Divergent synthesis of chiral cyclic azides via asymmetric cycloaddition reactions of vinyl azides

Nuligonda Thirupathi,Fang Wei,Zhenghu Xu,Chen-Ho Tung

doi:10.1038/s41467-019-11134-8

Nuligonda Thirupathi, Fang Wei + Show 2 more

Open Access

https://doi.org/10.1038/s41467-019-11134-8

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Abstract

Vinyl azides, bearing conjugated azide and alkene functional groups, have been recognized as versatile building blocks in organic synthesis. In general vinyl azides act as 3-atom (CCN) synthons through the fast release of molecular nitrogen and have been extensively utilized in the construction of structurally diverse N-heterocycles. Keeping the azide moiety intact in organic transformations to synthesis chiral azides is an important but challenging task. Herein, we report an enantioselective copper(II)/BOX-catalyzed cycloaddition of vinyl azides, generating diverse chiral cyclic azides. α-Aryl substituted vinyl azides react with unsaturated keto esters through an inverse-electron-demand hetero-Diels-Alder reaction to afford chiral azido dihydropyrans with excellent enatioselectivities. In contrast, cyclohexenyl azides undergo a diastereo- and enantio-selective Diels-Alder reaction giving important azido octahydronaphthalenes with three continuous stereogenic centers. Notable features of these reactions include a very broad scope, mild reaction conditions and 100% atom economy.

Highlights

Vinyl azides, bearing conjugated azide and alkene functional groups, have been recognized as versatile building blocks in organic synthesis
Chiral azides have been utilized as key intermediates in the total synthesis of many natural products, such as callipeltosides A and B5, and pharmaceuticals such as the antibiotic chloramphenicol[6]
Vinyl azides undergo a fast release of two nitrogens to generate vinyl nitrene or strained 2Haziridine intermediates, and subsequent cycloaddition or radical addition reactions lead to structurally diverse N-heterocycles[33,34,35,36,37,38,39,40] (Fig. 1a)

Summary

Introduction

Vinyl azides, bearing conjugated azide and alkene functional groups, have been recognized as versatile building blocks in organic synthesis. Vinyl azides can react with electrophiles to form iminium ions, or undergo Schmidt-type rearrangements driven by loss of a dinitrogen unit to afford functionalized amides[41] In this general denitrogenation reactivity mode, vinyl azides act as an important three-atom synthon in the construction of complex N-heterocyclic skeletons and have been extensively studied in recent years. Many important natural sesquiterpenoids and diterpenoids are isoprenoid decalins, for example, cadinene and cyperone are components of important essential oils from plants, and the natural indole sesquiterpenes pentacyclindole[47] and 5-epi-nakijinol E48 have important antiproliferative and cytotoxic activities Such decalin scaffolds are built by a long linear stepwise construction of a chiral triene structure, followed by an intramolecular DA reaction[45,50]. The intermolecular catalytic asymmetric Diels–Alder reaction not reported to date is a more effective synthetic route to access this scaffold

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