Total synthesis of erythromycin

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 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). 

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. 

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... 

It is fitting that Woodward s last major achievement was the total synthesis of erythromycin-A. the synthesis, which was carried out in classical Wbodwardian fashion, was communicated posthumously R.B. Woodward, et. l, . to. Chem. Soc., 103, 3210, 3213, 3215 (1981). 

The First Total Synthesis of Erythromycin A [Woodward, 198T (Scheme 4) [77]... 

Work concerned with providing solutions to the difficult stereochemical problems encountered in the synthesis of the macrolide and polyether antibiotics continues, and in this field pride of place must go to the total synthesis of erythromycin which has been completed by the collaborators of the late R. B. Woodward. 

A total synthesis of erythromycin A involved use of the thiogly-coside of the anhydro-thio sugar (12) which allowed easy glycosyl-... 

Woodward, R. B. etal "Asymmetric Total Synthesis of Erythromycin. 3. Total Synthesis of Erythromycin" J.Am. Chem. Soc. 1981, 103, 3215-3217. 

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