Enantioselective organocatalytic indole alkylations. Design of a new and highly effective chiral amine for iminium catalysis

Article abstract of DOI:10.1021/ja017255c

The indole framework has become widely identified as a "privileged" structure with representation in over 3000 natural isolates and 40 medicinal agents of diverse therapeutic action. A new strategy for asymmetric access to this important pharmacaphore has

Full text of DOI:10.1021/ja017255c

Published on Web 01/26/2002
Enantioselective Organocatalytic Indole Alkylations. Design of a New and
Highly Effective Chiral Amine for Iminium Catalysis
Joel F. Austin and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering,California Institute of Technology, Pasadena, California 91125
Received October 7, 2001
With the rapid growth of asymmetric catalysis1 has come an
increasing demand for chiral technologies that provide structural
motifs of established value in medicinal chemistry or complex target
synthesis. In this regard, the indole framework has become widely
identified as a “privileged” structure or pharmacaphore, with repre-
sentation in over 3000 natural isolates2 and 40 medicinal agents of
diverse therapeutic action.3 Surprisingly, however, asymmetric entry
to indolic architecture has been largely restricted to the derivati-
zation of enantiopure amino acids4 or the optical resolution of
racemic mixtures.5
Moreover, heteroaromatic nucleophiles that engage the activated-
Having established the capacity of iminium catalysis to mediate
iminium 3 (derived from catalyst 1) must encounter a retarding
interaction with the illustrated methyl substituent. In contrast, the
reactive enantioface of iminium ion 4 is free from steric obstruction
and, as such, should exhibit increased reactivity toward carbon-
carbon bond formation. In terms of our design criteria for
enantiocontrol,10 the catalyst-activated iminium ion 4 was antici-
the enantioselective coupling of pyrroles and R,â-unsaturated alde-
hydes (eq 1, 91-99% ee),6 we recently sought to extend this pow-
erful Friedel-Crafts strategy to indole nucleophiles. Despite struc-
tural similarities, it has long been established7 that the pyrrole
π-system is significantly more activated toward electrophilic sub-
stitution than the indole framework. Indeed, poor reaction rates and
pated to selectively populate the (E)-isomer to avoid nonbonding
enantioselectivities were observed in the addition of N-methylindole
interactions between the substrate olefin and the tert-butyl group.
to (E)-crotonaldehyde using imidazolidinone catalyst 1 (eq 2, 56%
As a result, the benzyl group on the catalyst framework will
ee, 83% yield after 48 h). In an effort to overcome this limitation
in indole reactivity, we embarked upon studies to identify a more
reactive amine catalyst that might enable less electron-rich het-
effectively shield the si-face of the activated olefin, leaving the
re-face exposed to indole addition.
Catalyst Application. As revealed in Table 1, the enantiose-
eroaromatics to undergo Friedel-Crafts alkylation. In this context,
lective alkylation of N-methylindole with (E)-crotonaldehyde using
we report the development of a new imidazolidinone catalyst 2
the tert-butyl-benzyl imidazolidinone catalysts 2a and 2b provided
the benzylic substituted indole (R)-5 with high levels of enanti-
oselectivity and reaction efficiency (entries 1 and 2, 1.5-4 h, g70%
yield, g85% ee). An enantioselectivity/temperature profile docu-
ments that optimal enantiocontrol is available at -83 °C with
catalyst 2a (entry 5, 84% yield, 92% ee). A survey of solvent
additives reveals that the use of i-PrOH (15% v/v in CH2Cl2) has
a dramatic influence on reaction rate without loss in enantiocontrol
(entry 6, 92% ee, 19 h). The superior levels of asymmetric induction
and efficiency exhibited by 2a to afford the substituted indole (R)-5
and its application to the first enantioselective organocatalytic indole
alkylation.8
Design of Catalyst 2. Preliminary kinetic studies have indicated
that the overall rates of iminium-catalyzed reactions are influenced
by the efficiency of both the initial iminium formation step and
the carbon-carbon bond-forming event. As such, we hypothesized
that catalyst 2 (MM3-2)9 should exhibit improved efficiency for
iminium formation and hence increased overall rate as the
participating nitrogen lone pair is positioned away from structural
impediment (cf. MM3-1, CH3-lone pair eclipsing orientation).
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1172 VOL. 124, NO. 7, 2002 J. AM. CHEM. SOC.
10.1021/ja017255c CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Effect of Cocatalyst and Temperature on the Alkylation of
N-Methylindole with Crotonaldehyde with Catalyst 2
Table 3. Enantioselective Organocatalyzed Alkylation of
Representative Indoles with (E)-Crotonaldehyde
entry
catalyst
cocatalyst
temp °C
time (h)
% yield
% eea,b
indole substituents
entry
R
Y
Z
temp (°C)
time (h)
% yield
% eea
1
2
3
4
5
6
2a
2b
2c
2b
2a
2a
TFA
p-TSA
-40
-40
-40
-83
-83
-83
1.5
4
22
48
31
19
70
98
88
15
84
82
85
88
88
80
92
92c
1
2
3
4
5
6
7
Me
H
H
H
H
H
H
H
Cl
H
H
-87
-60
-72
-60
-60
-87
-60
19
22
20
120
3
19
13
82
72
70
80
94
90
73
92b
91b
92
2-NO2PhCO2H
p-TSA
allyl
CH2Ph
H
H
89b
94c
96c
97c
TFA
TFA
H
Me
OMe
H
Me
H
a Product ratios determined by chiral HPLC. b Absolute configuration assigned
by chemical correlation to a known compound. c Reaction conducted with
CH2Cl2-i-PrOH (85:15 v/v) as solvent.
a Product ratios determined by chiral HPLC. b Absolute configuration deter-
mined by chemical correlation. c Reaction conducted with (E)-BzOCH2CHd
CHCHO.
Table 2. Organocatalyzed Alkylation of N-Methylindole with
Representative R,â-Unsaturated Aldehydes
procedure reveals that complex enantioenriched drug leads can be
rapidly accessed using this new organocatalytic protocol.
entry
R
temp °C
time (h)
% yield
% eea
1
2
3
4
5
6
Me
Pr
-83
-60
-50
-83
-55
-83
19
6
32
18
45
21
82
80
74
84
84
89
92b
93
i-Pr
93
CH2OBz
Ph
CO2Me
96b
90
91
a Product ratios determined by chiral HPLC. b Absolute configuration deter-
mined by chemical correlation.
In summary, we have further established LUMO-lowering
organocatalysis as a broadly useful concept for asymmetric synthesis
in the context of Friedel-Crafts indole alkylation. A full account
of this survey will be forthcoming.
in 92% ee and 82% yield prompted us to select this catalyst for
further exploration.
Experiments that probe the scope of the R,â-unsaturated aldehyde
substrate are summarized in Table 2. The reaction appears quite
tolerant with respect to the steric contribution of the olefin
substituent (R ) Me, Pr, i-Pr, CH2OBz, entries 1-4, g74% yield,
g92% ee). As revealed in entries 5 and 6, the reaction can
accommodate electron-deficient aldehydes that do not readily
participate in iminium formation (R ) CO2Me, 91% ee) as well as
stabilized iminium ions that might be less reactive toward Friedel-
Crafts alkylation (R ) Ph, 90% ee). To demonstrate preparative
utility, the addition of N-methylindole to crotonaldehyde was
performed on a 25 mmol scale with catalyst 2a to afford (R)-5 in
92% ee and 81% yield.
This amine-catalyzed conjugate addition is also general with
respect to indole architecture (Table 3). Variation in the N-
substituent (R ) H, Me, CH2Ph, allyl, entries 1-4) is possible
without significant loss in yield or enantioselectivity (g70% yield,
89-92% ee). Incorporation of alkyl and alkoxy substituents at the
C(4)-indole position reveals that electronic and steric modification
of the indole ring can be accomplished with little influence on
reaction selectivity (entries 5 and 6, g90% yield, 94% ee). As
revealed in entry 7, we have successfully utilized electron-deficient
nucleophiles in the context of a 6-chloro substituted indole (73%
yield, 97% ee). Such halogenated indole adducts should prove to
be valuable synthons for use in conjunction with organometallic
technologies (e.g., Buchwald or Hartwig,11 Stille12 couplings).
A demonstration of the utility of this organocatalytic alkylation
is presented in the synthesis of the indolobutyric acid 6 (eq 3), a
COX-2 inhibitor developed in association with the Merck rofecoxib
campaign.13 As outlined in eq 3, organocatalytic alkylation of the
5-methoxy-2-methylindole 7 with crotonaldehyde followed by
oxidation of the formyl moiety provides the COX-2 inhibitor 6 in
87% ee and in 82% yield over two steps. This operationally trivial
Acknowledgment. Financial support was provided by kind gifts
from Astra-Zeneca, Dupont, GlaxoSmithKline, Johnson and Johnson,
Materia, Merck Research Laboratories and Roche Biosciences. We
also thank Great Lakes for their generous donation of (S)-
phenylalanine.
Supporting Information Available: Experimental procedures and
spectral data for all compounds (PDF). See any current masthead page
for ordering information and Web access instructions.
References
(1) For lead references, see: ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H. Eds; Springer: Heidelberg, 1999.
(2) Based on a survey of the Beilstein database.
(3) For lead references, see: Kleeman, A.; Engel, J.; Kutscher, B.; Reichert,
D. Pharmaceutical Substances, 4th ed.; Thieme: New York, 2001.
(4) For example, oxitriptan: Schering AG. Pat. Appl. 6.10.1971.
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40, 160. (b) Johannsen, M. Chem. Commun. 1999, 2233.
(9) Monte Carlo simulation, MM3 force-field; Macromodel V6.5.
(10) As the two geometric iminium isomers will likely lead to enantiomeric
products, we felt it essential that the catalyst architecture should enforce
the selective formation of one iminium isomer.
(11) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413.
(b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
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Leblanc, Y.; Mancini, J.; Ouellet, M.; Percival, D.; Roy, P.; Skorey, K.;
Tagari, P.; Vickers, P.; Wong, E.; Xu, L.; Prasit, P. Bioorg. Med. Chem.
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