Enantioselective synthesis of pyrroloindolines by a formal [3 + 2] cycloaddition reaction

Article abstract of DOI:10.1021/ja107328g

(R)-BINOL?SnCl₄ was found to catalyze a formal [3 + 2] cycloaddition reaction between C(3)-substituted indoles and 2-amidoacrylates to provide pyrroloindolines. A variety of pyrroloindolines were prepared with high enantioselectivity in one step from simple precursors. This methodology is expected to facilitate the total synthesis of pyrroloindoline alkaloids, an important class of biologically active natural products.

Full text of DOI:10.1021/ja107328g

Published on Web 09/27/2010
Enantioselective Synthesis of Pyrroloindolines by a Formal [3 + 2]
Cycloaddition Reaction
Lindsay M. Repka, Jane Ni, and Sarah E. Reisman*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, DiVision of Chemistry
and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received August 23, 2010; E-mail: reisman@caltech.edu
2
to provide the C(3)-Friedel-Crafts type product 3 (R ) R ) H,
R ) R ) Me, Scheme 1).
Abstract: (R)-BINOL•SnCl
4
was found to catalyze a formal
9
3
4
[3 + 2] cycloaddition reaction between C(3)-substituted indoles
and 2-amidoacrylates to provide pyrroloindolines. A variety of
pyrroloindolines were prepared with high enantioselectivity in one
step from simple precursors. This methodology is expected to
facilitate the total synthesis of pyrroloindoline alkaloids, an
important class of biologically active natural products.
Table 1. Optimization Studies
Pyrroloindoline alkaloids are an important class of natural
1
products that exhibit an impressive array of promising biological
BINOL
(equiv)
yield
a
(%)
ee
c d
2
3
1
2
b
,
properties, including anticholinesterase, anti-inflammatory, and
anticancer activities. Owing to their medicinal relevance and
structural complexity, pyrroloindoline alkaloids have served as a
fertile area for the discovery and development of new chemical
entry
R , R
pdt
solvent
d.r.
(%)
4
1
2
3
4
5
6
7
8
9
Me, Me (8)
Me, Me (8)
Me, Me (8)
Me, Me (8)
Me, Me (8)
Me, Me (8)
CF , Me (9)
Me, Bn (10)
3
, Bn (11)
7a
7a
7a
7a
7a
7a
7b
7c
7d
7d
7d
7d
0.0
1.1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
64
86
96
94
93
82
77
81
81
86
58
0
6:1
4:1
5:1
5:1
5:1
5:1
6:1
2:1
3:1
4:1
3:1
–
–
e
64/83
62/81
63/83
61/79
51/72
86/nd
74/82
91/90
94/91
88/89
–
0.3
0.2
0.1
0.05
0.2
0.2
0.2
0.2
0.2
0.2
5
,6
reactions. As part of a program targeting new methods for the
total synthesis of alkaloid natural products, we sought to develop
a convergent method to prepare enantioenriched pyrroloindolines.
From a design perspective, it was hypothesized that pyrroloin-
dolines (5) could be assembled through the union of a C(3)-
substituted indole (1) and a 2-amidoacrylate (2) in what would
constitute a formal [3 + 2] cycloaddition reaction (Scheme 1). It
was envisioned that the reaction would proceed through a stepwise
mechanism in which a Lewis acid activates 2-amidoacrylate 2,
promoting conjugate addition by the indole to give iminium ion 4.
Subsequent intramolecular attack of the nucleophilic amide would
provide pyrroloindoline 5.
3
CF
10
11
12
CF
3
, Bn (11)
, Bn (11)
, Bn (11)
CF
CF
3
CHCl
CCl
3
3
4
a
b
1
Isolated yield of combined diastereomers. Determined by H NMR
analysis of crude reaction mixture. Determined by chiral stationary
phase SFC. ee of exo/endo diastereomers. 1.0 equiv of SnCl
used. nd ) not determined.
c
d
e
4
was
The proposed reaction would harness the intrinsic C(3)-nucleo-
philicity of the indole substrate and, in principle, could provide
rapid access to a variety of pyrroloindolines from simple C(3)-
substituted indole precursors. Although 2-amidoacrylates are
typically poor electrophiles for conjugate addition reactions due to
the electron-donating effects of the nitrogen lone pair, Piersanti
Preliminary experiments were conducted in which equimolar
mixtures of commercially available methyl 2-acetamidoacrylate (8)
and 1,3-dimethylindole (6) were exposed to various Lewis acids.
7
,8
We were pleased to find that strong Lewis acids such as EtAlCl
2
,
TiCl , and SnCl provided isolable quantities of the desired
4
4
pyrroloindoline 7a, as well as varying amounts of the C(2)-
Friedel-Crafts type product analogous to 3 (not shown). After a
preliminary survey of reaction parameters, the use of SnCl (1.2
4
2
and co-workers recently reported that EtAlCl promotes the reaction
1
2
of indole (1, R ) R ) R ) H) and methyl 2-acetamidoacrylate
equiv) in dichloroethane at room temperature was found to provide
pyrroloindoline 7a in 64% yield as a 6:1 mixture of exo and endo
diastereomers (Table 1, entry 1; exo diastereomer is shown).
At this stage we wished to determine the feasibility of accessing
enantioenriched pyrroloindolines using this formal [3 + 2] cy-
cloaddition reaction. To this end, a screen of chiral diol additives
anticipated to form chiral Lewis or Brønsted acid complexes with
Scheme 1. Proposed Reaction To Prepare Pyrroloindolines
1
0
SnCl
4
was conducted. Of the conditions evaluated, it was found
provided
that utilization of a 1.1:1 mixture of (R)-BINOL and SnCl
4
pyrroloindoline 7a in 86% yield as a 4:1 diastereomeric mixture
favoring exo-7a, which was formed in 64% ee (Table 1, entry
1
1,12
2
).
Interestingly, the minor, endo diastereomer was formed in
8
3% ee. In follow-up studies, a side-by-side comparison of two
reactions varying only by the presence or absence of (R)-BINOL
1
4418 9 J. AM. CHEM. SOC. 2010, 132, 14418–14420
10.1021/ja107328g  2010 American Chemical Society

C O M M U N I C A T I O N S
showed that it accelerates the rate of 7a formation and increases
the overall conversion.
withdrawing substituents provided uniformly high ee’s, although a
moderate decrease in yield was observed with electron-poor
substrates (Scheme 2, 13a-d). 1,3,6-Trimethylindole reacts smoothly
to give a 4:1 mixture of exo- and endo-13e in 91% yield (94% and
1
3
Scheme 2. Substrate Scope of Pyrroloindoline Formation
9
0% ee, respectively).
More functionalized substituents are also tolerated at C(3) of
the indole substrate. Pyrroloindolines bearing tert-butyldimethyl-
siloxyethyl (13f) and phenylethyl (13h) substituents are prepared
in moderate to good yield and high enantioselectivity (Scheme 2).
Most notably, use of N-methyl-1,2,3,4-tetrahydrocarbazole provided
a single diastereomer of pyrroloindoline 13g in 65% yield and 86%
ee. Using this reaction, the aza-propellane core of natural products
1
8
19
such as vincorine and minfiensine was prepared in only two
steps from commercially available 1,2,3,4-tetrahydrocarbazole.
Whereas the exo diastereomer predominates in the (R)-
BINOL•SnCl
4
-catalyzed formation of the pyrroloindolines shown
in Scheme 2, it is known that the endo diastereomer of similar
20,21
compounds is favored thermodynamically.
ment of a 4:1 mixture of exo-7d and endo-7d diastereomers (94%
and 91% ee, respectively) with excess DBU in CD Cl resulted in
Accordingly, treat-
2
2
epimerization to give a greater than 10:1 endo/exo mixture of
products after 72 h (Scheme 3). Interestingly, the endo-7d product
2
2
was recovered in 56% ee, faVoring the opposite enantiomer. In
a subsequent experiment, exposure of diastereomerically pure exo-
7
d to DBU (10 equiv) provided ent-endo-7d in 94% ee. Exposure
of diastereomerically pure endo-7d to the epimerization conditions
returned endo-7d without significant erosion of enantiomeric excess.
Taken together, these studies suggest that the initially formed exo
and endo diastereomers of 7d must be of opposite enantiomeric
series. From a synthetic perspective, the diastereomers can be
separated prior to subsequent functionalization to avoid erosion of
optical activity through this epimerization mechanism.
a
1
b
At this time the mechanism of the reaction remains to be
elucidated. As exo- and endo-7d have opposite configurations at
C(3), analysis of the diastereomeric and enantiomeric ratios suggests
that the first step of the reaction (conjugate addition) occurs with
modest levels of catalyst control, whereas the enolate protonation
Determined by H NMR analysis of mixture. Determined by chiral
c
4
stationary phase SFC or HPLC. 1.6 equiv of SnCl was employed.
Based on these observations, it was hypothesized that catalytic
quantities of (R)-BINOL may still provide pyrroloindoline 7a with
good levels of enantioselectivity. Indeed, use of as low as 10 mol
(R)-BINOL furnished 7a without significantly affecting the
observed enantioselectivity (Table 1, entries 3-5). Whereas 10 mol
(R)-BINOL provided comparable selectivities for the formation
2
3
step occurs with high levels of catalyst control. In effect, the
catalyst-controlled protonation step serves to resolve the mixture
%
Scheme 3. Epimerization Studies
%
of 7a, 20 mol % (R)-BINOL imparted consistently higher enanti-
oselectivities for more functionalized substrates (Vide infra) and
was therefore utilized in subsequent experiments. Control experi-
ments confirmed that no reaction occurred in the absence of SnCl
and that 1.2 equiv SnCl were required to drive the reaction to high
4
4
1
4
conversions.
In an effort to improve the enantioselectivity of the reaction,
1
5,16
the amide and ester groups of the acrylate were modified.
An
increase in ee was observed when methyl 2-trifluoroacetamidoacr-
ylate (9) was employed (Table 1, entry 7). A similar increase was
observed using benzyl 2-acetamidoacrylate (10, entry 8). Gratify-
ingly, these effects proved to be additive: use of benzyl 2-trifluo-
roacetamidoacrylate (11) provided pyrroloindoline 7d in 81% yield
and 91% ee. Preliminary studies indicated that chlorinated solvents
provided the best combination of yields and selectivities. A further
screen identified methylene chloride as the solvent of choice. Under
our optimized conditions, pyrroloindoline 7d was isolated in 86%
yield as a 4:1 mixture of exo and endo diastereomers, which are
1
7
formed in 94% and 91% ee, respectively (entry 10).
Having identified conditions to prepare 7d in high yields and
enantioselectivities, a survey of indole substrates was conducted.
Substrates substituted at C(5) with electron-donating and electron-
J. AM. CHEM. SOC. 9 VOL. 132, NO. 41, 2010 14419

C O M M U N I C A T I O N S
of enantiomeric intermediates. Yamamoto and co-workers have
(6) Selected references: (a) Taniguchi, M.; Hino, T. Tetrahedron 1981, 37,
487. (b) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem.
1
demonstrated that BINOL•SnCl
4
behaves as a Lewis acid assisted
Soc. 1994, 116, 11143. (c) Overman, L. E.; Paone, D. V.; Stearns, B. A.
J. Am. Chem. Soc. 1999, 121, 7702. (d) Austin, J. F.; Kim, S. G.; Sinz,
C. J.; Xiao, W. J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A.
Brønsted acid that promotes a number of enantioselective proton-
1
1a-b
ation reactions.
tivities to be observed when employing an excess of SnCl
to BINOL. The observation that at least 1 equiv of SnCl is required
for high conversions, coupled with the fact that use of strong
It is unusual, however, for high enantioselec-
2
004, 101, 5482. (e) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006,
4
relative
128, 6314. (f) Lindel, T.; Br a¨ uchle, L.; Golz, G.; B o¨ hrer, P. Org. Lett.
2
007, 9, 283. (g) Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science 2009,
4
3
24, 238. (h) Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
10886. (i) Espejo, V. R.; Li, X.-B.; Rainier, J. D. J. Am. Chem. Soc. 2010,
132, 8282.
2
4
4
Brønsted acids in the absence of SnCl fails to provide 7d, may
(
7) For the direct arylation of indoles to provide racemic dehydroindolines,
see: (a) Barton, D. H. R.; Bhatnagar, N. Y.; Blazejewski, J. C.; Charpiot,
B.; Fibet, J. P.; Lester, D. J.; Motherwell, W. B.; Papoula, M. T. B.;
Stanforth, S. P. J. Chem. Soc., Perkin Trans. 1 1985, 2657. (b) Eastman,
K.; Baran, P. S. Tetrahedron 2009, 65, 3149.
suggest that this reaction benefits from cooperative Lewis
acid-Brønsted acid activation.
In conclusion, a convergent method to prepare enantioenriched
pyrroloindolines is described. The optimal conditions employ (R)-
4
BINOL as a catalyst in the presence of stoichiometric SnCl and
(
8) For the direct preparation of enantioenriched pyrroloindolines from indoles,
see refs 6d and 6e.
(
9) Angelini, E.; Balsamini, C.; Bartoccini, F.; Lucarini, S.; Piersanti, G. J.
Org. Chem. 2008, 73, 5654.
provide access to functionalized pyrroloindolines in uniformly high
ee’s. The application of this methodology to the total synthesis of
pyrroloindoline natural products and studies aimed at understanding
the mechanism of this new transformation are the focus of ongoing
(
(
10) See Supporting Information.
11) For reports of asymmetric catalysis by BINOL•SnCl , see:(a) Ishihara, K.;
4
Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118,
1
2854. (b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc.
996, 118, 3049. (c) Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G.
1
2
5
research in our laboratory.
J. Am. Chem. Soc. 2005, 127, 12808. (d) Rauniyar, V.; Zhai, H. M.; Hall,
D. G. J. Am. Chem. Soc. 2008, 130, 8481. For a review, see: (e) Yamamoto,
H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924.
Acknowledgment. We thank Dr. Scott Virgil for insightful
discussions; Drs. Michael Day and Larry Henling for X-ray
crystallographic structural determination; and Prof. Brian Stoltz and
the Caltech Center for Catalysis and Chemical Synthesis for access
to analytical equipment. HRMS and X-ray crystallographic data
were obtained on instruments purchased through awards to the
California Institute of Technology by the NSF CRIF program (CHE-
(
12) The relative stereochemistry of exo-7b was confirmed by single crystal
X-ray diffraction; the relative stereochemistry of exo-7a and the remaining
compounds were assigned by analogy. The absolute stereochemistry has
not been confirmed at this time.
(
13) BINOL catalyzes the addition of allyl and alkynyl boronates to aldehydes. (a)
Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244. (b) Lou, S.;
Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006, 128, 12660. (c)
Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2007, 129, 4908. (d) Lou, S.;
Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398. (e)
Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.
0
639094, CHE-0541745). NMR spectra were obtained on a
(
14) Whereas organotin reagents are known for their toxicity, inorganic tin(IV)
spectrometer funded by the NIH (RR027690). Financial support
from the California Institute of Technology and the Baxter
Foundation is gratefully acknowledged.
compounds are relatively nontoxic: Howe, P.; Watts, P. Tin and Inorganic
4
Tin Compounds. World Health Organization: Switzerland, 2005. SnCl is
available from Sigma-Aldrich for $30/mol, and (R)-BINOL is approximately
$10 000/mol.
(
15) Acrylates 9, 10, and 11 are prepared in one step from the commercially
available materials. See Supporting Information for details.
16) A small screen of BINOL derivatives was also conducted, in which several
3,3′-difunctionalized-(R)-BINOL catalysts were found to provide diminished
rates and selectivities.
Supporting Information Available: Experimental details, charac-
terization data, and NMR spectral charts. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
(
17) Use of 3-methylindole provided the corresponding pyrroloindoline in 18%
yield as a 8:1 exo/endo mixture. The exo diastereomer was formed in 95%
ee.
References
(
18) Das, B. C.; Cosson, J. P.; Lukacs, G.; Potier, P. Tetrahedron Lett. 1974,
15, 4299.
(
1) Anthoni, U.; Christophersen, C.; Nielsen, P. H. Naturally Occurring
Cyclotryptophans and Cyclotryptamines. In Alkaloids: Chemical & Biologi-
cal PerspectiVes; Pelletier, S. W., Ed.; Pergamon: Oxford, 1999; Vol. 13,
pp 163-236.
(19) Massiot, G.; Thepenier, P.; Jacquier, M.-J.; Le Men-Olivier, L.; Delaude,
C. Heterocycles 1989, 29, 1435.
(20) See ref 6a.
(
2) Physostigmine, a reversible cholinesterase inhibitor: Shaw, K. T. Y.; Utsuki,
T.; Rogers, J.; Yu, Q. S.; Sambamurti, K.; Brossi, A.; Ge, Y. W.; Lahiri,
D. K.; Greig, N. H. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7605.
(21) Crich, D.; Bruncko, M.; Natarajan, S.; Teo, B. K.; Tocher, D. A.
Tetrahedron 1995, 51, 2215.
(22) As determined by chiral stationary phase SFC. See Supporting Information
for details.
(
3) Lansai B, an anti-inflammatory agent: (a) Tuntiwachwuttikul, P.; Taechowisan,
T.; Wanbanjob, A.; Thadaniti, S.; Taylor, W. C. Tetrahedron 2008, 64, 7583.
(23) A reversible, nonselective conjugate addition followed by a moderately
diastereoselective cyclization cannot be ruled out at this time. Diastereo-
merically pure solutions of endo-7d or exo-7d do not equilibrate upon re-
exposure to SnCl (1.2 equiv) and (R)-BINOL (0.2 equiv) in CD Cl .
(
b) Taechowisan, T.; Wanbanjob, A.; Tuntiwachwuttikul, P.; Liu, J. Food
Agric. Immunol. 2009, 20, 67.
(
4) Chaetocin, an HDAC inhibitor: (a) Isham, C. R.; Tibodeau, J. D.; Jin, W.;
Xu, R.; Timm, M. M.; Bible, K. C. Blood 2007, 2579. Leptosins, DNA
topoisomerase inhibitors: (b) Yanagihara, M.; Sasaki-Takahashi, N.;
Sugahara, T.; Yamamoto, S.; Shinomi, M.; Yamashita, I.; Hayashida, M.;
Yamanoha, B.; Numata, A.; Yamori, T.; Andoh, T. Cancer Sci. 2005, 96,
4
2
2
(24) For example, use of HCl (1.2 equiv) or diphenylphosphate (1.2 equiv) failed
to promote the formal [3 + 2] reaction.
(25) As we were preparing to submit this manuscript, similar findings for the
preparation of racemic pyrroloindolines were reported: Lucarini, S.;
Bartoccini, F.; Battistoni, F.; Diamantini, G.; Piersanti, G.; Righi, M.;
Spadoni, G. Org. Lett. 2010, 12, 3844.
8
16.
(
5) Reviews: (a) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151. (b)
Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488. (c)
Kim, J.; Movassaghi, M. Chem. Soc. ReV. 2009, 38, 3035.
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