S.R. Woodcock, S.R. Salvatore, B.A. Freeman et al.
Tetrahedron Letters xxx (xxxx) xxx
complications with a nitrodiene under palladium-catalyzed condi-
tions this work instead utilized t-butyl esters which could be
removed under mild acidic conditions [40,41].
(
9E,11E)-9-Nitrooctadeca-9,11-dienoic acid (5): Key interme-
diate t-butyl 9-nitrononanoate (1) was generated (Scheme 1) in
two steps from commercially available 9-bromononanoic acid.
The acid was esterified via oxalyl chloride activation to the acyl
chloride and subsequent addition of t-butanol in the presence of
catalytic DMAP (4-dimethylaminopyridine). Then, the primary
bromide of the resulting ester was displaced with silver nitrite in
ether over one to two weeks of stirring at room temperature.
Purification to remove unreacted starting material (and a nitrite
side product, not shown) afforded useful amounts of 1 in two steps,
4
0% overall yield. Nitroalkyl ester 1 was subsequently coupled to
commercially available 2-trans-nonenal (2) using triethylamine
TEA) as both base and solvent, stirred at rt for two days then
(
cooled to À20 °C and stirred for two additional days. While many
literature methods use a large excess of nitroalkane, this was inef-
ficient for our purposes. The desired nitro-allyl alcohol 3 was iso-
lated in 35% yield after chromatographic purification without 1,4
addition product observed. Next, the allylic alcohol group was acti-
vated by exposure to trifluoroacetic anhydride (TFAA) in dichloro-
methane, yielding allylic trifluoroacetyl ester 4. Upon isolation of
crude 4 (95%), the activated trifluoroacetate group could be elimi-
nated by exposure to potassium acetate or propionate (yields 30–
40%); however, upon consideration that the efficiency could be
enhanced by increased solubility of the carboxylate salt, we tested
tetrabutylammonium acetate and obtained an 82% yield of the
desired nitrodiene ester, which was deprotected with neat formic
acid (51%) to afford free 9-nitro-conjugated linoleic acid (5).
(9E,11E)-12-Nitrooctadeca-9,11-dienoic acid (11): The key
unsaturated aldehyde starting material for 12-nitro isomer 11, t-
butyl (E)-11-oxo-undec-9-enoate (7), was obtained from 9-dece-
noic acid in four steps (Scheme 2). Free 9-decenoic acid was readily
esterified with t-butanol [42] then oxidized to a 9,10-diol in quan-
titative yield with catalytic osmium tetroxide and N-methylmor-
pholine N-oxide (NMO). Given the poor chromatographic
behavior of these polar intermediates, the crude diol was prefer-
ably used directly in the next step. Oxidative cleavage with sodium
metaperiodate afforded the much more tractable t-butyl 9-oxono-
nanoate (6) for a total of 45% yield over three steps. This nine-car-
Fig. 1. Structures of synthetic targets 9- and 12-NO
Rumelenic acid (15).
2 2
-CLA (5 and 11) and 9-NO -
reduction [33], addition to glutathione and metabolic b-oxidation
34]—are also major inactivation and excretion mechanisms of
these compounds as evidenced by their presence in human urine
7,32]. Nitrodienes [35] themselves are unusually reactive motifs
[
[
in biological systems; strongly electrophilic and prone to add to
available thiols by reversible kinetically and thermodynamically-
driven reactions [8].
A prior report on NO
metic conversion of conjugated (9,11)-linoleic acid to nitro conju-
gated linoleic acid [36], which produced NO -CLA as a mixture of
two positional isomers. The need to further evaluate the role of
specific NO -CLA isomers motivates the synthesis of 9-NO -CLA
5) and 12-NO -CLA (11), the two most common isomers of NO
2
-CLA synthesis included a direct biomi-
2
2
2
(
2
2
-
CLA [5] found in vivo. Moreover, rumelenic acid is not commer-
cially available to be used as a substrate for biomimetic nitration
reactions. In this work, we describe our regiospecific synthesis of
the three major biologically-detectable nitro fatty acids.
The core of our synthetic design was the assembly of the nitro-
diene and protection/deprotection of the free fatty acid. The major
functional group is the nitrodiene (1-nitro-1,3-diene) moiety pre-
sent in both isomers, which would be the product of condensation
bon aldehyde was then homologated to an eleven-carbon
a,b
between a nitroalkane and an
a
,b-unsaturated aldehyde (Fig. 2).
unsaturated aldehyde by a Wittig-type reaction with a stabilized
ylide (formylmethylene-triphenylphosphorane), which afforded
the desired 7 in 70% yield.
Nitroalkenes are frequently produced from b-nitro-alcohols,
themselves the products of nitroaldol condensation between a pri-
mary nitroalkane and an aldehyde. Literature methods [37–39] for
Unsaturated aldehyde ester 7 was subsequently condensed
with a two-fold excess of 1-nitroheptane (8) using TEA as base
and solvent (Scheme 2), affording purified nitro-allyl alcohol 9 in
36% yield. The allylic alcohol group was subsequently trifluo-
roacetylated (10, 77%) and then eliminated with tetrabutylammo-
nium acetate to give the desired nitrodiene ester in 84% yield.
Deprotection with neat formic acid produced the desired 12-nitro
conjugated linoleic acid 11 in an improved 79% yield.
nitroaldol-type reactions only infrequently used
a,b-unsaturated
aldehydes, and were frequently reacted with high molar excess
of a simple nitroalkane (often nitromethane). The less common
nitrodiene has been formed by this approach but the intermediates
as well as the final product are noticeably less stable, and there are
additional side reactions available at each step of the synthesis,
such as the 1,4-conjugate addition as an unproductive side reaction
(
see discussion below).
Previous work with nitro-fatty acids utilized allyl esters as pro-
2
The final individual NO -CLA isomers 5 and 11 were obtained in
overall yields of 5.6% and 5.5% over six and seven steps, respec-
tively. The products were identical in all spectroscopic respects
tecting groups for the carboxylic acid, however to avoid potential
Fig. 2. Retrosynthetic strategy.
2
Woodcock, Steven R.
