Synthesis and structure of novel (S)-1,6-dialkylpiperazine-2,5-diones and (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones

Article abstract of DOI:10.1016/j.tetasy.2011.03.014

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6- trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis

Full text of DOI:10.1016/j.tetasy.2011.03.014

Tetrahedron: Asymmetry 22 (2011) 629–640
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and structure of novel (S)-1,6-dialkylpiperazine-2,5-diones
and (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones
a
a
ˇ a
ˇ a
Crt Malavašic , Uroš Grošelj , Amalija Golobic , Jure Bezenšek , Branko Stanovnik a,b, Katarina Stare a,b
,
ˇ
Jernej Wagger a, Jurij Svete a,b,
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerceva 5, PO Box 537, 1000 Ljubljana, Slovenia
b Centre of Excellence EN-FIST, Dunajska 156, 1000 Ljubljana, Slovenia
⇑
a
ˇ
a r t i c l e i n f o
a b s t r a c t
Article history:
Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were
prepared in three steps from the corresponding (S)- -amino acid esters comprising of reductive N-alkyl-
Received 2 February 2011
Accepted 28 March 2011
Available online 5 May 2011
a
ation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad
scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while
the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl
groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in
the presence of a carbonyl compound proved to be a simple, efficient and general method for the prep-
aration of stable (storable)
a-alkylamino acid ester hydrochlorides. The structures of the novel com-
pounds were determined by NMR and X-ray diffraction.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
isomer, and its 1-pentafluorophenyl analogue.10 As an extension, it
seemed reasonable to us to take a closer look at the structure–
property relationship. In order to find out how the substituents af-
fect the chiral solvating activity of (S)-1,6-dialkylpiperazine-2,5-
diones, a library of differently substituted diketopiperazines had
to be prepared first. In spite of the fact, that the synthesis of dike-
topiperazines is considered to be simple and approaches well elab-
orated,11 the preparation of our library of N-alkyldiketopiperazines
was not so easy. Herein, we report the synthesis and structure
determination of a series of novel (S)-1,6-dialkylpiperazine-2,5-
diones (S)-4a–k and (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones
4l–p as model compounds for testing and application as CSA in
NMR spectroscopy.
Diketopiperazines (piperazine-2,5-diones) are an important and
useful class of heterocyclic compounds with a cyclic dipeptide
structure, which have found widespread use and application in or-
ganic, medicinal, combinatorial and supramolecular chemistry. The
piperazine-2,5-dione moiety is a constituent of natural products,1
b-turn mimetics,2 synthetic receptors3 and organocatalysts.4 It is
not surprising that diketopiperazines belong to a family of ‘privi-
leged scaffolds’, which are often used as the key-building blocks
in medicinal chemistry and in the synthesis of combinatorial li-
braries.5 Due to their cyclic dipeptide structure with two amide
units located at the opposite sides of a six-membered ring, they
can readily assemble via intermolecular amide–amide C@Oꢀ ꢀ ꢀH–
N hydrogen bonds to form linear tape structures and planar layer
structures.6 Finally, chiral non-racemic piperazine-2,5-dione deriv-
atives are also important chiral auxiliaries, for example in the
2. Results and discussion
The synthesis of novel (S)-1,6-dialkylpiperazine-2,5-diones
4a,b,d–l was performed from amino acid esters 1a–h according
to a general three-step method comprising of N-alkylation,12 chlo-
roacetylation13 and cyclisation with ammonia.14 The first step of
the synthesis was reductive alkylation of the amino acid ester
hydrochlorides 1a–h, which was carried out by catalytic hydroge-
nation in the presence of 10% Pd–C, symmetrical ketone (cyclohex-
asymmetric synthesis of enantiopure a
-amino acids.7
Within this context, we have recently reported the chiral solvat-
ing properties of (S)-1-benzyl-6-methylpiperazine-2,5-dione,8
which was used as a chiral solvating agent (CSA) for the determi-
nation of enantiomeric excess of (S)-tert-butyl pyroglutamate8
and tryprostatin B analogues.9 Subsequent study on the interac-
tions with N-acylated
zyl-6-methylpiperazine-2,5-dione as
acylamino acids, however, this was not true for its 4-benzyl regio-
a
-amino acid esters confirmed (S)-1-ben-
anone, 2,3-dihydroindan-2-one and acetone), and
amount of 4-methylmorpholine. Removal of the catalyst by filtra-
tion followed by evaporation of the filtrate gave the crude -alkyl-
a catalytic
a
suitable CSA for
a-
a
⇑
Corresponding author. Tel.: +386 1 2419 100, fax: +386 1 2419 220.
E-mail address: jurij.svete@fkkt.uni-lj.si (J. Svete).
The presence of a tertiary amine was essential. In the absence of 4-methylmor-
pholine, conversion was incomplete.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.03.014

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Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
630
H
N
O
COOMe
NH2
COOMe
NH HCl
COOMe
i or ii or iii
iv
v
R1
R2
R1
Cl
R1
N
O
R1
N
R2
O
HCl
R2
1a-h
2a-k
3a-k
4a-k
Transformation
R1
R2
Yield (%)
2
4
1a→2a→4a
1a→2b→4b
1a→2c→4c
1a→2d→4d
1b→2e→4e
1c→2f→4f
1d→2g→4g
1e→2h→4h
1f→2i→4i
methyl
cyclohexyl
2-indanyl
benzhydryl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
95
73
51a
94
76
100
89
95
30
91
90
6
methyl
11
3
methyl
methyl
11
26
5
isopropyl
tert-butyl
isobutyl
benzyl
28
10
13
46
32
4'-nitrobenzyl
1g→2j→4j
1h→2k→4k
4'-tert-butoxybenzyl
CH2CH2COOMe
a) Yield of the crude intermediate.
Scheme 1. Reagents and conditions: (i) R2C@O, MeOH, 4-methylmorpholine (cat.), H2 (4 bar), 10% Pd–C, rt (synthesis of 2a,b,d–h,j,k); (ii) acetone, MeOH, AcOH, AcONa,
NaBH4, 0 °C (synthesis of 2i15); (iii) Ph2CHCl, MeCN, Et3N, reflux (synthesis of 2c18); (iv) ClCH2COCl, CH2Cl2, 4-methylmorpholine, 0 °C; (v) NH3, MeOH, rt; (vi) n-BuNH2,
MeOH, reflux.
amino acid ester hydrochlorides in quantitative yields. Subsequent
trituration of the crude products with ethyl acetate furnished the
pure compounds 2b,e–h,k,l in 73–100% yields. It is noteworthy that
these alkylations were highly chemoselective; dialkylation was not
observed, even in the presence of a large excess of acetone. Surpris-
ingly, the literature examples of this simple and general method for
the preparation of N-alkylated amino acids are quite rare.12 The sim-
plicity of isolation (see Experimental) makes this procedure superior
apply Fleet’s two step procedure comprising of amidation of Cbz-
protected amino acids 5 with an -isopropylamino acid ester 2 fol-
a
lowed by hydrogenolysis and simultaneous cyclisation of the so
formed dipeptide 6.19 Although N-acylations of sterically hindered
a
-alkylamino acids usually suffer from low yields,20 coupling of N-
benzyloxycarbonyl-a-amino acids 5 with N-isopropylamino acid
esters 2 turned out to be much more difficult than expected. At-
tempted acylation of N-isopropylalanine ester 2e with (S)-N-(ben-
zyloxycarbonyl)alanine 5a in the presence of various activating
(coupling) reagents, such as DCC, bis(pentafluorophenyl) carbonate
(BPC), EEDQ, CDI and 1-chloro-N,N,2-trimethylprop-1-en-1-amine
(Ghosez’s reagent) were all unsuccessful. The reluctance of 2e to-
wards acylation can be rationalised by steric hindrance of the
secondary amino group in 2e by two bulky alkyl groups.20
Accordingly, this problem could be circumvented by diminishing
the steric hindrance, that is, by replacement of the secondary iso-
propyl group with the primary propyl group. Catalytic hydro-
genations of amino acid esters 1a,b,d,e and h in the presence of
1.2 equiv of propanal were chemoselective to give the monoalkyla-
tion products 2l–p without noticeable overalkylation. In this
to the much more frequently used reductive alkylation of
a-amino
acid derivatives with complex hydrides, which usually requires a
more complicated workup comprising evaporation, extraction, chro-
matography and the preparation of a stable salt, for example, a
hydrochloride.15–17 Nevertheless, compounds 2c and 2i could not
be prepared by the above procedure. In order to avoid concomitant
reduction of a nitro group, isopropylation of 1f was performed with
NaBH4–acetone15 to give 2i in 30% yield. Reductive alkylation of 1a
with benzophenone did not take place, neither by hydrogenation
in the presence of Pt–C, nor by reduction with complex hydrides.
Therefore, compound 2d was prepared by N-alkylation of 1a with
chlorodiphenylmethane following the literature procedure.18 Next,
a-alkylamino esters 2a–k were treated with chloroacetyl chloride
manner, N-propylated a-amino acid esters, 2l–p were obtained
to give the intermediates 3a–k, which were subsequently cyclised
with methanolic ammonia to afford diketopiperazines 4a–k in 3–
46% yields (Scheme 1).
in 56–100% yields. Acylation of 2l–p with (S)-N-Cbz-alanine 5a
and (S)-N-Cbz-3-phenylalanine 5b with DCC or 1-chloro-N,N,2-
trimethylprop-1-en-1-amine as activating reagentsà gave the crude
In addition to the glycine-containing diketopiperazines 4a–k,
five novel (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones 4l–p with
two stereogenic centres were also prepared. Initially, we tried to
à
Other activating reagents (EEDQ, BPC, and CDI) were also tested, however, only
DCC and Ghosez’s reagent worked reasonably well.

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Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
631
COOMe
NH
COOMe
R1
O
HOOC
NHCOOBn
Me
N
+
coupling
NHCOOBn
5a
2e
6
H
N
O
R2
O
COOMe
NH2
COOMe
HCl
NH
COOMe
i
ii
iii
R1
R1
R1
O
R1
N
HCl
N
NHCOOBn
R2
1a,b,d,e,h
7l-p
4l-p
2l-p
Transformation
R1
R2
Yield (%)
2
4
1a→2l→4l
methyl
benzyl
methyl
methyl
methyl
methyl
100
85
64
35
33
45
36
1b→2m→4m
1d→2n→4n
1e→2o→4o
1h→2p→4p
isopropyl
isobutyl
benzyl
56
100
71
CH2CH2COOMe
Scheme 2. Reagents and conditions: (i) EtCHO, MeOH, H2 (3 bar), 10% Pd–C, rt; (ii) L-Z-alanine 5a or L-Z-phenylalanine 5b, DCC or Ghosez’s reagent, CH2Cl2,
4-methylmorpholine, rt; (iii) H2 (3 bar), 10% Pd–C, MeOH, rt.
dipeptides 7l–p. Subsequent hydrogenation in the presence of Pd-C
furnished the desired diketopiperazines 4l–p in 33–64% yields
(Scheme 2).
nals for the methyl protons appeared at 1.40–1.54 ppm. On the
other hand, the methyl protons of C- or N-benzyl substituted com-
pounds 4c, 4l and 4o, resonated at 0.82 ppm, 0.86 ppm, and
0.51 ppm, respectively. These unusually low d chemical shifts are
explained by shielding of the methyl protons by the aromatic ring,
which has also been observed previously in closely related com-
pounds.14 All of these structural data support an intramolecular
3. Structure determination
The structures of novel compounds 2a,b,d–g,i,j,l–n, 4a,b,d–p
and known compound 4c were determined by spectroscopic meth-
ods (IR, 1H and 13C NMR, and MS) and by elemental analyses for C,
H and N. Compounds 2f, 2j, 4j, 4l, 4m, 4n and 4p were not obtained
in analytically pure form. Their identities were confirmed by 13C
NMR and/or EI-HRMS. Physical and spectral data for the known
compounds 2c,18b 2h, 2k, 2o, 2p15a and 4c18a were consistent with
the literature data. Spectral data for the novel amine hydrochlo-
rides 2e and 2g were consistent with spectral data for known free
amines 2e16b-d,17 and 2g.12b
p?r interaction between the phenyl ring and the H–C(3) hydro-
gen atoms in 4o, while 1H NMR data indicate the possibility of this
type of interaction in compounds 4c and 4l. Interestingly, the
chemical shift of the methyl group in (S)-1-benzyl-6-methylpiper-
azine-2,5-dione 4q was also somewhat lower (d = 1.32 ppm), how-
ever the X-ray structure of 4q does not support a p?r interaction
between the phenyl ring and the H–C(6) hydrogen atoms (Fig. 7).9
4. Conclusion
The structures of compounds 4b, 4d, 4f, 4g, 4k and 4o were
determined by X-ray diffraction (Figs. 1–6). A preferred boat con-
formation of diketopiperazines 4b, 4d, 4f, 4g and 4k with the
C(6)-substituent in a pseudo axial position was in agreement with
the literature data for related compounds (Figs. 1–5).13,21,22 How-
ever, the structure of compound 4o was different: the ring was al-
most flat and, consequently, the substituents at positions 3 and 6
were no longer pseudo axial. Interestingly, the phenyl group was
oriented above the heterocyclic system and perpendicular to the
H–C bonds of the 3-Me group with the interatomic distance,
d(CH3ꢀ ꢀ ꢀC6H5) = 0.26 nm (Figs. 6 and 7). Another confirmation
came from comparison of d chemical shifts of the signals for the
methyl protons in 3- or 6-methyldiketopiperazines 4a–d,l–p. Typ-
ically, in compounds 4a,b,d,m,n,p devoid of benzyl groups, the sig-
In summary, a simple method for the synthesis of a-alkylamino
acid esters hydrochlorides 2 and polysubstituted N-alkylpiperazine-
2,5-diones 4 was developed. In total 16 (S)-1,6-dialkylpiperazine-
2,5-diones 4a–k and (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones
4l–p were prepared in three steps from commercially available
a
-amino acid esters 1a–h. With the exception of 4c,18 all other
diketopiperazines are novel. The synthetic method comprises of N-
alkylation of 1 followed by N-acylation and cyclisation. Reductive
N-alkylation of 1 by catalytic hydrogenation in the presence of a
symmetrical ketone or propanal proved to be a reliable and simple
method for the preparation of
reaction conditions and simple isolation of stable (storable)
alkylamino acid ester hydrochlorides 2 are the major advantage
a-alkylamino acid esters 2. Neutral
a-

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Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
Figure 1. Ortep view of the asymmetric unit of compound 4b at the 50% probability level of ellipsoids. H atoms are drawn as small spheres of arbitrary radii.
Figure 2. Ortep view of the asymmetric unit of compound 4d at the 50% probability
level of ellipsoids. H atoms are drawn as small spheres of arbitrary radii.
of this method over the commonly used reductive alkylation of a-
amino acid esters 1 with complex hydrides under essentially basic
conditions. In terms of scope and limitation, this three-step meth-
od has a broad scope with respect to the C-substituents, while the
choice of N-substituents is limited to primary and secondary alkyl
groups, due to steric hindrance of the amino group by bulky sub-
stituents in the N-acylation step.
Figure 3. Ortep view of the asymmetric unit of compound 4f at the 50% probability
level of ellipsoids. H atoms are drawn as small spheres of arbitrary radii.
(S)-a-Amino acid ester hydrochlorides 1a–h, (S)-Z-phenylala-
nine 5a, (S)-Z-alanine 5b, cyclohexanone, 2-indanone, diphenyl-
methyl chloride and propionaldehyde are commercially available.
Methyl (S)-2-(benzhydrylamino)propanoate (S)-2c was prepared
according to the literature procedures.19
5. Experimental
5.1. General methods
Sources of chirality: (i) L-alanine methyl ester hydrochloride
Melting points were determined on a Kofler micro hot stage.
The NMR spectra were obtained on a Bruker Avance DPX 300 at
300 MHz for 1H and 75.5 MHz for 13C nucleus, using CDCl3 and
DMSO-d6 as solvents with TMS as the internal standard. Optical
rotations were measured on a Perkin–Elmer 241MC Polarimeter.
Mass spectra were recorded on AutoSpecQ and Q-Tof Premier spec-
trometers and IR spectra on a Perkin–Elmer Spectrum BX FTIR
spectrophotometer. Microanalyses were performed on a Perkin–El-
mer CHN Analyzer 2400 II. Catalytic hydrogenations were carried
out on a Parr 3916EF Hydrogenation Apparatus (500 mL), at room
temperature under 4 bar of H2. Column chromatography was per-
formed on silica gel (Fluka, Silica Gel 60, particle size 0.035–
0.070 mm).
(Fluka AG), product number 05200, puriss., P99.0% (dried material
AT), ½a 2D0
ꢁ
¼ þ7:5 ꢂ 0:5 (c 2, MeOH), mp 107–110 °C, ee not speci-
fied; (ii)
L-valine methyl ester hydrochloride (Fluka AG), product
number 94670, puriss., P99.0% (dried material AT),
¼ þ23 ꢂ 1 (c 2, MeOH), mp 165–170 °C (dec.), ee not speci-
fied; (iii) -tert-leucine methyl ester hydrochloride (Aldrich), prod-
uct number 61891, puriss., P99.0% (dried material AT),
¼ þ17:5 ꢂ 1 (c 1, MeOH), ee not specified; (iv) -leucine
½
a 2D0
ꢁ
L
½
a 2D0
ꢁ
L
methyl ester hydrochloride (Fluka AG), product number 61890
puriss., P99.0% (dried material AT), ½a D20
¼ þ20 ꢂ 1 (c 4.5, MeOH),
ꢁ
ee P98%; (v) L-phenylalanine methyl ester hydrochloride (Fluka
AG), product number 78090 puriss., P99.0% (dried material AT),
¼ þ38ꢂ1:5 (c 2, MeOH), mp 155–162 °C (dec.), ee not specified;
½ ꢁ
a 2D0

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Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
633
Figure 4. Ortep view of the asymmetric unit of compound 4g at the 50% probability
level of ellipsoids. H atoms are drawn as small spheres of arbitrary radii.
Figure 6. Ortep view of the asymmetric unit of compound 4o at the 50% probability
level of ellipsoids. H atoms are drawn as small spheres of arbitrary radii.
5.2. General procedure for the reductive N-alkylation of
a-
amino acid esters 1a–e,g,h. Synthesis of
esters 2a,b,d–h,j–p
a-alkylamino acid
Under Ar, 10% Pd–C (500 mg) was added to a solution of
a-ami-
no acid ester hydrochloride 1a–e,g,h (10 mmol) in a mixture of
methanol (30 mL), symmetrical ketone (10 mmol)§ or propionalde-
hyde (0.87 mL, 12 mmol), and 4-methylmorpholine (4 drops). The
hydrogenation vessel was flushed five times with hydrogen, and
the mixture was hydrogenated (4 bar of H2, rt) for 12 h. The catalyst
was removed by filtration through a fritted funnel and washed with
methanol (10 mL). The combined filtrate was evaporated in vacuo to
give crude 2a,b,d–h,j–p in quantitative yields. The oily compound 2f
was used for further transformations without purification. The solid
compounds 2a,b,d,e,g,h,j–p were suspended in ethyl acetate
(50 mL), the suspensions were stirred at rt for 1 h, and the precipi-
tate was collected by filtration to give purified compounds
2a,b,d,e,g,h,j–p.
The following compounds were prepared in this manner.
5.2.1. Methyl (S)-2-(cyclohexylamino)propanoate hydrochloride
2a
Prepared from (S)-alanine methyl ester hydrochloride 1a
(1.396 g, 10 mmol) and cyclohexanone (1.036 mL, 981 mg,
10 mmol). Yield: 2.106 g (95%) of white crystals; mp 167–172 °C;
Figure 5. Ortep view of the asymmetric unit of compound 4k at the 50% probability
level of ellipsoids. H atoms are drawn as small spheres of arbitrary radii.
½
a 2D2
ꢁ
¼ þ1:5 (c 1, MeOH). 1H NMR (300 MHz, DMSO-d6): d 0.98–
1.16 (1H, m, 1H of C6H11); 1.16–1.32 (2H, m, 2H of C6H11); 1.32–
1.45 (2H, m, 2H of C6H11); 1.48 (3H, d, J = 7.1 Hz, CH3CH); 1.59
(1H, br d, J = 12.4 Hz, 1H of C6H11); 1.75 (2H, br d, J = 12.9 Hz, 2H
of C6H11); 2.01 (2H, br t, J = 12.4 Hz, 2H of C6H11); 3.04 (1H, br tt,
J = 3.5, 11.3 Hz, 1H of C6H11); 3.77 (3H, s, OCH3); 4.21 (1H, q,
J = 7.0 Hz, CH3CH); 9.10 and 9.49 (2H, 2 br s, 1:1, NH2þ). 13C NMR
(75.5 MHz, DMSO-d6): d 14.7, 23.96, 23.99, 24.7, 28.0, 28.5, 51.0,
52.8, 54.6, 169.8. m/z (ESI) = 186 (MH+). m/z (HRMS) Found:
186.1493 (MH+). C10H20NO2 requires: m/z = 186.1494. (Found: C,
(vi) (S)-(+)-4-nitrophenylalanine methyl ester hydrochloride
97% (Aldrich), product number 658421, ½a D20
ꢁ
¼ þ7:0ꢃ13:0 (c 1%,
water), ee not specified; (vii) O-tert-butyl-
L-tyrosine methyl ester
hydrochloride, P98.0%, product number 96627 (Aldrich), specific
rotation and ee not specified; (viii) -glutamic acid dimethyl ester
L
hydrochloride (Aldrich), product number 49560 puriss., P99.0%
(dried material AT), ½a D20
ꢁ ¼ þ26ꢂ1 (c = 5, H2O), ee not specified;
Z-Ala-OH (Fluka), puriss., P99.0%, product number 95850,
½ ꢁ ¼ ꢃ14:5ꢂ1 (c = 4%, AcOH), mp 84–87 °C, ee not specified;
a 2D0
Z-Phe-OH, 99%, product number 359807, ½a D20
ꢁ ¼ þ5 (c = 5, AcOH),
§
mp 85–87 °C, ee not specified.
Acetone was used in excess (5 mL).

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Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
634
π
σ interaction
d = 0.26 nm
R
H
O
H
H
H
H
R
δH (Me) = 0.51 ppm
N
N
O
N
O
H
O
N
O
N
H
N
H
H
H
less strained
pseudoaxial
conformers 4
strained
pseudoequatorial
4'
O
conformers
Compound 4o
δH (Me) = 0.82 ppm
δH (Me) = 1.32 ppm
H
H
δH (Me) = 0.82 ppm
H
H
H
H
H
H
H
H
H
H
O
O
O
N
N
N
N
N
O
N
O
H
H
H
H
O
H
Compound 4c
Compound 4l
Chemical Shift of 3(6)-CH3
Compound
Compound 4q
δ (ppm)
1.50
1.40
0.82
1.52
0.86
1.53
1.53
0.51
1.54
1.32
4a
4b
4c
4d
4l
4m
4n
4o
4p
4q24
Figure 7. Structural features of diketopiperazines 4.
54.26; H, 9.40; N, 6.33. C10H20ClNO2 requires: C, 54.17; H, 9.09; N,
6.32.); max (KBr) 3440, 2941, 2863, 2807, 2725, 2509, 1750 (C@O),
1448, 1428, 1328, 1316, 1227, 1168, 1113, 972 cmꢃ1
m/z = 220.1338. (Found: C, 60.86; H, 7.24; N, 5.46. C13H18ClNO2 re-
quires: C, 61.05; H, 7.09; N, 5.48.); mmax (KBr) 3447, 2936, 2748,
2688, 2451, 1750 (C@O), 1479, 1464, 1449, 1400, 1355, 1310,
m
.
1220, 1134, 1108, 757 cmꢃ1
.
5.2.2. Methyl (S)-2-(2,3-dihydro-1H-indan-2-ylamino)propano-
ate hydrochloride 2b
5.2.3. Methyl (S)-2-(isopropylamino)propanoate hydrochloride
2d
Prepared from (S)-alanine methyl ester hydrochloride 1a
(1.396 g, 10 mmol) and 2-indanone (1.322 g, 10 mmol). Yield:
Prepared from (S)-alanine methyl ester hydrochloride 1a
(1.396 g, 10 mmol) and acetone (5 mL, excess). Yield: 1.709 g
1.868 g (73%) of white crystals; mp 195–199 °C; ½a D23
¼ þ2:1 (c 1,
ꢁ
MeOH). 1H NMR (300 MHz, DMSO-d6): d 1.54 (3H, d, J = 7.1 Hz,
CHCH3); 3.12–3.36 (4H, m, 2 ꢄ CH2); 3.79 (3H, s, OCH3); 4.10
(1H, br quintet, J = 7.3 Hz, 2–H); 4.2 (1H, br q, J = 7.0 Hz, 2–H);
7.18–7.27 (4H, m, 4H of Ar); 9.70 and 10.05 (2H, 2br s, 1:1,
NH2þ). 13C NMR (75.5 MHz, DMSO-d6): d 14.8, 35.3, 35.5, 52.9,
53.5, 55.8, 124.4, 126.9, 139.4, 139.5, 169.8. m/z (ESI) = 220
(MH+). m/z (HRMS) Found: 220.1346 (MH+). C13H18NO2 requires:
(94%) of white crystals; mp 135–138 °C; ½a D23
¼ þ8:6 (c 1, MeOH).
ꢁ
1H NMR (300 MHz, DMSO-d6): d 1.24 and 1.27 (6H, 2d, 1:1,
J = 6.1 Hz, (CH3)2CH); 1.48 (3H, d, J = 7.1 Hz, CH3CH); 3.35 (1H, sep-
tet, J = 6.5 Hz, (CH3)2CH); 3.77 (3H, s, OCH3); 4.17 (1H, q, J = 7.0 Hz,
2–H); 9.14 and 9.47 (2H, 2br s, 1:1, NH2þ). 13C NMR (75.5 MHz,
DMSO-d6): d 14.7, 18.3, 18.7, 48.1, 51.5, 52.8, 169.8. m/z (ESI)
= 146 (M+). m/z (HRMS) Found: 146.1176 (MH+). C7H16NO2

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Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
635
requires: m/z = 146.1181. (Found: C, 46.52; H, 9.10; N, 7.80.
5.2.8. Methyl (S)-3-(4-tert-butoxyphenyl)-2-
C7H16ClNO2 requires: C, 46.28; H, 8.88; N, 7,71.); mmax (KBr)
3424, 2947, 2825, 2747, 2709, 2470, 2447, 1746 (C@O), 1438,
(isopropylamino)propanoate hydrochloride 2j
Prepared from (S)-O-tert-butyltyrosine methyl ester hydrochlo-
ride 1g (2.878 g, 10 mmol) and acetone (5 mL, excess). Yield:
1385, 1318, 1234, 1193, 1159, 1108 cmꢃ1
.
2.998 g (91%) of white crystals; mp 142–146 °C, ½a D21
ꢁ
¼ þ50:8 (c
5.2.4. Methyl (S)-2-(isopropylamino)-3-methylbutanoate
hydrochloride 2e
1.0, MeOH). 1H NMR (300 MHz, DMSO-d6):
d 1.28 (9H, s,
(CH3)3C); 1.29 and 1.30 (6H, 2br d, 1:1, partially overlapped by
the signal for (CH3)3C, J = 6.5 Hz, (CH3)2CH); 3.03 (1H, dd, J = 9.9,
13.4 Hz, 1H of CH2Ph); 3.30 (1H, br s, (CH3)2CH); 3.47 (1H, dd,
J = 4.9, 13.4 Hz, 1H of CH2Ph); 3.55 (3H, s, OCH3); 4.17 (1H, br s,
2-H); 6.92 and 7.16 (4H, 2d, 1:1, J = 8.5 Hz, C6H4); 9.44 and 10.34
(2H, 2br s, 1:1, NH2þ). 13C NMR (75.5 MHz, DMSO-d6): d 18.2,
19.0, 28.5, 34.8, 49.2, 52.4, 57.9, 77.8, 123.6, 129.1, 129.8, 154.2,
168.7. m/z (ESI) = 294 (MH+). m/z (HRMS) Found: 294.2064
(MH+). C17H28NO3 requires: m/z = 294.2069. (Found: C, 60.57; H,
8.44; N, 4.24. C17H28ClNO3ꢀ½H2O requires: C, 60.25; H, 8.63; N,
4.13); mmax (KBr) 3418, 2978, 1751, 1654, 1610, 1508, 1229,
Prepared from (S)-valine methyl ester hydrochloride 1b
(1.676 g, 10 mmol) and acetone (5 mL, excess). Yield: 1.593 g
(76%) of white crystals; mp 139–144 °C; ½a D22
¼ þ28:9 (c 1, MeOH).
ꢁ
1H NMR (300 MHz, DMSO-d6): d 0.95 and 1.05 (6H, 2d, J = 6.9 Hz,
(CH3)2CHCH); 1.26 and 1.28 (6H, 2d, 1:1, J = 6.1 Hz, (CH3)2CHNH);
2.40 (1H, br dq, J = 6.9, 11.1 Hz, (CH3)2CHCH); ꢅ3.3 (1H, m, over-
lapped by the signal for H2O, (CH3)2CHNH); 3.79 (3H, s, OCH3);
3.96–4.04 (1H, m, 2–H); 8.89 and 9.29 (2H, 2br s, 1:1, NH2þ). 13C
NMR (75.5 MHz, DMSO-d6): d 17.0, 17.9, 19.0, 19.5, 28.5, 50.1,
52.6, 61.7, 168.3. m/z (ESI) = 174 (MH+). m/z (HRMS) Found:
174.1488 (MH+). C9H20NO2 requires: m/z = 174.1494. (Found: C,
51.23; H, 9.93; N, 6.67. C9H20ClNO2 requires: C, 51.54; H, 9.61; N,
6.68.); mmax (KBr) 3462, 2977, 2712, 2669, 2508, 2415, 1737
(C@O), 1561, 1474, 1456, 1438, 1400, 1380, 1302, 1282, 1117,
1181 cmꢃ1
.
5.2.9. Dimethyl (S)-2-(isopropylamino)pentanedioate
hydrochloride 2k
1046 cmꢃ1
.
Prepared from (S)-glutamic acid dimethyl ester hydrochloride
1h (2.116 g, 10 mmol) and acetone (5 mL, excess). Yield: 2.284 g
(90%) of white crystals; mp 116 °C, lit.15a m.p. 131–135 °C;
5.2.5. Methyl (S)-2-(isopropylamino)-3,3-dimethylbutanoate
hydrochloride 2f
½
a 2D1
ꢁ
¼ þ30:8 (c 1, MeOH), lit15a
[a]
D = +58.8 (c 1, MeOH). 1H
Prepared from (S)-tert-leucine methyl ester hydrochloride 1c
(1.817 g, 10 mmol) and acetone (5 mL, excess). Yield: 2.227 g
NMR (300 MHz, DMSO-d6): d 1.26 and 1.28 (6H, 2d, J = 6.3 Hz,
(CH3)2CH); 2.09 (1H, td, J = 8.0, 15.0 Hz, 1H of CH2CH2COOMe);
2.17–2.30 (1H, m, 1H of CH2CH2COOMe); 2.40–2.62 (2H, m, over-
lapped by the signal for DMSO, CH2CH2COOMe); ꢅ3.3 (1H, m, over-
lapped by the signal for H2O, (CH3)2CHNH); 3.61 and 3.75 (6H, 2s,
1:1, 2 ꢄ OCH3); 4.13 (1H, br s, 2–H); 9.23 and 9.73 (2H, 2br s, 1:1,
NH2þ).
(100%) of viscous colourless oil; ½a D25
ꢁ
¼ þ29:7 (c 1, MeOH). 1H
NMR (300 MHz, DMSO-d6): d 1.07 (9H, s, (CH3)3C); 1.21 and 1.32
(6H, 2d, 1:1, J = 6.5 Hz, (CH3)2CH); ꢅ3.3 (1H, m, overlapped by
the signal for H2O, (CH3)2CH); 3.79 (3H, s, OCH3); 3.90 (1H, br d,
J = 9.3 Hz, 2–H); 8.57 and 8.80 (2H, 2br s, 1:1, NH2þ). 13C NMR
(75.5 MHz, DMSO-d6): d 17.5, 18.7, 26.2, 33.7, 51.4, 52.8, 64.8,
169.0. m/z (ESI) = 188 (MH+). m/z (HRMS) Found: 188.1655
(MH+). C10H22NO2 requires: m/z = 188.1651. mmax (KBr) 3439,
3239, 2960, 2629, 2540, 1728 (C@O), 1557, 1416, 1360, 1234,
5.2.10. Methyl (S)-2-(propylamino)propanoate hydrochloride 2l
Prepared from (S)-alanine methyl ester hydrochloride 1a
(1.396 g, 10 mmol) and propionaldehyde (0.87 mL, 12 mmol).
Yield: 1.811 g (100%) of white crystals; mp 183–186 °C;
1182 cmꢃ1
.
½
a 2D2
ꢁ
¼ þ1:8 (c 1, MeOH). 1H NMR (300 MHz, DMSO-d6): d 0.91
5.2.6. Methyl (S)-2-(isopropylamino)-4-methylpentanoate
hydrochloride 2g
(3H, t, J = 7.1 Hz, CH2CH2CH3); 1.48 (3H, d, J = 7.2 Hz, CHCH3);
1.67 (2H, sextet, CH2CH2CH3); 2.81 and 2.90 (2H, 2dd, J = 7.8,
11.9 Hz, CH2CH2CH3); 3.76 (3H, s, OCH3); 4.10 (1H, q, 2–H); 9.50
(2H, br s, NH2þ). 13C NMR (75.5 MHz, DMSO-d6): d 10.9, 14.3,
19.0, 46.6, 52.8, 54.1, 169.7. m/z (ESI) = 146 (MH+). m/z (HRMS)
Found: 146.1180 (MH+). C7H16NO2 requires: m/z = 146.1181.
(Found: C, 46.33; H, 9.13; N, 7.73. C7H16ClNO2 requires: C, 46.28;
H, 8.88; N, 7.71.); mmax (KBr) 3480, 2968, 2929, 2805, 2751, 2515,
2433, 1750 (C@O), 1480, 1436, 1334, 1300, 1223, 1194, 1112,
Prepared from (S)-leucine methyl ester hydrochloride 1d
(1.817 g, 10 mmol) and acetone (5 mL, excess). Yield: 1.990 g
(89%) of white crystals; mp 144–146 °C; ½a D22
¼ þ26:0 (c 1, MeOH).
ꢁ
1H NMR (300 MHz, DMSO-d6): d 0.88 and 0.90 (6H, 2d, J = 6.3 Hz,
(CH3)2CHCH2); 1.26 (6H, d, J = 6.5 Hz, (CH3)2CHNH); 1.60–1.84
(3H, m, (CH3)2CHCH2); ꢅ3.3 (1H, m, overlapped by the signal for
H2O, (CH3)2CHNH); 3.76 (3H, s, OCH3); 3.89 (1H, br s, 2–H); 9.36
and 10.12 (2H, 2br s, 1:1, NH2þ). 13C NMR (75.5 MHz, DMSO-d6):
d 17.9, 19.1, 21.2, 22.9, 24.2, 38.1, 48.9, 52.8, 55.1, 169.4. m/z
(ESI) = 188 (MH+). m/z (HRMS) Found: 188.1648 (MH+).
980 cmꢃ1
.
5.2.11. Methyl (S)-3-methyl-2-(propylamino)butanoate
hydrochloride 2m
C10H22NO2 requires: m/z = 188.1651. (Found: C, 53.60; H, 10.18;
N, 6.20. C10H22ClNO2 requires: C, 53.68; H, 9.91; N, 6.26.); mmax
Prepared from (S)-valine methyl ester hydrochloride 1b
(1.676 g, 10 mmol) and propionaldehyde (0.87 mL, 12 mmol).
Yield: 1.787 g (85%) of white crystals; mp 151–154 °C;
(KBr) 3454, 2958, 2874, 2810, 2668, 2631, 2529, 2496, 2426,
1734 (C@O), 1554, 1474, 1398, 1243, 1221 cmꢃ1
.
½
a 2D7
ꢁ
¼ þ27:4 (c = 1, MeOH). 1H NMR (300 MHz, DMSO-d6): d
5.2.7. Methyl (S)-2-(isopropylamino)-3-phenylpropanoate
hydrochloride 2h
0.89 (3H, t, J = 7.5 Hz, CH3CH2CH2); 0.93 and 1.04 (6H, 2d, 1:1,
J = 6.9 Hz, (CH3)2CH); 1.58–1.84 (2H, m, CH3CH2CH2); 2.42 (1H,
doublet of quintet, J = 4.2, 6.9 Hz, (CH3)2CH); 2.84 (2H, broad
signal, CH3CH2CH2); 3.78 (3H, s, OCH3); 3.94 (1H, broad signal,
2-H); 9.13 and 9.64 (2H, 2br s, 1:1, NH2þ). 13C NMR
(75.5 MHz, DMSO-d6): d 11.0, 16.8, 18.7, 19.6, 28.2, 48.2, 52.5,
64.3, 168.1. m/z (ESI) = 174 (MH+). m/z (HRMS) Found:
174.1496 (MH+). C9H20NO2 requires: m/z = 174.1494. (Found:
51.33; H, 9.80; N, 6.60. C9H20ClNO2 requires: C, 51.54; H,
9.61; N, 6.68); mmax (KBr) 3449, 2974, 2730, 1743 (C@O),
Prepared from (S)-3-phenylalanine methyl ester hydrochloride
1e (2.157 g, 10 mmol) and acetone (5 mL, excess). Yield: 2.448 g
(95%) of white crystals; mp 156–157 °C, lit.15a mp 154 °C;
½
a 2D1
ꢁ
¼ þ48:8 (c 1.2, MeOH), lit15a
[a]
D = +60.2 (c 1.2, MeOH). 1H
NMR (300 MHz, DMSO-d6): d 1.27 and 1.28 (6H, 2d, J = 6.4 Hz,
(CH3)2CH); 3.05 (1H, dd, J = 9.6, 13.5 Hz, 1H of CH2Ph); ꢅ3.3 (2H,
m, overlapped by the signal for H2O, 1H of CH2Ph and (CH3)2CH);
3.58 (3H, s, OCH3); 4.25 (1H, br dd, J = 4.4, 8.2 Hz, 2–H); 7.17–
7.41 (5H, m, Ph); 9.32 and 9.92 (2H, 2br s, 1:1, NH2þ).
1636, 1276, 1214 cmꢃ1
.

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Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
636
5.2.12. Methyl (S)-4-methyl-2-(propylamino)pentanoate
hydrochloride 2n
3.45 (1H, broad signal, (CH3)2CH); 3.33 (1H, dd, J = 9.6, 13.6 Hz,
1H of CH2Ph); 3.63 (3H, s, OCH3); 3.70 (1H, dd, J = 4.5, 13.6 Hz,
1H of CH2Ph); 4.38 (1H, broad signal, 2–H); 7.63 and 8.21 (4H,
2d, 1:1, J = 8.7 Hz, C6H4); 9.57 and 10.56 (2H, 2br s, 1:1, NH2þ).
13C NMR (75.5 MHz, DMSO-d6): d 18.1, 19.2, 34.9, 49.4, 52.7,
57.1, 123.5, 130.8, 142.9, 146.8, 168.3. m/z (ESI) = 267 (MH+). m/z
(HRMS) Found: 267.1350 (MH+). C13H19N2O4 requires: m/
z = 267.1345. (Found: C, 51.55; H, 6.33; N, 9.23. C13H19ClN2O4 re-
quires: C, 51.57; H, 6.33; N, 9.25.); mmax (KBr) 3454, 1755, 1604,
Prepared from (S)-leucine methyl ester hydrochloride (1d)
(1.817 g, 10 mmol) and propionaldehyde (0.87 mL, 12 mmol).
Yield: 1.253 g (56%) of white crystals; mp 120–122 °C;
½
a 2D5
ꢁ
¼ þ26:5 (c 1, MeOH). 1H NMR (300 MHz, DMSO-d6): d 0.90
(3H, t, J = 7.4 Hz, CH3CH2CH2); 0.903 and 0.907 (6H, 2d, 1:1,
J = 6.2 Hz, (CH3)2CH); 1.56–1.85 (5H, m, CH3CH2CH2 and
(CH3)2CHCH2); 2.70–2.85 and 2.85–2.99 (2H, 2 m, 1:1,
CH3CH2CH2); 3.77 (3H, s, OCH3); 3.97 (1H, dd, J = 5.1, 8.2 Hz, 2–
H); 9.29 and 9.65 (2H, 2br s, 1:1, NH2þ). 13C NMR (75.5 MHz,
DMSO-d6): d 10.9, 19.0, 21.2, 23.0, 24.2, 37.8, 47.2, 52.7, 57.6,
169.4. m/z (ESI) = 188 (MH+). m/z (HRMS) Found: 188.1660
(MH+). C10H22NO2 requires: m/z = 188.1651. (Found: C, 53.21; H,
10.13; N, 6.19. C10H22ClNO2 requires: C, 53.68; H, 9.91; N, 6.26.);
mmax (KBr) 3455, 2964, 2746, 2664, 1733 (C@O), 1636, 1548,
1520, 1346, 1220 cmꢃ1
.
5.4. General two-step procedure for the synthesis of (S)-1,6-
dialkylpiperazine-2,5-diones 4a–k
This general two-step procedure is a slight modification of the
known literature procedures for chloroacetylation of a-alkylamino
1259, 1219 cmꢃ1
.
acid esters13 and subsequent cyclisation with ammonia.14 A solu-
tion of chloroacetyl chloride (0.40 mL, 5 mmol) in dichloromethane
(2.5 mL) was added slowly to a stirred and cooled (0 °C, ice-bath)
suspension of 2 (5 mmol) and 4-methylmorpholine (1.38 mL,
12.5 mmol)– in dichloromethane (12.5 mL). The mixture was stirred
at 0 °C for 15 min. and at rt for 1.5 h. Then, 1 M hydrochloric acid
(5 mL) was added, the mixture was stirred at rt for 5 min and trans-
ferred to a separatory funnel. The phases were separated and the
aqueous phase was extracted with dichloromethane (3 ꢄ 15 mL).
The organic phases were combined, dried over anhydrous sodium
sulphate, filtered and the filtrate was evaporated in vacuo. The resi-
due was chromatographed over silica gel (EtOAc–hexanes, 1:1). Frac-
tions containing the product were combined and evaporated in
5.2.13. Methyl (S)-3-phenyl-2-(propylamino)propanoate
hydrochloride 2o
Prepared from (S)-3-phenylalanine methyl ester hydrochloride
1e (2.157 g, 10 mmol) and propionaldehyde (0.87 mL, 12 mmol).
Yield: 2.567 g (100%) of white crystals; mp 147–149 °C, lit.15a mp
128 °C; ½a 2D5
ꢁ
¼ þ47:5 (c 2, MeOH), lit.15a
[
a
]
D = +48.2 (c 2, MeOH).
1H NMR (300 MHz, DMSO-d6):
d
0.90 (3H, t, J = 7.4 Hz,
CH3CH2CH2); 1.68 (2H, br sextet, J = 7.2 Hz, CH3CH2CH2); 2.79–
3.00 (2H, m, CH3CH2CH2); 3.07 (1H, dd, J = 9.3, 13.6 Hz,
CH3CH2CH2); 3.40 (1H, dd, J = 4.8, 13.6 Hz, CH3CH2CH2); 3.60 (3H,
s, OCH3); 4.26 (1H, dd, J = 4.7, 9.1 Hz, 2–H); 7.20–7.38 (5H, m,
Ph); 9.38 and 9.84 (2H, 2br s, 1:1, NH2þ).
vacuo to give the crude N-alkyl-N-chloroacetyl-a-amino acid ester
3 as an oily residue, which was dissolved in methanol (10 mL),
cooled to 0 °C and then ammonia was bubbled through this solution
at 0 °C for 15 min. The reaction mixture was stirred at 0 °C for 0.5 h
and then at rt for 24 h. The volatile components were evaporated in
vacuo and the solid residue was suspended in dichloromethane
(25 mL) and the suspension was washed subsequently with 1 M
NaHSO4 (3 ꢄ 15 mL), satd aq NaHCO3 (3 ꢄ 15 mL) and brine
(3 ꢄ 15 mL). The organic phase was dried over anhydrous sodium
sulphate, filtered and the filtrate was evaporated in vacuo. The solid
residue was triturated with hot diethyl ether (5–10 mL), cooled to rt,
and the precipitate was collected by filtration to give diketopipera-
zines 4a–k.
5.2.14. Dimethyl (S)-2-(propylamino)pentanedioate
hydrochloride 2p
Prepared from (S)-glutamic acid dimethyl ester hydrochloride
1h (2.116 g, 10 mmol) and propionaldehyde (0.87 mL, 12 mmol).
Yield: 1.800 g (71%) of white crystals; mp 130–133 °C, lit.15a mp
121 °C; ½a 2D1
ꢁ
¼ þ26:9 (c 2, MeOH), lit.15a
[
a
]
D = +20.0 (c 2, MeOH).
1H NMR (300 MHz, DMSO-d6):
d
0.91 (3H, t, J = 7.4 Hz,
CH3CH2CH2); 1.67 (2H, br sextet, J = 7.4 Hz, CH3CH2CH2); 2.03–
2.29 (2H, m, CHCH2CH2COOMe); 2.41–2.62 (2H, m, overlapped by
the signal for DMSO, CH2CH2COOMe); 2.86 (2H, br quintet,
J = 7.4 Hz, CH3CH2CH2); 3.61 and 3.75 (6H, 2s, 1:1, 2 ꢄ OCH3);
4.07 (1H, br s, 2–H); 9.32 and 9.72 (2H, 2br s, 1:1, NH2þ).
The following compounds were prepared in this manner.
5.3. Synthesis of methyl (S)-2-(isopropylamino)-3-(4-
nitrophenyl)propanoate hydrochloride 2i
5.4.1. (S)-1-Cyclohexyl-6-methylpiperazine-2,5-dione 4a
Prepared from 2a (926 mg, 5 mmol). Yield: 66 mg (6%) of white
crystals; mp 285–290 °C; ½a D24
ꢁ
¼ þ137:4 (c 0.5, CH2Cl2). 1H NMR
This compound was prepared from (S)-3-(4-nitrophenyl)ala-
nine methyl ester hydrochloride 1f, NaBH4, and acetone following
the literature procedures for reductive alkylation of primary
amines hydrochlorides.15 A mixture of 1f (2.607 g, 10 mmol), anhy-
drous methanol (75 mL), and anhydrous sodium acetate (820 mg,
10 mmol) was stirred at rt for 5 min. Acetic acid (100%, 600 mg,
1.2 mL, 20 mmol) and acetone (2.2 mL, 30 mmol) were added and
the mixture was cooled to 0 °C (ice-bath). Then, NaBH4 (380 mg,
10 mmol) was added portion-wise and the stirring was continued
at 0 °C for 3 h and then at rt for 48 h. The reaction mixture was
evaporated in vacuo and the semi-solid residue was purified by
column chromatography (EtOAc). Fractions containing the product
were combined and evaporated in vacuo, the oily residue was dis-
solved in ethyl acetate (40 mL) and 2 M HCl–EtOAc (10 ml,
20 mmol) was added while stirring. The mixture was stirred at rt
for 15 min and the precipitate was collected by filtration to give
2i. Yield: 0.907 g (30%) of pale yellow crystals; mp 185–190 °C
(300 MHz, CDCl3): d 1.05–1.22 (1H, m, 1H of C6H11); 1.28–1.47
(3H, m, 3H of C6H11); 1.50 (3H, d, J = 7.1 Hz, CH3); 1.56–1.75 (3H,
m, 3H of C6H11); 1.76–1.97 (3H, m, 3H of C6H11); 3.82 (1H, dd,
J = 4.5, 17.0 Hz, 3–Ha); 3.98 (1H, dq, J = 1.3, 7.1 Hz, CHCH3); 4.04
(1H, d, J = 17.0 Hz, 3–Hb); 4.21 (1H, tt, J = 3.6, 11.8 Hz, 1–H of
C6H11); 6.26 (1H, br s, NH). 13C NMR (75.5 MHz, CDCl3): d 19.8,
25.3, 25.7, 25.9, 30.3, 31.3, 45.5, 53.1, 54.6, 164.1, 170.7. m/z
(ESI) = 211 (MH+). m/z (HRMS) Found: 211.1441 (MH+).
C11H19N2O2 requires: m/z = 211.1447. (Found: C, 62.82; H, 8.86;
N, 13.27. C11H18N2O2 requires: C, 62.83; H, 8.63; N, 13.32.); mmax
(KBr) 3263, 2977, 2931, 2854, 1661 (C@O), 1467, 1446, 1402,
1378, 1322, 1291, 1241, 1193, 1148, 1126, 1088, 1054, 998, 977,
893, 812, 778, 724 cmꢃ1
.
(sublimation), ½a D22
ꢁ
¼ þ52:2 (c 1.0, MeOH). 1H NMR (300 MHz,
–
Chloroacetylation of the free amino ester 2c required only 1.5 equiv (0.83 mL,
DMSO-d6): d 1.34 and 1.35 (6H, 2d, J = 6.4 Hz, (CH3)2CH); 3.30–
7.5 mmol) of 4-methylmorpholine.

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Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
637
5.4.2. (S)-1-(2,3-Dihydro-1H-inden-2-yl)-6-methylpiperazine-
2,5-dione 4b
0.5, CH2Cl2). 1H NMR (300 MHz, CDCl3): d 1.13 (9H, s, (CH3)3C);
1.36 and 1.65 (6H, 2d, 1:1, J = 6.8 Hz, (CH3)2CH); 3.28 (1H, septet,
J = 6.7 Hz, (CH3)2CH); 3.49 (1H, d, J = 1.3 Hz, 6–H); 3.71 (1H, dd,
J = 5.2, 17.1 Hz, 3–Ha); 4.05 (1H, d, J = 17.1 Hz, 3–Hb); 7.31 (1H,
br s, NH). 13C NMR (75.5 MHz, CDCl3): d 19.4, 21.0, 27.9, 38.5,
47.1, 57.9, 73.0, 166.2, 169.1. m/z (ESI) = 213 (MH+). m/z (HRMS)
Found: 213.1602 (MH+). C11H21N2O2 requires: m/z = 213.1603.
(Found: 62.17; H, 9.61; N, 12.98. C11H20N2O2 requires: C, 62.23;
H, 9.50; N, 13.20.); mmax (KBr) 3453, 2962, 1674 (C@O), 1459,
Prepared from 2b (1.096 g, 5 mmol). Yield: 135 mg (11%) of
white crystals; mp 216–220 °C; ½a D24
ꢁ
¼ þ123:4 (c 0.5, CH2Cl2). 1H
NMR (300 MHz, CDCl3): d 1.39 (3H, d, J = 7.0 Hz, CH3); 3.13 (2H,
br dd, J = 6.7, 16.0 Hz, 1’-Ha, 3’-Ha); 3.26 (2H, br dd, J = 8.0,
16.0 Hz, 1’-Hb, 3’-Hb); 3.90 (1H, br q, J = 7.1 Hz, 6-H); 3.92 (1H,
dd, J = 4.2, 17.3 Hz, 3-Ha); 4.03 (1H, d, J = 17.3 Hz, 3-Hb); 4.97
(1H, tt, J = 6.7, 8.0 Hz, 2’-H); 7.14–7.21 (4H, m, C6H4); 7.31 (1H,
br s, NH). 13C NMR (75.5 MHz, CDCl3): d 19.4, 36.6, 37.5, 45.5,
55.0, 56.2, 124.6, 124.7, 127.1, 127.2, 140.6, 140.7, 164.9, 171.0.
m/z (ESI) = 245 (MH+). m/z (HRMS) Found: 245.1295 (MH+).
1328, 1313, 1007 cmꢃ1
.
5.4.7. (S)-6-Isobutyl-1-isopropylpiperazine-2,5-dione 4g
Prepared from 2g (936 mg, 5 mmol). Yield: 300 mg (28%) of
C14H17N2O2 requires: m/z = 245.1290. (Found: C, 68.67; H, 6.70;
N, 11.45. C14H16N2O2 requires: C, 68.83; H, 6.60; N, 11.47.); mmax
(KBr) 3254, 3020, 2959, 2924, 1661 (C@O), 1463, 1448, 1431,
white crystals; mp 88–89 °C; ½a D19
ꢁ
¼ þ177:2 (c 0.5, CH2Cl2). 1H
NMR (300 MHz, CDCl3): d 0.96, 1.06, 1.24, and 1.25 (12H, 4d,
1:1:1:1, J = 6.9 Hz, 2 ꢄ (CH3)2CH); 1.51 (1H, ddd, J = 4.0, 10.6,
14.6 Hz, 1H of (CH3)2CHCH2); 1.80 (1H, ddd, J = 3.6, 11.3, 14.6 Hz,
1H of (CH3)2CHCH2); 1.76–1.91 (1H, m, (CH3)2CHCH2); 3.86 (1H,
dd, J = 5.0, 17.0 Hz, 3–Ha); 3.87 (1H, ddd, J = 1.3, 3.9, 11.0 Hz, 6–
H); 4.06 (1H, d, J = 17.0 Hz, 3–Hb); 4.51 (1H, septet, J = 6.9 Hz,
(CH3)2CH–N(1)); 7.41 (1H, br d, J = 3.0 Hz, NH). 13C NMR
(75.5 MHz, CDCl3): d 20.4, 20.8, 21.6, 23.9, 25.0, 42.6, 45.7, 47.2,
55.7, 165.1, 170.6. m/z (ESI) = 213 (M+). m/z (HRMS) Found:
213.1605 (MH+). C11H21N2O2 requires: m/z = 213.1603. (Found: C,
62.06; H, 9.67; N, 13.17. C11H20N2O2 requires: C, 62.23; H, 9.50;
N, 13.20.); mmax (KBr) 3275, 2953, 2871, 1691 (C@O), 1654 (C@O),
1462, 1441, 1393, 1376, 1317, 1295, 1207, 1182, 1131, 1105,
1403, 1324, 1289, 1265, 1244, 1129, 1089, 803, 781, 739 cmꢃ1
.
5.4.3. (S)-1-Benzhydryl-6-methylpiperazine-2,5-dione 4c
Prepared from 2c (1.347 g, 5 mmol). Yield: 50 mg (3%) of white
crystals; mp 190–193 °C, lit.18b mp 186–188 °C; ½a 2D5
¼ þ224:6 (c
ꢁ
0.5, CH2Cl2), lit.18b
½
a 2D0
ꢁ
¼ þ272:6 (concentration and solvent are
not given). 1H NMR (300 MHz, CDCl3): d 0.82 (3H, d, J = 7.1 Hz,
CH3); 4.03 (1H, dd, J = 4.3, 16.8 Hz, 3–Ha); 4.03 (1H, dq, J = 1.0,
7.1 Hz, 6–H); 4.12 (1H, d, J = 16.8 Hz, 3–Hb); 6.80 (1H, br s, NH);
7.05 (1H, br s, Ph2CH); 7.12 (2H, br d, J = 7.6 Hz, 2H of Ph); 7.25–
7.40 (8H, m, 8H of Ph). 13C NMR (75.5 MHz, CDCl3): d 18.1, 45.8,
54.9, 60.7, 127.2, 127.7, 128.8, 129.0, 129.1, 130.6, 138.1, 138.6,
165.2, 171.3. m/z (ESI) = 317 (MNa+). m/z (HRMS) Found:
317.1280 (MNa+). C18H18N2O2Na requires: m/z = 317.1266. (Found:
C, 73.16; H, 6.19; N, 9.37. C18H18N2O2 requires: C, 73.45; H, 6.16; N,
817, 768 cmꢃ1
.
5.4.8. (S)-6-Benzyl-1-isopropylpiperazine-2,5-dione 4h
9.52.);
m
max (KBr) 3243, 3131, 2925, 1695 (C@O), 1656 (C@O), 1491,
Prepared from 2h (1.107 g, 5 mmol). Yield: 125 mg (10%) of
1443, 1397, 1313, 1269, 1192, 1119, 1064, 750, 699 cmꢃ1
.
white crystals; mp 165–171 °C; ½a D24
ꢁ
¼ þ170:8 (c 0.5, CH2Cl2). 1H
NMR (300 MHz, CDCl3): d 1.32 and 1.41 (6H, 2d, 1:1, J = 6.9 Hz,
(CH3)2CH); 2.49 (1H, d, J = 16.8 Hz, 3–Ha); 3.09 (1H, dd, J = 5.1,
13.9 Hz, 1H of CH2Ph); 3.28 (1H, dd, J = 3.8, 13.2 Hz, 1H of CH2Ph);
3.36 (1H, dd, J = 4.1, 16.8 Hz, 3–Hb); 4.21 (1H, t, J = 4.4 Hz, 6–H);
4.47 (1H, septet, J = 6.9 Hz, (CH3)2CH); 7.16 (1H, br s, NH); 7.20–
7.28 (2H, m, 2H of Ph); 7.28–7.35 (3H, m, 3H of Ph). 13C NMR
(75.5 MHz, CDCl3): d 20.6, 21.5, 40.0, 45.2, 48.6, 59.2, 128.1,
129.1, 130.5, 135.2, 165.3, 169.8. m/z (ESI) = 247 (MH+). m/z
(HRMS) Found: 247.1451 (MH+). C14H19N2O2 requires: m/
z = 247.1447. (Found: C, 67.95; H, 7.56; N, 11.33. C14H18N2O2 re-
quires: C, 68.27; H, 7.37; N, 11.37.); mmax (KBr) 3276, 2975, 2937,
1684 (C@O), 1652 (C@O), 1445, 1329, 1306, 1216, 1183, 1115,
5.4.4. (S)-1-Isopropyl-6-methylpiperazine-2,5-dione 4d
Prepared from 2d (726 mg, 5 mmol). Yield: 95 mg (11%) of
white crystals; mp 236–240 °C; ½a D25
ꢁ
¼ þ169:8 (c 0.5, CH2Cl2). 1H
NMR (300 MHz, CDCl3): d 1.23 and 1.27 (6H, 2d, 1:1, J = 6.9 Hz,
(CH3)2CH); 1.52 (3H, d, J = 7.1 Hz, 6–CH3); 3.88 (1H, dd, J = 4.5,
17.0 Hz, 3–Ha); 3.97 (1H, dq, J = 0.9, 7.1 Hz, 6–H); 4.0 (1H, d,
J = 17.0 Hz, 3–Hb); 4.55 (1H, septet, J = 6.9 Hz, (CH3)2CH); 6.92
(1H, br s, NH). 13C NMR (75.5 MHz, CDCl3): d 19.9, 20.2, 21.1,
45.6, 46.9, 52.9, 164.3, 171.2. m/z (ESI) = 171 (MH+). m/z (HRMS)
Found: 171.1126 (MH+). C8H15N2O2 requires: m/z = 171.1134.
(Found: C, 56.32; H, 8.50; N, 16.42. C8H14N2O2 requires: C, 56.45;
H, 8.29; N, 16.46.); mmax (KBr) 3259, 2977, 2928, 1680 (C@O),
1654 (C@O), 1445, 1402, 1375, 1322, 1290, 1215, 1127, 1083,
1037, 809, 768, 724, 702 cmꢃ1
.
1055, 783 cmꢃ1
.
5.4.9. (S)-1-Isopropyl-6-(4-nitrobenzyl)piperazine-2,5-dione 4i
Prepared from 2i (1.331 g, 5 mmol). Yield: 621 mg (43%) of pale
5.4.5. (S)-1,6-Diisopropylpiperazine-2,5-dione 4e
yellow crystals; mp 141–144 °C; ½a D24
ꢁ
¼ þ157:9 (c 0.5, CH2Cl2). 1H
Prepared from 2e (866 mg, 5 mmol). Yield: 257 mg (26%) of
NMR (300 MHz, CDCl3): d 1.35 and 1.41 (6H, 2d, 1:1, J = 6.9 Hz,
(CH3)2CH); 2.97 (1H, d, J = 17.3 Hz, 3–Ha); 3.21 (1H, dd, J = 6.2,
13.8 Hz, 1H of CH2Ph); 3.30 (1H, dd, J = 4.2, 13.8 Hz, 1H of CH2Ph);
3.57 (1H, dd, J = 4.3, 17.3 Hz, 3–Hb); 4.25 (1H, t, J = 5.0 Hz, 6–H);
4.46 (1H, septet, J = 6.9 Hz, (CH3)2CH); 6.94 (1H, br d, J = 3.2 Hz,
NH); 7.44 and 8.18 (4H, 2 m, 1:1, J = 8.7 Hz, C6H4). 13C NMR
(75.5 MHz, CDCl3): d 20.4, 21.1, 39.6, 45.2, 48.6, 58.6, 123.9,
131.0, 142.8, 147.6, 164.5, 168.4. m/z (ESI) = 292 (MH+). m/z
(HRMS) Found: 292.1288 (MH+). C14H18N3O4 requires: m/
z = 292.1297. (Found: C, 57.98; H, 5.89; N, 14.35. C14H17N3O4 re-
quires: C, 57.72; H, 5.88; N, 14.42.); mmax (KBr) 3454, 1646, 1601,
white crystals; mp 110–112 °C; ½a D25
ꢁ
¼ þ113:6 (c 0.5, CH2Cl2). 1H
NMR (300 MHz, CDCl3): d 1.04, 1.17, 1.34, and 1.37 (12H, 4d,
1:1:1:1, J = 6.9 Hz, 2 ꢄ (CH3)2CH); 2.22 (1H, doublet of a septet,
J = 4.5, 7.0 Hz, (CH3)2CH–C(6)); 3.77 (1H, d, J = 4.4 Hz, 6–H); 3.83
(1H, dd, J = 4.4, 17.3 Hz, 3–Ha); 4.02 (1H, septet, J = 6.9 Hz,
(CH3)2CH–N(1)); 4.06 (1H, d, J = 17.3 Hz, 3–Hb); 7.87 (1H, br s,
NH). 13C NMR (75.5 MHz, CDCl3): d 16.8, 20.0, 20.1, 20.6, 33.4,
45.9, 50.7, 64.9, 164.7, 168.3. m/z (ESI) = 199 (MH+). m/z (HRMS)
Found: 199.1440 (MH+). C10H19N2O2 requires: m/z = 199.1447.
(Found: C, 60.34; H, 9.47; N, 14.01. C10H18N2O2 requires: C, 60.58;
H, 9.15; N, 14.13.);
m
max (KBr) 3437, 3197, 2970, 2877, 1697 (C@O),
1520, 1438, 1342, 1329 cmꢃ1
.
1660 (C@O), 1462, 1428, 1305, 1184, 1126, 1094, 1027, 760 cmꢃ1
.
5.4.10. (S)-6-(4-tert-Butoxybenzyl)-1-isopropylpiperazine-2,5-
dione 4j
5.4.6. (S)-6-tert-Butyl-1-isopropylpiperazine-2,5-dione 4f
Prepared from 2f (936 mg, 5 mmol). Yield: 55 mg (5%) of white
Prepared from 2j (1.439 g, 5 mmol). Yield: 810 mg (51%) of
crystals; mp 125–128 °C (from EtoAc/hexanes); ½a D22
ꢁ
¼ þ80:8 (c
white crystals; mp 142–144 °C; ½a D22
ꢁ
¼ þ137:3 (c 0.5, CH2Cl2). 1H

ˇ
ˇ
Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
638
NMR (300 MHz, CDCl3): d 1.33 and 1.39 (6H, 2d, 1:1, J = 6.9 Hz,
(CH3)2CH); 1.34 (9H, s, (CH3)3C); 2.51 (1H, d, J = 16.9 Hz, 3–Ha);
3.06 (1H, dd, J = 4.8, 14.0 Hz, 1H of CH2Ph); 3.24 (1H, dd, J = 3.9,
14.0 Hz, 1H of CH2Ph); 3.37 (1H, dd, J = 4.1, 16.9 Hz, 3–Hb); 4.19
(1H, t, J = 4.2 Hz, 6–H); 4.45 (1H, septet, J = 6.9 Hz, (CH3)2CH);
6.87 (1H, br d, J = 3.3 Hz, NH); 6.94 and 7.14 (4H, 2 m, 1:1,
J = 8.5 Hz, C6H4). 13C NMR (75.5 MHz, CDCl3): d 20.4, 21.2, 29.0,
39.0, 45.0, 48.5, 59.1, 78.8, 124.4, 129.7, 130.9, 155.3, 164.9,
169.5. m/z (ESI) = 319 (MH+). m/z (HRMS) Found: 319.2008
(MH+). C18H27N2O3 requires: m/z = 319.2022. Found: C, 66.27; H,
8.40; N, 8.56. C18H26N2O3ꢀ½H2O requires: C, 66.03; H, 8.31; N,
8.56.; mmax (KBr) 3446, 2979, 1652, 1503, 1447, 1326, 1237,
5.5.1. (3S,6S)-3-Benzyl-6-methyl-1-propylpiperazine-2,5-dione
4l
Prepared from 2l (182 mg, 1 mmol) and (S)-Z-Phe-OH (5b)
(299 mg, 1 mmol). Yield: 167 mg (64%) of
a colourless oil;
½
a 2D5
ꢁ
¼ ꢃ54:6 (c 0.5, CH2Cl2). 1H NMR (300 MHz, CDCl3): d 0.86
(3H, d, J = 7.0 Hz, 6–CH3); 0.90 (3H, t, J = 7.4 Hz, CH3CH2CH2);
1.40–1.57 (1H, m, 1H of CH3CH2CH2); 1.57–1.75 (1H, m, 1H of
CH3CH2CH2); 2.90 (1H, ddd, J = 5.3, 9.6, 13.7 Hz, 1H of CH3CH2CH2);
3.10 (1H, dd, J = 7.6, 13.6 Hz, 1H of CH2Ph); 3.20 (1H, dd, J = 3.9,
13.6 Hz, 1H of CH2Ph); 3.60 (1H, ddd, J = 6.3, 9.7, 13.6 Hz, 1H of
CH3CH2CH2); 3.78 (1H, q, J = 7.0 Hz, 6–H); 4.30 (1H, td, J = 3.5,
7.2 Hz, 3–H); 7.18–7.24 (2H, m, 2H of Ph); 7.26–7.36 (3H, m, 3H
of Ph); 7.47(1H, br s, NH). 13C NMR (75.5 MHz, CDCl3): d 11.4,
18.8, 20.4, 41.0, 46.6, 55.7, 56.9, 127.5, 128.8, 130.4, 135.7, 164.8,
169.2. m/z (ESI) = 261 (MH+). m/z (HRMS) Found: 261.1600
(MH+). C15H21N2O2 requires: m/z = 261.1603. mmax (NaCl) 3420,
1163 cmꢃ1
.
5.4.11. Methyl (S)-3-(1-isopropyl-2,5-dioxopiperazin-6-
yl)propanoate 4k
Prepared from 2k (1.086 g, 5 mmol). Yield: 393 mg (32%) of
2926, 1680 (C@O), 1653 (C@O), 1456, 1322, 1073, 751, 701 cmꢃ1
.
white crystals; mp 147–151 °C; ½a D24
ꢁ
¼ þ137:6 (c 0.5, CH2Cl2). 1H
NMR (300 MHz, CDCl3): d 1.27 and 1.32 (6H, 2d, 1:1, J = 6.9 Hz,
(CH3)2CH); 2.03 (1H, dddd, J = 6.0, 7.0, 10.7, 13.9 Hz, 3–Ha); 2.22
(1H, dddd, J = 4.1, 8.0, 12.0, 13.9 Hz, 3–Hb); 2.45–2.64 (2H, m, 2–
CH2); 3.71 (3H, s, OCH3); 3.87 (1H, dd, J = 4.6, 17.1 Hz, 5’–Ha);
3.94 (1H, dd, J = 3.8, 10.8 Hz, 2’–H); 4.07 (1H, d, J = 17.1 Hz, 5’–
Hb); 4.49 (1H, septet, J = 6.8 Hz, (CH3)2CH); 7.70 (1H, br d,
J = 3.1 Hz, NH). 13C NMR (75.5 MHz, CDCl3): d 20.0, 20.7, 28.2,
29.4, 45.4, 47.5, 51.9, 56.3, 164.6, 169.5, 172.7. m/z (ESI) = 265
(MNa+). m/z (HRMS) Found: 265.1160 (MNa+). C11H18N2O4Na re-
quires: m/z = 265.1164. (Found: C, 54.42; H, 7.70; N, 11.52.
5.5.2. (3S,6S)-6-Isopropyl-3-methyl-1-propylpiperazine-2,5-
dione 4m
Prepared from 2m (210 mg, 1 mmol) and (S)-Z-Ala-OH 5a
(223 mg, 1 mmol). Yield: 74 mg (35%) of colourless oil;
½
a 2D4
ꢁ
¼ þ39:8 (c 0.5, CH2Cl2). 1H NMR (300 MHz, CDCl3): d 0.91
(3H, t, J = 7.4 Hz, CH3CH2CH2); 1.02 and 1.17 (6H, 2d, 1:1,
J = 7.0 Hz, (CH3)2CH); 1.53 (3H, d, J = 7.1 Hz, 3–CH3); 1.55–1.75
(2H, m, CH3CH2CH2); 2.18 (1H, doublet of septet, J = 4.8, 6.9 Hz,
(CH3)2CH); 2.81 (1H, ddd, J = 5.8, 9.2, 13.6 Hz, 1H of CH3CH2CH2);
3.74 (1H, d, J = 4.8 Hz, 6–H); 3.87 (1H, ddd, J = 6.2, 9.2, 13.6 Hz,
1H of CH3CH2CH2); 4.13 (1H, dq, J = 3.3, 7.1 Hz, 3–H); 7.56 (1H,
br s, NH). 13C NMR (75.5 MHz, CDCl3): d 11.4, 18.1, 20.2, 20.4,
21.5, 32.0, 48.0, 51.6, 65.6, 167.1. m/z (ESI) = 213 (MH+). m/z
(HRMS) Found: 213.1598 (MH+). C11H21N2O2 requires: m/
z = 213.1603. mmax (NaCl) 3244, 2966, 1682, 1651, 1470, 1328,
C11H18N2O4 requires: C, 54.53; H, 7.49; N, 11.56.); mmax (KBr)
3262, 2970, 1728, 1688 (C@O), 1662 (C@O), 1444, 1430, 1318,
1299, 1269, 1257, 1208, 1167, 1108, 1022, 867, 822, 786,
767 cmꢃ1
.
5.5. General procedure for the preparation of 1,3,6-
trialkylpiperazine-2,5-diones 4l,m,o,p
1157, 1065 cmꢃ1
.
5.5.3. (3S,6S)-6-Benzyl-3-methyl-1-propylpiperazine-2,5-dione
4o
While stirring, DCC (206 mg, 1 mmol) was added to a cooled
(0 °C) mixture of (S)-Z-Ala-OH 5a (223 mg, 1 mmol) or (S)-Z-
Phe-OH 5b (299 mg, 1 mmol), a-propylamino acid ester hydro-
chloride 2l,m,o,p (1 mmol), dichloromethane (10 mL) and 4-
methylmorpholine (0.11 mL, 1 mmol) and the mixture was stir-
red at rt for 12 h. The precipitated DCU was removed by filtration
and washed with dichloromethane (3 ꢄ 5 mL). The combined fil-
trate was washed with 1 M NaHSO4 (3 ꢄ 5 mL), satd aq NaHCO3
(3 ꢄ 5 mL) and brine (3 ꢄ 5 mL). The organic phase was dried
over anhydrous sodium sulphate, filtered and the filtrate was
evaporated in vacuo. The residue was purified by column chro-
matography (50% EtOAc/hexanes). Fractions containing the prod-
uct were combined and evaporated in vacuo to give dipeptide 7
as an oily residue. The crude compound 7 was dissolved in meth-
anol (25 mL), the flask was flushed with Ar and 10% Pd–C
(100 mg) was added. The hydrogenation vessel was then flushed
five times with hydrogen and the mixture was hydrogenated
(4 bar of H2, rt) for 12 h. The catalyst was removed by filtration
Prepared from 2o (258 mg, 1 mmol) and (S)-Z-Ala-OH 5a
(223 mg, 1 mmol). Yield: 150 mg (58%) of white crystals; mp
221–223 °C; ½a 2D4
ꢁ
¼ þ52:6 (c 0.5, CH2Cl2). 1H NMR (300 MHz,
CDCl3): d 0.51 (3H, d, J = 7.1 Hz, 3–CH3); 0.94 (3H, t, J = 7.4 Hz,
CH3CH2CH2); 1.65 (2H, sextet, J = 7.5 Hz, CH3CH2CH2); 2.81 (1H,
dd, J = 7.1, 13.6 Hz, 1H of CH3CH2CH2); 3.17 (1H, dd, J = 4.7,
14.0 Hz, 1H of CH2Ph); 3.28 (1H, dd, J = 3.8, 14.0 Hz, 1H of CH2Ph);
3.88 (1H, dq, J = 2.6, 7.1 Hz, 3–H); 4.12 (1H, td, J = 7.8, 13.6 Hz, 1H
of CH3CH2CH2); 4.26 (1H, t, J = 4.2 Hz, 6–H); 6.83 (1H, br s, NH);
7.08–7.14 (2H, m, 2H of Ph); 7.21–7.34 (3H, m, 3H of Ph). 13C
NMR (75.5 MHz, CDCl3): d 11.5, 20.2, 20.7, 37.2, 46.0, 51.4, 60.7,
127.7, 129.0, 130.5, 135.0, 166.4, 167.0. m/z (EI) = 278 (MNH4þ).
m/z (HRMS) Found: 278.1870 (MNH4þ). C15H24N3O2 requires: m/
z = 278.1869. (Found: C, 69.23; H, 7.93; N, 10.72. C15H20N2O2 re-
quires: C, 69.20; H, 7.74; N, 10.76.); mmax (KBr) 3460, 3210, 3171,
2958, 2925, 2854, 1684, 1625, 1472, 1446, 1323, 1162, 709 cmꢃ1
.
through
a
fritted funnel and washed with methanol
5.5.4. Methyl 3-[(3S,6S)-3-methyl-2,5-dioxo-1-propylpiperazin-
6-yl]propanoate 4p
Prepared from 2p (254 mg, 1 mmol) and (S)-Z-Ala-OH 5a
(223 mg, 1 mmol). Yield: 93 mg (36%) of colourless oil;
(3 ꢄ 10 mL). The combined filtrate was evaporated in vacuo, the
residue was dissolved in dichloromethane (25 mL), and washed
with 1 M NaHSO4 (3 ꢄ 5 mL), satd aq NaHCO3 (3 ꢄ 5 mL), and
brine (3 ꢄ 5 mL). The organic phase was dried over anhydrous so-
dium sulphate, filtered, the filtrate was evaporated in vacuo and
the residue was purified by column chromatography. First, the
non-polar impurities were eluted with 50% EtOAc/hexanes, then
product 4 was eluted with 17% EtOH/EtOAc. Fractions containing
the product were combined and evaporated in vacuo to give
4l,m,o,p.
½
a 2D6
ꢁ
¼ þ47:1 (c 0.5, CH2Cl2). 1H NMR (300 MHz, CDCl3): d 0.93
(3H, t, J = 7.4 Hz, CH3CH2CH2); 1.54 (3H, d, J = 7.1 Hz, 5’–CH3);
1.55–1.76 (2H, m, CH3CH2CH2); 2.00 (1H, dddd, J = 5.8, 7.6, 9.3,
14.1 Hz, 1H of CH2CH2COOMe); 2.29 (1H, dtd, J = 3.5, 7.9, 14.1 Hz,
1H of CH2CH2COOMe); 2.43–2.68 (2H, m, CH2CH2COOMe); 2.88
(1H, ddd, J = 5.7, 8.9, 13.9 Hz, 1H of CH3CH2CH2); 3.70 (3H, s,
COOCH3); 3.85 (1H, ddd, J = 6.7, 9.0, 13.6 Hz, 1H of CH3CH2CH2);
3.91 (1H, dd, J = 3.6, 9.0 Hz, 2’–H); 4.10 (1H, dq, J = 3.4, 7.1 Hz,
The following compounds were prepared in this manner.

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Crt Malavašic et al. / Tetrahedron: Asymmetry 22 (2011) 629–640
639
5’–H); 7.46 (1H, br s, NH). 13C NMR (75.5 MHz, CDCl3): d 11.4, 20.5,
References
22.2, 28.2, 29.6, 46.4, 51.6, 52.0, 58.6, 166.9, 167.9, 173.0. m/z (ESI)
= 257 (MH+). m/z (HRMS) Found: 257.1505 (MH+). C15H21N2O4
requires: m/z = 257.1501; mmax (NaCl) 3442, 2959, 1732, 1680,
1. For an illustration see: (a) Sørensen, D.; Larsen Ostenfeld, T.; Christophersen, C.;
Nielsen Halfdan, P.; Anthoni, U. Phytochemistry 1999, 51, 1181; (b) Johnson, A.-
L.; Janosik, T.; Bergman, J. ARKIVOC 2002, viii, 57–61; (c) Lindgren, G.; Bohlin, L.
Tetrahedron Lett. 1986, 27, 3283–3284; (d) Johnson, A.-L.; Bergman, J.; Sjögren,
M.; Bohlin, L. Tetrahedron 2004, 60, 961–965; (e) Komagata, D.; Sawa, R.;
Kinoshita, N.; Imada, C.; Sawa, T.; Naganawa, H.; Hamada, M.; Okami, Y.;
Takeuchi, T. J. Antibiot. 1992, 45, 1681; (f) Kakinuma, K.; Rinehart, K. L. J.
Antibiot. 1974, 27, 733; (g) Avendano, C.; Cabezas, N.; de la Cuesta, E.; Gonzáles,
J. F. ARKIVOC 2005, ix, 30–38; (h) Usui, T.; Kondoh, M.; Cui, C.-B.; Mayumi, T.;
Osada, H. Biochem. J. 1998, 333, 543–548.
1652, 1456, 1325, 1166 cmꢃ1
.
5.5.5. (3S,6S)-6-Isobutyl-3-methyl-1-propylpiperazine-2,5-dione
4n
Amidation of 5a with 2n using Ghosez’s reagent was performed
following typical literature protocol.23 While stirring, 1-chloro-
N,N-2-trimethyl-1-propen-1-amine (Ghosez’s reagent) (160 mg,
2. Ressurreição, A. S. M.; Bordessa, A.; Civera, M.; Belvisi, L.; Gennari, C.; Piarulli,
U. J. Org. Chem. 2008, 73, 652–660.
3. Conza, M.; Wennemers, H. J. Org. Chem. 2002, 67, 2696–2698.
4. Schoenebeck, F.; Houk, K. N. J. Org. Chem. 2009, 74, 1464–1472.
5. Preparation of Pyrazines and Piperazines (1,4-Diazines), and of their Fused
Derivatives; Dörwald, F. Z., Ed., 2nd ed.Organic Synthesis on Solid Phase;
Wiley-VCH Verlag GmbH: Weinheim, 2002; pp 444–449.
160 lL, 1.2 mmol) was added to a cooled (0 °C) mixture of (S)-Z-
Ala-OH 5a (223 mg, 1 mmol) and anhydrous dichloromethane
(2 mL) and the mixture was stirred at 0 °C for 10 min. Then, a solu-
tion of 2n (224 mg, 1 mmol) in anhydrous dichloromethane (2 mL)
6. (a) MacDonald, J. C.; Whitesides, G. M. Chem. Rev. 1994, 94, 2383–2420; (b)
Archer, E. A.; Gong, H.; Krische, M. J. Tetrahedron 2001, 57, 1139–1159; (c) Du,
Y.; Creighton, C. J.; Tounge, B. A.; Reitz, A. B. Org. Lett. 2004, 6, 309–312.
7. For an illustration see: (a) Schoellkopf, U. Pure Appl. Chem. 1983, 55, 1799–
1806; (b) Hashimoto, Y.; Aoyagi, H.; Waki, M.; Kato, T.; Izumiya, N. Int. J. Pept.
Protein Res. 1983, 21, 11–15; (c)Asymmetric Heterogenous Catalytic
Hydrogenation; Harada, K., Ed.Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic: New York, 1985; Vol. 5, pp 345–383; (d) Bull, S. D.; Davies, S. G.;
O’Shea, M. D. J. Chem. Soc., Perkin Trans. 1 1998, 3657–3658; (e) Leeming, P.;
Fronczek, F. R.; Ager, D. J.; Laneman, S. A. Top. Catal. 2000, 13, 175–177; (f)
Bunuel, E.; Bull, S. D.; Davies, S. G.; Garner, A. C.; Savory, E. D.; Smith, A. D.;
Vickers, R. J.; Watkin, D. J. Org. Biomol. Chem. 2003, 1, 2531–2542; (g) Davies, S.
G.; Rodriguez, S. H.; Tamayo, J. A.; Cowley, A. R.; Concellon, C.; Garner, A. C.;
Parkes, A. L.; Smith, A. D. Org. Biomol. Chem. 2005, 3, 1435–1447; (h) Bull, S. D.;
Davies, S. G.; Epstein, S. W.; Garner, A. C.; Mujtaba, N.; Roberts, P. M.; Savory, E.
D.; Smith, A. D.; Tamayo, J. A.; Watkin, D. J. Tetrahedron 2006, 62, 7911–7925.
was added dropwise followed by addition of pyridine (178 lL,
2.2 mmol). The mixture was stirred at 0 °C for 3 h and then at rt
for 12 h. The reaction mixture was diluted with ethyl acetate
(50 mL) and washed with 1 M NaHSO4 (20 mL), water (20 mL), satd
aq NaHCO3 (20 mL) and brine (20 mL). The organic phase was dried
over anhydrous sodium sulphate, filtered and the filtrate was evap-
orated in vacuo. The residue was purified by column chromatogra-
phy (50% EtOAc/hexanes). Fractions containing the product were
combined and evaporated in vacuo to give dipeptide 7n as an oily
residue. Catalytic hydrogenation of crude 7n followed by isolation
of the product 4n was carried out in the same way as described
above for the preparation of compounds 4l,m,o,p. Yield: 74 mg
(33%) of colourless oil; ½a D25
ꢁ
¼ þ80:1 (c 0.5, CH2Cl2). 1H NMR
ˇ
8. Wagger, J.; Golic Grdadolnik, S.; Grošelj, U.; Meden, A.; Stanovnik, B.; Svete, J.
Tetrahedron: Asymmetry 2007, 18, 464–475.
(300 MHz, CDCl3): d 0.92 (3H, t, J = 7.4 Hz, CH3CH2CH2); 0.96 and
1.01 (6H, 2d, 1:1, J = 6.5 Hz, (CH3)2CH); 1.52 (3H, d, J = 7.1 Hz, 3–
CH3); 1.55–1.69 (3H, m, 1H of (CH3)2CHCH2 and CH3CH2CH2);
1.76 (1H, ddd, J = 4.8, 8.9, 13.8 Hz, 1H of (CH3)2CHCH2); 1.85–
1.99 (1H, m, (CH3)2CH); 2.70 (1H, ddd, J = 6.0, 8.5, 13.7 Hz, 1H of
CH3CH2CH2); 3.83 (1H, dd, J = 4.2, 4.7 Hz, 6–H); 3.92 (1H, ddd,
J = 7.1, 8.8, 13.9 Hz, 1H of CH3CH2CH2); 4.09 (1H, dq, J = 3.7,
7.2 Hz, 3–H); 7.51 (1H, br s, NH). 13C NMR (75.5 MHz, CDCl3): d
11.4, 20.5, 22.09, 22.14, 23.5, 25.0, 43.7, 46.5, 51.8, 58.3, 167.3,
169.1. m/z (ESI) = 227 (MH+). m/z (HRMS) Found: 227.1757
(MH+). C12H23N2O2 requires: m/z = 227.1760. mmax (NaCl) 3234,
9. (a) Wagger, J.; Grošelj, U.; Meden, A.; Svete, J.; Stanovnik, B. Tetrahedron 2008,
64, 2801–2815; (b) Wagger, J.; Svete, J.; Stanovnik, B. Synthesis 2008, 1436–
1442.
ˇ
ˇ
10. Malavašic, C.; Wagger, J.; Stanovnik, B.; Svete, J. Tetrahedron: Asymmetry 2008,
19, 1557–1567.
11. For a review on the synthesis of diketopiperazines see: Dinsmore, C. J.; Beshore,
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2958, 1680, 1651, 1456, 1321, 1151, 1070 cmꢃ1
.
13. Favero, V.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1997, 8, 599–612.
14. Shin, C.; Sato, K.; Ohtsuka, A.; Mikami, K.; Yoshimura, J. Bull. Chem. Soc. Jpn.
1973, 46, 3876–3880.
5.6. X-ray structure determination for compounds 4b, 4d, 4f, 4g,
4k, and 4o
15. The reductive alkylation of
a-amino acid esters with NaBH4: (a) Verardo,
G.; Geatti, P.; Pol, E.; Giumanini, A. G. Can. J. Chem. 2002, 80, 779–788; See
Single crystal X-ray diffraction data of compounds 4b, 4d, 4f, 4g,
4k and 4o were collected at room temperature on a Nonius Kappa
CCD diffractometer using the Nonius Collect Software.24 DENZO
and SCALEPACK25 were used for indexing and scaling of the data
and the structures were solved by means of SIR97.26 Refinement
was done using the XTAL3.627 programme package and the crystal-
lographic drawings were prepared by ORTEP-3.28 Crystal struc-
tures were refined on F values using the full-matrix least-squares
procedure. The non-hydrogen atoms were refined anisotropically
in all cases, while the positions of the hydrogen atoms were geo-
metrically calculated and their positional and isotropic atomic dis-
placement parameters were not refined. Crystallographic data
(excluding structure factors) have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary material
with the deposition numbers CCDC 801701–801706. Copies of
the data can be obtained, free of charge via http://www.ccdc.cam.
ac.uk/conts/retrieving.html.
ˇ
ˇ
ˇ
also: (b) Zerovnik, D.; Grošelj, U.; Kralj, D.; Malavašic, C.; Bezenšek, J.;
Dahmann, G.; Stare, K.; Meden, A.; Stanovnik, B.; Svete, J. Synthesis 2010,
3363–3373.
16. The reductive alkylation of
a-amino acid esters with NaBH3CN: (a)
Szardenings, K.; Burkoth, T. S.; Look, G. C.; Campbell, D. A. J. Org. Chem. 1996,
61, 6720–6722; (b) Anderson, J. C.; Cubbon, R.; Harding, M.; James, D. S.
Tetrahedron: Asymmetry 1998, 9, 3461–3490; (c) Anderson, J. C.; Cubbon, R. J.;
Harling, J. D. Tetrahedron: Asymmetry 2001, 12, 923–935.
17. The reductive alkylation
a-amino acid esters with NaBH(OAc)3: (a) Hoover, J.
M.; Petersen, J. R.; Pikul, J. H.; Johnson, A. R. Organometallics 2004, 23, 4614–
4620; (b) Hickman, A. J.; Hughs, L. D.; Jones, C. M.; Li, H.; Redford, J. E.;
Sobelman, S. J.; Kouzelos, J. A.; Johnson, A. R. Tetrahedron: Asymmetry 2009, 20,
1279–1285.
18. (a) Ramanathan, R.; Ghosal, A.; Miller, M. W.; Chowdhury, S. K.; Alton, K. B. U.S.
Pat. Appl. Publ., 2006, Cont.-in-part of U.S. Ser. No. 668,862; US 2006105964,
78 pp; Chem. Abstr. 2006, 144, 488682.; (b) Baroudy, B. M.; Clader, J. W.; Josien,
H. B.; Mccombie, S. W.; Mckittrick, B. A.; Miller, M. W.; Neustadt, B. R.; Palani,
A.; Smith, E. M.; Steensma, R.; Tagat, J. R.; Vice, S. F.; Laughlin, M. A.; Gilbert, E.;
Labroli, M. A. PCT Int. Appl., 2000, WO 2000066558, A1 20001109, 109 pp;
Chem. Abstr. 2000, 133, 488682.
19. Estevez, J. C.; Burton, J. W.; Estevez, R. J.; Ardron, H.; Wormald, M. R.;
Dwek, R. A.; Brown, D.; Fleet, G. W. J. Tetrahedron: Asymmetry 1998, 9,
2137–2154.
20. (a) Tung, R. D.; Rich, D. H. J. Am. Chem. Soc. 1985, 107, 4342–4343; (b) Li, P.; Xu,
J. C. Tetrahedron Lett. 1999, 40, 8301–8304; (c) Thern, B.; Rudolph, J.; Jung, G.
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Acknowledgement
We thank the Slovenian Research Agency for the financial sup-
port through grants P1-0179 and J1-0972.
21. Orena, M.; Porzi, G.; Sandri, S. J. Org. Chem. 1992, 57, 6532–6536.

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John Wiley & Sons: New York, 1994.
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