Synthesis of a novel benzyl-octahydropyrazino[1,2-a]pyrimidin-6-one derivative as a convenient internal bicyclic peptidomimetic

Article abstract of DOI:10.1016/j.tetlet.2008.01.137

A substituted hydropyrazino[1,2-a]pyrimidin-6-one derivative was synthesized stereoselectively via the intramolecular N-acyliminium ion cyclization between an amide nitrogen and an N^α-acetal derived from Cbz-protected aminopropyl-phenylalaninamide in very good yields. The formation of a single diastereomer is due to the low energy chairlike conformation of its bicyclic structure. This methodology provides a convenient tool to build internal bicyclic peptidomimetics.

Full text of DOI:10.1016/j.tetlet.2008.01.137

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Tetrahedron Letters 49 (2008) 2316–2319
Synthesis of a novel benzyl-octahydropyrazino[1,2-a]pyrimidin-6-one
derivative as a convenient internal bicyclic peptidomimetic
Byoung J. Min, Xuyuan Gu, Takashi Yamamoto, Ravil R. Petrov, Hongchang Qu,
Yeon Sun Lee, Victor J. Hruby *
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA
Received 3 May 2007; revised 29 January 2008; accepted 31 January 2008
Available online 7 February 2008
Abstract
A substituted hydropyrazino[1,2-a]pyrimidin-6-one derivative was synthesized stereoselectively via the intramolecular N-acyliminium
ion cyclization between an amide nitrogen and an Na-acetal derived from Cbz-protected aminopropyl-phenylalaninamide in very good
yields. The formation of a single diastereomer is due to the low energy chairlike conformation of its bicyclic structure. This methodology
provides a convenient tool to build internal bicyclic peptidomimetics.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Internal bicyclic peptidomimetics; N-Acylimnium ion cyclization; Acetals
It has been well recognized that b-turns are important
structural features in biologically active peptides and pro-
teins in terms of their function.1 A large amount of
research has been pursued to investigate peptide–protein
or protein–protein interactions that also could be induced
by small molecules bearing similar local structural
features.2 Recently, our group has developed the external
b-turn mimetics 1 (Fig. 1) containing the thiazolo[3,2-a]-
pyridine-5-one moiety via both solution and solid phase
synthesis.3 It has been known that for interactions with a
target protein, side chains of internal b-turn mimetics are
more accessible than those of external mimetics, which
are more sterically hindered by the support.4 Therefore,
we have designed and synthesized a novel internal bicyclic
scaffold for peptidomimetic 2 (Fig. 1). For structure
characterization and configuration assignment, a density
functional theory (DFT) calculation, solution NMR
spectroscopy, and X-ray crystallography were performed.
Compound 8 was designed as a model compound to
investigate the synthesis of 1,3,6,8-substituted tetrahydro-
H
N
Ri+2
O
R'i+1
S
n
R'i+2
O
n
N
H
H
N
Ri+1
O
N
X
O
N
O
Ri
N
H
O
Ri+3
NH
Ri+3
O
Ri
NH
2
(n = 0,1: X = O, H2)
1
(n = 0,1,2)
Fig. 1. Bicyclic external (1) and internal (2) b-turn mimetics.
2H-pyrazino[1,2-a]pyrimidine-4,7-diones (2) derivatives
(Scheme 1). The straightforward approach to this bicyclic
scaffold was to introduce an acetal moiety at the a-amino
group of the phenylalanine, which can be attacked first
by the amide to yield acyliminium ion 7 and then by the
carbamate nitrogen atoms in a one-pot fashion to construct
the bicyclic structure. The reaction was expected to give a
corresponding diastereomeric mixture, as the nucleophilic
attack may take place from both the si-face and re-face
of the planar iminium ion double bond.4,5 Surprisingly, a
single diastereomer was generated and isolated from the
reaction, and its purity was confirmed by HPLC. Here,
*
Corresponding author. Tel.: +1 520 621 6332; fax: +1 520 621 8407.
E-mail address: hruby@u.arizona.edu (V. J. Hruby).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.137

B. J. Min et al. / Tetrahedron Letters 49 (2008) 2316–2319
2317
Ph
Ph
H
N
H
N
H
N
b, c, d
H
N
H
N
O
a
H2N
HCl
N
H
Cbz
Boc
Cbz
N
H
Cbz
N+
O
O
5
O
4
3
Ph
O
Ph
O
Ph
O
Ph
H
H
g
f
e
N
H
N
H
O
N
N
N
Cbz
N
N
HN
Cbz
N
Cbz
Cbz
N
H
O
Cbz O
HN
Cbz
6
7
8
9
Scheme 1. Synthesis of 7-benzyl-octahydropyrazino[1,2-a]pyrimidin-6-one (9). Reagents and conditions: (a) Boc-L-Phe-OH, BOP, HOBt, NMM, DMF,
92%; (b) TFA, CH2Cl2; (c) 2,2-dimethoxyacetaldehyde, THF; (d) NaBH(OAc)3, AcOH, THF, 90% (3 steps overall); (e) Cbz-Cl, DIEA, CH2Cl2, 96%; (f)
formic acid, 89%; (g) H2, Pd/C, MeOH, 95%.
we provide details for the synthesis, the rationalization of
diastereoselectivity, and its absolute stereochemistry.
and piperazine rings have a chairlike conformation with
the benzyl group in an axial position (Fig. 2).9 In the struc-
tural conformation of 9, the anomeric effect could be one
possible factor for its chairlike structure, since the lone pair
of the nitrogen stabilizes the axial benzyl group in the
chairlike conformation more than the equatorial one in
the boatlike conformation.10
To confirm their configurations, density functional
theory (DFT) calculations were performed using the
GAUSSIAN 03 program.11 Structure optimization followed
by a frequency calculation was performed on 9 at the
B3LYP/6-31G(d) level (no imaginary frequencies were
found). Zeropoint energies (ZPEs) of the DFT results were
scaled by 0.9806.12 Compound 9 was studied to compare
the obtained calculated conformation with its X-ray crystal
structure. It turns out that the calculated structure of 9 was
shown to be well overlapped with the X-ray crystal struc-
ture. For simplicity with low calculational costs, the model
compounds of two diastereomers, in which a Cbz group at
position 1 in 9 was replaced by an acetyl group, were calcu-
lated by the same method.
(3-Aminopropyl)-carbamic acid benzyl ester 3 was con-
jugated with Na-Boc-L-Phe-OH using BOP, HOBt, and
NMM to afford amide 4 in 92% isolated yield (Scheme
1).6 After deprotection of the Na-Boc group by TFA,
reductive amination was performed by sequential additions
of 2,2-dimethoxyacetaldehyde and sodium triacetoxyboro-
hydride in the presence of a catalytic amount of acetic acid
in THF.7 This one-pot 3-step reaction generated the sec-
ondary amine 5 with an acetal moiety in 90% yield after
purification. The Cbz group was chosen to protect the sec-
ondary amine, though other protection groups could be
used for the orthogonal protection. After protection, the
corresponding acetal 6 was subjected to acid-catalyzed
cyclization in the presence of formic acid to give bicyclic
product 8 in 89% yield. Interestingly, this bicyclic product
8 only showed a single diastereomer both in crude NMR
and HPLC analyses. In order to confirm the stereochemis-
try and the optical purity of the diastereomer, various
NMR analyses were performed, but the result was not con-
clusive due to the existence of rotamers. Thus, the two Cbz
groups of 8 were removed by hydrogenation. The NMR
spectrum as well as HPLC analysis of product 9 clearly
indicated that compound 9 was a single diastereomer.8
The product was crystallized in a mixed solvent CH2Cl2,
EtOAc, and MeOH. The X-ray crystal structure of 9 con-
firmed that the bridged head hydrogen has a cis-configura-
tion to the hydrogen at position 7, and that the pyrimidine
As anticipated, diastereomer 10, whose pyrimidine ring
has a chairlike conformation, is more stable than diastereo-
mer 11, which has a twist boatlike conformation, implying
that the bis-acylated benzyl-octahydropyrazino[1,2-a]pyr-
imidin-6-one derivative also prefers a chairlike confor-
mation rather than a boatlike one (Fig. 3). The energy
difference between the two diastereromers is 1.5 kcal/mol,
which leads to a 9/1 product ratio. On the basis of the
H
H
N
9
6
2
3
1
HN
9a
7
N
4
O
Fig. 2. X-ray crystal structure of (7S,9aR)-7-benzyl-octahydropyrazino[1,2-a]pyrimidin-6-one, 9.

2318
B. J. Min et al. / Tetrahedron Letters 49 (2008) 2316–2319
Ac
N
H
Cbz
Ph
N
N
10
O
Ac
N
H
Cbz
N
Ph
N
11
O
10 (top)
11 (bottom)
Fig. 3. The lowest energy conformational structures of two diastereomers (10 and 11, stereoviews) from DFT calculation using GAUSSIAN 03.
results from the DFT calculation and X-ray crystal struc-
ture, the thermodynamically preferred diastereomer was
confirmed.
needs higher energy compared to the eliminated enamide
product 17. Therefore, compound 17 was the only iso-
lated product under the harsh reaction condition. Other
ring-size bicyclic constructions are currently under
investigation.
In summary, we have developed a simple and efficient
methodology to synthesize a substituted octahydropyr-
azino[1,2-a]pyrimidin-6-one as a scaffold for the formation
of internal bicyclic peptidomimetics. Installing an acetal
moiety on a-amino group following by tandem acid-cata-
lyzed N-acyliminium ion bicyclization was the key for this
transformation. The formation of the bicyclic scaffold is
considered to follow a thermodynamically driven pathway
to yield only a single diastereomer. We expect that this
methodology will bring a simple and efficient tool to
develop new types of peptide-based ligands.
An interesting result was found when the synthesis of
6,5-membered ring 19 (Scheme 2) was attempted. 6,5-
Bicyclic compound 19 could not be generated by the
same strategy (Scheme 2). Acetal 15 did not go on to
cyclization even with reaction times of up to 5 days
and heating for 4 h, but instead underwent b-elimination
to generate enamide product 17 in 10% yield, which was
the only isolated product along with the starting mate-
rial.13 We speculate that the elimination reaction is the
major side reaction for this type of tandem bicyclization.
Thermodynamically driven 6,6-membered bicyclic forma-
tion could be a stable pathway to yield the desired prod-
uct while the kinetically driven 6,5-membered bicyclic
Ph
H
Ph
H
N
a
O
N
Cbz
b, c, d
H2N
HCl
Cbz
N
H
N
H
Boc
Cbz
Ph
N
H
N
H
N
H
O
O
14
O
12
13
Ph
Ph
O
O
H
N+
e
f
N
O
N
Cbz
N
N
H
HN
N
N
N
Cbz
Cbz
g
Cbz
O
Cbz O
Cbz
19
16
15
Ph
O
Ph
O
NH2
N
N
N
HN
HN
Cbz
Cbz
18
17
Scheme 2. Synthesis of 1-(2-aminoethyl)-3-benzylpiperazin-2-one, 18. Reagents and conditions: (a) Boc-L-Phe-OH, BOP, HOBt, NMM, DMF, 95%; (b)
TFA, DCM; (c) 2,2-dimethoxyacetaldehyde, THF; (d) NaBH(OAc)3, AcOH, THF, 90% (3 steps overall); (e) Cbz-Cl, DIEA, DCM, 81%; (f) formic acid,
10%; (g) H2, Pd/C, MeOH, 60%.

B. J. Min et al. / Tetrahedron Letters 49 (2008) 2316–2319
2319
5. For reviews, see: (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron
1985, 41, 4367–4416; (b) Hiemstra, H.; Speckamp, W. N. In
Comprehensive Organic Chemistry; Trost, B. M., Ed.; Pergamon
Press: Oxford, 1991; Vol. 2, pp 1047–1082; (c) Baldwin, J. E.; Humle,
C.; Edwards, A. J.; Schofield, C. J. Tetrahedron Lett. 1993, 34, 1665–
1668; (d) Brodney, M. A.; Padwa, A. Tetrahedron Lett. 1997, 38,
6153–6156; (e) Lee, Y. S.; Min, B. J.; Park, Y. K.; Lee, J. Y.; Lee, S.
J.; Park, H. Tetrahedron 1999, 55, 12991–12996; (f) Maryanoff, C. A.;
Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431–1628.
Acknowledgments
This work was supported by grants from US Public
Health Service (DK 17420) and the National Institute on
Drug Abuse (DA 06284 and DA 13449). We thank Profes-
sor Richard Glass and Professor Hamish Christie (The
University of Arizona) for helpful discussions regarding
the reaction mechanism.
6. Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975,
16, 1219–1222.
Supplementary data
7. Ho, P. T.; Chang, D.; Zhong, J. W.; Musso, G. F. Peptide Res. 1993,
6, 10–12.
8. For details, see Supplementary data.
9. CCDC 639677 contains the supplementary crystallographic data for
this Letter. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
10. Ghosh, S. K.; Hsung, R. P.; Liu, J. J. Am. Chem. Soc. 2005, 127,
8260–8261.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.01.137.
References and notes
1. Rose, G. D.; Gierasch, L. M.; Smith, J. A. Adv. Protein Chem. 1985,
37, 1–109.
2. Burgess, K. Acc. Chem. Res. 2001, 34, 826–835.
11. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.; Johnson,
B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.; Petersson, G. A.;
Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrze-
wski, V. G.; Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B.
B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.;
Chen, W.; Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.;
Stewart, J. J. P.; Head-Gordon, M.; Gonzalez, C.; Pople, J. A.
GAUSSIAN 03, Revision B.05; Gaussian: Pittsburgh, PA, 2003.
12. (a) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502–16513;
(b) http://comp.chem.umn.edu/database/freq_scale.htm.
13. Similar type of the enamide formation has been reported in
synthesizing piperazine derivatives where the authors also suggested
that the acyliminium ion was the intermediate: Cheng, J.-F.; Chen,
M.; Arrhenius, T.; Nadzan, A. Tetrahedron Lett. 2002, 43, 6293–
6295.
3. (a) Ndungu, J. M.; Cain, J.; Davis, P.; Ma, S.-W.; Vanderah, T. W.;
Lai, J.; Porreca, F.; Hruby, V. J. Tetrahedron Lett. 2006, 47, 2233–
2236; (b) Gu, X.; Ying, J.; Min, B.; Cain, J. P.; Davis, P.; Willey, P.;
Navratilova, E.; Yamamura, H. I.; Porreca, F.; Hruby, V. J.
Biopolymers 2005, 80, 151–163; (c) Ndungu, J. M.; Gu, X.; Gross,
D. E.; Cain, J. P.; Carducci, M. D.; Hruby, V. J. Tetrahedron Lett.
2004, 45, 4139–4142.
4. (a) Eguchi, M.; Lee, M. S.; Nakanishi, H.; Stasiak, M.; Lovell, S.;
Kahn, M. J. Am. Chem. Soc. 1999, 121, 12204–12205; (b) Kim, H.-O.;
Nakanishi, H.; Lee, M. S.; Kahn, M. Org. Lett. 2000, 2, 301–302; (c)
Eguchi, M.; Lee, M. S.; Stasiak, M.; Kahn, M. Tetrahedron Lett.
2001, 42, 1237–1239; (d) Eguchi, M.; Shen, R. Y. W.; Shea, J. P.; Lee,
M. S.; Kahn, M. J. Med. Chem. 2002, 45, 1395–1398.