Erythromycin Woodward

Facing the challenge of synthesizing the antibiotic erythromycin A la, Woodward s group took advantage of a cyclic system to achieve diastereofacial selectivity, the so-called cyclic approach.3 This approach was taken to deal with the common problem of low diastereoselectivity associated with acyclic substances. 

Woodward s achievement in constructing the 10 chiral centers of lb relied on the cyclic substrate control approach. Erythromycin A (la) was finally synthesized by combining compound lb with a long chain residue. Although this achievement represented a historic milestone at that time, it also attested to the limitations of this popular traditional approach. 

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]. 

Let us consider Woodward s synthesis of erythronolide A -the aglycone of the antibiotic erythromycin A- which was published posthumously [2]. 

In his 1956 article in Perspectives in Organic Chemistry , the late Professor R. B. Woodward characterized the macrolide antibiotic erythromycin as a synthetic challenge which is ... quite hopelessly complex, especially in view of its plethora of asymmetric centers 70). Twenty-five years after making this dismal prognosis,... 

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. 

As an example, consider the preparation of the antibiotic erythromycin A (Fig. 1). The total chemical synthesis of erythromycin was first completed in R. B. Woodward s laboratory in 1981. It took 49 people and 49 steps, and resulted in an overall yield of <0.02% relative to starting material [1-3], In contrast, a lone bacterium can make a molecule of erythromycin A in a matter of seconds a liter of such bacteria can provide up to 100 mg of erythromycin in a matter of... 

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. 

This i-proline-mediated annulation received a considerable synthetic and mechanistic interest [41]. It was demonstrated that other amino acids, such as (R)-phenylalanine, could replace in some cases advantageously the i-proline [42]. Earlier applications in total syntheses appeared, however, as singular events, as in Woodward s synthesis of erythromycin (Scheme 1.5) [27]. Remarkably, in this synthesis a racemic lceto aldehyde 5 could be used for aldolization with D-proline... 

Scheme 1.5 The D-proline-mediated intramolecular aldol reaction in Woodward s erythromycin synthesis.

Mesitylmethylene acetals resemble benzylidene acetals in their reactivity but the two ortho methyl groups create steric strain that can be usefully exploited. Woodward s synthesis of Erythromycin gave an early indication of the value of mesitylmethylene acetals.76-78... 

Masamune et al. have reviewed in detail the effects of double asymmetric induction not only for epoxidation, but also for the aldol, Diels-Alder, and catalytic hydrogenation reactions. The merits of this strategy are illustrated by an analysis of Woodward s synthesis" of erythromycin A (1), which has 10 chiral centers. 

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]. 

Note The erythromycin molecule was synthesized by the Harvard chemist Robert Woodward. The synthesis was almost completed at the time of his death in 1979, and was finished by his associates in 1981. It is an extremely complex structure containing a lactone ring of 14 members with 10 asymmetric centers it also has two specialized sugar molecules, L-cladinose and D-desosamine. The reported molecular configuration is ... 

Owing to the complexity of the erythronolides, the problems involved in a synthetic approach seemed at one time insurmountable. The late R. B. Woodward once wrote, Erythromycin, with all of our advantages, looks at present hopelessly complex, particularly in view of its plethora of asymmetric centers. Yet Woodward s group completed a remarkable synthesis of erythromycin B after his death. 

Among the more beautiful and truly imaginative syntheses accomplished in the 1970s and 1980s was Woodward s synthesis of erythromycin A. In typical Woodwardian fashion, he recognized and indeed utilized the marked similarities in stereochemistry between fragments C-3 to C-8 and C-9 to C-13, each being constructed from the common intermediate 166. 

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