A facile and effective synthesis of lipophilic 2,6-diketopiperazine analogues

Article abstract of DOI:10.1016/j.tet.2008.05.005

Adamantane and cyclooctane lipophilic 2,6-diketopiperazines (2,6-DKPs) have been prepared by a simple and effective method, including the synthesis of the corresponding iminodiacetic amido-ester derivatives and their intramolecular cyclization. In this method, the key step of the imide formation was accomplished by a novel base-induced cyclization protocol, which involved the treatment of amido-ester 2,6-DKP precursors with potassium bis(trimethylsilyl)amide. Moreover, the cyclization methodology used allowed the synthesis of the respective 1-functionalized 2,6-DKPs in one pot and in excellent yields when the same primary amido-esters were treated with the previous base and the intermediate potassium imidate salts were then reacted with the electrophile benzyl bromoacetate. Hydrogenolysis of the benzyl 2,6-diketopiperazine acetates afforded the respective carboxylic acids, which constitute versatile intermediates in the synthesis of peptidomimetics and other bioactive molecules concerning our pharmacological studies.

Full text of DOI:10.1016/j.tet.2008.05.005

Tetrahedron 64 (2008) 6749–6754
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A facile and effective synthesis of lipophilic 2,6-diketopiperazine analogues
*
Christos Fytas, Grigoris Zoidis, George Fytas
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, GR-15771 Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Adamantane and cyclooctane lipophilic 2,6-diketopiperazines (2,6-DKPs) have been prepared by a sim-
ple and effective method, including the synthesis of the corresponding iminodiacetic amido-ester de-
rivatives and their intramolecular cyclization. In this method, the key step of the imide formation was
accomplished by a novel base-induced cyclization protocol, which involved the treatment of amido-ester
2,6-DKP precursors with potassium bis(trimethylsilyl)amide. Moreover, the cyclization methodology
used allowed the synthesis of the respective 1-functionalized 2,6-DKPs in one pot and in excellent yields
when the same primary amido-esters were treated with the previous base and the intermediate po-
tassium imidate salts were then reacted with the electrophile benzyl bromoacetate. Hydrogenolysis of
the benzyl 2,6-diketopiperazine acetates afforded the respective carboxylic acids, which constitute
versatile intermediates in the synthesis of peptidomimetics and other bioactive molecules concerning
our pharmacological studies.
Received 4 February 2008
Received in revised form 10 April 2008
Accepted 1 May 2008
Available online 3 May 2008
Keywords:
2,6-Diketopiperazines
Base-induced cyclization
Potassium bis(trimethylsilyl)amide
NMR
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives 13a,b, 14, 16a,b, and 17, as well as the 3-adamantyl-2,6-
diketopiperazine derivatives 12, 15, and 18 (Table 1), by a new ef-
The head to head cyclic dipeptide framework of the 2,6-dike-
topiperazine (2,6-DKP) is present in several biologically active
compounds, and it serves as an effective template for construction
of conformationally constrained analogues. Among the 2,6-dike-
topiperazine structures, the bis(2,6-diketopiperazine) derivatives
ICRF-154, ICRF-159, and ICRF-193 (Fig. 1) have been proved to be
promising antitumor agents, through the inhibition of DNA top-
oisomerase II,1 whereas some 1,4-disubstituted 2,6-DKP derivatives
were found to display potent in vitro inhibition of leukemia and
Hep cells’ growth.2 Additionally, flutimide3 (a fungus-derived en-
donuclease inhibitor of influenza virus) is a structural 2,6-diketo-
fective synthetic procedure outlined in Scheme 1. Particularly,
carboxylic acids 16–18 appeared as useful building blocks in the
preparation of our target compounds.
2. Results and discussion
The synthesis of 2,6-diketopiperazines (2,6-DKPs) by intra-
molecular cyclization of iminodiacetic acid derivatives (amido-es-
ters or amido-carboxylic acids) is well established.6 Acyclic 2,6-DKP
precursors commonly contain a primary or secondary amide group,
as a nucleophilic nitrogen source, and a carboxyl or ester group, as
the electrophilic moiety. Several variations of the reaction condi-
tions, depending on the nature of the iminodiacetic derivative and
the demands of the 2,6-DKP ring substitution, have appeared in the
literature.2,3,6,7 In the case of amido-ester 2,6-DKP precursors, the
base-catalyzed intramolecular cyclization reaction is the most
preferred route in producing 2,6-DKPs.
D3-piperazine motif (Fig. 1).
On the other hand, adamantane is frequently found in bi-
ologically active compounds across a number of different phar-
macological activities (antiviral, antibacterial, trypanocidal,
anticancer, and anti-Parkinsonic activity).4 The cage-like structure
of the adamantane, present in bioactive compounds, improves their
lipophilicity.5 Therefore, during last years the adamantane de-
rivatives have attracted considerable attention.
As part of our research, concerning pharmacological studies, we
were interested in preparing analogues incorporating the bulky
lipophilic adamantane or cyclooctane ring to the 2,6-DKP core
structure. Thus, we synthesized the novel adamantane and cyclo-
octane spiro heterocycles 10a,b and 11, and their 1-substituted
O
HN
O
OH
N
O
R1
R2
O
O
N
N
NH
N
O
ICRF-154 : R1=H, R2=H
Flutimide
ICRF-159 : R1=H, R2=CH3
ICRF-193 : R1=CH3, R2=CH3
* Corresponding author. Tel.: þ30 210 7274810; fax: þ30 210 7274747.
E-mail address: gfytas@pharm.uoa.gr (G. Fytas).
Figure 1. Structures of ICRF-154, ICRF-159, ICRF-193, and flutimide.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.005

6750
C. Fytas et al. / Tetrahedron 64 (2008) 6749–6754
Table 1
CH2CO2H
H
4
CH2CO2CH2C6H5
O
NH2
CO2Et
O
N
O
R
H
CN CO2Et
R
O
N
O
O
O
O
N
O
3
2
5
6
1'
8'
7'
1
R
H
9' 2'
R
H
N
H
N
H
R
3'N
10'
N
H
H
N
H
H
6'
H
5'
4'
10a: R¼H (96,a
)
13a: R¼H (90b)
16ac: R¼H
*
4a: R¼H (80)
4b: R¼CH3 (63)
7a: R¼H (68)
1
10b: R¼CH3 (93,a
)
13b: R¼CH3 (89b)
16bc: R¼CH3
*
7b: R¼CH3 (59)
CH2CO2H
CH2CO2CH2C6H5
H
4
1
N
H
O
CN
NH2
CO2Et
CO2Et
,HCl
O
7
N
O
O
N
O
O
N
O
5
6
3
2
8
N
9
N
H
10
13
N
H
N
H
H
1112
*
2
3
5 (75)
8 (70)
11 (50,a
)
14 (94b)
17c
CH2CO2CH2C6H5
CH2CO2H
H
1
4
N
H
O
NH2
CO2Et
3
CN
O
1
N
O
CO2Et
O
N
O
O
N
O
4
5
O
CH
2
6
2
10
5
3
9
N
,HCl
N
H
6
N
H
N
H
7
8
H
*
6 (52)
9 (53)
12 (95,a
)
15 (83b)
18c
Yield in brackets.
The symbol asterisk (*) denotes the quantitative yield, obtained by following the procedure in Section 4.8.2.
a
Yield obtained from the corresponding amido-ester compound using the procedure in Section 4.8.1.
Yield based on the amido-ester compound used.
Yield of debenzylation almost quantitative.
b
c
H
O
O
N
O
R
H
N
H
O
NH2
CO2Et
10-12
CN
CO2Et
R
H
a
b
O
R
N
H
N
H
CH2CO2CH2C6H5
N
CH2CO2H
H
O
O
N
O
7-9
4-6
1-3
e
R
H
R
H
N
H
N
H
13-15
16-18
Scheme 1. Reagents and conditions: (a) NaCN, H2NCH2CO2Et$HCl or H2NCH(CH3)CO2Et$HCl (L-enantiomer), DMSO/H2O (29:1), rt, 48 h and then HCl(g)/Et2O only for the amino-
nitriles 5 and 6 (Table 1); (b) (i) concd H2SO4, rt, 24 h; (ii) ice and then aq NH3 26% to pH¼8; (c) (i) (Me3Si)2NK, THF, 0–5 ꢀC and then rt, 1 h, argon; (ii) HCl 5% to pH¼4–5, 0–5 ꢀC and
then Na2CO3 to pH¼7–8 or (ii) CF3CO2H (1 equiv); (d) (i) (Me3Si)2NK, THF, 0–5 ꢀC and then rt, 1 h, argon; (ii) benzyl bromoacetate, DMF, rt, 48 h, argon; (e) H2/Pd/C 10%, EtOH, 50 psi,
rt, 3 h.
Herranz et al. have described a cyclization method involving the
NaOH treatment, under phase transfer conditions, of one primary
amido-ester precursor for 1 h, which led to the corresponding
1-unsubstituted 2,6-DKP in high yield.7b The 2,6-DKP cyclization
precursor used was prepared via hydrolysis of the corresponding N-
1-substituted 2,6-DKPs by refluxing them in THF for 3 days with
potassium tert-butoxide in an approximate yield of 70%. When the
Ugi coupling procedure was carried out using ketones under weak
basic conditions (1 equiv of triethylamine), the formation of 2,6-
DKPs was only observed in moderate to good yields, after a long
reaction time. The Ugi multicomponent reaction is useful in pro-
ducing 1-substituted 2,6-DKP derivatives; however, it is evident
that this reaction cannot lead to the 1-unsubstituted 2,6-DKP
compounds. Other syntheses of 1-substituted 2,6-DKPs including
a base-promoted intramolecular cyclization (K2CO3, DMF, 70 ꢀC) of
amido-ester precursors (prepared in four steps from N-protected
[(methoxycarbonyl)methyl]-a-amino nitrile, obtained by a modi-
fied Strecker synthesis. Although this synthetic pathway could be
utilized as a general method to produce 1-unsubstituted 2,6-DKPs
in good overall yields, to the best of our knowledge, it has not been
reported whether it can be used to transform primary amide-ester
2,6-DKP precursors into 1-functionalized 2,6-DKPs directly. In
a more recent paper, Herranz et al. described a NaH-mediated cy-
clization of a number of amido-ester precursors in THF to the cor-
responding 1-unsubstituted 2,6-DKPs in yields ranging from 20 to
95%.7c Surprisingly, in this paper the authors mentioned that the
selective functionalization of the previous 2,6-DKPs at the imidic
nitrogen in a separate reaction step, using alkyl halides and NaH as
base in THF, gave the respective 1-substituted 2,6-DKPs in very
poor yields and a complex mixture of side products. Another
a
-amino acids) both by solution-phase and by solid-phase meth-
odologies have been reported.7f Apart from the problems associated
with the configurational lability of the resulting 2,6-DKPs under
cyclization reaction conditions, both methodologies suffer from low
overall yields, while in some cases no 2,6-DKP was formed.
We herein wish to report an alternative synthetic approach to
2,6-DKP derivatives, which starts from ketones or aldehydes and
proceeds smoothly in good overall yields, through a three step re-
action sequence, as outlined in Scheme 1. In this approach, the key
step of the imide formation was accomplished by employing a more
efficient base-induced cyclization mode, involving the treatment of
the amido-ester precursors 7–9 with an equivalent amount of
strategy was reported by Ugi et al.,7d,e according to which
a-amino
acids react with equimolar amount of an aldehyde or ketone and
isocyanide in methanol to afford amido-ester derivatives in a re-
action time of 3–14 days. These intermediates can be cyclized to

C. Fytas et al. / Tetrahedron 64 (2008) 6749–6754
6751
potassium bis(trimethysilyl)amide in THF at rt for a short reaction
time. In comparison with the other bases, reported in the literature,
the use of potassium bis(trimethylsilyl)amide allows synthesis of
the 1-unsubstituted 2,6-DKPs 10–12 (route A) quantitatively as well
as the functionalization at the imidic nitrogen of 2,6-DKPs 13–15 in
one step and in excellent isolated yields (route B). It is noteworthy
that the yields for compounds 10–12 dropped by 20–30% when
sodium hydride was employed instead of potassium bis-
(trimethylsilyl)amide under the same reaction conditions.
promoted hydrolysis of the intermediate N-substituted
a
-amino
nitriles, as described above, or by means of other syntheses men-
tioned elsewhere.7a,b,8 Conversely to other base-mediated cycliza-
tion methodologies reported in the literature, ours offer the
advantage that primary amido-ester 2,6-DKP precursors can be
selectively converted to 1-functionalized 2,6-DKPs in one pot and
in excellent yields. Particularly attractive is the facile synthesis of
1-carboxyalkylated 2,6-DKPs, which could be utilized as building
blocks in the production of conformationally constrained
peptidomimetics based on the 2,6-DKP scaffold. Applications in
this direction have been achieved and will be published in due
course.
The synthetic pathway depicted in Scheme 1 could be gen-
eralized to obtain 2,6-DKP derivatives in high yields, by using
cyclic or aliphatic aldehydes or ketones and a variety of
acid esters as starting materials. The -amino carboxamides 7–9
were the key intermediates in the synthesis of the 2,6-DKP de-
rivatives 10–15 (Scheme 1). Given that -amino carboxamides can
be derived from their corresponding -amino nitriles, we utilized
the N-[(ethoxycarbonyl)methyl]- -amino nitriles 4–6 in our syn-
thetic strategy. The Strecker reaction is the most effective syn-
thetic route leading to -amino nitriles. Thus, the bulky carbonyl
compounds 1–3 were reacted with the appropriate -amino acid
ethyl ester hydrochloride and NaCN in a DMSO/H2O (29:1) mix-
ture at rt to provide the corresponding -amino nitriles 4–6 in
moderate to high yields (Table 1). The -amino nitriles 5 and 6, in
a-amino
a
4. Experimental section
4.1. General
a
a
a
Melting points were determined using a Bu¨chi capillary appa-
ratus and are uncorrected. FTIR spectra were recorded on a Perkin–
Elmer RX 1 FT-IR spectrometer. 1H and 13C NMR spectra were
recorded on a Bruker MSL 400 spectrometer, using CDCl3 or DMSO-
d6 as solvent and TMS as internal standard. Carbon multiplicities
were established by DEPT experiments. The 2D NMR experiments
(HMQC, COSY, and NOESY) were performed for the elucidation of
the structures of the new compounds. Microanalyses were carried
out by the Service Central de Microanalyse (CNRS), France, and the
results obtained had a maximum deviation of ꢁ0.4% from the
theoretical value.
a
a
a
a
contrast with their counterparts 4a and 4b, were not stable
enough to be purified by chromatography, and due to that, were
precipitated as hydrochloride salts. It is also of note that the
a
-amino nitrile hydrochlorides 5 and 6 were unstable and decom-
posed on standing at rt. Subsequent acid-promoted hydrolysis of
the -amino nitriles 4–6 with concd H2SO4 at rt afforded the
respective -amino carboxamides 7–9 in 53–70% isolated yields.
In the case of the -amino nitrile 4a, the corresponding hydro-
a
a
4.2. N-[2-Cyano(tricyclo[3.3.1.13,7]dec-2-yl)]glycine ethyl ester
(4a): typical procedure
a
lysis product 7a was formed along with its respective cyclization
material 10a in 5% yield. The small quantity of 10a was easily
separated by column chromatography.
To a stirred suspension of NaCN (1.37 g, 27.9 mmol) and ethyl
glycinate hydrochloride (3.9 g, 27.9 mmol) in 18 mL of DMSO/H2O
9:1 (v/v), a solution of adamantanone (4 g, 26.6 mmol) in 36 mL
DMSO was added in one portion. The reaction mixture was stirred
at rt for 48 h in a stoppered flask and then poured into ice/water
mixture (200 mL). The oily product formed was extracted with Et2O
(4ꢂ60 mL), and the combined extracts were washed with H2O
(4ꢂ50 mL) and dried (Na2SO4). After removal of the solvent in
vacuo, the residue was purified by column chromatography on
silica gel (n-hexane/Et2O 1:2) to afford pure amino nitrile 4a
(5.62 g, 80%) as white crystals; mp 73–75 ꢀC (dec, Et2O/n-pentane).
Treatment of the precursor compounds 7–9 with potassium
bis(trimethylsilyl)amide (1 equiv, THF, rt, 1 h) led to the corre-
sponding 2,6-DKPs 10–12 in the form of potassium imidate salts.
Eventually, the free 2,6-DKPs 10–12 were acquired by aq HCl (5%)
treatment of their potassium salts followed by neutralization with
Na2CO3 (route A). Using this procedure, the cyclooctane 2,6-DKP 11
was isolated in a significantly lower yield (50%) than those of the
adamantane counterparts 10a,b and 12, which were obtained in
very high yields (93–96%) (Table 1). Thus, we deduced that the
lower yield of compound 11 was due to its higher instability
(compared to 10a,b and 12) in the acidic aqueous medium. In fact,
as shown in Table 1, all compounds 10–12 were obtained quanti-
tatively (>99%) when their corresponding potassium salts were
treated with equivalent amount of CF3CO2H in non-aqueous con-
ditions (Section 4.8.2). Conversion of the amido-ester precursors 7–
9 to the respective 1-functionalized 2,6-DKP analogues 13–15 was
effected in excellent yields (83–94%) by treatment with potassium
bis(trimethylsilyl)amide in THF and subsequent SN2 reaction of the
intermediate potassium imidate salts with benzyl bromoacetate in
DMF within the same pot (route B). Finally, catalytic hydrogenolysis
of the benzyl esters 13–15 yielded the corresponding carboxylic
acids 16–18 quantitatively.
IR (mull):
(400 MHz, CDCl3):
n .
3314 (N–H), 2217 (C^N), 1737 (C]O) cmꢃ1 1H NMR
d
¼1.27 (t, 3H, J¼7.0 Hz, OCH2CH3), 1.52 (d, 2H,
J¼11.8 Hz, H-4e, H-9e), 1.69 (s, 2H, H-6), 1.75 (s, 1H, H-5), 1.77–2.03
(complex m, 6H, H-1, H-3, H-7, H-8e, H-10e, NH), 2.13 (d, 2H,
J¼13.2 Hz, H-8a, H-10a), 2.21 (d, 2H, J¼11.8 Hz, H-4a, H-9a), 3.49 (s,
2H, HNCH2CO2C2H5), 4.22 (q, 2H, J¼7.0 Hz, CH3CH2O) ppm. 13C NMR
(100 MHz, CDCl3):
d
¼14.1 (CH3), 26.5 (C-5), 26.7 (C-7), 30.3 (C-4, C-
9), 34.5 (C-8, C-10), 34.6 (C-1, C-3), 37.3 (C-6), 45.1
(HNCH2CO2C2H5), 61.2 (CH3CH2O), 61.9 (C-2), 121.9 (CN), 171.4
(CO2C2H5) ppm. Anal. Calcd for C15H22N2O2: C, 68.67; H, 8.45; N,
10.68. Found: C, 68.28; H, 8.37; N, 10.68.
4.3. (L)-N-[2-Cyano(tricyclo[3.3.1.13,7]dec-2-yl)]-
L-alanine
ethyl ester (4b)
3. Conclusions
From adamantanone (4 g, 26.6 mmol), ethyl L-alaninate hydro-
In this paper, we have developed mild and experimentally
convenient protocols for construction of 2,6-DKP derivatives. In the
critical step of our synthetic approach, amido-ester derivatives of
the iminodiacetic acid can be readily transformed into 1-unsub-
stituted 2,6-DKPs quantitatively by a novel base-mediated cycli-
zation methodology. The amido-ester 2,6-DKP precursors needed
could be prepared either via Strecker synthesis followed by acid-
chloride (4.28 g, 27.9 mmol), and NaCN (1.37 g, 27.9 mmol). Purifi-
cation of the crude product by column chromatography on silica gel
(n-hexane/Et2O 3:1, then 1:1) afforded pure amino nitrile 4b
28
(4.64 g, 63%) as white crystals; mp 43–45 ꢀC (n-pentane). [
a]
589
ꢃ22.5 (c 0.4, CHCl3). IR (mull):
(C]O) cmꢃ1 1H NMR (400 MHz, CDCl3):
OCH2CH3), 1.34 (d, 3H, J¼7.0 Hz, CH3), 1.51 (d, 2H, J¼11.3 Hz, H-4e,
n
3315 (N–H), 2218 (C^N), 1728
.
d¼1.27 (t, 3H, J¼7.1 Hz,

6752
C. Fytas et al. / Tetrahedron 64 (2008) 6749–6754
H-9e), 1.70 (s, 2H, H-6), 1.76 (s, 1H, H-5), 1.79–2.05 (complex m, 6H,
H-1, H-3, H-7, H-8e, H-10e, NH), 2.06–2.28 (complex m, 4H, H-4a,
H-8a, H-9a, H-10a), 3.53 (q, 1H, J¼7.0 Hz, HNCHCO2C2H5), 4.20
The precipitate was filtered off, washed with cold Et2O (4ꢂ25 mL),
and dried to afford amino nitrile hydrochloride 5 (5.50 g, 75%) as
a white solid; mp 68–71 ꢀC (dec). The IR and 1H NMR spectrum of
(sym. m, 2H, CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3):
d¼14.1
unpurified free amino nitrile 5 were measured. IR (film):
n 3329 (N–
(CH3CH2O), 20.9 (CH3), 26.5 (C-5), 26.6 (C-7), 30.3 (C-4), 30.5 (C-9),
34.0 (C-1), 34.2 (C-8), 34.7 (C-10), 36.0 (C-3), 37.4 (C-6), 51.6
(HNCHCO2C2H5), 61.0 (CH3CH2O), 61.2 (C-2), 122.2 (CN), 175.4
(CO2C2H5) ppm. Anal. Calcd for C16H24N2O2: C, 69.53; H, 8.75; N,
10.14. Found: C, 69.51; H, 8.62; N, 10.02.
H), 2220 (C^N), 1746 (C]O) cmꢃ1 1H NMR (400 MHz, CDCl3):
.
d
¼1.26 (t, 3H, J¼7.0 Hz, OCH2CH3), 1.45–1.77 (m, 11H, H-3, H-4, H-5,
H-6, H-7, NH), 1.80–1.97 (m, 4H, H-2, H-8), 3.49 (d, 2H, J¼5.2 Hz,
HNCH2CO2C2H5), 4.19 (q, 2H, J¼7.0 Hz, CH3CH2O) ppm.
Title compound 8 was synthesized from the above amino nitrile
hydrochloride 5 (2.90 g, 10.6 mmol) by treating with H2SO4 97%
(5.5 mL) according to the procedure described for the preparation
of compound 7a. After workup, the white solid amino carboxamide
8 was collected by vacuum filtration, washed with H2O (3ꢂ7 mL),
and dried (1.90 g, 70%); mp 103–105 ꢀC (CH2Cl2/n-pentane). IR
4.4. N-[2-Aminocarbonyl(tricyclo[3.3.1.13,7]dec-2-yl)]glycine
ethyl ester (7a): typical procedure
To the aminonitrile 4a (2 g, 7.62 mmol), H2SO4 97% (3.6 mL) was
added dropwise under ice cooling. After stirring at rt for 24 h, the
mixture was poured into ice (30 g) and neutralized with aq NH3
26%. The solid material formed was isolated by vacuum filtration,
washed with H2O (3ꢂ5 mL), dried, and finally purified by column
chromatography on silica gel (Et2O, then Et2O/AcOEt 1:1) to afford
the spirocyclic 2,6-DKP 10a (90 mg, 5%) as a side product and then
pure amino carboxamide 7a (1.46 g, 68%) as a white crystalline
(mull):
(400 MHz, CDCl3):
n .
3421, 3341, 3308, 3195, 1731, 1658, 1606 cmꢃ1 1H NMR
d¼1.25 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.34–1.69 (m,
12H, H-2, H-3, H-4, H-5, H-6, H-7, H-8), 1.82 (br s, 1H, NHCH2), 2.02
(q, 2H, J¼8.6, 9.8 Hz, H-2, H-8), 3.25 (s, 2H, HNCH2CO2C2H5), 4.16 (q,
2H, J¼7.2 Hz, CH3CH2O), 5.36 (br s, 1H, CONHH), 7.15 (br s, 1H,
CONHH) ppm. 13C NMR (100 MHz, CDCl3):
d¼14.1 (CH3), 21.6 (C-4,
C-6), 24.7 (C-5), 28.2 (C-3, C-7), 30.7 (C-2, C-8), 45.1
(HNCH2CO2C2H5), 61.1 (CH3CH2O), 64.3 (C-1), 172.3 (CO2C2H5),
178.8 (CONH2) ppm. Anal. Calcd for C13H24N2O3: C, 60.91; H, 9.44;
N, 10.93. Found: C, 60.71; H, 9.36; N, 11.18.
solid; mp 115–117 ꢀC (CH2Cl2/n-pentane). IR (mull):
n 3431, 3380,
3337, 3320, 3176, 1728, 1677, 1642 cmꢃ1. 1H NMR (400 MHz, CDCl3):
d
¼1.24 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.56 (d, 2H, J¼12.3 Hz, H-4e, H-
9e), 1.65 (s, 2H, H-6), 1.68–1.84 (m, 4H, H-5, H-7, H-8e, H-10e), 1.92–
2.16 (m, 7H, H-1, H-3, H-4a, H-8a, H-9a, H-10a, NHCH2), 3.30 (s, 2H,
HNCH2CO2C2H5), 4.14 (q, 2H, J¼7.1 Hz, CH3CH2O), 5.81 (br s, 1H,
CONHH), 6.19 (br s, 1H, CONHH) ppm. 13C NMR (100 MHz, CDCl3):
4.7. N-[Aminocarbonyl(tricyclo[3.3.1.13,7]dec-1-yl)methyl]
glycine ethyl ester (9)
d
¼14.1 (CH3), 26.6 (C-5), 27.0 (C-7), 32.1 (C-4, C-9), 32.5 (C-1, C-3),
1-Adamantanecarboxaldehyde 3 (2.00 g, 12.2 mmol) was reac-
ted with ethyl glycinate hydrochloride (1.79 g, 12.8 mmol) and
NaCN (627 mg, 12.8 mmol) according to the procedure described
for the preparation of compound 4a. After workup, the resulting
dry Et2O solution of free amino nitrile 6 was treated with ethereal
HCl under ice cooling. The precipitated white hydrochloride 69 was
filtered off, washed with cold Et2O (4ꢂ15 mL), and dried (1.98 g,
52%). Due to the instability of the amino nitrile hydrochloride 6 it
was not possible to determine a clear mp.
34.5 (C-8, C-10), 37.6 (C-6), 43.7 (HNCH2CO2C2H5), 60.9 (CH3CH2O),
64.1 (C-2), 172.5 (CO2C2H5), 176.9 (CONH2) ppm. Anal. Calcd for
C
15H24N2O3: C, 64.26; H, 8.63; N, 9.99. Found: C, 64.02; H, 8.60; N,
10.28.
4.5. (L)-N-[2-Aminocarbonyl(tricyclo[3.3.1.13,7]dec-2-yl)]-
L-alanine ethyl ester (7b)
Amino nitrile 4b (2.00 g, 7.24 mmol) was treated with H2SO4
Title compound 9 was synthesized from the above amino nitrile
hydrochloride 6 (1.80 g, 5.75 mmol) by treating with H2SO4 97%
(3.4 mL) according to the procedure described for the preparation
of compound 7a. After workup, the precipitate formed was filtered
off, washed with cold H2O (5ꢂ6 mL), dried, and then chromato-
graphed on a silica gel column (AcOEt) to afford pure amino
carboxamide 9 (900 mg, 53%) as a white crystalline solid; mp 119–
97% (3.4 mL) according to the procedure described for the prepa-
ration of compound 7a. After workup, the oily product formed was
extracted with CHCl3 (4ꢂ50 mL). The combined organic extracts
were washed with H2O (1ꢂ50 mL), dried (Na2SO4), and evaporated
to dryness under reduced pressure. The oily residue was chroma-
tographed on a silica gel column (Et2O, then Et2O/AcOEt 1:1) to
afford pure amino carboxamide 7b (1.25 g, 59%) as white crystals;
121 ꢀC (AcOEt/n-pentane). IR (mull):
n
3426, 3339, 3313, 3185, 1731,
¼1.23 (t, 3H, J¼7.2 Hz,
29
mp 111–113 ꢀC (Et2O). [
a
]
589 ꢃ18.5 (c 0.2, CHCl3). IR (mull):
n
3419,
1668,1624 cmꢃ1. 1H NMR (400 MHz, CDCl3):
d
3373, 3152, 1718, 1706, 1676 cmꢃ1
.
1H NMR (400 MHz, CDCl3):
OCH2CH3), 1.52–1.75 (m, 12H, H-2, H-4, H-6, H-8, H-9, H-10), 1.97 (s,
3H, H-3, H-5, H-7), 2.14 (br s,1H, NHCH2), 2.62 (s,1H, HNCHCONH2),
3.18 (d, 1H, JAB¼17.6 Hz, HNCH2ACO2C2H5), 3.41 (d, 1H, JAB¼17.6 Hz,
HNCH2BCO2C2H5), 4.14 (q, 2H, J¼7.2 Hz, CH3CH2O), 5.86 (br s, 1H,
CONHH), 6.71 (br s, 1H, CONHH) ppm. 13C NMR (100 MHz, CDCl3):
d
¼1.24 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.24 (d, 3H, J¼7.0 Hz, CH3), 1.46–
1.60 (m, 2H, H-4e, H-9e), 1.64 (br s, 2H, H-6), 1.68–1.88 (m, 5H, H-5,
H-7, H-8e, H-10e, NHCH),1.90–2.06 (m, 3H, H-3, H-8a, H-10a), 2.08–
2.17 (m, 2H, H-1, H-4a), 2.23 (dd, 1H, J¼12.4, 2.8 Hz, H-9a), 3.46 (q,
1H, J¼7.0 Hz, HNCHCO2C2H5), 4.11 (q, 2H, J¼7.1 Hz, CH3CH2O), 5.60
(br s, 1H, CONHH), 5.90 (br s, 1H, CONHH) ppm. 13C NMR (100 MHz,
d
¼14.1 (CH3), 28.4 (C-3, C-5, C-7), 35.2 (C-1), 36.8 (C-4, C-6, C-10),
39.2 (C-2, C-8, C-9), 49.7 (HNCH2CO2C2H5), 61.0 (CH3CH2O), 73.2
(NHCHCONH2),172.2 (CO2C2H5),174.8 (CONH2) ppm. Anal. Calcd for
CDCl3):
d
¼14.1 (CH3CH2O), 21.5 (CH3), 26.8 (C-5), 26.9 (C-7), 32.1 (C-
4), 32.2 (C-9), 32.6 (C-1), 33.8 (C-3), 34.4 (C-8), 34.7 (C-10), 37.6 (C-
6), 49.9 (HNCHCO2C2H5), 60.6 (CH3CH2O), 64.3 (C-2), 176.2
(CO2C2H5), 177.4 (CONH2) ppm. Anal. Calcd for C16H26N2O3: C,
65.28; H, 8.90; N, 9.52. Found: C, 65.34; H, 8.91; N, 9.71.
C16H26N2O3: C, 65.28; H, 8.90; N, 9.52. Found: C, 65.40; H, 8.98; N,
9.28.
4.8. General procedures for the synthesis of
compounds 10–12
4.6. N-(1-Aminocarbonylcyclooctyl)glycine ethyl ester (8)
4.8.1. General procedure I
Cyclooctanone (3.36 g, 26.6 mmol), ethyl glycinate hydrochlo-
ride (3.90 g, 27.9 mmol), and NaCN (1.37 g, 27.9 mmol) were reac-
ted according to the procedure described for the preparation of
compound 4a. After workup, the resulting dry Et2O solution of the
free amino nitrile 5 was treated with ethereal HCl under ice cooling.
Potassium bis(trimethylsilyl)amide (2 mmol) was added por-
tionwise to a stirred solution of the appropriate amide-esters 7–9
(2 mmol) in dry THF (20 mL) under ice cooling. After stirring at rt
for 1 h, under argon, the reaction mixture was evaporated to dry-
ness under reduced pressure. To the remaining white solid

C. Fytas et al. / Tetrahedron 64 (2008) 6749–6754
6753
(potassium imidate salt), H2O (5 mL) was added and the mixture
was slowly quenched with HCl 5% to pH¼4–5 under cooling and
then adjusted to pH¼7–8 with solid Na2CO3. The white precipitate
formed was isolated by vacuum filtration, washed with H2O (5 mL),
and dried. TLC showed one spot only corresponding to the desired
2,6-diketopiperazines 10–12 (Table 1).
for C14H20N2O2: C, 67.71; H, 8.12; N, 11.28. Found: C, 67.68; H, 8.15;
N, 11.34.
4.9. General procedure for the synthesis of compounds
13a–15
The appropriate amido-ester precursors 7a–9 (2 mmol) were
treated with potassium bis(trimethylsilyl)amide (2 mmol) in dry
THF (20 mL) at rt for 1 h under argon, as described above. The
solvent was then evaporated under reduced pressure and the
remaining white solid (potassium imidate salt) was dissolved in dry
DMF (10 mL). To this solution, benzyl bromoacetate (2.1 mmol)
dissolved in dry DMF (5 mL) was added dropwise. After being
stirred at rt for 48 h under argon, the reaction mixture was poured
into an ice/water mixture (40 mL) and extracted with Et2O
(4ꢂ35 mL). The organic phase was washed with brine (35 mL),
dried (Na2SO4), and evaporated under reduced pressure affording
crude compounds 13a–15, which were purified by column chro-
matography on silica gel, using EtOAc/n-hexane mixtures as eluents
(1:2, 1:6, 1:1, and 2:1).
4.8.2. General procedure II
Potassium bis(trimethylsilyl)amide (2 mmol) was added por-
tionwise to the appropriate amide-esters 7–9 (2 mmol), dissolved
in dry THF (20 mL) under ice cooling. After stirring at rt for 1 h
under argon, trifluoroacetic acid (1 equiv) was added to the re-
action mixture. The solvent was then evaporated under reduced
pressure, and the white solid residue was filtered through a short
column of silica gel, using a mixture of AcOEt/Et2O 1:1 as eluent, to
afford the corresponding 1-unsubstituded 2,6-diketopiperazines
10–12 in quantitative yield (Table 1).
4.8.2.1. Spiro[piperazine-2,20-tricyclo[3.3.1.13,7]decane]-3,5-dione
(10a). White crystals; yield >99%; mp 196–198 ꢀC (CHCl3/n-pen-
tane). IR (mull):
(400 MHz, CDCl3):
n .
3328, 3194, 3098, 1721, 1682 cmꢃ1 1H NMR
d
1H, H-1), 1.70–2.02 (complex m, 8H, H-10, H-30, H-50, H-60, H-70, H-
80e, H-100e), 2.25 (d, 2H, J¼12.4 Hz, H-40a, H-90a), 2.32 (d, 2H,
J¼12.8 Hz, H-80a, H-100a), 3.62 (s, 2H, H-6), 7.83 (br s, 1H, H-4) ppm.
¼1.52 (d, 2H, J¼12.4 Hz, H-40e, H-90e), 1.65 (s,
4.9.1. 3,5-Dioxospiro[piperazine-2,20-tricyclo[3.3.1.13,7]decane]-4-
acetic acid benzyl ester (13a)
White crystals; yield 90% (0.69 g); mp 111–112 ꢀC (Et2O/n-pen-
tane). IR (mull):
n
3310, 1740, 1722, 1690 cmꢃ1. 1H NMR (400 MHz,
13C NMR (100 MHz, CDCl3):
d
¼27.0 (C-50), 27.2 (C-70), 32.3 (C-40, C-
CDCl3):
d
¼1.52 (d, 2H, J¼12.9 Hz, H-40e, H-90e), 1.69 (br s, 5H, H-1,
90), 32.4 (C-10, C-30), 33.1 (C-80, C-100), 38.0 (C-60), 44.1 (C-6), 60.5
(C-2,20), 173.1, 174.8 (C-3, C-5) ppm. Anal. Calcd for C13H18N2O2: C,
66.64; H, 7.74; N, 11.96. Found: C, 66.59; H, 7.51; N, 12.07.
H-60, H-80e, H-100e), 1.83 (s, 1H, H-50), 1.87 (s, 1H, H-70), 1.98 (s, 2H,
H-10, H-30), 2.27 (d, 4H, J¼12.7 Hz, H-40a, H-80a, H-90a, H-100a), 3.72
(s, 2H, H-6), 4.51 (s, 2H, CH2CO2CH2Ph), 5.13 (s, 2H, CH2CO2CH2Ph),
7.26–7.37 (m, 5H, H-aromatic) ppm. 13C NMR (100 MHz, CDCl3):
4.8.2.2. (ꢃ)-S-6-Methylspiro[piperazine-2,20-tricyclo[3.3.1.13,7]decane]-
d
¼27.0 (C-50), 27.2 (C-70), 32.3 (C-40, C-90), 32.6 (C-10, C-30), 33.1 (C-
3,5-dione (10b). White crystals; yield >99%; mp 190–192 ꢀC
80, C-100), 38.0 (C-60), 40.6 (CH2CO2CH2Ph), 44.4 (C-6), 60.5 (C-2,20),
67.2 (CH2CO2CH2Ph), 128.2 (C-4 aromatic), 128.4 (C-3, C-5 aro-
matic), 128.6 (C-2, C-6 aromatic), 135.1 (C-1 aromatic), 168.0
(CO2CH2Ph),172.1,174.3 (C-3, C-5) ppm. Anal. Calcd for C22H26N2O4:
C, 69.09; H, 6.85; N, 7.33. Found: C, 68.84; H, 7.02; N, 7.06.
29
(CH2Cl2/n-pentane). [
a]
ꢃ14 (c 0.2, CHCl3). IR (mull):
n
3298,
589
3186, 3088, 1719, 1677 cmꢃ1. 1H NMR (400 MHz, CDCl3):
d
¼1.28 (br
s, 1H, H-1), 1.42 (d, 3H, J¼7.0 Hz, CH3), 1.47–1.58 (sym m, 2H, H-40e,
H-90e), 1.62–1.94 (complex m, 8H, H-30, H-50, H-60, H-70, H-80, H-
100e), 2.08 (s, 1H, H-10), 2.16 (d, 1H, J¼11.2 Hz, H-40a), 2.35 (d, 1H,
J¼12.6 Hz, H-90a), 2.93 (d, 1H, J¼12.9 Hz, H-100a), 3.61 (br d, 1H,
J¼5.4 Hz, H-6), 7.69 (br s, 1H, H-4) ppm. 13C NMR (100 MHz, CDCl3):
4.9.2. (ꢃ)-(S)-6-Methyl-3,5-dioxospiro[piperazine-2,20-
tricyclo[3.3.1.13,7]decane]-4-acetic acid benzyl ester (13b)
29
d
¼17.4 (CH3), 27.0 (C-50), 27.2 (C-70), 30.8 (C-10), 31.5 (C-40), 32.6 (C-
Colorless viscous oil; yield 89% (0.71 g); [
CHCl3). IR (film):
CDCl3):
a
]
589
ꢃ10.5 (c 0.2,
80), 33.2 (C-90), 33.8 (C-100), 34.7 (C-30), 38.0 (C-60), 48.7 (C-6), 61.4
(C-2,20), 175.2, 175.5 (C-3, C-5) ppm. Anal. Calcd for C14H20N2O2: C,
67.71; H, 8.12; N, 11.28. Found: C, 67.67; H, 8.17; N, 11.22.
n
3305, 1754, 1725, 1681 cmꢃ1. 1H NMR (400 MHz,
d
¼1.25 (br s, 1H, H-1), 1.42 (d, 3H, J¼7.0 Hz, CH3), 1.51 (t, 2H,
J¼10.8 Hz, H-40e, H-90e), 1.60–1.73 (m, 5H, H-60, H-80, H-100e), 1.82
(s, 1H, 50-H), 1.86 (s, 2H, H-30, H-70), 2.07 (s, 1H, H-10), 2.14
(d, 1H, J¼12.4 Hz, H-40a), 2.39 (d, 1H, J¼12.6 Hz, H-90a), 2.88 (d,
1H, J¼12.9 Hz, H-100a), 3.71 (q, 1H, J¼6.9 Hz, H-6), 4.39 (d,
1H, JAB¼16.7 Hz, CH2ACO2CH2Ph), 4.60 (d, 1H, JAB¼16.7 Hz,
CH2BCO2CH2Ph), 5.12 (s, 2H, CH2CO2CH2Ph), 7.26–7.42 (m, 5H, H-
4.8.2.3. 1,4-Diazaspiro[5,7]tridecane-3,5-dione (11). White crystals;
yield >99%; mp 213–215 ꢀC (CHCl3/Et2O). IR (mull):
n
3326, 3176,
¼1.42–1.80
3063, 1734, 1671 cmꢃ1 1H NMR (400 MHz, CDCl3):
. d
(complex m, 13H, H-1, H-7, H-8, H-9, H-10, H-11, H-12, H-13), 2.02–
2.19 (m, 2H, H-7, H-13), 3.64 (s, 2H, H-2), 7.77 (br s, 1H, H-4) ppm.
aromatic) ppm. 13C NMR (100 MHz, CDCl3):
d
¼18.5 (CH3), 27.0 (C-
13C NMR (100 MHz, CDCl3):
d
¼21.3 (C-9, C-11), 24.7 (C-10), 28.0 (C-
50), 27.2 (C-70), 30.9 (C-10), 31.5 (C-40), 32.5 (C-80), 33.1 (C-90), 33.9
(C-100), 34.9 (C-30), 38.0 (C-60), 41.0 (CH2CO2CH2Ph), 49.2 (C-6), 60.9
(C-2,20), 67.2 (CH2CO2CH2Ph), 128.3 (C-4 aromatic), 128.4 (C-3, C-5
aromatic), 128.5 (C-2, C-6 aromatic), 135.1 (C-1 aromatic), 168.1
(CO2CH2Ph), 174.6, 175.1 (C-3, C-5) ppm. EM-ES, m/z 397.3 (30)
[Mþ1]þ. Anal. Calcd for C23H28N2O4: C, 69.67; H, 7.12; N, 7.07.
Found: C, 69.37; H, 7.22; N, 7.35.
8, C-12), 30.6 (C-7, C-13), 45.0 (C-2), 59.8 (C-6), 172.0, 176.7 (C-3, C-
5) ppm. Anal. Calcd for C11H18N2O2: C, 62.83; H, 8.63; N, 13.32.
Found: C, 62.96; H, 8.59; N, 13.19.
4.8.2.4. 3-(Tricyclo[3.3.1.13,7]dec-1-yl)-2,6-piperazinedione (12). White
crystals; yield >99%; mp 207–209 ꢀC (dec, AcOEt). IR (mull):
n
3314,
3195, 3082, 1725, 1687 cmꢃ1 1H NMR (400 MHz, CDCl3):
. d
¼1.61–
1.76 (m, 10H, H-2, H-4, H-6, H-8, H-9, H-10 adamantane, H-4 pi-
perazine), 1.85 (d, 3H, J¼10.8 Hz, part of quartet, H-2, H-8, H-9
adamantane), 2.00 (s, 3H, H-3, H-5, H-7 adamantane), 2.98 (s, 1H,
H-3 piperazine), 3.53 (d, 1H, JAB¼18.3 Hz, HA-5 piperazine), 3.77 (d,
1H, JAB¼18.3 Hz, HB-5 piperazine), 8.00 (br s, 1H, H-1 piper-
4.9.3. 3,5-Dioxo-1,4-diazaspiro[5.7]tridecane-4-acetic acid benzyl
ester (14)
White crystals; yield 94% (0.67 g); mp 80–82 ꢀC (Et2O/n-pen-
tane). IR (mull):
CDCl3):
n
3308, 1747, 1719, 1673 cmꢃ1. 1H NMR (400 MHz,
¼1.44–1.78 (m,13H, H-1, H-7, H-8, H-9, H-10, H-11, H-12, H-
d
azine) ppm. 13C NMR (100 MHz, CDCl3):
d¼28.4 (C-3, C-5, C-7
13), 2.11 (q, 2H, J¼8.8 Hz, H-7, H-13), 3.75 (s, 2H, H-2), 4.53 (s, 2H,
adamantane), 36.7 (C-4, C-6, C-10 adamantane), 37.2 (C-1 ada-
mantane), 39.4 (C-2, C-8, C-9 adamantane), 48.4 (C-5 piperazine),
66.0 (C-3 piperazine), 172.0 (C-2, C-6 piperazine) ppm. Anal. Calcd
CH2CO2CH2Ph), 5.14 (s, 2H, CH2CO2CH2Ph), 7.30–7.46 (m, 5H, H-
aromatic) ppm. 13C NMR (100 MHz, CDCl3):
d¼21.2 (C-9, C-11), 24.7
(C-10), 27.9 (C-8, C-12), 30.9 (C-7, C-13), 40.0 (CH2CO2CH2Ph), 45.1

6754
C. Fytas et al. / Tetrahedron 64 (2008) 6749–6754
(C-2), 59.9 (C-6), 67.3 (CH2CO2CH2Ph),128.3 (C-4 aromatic),128.4 (C-
3, C-5 aromatic), 128.6 (C-2, C-6 aromatic), 135.1 (C-1 aromatic),
167.8 (CO2CH2Ph), 171.2, 176.1 (C-3, C-5) ppm. Anal. Calcd for
4.10.3. 3,5-Dioxo-1,4-diazaspiro[5.7]tridecane-4-acetic acid (17)
White solid; yield >99%; mp 201–203 ꢀC (dec, MeOH/Et2O). IR
(mull):
DMSO-d6):
(m, 4H, H-7, H-9, H-11, H-13), 1.96 (q, 2H, J¼9.0 Hz, H-7, H-13), 3.58
(s, 2H, H-2), 3.85 (br s, 2H, CO2H, NH), 4.24 (s, 2H, CH2CO2H) ppm.13
NMR (100 MHz, DMSO-d6):
n .
2472–2008, 1749, 1693, 1569 cmꢃ1 1H NMR (400 MHz,
C
20H26N2O4: C, 67.02; H, 7.31; N, 7.82. Found: C, 67.14; H, 7.39; N, 7.56.
d¼1.47 (br s, 8H, H-8, H-9, H-10, H-11, H-12), 1.55–1.70
4.9.4. 3-(Tricyclo[3.3.1.13,7]dec-1-yl)-2,6-dioxopiperazine-1-acetic
acid benzyl ester (15)
C
d
¼21.3 (C-9, C-11), 24.7 (C-10), 28.0 (C-8,
White crystals; yield 83% (0.66 g); mp 106–108 ꢀC (Et2O/n-
C-12), 30.5 (C-7, C-13), 40.0 (CH2CO2H), 44.9 (C-2), 59.4 (C-6), 169.6
(CO2H), 171.9, 176.5 (C-3, C-5) ppm. Anal. Calcd for C13H20N2O4: C,
58.19; H, 7.51; N, 10.44. Found: C, 57.98; H, 7.47; N, 10.21.
pentane). IR (mull):
(400 MHz, CDCl3):
¼1.62–1.78 (m, 9H, H-2, H-4, H-6, H-8, H-9, H-
n .
3339, 1745, 1727, 1669 cmꢃ1 1H NMR
d
10 adamantane), 1.80 (br s, 1H, H-4 piperazine), 1.86 (d, 3H,
J¼12.4 Hz, part of quartet, H-2, H-8, H-9 adamantane), 2.00 (br s,
3H, H-3, H-5, H-7 adamantane), 3.09 (s,1H, H-3 piperazine), 3.64 (d,
1H, JAB¼18 Hz, HA-5 piperazine), 3.91 (d, 1H, JAB¼18 Hz, HB-5 pi-
perazine), 4.52 (d, 1H, JAB¼16.8 Hz, CH2ACO2CH2Ph), 4.59 (d, 1H,
JAB¼16.8 Hz, CH2BCO2CH2Ph), 5.17 (s, 2H, CH2CO2CH2Ph), 7.30–7.41
4.10.4. 3-(Tricyclo[3.3.1.13,7]dec-1-yl)-2,6-dioxopiperazine-1-acetic
acid (18)
White solid; yield >99%; mp 206–208 ꢀC (dec, EtOH/Et2O). IR
(mull): n
3348,1752,1731,1637 cmꢃ1. 1H NMR (400 MHz, DMSO-d6):
d
¼1.56–1.74 (m, 9H, H-2, H-4, H-6, H-8, H-9, H-10 adamantane),1.81
(m, 5H, H-aromatic) ppm. 13C NMR (100 MHz, CDCl3):
d¼27.6
(d, 3H, J¼12.0 Hz, part of quartet, H-2, H-8, H-9 adamantane),1.93 (s,
3H, H-3, H-5, H-7 adamantane), 3.04 (s, 1H, H-3 piperazine), 3.15–
3.48 (v br s, 2H, CO2H, NH, under DMSO water peak), 3.55 (d, 1H,
JAB¼18.3 Hz, HA-5 piperazine), 3.67 (d, 1H, JAB¼18.3 Hz, HB-5 piper-
azine), 4.27 (s, 2H, CH2CO2H) ppm. 13C NMR (100 MHz, DMSO-d6):
(C-3, C-5, C-7 adamantane), 35.9 (C-4, C-6, C-10 adamantane), 36.7
(C-1 adamantane), 38.5 (C-2, C-8, C-9 adamantane), 39.2
(CH2CO2CH2Ph), 48.0 (C-5 piperazine), 65.5 (C-3 piperazine), 66.4
(CH2CO2CH2Ph), 127.3 (C-4 aromatic), 127.5 (C-3, C-5 aromatic),
127.7 (C-2, C-6 aromatic), 134.2 (C-1 aromatic), 166.8 (CO2CH2Ph),
170.3, 170.4 (C-2, C-6 piperazine) ppm. Anal. Calcd for C23H28N2O4:
C, 69.67; H, 7.12; N, 7.07. Found: C, 69.50; H, 7.27; N, 6.90.
d
¼27.9 (C-3, C-5, C-7 adamantane), 36.4 (C-4, C-6, C-10 adamantane),
36.9 (C-1 adamantane), 38.8 (C-2, C-8, C-9 adamantane), 39.6
(CH2CO2H), 48.3 (C-5 piperazine), 65.2 (C-3 piperazine), 169.0
(CO2H), 171.7, 171.8 (C-2, C-6 piperazine) ppm. Anal. Calcd for
4.10. General procedure for the hydrogenolysis of the benzyl
esters 13a–15 to the corresponding carboxylic acids 16a–18
C16H22N2O4:C, 62.73;H, 7.24;N, 9.15. Found:C, 62.85;H, 7.32;N,8.88.
Acknowledgements
A solution of the appropriate benzyl esters 13a–15 (2 mmol) in
abs EtOH was hydrogenated for 3 h at rt and 50 psi pressure in the
presence of 10% Pd/C. The catalyst was filtered off, washed with
portions of hot MeOH (3ꢂ15 mL), and the combined filtrates were
evaporated under reduced pressure to yield the corresponding
carboxylic acids 16a–18.
Dr. C.F. would like to thank the University of Athens (ELKE
Account KA: 70/4/7841) for the financial support.
References and notes
1. Hasinoff, B. B.; Abram, M. E.; Barnabe, N.; Khelifa, T.; Allan, W. P.; Yalowich, J. C.
Mol. Pharmacol. 2001, 59, 453–461.
2. Li, Q.; Shao, H. W.; Jiang, H. L.; Xie, Y. Y. Pharmazie 1995, 50, 447–449.
3. Singh, S. B.; Tomassini, J. E. J. Org. Chem. 2001, 66, 5504–5516 and references
cited therein.
4.10.1. 3,5-Dioxospiro[piperazine-2,20-tricyclo[3.3.1.13,7]decane]-4-
acetic acid (16a)
White solid; yield >99%; mp 206–208 ꢀC (dec, EtOH/Et2O). IR
4. (a) Kolocouris, N.; Foscolos, G. B.; Kolocouris, A.; Marakos, P.; Pouli, N.; Fytas, G.;
Ikeda, S.; De Clercq, E. J. Med. Chem. 1994, 37, 2896–2902; (b) Kolocouris, N.;
Kolocouris, A.; Foscolos, G. B.; Fytas, G.; Neyts, J.; Padalko, E.; Balzarini, J.; Snoeck,
R.; Andrei, G.; De Clercq, E. J. Med. Chem. 1996, 39, 3307–3318; (c) Zoidis, G.;
Kolocouris, N.; Foscolos, G. B.; Kolocouris, A.; Fytas, G.; Karayannis, P.; Padalko,
E.; Neyts, J.; De Clercq, E. Antiviral Chem. Chemother. 2003, 14, 153–164; (d) De
Clercq, E. Nat. Rev. Drug Discov. 2006, 5, 1015–1025; (e) Fytas, G.; Stamatiou, G.;
Foscolos, G. B.; Kolocouris, A.; Kolocouris, N.; Witvrouw, M.; Pannecouque, C.; De
Clercq, E. Bioorg. Med. Chem. Lett. 1997, 7, 1887–1890; (f) Papadaki-Valiraki, A.;
Papakonstantinou-Garoufalias, S.; Marakos, P.; Chytyroglou-Lada, A.; Hosoya, M.;
Balzarini, J.; De Clercq, E. Farmaco 1993, 48, 1091–1102; (g) Kelly, J. M.; Quack, G.;
Miles, M. M. Antimicrob. Agents Chemother. 2001, 45, 1360–1366; (h) Kolocouris,
N.; Zoidis, G.; Foscolos, G. B.; Fytas, G.; Prathalingham, S. R.; Kelly, J. M.; Naesens,
L.; De Clercq, E. Bioorg. Med. Chem. Lett. 2007, 17, 4358–4362; (i) Wang, J.-J.; Chen,
Y.-C.; Chi, C.-W.; Huang, K.-T.; Chern, Y.-T. Anticancer Drugs 2004, 15, 697–705
and the references cited therein; (j) Chakrabarti, J. K.; Hotten, T. M.; Sutton, S.;
Tupper, D. E. J. Med. Chem. 1976, 19, 967–969; (k) Zoidis, G.; Papanastasiou, I.;
Dotsikas, I.; Sandoval, A.; Dos Santos, R. G.; Papadopoulou-Daifoti, Z.; Vamva-
kides, A.; Kolocouris, N.; Felix, R. Bioorg. Med. Chem. 2005, 13, 2791–2798.
5. Gish, D. T.; Kelly, R. C.; Camiener, G. W.; Wechter, W. J. J. Med. Chem. 1971, 14,
1159–1162.
(mull):
d6):
n .
3334, 1749, 1729, 1630 cmꢃ1 1H NMR (400 MHz, DMSO-
d
¼1.44 (d, 2H, J¼12.1 Hz, H-40e, H-90e), 1.63 (d, 2H, J¼11.5 Hz,
H-80e, H-100e), 1.65 (s, 2H, H-60), 1.76 (s, 1H, H-50), 1.80 (s, 1H, H-70),
1.94 (s, 2H, H-10, H-30), 2.25 (td, 4H, J¼13.3, 14.5 Hz, H-40a, H-80a, H-
90a, H-100a), 2.80–3.91 (v br s, 2H, CO2H, NH, under DMSO water
peak), 3.59 (s, 2H, H-6), 4.27 (s, 2H, CH2CO2H) ppm. 13C NMR
(100 MHz, DMSO-d6):
d
¼26.6 (C-50), 26.9 (C-70), 31.8 (C-10, C-30),
32.0 (C-40, C-90), 32.7 (C-80, C-100), 37.8 (C-60), 40.3 (CH2CO2H), 43.9
(C-6), 59.4 (C-2, 20), 169.3 (CO2H), 172.2, 174.4 (C-3, C-5) ppm. Anal.
Calcd for C15H20N2O4: C, 61.63; H, 6.90; N, 9.58. Found: C, 61.85; H,
6.98; N, 9.39.
4.10.2. (ꢃ)-(S)-6-Methyl-3,5-dioxospiro[piperazine-2,20-
tricyclo[3.3.1.13,7]decane]-4-acetic acid (16b)
White solid; yield >99%; mp 132–134 ꢀC (Et2O/n-pentane).
28
[
a]
ꢃ17.5 (c 0.2, CHCl3). IR (mull):
n .
3306, 1726, 1686 cmꢃ1 1H
¼1.43 (d, 3H, J¼6.9 Hz, CH3), 1.47–1.59
589
6. For recent review on diketopiperazine syntheses, see: Dinsmore, C. J.; Beshore,
D. C. Tetrahedron 2002, 58, 3297–3312.
NMR (400 MHz, CDCl3):
d
(sym. m, 2H, H-40e, H-90e),1.61–1.77 (m, 5H, H-60, H-80, H-100e),1.83
(s, 1H, H-50), 1.87 (s, 2H, H-30, H-70), 2.09 (s, 1H, H-10), 2.13 (d,
1H, J¼15.2 Hz, H-40a), 2.36 (d, 1H, J¼12.4 Hz, H-90a), 2.88 (d, 1H,
J¼12.7 Hz, H-100a), 3.73 (q, 1H, J¼6.9 Hz, H-6), 4.38 (d, 1H,
JAB¼17.1 Hz, CH2ACO2H), 4.53 (d, 1H, JAB¼17.1 Hz, CH2BCO2H), 5.76
7. (a) Cignarella, G.; Testa, E. J. Med. Chem. 1968, 11, 612–615; (b) Suarez-Gea, M. L.;
Garcia-Lopez, M. T.; Herranz, R. J. Org. Chem. 1994, 59, 3600–3603; (c) Gonzalez-
Vera, J. A.; Garcia-Lopez, M. T.; Herranz, R. J. Org. Chem. 2005, 70, 3660–3666; (d)
Ugi, I.; Horl, W.; Hanusch-Kompa, C.; Schmid, T.; Herdtweck, E. Heterocycles
1998, 47, 965–975; (e) Ugi, I.; Demharter, A.; Horl, W.; Schmid, T. Tetrahedron
1996, 52, 11657–11664; (f) Perrotta, E.; Altamura, M.; Barani, T.; Bindi, S.; Gian-
notti, D.; Harmat, N. J. S.; Nannicini, R.; Maggi, C. A. J. Comb. Chem. 2001, 3, 453–
460; (g) Harfenist, M.; Hoerr, D. C.; Crouch, R. J. Org. Chem. 1985, 50, 1356–1359.
8. (a) Witiak, D. T.; Trivedi, B. K.; Campolito, L. B.; Zwilling, B. S.; Reiches, N. A.
J. Med. Chem. 1981, 24, 1329–1332; (b) Witiak, D. T.; Nair, R. V.; Schmid, F. A.
J. Med. Chem. 1985, 28, 1228–1234.
(br s, 2H, CO2H, NH) ppm. 13C NMR (100 MHz, CDCl3):
d¼18.4 (CH3),
27.0 (C-50), 27.2 (C-70), 30.9 (C-10), 31.5 (C-40), 32.5 (C-80), 33.0 (C-90),
33.9 (C-100), 34.8 (C-30), 38.0 (C-60), 40.7 (CH2CO2H), 49.1 (C-6), 61.0
(C-2,20), 173.6 (CO2H), 174.4, 175.0 (C-3, C-5) ppm. Anal. Calcd for
9. Tataridis, D.; Fytas, G.; Kolocouris, A.; Fytas, C.; Kolocouris, N.; Foscolos, G. B.;
Padalko, E.; Neyts, J.; De Clercq, E. Bioorg. Med. Chem. Lett. 2007, 17,
692–696.
C
16H22N2O4: C, 62.73; H, 7.24; N, 9.15. Found: C, 62.69; H, 7.34; N,
9.27.