Total synthesis of erythronolide

Kinoshita s erythronolide synthesis is based on the preparation of (9S)-9-dihydroerythronolide A (76), which is constructed from the three chiral segments, Ci-Cg (69), C7-C9 (70) and C10-C13 (72). 

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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... 

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... 

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>. 

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). 

The First Total Synthesis of Erythronolide B Corey, 197S]... 

Macrocyclic Lactones and Lactams.—Considerable activity in this area has continued during 1979. Following the earlier total synthesis of erythronolide B... 

The oxiran (2) played an important role in the total synthesis of erythronolide A stereoselective synthesis of (+) and (-)-tetrahydroceruIenin (3b) from D-glucose has been described, and the correct absolute configuration of ceru-lenin (3a) deduced. 

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