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Organic Chemistry Highlights

Total Synthesis

Monday, July 3, 2006
Douglass Taber
University of Delaware

Synthesis of Erythronolide A

Erythronolide A (4), with its array of ten stereogenic centers, is the parent of several classic antibiotics, including erythromycin. The key step in the total synthesis of 4 recently reported (Angew. Chem. Int. Ed. 2005, 44, 4036. DOI: 10.1002/anie.200500172) by Erick M. Carreira of the ETH Hönggerberg is the activation of 1 and subsequent diastereoselective 1,3-dipolar cycloaddition to 2 to give 3.

The synthesis of 1 started with two simple chirons, the alcohol 2, prepared by Noyori reduction of the acetylenic ketone followed by semi-hydrogenation, and the inexpensive (< one USD/gram) Roche alcohol (5). Functional group manipulation led to 6, which underwent smooth Mg-mediated cycloaddition to the enantiomerically-pure alcohol 2, to give 7. Addition of the Grignard reagent 8, also derived from the Roche ester (5), to the derived methyl ketone also proceeded with high diastereocontrol, to give the tertiary alcohol. Reduction of 9 and subsequent hydrolysis liberated the hydroxy ketone, which was reduced selectively to the syn diol. It is a tribute to the stability of tertiary triethylsilyl ethers that the TES protecting group put on at this stage survived all the way to the end of the synthesis.

While the diastereoselectivity of 1,3-dipolar cycloaddition was well-precedented in simpler systems, it was not clear that the diastereoselectivity would be maintained with such a complex substrate as 1. In fact, addition to 2 proceeded with > 99:1 dr. Wittig homologation of the derived methyl ketone proceeded with remarkable (33:1) geometric control, setting the stage for asymmetric dihydroxylation to put in place the last two stereocenters.

Controlled desilylation of 11 followed by selective oxidation delivered the seco acid 12. It had previously been shown by others that some cyclic protecting groups facilitate macrolactone formation, while others do not. Fortunately, the two cyclic protecting groups of 12 served well, and the macrolactonization proceeded efficiently. Protecting group removal and reductive unmasking of the hydroxy ketone then delivered erythronolide A (4).

Overall, this elegant synthesis is a showcase for the iterative use of the 1,3-dipolar cycloaddition of enantiomercially-pure allylic alcohols for the preparation of extended arrays of acyclic stereogenic centers.

D. F. Taber, Org. Chem. Highlights 2006, July 3.