Synthesis of polycyclic benzofused nitrogen heterocycles via a tandem ynamide benzannulation/ring-closing metathesis strategy. Application in a formal total synthesis of (+)-FR900482 |
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Authors: | Mak Xiao Yin Crombie Aimee L Danheiser Rick L |
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Affiliation: | Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. |
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Abstract: | A two-stage "tandem strategy" for the synthesis of benzofused nitrogen heterocycles is described that is particularly useful for the construction of systems with a high level of substitution on the benzenoid ring. The first stage in the strategy involves a benzannulation based on the reaction of cyclobutenones with ynamides. This cascade process proceeds via a sequence of four pericyclic reactions and furnishes a multiply substituted aniline derivative which can bear a variety of functionalized substituents at the position ortho to the nitrogen. In the second stage of the tandem strategy, ring-closing metathesis generates the nitrogen heterocyclic ring. This two-step sequence provides efficient access to highly substituted dihydroquinolines, benzazepines, benzazocines, and related benzofused nitrogen heterocyclic systems. The application of this chemistry in a concise formal total synthesis of the anticancer agents (+)-FR900482 and (+)-FR66979 is described. |
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