Total synthesis of lipoxin A4 and lipoxin B4 from butadiene

Article abstract of DOI:10.1016/S0040-4039(99)02201-7

The total synthesis of LXA₄ and LXB₄ has been achieved starting from butadiene via palladium catalyzed telomerization. Sharpless catalytic AE and C-2 inversion of the 2(S),3(S)-epoxy alcohols, using Myers CO₂/Cs₂CO₃ procedure, generated the asymmetric centers. The flexibility of the strategy allows an easy access to the linear eicosanoids. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02201-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 823–826
Total synthesis of lipoxin A4 and lipoxin B4 from butadiene
A. Rodríguez,a M. Nomen,a,† B. W. Spur,a,c,∗ J. J. Godfroid b and T. H. Lee c
aDepartment of Cell Biology, University of Medicine and Dentistry of New Jersey, SOM, Stratford, NJ 08084, USA
bLaboratorie de Pharmacochimie Moléculaire, Université Paris 7, Paris 75251, France
cDepartment of Allergy and Respiratory Medicine, UMDS, Guy’s and St. Thomas Hospital, London SE1 9RT, UK
Received 22 October 1999; revised 5 November 1999; accepted 5 November 1999
Abstract
The total synthesis of LXA4 and LXB4 has been achieved starting from butadiene via palladium catalyzed telo-
merization. Sharpless catalytic AE and C-2 inversion of the 2(S),3(S)-epoxy alcohols, using Myers CO2/Cs2CO3
procedure, generated the asymmetric centers. The flexibility of the strategy allows an easy access to the linear
eicosanoids. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: palladium catalyst; eicosanoids; inversion reaction; Katsuki–Sharpless reaction.
Samuelsson and Serhan investigated the interaction between lipoxygenase pathways and isolated two
new compounds, lipoxin A4 (1) and lipoxin B4 (2).1,2 These metabolites of arachidonic acid contain a
conjugated tetraene structure. Earlier reports showed that LXA4 and LXB4 blocked the effects of PAF
and LTB4 in human cells.3–6 In animal models of inflammation the activity of LXA4 was comparable to
corticosteroids.7 LXA4 was identified in the bronchoalveolar lavage fluid of humans with different lung
diseases.8 We could demonstrate that inhaled lipoxin A4 blocked the bronchoconstriction of leukotrienes
in asthmatic subjects.9
Chemical syntheses of LXA4 (1) and LXB4 (2) are required to produce sufficient quantities to study
their biological and pharmacological properties.10–15 2-Deoxy-D-ribose has been used in the chiral pool
synthesis of lipoxins.12,16 In this communication we describe a convenient synthesis of LXA4 (1) and
LXB4 (2) starting from butadiene via palladium catalyzed telomerization.
The dimerization of butadiene with acetic acid in the presence of Pd(Acac)2 (0.2%), tri-o-
tolylphosphite (0.2%) and NaOAc (3%) at room temperature produced a mixture of the octadienol
acetates 4 (13%), 5 (76%) and 6 (11%) in 90% yield after distillation (the ratio of isomers was
determined by 1H NMR) (Scheme 1).17–19
The chiral building block 7 was obtained directly from the mixture of octadienols 4a, 5a and 6a by
Sharpless cat. AE20 at −25°C to −15°C for 6 h (60% isolated yield, 79% based on 5a). The epoxidation
∗
†
Corresponding author. Tel: 1-856-566-7016; fax: 1-856-983-4953; e-mail: spurbw@umdnj.edu (B. W. Spur)
Deceased September 26, 1997.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02201-7
tetl 16129

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Scheme 1. (a) AcOH, Pd(Acac)2 cat., tri-o-tolylphosphite cat., NaOAc cat., rt; (b) K2CO3, Na2SO4, MeOH, rt
of the trans allyl alcohol 5a was preferred over the cis 6a and the 3-hydroxy allyl isomer 4a under these
reaction conditions. Compound 7 was transformed to the acetate 8 with Ac2O in pyridine at 0°C (Scheme
2) [>94% ee determined by 1H NMR using Eu(hfc)3 shift reagent in C6D6]. The transformation of 8 to
the epoxy acetate 9 was carried out as described by Sharpless (RuCl3, NaIO4) followed by treatment
with CH2N2 (71% yield).21 The cleavage of the acetate in the presence of the epoxide and the methyl
ester in 9 was readily achieved with cat. K2CO3 in the presence of anhydrous Na2SO4 in MeOH. Under
these conditions neither ester cleavage nor Payne rearrangements were observed. Simple filtration of the
Na2SO4 and normal work up gave 9a in 69% yield and >94% ee (Scheme 3).
Scheme 2. (a) Dimethyl-L-(+)tartrate (12%), Ti(i-PrO)4 (10%), TBHP, −25°C→−15°C, 6 h; (b) Ac2O, pyridine, 0°C, 12 h
The direct conversion of 9a to the C-2 inverted hydroxy carbonate 10, bearing the required 5S,6R-
configuration of LXA4, was achieved with 1 atm CO2 using Myers procedure (Cs2CO3 and 3 Å molecular
sieves in DMF at 40°C in 40% yield).22 Small quantities of the internal carbonate were detected but
were easily removed by flash chromatography. The hydrolysis of the cyclic carbonate in the presence
of the methyl ester in 10 could be accomplished by base catalyzed transesterification with cat. NaOMe
in MeOH at rt to give 11, the C1–C7 building block of LXA4, identical with material prepared from
2-deoxy-D-ribose.16,23
The epoxy alcohol 9a was converted to the chloro epoxide 12 with Ph3P in CCl4 at reflux in the
presence of a small quantity of NaHCO3 (52% isolated yield). Base catalyzed elimination with excess
of LDA at −70°C to rt, similar to Yadav procedure,24 afforded 13 (C1–C7 synthon of LXB4) in 86%
isolated yield. Other reaction conditions produced mixtures of Z and E-vinyl chlorides, besides starting
material and the required alkyne 13, similar as reported by Takano et al.25
The C13–C20 building block of LXA4 16 was obtained from 8 via hydrogenation to 14 [Rh (5 wt% on
alumina), 1 atm H2, 95% isolated yield]. Compound 14a was converted to 16 using the same reagents
and conditions as described for the transformation of 9a to 13 (Scheme 3). The C13–C20 building block
of LXB4 18 was obtained from 14a similar to the transformation of 9a to 11 (Scheme 3).
Compounds 11 and 18 were transformed to their tri-TES ethers and selectively oxidized in the
primary position as previously described.26 The synthesis of LXA4 (1) and LXB4 (2) were completed
13,14
using Nicolaou’s route
and were identical in all aspects with material prepared from 2-deoxy-D-
ribose.12,16,26
In summary, the total synthesis of LXA4 and LXB4 from butadiene has been achieved.27 The flexibility
of the strategy allows an easy access to the linear eicosanoids as shown in Scheme 3.11–14,23,26,28

825
Scheme 3. (a) NaIO4, RuCl3 cat., CCl4/CH3CN/H2O, 0°C; (b) CH2N2, Et2O, 0°C; (c) K2CO3 cat., Na2SO4, MeOH, rt; (d) CO2
(1 atm), Cs2CO3, 3 Å molecular sieves, DMF, 40°C; (e) NaOMe cat., MeOH; (f) CCl4, Ph3P, NaHCO3 cat., reflux; (g) LDA (15
equiv.), THF, −70°C→rt; (h) H2, Rh (5 wt% on alumina), EtOAc, rt
Acknowledgements
Financial support of this research in part by Laboratorios Lasa S.A., Barcelona (Spain), the Asthma
Research Council, UK and the Department of Cell Biology UMDNJ-SOM is gratefully acknowledged.

826
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1
27. Satisfactory spectroscopic data were obtained for all compounds. Selected spectra: 5: H NMR (CDCl3, 300 MHz): δ
5.8–5.6 (m, 2H), 5.5 (dtt, J=15.4, 6.4, 1.4 Hz, 1H), 5.0–4.8 (m, 2H), 4.4 (dd, J=6.3, 0.9 Hz, 2H), 2.0–1.9 (m and s, 7H),
1.4 (quint., J=7.5 Hz, 2H); 13C NMR (CDCl3, 75.5 MHz): δ 170.6, 138.2, 135.8, 124.0, 114.5, 64.9, 32.9, 31.3, 27.8, 20.6.
8: 1H NMR (CDCl3, 300 MHz): δ 5.9–5.7 (ddt, J=17.2, 10.4, 6.7 Hz, 1H), 5.1–4.9 (m, 2H), 4.4–4.3 (dd, J=12.3, 3.3 Hz,
1H), 3.9 (dd, J=12.3, 6.3 Hz, 1H), 3.0–2.9 (ddd, J=6.3, 3.3, 2.1 Hz, 1H), 2.9–2.8 (m, 1H), 2.1–2.0 (m, 2H), 2.1 (s, 3H),
1.7–1.4 (m, 4H); 13C NMR (CDCl3, 75.5 MHz): δ 170.8, 138.2, 115.0, 64.6, 56.4, 55.1, 33.2, 30.8, 24.9, 20.6. 9a: 1H NMR
(CDCl3, 300 MHz): δ 3.8 (dd, J=12.6, 2.4 Hz, 1H), 3.6 (s, 3H), 3.5 (dd, J=12.6, 4.5 Hz, 1H), 2.9–2.8 (m, 2H), 2.8–2.7 (br.
s, 1H), 2.3 (t, J=7.3 Hz, 2H), 1.8–1.6 (m, 2H), 1.6–1.4 (m, 2H); 13C NMR (CDCl3, 75.5 MHz): δ 173.7, 61.6, 58.2, 55.3,
51.3, 33.2, 30.6, 21.1. 11: 1H NMR (CDCl3, 300 MHz): δ 3.9–3.7 (m, 3H), 3.7 (s, 3H), 3.6–3.5 (m, 1H), 2.4 (t, J=7.2 Hz,
2H), 1.9–1.6 (m, 2H), 1.6–1.4 (m, 2H); 13C NMR (CDCl3, 75.5 MHz): δ 174.4, 73.7, 73.2, 63.3, 51.6, 33.5, 32.3, 20.9. 12:
1H NMR (CDCl3, 300 MHz): δ 3.7 (s, 3H), 3.6–3.5 (dd AB system, J=11.7, 5.7 Hz, 1H), 3.5–3.4 (dd AB system, J=11.7,
5.4 Hz, 1H), 3.0 (ddd, J=5.7, 5.4, 2.1 Hz, 1H), 2.9–2.8 (ddd, J=6.3, 4.8, 2.1 Hz, 1H), 2.4–2.3 (t, J=7.3 Hz, 2H), 1.9–1.7
1
(m, 2H), 1.7–1.5 (m, 2H); 13C NMR (CDCl3, 75.5 MHz): δ 173.6, 58.3, 56.8, 51.5, 44.5, 33.3, 30.7, 21.1. 17: H NMR
(CDCl3, 300 MHz): δ 4.6 (ddd, J=8.4, 6.5, 3.8 Hz, 1H), 4.5 (dd, J=8.4, 6.5 Hz, 1H), 4.4 (t, J=8.4 Hz, 1H), 3.9 (m, 1H), 2.7
(br. d, J=4.2 Hz, 1H), 1.5–1.2 (m, 8H), 0.9 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): δ 155.4, 78.7, 70.2, 65.1, 31.7,
1
31.4, 24.8, 22.3, 13.8. 18: H NMR (CDCl3/CD3OD, 300 MHz): δ 3.6–3.5 (dd AB system, J=11.4, 4.2 Hz, 1H), 3.5 (dd
AB system, J=11.4, 5.4 Hz, 1H), 3.5–3.4 (m, 1H), 3.4–3.3 (m, 1H), 1.5–1.1 (m, 8H), 0.8–0.7 (t, J=6.6 Hz, 3H); 13C NMR
(CDCl3/CD3OD, 75.5 MHz): δ 74.0, 73.0, 63.0, 32.6, 31.5, 25.1, 22.2, 13.4.
28. Radmark, O.; Serhan, C.; Hamberg, M.; Lundberg, U.; Ennis, M. D.; Bundy, G. L.; Oglesby, T. D.; Aristoff, P. A.; Harrison,
A. W.; Slomp, G.; Scahill, T. A.; Weissmann, G.; Samuelsson, B. J. Biol. Chem. 1984, 259, 13011–13016.