Asymmetric Diels-Alder reaction of 2-methyl-3-indolylmethanols via in situ generation of o -quinodimethanes

Article abstract of DOI:10.1021/ol302853m

An asymmetric Diels-Alder reaction of 2-methyl-3-indolylmethanols and α,β-unsaturated aldehydes has been developed that relies on in situ generation of active indole-2,3-quinodimethane intermediates under mild acidic conditions and uses a secondary chiral amine as iminium activation catalyst. An array of highly enantioenriched tetrahydrocarbazoles have been efficiently produced in fair to good yields.

Full text of DOI:10.1021/ol302853m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric DielsÀAlder Reaction of
2‑Methyl-3-indolylmethanols via in Situ
Generation of o‑Quinodimethanes
You-Cai Xiao,† Qing-Qing Zhou,† Lin Dong,† Tian-Yu Liu,‡ and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of
Education, West China School of Pharmacy, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu 610041, China, and College of
Pharmacy, Third Military Medical University, Chongqing 400038, China
ycchenhuaxi@yahoo.com.cn
Received October 17, 2012
ABSTRACT
An asymmetric DielsÀAlder reaction of 2-methyl-3-indolylmethanols and R,β-unsaturated aldehydes has been developed that relies on in situ
generation of active indole-2,3-quinodimethane intermediates under mild acidic conditions and uses a secondary chiral amine as iminium
activation catalyst. An array of highly enantioenriched tetrahydrocarbazoles have been efficiently produced in fair to good yields.
Chiral tetrahydrocarbazoles have been recognized as
important structural motifs in a diversity of natural prod-
ucts and pharmacological compounds (Figure 1).1 A num-
ber of asymmetric methodologies have been developed for
the construction of this type of cyclic architectures.2 Among
them, the catalytic stereoselective DielsÀAlder cycloaddi-
tions provide one of the most efficient and straightforward
protocols, while previously positioned 2-vinylindoles or
3-vinylindoles were commonly used as the diene counter-
parts in combination with diverse dienophiles (Scheme 1).3
† Sichuan University.
‡ Third Military Medical University.
(1) For selected examples, see: (a) Hesse, M. Alkaloids. Nature Curse
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or Blessing; Wiley-VCH: New York, 2002. (b) Bonjoch, J.; Sole, D. Chem.
Rev. 2000, 100, 3455. (c) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559. (d)
Majima, K.; Takita, R.; Okada, A.; Ohshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 15837. (e) Jiricek, J.; Blechert, S. J. Am. Chem.
Soc. 2004, 126, 3534. (f) Moyano, A.; Rios, R. Chem. Rev. 2011, 111,
4703. (g) Nikitenko, A.; Evrard, D.; Sabb, A. L.; Vogel, R. L.; Stack, G.;
Young, M.; Lin, M.; Harrison, B. L.; Potoski, J. R. Org. Process Res.
Dev. 2008, 12, 76and references cited therein.
(2) For selected asymmetric synthesis of tetrahydrocabazoles, see: (a)
Evans, D. A.; Fandrick, K. R. L.; Song, H.-J. J. Am. Chem. Soc. 2005,
127, 8942. (b) Han, X.; Widenhoefer, R. A. Org. Lett. 2006, 8, 3801. (c)
Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935. (d) Huang., H.;
Peters, R. Angew. Chem., Int. Ed. 2009, 48, 604. (e) Bandini, M.;
Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9533. (f) An, X.-L.;
Chen, J.-R.; Li, C.-F.; Zheng, F.-G.; Zou, Y.-Q.; Guo, Y.-C.; Xiao,
W.-J. Chem. Asian J. 2010, 5, 2258. (g) Bandini, M.; Eichholzer, A.;
Gualandi, A.; Quinto, T.; Savoia, D. ChemCatChem 2010, 2, 661. (h)
Figure 1. Selected examples of bioactive and natural products
containing tetrahydrocarbazole motif.
On the other hand, the o-quinodimethanes (oQDMs),
even though they have been widely employed to prepare
€
Muller, S.; Webber, M. J.; List, B. J. Am. Chem. Soc. 2011, 133, 18534. (i)
(3) (a) Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A. Angew.
Chem., Int. Ed. 2008, 47, 9236. (b) Wang, X.-F.; Chen, J.-R.; Cao, Y.-J.;
Cheng, H.-G.; Xiao, W.-J. Org. Lett. 2010, 12, 1140. (c) Zheng, C.; Li,
Y.; Zhang, J.; Chen, X.; Chai, Z.; Ma, W.; Zhao, G. Chem.;Eur. J.
Zhu, X.-Y.; An, X.-L.; Li, C.-F.; Zhang, F.-G.; Hua, Q.-L.; Chen, J.-R.;
Xiao, W.-J. ChemCatChem 2011, 3, 679. (j) Wu, Q.-F.; Zheng, C.; You,
S.-L. Angew. Chem., Int. Ed. 2012, 51, 1680. (k) Loh, C. C. J.; Raabe, G.;
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2010, 16, 5853. (d) Tan, B.; Hernandez-Torres, G.; Barbas, C. F., III.
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r
10.1021/ol302853m
XXXX American Chemical Society

many complex compounds, have been much less used in
catalytic asymmetric DielsÀAlder reactions, probably be-
cause of the instability and high reactivity of such dienes
and the deficiency of compatible catalytic systems.4 In
particular, a special type of oQDMs, indole-2,3-quinodi-
methanes, have also been well established as active inter-
mediates in the construction of tetrahydrocarbazoles
through DielsÀAlder cycloadditions.5 Nevertheless, only
very recently did Melchiorre and co-workers successfully
document the amine-catalyzed asymmetric DielsÀAlder
reaction of β-indolyl unsaturated aldehydes, from which
indole-2,3-quinodimethanes were generated and acted as
the active dienes.6 On the other hand, 3-indolemethanol
compounds has been disclosed as valuable alkylation
reagents by formation of vinylogous iminium ions under
diverse acidic conditions.7 As part of our continuing
interest in the direct transformations with indole sub-
strates,8 we envisaged that indole-2,3-quinodimethanes might
be produced from 2-methyl-3-indolemethanols through
tautomerization of the corresponding iminium ions, as
outlined in Scheme 1. Thus, an asymmetric DielsÀAlder
reaction of these active species and R,β-unsaturated alde-
hydes could be carried out by the iminium activation of a
chiral amine.9
Table 1. Screening Studiesa
entry cat. solvent
additive
yieldb (%)
drc
eed (%)
1
2
1a
1b
1c
1d
1d
1e
1a
1a
1a
1a
1a
1a
1a
CH2Cl2 AcOH
CH2Cl2 AcOH
CH2Cl2 AcOH
CH2Cl2 TFA
CH2Cl2 AcOH
CH2Cl2 TFA
toluene AcOH
62
10:1
9:1
93
94
90
56
3
53
7:1
4
trace
trace
trace
57
5
6
7
9:1
12:1
8:1
90
96
92
93
97
96
96
8
THF
AcOH
AcOH
43
9
CHCl3
58
10
11
12
13
CH2Cl2 PhCO2H
CH2Cl2 silica gele
CH2Cl2 M-K10f
CH2Cl2 M-K10g
37
9:1
48
10:1
10:1
10:1
65
71
a Unless otherwise noted, the reaction was carried out with 2a (0.12
mmol), 3a (0.1 mmol), acid (0.12 mmol), and catalyst 1 (0.02 mmol) in
solvent (1.0 mL) at 30 °C for 72 h. b Isolated yield of the major endo-
isomer 4a for two steps. c Determined by 1H NMR analysis of the crude
mixture. d Determined by chiral HPLC analysis. e 60 mg. f Montmor-
illonite K10 (60 mg). g Montmorillonite K10 (30 mg).
Scheme 1. Constructions of Chiral Tetrahydrocarbazoles via
DielsÀAlder Cycloadditions of Diverse Indole Compounds
substrates in dichloromethane, using R,R-diphenylproli-
nol O-TMS ether10 (1a) as the catalyst in the presence of
excess acetic acid. We indeed observed the expected
cycloadduct in high diastereoselectivity, along with the
dimerization byproduct of indole compound. Pleasingly,
the enantioselectivity of the major endo-diastereomer was
quite promising after conversion to the corresponding
(5) (a) Gallagher, T.; Magnus, P. Tetrahedron 1981, 37, 3889. (b)
Exon, C.; Gallagher, T.; Magnus, P. J. Am. Chem. Soc. 1983, 105, 4739.
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Soc. 1984, 106, 2105. (d) Magnus, P.; Cairns, P. M. J. Am. Chem. Soc.
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1986, 108, 217. (e) Diker, K.; de Maindreville, M. D.; Levy, J. Tetra-
hedron Lett. 1999, 40, 7459. (f) Cochard, F.; Laronze, M.; Sigaut, P.;
Sapi, J.; Laronze, J. Tetrahedron Lett. 2004, 45, 1703. (g) Royer, D.;
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Wong, Y.-S.; Ple, S.; Chiaroni, A.; Diker, K.; Levy, J. Tetrahedron 2008,
64, 9607.
(6) (a) Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am.
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Chem. Soc. 2011, 133, 15212. (b) Liu, Y.; Nappi, M.; Escudero-Adan,
E. C.; Melchiorre, P. Org. Lett. 2012, 14, 1310.
(7) (a) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.; Melchiorre,
P. Angew. Chem., Int. Ed. 2008, 47, 8707. (b) Cozzi, P. G.; Benfatti, F.;
Zoli, L. Angew. Chem., Int. Ed. 2009, 48, 1313. (c) Guo, Q.-X.; Peng,
Y.-G.; Zhang, J.-W.; Song, L.; Feng, Z.; Gong, L.-Z. Org. Lett. 2009, 11,
4620. (d) Jing, L.; Wei, J.; Zhou, L.; Huang, Z.; Li, Z.; Wu, D.; Xiang,
H.; Zhou, X. Chem.;Eur. J. 2010, 16, 10955. (e) Xu, B.; Guo, Z.-L.; Jin,
W.-Y.; Wang, Z.-P.; Peng, Y.-G.; Guo, Q.-X. Angew. Chem., Int. Ed.
2012, 51, 1059. (f) Fochi, M.; Gramigna, L.; Mazzanti, A.; Duce, S.;
Fantini, S.; Palmieri, A.; Petrini, M.; Bernardi, L. Adv. Synth. Catal.
2012, 354, 1373. (g) Wang, D.-S.; Tang, J.; Zhou, Y.-G.; Chen, M.-W.;
Yu, C.-B.; Duan, Y.; Jiang, G.-F. Chem. Sci. 2011, 2, 803.
Initially, (2-methyl-1H-indol-3-yl)(phenyl)methanol (2a)
and trans-cinnamaldehyde (3a) were selected as the model
(4) (a) Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P. Acc.
Chem. Res. 1984, 17, 35. (b) Grosch, B.; Orlebar, C. N.; Herdtweck, E.;
Massa, W.; Bach, T. Angew. Chem., Int. Ed. 2003, 42, 3693. (c) Nicolaou,
K. C.; Gray, D. L. F. J. Am. Chem. Soc. 2004, 126, 607. (d) Segura, J. L.;
Martın, N. Chem. Rev. 1999, 99, 3199.
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Y.-C. Angew. Chem., Int. Ed. 2011, 50, 10849.
B
Org. Lett., Vol. XX, No. XX, XXXX

with higher enantioselectivity, though the yield was still
fair (entry 11). To our delight, a cleaner reaction was
observed when montmorillonite K10 was used, leading to
better results in terms of yield, diastereoselectivity and
enantioselectivity (entries 10 and 11). We also tested
indole 2b with an N-methyl group, which exhibited much
lower reactivity and could not afford the desired cycloadduct.
With the established conditions in hand, we then ex-
ploredthescope and limitationsofbothtypesofsubstrates.
The reactions were catalyzed by amine 1a (20 mol %) in the
presence of montmorillonite K10 at 30 °C. The results are
summarized in Table 2. For a diversity of 2-methyl-1H-
indol-3-yl-arylmethanols with either electron-withdrawing
or -donating substitutions, good to excellent diastereo-
selectivity along with outstanding enantioselectivity has
been generally obtained in the reactions with cinnamal-
dehyde 3a (Table 2, entries 1À6). Nevertheless, a 2-thienyl-
substituted 3-indolemethanol gave a much lower dr value
in the cycloaddition, while the ee value was still remark-
able (entry 7). Notably, a 3-indolemethanol with a cyclo-
propyl group even showed higher reactivity, leading to
the corresponding cycloadduct 4h in excellent diastereo-
and enantioselectivity (entry 8). Unfortunately, 3-indole-
methanols bearing either other linear or branched alkyl
groups were unstable under the current catalytic system
and failed to produce the desired cycloadducts. In addi-
tion, similar good results were attained for 3-indole-
methanols with various substituents on the indole ring
(entries 9À11). Nevertheless, 3-indolemethanols with
other 2-alkyl groups, such as benzyl or n-butyl ones,
produced a complex mixture because of poor diastereo-
selectivity in the cycloaddition step. On the other hand, an
array of R,β-unsaturated aldehydes with diverse aryl or
heteroaryl substitutions were explored. The diastereo-
and enantioselectivity were generally high, and the isolated
yields were fair to moderate (entries 12À19). A β-pheny-
lethynyl-substituted enal substrate showed lower reac-
tivity, and a low yield was obtained (entry 20). We also
tried to apply R,β-unsaturated aldehydes with β-alkyl
substitutions. However, the major products came from
Table 2. Substrate Scope and Limitationsa
entry
R1
R2
R3
4
yieldb (%) drc eed (%)
1
2
3
4
5
6
7
Ph
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
71
58
60
63
61
68
43
65
56
53
53
73
47
56
52
63
57
63
53
30
10:1 96
10:1 98
9:1 97
4-BrC6H4
2-ClC6H4
3-MeC6H4
4-MeC6H4
H
H
H
H
6:1 99
8:1 99
1-naphthyl H
2-thienyl
8e cyclopropyl H
>19:1 93
2.5:1 99
>19:1 98
6:1 90
H
4g
4h
4i
9
Ph
5-Br Ph
5-Me Ph
7-Me Ph
10 Ph
11 Ph
12 Ph
13 Ph
14 Ph
15 Ph
16 Ph
17 Ph
4j
7:1 96
4k
4l
10:1 99
12:1 99
>19:1 90
10:1 96
>19:1 97
7:1 99
H
H
H
H
H
H
4-ClC6H4
4-FC6H4
4m
4n
4-CF3C6H4
4-EtOOCC6H4 4o
4-MeC6H4
2-furyl
4p
4q
4r
4s
16:1 99
>19:1 99
7:1 93
18e cyclopropyl H
19e cyclopropyl H
4-NO2C6H4
4-MeC6H4
20 Ph
H
phenylethynyl 4t
9:1 95
a Unless otherwise noted, reaction was carried out with 3-indole-
methanol 2 (0.12 mmol), enal 3 (0.1 mmol), catalyst 1a (0.02 mmol), and
Montmorillonite K10 (30 mg) in CH2Cl2 (1.0 mL) at 30 °C for 72 h.
b Isolated yields of the major endo-isomers for two steps c Determined by
1H NMR analysis of the crude mixture. d Determined by chiral HPLC
analysis. e For 8 h.
alcohol 4a (Table 1, entry 1). Similar results were obtained
when more bulky amine 1b or 1c was applied (entries 2 and 3).
However, prolinol11 (1d) and MacMillan’s catalyst9aÀc 1e did
not provide the desired product in combination with
either AcOH or trifluoroacetic acid (entries 4À6). A
survey of other reaction media revealed that the overall
results could not be improved (entries 7À9). In order to
reduce side reactions from labile indole substrate 2a, more
additives were investigated. While no reaction occurred in
the absence of any acid, benzoic acid gave the desired
product in a low yield (entry 10). Interestingly, using
amine 1a and simple silica gel could promote the reaction
(9) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2000, 122, 4243. (b) Northrup, A. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 2458. (c) Wilson, R. M.; Jen,
W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616. (d)
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Tanaka, Y.; Maruoka, K. Org. Lett. 2006, 8, 2687. (f) Gotoh, H.;
Hayashi, Y. Org. Lett. 2007, 9, 2859. (g) Ishihara, K.; Nakano, K.;
Akakura, M. Org. Lett. 2008, 10, 2893. (h) For a review on iminium
€
catalysis, see: Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007,
107, 5416.
(10) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh,
H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (c)
Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jørgensen, K. A.
Acc. Chem. Res. 2012, 45, 248.
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Chen, Y.-C. Adv. Synth. Catal. 2006, 348, 1818.
Figure 2. X-ray crystallographic structure of enantiopure alde-
hyde precursor of product 4f.
Org. Lett., Vol. XX, No. XX, XXXX
C

γ- or R-alkylation of the enal substrates via a dienamine
catalytic pathway.8a
would provide more opportunities in asymmetric
syntheses with in situ generated, highly reactive in-
dole-2,3-quinodimethanes.
Crystals suitable for X-ray crystallographic analysis
have been obtained from the corresponding aldehyde
precursor of product 4f. Thus, its absolute and relative
configuration could be ambiguously determined, showing
the normal endo-selectivity (Figure 2).
In conclusion, we have developed an asymmetric DielsÀ
Alder reaction of 2-methyl-3-indolemethanols and R,β-
unsaturated aldehydes that relies on in situ generation of
active indole-2,3-quinodimethane intermediates under mild
acidic conditions and uses a secondary chiral amine as
iminium activation catalyst. A spectrum of chiral tetrahy-
drocarbazoles have been efficiently produced from easily
available starting materials in fair to moderate yields, along
with high to excellent diastereo- and enantioselectivity.
We believe that the protocol presented in this work
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(21125206 and 21021001) and National Basic Research
Program of China (973 Program, 2010CB833300).
Supporting Information Available. Experimental pro-
cedures, structural proofs, NMR spectra, and HPLC
chromatograms of the products; X-ray data of the en-
antiopure aldehyde precursor of product 4f (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX