Catalytic asymmetric synthesis of pyrroloindolines via a rhodium(II)-catalyzed annulation of indoles

Article abstract of DOI:10.1021/ja4025337

Herein we report the synthesis of pyrroloindolines via a catalytic enantioselective formal [3+2] cycloaddition of C(3)-substituted indoles. This methodology utilizes 4-aryl-1-sulfonyl-1,2,3-triazoles as carbenoid precursors and the rhodium(II)-tetracarboxylate catalyst Rh₂(S-PTAD) ₄. A variety of aryl-substituted pyrroloindolines were prepared in good yields and with high levels of enantioinduction.

Full text of DOI:10.1021/ja4025337

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Synthesis of Pyrroloindolines via a Rhodium(II)-
Catalyzed Annulation of Indoles
Jillian E. Spangler and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
chemistry to Rh(II)-bound carbenoids derived from 4-vinyl-1-
ABSTRACT: Herein we report the synthesis of pyrrolo-
indolines via a catalytic enantioselective formal [3+2]
cycloaddition of C(3)-substituted indoles. This method-
ology utilizes 4-aryl-1-sulfonyl-1,2,3-triazoles as carbenoid
precursors and the rhodium(II)-tetracarboxylate catalyst
Rh2(S-PTAD)4. A variety of aryl-substituted pyrrolo-
indolines were prepared in good yields and with high
levels of enantioinduction.
sulfonyl-1,2,3-triazoles we found that the reaction of triazole 12
with 1,3-dimethyl indole (11) provides the expected indoline
product 13 (Scheme 2) after hydrolysis of the resultant N-
Scheme 2. Reaction of 1,3-Dimethylindole with 4-Vinyl-1-
sulfonyl-1,2,3-triazoles
yrroloindoline alkaloids comprise an important subclass of
P
alkaloid natural products1 and have exhibited promising
activity as potential anti-cancer,2a,b anti-nociceptive,2c anti-
biotic,2d and anti-inflammatory agents.2e Consequently, an
array of methods have been developed for the formation of
pyrroloindolines.3 As shown in Scheme 1, the majority of these
sulfonylimine.9 However, we were surprised to find the
corresponding reaction of triazole 14 provides pyrroloindoline
15, wherein the imine of the Rh(II)-bound carbenoid has
participated in a cycloaddition with the indole core.10
Scheme 1. Synthesis of Pyrroloindolines from Indoles
We recognized that this serendipitous discovery could offer a
new and complementary approach for the synthesis of
pyrroloindoline products via a formal [3+2] cycloaddition of
indoles and the formal dipole 10b. The novelty of this
transformation, in conjunction with the potential for synthesiz-
ing uniquely substituted pyrroloindoline architectures, prompt-
ed us to develop this reaction into a convergent method for the
enantioselective synthesis of pyrroloindoline products from 4-
aryl-1-sulfonyl-1,2,3-triazoles and C(3)-substituted indoles.
Our preliminary reaction development was conducted with
4-phenyl-1-(methanesulfonyl)-1,2,3-triazole 16a and an excess
of 1,3-dimethyl indole (11, 5.0 equiv) in the presence of 1.0
syntheses utilize indole precursors and can be classified into
two distinct reaction pathways. The more ubiquitous of these
techniques entails the reaction of a tryptamine precursor (1)
with a carbon- or heteroatom-based electrophile to induce an
intramolecular cyclization of the pendant amine.4 This process
can be rendered asymmetric with a variety of chiral organo-
catalysts and metal complexes.5,6 Alternatively, the pyrrolo-
indoline core can be accessed via a formal [3+2] cycloaddition
of an indole (4) with an intermediate that exhibits dipole-like
reactivity (5).7 This complementary approach can provide
access to pyrroloindoline products (7) with substitution
patterns that are inaccessible from tryptamines. While both of
these reaction classes enable diversification at the bridgehead
position of the pyrroloindoline core, substitution of the
pendant pyrrolidine ring cannot be readily achieved.
11a
mol % Rh2(S-PTAD)4 (18, Table 1). Polar solvents such as
chloroform and 1,2-dichloroethane, which are the optimal
solvents for most of the reactions of carbenoids derived from 1-
sulfonyl-1,2,3-triazoles,9 proved ineffective for this trans-
formation (entries 1−4). However, the use of nonpolar
hydrocarbon solvents provides substantially improved yields
of pyrroloindoline 17a with uniformly high levels of enantio-
induction (entries 5−7). When cyclohexane was employed as
the reaction solvent, pyrroloindoline 17a was obtained in 81%
isolated yield and 94% ee (entry 7). An examination of other
chiral Rh(II)-tetracarboxylate catalysts demonstrated that
Rh2(S-PTAD)4 is the optimal catalyst for this transformation.
In 2010 our group reported a method for a Rh(II)-catalyzed
annulation of indoles to provide indoline derivatives via a
formal [3+2] cycloaddition with carbenoids derived from vinyl
diazoacetates.8 In our recent attempts to extrapolate this
Received: March 11, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4025337 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a b
,
a−d
Table 1. Optimization of Pyrroloindoline Formation
Table 2. Scope of Triazole Component
a
Reactions run with 5.0 equiv of indole 11 unless otherwise indicated.
b
1
Products formed in >20:1 dr as determined by H NMR of crude
c
d
e
reaction mixture. Isolated yields. Determined by HPLC analysis. 2.5
equiv of indole 11. 1.0 equiv of indole 11.
f
11b
Rh2(S-PTTL)4 provided a similar level of enantioinduction
but a significantly lower yield of 17a (entry 10), while the
11c
11d
bulkier Rh2(S-NTTL)4
and Rh2(S-BTPCP)4
catalysts
11e
were ineffective (entries 11 and 13). Rh2(S-DOSP)4 (entry
12) gave a moderate yield of 17a with a low level of
enantioinduction.
a
b
Reactions run with 5.0 equiv of indole 11. Products formed in >20:1
c
1
dr as determined by H NMR of crude reaction mixture. Isolated
yields. ee determined by HPLC analysis after purification. Reaction
d
e
Having developed optimized reaction conditions for the
synthesis of pyrroloindoline 17a, we subsequently explored the
scope of this transformation with respect to the triazole
coupling partner. As shown in Table 2, a broad range of
triazoles (16) react to provide the corresponding pyrrolo-
indoline products in good yield and with high levels of
enantioinduction. Electron-donating and -withdrawing sub-
stituents in the para (entries 3, 4, 6−8, 10−12, 59−89% yield,
88−95% ee) or meta (entries 5 and 9, 56−71% yield, 88−94%
ee) position of the aryl ring are compatible with this
transformation. The use of 1-(ethanesulfonyl)-1,2,3-triazole
derivatives also provides the corresponding pyrroloindoline
products in good yield and with high levels of enantioselectivity
(entries 2 and 3, 84−86% yield, 90−92% ee). However, the
reaction was found to be sensitive to steric effects and the use
of bulkier 1-sulfonyl-1,2,3-triazoles (e.g., 1-Ts) fails to provide
any of the desired product. This reaction also proceeds well on
a large scale (5.0 mmol triazole 16, entry 1, 76% yield, 94% ee).
The absolute stereochemistry of compound 17b was
established by X-ray crystallography and extended to the
other pyrroloindoline products by analogy.12
As illustrated in Table 3, this enantioselective pyrroloindoline
formation is applicable to a range of C(3)-alkyl indoles (23).
An evaluation of substituents on the indolic nitrogen revealed
that N−H and N-allyl indoles are both compatible with this
transformation, although the products were formed with a
much lower level of enantioselectivity (entries 2 and 3, 62−64%
yield, 37−80% ee) than the corresponding N-methyl product
(entry 1, 100% yield, 92% ee). However, bulkier (TBS, Bn) or
electron-withdrawing (e.g., Ts, CO2Me, Boc) groups on the
indolic nitrogen are not tolerated. An array of electron-rich
conducted on 5.0 mmol scale.
(entries 5−8, 73−97% yield, 86−94% ee) and electron-
deficient indoles (entries 1 and 4, 96−100% yield, 92−93%
ee) substituted at C(5)−C(7) of the indolic core also provide
the corresponding pyrroloindoline products in excellent yields
and with high levels of enantiomeric excess. In contrast to the
parent 1,3-dimethyl indole (11), indole substrates that are
substituted on the aryl ring can be used in an equimolar ratio
with respect to the triazole coupling partner with only a slight
depreciation in yield. For example, with 1.0 equiv of the indole
coupling partner, pyrroloindoline 24a was isolated in 86% yield
and 92% ee (e.g., Table 3, entries 1, 4−7; compare to Table 1,
entries 8 and 9). We attribute this improved chemoselectivity to
a steric deactivation of the aniline motif in the product
pyrroloindolines toward reaction with an electrophilic Rh(II)-
bound carbenoid.13
Indoles with bulkier C(3)-substituents are also competent
substrates in this transformation (entries 9−12). C(3)-ethyl
and C(3)-butyl indoles react to provide the corresponding
pyrroloindoline products in good yield and with high levels of
enantioinduction (entries 9 and 10, 75−81% yield, 91−92%
ee). While 3-phenyl-1-methylindole provides 24k in modest
yield (entry 11, 49%, 89% ee), substitution of the aryl ring
substantially augments the yield of the desired product 24l
(entry 12, 72%, 89% ee). With these more hindered substrates
the use of 1-(methanesulfonyl)-1,2,3-triazoles is critical; the use
of bulkier 1-(ethanesulfonyl)-1,2,3-triazoles leads to both low
B
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Journal of the American Chemical Society
Communication
a−d
Table 3. Scope of Indole Substrate
Scheme 4. Proposed Mechanistic Pathways
Rh(II)-catalyzed cyclization of indoles to indolines via a formal
[3+2] cycloaddition reaction, wherein the regioselectivity of the
annulation was controlled by C(2)- or C(3)-substitution of the
indole core.8 While indoles that bear an electron-withdrawing
group on the indolic nitrogen (e.g., Boc, CO2Me, Ts) have
been reported to undergo a concerted cyclopropanation of the
C(2)−C(3) alkene with Rh(II)-bound carbenoids to provide
isolable cyclopropylindolines, their intermediacy in reactions
with electron-rich indoles is less established.4o−r,7e However,
the abnormal regioselectivity and the strong solvent effect
observed in this transformation have led us to speculate that
this reaction occurs via an initial cyclopropanation of the
C(2)−C(3) bond of the indole (29, Scheme 4, path b).
Subsequent ring opening of the strained cyclopropylindoline
intermediate and recombination would provide the observed
pyrroloindoline (28).16
In conclusion, we have developed a method for the catalytic
enantioselective synthesis of pyrroloindoline architectures via
the union of C(3)-substituted indoles and the Rh(II)-bound
carbenoids derived from 4-aryl-1-sulfonyl-1,2,3-triazoles. The
pyrroloindoline products synthesized in this manner are
uniquely substituted and can be stereodivergently hydro-
genated. As such, we envision that this methodology will
enable the synthesis of a novel class of pyrroloindoline alkaloids
for biological studies. Additional experiments and computa-
tional studies to further elucidate the mechanism of this
transformation are underway.
a
Reactions run with 5.0 equiv of indole 23 unless otherwise indicated.
b
1
Products formed in >20:1 dr as determined by H NMR of crude
c
d
reaction mixture. Isolated yields. ee determined by HPLC analysis
after purification. 1.0 equiv of indole 23.
e
yields (<15%) and poor levels of enantioselectivity for the
desired products.
Stereodivergent transformation of the pyrroloindoline
products to the corresponding saturated compounds can be
achieved via transition metal-catalyzed hydrogenation. As
shown in Scheme 3, hydrogenation of pyrroloindoline 17a
Scheme 3. Stereodivergent Hydrogenation
ASSOCIATED CONTENT
* Supporting Information
Procedures, characterization, and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
hmdavie@emory.edu
■
with Pd/C proceeds selectively from the concave face to
provide 25a (98% yield, 6.4:1 dr). However, the use of Pt2O
provides the diastereomeric product, 25b (72% yield, 14.2:1
dr), wherein the hydrogenation reaction has occurred
selectively from the convex face of 17a.14
Electron-rich N-alkyl indoles are generally proposed to react
with electrophilic Rh(II)-bound carbenoids via a zwitterionic-
type pathway due to substantial polarization of the C(2)−C(3)
olefin (Scheme 4, path a). In these reactions, the
regioselectivity of the indole toward a Friedel−Crafts-type
substitution is generally dictated by the steric bulk of the
Rh(II)-bound carbenoid, which can overcome the standard
electronic bias of the heterocycle. As such, C(3)-unsubstituted
indoles generally undergo reaction at C(3), while C(3)-
substituted indoles will react at C(2) with Rh(II)-bound
carbenoids.15 We observed this effect in our 2010 report of a
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-1213246). We would like to thank Professor Moham-
mad Movassaghi and members of the NSF CCI Center for
Selective C−H Functionalization (CHE-1205646) for helpful
discussions and Dr. John Bacsa, Emory University, for the X-ray
crystallographic analysis.
REFERENCES
■
(1) (a) Kobayashi, J.; Ishibashi, M. Alkaloids 1992, 41, 41−124.
(b) Anthoni, U.; Christophersen, C.; Nielsen, P. H. Naturally
Occurring Cyclotryptophans and Cyclotryptamines. In Alkaloids:
C
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Journal of the American Chemical Society
Communication
Chemical & Biological Perspectives; Pelletier, S. W., Ed.; Pergamon:
Oxford, 1999; Vol. 13, pp 163−236.
V. V. J. Am. Chem. Soc. 2009, 131, 18034−18035. (e) Grimster, N.;
Zhang, L.; Fokin, V. V. J. Am. Chem. Soc. 2010, 132, 2510−2511.
(f) Chuprakov, S.; Malik, J. A.; Zibinsky, M.; Fokin, V. V. J. Am. Chem.
Soc. 2011, 133, 10352−10355. (g) Selander, N. N.; Worrell, B. T.;
Chuprakov, S.; Velaparthi, S.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134,
14670−14673. (h) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed.
2013, 52, 1507−1510.
(2) (a) Usami, Y.; Yamaguchi, J.; Numata, A. Heterocycles 2004, 63,
1123−1129. (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, 816−824.
(c) Amador, T. A.; Verotta, L.; Nunes, D. S.; Elisabetsky, E. Planta
Med. 2000, 66, 770−772. (d) Zheng, C.-J.; Kim, C.-J.; Bae, K. S.; Kim,
Y.-H.; Kim, W.-G. J. Nat. Prod. 2006, 69, 1816−1819. (e) Taechowisan,
T.; Wanbanjob, A.; Tuntiwachwuttikul, P.; Liu, J. Food Agric. Immunol.
2009, 20, 67−77.
(10) Formal [3+2] reactivity was observed by the Fokin group in a
reaction of the Rh(II)-bound carbenoid derived from 4-phenyl-1-
(trifluoromethanesulfonyl)-1,2,3-triazole9e and in a recent report by
the Davies group in the synthesis of pyrroles from the reaction of 1-
sulfonyl-1,2,3-triazoles with furans. Parr, B. T.; Green, S. A.; Davies, H.
M. L. J. Am. Chem. Soc. 2013, 135, 4716−4718.
(3) For reviews, see: (a) Steven, A.; Overman, L. E. Angew. Chem.,
Int. Ed. 2007, 46, 5488−5508. (b) Crich, D.; Banerjee, A. Acc. Chem.
Res. 2007, 40, 151−161. (c) Kim, J.; Movassaghi, M. Chem. Soc. Rev.
2009, 38, 3035−3050. (d) Ruiz-Sanchis, P.; Savina, S. A.; Albericio, F.;
(11) (a) Reddy, R. P.; Davies, H. M. L. Org. Lett. 2006, 8, 5013−
5016. (b) Hashimoto, S.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami,
S. Tetrahedron Lett. 1993, 34, 5109−5112. (c) Ghanem, A.; Gardiner,
́
Alvarez, M. Chem.Eur. J. 2011, 17, 1388−1408.
M. G.; Williamson, R. M.; Muller, P. Chem.Eur. J. 2010, 16, 3291−
̈
(4) (a) Ohno, M.; Spande, T. F.; Witkop, B. J. Am. Chem. Soc. 1970,
92, 343−348. (b) Savige, W. E. Aust. J. Chem. 1975, 28, 2275−2287.
(c) Nakagawa, M.; Kato, S.; Kataoka, S.; Hino, T. J. Am. Chem. Soc.
1979, 101, 3136−3137. (d) Marsden, S. P.; Depew, K. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143−11144.
(e) Baran, P. S.; Guerrero, C. A.; Corey, E. J. J. Am. Chem. Soc. 2003,
125, 5628−5629. (f) Hewitt, P. R.; Cleator, E.; Ley, S. V. Org. Biomol.
Chem. 2004, 2, 2415−2417. (g) Song, H.; Yang, J.; Chen, W.; Qin, Y.
Org. Lett. 2006, 8, 6011−6014. (h) Movassaghi, M.; Schmidt, M. A.
Angew. Chem., Int. Ed. 2007, 46, 3725−3728. (i) Newhouse, T.; Baran,
P. S. J. Am. Chem. Soc. 2008, 130, 10886−10887. (j) Movassaghi, M.;
Schmidt, M. A.; Ashenhurst, J. A. Angew. Chem., Int. Ed. 2008, 47,
1485−1487. (k) Kim, J.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133,
14940−14943. (l) Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.;
Baran, P. S. Angew. Chem., Int. Ed. 2011, 50, 2716−2719. (m) Boyer,
N.; Movassaghi, M. Chem. Sci. 2012, 3, 1798−1803. (n) Kieffer, M. E.;
Chuang, K. V.; Reisman, S. E. Chem. Sci. 2012, 3, 3170−3174. (o) He,
B.; Song, H.; Du, Y.; Qin, Y. J. Org. Chem. 2009, 74, 298−304.
(p) Shen, L. Q.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem., Int. Ed.
2008, 47, 3618−3621. (q) Zhang, M.; Huang, X. P.; Shen, L. Q.; Qin,
Y. J. Am. Chem. Soc. 2009, 131, 6013−6020. (r) Zhang, D.; Song, H.;
Qin, Y. Acc. Chem. Res. 2011, 44, 447−457.
3295. (d) Qin, C.; Boyarskikh, V.; Hansen, J. H.; Hardcastle, K. I.;
Musaev, D. G.; Davies, H. M. L. J. Am. Chem. Soc. 2011, 133, 19198−
19204. (e) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.;
Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897−6907.
(12) See Supporting Information. This crystal structure has been
deposited in the Cambridge Database (CCDC927317).
(13) Hedley, S. J.; Ventura, D. L.; Dominiak, P. M.; Nygren, C. L.;
Davies, H. M. L. J. Org. Chem. 2006, 71, 5349−5356.
(14) The relative stereochemistry of 25a and 25b was assigned by
NOE studies (Supporting Information) and X-ray crystallography of
25a. This crystal structure has been deposited in the Cambridge
Database (CCD927318).
(15) For reviews, see: (a) Davies, H. M. L. Adv. Nitrogen Heterocycl.
1995, 1, 1−18. (b) Davies, H. M. L.; Hedley, S. J. Chem. Soc. Rev.
2007, 36, 1109−1119.
(16) We suspect that a concerted [3+2] cycloaddition would be
disfavored due to steric repulsion. A related mechanism was proposed
by Fox and co-workers. DeAngelis, A.; Shurtleff, V. W.; Dmitrenko, O.;
Fox, J. M. J. Am. Chem. Soc. 2011, 133, 1650−1653.
(5) (a) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D.
W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482−5487. (b) Jones, S.
B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
13606−13607. (c) Zheng, C.; Lu, Y.; Zhang, J.; Chen, X.; Chai, Z.;
Ma, W.; Zhao, G. Chem.Eur. J. 2010, 16, 5853−5857. (d) Lozano,
O.; Blessley, G.; Martinez del Campo, T.; Thompson, A. L.; Giuffredi,
G. T.; Bettati, M.; Walker, M.; Borman, R.; Gouverneur, V. Angew.
Chem., Int. Ed. 2011, 50, 8105−8109. (e) Cai, A.; Liu, C.; Liang, X.-W.;
You, S.-L. Org. Lett. 2012, 12, 4588−4590.
(6) (a) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314−
6315. (b) Benkovics, T.; Guzei, I. A.; Yoon, T. P. Angew. Chem., Int.
Ed. 2010, 49, 9153−9157. (c) Zhu, Y.; Rawal, V. H. J. Am. Chem. Soc.
2012, 134, 111−114. (d) Zhu, S.; Macmillan, D. W. C. J. Am. Chem.
̈
Soc. 2012, 134, 10815−10818. (e) Ozuduru, G.; Schuback, T.; Boysen,
̈
M. M. K. Org. Lett. 2012, 14, 4990−4993.
(7) (a) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872−
875. (b) Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc. 1992,
114, 5566−5572. (c) Link, J. T.; Overman, L. E. J. Am. Chem. Soc.
1996, 118, 8166−8167. (d) Oestreich, M.; Dennison, P. R.; Kodanko,
J. J.; Overman, L. E. Angew. Chem., Int. Ed. 2001, 40, 1439−1442.
(e) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004,
126, 14043−14053. (f) Repka, L. M.; Ni, J.; Reisman, S. E. J. Am.
Chem. Soc. 2010, 132, 14418−14420. (g) Kieffer, M. E.; Repka, L. M.;
Reisman, S. E. J. Am. Chem. Soc. 2012, 134, 5131−5137.
(8) Lian, Y.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 440−441.
(9) For other reactions of carbenoids derived from triazoles, see:
(a) Chuprakov, S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463−4466.
(b) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2007, 46, 4757−4759. (c) Horneff, T.; Chuprakov, S.; Chernyak,
N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972−
14974. (d) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin,
D
dx.doi.org/10.1021/ja4025337 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX