Enantioselective organocatalytic synthesis of quaternary α-amino acids bearing a CF3 Moiety

Article abstract of DOI:10.1021/ol103093r

A highly enantioselective Friedel-Crafts reaction catalyzed by a chiral phosphoric acid was developed. N-Boc-protected ethyl trifluoropyruvate imine was activated by 6 mol % of catalyst and reacted with a wide variety of indole derivatives to afford quate

Full text of DOI:10.1021/ol103093r

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1044–1047
Enantioselective Organocatalytic
Synthesis of Quaternary r-Amino Acids
Bearing a CF3 Moiety
Ralph Husmann, Erli Sugiono, Stefanie Mersmann, Gerhard Raabe, Magnus Rueping,
and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056
Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received December 21, 2010
ABSTRACT
A highly enantioselective Friedel-Crafts reaction catalyzed by a chiral phosphoric acid was developed. N-Boc-protected ethyl trifluoropyruvate
imine was activated by 6 mol % of catalyst and reacted with a wide variety of indole derivatives to afford quaternary R-amino acids in excellent
yields (up to 99%) and high enantioselectivities (up to 98:2 er).
The synthesis of quaternary carbon stereogenic
centers remains a challenging goal in organic synthesis.1
Also, the development of synthetic methods to produce
trifluoromethylated compounds in an enantioselective
fashion is highly desirable.2 The catalytic asymmetric
Friedel-Crafts (FC) reaction constitutes an important
C-C bond-forming transformation,3 and several exam-
pleswithtrifluoromethylketones aselectrophilescatalyzed
by chiral hydrogen donor catalysts have been published.4
Directed hydrogen bond interactions represent an impor-
tant mode of activation for asymmetric organocatalysis.5
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
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(d) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
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Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, 1995. (b)
Uneyama, K. In Enantiocontrolled Synthesis of Fluoro-Organic Com-
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470. For diastereoselective addition to trifluoromethyl imines, see: (h)
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tions, see: (a) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38,
2190. (b) Terrasson, V.; de Figueiredo, R. M.; Campagne, J. M. Eur. J.
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r
10.1021/ol103093r
Published on Web 01/24/2011
2011 American Chemical Society

Since the landmark discovery of Jacobsen in 1998, where
thiourea derivatives catalyzed the asymmetric Strecker
reaction,6 chiral Brønsted acid catalysis has gained much
attention in the field. After the TADDOL-catalyzed het-
ero-Diels-Alder reaction reported by Rawal,7 much
stronger hydrogen bond donors such as phosphoric acids
were found to catalyze Mannich-type reactions.8 A wide
variety of BINOL-derived phosphoric acids have been
developed since then, serving as versatile catalysts to per-
form highly enantioselective organocatalytic transforma-
tions.9
Table 1. Survey of Chiral Phosphoric Acids for the FC Reaction
Numerous protocols for FC reactions to the indole
moiety with electrophiles such as carbonyl compounds,4
R,β-unsaturated carbonyl derivatives,10 imines,4,11 and
nitroolefins12 catalyzed by chiral Brønsted acids are
known. However, to the best of our knowledge, no FC
reactions with trifluoropyruvate-derived imines catalyzed
by chiral BINOL-derived phosphoric acids have been
described. Here, we present an enantioselective aminoalk-
ylation of indole derivatives giving quaternary R-amino
acids in good to excellent yields and high enantio-
selectivities.13
entrya
catalyst
product
yield (%)b
erc
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
4a
4a
4a
4a
4a
4a
4b
4c
4d
25
16
39
78
37
99
71
96
73
37:63
37:63
30:70
56:44
51:49
96:4
(5) For general reviews on hydrogen bonds, see: (a) Meot-Ner
(Mautner), M. Chem. Rev. 2005, 105, 213. (b) Rozas, I. Phys. Chem.
Chem. Phys. 2007, 9, 2782. Hydrogen Bonding in Organic Synthesis;
Pihko, P., Ed.; Wiley-VCH: Weinheim, 2009. For reviews on hydrogen bond
mediated catalysis, see: (c) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289.
(d) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem., Int. Ed.
2005, 44, 1758. (e) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 1520. (f) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713. (g) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516. (h) Takemoto,
Y. Chem. Pharm. Bull. 2010, 58, 593. (i) Knowles, R. R.; Jacobsen, E. N.
Proc. Natl. Acad. Sci. 2010, 107, 20678. For a special issue on
organocatalysis, see: (j) Chem. Rev. 2007, 107, 5413.
3f
87:13
50:50
91:9
3f
3f
a Reaction conditions: 1a (1 equiv), 2 (1.2 equiv), and 3 (0.06 equiv) in
toluene (0.1 M) at -78 °C for 3 h. b Yield after column chromatography.
c The R:S ratio was determined by HPLC analysis on a chiral stationary
phase.
Initially, we investigated the reaction of indole with N-
Boc-protected 3,3,3-trifluoropyruvate imine14 in the pre-
sence of a chiral phosphoric acid catalyst in toluene (Table 1).
The reaction proceeded at -78 °C and was complete after
3 h.15-17 Catalysts with various substitution patterns on
the 3,30 position of the binaphthyl scaffold were examined
(entries 1-6) and the 2,4,6-triisopropylphenyl-substituted
catalyst (TRIP,15 entry 6) was found to be the best in terms
of yield and enantioselectivity. Substrates with alternative
protecting groups on the imine nitrogen were also tested.
The Cbz-protected imine gave the desired product in good
yield (71%, entry 7), but with only moderate er (87:13).
The imine with a benzoyl protecting group reacted well to
give the quaternary amino acid derivative in high yield
(96%, entry 8) but surprisingly as a racemate. Use of the
methyl imino ester (entry 9) resulted in a lower yield (73%)
and an er of 91:9.
(6) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120,
4901. (b) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2000, 39, 1279. (c) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 10012.
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2003, 424, 146.
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Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356.
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Terada, M. Synthesis 2010, 1929. (b) Kampen, D.; Reisinger, C. M.; List,
B. Top. Curr. Chem. 2010, 291, 395. (c) Rueping, M.; Koenigs, R. M.;
Atodiresei, I. Chem.;Eur. J. 2010, 16, 9350. (d) Zamfir, A.; Schenker,
S.; Freund, M.; Tsogoeva, S. B. Org. Biomol. Chem. 2010, 8, 5262.
(10) (a) Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M.
Angew. Chem., Int. Ed. 2008, 47, 593. (b) Tang, H.-Y.; Lu, A.-D.; Zhou,
Z.-H.; Zhao, G.-F.; He, L.-N.; Tang, C.-C. Eur. J. Org. Chem. 2008,
1406. (c) Scettri, A.; Villano, R.; Acocella, M. R. Molecules 2009, 14,
3030. (d) Bachu, P.; Akiyama, T. Chem. Commun. 2010, 46, 4112. (e)
Sakamoto, T.; Itoh, J.; Mori, K.; Akiyama, T. Org. Biomol. Chem. 2010,
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2010, 51, 4658.
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Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem.
2008, 180. (c) Kang, Q.; Zhao, Z.-A.; You, S.-L. Tetrahedron 2009, 65,
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Chem. Soc. 2006, 128, 8156.
€
(14) Burger, K.; Hoss, E.; Gaa, K. Chem. Ztg. 1989, 113, 243.
(15) The free acid catalysts were prepared according to literature
procedures: Klussmann, M.; Ratjen, L.; Hoffmann, S.; Wakchaure, V.;
Goddard, R.; List, B. Synlett 2010, 2189.
(12) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008,
47, 4016.
(16) No reaction was observed in the absence of a chiral phosphoric
acid.
(13) For the first organocatalytic alkylation of ketimines, see: (a)
Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004,
43, 4476. For a FC reaction of indoles and R-aryl enamides, see: (b) Jia,
Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew. Chem.,
Int. Ed. 2007, 46, 5565. For a recent review on organocatalytic
functionalization of indoles, see: (c) Bartoli, G.; Bencivenni, G.; Dalpoz-
zo, R. Chem. Soc. Rev. 2010, 39, 4449.
(17) Special care should be taken in collecting the entire product after
column chromatography because self-disproportionation of enantio-
mers can occur. No such effect was observed upon sublimation under
high vacuum at room temperature. For such phenomena, see: (a)
Soloshonok, V. A. Angew. Chem., Int. Ed. 2006, 45, 766. (b) Soloshonok,
V. A.; Ueki, H.; Yasumoto, M.; Mekala, S.; Hirschi, J. S.; Singleton,
D. A. J. Am. Chem. Soc. 2007, 129, 12112.
Org. Lett., Vol. 13, No. 5, 2011
1045

the free N-H of the indole to interact with the chiral
phosphoric acid.
Table 2. Scope of the Catalytic Enantioselective FC Reaction
Figure 1. (A) Experimental ECD spectrum of 4a. (B) Averaged
calculated ECD spectrum of (S)-4a.
The absolute configuration of a representative product was
determined by comparison of calculated and measured ECD
spectra (Figure 1). A conformational search for (S)-4a was
performed using the program Spartan ’02.19 Geometry
optimizations of all conformers and TD-DFT20 calculations
applying the B3LYP functional21 and the 6-311þþG** basis
set were accomplished with the program Gaussian 0922 to
obtain the theoretical ECD spectrum (B in Figure 1). The
Boltzmann weighted spectrum of (S)-4a is close to the mirror
image of the experimental spectrum (A in Figure 1),23 reveal-
ing the absolute configuration of 4a to be most likely R. On
the basis of analogy and considering the same algebraic sign
of the optical rotation, the absolute configurations of pro-
ducts 4b and 4d-n were also assigned as R.24
a-c As in Table 1. d A longer reaction time (10 h) was needed for full
conversion.
Deprotection of the 6-chloro derivative 4l was effected
with trifluoroacetic acid in dichloromethane. After basic
workup, the desired free amino ester was obtained in 98%
yield without affecting the stereochemisty (Scheme 1).
The optimized conditions were then employed to exam-
ine the reaction scope (Table 2). Use of 5-halogenated
indole derivatives afforded the products in excellent yields.
However, in the case of 5-bromoindole the yield was slightly
lower (85%, entry 3) as compared to the 5-fluoro- or
5-chloro-substituted indoles (99% in both cases, entries 1
and 2). The enantiomeric ratios of the adducts 4e and 4g
were 96:4 and that for 4f was 95:5. Electron-rich indoles
also reacted readily. 5-Methyl- and 5-methoxyindole furn-
ished the desired products in excellent yields (99% in both
cases, entries 4 and 5) and high enantioselectivities (94:6 for
4h and 93:7 for 4i). Methyl indole-5-carboxylate needed a
prolonged reaction time for full conversion and yielded
65% of product with an enantiomeric ratio of 95:5 (entry 6).
With 6-fluoro-, 6-chloro-, and 7-methyl-substituted in-
doles (entries 7-9) the reaction went smoothly, giving
the best result in terms of enantioselectivity (98:2 er) for
4l. N-Methylindole gave the product in low yield and in an
almost racemic form (entry 10). This is in accordance with
findings by Zhou13b and You18 confirming the necessity of
(19) Spartan, Version 02; Wavefunction, Inc.: Irvine, CA, 2002.
(20) Bauernschmitt, R.; Ahlrichs, R. Chem. Phys. Lett. 1996, 256,
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Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157,
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Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
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K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
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A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
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J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz,
J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.1; Gaussian, Inc.:
Wallingford, CT, 2009.
(23) The experimental ECD spectrum was recorded at room tem-
perature using a 1.08 ꢀ 10-3 mol L-1 solution of 4a (er = 96:4) in
CH3CN (path length 0.1 cm) on a AVIV 62DS circular dichroism
spectrometer.
(18) Sheng, Y.-F.; Gu, Q.; Zhang, A.-J.; You, S.-L. J. Org. Chem.
2009, 74, 6899.
(24) See Supporting Information for optical rotation values.
1046
Org. Lett., Vol. 13, No. 5, 2011

derived imine proved most effective in terms of yield and
stereoselectivity. A wide variety of substituents in the 5-, 6-,
and 7-positions of the indole were tolerated. The absolute
configuration of a representative product was determined
by comparison of calculated and experimental ECD spec-
tra. Deprotection of the Boc-derivative was accomplished
giving the amino acid ester in excellent yield while retaining
the stereochemical information.
Scheme 1. Amino Acid Ester 5 by Deprotection of 4l
Acknowledgment. We are grateful to the Fonds der
Chemischen Industrie and the Deutsche Forschungsge-
meinschaft (DFG) within the SPP 1179 (“Organocatalysis”)
for financial support.
In summary, we developed the first chiral Brønsted acid
catalyzed FC reaction to form quaternary R-amino acids
bearing a CF3 group.25 The N-Boc-protected trifluoropyruvate-
Supporting Information Available. Experimental and
computational procedures as well as spectral data for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(25) During the preparation of this manuscript, an elegant organo-
catalytic enantioselective Strecker synthesis of quaternary R-trifluoro-
methyl amino acids was described: Enders, D.; Gottfried, K.; Raabe, G.
Adv. Synth. Catal. 2010, 352, 3147.
Org. Lett., Vol. 13, No. 5, 2011
1047