Asymmetric Bronsted acid catalysis: Enantioselective nucleophilic substitutions and 1,4-additions

Article abstract of DOI:10.1002/anie.200703668

(Chemical Equation Presented) Executive decision: Depending on the catalyst (both N-triflylphosphoramides), the highly enantioselective Bronsted acid catalyzed addition of indoles to α,β-unsaturated carbonyl compounds provides either α-keto esters (up to 92% ee, left side of the scheme), or a novel type of bisindole (right), which displays atropisomerism. The α-keto esters can also be converted into amino acids by a one-pot 1,4-addition-reductive amination reaction.

Full text of DOI:10.1002/anie.200703668

Angewandte
Chemie
DOI: 10.1002/anie.200703668
Organocatalysis
Asymmetric Brønsted Acid Catalysis: Enantioselective Nucleophilic
Substitutions and 1,4-Additions**
Magnus Rueping,* Boris J. Nachtsheim, Stefan A. Moreth, and Michael Bolte
Dedicated to Professor Dr. Dieter Seebach on the occasion of his 70th birthday
Asymmetric alkylations of electron-rich arenes such as
indoles are of great importance for the synthesis of many
natural products and pharmaceuticals.[1] Hence, different
approaches have been undertaken to develop catalytic
enantioselective additions of indoles to a,b-unsaturated
carbonyl compounds. To date, these have been based on the
application of chiral transition-metal complexes[2] or secon-
dary amines, the latter of which function through covalent
activation, forming intermediary iminium ions.[3] In this
context the use of b,g-unsaturated a-keto esters is of
particular interest since they not only exhibit a higher
reactivity but also can be functionalized readily to the
corresponding amino acids or a-hydroxy acids.
Therefore, our investigations started with the examination
of the Brønsted acid catalyzed addition of N-methylindole
(1a) to the a-keto ester 2a. While no reaction was observed
when weak Brønsted acids, such as carbonic acids or diphenyl
phosphate, were used, catalytic amounts of N-triflylphosphor-
amide 5a resulted in product formation. However, in addition
to the desired 1,4-addition product 3a, the bisindole 4a was
isolated as the main product (Scheme 1).
Given the frequent occurrence of the indole core structure
in biologically active substances and natural products[4]
together with the possibility of activating carbonyl function-
alities with chiral Brønsted acids,[5–6] the development of an
enantioselective, metal-free, noncovalently catalyzed Frie-
del–Crafts alkylation of indoles appeared to be of great
significance. This would not only be the first example of such
an organocatalyzed transformation, but more importantly it
would give simple and direct access to optically pure a-keto
and a-amino acids. We report here on the development of
such a reaction, a highly enantioselective Brønsted acid
catalyzed addition of indoles to a,b-unsaturated carbonyl
compounds.
In continuing studies on the Bønsted acid catalyzed
asymmetric Nazarov cyclization of divinyl ketones[5]
[Eq. (1)], we assumed that an enantioselective Friedel–
Crafts alkylation of indoles through the noncovalent activa-
tion of a-keto esters using N-triflylphosphoramides [Eq. (2)]
should also be feasible.
Scheme 1. Brønsted acid catalyzed reaction of N-methylindole (1a)
with a-keto ester 2a to form bisindole 4a.
[*] Prof. Dr. M. Rueping, B. J. Nachtsheim, S. A. Moreth
Degussa Endowed Professorship
Institute of Organic Chemisty and Chemical Biology
Johann Wolfgang Goethe-Universität Frankfurt am Main
Max-von-Laue Strasse 7, 60438 Frankfurt am Main (Germany)
Fax: (+49)69-798-29248
The Lewis or Brønsted acid catalyzed formation of
bisindoles starting from aldehydes, ketones, and 1,2-diketones
is well known,[7] and several naturally occurring alkaloids
contain this structural element.[8] However, the remarkable
regioselectivity observed in the reaction of indoles with b,g-
unsaturated a-keto esters favoring the 1,2-addition with the
generation of bisindole 4a has not previously been reported.
Figure 1 shows the X-ray crystal structure of 4a. In contrast to
all previously reported bisindoles, 4a exhibits atropisomerism
as a result of the rotation barrier about the bonds to the
quaternary carbon bond. The bisindole atropisomers are not
only observed in the X-ray crystal structure but can also be
E-mail: M.rueping@chemie.uni-frankfurt.de
Dr. M. Bolte
Institute of Inorganic and Analytical Chemistry
Universität Frankfurt
Marie-Curie-Strasse 11, 60439 Frankfurt (Germany)
[**] The authors acknowledge Degussa GmbH and the DFG (Schwer-
punktprogramm Organokatalyse) for financial support as well the
Fonds der Chemischen Industrie for a stipend given to B.J.N.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 593 –596
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
593

Communications
This Brønsted acid catalyzed transformation to form
enantiomerically enriched bisindoles is not only mechanisti-
cally of great interest but also provides enantioselective
access to these atropisomers. To obtain more information
about the mechanism, we prepared the racemic compound
6
[11] and converted this into 4a under the reaction conditions
used previously (Scheme 2). Bisindole 4a was obtained in an
Figure 1. X-ray crystal structure of bisindole 4a; elemental cell consist-
ing of two atropisomers (ellipsoids drawn at the 50% probability
level).
Scheme 2. Brønsted acid catalyzed enantioselective nucleophilic sub-
stitution to give the enantiomerically enriched bisindole 4a.
separated chromatographically which additionally demon-
strates their stability in solution.[9]
Based on the observation that
these new bisindoles display atropiso-
merism, we decided to examine the
enantiomeric ratio of 78:22. With regard to the reaction
mechanism, we conclude that 6 undergoes a Brønsted acid
catalyzed nucleophilic substitution, starting with the elimi-
nation which results in the formation of the ion pair I+ 5 fÀ.
Subsequent reaction with N-methylindole (1a) then leads to
enantiomerically enriched bisindole 4a.
chiral N-triflylphosphoramides 5b–
5h[10] in the addition of N-methylin-
dole to b,g-unsaturated a-keto esters
(Table 1). Indeed, after optimizing the
We were also interested in product 3a, which may be
reaction by varying the temperature,
derived from a Brønsted acid catalyzed 1,4-addition
solvent, catalyst loading, and concen-
tration, we succeeded in obtaining
bisindole 4a in an atropisomeric ratio of 81:19 when
5 mol% of Brønsted acid 5 f was used (Table 1, entry 5).
(Scheme 1). Given that in the presence of catalytic quantities
of N-triflylphosphoramide 5b–h, 3a was obtained only as a
side product with a yield less than 10% and low enantiose-
lectivities, we decided to prepare the silylated N-triflylphos-
phoramides 8a and 8b, Brønsted acids with improved steric
and electronic properties.[12]
Table 1: Different N-triflylphosphoramides in the 1,2-addition of
N-methylindole 1a to a-keto ester 2a.
Analogous to the N-triflylphosphoramides 5a–h, the
catalyst 8a provided predominantly bisindole 4a, while 8b
resulted in the formation of the addition product 3a. This may
be attributed to the steric properties of the catalyst. The 3,3’-
Entry[a]
Catalyst
Ar
e.r.[b]
1
2
3
4
5
6
7
5b
5c
5d
5e
5 f
phenyl
58:41
52:49
65:35
52:49
81:19
72:29
54:47
4-NO2C6H4
1-naphthyl
2-naphthyl
9-phenanthryl
anthracyl
À
À
C Si bond is longer than the corresponding C C bond in
catalysts 5b–h, and the spherically arranged phenyl groups on
the silicon atoms increase the steric demand at the catalytic
center, resulting in better shielding of the carbonyl groups in
the activation process and giving rise to the preferred
regioselective addition of indole in 4-position.
5g
5h
3,5-(CF3)-phenyl
[a] Reaction conditions: 2a, 5 mol% 5b–h, 1a (1.5 equiv). [b] Deter-
mined by HPLC analysis using a Chiralcel OD-H column.
594
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 593 –596

Angewandte
Chemie
Table 3: Scope of the enantioselective, Brønsted acid catalyzed indole
addition.
Following the initial results with the new Brønsted acid 8b
we again examined the reaction conditions (Table 2). The
enantioselective Brønsted acid catalyzed indole addition can
be conducted in diethyl ether as well as in various chlorinated
Table 2: Optimization of the reaction conditions for the Brønsted acid
catalyzed enantioselective 1,4-addition.
Entry[a]
R1
R2
R3
T [h]
Yield [%][c]
e.r. [%][c]
1
2
3
4
5
6
7
8
9
10
PhMe
PhEt
PhMe
PhMe
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
2-naphthyl
H
H
5-Br
7-Me
15
24
24
22
Me
Me
Me
Me
Me
Me
62
81
43
78
94:6
93:7
93:7
92:8
65
60
69
55
88
Entry[a]
Solvent
T [8C]
t [h]
Yield [%][b]
e.r.[c]
H
H
H
Br
H
H
22
24
20
22
18
18
94:7
95:5
96:4
90:10
93:7
95:5
1
2
3
4
5
6
7
Et2O
Et2O
RT
24
36
16
20
18
16
15
16
24
20
20
18
62
–
53:47
–
À40
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
RT
44
72
58
82
62
44
36
53
62
67
65:34
76:21
84:15
83:16
94:6
94:6
91:9
66:34
70:29
70:28
À40
À78
À40
À75
À75
À75
RT
70
[a] Reaction conditions: 2, 5 mol% 8b, 1 (1.5 equiv) at À758C. [b] Yield
of product isolated after flash chromatography. [c] Determined by HPLC
analysis using a chiral stationary phase.
8[d]
9[e]
10
11
12
CHCl3
ClCH2CH2Cl
À40
À40
[a] Reaction conditions: 2a, 5 mol% 8b, 1 (1.5 equiv). [b] Yield of
product isolated after flash chromatography. [c] Determined by HPLC
analysis using a Chiralcel OD-H column. [d] Using 10 mol% 8b.
[e] Using 2 mol% 8b.
or aromatic solvents (Table 2). The best enantioselectivities
were obtained in dichloromethane at À758C (Table 2,
entries 7–9). With regard to the catalyst loading, the best
results were achieved with 5 mol% 8b. Neither higher
loadings of 8b (10 mol%) nor lower loadings (2mol%)
improved the yields and enantioselectivities (Table 2,
entries 8 and 9). Under these optimized reaction conditions
we subjected various indoles 1 as well as b,g-unsaturated a-
keto esters 2 in the asymmetric Brønsted acid catalyzed 1,4-
addition (Table 3). In general the differently substituted a-
keto esters 3 were isolated in good yields and in excellent
enantiomeric ratios (up to 96:4 e.r.).
This Brønsted acid catalyzed indole addition reaction
provides the corresponding a-keto esters which can be used as
precursors for the synthesis of amino acids. Based on our
previously reported highly enantioselective Brønsted acid
catalyzed reactions,[13] such as the first transfer hydrogena-
tions[14] with Hantzsch dihydropyridine as the hydride source,
we assumed that an N-triflylphosphoramide-catalyzed reac-
tion sequence consisting of a 1,4-addition followed by a
reductive amination should result in the corresponding amino
acids (Scheme 3). Thus, the double Brønsted acid catalyzed
reaction sequence starting with the reaction of indole 1a with
2b gave the intermediate a-keto ester (Table 3, entry 9),
which under the reduction conditions previously described
was directly transformed into amino acid 7.
Scheme 3. Brønsted acid catalyzed Friedel–Crafts alkylation/reductive
amination sequence. a) 2b, 5 mol% 8b, 1a (1.5 equiv), CH2Cl2,
À758C; b) Hantzschdihydropyridine (1.5 equiv), p-anisidine, MS 4 Š
(43%, d.r. 1.3:1). PMP=p-methoxyphenyl
Brønsted acid catalyzed activation of a,b-unsaturated car-
bonyl compounds, but it also provides the corresponding a-
keto esters 3 in good yields and with excellent enantioselec-
tivities. A double Brønsted acid catalyzed reaction sequence
comprising a Friedel–Crafts alkylation followed by a reduc-
tive amination enables convenient and direct access to new
amino acids. Depending on the selection of the chiral
triflylphosphoramide catalyst, it is possible to synthesize
previously unknown atropisomeric bisindoles in an unprece-
dented asymmetric 1,2-addition. Based on the experimental
results we propose that the reaction mechanism of the
transformation reported here is a Brønsted acid catalyzed
enantioselective, nucleophilic substitution. Furthermore, the
enantioselective reactions introduced here demonstrate the
great potential of the acidic triflylphosphoramides as efficient
and highly reactive chiral Brønsted acid catalysts. Moreover,
the enantioselective Brønsted acid catalyzed, noncovalent
activation of a-keto esters as well as of the unsaturated
carbonyl compounds allows further transformations with
diverse nucleophiles to be carried out, which is the subject
of current studies.
In summary we have reported here on the a Brønsted acid
catalyzed enantioselective Friedel–Crafts alkylation of
indoles as well as a highly enantioselective 1,4-addition.
This efficient method is not only the first example of a
Received: August 10, 2007
Angew. Chem. Int. Ed. 2008, 47, 593 –596
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
595

Communications
[6] D. Nakashima, H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 9626.
[7] Selected more recent examples: a) J. S. Yadav, B. V. S. Reddy, S.
Sunitha, Adv. Synth. Catal. 2003, 345, 349; b) T. J. K. Gibbs,
N. C. O. Tomkinson, Org. Biomol. Chem. 2005, 3, 4043; c) D. G.
Gu, S. J. Ji, Z. Q. Jiang, M. F. Zhou, T. P. Loh, Synlett 2005, 959;
d) S. M. Ma, S. C. Yu, Org. Lett. 2005, 7, 5063; e) V. Nair, K. G.
Abhilash, N. Vidya, Org. Lett. 2005, 7, 5857; f) H. M. Li, Y. Q.
Wang, L. Deng, Org. Lett. 2006, 8, 4063; g) S. Shirakawa, S.
Kobayashi, Org. Lett. 2006, 8, 4939.
[8] a) E. Fahy, B. C. M. Potts, D. J. Faulkner, K. Smith, J. Nat. Prod.
1991, 54, 564; b) R. Bell, S. Carmeli, N. Sar, J. Nat. Prod. 1994,
57, 1587; c) G. Bifulco, I. Bruno, R. Riccio, J. Lavayre, G. Bourdy,
J. Nat. Prod. 1995, 58, 1254; d) T. R. Garbe, M. Kobayashi, N.
Shimizu, N. Takesue, M. Ozawa, H. Yukawa, J. Nat. Prod. 2000,
63, 596.
[9] Atropisomerism of bisindoles has not been reported to date. We
are currently conducting experiments to determine the stability,
rotation barriers, etc.
[10] N-Triflylphophoramides 5b–h have been prepared in analogy to
the procedure described in references [5] and [6].
[11] The preparation of 6 is described in the Supporting Information.
[12] The synthesis of the new N-triflylphophoramides 8a and 8b will
be described separately.
[13] a) M. Rueping, E. Sugiono, C. Azap, Angew. Chem. 2006, 118,
2679; Angew. Chem. Int. Ed. 2006, 45, 2617; b) M. Rueping, C.
Azap, Angew. Chem. 2006, 118, 7996; Angew. Chem. Int. Ed.
2006, 45, 7832; c) M. Rueping, E. Sugiono, T. Theissmann, A.
Kuenkel, A. Kꢀckritz, A. Pews Davtyan, N. Nemati, M. Beller,
Org. Lett. 2007, 9, 1065; d) M. Rueping, E. Sugiono, F. R.
Schoepke, Synlett 2007, 144; e) M. Rueping, E. Sugiono, S. A.
Moreth, Adv. Synth. Catal. 2007, 349, 759; f) M. Rueping, A. P.
Antonchick, C. Brinkmann, Angew. Chem. 2007, 119, 7027;
Angew. Chem. Int. Ed. 2007, 46, 6903.
[14] a) M. Rueping, C. Azap, E. Sugiono, T. Theissmann, Synlett
2005, 2367; b) M. Rueping, E. Sugiono, C. Azap, T. Theissmann,
M. Bolte, Org. Lett. 2005, 7, 3781; c) M. Rueping, T. Theissmann,
A. P. Antonchick, Synlett 2006, 1071; d) M. Rueping, A. P.
Antonchick, T. Theissmann, Angew. Chem. 2006, 118, 3765;
Angew. Chem. Int. Ed. 2006, 45, 3683; e) M. Rueping, A. P.
Antonchick, T. Theissmann, Angew. Chem. 2006, 118, 6903;
Angew. Chem. Int. Ed. 2006, 45, 6751; f) M. Rueping, A. P.
Antonchick, Angew. Chem. 2007, 119, 4646; Angew. Chem. Int.
Ed. 2007, 46, 4562.
Keywords: alkylation · atropisomers · Michael addition ·
nucleophilic substitution · organocatalysis
.
[1] Reviews: a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; b) M.
Bandini, A. Eichholzer, A. Umani-Ronchi, Mini-Rev. Org.
Chem. 2007, 4, 115; c) M. Bandini, A. Melloni, A. Umani-
Ronchi, Angew. Chem. 2004, 116, 560; Angew. Chem. Int. Ed.
2004, 43, 550.
[2] Asymmetric Friedel–Crafts alkylations of a,b-unsaturated car-
bonyl compounds: Copper-catalyzed: a) K. B. Jensen, J.
Thorhauge, R. G. Hazell, K. A. Jørgensen, Angew. Chem. 2001,
113, 164; Angew. Chem. Int. Ed. 2001, 40, 160; b) J. Zhou, Y.
Tang, J. Am. Chem. Soc. 2002, 124, 9030; c) K. A. Jørgensen,
Synthesis 2003, 1117; d) M. Bandini, M. Fagioli, M. Garavelli, A.
Melloni, V. Trigari, A. Umani-Ronchi, J. Org. Chem. 2004, 69,
7511; e) C. Palomo, M. Oiarbide, B. G. Kardak, J. M. Garcia, A.
Linden, J. Am. Chem. Soc. 2005, 127, 4154; f) Y. X. Jia, S. F. Zhu,
Y. Yang, Q. L. Zhou, J. Org. Chem. 2006, 71, 75; g) S. Yamazaki,
Y. Iwata, J. Org. Chem. 2006, 71, 739; h) R. Rasappan, M. Hager,
A. Gissibl, O. Reiser, Org. Lett. 2006, 8, 6099. Scandium-
catalyzed: i) D. A. Evans, K. A. Scheidt, K. R. Fandrick, H. W.
Lam, J. Wu, J. Am. Chem. Soc. 2003, 125, 10780; j) D. A. Evans,
K. R. Fandrick, H.-J. Song, J. Am. Chem. Soc. 2005, 127, 8942;
k) D. A. Evans, K. R. Fandrick, H.-J. Song, K. A. Scheidt, R. Xu,
J. Am. Chem. Soc. 2007, 129, 10029.
[3] Asymmetric Lewis base catalyzed Friedel–Crafts alkylation of
a,b-unsaturated carbonyl compounds: a) J. F. Austin, D. W. C.
MacMillan, J. Am. Chem. Soc. 2002, 124, 1172; b) N. A. Paras,
D. W. C. MacMillan, J. Am. Chem. Soc. 2001, 123, 4370; c) N. A.
Paras, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124, 7894;
d) N. Halland, T. Hansen, K. A. Jørgensen, Angew. Chem. 2003,
115, 5105; Angew. Chem. Int. Ed. 2003, 42, 4955; e) J. F. Austin,
S. G. Kim, C. J. Sinz, W. J. Xiao, D. W. C. MacMillan, Proc. Natl.
Acad. Sci. USA 2004, 101, 5482; f) Y. Huang, A. M. Walji, C. H.
Larsen, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 15051;
g) W. Zhou, L.-W. Xu, L. Li, L. Yang, C.-G. Xia, Eur. J. Org.
Chem. 2006, 5225; h) G. Bartoli, M. Bosco, A. Carlone, F.
Pesciaioli, L. Sambri, P. Melchiorre, Org. Lett. 2007, 9, 1403.
[4] M. Somei, F. Yamada, Nat. Prod. Rep. 2004, 21, 278.
[5] M. Rueping, W. Ieawsuwan, A. P. Antonchick, B. J. Nachtsheim,
Angew. Chem. 2007, 119, 2143; Angew. Chem. Int. Ed. 2007, 46,
2097.
596
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 593 –596