Cyclizations of α-keto ester modified aspartic acids in peptides

Article abstract of DOI:10.1055/s-2006-944203

Aspartic acid peptides with α-keto ester modification can cyclize to form γ-lactam derivatives. This reaction represents an easy access to conformationally restricted peptidomimetics. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944203

1
774
LETTER
Cyclizations of a-Keto Ester Modified Aspartic Acids in Peptides
C
W
yclizations of
a
-
KetoE
o
ster Modifie
l
d
A
spa
f
rtic
A
cid
g
s
inPeptide sa ng Seufert, Antoine Fleury, Bernd Giese*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2670976; E-mail: bernd.giese@unibas.ch
Received 20 April 2006
HO
Abstract: Aspartic acid peptides with a-keto ester modification can
cyclize to form g-lactam derivatives. This reaction represents an
easy access to conformationally restricted peptidomimetics.
H
N
H
O
CO2Bn
O
N
R1
R2
Key words: a-keto ester, cyclizations, g-lactams, diastereoselec-
tivity, peptidomimetics
O
BocHN
5
Recently we reported the synthesis of hydroxypyrrolidi-
nones 4 from aspartates 1. The reaction sequence started
hν
1
with the transformation of the side chain into an a-keto
ester 2 and subsequent photocyclization, where diradical
MeO2C
O
3
is an intermediate (Scheme 1). This new reductive
O
H
photocyclization was applied to aspartic acid derivatives
BocHN
N
CO2Bn
N
(
(
X = Boc) and to dipeptides with N-terminal amino acids
X = Boc-Gly or Boc-Pro).
H
R1
O
R2
6
–9
Et3N 76–90%
OH
CO2CH3
CO2CH3
O
O
HO
hν
CO2Me
OH
OH
CO Me
Ot-Bu
Ot-Bu
Ot-Bu
2
O
XHN
XHN
XN
O
+
CO2Bn BocHN
BocHN
N
N
CO2Bn
O
O
O
N
N
H
H
1
2
3
R1
R2
R1
R2
O
O
cis-10–13
trans-10–13
HO
–
6
CH2O
Scheme 2
1–91%
O
CO2t-Bu
N
X
4
Variation of the N-terminal amino acid had only a small
effect on the diastereoselectivity (Table 1).
Scheme 1 Reductive photocyclization of a-keto ester 2.
DFT calculations indicate that the C-terminal amino acids
in cis and trans products 11–13 adopt preferred 1,3-allylic
In order to use this cyclization reaction in larger peptides strain conformations A and B (Figure 1). The preference
we also attached an amino acid at the C-terminal end of of the cis-configured g-lactams 11–13 might be caused by
the substituted aspartate and were surprised to see, that the an intramolecular hydrogen bond between the OH group
photoreaction of tripeptides 6–9 did not yield 5 as main and the benzyl ester.6
2
product.
However, in the presence of triethylamine, a smooth
Table 1 Diastereoselectivities of the g-Lactams 10–13
cyclization to g-lactams 10–13 occurred in 76–90% yield
3
,4
R2
1
1
Educt
Product
R = H
cis/trans
57:43
87:13
94:6
R = CH
(
Scheme 2). The cis/trans ratio of the two diastereomers
3
depended on the size of the side chain of the C-terminal
cis/trans
52:48
92:8
5
amino acid. Thus, with glycine (6 → 10) no selectivity
was observed, whereas the bulky isopropyl group of
6
7
8
9
H
10
11
12
13
valine (9 → 13) strongly favored the cis diastereomer.
CH3
CH CH(CH )
2
3 2
SYNLETT 2006, No. 11, pp 1774–1776
1
2
.0
7
.2
0
0
6
CH(CH3)2
95:5
90:10
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944203; Art ID: D11206ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Cyclizations of a-Keto Ester Modified Aspartic Acids in Peptides
1775
CO2Me
OH
OH
N
larger peptides, for example heptamer 17. Ozonolysis in
the presence of methanol and cyclization of the obtained
a-keto ester with triethylamine finally yielded g-lactam
peptide 18 (Scheme 4). Using the Fmoc-protected deriva-
tive of 16 solid-phase peptide synthesis was also possible.
CO2Me
CO2Bn
R2
2
CO Bn
R2
+
N
XHN
XHN
O
A (cis)
H
O
H
B (trans)
CN
Figure 1 Preferred conformations of the g-lactams 11–13.
HO
Ph3P
O
O
(i)
Cyclizations also occur under slightly acidic conditions.7
For example, conversion of a-keto ester 7 with acidic
silica gel led to g-lactam 11, but with a reversed cis/trans
ratio of 20:80. Subsequent treatment with triethylamine
changed the cis/trans ratio to 87:13. These experiments
suggest that the cyclization products under basic condi-
tions, as described in Table 1, are formed under thermo-
dynamic control, whereas acidic silica gel induces kinetic
9
6%
OBn
OH
BocHN
BocHN
O
O
1
5
16
CN
Ph3P
O
O
H
(ii)
8
control with the trans isomer as preferred product. The
N
Boc-Phe-Ala-Gly-HN
NH-Ala-Phe-OBn
86%
favored formation of the trans diastereomer under kinetic
conditions might be explained by conformations 14b, in
which two carbonyl groups point into opposite directions.
Thus, the dipole moment of 14b should be smaller than
that of 14a (Scheme 3).
O
17
HO CO Me
2
O
N
OH
CO2Me
Boc-Phe-Ala-Gly-HN
NH-Ala-Phe-OBn
O
O
O
XHN
N CO Bn
2
XHN
NH
CO2Bn
18 (cis:trans = 80:20)
CO2Me
O
Scheme 4 Reagents and conditions: (i) a) Ph P=CHCN, EDC,
3
14a
cis-11
DMAP, CH Cl , 0 °C, 18 h; b) Pd/C, H , THF, 20 °C, 18 h; (ii) a) O ,
2
2
2
3
CH Cl , MeOH, –78 °C, 30 min; b) Et N, CH Cl , 20 °C, 30 min.
2
2
3
2
2
MeO2C
In summary, we report cyclization reactions of a-keto
ester modified aspartic acids in peptides. The diastereo-
selectivity of the obtained g-lactam peptides highly de-
pends on the amino acid sequence and the reaction
conditions. Applied to larger peptides, this cyclization
reaction represents an easy access to conformationally
restricted peptidomimetics.
O
H
N
CO2Bn
XHN
O
7
CO2Me
OH
O
Acknowledgment
CO2Me
XHN
N
CO2Bn
NH
CO2Bn
XHN
This work was supported by the Swiss National Science
Foundation.
O
O
14b
trans-11
References and Notes
Scheme 3 Transition states of the cyclization.
(
(
1) Obkircher, M.; Seufert, W.; Giese, B. Synlett 2005, 1182.
2) During this reaction at least four different products were
formed, with 5 only as a minor component.
The cyclization products 10–13 are peptidomimetics,
which are conformationally restricted because of the g-
lactam structure. The incorporation of lactams in peptides
often leads to significantly higher biological activity com-
(
3) General Cyclization Procedure.
The a-keto ester modified aspartic acid peptides 6–9 were
dissolved in 20 mL CH Cl . After addition of 2 mL Et N, the
2
2
3
9
solution was stirred for 30 min at r.t. The solvents were
evaporated and the residue purified by column
chromatography yielding g-lactams 10–13 as mixture of two
diastereomers.
pared to that of natural peptides. We therefore introduced
the g-lactam moiety into larger peptides by this cycliza-
tion strategy. The most efficient way was using the phos-
phoran-modified aspartic acid 16 as a building block,
which could be synthesized in two steps starting from the
partially protected aspartic acid 15. By standard peptide
coupling methods in solution, 16 was incorporated into
1
Spectroscopic Data for cis-13 (R = H) as an Example.
1
H NMR (500 MHz, CDCl ): d = 0.93 (d, J = 6.9 Hz, 3 H),
3
1.03 (d, J = 6.6 Hz, 3 H), 1.45 (s, 9 H), 2.14 (dd, J = 13.5, 9.3
Hz, 1 H), 2.74 (dsept, J = 9.6, 6.7 Hz, 1 H), 3.01 (dd,
Synlett 2006, No. 11, 1774–1776 © Thieme Stuttgart · New York

1
776
W. Seufert et al.
LETTER
J = 13.5, 8.9 Hz, 1 H), 3.48 (s, 3 H), 3.63 (d, J = 9.7 Hz, 1
H), 3.83–3.86 (m, 2 H), 4.53 (m, 1 H), 4.99 (s, 1 H), 5.08 (d,
J = 12.3 Hz, 1 H), 5.12 (d, J = 12.3 Hz, 1 H), 5.34 (br t, 1 H),
(5) The cis and trans refer to the relative configuration of the
amine and the hydroxy substituent. Assignment of the
diastereomers was made on the basis of NOESY
experiments.
1
3
7.06 (d, J = 5.7 Hz, 1 H), 7.30–7.37 (m, 5 H). C NMR (126
MHz, CDCl ): d = 20.1 (CH ), 21.0 (CH ), 27.8 (CH), 28.4
(6) DFT calculations (B3LYP) indicate that the cis diastereomer
A is thermodynamically slightly more stable than the trans
diastereomer B. Only in the cis isomer A does an H bond (1.9
Å) between the OH and the benzyl ester exist.
(7) A similar cyclization under acidic conditions has been
described recently: Takeuchi, Y.; Nagao, Y.; Toma, K.;
Yoshikawa, Y.; Akiyama, T.; Nishioka, H.; Abe, H.;
Harayama, T.; Yamamoto, S. Chem. Pharm. Bull. 1999, 47,
1284.
(8) The preferred formation of trans products under slightly
acidic conditions was also observed with peptides 6 and 9.
Not only acidic silica gel but also acetic acid could be used.
(9) (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J.
R.; Saperstein, R. Science 1980, 210, 656. (b)Freidinger, R.
M. J. Med. Chem. 2003, 46, 5553.
3
3
3
(
(
(
(
CH ), 39.5 (CH ), 44.2 (CH ), 50.3 (CH), 53.6 (CH ), 61.1
3 2 2 3
CH), 67.3 (CH ), 80.5 (C), 86.5 (C), 128.5 (CH), 128.6
2
CH), 128.7 (CH), 135.4 (C), 156.2 (C), 169.7 (C), 170.5
C), 171.5 (C), 171.5 (C). MS (ESI): m/z (%) = 560 (2) [M +
+
+
+
K] , 544 (100) [M + Na] , 488 (2) [M – t-Bu + Na] . Anal.
Calcd for C H N O : C, 57.57; H, 6.76; N, 8.06. Found: C,
2
5
35
3
9
57.62; H, 6.75; N, 8.01.
(
4) To our knowledge, such a cyclization of an amide group into
an a-keto ester under basic conditions has been described
only with b-lactams leading to six-membered rings:
(
a) Bryan, D. B.; Hall, R. F.; Holden, K. G.; Huffman, W. F.;
Gleason, J. G. J. Am. Chem. Soc. 1977, 99, 2353.
b) Aszodi, J.; Chantot, J.-F.; Collard, J.; Teutsch, G.
(
Heterocycles 1989, 28, 1061. (c) Arnoldi, A.; Merlini, L.;
Scaglioni, L. J. Heterocycl. Chem. 1987, 24, 75.
Synlett 2006, No. 11, 1774–1776 © Thieme Stuttgart · New York