developing concise regio- and stereochemically pure syn-
theses of all possible isomers, which are essential to dissect
the biological targets of these compounds. The synthesis of
two of the natural isomers of nitrooleic acid (OA-NO2, 5
and 10) was recently reported.7 Herein, we discuss our
regiospecific and stereoselective general strategy for all four
possible nitrated oleic acids: (E)- and (Z)-, 9- and 10-
octadec-9-enoic acids (5, 10, 11, 13).
Scheme 2. Synthesis of (E)-9-Nitro-octadec-9-enoic Acid (5)
Direct nitration of lipids by production of radical NO2 or
+
cationic NO2 has been used to synthesize nitrated linoleic
and oleic acids.8 These methods, although useful, produce a
mixture of isomers in low yield, along with byproducts such
as nitronate esters and allylic nitroalkanes. Workers more
recently synthesized nitrooleic acid by phenylselenation and
nitration of oleic acid followed by oxidative elimination to
produce a statistical distribution of (E)-9- and 10-nitro regio-
isomers (5 + 10).6 Our current approach is built around a
nitroaldol addition (Henry reaction),9 which fixes the regio-
chemistry of the nitro group by combining known precursors.
Activation/dehydration then forms the nitroalkene moiety by
activating the hydroxyl group and eliminating via catalytic
base.10 Under mild conditions, this reaction gives clean
stereoisomers and few side products. Finally, an additional
isomerization step affords the alternative stereoisomers.
The nitroaldol condensation of 1 and 2 (Scheme 2) was
performed neat13 with a catalytic amount (10 mol %) of DBU
as base affording â-hydroxynitro 3 in good yield (81%) as
a 1:1 mixture of diastereomers.14 â-Hydroxynitro ester 3 was
acetylated10a in acetic anhydride with a catalytic amount of
p-toluenesulfonic acid to produce â-acetoxynitro ester 4 in
high yield. Finally, the protected nitroalkene15 (5a) was
generated by base-induced (0.5 equiv of sodium carbonate)
elimination with azeotropic removal of water, to give
stereoselectively clean (E)-isomer nitroalkenes in 84% yield
without isomerization or deconjugation of the double bond
to form allylic nitroalkanes. The elimination occurs by an
E2 or E1cb mechanism. Although the reaction produced a
clean (E)-isomer, this could also be the result of rapid
isomerization of any (Z)-isomer formed to an (E)-isomer
during the long reaction time. However, observation of the
reaction progress by 1H NMR (a tube-scale reaction) showed
no intermediate formation of a (Z)-isomer.
Synthesis of (E)-9-Nitro-octadec-9-enoic Acid (5). Syn-
thesis of 5 began with commercially available nonyl aldehyde
(1) and 9-bromononanol (Scheme 1). 9-Bromononanol was
Scheme 1. Synthesis of Precursor 2
The base sensitivity of both nitroalkanes and nitroalkenes
led us to use consistently acidic conditions when possible
throughout the reaction series, in both reaction and workup.
Common deallylation methods16 and reagents are incompat-
ible with nitroalkenes (basicity and/or nucleophilicity). We
found that palladium-catalyzed isomerization in the presence
of formic acid17 as a hydride donor promoted facile ester
cleavage and recovery of the free acid in nearly quantitative
yield (95%), affording 5 in 56% yield for four steps.
oxidized11 (Jones’ reagent, 67%) to the carboxylic acid,
protected as the allyl ester (92%), and nitrated by the method
of Kornblum12 (68%) to yield 9-nitro-nonanoic acid, allyl
ester (2), in overall 42% yield.
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