A two-step synthesis of the bioprotective agent JP4-039 from N-Boc-l-leucinal

Article abstract of DOI:10.1016/j.tet.2013.10.059

An expedited synthesis of the bioprotective agent JP4-039 is described from N-Boc-l-leucinal in 50% overall yield. The synthesis involves the use of an α,unsaturated diazoketone as the key intermediate, followed by a photochemical Wolff rearrangement in t

Full text of DOI:10.1016/j.tet.2013.10.059

Tetrahedron 70 (2014) 3291e3296
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A two-step synthesis of the bioprotective agent JP4-039 from N-Boc-
L
-leucinal
*
Barbara Bernardim, Antonio C.B. Burtoloso
~
~
~
Instituto de Química de Sao Carlos, Universidade de Sao Paulo, Sao Carlos, SP CEP 13560-970, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedited synthesis of the bioprotective agent JP4-039 is described from N-Boc-L-leucinal in 50%
Received 15 September 2013
Received in revised form 17 October 2013
Accepted 21 October 2013
overall yield. The synthesis involves the use of an a,b-unsaturated diazoketone as the key intermediate,
followed by a photochemical Wolff rearrangement in the presence of 4-amino-TEMPO (4-AT).
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 25 October 2013
Keywords:
Bioprotective agents
L-Leucine
Unsaturated diazoketones
Wolff rearrangement
Diazophosphonates
1. Introduction
reactive oxygen species, such as superoxide and nitric oxide.5 For
example, when compared to control irradiated cells, JP4-039 en-
X-rays have been used for a long time in the diagnosis of illness
and as a treatment for it, especially in the case of cancer.1 One of the
utilities of radiation is the well-known radiotherapy, which works
by damaging the DNA of cancerous cells, leading to their death.
Although normal cells can also be damaged (to a lesser extent) after
exposure to this ionizing irradiation, microenvironment is known
to modulate repair of them under conditions that inhibit cell di-
vision. A major mechanism in cell death during radiotherapy in-
volves the formation of reactive oxygen species (ROS) in
mitochondria after ionizing irradiation.2 Thus, molecules that are
effective in scavenge these ROS and able to concentrate at the mi-
tochondria, can be of extremely importance as radiation protectors
and mitigators.3,4 The lead compound JP4-039 (Fig. 1), inspired by
the antibiotic gramicidin S, is a mitochondria-target nitroxide that
has been proven to be of extremely effectiveness at scavenging
hanced cell repair and increased clonogenic cell survival by an or-
der of 5e13 times.6,7
JP4-039 is also considered an isostere of the leucine-glycine
peptide.8 Considering the well-known characteristic of peptides
in being easily hydrolyzed in vivo by peptidases, E-alkene isosteres
(containing an allylic amine fragment) come as interesting mimics
to be used in chemical-biology.8 Regarding the preparation of JP4-
039, only one synthesis is described in the literature.9 The research
group of Peter Wipf has been involved for some years with the
synthesis of many nitroxides of biological importance, including
JP4-039 itself.2,3,5e14 Their approach involves a beautiful one-pot
hydrozirconation-transmetalationeaddition to a chiral sulfina-
mide as the key reaction and furnishes JP4-039 in six steps from
a chiral sulfinamide (Scheme 1).
O
S
NH2.HCl OTBDPS
4 steps
H
N
JP4-039
N
t-Bu
2 steps
Scheme 1. Synthesis of JP4-039 by Wipf.
NHBoc
O
N
O
JP4-039
2. Results and discussion
Fig. 1. Structure of JP4-039.
In the last few years, our research group have been involved
with the uncommon chemistry of -unsaturated diazo-
ketones.15e18 Possessing a diazo group, a ketone function and
a,b
* Corresponding author. Tel.: þ55 16 3373 8641; fax: þ55 16 3373 9952; e-mail
addresses: antonio@iqsc.usp.br, aburtoloso@gmail.com (A.C.B. Burtoloso).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.059

3292
B. Bernardim, A.C.B. Burtoloso / Tetrahedron 70 (2014) 3291e3296
a double bond all together in a single molecule,
a
,
b
-unsaturated
We next submitted these diazoketones to the photochemical
Wolff rearrangement in the presence of different amines as nu-
cleophiles, such as primary, secondary, and aromatic ones. Al-
though there are plenty of examples of both the thermal and
photochemical Wolff rearrangements from saturated diazoketones
using amines as nucleophiles,23e27 no example is found from the
diazoketones constitute versatile building blocks in synthesis and
could already be applied in the straightforward preparation of
several nitrogen-heterocycles. One of their utilities is the ability of
generating b,g-unsaturated esters in the presence of alcohols, via
the well-known Wolff rearrangement.16 Considering that, we
wondered if we could also apply these interesting platforms in the
a,b-unsaturated ones. In fact, we were inquisitive about the be-
direct synthesis of
that -unsaturated amides are generally prepared from the cor-
responding -unsaturated carboxylic acids, which are not readily
available or easy to prepare when compared the -unsaturated
ones. Moreover, as mentioned above, the addition of an amino
group in the position of these amides can led to alkene peptide
b
,
g
-unsaturated amides. It is interesting to note
havior of such diazoketones, especially chiral diazoketone 3, in the
presence of these bases due to the presence of an acidic proton in
b
,g
b
,
g
their
diazoketone 4 and 1 equiv of benzylamine with an Osram 150
Xenon arc lamp for 20 min at 25 ꢀC, furnished
-unsaturated
g position. Positively, irradiation of an acetonitrile solution of
a,b
b,g
d
amide 5 in 98% yield with no need of purification (Scheme 4). A
similar result was obtained when chiral diazoketone 3 was treated
with aniline. For this specific case, as depicted in Fig. 2, no epi-
merization is observed during the formation of diazoketone 3 and
the Wolff rearrangement.
isosteres, mimics that do not undergo the undesirable pharmaco-
kinetic properties generally observed in real peptides. Herein, we
would like to demonstrate how
(easily prepared from aldehydes) are interesting platforms to pre-
pare these important -unsaturated amides, as well as how
a,b-unsaturated diazoketones
b,g
a single-step synthesis of the bioprotective agent JP4-039 could be
achieved from these building blocks (Scheme 2).
MeCN, hν,
O
N2
20 min, 25 o
BnNH2
C
N
N
H
N
Cbz
Cbz
4
5 98%
O
O
P
O
Wolff rearrangement
MeCN, hν,
EtO
O
O
O
H
N
EtO
20 min, 25 o
C
O
R2NH, hν
N2
R
R
NR2
PhNH2
R
N2
HN
HN
O
70%
N2
α,β-unsatured diazoketones
aldehydes
Boc
Boc
3
6
β,γ-unsaturated amides
Scheme 4. Synthesis of
and 4.
b,g-unsaturated amides from a,b-unsaturated diazoketones 3
O
peptide isosteres
R2N
NR2
H
N
2 steps
O
NHBoc
N-Boc-L-leucinal
NHBoc
JP4-039
O
N
O
Scheme 2. Synthesis of b,g-unsaturated amides from a,b-unsaturated diazoketones.
We started our work by preparing four structurally different
unsaturated diazoketones, in order to evaluate the Wolff rear-
rangement in the presence of amines. Employing our recently de-
scribed olefination methodology,15 diazoketones 1e4 were
prepared in 64e92%. These four examples represent unsaturated
diazoketones containing aliphatic, aryl, acyclic-amino, and cyclic-
amino groups, respectively (Scheme 3). Unlike butyraldehyde and
benzaldehyde, the amino-aldehydes employed in this study are not
commercially available and were easily prepared from the N-pro-
tected amino-acid after borane19 reduction and Swern20,21 or Par-
ikheDoering oxidation.19,22 In the case of diazoketone 3, chiral
HPLC studies showed that no epimerization occurred during the
HornereWadswortheEmmons olefination.
O
P
O
NaH, THF, 0 oC, 5 min.
O
Fig. 2. Chiral HPLC studies. A: racemic compound; B: chiral compound derived from N-
Boc-L-leucinal.
Then, RCHO
-78 to -30 oC
EtO
R
EtO
N2
N2
O
O
O
N2
After this preliminary study, and to show the scope of this
transformation, diazoketones 1e4 were irradiated in the presence
of benzylamine, aniline, p-methoxy aniline, diallylamine, and cy-
N
N2
83% (> 99% ee)
NHBoc
Cbz
N2
1
N2
64%
2
80%
O
3
4
92%
clohexylamine to give
b,g-unsaturated amides 7e21 in
yields varying from 50 to 98% (Fig. 3). Unlike the photochemical
Scheme 3. Synthesis of structurally different
a,b-unsaturated diazoketones from
aldehydes.
reactions involving diazoketones 1, 3, and 4, reactions employing

B. Bernardim, A.C.B. Burtoloso / Tetrahedron 70 (2014) 3291e3296
3293
unsaturated diazoketone 2 were accompanied by some isomeri-
zation of the double bond to the Z isomer.
This method overcomes a drawback in the synthesis of these types
of amides, which are generally prepared after several steps.
4. Experimental
H
N
Ph
NH
4.1. General methods
Ph
Bn
7
N
O
O
O
NH
12
83%
Cbz
Ph
Ph
76%
All solvents were dried and distilled prior to use by standard
procedures. Reagents were purchased at the highest commercial
quality and used without further purification, unless otherwise
stated. Reactions were monitored by thin-layer chromatography
(TLC), carried out on 0.25 mm silica gel plates using UV light as
visualizing agent and potassium permanganate in aqueous KOH for
staining. Column chromatography was performed using silica gel
60 (particle size 0.063e0.210 mm). Unless stated otherwise, all of
the yields refer to isolated products after flash column chroma-
tography. The solvent mixtures employed in TLC analysis and in
flash column chromatography purifications are reported as volume
by volume and in percentages. Proton nuclear magnetic resonance
(1H NMR) spectra were recorded using 400 or 500 MHz equipment.
17
O
N
66%
H
N
HN
8
90%
N
O
13
98%
Cbz
O
18
63%
H
N
N
O
NH
Ph
19
O
9
N
O
O
14
OMe
50%
Cbz
95%
98%
Ph
NH
For 1H NMR spectra, chemical shifts (
d) are referenced from TMS
Ph
NH
N
15
(0.00 ppm). Coupling constants (J) are reported in hertz. For mul-
tiplicities the following abbreviations were used: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet; bs;
broad singlet; dt, double triplet. Carbon nuclear magnetic reso-
nance (13C NMR) spectra were recorded using an NMR spectrom-
NHBoc
O
64%
O
20
96%
10
93%
Bn
NH
H
H
N
N
Ph
OMe
Bn
16
11
21
O
NHBoc
70%
O
O
50%
64%
eter at 100 or 125 MHz. For 13C NMR spectra, chemical shifts (
d) are
given from CDCl3 (77.0 ppm) or MeOH (49.0 ppm). Photochemical
reactions were carried out using UV light generated by an Osram
150 Xenon lamp accommodated in an Oriel Model 8500 Universal
arc lamp source with focusing quartz lens, a water-filled infrared
filter, and a thermostated cell holder. Infrared spectra were ob-
tained using FT-IR at 4.0 cmꢁ1 resolution and are reported in
wavenumbers. High resolution mass spectra (HRMS) were recorded
using electron spray ionization (ESI) (hybrid linear ion trapeorbi-
trap FT-MS and QqTOF/MSeMicrotof-QII model).
Fig. 3. Two-step synthesis of several b,g-unsaturated amides from aldehydes.
Finally, to show the applicability of the present method, diazo-
ketone 3 was converted to the bioprotective agent JP4-039 in 65%
yield after irradiation in the presence of 4-amino-TEMPO. All the
spectroscopic data are in complete accordance with those reported
by Wipf.9 To accomplish that, commercially available N-Boc-
L-leu-
cine was first reduced in the presence of borane dimethyl sulfide
complex,28 followed by oxidation with SO3$Py.19,22 Olefination of
known leucinal 22 with the sodium anion of a diazophosphonate at
ꢁ78 to ꢁ40 ꢀC gave diazoketone 3 in 83% yield (>99% ee). Next,
photochemical Wolff rearrangement with commercially available
4-amino-TEMPO furnished JP4-039 in 65% yield (Scheme 5).
4.2. General procedure for HornereWadswortheEmmons
reaction
4.2.1. (E)-1-Diazohept-3-en-2-one (1). To a suspension of NaH (60%
in mineral oil) (80.0 mg, 2.00 mmol, 2.2 equiv) in dry THF (6.0 mL),
under argon atmosphere and at 0 ꢀC, was added a 0.15 M solution of
diethyl 3-diazo-2-oxopropylphosphonate (400 mg, 1.8 mmol,
2.0 equiv) in dry THF. After that, the mixture was stirred for 5 min at
this temperature, the system was cooled to ꢁ78 ꢀC and then a 0.1 M
solution of butyraldehyde (65.5 mg, 0.91 mmol, 1.0 equiv) in dry
THF was added dropwise. After 1 h, the temperature was allowed to
rise naturally to ꢁ30 ꢀC, when a saturated aqueous NH4Cl solution
(25 mL) was added to the reaction vessel. Next, the aqueous layer
was extracted with dichloromethane (3ꢂ20 mL), and the combined
organic layers were dried over Na2SO4, filtered, and evaporated in
rotary evaporator. Purification by flash column chromatography
(30% EtOAc/hexanes) afforded diazoketone 1 (82.0 mg, 0.59 mmol,
O-Na+
P
O
1) BH3.SMe2,
EtO
EtO
O
O
THF, 25 oC, 12h;
N2
OH
NHBoc
-78 to -40 o
C
2) Parikh-Doering
oxidation;
22 NHBoc
66% after 2 steps
O
H
N
,
MeCN hν,
15 min, r.t
NHBoc
O
JP4-039
N
NHBoc
N2
H2N
N
O
65%
3 83% (>99% ee)
64%) as a stable yellow oil: 1H NMR (400 MHz, CDCl3)
d 6.80 (dt,
O
[α]D23 +35.3 (c 0.1, CH2Cl2);
lit: +35.6 (c 0.5, CH2Cl2);
J¼15.4, 7.0 Hz, 1H), 5.98 (d, J¼15.5 Hz, 1H), 5.29 (s, 1H), 2.17 (dq,
J¼7.2, 1.5 Hz, 2H), 1.48 (sxt, J¼7.4 Hz, 2H), 0.93 (t, J¼7.4 Hz, 3H); 13
C
Scheme 5. A two-step synthesis of JP4-039 from N-Boc-L-leucinal.
NMR (100 MHz, CDCl3) d 185.0,145.3,127.5, 55.1, 34.4, 21.5,13.8; FT-
IR (neat, cmꢁ1): 2962, 2933, 2100,1656,1606,1367, 975; HRMS (ESI)
calcd for C7H10N2NaO [MþNa]þ 161.0685, found 161.0686; Rf 0.30
(20% EtOAc/hexanes).
3. Conclusion
As a conclusion, we have demonstrated that
diazoketones are interestingbuilding blocks for the directsynthesis of
-unsaturated amides. When employed unsaturated diazoketones
derived from amino-aldehydes, peptide isoesters are prepared as was
illustrated during the short synthesis of the lead nitroxide JP4-039.
a,b-unsaturated
4.2.2. (E)-1-Diazo-4-phenylbut-3-en-2-one (2). 80% yield as a yel-
b,g
low solid. 1H NMR (500 MHz, CDCl3)
d
7.59 (d, J¼15.8 Hz, 1H),
7.55e7.52 (m, 2H), 7.40e7.36 (m, 3H), 6.60 (d, J¼15.8 Hz, 1H), 5.44
(s, 1H); 13C NMR (100 MHz, CDCl3)
184.2, 140.7, 134.4, 130.3, 128.9,
d

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B. Bernardim, A.C.B. Burtoloso / Tetrahedron 70 (2014) 3291e3296
128.2, 123.6, 56.2; FT-IR (neat, cmꢁ1): 3070, 2098, 1636, 1584, 1450,
1373, 1149, 973, 759; HRMS (ESI) calcd for C10H8N2NaO [MþNa]þ
195.05288, found 195.0628; mp 58e62 ꢀC; Rf 0.30 (25% EtOAc/
hexanes).
CDCl3) d 5.64e5.56 (m, 1H), 5.54e5.45 (m, 1H), 3.79e3.69 (m, 1H),
2.90 (dd, J¼7.0, 0.8 Hz, 2H), 2.03 (q, J¼7.5 Hz, 2H),1.92e1.84 (m, 2H),
1.71e1.63 (m, 2H), 1.59 (dq, J¼7.4, 3.6 Hz, 1H), 1.45e1.30 (m, 4H),
1.20e1.05 (m, 3H), 0.90 (t, J¼7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
170.3,136.3,123.0, 48.0, 40.7, 34.6, 33.1, 25.5, 24.8, 22.3,13.6; FT-IR
4.2.3. (S,E)-tert-Butyl(8-diazo-2-methyl-7-oxooct-5-en-4-yl) carba-
mate (3). 83% yield as a yellow solid. N-Boc-L-leucinal was freshly
(neat, cmꢁ1): 3296, 3070, 2956, 2929, 2854, 1637, 1546, 1446, 1409,
1247, 1078, 970, 891; mp 57e63 ꢀC; HRMS (ESI) calcd for C13H24NO
[MþH]þ 210.1852, found 210.1859; Rf 0.15 (20% EtOAc/hexanes).
prepared from N-Boc-L-leucinol by ParikheDoering oxidation. In
this specific case, the HWE reaction was finished at ꢁ40 ꢀC to avoid
23
the epimerization. [
a
]
ꢁ34.1 (c 0.66, CHCl3); 1H NMR (500 MHz,
4.3.4. (E)-N,N-Diallylhept-3-enamide (10). No purification was
D
CDCl3)
d
6.66 (dd, J¼15.3, 5.8 Hz,1H), 6.06 (d, J¼15.3 Hz,1H), 5.32 (s,
necessary, 93% yield as colorless oil: 1H NMR (500 MHz, CDCl3)
1H), 4.45 (s, 1H), 4.30 (s, 1H), 1.74e1.55 (m, 2H), 1.43 (s, 9H), 1.38 (t,
d 5.80e5.70 (m, 2H), 5.61e5.48 (m, 2H), 5.23e5.08 (m, 4H), 3.97 (d,
J¼7.1 Hz, 1H), 0.92 (d, J¼6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3)
J¼6.0 Hz, 2H), 3.87 (dt, J¼4.8, 1.6 Hz, 2H), 3.07 (dd, J¼6.1,1.0 Hz, 2H),
d
184.4, 155.2,144.7, 126.2, 79.9, 55.9, 50.1, 44.1, 31.1, 29.8, 28.5, 24.9,
2.04e1.98 (q, J¼7.0 Hz, 2H),1.38 (sxt, J¼7.4 Hz, 2H), 0.88 (t, J¼7.4 Hz,
22.8, 22.4; FT-IR (neat, cmꢁ1): 3365, 3105, 2968, 2929, 2914, 2100,
1680, 1660, 1614, 1521, 1367,1330, 1284,1238, 1172,1157,1105, 1004,
760; HRMS (ESI) calcd for C14H23N3NaO3 [MþNa]þ 304.16316,
found 304.1646; mp 94e96 ꢀC; Rf 0.38 (30% EtOAc/hexanes); Chiral
HPLC studies were performed in a CHIRALPAKÒ AD-H column
3H); 13C NMR (125 MHz, CDCl3)
d 171.6, 133.8, 133.3, 133.0, 123.1,
117.2, 116.7, 49.2, 47.8, 37.5, 34.6, 22.3, 13.6; FT-IR (neat, cmꢁ1):
3082, 2958, 2927, 2872, 1653, 1463, 1411, 1284, 1249, 1217, 1193,
1136, 1116, 993, 968, 921; HRMS (ESI) calcd for C13H21NNaO
[MþNa]þ 230.1515, found 230.1519; Rf 0.30 (20% EtOAc/hexanes).
(particle size: 5
isopropanol), 1.5 mL/min,
m
m; dimensions: 4.6 mmꢂ250 mm), 98:2 (hexane/
l
254 nm.
4.3.5. (E)-N-(4-Methoxyphenyl)hept-3-enamide (11). Purification
by flash column chromatography (30% EtOAc/hexanes), 50% yield as
4.2.4. (E)-Benzyl-2-(4-diazo-3-oxobut-1-en-1-yl)piperidine-1-
a white solid: 1H NMR (500 MHz, CDCl3)
d
7.39 (d, J¼9.0 Hz, 2H),
carboxylate (4). 92% yield as a yellow oil. 1H NMR (400 MHz, CDCl3)
7.27 (s, 1H), 6.85 (d, J¼9.0 Hz, 2H), 5.77e5.58 (m, 2H), 3.78 (s, 3H),
3.09 (dd, J¼7.0, 0.7 Hz, 2H), 2.09 (q, J¼7.1 Hz, 2H),1.45 (sxt, J¼7.4 Hz,
d
7.47e7.30 (m, 5H), 6.78 (dd, J¼15.6, 4.3 Hz, 1H), 5.91 (d, J¼14.9 Hz,
1H), 5.25 (s, 1H), 5.16 (d, J¼12.3 Hz, 1H), 5.12 (d, J¼12.4 Hz, 1H), 5.03
(s, 1H), 4.07 (d, J¼12.8 Hz, 1H), 2.88 (t, J¼11.4 Hz, 1H), 1.89e1.60 (m,
2H), 0.94 (t, J¼7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 169.2, 156.4,
137.3, 130.9, 122.6, 121.6, 114.1, 55.5, 41.4, 34.64, 22.3, 13.7; FT-IR
(neat, cmꢁ1): 3311, 2954, 2926, 1654, 1600, 1541, 1514, 1465, 1409,
1247, 1172, 1029, 964, 825; HRMS (ESI) calcd for C14H19NNaO2
[MþNa]þ, 256.13082 found 256.13080; mp 71e77 ꢀC; Rf 0.45 (30%
EtOAc/hexanes).
4H), 1.52e1.36 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 183.8, 155.6,
142.8, 136.6, 128.5, 128.3, 128.0, 127.9, 67.3, 56.0, 52.0, 40.4, 29.1, 25.2,
19.7; FT-IR (neat, cmꢁ1) 3076, 3029, 2933, 2852, 2100, 1693, 1654,
1606, 1415, 1359, 1170; HRMS (ESI) calcd for C17H19N3NaO3 [MþNa]þ
336.13186, found 336.13092; Rf 0.33 (50% EtOAc/hexanes).
4.3.6. (E)-Benzyl
dine-1-carboxylate (5). No purification was necessary, 98% yield as
a colorless oil: 1H NMR (500 MHz, CDCl3)
7.40e7.19 (m, 10H), 5.95
2-(4-(benzylamino)-4-oxobut-1-en-1-yl)piperi-
4.3. General procedure for Wolff rearrangement
d
4.3.1. (E)-N-Phenylhept-3-enamide (7). To a solution of diazoketone
1 (29.7 mg, 0.215 mmol) in acetonitrile (10 mL) was added aniline
(20 mL, 1.0 equiv) in a 1 cm optical path quartz cell. The solution was
irradiated with an Osram 150 Xenon arc lamp for 20 min under
magnetic stirring at room temperature (nitrogen gas evolution
observed). Next, the solvent was evaporated in rotary evaporator.
Purification by flash column chromatography (30% EtOAc/hexanes)
afforded amide 7 as a white solid (33.2 mg, 0.163 mmol, 76%): 1H
(s, 1H), 5.66e5.57 (m, 2H), 5.09e5.02 (m, 2H), 4.84 (s, 1H), 4.40 (d,
J¼5.7 Hz, 2H), 3.99 (d, J¼13.1 Hz, 1H), 3.06e2.98 (m, 2H), 2.86 (t,
J¼12.0 Hz, 1H), 1.76e1.65 (m, 2H), 1.63e1.52 (m, 2H), 1.50e1.36 (m,
2H); 13C NMR (100 MHz, CDCl3)
d 170.4, 155.7, 138.1, 136.8, 133.7,
128.7, 128.4, 127.9, 127.7, 127.7, 127.5, 124.4, 67.0, 52.2, 43.6, 40.3,
40.1, 29.0, 25.3, 19.4; FT-IR (neat, cmꢁ1): 3510, 3307, 3064, 3032,
2937, 2858, 1693, 1654, 1540, 1423, 1263, 1170, 1091, 1029, 972, 916,
744, 698; HRMS (ESI) calcd for C24H28N2NaO3 [MþNa]þ 415.1992,
found 415.1990; Rf 0.28 (50% EtOAc/hexanes).
NMR (500 MHz, CDCl3)
d
7.50 (d, J¼7.7 Hz, 2H), 7.39 (t, J¼7.0 Hz,
3H), 7.10 (t, J¼7.4 Hz, 1H), 5.78e5.70 (m, 1H), 5.67e5.58 (m, 1H),
3.11 (d, J¼7.0 Hz, 2H), 2.10 (q, J¼6.9 Hz, 2H), 1.46 (sxt, J¼7.4 Hz, 2H),
0.94 (t, J¼7.4 Hz, 3H); FT-IR (neat, cmꢁ1): 3300, 3197, 3138, 3026,
2958, 2927, 1658, 1600, 1546, 1498, 1442, 1327, 1251, 1176, 1112,
4.3.7. (E)-Benzyl
dine-1-carboxylate (12). No purification was necessary, 83% yield as
a pale yellow oil: 1H NMR (400 MHz, CDCl3)
2-(4-oxo-4-(phenylamino)but-1-en-1-yl)piperi-
d
7.52 (d, J¼7.9 Hz, 2H),
1080, 1031, 970, 754, 692; 13C NMR (125 MHz, CDCl3)
d
169.4, 137.8,
7.37e7.27 (m, 8H), 7.10 (t, J¼7.9 Hz, 1H), 5.79e5.62 (m, 2H), 5.13 (d,
J¼4.3 Hz, 2H), 4.89e4.83 (m, 1H), 4.03 (d, J¼11.8 Hz, 1H), 3.15 (d,
J¼6.5 Hz, 2H), 2.99 (t, J¼11.8 Hz, 1H), 1.82e1.72 (m, 2H), 1.69e1.61
137.4, 129.0, 124.3, 122.5, 119.6, 41.7, 34.6, 22.3, 13.7; mp 33e35 ꢀC;
HRMS (ESI) calcd for C13H17NNaO [MþNa]þ 226.1202, found
226.1202; Rf 0.42 (30% EtOAc/hexanes).
(m, 2H), 1.54e1.40 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 168.8,
155.9, 137.8, 136.7, 134.7, 128.9, 128.5, 128.0, 127.8, 124.3, 124.0,
119.7, 67.1, 52.7, 41.2, 29.7, 29.1, 25.2, 19.5; FT-IR (neat, cmꢁ1): 3506,
3311, 3062, 3034, 2926, 2854, 1693, 1674, 1600, 1544, 1498, 1442,
1425, 1344, 1261, 1172, 1091, 1029, 972, 906, 756, 696; HRMS (ESI)
calcd for C23H27N2O3 [MþH]þ 379.2016, found 379.2022; Rf 0.38
(50% EtOAc/hexanes).
4.3.2. (E)-N-Benzylhept-3-enamide (8). No purification was neces-
sary, 90% yield as a white solid: 1H NMR (400 MHz, CDCl3)
d
7.37e7.23 (m, 5H), 5.95 (s, 1H), 5.67e5.48 (m, 2H), 4.43 (d,
J¼5.8 Hz, 2H), 2.99 (d, J¼7.4 Hz, 2H), 2.05 (q, J¼7.4 Hz, 2H), 1.38 (sxt,
J¼7.4 Hz, 2H), 0.87 (t, J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
171.4, 138.4, 136.7, 128.8, 127.8, 127.6, 122.7, 43.7, 40.7, 34.7, 22.4,
13.7; FT-IR (neat, cmꢁ1): 3294, 3084, 3064, 3032, 2956, 2926, 2872,
1639, 1546, 1454, 1415, 1369, 1238, 1080, 1028, 964, 694; mp
38e41 ꢀC; HRMS (ESI) calcd for C14H20NNaO [MþNa]þ 240.1359,
found 240.1360; Rf 0.13 (20% EtOAc/hexanes).
4.3.8. (E)-Benzyl 2-(4-(cyclohexylamino)-4-oxobut-1-en-1-yl)piperi-
dine-1-carboxylate (13). No purification was necessary, 98% yield as
a pale yellow oil: 1H NMR (500 MHz, CDCl3)
d 7.38e7.27 (m, 5H),
5.65e5.54 (m, 2H), 5.48 (s, 1H), 5.13 (s, 2H), 4.88e4.83 (m, 1H), 4.03
(d, J¼13.0 Hz, 1H), 3.78e3.68 (m, 1H), 2.94 (d, J¼5.8 Hz, 2H),
1.91e1.82 (m, 2H), 1.79e1.55 (m, 8H), 1.55e1.29 (m, 4H), 1.20e1.01
4.3.3. (E)-N-Cyclohexylhept-3-enamide (9). No purification was
necessary, 95% yield as a pale yellow solid: 1H NMR (500 MHz,
(m, 3H); 13C NMR (125 MHz, CDCl3)
d 169.6, 155.7, 136.8, 133.5,

B. Bernardim, A.C.B. Burtoloso / Tetrahedron 70 (2014) 3291e3296
3295
128.4, 127.9, 127.7, 124.8, 67.0, 52.2, 48.1, 40.3, 33.0, 32.9, 29.1, 25.5,
25.3, 24.8, 19.4; FT-IR (neat, cmꢁ1): 3305, 3064, 3034, 2933, 2854,
1699, 1651, 1543, 1448, 1423, 1352, 1336, 1261, 1170, 1091, 1041, 974,
734, 698; HRMS (ESI) calcd for C23H33N2O3 [MþH]þ 385.2485,
found 385.2483; Rf 0.28 (50% EtOAc/hexanes).
126.2, 123.4, 117.4, 116.8, 49.3, 48.0, 37.7; FT-IR (neat, cmꢁ1): 3082,
3059, 3024, 2980, 2954, 2926, 2854, 1654, 1463, 1448, 1413, 1217,
1193, 1132, 991, 966, 925, 742, 694; HRMS (ESI) calcd for C16H20NO
[MþH]þ 242.1539, found 242.1551; Rf 0.38 (30% EtOAc/hexanes).
4.3.14. (E)-N-(4-Methoxyphenyl)-4-phenylbut-3-enamide
(19). Purification by flash column chromatography (30% EtOAc/
hexanes), 50% yield as a white solid: 1H NMR (500 MHz, CDCl3)
4.3.9. (E)-Benzyl 2-(4-(diallylamino)-4-oxobut-1-en-1-yl)piperidine-
1-carboxylate (14). No purification was necessary, 98% yield as
a colorless oil: 1H NMR (400 MHz, CDCl3)
d
7.37e7.27 (m, 5H),
d
7.43e7.38 (m, 4H), 7.34 (t, J¼7.5 Hz, 2H), 7.30e7.26 (m, 2H),
5.82e5.63 (m, 3H), 5.56e5.47 (m, 1H), 5.24e5.08 (m, 6H), 4.89 (s,
1H), 4.08e3.95 (m, 3H), 3.87e3.82 (m, 2H), 3.11 (d, J¼6.5 Hz, 2H),
2.92 (td, J¼13.0, 2.4 Hz, 1H), 1.82e1.34 (m, 6H); 13C NMR (100 MHz,
6.87e6.83 (m, 2H), 6.65e6.60 (m, 1H), 6.38 (dt, J¼15.8, 7.3 Hz, 1H),
3.78 (s, 3H), 3.31 (dd, J¼7.3, 1.2 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d
168.6, 156.5, 136.4, 135.3, 130.7, 127.9, 126.4, 121.9, 121.9, 116.4,
CDCl3)
d
171.2, 155.8, 137.1, 133.3, 132.9, 131.5, 128.6, 128.0, 127.9,
114.0, 55.4, 41.7; FT-IR (neat, cmꢁ1): 3288, 3197, 3140, 3082, 2931,
1654, 1606, 1558, 1512, 1411, 1298, 1247, 1170, 1033, 964, 829; HRMS
(ESI) calcd for C17H17NNaO2 [MþNa]þ 290.11515, found 290.11545;
mp 128e131 ꢀC; Rf 0.38 (30% EtOAc/hexanes).
125.3, 117.4, 116.9, 67.1, 52.2, 49.4, 48.0, 40.3, 37.3, 29.1, 25.7, 19.6;
FT-IR (neat, cmꢁ1): 3032, 2937, 2860, 1697, 1651, 1498, 1419, 1352,
1261, 1170, 1091, 1041, 993, 972, 923, 765, 744, 698; HRMS (ESI)
calcd for C23H31N2O3 [MþH]þ 383.2329, found 383.2336; Rf 0.38
(50% EtOAc/hexanes).
4.3.15. (S,E)-tert-Butyl (2-methyl-8-oxo-8-(phenylamino)oct-5-en-
4-yl)carbamate (6). Purification by flash column chromatography
4.3.10. (E)-N,4-Diphenylbut-3-enamide (15). 94% (EþZ); After pu-
rification by flash column chromatography (30% EtOAc/hexanes),
pure 15 was obtained in 64% yield as a white solid: 1H NMR
(30% EtOAc/hexanes), 70% yield as a colorless oil: [
a
]
23 þ18.8 (c 0.1,
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.09 (s, 1H), 7.67 (d, J¼7.6 Hz,
2H), 7.35e7.27 (m, 2H), 7.08 (t, J¼7.4 Hz,1H), 5.79 (dt, J¼15.0, 7.5 Hz,
1H), 5.56 (dd, J¼15.4, 7.0 Hz, 1H), 4.56 (s, 1H), 4.15e4.01 (m, 1H),
3.15 (d, J¼7.4 Hz, 2H), 1.69 (sep, J¼6.7 Hz, 1H), 1.48e1.34 (m, 11H),
(500 MHz, CDCl3)
d
7.51 (d, J¼7.8 Hz, 2H), 7.41 (d, J¼7.4 Hz, 3H),
7.38e7.27 (m, 5H), 7.12 (q, J¼7.5 Hz, 1H), 6.63 (d, J¼15.9 Hz, 1H),
6.38 (dt, J¼15.7, 7.3 Hz, 1H), 3.33 (dd, J¼7.3, 0.8 Hz, 2H); 13C NMR
0.94 (dd, J¼6.6, 1.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 169.2,
(125 MHz, CDCl3)
d
168.8, 137.6, 136.4, 135.4, 129.0, 128.8, 128.0,
155.6, 138.2, 129.0, 128.8, 124.1, 123.1, 120.1, 79.6, 51.7, 40.9, 28.41,
28.3, 24.6, 22.5; FT-IR (neat, cmꢁ1): 3319, 2956, 2929, 2870, 1670,
1697, 1600, 1541, 1498, 1442, 1367, 1311, 1249, 1249, 1172, 1026, 972,
750; HRMS (ESI) calcd for C20H31N2O3 [MþH]þ 347.23292, found
347.23260; Rf 0.43 (30% EtOAc/hexanes); Chiral HPLC studies were
126.4, 124.5, 121.8, 119.9, 41.9; FT-IR (neat, cmꢁ1): 3290, 3261, 3197,
3140, 3082, 3057, 3026, 2953, 2922, 2850, 1660, 1647, 1598, 1550,
1496, 1442, 1330, 1307, 1249, 966, 754, 690; mp 87e91 ꢀC; HRMS
(ESI) calcd for C16H15NNaO [MþNa]þ 260.1046, found 260.1052; Rf
0.42 (30% EtOAc/hexanes).
performed in a CHIRALPAKÒ AD-H column (particle size: 5
m
m;
dimensions: 4.6 mmꢂ250 mm), 95:5 (hexane/isopropanol), 1.5 mL/
min, 254 nm.
4.3.11. (E)-N-Benzyl-4-phenylbut-3-enamide (16). 95% (EþZ); After
purification by flash column chromatography (30% EtOAc/hexanes),
pure 16 was obtained in 64% yield as a white solid: 1H NMR
l
4.3.16. (S,E)-tert-Butyl (8-diazo-2-methyl-7-oxooct-5-en-4-yl) car-
(500 MHz, CDCl3)
d
7.39e7.22 (m, 10H), 6.54 (d, J¼15.8 Hz, 1H), 6.31
bamate (20). Purification by flash column chromatography (30%
(dt, J¼15.8, 7.3 Hz, 1H), 5.96 (s, 1H), 4.46 (d, J¼5.8 Hz, 2H), 3.21 (dd,
EtOAc/hexanes), 96% yield as a pale oil: [
NMR (400 MHz, CDCl3)
a
]
20 þ11.4 (c 0.1, CH3Cl); 1H
D
J¼7.3, 1.2 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d
170.5, 138.1, 136.5,
d
5.93 (s, 1H), 5.72e5.59 (m, 1H), 5.44 (ddt,
134.8, 128.7, 128.6, 127.8, 127.8, 127.5, 126.3, 122.2, 43.7, 40.8; FT-IR
(neat, cmꢁ1): 3238, 3055, 3035, 2954, 2922, 2875, 2850, 1633, 1548,
1411,1238, 981, 968, 756, 698; mp 125e129 ꢀC; HRMS (ESI) calcd for
J¼15.4, 6.8, 1.1 Hz, 1H), 4.47 (s, 1H), 4.07e3.98 (m, 1H), 3.73 (dddd,
J¼14.8, 11.0, 8.1, 4.0 Hz, 1H), 2.93 (d, J¼7.4 Hz, 2H), 1.91e1.82 (m,
2H), 1.74e1.55 (m, 4H), 1.43 (s, 9H), 1.40e1.26 (m, 4H), 1.21e1.05 (m,
C
17H18NO [MþH]þ 252.1383, found 252.1391; Rf 0.23 (30% EtOAc/
3H), 0.91 (dd, J¼6.6, 2.1 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 169.8,
hexanes).
155.3, 136.9, 123.5, 79.3, 51.7, 48.3, 44.0, 40.0, 33.0, 32.9, 29.7, 28.4,
25.5, 24.9, 24.9, 24.6, 22.5; FT-IR (neat, cmꢁ1): 3329, 3300, 2949,
2954, 2856, 1683, 1635, 1541, 1365, 1251, 1178, 972; HRMS (ESI)
calcd for C20H37N2O3 [MþH]þ 353.2798, found 353.2720; Rf 0.25
(30% EtOAc/hexanes).
4.3.12. (E)-N-Cyclohexyl-4-phenylbut-3-enamide (17). 94% (EþZ);
After purification by flash column chromatography (30% EtOAc/
hexanes), pure 17 was obtained in 66% yield as a white solid: 1H
NMR (400 MHz, CDCl3)
d 7.41e7.36 (m, 2H), 7.35e7.30 (m, 2H),
7.28e7.22 (m, 1H), 6.53 (d, J¼15.9 Hz, 1H), 6.29 (dt, J¼15.8, 7.3 Hz,
1H), 5.47 (s, 1H), 3.83e3.73 (m, 1H), 3.13 (dd, J¼7.3, 1.3 Hz, 2H),
1.95e1.86 (m, 2H), 1.73e1.64 (m, 2H), 1.61 (ddd, J¼12.9, 6.2, 3.6 Hz,
1H), 1.43e1.30 (m, 2H), 1.19e1.04 (m, 3H); 13C NMR (100 MHz,
4.3.17. (S,E)-tert-Butyl (8-diazo-2-methyl-7-oxooct-5-en-4-yl) car-
bamate (21). Purification by flash column chromatography (30%
20
EtOAc/hexanes), 70% yield as a colorless oil: [
a
]
D
þ17.3 (c 0.1,
CH3Cl); 1H NMR (500 MHz, CDCl3)
d
7.33e7.21 (m, 5H), 6.66 (s, 1H),
CDCl3)
d
169.6, 136.7, 134.5, 128.6, 127.7, 126.3, 122.7, 77.3, 77.0, 76.7,
5.74e5.67 (m, 1H), 5.45 (dd, J¼15.4, 7.0 Hz, 1H), 4.52e4.34 (m, 3H),
48.3, 41.1, 33.1, 25.5, 24.8; FT-IR (neat, cmꢁ1): 3286, 3062, 3030,
2931, 2852, 1635, 1546, 1446, 1346, 1247, 960, 891, 690; mp
89e96 ꢀC; HRMS (ESI) calcd for C16H21NNaO [MþNa]þ 266.1515,
found 266.1515; Rf 0.33 (30% EtOAc/hexanes).
4.01 (q, J¼7.2 Hz, 1H), 3.02 (d, J¼7.4 Hz, 2H), 1.62 (dq, J¼13.5, 6.7 Hz,
1H), 1.35 (s, 9H), 1.34e1.28 (m, 2H), 0.89 (dd, J¼6.6, 5.1 Hz, 6H); 13
C
NMR (125 MHz, CDCl3) d 170.8,155.4,138.5,137.1,128.5,127.6,127.2,
123.8, 79.4, 51.4, 43.8, 43.5, 39.9, 28.3, 24.6, 22.4; FT-IR (neat, cmꢁ1):
3342, 3032, 2981, 2954, 2929, 1678, 1637, 1525, 1367, 1294, 1170,
975; HRMS (ESI) calcd for C21H32N2NaO3 [MþNa]þ 383.2305, found
383.2302; Rf 0.30 (30% EtOAc/hexanes).
4.3.13. (E)-N,N-Diallyl-4-phenylbut-3-enamide (18). 77% (EþZ); Af-
ter purification by flash column chromatography (30% EtOAc/hex-
anes), pure 18 was obtained in 63% yield as a colorless oil: 1H NMR
(400 MHz, CDCl3)
d
7.39e7.34 (m, 2H), 7.33e7.27 (m, 2H), 7.24e7.19
4.3.18. (S,E)-N-(2,2,6,6-Tetramethyl-1-oxo-piperidin-4-yl)-5-(tert-
(m, 1H), 6.46 (d, J¼16.1 Hz, 1H), 6.38 (dt, J¼16.0, 6.3 Hz, 1H),
5.85e5.73 (m, 2H), 5.27e5.11 (m, 4H), 4.01 (d, J¼6.0 Hz, 2H), 3.93
(dt, J¼4.7, 1.6 Hz, 2H), 3.30 (dd, J¼6.3, 0.9 Hz, 2H); 13C NMR
butoxycarbonylamino)-7-methyloct-3-enamide. Purification
by
flash column chromatography (60% EtOAc/hexanes), 65% yield as
a peach colored solid: mp 51e60 ꢀC; [
a]
23 þ35.3 (c 0.1, CH2Cl2); FT-
D
(125 MHz, CDCl3)
d
171.0, 137.0, 133.2, 132.9, 132.6, 128.5, 127.4,
IR (neat, cmꢁ1): 3321, 2972, 2956, 2931, 2870, 1685, 1670, 1645,

3296
B. Bernardim, A.C.B. Burtoloso / Tetrahedron 70 (2014) 3291e3296
2. Hoye, A. T.; Davoren, J. E.; Wipf, P.; Fink, M. P.; Kagan, V. E. Acc. Chem. Res. 2008,
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1525, 1458, 1390, 1317, 1300, 1244, 1175, 1043, 972; HRMS (ESI)
calcd for C23H42N3NaO4 [MþNa]þ 447.3068, found 447.3071; Rf 0.28
(60% EtOAc/hexanes). For NMR analysis, a sample of this nitroxide
Chem. 2007, 5, 307e309.
4. Balaban, R. S.; Nemoto, S.; Finkel, T. Cell 2005, 120, 483e495.
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J. S.; Wipf, P. Org. Biomol. Chem. 2013, 11, 4147e4153.
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Wipf, P. Org. Lett. 2011, 13, 2318e2321.
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(20.0 mg, 0.047 mmol) was dissolved in dry MeOH (0.5 mL) and L-
ascorbic acid (8.3 mg, 0.047 mmol) was added. Complete discol-
oration of the solution occurred within a few seconds. After stirring
at room temperature for 10 min, the solvent was removed in vacuo.
The resulting residue was dissolved in EtOAc and washed with
water. The aqueous phase was extracted twice with EtOAc, and the
combined organic layers were dried (Na2SO4), filtered, and con-
centrated in vacuo to yield 16.1 mg (80%) of the corresponding
hydroxylamine9 as a white foam (23): 1H NMR (500 MHz, CD3OD)
d
6.60 (s, 1H), 5.69e5.61 (m, 1H), 5.50 (dd, J¼15.3, 6.0 Hz, 1H),
4.16e3.95 (m, 2H), 2.88 (d, J¼6.9 Hz, 2H), 1.72 (dt, J¼15.9, 7.9 Hz,
2H), 1.66e1.54 (m, 1H), 1.43 (s, 9H), 1.43e1.26 (m, 4H), 1.17 (s, 6H),
1.15 (s, 6H), 0.91 (d, J¼5.7 Hz, 6H); 13C NMR (125 MHz, CD3OD)
d
173.3,157.9,136.6,124.3, 79.9, 59.9, 51.7, 45.9, 45.2, 42.2, 40.7, 32.7,
28.8, 25.9, 23.1, 22.6, 20.3.
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Kagan, V. E.; Wang, H.; Greenberger, J. S. Int. J. Radiat. Oncol. 2011, 80,
860e868.
Acknowledgements
We would like to thank FAPESP (Research Supporting Founda-
tion of the State of Sao Paulo) for financial support (2012/04685-5)
and a fellowship to B.B. (2012/22274-2). We also thank CNPq for
a research fellowship to A.C.B.B. (307905/2009-8), IQSC-USP for
facilities and HRMS acquisitions (FAPESP 2009/54040-8). The au-
thors are also grateful for structural support offered by the Uni-
14. Wipf, P.; Xiao, J.; Jiang, J.; Belikova, N. A.; Tyurin, V. A.; Fink, M. P.; Kagan, V. E. J.
Am. Chem. Soc. 2005, 127, 12460e12461.
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17. Bernardim, B.; Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2012, 77, 9926e9931.
18. Bernardim, B.; Lordello, L.; Burtoloso, A. C. B. Curr. Top. Med. Chem. 2013, 13,
2099e2103.
~
versity of Sao Paulo through the NAP-CatSinQ (Research Core in
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9e24.
Catalysis and Chemical Synthesis).
20. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651e1660.
21. Minato, D.; Nagasue, Y.; Demizu, Y.; Onomura, O. Angew. Chem., Int. Ed. 2008, 47,
9458e9461.
Supplementary data
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.10.059.
References and notes
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