Angewandte
Communications
Chemie
In conclusion, a conjugate addition/asymmetric protona-
tion/aza-Prins cyclization reaction to prepare enantioenriched
indolines has been developed. This reaction provides direct
access to functionalized heterocyclic products in a single step
from simple indole derivatives, and is the first example of
a transformation in which a ZrCl4·BINOL complex serves as
a chiral LBA. This transformation demonstrates the utility of
asymmetric cascade catalysis for rapidly generating molecules
of complexity.
Experimental Section
General procedure for the conjugate addition/asymmetric protona-
tion/Prins cyclization cascade: To a flame-dried flask were added
indole (0.20 mmol, 1.00 equiv), acrylate (0.24 mmol, 1.20 equiv), (R)-
3,3’-dibromo-BINOL (0.04 mmol, 0.20 equiv), and 2,6-dibromophe-
nol (0.20 mmol, 1.00 equiv) under an N2 atmosphere. The flask was
charged with CH2Cl2 (1.5 mL), followed by addition of TMSCl
(0.2 mmol, 1.00 equiv) and ZrCl4 (0.32 mmol, 1.60 equiv unless
specifically indicated). The mixture was stirred at room temperature
for 24 h. The reaction was quenched by diluting with 1 mL MeCN and
1 mL 1m HCl, followed by addition of 5 mL H2O. The aqueous layer
was extracted with ethyl acetate (3 5 mL) and the combined organic
layers were washed with saturated NaHCO3(aq) (10 mL). The aqueous
layer was back extracted with EtOAc (10 mL) and the combined
organic layers were dried (Na2SO4), filtered, and concentrated. The
crude residue was purified by silica gel chromatography.
Acknowledgments
We thank Prof. Brian Stoltz, Dr. Scott Virgil, and the Caltech
Center for Catalysis and Chemical Synthesis for access to
analytical equipment. Victor W. Mak is gratefully acknowl-
edged for checking of the experimental procedure. We also
thank Dr. Michael Takase and Larry Henling for assistance
with X-ray structure analysis. NMR spectra were obtained on
a spectrometer funded by the National Institutes of Health
(NIH) (RR027690). J.N. is grateful for a pre-doctoral fellow-
ship from NSERC. S.E.R. is an American Cancer Society
Research Scholar. Financial support from the NIH (NIGMS
RGM097582A) and the donors of the American Chemical
Society PRF is gratefully acknowledged.
Figure 2. Mechanistic investigations of the conjugate addition/asym-
metric protonation/aza-Prins cyclization. Standard reaction conditions:
7c (1.0 equiv), [D](Z)-2a (1.0 equiv), (R)-3,3’-dibromo-BINOL (20 mol
%), ZrCl4 (1.6 equiv), 2,6-dibromophenol (1.0 equiv), TMSCl
(1.0 equiv), CH2Cl2, 238C. DBU=1,8-diazabicyclo[5-4-0]undec-7-ene.
which enables the isomerization of [D](Z)-2a by rotation
À
around the C C bond of the intermediate 16.
It is also interesting to note the divergence in the
stereochemical outcome of the aza-Prins cyclizations of the
C3- and N-linked substrates (8 and 10, respectively). For the
polycyclic indoline 10, the configuration at the chlorine-
bearing carbon atom results from equatorial trapping of the
carbocation 18 (Figure 2c), and is consistent with a process
that is driven by orbital alignment.[13,14] In contrast, the
configuration at the chlorine-bearing carbon atom of 8 results
from cyclization through an anti-periplanar arrangement
between the alkene and iminium ion (19), followed by axial
trapping of 20 by chloride. This diastereoselection is opposite
to that observed by Hanessian and co-workers in their studies
of aza-Prins reactions of structurally similar N-acyloxy
iminium ions.[14] However, Rychnovsky and co-workers have
reported that TMSBr-mediated oxonia-Prins reactions of a-
bromoethers result in axial trapping.[15] In the present case,
the origin of the axial-selective trapping is unclear.[16]
Keywords: cyclizations · enantioselectivity · heterocycles ·
Lewis acids · zirconium
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3398–3402
Angew. Chem. 2016, 128, 3459–3463
b) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem.
114, 2390; b) J.-C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan,
[5] For a review of catalytic asymmetric dearomatization reactions,
including indole dearomatization, see: C.-X. Zhuo, W. Zhang, S.-
Angew. Chem. Int. Ed. 2016, 55, 3398 –3402
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