Polyunsaturated nitroalkanes and nitro-substituted fatty acids

Article abstract of DOI:10.1055/s-2001-11433

Nitroalkanes 4 are readily prepared from naturally derived polyunsaturated fatty alcohols 1 via succesive conversion to the corresponding haloalkanes 2 and 3, and reaction with silver nitrite. Reaction of nitroalkanes 4a,b with methyl acrylate, followed by ester hydrolysis, affords nitro-substituted fatty acids 6a,b and 8a,b. Oxidation of alcohols 1a,b gives the corresponding aldehydes 9a,b, which react by Henry condensation with nitromethane to give β-hydroxynitroalkanes 10a,b.

Full text of DOI:10.1055/s-2001-11433

PAPER
451
Polyunsaturated Nitroalkanes and Nitro-Substituted Fatty Acids
a
a
a
b
b
c
Christopher J. Easton,* Ling Xia, Michael J. Pitt, Antonio Ferrante, Alfred Poulos, Deborah A. Rathjen
a
Research School of Chemistry, Australian National University, Canberra ACT 0200, Australia
b
Adelaide Medical Centre for Women and Children, North Adelaide SA 5006, Australia
c
Peptide Technology (Australia) Ltd, North Ryde NSW 2113, Australia
Fax +61(2)61258114; E-mail: easton@rsc.anu.edu.au
Received 18 September 2000
ment with triphenylphosphine and carbon tetrabromide
according to the method of Hayashi et al. afforded the
Abstract: Nitroalkanes 4 are readily prepared from naturally de-
rived polyunsaturated fatty alcohols 1 via succesive conversion to
the corresponding haloalkanes 2 and 3, and reaction with silver ni-
trite. Reaction of nitroalkanes 4a,b with methyl acrylate, followed
8
corresponding bromides 2a e. Short chain bromoalkanes
9
react with silver nitrite to give nitroalkanes but the bro-
by ester hydrolysis, affords nitro-substituted fatty acids 6a,b and mides 2a e were inert to such treatment. Instead they
8
9
a,b. Oxidation of alcohols 1a,b gives the corresponding aldehydes
a,b, which react by Henry condensation with nitromethane to give
were first treated with sodium iodide to give the iodides
a e, which were used without purification and convert-
ed to the nitroalkanes 4a e, respectively.
3
-
hydroxynitroalkanes 10a,b.
Key words: Michael additions, carboxylic acids, lipids, Henry re-
actions, nitroalkanes
i
ii
R
CH OH
R
CH Br
R
CH2I
2
2
a-e
2-96%
a-e
1
2
3
9
Although polyunsaturated fatty acids (PUFAs) display a
broad spectrum of physiological activities, their utility to
address associated plant and mammalian conditions, in-
cluding allergic and autoimmune diseases, is limited.1
This can be attributed, at least in part, to the metabolic
breakdown of the PUFAs and to the fact that a particular
disease state often relates to only one of the many bio-
chemical interactions of the PUFAs. In connection with
studies of analogues of the naturally occurring PUFAs
which are resistant to -oxidation and more specific in
iii
a-e
5
1-56%
2 steps)
(
CO2H
CO2Me
v
iv
a,b
72,76%
R
R
R CH NO
2 2
a,b
5,93%
NO2
NO2
8
4
6
5
vi
a,b
6,95%
8
2
4
2
3
their other biochemical reactions, oxa and thia PU-
FAs have been prepared, and it has been demonstrated
that they induce physiological responses different to those
CO H
CO Me
2
2
4
brought about by the natural compounds. Nevertheless,
v
a,b
these modified PUFAs are incorporated into lipids, which
complicates their biochemical profiles. In an attempt to
avoid this, we targeted PUFA analogues having the car-
boxy group replaced by a nitro substituent. We anticipated
that this substitution would prevent the compounds from
R
NO2
CO H
R
NO2
CO Me
88,90%
2
2
8
7
a: R = CH (CH )
3
2 16
-
oxidation and incorporation into lipids, but not neces-
b: R = (all-Z)-CH (CH ) (CH=CHCH ) (CH )
3
2 4
2 4
2 2
sarily prohibit other biochemical interactions. Nitroal-
kanes are known to be enzyme substrates and inhibitors.
c: R = (Z,Z,Z)-CH CH (CH=CHCH ) (CH )
2 6
d: R = (Z,Z,Z)-CH (CH ) (CH=CHCH ) (CH )
3
2
2 3
3
2 4
2 3
2 3
For example, nitroethane inactivates D-amino acid oxi- e: R = (all-Z)-CH CH (CH=CHCH ) CH
3
2
2 6
2
5
dase in the presence of cyanide, 3-nitropropanoate inac-
Reagents and conditions: i) PPh /CBr /CH Cl , r.t.; ii) NaI/anhyd
3
4
2
2
tivates the flavoenzyme succinate dehydrogenase acetone, r.t.; iii) AgNO /Et O, r.t.; iv) methyl acrylate/NaOH/Bu NI/
2
2
4
6
(
probably by acting as a succinate mimic), 3-nitrolactate CH
2
Cl
2
, reflux; v) LiOH/DME, r.t.; vi) methyl acrylate/DBU/CH
2
Cl
2
,
r.t.
inhibits fumarase and is a substrate for malate dehydroge-
7
nase, and nitroalkanes are generally good substrates for Scheme 1
5
heme-dependent oxidases and peroxidases. Accordingly,
we now report the synthesis of polyunsaturated nitroal-
kanes and nitro-substituted fatty acids.
In order to prepare nitro-substituted fatty acids, a variety
of reactions of nitroalkanes were investigated. Carboxyla-
tion using the method of Finkbeiner et al. was examined.
Accordingly reaction of 1-nitropropane with magnesium
methyl carbonate afforded 2-nitrobutanoic acid, but 1-ni-
trooctadecane (4a) was recovered unchanged when treat-
The polyunsaturated fatty alcohols 1b e and the saturated
analogue, octadecanol (1a), are commercially available
and were used as starting materials in the present work,
the latter to develop the synthetic methods. Their treat-
1
0
Synthesis 2001, No. 3, 451–457 ISSN 0039-7881 © Thieme Stuttgart · New York

4
52
C. J. Easton et al.
PAPER
ed under the same conditions. Apparently the aliphatic To obtain substituted nitroalkanes, the alcohols 1a, b were
chain prevents reaction in the latter case. 1-Nitrooctade- oxidised to the corresponding aldehydes 9a, b using pyri-
cane (4a) was treated with butyllithium then methyl dinium chlorochromate.15 Henry condensation of these
16
1
1
chloroformate to give methyl 2-nitrononadecanoate. compounds with nitromethane in the presence of Am-
1
7
However, all attempts to hydrolyse this material to give berlyst A-21 afforded the 2-hydroxynitroalkanes 10a, b,
-nitrononadecanoic acid failed, the reactions instead af- which reacted with methanesulfonyl chloride and
2
18
fording the nitroalkane 4a. This product may be attributed triethylamine to give the corresponding , -unsaturated
to rapid decarboxylation of the monoanion of 2-nitronon- nitroalkanes. Unfortunately it was not possible to isolate
adecanoic acid, since the analogous process has been re- pure samples of these analogues of
-unsaturated fatty
ported for 2-nitroacetic acid.1 Given that this acids, because they equilibrated with the corresponding
decarboxylation would be expected to affect the integrity -unsaturated nitroalkanes and the mixtures of isomers
2
of 2-nitrocarboxylic acids during physiological studies at decomposed on chromatography.
near neutral pH, the synthesis of compounds of this type
was not further pursued.
CO H
2
NO2
CO H
NO2
4a
8a
2
NO2
4
b
c
CO2H
NO2
CO H
NO2
NO2
8b
4
2
4
d
e
OH
NO2
i
ii
R
CH2OH
R
CHO
R
CH CH2NO2
4
a,b
6,81%
a,b
89,90%
1
9
10
7
a: R = CH (CH )
3
2 16
b: R = (all-Z)-CH (CH ) (CH=CHCH ) (CH )
3
2 4
2 4
2 2
The nitroalkane 4a was inert when treated with butyllith-
ium and -haloacetates, indicating that long chain 3-nitro-
carboxylates could not be prepared using this approach.
However, the nitroalkanes 4a, b reacted with sodium hy-
Reagents and conditions: i) pyridinium chlorochromate/CH Cl , r.t.;
2
2
ii) CH NO /Amberlyst A-21/Et O, reflux
3
2
2
Scheme 2
1
3
droxide and methyl acrylate in the presence of tetrabuty-
1
4
lammonium iodide to give the -nitro esters 5a, b, which
were hydrolysed using lithium hydroxide to afford the
corresponding nitro acids 6a, b. Using 1,8-diazobicyc-
lo[5.4.0]undec-7-ene (DBU) as the base, in place of sodi-
um hydroxide, the nitroalkanes 4a, b reacted by sequential
Michael additions with methyl acrylate to give the diesters
OH
NO2
10a
OH
7
a, b, which hydrolysed to the nitro diacids 8a, b.
NO2
10b
NO2
COOH
6a
The reactions described above were carried out under ni-
trogen and in the dark. After purification the compounds
were stored at 30 C under nitrogen. By taking these pre-
cautions there were no complications from isomerisation
or autoxidation of the methylene-interrupted polyenes.
NO2
COOH
6b
Synthesis 2001, No. 3, 451–457 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Polyunsaturated Nitroalkanes and Nitro-Substituted Fatty Acids
453
Such reactions result in the formation of conjugated IR (film): = 3001 (s), 2960 (s), 2920 (s), 2850 (s), 1460 (m), 1430
1
(
1
m), 1395 (w), 1270 (w), 720 (w) cm .
dienes and none of the compounds showed absorption at
2
34 nm which is characteristic of this structural feature.19
H NMR (CDCl , 300 MHz): = 0.98 (t, 3 H, J = 7.5 Hz, C18-H3),
3
1
1
.30 1.45 (m, 10 H, C3-H , C4-H , C5-H , C6-H , C7-H ), 1.81
2 2 2 2 2
.88 (m, 2 H, C2-H ), 2.03 2.11 (m, 4 H, C8-H , C17-H ), 2.80
2
2
2
Octadecan-1-ol (1a) was obtained from Aldrich Chemical Co.
Arachidonyl alcohol (1b), linolenyl alcohol (1c), gamma linolenyl
alcohol (1d) and docosahexaenyl alcohol 1e were purchased from
Nu-Chek Prep. Inc. (Elysian, Minnesota, USA). Petroleum ether
used had bp 40 60 °C.
2.83 (m, 4 H, C11-H , C14-H ), 3.41 (t, 2 H, J = 6.8 Hz, C1-H ),
5.30 5.42 (m, 6 H, C9-H, C10-H, C12-H, C13-H, C15-H, C16-H).
2
2
2
13
C NMR (CDCl , 300 MHz): = 14.9, 21.1, 26.1, 26.2, 27.8, 28.7,
3
2
1
9.3, 29.8, 29.9, 30.2, 33.4, 34.6, 127.7, 128.3, 128.8 (2 C), 130.8,
32.5.
+
+
MS (EI): m/z (%) = 328 (M , 14), 326 (M , 14), 272 (42), 270 (41),
49 (13), 135 (28), 121 (33), 108 (92), 95 (53), 79 (100), 67 (72), 55
59).
1
-Bromooctadecane (2a); Typical Procedure
1
(
Octadecan-1-ol (1a; 520 mg, 1.92 mmol) and Ph P (550 mg,
2
3
.10 mmol) were dissolved in CH Cl (25 mL). The mixture was
2 2
cooled in an ice bath and CBr (630 mg, 1.90 mmol) was added with
Anal. calcd for C H Br: C, 66.05; H, 9.54. Found: C, 65.82; H,
4
18 31
stirring. The mixture was allowed to warm to r.t. and was stirred
9.32.
overnight, then it was concentrated under a stream of N and the res-
idue was subjected to flash column chromatography on silica gel,
eluting with hexane, to afford 2a (605 mg, 96%) as a waxy solid; mp
2
(
Z,Z,Z)-1-Bromooctadeca-6,9,12-triene (2d)
From gamma linolenyl alcohol (1d) (143 mg, 0.54 mmol), using the
procedure described above for preparation of 2a, (Z,Z,Z)-1-bro-
mooctadeca-6,9,12-triene (2d) (170 mg, 96%) was obtained as a co-
lourless oil.
2
6 28 °C.
IR (KBr): = 2920 (s), 2848 (s), 1468 (s), 1378 (w), 1254 (w), 1144
1
(
m), 720 (m), 658 (s) cm .
IR (film): = 3002 (s), 2950 (s), 2920 (s), 2850 (s), 1460 (s), 1378
(w), 1260 (w), 715 (m), 648 (m) cm .
1
1
H NMR (CDCl , 300 MHz): = 0.87 (t, 3 H, J = 6.7 Hz, C18-H3),
3
1
.25 1.32 [m, 30 H, (C3-17)-H )], 1.82 1.85 (m, 2 H, C2-H ), 3.40
1
2
2
H NMR (CDCl , 300 MHz): = 0.89 (t, 3 H, J = 6.8 Hz, C18-H3),
3
(
t, 2 H, J = 6.8 Hz, C1-H2).
1
.29 1.45 (m, 10 H, C3-H , C4-H , C15-H , C16-H , C17-H ),
2 2 2 2 2
1
3
C NMR (CDCl , 300 MHz): = 14.7, 23.2, 28.7, 29.3, 29.9, 30.0,
1.82 1.91 (m, 2 H, C2-H ), 2.02 2.17 (m, 4 H, C5-H , C14-H ),
3
2
2
2
3
0.1, 30.1(6), 30.2(3), 32.5, 33.4, 34.6.
2.79 2.83 (m, 4 H, C8-H , C11-H ), 3.40 (t, 2 H, J = 6.7 Hz, C1-
2 2
+
+
H ), 5.30 5.41 (m, 6 H, C6-H, C7-H, C9-H, C10-H, C12-H, C13-
H).
2
MS (EI): m/z (%) = 334 (M , 8), 332 (M , 10), 253 (25), 151 (27),
49 (28), 137 (67), 135 (69), 113 (19), 97 (30), 85 (50), 71 (70), 57
100).
1
(
1
3
C NMR (CDCl , 300 MHz): = 14.7, 23.2, 26.2, 27.6, 27.8, 28.4,
3
+
+
29.3, 29.9, 32.1, 33.3, 34.5, 128.2, 128.6(5), 128.7(1), 129.0, 130.3,
31.0.
HRMS: m/z calcd for C H Br 334.2058 (M ) and 332.2078 (M ).
Found: 334.2070 and 332.2086.
1
8
37
1
+
+
MS (EI): m/z (%) = 328 (M , 10), 326 (M , 8), 230 (49), 228 (50),
50 (66), 135 (15), 121 (25), 107 (32), 93 (59), 79 (100), 67 (95), 55
64).
(
all-Z)-1-Bromoeicosa-5,8,11,14-tetraene (2b)
1
(
From arachidonyl alcohol (1b; 740 mg, 2.54 mmol), using the pro-
cedure described above for preparation of 2a, (all-Z)-1-bromoe-
icosa-5,8,11,14-tetraene (2b) (826 mg, 93%) was obtained as a
colourless oil.
+
+
HRMS: m/z calcd for C H Br 328.1589 (M ) and 326.1609 (M ).
1
8
31
Found: 328.1592 and 326.1611.
IR (film): = 3012 (s), 2958 (s), 2927 (s), 2856 (s), 1653 (m), 1456
(all-Z)-1-Bromodocosa-4,7,10,13,16,19-hexaene (2e)
From docosahexaenyl alcohol 1e (201 mg, 0.64 mmol), using the
procedure described above for preparation of 2a, (all-Z)-1-bromo-
docosa-4,7,10,13,16,19-hexaene (2e) (221 mg, 92%) was obtained
as a colourless oil.
(
(
1
m), 1394 (m), 1251 (m), 1199 (w), 1041 (m), 915 (w), 807 (w), 715
s) cm .
1
H NMR (CDCl , 300 MHz): = 0.89 (t, 3 H, J = 6.8 Hz, C20-H3),
3
1
.29 1.38 (m, 6 H, C17-H , C18-H , C19-H ), 1.47 1.56 (m, 2 H,
2 2 2
C3-H ), 1.83 1.93 (m, 2 H, C2-H ), 2.03 2.14 (m, 4 H, C4-H ,
IR (film): = 3008 (s), 2960 (s), 2928 (s), 2868 (s), 1650 (m), 1434
(s), 1392 (s), 1348 (w), 1322 (w), 1266 (s), 1244 (s), 1068 (m), 1044
(m), 928 (m), 714 (s) cm .
2
2
2
C16-H ), 2.80 2.83 (m, 6 H, C7-H , C10-H , C13-H ), 3.42 (t, 2 H,
2
2
2
2
1
J = 6.8 Hz, C1-H ), 5.30 5.41 (m, 8 H, C5-H, C6-H, C8-H, C9-H,
2
C11-H, C12-H, C14-H, C15-H).
1
H NMR (CDCl , 300 MHz): = 0.98 (t, 3 H, J = 7.5 Hz, C22-H3),
3
1
3
C NMR (CDCl , 300 MHz): = 14.7, 23.2, 26.2, 26.9, 27.8, 28.7,
1.85 2.30 (m, 6 H, C2-H , C3-H , C21-H ), 2.80 2.90 (m, 10 H,
3
2
2
2
2
1
9.9, 32.1, 32.9, 34.3, 128.1, 128.4, 128.7 (2 C), 129.0, 129.1,
29.9, 131.1.
C6-H , C9-H , C12-H , C15-H , C18-H ), 3.42 (t, 2 H, J = 6.6 Hz,
2 2 2 2 2
C1-H ), 5.31 5.45 (m, 12 H, C4-H, C5-H, C7-H, C8-H, C10-H,
2
+
+
C11-H, C13-H, C14-H, C16-H, C17-H, C19-H, C20-H).
MS (EI): m/z (%) = 354 (M , 5), 352 (M , 6), 283 (8), 281 (8), 256
(
(
1
3
15), 254 (15), 216 (25), 214 (25), 150 (34), 119 (29), 105 (36), 93
53), 91 (56), 79 (100), 67 (75).
C NMR (CDCl , 300 MHz): = 14.4, 20.5, 25.5, 25.6, 32.5 33.2,
3
127.0, 127.8(5), 127.9(4), 128.0(6), 128.1(1) (2 C), 128.1(8) (2 C),
128.2(4), 128.6, 129.5, 132.0.
+
+
HRMS: m/z calcd for C H Br 354.1745 (M ) and 352.1766 (M ).
2
0
33
+
+
Found: 354.1748 and 352.1772.
MS (EI): m/z (%) = 378 (M , 10), 376 (M , 10), 349 (20), 347 (20),
3
1
09 (46), 307 (53), 244 (75), 242 (74), 227 (49), 202 (30), 200 (30),
73 (12), 133 (34), 119 (45), 108 (50), 91 (65), 79 (100), 67 (66).
Anal. calcd for C H Br: C, 67.98; H, 9.41. Found: C, 68.05; H,
2
0
33
9
.28.
+
+
HRMS: m/z calcd for C H Br 378.1745 (M ) and 376.1766 (M ).
Found: 378.1742 and 376.1760.
2
2
33
(
Z,Z,Z)-1-Bromooctadeca-9,12,15-triene (2c)
From linolenyl alcohol (1c) (102 mg, 0.39 mmol), using the proce-
dure described above for preparation of 2a, (Z,Z,Z)-1-bromooctade-
ca-9,12,15-triene (2c) (118 mg, 93%) was obtained as a colourless
oil.
1
-Nitrooctadecane (4a); Typical Procedure
To a solution of 1-bromooctadecane (2a; 480 mg, 1.44 mmol) in an-
hyd acetone (25 mL) at r.t. was added NaI (430 mg, 2.87 mmol).
Synthesis 2001, No. 3, 451–457 ISSN 0039-7881 © Thieme Stuttgart · New York

4
54
C. J. Easton et al.
PAPER
+
The mixture was stirred at r.t. overnight, then the solvent was re-
MS (EI): m/z (%) = 293 (M , 24), 276 (14), 264 (5), 246 (5), 237
(32), 224 (17), 135 (26), 121 (35), 108 (63), 95 (84), 93 (75), 91
(69), 79 (100), 67 (95).
moved in vacuo. The residue was mixed with sat. aq NaHSO solu-
3
tion (25 mL) and the mixture was extracted with Et O (3 î 25 mL).
2
The combined extracts were dried (Na SO ) and the solvent was re-
2
4
Anal. calcd for C H NO : C, 73.67; H, 10.65; N, 4.77. Found: C,
1
8
31
2
moved in vacuo. The residue (502 mg) was dissolved in anhyd Et O
2
7
3.69; H, 10.57; N, 4.85.
and AgNO (406 mg, 2.64 mmol) was added. After stirring for 3 d,
2
(
Z,Z,Z)-1-Nitrooctadeca-6,9,12-triene (4d)
the mixture was filtered through a bed of Celite and the filtrate was
Following the procedure described above for preparation of 1-ni-
trooctadecane (4a), (Z,Z,Z)-1-bromooctadeca-6,9,12-triene (2d;
evaporated under a stream of dry N . The residue was subjected to
2
flash column chromatography on silica gel (Et O/hexane, 5:95) to
2
1
5
22 mg, 0.37 mmol) gave crude iodide 3d (15 mg), and 4d (56 mg,
1%) as a colourless oil.
give crude iodide 3a (97 mg) and 1-nitrooctadecane (4a) (220 mg,
5
1%) as a white solid; mp 41 42 °C.
IR (film): = 3012 (s), 2956 (s), 2928 (s), 2858 (s), 1652 (m), 1555
IR (film): = 2954 (s), 2919 (s), 2850 (s), 1563 (s), 1470 (m), 1385
1
(s), 1464 (s), 1435 (s), 1382 (s), 1266 (m), 1159 (w), 1067 (w), 1040
(
w), 1147 (w), 742 (w), 720 (m), 650 (w) cm .
1
(
w), 970 (w), 914 (w), 720 (s), 614 (w) cm .
1
H NMR (CDCl , 300 MHz): = 0.88 (t, 3 H, J = 6.6 Hz, C18-H3),
3
1
H NMR (CDCl , 300 MHz): = 0.88 (t, 3 H, J = 7.1 Hz, C18-H3),
1
4
.25 1.34 [m, 30 H, (C3-C17)-H ], 1.96 2.05 (m, 2 H, C2-H ),
.38 (t, 2 H, J = 7.1 Hz, C1-H2).
3
2
2
1
2
.29 1.43 (m, 10 H, C3-H , C4-H , C15-H , C16-H , C17-H ),
2 2 2 2 2
.01 2.08 (m, 6 H, C2-H , C5-H , C14-H ), 2.78 2.82 (m, 4 H, C8-
1
3
2
2
2
C NMR (CDCl , 300 MHz): = 14.7, 23.3, 26.7, 28.0, 29.4, 29.8,
3
H , C11-H ), 4.38 (t, 2 H, J = 7.1 Hz, C1-H ), 5.34 5.40 (m, 6 H,
2
2
2
2
9.9, 30.0, 30.1, 30.2, 30.3, 32.5, 76.3.
C6-H, C7-H, C9-H, C10-H, C12-H, C13-H).
+
MS (EI): m/z (%) = 299 (M , <1), 282 (4), 264 (20), 252 (7), 238
13
C NMR (CDCl , 300 MHz): = 14.7, 23.2, 26.2, 26.4, 27.4, 27.8,
3
(
9
7), 224 (7), 210 (5), 196 (4), 154 (5), 139 (7), 125 (20), 111 (40),
7 (74), 83 (87), 69 (95), 57 (100), 55 (96).
2
7.9, 29.4, 29.9, 32.1, 76.2, 128.1, 128.5, 129.0 (2 C), 129. 9, 131.0.
+
MS (EI): m/z (%) = 293 (M , 31), 276 (25), 258 (12), 246 (4), 222
Anal. calcd for C H NO : C, 72.19; H, 12.45; N, 4.68. Found: C,
18
37
2
(7), 195 (72), 150 (36), 137 (18), 105 (25), 91 (84), 81 (80), 80 (79),
7
2.33; H, 12.77; N, 4.57.
all-Z)-1-Nitroeicosa-5,8,11,14-tetraene (4b)
According to the procedure described above for preparation of 4a,
all-Z)-1-bromoeicosa-5,8,11,14-tetraene (2b) (782 mg,
.21 mmol) gave the crude iodide 3b (71 mg), and 4b (397 mg,
6%) as a colourless oil.
7
9 (100), 67 (82), 55 (60).
(
Anal. calcd for C H NO : C, 73.67; H, 10.65; N, 4.77. Found: C,
1
8
31
2
7
3.56; H, 10.56; N, 4.74.
(
2
5
(
all-Z)-1-Nitro-4,7,10,13,16,19-docosahexaene (4e)
Following the procedure described above for preparation of 4a, (all-
Z)-1-bromodocosa-4,7,10,13,16,19-hexaene (2e; 165 mg, 0.44
mmol) gave crude iodide 3e (27 mg) and, 4e (80 mg, 53%) as a co-
lourless oil.
IR (film): = 3013 (s), 2957 (s), 2928 (s), 2857 (s), 1648 (w), 1555
s), 1457 (m), 1435 (m), 1381 (s), 1267 (w), 1106 (w), 1047 (w),
(
9
1
69 (w), 914 (w), 716 (m) cm .
IR (film): = 3014 (s), 2962 (s), 2926 (s), 2873 (s), 2854 (s), 1653
1
H NMR (CDCl , 300 MHz): = 0.89 (t, 3 H, J = 6.8 Hz, C20-H3),
3
(
(
1
m), 1554 (s), 1434 (s), 1381 (s), 1352 (m), 1267 (m), 1069 (w), 917
w), 712 (s), 611 (w) cm .
1
.20 1.51 (m, 8 H, C3-C , C17-H , C18-H , C19-H ), 1.99 2.16
1
2
2
2
2
(
m, 6 H, C2-H , C4-H , C16-H ), 2.79 2.86 (m, 6 H, C7-H , C10-
2 2 2 2
H NMR (CDCl , 300 MHz): = 0.98 (t, 3 H, J = 7.6 Hz, C22-H3),
H , C13-H ), 4.39 (t, 2 H, J = 7.0 Hz, C1-H ), 5.32 5.43 (m, 8 H,
3
2
2
2
2
.05 2.23 (m, 6 H, C2-H , C3-H , C21-H ), 2.78 2.85 (m, 10 H,
C5-H, C6-H, C8-H, C9-H, C11-H, C12-H, C14-H, C15-H).
2 2 2
C6-H , C9-H , C12-H , C15-H , C18-H ), 4.38 (t, 2 H, J = 6.7 Hz,
1
3
2
2
2
2
2
C NMR (CDCl , 300 MHz): = 14.6, 23.1, 26.2, 26.7, 26.9, 27.5,
3
C1-H ), 5.31 5.47 (m, 12 H, C4-H, C5-H, C7-H, C8-H, C10-H,
2
2
1
7.8 29.9, 32.1, 76.1, 128.1, 128.4, 128.5, 128.9, 129.2 (2 C), 129.6,
31.1.
C11-H, C13-H, C14-H, C16-H, C17-H, C19-H, C20-H).
1
3
C NMR (CDCl , 300 MHz): = 14.8, 21.1, 24.4, 26.1, 26.2, 27.7,
+
3
MS (EI): m/z (%) = 319 (M , 6), 302 (14), 220 (27), 205 (15), 190
7
1
5.4, 127.6, 128.3, 128.4, 128.5(5), 128.6(0), 128.9 (3 C), 129.1,
29.2, 130.9, 132.6.
(
(
11), 181 (24), 177 (20), 164 (25), 150 (41), 119 (48), 105 (63), 91
90), 79 (100), 67 (97), 55 (77).
+
MS (EI): m/z (%) = 343 (M , 10), 326 (59), 314 (21), 274 (44), 215
Anal. calcd for C H NO : C, 75.19; H, 10.41; N, 4.38. Found: C,
20
33
2
(
(
55), 207 (42), 167 (16), 145 (18), 131 (16), 119 (36), 105 (48), 91
77), 79 (100), 67 (78), 55 (42).
7
4.92; H, 10.40; N, 4.43.
Z,Z,Z)-1-Nitro-9,12,15-octadecatriene (4c)
Following the procedure described above for preparation of 4a,
Z,Z,Z)-1-bromooctadeca-9,12,15-triene (2c; 79 mg, 0.24 mmol)
(
Anal. calcd for C H NO : C, 76.92; H, 9.68; N, 4.08. Found: C,
2
2
33
2
7
6.52; H, 9.87; N, 4.26.
(
gave the crude iodide 3c (12 mg), and 4c (37 mg, 53%) as a colour-
less oil.
Methyl 4-Nitroheneicosanoate (5a); Typical Procedure
A solution of NaOH (136 mg, 3.4 mmol) and Bu NI (158 mg,
4
IR (film): = 3011 (s), 2962 (s), 2929 (s), 2856 (s), 1652 (w), 1554
0
.43 mmol) in H O (10 mL) was added to a solution of 4a (510 mg,
2
(
9
s), 1463 (m), 1435 (m), 1383 (m), 1268 (w), 1148 (w), 1069 (w),
68 (m), 912 (w), 724 (m), 614 (w) cm .
1.70 mmol) and methyl acrylate (442 mg, 5.13 mmol) in CH Cl (10
mL) at r.t. The mixture was stirred and heated at reflux for 24 h, then
it was cooled and the layers were separated. The organic phase was
2 2
1
1
H NMR (CDCl , 300 MHz): = 0.98 (t, 3 H, J = 7.5 Hz, C18-H3),
3
washed with H O (2 î 25 mL) and dried (Na SO ). The solvent was
1
.25-1.33 (m, 10 H, C3-H , C4-H , C5-H , C6-H , C7-H ), 1.97
2
2
4
2
2
2
2
2
evaporated and the residue was subjected to flash column chroma-
2
.06 (m, 6 H, C2-H , C8-H , C17-H ), 2.79 2.81 (m, 4 H, C11-H ,
2
2
2
2
tography on silica gel (Et O/hexane, 5:95) to give 5a (498 mg, 76%)
C14-H ), 4.37 (t, 2 H, J = 7.1 Hz, C1-H ), 5.36 5.40 (m, 6 H, C9-
2
2
2
as a waxy solid.
H, C10-H, C12-H, C13-H, C15-H, C16-H).
1
3
IR (nujol): = 2924 (s), 2853 (s), 1744 (s), 1554 (s), 1466 (m), 1439
C NMR (CDCl , 300 MHz): = 14.9, 21.1, 26.1, 26.2, 26.8, 27.7,
3
(
m), 1367 (m), 1201 (m), 1175 (m), 1120 (m), 829 (w), 722 (w)
2
1
8.0, 29.4, 29.6, 29.7, 30.1, 76.3, 127.7, 128.4, 128.8, 128.9, 130.7,
32.5.
1
cm .
Synthesis 2001, No. 3, 451–457 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Polyunsaturated Nitroalkanes and Nitro-Substituted Fatty Acids
455
1
H NMR (CDCl , 300 MHz): = 0.87 (t, 3 H, J = 6.7 Hz, C21-H3),
(15), 151 (17), 137 (20), 125 (25), 110 (73), 97 (100), 83 (64), 69
3
1
.19 1.25 [m, 30 H, (C6-C20)-H ], 1.69 1.78 (m, 1 H), 1.92 2.30
(64), 55 (73).
2
(
4
m, 3 H), 2.32 2.40 (m, 2 H, C2-H ), 3.69 (s, 3 H, OCH ), 4.50
.59 (m, 1 H, C4-H).
+
2
3
HRMS: m/z calcd for C H NO 354.3008 (M
OH) . Found
2
1
40
3
3
54.3006.
1
3
C NMR (CDCl , 300 MHz): = 14.7, 23.3, 26.2, 29.2, 29.5, 29.8,
3
Anal. calcd for C H NO : C, 67.88; H, 11.12; N, 3.77. Found: C,
2
1
41
4
2
9.9, 30.0, 30.1, 30.2, 30.3, 30.5, 32.5, 34.5, 52.5, 88.4, 173.0.
6
7.58; H, 11.08; N, 3.81.
+
MS (EI): m/z (%) = 386 [(M + 1) , 25], 368 (12), 354 (18), 339 (20),
3
1
(
all-Z)-4-Nitrotricosa-8,11,14,17-tetraenoic Acid (6b)
05 (24), 287 (28), 263 (18), 221 (15), 193 (10), 179 (15), 165 (21),
51 (26), 137 (31), 123 (36), 111 (52), 97 (76), 83 (86), 69 (88), 55
100).
Following the procedure described above for preparation of 6a, me-
thyl (all-Z)-4-nitrotricosa-8,11,14,17-tetraenoate (5b; 230 mg,
.57 mmol) gave 6b (207 mg, 93%) as a colourless oil.
IR (film): = 3611 3317 (br), 3013 (m), 2922 (s), 2852 (m), 2693
m), 2361 (w), 1714 (s), 1551 (s), 1441 (s), 1379 (m), 1360 (m),
(
0
+
HRMS: m/z calcd for C H NO 386.3270 (M + H) . Found
3
2
2
44
4
86.3275.
(
Anal. calcd for C H NO : C, 68.53; H, 11.24; N, 3.63. Found: C,
1270 (m), 1071 (m), 969 (w), 916 (m), 844 (m), 824 (w), 720 (m)
cm .
22
43
4
1
6
8.39; H, 11.53; N, 3.50.
1
Methyl (all-Z)-4-Nitrotricosa-8,11,14,17-tetraenoate (5b)
H NMR (CDCl , 300 MHz): = 0.89 (t, 3 H, J = 7.1 Hz, C23-H3),
3
Following the procedure described above for the preparation of 5a,
1.27 1.44 (m, 8 H, C6-H , C20-H , C21-H , C22-H ), 1.70 1.82
2
2
2
2
(
all-Z)-1-nitro-5,8,11,14-eicosatetraene (4b; 650 mg, 2.03 mmol)
(m, 1 H), 1.93 2.27 (m, 7 H), 2.40 2.48 (m, 2 H, C2-H ), 2.78
2
gave 5b (594 mg, 72%) as a colourless oil.
2.86 (m, 6 H, C10-H , C13-H , C16-H ), 4.56 4.59 (m, 1 H, C4-H),
2
2
2
5
.30 5.43 (m, 8 H, C8-H, C9-H, C11-H, C12-H, C14-H, C15-H,
IR (film): = 3065 (w), 3013 (m), 2956 (s), 2930 (s), 2859 (m),
C17-H, C18-H).
13
1
737(s), 1552 (s), 1439 (m), 1363 (w), 1267 (w), 1263 (w), 1259
1
(
w), 1204 (m), 1178 (m), 981 (w) cm .
C NMR (CDCl , 300 MHz): = 14.7, 23.1, 26.1, 26.2, 26.9, 27.8,
3
1
28.9, 29.9, 30.2, 32.1, 33.9, 88.1, 128.1, 128.4, 128.5, 128.9, 129.1,
H NMR (CDCl , 300 MHz): = 0.88 (t, 3 H, J = 6.8 Hz, C23-H3),
3
1
29.2, 129.7, 131.1, 176.8.
1
(
2
4
.24 1.45 (m, 8 H, C6-H , C20-H , C21-H , C22-H ), 1.70 1.81
2 2 2 2
+
m, 1 H), 1.91 2.27 (m, 7 H), 2.32 2.40 (m, 2 H, C2-H ), 2.73
MS (EI): m/z (%) = 391 (M , 8), 345 (8), 320 (4), 293 (13), 280 (8),
253 (10), 203 (15), 190 (25), 177 (28), 164 (42), 150 (46), 131 (34),
110 (100), 91 (72), 79 (93), 67 (97).
2
.83 (m, 6 H, C10-H , C13-H , C16-H ), 3.68 (s, 3 H, OCH ), 4.51
2 2 2 3
.58 (m, 1 H, C4-H), 5.29 5.44 (m, 8 H, C8-H, C9-H, C11-H, C12-
H, C14-H, C15-H, C17-H, C18-H).
+
HRMS: m/z calcd for C H NO 391.2723 (M ). Found 391.2725.
2
3
37
4
1
3
C NMR (CDCl , 300 MHz): = 14.7, 23.1, 26.1, 26.2, 26.9, 27.8,
3
Anal. calcd for C H NO : C, 70.55; H, 9.52; N, 3.58. Found: C,
2
3
37
4
2
1
9.2, 29.9, 30.3, 30.5, 32.1, 33.9, 52.5, 88.2, 128.1, 128.4, 128.6,
28.9, 129.2 (2 C), 129.6, 131.1, 172.9.
7
0.29; H, 9.86; N, 3.43.
+
MS (EI): m/z (%) = 405 (M , 7), 374 (8), 359 (5), 327 (4), 307 (15),
2
(
(
Dimethyl 4-Heptadecyl-4-nitroheptane-1,7-dicarboxylate (7a);
Typical Procedure
A solution containing 1-nitrooctadecane (4a; 50 mg, 0.17 mmol),
methyl acrylate (88 mg, 1.02 mmol) and DBU (13 mg, 0.085 mmol)
94 (6), 267 (4), 229 (5), 215 (10), 190 (13), 177 (27), 164 (33), 150
36), 147 (24), 131 (35), 119 (43), 105 (54), 91 (70), 79 (93), 67
100), 55 (56).
+
in CH Cl (2 mL) was kept at r.t. for 24 h, then it was acidified with
HRMS: m/z calcd for C H NO 405.2879 (M ). Found 405.2870.
2 2
2
4
39
4
HCl (10%, 5 mL) and the mixture was extracted with CH Cl (2 î
2
2
Anal. calcd for C H NO : C, 71.08; H, 9.69; N, 3.45. Found: C,
24
39
4
1
0 mL). The combined extracts were dried (Na SO ) and concen-
2 4
7
1.50; H, 10.03; N, 3.34.
trated, and the residue was subjected to flash column chromatogra-
phy on silica gel (EtOAc/petroleum ether, 15:85), to give 7a
4
-Nitroheneicosanoic Acid (6a); Typical Procedure
(76 mg, 95%) as a colourless oil.
Methyl 4-nitroheneicosanoate (5a; 47 mg, 0.38 mmol) was dis-
solved in 1,2-dimethoxyethane (DME) (2 mL) and sat. aq LiOH so-
lution (2 mL) was added. The mixture was left for 24 h, then it was
acidified with dil HCl (10%, 10 mL) and the mixture was extracted
with EtOAc (2 î 10 mL). The extracts were concentrated under a
IR (film): = 2954 (m), 2914 (s), 2849 (s), 1744 (s), 1732 (s), 1537
(
(
(
(
1
s), 1470 (s), 1458 (s) 1439 (s), 1378 (s), 1355 (s), 1319 (s), 1298
s), 1203 (s), 1180 (s), 1129 (s), 1110 (m), 1071 (m), 1022 (m), 986
s), 894 (s), 864 (m), 842 (s), 826 (s), 807 (m), 788 (m), 717 (s), 705
1
m) cm .
stream of dry N and the residue was subjected to flash column
2
chromatography on silica gel (Et O/hexane, 100:20, then Et O/hex-
H NMR (CDCl , 300 MHz): = 0.88 (t, 3 H, J = 6.8 Hz, C17'-H3),
2
2
3
ane/AcOH, 60:40:1) to afford 6a (121 mg, 85%) as a white solid;
mp 55 56 °C.
1.16 1.25 [m, 30 H, (C2'-C16')-H ], 1.85 1.91 (m, 2 H, C1'-H ),
2
2
2.23 2.28 (m, 8 H, C2-H , C3-H , C5-H , C6-H ), 3.69 (s, 6 H,
2
2
2
2
OCH3).
IR (KBr): = 3500 2600 (br), 2955 (m), 2919 (s), 2849 (s), 1698
1
3
(
s), 1615 (w), 1543 (s), 1467 (m), 1445 (m), 1413 (w), 1360 (w),
C NMR (CDCl , 300 MHz): = 14.7, 23.3, 24.1, 29.1, 29.8, 29.9,
3
1
1
334 (w), 1266 (w), 923 (w), 827 (w), 723 (w), 612 (w) cm- .
30.0(5), 30.1(2), 30.3, 30.9, 32.5, 36.0, 52.5, 93.3, 173.0.
1
+
H NMR (CDCl , 300 MHz): = 0.87 (t, 3 H, J = 7.1 Hz, C21-H3),
MS (CI): m/z = 489 (M + NH ) .
3
4
1
.20 1.28 [m, 30 H, (C6-C20)-H ], 1.69 1.78 (m, 1 H), 1.98-2.30
+
2
MS (EI): m/z (%) = 440 [(M OCH ) , 9], 425 (28), 393 (100), 392
(
(35), 81 (53).
3
(
m, 3 H), 2.39 2.48 (m, 2 H, C2-H ), 4.53 4.60 (m, 1 H, C4-H).
2
83), 364 (19), 333 (18), 305 (14), 194 (11), 168 (42), 138 (82), 109
1
3
C NMR (CDCl , 300 MHz): = 14.7, 23.3, 26.2, 28.8, 29.5, 29.8,
3
2
9.9, 30.0, 30.1, 30.2(6), 30.3(3), 32.5, 34.4, 88.2, 177.5.
+
HRMS: m/z calcd for C H NO 440.3376 (M – OCH ) . Found
440.3379.
2
5
46
5
3
+
MS (CI): m/z = 389.3 (M + NH ) .
4
+
MS (EI): m/z (%) = 354 [(M OH) , 2], 323 (19), 321 (19), 305
17), 287 (14), 263 (12), 236 (5), 221 (9), 193 (10), 179 (15), 165
Anal. calcd for C H NO : C, 66.21; H, 10.47; N, 2.97. Found: C,
66.63; H, 10.91; N, 2.71.
2
6
49
6
(
Synthesis 2001, No. 3, 451–457 ISSN 0039-7881 © Thieme Stuttgart · New York

4
56
C. J. Easton et al.
PAPER
Dimethyl 4-[(all-Z)-Nonadeca-4,7,10,13-tetraenyl]-4-nitrohep-
tane-1,7-dicarboxylate (7b)
1321 (s), 1291 (s), 1231 (s), 1068 (m), 989 (m), 918 (s), 833 (s), 807
(m), 803 (m), 732 (m), 678 (m), 622 (w) cm .
1
Following the procedure described above for synthesis of 7a, (all-
Z)-1-nitroeicosa-5,8,11,14-tetraene (4b; 96 mg, 0.30 mmol) gave
1
H NMR (CDCl , 300 MHz): = 0.89 (t, 3 H, J = 6.9 Hz, C19’-H3),
3
1
1
.21 1.38 (m, 8 H, C2’-H , C16’-H , C17’-H , C18’-H ), 1.85
2 2 2 2
7
b (127 mg, 86%) as a colourless oil.
IR (film): = 3012 (m), 2955 (m), 2929 (m), 2857 (m), 1742 (s),
540 (s), 1438 (m), 1379 (w), 1351 (m), 1321 (m), 1260 (m), 1200
.91 (m, 2 H, C1’-H ), 2.03 2.09 (m, 4 H, C3’-H , C15’-H ), 2.26
2
2
2
2.38 (m, 8 H, C1-H , C2-H , C4-H , C5-H ), 2.77 2.86 (m, 6 H,
C6’-H , C9’-H , C12’-H ), 5.25 5.47 (m, 8 H, C4’-H, C5’-H, C7’-
H, C8’-H, C10’-H, C11’-H, C13’-H, C14’-H).
2
2
2
2
1
2 2 2
1
(m), 1176 (m), 990 (w), 721 (w) cm .
1
13
H NMR (CDCl , 300 MHz): = 0.88 (t, 3 H, J = 6.8 Hz, C19’-H3),
C NMR (CDCl , 300 MHz): = 14.7, 23.1, 23.9, 26.2, 27.2, 27.8,
3
3
1
1
2
.25 1.35 (m, 8 H, C2’-H , C16’-H , C17’-H , C18’-H ), 1.86
29.2, 29.7, 29.9, 32.1, 36.4, 93.4, 128.1, 128.3, 128.4, 128.9 (2 C),
129.2, 130.0, 131.1, 178.8.
2
2
2
2
.92 (m, 2 H, C1’-H ), 2.03 2.10 (m, 4 H, C3’-H , C15’-H ), 2.25
2
2
2
.37 (m, 8 H, C2-H , C3-H , C5-H , C6-H ), 2.78 2.86 (m, 6 H,
+
2
2
2
2
MS (EI): m/z (%) = 463 (M , 16), 446 (4), 416 (24), 397 (6), 365 (4),
C6’-H , C9’-H , C12’-H ), 3.69 (s, 6 H, OCH ), 5.31 5.43 (m, 8 H,
C4’-H, C5’-H, C7'-H, C8’-H, C10’-H, C11’-H, C13’-H, C14’-H).
2
2
2
3
3
1
43 (8), 305 (6), 278 (10), 245 (12), 231 (12), 217 (14), 203 (22),
92 (20), 177 (56), 164 (42), 157 (38), 145 (30), 138 (50), 119 (54),
1
3
C NMR (CDCl , 300 MHz): = 14.6, 23.1, 24.1, 26.2, 27.4, 27.8,
106 (72), 93 (82), 91 (76), 80 (72), 79 (100), 69 (46), 67 (98), 55
(64).
3
2
1
9.1, 29.9, 30.9, 32.1, 35.4, 52.6, 93.2, 128.1, 128.3, 128.5, 128.9,
29.1, 129.2, 129.9, 131.1, 172.9.
+
HRMS: m/z calcd for C H NO 463.2934 (M ). Found 463.2942.
2
6
41
6
+
MS (EI): m/z (%) = 491 (M , 16), 460 (72), 444 (50), 429 (28), 413
Anal. calcd for C H NO : C, 67.36; H, 8.91; N, 3.02. Found: C,
2
6
41
6
(
(
(
70), 393 (42), 381 (28), 357 (36), 333 (14), 301 (50), 207 (26), 181
32), 164 (34), 150 (40), 133 (40), 121 (50), 106 (71), 93 (86), 80
78), 79 (100), 67 (98), 55 (60).
6
7.51; H, 9.23; N, 2.92.
Octadecanal (9a); Typical Procedure
Pyridinium chlorochromate (6 g, 27.83 mmol) was suspended in
+
HRMS: m/z calcd for C H NO 491.3247 (M ). Found 491.3247.
2
8
45
6
CH Cl (30 mL), and octadecan-1-ol (1a) (5.02 g, 18.57 mmol) in
Anal. calcd for C H NO : C, 68.40; H, 9.22; N, 2.85. Found C,
2
2
28
45
6
CH Cl (15 mL) was then rapidly added at r.t. The solution became
6
8.77; H, 9.57; N, 2.85.
2
2
briefly homogeneous before the deposition of the black insoluble
reduced reagent. After 2 h, the black mixture was diluted with five
4
-Heptadecyl-4-nitroheptane-1,7-dicarboxylic Acid (8a); Typi-
volumes of anhyd Et O, the solvent was decanted, and the black sol-
2
cal Procedure
id was washed twice with Et O. The crude product was isolated by
2
Dimethyl 4-heptadecyl-4-nitroheptane-1,7-dicarboxylate (7a;
filtration of the organic solutions through Florisil and concentration
of the filtrate under reduced pressure. Purification by flash column
1
38 mg, 0.29 mmol) was dissolved in DME (2 mL) and sat. aq
LiOH solution (2 mL) was added. The mixture was allowed to stay
for 22 h, then it was acidified with diluted HCl (10%, 10 mL) and
extracted with EtOAc (2 î 10 mL). The extracts were concentrated
chromatography on silica (Et O/hexane, 4:96) gave octadecanal
2
(
9a) (4.02 g, 81%) as a white solid; mp 43 44 °C.
under a stream of dry N and the residue was subjected to flash col-
umn chromatography on silica gel (EtOAc/petroleum ether, 15:85)
IR (nujol): = 2960 (s), 2910 (s), 2850 (s), 2705 (w), 1730 (s), 1460
(s), 1375 (s), 720 (w) cm- .
2
1
to afford 8a (93 mg, 90%) as a white solid; mp 102 °C.
1
H NMR (CDCl , 300 MHz): = 0.88 (t, 3 H, J = 6.4 Hz, C18-H2),
3
IR (nujol): = 3600 2700 (br), 2919 (s), 2852 (s), 1740 (s), 1700
1.28 [m, 28 H, (C4-C17)-H ], 1.58 1.65 (m, 2 H, C3-H ), 2.42 (t, 2
2
2
(w), 1652 (w), 1534 (s), 1467 (m), 1454 (m), 1428 (m), 1353 (w),
H, J = 7.3 Hz, C2-H ), 9.76 (s, 1 H, CHO).
2
1
8
1
323 (m), 1282 (m), 1267 (w), 1234 (m), 1224 (s), 894 (w), 834 (w),
14 (w), 721 (w) cm .
13
C NMR (CDCl , 300 MHz): = 14.7, 22.7, 23.3, 29.7, 29.9, 30.0,
1
3
3
0.1, 30.3, 32.5, 44.5, 203.6.
H NMR (CDCl , 300 MHz): = 0.88 (t, 3 H, J = 6.8 Hz, C17’-H3),
+
3
MS (EI): m/z (%) = 268 (M , 4), 250 (34), 224 (17), 222 (18), 208
1
2
.17 1.30 [m, 30 H, (C2’-C16’)-H ], 1.85 1.91 (m, 2 H, C1’-H ),
2
2
(
(
6), 194 (10), 182 (8), 166 (8), 152 (10), 137 (20), 124 (30), 110
42), 96 (74), 82 (100), 71 (82), 69 (69), 57 (53), 55 (57).
.26 2.40 (m, 8 H, C1-H , C2-H , C4-H , C5-H ).
2
2
2
2
1
3
C NMR (CDCl , 300 MHz): = 14.7, 23.3, 23.9, 29.1, 29.4, 29.8,
+
3
HRMS: m/z calcd for C H O 268.2766 (M ). Found: 268.2765.
1
8
36
2
9.9(0), 29.9(3), 30.0, 30.1, 30.2, 30.3, 32.5, 37.7, 93.8, 179.2.
Anal. calcd for C H O: C, 80.53; H, 13.51. Found: 80.46, H,
+
18 36
MS (CI): m/z = 461 (M + NH ) .
4
1
3.49.
+
MS (EI): m/z (%) = 426 [(M-OH) , 1], 397 (3), 379 (68), 377 (70),
59 (56), 350 (28), 332 (42), 323 (56), 305 (30), 168 (77), 157
(
all-Z)-Eicosa-5,8,11,14-tetraenal (9b)
3
According to the procedure described above for preparation of 9a,
arachidonyl alcohol (1b) (402 mg, 1.38 mmol) gave 9b (303 mg,
(
(
100), 138 (56), 129 (56), 111 (58), 97 (58), 81 (58), 71 (64), 57
68).
7
6%) as a colourless oil.
+
HRMS: m/z calcd for C H NO 426.3219 (M
4
OH) . Found
2
4
44
5
IR (film): = 3005 (s), 2960 (s), 2910 (s), 2850 (s), 1730 (s), 1460
26.3229.
1
(
w), 1390 (w), 1160 (w), 920 (w) cm .
Anal. calcd for C H NO : C, 64.98; H, 10.22; N, 3.16. Found: C,
1
24
45
6
H NMR (CDCl , 300 MHz): = 0.89 (t, 3 H, J = 6.8 Hz, C20-H3),
3
6
4.55; H, 10.69; N, 2.81.
1
.28 1.34 (m, 6 H, C17-H , C18-H , C19-H ), 1.69 1.74 (m, 2 H,
2 2 2
4
-[(all-Z)-Nonadeca-4,7,10,13-tetraenyl]-4-nitroheptane-1,7-
C3-H ), 2.04 2.14 (m, 4 H, C4-H , C16-H ), 2.42 2.45 (m, 2 H,
2
2
2
dicarboxylic Acid (8b)
C2-H ), 2.79 2.85 (m, 6 H, C7-H , C10-H , C13-H ), 5.34 5.40
2 2 2 2
Following the procedure described above for synthesis of 8a, dim-
ethyl 4-[(all-Z)-nonadeca-4,7,10,13-tetraenyl]-4-nitroheptane-1,7-
dicarboxylate (7b; 110 mg, 0.22 mmol) gave 8b (90 mg, 88%) as a
white solid; mp 50 51 °C.
(m, 8 H, C5-H, C6-H, C8-H, C9-H, C11-H, C12-H, C14-H, C15-
H), 9.78 (s, 1H, CHO).
13
C NMR (CDCl , 300 MHz): = 14.5, 22.3, 23.0, 2 6.1, 26.9, 27.6,
3
2
9.7, 31.9, 43.7, 127.9, 128.2, 128.4, 128.7, 129.0, 129.2, 129.5,
IR (film): = 3400-2300 (br), 3013 (s), 2955 (s), 2927 (s), 2855 (s),
130.9, 202.9.
2
734 (m), 2630 (m), 1742 (s), 1714 (s), 1538 (s), 1439 (s), 1353 (s),
Synthesis 2001, No. 3, 451–457 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Polyunsaturated Nitroalkanes and Nitro-Substituted Fatty Acids
457
+
MS (EI): m/z (%) = 288 (M , <1), 244 (1), 234 (1), 217 (2), 203 (3), References
1
77 (9), 164 (13), 150 (30), 131 (12), 119 (19), 106 (59), 93 (56), 91
(
1) (a) Essential Fatty Acids and Eicosanoids, Invited Papers
(
64), 80 (77), 79 (100), 67 (93), 55 (43).
from the Third International Congress of the American Oil
Chemists Society; Sinclair, A.; Gibson, R., Eds.; American
Oil Chemists Society: Champaign, Illinois, 1992.
+
HRMS: m/z calcd for C H O 288.2453 (M ). Found: 288.2449.
2
0
32
Anal. calcd for C H O: C, 83.27; H, 11.18. Found: C, 83.28; H,
20
32
1
1.12.
(b) Bremer, J.; Osmundsen, H. In New Comprehensive
Biochemistry, Vol. 7: Fatty Acid Metabolism and its
Regulation; Numa, S., Ed.; Elsevier: Amsterdam, 1984, pp
1
-Nitrononadecan-2-ol (10a); Typical Procedure
113 154.
To a solution of octadecanal (9a; 2.22 g, 8.28 mmol) and ni-
tromethane (1.52 g, 24.90 mmol) in anhyd Et O (10 mL) was added
Amberlyst A-21 (1.2 g) at r.t. The mixture was stirred and heated at
reflux for 48 h. After removal of the Amberlyst A-21 by filtration,
the filtrate was concentrated under reduced pressure. Flash column
chromatography of the residue (EtOAc/petroleum ether, 5:95) gave
(
(
2) (a) Pitt, M. J.; Easton, C. J.; Moody, C. J.; Ferrante, A.;
2
Poulos, A.; Rathjen, D. A. Synthesis 1997, 1240.
(
b) Pitt, M. J.; Easton, C. J.; Robertson, T. A.; Kumaratilake,
L. M.; Ferrante, A.; Poulos, A.; Rathjen, D. A. Tetrahedron
Lett. 1998, 39, 4401.
3) (a) Lau, S. M.; Brantley, R. K.; Thorpe, C. Biochemistry 1988,
1
0a (2.41 g, 89%) as a white solid; mp 55 56 °C.
2
(
1
7, 5089.
b) Spydevold, Ø.; Bremer, J. Biochim. Biophys. Acta 1989,
003, 72.
IR (nujol): = 3500 3300 (br), 2960 (s), 2910 (s), 2850 (s), 1550
1
(
m), 1460 (s), 1375 (s), 720 (w) cm .
1
H NMR (CDCl , 300 MHz): = 0.86 0.90 (m, 3 H, C19-H ), 1.26
(c) Skrede, S.; Sørensen, H. N.; Larsen, L. N.; Steineger, H.
H.; Høvik, K.; Spydevold, Ø. S.; Horn, R.; Bremer, J.
Biochim. Biophys. Acta 1997, 1334, 115.
3
3
[
m, 30 H, (C4-C18)-H ], 1.43 1.55 (m, 2 H, C3-H ), 2.22 2.43 (br
2
2
s, 1 H, OH), 4.28 4.46 (m, 3 H, C1-H , C2-H).
2
(
d) Pitt, M. J.; Easton, C. J.; Ferrante, A.; Poulos, A.; Rathjen,
1
3
C NMR (CDCl , 300 MHz): = 14.7, 23.3, 25.7, 29.8(8), 29.9(2),
3
D. A. Chem. Phys. Lipids 1998, 92, 63.
3
0.0, 30.1, 30.2, 30.3, 32.5, 34.3, 69.2, 81.2.
(
4) (a) Ferrante, A.; Poulos, A.; Pitt, M. J.; Easton, C. J.; Sleigh,
M. J.; Rathjen, D. A.; Widmer, F. Methods of Treating
Immunopathologies Using Polyunsaturated Fatty Acids PCT
Int. Appl. WO 97 38688 (1997); Chem. Abstr. 1997, 127,
+
MS (CI): m/z = 347 (M + NH ) .
4
+
MS (EI): m/z (%) = 311 [(M H O) , 3], 294 (32), 282 (9), 276
(
1
8
2
27), 267 (31), 250 (34), 240 (6), 222 (15), 208 (8), 194 (9), 179 (7),
65 (10), 151 (16), 137 (37), 123 (62), 109 (85), 97 (95), 95 (100),
3 (100), 69 (88), 57 (92), 55 (92).
3
(
31322.
b) Ferrante, A.; Poulos, A.; Easton, C. J.; Pitt, M. J.;
Robertson, T. A.; Rathjen, D. A. Modified Polyunsaturated
Fatty Acids PCT Int. Appl. WO 96 11908 (1996); Chem.
Abstr. 1996, 125, 58194.
+
HRMS: m/z calcd for C H NO 311.2824 (M H O) . Found:
3
1
9
37
2
2
11.2831.
Anal. calcd for C H NO : C, 69.25; H, 11.93, N, 4.25. Found: C,
(5) Alston, T. A.; Porter, D. J. T.; Bright, H. J. Acc. Chem. Res.
1983, 16, 418.
1
9
39
3
6
9.54, H, 12.18, N, 4.13.
all-Z)-1-Nitroheneicosa-6,9,12,15-tetraen-2-ol (10b)
According to the procedure described above for synthesis of 10a,
all-Z)-eicosa-5,8,11,14-tetraenal (9b) (220 mg, 0.76 mmol) gave
0b (240 mg, 90%) as a colourless oil.
IR (film): = 3600-3300 (br), 3005 (s), 2960 (s), 2910 (s), 2850 (s),
650 (w), 1550 (s), 1460 (m), 1440 (m), 1380 (s), 1260 (w), 910
(
6) Coles, C. J.; Edmondson, D. E.; Singer, T. P. J. Biol. Chem.
979, 254, 5161.
(
1
(
(
7) Porter, D. J. T.; Bright, H. J. J. Biol. Chem. 1980, 255, 4772.
8) Hayashi, H.; Nakanishi, K.; Brandon, C.; Marmur, J. J. Am.
Chem. Soc. 1973, 95, 8749.
(
1
(9) Kornblum, N.; Taub, B.; Ungnade, H. E. J. Am. Chem. Soc.
1
1954, 76, 3209.
1
(
w), 720 (s) cm .
(10) (a) Stiles, M.; Finkbeiner, H. L. J. Am. Chem. Soc. 1959, 81,
1
505.
H NMR (CDCl , 300 MHz): = 0.87 0.91 (m, 3 H, C21-H3),
3
(
b) Finkbeiner, H. L.; Wagner, G. W. J. Org. Chem. 1963, 28,
15.
11) Seebach, D.; Lehr, F. Angew. Chem., Int. Ed. Engl. 1976, 15,
05.
12) (a) Finkbeiner, H. L.; Stiles, M. J. Am. Chem. Soc. 1963, 85,
16.
(b) Feuer, H.; Hass, H. B.; Warren, K. S. J. Am. Chem. Soc.
949, 71, 3078.
13) Chasar, D. W. Synthesis 1982, 841.
1
.27 1.39 (m, 6 H, C18-H , C19-H , C20-H ), 1.50 1.56 (m, 4 H,
2 2 2
2
C3-H , C4-H ), 2.02 2.16 (m, 4 H, C5-H , C17-H ), 2.40 2.60 (br
s, 1 H, OH), 2.80 2.86 (m, 6 H, C8-H , C11-H , C14-H ), 4.29
4
H, C10-H, C12-H, C13-H, C15-H, C16-H).
1
2
2
2
2
(
(
2
2
2
5
.45 (m, 3 H, C1-H , C2-H), 5.30 5.45 (m, 8 H, C6-H, C7-H, C9-
2
6
3
C NMR (CDCl , 300 MHz): = 14.5, 23.0, 25.5, 26.0, 27.1, 27.6,
3
2
1
9.7, 31.9, 33.5, 68.9, 81.0, 127.9, 128.2, 128.5, 128.6, 129.0,
29.1, 129.5, 130.9.
1
(
+
MS (EI): m/z (%) = 349 (M , <1), 314 (1), 251 (2), 234 (1), 217 (2),
2
(
(14) Baldwin, J. E.; Au, A.; Christie, M.; Haber, S. B.; Hesson, D.
J. Am. Chem. Soc. 1975, 97, 5957.
(15) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 31, 2647.
16) Rosini, G.; Ballini, R. Synthesis 1988, 833.
17) Ballini, R.; Bosica, G.; Forconi. P. Tetrahedron 1996, 52,
1677.
03 (3), 177 (6), 164 (10), 150 (24), 131 (13), 119 (21), 106 (43), 93
57), 91 (71), 79 (100), 67 (92), 55 (48).
(
(
+
HRMS: m/z calcd for C H NO 349.2617 (M ). Found: 349.2614.
2
1
35
3
Anal. calcd for C H NO : C, 72.17; H, 10.09, N, 4.01. Found: C,
2
1
35
3
7
2.25, H, 9.91; N, 3.64.
(18) Melton, J.; McMurry, J. E. J. Org. Chem. 1975, 40, 2138.
(
19) (a) Porter, N. A.; Wolf, R. A.; Yarbro, E. M.; Weenen, H.
Biochem. Biophys. Res. Commun. 1979, 89, 1058.
Acknowledgement
(
b) Porter, N. A.; Logan, J.; Kontoyiannidou, V. J. Org. Chem.
979, 44, 3177.
c) Terao, J.; Matsushita, S. Agric. Biol. Chem. 1981, 45, 587.
1
(
The authors gratefully acknowledge financial support of this work
by Peptech (Australia) Ltd.
Article Identifier:
437-210X,E;2001,0,03,0451,0457,ftx,en;P06500SS.pdf
1
Synthesis 2001, No. 3, 451–457 ISSN 0039-7881 © Thieme Stuttgart · New York