Intramolecular sulfur-assisted NaBH4 reduction of esters synthesis of 5-oxo-ETE and 5-oxo-12-HETE

Article abstract of DOI:10.1016/S0040-4039(00)00943-6

Ester groups are reduced very efficiently in sulfur-containing molecules situated at close proximity to the ester group. We have used this procedure to regioselectively, efficiently and in high yield reduce an ester group in the presence of another ester group further removed from the sulfur atom. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00943-6

Tetrahedron Letters 41 (2000) 5653±5657
Intramolecular sulfur-assisted NaBH4 reduction of esters
synthesis of 5-oxo-ETE and 5-oxo-12-HETE
Subhash P. Khanapure,a,y Goutam Saha,a Sashikala Sivendran,a William S. Powellb
and Joshua Rokacha,*
aClaude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 W. University Blvd.,
Melbourne, FL 32901, USA
bMeakins-Christie Laboratories and Department of Medicine, McGill University, 3626 St-Urbain St.,
Montreal, QC H2X 2P2, Canada
Received 27 April 2000; accepted 17 May 2000
Abstract
Ester groups are reduced very eciently in sulfur-containing molecules situated at close proximity to the
ester group. We have used this procedure to regioselectively, eciently and in high yield reduce an ester
group in the presence of another ester group further removed from the sulfur atom. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: NaBH4; MeOH; 5-oxo-ETE.
5-Oxo-ETE 1 is a product of the 5-lipoxygenase pathway and a new mediator of in¯ammation.
It is a potent chemotactic agent for neutrophils, but the major target for 5-oxo-ETE is the human
eosinophil. It induces pulmonary in®ltration of eosinophils in vivo,1,2 raising the possibility that it
may play an important role in the recruitment of these cells to the lungs of asthmatics.
We have reported a synthesis of 5-oxo-ETE 1,3 tetradeutero derivative 24 for the development
3
of a GC and LC/MS assay, and H-5-oxo-ETE 34 for the study of its metabolism and for the
generation of a binding assay. In addition, we have performed the total synthesis of 6,7-dihydro-
5-oxo-ETE 43 and 5-oxo-12-HETE 55 (Scheme 1) and have used the synthetic products to identify
their formation in neutrophils and platelets, respectively. All these syntheses are convergent and
have in common a dithiolane derivative 9 as the key intermediate synthon (Scheme 2). It was
prepared in moderate yields from dithiolane ester 6 via aldehyde 7. The low yield is the result of
o-alkylation of dithiolane carboxaldehyde 7.4 5-Oxo-ETE 1, its derivatives 2 and 3, as well as 5
* Corresponding author.
y
Present address: NitroMed, Inc., 12 Oak Park Drive, Bedford, MA 01730, USA.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00943-6

5654
are unstable compounds and repeated preparation and puri®cation are necessary. For that
reason, we decided to look into improving the synthesis of 9 (Scheme 2).
Scheme 1.
Scheme 2.
We performed the synthesis of the diester 17 as shown in Scheme 4 from commercial 6 and
attempted the reduction with NaBH4. We wanted to ®nd out if the C-6 carboxylic ester of 17
could be selectively reduced in the presence of the one at C-1. The carbon numbering used
corresponds to the position of the synthon in 5-oxo-ETE 1. The rationale behind the attempt is
based on our previous experience (Scheme 3) in which an ester was reduced with NaBH4 with the
assistance of a proximal alcohol group.6,7 Since then, several such cases have been reported.8 In
the speci®c case we were interested in, we were hoping that the sulfur in 17 would assist in the
reduction of the nearest ester group.
Scheme 3.

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Scheme 4.
The reduction of the ester at C-6 proceeded better than anticipated and 18 was obtained in high
yield by treatment of 17 with 4 equivalents of NaBH4 in ethanol or ether/MeOH. The syntheses
of 5-oxo-ETE and its tetradeutero and its tetratritiated derivatives were completed as described
by us previously and summarized in Scheme 2.
We were impressed with the regioselectivity and eciency of this reduction and decided to
explore its scope and selectivity. Table 1 shows the cases studied. The esters 19 and 21 in entries 1
and 2 are easily reduced as anticipated, the esters bearing the same relationships to the sulfur as
the one in 17 (Scheme 4). Entry 3 is an example of an open chain sul®de. In entry 4, the ester is
Table 1

5656
further removed from the sulfur as compared to 1 and 2. In this case, too, the reduction is rapid
and ecient and, as in all the preceding cases, only a single product is observed on TLC and by
NMR.9 In fact, a chromatographic puri®cation is not necessary as the product can be used as such
for further chemical elaboration. Entry 5 shows the ®rst selective reduction of the carboxylate ester
close to the sulfur in the dithiolane ring. As mentioned previously, 9 is the synthon that we used
for the synthesis of several oxo-eicosanoid mediators as shown in Scheme 2. The reduction in this
case was done under the same conditions as the other cases. Only the carboxylate ester near the
sulfur atom is reduced. This means that the ester at position 1 in 17 is out of reach of the sulfur
NaBH4 complex, which we assume is necessary in order to reduce the nearby ester. Entry 7 shows
the reduction of 17 using this time DIBAL-H. As expected, and in contrast to entry 5, the less
hindered carboxylate ester group at position 1 is reduced selectively, and a high yield of 29 is
obtained. Entry 6 is another example showing the selective reduction of the proximal ester. This
synthon 28 can be used to construct such metabolites as 20-hydroxy 15-oxo-ETE, a potential
15-HETE metabolite in neutrophils. Entry 8 is an example of an ester without sulfur in the
molecule. Under the usual reaction conditions, ether/MeOH/NaBH4, ester 30 has been reduced in
38 h in high yield. The reduction in this case most probably occurs due to the formation of a
methoxy borohydride species. Reduction of ester groups, using NaBH4/alcohols/other
solvents under re¯ux conditions has been reported.10 16 In one report the reductive species
implicated appears to be trimethoxy sodium borohydride.17
The following is a typical procedure we used in the reductions in Table 1 (entries 1±6 and 8). To
a solution of 2-carboethoxy-1,3-dithiane 21 (1 mmol) in anhydrous ether (3 ml) was added
NaBH4 (4 mmol) with stirring under argon. To this reaction mixture was added dry MeOH (1 ml)
dropwise at room temperature and stirred for 15 min. Solvent was concentrated under reduced
pressure. The residue was neutralized with 1N HCl and extracted with EtOAc. The organic layer
was washed with brine, dried, and concentrated to a€ord the alcohol. Filtration through SiO2
gave the analytically pure alcohol 22 in quantitative yield.
There is little doubt that in the reduction described in entries 1 to 6, a complex between the
NaBH4 and sulfur is formed and is assisting in the reduction of a close-by ester. It is likely that
species such as mono, di and trimethoxy borohydrides participate in this complexation to perform
the reduction. In fact, it seems unlikely that distance alone without activation of NaBH4 can be
the factor in such an ecient `intramolecular' NaBH4 reduction. Most likely a more reactive
hydride species is being formed between the sulfur and NaBH4 and/or mono, di and trimethoxy
borohydride. The fact that it took 38 h to reduce an ester (entry 8), compared to 10 to 15 min in
entries 1 to 6, is an indication that extra activation of the methoxy borohydrides by complexation
with the sulfur is necessary to perform a reduction approximately 150 times faster (15 min versus
38 h). Further support for the involvement of methoxy or alkoxy borohydride species in the
complexation with sulfur is provided by the fact that 30, on attempted reduction with NaBH4 in
dioxane, is recovered unchanged as expected after 38 h. Under the same conditions 19 a€orded a
17% yield of 20, perhaps indicating that NaBH4 itself can complex with sulfur in 19 providing
slightly augmented nucleophilicity of the hydrides. However, since our reductions in entries 1±6
are completed within 15 min, it is perhaps safe to assume that under these conditions mostly
methoxy borohydride species are implicated in the intramolecular sulfur-assisted NaBH4
reductions.
It is noteworthy that the reduction in entry 8 proceeds cleanly in high yield albeit with long
reaction time. This can provide an interesting option for a mild selective and ecient reduction of
non-activated esters in complex molecules.

5657
Acknowledgements
We wish to acknowledge NIH support under Grants DK-44730 (J.R.), NSF for an AMX-360
NMR instrument (Grant CHE-90-13145), and MRC of Canada under Grant MT-6254 (W.S.P.).
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