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Synthesis

Ladder Polyethers In A Snap

Directing group governs regioselective epoxide opening, then is jettisoned

by Bethany Halford
January 16, 2006 | APPEARED IN VOLUME 84, ISSUE 3

Cascade
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Ladder polyether forms by regioselective epoxide opening that is sequentially directed by trimethylsilyl groups, which are not retained in the final product.
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Ladder polyether forms by regioselective epoxide opening that is sequentially directed by trimethylsilyl groups, which are not retained in the final product.

Because they are bioactive and difficult to synthesize, the marine natural products known as ladder polyethers-so called because of their extended structure of fused heterocycles-have intrigued synthetic chemists for decades. Now, chemists at MIT have reported the shortest route yet to the tetrahydropyran tetrad common to the majority of these compounds (J. Am. Chem. Soc. 2006, 128, 1056).

The efficient synthesis, developed by chemistry professor Timothy F. Jamison, postdoctoral fellow Graham L. Simpson, and graduate students Timothy P. Heffron and Est??baliz Merino, employs an epoxide-opening cascade reaction that zips the structure in one step.

Chemists have hypothesized for 20 years that ladder polyethers are biosynthesized via this type of cascade. But until now, Jamison says, no one had been able to use this route to make tetrahydropyran tetrads.

The MIT group's approach relies on a "disappearing" trimethylsilyl (TMS) group. This moiety regioselectively directs the epoxide opening so that a six-membered tetrahydropyran forms, rather than a five-membered tetrahydrofuran. After cyclization, the TMS group leaves the molecule before the next epoxide-opening reaction in the cascade.

Jamison and colleagues discovered the departing directing group while tweaking cyclization conditions. The strong Lewis acids typically used to open epoxides failed to give them the desired product. When the chemists used Cs2CO3 and methanol, however, not only did they achieve the desired cyclization, but to their surprise, the TMS groups were not retained in the final product.

"That was a 'jumping up and down in the lab' result," Jamison says. After a bit more fine-tuning, the group was able to make the tetrad in just one step. These and related tetrads, Jamison notes, may serve as building blocks for making relatively large amounts of these rare, bioactive ladder polyethers.

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