First total synthesis of 7(S),17(S)-Resolvin D5, a potent anti-inflammatory docosanoid

Article abstract of DOI:10.1016/j.tetlet.2005.03.175

The first total synthesis of 7(S),17(S)-Resolvin D5, a lipid mediator derived from docosahexaenoic acid, has been achieved. The chiral centers were generated via a Co-salen hydrolytic kinetic resolution of a terminal epoxide with >99% ee. Key steps include Takai olefination, Pd⁰/Cu ^I coupling and simultaneous deprotection and ester cleavage with lipase from Candida rugosa.

Full text of DOI:10.1016/j.tetlet.2005.03.175

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3623–3627
First total synthesis of 7(S),17(S)-Resolvin D5, a potent
anti-inflammatory docosanoid
*
´
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 15 March 2005; accepted 25 March 2005
Available online 11 April 2005
Abstract—The first total synthesis of 7(S),17(S)-Resolvin D5, a lipid mediator derived from docosahexaenoic acid, has been
achieved. The chiral centers were generated via a Co-salen hydrolytic kinetic resolution of a terminal epoxide with >99% ee. Key
steps include Takai olefination, Pd0/CuI coupling and simultaneous deprotection and ester cleavage with lipase from Candida rugosa.
Ó 2005 Elsevier Ltd. All rights reserved.
Serhan et al. have recently described that docosahexa-
enoic and eicosapentaenoic acids are converted in vivo
to a new class of lipid mediators named Resolvins (res-
olution phase interaction products).1–6 These novel lipid
mediators have potent anti-inflammatory activities
in the pico to nanomolar range, explaining the health
benefit of x-3 fatty acids in humans.7 Their extremely
low availability from natural sources and our interest
to explore their biological activities prompt us to pre-
pare these compounds by total chemical synthesis. We
recently reported the total synthesis of Resolvin D2.8
In this communication, we wish to report the first total
synthesis of 7(S),17(S)-Resolvin D5 (1). Our synthetic
strategy is based on the retrosynthetic analysis shown
in Figure 1. Both chiral centers, 7(S) and 17(S), were ob-
tained from (+)-benzyl glycidyl ether (7). The similarity
of the structure around the chiral centers allowed the use
Figure 1.
Keywords: Resolvins; Hydrolytic kinetic resolution; Palladium catalyst; Takai reaction; Lindlar reduction.
*
Corresponding author. Tel.: +1 856 566 7016; fax: +1 856 566 6195; e-mail: spurbw@umdnj.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.175

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A. R. Rodrıguez, B. W. Spur / Tetrahedron Letters 46 (2005) 3623–3627
3624
of the same strategy to build up the key intermediates.
All cis double bonds were obtained via Lindlar reduc-
tion whereas the trans double bonds resulted from Takai
olefination.
was removed with a catalytic amount of pyridinium
p-toluenesulfonate (PPTS) in MeOH at rt to give 10
(88%). Compound 10 was transformed via Jones oxida-
tion, followed by in situ esterification with 2,2-dimeth-
oxypropane, MeOH, 10% TMSCl, into the methyl
ester 11 in 93% yield.15 Lindlar reduction of 11 in hex-
ane at rt gave 12 in 98% yield. The deprotection of the
benzyl group in the presence of the benzoate and the
methyl ester was achieved with EtSH, AlCl3 in CH2Cl2
at À35 °C to give 13 in 86% yield.16 Swern oxidation
with PyÆSO3 in CH2Cl2 at rt gave the aldehyde 14 in
86% yield after chromatography. The C1–C9 fragment
15 was obtained via Takai olefination of 14 CrCl2/
CHI3/THF at rt in 52% isolated yield.17
As outlined in Scheme 1, compound 7 was obtained
from racemic benzyl glycidyl ether (2) via Jacobsen
hydrolytic kinetic resolution with 0.55 equiv of H2O in
the presence of 0.1% (R,R)-salen-Co catalyst 6 [45%
yield (90% theoretical) and >99% ee].9,10
The C1–C9 fragment 15 was obtained from 7 and com-
mercial 2-(4-pentynyloxy)tetrahydro-2H-pyran (4),11 as
outlined in Scheme 2. Lithiation of 4 with BuLi in
THF at À70 °C, followed by warming to rt, and reaction
with 7 under Yamaguchi conditions (BF3ÆEt2O at
À78 °C) gave 8 in 85% isolated yield.12–14 Compound
8 was converted into the benzoate 9 in 92% yield with
2 equiv of benzoyl chloride in pyridine. The THP group
The C15–C22 fragment 21 was obtained from the chiral
glycidyl ether 7 as outlined in Scheme 3. Lithiation of
1-butyne (5) in THF with BuLi at À70 °C, followed by
warming to rt, and subsequent reaction with 7 under
Scheme 1. Reagents and conditions: (a) (R,R)-(salen)Co(III)(OAc) catalyst (6), H2O, 0 °C to rt.
Scheme 2. Reagents and conditions: (a) n-BuLi, BF3ÆEt2O, THF, À70 °C; (b) BzCl, pyridine, 0 °C to rt; (c) pyridinium p-toluenesulfonate, MeOH, rt;
(d) Jones reagent, acetone, 0 °C; (e) 10% TMSCl, MeOH, 2,2-dimethoxypropane, rt; (f) H2, Lindlar cat., hexane; (g) EtSH, AlCl3, CH2Cl2, À35 °C;
(h) PyÆSO3, DMSO, CH2Cl2, Et3N; (i) CrCl2, CHI3, THF, rt.

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A. R. Rodrıguez, B. W. Spur / Tetrahedron Letters 46 (2005) 3623–3627
3625
Scheme 3. Reagents and conditions: (a) 1-butyne (5), n-BuLi, BF3ÆEt2O, THF, À70 °C; (b) BzCl, pyridine, 0 °C to rt; (c) H2, Lindlar cat., hexane; (d)
EtSH, AlCl3, CH2Cl2, À35 °C; (e) PyÆSO3, DMSO, CH2Cl2, Et3N; (f) CrCl2, CHI3, THF, rt.
Yamaguchi conditions produced 16 in 80% yield.12–14
Compound 16 was converted into the benzoate 17 with
2 equiv of benzoyl chloride in pyridine (94%). Lindlar
hydrogenation of 17 in hexane produced 18 in 96%
yield. Deprotection of the benzyl group was achieved
as described in the synthesis of the C1–C9 fragment 15
with EtSH, AlCl3 in CH2Cl2 at À35 °C to give 19 in
85% yield after chromatography. Swern oxidation with
PyÆSO3 in CH2Cl2 at rt gave the aldehyde 20 (84%).
The trans-vinyl iodide 21 was generated using the Takai
laouꢀs procedure with AgNO3 in MeOH followed by
short treatment with NaCN.19,20 The second Pd0/CuI
coupling of 15 with 23 produced the Resolvin precursor
24 in 54% yield. Compound 25 was obtained from 24 by
controlled hydrogenation (Lindlar catalyst, deactivated
with Et3N, in hexane) in 84% yield. Hydrolysis of 25
under mild basic conditions cleaved the methyl ester
but not the benzoate groups. Stronger alkaline condi-
tions led to the decomposition of the product. Simulta-
neous cleavage of the benzoate protective groups and
hydrolysis of the methyl ester was achieved using lipase
from Candida rugosa (EC 3.1.1.3, type VII, Sigma) at
pH 7.2 affording Resolvin D5 (1) (75%) (Scheme 4).21,22
1
olefination.17 The H NMR spectrum of 21 showed the
presence of 20% of the cis-vinyl iodide that was difficult
to remove at this stage.
The Pd0/CuI coupling of crude 21 with 2 equiv of 1-tri-
methylsilyl-1,4-pentadiyne (3)18 in benzene for 1 h
gave exclusive the trans-ene-diyne 22 in 50% yield.
Under these conditions only the more reactive trans-
vinyl iodide 21 reacted. The cleavage of the terminal
TMS group to generate 23 was achieved using Nico-
In summary, a concise total synthesis of 7(S),17(S)-
Resolvin D5 has been achieved, making this novel
anti-inflammatory lipid mediator from docosahexaenoic
acid available for further biological investigations. The
synthesis of other Resolvins, Docosatrienes, and Neuro-
protectins will be reported in due course.
Scheme 4. Reagents and conditions: (a) Pd(PPh3)4, CuI, n-PrNH2, benzene, rt; (b) AgNO3, MeOH, H2O, NaCN; (c) H2, Lindlar cat., Et3N, hexane;
(d) lipase from Candida rugosa, H2O (CaCl2, NaCl), THF.

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A. R. Rodrıguez, B. W. Spur / Tetrahedron Letters 46 (2005) 3623–3627
3626
11: 1H NMR (CDCl3, 300 MHz): 8.1–8.0 (m, 2H), 7.6–7.5
Acknowledgements
(m, 1H), 7.5–7.4 (m, 2H), 7.4–7.2 (m, 5H), 5.4–5.2 (m, 1H),
4.7–4.5 (2d ABsystem, J = 12.0 Hz, 2H), 3.8–3.7 (m, 2H),
3.6 (s, 3H), 2.8–2.6 (m, 2H), 2.5–2.4 (m, 4H); 13C NMR
(CDCl3, 75.5 MHz): d 172.50, 166.03, 138.18, 133.06,
130.38, 129.84 (2C), 128.44 (2C), 128.39 (2C), 127.72,
127.69 (2C), 80.54, 75.86, 73.31, 71.65, 69.86, 51.59, 33.55,
21.23, 14.61. Compound 12: 1H NMR (CDCl3, 300 MHz):
d 8.1–8.0 (m, 2H), 7.6–7.5 (m, 1H), 7.5–7.4 (m, 2H), 7.4–7.2
(m, 5H), 5.5–5.4 (m, 2H), 5.4–5.2 (m, 1H), 4.7–4.5 (2d
ABsystem, J = 12.0 Hz, 2H), 3.7–3.6 (m, 2H), 3.6 (s, 3H),
2.6–2.5 (m, 2H), 2.5–2.2 (m, 4H); 13C NMR (CDCl3,
75.5 MHz): d 173.41, 166.07, 138.08, 132.89, 130.75, 130.40,
129.67 (2C), 128.35 (2C), 128.30 (2C), 127.61, 127.57 (2C),
125.35, 73.16, 72.90, 70.59, 51.43, 33.74, 28.87, 22.76.
Compound 14: 1H NMR (CDCl3, 300 MHz): d 9.6 (d,
J = 0.9 Hz, 1H), 8.1–8.0 (m, 2H), 7.6–7.5 (m, 1H), 7.5–7.4
(m, 2H), 5.6–5.4 (m, 2H), 5.3–5.2 (m, 1H), 3.6 (s, 3H), 2.8–
2.6 (m, 2H), 2.5–2.2 (m, 4H); 13C NMR (CDCl3,
75.5 MHz): d 198.13, 173.27, 166.07, 133.57, 131.91,
129.87 (2C), 129.17, 128.54 (2C), 123.67, 78.02, 51.43,
33.48, 27.03, 22.69. Compound 15: 1H NMR (CDCl3,
300 MHz): d 8.0 (m, 2H), 7.6–7.5 (m, 1H), 7.5–7.4 (m, 2H),
6.7–6.6 (dd, J = 15.0, 6.3 Hz, 1H), 6.6–6.4 (d, J = 15.0 Hz,
1H), 5.6–5.4 (m, 3H), 3.7 (s, 3H), 2.7–2.4 (m, 2H), 2.4–2.3
(m, 4H); 13C NMR (CDCl3, 75.5 MHz): d 173.41, 165.59,
143.50, 133.21, 131.46, 130.16, 129.74 (2C), 128.50 (2C),
124.48, 80.00, 75.43, 51.48, 33.72, 31.77, 22.88. Compound
16: 1H NMR (CDCl3, 300 MHz): d 7.4–7.2 (m, 5H), 4.6–4.5
(s, 2H), 4.0–3.8 (m, 1H), 3.6–3.4 (m, 2H), 2.5–2.4 (m, 2H),
2.2–2.0 (m, 2H), 1.1 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3,
75.5 MHz): d 138.17, 128.48 (2C), 127.80, 127.76 (2C),
84.28, 74.86, 73.43, 73.08, 69.20, 23.89, 14.02, 12.28.
Compound 17: 1H NMR (CDCl3, 300 MHz): d 8.1 (m,
2H), 7.6–7.5 (m, 1H), 7.5–7.4 (m, 2H), 7.4–7.2 (m, 5H), 5.4–
5.2 (m, 1H), 4.7–4.5 (2d ABsystem, J = 12.3 Hz, 2H), 3.8
(m, 2H), 2.8–2.6 (m, 2H), 2.2–2.0 (m, 2H), 1.1 (t, J = 7.5 Hz,
3H); 13C NMR (CDCl3, 75.5 MHz): d 166.01, 138.24,
132.95, 130.50, 129.82 (2C), 128.39 (2C), 128.33 (2C),
127.65 (3C), 84.03, 74.20, 73.29, 71.87, 69.98, 21.27, 13.93,
Financial support of this research in part by USDA (95-
37200-1648) and the Department of Cell Biology
UMDNJ–SOM is gratefully acknowledged.
References and notes
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Beaucourt, J.-P. J. Org. Chem. 1989, 54, 500–503.
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1
12.23. Compound 18: H NMR (CDCl3, 300 MHz): d 8.1
(m, 2H), 7.6–7.5 (m, 1H), 7.5–7.4 (m, 2H), 7.4–7.2 (m, 5H),
5.6–5.5 (m, 1H), 5.5–5.3 (m, 2H), 4.7–4.5 (2d ABsystem,
J = 12.0 Hz, 2H), 3.7 (m, 2H), 2.6–2.5 (m, 2H), 2.2–2.0
(m, 2H), 1.0 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3,
75.5 MHz): d 166.18, 138.28, 134.99, 132.85, 130.67,
129.73 (2C), 128.39 (2C), 128.31 (2C), 127.62, 127.60 (2C),
123.05, 73.19 (2C), 70.70, 28.81, 20.51, 13.94. Compound
19: 1H NMR (CDCl3, 300 MHz): d 8.0 (m, 2H), 7.5 (m, 1H),
7.4 (m, 2H), 5.6–5.4 (m, 1H), 5.4–5.3 (m, 1H), 5.2–5.0 (m,
1H), 3.8 (m, 2H), 2.7–2.6 (m, 1H), 2.6–2.4 (m, 2H), 2.2–2.0
(m, 2H), 0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3,
75.5 MHz): d 166.72, 135.07, 133.00, 130.31, 129.67 (2C),
128.33 (2C), 122.81, 75.76, 64.11, 28.47, 20.46, 13.84.
Compound 20: 1H NMR (CDCl3, 300 MHz): d 9.6 (d,
J = 0.6 Hz, 1H), 8.1 (m, 2H), 7.6 (m, 1H), 7.5–7.4 (m, 2H),
5.7–5.5 (m, 1H), 5.5–5.3 (m, 1H), 5.3–5.2 (br t, J = 6.4 Hz,
1H), 2.8–2.6 (m, 2H), 2.2–2.0 (m, 2H), 0.9 (t, J = 7.5 Hz,
3H); 13C NMR (CDCl3, 75.5 MHz): d 198.27, 166.16,
136.09, 133.55, 129.93 (2C), 129.36, 128.56 (2C), 121.34,
78.27, 27.11, 20.55, 13.80. Compound 22: 1H NMR
(CDCl3, 300 MHz): d 8.1–8.0 (m, 2H), 7.6–7.5 (m, 1H),
7.5–7.4 (m, 2H), 6.2–6.1 (dd, J = 15.9, 6.6 Hz, 1H), 5.8–5.7
(m, 1H), 5.6–5.4 (m, 2H), 5.4–5.2 (m, 1H), 3.3 (d,
J = 2.1 Hz, 2H), 2.6–2.4 (m, 2H), 2.2–2.0 (m, 2H), 1.0–0.9
(t, J = 7.5 Hz, 3H), 0.2 (s, 9H); 13C NMR (CDCl3,
75.5 MHz): d 165.72, 140.40, 135.34, 133.06, 130.43,
129.71 (2C), 128.42 (2C), 122.45, 112.19, 99.38, 85.40,
84.73, 78.40, 73.76, 32.11, 20.65, 13.91, 11.43, À0.24 (3C).
´
14. Rodrıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.;
Lee, T. H. Tetrahedron 2001, 57, 25–37.
´
15. Rodrıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Tetrahedron Lett. 1998, 39, 8563–8566.
16. Node, N.; Nishide, K.; Sai, M.; Ichiwa, K.; Fuji, K.;
Fujita, E. Chem. Lett. 1979, 97–98.
17. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408–7410.
18. Nicolaou, K. C.; Webber, S. E. J. Am. Chem. Soc. 1984,
106, 5734–5736.
19. Nicolaou, K. C.; Veale, C. A.; Webber, S. E.; Katerino-
poulos, H. J. Am. Chem. Soc. 1985, 107, 7515–7518.
20. Nicolaou, K. C.; Webber, S. E. Synthesis 1986, 453–461.
21. Vorlova, S.; Bornscheuer, U. T.; Gatfield, I.; Hilmer, J.
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22. Satisfactory spectroscopic data were obtained for all
compounds. Selected physical data: Compound 10: 1H
NMR (CDCl3, 300 MHz): d 8.1–8.0 (m, 2H), 7.6–7.5 (m,
1H), 7.5–7.4 (m, 2H), 7.4–7.2 (m, 5H), 5.4–5.2 (m, 1H), 4.7–
4.5 (2d ABsystem, J = 12.3 Hz, 2H), 3.8–3.7 (m, 2H), 3.7–
3.6 (t, J = 6.3 Hz, 2H), 2.8–2.6 (m, 2H), 2.3–2.2 (m, 2H),
1.8–1.6 (quint., J = 6.3 Hz, 2H); 13C NMR (CDCl3,
75.5 MHz): d 166.07, 138.19, 133.07, 130.40, 129.83 (2C),
128.44 (2C), 128.40 (2C), 127.72, 127.69 (2C), 81.77, 75.65,
73.32, 71.77, 70.02, 61.68, 31.35, 21.36, 15.17. Compound

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A. R. Rodrıguez, B. W. Spur / Tetrahedron Letters 46 (2005) 3623–3627
3627
Compound 23: 1H NMR (CDCl3, 300 MHz): 8.0 (m, 2H),
7.6–7.5 (m, 1H), 7.4 (m, 2H), 6.2–6.1 (dd, J = 15.9, 6.6 Hz,
1H), 5.8–5.7 (m, 1H), 5.6–5.4 (m, 2H), 5.4–5.2 (m, 1H), 3.3–
3.2 (br s, 2H), 2.6–2.4 (m, 2H), 2.2–2.0 (m, 3H), 1.0–0.9 (t,
J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d 165.68,
140.65, 135.34, 133.04, 130.43, 129.70 (2C), 128.42 (2C),
122.42, 111.97, 84.28, 78.64, 77.75, 73.70, 68.88, 32.09,
20.64, 13.89, 10.10. Compound 24: 1H NMR (CDCl3,
300 MHz): d 8.0 (m, 4H), 7.6–7.5 (m, 2H), 7.5–7.3 (m, 4H),
6.2–6.0 (2dd, J = 15.9, 6.3 Hz, 2H), 5.8–5.7 (m, 2H), 5.6–5.2
(m, 6H), 3.6 (s, 3H), 3.4–3.3 (br s, 2H), 2.6–2.4 (m, 4H), 2.4–
22.91, 20.70, 14.01, 11.06. Compound 25: 1H NMR
(CDCl3, 300 MHz): d 8.1–8.0 (m, 4H), 7.6–7.5 (m, 2H),
7.5–7.3 (m, 4H), 6.6 (m, 2H), 6.0–5.9 (m, 2H), 6.2–6.0 (m,
2H), 5.6–5.3 (m, 8H), 3.6 (s, 3H), 3.1–3.0 (br t, J = 7.5 Hz,
2H), 2.7–2.4 (m, 4H), 2.4–2.2 (m, 4H), 2.1–1.9 (m, 2H), 0.9
(t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d 173.36,
165.78 (2C), 134.84, 132.85, 132.80, 131.54, 131.31, 130.68
(2C), 130.49, 130.24, 130.15, 129.62, (4C), 128.34 (2C),
128.31 (2C), 128.22 (2C), 127.85, 127.68, 125.30, 122.94,
74.72, 74.53, 51.48, 33.85, 32.65, 32.57, 26.63, 23.01, 20.75,
1
14.06. Compound 1: H NMR (CD3CN, 300 MHz): d 6.6
2.2 (m, 4H), 2.1–1.9 (m, 2H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13
C
(br dd, J = 15.0, 11.1 Hz, 2H), 6.1–6.0 (t, J = 11.1 Hz, 2H),
6.2–6.0 (dd, J = 15.0, 6.0 Hz, 2H), 5.6–5.3 (m, 6H), 4.1–4.2
(m, 2H), 3.1 (br t, J = 7.6 Hz, 2H), 2.4–2.2 (m, 8H), 2.2–2.1
(m, 2H), 1.0–0.9 (t, J = 47.5 Hz, 3H). UV (CH3CN) kmax
225, 244 nm. HPLC/API–ES/MS (m/z): 383.6 [M+Na+]+.
NMR (CDCl3, 75.5 MHz): d 173.31, 165.52, 165.48, 140.39,
140.17, 135.22, 133.01, 132.97, 131.04, 130.19 (2C), 129.58
(4C), 128.34 (4C), 124.70, 122.31, 112.16, 111.94, 84.78,
84.59, 78.41, 78.33, 73.68, 73.49, 51.51, 33.72, 32.14, 32.10,