Synthesis of gem-diamino acid derivatives by a Hofmann rearrangement

Article abstract of DOI:10.1007/s00726-012-1428-2

Starting from commercially available N-protected l-α-amino acids, N,N′-protected gem-diaminic units were obtained by a two-step methodology. A Hofmann reaction performed using a primary alcohol as the solvent to trap the isocyanate intermediate represents the key step of the new synthetic procedure. Then, the methodology was applied to α-carbamoyl α′-carboxyl aziridines, also functionalized with l-α-amino esters and stable gem-diaminic units characterized by an aziridine ring and by a retro-peptide modification were obtained. The use of the latter units in the retro-peptide chemistry allows to obtain modified peptides containing an aziridine ring able to behave as an electrophilic site and as a biomimetic structural analog of proline.

Full text of DOI:10.1007/s00726-012-1428-2

Amino Acids
DOI 10.1007/s00726-012-1428-2
ORIGINAL ARTICLE
Synthesis of gem-diamino acid derivatives
by a Hofmann rearrangement
•
Emanuele Aresu Stefania Fioravanti
•
•
Simona Gasbarri Lucio Pellacani
•
Federico Ramadori
Received: 26 September 2012 / Accepted: 4 November 2012
Ó Springer-Verlag Wien 2012
Abstract Starting from commercially available N-pro-
tected L-a-amino acids, N,N0-protected gem-diaminic units
were obtained by a two-step methodology. A Hofmann
reaction performed using a primary alcohol as the solvent
to trap the isocyanate intermediate represents the key step
of the new synthetic procedure. Then, the methodology
was applied to a-carbamoyl a0-carboxyl aziridines,
also functionalized with L-a-amino esters and stable gem-
diaminic units characterized by an aziridine ring and by a
retro-peptide modification were obtained. The use of the
latter units in the retro-peptide chemistry allows to obtain
modified peptides containing an aziridine ring able to
behave as an electrophilic site and as a biomimetic struc-
tural analog of proline.
similar biological effects. It is possible to design these
molecules in such a way that they show similar biological
effects as their peptide role models but with enhanced
properties like a higher proteolytic stability, higher bio-
availability and also often with improved selectivity or
¨
potency (Grauer and Konig 2009; Liskamp et al. 2011;
Deshmukh and Purohit 2012). In the field of peptidomi-
metic synthesis, many efforts have been devoted to design
and obtain retro-peptidic structures that are characterized by
two inversion points of a natural peptide sequence, namely a
malonyl residue and a gem-diaminic residue. gem-Diam-
inoalkyl and malonyl units can be inserted in the terminal
positions or within the peptide sequence to give partially
modified retro-peptides in all cases. In fact, the incorpora-
tion of a gem-diaminoalkyl residue and a malonyl unit
results in a good structural complementarity between the
parent peptide and the modified retro isomer (Chorev and
Goodman 1993; Fletcher and Campbell 1998; Volonterio
et al. 2003; Gilmore et al. 2006).
Keywords Aminals ꢀ Amino acids ꢀ Aziridines ꢀ
Peptidomimetics
Introduction
Recently, a new and efficient strategy to synthesize non-
symmetric malonyl peptidic units (Fioravanti et al. 2007)
and their further modifications (Fioravanti et al. 2010a, b)
have been reported by us. To the best of our knowledge,
only few methods are reported in the literature to synthe-
size gem-diaminic residues. The most common approach
starts from an a-aminoacyl azide that undergoes a Curtius
rearrangement at high temperatures to give the corre-
sponding gem-diaminic unit as a hydrochloride salt after an
acid solution workup (De Bons and Loudon 1980; Chorev
and Goodman 1983), usually highly unstable and not
storable (Fife et al. 1978; Moad and Benkovic 1978;
Moutevelis-Minakakis and Photaki 1985). gem-Diamines
have also been synthesized by a Mannich condensation of
N-protected a-aminoacidic amides and benzotriazole with
aldehydes, followed by a treatment with a methanolic NH3
Peptidomimetics typically are small protein-like molecules
designed to mimic natural peptides or proteins. Their
structure was derived from natural peptides and they should
have the ability to bind to their natural targets in the same
way as the natural sequences and hence should produce
E. Aresu ꢀ S. Fioravanti (&) ꢀ S. Gasbarri ꢀ L. Pellacani ꢀ
F. Ramadori
Dipartimento di Chimica, Universita degli Studi di Roma
`
‘‘La Sapienza’’, P.le Aldo Moro 5, 00185 Rome, Italy
e-mail: stefania.fioravanti@uniroma1.it
L. Pellacani
e-mail: lucio.pellacani@uniroma1.it
123

E. Aresu et al.
Scheme 1 N,N0-protected
gem-diaminic units by a two-
step methodology
O
R'
O
R'
O
R'
O
OH
NH2
OR''
RO
N
RO
N
RO
N
N
H
H
H
H
O
O
1
2
P−
g
AA−P'
Scheme 2 Hofmann
rearrangement of 2a
O
Cbz
OH
BTI
MeOH, 24 h
O
Cbz
NH2
N
Cbz
C
N
Cbz
N
N
H
H
N
H
N
OMe
O
O
H
H
1a
2a
I
3a (85 % yield)
molar ratios 2a:BTI=1:1.2
Table 1 Synthesis of stable N,N0-protected aminals
solution (Rowland et al. 2005) or through a Brønsted acid-
catalyzed imine amidation reaction (Katritzky et al. 1990).
O
R'
O
R'
O
NH2
RO
N
RO
N
N
OR''
H
H
H
O
2a-f
3a-f
Results and discussion
Entry
R
R0
R00
P–gAA–P0
Yield (%)
Continuing our studies on the retro-peptide synthesis, we
here report a new two-step methodology (Scheme 1)
1
2
3
4
5
6
Bn
Bn
H
Me
3a
3b
3c
3d
3e
3f
85
83
78
67
74
81
H
Allyl
Me
involving a-aminoacidic amides
2 considered in a
t-Bu
t-Bu
t-Bu
t-Bu
H
Hofmann rearrangement reaction to obtain stable N,N0-
protected gem-diaminic units starting from commercially
available N-protected L-a-amino acids 1 (Zhu et al. 2011).
N-Carboxybenzylglycine (1a) was chosen as suitable
substrate to find the optimal reaction conditions and was
converted into the corresponding amide 2a by classical
procedures (North and Pattenden 1990). Then, an oppor-
tune alcohol such as methanol was considered to trap the
classical isocyanate intermediate I that is formed in the
Hofmann rearrangement (Myers et al. 2004; Angelici et al.
2008). Under these conditions stable N,N0-protected gem-
diaminic building blocks can be directly obtained, stored
and deprotected just before use. So, the Hofmann reaction
was successfully performed at room temperature, using a
slight excess of [bis(trifluoroacetoxy)iodo]benzene (BTI)
and the expected stable N,N’-protected aminal 3a was
obtained in good yields (Scheme 2).
Bn
i-Pr
H
Me
Me
Allyl
Interested in extending our studies, our synthetic strat-
egy was also applied to a-alkoxycarbonyl a0-carbamoyl
aziridines (Fioravanti et al. 2008, 2009), more complex
compounds that can be regarded as interesting building
blocks for the synthesis of modified retro-peptides con-
taining electrophilic sites. Their synthesis was obtained by
direct amination reaction of the corresponding (E)-acrylo-
nitriles (Fioravanti et al. 2004) using ethyl nosyloxycar-
bamate (NsONHCO2Et, Ns = 4-NO2C6H4SO2) as the
aminating agent under heterogeneous conditions (Pellacani
et al. 2011). The aziridination reactions take place with
total retention of the starting alkene configuration.
Then, the reaction was performed starting from some
different a-aminoacidic amides using allyl alcohol also as
the solvent. In all cases gem-diaminic units were obtained
in satisfactory yields and with total retention of the a-
amino acid configuration, as required by the Hofmann
transposition (Gribble 2009). The results are reported in
Table 1.
After selective hydrolysis of the cyano group to amide
group, the Hofmann rearrangement was performed on 6a
following the standardized conditions, but after 24 h the
expected product 7a was observed only in unsatisfactory
1
yield (B21 %), as detected by H NMR spectra. No better
results were observed even by increasing the molar amounts
of BTI and/or lengthening the reaction times. Finally 7a was
obtained in satisfactory yields (66 %) by heating the reac-
tion mixture at 50 °C during 18 h (Scheme 4).
The reaction was extended also to different substituted
a-carbamoyl a0-carboxyl aziridines, and the results are
reported in Table 2.
As reported in Table 1, gem-diaminic units 3a–f, that
can be stored for long times (2 months), have always two
different protecting groups on the nitrogen atoms and
therefore they can be selectively deprotected to undergo a
coupling reaction giving partially modified retro-peptides.
To test this, 3f was successfully considered in a tandem
deprotection–coupling reaction (Thieriet et al. 1999) with
2,5-dioxopyrrolidin-1-yl ethyl malonate 4 to give gem-di-
aminic unit 5 (Scheme 3).
The Hofmann rearrangement has been successful also
with gem-dicarbamoyl aziridines carrying a natural amino
acid residue (entries 5–8), leading to complex and
123

Synthesis of gem-diamino acid
Scheme 3 Synthesis of 5 by a
tandem deprotection–coupling
reaction
O
O
O
O
O
O
Cl
OEt
O
O
O
Boc
Alloc
Boc
ii
i
+
+
OEt
N
N
N
N
OEt
N
H
H
H
H
OH
N
O
4 (68%)
3f
5 (52%)
O
i
= CH2Cl2, Et3N, 5 h r.t.;
ii = CH2Cl2, PhSiH3, Pd(PPh3)4 1 h r.t., 40 °C overnight
was successfully reported. The reaction was extended also
to different substituted a-carbamoyl a0-carboxyl aziridines,
leading to the synthesis of gem-diaminic units character-
ized by an aziridine ring and a retro-peptide modification.
The former represents an important feature for the syn-
thesis of modified peptides containing electrophilic sites
that undergo ring opening reactions with a wide range of
nucleophiles like potential protease inhibitors (Martina
et al. 2005). Moreover it is known that alkoxycarbonyl
aziridines represent biomimetic proline analogs, as shown
by the comparison between the conformations of the azi-
ridine carboxylic acid containing peptides and the corre-
sponding proline peptides (Okawa and Nakajima 1981).
O
O
H2N
O
OEt
OEt
N CO2Et
H
N
BTI, MeOH
50 °C, 18 h
MeO
N CO2Et
O
6a
Scheme 4 Hofmann rearrangement of 6a
7a (66%)
Table 2 Synthesis of a-carbamoyl a0-carboxyl aziridines
O
O
H2N
O
Y
Y
BTI, R'OH
O
R'O
50 °C
N
CO2Et
N
N
CO2Et
H
18 h, overnight
R
R
6a-h
7a-h
Entry
6a
Y
R
R0
7
Yields
(%)
Experimental
1
2
3
4
5
a
b
c
OEt
OEt
OEt
OEt
Et
Et
Me
a
b
c
66
58
64
49
45
IR spectra were recorded on a Perkin-Elmer 1600 FTIR
1
Allyl
Me
spectrophotometer with CHCl3 as the solvent. H NMR
i-Bu
i-Bu
i-Bu
spectra were recorded at 200 and 300 MHz and 13C NMR
spectra at 50 and 75 MHz with Varian Gemini and Varian
XL instruments. CDCl3 was used as the solvent and CHCl3
as the internal standard. HRMS and ES Q-TOF analyses
were performed using a Micromass Q-TOF spectrometer
equipped with an ESI source and a syringe pump. Com-
pounds 6a–h were obtained as reported before (Fioravanti
et al. 2008).
d
e
Allyl
Me
d
e
O
HN
O
6
fb
i-Bu
Me
f
53
Ph
O
O
O
HN
O
O
O
7
8
a
g
i-Bu
Allyl
Allyl
g
59
56
HN
HN
Synthesis of N,N0-protected gem-diamines 3:
general procedure
h
Ph
h
To a solution of N-protected a-amino acid (0.78 mmol) in
2 mL of anhydrous THF, triethylamine (1 mmol) was
slowly added. Then, the solutions were cooled at -78 °C
under a nitrogen atmosphere and ethyl chloroformate
(0.9 mmol) was added dropwise. The reaction mixtures
were allowed to warm to -30 °C over 3 h and a 30 %
ammonia solution (8.8 mL) was added. The reactions were
allowed to warm to room temperature and stirred for 1 h.
The solvents were evaporated in vacuo, the residues
recovered with EtOAc (10 mL), washed with H2O
(4 9 10 mL) and dried over Na2SO4. The recombined
organic layers were concentrated in vacuo. The obtained a-
aminoacidic amides (1 mmol) were added to a solution of
Reaction time, 18 h for entries 1–4; overnight for entries 5–8
b
1
Diastereomeric ratio C95 % determined by H NMR spectroscopy
of the crude mixtures
interesting gem-diaminic units characterized by three dif-
ferent sites of molecular grown.
Conclusion
In conclusion, the synthesis of stable gem-diaminic units by
a Hofmann reaction performed under very mild conditions
123

E. Aresu et al.
[bis(trifluoroacetoxy)iodo]benzene (BTI, 1.2 mmol) in
2.5 mL of the opportune alcohol. The reactions were
H), 2.06–2.18 (m, 1 H), 3.63 (s, 3 H), 5.58–6.17 (m, 1 H),
7.01 (br, 2 H). 13C NMR (CDCl3, 75.5 MHz, d): 15.6 (2 C),
27.5 (3 C), 30.7, 51.4, 62.5, 81.8, 156.9, 158.0. HR-MS
(ESI-TOF) (m/z) calcd for C11H22N2NaO4 (M ? Na)?:
269.1477; found, 269.1483.
1
checked by H NMR and ES Q-TOF analyses. After 6 h,
the solvent was evaporated in vacuo and the residues were
stirred with dry diethyl ether (30 min) at room temperature
and then filtered off.
Allyl tert-butyl methylenebiscarbamate (3f)
Benzyl methyl methylenebiscarbamate (3a)
1
Yellow oil, 81 %. IR: 3431, 3349, 1713, 1677 cm-1. H
Yellow oil, 85 %. IR: 3436, 3354, 1713, 1678 cm-1. H
NMR (CDCl3, 300 MHz, d): 1.41 (s, 9 H), 4.36–4.42 (m, 2
H), 4.60–4.65 (m, 2 H), 5.15–5.34 (m, 2 H), 5.80–5.91 (m,
1 H), 7.05 (br, 2 H). 13C NMR (CDCl3, 75.5 MHz, d): 27.9
(3 C), 42.1, 66.7, 80.7, 116.4, 135.0, 154.8, 156.0. HR-MS
(ESI-TOF) (m/z) calcd for C10H18N2NaO4 (M ? Na)?:
253.1164; found, 253.1160.
1
NMR (CDCl3, 300 MHz, d): 3.68 (s, 3 H), 4.42–4.61 (m, 2
H), 5.11 (s, 2 H), 5.71 (br, 2 H), 7.33–7.38 (m, 5 H). 13C
NMR (CDCl3, 75.5 MHz, d): 53.5, 56.1, 66.9, 126.2 (2 C),
128.4, 129.0 (2 C), 139.9, 155.2, 156.1. HR-MS HR-MS
(ESI-TOF) (m/z) calcd for C11H14N2NaO4 (M ? Na)?:
261.0851; found, 261.0857.
Synthesis of ethyl 3-({[(tert-
butoxycarbonyl)amino]methyl}amino)-
3-oxopropanoate (5)
Allyl benzyl methylenebiscarbamate (3b)
Orange oil, 83 %. IR: 3435, 3351, 1712, 1676 cm-1. H
1
NMR (CDCl3, 300 MHz, d): 3.94–4.15 (m, 2 H), 4.39–4.60
(m, 2 H), 4.96–5.08 (m, 2 H), 5.15–5.34 (m, 2 H),
To a solution of ethyl 3-chloro-3-oxopropanoate (10 mmol)
and Et3N (11 mmol) in anhydrous CH2Cl2, N-hydroxy-
succinimide (11 mmol) was added and the reaction mixture
was stirred at room temperature (5 h). After evaporating the
solvent, the crude mixture was extracted with brine and 4
was used without further purification. Then, to a solution of
3f in anhydrous CH2Cl2 and under an argon atmosphere
2 eq of PhSiH3, 1.1 eq of 4 and 2 mol % of Pd(PPh3)4 were
added at room temperature. After 1 h of stirring, the reac-
tion was refluxed overnight. The crude mixture was washed
with H2O and dried over Na2SO4 and the solvent removed
in vacuo. A fast purification on silica gel (hexane/
EtOAc = 1:1) gave the purified expected compound.
5.81–5.98 (m, 1 H), 6.14 (br, 2 H), 7.35–7.41 (m, 5 H). 13
C
NMR (CDCl3, 75.5 MHz, d): 42.1, 64.3, 66.7, 108.9, 129.5
(2 C), 130.2, 134.7 (2 C), 135.0 (allylic CH), 138.1, 154.8,
156.0. HR-MS (ESI-TOF) (m/z) calcd for C13H16N2NaO4
(M ? Na)?: 287.1008; found, 287.1012.
tert-Butyl methyl methylenebiscarbamate (3c)
1
Yellow oil, 78 %. IR: 3433, 3355, 1712, 1677 cm-1. H
NMR (CDCl3, 300 MHz, d): 1.44 (s, 9 H), 3.61 (s, 3 H),
4.40–4.64 (m, 2 H), 6.27 (br, 2 H). 13C NMR (CDCl3,
75.5 MHz, d): 27.7 (3 C), 53.5, 56.1, 81.8, 158.2, 159.1.
HR-MS (ESI-TOF) (m/z) calcd for C8H16N2NaO4
(M ? Na)?: 227.1008; found, 227.1002.
2,5-Dioxopyrrolidin-1-yl ethyl malonate (4)
1
Pale oil, 68 %. IR: 1735, 1700 cm-1. H NMR (CDCl3,
tert-Butyl methyl [(1 S)-2-phenylethane-1,
1-diyl]biscarbamate (3d)
300 MHz, d): 1.21 (t, J = 7.1, 3 H); 2.77 (s, 4 H); 3.60 (s,
2 H); 4.15 (q, J = 7.1, 2 H). 13C NMR (CDCl3, 75.5 MHz,
d): 14.1, 26.3 (2 C), 38.4, 61.5, 168.9, 169.4 (2 C), 180.2.
HR-MS (ESI-TOF) (m/z) calcd for C9H11NNaO6
(M ? Na)?: 252.0484; found, 252.0492.
Orange oil, 67 %. IR: 3435, 3353, 1713, 1679 cm-1. H
1
NMR (CDCl3, 300 MHz, d): 1.42 (s, 9 H), 2.92–3.18 (m, 2
H), 3.63 (s, 3 H), 5.67–6.11 (m, 1 H), 7.01 (br, 2 H),
7.32–7.41 (m, 5 H). 13C NMR (CDCl3, 75.5 MHz, d): 27.5
(3 C), 42.1, 49.6, 63.3, 81.8, 126.8, 128.3 (2 C), 129.0 (2
C), 135.8, 158.1, 159.0. HR-MS (ESI-TOF) (m/z) calcd for
C15H22N2NaO4 (M ? Na)?: 317.1477; found, 317.1481.
Ethyl 3-({[(tert-butoxycarbonyl)amino]methyl}amino)-
3-oxopropanoate (5)
Deep yellow oil, 52 %. IR: 3448, 3375, 1719, 1648 cm-1
.
1H NMR (CDCl3, 300 MHz, d): 1.23 (t, J = 7.1, 3 H); 1.41
(s, 9 H); 3.65 (s, 2 H); 4.16 (q, J = 7.1, 2 H); 4.30–4.61 (m,
2 H), 7.03 (br, 2 H). 13C NMR (CDCl3, 75.5 MHz, d): 13.9;
28.1 (3 C); 48.8; 61.4; 65.6, 80.0; 158.9; 172.3; 172.9. HR-
MS (ESI-TOF) (m/z) calcd for C11H20N2NaO5 (M ? Na)?:
283.1270; found, 283.1276.
tert-Butyl methyl[(1 S)-2-methylpropane-1,
1-diyl]biscarbamate (3e)
Deep yellow, 74 %. IR: 3435, 3353, 1716, 1680 cm-1. H
1
NMR (CDCl3, 300 MHz, d): 0.82–0.90 (m, 6 H), 1.43 (s, 9
123

Synthesis of gem-diamino acid
Synthesis of N,N0-protected gem-diamines 7: general
procedure
1.24 (t, J = 7.4 Hz, 3 H), 1.33 (t, J = 7.0 Hz, 3 H),
1.51–1.69 (m, 1 H), 1.73–1.82 (m, 2 H), 3.12 (t,
J = 6.5 Hz, 1 H), 3.96–4.15 (m, 2 H), 4.20–4.45 (m, 4 H),
5.36–5.43 (m, 2 H), 5.81–6.02 (m, 1 H), 7.04 (br, 1 H). 13C
NMR (CDCl3, 75.5 MHz, d): 13.8, 14.3, 22.3 (2 C), 28.2,
37.2, 41.2, 61.4, 61.9, 62.8, 66.7, 108.5, 136.5, 155.2,
171.9, 172.4. HR-MS (ESI-TOF) (m/z) calcd for
C16H26N2NaO6 (M ? Na)?: 365.1689; found, 365.1693.
To a solution of BTI (1.2 mmol) in 2.5 mL of the oppor-
tune alcohol, aziridine 6 (1 mmol) was added. The reac-
1
tions were warmed at 50 °C and checked by H NMR and
ES Q-TOF analyses. After 18 h, the solvent was evapo-
rated in vacuo and the crude was purified by flash chro-
matography on silica gel (hexane/EtOAc = 3:7).
Ethyl 3-isobutyl-2-[(methoxycarbonyl)amino]-2-{[(2-
methoxy-2-oxoethyl)amino]carbonyl}aziridine-1-
carboxylate (7e)
Diethyl 3-ethyl-2-[(methoxycarbonyl)amino]aziridine-1,
2-dicarboxylate (7a)
Deep yellow oil, 66 %. IR: 3518, 1772, 1731 cm-1. H
1
Deep yellow oil, 45 %. IR: 3424, 3041, 1748, 1701 cm-1
.
1H NMR (CDCl3, 300 MHz, d): 0.87 (d, J = 6.5 Hz, 6 H),
1.27 (t, J = 7.4 Hz, 3 H), 1.56–1.78 (m, 1 H), 2.28 (t,
J = 6.9 Hz, 2 H), 3.24 (t, J = 7.1 Hz, 1 H), 3.62 (s, 3 H),
3.68 (s, 3 H), 4.02–4.13 (m, 4 H), 8.15 (br, 1 H), 8.43 (br, 1
H). 13C NMR (CDCl3, 75.5 MHz, d): 14.3, 22.2 (2 C),
23.6, 36.7, 38.1, 40.1, 52.7, 53.3, 61.3, 62.2, 154.3, 155.2,
171.9, 172.3. HR-MS (ESI-TOF) (m/z) calcd for
C15H25N3NaO7 (M ? Na)?: 382.1590; found, 382.1587.
NMR (CDCl3, 300 MHz, d): 1.12 (t, J = 6.6 Hz, 3 H), 1.26
(t, J = 7.4 Hz, 3 H), 1.34 (t, J = 7.0 Hz, 3 H), 1.72–1.81
(m, 2 H), 3.09 (t, J = 6.5 Hz, 1 H), 3.68 (s, 3 H), 4.07–4.42
(m, 4 H), 6.54 (br, 1 H). 13C NMR (CDCl3, 75.5 MHz, d):
8.9, 13.8, 14.3, 22.0, 41.2, 51.9, 61.4, 61.9, 62.8, 155.2,
171.9, 172.4. HR-MS (ESI-TOF) (m/z) calcd for
C12H20N2NaO6 (M ? Na)?: 311.1219; found, 311.1227.
Diethyl 2-{[(allyloxy)carbonyl]amino}-3-ethylaziridine-
1,2-dicarboxylate (7b)
Ethyl 2-[(methoxycarbonyl)amino]-2-({[(1S)-1-benzyl-2-
methoxy-2-oxoethyl]amino}carbonyl)-3-(2-
methylpropyl)aziridine-1-carboxylate (7f)
Deep yellow oil, 58 %. IR: 3521, 1770, 1732, 1637 cm-1
.
1H NMR (CDCl3, 300 MHz, d): 1.14 (t, J = 6.6 Hz, 3 H);
1.28 (t, J = 7.4 Hz, 3 H), 1,32 (t, J = 7.0 Hz, 3 H),
1.68–1.79 (m, 2 H), 3.11 (t, J = 6.5 Hz, 1 H), 3.95–4.17 (m,
2 H), 4.20–4.55 (m, 4 H), 5.15–5.33 (m, 2 H), 5.83–5.98 (m,
1 H), 6.56 (br, 1 H). 13C NMR (CDCl3, 75.5 MHz, d): 9.1,
15.5, 16.0, 22.1, 41.3, 61.4, 61.9, 62.8, 66.9, 116.8, 135.2,
155.3, 169.9, 171.6. HR-MS (ESI-TOF) (m/z) calcd for
C14H22N2NaO6 (M ? Na)?: 337.1376; found, 337.1384.
1
Orange oil, 53 %. IR: 3426, 3401, 1736, 1731 cm-1. H
NMR (CDCl3, 300 MHz, d): 1.02 (d, J = 6.6 Hz, 6 H),
1.35 (t, J = 7.1 Hz, 3 H), 1.53-1.83 (m, 2 H), 1.86–1.95
(m, 1 H), 3.14 (dd, J = 7.4 Hz, 1 H), 3.16–3.29 (m, 2 H),
3.68 (s, 3 H), 3.72 (s, 3 H), 4.04 (q, J = 7.1 Hz, 2 H), 4.80-
4.92 (m, 1 H), 7.01–7.64 (m, 5 H), 8.80 (br, 1 H), 9.43 (br,
1 H). 13C NMR (CDCl3, 75.5 MHz, d): 14.5, 22.1 (2 C),
23.6, 29.7, 31.9, 37.6, 47.3, 52.5, 53.6, 61.6, 63.0, 127.4,
129.0 (2 C), 130.2 (2 C), 137.5, 154.8, 155.2, 172.2, 172.5.
HR-MS (ESI-TOF) (m/z) calcd for C22H31N3NaO7
(M ? Na)?: 472.2060; found, 472.2065.
Diethyl 3-isobutyl-2-[(methoxycarbonyl)amino]aziridine-
1,2-dicarboxylate (7c)
1
Deep yellow oil, 64 %. IR: 3516, 1771, 1734 cm-1. H
NMR (CDCl3, 300 MHz, d): 0.77 (d, J = 6.5 Hz, 6 H),
1.26 (t, J = 7.4 Hz, 3 H), 1,34 (t, J = 7.0 Hz, 3 H),
1.52–1.68 (m, 1 H), 1.72–1.81 (m, 2 H), 3.11 (t,
J = 6.5 Hz, 1 H), 3.69 (s, 3 H), 4.05–4.41 (m, 4 H), 6.54
(br, 1 H). 13C NMR (CDCl3, 75.5 MHz, d): 13.8, 14.3, 22.3
(2 C), 28.2, 37.2, 41.2, 52.2, 61.4, 61.9, 62.8, 155.2, 171.9,
172.4. HR-MS (ESI-TOF) (m/z) calcd for C14H24N2NaO6
(M ? Na)?: 339.1532; found, 339.1538.
Ethyl 2-[(allyloxycarbonyl)amino]-3-isobutyl-2-(2-
methoxy-2-oxoethylcarbamoyl)aziridine-1-
carboxylate (7g)
Deep yellow oil, 59 %. IR: 3424, 3403, 1746, 1699,
1638 cm-1 1H NMR (CDCl3, 300 MHz, d): 0.88 (d,
.
J = 6.5 Hz, 6 H), 1.34 (t, J = 7.1 Hz, 3 H), 1.57–1.79 (m,
1 H), 2.21–2.30 (m, 2 H), 3.23 (t, J = 7.1 Hz, 1 H), 3.68 (s,
3 H), 3.84–4.01 (m, 2 H), 4.05-4.15 (m, 4 H), 5.15–5.32
(m, 2 H), 5.82–5.96 (m, 1 H), 8.10 (br, 1 H), 8.33 (br, 1 H).
13C NMR (CDCl3, 75.5 MHz, d): 14.3, 22.1(2 C), 23.8,
35.9, 38.3, 41.1, 52.0, 61.6, 61.2, 66.9, 115.6, 134.9, 155.5,
155.8, 171.5, 172.1. HR-MS (ESI-TOF) (m/z) calcd for
C17H27N3NaO7 (M ? Na)?: 408.1747; found, 408.1752.
Diethyl 2-{[(allyloxy)carbonyl]amino}-3-isobutylaziridine-
1,2-dicarboxylate (7d)
Deep yellow oil, 49 %. IR: 3515, 1774, 1731, 1638 cm-1
1H NMR (CDCl3, 300 MHz, d): 0.75 (d, J = 6.5 Hz, 6 H),
.
123

E. Aresu et al.
for peptidomimetics by an efficient Knoevenagel reaction. Amino
Acids 39:461–470. doi:10.1007/s00726-009-0462-1
Fioravanti S, Gasbarri S, Pellacani L, Ramadori F, Tardella PA (2010b)
Synthesis of epoxy and aziridino malonyl peptidomimetics.
Tetrahedron 66:9401–9404. doi:10.1016/j.tet.2010.09.097
Fletcher MD, Campbell MM (1998) Partially modified retro-inverso
peptides: development, synthesis, and conformational behavior.
Chem Rev 98:763–796. doi:10.1021/cr970468t
Gilmore BF, Lynas JF, Harriott P, Healy A, Walker B (2006) Peptides
containing acylated C-terminal gem diamines: novel irreversible
inactivators of the cysteine and serine proteinases. Chem Biol
Drug Des 67:364–369. doi:10.1111/j.1747-0285.2006.00390.x
Ethyl 2-[(allyloxycarbonyl)amino]-2-(2-methoxy-2-
oxoethylcarbamoyl)-3-phenylaziridine-1-carboxylate (7h)
Deep yellow oil, 56 %. IR: 3422, 3400, 1746, 1698,
1636 cm-1 1H NMR (CDCl3, 300 MHz, d): 1.35 (t,
.
J = 7.1 Hz, 3 H), 3.20 (s, 1 H), 3.69 (s, 3 H), 3.84–4.03
(m, 2 H), 4.06–4.17 (m, 4 H), 5.13–5.36 (m, 2 H),
5.81–5.98 (m, 1 H); 7.15–7.43 (m, 5 H), 7.99 (br, 1 H),
8.09 (br, 1 H). 13C NMR (CDCl3, 75.5 MHz, d): 13.8, 35.9,
41.1, 52.1, 61.6, 61.2, 66.9, 115.6, 128.3, 129.6 (2 C),
133.1 (2 C), 135.0, 138.6, 155.5, 155.8, 171.5, 172.1. HR-
MS (ESI-TOF) (m/z) calcd for C19H23N3NaO7 (M ? Na)?:
428.1434; found, 428.1441.
¨
Grauer A, Konig B (2009) Peptidomimetics—a versatile route to
biologically active compounds. Eur J Org Chem 5099–5111. doi:
10.1002/ejoc.200900599
Gribble GW (2009) Hofmann rearrangement. In: Li JJ (ed) Name
reactions for homologations part II. John Wiley & Sons,
Hoboken, pp 164–199
Katritzky AR, Urodgi L, Mayence A (1990) Benzotriazole-assisted
synthesis of monoacyl aminals and their peptide derivatives.
J Org Chem 55:2206–2214. doi:10.1021/jo00294a042
Liskamp RMJ, Rijkers DTS, Kruijtzer JAW, Kemmink J (2011)
Peptides and proteins as a continuing exciting source of
inspiration for peptidomimetics. ChemBioChem 12:1626–1653.
doi:10.1002/cbic.201000717
`
Acknowledgments Universita degli Studi di Roma ‘‘La Sapienza’’
is gratefully acknowledged for financial support.
Conflict of interest The authors declare that they have no conflict
of interest.
References
Martina E, Stiefl N, Degel B, Schulz F, Breuning A, Schiller M, Vicik
R, Baumann K, Ziebuhr J, Schirmeister T (2005) Screening of
electrophilic compounds yields an aziridinyl peptide as new
active-site directed SARS-CoV main protease inhibitor. Bioorg
Med Chem Lett 15:5365–5369. doi:10.1016/j.bmcl.2005.09.012
Moad G, Benkovic SJ (1978) On the mechanism of decomposition
of geminal diamines. J Am Chem Soc 100:5495–5499. doi:
10.1021/ja00485a038
Moutevelis-Minakakis P, Photaki I (1985) Some applications of the
Curtius rearrangement. J Chem Soc, Perkin Trans 1:2277–2281.
doi:10.1039/P19850002277
Myers AC, Kowalski JA, Lipton MA (2004) Facile incorporation of
urea pseudopeptides into protease substrate analogue inhibitors.
Bioorg Med Chem Lett 14:5219–5222. doi:10.1016/j.bmcl.2004.
07.092
North M, Pattenden G (1990) Synthetic studies towards cyclic
peptides. Concise synthesis of thiazoline and thiazole containing
amino acids. Tetrahedron 46:8267–8290. doi:10.1016/S0040-
4020(01)81482-4
Okawa K, Nakajima K (1981) Studies on 2-aziridinecarboxylic acid
peptides: their reaction and uses. Biopolymers 20:1811–1821.
doi:10.1002/bip.1981.360200906
Pellacani L, Fioravanti S, Tardella PA (2011) Ethyl nosyloxycarba-
mate, a chameleonic aminating agent. Curr Org Chem 15:1465–
1481. doi:10.2174/138527211795378092
Rowland GB, Zhang H, Rowland EB, Chennamadhavuni S, Wang Y,
Antilla JC (2005) Brønsted acid-catalyzed imine amidation.
J Am Chem Soc 127:15696–15697. doi:10.1021/ja0533085
Angelici G, Contaldi S, Green SL, Tomasini C (2008) Synthesis
of imidazolidin-2-one-4-carboxylate and of (tetrahydro)
pyrimidin-2-one-5-carboxylate via an efficient modification of
the Hofmann rearrangement. Org Biomol Chem 6:1849–1852.
doi:10.1039/B801909F
Chorev M (2005) The partial retro-inverso modification: a road
traveled together. Biopolymers 80:67–84. doi:10.1002/bip.20219
Chorev M, Goodman M (1983) Partially modified retro-inverso
peptides. Comparative Curtius rearrangements to prepare 1,1-
diaminoalkane derivatives. Int J Pept Protein Res 21:258–268.
doi:10.1111/j.1399-3011.1983.tb03103.x
Chorev M, Goodman M (1993) A dozen years of retro-inverso
peptidomimetics. Acc Chem Res 26:266–273. doi:10.1021/
ar00029a007
De Bons JE, Loudon GM (1980) Protected diaminomethane. J Org
Chem 45:1703–1704. doi:10.1021/jo01297a042
Deshmukh R, Purohit HJ (2012) Peptide scaffolds: flexible molecular
structures with diverse therapeutic potentials. Int J Pept Res Ther
18:125–143. doi:10.1007/s10989-011-9286-4
Fife TH, Hutchins JEC, Pellino AM (1978) General acid catalyzed
imidazolidine hydrolysis. Hydrolysis of 2-(tert-butyl)-N, N0-
dimethyl-1,3-imidazolidine and 2-(p-methoxyphenyl)-N-isopro-
pyl-N0-phenyl-1,3-imidazolidine. J Am Chem Soc 100:6455–
6462. doi:10.1021/ja00488a032
Fioravanti S, Morreale A, Pellacani L, Tardella PA (2004) Synthesis
of N-protected cyano aziridines. Synlett 1083–1085. doi:
10.1055/s-2004-820047
Fioravanti S, Morreale A, Pellacani L, Ramadori F, Tardella PA
(2007) Solution-phase parallel synthesis of dissymmetric disub-
stituted malonamides carrying amino ester residues. Synlett
2759–2761. doi:10.1055/s-2007-986659
´
Thieriet N, Gomez-Martinez P, Guibe F (1999) Tandem deprotection-
coupling of Na-alloc-amino acids by use of ternary systems Pd
cat/PhSiH3/carboxy-activated amino acid. Tetrahedron Lett
40:2505–2508. doi:10.1016/S0040-4039(99)00240-3
´
Volonterio A, Bellosta S, Bravin F, Bellucci MC, Bruche L, Colombo
G, Malpezzi L, Mazzini S, Meille SV, Meli M, Ramırez de
´
Fioravanti S, Massari D, Morreale A, Pellacani L, Tardella PA (2008)
Solution-phase synthesis of 2-cyano and 2-amido aziridinyl pep-
tides. Tetrahedron 64:3204–3211. doi:10.1016/j.tet.2008.01.098
Fioravanti S, Morea S, Morreale A, Pellacani L, Tardella PA (2009)
One-pot synthesis of chiral multifunctionalized aziridines. Tet-
rahedron 65:484–488. doi:10.1016/j.tet.2008.11.017
Arellano C, Zanda M (2003) Synthesis, structure and conformation
of partially-modified retro- and retro-inverso w[NHCH(CF3)]Gly
peptides. Chem Eur J 9:4510–4522. doi:10.1002/chem.200304881
Zhu S, Dong J, Fu S, Jiang H, Zeng W (2011) Cu(II)-Catalyzed
intermolecular amidation of C-acylimine: a convenient access to
gem-diamino acid derivatives. Org Lett 13:4914–4917. doi:
10.1021/ol2019955
Fioravanti S, Gasbarri S, Morreale A, Pellacani L, Ramadori F, Tardella
PA (2010a) Short malonyl dehydro peptides as potential scaffolds
123