Synthesis and regioselective functionalization of piperazin-2-ones based on Phe-Gly pseudodipeptides

Article abstract of DOI:10.1002/ejoc.201201221

The synthesis of 1,4-unsubstituted piperazin-2-ones by one-pot reductive cyclization of PheΨ[CH(CN)NH]Gly pseudodipeptides is described. Studies on the reactivity of the piperazin-2-one ring showed a higher reactivity at the N⁴ position than at the N¹ position. The stepwise regioselective functionalization of piperazin-2-one derivatives showed great potential for molecular diversity generation. An easy methodology for the synthesis of the piperazin-2-ones by one-pot reductive cyclization of PheΨ[CH(CN)NH]Gly pseudodipeptides is described. Study of the reactivity of the piperazin-2-one ring has shown that regioselective functionalization at the N¹ and N⁴ positions is possible, and hence great potential for molecular diversity generation Copyright

Full text of DOI:10.1002/ejoc.201201221

FULL PAPER
DOI: 10.1002/ejoc.201201221
Synthesis and Regioselective Functionalization of Piperazin-2-ones Based on
Phe-Gly Pseudodipeptides
Angel M. Valdivielso,[a] Pilar Ventosa-Andrés,[a] M. Teresa García-López,[a]
Rosario Herranz,[a] and Marta Gutiérrez-Rodríguez*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Pseudodipeptides / Molecular diversity / Regioselectivity
The synthesis of 1,4-unsubstituted piperazin-2-ones by one-
pot reductive cyclization of PheΨ[CH(CN)NH]Gly pseudodi-
peptides is described. Studies on the reactivity of the piper-
azin-2-one ring showed a higher reactivity at the N4 position
than at the N1 position. The stepwise regioselective function-
alization of piperazin-2-one derivatives showed great poten-
tial for molecular diversity generation.
Introduction
Results and Discussion
The piperazine ring is recognized as a privileged scaffold
due to its recurrent presence in biologically active com-
pounds.[1] At present there are 165 drug entries for this
heterocycle in the DrugBank database.[2] Specifically, the
piperazin-2-one system is present in diverse natural prod-
ucts, such as pseudotheonamides,[3] marcfortine B,[4] ergo-
Our synthetic approach for building the piperazin-2-one
ring involves two key steps: a modified Strecker reaction for
the synthesis of cyanomethylamino pseudodipeptides, fol-
lowed by a reductive cyclization. To study this approach,
the pseudodipeptides Boc-PheΨ[(RS)CH(CN)NH]Gly-
OMe (3, Scheme 1) [15] were prepared by treatment of the
N-protected α-amino aldehyde 1 with the amino acid
methyl ester 2 and TMSCN, by the methodology developed
in our group.[16] The pseudodipeptide 3 was obtained as an
epimeric mixture at the stereogenic centre of the peptide
bond surrogate [(1R)/(1S) 1:3], which could not be resolved.
Consistently with previous results, no epimerization was
observed at the chiral centre of the α-amino alde-
hyde.[12a,16–17]
[6]
peptines[5] and guadinomine C2 In addition, the piper-
azin-2-one skeleton has been used to introduce conforma-
tional restriction in peptides and in the design of peptido-
mimetics such as neurokinin,[7] cholecystokinin[8] and neuro-
peptide S[9] and of fibrinogen antagonists,[10] melanocortin-
4 receptor agonists[7] and inhibitors of different proteases[11]
Furthermore, this scaffold has been proposed as a mimetic
of γ turn[12] and α helix[13] peptide secondary structures.
The development of new approaches to the synthesis of chi-
ral piperazin-2-one derivatives with diverse substitution at
different ring positions to increase molecular diversity in
medicinal chemistry is therefore of particular significance.
In this context, different methods for the construction of
piperazin-2-ones have been reported and have recently been
reviewed.[1,14]
As part of our ongoing medicinal chemistry project de-
voted to the search for piperazin-2-one-based peptidomi-
metics as PAR1 antagonists, here we report the synthesis
of 1,4-unsubstituted piperazin-2-ones derived from Phe-Gly
dipeptides and their regioselective functionalization at the
N1 and N4 positions, including the synthesis of fused bi-
cyclic derivatives.
To assign the configurations at the new chiral centre in
the two epimers of 3, they were transformed into the corre-
sponding mixture of imidazolidin-2-ones 4 (Scheme 1) by a
sequence of N-Boc removal and treatment with bis(tri-
1
chloromethy1)carbonate. In the H NMR spectrum of the
epimeric mixture, the major isomer (5S)-4 showed a J4,5
value of 8 Hz consistent with a H4,H5 relative cis orienta-
tion, whereas in the minor isomer (5R)-4 the value of this
constant was 4.5 Hz, indicative of a H4,H5 trans relative
orientation.[16] Furthermore, this assignment was confirmed
by the stronger NOE effect between the H4,H5 protons ob-
served for the major isomer in the NOESY 1D spectrum of
the mixture (Scheme 1).
Reductive cyclization of pseudodipeptides 3 by catalytic
hydrogenation with in situ lactamization, in the presence of
Raney Ni as catalyst,[17] led to the 5-substituted piperazin-
2-ones 5 (Scheme 2, below) in 65% yield. The dia-
stereomeric ratio remained unchanged in this reductive cy-
clization [(R)/(S) 3:1].[18]
[a] Instituto de Química Médica (IQM-CSIC),
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: +34-915644853
E-mail: mgutierrez@iqm.csic.es
Homepage: http://www.iqm.csic.es/paginas/peptidomimeticos/
index_ing.html
Received: September 12, 2012
To explore access to molecular diversity in the piperazin-
2-one scaffold, an exploratory study on the reactivity at the
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201221.
Eur. J. Org. Chem. 2013, 155–161
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Scheme 1. Synthesis and configuration assignment of piperazin-2-ones.
N1 and N4 positions was carried out. Firstly, we examined
In view of the low N1 reactivity, N1-alkylation of 6 with
regioselective alkylation. To this end, alkylation of the epi- BnBr under microwave heating conditions at 150 °C in the
meric mixture of 5 with benzyl bromoacetate with use of presence of different bases was also studied (Table 2), with
different bases and reaction conditions was studied.
the reaction being checked by HPLC-MS after 10, 20 and
As shown in Table 1, the base plays a critical role in the 30 min. After 30 min, the reactions were complete, except
monoalkylation/dialkylation product ratio. When NaH in the case of the use of K2CO3 (Table 2, Entry 1), in which
(Entry 1) and Cs2CO3 (Entry 2) were used, the reaction the starting material remained unchanged. The low yields
took more than 5 d, and the monoalkylated piperazin-2- obtained in the presence of NaH (Table 2, Entry 2) or DBU
ones 6 were obtained together with variable amounts of the (Table 2, Entry 7) were due to the formation of high per-
dialkylated products 7. When K2CO3 (Table 1, Entry 3) was centages of decomposition products. The best bases were
used, however, epimers 6 were obtained as the sole reaction Cs2CO3 (Table 2, Entry 3) and phosphazene base P1-tBu
products. To decrease the reaction time, we studied the reac- (Table 2, Entry 6), which led to the piperazin-2-ones 8 in
tion under microwave heating conditions at 100 °C and 70–75% yield.
150 °C in the presence of K2CO3 as alkylating reagent.
Interestingly, under these condition, with heating at 150 °C
for 10 min, the desired 4-alkylated piperazin-2-ones 6 were
Table 2. Reaction conditions for the N1-benzylation of 6.
obtained regiospecifically in 95% yield (Table 1, Entry 8).
Table 1. Regioselective alkylation at N4.
Entry
Base
8, yield /%[a]
1
2
3
4
5
6
7
K2CO3
NaH
Cs2CO3
BEMP
0[b]
28[c]
95 (70)[d]
93
Entry Base
Equiv. T [°C]
Base
t
Yield [%][a]
BTPP
90
6
7
phosphazene base P1-tBu
DBU
98 (75)[d]
0[c]
1
2
3
4
5
6
7
8
NaH
1.1
60
60
60
6 d
5 d
3 d
43[b]
67[b]
89[b]
63
5[b]
17[b]
0
0
0
Cs2CO3 1.1
K2CO3 1.1
K2CO3 1.1
K2CO3 1.1
K2CO3 1.1
K2CO3 1.5
[a] Calculated by HPLC [Sunfire C18 (4.6ϫ150 mm, 3.5 μm), gra-
dient 10–100% A in B for 30 min]. [b] Starting material remained
unchanged. [c] Starting material decomposition. [d] Isolated com-
pound.
100 (MW)[c] 5 min
150 (MW)
150 (MW)
150 (MW)
150 (MW)
5 min
70
20 min 78
10 min 90
10 min 95
0
0
1
K2CO3
2
Although, it was not possible to resolve the epimeric
mixtures, the epimeric ratio remained constant through the
different alkylation reactions. The fact that no racemization
[a] Calculated by HPLC [Sunfire C18 (4.6ϫ150 mm, 3.5 μm), gra-
dient 10–100% A in B for 30 min]. [b] Isolated compounds. [c] MW:
microwave heating.
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Synthesis and Functionalization of Phe-Gly-Based Piperazin-2-ones
had occurred was unequivocally demonstrated by further protecting groups. As shown in Scheme 3, treatment of the
debenzylation and subsequent coupling with different piperazin-2-ones 5 with Cbz-Cl or Fmoc-Cl gave the corre-
amino acids.[19]
sponding N4-protected derivatives 10 and 11 regiospecifi-
After the alkylation studies, we explored the reaction of cally in excellent yields. Next, the N1-alkylation of 10 under
the piperazin-2-ones 5 with benzyl isocyanate with the aim the optimized conditions (Cs2CO3 at 150 °C, MW; see
of preparing urea derivatives. As shown in Scheme 2, this above, Table 2, Entry 3) was tried. Under these conditions,
reaction provided the corresponding ureas 9 regiospecifi- the N1-alkylated piperazin-2-ones 12 were detected by
cally in good yields (86%).
HPLC-MS (55% yield), together with the Cbz-deprotected
byproduct (45%). After a new study of reaction conditions
(base, temperature and solvent), the Cbz removal was avo-
ided and the N1-alkylated derivatives 12 were obtained re-
gioselectively in 80% yield by use of NaH as base in THF/
DMF (9:1) at 0 °C. Next, Pd(C)-catalysed hydrogenolysis
of 12, at room temperature, gave the corresponding 4-de-
protected piperazin-2-ones 13 in good yield (78%).
Finally, because skeletal diversity is one of the key fac-
tors for molecular diversity, we studied the potential of the
Scheme 2. Synthesis of ureas.
In view of the higher reactivity of the N4 position, pro- stepwise N1,N4-functionalization to transform the piper-
tection of this position was studied as a strategy for regiose- azine ring into fused bicyclic scaffolds. Thus, as shown in
lective functionalization of the N1 in preference to the N4 Scheme 4, N-Boc removal from 5, followed by treatment
position. To this end, the benzyloxycarbonyl (Cbz) and 9- with triphosgene in the presence of TEA, led to the imid-
fluorenylmethoxycarbonyl (Fmoc) groups were chosen as azo[1,5-a]pyrazines 14 (60% yield). On the other hand, N-
Scheme 3. N4-Protection and N1-alkylation.
Scheme 4. Building of bicyclic skeletons.
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136.0, 155.5, 171.3 ppm. Epimer (S)-3: δ = 28.1, 38.2, 48.4, 52.0,
53.9, 80.3, 117.5, 127.0, 128.7, 129.0, 136.0, 155.5, 171.0 ppm. ES-
MS: m/z = 348.4 [M + 1]+. C18H25N3O4 (347.41): calcd. C 62.23,
H 7.25, N 12.10; found C 62.21, H 7.19, N 12.01.
Boc removal from the 4-(benzyloxycarbonylmethyl)piper-
azin-2-ones 6 and 8, followed by microwave heating in the
presence of TEA, led to the pyrazino[1,2-a]pyrazines 15
(80% yield) and 16 (85% yield), respectively. These new
skeletons contain accessible diversity points that could al-
low the further incorporation of additional functionalities.
(4S,5RS)-5-Cyano-1-(methoxycarbonylmethyl)-4-phenylmethylimid-
azolidin-2-one (4): The epimeric mixture of α-aminonitriles 3 (R/S
1:3, 100 mg, 0.28 mmol) was dissolved in a solution of HCl (3.4 n)
in EtOAc (5 mL) and the mixture was stirred at room temperature
for 30 min. Afterward, the solvent was evaporated to dryness, the
residue was dissolved in CH3CN/H2O (1:3, 2 mL), and the solution
was lyophilized. The residue was dissolved in dichloromethane
Conclusions
In summary, we have outlined an easy methodology
to obtain N1,N4-unsubstituted piperazin-2-ones in one- (10 mL), and TEA (78 μL, 0.56 mmol) was added. After the system
had been stirred at 0 °C for 15 min, triphosgene (33 mg, 0.11 mmol)
and TEA (93 μL, 0.67 mmol) were added, and the mixture was
stirred at 0 °C for 2 h. The reaction mixture was diluted with
dichloromethane (10 mL), washed with H2O (2ϫ 5 mL) and brine
(5 mL) and dried with Na2SO4, and the solvents were evaporated
to dryness. The residue was purified by flash chromatography, with
a 0–15% MeOH gradient in dichloromethane as mobile phase, to
afford an epimeric mixture of 2-oxoimidazolidines 4 [(5R)/(5S) 1:3]
as a foam (46 mg, 60%). HPLC: 15.62 min [(5R)-4] and 15.94 min
[(5S)-4]. 1H NMR (400 MHz, CDCl3), epimer (5R)-4: δ = 2.96 (m,
2 H), 3.69 (d, J = 18.5 Hz, 1 H), 3.79 (s, 3 H), 4.12 (m, 1 H), 4.51
(d, J = 18.5 Hz, 1 H), 4.56 (d, J = 4.5 Hz, 1 H), 5.06 (s, 1 H), 7.21–
7.40 (m, 5 H) ppm. Epimer (5S)-4: δ = 3.04 (dd, J = 9.5, 13.5 Hz,
1 H), 3.16 (dd, J = 5, 13.5 Hz, 1 H), 3.71 (d, J = 18.5 Hz, 1 H),
3.76 (s, 3 H), 4.19 (m, 1 H), 4.55 (d, J = 18.5 Hz, 1 H), 4.86 (s, 1
H), 4.91 (d, J = 8 Hz, 1 H), 7.21–7.40 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3), epimer (5R)-4: δ = 41.0, 42.5, 50.9, 52.5, 55.9,
116.0, 127.6, 128.5, 129.2, 134.8, 158.4, 169.2 ppm. Epimer (5S)-4:
δ = 38.7, 42.9, 51.8, 52.5, 52.9, 114.3, 127.6, 128.5, 129.2, 135.2,
158.7, 169.2 ppm. ES-MS: m/z = 274.4 [M + 1]+. C14H15N3O3
(273.29): calcd. C 61.53, H 5.53, N 15.38; found C 61.42, H 5.39,
N 15.14.
pot fashion from PheΨ[(RS)CH(CN)NH]Gly pseudodi-
peptides, which are readily available through a three-com-
ponent Strecker reaction. Study of the reactivity in the pip-
erazin-2-one ring has shown that through appropriate con-
trol of reaction conditions, regioselective functionalization
of either the N1 or the N4 position is possible. Furthermore,
piperazin-2-ones as described here are good intermediates
for the building of new bicyclic skeletons. The application
of these methodologies to the field of protein-ligand modu-
lators is in progress and will be reported elsewhere.
Experimental Section
General Method: All reagents were of commercial quality. Solvents
were dried and purified by standard methods. Analytical TLC was
performed on aluminium sheets coated with a layer (0.2 mm) of
silica gel (60 F254). Silica gel 60 (230–400 mesh) was used for flash
chromatography. Analytical HPLC was performed with a Sun-
fire C18 (4.6ϫ 150 mm, 3.5 μm) column, a flow rate of 1 mLmin–1
and a tuneable UV detector set at 214 nm. A 10–100% gradient of
CH3CN (solvent A) in 0.05% TFA in H2O (solvent B) over 30 min
1
(5RS)-5-[(1S)-1-tert-Butoxycarbonylamino-2-phenylethyl]piperazin-
2-one (5): Raney Ni (1.50 g) was added to a solution of 3 [(2R)/
(2S) 1:3, 1.00 g, 2.88 mmol] in MeOH (15 mL) and the mixture
was hydrogenated at 1 atm of H2 and room temperature for 5 h.
Afterwards, the reaction mixture was filtered through celite and the
solvent was evaporated under reduced pressure. The residue was
purified by flash chromatography, with a 0–6% MeOH gradient in
dichloromethane as mobile phase, to afford the epimeric mixture
of piperazin-2-ones 5 [(5R)/(5S) 3:1] as a white solid (598 mg, 65%).
HPLC: tR = 12.04 min [(5R)-5] and 12.34 min [(5S)-5]. 1H NMR
(400 MHz, CDCl3), epimer (5R)-5: δ = 1.36 (s, 3 H), 2.90 (m, 1 H),
2.92 (m, 1 H), 2.97 (dd, J = 5, 14 Hz, 1 H), 3.24, 3.30 (m, 2 H),
3.48 (d, J = 18 Hz, 1 H), 3.60 (d, J = 18 Hz, 1 H), 3.88 (m, 1 H),
6.13 (s, 1 H), 7.11–7.37 (m, 5 H) ppm. Epimer (5S)-5: δ = 1.38 (s,
3 H), 2.90 (m, 3 H), 3.22, 3.40 (m, 2 H), 3.42 (d, J = 17.5 Hz, 1
H), 3.58 (d, J = 17.5 Hz, 1 H), 3.90 (m, 1 H), 6.02 (s, 1 H), 7.11–
7.37 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3), epimer (5R)-5:
δ = 28.4, 37.2, 45.6, 49.1, 53.4, 54.8, 80.0, 126.8, 128.8, 129.5, 137.3,
155.9, 169.9 ppm. Epimer (5S)-5: δ = 28.4, 38.9, 45.6, 49.3, 52.8,
53.4, 80.0, 126.9, 128.9, 129.3, 137.5, 155.6, 170.2 ppm. ES-MS:
m/z = 320.2 [M + 1]+. C17H25N3O3 (319.40): calcd. C 63.93, H
7.89, N 13.16; found C 63.76, H 8.04, N 13.31.
was used as mobile phase. H NMR spectra were recorded at 300
or 400 MHz, with TMS as reference, and 13C NMR spectra were
recorded at 75 or 100 MHz. The NMR spectra assignment was
based on COSY, HSQC, and HMBC spectra. ESI-MS was per-
formed, in positive mode with MeOH as solvent. MW experiments
were carried out with an EmrysTM Synthesizer MW reactor
(Biotage AB, surface IR sensor).
Boc-PheΨ[(RS)CH(CN)NH]Gly-OMe
(3):
TEA
(1.1 mL,
7.96 mmol) was added to a solution of H-Gly-OMe·HCl (1.00 g,
7.96 mmol) in MeOH (40 mL). After 15 min stirring at room tem-
perature, the mixture was cooled to –20 °C and ZnCl2 (542 mg,
3.98 mmol) was added, followed by Boc-Phe-H[20] (992 mg,
3.98 mmol). The solution was stirred for 1 h at –20 °C, TMSCN
was then added (896 μL, 7.16 mmol), and the mixture was stirred
at 0 °C for 24 h. The solvent was removed under reduced pressure
and the residue was dissolved in EtOAc (50 mL). The solution was
washed with H2O (2؋ 25 mL) and brine (25 mL) and dried with
Na2SO4, and the solvents were evaporated to dryness to give the
epimeric mixture of α-aminonitriles 3 (R/S = 1:3) as a foam (1.24 g,
90%). HPLC: tR = 21.84 min [(R)-3] and 21.65 min [(S)-3]. 1H
NMR (400 MHz, CDCl3), epimer (R)-3: δ = 1.35 (s, 9 H), 2.84 (dd,
J = 8.5, 14 Hz, 1 H), 3.12 (dd, J = 6, 14 Hz, 1 H), 3.50 (m, 1 H),
3.70 (d, J = 6 Hz, 1 H), 3.72 (s, 3 H), 4.14 (m, 1 H), 4.83 (m, 1 H),
(5RS)-4-Benzyloxycarbonylmethyl-5-[(1S)-1-tert-butoxycarbonyl-
7.11–7.29 (m, 5 H) ppm. Epimer (S)-3: δ = 1.36 (s, 9 H), 2.90 (dd, amino-2-phenylethyl]piperazin-2-one (6): Benzyl bromoacetate
J = 7.5, 14 Hz, 1 H), 2.96 (dd, J = 9.5, 14 Hz, 1 H), 3.5 (m, 2 H),
3.69 (s, 3 H), 3.72 (d, J = 6 Hz, 1 H), 4.24 (m, 1 H), 4.83 (m, 1 H),
7.11–7.29 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3), epimer (R)-
3: δ = 28.1, 38.2, 48.3, 52.0, 53.4, 80.3, 118.1, 126.9, 128.6, 129.1,
(68 μL, 0.34 mmol) and K2CO3 (47 mg, 0.34 mmol) were added un-
der argon to a solution of 5 [(5R)/(5S) 3:1, 100 mg, 0.31 mmol] in
anhydrous CH3CN (5 mL), and the mixture was stirred for 3 d at
60 °C. Afterwards, the solvent was removed under reduced pressure
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Synthesis and Functionalization of Phe-Gly-Based Piperazin-2-ones
and the residue was dissolved in dichloromethane (100 mL). The
solution was washed with H2O (2ϫ 25 mL) and brine (25 mL) and
dried with Na2SO4, and the solvents were evaporated to dryness.
The residue was purified by flash chromatography, with 0–6%
MeOH gradient in dichloromethane as mobile phase, to afford the
2 H), 3.56 (d, J = 17.5 Hz, 1 H), 4.08 (d, J = 17.5 Hz, 1 H), 4.09
(m, 1 H), 4.42 (m, 2 H), 4.55 (d, J = 5.5 Hz, 1 H), 4.92 (d, J =
9 Hz, 1 H), 5.28 (m, 1 H), 6.66 (m, 1 H), 7.11–7.33 (m, 10 H) ppm.
Epimer (5S)-9: δ = 1.30 (s, 3 H), 2.75 (m, 1 H), 2.95 (dd, J = 5,
14 Hz, 1 H), 3.18 (m, 1 H), 3.58 (m, 1 H), 3.90 (d, J = 17 Hz, 1
H), 4.08 (m, 1 H), 4.09 (m, 1 H), 4.42 (m, 2 H), 4.55 (m, 1 H), 4.90
epimeric mixture 6 [(5R)/(5S) 3:1] as a foam (131 mg, 90%). HPLC:
1
tR = 21.41 min. H NMR (400 MHz, CDCl3), epimer (5R)-6: δ = (m, 1 H), 5.36 (m, 1 H), 6.55 (m, 1 H), 7.11–7.33 (m, 10 H) ppm.
1.34 (s, 3 H), 2.94 (m, 3 H), 3.35 (m, 1 H), 3.44 (d, J = 18 Hz, 1
H), 3.45 (m, 1 H), 3.50 (m, 2 H), 3.66 (d, J = 18 Hz, 1 H), 4.02
13C NMR (100 MHz, CDCl3), epimer (5R)-9: δ = 28.2, 37.6, 41.6,
45.1, 51.0, 51.2, 79.8, 126.4, 127.8, 128.4, 128.6, 128.9, 137.7, 139.0,
(m, 1 H), 4.45 (d, J = 8 Hz, 1 H), 5.16 (s, 2 H), 6.29 (m, 1 H), 155.7, 156.5, 166.4 ppm. Epimer (5S)-9: δ = 28.2, 37.6, 41.6, 45.1,
7.10–7.41 (m, 10 H) ppm. Epimer (5S)-6: δ = 1.36 (s, 3 H), 2.86
(m, 1 H), 2.94 (m, 2 H), 3.28 (m, 1 H), 3.44 (m, 1 H), 3.45 (m, 1
H), 3.50 (m, 2 H), 3.64 (d, J = 17.5 Hz, 1 H), 3.91 (m, 1 H), 5.02
(d, J = 8 Hz, 1 H), 5.14 [d, J = 5 Hz, 2 H], 6.25 (m, 1 H), 7.10–
7.41 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3), epimer (5R)-6:
δ = 28.2, 37.6, 40.7, 51.4, 52.8, 53.9, 58.0, 66.7, 79.8, 126.6, 128.5,
128.6, 129.4, 135.3, 137.2, 155.4, 169.4, 170.2 ppm. Epimer (5S)-6:
δ = 28.3, 38.4, 40.7, 51.4, 52.4, 54.1, 58.0, 66.7, 79.8, 126.6, 128.5,
128.6, 129.2, 135.3, 137.4, 155.4, 169.4, 170.4 ppm. ES-MS: m/z =
468.4 [M + 1]+. C26H33N3O5 (467.56): calcd. C 66.79, H 7.11, N
8.99; found C 66.70, H 7.21, N 9.08.
51.0, 51.2, 79.6, 126.7, 127.3, 127.4, 127.6, 129.0, 137.0, 138.9,
155.9, 157.2, 166.4 ppm. ES-MS: m/z = 453.5 [M + 1]+.
C25H32N4O4 (452.55): calcd. C 66.35, H 7.13, N 12.38; found C
66.08, H 6.95, N 12.21.
(5RS)-4-Benzyloxycarbonyl-5-[(1S)-1-tert-butoxycarbonylamino-2-
phenylethyl]piperazin-2-one (10): Propylene oxide (66 μL,
0.93 mmol) and benzyl chloroformate (135 μL, 0.93 mmol) were
added at 0 °C to a solution of 5 [(5R)/(5S) 3:1, 100 mg, 0.31 mmol]
in dichloromethane (25 mL), and the mixture was stirred for 24 h
at room temperature. Afterwards, the solvent was evaporated under
reduced pressure and the residue was purified by flash chromatog-
raphy, with 0–6% MeOH gradient in dichloromethane as mobile
phase, to afford the epimeric mixture 10 [(5R)/(5S) 3:1] as a foam
(127 mg, 90 %). HPLC: 20.89 min. 1H NMR (400 MHz, [D6]-
DMSO), epimer (5R)-10: δ = 1.23 (s, 3 H), 2.58 (m, 2 H), 3.22 (d,
J = 13 Hz, 1 H), 3.26 (m, 1 H), 3.57 (d, J = 18 Hz, 1 H), 3.87 (m,
1 H), 4.08 (d, J = 18 Hz, 1 H), 4.20 (m, 1 H), 5.11 (m, 2 H), 6.98
(d, J = 9 Hz, 1 H), 7.05–7.27, 7.27–7.46 (2ϫm, 10 H), 7.98 (m, 1
H) ppm. Epimer (5S)-10: δ = 1.23 (s, 3 H), 2.62 (m, 2 H), 3.20 (m,
1 H), 3.25 (m, 1 H), 3.60 (m, 1 H), 3.87 (m, 1 H), 4.12 (d, J =
18 Hz, 1 H), 4.22 (m, 1 H), 5.11 (m, 2 H), 6.60 (d, J = 9 Hz, 1 H),
7.05–7.27, 7.27–7.46 (2ϫm, 10 H), 7.98 (m, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO), epimer (5R)-10: δ = 28.2, 36.7, 39.6, 44.0,
50.2, 51.1, 66.7, 77.8, 128.0, 128.4, 129.1, 136.8, 138.7, 154.7, 155.6,
165.7 ppm. Epimer (5S)-10: δ = 28.2, 36.7, 39.6, 43.7, 50.6, 51.4,
66.0, 77.8, 125.9, 127.7, 127.8, 136.5, 138.5, 154.9, 155.6,
165.7 ppm. ES-MS: m/z = 454.7 [M + 1]+. C25H31N3O5 (453.54):
calcd. C 66.21, H 6.89, N 9.27; found C 66.30, H 7.04, N 9.37.
(5RS)-1-Benzyl-4-benzyloxycarbonylmethyl-5-[(1S)-1-tert-butoxy-
carbonylamino-2-phenylethyl]piperazin-2-one (8): Benzyl bromide
(78 μL, 0.66 mmol) and Cs2CO3 (215 mg, 0.66 mmol) were added
under argon to a solution of 6 [(5R)/(5S) 3:1, 100 mg, 0.22 mmol)
in anhydrous CH3CN (5 mL), and the mixture was stirred for
30 min at 150 °C with MW heating. Afterwards, the solvent was
removed under reduced pressure and the residue was dissolved in
EtOAc (100 mL). The solution was washed with H2O (2ϫ 25 mL)
and brine (25 mL) and dried with Na2SO4, and the solvents were
evaporated to dryness. The residue was purified by flash
chromatography, with 20–50% EtOAc gradient in hexane as mobile
phase, to afford the epimeric mixture 8 [(5R)/(5S) 3:1] as a foam
(86 mg, 70 %). HPLC: tR = 26.61 min. 1H NMR (300 MHz,
CDCl3), epimer (5R)-8: δ = 1.32 (s, 3 H), 2.74 (m, 2 H), 2.95 (m,
1 H), 3.19 (dd, J = 7.5, 12.5 Hz, 1 H), 3.31 (dd, J = 5, 12.5 Hz, 1
H), 3.40 (d, J = 17 Hz, 1 H), 3.57 (m, 2 H), 3.61 (d, J = 17 Hz, 1
H), 3.97 (m, 1 H), 4.25 (d, J = 9 Hz, 1 H), 4.45 (d, J = 14.5 Hz, 1
H), 4.73 (d, J = 14.5 Hz, 1 H), 5.13 (s, 2 H), 7.10–7.40 (m, 15
H) ppm. Epimer (5S)-8: δ = 1.34 (s, 3 H), 2.74 (m, 2 H), 2.95 (m,
1 H), 3.17 (m, 1 H), 3.33 (m, 1 H), 3.40 (m, 1 H), 3.57 (m, 2 H),
3.61 (m, 1 H), 3.75 (m, 1 H), 4.26 (d, J = 9 Hz, 1 H), 4.41 (m, 1
H), 4.63 (m, 1 H), 5.15 (s, 2 H), 7.10–7.40 (m, 15 H) ppm. 13C
NMR (75 MHz, CDCl3), epimer (5R)-8: δ = 28.2, 37.6, 44.6, 49.7,
51.2, 52.8, 54.4, 57.9, 66.8, 79.8, 126.7, 127.9, 128.6, 128.7, 128.9,
129.4, 135.4, 136.4, 137.2, 155.2, 167.2, 170.2 ppm. Epimer (5S)-8:
δ = 28.2, 37.6, 45.2, 49.8, 51.2, 52.8, 54.4, 58.2, 66.7, 79.8, 126.7,
127.9, 128.4, 128.5, 128.6, 129.3, 134.4, 136.4, 137.2, 155.2, 168.3,
170.3 ppm. ES-MS: m/z = 558.2 [M + 1]+. C33H39N3O5 (557.69):
calcd. C 71.07, H 7.05, N 7.53; found C 71.19, H 6.92, N 7.62.
(5RS)-5-[(1S)-1-tert-Butoxycarbonylamino-2-phenylethyl]-4-[(9H-
fluoren-9-yl)methoxycarbonyl]piperazin-2-one (11): Propylene oxide
(220 μL, 3.1 mmol) and Fmoc chloride (88 mg, 0.34 mmol) were
added at 0 °C to a solution of 5 [(5R)/(5S) 3:1, 100 mg, 0.31 mmol]
in dichloromethane (25 mL), and the mixture was stirred overnight
at room temperature. Afterwards, the solvent was evaporated under
reduced pressure and the residue was purified by flash chromatog-
raphy, with 0–6% MeOH gradient in dichloromethane as mobile
phase, to afford the epimeric mixture of N-Fmoc-protected pipera-
zin-2-ones 11 [(5R)/(5S) 3:1] as a white solid (153 mg, 91%). HPLC:
27.45 min. 1H NMR [400 MHz, (CD3)2CO], epimer (5R)-11: δ =
1.28 (s, 3 H), 2.77 (m, 2 H), 3.48 (m, 2 H), 3.60 (d, J = 18 Hz, 1
H), 4.11 (m, 1 H), 4.15 (m, 1 H), 4.35 (m, 1 H), 4.38 (m, 1 H),
4.51, 4.57 (2ϫm, 2 H), 6.13 (d, J = 9.5 Hz, 1 H), 7.10 (m, 1 H),
7.11–7.48, 7.63–7.99 (2ϫm, 13 H) ppm. Epimer (5S)-11: δ = 1.18
(s, 3 H), 2.74 (m, 2 H), 3.46, 3.65 (2ϫm, 2 H), 3.80 (d, J = 18 Hz,
1 H), 4.01 (m, 1 H), 4.06 (m, 1 H), 4.29 (m, 1 H), 4.35 (m, 1 H),
4.37, 4.65 (2ϫm, 2 H), 6.03 (d, J = 9.5 Hz, 1 H), 7.01 (m, 1 H),
7.11–7.48, 7.63–7.99 (2 ϫ m, 13 H) ppm. 13C NMR [100 MHz,
(CD3)2CO], epimer (5R)-11: δ = 28.5, 38.5, 41.4, 45.5, 48.2, 51.6,
53.2, 68.1, 78.9, 120.7, 126.0, 126.9, 128.0, 128.6, 128.9, 130.1,
(5RS)-4-Benzylaminocarbonyl-5-[(1S)-1-tert-butoxycarbonylamino-
2-phenylethyl]piperazin-2-one (9): Benzyl isocyanate (39 μL,
0.31 mmol) was added to a solution of 5 [(5R)/(5S) 3:1, 100 mg,
0.31 mmol] in dichloromethane (25 mL), and the mixture was
stirred for 3 h at room temperature. Afterwards, the mixture was
diluted with dichloromethane (50 mL), the solution was washed
with H2O (2ϫ 25 mL) and brine (25 mL) and dried with Na2SO4,
and the solvents were evaporated to dryness. The residue was puri-
fied by flash chromatography, with 0–6 % MeOH gradient in
dichloromethane as mobile phase, to afford the epimeric mixture
of ureas 9 [(5R)/(5S) 3:1] as a foam (123 mg, 86 %). HPLC: 139.7, 142.2, 145.0, 155.5, 156.3, 166.2 ppm. Epimer (5S)-11: δ =
1
18.49 min [(5R)-9] and 18.89 min [(5S)-9]. H NMR (400 MHz, 28.2, 38.7, 42.3, 46.3, 48.2, 51.9, 53.6, 68.4, 78.9, 120.7, 126.0,
CDCl3), epimer (5R)-9: δ = 1.29 (s, 3 H), 2.82 (m, 2 H), 3.45 (m,
126.9, 128.0, 128.6, 128.9, 130.1, 139.7, 142.2, 145.1, 155.3, 156.3,
Eur. J. Org. Chem. 2013, 155–161
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159

M. Gutiérrez-Rodríguez et al.
166.6 ppm. ES-MS: m/z = 564.7 [M + Na]+. C32H35N3O5 (541.65): (8aRS)-(1S)-1-Benzyl-3,6-dioxooctahydroimidazo[1,5-a]pyrazine
FULL PAPER
calcd. C 70.96, H 6.51, N 7.76; found C 70.78, H 6.63, N 7.68.
(14): The epimeric mixture of piperazin-2-ones 5 [(5R)/(5S) 3:1,
100 mg, 0.31 mmol] was dissolved in a solution of HCl in EtOAc
(3.4 n, 5 mL), and the mixture was stirred at room temperature
for 30 min. Afterwards, the solvent was evaporated to dryness, the
residue was dissolved in CH3CN/H2O (1:3, 2 mL), and the solution
was lyophilized. TEA (87 μL, 0.62 mmol) was then added to a solu-
tion of the lyophilized powder in dichloromethane (10 mL) and the
mixture was stirred for 15 min at 0 °C. Afterwards, TEA (101 μL,
0.73 mmol) followed by triphosgene (36 mg, 0.12 mmol) were
added, and the mixture was stirred at 0 °C for 2 h. The solution
was diluted with dichloromethane (10 mL), washed with H2O (2ϫ
5 mL) and brine (5 mL) and dried with Na2SO4, and the solvents
were evaporated to dryness. The residue was purified by flash
chromatography, with 0–6% MeOH gradient in dichloromethane
as mobile phase, to afford the epimeric mixture of imidazopyraz-
ines 14 [(8aR)/(8aS) 3:1, 46 mg, 60%] as a foam. HPLC: 10.62 min.
1H NMR (400 MHz, [D6]DMSO), epimer (8aR)-14: δ = 2.77 (d, J
= 7.5 Hz, 2 H), 2.94 (ddd, J = 4, 5, 12 Hz, 1 H), 3.37 (t, J = 12 Hz,
1 H), 3.43 (d, J = 18 Hz, 1 H), 3.72 (ddd, J = 5, 7.5, 12 Hz, 1 H),
3.93 (d, J = 18 Hz, 1 H), 4.09 (q, J = 7.5 Hz, 1 H), 6.79 (m, 1 H),
7.14–7.40 (m, 5 H), 7.95 (d, J = 4 Hz, 1 H) ppm. Epimer (8aS)-14:
δ = 2.77 (m, 2 H), 2.68 (m, 1 H), 2.85 (dd, J = 5, 13 Hz, 1 H), 3.40
(d, J = 18 Hz, 1 H), 3.50 (m, 1 H), 3.83 (d, J = 18 Hz, 1 H), 4.09
(m, 1 H), 6.94 (m, 1 H), 7.14–7.40 (m, 5 H), 7.84 (d, J = 5 Hz, 1
H) ppm. 13C NMR (100 MHz, [D6]DMSO), epimer (8aR)-14: δ =
35.4, 39.8, 44.2, 52.9, 53.3, 127.1, 129.2, 129.4, 138.5, 160.7,
166.9 ppm. Epimer (8aS)-14: δ = 35.4, 44.2, 44.3, 54.6, 55.0, 127.2,
129.1, 130.0, 137.7, 159.7, 167.0 ppm. ES-MS:: m/z = 246.3 [M +
1]+. C13H15N3O2 (%):C: 63.66, H: 6.16, N: 17.13; found C: 63.80,
H: 6.02, N: 17.28.
(5RS)-4-Benzyloxycarbonyl-5-[(1S)-1-tert-butoxycarbonylamino-2-
phenylethyl]-1-(methoxycarbonylmethyl)piperazin-2-one (12):
Methyl bromoacetate (24 μL, 0.27 mmol) and sodium hydride
(11 mg, 0.44 mmol) were added under argon at 0 °C to a solution
of the epimeric mixture of piperazin-2-ones 10 [(5R)/(5S) 3:1,
100 mg, 0.22 mmol] in THF/DMF (9:1, 5 mL), and the mixture
was stirred for 1 h. Afterwards, the mixture was diluted with EtOAc
(50 mL) and the reaction was quenched by addition of H2O
(10 mL). The aqueous layer was extracted with EtOAc (2ϫ 10 mL),
the combined organic layers were washed with brine (20 mL) and
dried with Na2SO4, and the solvents were evaporated to dryness.
The residue was purified by flash chromatography, with 0–4%
MeOH gradient in dichloromethane as mobile phase, to afford the
epimeric mixture 12 [(5R)/(5S) 3:1, 93 mg, 80%] as a foam. HPLC:
1
23.89 min [(5R)-12] and 23.66 min [(5S)-12]. H NMR [400 MHz,
(CD3)2CO], epimer (5R)-12: δ = 1.31 (s, 3 H), 2.85 (m, 2 H), 3.58
(dd, J = 2, 13 Hz, 1 H), 3.71 (s, 3 H), 3.81 (dd, J = 4.5, 13 Hz, 1
H), 3.95 (m, 1 H), 4.14 (m, 1 H), 4.23 (m, 1 H), 4.26 (m, 1 H), 4.40
(m, 1 H), 4.44 (m, 1 H), 5.19 (m, 2 H), 6.28 (d, J = 9.5 Hz, 1 H),
7.09–7.51 (m, 10 H) ppm. Epimer (5S)-12: δ = 1.31 (s, 3 H), 2.85
(m, 1 H), 3.16 (t, J = 13.5 Hz, 1 H), 3.71 (s, 3 H), 3.73 (m, 1 H),
3.82 (m, 1 H), 3.92 (m, 1 H), 3.95 (m, 1 H), 4.23 (m, 1 H), 4.31
(m, 1 H), 4.40 (m, 1 H), 4.44 (m, 1 H), 5.70 (m, 2 H), 5.85 (d, J =
8 Hz, 1 H), 7.09–7.51 (m, 10 H) ppm. 13C NMR [100 MHz, (CD3)2-
CO], epimer (5R)-12: δ = 28.5, 38.3, 46.2, 48.0, 49.0, 52.3, 52.4,
53.2, 67.9, 80.0, 126.9, 129.0, 129.3, 129.9, 137.8, 139.6, 155.3,
156.4, 165.6, 170.7 ppm. Epimer (5S)-12: δ = 28.5, 38.2, 46.0, 48.0,
48.8, 52.2, 52.5, 53.7, 67.9, 80.0, 128.6, 128.8, 128.9, 130.3, 137.8,
139.4, 155.0, 156.4, 165.6, 170.4 ppm. ES-MS: m/z = 548.7 [M +
Na]+. C28H35N3O7 (525.60): calcd. C 63.98, H 6.71, N 7.99; found
C 63.81, H 6.85, N 7.91.
General Procedure for the Synthesis of Pyrazino[1,2-a]pyrazines: An
epimeric mixture of the corresponding 4-(benzyloxycarbonylmeth-
yl)piperazin-2-ones 6 or 8 [(5R)/(5S) 3:1, 0.17 mmol] was dissolved
in a solution of HCl in EtOAc (3.4 n, 5 mL), and the mixture was
stirred at room temperature for 30 min. Afterwards, the solvent was
evaporated to dryness, the residue was dissolved in CH3CN/H2O
(1:3, 2 mL), and the solution was lyophilized. TEA (24 μL,
0.68 mmol) was then added to a solution of the lyophilized powder
in CH3CN (5 mL), and the mixture was stirred for 30 min at 100 °C
under MW heating conditions. Afterwards, the solvent was evapo-
rated to dryness and the residue was purified by flash chromatog-
raphy, with a 0–6% MeOH gradient in dichloromethane as mobile
phase, to afford the epimeric mixture of pyrazino[1,2-a]pyrazines
[(9aR)/(9aS) 3:1] as a foam.
(5RS)-5-[(1S)-1-tert-Butoxycarbonylamino-2-phenylethyl]-1-(meth-
oxycarbonylmethyl)piperazin-2-one Hydrochloride (13): Pd(C)
(10 mg) and a solution of HCl in EtOAc (3.4 n, 100 μL, 0.34 mmol)
were added to a solution of 12 [(5R)/(5S) 3:1, 90 mg, 0.17 mmol]
in MeOH (5 mL), and the mixture was hydrogenated at 1 atm H2
and room temperature for 1 h. Afterwards, the reaction mixture
was filtered through celite and the solvent was evaporated under
reduced pressure. The residue was purified by reversed-phase
chromatography (Biotage Snap Cartridge C18, 12 g) with a 0–100%
CH3CN gradient in H2O as mobile phase. The purified compound
was dissolved in CH3CN/H2O (1:3, 2 mL) and the solution was
lyophilized to obtain 13 [(5R)/(5S) 3:1] as a lyophilized powder
(598 mg, 78%). HPLC: 12.97 min [(5R)-13] and 13.35 min [(5S)-
13]. 1H NMR (400 MHz, [D6]DMSO), epimer (5R)-13: δ = 1.28 (s,
3 H), 2.67 (dd, J = 10.5, 14 Hz, 1 H), 2.80 (dd, J = 4.5, 14 Hz, 1
H), 3.60 (m, 1 H), 3.69 (s, 3 H), 3.71 (m, 1 H), 3.72 (m, 1 H), 3.74
(d, J = 17 Hz, 1 H), 3.85 (d, J = 17 Hz, 1 H), 4.12 (m, 1 H), 4.17
(d, J = 17 Hz, 1 H), 4.30 (d, J = 17 Hz, 1 H), 7.16 (d, J = 9.5 Hz,
1 H), 7.18–7.39 (m, 5 H), 9.58 (m, 2 H) ppm. Epimer (5S)-13: δ =
1.23 (s, 3 H), 2.71 (dd, J = 11.5, 14 Hz, 1 H), 2.83 (m, 1 H), 3.60
(m, 1 H), 3.64 (m, 1 H), 3.68 (s, 3 H), 3.71 (m, 1 H), 3.74 (d, J =
17 Hz, 1 H), 3.91 (d, J = 17 Hz, 1 H), 3.98 (m, 1 H), 4.16 (d, J =
17 Hz, 1 H), 4.27 (d, J = 17 Hz, 1 H), 6.98 (d, J = 9.5 Hz, 1 H),
7.18–7.39 (m, 5 H), 9.58 (m, 2 H) ppm. 13C NMR (100 MHz, [D6]-
DMSO), epimer (5R)-13: δ = 28.2, 36.4, 45.0, 47.8, 51.4, 52.1, 55.0,
78.6, 126.5, 128.3, 129.0, 137.6, 155.8, 162.3, 169.0 ppm. Epimer
(5S)-13: δ = 28.1, 35.9, 45.0, 48.5, 50.9, 52.1, 54.9, 78.4, 126.5,
128.1, 129.3, 137.6, 155.5, 162.3, 169.0 ppm. ES-MS: m/z = 392.6
[M – Cl]+. C20H29N3O5·HCl: C 56.13, H 7.07, N 9.82; found C
56.32, H 6.96, N 9.71.
(1S,9aRS)-1-Benzyl-3,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrazine
(15): (35 mg, 80 %). HPLC: 9.08 min [(9aR)-15] and 9.28 min
[(9aS)-15]. 1H NMR (400 MHz, CDCl3), epimer (9aR)-15: δ = 2.60
(dd, J = 10, 13 Hz, 1 H), 2.76 (dd, J = 6, 13 Hz, 1 H), 3.23 (d, J
= 18 Hz, 1 H), 3.31 (m, 1 H), 3.37 (m, 1 H), 3.43 (d, J = 12.5 Hz,
1 H), 3.46 (d, J = 12.5 Hz, 1 H), 3.60 (d, J = 18 Hz, 1 H), 3.75 (t,
J = 13 Hz, 1 H), 4.08 (m, 1 H), 6.08 (m, 1 H), 6.87 (m, 1 H), 7.16–
7.21, 7.27–7.41 (m, 5 H) ppm. Epimer (9aS)-15: δ = 2.69 (dd, J =
9.5, 13.5 Hz, 1 H), 2.83 (m, 1 H), 2.99 (dd, J = 7, 13.5 Hz, 1 H),
3.12 (d, J = 14.5 Hz, 1 H), 3.16 (d, J = 14.5 Hz, 1 H), 3.36 (m, 1
H), 3.46 (m, 2 H), 3.48 (t, J = 13 Hz, 1 H), 3.56 (m, 1 H), 6.08 (m,
1 H), 6.94 (m, 1 H), 7.16–7.21, 7.27–7.41 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3), epimer (9aR)-15: δ = 36.5, 37.7, 51.5, 51.7,
54.3, 55.5, 127.6, 128.9, 129.3, 135.2, 168.2, 168.7 ppm. Epimer
(9aS)-15: δ = 40.3, 42.7, 54.4, 54.7, 54.8, 55.5, 127.5, 128.9, 129.2,
135.3, 167.6, 168.7. 16.39 ppm.
(1S,9aRS)-1,8-Dibenzyl-3,7-dioxooctahydro-1H-pyrazino[1,2-a]pyr-
azine (16): (41 mg, 85%). HPLC: 15.46 min [(9aR)-16] and
160
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Synthesis and Functionalization of Phe-Gly-Based Piperazin-2-ones
1
[6] T. Hirose, T. Sunazuka, S. Tsuchiya, T. Tanaka, Y. Kojima, R.
15.69 min [(9aS)-16]. H NMR (400 MHz, CDCl3), epimer (9aR)-
¯
Mori, M. Iwatsuki, S. Omura, Chem. Eur. J. 2008, 14, 8220–
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16: δ = 2.48 (dd, J = 10 and 13 Hz, 1 H), 2.70 (dd, J = 6 and
13 Hz, 1 H), 3.16 (dd, J = 5 and 12 Hz, 1 H), 3.37 (m, 1 H), 3.40
(m, 2 H), 3.41 (d, J = 17.5 Hz, 1 H), 3.59 (dd, J = 12 and 14 Hz,
1 H), 3.65 (d, J = 17.5 Hz, 1 H), 3.99 (m, 1 H), 4.51 (d, J = 15 Hz,
1 H), 4.80 (d, J = 15 Hz, 1 H), 5.70 (m, 1 H), 6.99–7.12, 7.19–7.46
(m, 10 H) ppm. Epimer (9aS)-16: δ = 2.54 (dd, J = 9.5 and 13.5 Hz,
1 H), 2.81 (m, 2 H), 3.11 (d, J = 17 Hz, 1 H), 3.23 (d, J = 17 Hz,
1 H), 3.32 (m, 2 H), 3.36 (d, J = 17 Hz, 1 H), 3.48 (m, 1 H), 3.57
(d, J = 17 Hz, 1 H), 4.54 (d, J = 15 Hz, 1 H), 4.70 (d, J = 15 Hz,
1 H), 5.74 (m, 1 H), 6.99–7.12, 7.19–7.46 (m, 10 H) ppm. 13C NMR
(100 MHz, CDCl3), epimer (9aR)-16: δ = 37.7, 40.6, 50.1, 51.6,
52.6, 54.4, 55.9, 127.6, 127.9, 128.1, 128.8, 128.9, 129.2, 135.1,
136.0, 165.6, 167.9 ppm. Epimer (9aS)-16: δ = 40.2, 47.5, 49.5, 54.4,
54.9, 55.6, 55.8, 127.6, 127.9, 128.2, 128.9, 129.1, 129.2, 135.0,
135.9, 166.5, 167.4 ppm. ES-MS: m/z 350.0 [M + 1]+. C21H23N3O2
(%):C: 72.18, H: 6.63, N: 12.03; found C: 72.31, H: 6.57, N: 12.14.
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Supporting Information (see footnote on the first page of this arti-
cle): Copies of H and 13C NMR spectra for all new compounds.
1
Acknowledgments
This work was supported by the Spanish Ministerio de Ciencia e
Innovación (grant SAF2009-09323. A. M. V. was the recipient of a
postgraduate FPU fellowship from the Spanish Ministerio de Edu-
cación y Ciencia (MEC). A. M. V. also thanks the Spanish Society
of Therapeutic Chemistry (SEQT) for a Jassen-Cilag Award for
young researchers (XV Edition, 2011). P. V. was the recipient of a
FPI fellowship from the Spanish Ministerio de Ciencia e Innova-
ción (MICINN).
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Received: 12 September, 2012
Published Online: November 21, 2012
Eur. J. Org. Chem. 2013, 155–161
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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