First total synthesis of 7(S),16(R),17(S)-Resolvin D2, a potent anti-inflammatory lipid mediator

Article abstract of DOI:10.1016/j.tetlet.2004.09.129

A total synthesis of a biological highly active lipid mediator derived from docosahexaenoic acid is described. The first total synthesis of 7(S),16(R),17(S)-Resolvin D2, a lipid mediator derived from docosahexaenoic acid, has been achieved. The key features of our synthetic strategy encompass a Co-salen hydrolytic kinetic resolution of a terminal epoxide combined with a chiral pool strategy.

Full text of DOI:10.1016/j.tetlet.2004.09.129

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8717–8720
First total synthesis of 7(S),16(R),17(S)-Resolvin D2, a potent
anti-inflammatory lipid mediator
*
´
Ana R. Rodrıguez and Bernd W. Spur
Department of Cell Biology, University of Medicine and Dentistry of New Jersey, SOM, Stratford, NJ 08084, USA
Received 10 September 2004; accepted 20 September 2004
Available online 7October 2004
Abstract—The first total synthesis of 7(S),16(R),17(S)-Resolvin D2, a lipid mediator derived from docosahexaenoic acid, has been
achieved. The key features of our synthetic strategy encompass a Co-salen hydrolytic kinetic resolution of a terminal epoxide com-
bined with a chiral pool strategy.
Ó 2004 Elsevier Ltd. All rights reserved.
Recently, Serhan and co-workers reported a new class of
lipid mediators derived from docosahexaenoic acid that
posses potent anti-inflammatory and immunoregulatory
activities in the low pico to nanomolar range.1–5 These
new compounds are formed in vivo via cell–cell interac-
tion and were named Resolvins (resolution phase inter-
action products).6 Docosahexaenoic acid is highly
enriched in brain, synapses and retina. Deficiencies of
this x-3 fatty acid are associated with Alzheimer disease,
stroke, hyperactivity, schizophrenia and peroxisomal
disorders.7
Serhanꢀs work has established for the first time the
Figure 1.
molecular basis and the mechanism of x-3 fatty acids
immune protective action. Since from natural sources
only tiny amounts are available they have to be prep-
ared by total chemical synthesis in order to expedite
Figure 2.
Keywords: Resolvins; Hydrolytic kinetic resolution; Palladium catalyst; Takai reaction; Reduction.
*
Corresponding author. Tel.: +1 856 566 7016; fax: +1 856 566 6195; e-mail: spurbw@umdnj.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.129

´
A. R. Rodrıguez, B. W. Spur / Tetrahedron Letters 45 (2004) 8717–8720
8718
shown in the retrosynthetic scheme (Fig. 2), the chiral
centre at C-7was obtained via a Jacobsen hydrolytic
kinetic resolution of a terminal epoxide whereas the cen-
tres at C-16 and C-17arise from a chiral pool strategy.
The C1–C9 fragment was obtained from commercial
pentynoic acid (6) as outlined in Scheme 1. Alkylation
of the di-magnesium complex of pentynoic acid with allyl
bromide (7) in THF, in the presence of a catalytic
amount of CuBr–Me2S,10 afforded crude oct-7-en-4-
ynoic acid (8) that was in situ esterified with 2,2-dimeth-
oxypropane/MeOH/10% TMSCl11 to give 9. Epoxida-
tion with 3-chloroperoxybenzoic acid in the presence
of NaHCO3 in CH2Cl2 at 0°C furnished epoxide 10.
Jacobsenꢀs hydrolytic kinetic resolution with H2O in
the presence of 5% (R,R)-salen-Co catalyst in Et2O furn-
ished the diol 11 with >94% ee as determined by chi-
ral HPLC of the dibenzoate derivative.12,13 Employing
the (S,S)-salen-Co catalyst the enantiomer was
obtained with >95% ee. Diol 11 was converted into
the di-TES-ether 13 with 4equiv TESCl/imidazole/
Et3N/DMF in 84% yield.14 Lindlar reduction in hexane
cleanly produced the cis-alkene 14 in quantitative yield.
Chemoselective oxidation of the primary TES-ether
using Swern reagent produced the aldehyde 15 in 54%
yield.15 The C1–C9 fragment (2) was obtained from 15
by Takai olefination CrCl2/CHI3/THF 0°C in 50%.16,17
Scheme 1. Reagents and conditions: (a) MeMgBr, CuBrÆMe2S, THF,
0°C to rt; (b) 10% TMSCl, MeOH, 2,2-dimethoxypropane, rt; (c)
MCPBA, NaHCO3, CH2Cl2, 0°C to rt; (d) (R,R)-(salen)Co(III)(OAc)
catalyst, Et2O/H2O, 0°C to rt; (e) flash chromatography separation; (f)
TESCl, imidazole, Et3N, DMF, 0°C to rt; (g) Lindlar cat., Et3N,
hexane; (h) (COCl)2, DMSO, CH2Cl2, Et3N, À78°C to rt; (i) CrCl2,
CHI3, THF, 0°C.
The C10–C22 fragment was obtained in five steps from
3,4-O-isopropylidene-2-deoxy-D-ribose,18 as outlined in
Scheme 2. Wittig reaction with 2.5equiv of phosphorane
5, generated in situ from the phosphonium bromide 16
in THF and NaN(TMS)2, produced the cis-alkene
17,19 containing 5–20% of the unwanted trans-isomer
as identified by 13C NMR (cis-isomer 124.0,
134.4ppm, trans-isomer 124.4, 135.2ppm). However, if
the reaction was carried out in Et2O at À78°C followed
by slowly warming up to 0°C, 17 was produced without
detectable amounts of the trans-isomer. Oxidation of 17
with PCC20 in the presence of sodium acetate in CH2Cl2
continuing biological and pharmacological investiga-
tions. These natural products could be novel lead struc-
tures for the development of drugs that inhibit PMN
infiltration at the side of inflammation and to circum-
vent side effects of current anti-inflammatory drugs.8,9
In this communication we wish to report the first total
synthesis of 7(S),16(R),17(S)-Resolvin D2 (Fig. 1). As
Scheme 2. Reagents and conditions: (a) NaN(TMS)2, Et2O, À7 8 to 0°C; (b) PCC, NaOAc, CH2Cl2; (c) BuLi, THF, À7 8 to 0°C; (d) I2, benzene, rt;
(e) KF, 18-crown-6, DMF, rt.

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A. R. Rodrıguez, B. W. Spur / Tetrahedron Letters 45 (2004) 8717–8720
8719
Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, CuI, n-PrNH2, benzene, rt; (b) pyridinium, p-toluenesulfonate, CH3OH, rt; (c) 1N HCl, CH3OH/
H2O, rt; (d) Zn(Cu/Ag), aq CH3OH, 40°C; (e) 1N LiOH, THF, 0°C, then EtOAc, satd NaH2PO4.
gave the isopropylidene aldehyde 18 in 70% yield after
chromatography. Wittig reaction of 18 with 1.6equiv
of [2(E)-5-trimethylsilyl-2-penten-4-ynyl] triphenylphos-
phonium bromide/n-Bu–Li21,22 in THF at À78°C pro-
duced 20 as a mixture of cis- and trans-isomers.
However, 20 could be easily isomerized with a catalytic
amount of iodide in benzene to give the trans,trans-en-
yne 21. Cleavage of the terminal TMS-group was
achieved with KF and 5% 18-crown-6 in DMF in 83%
isolated yield.23
References and notes
1. Serhan, C. N.; Hong, S.; Gronert, K.; Colgan, S. P.;
Devchand, P. R.; Mirick, G.; Moussignac, R. L. J. Exp.
Med. 2002, 196(8), 1025–1037.
2. Hong, S.; Gronert, K.; Devchand, P. R.; Moussignac, R.
L.; Serhan, C. N. J. Biol. Chem. 2003, 278(17), 14677–
14687.
3. Marcheselli, V. L.; Hong, S.; Lukiw, W. J.; Tian, X. H.;
Gronert, K.; Musto, A.; Hardy, M.; Gimenez, J. M.;
Chiang, N.; Serhan, C. N.; Bazan, N. G. J. Biol. Chem.
2003, 278(44), 43807–43817, Erratum in:. J. Biol. Chem.
2003, 278(51), 51974.
4. Mukherjee, P. K.; Marcheselli, V. L.; Serhan, C. N.;
Bazan, N. G. Proc. Natl. Acad. Sci. U.S.A. 2004, 101(22),
8491–8496.
5. Serhan, C. N.; Chiang, N. Rheum. Dis. Clin. N. Am. 2004,
30(1), 69–95.
6. Serhan, C. N.; Gotlinger, K.; Hong, S.; Arita, M. Prostag.
Oth. Lipid Mediators 2004, 73(3–4), 155–172.
7. Horrocks, L. A.; Farooqui, A. A. Prostag. Leukotr. Ess.
2004, 70, 361–372.
8. Takai, D.; Nagase, T.; Shimizu, T. Nat. Immunol. 2004, 5,
357–358.
9. Gilroy, D. W.; Lawrence, T.; Perretti, M.; Rossi, A. G.
Nat. Rev. Drug Discovery 2004, 3, 401–416.
10. Corey, E. J.; Su, W.-g. Tetrahedron Lett. 1984, 25, 5119–
5122.
Coupling of 2 with 22 in the presence of Pd0/CuI,21
furnished the Resolvin precursor 23 that was, without
purification converted to 24 with pyridinium p-toluene-
sulfonate in MeOH. Removal of the isopropylidene
group was best achieved with 1N HCl in MeOH/H2O
at room temperature for 15min to give 25. Stereospecific
(Z)-reduction of the conjugate trienyne 25 to the tetra-
ene 26 was carried out with fresh prepared Zn(Cu/
Ag)24 in 1:1 CH3OH/H2O at 40°C for 5h in 70% yield
after HPLC purification. Mild alkaline hydrolysis of
7(S),16(R),17(S)-Resolvin D2 methyl ester (26) with
1N LiOH in THF at 0°C followed by acidification with
NaH2PO4 in the presence of EtOAc gave
7(S),16(R),17(S)-Resolvin D2 (1) (Scheme 3).
11. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Tetrahedron Lett. 1998, 39, 8563–8566.
12. The enantiomeric excess was determined by Chiral-HPLC
[column: Chiracel OF, mobile phase: hexane/i-PrOH
(75:25) k = 265nm].
13. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307–1315.
14. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J.-J.;
Lee, T. H. Tetrahedron 2001, 57, 25–37.
In conclusion,
a
concise total synthesis of
7(S),16(R),17(S)-Resolvin D2 has been achieved,25 mak-
ing this novel lipid mediator available for further biologi-
cal and pharmacological testing. The synthesis of other
Resolvins, Docosatrienes and Neuroprotectins will be
reported in due course.
Acknowledgements
15. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Tetrahedron Lett. 1999, 40, 5161–5164.
16. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408–7410.
Financial support of this research in part by USDA (95–
37200–1648) and the Department of Cell Biology
UMDNJ–SOM is gratefully acknowledged.

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A. R. Rodrıguez, B. W. Spur / Tetrahedron Letters 45 (2004) 8717–8720
8720
17. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2003, 44,
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18. Corey, E. J.; Marfat, A.; Munroe, J.; Kim, K. S.; Hopkins,
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19. Morris, J.; Wishka, D. G. Tetrahedron Lett. 1986, 27, 803–
806.
4.6–4.5 (m, 1H), 4.2–4.1 (dt, J = 8.1, 6.3Hz, 1H), 2.3–2.1
(m, 2H), 2.0 (m, 2H), 1.5 (s, 3H), 1.3 (s, 3H), 0.9 (t,
J = 7.5Hz, 3H), 0.2 (s, 9H); 13C NMR (CDCl3,
75.5MHz): d 141.65, 134.13, 132.12 (2C), 124.04, 112.05,
108.44, 104.15, 97.74, 78.59, 78.51, 28.67, 28.01, 25.42,
20.68, 13.91, 0.26 (3C). Compound 25: 1H NMR (d6-
benzene, 300MHz): d 6.7(dd, J = 15.6, 11.1Hz, 1H), 6.3–
6.1 (m, 3H), 5.8 (dd, J = 15.6, 2.1Hz, 1H), 5.7–5.6 (dd,
J = 15.3, 6.3Hz, 1H), 5.6–5.3 (m, 4H), 4.1–3.9 (m, 2H),
3.6–3.5 (m, 1H), 3.4 (s, 3H), 2.4–2.1 (m, 8H), 2.0 (m,
2H), 1.8–1.7(br s, 1H), 1.7(br s, 1H), 1.6 (br s, 1H), 0.9
(t, J = 7.5Hz, 3H), 0.2 (s, 9H); 13C NMR (d6-benzene,
75.5MHz): d 173.47, 146.22, 141.56, 135.13, 135.07,
132.07, 131.64, 126.75, 125.48, 112.78, 110.59, 91.96,
90.53, 75.24, 74.66, 71.74, 51.38, 35.70, 34.06, 30.77,
23.40, 21.31, 14.60. HPLC/API–ES/MS (m/z): 411
[M+Na+]+. Compound 26: 1H NMR (CD3CN,
300MHz): d 6.9–6.7(m, 2H), 6.5–6.3 (m, 2H), 6.1–6.0
(m, 2H), 5.9–5.7(m, 2H), 5.6–5.4 (m, 4H), 4.2 (m, 1H),
4.1–4.0 (m, 1H), 3.6 (s, 3H), 3.6–3.5 (m, 1H), 3.2–3.1 (br d,
J = 4.8Hz, 1H), 3.0 (br d, J = 4.8Hz, 1H), 2.9–2.8 (br d,
J = 5.1Hz, 1H), 2.4–2.0 (m, 10H), 1.0 (t, J = 7.5Hz, 3H);
13C NMR (CD3CN, 75.5MHz): d 174.03, 138.75, 134.58,
134.02, 133.93, 132.28, 130.55, 129.87, 129.76, 128.47,
127.29, 126.12, 125.52, 75.30, 75.05, 71.86, 51.46, 35.67,
34.01, 30.84, 23.21, 20.85, 13.97. UV (EtOH) kmax 289,
302, 316nm. HPLC/API–ES/MS (m/z): 413 [M+Na+]+.
Compound 1: 1H NMR (CD3CN, 300MHz): d 6.9–6.7(m,
2H), 6.5–6.3 (m, 2H), 6.1–6.0 (m, 2H), 5.9–5.7(m, 2H),
5.6–5.4 (m, 4H), 4.3–4.1 (m, 1H), 4.1–4.0 (m, 1H), 3.6–3.5
(m, 1H), 2.5–2.0 (m, 8H), 1.0 (t, J = 7.5Hz, 3H); 13C
NMR (CD3CN, 75.5MHz): d 175.0, 139.81, 135.59,
135.03, 134.93, 133.30, 131.67, 130.90, 130.77, 129.50,
128.26, 127.15, 126.49, 76.29, 76.03, 72.88, 36.65, 31.84,
31.20, 24.13, 21.89, 15.04. UV (EtOH) kmax 289, 302,
316nm. HPLC/API–ES/MS (m/z): 399 [M+Na+]+.
20. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16,
2647–2650.
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oulos, H. J. Am. Chem. Soc. 1985, 107, 7515–7518.
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25. Satisfactory spectroscopic data were obtained for all
compounds. Selected physical data: compound 11: 1H
NMR (CDCl3, 300MHz): d 3.9–3.8 (m, 1H), 3.8–3.7(m,
1H), 3.7(s, 3H), 3.6–3.5 (m, 1H), 2.6–2.4 (m, 4H), 2.4–2.3
(m, 2H); 13C NMR (CDCl3, 75.5MHz): d 172.72, 81.13,
76.79, 70.35, 65.53, 51.70, 33.59, 23.84, 14.73. Compound
2: 1H NMR (CDCl3, 300MHz): d 6.6 (dd, J = 14.4, 6.0Hz,
1H), 6.2 (dd, J = 14.4, 1.2Hz, 1H), 5.5–5.4 (m, 2H), 4.0–
3.9 (m, 1H), 3.4 (s, 3H), 2.4–2.1 (m, 6H), 1.0 (t, J = 7.8Hz,
9H), 0.6 (q, J = 7.8Hz, 6H); 13C NMR (CDCl3,
75.5MHz): d 173.18, 149.68, 130.98, 126.60, 76.67, 75.53,
51.31, 36.17, 34.33, 23.62, 7.25 (3C), 5.56 (3C). Compound
1
17: H NMR (CDCl3, 300MHz): d 5.6–5.4 (m, 1H), 5.4–
5.2 (m, 1H), 4.3–4.1 (m, 2H), 3.7–3.6 (m, 2H), 2.5–2.2 (m,
2H), 2.1–2.0 (m, 2H), 2.0 (br s, 1H), 1.5 (s, 3H), 1.4 (s,
3H), 1.0 (t, J = 7.5Hz, 3H); 13C NMR (CDCl3, 75.5MHz):
d 134.40, 124.00, 108.20, 77.90, 76.87, 61.70, 28.03, 27.32,
25.32, 20.70, 13.86. Compound 21: 1H NMR (CDCl3,
300MHz): d 6.6 (dd, J = 15.3, 11.1Hz, 1H), 6.3 (dd,
J = 15.3, 11.1Hz, 1H), 5.8–5.7(dd, J = 15.3, 7.8Hz, 1H),
5.6 (d, J = 15.3Hz, 1H), 5.5–5.4 (m, 1H), 5.4–5.2 (m, 1H),