Journal of the American Chemical Society
COMMUNICATION
tetrahydrocarbazoles by utilizing the first catalytic asymmetric
Fischer indolization. Key features of this process are the intro-
duction of the new and powerful chiral phosphoric acid catalyst
5f as well as the identification of a cation exchange resin for the
efficient removal of ammonia from the reaction mixture. This
combination allows the reaction to be performed at low tem-
perature and with only substoichiometric quantities of a chiral
Brønsted acid. We expect these findings to be of great value for
improved syntheses of indole derivatives as well as for new
developments in the field of chiral Brønsted acid catalysis. Further
exploration of the potential of our spirocyclic phosphoric acids and
studies of related transformations are currently ongoing.
(8) Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458.
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Diego) 2008, 65, 181.
(11) For selected examples, see: (a) BaeyerÀVilliger oxidations:
Reetz, M. T.; Brunner, B.; Schneider, T.; Schulz, F.; Clouthier, C. M.;
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(d) Ring expansions with diazoacetates: Hashimoto, T.; Naganawa, Y.;
Maruoka, K. J. Am. Chem. Soc. 2011, 133, 8834.
(12) Li, L.; Seidel, D. Org. Lett. 2010, 12, 5064. See also: Ren, L.;
Lei, T.; Gong, L.-Z. Chem. Commun. 2011, 47, 11683.
’ ASSOCIATED CONTENT
(13) For reviews of chiral phosphoric acid catalysis, see: (a) Terada,
M. Synthesis 2010, 1929. (b) Kampen, D.; Reisinger, C. M.; List, B. Top.
Curr. Chem. 2010, 291, 395. (c) Akiyama, T. Chem. Rev. 2007, 107, 5744.
(14) For examples of enantioselective [3,3]-sigmatropic rearrange-
ments catalyzed by chiral Brønsted acids, see: (a) Uyeda, C.; Jacobsen,
E. N. J. Am. Chem. Soc. 2008, 130, 9228. (b) Rueping, M.; Antonchick,
A. P. Angew. Chem., Int. Ed. 2008, 47, 10090. Angew. Chem. 2008,
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S
Supporting Information. Experimental procedures, com-
b
pound characterization, NMR spectra, HPLC traces, and X-ray data
for 2b. This material is available free of charge via the Internet at
’ AUTHOR INFORMATION
Corresponding Author
(15) When the reaction was conducted under reflux conditions and a
slight argon stream, full conversion was achieved with a 10 mol % loading
of a Brønsted acidic catalyst. However, we failed to obtain useful
enantioselectivities under these reaction conditions.
’ ACKNOWLEDGMENT
(16) For selected examples, see: (a) Yamada, S.; Chibata, I.; Tsurui,
R. Pharm. Bull. 1953, 1, 14. (b) Wahab, B.; Ellames, G.; Passey, S.; Watts,
P. Tetrahedron 2010, 66, 3861. (c) For a review of heterogeneous
catalysis of the Fischer indole synthesis, see: Downing, R. S.; Kunkeler,
P. J. In Fine Chemicals through Heterogeneous Catalysis; Sheldon, R. A.,
Bekkum, H., Eds.; Wiley-VCH: New York, 2001; pp 178À183.
(17) SPINOL-derived phosphoric acids were independently intro-
duced by three research groups. See: (a) Xu, F.; Huang, D.; Han, C.;
Shen, W.; Lin, X.; Wang, Y. J. Org. Chem. 2010, 75, 8677. (b) Coriꢀc, I.;
M€uller, S.; List, B. J. Am. Chem. Soc. 2010, 132, 8536. (c) Xing, C.-H.;
Liao, Y.-X.; Ng, J.; Hu, Q.-S. J. Org. Chem. 2011, 76, 4125.
(18) Other acidic additives such as acetic acid or benzoic acids had
detrimental effects on the stereochemical outcome of the reaction (also
see the SI).
(19) For an example of a study showing how varying N-benzyl
groups in tetrahydrocarbazoles affects the biological activity, see: Li, L.;
Beaulieu, C.; Carriere, M.-C.; Denis, D.; Greig, G.; Guay, D.; O’Neill, G.;
Zamboni, R.; Wang, Z. Bioorg. Med. Chem. Lett. 2010, 20, 7462.
(20) For examples of biologically active 3-aminotetrahydrocarba-
zoles, see: (a) B€oshagen, H.; Rosentreter, U.; Lieb, F.; Oediger, H.;
Seuter, F.; Perzborn, E.; Fiedler, V.-B. Cycloalkano[1,2-b]indole-sulfo-
namides. EP 0242518, 1987. (b) Wood, P. L.; McQuade, P. S. Prog.
Neuro-Psychopharmacol. Biol. Psychiatry 1984, 8, 773. (d) King, F. D.;
Gaster, L. M.; Kaumann, A. J.; Young, R. C. Use of tetrahydrocarbazone
derivatives as 5HT1 receptor agonists. WO 9300086, 1993.
We gratefully acknowledge generous support from the Max
Planck Society and the Fonds der Chemischen Indutrie (fellowship
for S.M.). We also thank Jens Truckenbrodt, Matthias Miosga, and
our HPLC and X-ray departments for their support.
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dx.doi.org/10.1021/ja2092163 |J. Am. Chem. Soc. 2011, 133, 18534–18537