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Enantioselective halocyclization of polyprenoids induced by nucleophilic phosphoramidites

Abstract

Polycyclic bio-active natural products that contain halogen atoms have been isolated from a number of different marine organisms1. The biosynthesis of these natural products appears to be initiated by an electrophilic halogenation reaction at a carbon–carbon double bond2,3,4 via a mechanism that is similar to a proton-induced olefin polycyclization5,6,7,8. Enzymes such as haloperoxidases generate an electrophilic halonium ion (or its equivalent), which reacts with the terminal carbon–carbon double bond of the polyprenoid, enantioselectively inducing a cyclization reaction that produces a halogenated polycyclic terpenoid. Use of an enantioselective halocyclization reaction is one possible way to chemically synthesize these halogenated cyclic terpenoids; although several brominated cyclic terpenoids have been synthesized via a diastereoselective halocyclization reaction that uses stoichiometric quantities of a brominating reagent9,10,11,12, the enantioselective halocyclization of isoprenoids induced by a chiral promoter has not yet been reported. Here we report the enantioselective halocyclization of simple polyprenoids using a nucleophilic promoter. Achiral nucleophilic phosphorus compounds are able to promote the diastereoselective halocyclization reaction to give a halogenated cyclic product in excellent yields. Moreover, chiral phosphoramidites promote the enantioselective halocyclization of simple polyprenoids with N-iodosuccinimide to give iodinated cyclic products in up to 99% enantiomeric excess and diastereomeric excess. To the best of our knowledge, this is the first successful example of the enantioselective halopolycyclization of polyprenoids.

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Figure 1: Nucleophilic promoters versus Lewis acid promoters for the activation of N- halosuccinimides, and halocyclization of 4-(homogeranyl)toluene ( 1 ) to 2.
Figure 2: Possible reaction mechanism.

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Acknowledgements

Financial support for this project was provided by the JSPS (KAKENHI), the 21st Century COE Program “Nature-Guided Materials Processing” of MEXT, the Banyu Award in Synthetic Organic Chemistry, Japan, and the Suzuken Memorial Foundation.

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Correspondence to Kazuaki Ishihara.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains Supplementary Notes providing the full experimental details for the synthesis of homo(polyprenyl)arenes and chiral phosphoramidites, the procedure of halocyclization and transhalogenation, and the characterization of all new compounds. (PDF 675 kb)

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Sakakura, A., Ukai, A. & Ishihara, K. Enantioselective halocyclization of polyprenoids induced by nucleophilic phosphoramidites. Nature 445, 900–903 (2007). https://doi.org/10.1038/nature05553

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