized using aldol methodology denticulatin A [143] ionomycin [144] 6-deoxyerythronolide B [124] erythronolide B [129,145] tirandimycin A [146] Prelog-Djerassi lactone [124,125], Stereocenters created in the aldol addition are indicated ( ).

Summary A short linear synthesis of erythronolide is discussed as an exemplary case to demonstrate how changes in the attitude towards new synthetic methods increased the efficiency of natural product synthesis. 

Erythromycin A (1) is a member of an important l ily of therapeutically useful antibiotics. The structure of 1 is shown on Erythronolide-5. This natural product consists of an aglycone (see 2 in Erythronolide-1) linked to two unusual monosaccharides (L-cladinose and D-desosamine) via glycosidic bonds to the C3 and C5 hydroxyl groups, respectively. We will conclude by examining two syntheses, one of erythronolide A (2) and the other of erythromycin A. Before jumping into the synthesis, I will make a few comments. 

In principle, all that remained to do to reach erythronolide (2) was to deprotect the Ci3 hydroxyl group of 62, conduct the macrolactonization, remove the acetonides, and carry out an oxidation state adjustment at C9. Of course this was easier said than done. The macrolactonization turned out to be very difficult. The Woodward group degraded Erythromycin A (1) to 17 thiopy-ridyl ester substrates, only three of which underwent lactonization under the Corey-Nicolaou conditions. Two of these derivatives gave low yields, but 63 cyclized to 64 in good yield. This effort established that (1) the 5-configuration was essential at C9 and (2) the C3-C5 and C9-C11 diol units had to be protected as cyclic acetals. Based on this information, carbamate-acetal 65 was eventually prepared Ifom the natural product and found to cyclize to 66 in 70% yield. Thus, to complete a total synthesis, it was necessary to convert w-acetorude 62 to 65, and move 66 forward to erythromycin A (1). 

Myles DC, Danishefsky SJ. The synthesis of polyoxygenated natural products via fully synthetic branched pyranose derivatives application to the erythronolide problem. Pure Appl. Chem. 1989 61 1235-1242. 

This groundbreaking experiment initiated a period of frenetic activity in the natural products community, which established that non-aromatic compounds can likewise be biosynthesized by condensation of esters according to what became known as the Collie-Birch polyketide hypothesis [27, 28). In this regard, impressive radiolabeling studies by Cane established the propionate origin of the carbon framework in erythronolide A, one of the classic macrolide antibiotics (Figure 4.1) [29]. 

A.iv. Reaction with Acid Chlorides. As briefly mentioned in Section 8.4.C.ii, the reaction of a dialkyl cuprate and an acid chloride is a preferred method to synthesize ketones.399,400 -phe reaction with acyl halides usually requires low temperatures to isolate the ketone product.388,387 -p is method is usually preferable to and more general than one that uses dialkylcadmium reagents (sec. 8.4.C.ii). Masamune et al. used this reaction to convert acid 422 to ketone 423 in a synthesis of erythronolide. In this case, oxalyl chloride was used to prepare the requisite acid chloride because of the sensitive nature of the molecule. 

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