Total synthesis of aspirin-triggered 15-epi-lipoxin A4

Article abstract of DOI:10.1016/S0040-4039(01)01187-X

The total synthesis of aspirin-triggered 15-epi-LXA₄ has been achieved using a chiral pool strategy for the C1-C12 fragment starting from 2-deoxy-D-ribose. Sharpless catalytic AE generated the C15 chiral center with >98% ee. The stereospecific (Z)-reduction of the conjugated trienyne to the tetraene was achieved with Zn(Cu/Ag) in aq. CH₃OH at rt.

Full text of DOI:10.1016/S0040-4039(01)01187-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6057–6060
Total synthesis of aspirin-triggered 15-epi-lipoxin A4
Ana R. Rodr ´ı guez and Bernd W. Spur*
Department of Cell Biology, University of Medicine and Dentistry of New Jersey, SOM, Stratford, NJ 08084, USA
Received 30 May 2001; revised 27 June 2001; accepted 29 June 2001
Abstract—The total synthesis of aspirin-triggered 15-epi-LXA has been achieved using a chiral pool strategy for the C1–C12
4
fragment starting from 2-deoxy-D-ribose. Sharpless catalytic AE generated the C15 chiral center with >98% ee. The stereospecific
(
Z)-reduction of the conjugated trienyne to the tetraene was achieved with Zn(Cu/Ag) in aq. CH OH at rt. © 2001 Elsevier
3
Science Ltd. All rights reserved.
In 1984, Samuelsson and Serhan isolated a new class of
arachidonic acid metabolites. These compounds, pro-
duced by cell–cell interaction, were named lipoxin A
obtain sufficient quantities by chemical synthesis. We
have previously reported the total synthesis of LXA
and LXB4. In this communication we describe the
4
18
1
and B. Their structures have been established by total
total synthesis of aspirin-triggered 15-epi-lipoxin A (1).
4
2
–8
syntheses.
activities distinct from other eicosanoids.
was identified in the bronchoalveolar lavage fluid of
The lipoxins showed potent biological
As shown in the retrosynthetic analysis (Fig. 1) 2-
9–13
Lipoxin A4
deoxy-D-ribose (4) and 2-(E)-octen-1-ol (5) were the
required starting materials.
1
4
humans with different lung diseases.
We could
demonstrate that inhaled lipoxin A blocked the bron-
choconstriction of leukotrienes in asthmatic subjects.
More recently Serhan et al. discovered that aspirin
triggers a switch in the biosynthesis of lipoxins and
The key fragment A (2) was obtained from 2-deoxy-D-
4
15
ribose (4) in seven steps as outlined in Scheme 1.
Compound 4 was transformed to its isopropylidene
derivative 6 with 2-methoxypropene and cat. PPTS in
initiates the formation of 15-epi-lipoxin A (1), that is
EtOAc. Wittig reaction of
6
with methyl
4
biologically more active than LXA as an anti-inflam-
(triphenylphosphoranylidene)acetate in THF at reflux-
followed by catalytic hydrogenation with Rh (5 wt.%
on alumina) in MeOAc afforded 7 in 65% overall
4
matory agent. Subsequent studies showed that 1 was
16,17
twice as active as dexamethasone in animal models.
1
9
Due to their minute quantities from natural sources
and in order to explore their full potential as a new lead
structure for anti-inflammatory drugs, it is necessary to
yield. Swern oxidation of 7 with SO ·Py/DMSO in
3
CH Cl at 0°C gave the aldehyde 8 in 86% yield after
chromatography. Wittig reaction of 8 with [2(E)-5-
2
2
20
Figure 1.
Keywords: palladium catalyst; eicosanoids; Katsuki–Sharpless reaction; reduction.
*
Corresponding author. Tel.: +1-856-566-7016; fax: +1-856-566-619; e-mail: spurbw@umdnj.edu
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01187-X

6
058
A. R. Rodr ´ı guez, B. W. Spur / Tetrahedron Letters 42 (2001) 6057–6060
Scheme 1. Reagents and conditions: (a) 2-Methoxypropene, PPTS cat., EtOAc, rt; (b) Ph PꢀCH–COOMe, benzoic acid cat., THF,
3
+
reflux; (c) H , Rh (5 wt.% on alumina), MeOAc, rt; (d) SO ·Py, DMSO, Et N, CH Cl , 0°C; (e) (E)-TMS–CꢁC–CHꢀCH–CH –P
2
3
3
2
2
2
−
Ph Br , n-BuLi, THF, −78°C; (f) I , benzene, rt; (g) KF, 18-crown-6, DMF, rt.
3
2
trimethylsilyl-2-penten-4-ynyl] triphenylphosphonium
bromide/n-BuLi in THF at −78°C, followed by iso-
lidene and silyl groups with 2N HCl in THF/CH OH/
H O afforded crystalline 13 in 71% yield. The
2
3
3
merization with a catalytic amount of iodine in benzene
and cleavage of the TMS-group with KF and 18-
crown-6 (5%) in DMF gave fragment A (2) in 75%
yield.
semihydrogenation of triple bonds in the presence of
conjugated double bonds is still a challenging task.
Lindlar reduction and modifications produced to some
extent the all trans isomer and/or the over-reduced
3,28,29
products.
However, the method introduced by
The second required fragment, fragment B (3), was
readily available from 2(E)-octen-1-ol (5) as outlined in
Scheme 2. Sharpless cat. AE gave the epoxy alcohol 9
which was obtained with >98% ee after simple recrys-
Boland using Zn(Cu/Ag) in aq. MeOH at rt gave
30,31
excellent results.
No sign of over-reduction was
observed even after 36 h reaction. The preparation of
the Zn(Cu/Ag) had to be modified, only if the Zn was
activated with 2N HCl for 1–2 min, prior to the prepa-
2
1
tallization from hexane at 4°C. Compound 9 was
converted to (R)-1-octyn-3-ol (10), similar as described
3
2,33
ration of the alloy, a clean reaction occurred.
The
2
2,23
by Yadav,
and further transformed into the 1-
so prepared alloy was dried under vacuum and could be
stored for extended periods of time at −20°C under
bromo-1-alkyne 11 with NBS, in the presence of a cat.
24
amount of AgNO , in quantitative yield. The stereose-
3
argon. Mild alkaline hydrolysis of 15-epi-LXA methyl
4
lective reduction to the trans-vinylbromide 12 was
accomplished with LiAlH /AlCl in ether at 0°C in 83%
ester (14) at 0°C in THF followed by acidification and
extraction with EtOAc gave 15-epi-lipoxin A4 (1)
(Scheme 3).
4
3
2
5
®
yield. Neither LiAlH alone nor Red–Al gave satis-
4
2
6
factory results.
Standard silyl protection of the
hydroxy group in 12 with TBSCl and imidazole in
DMF gave 3 in 84% yield.
In conclusion, a concise total synthesis of aspirin-trig-
34
gered 15-epi-LXA has been achieved, which makes
4
I 3,27
Coupling of 2 with 3 in the presence of Pd°/Cu ,
this interesting compound available for further biologi-
cal and pharmacological testing.
followed by simultaneous deprotection of the isopropy-
Scheme 2. Reagents and conditions: (a) Dimethyl D-(−) tartrate (15%), Ti(i-PrO) (10%), TBHP, CH Cl , −25 to 15°C; (b) CCl ,
4
2
2
4
Ph P, NaHCO cat., reflux; (c) LDA (5 equiv.), THF, −30°C“rt; (d) NBS, AgNO cat., acetone, rt; (e) LiAlH , AlCl , ether, 0°C;
3
3
3
4
3
(
f) TBSCl, imidazole, DMF, 0°C“rt.

A. R. Rodr ´ı guez, B. W. Spur / Tetrahedron Letters 42 (2001) 6057–6060
6059
Scheme 3. Reagents and conditions: (a) Pd(PPh ) , CuI, n-PrNH , benzene, rt; (b) 2N HCl, THF/CH OH/H O, rt; (c) Zn(Cu/Ag),
3
4
2
3
2
+
aq. CH OH, 25–30°C; (d) 1N LiOH, THF, 0°C, then H pH 5.5.
3
Acknowledgements
11. Grandordy, B. M.; Lacroix, H.; Mavoungou, E.; Krilis,
S.; Crea, A. E. G.; Spur, B. W.; Lee, T. H. Biochem.
Biophys. Res. Commun. 1990, 167, 1022–1029.
Financial support of this research in part by USDA
12. Soyombo, O.; Spur, B. W.; Lee, T. H. Allergy 1994, 49,
(
95-37200-1648) and the Department of Cell Biology
230–234.
UMDNJ–SOM is gratefully acknowledged.
1
3. Lee, T. H.; Lympany, P.; Crea, A. E. G.; Spur, B. W.
Biochem. Biophys. Res. Commun. 1991, 180, 1416–1421.
4. Lee, T. H.; Crea, A. E. G.; Gant, V.; Spur, B. W.;
Marron, B. E.; Nicolaou, K. C.; Reardon, E.; Brezinski,
M.; Serhan, C. N. Am. Rev. Resp. Dis. 1990, 141, 1453–
1
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1
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989, 32, 4181–4184.
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. Gravier-Pelletier, C.; Dumas, J.; Le Merrer, Y.; Depezay,
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0. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
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Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
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. Rodr ´ı guez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Tetrahedron Lett. 1999, 40, 5161–5164.
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6
060
A. R. Rodr ´ı guez, B. W. Spur / Tetrahedron Letters 42 (2001) 6057–6060
2
2
2
2
2
2
3. Takano, S.; Sugihara, Y.; Ogasawara, K. Heterocycles
1H), 1.8–1.6 (m, 2H), 1.5–1.4 (m, 2H), 1.4–1.2 (m, 4H),
13
1
994, 39, 59–66.
0.9 (t, J=6.6 Hz, 3H); C NMR (CDCl , 75.5 MHz): l
3
4. Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R.
Angew. Chem., Int. Ed. Engl. 1984, 23, 727–729.
5. Bohlmann, F.; Rotard, W. Liebigs Ann. Chem. 1982,
81.28, 63.41, 44.76, 37.54, 31.30, 24.58, 22.40, 13.81.
1
Compound 3: H NMR (CDCl , 300 MHz): l 6.2 (m,
3
2H), 4.2–4.0 (m, 1H), 1.6–1.2 (m, 8H), 1.0–0.8 (s overlap-
13
1
216–1219.
6. Jones, K. T.; Denmark, S. E. Org. Synth. 1985, 64,
82–188.
ping t, 12H), 0.04 (s, 3H), 0.03 (s, 3H); C NMR
CDCl , 75.5 MHz): l 141.17, 105.48, 73.09, 37.70, 31.65,
(
3
1
2
5.72 (3C), 24.45, 22.48, 18.07, 13.90, −4.64, −4.99. Com-
7. Tsuji, J. Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; John Wiley: New York, 1995.
8. Choi, J.; Yoon, N. M. Tetrahedron Lett. 1996, 37, 1057–
1
pound 2: H NMR (CDCl , 300 MHz): l 6.7 (dd, J=
3
1
(
4
(
5.6, 10.8 Hz, 1H), 6.3 (dd, J=15.3, 10.8 Hz, 1H), 5.7
dd, J=15.3, 7.8 Hz, 1H), 5.6 (dd, J=15.6, 2.3 Hz, 1H),
.5 (t, J=7.8 Hz, 1H), 4.2–4.1 (m, 1H), 3.6 (s, 3H), 3.0
d, J=2.3 Hz, 1H), 2.3 (t, J=7.5 Hz, 2H), 1.9–1.6 (m,
1
060.
2
3
9. Ho, T.-L.; Liu, S.-H. Synth. Commun. 1987, 17, 969–974.
0. Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. Helv.
Chim. Acta 1987, 70, 1025–1040.
13
2H), 1.5 (s, 3H), 1.5–1.3 (m, 2H), 1.3 (s, 3H); C NMR
(
CDCl , 75.5 MHz): l 173.82, 142.33, 132.41, 131.93,
3
31. Alami, M.; Crousse, B.; Linstrumelle, G.; Mambu, L.;
1
2
11.03, 108.49, 82.57, 80.01, 78.61, 78.16, 51.39, 33.64,
9.90, 28.07, 25.47, 21.61. Compound 13: H NMR
Larchev eˆ que, M. Tetrahedron: Asymmetry 1997, 8, 2949–
1
2
958.
(
CDCl , 300 MHz): l 6.6 (dd, J=15.6, 10.8 Hz, 1H),
3
32. Zn (1.05 g, 16.1 mmol) was stirred for 2 min with 2N
HCl (5 mL) under argon. The residue was washed with
6
6
1
5
.4–6.3 (dd, J=15.0, 10.8 Hz, 1H), 6.2–6.1 (dd, J=15.9,
.3 Hz, 1H), 5.9–5.7 (m, 3H), 4.2–4.1 (m, 2H), 3.8–3.6 (m,
H), 3.7 (s, 3H), 2.4–2.3 (t, J=7.0 Hz, 2H), 1.9–1.6 (m,
2
N HCl (3×5 mL) and H O (5×5 mL) before it was
2
resuspended in H O (6 mL) under argon. Cu(OAc) ·H O
2
2
2
13
H), 1.6–1.2 (m, 10H), 0.9 (t, J=6.9 Hz, 3H); C NMR
(105 mg, 0.53 mmol) was added and stirred for 15 min,
(
CDCl , 75.5 MHz): l 174.28, 145.90, 140.52, 133.26,
3
then AgNO (105 mg, 0.62 mmol) was added and stirred
3
1
5
1
6
32.27, 112.34, 109.91, 90.79, 89.28, 75.23, 73.80, 72.37,
for 15 additional min. The Zn(Cu/Ag) alloy was filtered
1.55, 36.94, 33.62, 31.63, 31.30, 24.84, 22.48, 20.96,
through a glass frit and washed successively with H O (20
2
1
3.89. Compound 14: H NMR (CD CN, 300 MHz): l
3
mL), CH OH (20 mL), acetone (20 mL) and ether (20
3
.9–6.7 (m, 2H), 6.5–6.3 (m, 2H), 6.2–6.0 (m, 2H), 5.9–5.7
mL). The powder was dried under vacuo and stored at
(
m, 2H), 4.2–4.1 (m, 1H), 4.1–3.9 (m, 1H), 3.6 (s, 3H),
−
20°C under argon. To a solution of 13 (10 mg, 0.027
3
2
2
.6–3.4 (m, 1H), 3.1 (d, J=5.4 Hz, 1H), 2.9–2.8 (m, 2H),
mmol) in CH OH (10 mL) under argon was added H O
3
2
.4–2.3 (t, J=7.2 Hz, 2H), 1.9–1.6 (m, 2H), 1.6–1.4 (m,
(5 mL) followed by Zn(Cu/Ag) (300 mg). The suspension
13
H), 1.4–1.2 (m, 8H), 0.9 (t, J=6.9 Hz, 3H); C NMR
was stirred in the dark at 25–30°C for 15 h. HPLC/API–
ES/MS showed complete transformation to 14. The sus-
(
CD CN, 75.5 MHz): l 174.27, 139.34, 134.32, 133.61,
3
1
5
1
6
31.91, 129.73, 129.26, 128.22, 124.93, 75.37, 74.17, 71.84,
pension was diluted with CH CN (20 mL) and filtered.
3
1.13, 37.47, 33.70, 31.78, 31.73, 25.12, 22.56, 21.44,
Evaporation under reduced pressure followed by HPLC
purification gave 14 in 77% yield. [Column: Zorbax SB–
C18 21.2×250 mm; CH OH/H O 65/35; flow: 10 mL/min;
1
3.53. Compound 1: H NMR (CD CN, 300 MHz): l
3
.8–6.6 (m, 2H), 6.4–6.2 (m, 2H), 6.1–5.9 (m, 2H), 5.9–5.7
3
2
(
(
2 dd, J=14.4, 6.6 Hz and J=15.3, 6.6 Hz, 2H), 4.1–4.0
m, 1H), 4.0–3.9 (m, 1H), 3.5–3.4 (ddd, J=9.3, 4.5, 3.3
R 53 min]. UV (CH CN) u
289, 302, 316 nm (m=
t
3
max
7
0000).
3
3. When the reaction was performed in CD OD/D O the
Hz, 1H), 2.3–2.2 (t, J=7.2 Hz, 2H), 1.8–1.6 (m, 2H),
1.6–1.4 (m, 2H), 1.4–1.2 (m, 8H), 0.9 (t, J=6.9 Hz, 3H);
3
2
1
1,12-dideuterio-15-epi-LXA4 methyl ester was cleanly
13
produced.
C NMR (CD CN, 75.5 MHz): l 174.85, 139.57, 134.58,
3
3
4. Satisfactory spectroscopic data were obtained for all
133.86, 132.12, 129.96, 129.50, 128.44, 125.18, 75.57,
74.44, 72.05, 37.69, 33.64, 31.98, 31.94, 25.30, 22.74,
21.56, 13.69.
1
compounds. Selected spectra: Compound 11: H NMR
(
CDCl , 300 MHz): l 4.4 (t, J=6.6 Hz, 1H), 2.0 (br. s,
3
.