An enantioselective approach to highly substituted tetrahydrocarbazoles through hydrogen bonding-catalyzed cascade reactions

Article abstract of DOI:10.1021/ol1001818

Chemical Equation Presentation A hydrogen bonding-mediated double Michael addition-aromatization cascade of 2-propenylindoles and nitroolefins has been disclosed. The methodology allows an efficient synthesis of diverse and structurally complex tetrahydrocarbazoles In good to excellent enantioselectivities and diastereoselectivities.

Full text of DOI:10.1021/ol1001818

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1140-1143
An Enantioselective Approach to Highly
Substituted Tetrahydrocarbazoles
through Hydrogen Bonding-Catalyzed
Cascade Reactions
Xu-Fan Wang, Jia-Rong Chen, Yi-Ju Cao, Hong-Gang Cheng, and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal UniVersity, 152 Luoyu Road, Wuhan,
Hubei 430079, China
wxiao@mail.ccnu.edu.cn
Received January 25, 2010
ABSTRACT
A hydrogen bonding-mediated double Michael addition-aromatization cascade of 2-propenylindoles and nitroolefins has been disclosed. The
methodology allows an efficient synthesis of diverse and structurally complex tetrahydrocarbazoles in good to excellent enantioselectivities
and diastereoselectivities.
Tetrahydrocarbazoles have become recognized as common
structural components of a diverse array of naturally occur-
ring alkaloids and pharmacological agents of various thera-
peutic actions.1 The development of novel and highly
efficient methods to construct this cyclic architecture is
therefore of great importance from both industrial and
academic points of view.2 In this regard, the catalytic
intramolecular alkylation of alkenyl indoles using transition
metal complexes has emerged as a preeminent strategy for
the tetrahydrocarbazole synthesis in the past few years.2b-l
However, in contrast to many nonasymmetric procedures,
catalytic enantioselective approaches to tetrahydrocarbazoles
are rare; these include intramolecular hydroarylations of
indole-substituted alkenes or allenes catalyzed by chiral
scandium(III),2e platinum(II),2d,g and gold(I)2h,i,l complexes,
respectively. To our knowledge, the analogous asymmetric
intermolecular reaction, which directly results in the con-
struction of the tetrahydrocarbazole skeleton with a wide
range of functionalities, has not been realized yet.
Besides transition metal catalysis, asymmetric organoca-
talysis is now well established as a powerful tool for the
preparation of optically active compounds from simple and
(2) For selected examples for the synthesis of tetrahydrocarbazoles, see:
(a) Nazare´, M.; Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew.
Chem., Int. Ed. 2004, 43, 4526. (b) Willis, M. C.; Brace, G. N.; Holmes,
I. P. Angew. Chem., Int. Ed. 2005, 44, 403. (c) Liu, C.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2004, 126, 10250. (d) Liu, C.; Han, X.; Wang, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 3700. (e) Evans, D. A.;
Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942. (f) Liu,
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10.1021/ol1001818  2010 American Chemical Society
Published on Web 02/10/2010

readily available starting materials.3 In this context, it
becomes clear that small organic molecules capable of
activating substrates through hydrogen bondings possess
tremendous potential in the development of novel asymmetric
processes.4 Although remarkable advances have been achieved,
the vast majority of hydrogen bonding catalysis is based on
either chiral phosphoric acids5 or thioureas,6 and strategies
based on simple hydrogen bonding donors (e.g., bis-
sulfonamide such as 3) remain largely unexplored (especially
their applications to cascade reactions7).8 From a practical
and atom-economic perspective, the exploration of the
hydrogen bonding catalysis by means of simple and readily
accessible small molecules is highly desirable.
As part of our ongoing project on the heterocycle-oriented
methodology development,9 we describe herein a novel
double Michael addition-aromatization reaction cascade of
2-propenylindoles with nitroolefins catalyzed by a chiral bis-
sulfonamide, which can efficiently generate three consecutive
stereogenic centers in one operation. Importantly, this
procedure allows a rapid access to diverse and structurally
complex tetrahydrocarbazole derivatives in excellent enan-
tioselectivities (up to 98% ee) and diastereoselectivities (up
to 99:1 dr). This is a prominent example of asymmetric
cascade reactions10 catalyzed only by a simple chiral
hydrogen bonding donor.
We initially studied the reaction of 2-alkenyl indoles 1a,b
and trans-ꢀ-nitrostyrene 2a in dichloromethane to examine
the feasibility of the cascade protocol (eq 1). When the
reaction was performed with 1a and 2a at room temperature,
two products, a formal [4+2] adduct 4a and Friedel-Crafts
alkylation product 5a, were obtained in 46% and 44% yield,
respectively. Encouraged by this result, we examined the
reaction in detail by varying R,1 R2, chiral hydrogen bonding
catalysts, solvents, and temperature in an attempt to increase
the yield of the tetrahydrocarbazole product.11 After an
extensive screen of the catalysts, bis-sulfonamide catalyst
3, which was easily prepared from simple and commercially
available chiral diamines,12 was identified as the most
promising catalyst. In particular, it was found that the reaction
provided stereochemically enriched tetrahydrocarbazole 4b
in 82% isolated yield, 92:8 dr, and 59% ee with the
corresponding alkylation product 5b only in trace amount,
when 1-methyl-2-propenylindole 1b was employed as the
substrate in the presence of 10 mol % of 3 at -40 °C (eq
1). Having further recognized water-saturated dichlo-
romethane as the solvent of choice and -78 °C as the optimal
reaction temperature for this transformation, we then exam-
ined a diverse range of additives in an effort to elevate the
stereoselectivity of the process (Table 1). While variation
of additives has a pronounced effect on the stereochemistry
of the reaction (Table 1, entries 2 and 3 vs entries 9 and
10), moderate levels of enantioselectivity were observed for
various Brønsted acids. Notably, the superior levels of
asymmetric induction and efficiency exhibited by catalytical
amounts of 3 and acetic acid in H2O-saturated CH2Cl2 at
-78 °C (Table 1, entry 7, 88:12 dr and 87% ee) prompted
us to use these conditions for further exploration.
(3) (a) Berkessel, A.; Gro˜ger, H. In Asymmetric Organocatalysis-From
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41, 31.
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N. Pure Appl. Chem. 2004, 76, 1967. (b) Guo, H.; Ma, J. Angew. Chem.,
Int. Ed. 2006, 45, 354. (c) Pellissier, H. Tetrahedron 2006, 62, 2143. (d)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134. (e) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem.,
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Experiments that probe the scope of both 2-propenylin-
doles (1) and nitroolefins (2) are summarized in Table 2.
Under optimized conditions, a wide range of aromatic
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bifunctional catalysts, see: (a) Wang, Y.; Liu, X.-F.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 3928. (b) Rueping, M.; Antonchick, A. P.; Theissmann, T.
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Org. Lett., Vol. 12, No. 5, 2010
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Table 1. Effect of Various Additives on the Stereoselectivity of
Table 2. Effect of Various Additives on the Stereoselectivity of
the Cascade Reactiona
the Cascade Reactiona
entry
additive
yield (%)b
drc
ee (%)c
entry
R3
R4
C6H5
yield (%)b
drc
ee (%)c
1
2
3
4
5
6
7
8
85
79
78
77
88
82
80
82
93
86
88:12
83:17
85:15
73:27
89:11
85:15
88:12
70:30
85:15
76:24
78
83
83
84
82
86
87
84
70
60
1
2
3
4
5
6
7
8
9
10
11
12
13
14
5-H
5-H
5-H
5-H
5-H
5-H
5-H
5-H
5-H
4b: 80
4c: 86
4d:d 75
4e: 63
4f: 63
4g: 68
4h: 70
4i: 69
4j: 68
88:12
92:8
95:5
99:1
80:20
99:1
95:5
83:17
96:4
84:16
89:11
99:1
87
88
89
90
98
90
90
82
82
86
88
88
92
90
HClO4
4-FC6H4
CF3COOH
HCOOH
L-tartric acid
PhCOOH
HOAc
PhOH
4 ÅMS
MgSO4
4-ClC6H4
3-BrC6H4
2-ClC6H4
3,4-F2C6H3
4-MeC6H4
2-furanyl
2-thienyl
9d
10d
5-CH3
5-CH3
5-Cl
4-MeOC6H4 4k: 70
a The reaction was carried out with 1 equiv of 2a, 1.6 equiv of 1b (Z/E:
1/1), 10 mol % of 3, and 10 mol % of additive in H2O-saturated CH2Cl2 at
-78 °C. b Isolated yield. c Determined by chiral HPLC analysis. d Anhydrous
CH2Cl2 was used in this case.
2-furanyl
4-FC6H4
4-ClC6H4
4l: 75
4m: 55
4n: 42
4o: 49
5-Cl
99:1
99:1
6-Cl, 7-CH3 C6H5
a The reaction was carried out with 1.6 equiv of 1 (Z/E: 1/1 to 2/1), 1
equiv of 2, 10 mol % 3/HOAc in H2O-saturated CH2Cl2 at -78 °C. b Isolated
yield. c Determined by chiral HPLC analysis. d The absolute configuration
of 4d was determined by X-ray crystal-structure analysis. The absolute
configurations of the other products were assigned by analogy.
nitroolefins underwent reactions with 2-propenylindole 1b
in high yields and stereoselectivities (Table 2, entries 1-9).
The reaction sequence displays substantial generality with
respect to the electronic and steric contribution of the
substituent on the benzene ring of the nitroolefin component
(Table 2, entries 1-7). Note that o-, m-, and p-halogen-
substituted ꢀ-nitrostyrenes were successfully employed in
this hydrogen bonding-mediated transformation to generate
the corresponding tetrahydrocarbazoles with high to excellent
enantioselectivities (up to 98% ee) and diastereoselectivities
(up to 99:1 dr) (Table 2, entries 2-5). Incorporation of two
substituents at the meta- and para-positions of the nitrostyrene
could be accomplished with little influence on the reaction
efficiency (Table 2, entry 6, 68% yield, 99:1 dr, 90% ee).
As highlighted in entries 8 and 9, the nitroolefin bearing a
heteroaromatic substituent also proved to be a suitable
reaction partner (68% yield, 83:17 dr, 82% ee).
As revealed in entries 1 and 10 to 14 of Table 2, this
hydrogen bonding-catalyzed cascade reaction is also general
with respect to indole architecture. Significant structural
variation in the indole ring can be well tolerated. The
electronic nature of the indole ring does not affect the
selectivity much (Table 2, entries 10 vs 1 and entries 12 vs
1). Perhaps more significant, we have successfully utilized
electron-deficient 2-propenylindoles in the context of a
5-chloro-substituted 2-vinylindole (Table 2, entries 12 and
13). Such halogenated tetrahydocarbazoles can be further
manipulated through transition metal-catalyzed couplings.13
Furthermore, disubstituted vinyl indole derivatives (Table 2,
entry 14) can readily participate in this reaction and afford
a polysubstituted enantioenriched tetrahydrocarbazole in
excellent stereoselectivities (99:1 dr, 90% ee). In the case
of aliphatic nitroalkenes, the reaction also proceeded smoothly,
albeit with diminished stereoselectivity.11 The absolute
configuration was unambiguously determined to be
(2S,3R,4R) by X-ray crystallographic analysis of 4d,14 and
the stereochemistry of other products could be tentatively
assigned by assuming an analogous enantioinduction (Scheme
1).
To identify the possible reaction mechanism between
Diels-AlderpathwayanddoubleMichaeladdition-aromatization
sequence, we carried out the cyclization reaction between
1b and 2a on gram scale (Scheme 2).11 It was found that
the Z-isomer of vinylindole was consumed much faster than
the E-isomer, which proved that a stepwise process was more
possible. Moreover, the exclusive formation of 5a and the
fact that the Diels-Alder adduct10i was not observed make
the cascade cycle more favorable (eq 1 and Scheme 1).
Therefore, a plausible catalytic cycle involving double
Michael addition-aromatization cascade is outlined in
Scheme 1. We presumed that the exposure of nitroolefin 2
to chiral hydrogen bonding donor 3 would generate an
(14) The crystallographic coordinates have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. 734894. These data
can be obtained free of charge from the Cambridge Crystallographic Data
Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.ccdc.ca-
m.ac.uk/daa_ request/cif.
(13) For selected reviews on organometallic technologies, see: (a) Krief,
A.; Laval, A.-M. Chem. ReV. 1999, 99, 745. (b) Beletskaya, I. P.; Cheprakov,
A. V. Chem. ReV. 2000, 100, 3009.
1142
Org. Lett., Vol. 12, No. 5, 2010

electrophilic complex A8a,d that could then enantioselectively
intercept a nucleophilic 2-propenylindole 1 through a
Friedel-Crafts-type Michael addition. A new active inter-
mediate B that contains both iminium and nitronate
components9b will be produced to accomplish the intramo-
lecular Michael addition to form C. Subsequently, a rapid
optically pure 4b in 47% yield. Elaborations of 4b to
Frovatriptan and Ramatroban analogues were accomplished
by using three-step and two-step procedures, respectively.
Significantly, this operationally trivial procedure shows that
complex drug candidates can be easily accessed by this
hydrogen bonding catalytic methodology.
In conclusion, we have developed a hydrogen bonding-
mediated double Michael addition-aromatization cascade of
2-propenylindoles and nitroolefins. This strategy allows rapid
and efficient access to diverse and structurally complex
tetrahydrocarbazoles from simple starting materials and
readily available chiral diamine-derived catalyst. Further
investigations aimed at expanding the substrate scope and
characterizing the medical properties of the products are
currently underway.
Scheme 1
.
Proposed Reaction Pathway for the Cascade
Sequence
Scheme 2. Derivatization of the Cascade Adduct 4b
[1,3]-H migration would regenerate the aromaticity of indole
ring, and therefore afford the corresponding tetrahydrocar-
bazole 4. The Friedel-Crafts alkylation product 5 would
arise from the rearomatization of B.
A demonstration of the synthetic potential of the present
methodology is presented in the synthesis of Frovatriptan15
and Ramatroban16 analogues. As outlined in Scheme 2,
treatment of 1b (1.92 g, 11.2 mmol) with 2a (1.04 g, 7 mmol)
provides tetrahydrocarbazole 4b in one step, 81% yield, 86:
14 dr, and 84% ee. A single recrystallization provided almost
Acknowledgment. We are grateful to the National Science
Foundation of China (20872043 and 20672040) and the
Program for Academic Leader in Wuhan Municipality
(200851430486) for support of this research.
Supporting Information Available: Experimental pro-
cedures and compound characterization data including X-ray
crystal data (CIF) for 4d. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Frovatriptan is a triptan drug developed by Vernalis for the treatment
of migraine headaches, in particular those associated with menstruation.
See: Easthope, S. E.; Goa, K. L. CNS Drugs 2001, 15, 969.
(16) Ramatroban is a drug used to treat coronary artery disease and
asthma, which is developed in association with Bayer. See: Ishizuka, T.;
Matsui, T.; Okamoto, Y.; Ohta, A.; Shichijo, M. CardioVasc. Drug ReV.
2004, 22, 71.
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