Organic Letters
Letter
to B), (ii/iii) oxidation of Pd(II) to Pd(IV) by C6F5I and
abstraction of iodine by the silver salt (to form C), (iv) a new
type of C−C bond cleavage with the concomitant rearrange-
ment of the skeleton to form a Pd(IV) intermediate E, and (v)
reductive elimination leading to the chiral polycyclic alkaloid
11a as a single enantiomer. The product 11a and related
products 11b and 11c were obtained in good yields. The
structure of 11a was further confirmed by single-crystal X-ray
diffraction. Features of this reaction involve not only the highly
site-selective activation favoring tertiary C(sp3)−H bond over
secondary or primary C(sp3)−H bonds, but also an
uncommon, stereoselective formation of a cyclopropane
through four-membered bridged ring contraction.14 This is a
new type of C−C bond activation,15,16 where the electron-pair
from a C−C bond is involved in a new C−C bond-forming
reaction that proceeds with the complete reversal of
configuration at a tertiary stereogenic center. Further, a cationic
metal “leaving group” is involved and the process results in the
formation of an all carbon quaternary center. To the best of our
knowledge, this is the first example of such a reaction, and the
overall scheme represents the facial skeletal rearrangement of a
terpenoid into a new scaffold of an alkaloid-like structure.
In conclusion, we have developed a strategy for using an
intramolecular palladium-catalyzed amination of unactivated γ
or δ C(sp3)−H with readily available aliphatic straight-chain
and cycloalkyl amine substrates to construct complex polycyclic
nitrogen-containing heterocycles. The reaction exhibits high
functional group tolerance and enables the synthesis of various
azabicyclic scaffolds, including azabicyclo[x.1.1] (x = 3, 4, 5, 7,
9), [3.2.1], and [4.2.0] skeletons, simple azetidines, and
azetidine with a chiral spiro-quaternary carbon center. This
method is also suitable for late-stage functionalization of
naturally derived amines for increasing the complexity of their
basic skeletons. Among the [3.2.1]-heterobicyclic compounds
that are accessible by this route are members of tropane class of
alkaloids. In the case of a natural substrate, (−)-cis-myrtanyl-
amine derivative (−)-10, a new type of C−C bond activation
initiated by a highly site-selective palladium-catalyzed tertiary
C(sp3)−H bond activation is followed by stereoselective
formation of a cyclopropane via a ring contraction that involves
inversion of configuration at a quaternary center. The reaction
seems to involve a cationic Pd(IV) species as a leaving group.
We anticipate that this approach will be useful for the
construction of more complex alkaloid-like structures with
potential applications in medicinal chemistry and also in natural
product synthesis.
AUTHOR INFORMATION
Corresponding Authors
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ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We gratefully thank “Hundred Talents Project” of CAS, “High-
end Science and Technology Talents Program” of Yunnan
Province (2011HA008), the NSFC (21472198, 21772236),
and Grant (2014FA039) from Yunnan Province and KPTI
program of Hubei Province (2016ACA138) of China for
financial support. Dr. Xiaonian Li is acknowledged for the X-ray
crystallographic analysis work. We acknowledge Prof. T. V.
RajanBabu (Ohio State University) for his encouragement and
comments on this project.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
1
Experimental details, spectral data, H and 13C NMR
spectra, X-ray crystallographic data for compounds
( )-2g, ( )-2h, ( )-3c, ( )-8, and (+)-11a, and
synthetic applications for the preparation of compounds
X-ray crystallographic data for compound ( )-2g (CIF)
X-ray crystallographic data for compound ( )-2h (CIF)
X-ray crystallographic data for compound ( )-3c (CIF)
X-ray crystallographic data for compound ( )-8 (CIF)
X-ray crystallographic data for compound ( )-11a (CIF)
(13) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192.
(14) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485.
(15) Jones, W. D. Nature 1993, 364, 676.
(16) C−C Bond Activation; Dong, G.-B., Eds.; Springer: Berlin, 2014.
D
Org. Lett. XXXX, XXX, XXX−XXX