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Synthetic Shortcut To Erythromycin Precursor

Organic Synthesis: Recently developed reactions shorten path to 6-deoxyerythronolide B

by Stu Borman
March 15, 2013 | A version of this story appeared in Volume 91, Issue 11

Two crotylations shorten the total synthesis of 6-deoxyerythronolide B.
A reaction scheme describes a new route to 6-deoxyerythronolide B.
Two crotylations shorten the total synthesis of 6-deoxyerythronolide B.

Using two recently developed carbonyl addition reactions—known as crotylations—chemists have assembled the natural product 6-deoxyerythronolide B in a record-breaking 14 steps, down from the previous record of 23. The crotylations could ease synthesis of other complex compounds for drug discovery and fundamental research applications.

6-Deoxyerythronolide B is a close relative of the large-ring antibiotic erythromycin. The synthesis of erythromycin and associated compounds has posed major challenges since 1952, when Eli Lilly & Co. first commercialized the drug.

The late Harvard University synthetic organic chemist Robert Burns Woodward expressed pessimism about prospects for such syntheses in 1956: “Erythromycin, with all of our advantages, looks at present time quite hopelessly complex, particularly in view of its plethora of asymmetric centers.” Nevertheless, at least 17 total syntheses of the antibiotic and related compounds have now been carried out, beginning in 1978 and 1979 with 33- and 39-step processes by Harvard chemistry professor E. J. Corey’s group. Woodward’s group completed a 55-step synthesis in 1981. And several groups have achieved 23-step syntheses, such as one—reported in 2009—of 6-deoxyerythronolide B by University of Illinois, Urbana-Champaign, chemistry professor M. Christina Whiteand coworkers.

Chemistry professor Michael J. Krische and coworkers at the University of Texas, Austin, have now gotten the process down to 14 steps (J. Am. Chem. Soc., DOI: 10.1021/ja4008722) with crotylations they developed in the past two years. The procedure uses a ruthenium-catalyzed alcohol C–H crotylation (J. Am. Chem. Soc., DOI:10.1021/ja311208a) to initiate assembly of “Fragment A” and an iridium-catalyzed double crotylation (J. Am. Chem. Soc., DOI: 10.1021/ja204570w) to assemble “Fragment B.” The fragments are joined to create the natural product.

The predominant double crotylation product is one of 16 possible stereoisomers, an unusual degree of stereoselectivity. The reaction generates half of 6-deoxyerythronolide B’s 10 stereocenters in one shot.

White calls the new research “an impressive synthesis of a classic and important target. By enabling novel bond formations that use simple starting materials and reduce functional group manipulations, transition-metal-catalyzed transformations like the ones developed in the Krische group can dramatically streamline the syntheses of complex molecules.”



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