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‘Green’ Route To Chromanols

Organic Chemistry: Organocatalysis creates tocopherol’s chiral core

by Stu Borman
July 18, 2014 | A version of this story appeared in Volume 92, Issue 29

A reaction scheme showing a catalytic synthesis of chiral chromanol.
An enantioselective oxidative reaction produces optically active chromanols, which can then be made into tocopherols and related compounds.

Researchers have developed a “green” method for creating chiral chromanols, two-ring aromatic structures that can be elaborated into bioactive compounds such as tocopherols. The antioxidant and other properties of tocopherols and related compounds make them good prospects for drug discovery, but they are difficult to synthesize.

Natural sources of tocopherols and related compounds are sparse, and catalytic methods used to produce their chiral chromanol cores are often hampered by low catalyst activity, modest enantioselectivity, toxicity, or high cost. So tocopherols are synthesized commercially as a mixture of eight stereoisomers. And no asymmetric synthesis of α-tocopherol, the most bioactive form of vitamin E, is available.

Kazuaki Ishihara and coworkers at Nagoya University, in Japan, have now devised a highly efficient, enantioselective, environmentally benign, and inexpensive organocatalytic synthesis of chromanols. The procedure uses a chiral hypoiodite oxidative organocatalyst and a peroxide cooxidant to catalyze cyclic ether formation in single-ring aromatic substrates. The resulting chiral chromanol products can be derivatized into tocopherols, tocotrienols, and other compounds (Science 2014, DOI: 10.1126/science.1254976).

The synthesis “stands out as an innovative and potentially practical strategy, in light of its high turnover, intriguing mechanism, and environmentally benign oxidative conditions,” says Hong C. Shen, head of medicinal chemistry at Roche Innovation Center Shanghai.

Biocatalysis specialist Wolf-D. Woggon of the University of Basel agrees that it’s “an excellent approach to chiral chromanols.” But he adds that elaborating chromanols to tocopherols is complex, making this route uncompetitive with an earlier organocatalytic method (Angew. Chem. Int. Ed. 2008, DOI: 10.1002/anie.200801765). Ishihara responds that not only tocopherols but also other bioactive and pharmaceutically interesting compounds “can be synthesized in short steps from our chromanol products.”


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