DOI: 10.1002/chem.201503355
Full Paper
&
Synthesis Design
Facile Installation of 2-Reverse Prenyl Functionality into Indoles
by a Tandem N-Alkylation–Aza-Cope Rearrangement Reaction and
Its Application in Synthesis
Xiaobei Chen,*[a, b] Huaqiang Fan,[a] Shilei Zhang,[b, c] Chenguang Yu,[b] and Wei Wang*[a, b]
Abstract: An unprecedented tandem N-alkylation–ionic aza-
Cope (or Claisen) rearrangement–hydrolysis reaction of read-
ily available indolyl bromides with enamines is described.
Due to the complicated nature of the two processes, an op-
erationally simple N-alkylation and subsequent microwave-ir-
radiated ionic aza-Cope rearrangement–hydrolysis process
has been uncovered. The tandem reaction serves as a power-
ful approach to the preparation of synthetically and biologi-
cally important, but challenging, 2-reverse quaternary-cen-
tered prenylated indoles with high efficiency. Notably, un-
usual nonaromatic 3-methylene-2,3-dihydro-1H-indole archi-
tectures, instead of aromatic indoles, are produced. Further-
more, the aza-Cope rearrangement reaction proceeds highly
regioselectively to give the quaternary-centered reverse
prenyl functionality, which often produces a mixture of two
regioisomers by reported methods. The synthetic value of
the resulting nonaromatic 3-methylene-2,3-dihydro-1H-
indole architectures has been demonstrated as versatile
building blocks in the efficient synthesis of structurally di-
verse 2-reverse prenylated indoles, such as indolines, indole-
fused sultams and lactams, and the natural product bruceol-
line D.
Introduction
theses make them attractive targets for synthesis and mecha-
nism-of-action studies.[3]
2-Reverse prenylated indole natural products are widely dis-
tributed in a number of terrestrial and marine fungi.[1] These
natural products display a broad spectrum of biological and
pharmacological activities, including cytotoxicity against
a number of cancer cell lines, antimicrobial and antiviral activi-
ties, and effects on the central nervous systems, which are dis-
tinct from the non-prenylated parent structures (Figure 1).[2]
Their intriguing biological properties underscore their potential
application as useful probes to elucidate the biological path-
ways and mechanisms and targets involved. They can also
serve as lead compounds for the development of new thera-
peutic agents. A combination of their activity, questions about
their modes of biological action, and challenges of their syn-
2-Reverse prenylated indole alkaloids are among the most
challenging class of natural products currently targeted by the
synthesis community. The structures of 2-reverse prenylated
indole alkaloids feature the same core unit of the 2-reverse
prenylated indole component (Figure 1). Therefore, construc-
tion of the challenging quaternary-centered reverse prenyl unit
in the indole scaffold is critical to their syntheses. The lack of
versatile, efficient synthetic methodologies is one of the major
bottlenecks in this field. More than a decade has passed, since
the only useful method developed by Danishefsky in 1999 was
reported [Scheme 1, Eq. (1)].[4] The strategy involves two steps:
in situ 3-chlorination of an indole by treatment with tBuOCl is
followed by a reaction with prenyl 9-BBN through a nucleophil-
ic substitution rearrangement to give the desired 2-reverse
prenylated indoles. The reaction has been successfully
used as a key step in the total synthesis of the indole alkaloids
gypsetin,[5] (+)-ambiguine H,[5] and asterriquinone B1.[6] An al-
ternative approach is the Cope rearrangement reaction
[Scheme 1, Eq. (2)].[7] Although the process looks more appeal-
ing because it uses readily accessible starting materials, the
poor reaction efficiency limits its synthetic application. Not
only was the yield (27%) far from satisfactory, two isomers
were also produced in the transformation studied by Sakamo-
to et al.[7c]
[a] Dr. X. Chen, H. Fan, Prof. Dr. W. Wang
School of Pharmacy, East China University of Science and Technology
130 Mei-Long Road, Shanghai 200237 (P. R. China)
[b] Dr. X. Chen, Prof. Dr. S. Zhang, C. Yu, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico, MSC03 2060
Albuquerque, NM 87131-0001 (USA)
Fax: (+1)505-277-2609
Herein, we report the results of an investigation that has led
to an unprecedented tandem N-alkylation–ionic aza-Cope rear-
rangement–hydrolysis reaction (Scheme 2).[8] The process
serves as a useful strategy for the facile installation of the chal-
lenging 2-reverse quaternary-centered prenyl functionality into
[c] Prof. Dr. S. Zhang
College of Pharmaceutical Sciences, Soochow University
199 Ren’ai Road, Suzhou 215123 (P.R. China)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2016, 22, 716 – 723
716
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