Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade michael addition-cyclization of tryptamines

Article abstract of DOI:10.1021/ol302043s

Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade Michael addition-cyclization of tryptamines has been realized. With 5 mol % of chiral phosphoric acid, enantioenriched pyrroloindoline derivatives were obtained

Full text of DOI:10.1021/ol302043s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Enantioselective Construction of
Pyrroloindolines via Chiral Phosphoric
Acid Catalyzed Cascade Michael
AdditionÀCyclization of Tryptamines
Quan Cai, Chuan Liu, Xiao-Wei Liang, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@sioc.ac.cn
Received July 24, 2012
ABSTRACT
Enantioselective construction of pyrroloindolines via chiral phosphoric acid catalyzed cascade Michael additionÀcyclization of tryptamines has
been realized. With 5 mol % of chiral phosphoric acid, enantioenriched pyrroloindoline derivatives were obtained in good yields and
enantioselectivity (up to 95% yield and 83% ee) from readily available tryptamines and enones.
Alkaloids containing a pyrroloindoline unit are a very
attractive class of natural products for their structural
complexity and significant biological properties.1 The
synthesisof these pyrroloindoline derived natural products
and relevant pharmaceuticals has attracted enormous
attention.2 Biosynthetically, the pyrroloindoline units stem
from the tryptophan and tryptophan-containing peptide.2c
Due to the ready availability of the tryptamine derivatives,
catalytically asymmetric synthesis of the pyrroloindoline
compounds via a dearomatization reaction of tryptamines
is highly desirable.3
Recently, we found that, in the presence of a catalytic
amount of chiral phosphoric acid (1a, Ar = 9-phenanthryl),4
the reaction of tetrahydrocarbazole with phenyl vinyl
ketone (2a) provides the indolenine product 3 with a
17% yield and 68% ee (eq 1).5 The low yield of this
reaction is likely due to the fact that the basic imine
(1) (a) Anthoni, U.; Christophersen, C.; Nielsen, P. H. Naturally
Occurring Cyclotryptophans and Cyclotryptamines. In Alkaloids: Chem-
ical & Biological Perspectives; Pelletier, S. W., Ed.; Pergamon: Oxford,
1999; Vol. 13, pp 163À236. (b) Barrow, C. J.; Cai, P.; Snyder, J. K.;
Sedlock, D. M.; Sun, H. H.; Cooper, R. J. Org. Chem. 1993, 58, 6016. (c)
Hochlowski, J. E.; Mullally, M. M.; Spanton, S. G.; Whittern, D. N.;
Hill, P.; McAlpine, J. B. J. Antibiot. 1993, 46, 380. (d) Fukuyama, T.;
Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127. (e) 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. (f) 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. (g)
Isham, C. R.; Tibodeau, J. D.; Jin, W.; Xu, R.; Timm, M. M.; Bible, K. C.
Blood 2007, 2579.
(3) For a review: (a) Loh, C. C. J.; Enders, D. Angew. Chem., Int. Ed.
2012, 51, 46. For selected examples: (b) 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. (c) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006,
128, 6314. (d) Jones, S. B.; Simmons, B.; MacMillan, D.W. C. J. Am.
Chem. Soc. 2009, 131, 13606. (e) Zheng, C.; Lu, Y.; Zhang, J.; Chen, X.;
Chai, Z.; Ma, W.; Zhao, G. Chem.;Eur. J. 2010, 16, 5853. (f) 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. (g) Jones, S. B.; Simmons, B.; Mastracchio,
A.; MacMillan, D. W. C. Nature 2011, 475, 183. (h) Cera, G.;
Chiarucci, M.; Mazzanti, A.; Mancinelli, M.; Bandini, M. Org. Lett.
2012, 14, 1350. (i) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc.
2012, 134, 10815.
(2) For reviews: (a) Steven, A.; Overman, L. E. Angew. Chem., Int.
Ed. 2007, 46, 5488. (b) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40,
151. (c) Ruiz-Sanchis, P.; Savina, S. A; Albericio, F.; Alvarez, M.
ꢀ
Chem.;Eur. J. 2011, 17, 1388. (d) Zhang, D.; Song, H.; Qin, Y. Acc.
Chem. Res. 2011, 44, 447.
r
10.1021/ol302043s
XXXX American Chemical Society

functional group in the product (3) interferes with an
acidic catalyst to result in a low turnover number. We
envisioned that a preinstalled nucleophile in the substrate
would capture the imine group in the product to afford a
less basic aniline derivative. Recently, we have developed
asymmetric MichaelÀMannich cacade reactions of indo-
lyl derivatives catalyzed by a chiral primary amine and
an acid cocatalyst.6 Therefore, we envisaged that the
employment of substrates with a pendant heteronuleo-
phile tethered on the C3 position of indoles, such as
tryptamine derivatives, in the chiral phosphoric acid
catalyzed addition to vinyl ketones could provide the
privileged pyrroloindoline products. Herein, we describe
such an enantioselective cascade Michael additionÀ
cyclization of tryptamines and vinyl ketone catalyzed by
a chiral phosphoric acid.
Table 1. Optimization of the Reaction Conditions for the
Michael AdditionÀCyclization of Tryptamine Derivatives
yield
(%)b
ee
entrya
(S)-1, Ar
5, R
(%)c
1d
2
1b, 3,5-(CF3)2-C6H3
1c, 4-NO2-C6H4
5a, CO2Et
5a, CO2Et
5a, CO2Et
5a, CO2Et
5a, CO2Et
5a, CO2Et
5a, CO2Et
5a, CO2Et
5a, CO2Et
5b, CO2Me
5c, CO2nPr
5d, CO2nBu
5e, CO2Ph
5f, Boc
95
95
93
95
91
93
49
93
91
95
96
97
93
84
87
81
72
62
3
3
1d, 1-naphthyl
4
1e, 2-naphthyl
50
11
33
68
51
59
67
71
72
67
75
79
83
5
1f, 9-anthryl
6
1g, 4-biphenyl
7
1h, SiPh3
8
1i, 2,4,6-(iPr)3-C6H2
1j, 4-tBu-2,6-(iPr)2- C6H2
1b, 3,5-(CF3)2-C6H3
1b, 3,5-(CF3)2-C6H3
1b, 3,5-(CF3)2-C6H3
1b, 3,5-(CF3)2-C6H3
1b, 3,5-(CF3)2-C6H3
1b, 3,5-(CF3)2-C6H3
1b, 3,5-(CF3)2-C6H3
9
10d
11d
12d
13d
14
15e
16e,f
5f, Boc
5f, Boc
a Reaction conditions: 5 mol % (S)-1, 0.1 mol/L of 4 in toluene,
3 equiv of 2a. b Isolated yield. c Determined by HPLC analysis (Chiralpak
d
e
˚
We first studied the Michael additionÀcyclization with
ethyl carbamate protected tryptamine (4a) and phenyl
vinyl ketone (2a) as the starting materials. To our delight,
in the presence of 5 mol % (S)-1a in toluene, the dear-
omatization reaction of tryptamine derivative 4a pro-
ceeded smoothly to afford pyrroloindoline product 5a in
70% yield and 55% ee (eq 2). It should be noted that the
in situ generated secondary amine proceeded in another
Michael addition to afford the N-alkylated product.
To increase the enantioselectivity of this reaction, var-
ious chiral phosphoric acids were investigated (Table 1). It
indicated that (S)-1b bearing 3,5-bis(trifluoromethyl)-
phenyl groups gave the best enantioselectivity (72% ee,
entry 1, Table 1). Further studies revealed that the protect-
ing group on the amine side chain could influence the
enantioselectivity (entries 10À14, Table 1). tert-Butyl car-
bamate protected tryptamine 4f provided the correspond-
ing dearomatized product 5f with the highest ee (75% ee,
AD-H). 5 mol % (R)-1b was used as the catalyst. 50 mg of 4 A molecular
sieves per 0.1 mmol of 4 were used. f The reaction was carried out at À20 °C.
entry 15, Table 1). Furthermore, decreasing the temperature
resulted in a prolonged reaction time but with an
increased ee value (81% yield, 83% ee, 72 h, entry 16,
Table 1).
To ascertain the generality of this cascade reaction,
various tryptamine derivatives and enones were tested
(Table 2). In most cases, the reaction went smoothly to
provide the desired products in good yields and enantio-
selectivity (83À95% yield, 50À83% ee). Typtamine deri-
vatives bearing electron-donating groups on indole were
suitable substrates for this reaction to afford the pyrro-
loindoline products in 87À93% yield and 71À77% ee
(entries 1À2, Table 2). However, introduction of an electron-
withdrawing group such as 5-Cl on the indole resulted in a
low yield due to the decreased nucleophilic ability (33% yield
and 84% ee, entry 3, Table 2). Remarkably, raising the
reaction temperature to 0 °C led to dramatically increased
yields and good enantioselectivity (89À97% yield and
76À83% ee, entries 4-9, Table 2). Furthermore, various
enones were also examined, and the desired products were
obtained in 84À93% yields with 74À82% ee (entries 9À12,
Table 2). But when methyl vinyl ketone (MVK) was used, the
enantioselectivity was slightly decreased (95% yield and
50% ee, entry 13, Table 2). This methodology could also be
used to synthesize a tetrahydrofuroindole derivative in an
˚
entry 14, Table 1). When 4 A molecular sieves (MS) were
employed as an additive, the reaction proceeded with a
higher yield and enantioselectivity (87% yield, 79% ee,
(4) For recent reviews on chiral phosphoric acid catalysis, see: (a)
Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Yu, X.; Wang, W. Chem.;
Asian J. 2008, 3, 516. (c) Terada, M. Synthesis 2010, 12, 1929. (d)
Kampen, D.; Reisinger, C. M.; List, B. Top. Curr. Chem. 2010, 291,
395. (e) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156. (f)
Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011, 40, 4539.
(5) Cai, Q.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2010, 49,
8666.
(6) Cai, Q.; You, S.-L. Org. Lett. 2012, 14, 3040.
(7) For details, see the Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX

was conducted.7 Fortunately, we found that, in the presence
of 5 mol % (S)-1j, the reaction of 4d with MVK (3 equiv)
furnished the desired product in 93% yield and 77% ee
(Scheme 1).
Table 2. Substrate Scope for the Michael AdditionÀCyclization
of Tryptamine Derivatives
Scheme 1. Reaction of 4d with MVK
5,
yield
(%)b
ee
entrya
4, R1, X
2, R2
2a, C6H5
(%)c
1
4g, 5-Me, NBoc
4h, 5-MeO, NBoc
4i, 5-Cl, NBoc
4i, 5-Cl, NBoc
4j, 5-F, NBoc
4k, 6-Cl, NBoc
4l, 6-F, NBoc
4m, 6-Br, NBoc
4f, H, NBoc
5g, 93
5h, 87
5i, 33
5i, 89
5j, 97
5k, 92
5l, 90
5m, 94
5n, 93
5o, 95
5p, 85
5q, 84
5r, 95
5s, 94
77
71
84
79
76
83
81
83
79
80
82
74
50
55
2
2a, C6H5
In conclusion, we have developed an efficient synthesis
of pyrroloindoline derivatives in excellent yields with good
enantioselectivity. This chiral phosphoric acid catalyzed
Michael additionÀcyclization cascade reaction allows a
facile access to enantioenriched pyrroloindoline deriva-
tives from readily available tryptamine derivatives and
enones. Further application of this methodology to the
synthesis of natural products containing the pyrroloindo-
line core is currently underway in our laboratory.
3
2a, C6H5
4d
5d
6d
7d
8e
9
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2a, C6H5
2b, 4ÀCl-C6H4
2c, 4ÀBr-C6H4
2d, 2-naphthyl
2e, 4-NO2ÀC6H4
2f, Me
10
11
12
13d
14d
4f, H, NBoc
4f, H, NBoc
4f, H, NBoc
4f, H, NBoc
4n, H, O
2a, C6H5
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program 2010CB833300),
the National Natural Science Foundation of China
(20923005, 21025209, 21121062), and the Chinese Academy
of Sciences for generous financial support.
a Reaction conditions: 5 mol % (S)-1, 0.1 mol/L of 4 in toluene,
˚
3 equiv of 2, 50 mg of 4 A molecular sieves per 0.1 mmol of 4 were added,
À20 °C. b Isolated yield. c Determined by HPLC analysis. d The reaction
was carried out at 0 °C. e The absolute configuration of the products was
determined by an X-ray analysis of enantiopure derivative of 5m.7
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
excellent yield but with a moderate enantioselectivity (94%
yield and 55% ee, entry 14, Table 2).
To extend the substrate scope, further optimization of
the reaction conditions using MVK as the Michael acceptor
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
C