Synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11, 13-hexadecatetraenoate, an analogue of 15R-lipoxin A4

Article abstract of DOI:10.1016/S0960-894X(03)00667-X

We describe a method for the synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11, 13-hexadecatetraenoate, a compound that has been described as a metabolically stable analogue of 15R-lipoxin A₄.

Full text of DOI:10.1016/S0960-894X(03)00667-X

Bioorganic & Medicinal ChemistryLetters 13 (2003) 3223–3226
Synthesis of Methyl (5S,6R,7E,9E,11Z,13E,15S)-16-
(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-
hexadecatetraenoate, an Analogue of 15R-Lipoxin A4
Eifion D. Phillips,* Hui-Fang Chang, Christopher R. Holmquist and John P. McCauley
Department of Chemistry, AstraZeneca R&D Wilmington, 1800 Concord Pike, Wilmington, DE 19850, USA
Received 14 April 2003; revised 18 June 2003; accepted 24 June 2003
Abstract—We describe a method for the synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-
7,9,11,13-hexadecatetraenoate, a compound that has been described as a metabolicallystable analogue of 15 R-lipoxin A4.
# 2003 Elsevier Ltd. All rights reserved.
Lipid mediators playkeyroles in inflammation and
other physiological and pathophysiological responses.
Among these, lipoxin A4 (1) and other lipoxins serve to
dampen immune responses, and mediate the resolution
of inflammation, in contrast to the roles of other
‘proinflammatory’ mediators.1ꢀ6 These compounds are
interesting biological properties, no method for its
synthesis has been described to date. In this communi-
cation, we describe a synthesis of compound 2 (Fig. 1).
Our synthesis follows the approach illustrated in Figure 2,
involving a cis reduction of the acetylenic precursor 3,
which is prepared through the formation of the C12-
C13 bond via a cross-coupling of the two fragments 4
and 5. Similar synthetic strategies have been successfully
applied in previous syntheses of lipoxins and lipoxin
analogues.14ꢀ18
rapidlyinactivated in vivo; thus lipoxin A is rapidly
4
metabolized, primarilyto the C15 ketone. 7,8 As a result,
there has been interest in the development of metaboli-
callystable lipoxin A analogues as tools to studythe
4
effects of these mediators, and metabolicallystable
lipoxin analogues formed bymodification in the region
of the metabolically labile C15 hydroxyl, have been
described.9 Among these, compound 2, methyl
(5S,6R,7E,9E,11Z,13E,15S,)-16-(4-fluorophenoxy)-5,6,
15-trihydroxy-hexadeca-7,9,11,13-tetraenoate, ‘15-epi-
16-(para-fluoro)-phenoxy-LXA4’, has been identified as
being of particular interest,1,4ꢀ6 and reported to show
both enhanced metabolic stabilityand activityin vivo.
For example, compound 2 has been reported to inhibit
TNF-a-induced neutrophil recruitment in vivo,10 and to
The synthesis of the carboxy terminus fragment 4 from
2-deoxy-d-ribose (6) has been described previouslyin
the context of lipoxin synthesis18, 19 and was performed
as shown in Scheme 1. Thus, 6, protected as its iso-
propylidine acetal derivative 7, was converted to alde-
hyde 10 via
a
Wittig reaction with methyl
(triphenylphosphoranylidine)acetate to give unsaturated
ester 8, catalytic hydrogenation over 10% Pd/C to give
20
compound 9, followed bySwern oxidation
of the
11
inhibit inflammatoryangiogenesis. Other studies have
demonstrated the activityof the compound in reducing
12
disease severityin a dextran sulfate model of colitis,
and that the compound is protective in ischemic acute
renal failure.13 However, while compound 2 has been
identified as an important pharmacological tool for
studying the activity of lipoxins in vivo, with reports of
*Corresponding author. Tel.: +1-302-886-2423; fax: +1-302-886-
5382; e-mail: eifion.phillips@astrazeneca.com
Figure 1.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00667-X

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E. D. Phillips et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3223–3226
Scheme 2. Reagents and conditions: (a) (i) EtMgCl, THF, 0 ꢁC;
(ii) TMSCl, 50 ꢁC; (iii) SiO2 chromatography(90% yield); (b) NBS,
Ph3P, CH2Cl2, 0 ꢁC!rt (74% yield); (c) P(OEt)3, toluene, Á (90%
yield).
sodium periodate in dichloromethane. Addition of E-2-
(tri-n-butylstannyl)vinyllithium, prepared in situ from
E-1,2-bis(tri-n-butylstannyl)ethylene24 bytreatment
with n-butyllithium (THF, ꢀ78!16 ꢁC, 30 min) then
gave the racemic vinylstannane 21. Due to its high
molecular weight, relativelylarge quantities of bis(tri-
n-butylstannyl)ethylene were needed in the preparation
of 21 bythis procedure. Therefore 21 was more con-
venientlyprepared byaddition of lithium 2-trimethyl-
silylacetylide to 18 to give 19, TMS deprotection to give
the acetylenic alcohol 20, followed byselective trans
addition of tri-n-butyltin hydride under free radical
conditions. Vinylstannane 21 was then converted to the
racemic vinylic bromide 22 bytreatment with NBS in
dichloromethane.
Scheme 1. Reagents and conditions: (a) 2-methoxypropene, PPTS,
EtOAc, rt (43% yield); (b) Ph3P¼CHCO2Me, BzOH (cat.), THF, Á
(81% yield) (c) H2, 10% Pd/C (cat.), EtOH (87% yield); (d) (COCl)2,
DMSO, CH2Cl2, ꢀ78 ꢁC, then Et3N, ꢀ78 ꢁC!rt (86% yield); (e) 15,
LiNTMS2, toluene, ꢀ78 ꢁC (36% yield); (f) KF, 18-crown-6, DMF, rt
(99% yield).
In an attempt to obtain the S enantiomer (5) of bromide
22 required for the coupling with 4, kinetic resolution of
the stannane 21 was performed bysubjecting this race-
mic allylic alcohol to Sharpless epoxidation25 conditions
using (+)-diisopropyl l-tartrate and recovering the
unreacted S-enantiomer 23 (38% yield, 67% ee).26
Compound 21 was then converted to bromide 5 by
treatment with NBS, as described above. Optimization
of the conditions for the kinetic resolution of 21 to give
improved ee would be needed to provide an acceptable
synthesis of bromide 5. However, we found that the
racemic vinylic bromide 22 could be convenientlyand
effectivelyresolved directlybychiral supercritical fluid
chromatography(SFC) performed using Chiral Tech-
nologies Chiralpak1 ADTM columns. Analytical
separations were carried out on a Berger Analytical
SFC instrument with a 4.6Â250 mm 10 mm particle size
column using 20% MeOH in CO2 as the eluant at 2.2
mL/min flow, giving a resolution of R=7 in a run time
of 6 min. Preparative chromatographywas performed
on a Berger PrepSFCTM instrument with a 21Â250 mm
10 mm particle size column, using the same eluant at a
50 mL/min flow and a compound loading of the racemic
mixture of 30 mg per injection. The later eluting,
desired, S enantiomer (5) was collected with 84%
recoveryand in >99% ee, as determined either byana-
resulting alcohol. In literature syntheses,14ꢀ18 the lipoxin
A4 C7–C8 double bond has then been formed bya
Wittig reaction of aldehyde 10 (or the corresponding
intermediate with a bis-(t-butyldimethylsilyl)-protected
C5–C6 diol) giving largelythe undesired cis C7–C8
geometry, followed by isomerization with iodine to the
desired trans geometry. In our hands, the isomerization
proceeded onlyslowlyand with significant decomposi-
tion. However, a useful variant to this procedure was
adopted in which a Wadsworth–Emmons alkene for-
mation21 with phosphonate 15 formed the desired trans-
stereoisomer (11) exclusively. Phosphonate 15 was pre-
pared bythe route shown in Scheme 2. Thus, protection
of the terminal acetylene of 12 bytreatment with ethyl-
magnesium chloride, followed bychlorotrimethylsilane
gave alcohol 13. Treatment of 13 with NBS/triphenyl-
phosphine gave bromide 14. Phosphonate 15 was then
22
formed bythe Arbusov reaction
triethylphosphite.
of bromide 14 with
1
The synthesis of the p-fluorophenoxyfragment 5 was
achieved using the route shown in Scheme 3. 2-(p-
Fluorophenoxy)acetaldehyde (18) was prepared23 by
alkylation of p-fluorophenol with 3-chloropropane-1,2-
diol (16) (K2CO3, DMF), followed byoxidative clea-
vage of the resulting diol (17) with silica-supported
lytical chiral SFC or by H NMR in CDCl3 using the
chiral shift reagent (S)-1-anthracen-9-yl-2,2,2-tri-
fluoroethanol-d11.
Completion of the synthesis then required the organo-
metallic cross-coupling of the fragments 4 and 5,

E. D. Phillips et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3223–3226
3225
Scheme 3. Reagents and conditions: (a) p-FC6H4OH, K2CO3, MeCN, Á (56% yield); (b) NaIO4/SiO2, CH2Cl2 (98% yield); (c) E-nBu3SnCH¼
CHLi, THF, ꢀ20 ꢁC (45% yield); (d) Me3SiCꢂCLi, Et2O, ꢀ30 ꢁC!rt (71% yield); (e) NaOH (76% yield); (f) nBu3SnH, AIBN, 150 ꢁC (50% yield);
(g) NBS, CH2Cl2, 0 ꢁC (95% yield); (h) tBuOOH, Ti(OiPr)4, (+)-DIPT, CH2Cl2, ꢀ20 ꢁC (67% ee, 38% yield); (i) chiral supercritical fluid chroma-
tography(99% ee, 42% yield).
observed when Lindlar reduction is used to form the
C11–C12 cis double bond.
In summary, methyl (5S,6R,15S,7E,9E,11Z,13E,15S)-
16 - (4 - fluorophenoxy) - 5,6,15 - trihydroxyhexadeca-
7,9,11,13-tetraenoate, ‘15-epi-16-(para-fluoro)-phenoxy-
LXA4’, has been described as a compound that acts as a
metabolicallystable, biologicallyactive, analogue of
lipoxin A4. This communication provides a concise,
practical, route for the synthesis of this compound.
Acknowledgements
We thank Drs. P. Bernstein, J. Campbell and C. Veale
for helpful discussions, Drs. M. Chapdelaine and W.
Michne for comments on the manuscript, and Drs. X.
Ye, J. Hall, and T. Blake for NMR and MS data.
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