Organic Letters
Letter
to saturated aldehydes. Instead, the readily available saturated
aldehyde 16 was then selected as a surrogate for prenal.18 The
Ga(OTf)3 catalyzed three-component reaction of indole,
aldehyde 16, and diene 3 afforded the desired cyclohepta[b]-
indole product 17 under Wu’s conditions. The reaction was
further optimized with the more precious diene component 3
as the limiting reagent. Slow addition of a solution of 3 over 2
h via syringe pump to the reaction mixture led to the formation
of the desired product 17 and its diastereomer. The reaction
was modest in yield and selectivity, but it is scalable and more
than 1 g of cyclohepta[b]indole products have been obtained
in a single reaction. The pure major isomer 17 could be
obtained via crystallization.
exotines from a [4 + 3] cycloaddition reaction is proposed
based on our findings. Additionally, we developed an efficient
route to 8-substituted coumarin natural products such as
gleinadiene (3) and coumurrayin (9).
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
Experiment procedures and analytical data for new
The thioether group of compound 17 was selectively
oxidized in the presence of the indole and alkene
functionalities using m-CPBA at low temperature. Thermal
elimination of the resulting sulfoxide in refluxing toluene
afforded a complex mixture, while a clean reaction was
obtained in the presence of basic additives such as K2CO3 or
Et3N. Iso-exotine B (18) bearing an external alkene was
formed in good yield as a 7/1 mixture with exotine B (2).
Conversion of iso-exotine B (18) to exotine B (2) was found
to be challenging; only Crabtree’s catalyst in acetone or THF
resulted in productive isomerization to 2.19 The reaction had
to be carefully controlled, since a second isomerization product
derived from the positional shift of the endocyclic olefin was
obtained racemic exotine B fully matched the reported data for
the natural isolate (Scheme 4).
AUTHOR INFORMATION
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Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank New York University for financial support and Dr.
Chin Lin (NYU) for assistance with NMR spectrometry and
mass spectrometry. NMR spectra were acquired using the TCI
cryoprobe supported by The National Institutes of Health
(OD016343). J.M. thanks the German Academic Scholarship
Foundation for a PhD fellowship and New York University for
a MacCracken PhD fellowship.
Scheme 4. Total Synthesis of Exotine B
REFERENCES
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Based on our studies on the chemical synthesis of exotine B,
an alternative biosynthesis of exotines could be proposed
(Scheme 1b). Protonation of diene 5 or its tautomer 5′ would
generate a conjugate cationic intermediate, which could
undergo a [4 + 3] cycloaddition reaction with gleinadiene
(3) to form the cyclohepta[b]indole structure and give natural
product exotine B (2). Since exotine B was found to be
optically active, an enzymatic pathway is probably operative
during this process.
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