A peptide-catalyzed asymmetric Stetter reaction

Article abstract of DOI:10.1039/b414574g

Thiazolylalanine, in appropriately functionalized form, has been found to function as an enantioselective catalyst for an intramolecular Stetter reaction. Incorporation of the residue in a number of environments has resulted in a family of catalysts that

Full text of DOI:10.1039/b414574g

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A peptide-catalyzed asymmetric Stetter reaction{
Steven M. Mennen, Jarred T. Blank, Michelle B. Tran-Dube´, Jason E. Imbriglio and Scott J. Miller*
Received (in Corvallis, OR, USA) 20th September 2004, Accepted 2nd November 2004
First published as an Advance Article on the web 29th November 2004
DOI: 10.1039/b414574g
Our studies began with an examination of the intramolecular
Stetter cyclization depicted in eqn. 2 (Table 1). In terms of a
catalyst scaffold, we examined simple derivatives of Taz in order to
establish whether or not the single residue would provide a
catalytically active substructure. To our surprise, simple derivatives
of the single amino acid (4a–f) proved to afford appreciable
selectivity in the cyclization. When catalyst 4a was employed under
optimized conditions (20 mol%, see Table 1), a modest selectivity
of 42% ee was observed in the product, which was isolated in low
yield. Of note, when the urethane nitrogen was alkylated as in
catalyst 4b, the enantioselectivity was completely eroded (,5% ee).
The nature of the nitrogen protecting group was also found to
have a considerable effect on selectivity. For example, exchange of
BOC for acetyl resulted in an increase in both yield and selectivity
(catalyst 4c, 63% ee, 38% isolated yield). Examination of tosyl
amides also provided an improvement with catalyst 4d delivering
70% ee at low conversion. The quaternizing agent was also found
to play a significant role in the performance of the catalyst. For
example, the methyl thiazolium salt 4f delivered similar results
(73% ee, 10% yield). On the other hand, quaternization with benzyl
(4e) affords a catalyst that delivers the product with 80% ee, and
an improved level of efficiency such that the product may be
isolated in 40% yield.
Thiazolylalanine, in appropriately functionalized form, has
been found to function as an enantioselective catalyst for an
intramolecular Stetter reaction. Incorporation of the residue in
a number of environments has resulted in a family of catalysts
that promote the cyclization of a test substrate with up to 81%
enantiomeric excess.
The range of reactions that may be catalyzed by simple organic
molecules, including peptides, is undergoing an expansion.1 His-
torically, among the early examples of this strategy in asymmetric
catalysis are those that stem from acyl anion catalysis in the
context of the biomimetic study of thiamine-dependent enzymes.
Following the pioneering studies of Breslow2 and Sheehan,3 highly
selective catalysts based on triazolium-derived catalysts have been
documented in the context of both the benzoin (eqn. 1) and Stetter
reactions (eqn. 2) by Enders4 and Rovis.5 Our interest in this area
stems from the study of families of peptides that might be suitable
catalysts for a range of organic reactions.6 In this context, we have
initiated a study of thiazolylalanine (Taz)7 derivatives as catalysts
for reactions in the benzoin and Stetter classes.
ð1Þ
ð2Þ
We have previously documented that histidine-derived peptides
(3) may function as catalysts for a range of enantioselective
reactions including acylation,8 phosphorylation,9 azide conjugate
addition,10 the Morita–Baylis–Hillman process11 and sulfinyl
transfer.12 We speculated that the scope of these catalysts might
be extended by the exchange of imidazole for thiazolium as in
catalyst family 4.
We next sought to improve upon the efficiency of the reaction in
terms of both yield and overall selectivity. In order to do so, we
sought to embed Taz in an appropriate scaffold such that
selectivity and conversion would improve. We suspected, based on
Table 1 Results of Stetter cyclization (eqn. 2) with catalysts 4a–4fa
Entry
R1
R2
R3
R4/X2
Ee (%)
Yield
1, 4a
2, 4b
3, 4c
4, 4d
5, 4e
6, 4f
a
MeO
MeO
MeO
MeO
MeO
MeO
H
Me
H
H
H
Boc
Boc
Ac
Ts
Ts
Ts
Et/I2
Et/I2
Et/I2
Et/I2
Bn/Br2
Me/I2
42
0
63
70
80
73
,10
11
38
10
40
,10
H
Each reaction was performed in CH2Cl2 with 20 mol% catalyst and
100 mol% DIPEA. Reactions were run for 48 at uC.
h
4
{ Electronic supplementary information (ESI) available: experimental
section and analytical data. See http://www.rsc.org/suppdata/cc/b4/
b414574g/
Enantioselectivities were determined by chiral HPLC and yields refer
to the mass of isolated, pure compound after silica gel
chromatography.
*scott.miller.1@bc.edu
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Chem. Commun., 2005, 195–197 | 195

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Table 2 Results of Stetter cyclizations with catalysts 5a–5d
Table 4 Results of Stetter cyclizations (eqn. 3) with substrates 8a–8e
Entrya
Pro
AA
a-(Me)Bn
R2/X2
Ee (%)
Yield
Ee (%)
(0.25 M)
Yield
(0.25 M)
Ee (%)
(0.4 M)
Yield
(0.4 M)
Entrya
R
1, 5a
2, 5b
3, 5c
4, 5d
a
L
(R)
(S)
(R)
(S)
Et/I2
Et/I2
Et/I2
Et/I2
14
15
21
18
15
17
14
11
D-Val
D-Val
L-Val
L-Val
1, 8a
2, 8b
3, 8c
4, 8d
5, 8e
a
5-Me
3-Me
5-MeO
4-MeO
5-NO2
72
73
69
73
0
32
45
13
17
78
75
69
64
76
0
45
43
47
39
88
L
D
D
Each reaction was performed in CH2Cl2 with 20 mol% catalyst and
100 mol% DIPEA. Reactions were run for 48 at 25 uC.
h
See legend for Table 2.
Enantioselectivities were determined by chiral HPLC and yields refer
to the mass of isolated, pure compound after silica gel
chromatography. See ESI.
allowed isolation of 2 with up to 73% ee and 67% isolated yield
(Table 3).
literature precedent, that one of the problems with the single
amino acid catalysts was that catalyst decomposition occurs
when the thiazolium-derived carbene is not sufficiently protected
from dimerization.13 We then chose incorporation of Taz into
peptide sequences that might (a) provide steric hindrance to
inhibit decomposition, and (b) provide conformational control
over enantioselectivity. In order to explore these questions,
several Taz-derived peptide catalysts were examined. Catalysts
wherein Taz was located at the N-terminal position (5a–5d)
were compared to those where Taz was inserted at the C-terminal
end (6a–6d).
We then wished to establish the role of substrate structure on
reaction selectivity (Table 4, eqn. 3, 8a–e). While enantioselec-
tivities using catalyst 7e were similar with a range of electron
donating substituents in various positions (8a–8d: 69–73% ee),
yields were modest under standard conditions (17–45%). However,
increasing the concentration from 0.25 M in the substrate to 0.4 M
produced higher yields, albeit with the sacrifice of selectivity.
Finally, we have noted that electron withdrawing substituents lead
to products with low ee, in part due to product racemization under
the reaction conditions.14
The results for the two families of catalysts suggested that
embedding Taz in a peptide could provide enhancements in
catalyst stability, but that improvements in % ee were less
readily observed. As indicated in Table 2, a representative set of
catalysts that had variations in residue stereochemical configura-
tion, side-chain identity, and N-terminal protecting group was
synthesized and screened. Notably, the stereochemical identity
of the C-terminal amide substituent plays a minimal role in
dictating enantioselectivity. In each case, enantioselectivity was
reduced in comparison to the modified single Taz-residue (ee: 11%
to 17%). A similar result was obtained upon screening catalysts
6a–6d. With this group, enantioselectivities still remained unac-
ceptably low.
(3)
It is interesting to note that in terms of enantioselectivity, we
have not yet found a catalytic Taz-peptide that is significantly
better than those related to 4d–4f. X-Ray structural analysis of 4f
reveals that there may be a compact structure for the catalyst that
contributes to a stereo defined environment (Fig. 1).15
In summary, we have demonstrated that appropriately function-
alized Taz derivatives may be used to catalyze an enantioselective
Stetter reaction. Future studies will endeavor to optimize the
catalysts and the scope of their functions.16
On the other hand, incorporation of Taz in an internal position
within a small peptide did allow us to observe significant
enantioselectivity, while retaining some improvement in the
isolated yield of 2. For example, catalysts in family 7 have
Table 3 Results of Stetter cyclizations with catalysts 7a–7e
Entrya
a-Nap
R
Ee (%)
Isolated yield
1, 7a
2, 7b
3, 7c
4, 7d
5, 7e
a
R
S
S
S
S
55
81
80
65
73
20
20
28
22
67
L-Phe
D-Phe
L-Phe
L-Val
L-Thr(Bn)
See legend for Table 2.
Fig. 1 X-Ray structure for catalyst 4f.
196 | Chem. Commun., 2005, 195–197
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Steven M. Mennen, Jarred T. Blank, Michelle B. Tran-Dube´,
Jason E. Imbriglio and Scott J. Miller*
8 G. T. Copeland and S. J. Miller, J. Am. Chem. Soc., 2001, 123,
6496–6502.
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, MA, 02467, USA. E-mail: scott.miller.1@bc.edu;
Fax: +1 617-552-2473; Tel: +1 617-552-3620
9 (a) B. R. Sculimbrene and S. J. Miller, J. Am. Chem. Soc., 2001, 123,
10125–10126; (b) B. R. Sculimbrene, A. J. Morgan and S. J. Miller,
J. Am. Chem. Soc., 2002, 124, 11653–11656; (c) B. R. Sculimbrene,
A. J. Morgan and S. J. Miller, Chem. Commun., 2003, 1781–1785.
10 D. J. Guerin and S. J. Miller, J. Am. Chem. Soc., 2002, 124, 2134–2136.
11 J. E. Imbriglio, M. M. Vasbinder and S. J. Miller, Org. Lett., 2003, 5,
3741–3743.
12 J. W. Evans, M. B. Fierman, S. J. Miller and J. A. Ellman, J. Am.
Chem. Soc., 2004, 126, 8134–8135.
13 Y.-T. Chen and F. Jordan, J. Org. Chem., 1991, 56, 5029–5038.
14 We have shown that resubmission of optically enriched 3 (RLNO2) to
the reaction conditions leads to a reduction in ee of the product over
time.
Notes and references
1 (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43,
5138–5175; (b) E. R. Jarvo and S. J. Miller, Tetrahedron, 2002, 58,
2481–2495; (c) Acc. Chem. Res., 2004, 37, Special Issue.
2 (a) R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719–3726; (b) R. Breslow
and R. Kim, Tetrahedron Lett., 1994, 35, 699–702; (c) R. Breslow and
C. Schmuck, Tetrahedron Lett., 1996, 37, 8241–8242.
3 (a) J. C. Sheehan and D. H. Hunneman, J. Am. Chem. Soc., 1966, 88,
3666–3667; (b) J. C. Sheehan and T. Hara, J. Org. Chem., 1974, 39,
1196–1199.
4 D. Enders and T. Balensiefer, Acc. Chem. Res., 2004, 37, 534–541.
5 (a) M. S. Kerr, J. R. de Alaniz and T. Rovis, J. Am. Chem. Soc., 2002,
124, 10298–10299; (b) M. S. Kerr and T. Rovis, Synlett, 2003, 12,
1934–1936.
15 Crystal data for 4f: C15H19IN2O4S2, M 5 482.34, triclinic, a 5 7.2693(6)
˚
˚
˚
A, a 5 80.624(2)u, b 5 7.7618(7) A, b 5 72.296(2)u, c 5 8.7263(7) A,
3
˚
c 5 85.313(2)u, U 5 462.51(7) A , T 5 193(2) K, space group P1, Z 5 1,
m 5 1.978 mm21, 3450 reflections collected (R1 5 0.0190, wR2 5 0.0477),
2761 independent reflections (R(int) 5 0.0300, R1 5 0.0190,
wR2 5 0.0477){.
16 This work was supported by the U.S. National Science Foundation
(CHE-0236591). We are grateful to Merck and Pfizer for additional
support, and to Synthetech (Albany, OR) for a generous donation of
Taz.
6 S. J. Miller, Acc. Chem. Res., 2004, 37, 601–610.
7 B. Imperiali, K. A. McDonnell and M. Shogren-Knaak, Top. Curr.
Chem., 1999, 202, 1–38.
{ CCDC 251033. See http://www.rsc.org/suppdata/cc/b4/b414574g/ for
crystallographic data in .cif or other electronic format.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 195–197 | 197