Please cite this article in press as: Saito et al., Selective Transformation of Strychnine and 1,2-Disubstituted Benzenes by C–H Borylation, Chem
Article
Selective Transformation of Strychnine
and 1,2-Disubstituted
Benzenes by C–H Borylation
Yutaro Saito,1,4 Kotono Yamanoue,2,3 Yasutomo Segawa,1,2, and Kenichiro Itami
*
SUMMARY
The Bigger Picture
The derivatization of complex
natural organic compounds has
recently received much attention,
especially in the field of drug
discovery. Even though many
complex organic molecules are
readily available from natural
sources, their controlled synthesis
is difficult. Yet, the derivatization
of complex natural compounds
enables the rapid construction of
libraries of drug candidates with
structural complexity and diverse
functionality. Herein, we report a
site-selective C–H borylation
reaction of an arene moiety in a
variety of 1,2-disubstituted
C–H functionalizations of complex molecules such as natural products, pharma-
ceuticals, and p-conjugated systems are at the heart of constructing and modi-
fying organic molecules, whereby the selectivity and predictability are of the
utmost importance. Herein, we report the highly C3-selective C–H borylation
of strychnine along with olefin isomerization, catalyzed by an iridium complex
with a diphosphine ligand. This method enabled us to rapidly produce 15 strych-
nine derivatives by using the corresponding C3-borylated and isomerized
analog as the common synthetic intermediate. The present catalyst system
was also generally effective for the C–H functionalization of unsymmetric 1,2-
disubstituted benzene derivatives, including fused p-systems (xanthenes, fluo-
renes, naphthalenes, and anthracenes) and pharmaceuticals (Nifedipine), in
which the C–H positions furthest away from the bulky groups were borylated
with high selectivity.
INTRODUCTION
Methods for the functionalization of complex natural organic compounds have
received much attention in recent years, especially in the context of drug discov-
ery.1–5 Even though many complex organic molecules are readily available from nat-
ural sources, their artificial synthesis remains challenging. Accordingly, the derivati-
zation of complex natural compounds offers an effective strategy for the rapid
construction of libraries of drug candidates with high structural complexity and
diverse functionality. Meanwhile, the methods for the selective introduction of func-
tional groups into complex structures are still relatively limited, and therefore, sim-
ple and predictable functionalization methods are urgently required.6–12
benzenes. We demonstrated that
a variety of strychnine derivatives
(15 examples) were readily
prepared by using a common
synthetic intermediate. This result
indicates that such mild and site-
selective C–H functionalizations
could find applications in
medicinal chemistry and materials
science.
Strychnine, the indole alkaloid isolated from the seeds of Strychnos nux-vomica,13,14
represents one of the most famous natural products, given its very complex structure
and long history in natural-product synthesis and medicinal science.15–18 Strychnine
(C21H22N2O2) contains tertiary amine, amide, alkene, ether, and indoline moieties
with six asymmetric carbon atoms, including a quaternary carbon center. Strychnine
is severely neurotoxic, as it inhibits the chloride channel of the glycine receptor.19
Even though various health benefits have been reported,20 strychnine has been
used predominantly as a poison in e.g., rodenticides. Considering the lower toxicity
of brucine, which is a natural analog of strychnine with dimethoxy groups at the ar-
omatic C–H positions (C2 and C3),21 and the X-ray crystal structure analysis of the
human glycine receptor bound to strychnine,22 it seems feasible to expect a signif-
icantly reduced toxicity from strychnine derivatives that contain substituents at C2
and/or C3.
Chem 6, 1–9, April 9, 2020 ª 2020 Elsevier Inc.
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