Mining Sequence Space for Asymmetric Aminocatalysis: N-Terminal Prolyl-Peptides Efficiently Catalyze Enantioselective Aldol and Michael Reactions

Article abstract of DOI:10.1055/s-2003-41490

N-Terminal prolyl-peptides efficiently catalyze asymmetric aldol and Michael reactions between acetone and p-nitrobenzaldehyde or β-nitrostyrene, respectively.

Full text of DOI:10.1055/s-2003-41490

CLUSTER
1901
Mining Sequence Space for Asymmetric Aminocatalysis: N-Terminal Prolyl-
Peptides Efficiently Catalyze Enantioselective Aldol and Michael Reactions
N
-
T
erminal
Prolyl
a
Peptides as
r
Catalys
r
ts in
O
rg
y
anic
S
olvents J. Martin, Benjamin List*1
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Fax +1(858)7847028; E-mail: blist@scripps.edu.
Received 28 February 2003
less efficient than that by proline, and that it provides the
Abstract: N-Terminal prolyl-peptides efficiently catalyze asym-
product in only 20% ee.
metric aldol and Michael reactions between acetone and p-nitro-
benzaldehyde or b-nitrostyrene, respectively.
Next, we found the same peptides to also catalyze direct
asymmetric Michael reactions between acetone and trans-
b-nitrostyrene with good results (Table 2). Here, enanti-
oselectivities of up to 31% were observed. Though still
modest, these enantioselectivities constitute a significant
improvement over the 7% ee realized in the corresponding
proline-catalyzed reaction.
Key words: organocatalysis, enamine catalysis, aminocatalysis,
peptides
Enantioselective organocatalysis with amines, also
termed asymmetric aminocatalysis, is a useful strategy for
several important carbonyl reactions.2 Among the
catalysts studied so far, the amino acid proline has
arguably been the most successful in enamine involving
reactions.3–6 Its popularity is based on the efficiency and
stereoselectivity often encountered in proline-catalyzed
reactions and on its inexpensive and non-toxic nature.
Despite these attractive features, there is still room for
improvement. For example, potentially useful donors
such as acetaldehyde7 and acetophenone8 can not readily
be used, stereoselectivities and yields can be sub-optimal,
and a-unbranched aldehydes are notorious acceptors in
proline-catalyzed aldol reactions.4c In addition, there are
several interesting enamine involving reactions that can
not be catalyzed by proline. To address these
shortcomings, a readily available and diversifiable
substance-class from which improved enamine catalysts
could be selected is highly desirable. Here we show for
the first time that N-terminal prolyl-peptides efficiently
catalyze asymmetric aldol and Michael reactions.
Pioneered by Miller9 and Jacobsen10 catalytic peptides
and peptide-like molecules were recently introduced as
asymmetrc catalysts.11 Their structural and chemical
diversity, accessibility, and inherent chirality could make
them ideal asymmetric organocatalysts for a variety of
reactions. We speculated that the infinite sequence space
of N-terminal prolyl peptides might be a good source for
the discovery of novel enamine catalysts. To test this
hypothesis we have studied di- and tripeptide-catalyzed
aldol reactions of acetone with p-nitrobenzaldehyde. To
our delight, we found all tested peptides to show efficient
catalytic activity producing the aldol product in good
yields (62–90%) and enantioselectivities (31–77%,
Table 1). These results are particularly remarkable in light
of the observation that catalysis by proline amide is much
Table 1 Peptide-Catalyzed Aldol Reactions
O
O
O
OH
Cat (30 mol %)
DMSO, 18 h (rt)
NO2
+
H
NO2
Entry
Catalyst
Yield (%)a
ee (%)b
76
1
2
Pro-OH
68
90
77
75
72
89
91
87
62
68
85
Pro-Ala
70
3
Pro-Trp
65
4
Pro-Asp
74
5
Pro-Glu
68
6
Pro-Val
70
7
Pro-Arg
31
8
Pro-Ser
77
9
Pro-Lys·HCl
Pro-Gly-Gly
Pro-His-Ala
66
10
11
53
56
a Yields were determined by preparative TLC. As the major side prod-
uct the aldol condensation product has been identified.
b Enantiomeric excess (ee) values were determined from chiral sta-
tionary-phase HPLC analysis.
In conclusion we show that N-terminal prolyl peptides are
promising asymmetric aminocatalysts. Although only
modest enhancements compared to proline catalysis were
realized so far, our results suggest that screening larger li-
braries of N-terminal prolyl peptides could provide effec-
tive catalysts with improved enantioselectivities and
yields.12 In addition we expect N-terminal prolyl peptides
SYNLETT 2003, No. 12, pp 1901–1902
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Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41490; Art ID: Y00103ST
© Georg Thieme Verlag Stuttgart · New York

1902
H. J. Martin, B. List
CLUSTER
(2) For some recent reviews and highlights, see: (a) Gröger, H.;
Wilken, J. Angew. Chem. Int. Ed. 2001, 40, 529. (b) Dalko,
P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726.
(c) List, B. Synlett 2001, 1675. (d) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481. (e) List, B. Tetrahedron 2002,
58, 5572. (f) Borman, S. Chem. Eng. News 2002, 80(50),
35. (g) Movassaghi, M.; Jacobsen, E. N. Science 2003, 298,
1904. (h) Paraskar, A. S. Synlett 2003, 582.
Table 2 Peptide-Catalyzed Michael Reactions
O2N
NO2
O
O
Cat (30 mol %)
DMSO, 36 h (rt)
+
Entry
Catalyst
Yield (%)a
ee (%)b
(3) (a) Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623,
1971. (b) Eder, U.; Sauer, G.; Wiechert, R. German Patent
DE 2014757, 1971. (c) Eder, U.; Sauer, G.; Wiechert, R.
Angew. Chem., Int. Ed. Engl. 1971, 10, 496. (d) Hajos, Z.
G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (e)Related
enantiogroup-differentiating aldol cyclodehydrations have
been described, see: Agami, C.; Platzer, N.; Sevestre, H.
Bull. Soc. Chim. Fr. 1987, 2, 358.
(4) For the first proline-catalyzed asymmetric intermolecular
aldol, Mannich-, Michael-, and a-amination reactions, see
(a) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
2000, 122, 2395. (b) Notz, W.; List, B. J. Am. Chem. Soc.
2000, 122, 7386. (c) List, B.; Pojarliev, P.; Castello, C. Org.
Lett. 2001, 3, 573. (d) List, B. J. Am. Chem. Soc. 2000, 122,
9336. (e) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J.
J. Am. Chem. Soc. 2002, 124, 827. (f) List, B.; Pojarliev, P.;
Martin, H. J. Org. Lett. 2001, 3, 2423. (g) List, B. J. Am.
Chem. Soc. 2002, 124, 5656.
(5) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798. (b) Cordova, A.; Watanabe, S.; Tanaka, F.;
Notz, W.; Barbas, C. F. III J. Am. Chem. Soc. 2002, 124,
1866. (c) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K.
A. Chem. Commun. 2002, 620. (d) Bøgevig, A.; Juhl, K.;
Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 1790. (e) Halland, N.;
Aburel, P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2003,
42, 661. (f) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett
2001, 1245.
1
2
Pro-OH
97
71
68
75
91
65
65
81
66
79
70
7
Pro-Ala
5
3
Pro-Trp
0
4
Pro-Asp
Pro-Glu
3
5
8
6
Pro-Val
31
19
8
7
Pro-Arg
8
Pro-Ser
9
Pro-Lys·HCl
Pro-Gly-Gly
Pro-His-Ala
8
10
11
10
7
a Yields were determined by preparative TLC. No side products have
been identified.
b Enantiomeric excess (ee) values were determined from chiral sta-
tionary-phase HPLC analysis.
to become useful catalysts for a variety of other important
aminocatalytic transformations.
(6) For pioneering experiments on enantioselective iminium
catalysis, see: Brown, S. P.; Goodwin, N. C.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2003, 125, 1192; and references
therein.
(7) Córdova, A.; Notz, W.; Barbas, C. F. III J. Org. Chem. 2002,
67, 301.
Acknowledgment
Support by the NIH (GM-63914) is gratefully acknowledged. We
thank William T. Biller for technical assistance.
(8) For the only exception, see: Enders, D.; Seki, A. Synlett
2002, 26.
(9) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus,
P. J. Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638.
(10) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2000, 39, 1279.
References
(1) New Address: Max-Plank-Institut für Kohlenforschung,
45470 Mülheim an der Ruhr, Germany.
E-mail: list@mpi-muelheim-mpg.de
(11) For the use of peptide-derived ligands in asymmetric
transition metal catalysis, also see: Luchaco-Cullis, C. A.;
Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2001, 40, 1456; and references therein.
(12) After this manuscript has been accepted for publication,
related results were reported by: Kofoed, J.; Nielsen, J.;
Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445.
Synlett 2003, No. 12, 1901–1902 © Thieme Stuttgart · New York