Synthesis of enantiomerically pure nitronyl nitroxide radicals through chiral pool

Article abstract of DOI:10.2174/157017812801264692

Two pairs of new optically active nitronyl nitroxides derived from N-Boc-D- or L- prolinol are described. The synthetic route consist of (1) the synthesis of chiral aryl aldehydes by Mitsunobu reaction, (2) the condensation of the 2,3-bis(hydroxylamino)-2

Full text of DOI:10.2174/157017812801264692

314
Letters in Organic Chemistry, 2012, 9, 314-319
Synthesis of Enantiomerically Pure Nitronyl Nitroxide Radicals Through
Chiral Pool
Xiang-Yang Qina, Yue Mab, Qiao-Feng Wanga, Chao Wangb, Xiao-Li Sun and
Peng Liu*,a
aDepartment of Chemistry, School of Pharmacy, Fourth Military Medical University, Xi’an, Shanxi 710032, P. R. China
bDepartment of Chemistry, Nankai University, Tianjin 300071, P. R. China
Received November 26, 2011: Revised March 12, 2012: Accepted March 12, 2012
Abstract: Two pairs of new optically active nitronyl nitroxides derived from N-Boc-D- or L- prolinol are described. The
synthetic route consist of (1) the synthesis of chiral aryl aldehydes by Mitsunobu reaction, (2) the condensation of the 2,3-
bis(hydroxylamino)-2,3-dimethylbutane with chiral aldehydes to give 1,3-dihydroxyimidazolidine, and (3) the final
oxidation of 1,3-dihydroxyimidazolidine with aqueous NaIO4 at 0 ˚C. These two pairs have been specifically designed for
further assessing the differences in activity of chiral nitronyl nitroxides and for developing chiral molecular magnetic
material by the metal-radical complexes approach.
Keywords: Chiral nitronyl nitroxides, N-Boc-D- or L- prolinol, chiral pool.
INTRODUCTION
benzoic acid components through treatment with diethyl
azodicarboxylate and triphenylphosphine under mild, neutral
conditions (Scheme 1). The results are shown in Table 1.
However, it was quite difficult to separate and purify
production. In order to purify the production, the side
In recent years, stable nitroxyl nitroxide radicals, with
membrane-permeable, low molecular weight, and mimic
metal-independent superoxide dismutase [1, 2], have been
used as biophysical tools for many years. A biologically
relevant effect of nitroxides includes their ability to protect
cardiomyocytes [3], to inhibit the formation of DNA strand
breaks [4], and to be employed as radioprotectors [5],
anticancer agents [6]. However differences in the activity of
chiral nitroxyl nitroxides have not been reported, as
biological molecules can discriminate between enantiomers.
There are only few examples of chiral nitroxides [7-11],
although chiral nitroxides are well chosen as potential
precursors of chiral molecule-based magnets. From these
perspectives, in this article we reported using N-Boc-D-or L-
prolinol as chiral pool to synthesize three pairs of chiral
nitronyl nitroxide radicals.
product
triphenylphosphine
oxide
and
diethyl
hydrazinedicarboxylate must be firstly precipitated by ether
after the reaction and then filtered. The filtrate was
evaporated in vacuum and the crude product was purified by
chromatography on silica. The experimental results show
that the yields decrease as steric hindrance increases and the
yields of esterification of carboxylic acids are less than those
of alkylation of phenols.
By condensation of the chiral aryl aldehydes described
above with 2,3-bis(hydroxylamino)-2,3-dimethylbutane in
methanol
solution
at
room
temperature,
1,3-
dihydroxyimidazolidines were slowly obtained as stable
white solids and then treated with aqueous NaIO4 to yield
stable blue nitronyl nitroxides (Scheme 2).
RESULTS AND DISCUSSION
In general, chiral nitronyl nitroxides can be achieved
either by [12] (i) the incorporation of asymmetric groups, (ii)
the isolation of atropoisomeric or conformational
enantiomers, or (iii) a combination of the two. Among these
three methods, to incorporate chirality with the use of
asymmetric groups is relatively simple. According to
Ullman’s pioneering work [13], any aldehydes may give rise
to a nitronyl nitroxide. So, chiral aldehydes should be
obtained firstly. By the Mitsunobu reaction [14],
intermolecular dehydration reactions occurred as N-
protected-L or D-prolinol was reacted with phenolic or
EPR Spectra of Monoradicals
Due to its sensitivity and accuracy, EPR spectroscopy is
the best tool for the study of free radical [13]. As shown in
Fig. (1), the EPR spectra of all nitronyl nitroxides in
dichlormethane show 5 major lines similar to each other in
the ratio 1∶2∶3∶2∶1, which is expected due to coupling with
two identical nitrogens (Fig. 1).
Optical Spectra
The electronic absorption of the nitronyl nitroxides is
identical to that of the tetramethylated analogues [13]. The
n→π* transitions of the radical moiety of the aryl nitronyl
nitroxides centered at about 600 nm, while the π→π*
transition occurs at 360 nm.
*Address correspondence to this author at the Department of Chemistry,
Fourth Military Medical University, Xi’an, Shanxi 710032, P. R. China;
Tel: +86 29 84774473-800; Fax: +86 29 84776945;
E-mail: pengliu@fmmu.edu.cn
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis of Enantiomerically Pure Nitronyl Nitroxide Radicals
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
315
R1
O
N
Boc
D or L
R1-OH
OH
PPh3/DEAD
THF, r.t.
+
O
N
R2-COOH
R2
Boc
O
C
D or L
N
CHO
Boc
D or L
CHO
CHO
R2 =
R1 =
or
O
Scheme 1. Synthesis of chiral aryl aldehydes.
Table 1. The Mitsunobu Reaction of N-protected-L or D-prolinol
Entry
Aromatic Aldehydes
Product
Time(h)
Yield(%)
Optical Rotation*
O
CHO
-66.5 c
N
1
CHO
13
84.8
HO
Boc
(L) 1a
O
CHO
N
2
3
HO
13
13
87.3
69.2
+66.4 d
CHO
Boc
(D) 1b
CHO
CHO
O
-67.2
N
HO
O
Boc
O
!L"2a
CHO
CHO
O
4
13
68.1
+67.2
N
HO
O
O
Boc
(D)2b
O
CHO
O
C
-54.6 e
+54.4 f
N
5
6
HOOC
CHO
13
13
62.3
63.5
Boc
(L) 3a
O
C
CHO
O
N
HOOC
CHO
Boc
(L) 3a
*[α]D20, (c=1.1,CH2Cl2).

316 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Qin et al.
OH
O
NHOH
N
R
H
N
NaIO4, 0 ˚C
CH2Cl2
CH3OH
r.t.
R
+
RCHO
N
N
O
NHOH
OH
3
1
2
Scheme 2. Synthesis of chiral nitronyl nitroxides.
Fig. (1). Typical ESR spectra of nitroxyls in dichloromethane.
The infrared spectra of the nitronyl nitroxides are
noteworthy in that the characteristic bands were observed at
1350-1375 cm-1, arising from N-O stretching frequency [15].
Bodenseewerk, Überlingen, Germany). High resolution mass
spectroscopy (HRMS) was carried out on a Varian 7.0T ESI-
FTICR-MS (Varian. U.S.A.) instument. IR was recorded on
a Bruker tensor 27 (Bruker Optics, German) instument.
Ultra-violet absorption spectra were recorded on a Jasco V-
570 UV/vis/NIR spectrophotometer (Jasco, Japan). The EPR
CONCLUSION
spectra were obtained using
spectrometer on solutions of radicals dissolved in
dichloromethane.
a
Bruker ESP 300E
In summary, a group of chiral nitronyl nitroxide radicals
were synthesized through a chiral pool. The isolated radicals
were quite stable and, in most cases, could be stored at room
temperature for months without decomposition. The
chemical structures of the radicals were characterised by
UV-Vis, IR, HMRS, and EPR. These chiral nitronyl
nitroxide radicals could be used as biophysical tools to
assess the differences in activity of chiral nitronyl nitroxides
and as new chiral ligands to synthesize metal-nitroxide
complexes with MchD effect. This method represents new
thinking for the synthesis of chiral nitronyl nitroxide
radicals, In other words, by modifying natural chiral
molecule into chiral pool, plenty of chiral nitronyl nitroxide
radicals could be easily obtained. The results are shown in
Table 2.
2, 3-bis (hydroxylamino)-2, 3-dimethylbutane was
prepared by a published method [16]. N-Boc-L or D-prolinol
was prepared in our laboratory. All other chemical reagents
were purchased from the Nanjing Tianzun Zezhong
Chemical Limited Company (Nanjing, China). THF was
distilled under N2 from Na/benzophenone and CH2Cl2 was
distilled from CaH2. The other chemical reagents were used
without further purification.
Synthesis of L or D-tert-butyl 2-((4-Formylphenoxy)
Methyl) Pyrrolidine-1-carboxylate [1a and 1b] (General
Procedure for Synthesis of Chiral Aromatic Aldehydes)
Triphenyl phosphine (1.55 g, 6 mmol), p-Hydroxy-
benzaldehyde (0.61 g, 5 mmol) and N-Boc- L- prolinol (1.2
g, 6 mmol) were dissolved in dry THF (70 ml) with vigorous
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a
Bruker AV-300 NMR spectrometer (400 MHz) (Bruker,
Karlsruhe, Germany), with CDCl3 as solvent and TMS as
internal reference. Optical rotation values were measured at
20 0C on a PerkinElmer 343 polarimeter (PerkinElmer
0
stirring under an atmosphere of nitrogen at 0 C. A solution
of diethyl azodicarboxylate (1 g, 6 mmol) in dry THF (15
0
ml) was added dropwise over a period of 1 h at 0 C. The
mixture was warmed to room temperature and stirred for

Synthesis of Enantiomerically Pure Nitronyl Nitroxide Radicals
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
317
Table 2. The Chiral Nitronyl Nitroxide Radicals
Entry
Chiral Aldehydes
Product
Time(h) Yield(%)
Color
O
N
O
CHO
O
N
1
24
24
46.4
46.9
deep blue
O
N
N
Boc
(L) 1a
Boc
4a
O
N
O
CHO
O
N
2
deep blue
O
N
N
Boc
(D) 1b
Boc
4b
O
CHO
N
O
N
3
24
27.6
deep blue
N
O
O
O
Boc
N
O
(L) 2a
Boc
5a
O
CHO
N
O
N
O
4
24
28.1
deep blue
N
O
O
Boc
N
O
(D) 2b
Boc
5b
O
O
O
N
O
C
CHO
N
5
6
24
24
36.3
36.9
deep blue
deep blue
O
C
N
Boc
N
(L) 3a
Boc
6a
O
O
O
O
C
N
O
C
CHO
N
O
N
Boc
N
(D) 3b
Boc
6b
O
12 h. THF was removed in vacuo. Ether was added to the
residue to precipitate triphenylphosphine oxide and diethyl
hydrazinedicarboxylate, which were then filtered off. The
filtrate was evaporated. The crude product wad purified by
column chromatography on silica gel using hexane/acetone
(4:1) as eluant, giving a colorless oil product (1.29 g,
84.8%). MS(m/z): 328.15 (MNa+); IR(KBr): 1395, 1366,
2878, 2975 (ν CH3), 1162, 1109, 1027 (ν C-C ring of
pyrrolidine), 1694, 2732 ( ν CHO), 1310, 1256, 1694 (ν ester
bond and amide bond), 1601, 1509, 1578, 1456, 833 (ν

318 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Qin et al.
benzene ring); 1H NMR(CDCl3): 9.82 (s,1H, -CHO), 7.78 (d,
2H, J=6.0 Hz, -ArH), 7.01 (d, 2H, J=9.0 Hz, -ArH), 4.20 (d,
2H, -CH2), 3.87 (m, 1H, -CH), 3.35 (t, 2H, -CH2), 1.97 (m,
2H,-CH2), 1.77 (m, 2H, -CH2), 1.42(s, 9H, -CH3); 13C NMR
δ(CDCl3): 190.7, 163.9, 154.7, 131.9, 129.9, 114.8, 79.8,
60.0, 55.7, 46.9, 28.4, 24.0, 22.6.
(ν C-C ring of pyrrolidine), 834, 1605, 1529, 1454 (ν
CH2Cl2
benzene ring); UV(
!
): 285 (benzene ring, π→π*), 368
max
(ONCNO, π→π*,ε=6.65×103 L/(mol·cm)), 550-600 (n→ π*).
EPR(CH2Cl2): g factor, 2.0032; aN, 7.684. As anticipated,
nitronyl nitroxide radicals showed no nmr signal. D
configuration product was synthesized by the same method.
D-tert-butyl 2-((4-formyl-2-methoxyphenoxy) Methyl)
Pyrrolidine-1-Carboxylate [2b]
D-tert-butyl 2-[(4-(4,5–Dihydro-4, 4, 5, 5–Tetramethyl–3–
Oxido-1H-Imidazol-3-Ium-1-Oxyl-2-yl)-2-Methoxyphen-
oxy)Methyl] Pyrrolidine-1-Carboxylate [5b]
A
colorless oil product; MS(m/z): 358.16(MNa+);
IR(KBr): 1396, 1366, 2974, 2878 (ν CH3), 1167, 1136, 1024,
910 (ν C-C ring of pyrrolidine), 1688, 2833, 2723 ( ν CHO),
1688, 1342, 1310, 1270 (ν ester bond and amide bond),
1587, 1510, 866, 811, 731 (ν benzene ring); 1H
NMR(CDCl3): 9.80 (s, 1H, -CHO), 7.37 (d, 1H, J=3.0 Hz, -
ArH), 7.28 (s, 1H, -ArH), 7.04 (d, 1H, J=6.0 Hz, -ArH), 4.27
(d, 2H, -CH2), 4.04 (m, 1H, -CH), 3.87(s, 3H, -CH3), 3.38 (t,
2H, -CH2), 2.06 (m, 2H, -CH2), 1.83 (m, 2H, -CH2), 1.43 (s,
9H, -CH3); 13C NMR δ(CDCl3): 190.98, 154.8, 153.9, 149.8,
129.9, 126.5, 111.8, 109.0, 79.9, 68.7, 60.0, 55.9, 46.9, 28.4,
23.6, 22.6. L configuration product 2a was synthesized by a
published method [17].
Deep blue solid product; MS (m/z): 485.24 (MNa+);
IR(KBr): 1358, 1125, 1168 (ν NO), 1391, 2976, 2876 (ν
CH3), 1232, 1026, 909 (ν C-C ring of pyrrolidine), 1692,
1327,1267 (ν ester bond and amide bond ), 1599, 1491,
CH2Cl2
max
1530, 1455, 867, 810 (ν benzene ring); UV-vis(
!
):
289 (benzene ring, π→π*), 342 (ε=4.4×103 L/(mol·cm)), 368
(ONCNO, π→π*), 560—630 (n→π*). EPR (CH2Cl2): g
factor, 2.0032; aN, 7.684.
L configuration product 5a was synthesized by a
published method [17].
L or D-tert-Butyl 2-((4-Formylbenzoyloxy)Methyl)Pyrro-
lidine-1-Carboxylate [3a and 3b]
L or D-tert-butyl 2-[(4-(4,5-Dihydro-4,4,5,5–Tetramethy
l–3–Oxido-1H-Imidazol-3-Ium-1-oxyl-2-yl) benzoyloxy)
Methyl] Pyrrolidine-1-Carboxylate [3a and 3b]
A colorless oil product; MS(m/z): 356.14 (MNa+);
IR(KBr): 1394, 1366, 2879, 2975 (ν CH3), 1168, 1104, 1016,
908 (ν C-C ring of pyrrolidine), 1696, 2732, 2825 ( ν CHO),
1696, 1274, 1021 (ν ester bond and amide bond), 1600,
1577, 1477, 1508, 1455, 855, 759 (ν benzene ring); 1H
NMR(CDCl3): 10.06 (s,1H, -CHO), 8.18 (d, 2H, J=9.0 Hz, -
ArH), 7.94 (d, 2H, J=6.0 Hz, -ArH), 4.38 (d, 2H, -CH2), 3.94
(m, 1H, -CH), 3.40 (t, 2H, -CH2), 1.96 (m, 2H, -CH2), 1.78
(m, 2H, -CH2), 1.44 (s, 9H, -CH3); 13C NMR δ(CDCl3):
191.6, 165.3, 154.6, 139.1, 135.1, 130.2, 129.5, 79.8, 65.7,
55.5, 47.5, 28.4, 24.0, 23.0.
Deep blue solid product；MS(m/z): 483.23 (MNa+); IR
(KBr): 1365, 1168 (ν NO), 1394, 2879, 2976(ν CH3), 1051,
1019, 908 (ν C-C ring of pyrrolidine), 1309, 1273, 1107,
1724, 1693 (ν ester bond and amide bond), 1608, 1508,
CH2Cl2
max
1453, 858 (ν benzene ring); UV(
!
): 294(benzene ring,
π→π*), 380 (ONCNO, π→ π*,ε=4.2×103 L/(mol·cm)), 550,
553, 560 (n→π*). EPR (CH2Cl2): g factor, 2.0032; aN, 7.572.
CONFLICT OF INTEREST
Declared none.
Synthesis of L-tert-butyl 2- [ (4- (4, 5-Dihydro-4, 4, 5, 5-
Tetramethyl-3-Oxido-1
H-Imidazol-3-Ium-1-oxyl-2-yl)
Phenoxy) Methyl] Pyrrolidine-1-Carboxylate [4a and 4b]
(General Procedure for Synthesis of Chiral Nitronyl
Nitroxide Radicals)
ACKNOWLEDGEMENT
This work was supported by the National Science
Foundation of China (No. 21172261).
A solution of L-tert-butyl 2-((4-formylphenoxy) methyl)
pyrrolidine-1-carboxylate (1.12 g, 3.68 mmol) and 2,3-bis
(hydroxylamino) -2,3-dimethylbutane (0.54 g, 3.68 mmol) in
methanol (20 ml) was stirred at room temperature for 24 h .
After the reaction, the methanol was removed and the
residue was suspended in 40 ml dichlormethane, aqueous
NaIO4 (0.71 g, 3.35 mmol in 20 ml) was added dropwise
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
web site along with the published article.
0
over a period of 5 min at 0 C，and the mixture was stirred
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