Synthesis of epoxy and aziridino malonyl peptidomimetics

Article abstract of DOI:10.1016/j.tet.2010.09.097

Short malonyl dehydro peptides have been epoxidized using H ₂O₂/Na₂WO₄ dihydrate. The obtained diastereomeric epoxides were separated by HPLC and successfully tested in the ring opening reaction with N-Boc l-cysteine methyl ester, to indicate their electrophilic behavior. Moreover, by a simple two-step reaction, the epoxy malonyl peptides can be converted into the corresponding aziridino malonyl peptides.

Full text of DOI:10.1016/j.tet.2010.09.097

Tetrahedron 66 (2010) 9401e9404
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of epoxy and aziridino malonyl peptidomimetics
*
*
*
Stefania Fioravanti , Simona Gasbarri, Lucio Pellacani , Federico Ramadori, Paolo A. Tardella
ꢀ
Dipartimento di Chimica, Universita degli Studi di Roma ‘La Sapienza’, P.le Aldo Moro 5, I-00185 Roma, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2010
Received in revised form 9 September 2010
Accepted 28 September 2010
Available online 24 October 2010
Short malonyl dehydro peptides have been epoxidized using H2O2/Na2WO4 dihydrate. The obtained di-
astereomeric epoxides were separated by HPLC and successfully tested in the ring opening reaction with N-
Boc L-cysteine methyl ester, to indicate their electrophilic behavior. Moreover, by a simple two-step re-
action, the epoxy malonyl peptides can be converted into the corresponding aziridino malonyl peptides.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Saverio Florio on the
occasion of his 70th birthday
Keywords:
Epoxides
Aziridines
Sodium tungstate
Retro-peptides
O
O
AA OR
AA OR
R''
1. Introduction
O
O
O
O
O
O
1. H-AA-OR
2. H-AA'-OR'
Peptides possess a broad spectrum of biological roles. The
pharmacological properties of most peptides preclude their use as
drugs. During the last 20 years peptidomimetics have aroused in-
terest as compounds able to resolve applicative problems related to
low bioavailability and short biological half-life of natural peptides.
Most peptidomimetics1 have been used as enzyme inhibitors
especially proteases, which are involved in numerous important
physiological processes including protein turnover, digestion, blood
coagulation and wound healing, fertilization, cell differentiation and
growth, cell signaling, the immune response, and apoptosis.2 These
peptidomimetics present a functional group, usuallyan electrophilic
moiety, which reacts with a nucleophilic amino acid within the ac-
tive site of the enzyme.3 Screenings of electrophilic building blocks
have revealed thatthe activityof the small heterocyclic ringhas been
enhanced when they are linked to appropriate amino acids, sub-
strate analogue peptides or peptidomimetics.4 Therefore, peptidyl
epoxides were found to be stable under various conditions, in-
cluding in human serum.5
AA' OR'
1
AA' OR'
2
rAA-mΔ2AA''-AA'
rAA-mGly-AA'
Scheme 1.
non-symmetric malonyl peptides (rAA-mGly-AA0)7,8 and different
aldehydes (Scheme 1).
Carrying on our studies in this field, the synthesis of more com-
plex peptidomimetics characterized bya retro-peptide modification
and an oxirane ring was considered starting from the reported
MDHPs by epoxidation reaction of the alkene.
2. Results and discussion
Inspired by our results on the epoxidation of the alkylidene and
arylidene cyano acetates carrying L-a-amino ester residues by using
m-CPBA and K2CO3,9 the symmetric N,N0-Boc protected malonyl
dehydrodipeptide 2a was chosen to test the epoxidation reaction
conditions (Scheme 2).
Recently we have reported an efficient method for the con-
struction of short dehydro malonyl peptides (MDHPs) rAA-
O
O
O
O
m
D2AA00-AA’ 26 by a Knoevenagel condensation reaction between
O
O
O
O
t-Bu
N
H
N
H
t-Bu
t-Bu
N
H
N
H
t-Bu
O
O
O
O
O
* Corresponding authors. Tel.: þ39 0649913673 (L.P.); fax: þ39 06490631; e-mail
addresses: stefania.fioravanti@uniroma1.it (S. Fioravanti), lucio.pellacani@uni-
roma1.it (L. Pellacani).
2a
3a
Scheme 2.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.097

9402
S. Fioravanti et al. / Tetrahedron 66 (2010) 9401e9404
O
H
O
O
Surprisingly, the dehydro malonyl peptide did not react with
O
O
m-CPBA and K2CO3 and 2a was quantitatively recovered. There-
fore, the epoxidation was attempted using different reaction
conditions.
t-Bu
N
H
N
H
t-Bu
O
O
O
O
First, hydrogen peroxide was considered and different solvents,
organic or inorganic bases, and reaction temperatures were tested
as reported in Table 1. The reaction was performed in the presence
of 1 M solution of NaOH,10 but 1H NMR spectroscopy and ES Q-TOF
MS analyses on the crude mixtures showed a complex mixture of
different compounds (entry 2).
3c
major
yield 75%, dr >95:5
Fig. 1.
spectroscopy analysis. In fact, the epoxide proton of the major
isomer presents a coupling constant (J¼7.7 Hz) higher than that of
the minor isomer (J¼4.7 Hz) and compatible with that reported in
the literature for the anti isomer of similar epoxides.14
Table 1
Optimization of epoxidation reaction conditions
The selective ring opening reactions15 of the 1,3-dioxolane ring,
followed by oxidation of the primary alcohol, can provide a new
Entry
Oxidant
Base
Solvent
T (ꢀC)
Time
Yield (%)
1
2
3
4
5
6
m-CPBA
H2O2
H2O2
H2O2
H2O2
H2O2
K2CO3
NaOH
DABCO
K2CO3
K2CO3
CH2Cl2
MeOH
CH3CN
EtOH
EtOH
EtOH
25
25
25
45
45
78
24 h
17 h
15 d
6 h
15 d
6 h
d
d
35
23
30
98
scaffold carrying an a-hydroxy moiety for the construction of more
complex compounds with potential pharmacological activity.
To mimic the nucleophilic attack of the thiolate group within the
cysteine proteases on oxiranes as recently suggested by molecular
mechanics and semiempirical quantum mechanic studies,16 N-Boc
Na2WO4$2H2O
L
-cysteine methyl ester was treated with NaH in dry THF and then
The use of DABCO gave the expected epoxy peptide 3a in un-
satisfactory yields and long times (15 d). Also the reaction performed
using potassium carbonate and/or heating the mixture for a long time
gave poor yields. Finally, an equivalent of Na2WO4 dihydrate11 gave
theexpected epoxypeptide 3a inhighyield(98%), after 6 h at refluxin
EtOH.12
3a was added to the solution.17 After 4 h, 1H NMR spectroscopy and
ES Q-TOF MS analyses performed on the crude mixture, confirmed
the expected diastereomeric mixture 4a (Scheme 4), suggesting the
effective potential cysteine protease inhibitor activity also for the
epoxy malonyl peptides here reported.
Using the optimal conditions, the epoxidation reactions were
performed on symmetric malonyl dehydro peptides 2aec and on
non-symmetric analogous compounds 2dei (Scheme 3), after
separation of E and Z isomers13 by flash chromatography on silica
gel. The results are reported in Table 2.
O
O
SH
OH
O
O
O
O
O
t-Bu
N
H
N
H
t-Bu
Boc
O
N
H
O
O
O
O
t-Bu
N
H
N
H
t-Bu
O
S
H
N
O
O
NaH, THF, 4 h, r.t.
Boc
O
O
3a
4a (78%)
R'''
O
O
R'''
O
O
Scheme 4.
O
O
O
O
.
R'
N
H
N
H
R'' Na2WO4 2H2O
R'
N
H
N
H
R''
O
R
O
O
O
O
Moreover, these compounds can be regarded as new intriguing
H2O2, EtOH
R
MDPHs
3a-i
building blocks for the construction of more complex bioorganic
molecules or as ideal substrates to obtain peptidomimetics carrying
different heterocyclic rings (Scheme 5). Thus, the reaction of 3a
with sodium azide followed by reduction with triphenylphosphine
led to the analogous aziridino retro-peptide 5a.18
2a-c R'''= H
(E)-2d-f R'''= Bn
(Z)-2g-i R'''= Bn
Scheme 3.
Table 2
Epoxidation of malonyl dehydro peptides
Entry MDPH
R
R0
R00
Epoxide Yield (%)
dr
1
2
3
2a
2b
2c
i-Bu
Ph
t-Bu t-Bu 3a
t-Bu t-Bu 3b
98
95
79
d
d
(R)-2,2-Dimethyl-1, t-Bu t-Bu 3c
>19:1
Scheme 5.
3-dioxolan-4-yl
4
5
6
7
8
9
(E)-2d i-Bu
(E)-2e Ph
(E)-2f Ph
(Z)-2g i-Bu
(Z)-2h Ph
(Z)-2i Ph
Me
Me
Me
Me
Me
Me
Me
Me
t-Bu 3f
Me
Me
t-Bu 3i
3d
3e
97
83
72
87
94
83
1.8:1
1.3:1
1.5:1
1.7:1
1.2:1
1.4:1
3. Conclusion
In conclusion, starting from short malonyl dehydro peptides
(MDPHs), new peptidomimetics characterized by a retro-peptide
modification and an oxirane ring have been obtained. The func-
tionalization of the double bond leads to the synthesis of more
complex molecules by an epoxidation reaction performed with
Na2WO4 dihydrate. The diastereomeric epoxides, that can be sep-
arated by HPLC, have been demonstrated to be reactive substances
toward L-cysteine, suggesting their possible activities as inhibitors
of cysteine proteases. Finally, aziridino malonyl peptides can be
synthesized by a simple two-step reaction from epoxy analogues.
3g
3h
In all cases the expected epoxides 3 were obtained in good
yields and the diastereomeric ratios were determined on the crude
mixtures by HPLC-RI analyses. A moderate diastereoselectivity was
observed, except for 3c (entry 3). Nevertheless, we underline that,
at this stage of the research, it is important to access each of the
new diastereomeric epoxides 3dei, considering the possible dif-
ferent biological behavior between stereoisomers. In fact, it is well-
known that the potency and selectivity of enzyme inhibitors can be
affected by the conformation of inhibitors. For compounds 3dei,
separation conditions by HPLC using an analytical column have
been found for each diastereomeric couple.
4. Experimental section
4.1. General
Regarding 3c (Fig.1), the R configuration of the new chiral center
IR spectra were recorded on a PerkineElmer 1600 FTIR spectro-
of the major isomer obtained can be assigned by 1H NMR
photometer in CHCl3 as the solvent. 1H NMR spectra were recorded at

S. Fioravanti et al. / Tetrahedron 66 (2010) 9401e9404
9403
Varian Gemini 200 and Varian XL-300 MHz and 13C NMR spectra at 50
and 75 MHz. The NOESY experiments were performed at Bruker
300 MHz. 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. HPLC analyses were performed with an instrument
Varian 9002 equipped with a Varian 9050 RI-4 differential re-
fractometer, or a Varian 9050 UV/Vis detector using an analytical col-
umn (3.9ꢁ300 mm, flow rate 1.3 mL/min). Eluents were mixtures of
HPLC grade hexane and ethyl acetate. NaH (55e65% suspension in
mineral oil) was washed twice with pentane and dried under nitrogen.
3.75 (s, 3H), 4.00e4.13 (m, 2H), 4.75e4.88 (m, 1H), 7.08e7.16 (m, 5H),
7.68e7.86 (m, 2H, 2NH); dC 22.2, 22.5, 26.2, 35.4, 37.8, 41.0, 52.4, 53.2,
59.9, 61.5, 64.4,127.1,128.6 (2),129.2 (2),135.6,165.4,166.0,169.2,171.0.
4.2.5. Methyl (2S)-2-{[(2R,3R)(2S,3S)-(2-{[(2-methoxy-2-oxoethyl)
amino]carbonyl}-3-phenyloxiran-2-yl)carbonyl]amino}-3-phenyl-
propanoate (3e). Yield: 0.183 g, 83%; deep yellow oil; nmax: 3413,
3331, 1743, 1672, 1645 cmꢂ1
. HRMS (ES Q-TOF) calcd for
C23H24N2NaO7 (MþNa)þ: 463.1481; found: 463.1477. Major: dH
2.92e3.31 (m, 2H), 3.76 (s, 6H), 4.06e4.17 (m, 2H), 4.39 (s, 1H),
4.82e4.98 (m, 1H), 7.25e7.47 (m, 10H), 7.88e8.03 (m, 2H, 2NH); dC
29.7, 41.1, 52.4, 53.5 (2), 61.5, 64.4, 126.8 (2), 127.2, 128.3 (2), 128.6,
128.9 (2), 129.3 (2), 131.4, 135.7, 163.9 (2), 165.0 (2). Minor: dH
2.92e3.31 (m, 2H), 3.75 (s, 6H), 4.19e4.26 (m, 2H), 4.45 (s, 1H),
4.82e4.98 (m, 1H), 7.12e7.23 (m, 10H), 7.88e8.03 (m, 2H, 2NH); dC
29.7, 41.1, 52.4, 53.4 (2), 61.6, 64.3, 126.7 (2), 127.3, 128.2 (2), 128.6,
128.7 (2), 129.3 (2), 131.3, 135.8, 163.8 (2), 165.1 (2).
4.2. Synthesis of epoxy malonyl peptides (3aei). General
procedure
A round-bottom flask was charged with a solution of a malonyl
dehydro peptide 2aei (0.5 mmol) in 1 mL of EtOH and sodium
tungstate dihydrate (0.5 mmol) and 0.40 mL of 40% hydrogen per-
oxide. The reaction mixture was warmed at 70e80 ꢀC and followed
by 1H NMR spectroscopy analysis. After 6 h the disappearance of
the vinyl proton signal was observed. After removal of the solvent,
10 mL of diethyl ether was added and the crude mixture was
washed with water (2ꢁ10 mL) and dried over MgSO4 to give the
epoxide.
4.2.6. Methyl (2S)-2-{[(2R,3R)(2S,3S)-(2-{[(2-tert-butoxy-2-oxoethyl)
amino]carbonyl}-3-phenyloxiran-2-yl)carbonyl]amino}-3-phenyl-
propanoate (3f). Yield: 0.173 g, 72%; deep yellow oil; nmax: 3402,
3326, 1738, 1694 cmꢂ1. HRMS (ES Q-TOF) calcd for C26H30N2NaO7
(MþNa)þ: 505.1951; found: 505.1949. Major: dH 1.49 (s, 9H), 2.93 (d,
J¼6.0 Hz, 2H), 3.58 (s, 3H), 3.96e4.03 (m, 2H), 4.39 (s, 1H), 4.83e4.94
(m, 1H), 6.87e6.93 (m, 5H), 7.29e7.37 (m, 5H), 7.83e7.90 (m, 1H,
1NH), 8.17e8.23 (m, 1H, 1NH); dC 29.2 (3), 38.3, 41.3, 53.1, 54.7, 61.3,
64.5, 82.5, 126.8 (2), 127.2, 128.3 (2), 128.5, 128.7 (2), 129.2 (2), 131.3,
135.7, 163.9 (2), 165.0 (2). Minor: dH 1.49 (s, 9H), 2.93 (d, J¼6.0 Hz,
2H), 3.53 (s, 3H), 3.96e4.03 (m, 2H), 4.45 (s, 1H), 4.83e4.94 (m, 1H),
6.78e6.84 (m, 5H), 7.16e7.25 (m, 5H), 7.48e7.56 (m, 1H, 1NH),
8.26e8.31 (m, 1H, 1NH); dC 29.5 (3), 37.6, 41.5, 53.1, 54.8, 61.5, 64.4,
82.6, 126.7 (2), 127.3, 128.2 (2), 128.5, 128.8 (2), 129.3 (2), 131.4, 135.6,
163.8 (2), 165.1 (2).
4.2.1. Di-tert-butyl 2,20-[(3-isobutyloxirane-2,2-diyl)bis(carbonylimino)]
diacetate (3a). Yield: 0.203 g, 98%; light yellow oil; nmax: 3401, 3318,
1736, 1689 cmꢂ1
. HRMS (ESI Q-TOF) calcd for C20H34N2NaO7
(MþNa)þ: 437.2264; found: 437.2273; dH 0.95 (d, J¼6.6 Hz, 3H), 0.99
(d, J¼6.6 Hz, 3H), 1.47 (s, 18H), 1.57e1.64 (m, 2H), 1.75e1.92 (m, 1H),
3.32 (t, J¼6.1 Hz, 1H), 3.81e4.16 (m, 4H), 7.63e7.69 (m, 1H, NH),
7.94e8.00 (m, 1H, NH); dC 22.2, 22.5, 26.3, 28.0 (6), 35.5, 41.9, 42.0,
59.9, 64.2, 82.3, 82.4, 165.5, 166.2, 167.8, 168.0.
4.2.2. Di-tert-butyl 2,20-[(3-phenyloxirane-2,2-diyl)bis(carbonylimino)]
4.2.7. Methyl (2S)-2-({[(2R,3S)(2S,3R)-3-isobutyl-2-{[(2-methoxy-2-
oxoethyl)amino]carbonyl}oxiran-2-yl]carbonyl}amino)-3-phenyl-
propanoate (3g). Yield: 0.183 g, 87%; yellow oil; nmax: 3401, 3330,
1731,1695 cmꢂ1. HRMS (ES Q-TOF) calcd for C21H28N2NaO7 (MþNa)þ:
443.1794; found: 443.1798. Major: dH 0.88 (d, J¼6.4 Hz, 3H), 0.92 (d,
J¼6.4 Hz, 3H), 1.22e1.32 (m, 2H), 1.63e1.84 (m, 1H), 2.94e3.31 (m,
3H), 3.72 (s, 6H), 4.02 (d, J¼5.5 Hz, 2H), 4.78e4.93 (m, 1H), 7.22e7.34
(m, 5H), 7.86e8.03(m, 2H, 2NH); dC 23.4 (2), 23.7, 32.6, 38.3, 42.1, 54.6,
58.7 (2), 63.2, 66.3,128.5,129.1 (2),129.9 (2),136.3,167.7,169.4,170.6,
171.5. Minor: dH 0.86 (d, J¼6.4 Hz, 3H), 0.95 (d, J¼6.4 Hz, 3H),
1.22e1.32 (m, 2H), 1.53e1.61 (m, 1H), 2.94e3.31 (m, 3H), 3.72 (s, 6H),
4.05 (d, J¼5.5 Hz, 2H), 4.76e4.91 (m,1H), 7.11e7.19 (m, 5H), 7.86e8.03
(m, 2H, 2NH); dC 23.4 (2), 23.7, 32.5, 38.2, 41.9, 54.2, 58.6(2), 63.4, 66.3,
128.3, 129.0 (2), 129.9 (2), 136.2, 167.5, 169.4, 170.4, 171.5.
diacetate (3b). Yield: 0.206 g, 95%; deep yellow oil; nmax: 3401, 3330,
1730, 1689 cmꢂ1
. HRMS (ESI Q-TOF) calcd for C22H30N2NaO7
(MþNa)þ: 457.1951; found: 457.1948; dH 1.42 (s, 9H), 1.48 (s, 9H),
3.52e4.14 (m, 4H), 4.44 (s, 1H), 7.29e7.42 (m, 5H), 8.17e8.22 (m, 2H,
2NH); dC 27.9 (3), 28.0 (3), 41.7, 42.2, 62.1, 64.2, 82.5 (2), 126.7 (2),
128.2 (2), 128.8, 131.5, 164.2, 165.1, 167.6, 168.0.
4.2.3. Di-tert-butyl 2,20-{[(3S)-3-((4R)-2,2-dimethyl-1,3-dioxolan-4-
yl)oxirane-2,2-diyl]bis(carbonylimino)}diacetate (3c). Yield: 0.182 g,
79%; deep yellow oil; nmax: 3404, 3324,1735,1687 cmꢂ1. HRMS (ES Q-
TOF) calcd for C21H34N2NaO9 (MþNa)þ: 481.2162; found: 481.2159.
Major:dH 1.43 (s, 6H),1.47 (s,18H), 3.41 (d, J¼7.7 Hz,1H),3.60e3.67(m,
2H), 3.88e4.01 (m, 4H), 4.02e4.17 (m, 1H), 7.75e7.82 (m, 1H, 1NH),
8.05e8.11 (m, 1H, 1NH); dC 25.9 (2), 29.4 (3), 29.5 (3), 41.3, 41.7, 62.5,
66.3, 70.8, 72.0, 81.9, 82.0, 113.4, 168.7, 169.3, 175.8, 176.5. Minor: dH
1.43 (s, 6H), 1.47 (s, 18H), 3.34 (d, J¼4.7 Hz, 1H), 3.60e3.67 (m, 2H),
3.78e3.85 (m, 4H), 4.19e4.34 (m, 1H), 7.61e7.67 (m, 1H, 1NH),
7.75e7.82 (m, 1H, 1NH); dC 26.4 (2), 28.6 (3), 29.4 (3), 41.2, 41.8, 62.6,
66.3, 70.8, 72.1, 81.9, 82.2, 113.9, 169.2, 169.5, 175.5, 176.2.
4.2.8. Methyl (2S)-2-{[(2R,3S)(2S,3R)-(2-{[(2-methoxy-2-oxoethyl)
amino]carbonyl}-3-phenyloxiran-2-yl)carbonyl]amino}-3-phenyl-
propanoate (3h). Yield: 0.207 g, 94%; deep yellow oil; nmax: 3396,
3328, 1742, 1696 cmꢂ1. HRMS (ES Q-TOF) calcd for C23H24N2NaO7
(MþNa)þ: 463.1481; found: 463.1484. Major: dH 2.93 (d, J¼6.0 Hz, 2H),
3.54 (s, 6H), 4.17e4.29 (m, 2H), 4.39 (s, 1H), 4.81e4.96 (m, 1H),
6.87e6.96 (m, 5H), 7.24e7.40 (m, 5H), 7.88e7.99 (m, 1H, 1NH),
8.20e8.28 (m,1H,1NH); dC 38.0, 41.5, 53.4 (2), 53.6, 61.6, 66.8,126.9 (2),
128.3,128.6 (2),129.0,129.2 (4),131.6,136.7,170.8 (2),176.0 (2). Minor:
dH 2.93 (d, J¼6.0 Hz, 2H), 3.59 (s, 6H), 4.06e4.14 (m, 2H), 5.08e5.20 (m,
1H), 6.78e6.85 (m, 5H), 7.15e7.23 (m, 5H), 7.46e7.57 (m, 1H, 1NH),
8.29e8.36 (m,1H,1NH); dC 38.2, 41.6, 53.3 (2), 53.6, 61.6, 66.8,126.8 (2),
128.4, 128.5 (2), 129.0, 129.3 (4), 131.7, 136.7, 171.6 (2), 176.3 (2).
4.2.4. Methyl (2S)-2-({[(2R,3R)(2S,3S)-3-isobutyl-2-{[(2-methoxy-2-
oxoethyl)amino]carbonyl}oxiran-2-yl]carbonyl}amino)-3-phenyl-
propanoate (3d). Yield: 0.204 g, 97%; yellow oil; nmax: 3405, 3328,
1736, 1695 cmꢂ1. HRMS (ES Q-TOF) calcd for C21H28N2NaO7 (MþNa)þ:
443.1794; found: 443.1801. Major: dH 0.91 (d, J¼6.7 Hz, 6H), 1.50e1.63
(m, 2H), 1.67e1.88 (m, 1H), 2.94e3.27 (m, 2H), 3.14e3.20 (m, 1H), 3.72
(s, 3H), 3.73 (s, 3H), 4.14e4.27 (m, 2H), 4.75e4.88 (m, 1H), 7.23e7.29
(m, 5H), 7.68e7.86 (m, 2H, 2NH); dC 22.2, 22.5, 26.3, 35.4, 37.9, 41.2,
52.4, 53.4, 59.9, 61.5, 64.4, 127.2, 128.6 (2), 129.2 (2), 135.7, 165.2, 166.0,
168.8, 171.2. Minor: dH 0.96 (d, J¼6.7 Hz, 6H), 1.50e1.63 (m, 2H),
1.67e1.88 (m, 1H), 2.94e3.27 (m, 2H), 3.03e3.10 (m, 1H), 3.73 (s, 3H),
4.2.9. Methyl (2S)-2-{[(2R,3S)(2S,3R)-(2-{[(2-tert-butoxy-2-oxoethyl)
amino]carbonyl}-3-phenyloxiran-2-yl)carbonyl]amino}-3-phenyl-
propanoate (3i). Yield: 0.200 g, 83%; deepyellow oil; nmax: 3402, 3326,

9404
S. Fioravanti et al. / Tetrahedron 66 (2010) 9401e9404
1738,1694 cmꢂ1. HRMS (ES Q-TOF) calcd for C26H30N2NaO7 (MþNa)þ:
505.1951; found: 505.1947. Major: dH 1.42 (s, 9H), 2.92e3.30 (m, 2H),
3.74 (s, 3H), 4.13e4.26 (m, 2H), 4.39 (s, 1H), 4.83e4.97 (m, 1H),
6.86e6.94 (m, 5H), 7.24e7.48 (m, 5H), 7.93e8.08 (m, 2H, 2NH); dC 28.0
(3), 38.0, 41.8, 52.4, 53.5, 61.6, 64.2, 82.5, 126.8 (2), 128.2, 128.6 (2),
128.9, 129.3 (4), 131.4, 135.6, 163.8, 164.9, 170.7, 171.2. Minor: dH 1.41 (s,
9H), 2.92e3.30 (m, 2H), 3.75 (s, 3H), 4.13e4.26 (m, 2H), 4.45 (s, 1H),
5.31e5.38(m,1H), 6.78e6.85 (m, 5H), 7.12e7.22(m,5H),7.93e8.08 (m,
2H, 2NH); dC 29.7 (3), 38.0, 41.8, 52.5, 53.5, 61.6, 64.3, 82.5, 126.7 (2),
128.2, 128.6 (2), 128.7, 129.3 (4), 131.4, 135.7, 163.7, 165.0, 170.6, 171.1.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.09.097.
References and notes
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€
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4.2.10. tert-Butyl [(2-{[(2-tert-butoxy-2-oxoethyl)amino]carbonyl}-
2-hydroxy-(R,S)-3-({2-[tert-butoxycarbonylamino]-3-methoxy-3-ox-
opropyl}thio)-5-methylhexanoyl)amino]acetate (4a). Yield: 0.269 g,
83%; deep yellow oil; nmax: 3402, 3326, 1738, 1694 cmꢂ1. HRMS (ES Q-
TOF) calcd for C29H51N3NaO11S (MþNa)þ: 672.3142; found: 672.3138.
Major: dH 0.84e0.92 (m, 6H), 1.43 (s, 18H), 1.45 (s, 9H), 1.63e1.75 (m,
2H),1.81e1.95(m,1H), 2.25(br,1H,1OH), 2.90e3.00 (m,1H), 3.26e3.37
(m, 2H), 3.75 (s, 3H), 3.88e3.96 (m, 4H), 5.68e5.83 (m, 1H), 7.67e7.81
(m, 3H, 3NH); dC 23.6 (2), 24.7, 27.8 (3), 28.1 (6), 29.5, 30.1, 42.1, 42.2 (2),
52.4, 53.3, 80.0, 82.2 (two), 125.3, 154.9, 167.4, 167.8, 169.5, 170.3, 171.2.
Minor: dH 0.84e0.92 (m, 6H), 1.44 (s, 18H), 1.46 (s, 9H), 1.63e1.75 (m,
2H),1.81e1.95 (m,1H), 2.25 (br,1H,1 OH), 2.90e3.00 (m,1H), 3.47e3.62
(m, 2H), 3.75 (s, 3H), 3.97e4.04 (m, 4H), 5.68e5.83 (m, 1H), 7.67e7.81
(m, 3H, 3NH); dC 23.6 (2), 24.7, 27.8 (3), 28.1 (6), 29.5, 30.1, 42.0, 42.2 (2),
52.4, 53.3, 79.7, 82.2 (2), 125.3, 155.1, 167.4, 167.9, 169.6, 170.5, 171.1.
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4.2.11. Di-tert-butyl 2,20-[(3-isobutylaziridine-2,2-diyl)bis(carbon-
ylimino)]diacetate (5a). Yield: 0.144 g, 70%; yellow oil; nmax: 3443,
3400, 1740, 1697 cmꢂ1. HRMS (ES Q-TOF) calcd for C20H35N3NaO6
(MþNa)þ: 436.2424; found: 436.2421; dH 0.85e0.94 (m, 6H), 1.40
(s, 18H), 1.54 (dd, J¼5.8 Hz, J¼7.4 Hz, 2H), 1.72e1.81 (m, 1H),
2.57e2.82 (m, 1H), 3.24e3.29 (m, 1H), 3.89 (dd, J¼5.5, 18.3 Hz, 4H),
7.90e7.94 (m,1H, 2NH); dC 22.2 (2), 22.4, 27.9 (6), 41.6, 41.8 (2), 53.3,
64.1, 81.6 (2), 165.3, 166.0, 167.7, 167.9.
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18. These compounds could not be obtained by direct amination of malonyl
dehydropeptides with a nosyloxycarbamate (NsONHCO2R, Ns¼C6H4SO2) in
the presence of a base, according to aziridination procedure reported by us
Acknowledgements
for different
a-amino acidic-substituted cyano olefins: Fioravanti, S.; Mas-
ꢀ
Italian MIUR and Universita degli Studi di Roma ‘La Sapienza’ are
sari, D.; Morreale, A.; Pellacani, L.; Tardella, P. A. Tetrahedron 2008, 64,
3204e3211.
gratefully acknowledged for financial support (PRIN 2007FJC4SF_005).