Halogen-Induced Cyclization | February 26, 2007 Issue - Vol. 85 Issue 9 | Chemical & Engineering News
Volume 85 Issue 9 | p. 9 | News of The Week
Issue Date: February 26, 2007

Halogen-Induced Cyclization

Long-sought enantioselective reaction leads to halogenated steroidal compounds
Department: Science & Technology
Ishihara (center, with model of chiral phosphoramidite) developed the new reaction with coworkers Atsushi Ukai (left, with substrate) and Akira Sakakura (right, with polycyclic product).
Credit: Kazuaki Ishihara
Ishihara (center, with model of chiral phosphoramidite) developed the new reaction with coworkers Atsushi Ukai (left, with substrate) and Akira Sakakura (right, with polycyclic product).
Credit: Kazuaki Ishihara

SOME MARINE organisms have a knack for making steroidal compounds containing halogens. Chemists have long tried to do the same thing, because such compounds can be useful, for example, in treating skin diseases. Now, Japanese researchers have made a significant advance in imitating how such compounds are made in nature. Specifically, they have achieved the first nonenzymatic, highly enantioselective cyclization induced by insertion of a halogen atom.

The reaction emulates biological processes in which halogenated polycyclic steroidlike compounds are produced by enzymatic halocyclization of linear precursors and a series of subsequent ring closures. Scientists would like to carry out such reactions to synthesize similar natural-product-like compounds for drug screening and fundamental research.

In 2004, chemistry professors Kazuaki Ishihara and coworkers at Nagoya University, in Japan, and Hisashi Yamamoto of the University of Chicago demonstrated a hydrogen-induced enantioselective cyclization. But that reaction doesn't make halogenated products.

Ishihara and coworkers have now taken an initial step toward an efficient route to such halogenated compounds with their nonenzymatic enantioselective halocyclization (Nature 2007, 445, 900). The method "provides access to polycyclic 3-iodoterpenoids with high enantioselectivities much more easily than the conventional multistep syntheses" that would otherwise be needed, the researchers note.

Key to the reaction is a chiral phosphoramidite reagent that activates an iodine atom from N-iodosuccinimide, transfers it enantioselectively to a linear substrate, and induces cyclization. The reaction thus inserts iodine rather than the more useful halogens-chlorine, fluorine, and bromine. But iodine can be replaced by other halogens, hydrogen, or other functional groups in a subsequent step. The reaction is stoichiometric, not catalytic, which would be preferable.

Credit: Kazuaki Ishihara
C&EN news of the week
Credit: Kazuaki Ishihara

Associate professor of chemistry Phil S. Baran and graduate student Thomas Maimone of Scripps Research Institute comment in Nature that the reaction's development is "a tremendous advance." With this achievement, they note, "the foundation is in place for catalytic versions of this reaction" and, at long last, a more efficient way to synthesize halogenated, naturally occurring compounds.

"Although optically active polyhalogenated compounds are quite popular in marine natural products, there are no methodologies available to mimic the process," Yamamoto says. "The reported method seems to be general and widely applicable for a number of asymmetric syntheses. I do hope it will be further improved to a catalytic version."

Chemistry professor Thomas Wirth of Cardiff University, in Wales, notes that the reaction's selectivities of 91-99% are impressive but that its scope, "judged by the examples presented in the paper, is narrow." The reaction's inability to directly introduce halogens other than iodine suggests the system could be quite specialized, he adds. "However, this research will surely trigger efforts by other groups."

David O'Hagan, a chemistry professor at the University of St. Andrews, in Scotland, believes the new process, which he calls "impressive," could be "widely applicable to many synthesis problems and challenges and can be developed in different labs in different directions. It moves the field forward with the discovery of a novel strategy and clear scope for improvement and diversification."

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