Erythronolides

A comparison of the 1979 and 1989 syntheses of similar erythronolide targets reveals some typical differences which indicate the experimental progress made in this period ... 

NaN02, 1 N HCl, CH3OH, H2O, 0°, 3 h, 76% yield. In the last step of a synthesis of erythronolide A, acid-catalyzed hydrolysis of an acetonide failed because the carbonyl-containing precursor was unstable to acidic hydrolysis (3% MeOH, HCl, 0°, 30 min, conditions developed for the synthesis of erythronolide B). Consequently the carbonyl group was protected... 

Erythronolide B, the biosynthetic progenitor of the erythromycin antibiotics, was synthesized for the first time, using as a key step a new method for macrolactone ring closure (double activation) which had been devised specifically for this problem. Retrosynthetic simplification included the clearance of the stereocenters at carbons 10 and 11 and the disconnection of the 9,10-bond, leading to precursors A and B. Cyclic stereocontrol and especially the Baeyer-Villiger and halolactonization transforms played a major role in the retrosynthetic simplification of B which was synthesized starting from 2,4,6-trimethylphenol. 

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. 

Erylhronoljde B is the biological precursor of erythromycin, a broad-spectrum antibiotic. How many chirality centers does erythronolide B have ... 

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. 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

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. 

The best conditions for the a-regioselective coupling of a chiral, highly substituted, lithiated allyl sulfide to a chiral aldehyde were carefully worked out for the key step in an erythronolide B total synthesis108. 

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