Novel approach to the synthesis of perhydropyrazino[1,2-a]pyrazine derivatives from amino alcohols

Article abstract of DOI:10.1016/j.tetlet.2005.10.130

2,4,7-Trisubstituted hydrogenated pyrazino[1,2-a]pyrazines as potential β-turn mimetics were prepared for the first time in a stereoselective synthesis from hexahydro[1,2,3]triazolo[1,5-a]pyrazines.

Full text of DOI:10.1016/j.tetlet.2005.10.130

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 51–54
Novel approach to the synthesis of
perhydropyrazino[1,2-a]pyrazine derivatives from amino alcohols
Tatyana V. Lukina,a Sergey I. Sviridov,b,* Sergey V. Shorshnev,b
Grigory G. Aleksandrovb and Aleksandr E. Stepanova
aM. V. Lomonosov Moscow State Academy of Fine Chemical Technology, Malaya Pirogovskaya 1, 119435 Moscow,
Russian Federation
bChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russian Federation
Received 16 August 2005; revised 12 October 2005; accepted 25 October 2005
Available online 11 November 2005
Abstract—2,4,7-Trisubstituted hydrogenated pyrazino[1,2-a]pyrazines as potential b-turn mimetics were prepared for the first time
in a stereoselective synthesis from hexahydro[1,2,3]triazolo[1,5-a]pyrazines.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The synthesis of new types of b-turn mimetics is of great
interest in medicinal chemistry, as potential agonists/
antagonists of various protein receptors. In the series
of hydrogenated bicyclic heterocycles the derivatives
of tetrahydro-2H-pyrazino[1,2-a]pyrimidine-4,7-diones1
and bicyclic diketopiperazines2 are known as such
mimetics. Moreover, the related perhydropyrazino[1,2-
a]pyrazines proved to have interesting biological
activity.3
tuent R1. More bulky substituents, for example, R1 = i-
Pr, accelerated the reaction. An exceptional case was
the unsubstituted triazoline (1, R1 = H) which reacted
rather rapidly. The yield of products 2 increased when
CaCO3 was added to reaction mixtures. Evidently, this
substance suppresses a number of side processes without
participating in the reaction. The standard procedure for
the substitution of a halogen atom with the azide group
resulted in product 3.6
We report here, a novel stereoselective approach to
2,4,7-trisubstituted hexahydro-2H-pyrazino[1,2-a]pyra-
zin-3(4H)-ones as a new class of such compounds. The
method allows for the modification of the substituents
R1, R2, and R3 and, therefore, could lead to a great vari-
ety of products.
Our attempts to cyclize of the Ns-protected intermedi-
ates 3 (e.g., using PPh3 for reduction of the N3-function)
were unsuccessful. Therefore, we were forced to
exchange the endocyclic amino protecting group with
Boc, and obtained the compounds 4.7 These products
were readily cyclized to form the desired bicyclic com-
pounds 5 under catalytic hydrogenation conditions.
Subsequent N-alkylation under standard conditions re-
sulted in piperazines 6 (Table 1).8,9 To our surprise,
We used hexahydro[1,2,3]triazolo[1,5-a]pyrazines 1 as
starting compounds, the synthesis of which from amino
alcohols was developed recently in our laboratory
(Scheme 1).4 We showed that the cyclization is character-
ized by a high degree of diastereoselectivity and affords
single stereoisomers.4 Triazolines 1 readily undergo ring
opening with various electrophiles.4 Thus, they reacted
effectively with bromoacetic ester to form esters 2.5 We
found that the rate of this reaction depended on substi-
Table 1. Preparation of compounds 6a–g
20
Entry R1
R2
½aꢀD (c, MeOH) Yielda 6a–g (%)
6a
6b
6c
6d
6e
6f
Et
Et
Et
Et
Et
Me
i-Bu
Racemic
Racemic
28
42
45
15
22
34
19
MeOCH2CH2 Racemic
Et2NCH2CH2 Racemic
4-FC6H4CH2 Racemic
i-Pr Me
Bn Me
ꢁ85 (c 1)
Keywords: b-Turn mimetics; Piperazines; Pyrazino[1,2-a]pyrazines.
6g
+375 (c 1)
*
Corresponding author. Fax: +7 095 956 49 48; e-mail:
sviridov@chembridge.ru
a From 1a–c.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.130

52
T. V. Lukina et al. / Tetrahedron Letters 47 (2006) 51–54
Ns
R1
Ns
ii
N
i
Ns
R1
N
Br
EtOOC
N3
N
N
N
N
R1
EtOOC
N
N
iii
2a-c
3a-c
a-c
1
1
R2
Boc
R1
9a
Boc
Boc
R1
iv
v
HN
N
N
N
N3
N
N
N
O
R1
O
EtOOC
N
5
6a-g
5a-c
4
a-c
R2
R2
Boc
vi
vii
.
N
NH HCl
R1
N
N
Ns -o-Nitrobenzenesulfonyl
N
N
O
R1
O
R3
8a-k
R3
7a-k
Scheme 1. Reagents and conditions: (i) BrCH2COOEt, CaCO3/MeCN; (ii) NaN3/DMF; (iii) HOCH2CH2SH, DBU/MeCN then Boc2O/CH2Cl2;
(iv) H2/Pd–C/MeOH; (v) R2Hal, NaH/DMF; (vi) LDA, HMPA, R3Hal/THF, ꢁ78 ꢁC; (vii) HCl/dioxane.
there are many examples of 3-C-alkylation of 4-N-acyl-
ated piperazin-2-ones (mostly 4-N-Boc derivatives),10
but no examples of such alkylation for 4-N-alkylated
derivatives. We found that piperazinones 6 (as well as
simple derivatives that we used as model compounds)
formed Li-enolates in the presence of LDA/HMPA,
which reacted with alkyl halides affording products 7
in good yields.11 If an excess of the alkylating agent
was used, it was possible to obtain a C,C-bisalkylated
product. It should be noted that the alkylation occurred
with a high degree of diastereoselectivity yielding single
products. The electrophilic attack occurs in all probabil-
ity from the least hindered side of the enolate and is
determined by the presence of two axial hydrogen atoms
at positions 6 and 9a.
8b, and a single product formed in the reaction, we
attributed the stereochemistry identical to that of 8b
(Fig. 1).13
The target products 8 containing a free amino group and
thus useful for the construction of b-turn mimetic
libraries (Table 2). The structures of compounds 8 were
confirmed by 1H NMR spectroscopic analysis.12
1
The assignment of the H and 13C NMR spectra in-
volved 1H–1H COSY, 1H–13C HMBC, and 1H–13C
HSQC experiments. However, the conclusions based
on the NMR data did not enable us to assign unambig-
uously the stereochemistry of the new chiral center.
Therefore, we used X-ray crystallographic analysis
that unequivocally confirmed the structure of 8b. Since
the NMR spectra of 8a and 8c–k are similar to that of
Figure 1. X-ray crystal structure of compound 8b.
Table 2. Preparation of the hexahydro-2H-pyrazino[1,2-a]pyrazin-3(4H)-one, hydrochlorides 8a–k
20
Entry
R1
R2
R3
½aꢀD (c, MeOH)
Yielda 8a–k (%)
8a
8b
8c
8d
8e
8f
Et
Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
Bn
Bn
Me
Me
i-Bu
MeOCH2CH2
Et2NCH2CH2
4-FC6H4CH2
Me
i-PrCH2CH2
4-BrC6H4CH2
4-ClC6H4CH2
3-CH3OC6H4CH2
3-CH3OC6H4CH2
4-ClC6H4CH2
3-CH3OC6H4CH2
3-CH3OC6H4CH2
4-ClC6H4CH2
Racemic
Racemic
Racemic
Racemic
Racemic
Racemic
Racemic
+110 (c 1)
+100 (c 1)
ꢁ120 (c 1)
ꢁ70 (c 1)
36
45
34
42
20
27
42
47
45
23
25
8g
8h
8i
Me
MeOCH2CH2
Me
Me
8j
8k
i-PrCH2CH2
3-CH3OC6H4CH2
a From 6a–c.

T. V. Lukina et al. / Tetrahedron Letters 47 (2006) 51–54
53
of NaHCO3. The product was extracted with ethyl acetate
(3 · 50 mL). The extract was dried with Na2SO4 and
evaporated to give the free amine (2.98 g, 60%). This
substance was dissolved in dichloromethane (100 mL),
We have described a novel approach to 2,4,7-trisubsti-
tuted hexahydro-2H-pyrazino[1,2-a]pyrazin-3(4H)-ones,
which enables the synthesis of a wide variety of these
compounds in relatively good yields. Due to the high
diastereoselectivity, this method is appropriate for the
synthesis of optically pure products starting from read-
ily available chiral amino alcohols.
and
a solution of di-tert-butyl dicarbonate (2.56 g,
12 mmol) in dichloromethane (30 mL) was added drop-
wise under stirring for 30 min. The reaction mixture was
washed with a saturated solution of Na2CO3 (3 · 50 mL).
The organic layer was dried with Na2SO4 and evaporated
1
to afford compound 4a as an oil (3.78 g, 91%). H NMR
References and notes
(CDCl3, 400 MHz): d 0.87 (3H, t, J = 7.3 Hz), 1.28 (3H, t,
J = 7.3 Hz), 1.46 (9H, s), 1.60–1.70 (1H, m), 1.72–1.86
(1H, m), 2.69–2.91 (4H, m), 3.30–3.55 (4H, m), 3.83–4.02
(2H, m), 4.17 (2H, q, J = 7.3 Hz).
1. Eguchi, M.; Lee, M. S.; Nakanishi, H.; Stasiak, M.;
Lovell, S.; Kahn, M. J. Am. Chem. Soc. 1999, 121, 12204–
12205.
2. Golebiowski, A.; Klopfenstein, S. R.; Chen, J. J.; Shao, X.
Tetrahedron Lett. 2000, 41, 4841–4844.
3. (a) Hirschmann, R.; Nicolau, K. C.; Pietranico, S.; Leahy,
E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P. G.;
Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith,
A. B., III; Reisine, T.; Raynor, P. A.; Maechler, L.;
Donaldson, C.; Vale, W.; Freidinger, R. M.; Cascieri, M.
R.; Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550–
12568; (b) Hirschmann, R. Angew. Chem., Int. Ed. Engl.
1991, 30, 1278–1283.
8. Cyclization: Compound 4a (3.78 g, 1 mol) was dissolved in
methanol (40 mL), and 10% Pd/C (150 mg) was added to
the solution under argon. The reaction was carried out in a
Parr apparatus (hydrogen pressure 40 psi, 40 ꢁC) for 8 h,
after which the reaction mixture was passed through Celite
and evaporated. The residue was purified by column
chromatography (silica gel, dichloromethane/ethyl acetate
1:1) to give compound 5a as a white powder (2.38 g, 63%),
mp 149–151 ꢁC (ethyl acetate/hexane, 1:1).1H NMR
(CDCl3, 400 MHz): d 0.88 (3H, t, J = 7.3 Hz), 1.46 (9H,
s), 1.56–1.94 (2H, m), 2.22 (1H, dd, J = 11.3, 3.7 Hz),
2.26–2.35 (1H, m), 2.58–2.65 (1H, m), 2.67–2.70 (1H, m),
2.76 (1H, d, J = 16.6 Hz), 3.11 (1H, dd, J = 11.0, 10.8 Hz),
3.23 (1H, dt, J = 11.5, 3.7 Hz), 3.39 (1H, d, J = 16.6 Hz),
3.81–4.18 (2H, m), 6.12–6.26 (1H, m). C14H25N3O3,
found: C, 59.37; H, 8.94; N, 14.80. Calcd: C, 59.34; H,
8.89; N, 14.83.
4. Lukina, T. V.; Sviridov, S. I.; Shorshnev, S. V.; Alexan-
drov, G. G.; Stepanov, A. E. Tetrahedron Lett. 2005, 46,
1205–1207.
5. Triazoline ring opening: CaCO3 (3.5 g, 30 mmol) was
added to a solution of compound 1a (9.5 g, 30 mmol)
and ethyl bromoacetate (5.14 g, 35 mmol) in anhydrous
acetonitrile (1000 mL). The reaction mixture was stirred at
room temperature for 2 days and evaporated. The residue
was dissolved in MeOH, and the solution was passed
through Celite. The product was purified by column
chromatography (silica gel, hexane/dichloromethane 2:1)
to afford compound 2a (6.7 g, 50%) as an oil. 2a (R1 = Et):
1H NMR (CDCl3, 400 MHz): d 0.83 (3H, t, J = 7.2 Hz),
1.23 (3H, t, J = 7.2 Hz), 1.70–1.94 (2H, m), 2.78 (1H, dd,
J = 11.9, 1.5 Hz), 2.92–2.98 (1H, m), 3.00 (1H, dd,
J = 11.9, 3.7 Hz), 3.28 (1H, dd, J = 10.8, 13.5 Hz), 3.30
(1H, d, J = 17.4 Hz), 3.44 (1H, dd, J = 11.6, 2.2 Hz), 3.51
(1H, dd, J = 11.6, 4.6 Hz), 3.58 (1H, d, J = 17.4 Hz), 3.71
(1H, dd, J = 13.7, 3.7 Hz), 3.77–3.84 (1H, m), 4.12 (2H, q,
J = 7.2 Hz), 7.62–7.73 (3H, m), 8.03–8.09 (1H, m).
6. Substitution of the halogen atom with the azide group:
Sodium azide (1.85 g, 28 mmol) was added to a solution of
compound 2a (6.7 g, 14 mmol) in DMF (150 mL). The
reaction mixture was stirred for 24 h at room temperature
and then extracted with ether. The extract was washed
with a 30% solution of Na2CO3 then brine, dried over
Na2SO4, and evaporated to furnish an oil 3a (5.97 g, 97%).
9. N-Alkylation: Sodium hydride (0.23 g, 9 mmol, 60% w/w
dispersion in mineral oil) was added to a solution of
compound 5a (1.6 g, 6 mmol) in DMF (5 mL). The
reaction mixture was stirred for 30 min at room temper-
ature. Methyl iodide (0.88 g, 6 mmol) was then added
under stirring. After 2 h, the product was extracted with
ether. The extract was washed with a 30% solution of
Na2CO3 then brine, dried with Na2SO4, and evaporated to
afford white powder 6a (0.5 g, 89%), mp 144–146 ꢁC (ethyl
1
acetate/hexane, 1:1). H NMR (CDCl3, 400 MHz): d 0.88
(3H, t, J = 7.3 Hz), 1.46 (9H, s), 1.55–1.91 (2H, m), 2.20
(1H, dd, J = 11.3, 3.7 Hz), 2.32–2.42 (1H, m), 2.60–2.71
(2H, m), 2.76 (1H, d, J = 16.6 Hz), 2.94 (3H, s), 3.09–3.15
(2H, m), 3.42 (1H, d, J = 16.6 Hz), 3.82–4.18 (2H, m).
C15H27N3O3, found: C, 60.57; H, 9.17; N, 14.10. Calcd: C,
60.58; H, 9.15; N, 14.13.
10. (a) Schanen, V.; Cherrier, M.; Melo, S.; Quirion, J.;
Husson, H. Synthesis 1996, 7, 833–837; (b) Pohlmann, A.;
Schanen, V.; Guillaume, D.; Quirion, J.; Husson, H. J.
Org. Chem. 1997, 62, 1016–1022.
11. C-alkylation: N-butyllithium (1.2 mL, 20 mmol, 15% solu-
tion in n-hexane) and HMPA (345 mg, 20 mmol) were
added under argon, at ꢁ78 ꢁC, to a solution of diisoprop-
ylamine (227 mg, 22 mmol) in anhydrous THF (3 mL).
After 30 min, a solution of compound 6a (R2 = Me,
500 mg, 16 mmol) in anhydrous THF (5 mL) was added.
The reaction mixture was warmed to ꢁ40 ꢁC over 1 h, and
a solution of p-bromobenzyl bromide (240 mg, 16 mmol)
in anhydrous THF (5 mL) was added dropwise. When the
reaction mixture reached 5 ꢁC, it was treated with a 30%
aqueous solution of citric acid (30 mL). The product was
extracted with ethyl acetate (3 · 5 mL). The extract was
dried with Na2SO4 and evaporated. The residue was
purified by column chromatography (silica gel, hexane/
dichloromethane 1:1) to afford the oil 7b (450 mg, 60%).
1H NMR (CDCl3, 400 MHz): d 0.91 (3H, t, J = 7.4 Hz),
1.45 (9H, s), 1.65–1.93 (2H, m), 2.29 (1H, dd, J = 11.3,
3.9 Hz), 2.41–2.54 (2H, m), 2.81 (3H, s), 2.80 (1H, d,
1
Compound 3a (R1 = Et): H NMR (CDCl3, 400 MHz): d
0.83 (3H, t, J = 7.2 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.71–1.92
(2H, m), 2.79 (1H, dd, J = 11.9, 1.5 Hz), 2.94–2.99 (1H,
m), 3.10 (1H, dd, J = 11.9, 3.7 Hz), 3.30 (1H, dd, J = 10.8,
13.5 Hz), 3.32 (1H, d, J = 17.4 Hz), 3.46 (1H, dd, J = 11.6,
2.2 Hz), 3.52 (1H, dd, J = 11.6, 4.6 Hz ), 3.58 (1H, d,
J = 17.4 Hz), 3.71 (1H, dd, J = 13.7, 3.7 Hz), 3.77–3.85
(1H, m), 4.14 (2H, q, J = 7.2 Hz), 7.60–7.72 (3H, m), 8.04–
8.08 (1H, m).
7. Replacement of the protective group: Azide 3a (8.56 g,
20 mmol) was dissolved in anhydrous acetonitrile. DBU
(2.98 g, 20 mmol) and 2-mercaptoethanol (1.52 g,
20 mmol) were added to the reaction mixture which was
stirred at room temperature for 8 h and evaporated. Ether
(150 mL) and 30% aqueous solution of citric acid (60 mL)
were added to the residue. The aqueous layer was
separated and neutralized with a 30% aqueous solution

54
T. V. Lukina et al. / Tetrahedron Letters 47 (2006) 51–54
J = 11.3 Hz), 2.97 (1H, d, J = 11.3 Hz), 3.02–3.09 (1H,
m), 3.14–3.21 (2H, m), 3.22–3.30 (1H, m), 3.67–4.19 (2H,
m), 7.10 (2H, d, J = 8.31 Hz), 7.36 (2H, d, J = 8.31 Hz).
s, OCH3), 6.81–6.96 (3H, m, Ph), 7.31 (1H, t, J = 8.1 Hz,
Ph). C18H27N3O2ÆHClÆH2O, found: C, 68.09; H, 8.62; N,
13.23. Calcd: C, 68.11; H, 8.57; N, 13.24.
12. Removal of the Boc-group: A 4.0 M solution of HCl in 1,4-
dioxane (1 mL) was added dropwise to a solution of
compound 7g (450 mg, 10 mmol) in 1,4-dioxane (1 mL) at
room temperature. The precipitate formed was separated
by filtration and dried to give compound 8g as white
powder (345 mg, 98%), mp 127–130 ꢁC (ethyl ester). 1H
NMR (D2O, 400 MHz): d 1.05 (3H, t, J = 7.4 Hz,
CH2CH3), 1.73–1.86 and 1.99–2.13 (each 1H, m,
CH2CH3), 2.66 (1H, dd, J = 13.5, 3.2 Hz, 6-CH2), 2.75–
2.82 (1H, m, 1-CH2), 2.84 (3H, s, NCH3), 2.97 (1H, d,
J = 7.6 Hz, 9-CH2), 3.06 (1H, d, J = 2.9 Hz, 1-CH2), 3.11
(2H, dd, J = 9.3, 3.9 Hz, 10-CH2), 3.21 (1H, d, J = 9.7 Hz,
9-CH2), 3.29 (1H, dd, J = 13.2, 1.7 Hz, 6-CH2), 3.44 (1H,
t, J = 3.9 Hz, 4-CH), 3.49–3.56 (1H, m, 7-CH), 3.83 (3H,
13. Crystallographic data for compound 8b: C17H24BrN3OÆH-
ClÆH2O, Mr = 420.78, orthorhombic space group Pbca,
˚
a = 8.5880(10), b = 13.007(3), c = 35.007(5) A, a = 90ꢁ,
3
˚
b = 90ꢁ, c = 90ꢁ, V = 3910.4(12) A , Z = 8, T =
293(2) K, F(000) = 1744, l = 2.253 mmꢁ1, hmax = 25.17ꢁ,
3622 reflections measured and 3517 unique (Rint = 0.0357)
reflections, full matrix least-squares refinement on F2, R1
(obs) = 0.2082, and wR2 (all data) = 0.1728. Supplemen-
tary data in the form of CIFs have been deposited with the
Cambridge Crystallographic Data Centre (CCDC
279331). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].