Solution-phase synthesis of 2-cyano and 2-amido aziridinyl peptides

Article abstract of DOI:10.1016/j.tet.2008.01.098

Starting from a library of 2-l-α-amino acyl (E)-acrylonitriles, different short 2-cyano and 2-amido aziridinyl peptides, potential protease inhibitors, were obtained under parallel solution-phase conditions. The transformations include careful selection o

Full text of DOI:10.1016/j.tet.2008.01.098

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3204e3211
www.elsevier.com/locate/tet
Solution-phase synthesis of 2-cyano and 2-amido aziridinyl peptides
*
Stefania Fioravanti , Davide Massari, Alberto Morreale, Lucio Pellacani , Paolo A. Tardella
*
*
Dipartimento di Chimica, Universita` degli Studi ‘La Sapienza’, P.le Aldo Moro 2, I-00185 Roma, Italy
Received 26 September 2007; received in revised form 4 January 2008; accepted 24 January 2008
Available online 31 January 2008
Abstract
Starting from a library of 2-L-a-amino acyl (E)-acrylonitriles, different short 2-cyano and 2-amido aziridinyl peptides, potential protease
inhibitors, were obtained under parallel solution-phase conditions. The transformations include careful selection of conditions for aziridine
deprotection and cyano group partial hydrolysis.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
4, through the free aziridines 3, and of 2-amido aziridinyl
peptides 5 and 6, starting from (E)-acrylonitriles 1 bearing
different L-a-amino ester residues (Scheme 1).
The presence of small heterocycles, such as epoxides, aziri-
dines, and thiiranes in peptide sequences is an important feature
for the synthesis of electrophilic modified peptides, for their bi-
ological and pharmacological significance.1 Among these small
heterocycles, the aziridine functionality represents a valuable
synthetic building block2 due to its ability to undergo ring open-
ing reactions with a wide range of nucleophiles.3 We report here
a solution-phase synthesis of 1-protected 2-cyano aziridinyl
peptides 2, versatile building blocks to obtain aziridinyl peptides
The chemical behavior of aziridines has prompted the prep-
aration of short peptides incorporating this subunit.4 However,
to date the reported procedures require many reaction steps
and suffer from low yields5 as well as from the incompatibility
of the required protecting groups on the aziridine amine func-
tion, mainly with established solid-phase peptide synthesis
protocols.6 Versatile and rapid routes to synthesize modified
peptides containing an aziridine ring would be welcomed.
Moreover, the aziridine ring substituents play an important
role, modifying the reactivity and influencing the toxicity and
above all the lipophilicity of these compounds. Studies on
2-cyano aziridines assigned an additional role to the cyano
group for their pharmacological activity. In fact, the CN resi-
due has been reported to react fast with cysteine at room
temperature, behaving directly as the inhibitor of the active
site of the cysteine proteases.7
We found that N-protected O-sulfonyl hydroxylamine deriv-
atives8 in the presence of inorganic bases can behave as good
aziridinating agents of EWG (electron-withdrawing group)
functionalized alkenes.9 Therefore the latter were converted in
high yields into their corresponding N-acyloxy aziridines bear-
ing the most common EWG and different alkyl or aryl groups.
These compounds can be regarded as interesting precursors of
various natural or unnatural aminated compounds. Moreover,
O
O
O
O
NC
R'
NC
Y N
R'
AA OMe
H2N
AA OMe
AA OMe
Y N
R'
1
Y = CO -R''
5
Y = CO -R''
Y = H
O
2
3
2
2
O
O
NC
H2N
AA OMe
AA OMe
Boc
AA' N
R'
Boc AA' N
R'
6
4
Scheme 1. Strategy for the synthesis of 2-cyano and 2-amido aziridinyl
peptides.
* Corresponding authors. Tel.: þ39 0649913673; fax: þ39 06490631.
E-mail address: lucio.pellacani@uniroma1.it (L. Pellacani).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.098

S. Fioravanti et al. / Tetrahedron 64 (2008) 3204e3211
3205
drb
Table 1
Aziridination of (E)-1 with NsONHeBoc
it is known that aziridines are activated toward nucleophilic ring
opening not only through the protonation of the aziridine
nitrogen but also by N-acylation.10
Entry
Product
R
R0
Yielda (%)
1
2
3
4
5
6
7
8
9
a
2a
2b
2c
2d
2e
2f
H
Et
82
85
91
81
86
91
90
90
93
d
d
H
Pentyl
iBu
2. Results and discussion
H
d
iPr
iPr
iPr
Bn
Bn
Bn
Et
2:1
2:1
2:1
2:1
3:1
16:1
Here we report a combinatorial ensemble of twenty-six
N-functionalized aziridinyl peptides, 7 of which carry on the
aziridine nitrogen another L-a-amino acidic residue and 2
malonic residues. Among them, 4 new amido aziridinyl peptides
are synthesized by a highly selective hydrolysis of the cyano
group.
Pentyl
iBu
2g
2h
2ic
Et
Pentyl
iBu
After filtration through plugs filled with silica gel using a 9:1 hexane/ethyl
acetate mixture.
b
Determined by 1H NMR spectroscopy and HPLC/UVanalyses of the crude
2.1. Synthesis of 2-cyano aziridinyl peptides
mixtures.
c
Ref. 11.
Very recently we prepared an array of peptides 1 starting
from active methylene compounds, obtained from cyanoacetic
acid and a-amino esters, and different aldehydes by Knoeve-
nagel condensation reaction on Al2O3 (Scheme 2).11
of applications. In fact, it is important to access each of the
new diastereomeric products, because of the possible drastic
difference of reactivity in biological matrices between stereo-
R
OMe
O
R
.
O
R
HCl H2N
O
NC
OMe
O
R'CHO
Al2O3, CH2Cl2
NC
OMe
N
H
NC
N
H
OH
DCC-coupling
O
O
R'
1
Scheme 2. Synthesis of (E)-acrylonitriles 1.
Aziridine ring synthesis was tested using different nosyloxy-
carbamates (NsONHeY, Ns¼4-NO2C6H4SO2) in CH2Cl2 and
in the presence of CaO as the base. The reactions were success-
fully carried out using aminating reagents with different Y
groups (CO2Et,12 Boc,8 Fmoc13) giving directly the N-acyloxy
aziridines 2. Full retention of the starting alkene configuration
was always observed. The best results both for yields and dia-
stereoselectivity were obtained by using tert-butyl nosyloxycar-
bamate (NsONHeBoc).
The aziridine library was constructed performing the ami-
nation reactions in a Carousel reaction station under heteroge-
neous phase conditions (CaO/CH2Cl2) at 0 ꢀC (Scheme 3). For
all reported reactions, substrate/NsONHeBoc/CaO molar
ratio was 1:2:2.
isomers. In all cases a separation of the diastereomeric mixture
is desirable and actually performed by HPLC.
Since the discovery of epoxysuccinyl peptide E-64 in 1978
as a potent cysteine protease inhibitor,14 a variety of inhibitors
containing small rings, as electrophilic building blocks res-
ponsible for enzyme inhibition, have been developed.15 The
aziridinyl peptides 2 can be regarded as potential bioactive
compounds, because the aziridine ring can be opened by nu-
cleophiles not only through the cleavage of the CeN bond,5a
but also through the cleavage of the CeC bond.16 The advan-
tage of an aziridine moiety compared to an epoxide ring is the
option to lengthen the peptide chain via the aziridine N-atom.
Addressing our interest in the synthesis of more complex
peptidomimetic structures, the selective removal of the Boc
protecting group results in a crucial step for obtaining a new
functionalization site. Classic acidic conditions are not suit-
able for Boc removal, due to the presence of labile functional
groups. The use of BF3$Et2O17 gave free aziridines, but in low
yields. Finally, the deprotection reaction was successfully car-
ried out using TBAF/THF18 and the deprotected 2-cyano azir-
idinyl peptides 3 were obtained in the yields as reported in
Table 2, after purification by flash chromatography.
O
R
O
R
NC
R'
OMe
NC
Boc N
R'
OMe
N
H
N
H
NsONH−Boc
CaO, CH2Cl2
O
O
1
2
Scheme 3. Synthesis of 1-Boc 2-cyano aziridinyl peptides.
N-Boc protected aziridinyl peptides 2 were obtained, after
simple filtration of the crude reaction mixtures, in high yields
and in the diastereomeric ratios as reported in Table 1.
A moderate diastereoselectivity was observed, except when
phenylalanine methyl ester is used in combination with a hin-
dered group on the carbonecarbon double bond (entry 9).
Nevertheless, we underline that, at this stage of the research,
a complete stereoselectivity can paradoxically result in a limit
In order to introduce another a-amino acidic unit (entries
1e6) the DCC coupling procedure was chosen. Free cyano azir-
idines were made to react with commercially available N-Boc
protected L-a-amino acids, namely BoceL-Ala and BoceL-
Val, at room temperature. After work-up, 1-amino acyl 2-cyano
aziridinyl peptides 4 carry the N-Boc that can be removed allow-
ing a new possible site for peptide growth. As a different func-
tionalization, a malonic unit was introduced on the aziridine

3206
S. Fioravanti et al. / Tetrahedron 64 (2008) 3204e3211
Table 2
Synthetic elaboration of N-Boc protected aziridinyl peptides
O
R
O
O
R
NC
Y N
iBu
OMe
OMe
30% H2O2, Na2CO3
(CH3)2CO, rt, 18 h
H2N
N
H
N
H
Entry
R
R0
Product Yielda (%) R00
Product Yieldb (%)
Y N
O
O
iPr
4a
91
89
93
88
95
90
96
iBu
1
2
3
4
5
6
7
a
H
Et
3a
61
43
58
51
65
73
73
2c,i; 4c; 4'i
5c,i; 6c; 6'i
H
iBu 3c
CH3 4c
CH3 4d
CH3 4f
CH3 4g
iPr
iPr
Et
iBu 3f
3g
3d
Scheme 5. Selective hydrolysis of the cyano group.
Bn Et
C-Terminal modified amido peptides 5 and 6 were cleanly
obtained in high yields and purity (HPLC/UV) for all selected
aziridines without further purification. Remarkably, the ter-
tiary CN groups carried on multifunctional heterocycles 2c,
2i, 4c, and 40i were successfully converted into the desired
amido function at room temperature, using an H2O2/Na2CO3
aqueous solution.22 The results are reported in Table 3.
The selective hydrolysis led to construction of a malonic unit
that is one of the most important structural modifications of the
backboneofa natural peptide, allowing the reversalof the direction
of the peptide bond and then the preparation of retro-peptides.23
Bn iBu 3i
Bn iBu 3i
iPr
4i
40i
d
After purification by flash chromatography on silica gel (eluent: 8:2
hexane/ethyl acetate).
b
After purification by flash chromatography on silica gel (eluent: 7:3
hexane/ethyl acetate).
nitrogen by the reaction of 3i with ethyl malonyl chloride lead-
ing to the N-malonyl 2-cyano aziridinyl peptide 40i, a methylene
active compound suitable for further synthetic elaborations
(Scheme 4).
O
R
O
R
NC
OMe
NC
N
R'
OMe
N
H
TBAF 1 M
THF, 50 °C
N
H
Y
N
H
O
O
R'
2
3
R''
O
O
OH
R
Boc HN
Cl
Et3N
OEt
DCC
O
O
O
R
R''
NC
N
OMe
NC
OMe
N
H
N
H
EtO
N
Boc
HN
O
O
R'
R'
O
O
O
4
4'
Scheme 4. Deprotection and functionalization of aziridine nitrogen.
Table 3
Synthesis of 2-amido aziridinyl peptides
The results of synthetic elaborations of N-Boc protected
aziridinyl peptides 2 were reported in Table 2.
Entry
Substrate
R
Y
Product
Yield (%)
Recently, structures similar to aziridines 4, also as a mixture
of diastereomers, were tested like potential inhibitors of the
Mpro, the main coronavirus protease.19
1
2
3
4
2c
2i
H
Boc
Boc
5c
5i
81
93
91
90
Bn
H
4c
40i
BoceL-Ala
COCH2CO2Et
6c
60i
Bn
2.2. Synthesis of 2-amido aziridinyl peptides
3. Conclusions
The cyano group can be regarded as the precursor of other
important functionalities, through selective chemical transfor-
mations. It is known that the presence of a C-terminal a-amido
group on the peptide chain is essential for the biological activ-
ity of many peptide hormones.20
The hydrolysis of the cyano group can be achieved by means
of several procedures, most of which are unsuitable for the pres-
ervation of aziridine rings and peptide bonds. In general the
selective hydrolysis of nitriles to amides is not an easy goal, of-
ten suffering from low yields. In addition, tertiary nitriles are
especially resistant toward hydrolysis and few successful exam-
ples are reported in the literature.21
A method for the preparation of cyano and amido peptides
has been introduced. The strategy employs a-amino acidic
functionalized (E)-acrylonitriles as building blocks to obtain
libraries of different polyfunctionalized aziridines under paral-
lel solution-phase conditions. The employment of L-a-amino
acids for the construction of the starting acrylonitrile library
can simplify the generation of biologically active compounds.
4. Experimental section
This hydrolysis was attempted on representative members
of 2-cyano aziridines, the N-Boc 2-cyano aziridines 2c and
2i,11 the aziridinyl peptide 4c, and the N-malonyl 2-cyano
aziridinyl peptide 40i (Scheme 5).
4.1. General methods
GC analyses were performed with an HP 5890 Series II gas
chromatograph equipped with a capillary column (methyl

S. Fioravanti et al. / Tetrahedron 64 (2008) 3204e3211
3207
silicone, 12.5 mꢁ0.2 mm) and a FID detector. IR spectra were
.
meter in CHCl3 as the solvent, and reported in cmꢂ1 1H
2H), 1.80e1.96 (m, 1H), 3.16 (t, J¼6.6 Hz, 1H), 3.78 (s,
3H), 4.10 (d, J¼6.6 Hz, 2H), 7.02e7.11 (br, 1H). 13C NMR:
21.9, 22.4, 27.8, 38.0, 39.4, 41.9, 48.6, 52.6, 83.4, 114.6,
155.9, 161.0, 168.0. HRMS (ES Q-TOF) calcd for
C16H26N3O5 (MþH)þ: 340.1867, found: 340.1881.
recorded on a PERKIN ELMER 1600 FT/IR spectrophoto-
NMR and 13C NMR spectra were recorded at 300 and
75 MHz or at 200 and 50 MHz with a Varian XL-300 or Gem-
ini 200 NMR spectrometer, respectively, and reported in d
units. CDCl3 was used as the solvent and CHCl3 as the internal
standard. ESI MS analyses were performed using a Micromass
Q-TOF Micro quadrupole-time of flight (TOF) mass spectro-
meter equipped with an ESI source and a syringe pump. The
experiments were conducted in the positive ion mode. HPLC
analyses were performed with a VARIAN 9002 instrument us-
ing an analytical column (3.9ꢁ300 mm, flow rate 1.3 mL/min;
detector: 254 nm) equipped with a Varian RI-4 differential re-
fractometer, or a Varian 9050 UV/Vis detector. Eluents were
HPLC grade. Analytical thin layer chromatography (TLC)
was carried out on precoated (0.25 mm) silica gel plates. Silica
gel 230e400 mesh was used for column chromatography. All
solvents were dried following reported standard procedures.
4.2.4. tert-Butyl (2R*,3R*)-2-cyano-3-ethyl-2-{[(1S)-1-
(methoxycarbonyl)-2-methylpropyl]carbamoyl}aziridine-1-
carboxylate (2d)
Pale yellow oil, 81%. IR: 3400, 2251, 1740, 1684 cmꢂ1. 1H
NMR (major isomer): 0.90e0.98 (m, 6H), 1.12 (t, J¼6.6 Hz,
3H), 1.42 (s, 9H), 1.59e1.78 (m, 2H), 2.12e2.28 (m, 1H),
3.02 (t, J¼6.6 Hz, 1H), 3.75 (s, 3H), 4.46e4.52 (m, 1H),
1
6.85e6.98 (br, 1H). H NMR (minor isomer): 0.81e0.89 (m,
6H), 1.13 (t, J¼6.6 Hz, 3H), 1.40 (s, 9H), 1.71e1.75 (m,
2H), 2.14e2.24 (m, 1H), 3.06 (t, J¼6.6 Hz, 1H), 3.74 (s,
3H), 4.60e4.67 (m, 1H), 6.80e6.90 (br, 1H). 13C NMR (major
isomer): 10.5, 17.6, 18.8, 23.3, 27.8, 31.8, 39.6, 50.4, 52.4,
58.2, 83.3, 114.5, 155.9, 160.5, 171.1. 13C NMR (minor iso-
mer): 9.6, 17.7, 18.7, 23.1, 27.9, 31.8, 39.4, 50.4, 52.3, 58.1,
83.4, 114.2, 155.7, 160.7, 171.0. HRMS (ES Q-TOF) calcd
for C17H28N3O5 (MþH)þ: 354.2023, found: 354.2039.
4.2. Synthesis of 1-Boc 2-cyano aziridinyl peptides: general
procedure
CaO (2 mmol) and NsONHeBoc (2 mmol) were added to
a stirred solution of (E)-acrylonitriles 1aei (1 mmol) in
CH2Cl2 at 0 ꢀC. After the reaction was complete (TLC, 4 h),
the crude aziridines were filtered through plugs filled with sil-
ica gel using a 9:1 hexane/ethyl acetate mixture, and the prod-
ucts 2aei were obtained as oils after solvent removal. The
diastereomeric mixtures of 1-Boc 2-cyano aziridinyl peptides
2deh were separated by HPLC using an 8:2 hexane/ethyl
acetate mixture (flow 1.3 mL/min) as the eluent.
4.2.5. tert-Butyl (2R*,3R*)-2-cyano-2-{[(1S)-1-(methoxy-
carbonyl)-2-methylpropyl]carbamoyl}-3-pentylaziridine-1-
carboxylate (2e)
Pale yellow oil, 86%. IR: 3402, 2254, 1738, 1679 cmꢂ1. 1H
NMR (major isomer): 0.92e0.99 (m, 9H), 1.23e1.64 (m, 6H),
1.43 (s, 9H), 1.66e1.77 (m, 2H), 2.13e2.28 (m, 1H), 3.07 (t,
J¼6.9 Hz, 1H), 3.76 (s, 3H), 4.46e4.54 (m, 1H), 6.94e6.97
1
(br, 1H). H NMR (minor isomer): 0.85e0.93 (m, 9H), 1.24e
1.61 (m, 6H), 1.41 (s, 9H), 1.62e1.75 (m, 2H), 2.13e2.28 (m,
1H), 3.10 (t, J¼6.9 Hz, 1H), 3.76 (s, 3H), 4.47e4.53 (m, 1H),
6.95e7.01 (br, 1H). 13C NMR (major isomer): 13.8, 17.6, 18.6,
22.3, 26.0, 27.7, 29.6, 31.0, 31.3, 39.7, 49.3, 52.5, 58.2, 83.2,
114.7, 156.0, 160.5, 171.1. 13C NMR (minor isomer): 13.8,
17.7, 18.7, 22.3, 26.0, 27.7, 29.4, 31.0, 31.3, 39.6, 49.4, 52.4,
58.1, 83.4, 114.4, 155.8, 160.7, 171.0. HRMS (ES Q-TOF) calcd
for C20H34N3O5 (MþH)þ: 396.2493, found: 396.2506.
4.2.1. tert-Butyl (2R*,3R*)-2-cyano-3-ethyl-2-[(2-methoxy-
2-oxoethyl)carbamoyl]aziridine-1-carboxylate (2a)
Pale yellow oil, 82%. IR: 3402, 2250, 1736, 1697 cmꢂ1 .1H
NMR: 1.14 (t, J¼7.7 Hz, 3H), 1.42 (s, 9H), 1.63e1.82 (m,
2H), 3.07 (t, J¼6.6 Hz, 1H), 3.77 (s, 3H), 4.08 (d, J¼6.6 Hz,
2H), 7.04e7.18 (br, 1H). 13C NMR: 10.9, 23.5, 28.1, 39.7,
42.2, 50.9, 52.9, 83.8, 114.5, 155.9, 161.2, 169.1. HRMS
(ES Q-TOF) calcd for C14H22N3O5 (MþH)þ: 312.1554,
found: 312.1563.
4.2.6. tert-Butyl (2R*,3R*)-2-cyano-3-isobutyl-2-{[(1S)-1-
(methoxycarbonyl)-2-methylpropyl]carbamoyl}aziridine-1-
carboxylate (2f)
4.2.2. tert-Butyl (2R*,3R*)-2-cyano-2-[(2-methoxy-2-
Pale yellow oil, 91%. IR: 3401, 2255, 1744, 1680 cmꢂ1. 1H
NMR (major isomer): 0.92e1.05 (m, 12H), 1.42 (s, 9H),
1.59e1.66 (m, 2H), 1.82e1.96 (m, 1H), 2.18e2.37 (m, 1H),
3.17 (t, J¼6.6 Hz, 1H), 3.75 (s, 3H), 4.49e4.54 (m, 1H),
oxoethyl)carbamoyl]-3-pentylaziridine-1-carboxylate (2b)
Pale yellow oil, 85%. IR: 3404, 2252, 1738, 1694 cmꢂ1. 1H
NMR: 0.89 (t, J¼6.6 Hz, 3H), 1.20e1.62 (m, 6H), 1.43 (s,
9H), 1.64e1.80 (m, 2H), 3.11 (t, J¼6.6 Hz, 1H), 3.78 (s,
3H), 4.08 (d, J¼6.6 Hz, 2H), 7.00e7.09 (br, 1H). 13C NMR:
14.3, 22.7, 26.4, 28.1, 29.9, 31.4, 39.8, 42.2, 49.9, 53.0,
83.7, 114.6, 156.0, 161.2, 169.1. HRMS (ES Q-TOF) calcd
for C17H28N3O5 (MþH)þ: 354.2023, found: 354.2030.
1
6.92e6.98 (br, 1H). H NMR (minor isomer): 0.94e1.04 (m,
12H), 1.42 (s, 9H), 1.56e1.68 (m, 2H), 1.85e1.99 (m, 1H),
2.18e2.30 (m, 1H), 3.12 (t, J¼6.6 Hz, 1H), 3.77 (s, 3H),
4.50e4.55 (m, 1H), 6.94e6.97 (br, 1H). 13C NMR (major iso-
mer): 17.6, 18.8, 21.9, 22.4, 26.6, 27.7, 31.1, 38.1, 39.6, 48.3,
52.4, 58.2, 83.2, 114.7, 156.0, 160.5, 171.1. 13C NMR (minor
isomer): 17.7, 18.7, 21.9, 22.5, 26.8, 27.6, 31.2, 37.8, 39.6,
48.3, 52.3, 58.1, 83.3, 114.6, 155.9, 160.6, 170.9. HRMS
(ES Q-TOF) calcd for C19H32N3O5 (MþH)þ: 382.2386,
found: 382.2401.
4.2.3. tert-Butyl (2R*,3R*)-2-cyano-3-isobutyl-2-[(2-
methoxy-2-oxoethyl)carbamoyl]aziridine-1-carboxylate (2c)
Pale yellow oil, 91%. IR: 3404, 2249, 1735, 1689 cmꢂ1. 1H
NMR: 1.03 (d, J¼6.6 Hz, 6H), 1.43 (s, 9H), 1.54e1.70 (m,

3208
S. Fioravanti et al. / Tetrahedron 64 (2008) 3204e3211
4.2.7. tert-Butyl (2R*,3R*)-2-{[(1S)-1-benzyl-2-methoxy-2-
oxoethyl]carbamoyl}-2-cyano-3-ethylaziridine-1-
carboxylate (2g)
2H), 2.26e2.35 (m, 1H), 2.48e2.60 (m, 1H), 3.78 (s, 3H),
4.06e4.17 (m, 2H), 6.85e7.90 (br, 1H). 13C NMR: 10.8,
24.2, 34.7, 42.1, 47.5, 52.7, 114.0, 164.7, 170.5. HRMS (ES
Q-TOF) calcd for C9H14N3O3 (MþH)þ: 212.1030, found:
212.1041.
Yellow oil, 90%. IR: 3405, 2250, 1742, 1682 cmꢂ1. H
NMR (major isomer): 1.11 (t, J¼7.5 Hz, 3H), 1.44 (s, 9H),
1.48e1.61 (m, 2H), 2.91 (t, J¼6.6 Hz, 1H), 3.13 (d,
J¼6.0 Hz, 2H), 3.72 (s, 3H), 4.76e4.86 (m, 1H), 6.88e6.96
1
4.3.2. (2R*,3R*)-2-Cyano-3-isobutyl-2-[(2-methoxy-2-
oxoethyl)carbamoyl]aziridine (3c)
Pale yellow oil, 43%. IR: 3434, 3400, 2242, 1748,
1
(br, 1H), 7.07e7.18 (m, 2H), 7.24e7.35 (m, 3H). H NMR
(minor isomer): 1.24 (t, J¼7.5 Hz, 3H), 1.42 (s, 9H), 1.58e
1.84 (m, 2H), 2.97 (t, J¼6.6 Hz, 1H), 3.16 (d, J¼6.0 Hz,
2H), 3.73 (s, 3H), 4.76e4.86 (m, 1H), 6.88e6.96 (br, 1H),
7.08e7.15 (m, 2H), 7.23e7.36 (m, 3H). 13C NMR (major iso-
mer): 10.4, 23.1, 27.7, 37.6, 39.4, 50.5, 52.5, 54.0, 83.4, 114.1,
127.5, 128.8, 129.1, 134.9, 155.7, 160.4, 170.5. 13C NMR (mi-
nor isomer): 10.4, 23.0, 27.6, 37.6, 39.3, 50.5, 52.5, 53.9, 83.4,
114.0, 127.4, 128.7, 129.1, 134.9, 155.6, 160.4, 170.6. HRMS
(ES Q-TOF) calcd for C21H28N3O5 (MþH)þ: 402.2023,
found: 402.2028.
1692 cmꢂ1
.
1H NMR: 0.97 (d, J¼6.9 Hz, 6H), 1.45e1.55
(m, 2H), 1.77e1.86 (m, 1H), 2.24e2.42 (m, 1H), 2.53e2.60
(m, 1H), 3.75 (s, 3H), 4.02e4.18 (m, 2H), 6.91e7.10 (br,
1H). 13C NMR: 22.4, 26.7, 34.6, 39.0, 42.0, 45.0, 52.5,
116.7, 164.7, 169.0. HRMS (ES Q-TOF) calcd for
C11H18N3O3 (MþH)þ: 240.1343, found: 240.1347.
4.3.3. (2R*,3R*)-2-Cyano-3-ethyl-2-{[(1S)-1-(methoxy-
carbonyl)-2-methylpropyl]carbamoyl}aziridine (3d)
Pale yellow oil, 58%. IR: 3420, 3404, 2249, 1742,
.
1691 cmꢂ1 1H NMR: 0.86e1.16 (m, 9H), 1.43e1.60 (m,
2H), 1.74e1.82 (m, 1H), 2.18e2.29 (m, 1H), 2.46e2.60 (m,
1H), 3.76 (s, 3H), 4.36e4.52 (m, 1H), 6.86e7.07 (br, 1H).
13C NMR: 11.0, 17.4, 18.2, 24.6, 30.3, 38.6, 48.9, 52.0,
57.7, 115.1, 160.5, 169.9. HRMS (ES Q-TOF) calcd for
C12H20N3O3 (MþH)þ: 254.2976, found: 254.2984.
4.2.8. tert-Butyl (2R*,3R*)-2-{[(1S)-1-benzyl-2-methoxy-2-
oxoethyl]carbamoyl}-2-cyano-3-pentylaziridine-1-
carboxylate (2h)
Yellow oil, 90%. IR: 3402, 2249, 1745, 1684 cmꢂ1. H
1
NMR (major isomer): 0.88 (t, J¼6.6 Hz, 3H), 1.22e1.73
(m, 8H), 1.43 (s, 9H), 2.94 (t, J¼6.6 Hz, 1H), 3.12 (d,
J¼6.0 Hz, 2H), 3.72 (s, 3H), 4.78e4.85 (m, 1H), 6.92e6.96
1
(br, 1H), 7.11e7.16 (m, 2H), 7.25e7.33 (m, 3H). H NMR
4.3.4. (2R*,3R*)-2-Cyano-3-isobutyl-2-{[(1S)-1-(methoxy-
carbonyl)-2-methylpropyl]carbamoyl}aziridine (3f)
Pale yellow oil, 51%. IR: 3425, 3404, 2250, 1741,
(minor isomer): 0.89 (t, J¼6.6 Hz, 3H), 1.25e1.72 (m, 8H),
1.42 (s, 9H), 3.00 (t, J¼6.6 Hz, 1H), 3.15 (d, J¼6.0 Hz,
2H), 3.73 (s, 3H), 4.78e4.85 (m, 1H), 6.86e6.93 (br, 1H),
7.07e7.12 (m, 2H), 7.23e7.30 (m, 3H). 13C NMR (major iso-
mer): 13.8, 22.3, 25.9, 26.7, 27.6, 30.9, 37.5, 39.4, 49.5, 52.5,
54.0, 83.4, 114.1, 127.4, 128.8, 129.1, 134.9, 155.8, 160.5,
170.5. 13C NMR (minor isomer): 13.8, 22.3, 25.9, 27.1,
27.7, 31.0, 37.6, 39.4, 49.5, 52.5, 53.9, 83.4, 114.1, 127.4,
128.7, 129.1, 134.9, 155.7, 160.4, 170.6. HRMS (ES Q-
TOF) calcd for C24H34N3O5 (MþH)þ: 444.2493, found:
444.2512.
1
1688 cmꢂ1. H NMR: 0.84e1.06 (m, 12H), 1.55e1.78 (m,
2H), 1.80e2.00 (m, 1H), 2.10e2.34 (m, 2H), 3.08e3.19 (m,
1H), 3.78 (s, 3H), 4.52e4.61 (m, 1H), 6.85e7.00 (br, 1H).
13C NMR: 17.8, 18.6, 22.3, 22.9, 26.6, 30.4, 39.2, 49.7 52.4,
58.0, 115.2, 160.2, 171.0. HRMS (ES Q-TOF) calcd for
C14H24N3O3 (MþH)þ: 282.1812, found: 282.1821.
4.3.5. (2R*,3R*)-2-{[(1S)-1-Benzyl-2-methoxy-2-
oxoethyl]carbamoyl}-2-cyano-3-ethylaziridine (3g)
Yellow oil, 65%. IR: 3563, 3402, 2245, 1749, 1689 cmꢂ1
.
4.3. Deprotection of 1-Boc 2-cyano aziridinyl peptides:
general procedure
1H NMR: 1.15 (t, J¼7.2 Hz, 3H), 1.42e1.59 (m, 2H), 2.25
(d, J¼6.0 Hz, 1H), 2.43e2.57 (m, 1H), 3.18 (d, J¼6.0 Hz,
2H), 3.74 (s, 3H), 4.80e4.85 (m, 1H), 6.70e6.92 (br, 1H),
7.11e7.16 (m, 2H), 7.24e7.36 (m, 3H). 13C NMR: 10.09,
27.1, 37.7, 39.3, 45.0, 52.3, 54.8, 115.9, 127.3, 128.8, 129.2,
134.9, 164.1, 170.5. HRMS (ES Q-TOF) calcd for
C16H20N3O3 (MþH)þ: 302.3477, found: 302.3462.
To a THF solution of 2a, 2c, 2d, 2f, 2g, and 2i (0.2 mmol of
pure major diastereomer) a solution of tetrabutylammonium
fluoride (TBAF, 1 M in THF) in equimolar amount was added,
and the mixture was stirred under reflux for 20 min. The crude
mixture was then dissolved in ethyl acetate and washed with
a saturated aqueous solution of NaHCO3 in a separator funnel.
The organic layer was dried over Na2SO4 and filtered. The
deprotected 2-cyano aziridinyl peptides 3 were obtained as
pure compounds after chromatographic purification on silica
gel (eluent: 8:2 hexane/ethyl acetate mixture).
4.3.6. (2R*,3R*)-2-{[(1S)-1-Benzyl-2-methoxy-2-oxoethyl]-
carbamoyl}-2-cyano-3-isobutylaziridine (3i)
Yellow oil, 73%. IR: 3563, 3402, 2245, 1749, 1689 cmꢂ1
.
1H NMR: 0.95 (d, J¼6.6 Hz, 6H), 1.39e1.59 (m, 2H), 1.75e
1.85 (m, 1H), 2.27 (m, 1H), 2.44e2.52 (m, 1H), 3.20 (m,
2H), 3.74 (s, 3H), 4.73e4.90 (m, 1H), 6.82e6.96 (br, 1H),
7.09e7.18 (m, 2H), 7.24e7.35 (m, 3H). 13C NMR: 22.4,
26.6, 34.6, 37.6, 39.0, 44.8, 52.5, 54.2, 116.4, 127.4, 128.6,
129.0, 135.1, 163.9, 170.6. HRMS (ES Q-TOF) calcd for
C18H24N3O3 (MþH)þ: 330.1812, found: 330.1826.
4.3.1. (2R*,3R*)-2-Cyano-3-ethyl-2-[(2-methoxy-2-
oxoethyl)carbamoyl]aziridine (3a)
Pale yellow oil, 61%. IR: 3425, 3400, 2246, 1740,
1
1698 cmꢂ1. H NMR: 1.11 (t, J¼7.2 Hz, 3H), 1.58e1.76 (m,

S. Fioravanti et al. / Tetrahedron 64 (2008) 3204e3211
3209
4.4. Synthesis of 1-amino acyl 2-cyano aziridinyl peptides:
general procedure
58.5, 84.9, 115.9, 155.2, 155.6, 165.0, 169.2. HRMS (ES Q-
TOF) calcd for C22H37N4O6 (MþH)þ: 453.2708, found:
453.2708, 453.2692.
To a CH2Cl2 solution of the 2-cyano peptides 3a, 3c, 3d, 3f,
3g, and 3i (0.5 mmol of pure major diastereomers) commercial
BoceL-Ala or BoceL-Val and DCC in equimolar amounts and
DMAP in catalytic amounts were added at room temperature.
The reactions were followed by TLC until completion (24 h).
After filtration, aziridinyl peptides 4 were obtained as pure
compounds after flash chromatography on silica gel (eluent:
7:3 hexane/ethyl acetate mixture).
4.4.5. Methyl (2S)-2-[({(2R*,3R*)-1-[L-N-(tert-butoxy-
carbonyl)alanyl]-2-cyano-3-ethylaziridin-2-yl}carbonyl)-
amino]-3-phenylpropanoate (4g)
Pale orange oil, 95%. IR: 3502, 3400, 2244, 1746,
1
1692 cmꢂ1. H NMR: 1.05 (t, J¼7.2 Hz, 3H), 1.34e1.64 (m,
14H), 1.82e2.05 (m, 1H), 2.00e2.34 (br, 1H), 2.90e3.32
(m, 1H), 3.15 (d, J¼6.0 Hz, 2H), 3.76 (s, 3H), 4.71e4.85
(m, 1H), 6.81e6.92 (br, 1H), 6.97e7.06 (m, 2H), 7.12e7.36
(m, 3H). 13C NMR: 11.6, 23.8, 26.9, 27.8, 34.6, 39.4, 42.0,
45.2, 52.6, 54.2, 84.9, 116.5, 127.7, 128.6, 129.3, 135.1,
155.1, 155.4, 164.7, 169.1. HRMS (ES Q-TOF) calcd for
C24H33N4O6 (MþH)þ: 473.2395, found: 473.2408.
4.4.1. Methyl ({[(2R*,3R*)-1-(L-N-[(tert-butoxycarbonyl)-
valyl-2-cyano-3-ethylaziridin-2-yl]carbonyl}amino)acetate
(4a)
Yellow oil, 89%. IR: 3679, 3435, 2251, 1747, 1698 cmꢂ1. 1H
NMR: 1.09 (t, J¼7.2 Hz, 3H), 1.30e1.72 (m, 18H), 2.45e2.64
(br, 1H), 2.90e3.24 (m, 1H), 3.67e3.70 (m, 1H), 3.78 (s, 3H),
4.03e4.17 (m, 2H), 7.01e7.12 (br, 1H). 13C NMR: 11.2, 22.3,
22.9, 25.7, 27.9, 34.2, 39.6, 41.8, 45.5, 53.0, 85.1, 115.8, 155.3,
155.5, 164.2, 170.1. HRMS (ES Q-TOF) calcd for C19H31N4O6
(MþH)þ: 411.2238, found: 411.2249.
4.4.6. Methyl (2S)-2-[({(2R*,3R*)-1-[L-N-(tert-butoxy-
carbonyl)valyl]-2-cyano-3-isobutylaziridin-2-yl}carbonyl)-
amino]-3-phenylpropanoate (4i)
Pale orange oil, 90%. IR: 3502, 3400, 2244, 1746,
1
1692 cmꢂ1. H NMR: 0.76e1.02 (m, 12H), 1.34e1.46 (m,
2H), 1.41 (s, 9H), 1.48e1.66 (m, 1H), 1.69e1.92 (m, 1H),
2.00e2.34 (br, 1H), 2.90e3.32 (m, 3H), 3.67 (s, 3H), 3.98e
4.20 (m, 1H), 4.71e4.85 (m, 1H), 6.92e7.05 (br, 1H), 7.12e
7.36 (m, 5H). 13C NMR: 17.5, 18.6, 21.9, 22.1, 22.6, 26.5,
27.8, 34.5, 37.4, 39.2, 44.4, 52.5, 53.9, 54.6, 85.0, 115.8,
127.3, 128.5, 129.0, 135.1, 155.0, 155.3, 164.7, 169.3. HRMS
(ES Q-TOF) calcd for C28H41N4O6 (MþH)þ: 529.3021, found:
529.3038.
4.4.2. Methyl [({(2R*,3R*)-1-[L-N-(tert-butoxycarbonyl)-
alanyl]-2-cyano-3-isobutylaziridin-2-yl}carbonyl)amino]-
acetate (4c)
Yellow oil, 91%. IR: 3683, 3436, 2249, 1749, 1698 cmꢂ1
.
1H NMR: 0.96e1.05 (m, 6H), 1.35e1.75 (m, 13H), 1.80e
1.98 (m, 2H), 2.42e2.64 (br, 1H), 3.08e3.19 (br, 1H),
3.67e3.71 (m, 1H), 3.78 (s, 3H), 4.01e4.15 (m, 2H), 7.04e
7.16 (br, 1H). 13C NMR: 17.8, 18.6, 26.7, 27.6, 28.3, 34.6,
39.4, 42.0, 45.2, 52.6, 84.9, 116.5, 155.1, 155.4, 164.7,
169.1. HRMS (ES Q-TOF) calcd for C19H31N4O6 (MþH)þ:
411.2238, found: 411.2247.
4.4.7. Synthesis of ethyl 3-[(2R*,3R*)-2-cyano-3-isobutyl-2-
({[(1S)-1-benzyl-2-methoxy-2-oxoethyl]carbamoyl}aziridin-
1-yl)]-3-oxopropanoate (40i)
To a stirred solution of 3i (1 mmol) in anhydrous CH2Cl2
ethyl malonyl chloride (1 mmol) was added dropwise at
0 ꢀC. Then triethylamine (1 mmol) dissolved in anhydrous
CH2Cl2 was gently added to the mixture. The solution was
then stirred for additional 15 min and then filtered through
a plug filled with a layer of silica gel. Compound 40i was ob-
tained after solvent removal, as an orange oil, 96%. IR: 3563,
4.4.3. Methyl (2S)-2-[({(2R*,3R*)-1-[L-N-(tert-butoxy-
carbonyl)alanyl]-2-cyano-3-ethylaziridin-2-yl}carbonyl)-
amino]-3-methylbutanoate (4d)
Yellow oil, 93%. IR: 3540, 3406, 2252, 1742, 1688 cmꢂ1
.
1H NMR: 0.79e1.03 (m, 6H), 1.11 (t, J¼7.2 Hz, 3H), 1.20e
1.24 (m, 3H), 1.42e1.64 (m, 11H), 1.71e1.89 (m, 1H),
2.10e2.40 (m, 1H), 2.41e2.58 (br, 1H), 3.60e3.89 (m, 1H),
3.76 (s, 3H), 4.46e4.55 (m, 1H), 6.78e7.00 (br, 1H). 13C
NMR: 11.6, 17.4, 18.5, 22.0, 22.7, 26.8, 27.8, 34.6, 39.4,
42.0, 45.2, 52.6, 84.9, 116.5, 155.1, 155.4, 164.7, 169.1.
HRMS (ES Q-TOF) calcd for C20H33N4O6 (MþH)þ:
425.2395, found: 425.2403.
1
2245, 1742, 1694 cmꢂ1. H NMR: 0.99 (d, J¼6.0 Hz, 6H),
1.24e1.30 (m, 3H), 1.45e1.90 (m, 3H), 2.24e2.30 (m, 1H),
3.05e3.25 (m, 4H), 3.78 (s, 3H), 4.16e4.25 (m, 2H), 4.76e
4.94 (m, 1H), 7.08e7.35 (m, 6H). 13C NMR: 14.0, 21.9,
22.4, 26.6, 37.7, 38.1, 44.0, 48.3, 52.5, 54.2, 61.5, 114.1,
127.5, 128.7, 129.2, 134.9, 160.4, 166.1, 170.4, 172.6.
HRMS (ES Q-TOF) calcd for C23H30N3O6 (MþH)þ:
444.2129, found: 444.2136.
4.4.4. Methyl (2S)-2-[({(2R*,3R*)-1-[L-N-(tert-butoxy-
carbonyl)alanyl]-2-cyano-3-isobutylaziridin-2-
yl}carbonyl)amino]-3-methylbutanoate (4f)
4.5. Synthesis of 2-amido aziridinyl peptides: general
procedure
Yellow oil, 88%. IR: 3540, 3406, 2252, 1742, 1688 cmꢂ1
.
1H NMR: 0.80e1.05 (m, 12H), 1.20e1.26 (m, 3H), 1.40e
1.61 (m, 12H), 1.79e1.98 (m, 1H), 2.10e2.39 (m, 1H),
2.44e2.62 (br, 1H), 3.68e3.85 (m, 1H), 3.76 (s, 3H), 4.41e
4.50 (m, 1H), 6.75e6.98 (br, 1H). 13C NMR: 17.8, 18.6,
21.9, 22.3, 22.6, 27.0, 27.6, 34.5, 39.5, 42.3, 44.9, 52.7,
To cyano aziridinyl peptides 2c, 2i, 4c, and 40i (0.5 mmol)
dissolved in acetone (4.0 mL), an 1 N aqueous solution of
Na2CO3 (0.5 mL, 0.25 mmol) and 30% H2O2 (1.7 mL,
15.0 mmol) were added. The mixture was stirred for 18 h at

3210
S. Fioravanti et al. / Tetrahedron 64 (2008) 3204e3211
room temperature. After reaction completion (TLC), the sol-
vent was removed under vacuum, and the resulting aqueous
mixture was extracted with CH2Cl2. The products were
obtained with high purity after solvent removal.
Acknowledgements
This research was carried out within the framework of the
National Project ‘Stereoselezione in Sintesi Organica. Meto-
dologie ed Applicazioni’, supported by the Italian Ministero
`
dell’Istruzione dell’Universita e della Ricerca (MIUR) and
by the Universita degli Studi di Roma ‘La Sapienza’.
4.5.1. tert-Butyl (2R*,3R*)-2-carbamoyl-3-isobutyl-2-[(2-
methoxy-2-oxoethyl)carbamoyl]aziridine-1-carboxylate (5c)
Viscous yellow oil, 81%. IR: 3511, 3392, 3324, 1797, 1732,
1698, 1667 cmꢂ1. 1H NMR: 0.96 (d, J¼6.0 Hz, 6H), 1.21e1.27
(m, 2H), 1.44 (s, 9H), 1.78e1.84 (m, 1H), 2.94e3.14 (br, 1H),
3.72 (s, 3H), 4.04e4.06 (m, 2H), 6.42e6.51 (br, 1H), 6.83e
7.00 (br, 1H), 8.74e8.94 (br, 1H). 13C NMR: 22.0, 22.4, 27.8,
36.3, 41.6, 49.2, 49.5, 52.3, 82.1, 157.8, 164.5, 169.8, 170.0.
HRMS (ES Q-TOF) calcd for C16H28N3O6 (MþH)þ:
358.1973, found: 358.1984.
`
Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.01.098.
References and notes
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8005e8008 and references therein.
4.5.2. tert-Butyl (2R*,3R*)-2-{[(1S)-1-benzyl-2-methoxy-2-
oxoethyl]carbamoyl}-2-carbamoyl-3-isobutylaziridine-1-
carboxylate (5i)
3. (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599e619; (b) Swee-
ney, J. B. Chem. Soc. Rev. 2002, 31, 247e258; (c) Hu, X. E. Tetrahedron
2004, 60, 2701e2743.
Viscous orange oil, 93%. IR: 3511, 3394, 3322, 1734,
1
4. (a) Okawa, K.; Nakajima, K. Biopolymers 1981, 20, 1811e1821; (b)
Korn, A.; Rudolph-Bohner, S.; Moroder, L. Tetrahedron 1994, 50,
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(b) Berry, M. B.; Craig, D. Synlett 1992, 41e44.
1697, 1665 cmꢂ1. H NMR: 0.95 (d, J¼6.0 Hz, 6H), 1.21e
¨
1.28 (m, 2H), 1.45 (s, 9H), 1.78e1.80 (m, 1H), 2.78e2.98
(br, 1H), 3.00e3.18 (m, 2H), 3.68 (s, 3H), 4.68e4.87 (m,
1H), 6.24e6.42 (br, 1H), 6.62e6.90 (br, 1H), 7.07e7.38
(m, 5H), 8.78e8.94 (br, 1H). 13C NMR: 22.0, 22.4, 26.7,
27.9, 35.4, 36.2, 37.7, 49.3, 52.2, 54.1, 82.0, 127.0, 128.4,
129.2, 135.8, 157.8, 163.7, 169.9, 171.1. HRMS (ES Q-
TOF) calcd for C23H34N3O6 (MþH)þ: 448.2442, found:
448.2456.
´
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4.5.3. Methyl [({(2R*,3R*)-1-[L-N-(tert-butoxy-
carbonyl)alanyl]-2-carbamoyl-3-isobutylaziridin-2-
yl}carbonyl)amino]acetate (6c)
10. (a) Mitsunobu, O. Comprehensive Organic Chemistry; Trost, B. M., Ed.;
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Davis, F. A. Synthesis 2000, 1347e1365.
Viscous yellow oil, 91%. IR: 3504, 3380, 3323, 1752,
1
1689, 1658 cmꢂ1. H NMR: 0.91e1.01 (m, 9H), 1.23e1.57
11. Fioravanti, S.; Pellacani, L.; Tardella, P. A.; Morreale, A.; Del Signore, G.
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1083e1085.
(m, 10H), 1.72e1.86 (m, 2H), 2.38e2.55 (m, 2H), 3.72e
3.80 (m, 1H), 3.75 (s, 3H), 4.01e4.15 (m, 2H), 5.70e5.90
(br, 1H), 6.82e7.01 (br, 1H), 8.95e9.16 (br, 1H). 13C
NMR: 17.6, 18.8, 26.7, 27.5, 28.3, 34.5, 39.8, 42.0, 45.2,
53.0, 84.9, 155.0, 155.4, 164.5, 169.3, 170.2. HRMS (ES Q-
TOF) calcd for C19H33N4O7 (MþH)þ: 429.2344, found:
429.2352.
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2000, 8, 1281e1291.
4.5.4. Ethyl 3-[(2R*,3R*)-2-carbamoyl-3-isobutyl-2-
({[(1S)-1-benzyl-2-methoxy-2-oxoethyl]carbamoyl}aziridin-
1-yl)]-3-oxopropanoate (60i)
Viscous orange oil, 90%. IR: 3563, 2245, 1742, 1694 cmꢂ1
.
16. Claus, P. K. Methoden der Organischen Chemie (Houben-Weyl); Klamann,
D., Hagemann, H., Eds.; Thieme: Stuttgart, 1990; Vol. E 14b; Part 1,
pp 88e91.
17. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd
ed.; Wiley: New York, NY, 1999.
1H NMR: 0.99 (d, J¼6.0 Hz, 6H), 1.24e1.30 (m, 3H), 1.45e
1.90 (m, 3H), 2.24e2.30 (m, 1H), 3.05e3.25 (m, 4H), 3.78 (s,
3H), 4.16e4.25 (m, 2H), 4.80e4.89 (m, 1H), 6.20e6.28 (br,
1H), 6.60e6.81 (br, 1H), 7.08e7.35 (m, 5H). 8.84e9.03 (br,
1H). 13C NMR: 14.1, 22.0, 22.4, 26.8, 37.5, 38.1, 44.4, 48.4,
52.8, 53.9, 61.8, 127.5, 128.7, 129.2, 134.9, 160.4, 166.1,
170.1, 170.6, 172.6. HRMS (ES Q-TOF) calcd for
C23H32N3O7 (MþH)þ: 462.2235, found: 462.2247.
´ ´
18. Jacquemard, U.; Beneteau, V.; Lefoix, M.; Routier, S.; Merour, J.-Y.;
´
Coudert, G. Tetrahedron 2004, 60, 10039e10047.
19. Martina, E.; Stiefl, N.; Degel, B.; Schulz, F.; Breuning, A.; Schiller, M.;
Vicik, R.; Baumann, K.; Ziebuhr, J.; Schirmeister, T. Bioorg. Med.
Chem. Lett. 2005, 15, 5365e5369.
ꢀ
ˇ
´
20. Cerovsky, V.; Kula, M.-R. Angew. Chem., Int. Ed. 1998, 37, 1885e1887.

S. Fioravanti et al. / Tetrahedron 64 (2008) 3204e3211
3211
21. (a) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989, 949e950; (b)
Cushman, M.; Jurayj, J.; Moyer, J. D. J. Org. Chem. 1990, 55, 3186e
3194; For a recent biotransformation of the nitrile group into an amido
function: Wang, J.-Y.; Wang, D.-X.; Zheng, Q.-Y.; Huang, Z.-T.; Wang,
M.-X. J. Org. Chem. 2007, 72, 2040e2045.
22. It was reported that the hydrolysis of similar nitriles does not take place
with H2O2: Jiang, X.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G.
J. Org. Chem. 2004, 69, 2327e2331.
23. (a) Sasubilli, R.; Gutheil, W. G. J. Comb. Chem. 2004, 6, 911e915; (b)
Chorev, M. Biopolymers 2005, 80, 67e84.