Weak Bronsted acid-thiourea co-catalysis: Enantioselective, catalytic protio-pictet-spengler reactions

Article abstract of DOI:10.1021/ol802887h

The development of one-pot imine formation and asymmetric Pictet-Spengler reactions cocatalyzed by a chiral thiourea and benzoic acid is described. Optically active tetrahydro-β-carbolines, ubiquitous structural motifs in biologically active natural produ

Full text of DOI:10.1021/ol802887h

ORGANIC
LETTERS
2009
Vol. 11, No. 4
887-890
Weak Brønsted Acid-Thiourea
Co-catalysis: Enantioselective, Catalytic
Protio-Pictet-Spengler Reactions
Rebekka S. Klausen and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
jacobsen@chemistry.harVard.edu
Received December 15, 2008
ABSTRACT
The development of one-pot imine formation and asymmetric Pictet-Spengler reactions cocatalyzed by a chiral thiourea and benzoic acid is
described. Optically active tetrahydro-ꢀ-carbolines, ubiquitous structural motifs in biologically active natural products, are obtained in high ee
directly from tryptamine and aldehyde precursors.
The Pictet-Spengler reaction is an important biosynthetic
and laboratory method for the synthesis of tetrahydroiso-
quinolines and tetrahydro-ꢀ-carbolines, structural motifs in
a diverse array of biologically active natural and unnatural
products.1,2 Whereas synthetically valuable diastereoselective
Pictet-Spengler reactions are well-known,3 catalytic, enan-
tioselective variants have only recently been developed.4
Chiral Lewis acids have not proven to be generally useful
for the Pictet-Spengler reaction, a likely result of catalyst
inhibition by the Lewis basic product.5 Greater success has
been achieved with Brønsted acid or hydrogen bond donor
catalysts, albeit with specialized substrates.6 Thus, asym-
metric catalysis of Pictet-Spengler-type reactions has been
reported with N-acyliminium ions4a or N-sulfenyliminium
ions4b or with substrates biased toward cyclization and
against competing aldol pathways by gem-disubstitution
adjacent to the reactive imine.4c An enantioselective, catalytic
Pictet-Spengler protocol with broad substrate scope that
affords unprotected tetrahydro-ꢀ-carboline products directly
from simple tryptamine derivatives would represent a
significant advance.
We have recently advanced a mechanistic model for
asymmetric catalysis by thiourea derivatives in which
(4) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558–10559. (b) Wanner, M. J.; van der Haas, R. N. S; de Cuba, K. R.;
van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485–
7487. (c) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
1086–1087. (d) Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de Gelder,
R.; van Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2008, 73, 6405–
6408.
(1) (a) Maresh, J. J.; Giddings, L.-A.; Friedrich, A.; Loris, E. A.; Panjikar,
S.; Trout, B. L.; Stockigt, J.; Peters, B.; O’Connor, S. E. J. Am. Chem.
Soc. 2008, 130, 710–723. (b) Luk, L. Y. P.; Bunn, S.; Liscombe, D. K.;
Facchini, P. J.; Tanner, M. E. Biochemistry 2007, 46, 10153–10161
(2) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797–1842
.
.
(3) For examples of diastereoselective Pictet-Spengler reactions of
tryptophan derivatives and applications to total synthesis, see: (a) Zhou,
H.; Liao, X.; Cook, J. M. Org. Lett. 2004, 6, 249–252, and references therein.
For an example of a diastereoselective Pictet-Spengler reaction of a
tryptamine and a chiral aldehyde, see: (b) Yamashita, T.; Kawai, N.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2005, 127, 15038–15039.
(c) For a complete list of methods for the preparation of enantioenriched
tetrahydro-ꢀ-carbolines, see the Supporting Information.
(5) Superstoichiometric amounts of diisopinocampheylchloroborane
(Ipc2BCl) promote Pictet-Spengler reactions of N-ꢀ-hydroxytryptamines.
Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi, K.;
Nakagwawa, M. J. Org. Chem. 1998, 63, 6348–6354.
(6) (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520–1543. (b) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713–
5743.
10.1021/ol802887h CCC: $40.75
Published on Web 01/29/2009
2009 American Chemical Society

tion given the prevalence of methoxy- and hydroxy-
substituted tetrahydro-ꢀ-carbolines in natural products.10
Moreover, elevated temperatures (>-30 °C) were required
for acyl-Pictet-Spengler reactions of aryl imines, conditions
under which the thiourea catalyst was subjected to decom-
position via rapid S-acetylation. We reasoned that greater
generality in the imine component would be possible in a
nonacylative reaction. Imine 2a was screened against a
variety of representative thiourea catalysts11 and achiral
Brønsted acids. In combination with acetic acid (AcOH),
catalysts 4a12 and 7a13 provided tetrahydro-ꢀ-carboline 3a
in high yield and 85% and -87% ee, respectively (Scheme
2). Notably, no product was observed in the absence of
AcOH.
These initial results were obtained at room temperature,
conditions under which imine formation is rapid. We
therefore explored an operationally simpler protocol involv-
ing one-pot imine formation and thiourea-catalyzed Pictet-
Spengler reaction. Treatment of tryptamine 9a and p-chloro-
benzaldehyde with catalyst 4a in toluene provided product
3a in 88% ee and 54% yield (Table 1, entry 1). In contrast,
sulfinamide 7a was a poor catalyst under in situ imine
formation conditions, providing product in only 13% yield.
A systematic evaluation of the influence of catalyst structure
on both enantioselectivity and rate revealed that valine-
derived catalyst 4b afforded optimal results (entry 2).14 This
simple compound is prepared in 69% yield in three steps
from commercially available N-methylbenzylamine and
either D- or L-valine; only a single chromatographic purifica-
tion is required. A screen of carboxylic acids revealed an
increase in both enantioselectivity and rate with benzoic acid
(PhCO2H) (entry 2 vs 4).15 Under the in situ imine-formation
conditions, highest yields and enantioselectivities were
obtained in reactions carried out at lower concentration
(entries 4-6).
Figure 1. Generation of N-acyliminium ion via anion binding by
a thiourea catalyst.
substrate activation takes place via thiourea-mediated chloride
abstraction to generate highly reactive N-acyliminium ions
or oxocarbenium ions (Figure 1).7 This hypothesis suggests
that a variety of other cationic intermediates, including
protioiminium ions, could be activated toward enantioselec-
tive addition by analogous anion-binding mechanisms. In
particular, we envisaged a catalytic cycle in which imine
protonation is induced by a thiourea catalyst associated via
H-bonding to the conjugate base of a weak Brønsted acid
additive (Scheme 1).8 Cyclization of the highly reactive
protioiminium ion followed by rearomatization would re-
generate the Brønsted acid cocatalyst. Herein, we report that
chiral thiourea derivatives in combination with benzoic acid
promote catalytic asymmetric Pictet-Spengler reactions of
electronically and sterically diverse imines, providing un-
protected tetrahydro-ꢀ-carbolines in high ee and yield.
Scheme 1. Brønsted Acid and H-Bond Donor Co-catalysis
A variety of substituted benzaldehyde derivatives proved
to be suitable substrates in combination with 9a, providing
tetrahydro-ꢀ-carboline products 3a-g in good to excellent
ee’s and yields (Table 2, entries 1-7). Substitution is
tolerated at all ring positions of the aldehyde, with the
shortest reaction times observed for ortho- and meta-
substituted derivatives (entries 3-5). Less electron-rich
tryptamines 9b and 9c also participated effectively in the
condensation/cyclization reaction (89-99% ee), although
(9) Four substrates: 44-86% ee. Taylor, M. S. Dissertation, Harvard
University, 2005.
(10) Examples of methoxy- and hydroxy-substituted indole alkaloids
include reserpine, tubulosine, and the eudimistin family of natural products.
Osorio, E. J.; Robledo, S. M.; Bastida, J. The Alkaloids, 1st ed.; Cordell,
G. A., Ed.; Academic Press: San Diego, CA, 2008; Vol. 66, Chapter 2, pp
149-159.
We selected 6-methoxytryptamine derivative 2a as a model
substrate. Methoxy-substituted tryptamine derivatives un-
dergo cyclization in low enantioselectivity in the previously
reported acyl-Pictet-Spengler reaction,9 a significant limita-
(11) The catalysts shown in Scheme 2are available from Sigma-
Aldrich.
(12) Catalysts analogous to 4a were first developed in the context of
enantioselective Mannich-type reactions. Wenzel, A. G.; Lalonde, M. P.;
Jacobsen, E. N. Synlett 2003, 12, 1919–1922.
(7) (a) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N.
J. Am. Chem. Soc. 2007, 129, 13404–13405. (b) Reisman, S. E.; Doyle,
A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198–7199.
(8) For an example of a nonstereoselective application of this principle
employing mandelic acid and achiral thiourea in the catalytic alcoholysis
of styrene oxides, see: Weil, T.; Kotke, M.; Kleiner, C. M.; Schreiner, P. R.
Org. Lett. 2008, 10, 1513–1516.
(13) Catalyst 7a promotes enantioselective allylation of acyl hydrazones.
Tan, K. L.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46, 1315–1317.
(14) For a complete description of catalyst screening and reaction
optimization, see the Supporting Information.
(15) Stronger acids, such as hydrogen chloride and methanesulfonic acid,
provided product in low yield and ee, potentially due to catalyst inhibition
due to protonation of the Lewis basic product.
888
Org. Lett., Vol. 11, No. 4, 2009

Scheme 2.
Screen of Representative (Thio)urea Catalystsa
a
1
Yield determined by H NMR on a 0.05 mmol scale. Enantioselectivity determined by chiral SFC analysis of the N-Boc derivative.
elevated acid loadings and temperatures and extended
reaction times were required to achieve useful product yields
(entries 8-10).
with 9a (entries 12-14). In contrast, less nucleophilic
tryptamines such as 9b and 9c were unreactive under neutral
conditions. The basis for this intriguing difference in
reactivity is not well understood at this stage. For substrates
such as 9b, use of acidic additive was necessary (e.g., entry
Aliphatic aldehydes displayed unexpected reactivity with
tryptamine 9a in protio-Pictet-Spengler cyclizations cata-
lyzed by 4b. Isobutyraldehyde underwent rapid reaction
under the conditions optimized for aromatic aldehydes,
affording product 3k in 60% conversion and 88% ee after
4 h at room temperature (entry 11). In contrast to aryl
substrates, however, cyclization was also observed in the
absence of PhCO2H. In fact, the enantioselectivity increased
to 94% in the absence of acid additive, although much longer
reaction times were required (entry 12). Both linear and
R-branched aldehydes participated effectively in cyclizations
Table 2. Substrate Scope of the Thiourea and Benzoic Acid
Catalyzed Pictet-Spengler Reaction
PhCO2H time yieldb eec
product (mol %) (h) (%) (%)
entry tryptamine
Ra
Table 1. Optimization Studies of the One-Pot Pictet-Spengler
1
2
3
4
5
9a
9a
9a
9a
9a
9a
9a
9b
9b
9c
9a
9a
9a
9a
9b
p-ClC6H4
p-FC6H4
p-BrC6H4
m-BrC6H4
o-BrC6H4
p-MeOC6H4
Ph
p-ClC6H4
o-BrC6H4
o-BrC6H4
i-Pr
3a
3b
3c
3d
3e
3f
3g
3h
3i
20
20
20
20
20
20
20
40
40
100
20
0
66 78
78 81
74 79
19 87
11 74
91 78
70 94
14 d 73
87 82
10 d 45
94
92
94
94
95
85
86
89
99
95
Reaction
6
7
8d
9d
10d
11
12
13
14
15d
3j
yielda (%)
eeb (%)
3k
3k
3l
3m
3n
4
60e 88
entry
catalyst
RCO2H
[9a] (M)
i-Pr
88 90
5 d 84
18 74
36 39
94
95
86
88
1
2
3
4
5
6
4a
4b
7a
4b
4b
4b
AcOH
AcOH
AcOH
PhCO2H
PhCO2H
PhCO2H
0.05
0.05
0.05
0.05
0.10
0.20
54
48
13
74
60
39
88
92
-79
94
93
92
CH(Et)2
n-pentyl
i-Pr
0
0
20
a All aldehydes were purified immediately prior to use. See the
Supporting Information for details. b Isolated yield after column chroma-
tography for 0.50 mmol scale reactions, unless noted otherwise. c Determined
by chiral SFC analysis of the N-Boc derivative. d Reaction carried out at
35 °C. e Yield determined by 1H NMR spectroscopy on a 0.05 mmol scale.
a Yield determined by 1H NMR spectroscopy on a 0.05 mmol scale.
b Determined by chiral SFC analysis of the N-Boc derivative.
Org. Lett., Vol. 11, No. 4, 2009
889

15), with reactions proceeding in high ee and in modest yield
due to the competitive aldol pathways.
Acknowledgment. This work was supported by the NIH
(GM-43214). We thank Mathieu Lalonde (Harvard Univer-
sity) for crucial, helpful discussions and Cristina Fernandez
(Harvard University) for experimental assistance.
We have identified a readily accessible chiral thiourea
catalyst that promotes highly enantioselective Pictet-Spengler
reactions for electronically and structurally diverse substrates
under mild and operationally simple conditions. This method
provides unprotected tetrahydro-ꢀ-carbolines in one step from
tryptamine and aldehyde derivatives. Our current efforts are
directed toward elucidation of the mechanism of co-catalysis
by achiral Brønsted acids and application of this principle
to other enantioselective reactions of synthetic interest.
Supporting Information Available: Complete experi-
mental procedures and characterization data for products and
isolated intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL802887H
890
Org. Lett., Vol. 11, No. 4, 2009