Erythronolide aglycone

The combination of the (S)-enolate 2 with aldehyde 1 is one of the key steps in the syntheses of the macrolide aglycone 6-deoxy-erythronolide B131 and tylonolidc16. 

Erythromycin is a macrolide antibiotic consisting of the aglycone, erythronolide A the aminosugar, desosamine and the neutral sugar, cladinose. 

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

Two superior, alternative reagents for the Corey method are the disulfides 23 and 24 [19], For example, in the first synthesis [20] of erythronolide B (27), the aglycone of the important antibiotic erythromycin B, cyclization of the hydroxy acid 25 to the 14-membered lactone 26 was effected in 50% yield via the thiol ester of 4-r-butyl-iV-isopropyl-2-mercaptoimidazole by heating in dry toluene under reflux (Scheme 9). 

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]. 

Erythromycins. Erythromycin A (14, R = OH, R = CH3, R" = H), the most widely used macrolide antibiotic, was the principal product found in culture broths of Streptomyces erythreus (39), now reclassified as Saccharopolyspora eythraea (40). It contains a highly substituted aglycone, erythronolide A, (16, R = R = OH) to which desosamine (1, R = OH, R = H) and dadinose (8, R = CH3) are attached (41). The complete stereochemistry of erythromycin A was established 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, erythronolide A (16, R = R = OH), whereas erythronolide B (16, R = H, R = OH) was obtained from fermentation (63,64). Biosynthesis of erythromycin proceeds via 6-deoxyerythronolide B (16, R = R/ = H) and then erythronolide B (64,65). The first total synthesis of erythromycin-related compounds was erythronolide B (66) syntheses of erythronolide A and 6-deoxyerythronolide B soon followed (67,68). 

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. 

An important intermediate in the construction of the C-1 to C-6 ring fragment (605 see Scheme 84) of erythronolide B aglycone (600) is the highly functionalized tetrahydropyran 604. Amazingly, all the stereochemistry associated with this molecule can be traced back to the simple lactaldehyde derivative 589. 

R = H), the first total synthesis of the 12-hydroxy-derivative erythronolide A (14 R = OH) has now been described by the Corey group. Erythronolide A (14 R = OH) is the aglycone of the medically important antibiotic erythromycin... 

Although macrolides are of contemporary interest, the first major steps toward successful macrolide syntheses were reported in the 1970 s. Thus, for historical reasons, we will look at two approaches to the classical target erythromycin A and its aglycone, erythronolide-A. 

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. 

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