Erythromycin total synthesis

Erythromycins. Erythromycin A (14, R = OH, R = CH3, R" = H), the most widely used macroHde antibiotic, was the principal product found in culture broths of Streptomjces eTythreus (39), now reclassified as Saccharopoljspora eythraea (40). It contains a highly substituted aglycone, erythronoHde A, (16, R = R = OH) to which desosamine (1, R = OH, R = H) and cladinose (8, R = CH ) are attached (41). The complete stereochemistry of erythromycin A was estabUshed by x-ray analysis of its hydroiodide dihydrate (42) total synthesis of erythromycin A was a landmark achievement (43), a task previously considered hopeless (44). 

Chemical degradation of erythromycin A yielded its aglycone, erythronoHde A (16, R = R = OH), whereas erythronoHde B (16, R = H, R = OH) was obtained from fermentation (63,64). Biosynthesis of erythromycin proceeds via 6-deoxyerythronoHde B (16, R = R = H) and then erythronoHde B (64,65). The first total synthesis of erythromycin-related compounds was erythronoHde B (66) syntheses of erythronoHde A and 6-deoxyerythronoHde B soon foUowed (67,68). 

The fungus Streptomyces erythreus is the source of a number of structurally related macrolide antibiotics that are collectively known as the erythromycins. The erythromycins occupy a prominent position in medicine by virtue of their useful antibacterial properties. Their use in therapy over the course of the last three decades has been widespread, and has resulted in the saving of many human lives. In this chapter, we address the landmark total synthesis of erythronolide B (1), the biosynthetic precursor of all the erythromycins, by E.J. Corey and his coworkers which was carried out at Harvard in the 1970s.1... 

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. 

During recent years, cross metathesis has found a wide range of applications in total synthesis. CM has been the key step in the syntheses of (-)-lasubine 11 [134], (+)-7a-ept-7-deoxycasuarine [135], and melithiazole C [136] to name just a few examples. It has been used for the modification of tetrapyrrolic macrocycles [137] as well as erythromycin derivatives [138], the dimerisation of steroids [139] and the synthesis of prostaglandin analogues [140]. 

The most impressive application of 2-thiopyridyl and 2-thiopyrimidinyl donors is in the area of antibiotics. Thus, Woodward et al. [481] successfully completed the total synthesis of erythromycin by using S Pyrm glycoside of D-desosamine and S Pyr-glycoside of L-cladinose as glycosyl donors to the subsequent glycosylation with erythronalide A. This methodology was also successfully used in the synthesis of oleandomycin [482,483], erythromycin A [484] and erythromycin B [485]. 

A as-fused dithiadecalin ring system has been utilized as an important building block in the asymmetric total synthesis of erythromycin (81JA3210, 3213, 3215). Coupling of the... 

Chemistry of the glycoside linkage. Exceptionally fast and efficient formation of glycosides by remote activation, Carbohydr. Res. 80 07 (1980). (e) K. Wiesner, T. Y. R. Tsai, and H. Jiu, On cardioactive steroids. XVI. Stereoselective P-glycosylation of digitoxose the synthesis of digitoxin, Helv. Chim. Acta 60 300 (1985). (f) R. B. Woodward (and 48 collaborators), Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin, J. Am Chem. Soc. 103 3215 (1981). (g) P. G. M. Wuts and S. S. Bigelow, Total synthesis of oleandrose and the avermecin disaccharide, benzyl ot-L-oleandrosyl-ot-L-4-acetOxyoleandroside, J. Org. Chem. 43 3489 (1983). 

In the total synthesis of optically active erythromycin A reported by Woodward and collaborators (87), the bicyclic compound 142 (Fig. 1) was used to produce the two segments Cg-C)5 (143) and Cg-Cg (144) of erythronolide A. These two segments were then combined (-145) and converted into 146). Aldol condensation of a propionate ester derivative with 146 gave the erythronolide A secoacid derivative J 47 (Fig. 2) which was successfully transformed into erythromycin A (149) through a series of chemical transformations where compound 148 was one of the key intermediates. 

RB Woodward, E Logusch, KP Nambiar, K Sakan, D Ward, B-W Au-Yeung, P Balaram, LJ Browne, PJ Card, CH Chen, RB Chenevert, A Fliri, K Frobel, H-J Gais, DG Garrat, K Hayakawa, W Heggie, DP Hesson, D Hoppe, 11 loppe et al. Asymmetric total synthesis of erythromycin. 1. Synthesis of erythronolide A seco acid derivative via asymmetric induction. J Am Chem Soc 103 3210-3213, 1981. 

Masamune et al. used this aldol strategy to achieve the total synthesis of 6-deoxyerythronolide B (6), a common biosynthetic precursor leading to all the erythromycins presently known4 (Scheme 2.1e). The highlight of the synthesis is... 

The total synthesis of erythronolide B, the biosynthetic progenitor of all the erythromycins, employed a Baeyer-Villiger oxidation of the substituted cyclohexanone (31 equation 18). The oxidation was surprisingly slow using customary procedures, but Corey et alP found that forcing conditions provided the required lactone (32). 

An asymmetric aldolization was successfully applied to the preparation of gibbane. The total synthesis of the macrolide antibiotic erythromycin was developed involving an asymmetric aldolization step catalyzed by proline. Since the mid-1970s, a flood of papers has appeared dealing with the asymmetric aldolization of various triketones. Some results are listed for comparison in Table 1. 

S. Hanessian, C. Bacquet, and N. Lehong, Chemistry of the glycosidic linkage, exceptionally fast and efficient formation of glycosides by remote activation, Cabohydr. Res. S0 C17 (1980). R. B. Woodward, et al. Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin, J. Am. Chem. Soc. 103 3215 (1981). 

Erythromycins, the representative and medicinally important macrolide antibiotics, have been widely studied and are still undoubtedly one of the most challenging target molecules for many synthetic organic chemists (O Fig. 3). Woodward and coworkers accomplished the first total synthesis of erythromycin A (18) in 1981 [8,9,10]. Corey and coworkers synthesized erythronolides A (20) and B (21), the aglycons of erythromycins A (18) and B (19), in 1978 [11,12] and 1979 [13]. 

The C10-C13 segment 24 was prepared from D-ribose (35) (O Scheme 2). In this case, selective protection of the hydroxy groups was realized by isopropylidenation (from 35 to 36). One of the other procedures for conversion of cyclic monosaccharides to acyclic derivatives is nucleophilic addition to the anomeric position in free monosaccharides. Grignard reagent, MeMgl, was added to 36 to provide 37 as the sole product. The subsequent manipulation of 37 to the C10-C13 segment 24, which is not restricted in monosaccharides chemistry, is summarized in O Scheme 2. After the completion of the synthesis of erythronolide A (20), Toshima, Nakata, Tatsuta, Kinoshita, and coworkers achieved the total synthesis of erythromycin A (18) by their own glycosidation method [18,19]. 

The high syn stereoselectivity attained in zirconium enolate aldol reactions has proved useful in complex natural product synthesis. The zirconium-mediated aldol reaction of the chiral ethyl ketone (9) with a chiral aldehyde has been used by Masamune et al. to give selectively adduct (10), which was further elaborated into the ansa chain of rifamycin S (equation 1). Good enolate diastereofacial selectivity is also obtained here and leads to a predominance of one of the two possible syn adducts. A zirconium enolate aldol reaction also features in the Deslongchamps formal total synthesis of erythromycin A, where the di(cyclopentadienyl)chiorozirconium enolate from methyl propionate adds with high levels of Cram selectivity to the chiral aldehyde (11) to give the syn adduct (12 equation 2). A further example is... 

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