A convenient and versatile synthesis of 6,5- and 7,5-fused bicyclic lactams as peptidomimetics

Article abstract of DOI:10.1016/S0040-4039(01)00909-1

Chemo-selective reduction of the pyroglutamate ring carbonyl in a serine-pyroglutamate or homoserine to pyroglutamate dipeptide gave a hemiaminal. Treatment of the hemiaminal with a catalytic amount of TFA in CH₂Cl₂ generated an N-ac

Full text of DOI:10.1016/S0040-4039(01)00909-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4943–4945
A convenient and versatile synthesis of 6,5- and 7,5-fused
bicyclic lactams as peptidomimetics
Xiaojun Zhang,* Wen Jiang and Aaron C. Schmitt
Chemical & Physical Sciences, DuPont Pharmaceuticals Company, Experimental Station, PO Box 80500, Wilmington,
DE 19880, USA
Received 1 April 2001; accepted 22 May 2001
Abstract—Chemo-selective reduction of the pyroglutamate ring carbonyl in a serine-pyroglutamate or homoserine to pyrogluta-
mate dipeptide gave a hemiaminal. Treatment of the hemiaminal with a catalytic amount of TFA in CH2Cl2 generated an
N-acyliminium ion that was intramolecularly trapped by the side-chain hydroxyl to give a 6,5 or 7,5-bicyclic lactam. © 2001
DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.
Design and synthesis of novel bicyclic lactams as pepti-
domimetics is currently an area of intensive research in
the field of peptide and medicinal chemistry.1–3 The
backbone structure of these scaffolds maintains impor-
tant conformational information derived from a parent
peptide lead. They can effectively mimic the peptide
binding conformation and incorporate critical hydro-
gen-bond donors and acceptors such as an amide NH
and carbonyl groups. One example of such scaffolds is
bicyclic lactam A, based on proline (Fig. 1), which has
been studied as both reverse turn and extended confor-
mation inducer.4,5
reported an alternative approach to the 6,5-system
involving ozonolysis of a dipeptide C, followed by
cyclization of the N-acyliminium intermediate.8 This
approach, however, required a chiral synthesis of
homoallyl glycine, an unnatural amino acid. Both
approaches also lack easy methods to attach additional
functional groups off the proline ring.
We report here a more versatile synthetic sequence to A
involving a chemo-selective reduction of the pyrogluta-
mate ring carbonyl in dipeptide D, followed by an
intramolecular trapping of the N-acylimminium ion
generated in situ from the hemiaminal. The advantage
of this approach is it allows easy introduction of sub-
stituents off the proline ring by alkylation of the pyro-
glutamate, a reaction well documented in the litera-
ture.9–11
Although both the 6,5 and 7,5-systems of lactam A
have been prepared previously,
a more versatile
approach is still highly desired due to certain limita-
tions of previous methods. Marshall, et al reported an
electrooxidation–cyclization sequence to produce both
6,5- and 7,5- systems from an Xaa-Pro dipeptide B.6,7
This simple sequence gave a good yield for the 7,5-sys-
tem, but low yields for the 6,5-system. Baldwin et al.
To prepare (3S,6S,9S)-6,5-bicyclic lactam 4, the sodium
salt of (S)-ethyl pyroglutamate was reacted with com-
mercially available Boc-(
L
)-ser(Bzl)-ONp in toluene to
R
R
HO
O
n
O
n
HO
BocHN
HO
n
H
N
N
N
N
BocHN
BocHN
CO2CH3
BocHN
H
CO2Et
O
CO2H
O
O
O
CO2CH3
A (n = 1, 2)
B (n= 1, 2)
D (n = 1, 2)
C
Figure 1. Bicyclic lactam A and precursors.
Keywords: 6,5- and 7,5-fused bicyclic lactams; peptidomimetics; N-acyliminium ion.
* Corresponding author. Fax: (302)-695-2209; e-mail: xiaojun.zhang@dupontpharma.com
0040-4039/01/$ - see front matter © 2001 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00909-1

4944
X. Zhang et al. / Tetrahedron Letters 42 (2001) 4943–4945
give a dipeptide 1 (Scheme 1).12 Deprotection of the
benzyl group of 1 and reduction of 2 with LiBEt3H in
THF at −78°C gave hemiaminal 3. Preferential reduc-
tion of the ring carbonyl was anticipated based on its
reactivity towards nucleophiles.13,14 Attempts to purify
ring-fused carbon was identified to be 10S by NOE
experiments.
Attaching functional groups to the proline ring to pick
up additional binding with a target enzyme or receptor
in these bicyclic systems can be important. This can be
achieved by a stereoselective alkylation of the pyroglu-
tamate precursor with a wide variety of electrophiles.9
For example (Scheme 3), the lithium enolate of N-Boc-
(S)-ethyl pyroglutamate 14 was alkylated with cin-
namyl bromide to give compound 15.9 Removal of the
1
3 by silica-gel column resulted in its decompostion. H
NMR of 3 is complicated by the presence of two
diastereomers and the equilibrium between the aminal
and the aldehyde form. Its structure was thus, proved
by the following chemical transformation: cyclization in
CH2Cl2 in the presence of TFA (25% mol) gave the
6,5-bicyclic lactam
diastereomer (3R,6S,9R)-7 was prepared in 50% iso-
lated yield from 6 using Boc-( )-Ser(Bzl)-OH as start-
4
in good yield. Similarly,
Boc group and amide formation of 16 with Boc-(D)-
ser(Bzl)-OSu gave dipeptide 17. Following the same
chemistry described above, removal of the benzyl pro-
tection in 17, selective reduction of the pyroglutamate
ring carbonyl in 18, and cyclization of hemiaminal 19
afforded 6,5-system 20 carrying a phenylpropyl group
off the proline. Again, the stereo configuration at the
ring-fused carbon was established as 9R by NOE exper-
iments, similar to that obtained in compound 7. The
stereochemistry of the phenpropyl off the proline ring
was retained based on NOE studies. The ethyl ester 20
was cleanly hydrolyzed to its acid 21, which could be
readily incorporated into other peptides.
D
ing material. Isolation of bicyclic lactams 4 and 7
suggests intermediacy of an N-acyliminium ion and its
trapping by the side chain hydroxyl group.15
1
Compounds 4 and 7 were fully characterized by H,
13C, DEPT and HRMS. The stereo configuration at the
ring-fused carbon was established by NOE experiments,
and by comparison with literature data.5,7 Isolation of
the 9S conformer for 4 and the 9R for 7 is consistent
with the previous observation that the cyclization is not
influenced by the chirality of proline, rather dictated by
the chirality of serine.6 During the hydrolysis of the
ester 4, epimerization at the serine a-carbon occurred,
giving a 1:1 mixture of the acids 5.7 However, hydroly-
sis of 7 gave clean formation of the acid 8, with no
In summary, we have developed a versatile procedure
to prepare both 6,5- and 7,5-bicyclic lactam pepti-
domimetics based on a chemo-selective reduction of the
pyroglutamate ring carbonyl, followed by an
intramolecular trapping of an N-acyliminium ion by
side-chain hydroxyl groups. Furthermore, due to the
ready availability of starting materials and the ability to
incorporate additional functionality on the proline ring,
we consider this to be a valuable addition to previous
methodologies.
1
epimerization detected by H NMR.
Starting from Boc-(L)-homoser(Bzl)-OH, the 7,5-system
was also conveniently prepared. Compound 12 was
isolated in 35% yield from 9 in three steps (Scheme 2).
As in the case of 4, the stereo configuration at the
H
N
H
N
RO
O
HO
HO
O
O
d
b
c
3
N
N
BocHN
6
BocHN
BocHN
BocHN
H
CO2Et
CO2Et
CO2Et
COOH
O
O
O
O
R = Bn, 1
R = H, 2
3
4
5
a
H
N
O
O
N
HO
BocHN
O
O
b, c
d
N
BocHN
BocHN
CO2H
CO2Et
CO2Et
O
O
6
7
8
Scheme 1. Synthesis of 6,5-bicyclic lactams. (a) H2, Pd/C, MeOH; (b) LiBEt3H, THF, −78°C; (c) TFA (cat.), CH2Cl2, 50°C, 50%;
(d) LiOH, H2O/THF, 100%.
H
OR
O
OH
HO
O
O
c
b
N
BocHN
d
N
N
BocHN
BocHN
O
CO2R
CO2Et
CO2Et
O
11
R = Et, 12
R = H, 13
R = Bn, 9
R = H, 10
a
Scheme 2. Synthesis of 7,5-bicyclic lactam. (a) H2, Pd/C, MeOH; (b) LiBEt3H, THF, −78°C; (c) TFA (cat.), CH2Cl2, 50°C, 35%;
(d) LiOH, H2O/THF, 100%.

X. Zhang et al. / Tetrahedron Letters 42 (2001) 4943–4945
4945
Ph
Ph
Ph
c
b
a
O
O
BnO
CO2Et
O
N
Boc
N
BocHN
CO2Et
CO2Et
O
O
N
Boc
N
H
CO2Et
14
16
15
17
Ph
Ph
f
Ph
H
e
O
O
d
O
HO
O
HO
BocHN
HO
BocHN
N
N
N
BocHN
g
CO2R
CO2Et
CO2Et
O
18
R = Et, 20
R = H, 21
19
Scheme 3. Synthesis of 6,5-bicyclic lactam carrying functional group off the proline ring. (a) LHMDS, THF, cinnamyl bromide,
−78°C, 60%; (b) TFA, CH2Cl2; (c) 1. LHMDS, THF, −30°C, 2. Boc-( )-Ser(Bzl)-OSu, 85% for two steps; (d) H2, Pd/C, MeOH;
(e) LiBEt3H, THF, −78°C; (f) TFA (cat.), CH2Cl2, 50°C, 35% for three steps; (g) LiOH, H2O/THF, 100%.
D
Acknowledgements
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We thank Dr. Carl Decicco for his support of this
work, Dr. David Nugiel for his critical reading of the
manuscript and Dr. Laurie Galya for all the H NOE
1
experiments.
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