Total synthesis erythronolide

The first total synthesis of erythronolide A was accomplished from iodide A and lactone B, the same intermediate which had been used for the synthesis of erythronolide B. The pronounced acid sensitivity of erythronolide A necessitated a digression of the final steps of the synthesis from those used for the earlier synthesis of erythronolide B. 

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... 

The first total synthesis of erythronolide B (1) by Corey stands as an event of great historical significance in synthetic chemistry it provides a powerful illustration of the utility of Corey s methods of macrolactonization and it demonstrates, in a particularly insightful way, the value of using readily accessible six-membered ring templates for the assembly of contiguous arrays of stereo-genic centers. 

Having retraced the efficient and elegant sequences of reactions that have led to the synthesi of key intermediates 11 and 12, we are now in a position to address their union and the completion of the total synthesis of erythronolide B. Taken together, intermediates 11 and 12 contain all of the carbon atoms of erythronolide B, and although both are available in optically active form of the required absolute configuration, racemic 11 and enantiomerically pure 12... 

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). 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

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. 

The key step in the stereoselective total synthesis of erythronolide A is the Mg(II)-mediated 1,3-dipolar cycloaddition of the functionalized nitrile oxide (45) with the allylic alcohol (46) to produce the isoxazoline (47) as a single diastereomer in high... 

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. 

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). 

Enantiopure isoxazolines were synthesized using both chiral nitrile oxides and chiral dipolarophiles. For example Mg(ll)-directed 1,3-dipolar cycloaddition of nitrile oxides with chiral allylic alcohols 482 generated isoxazolines 483 (Scheme 111) <2001AGE2082>. Later, this cycloaddition was applied in a total synthesis of erythronolide A 484 (Scheme 111) <2005AGE4036>. 

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]. 

Kim has also studied the corresponding acylation of homocuprates by S-(2-pyridyl) thioates, discussed earlier in the context of total synthesis of monensin and erythronolide A (Sections 1.13.2.2 and 1.13.3.2). Under the standard anaerobic conditions necessary for cuprate formation, good yields of ketones could be derived from acylation of lithium dimethylcuprate (or lithium dibutylcuprate) by S-(2-pyridyl) thiobenzoate and other simple S-(pyridyl) thiol esters (equation 71). Interestingly, if the homocuprate is intentionally placed under an oxygen atmosphere before acylation and then reacted with the S-(2-pyridyl) thioate in oxygen at -78 C, one obtains good yields of the ctnresponding ester (equation 72). 

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). 

So we concentrated on the synthesis of fragment 129. The two stereogenic centers at C-7 and C-8 were established from (7 )-2,3-isopropylidene glyceraldehyde 132 as shown in Scheme 22 via a sequence already employed in the total synthesis of erythronolide B (18). Stereotriad 135 is available in multigram quantities on this route via 133 and 134 (Scheme 22). After protection of the secondary OH as a p-methoxybenzyl (PMB) ether the base induced 1,3-rearrangement was achieved under standard conditions to furnish the desired olefin 137 (Scheme 23). 

This process was developed in connection with a projected total synthesis of the macrolide erythronolide B. 

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