Total synthesis of the macrophage derived anti-inflammatory lipid mediator Maresin 1

Article abstract of DOI:10.1016/j.tetlet.2012.05.143

The total synthesis of Maresin 1, an endogenous macrophage pro-resolving lipid mediator derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-group at C7 was obtained via a Jacobsen hydrolytic kinetic resolution of a terminal epoxide whereas the center at C14 arises from a chiral pool strategy starting from 2-deoxy-d-ribose. Pd⁰/Cu^I Sonogashira coupling of the two key fragments and Zn(Cu/Ag) reduction completed the total synthesis of Maresin 1.

Full text of DOI:10.1016/j.tetlet.2012.05.143

Tetrahedron Letters 53 (2012) 4169–4172
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of the macrophage derived anti-inflammatory lipid mediator
Maresin 1
⇑
Ana R. Rodriguez, Bernd W. Spur
Department of Cell Biology, University of Medicine and Dentistry of New Jersey, SOM, Stratford, NJ 08084, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of Maresin 1, an endogenous macrophage pro-resolving lipid mediator derived from
docosahexaenoic acid, has been achieved. The chiral hydroxy-group at C7 was obtained via a Jacobsen
hydrolytic kinetic resolution of a terminal epoxide whereas the center at C14 arises from a chiral pool
strategy starting from 2-deoxy-
Zn(Cu/Ag) reduction completed the total synthesis of Maresin 1.
Received 9 May 2012
Revised 25 May 2012
Accepted 29 May 2012
Available online 7 June 2012
D
-ribose. Pd0/CuI Sonogashira coupling of the two key fragments and
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Maresin 1
Total synthesis
Inflammation resolution
Hydrolytic kinetic resolution
Takai olefination
Sonogashira coupling
The role of inflammation in diseases such as atherosclerosis,
asthma, Alzheimer’s disease, and cancer is well documented.1–3
Interventions with eicosapentaenoic and docosahexaenoic acids
(fish oil) were investigated to explore their effects on neutrophil
function and leukotriene generation, and clinical improvements
have been reported.4–6 Serhan et al. investigated the molecular
mechanism that controls acute inflammation and its resolution.
They could show that during the resolution phase of inflammation
enzymatic metabolism of these polyunsaturated fatty acids pro-
duced a series of powerful anti-inflammatory lipid mediators, the
Resolvins, and Neuroprotectin D1.7 Recently they discovered a
novel macrophage derived mediator of inflammation resolution
named Maresin 1 (Macrophage mediator in resolving inflamma-
tion).8 Later on the complete stereochemical structure of Maresin
1 was established as (4Z,7R,8E,10E,12Z,14S,16Z,19Z)-7,14-dihy-
droxy-4,8,10,12,16,19-docosahexaenoic acid.9 This product is
formed in vivo from docosahexaenoic acid via S-selective 14-lipox-
ygenation to produce the hydroperoxide intermediate that under-
goes epoxide formation followed by enzymatic hydrolysis to
produce Maresin 1 (Fig. 1). Maresin 1 is a potent mediator that
inhibits PMN infiltration, stimulates macrophage phagocytosis of
apoptotic cells and controls pain similar to Resolvin E1.8,9
the limited availability from natural sources requires their
preparation by total syntheses.10–23
The first total synthesis of Maresin 1 was reported by Inoue
co-workers.16 The key features of Inoue’s strategy encompass the
BF3-mediated alkyne attack on an epoxide, chiral titanium complex
promoted enantioselective alkyne addition to an aldehyde, and a
modified Julia–Kocienski olefination.
In this Letter, we wish to report a different synthetic strategy to-
ward the total synthesis of Maresin 1 [MaR1; (4Z,7R,8E,10E,12Z,14S,
16Z,19Z)-7,14-dihydroxy-4,8,10,12,16,19-docosahexaenoic acid;
(1)]. As shown in the retrosynthetic approach to Maresin 1
(Fig. 2), the chiral center at C7 was obtained via a Jacobsen hydro-
lytic kinetic resolution of a terminal epoxide whereas 2-deoxy-D-ri-
bose was used as the source of chirality for C17. Pd0-CuI catalyzed
Sonogashira coupling followed by Zn(Cu/Ag) reduction provided
Maresin 1 (1).
The synthesis of the C1–C11 chiral fragment 2 was achieved as
outlined in Scheme 1. CuI catalyzed coupling of allyl bromide (6)
with 4-pentyn-1-ol (7) in H2O according to the method of Bieber
and Da Silva.24 gave cleanly 7-octen-4-yn-1-ol (8) that was purified
by vacuum distillation (bp 90–100 °C/7 mmHg). Jones oxidation of
8 followed by esterification with CH3OH/2,2-dimethoxypropane in
the presence of a catalytic amount of TMSCl at room temperature
gave 9 (90%).25 Epoxidation with 3-chloroperoxybenzoic acid in
CH2Cl2 in the presence of NaHCO3 at 0 °C gave the racemic epoxy
ester 4. Jacobsen hydrolytic kinetic resolution of 4 with H2O in
the presence of 5% (S,S)-salen-Co catalyst in ether furnished the
chiral diol 10 with >95% ee.11,26 Diol 10 was converted into the
The growing interest to study the pharmacological properties of
the Resolvins, Neuroprotectin D1, and Maresin 1 combined with
⇑
Corresponding author. Tel.: +1 856 566 7016; fax: +1 856 566 6195.
E-mail address: spurbw@umdnj.edu (B.W. Spur).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.143

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A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 4169–4172
Figure 1. Biosynthesis of Maresin 1.
Figure 2. Retrosynthetic approach to Maresin 1.
Scheme 1. Reagents and conditions: (a) Na2SO3, cat. CuI, K2CO3, H2O, 92%; (b) Jones reagent, acetone, 69%; (c) 10% TMSCl, CH3OH, 2,2-dimethoxypropane, rt, 90%; (d) MCPBA,
NaHCO3, CH2Cl2, 0 °C, 75%; (e) (S,S)-(salen)Co(III)(OAc) catalyst, H2O, ether, 0 °C to rt, 45%; (f) TESCl, imidazole, Et3N, DMF, 0 °C to rt, 95%; (g) H2, Lindlar cat., hexane, 99%; (h)
(COCl)2, DMSO, CH2Cl2 then Et3N, 83%; (i) Ph3P@CH–CHO, benzene, 70 °C, 43%; (j) CrCl2, CHI3, THF, 0 °C, 69%.
di-TES-ether 11 with 4.1 equiv TESCl in DMF in 95% yield.11 Lindlar
reduction of 11 in hexane produced the (Z)-alkene 12 in quantita-
tive yield. Chemoselective oxidation of the primary TES-ether with
the Swern reagent produced the aldehyde 13 in 83% yield.27,28
Wittig homologation of 13 with 2 equiv of triphenylphosphoranyl-
2.1 equiv of (Z)-3-(hexen-1-ylidene)triphenylphosphorane,31 gen-
erated in situ from the corresponding phosphonium iodide with
BuLi (2 equiv) in THF at ꢀ78 °C, produced the Z,Z-skipped diene
16 in 81% yield. Compound 16 was converted into the iodide 17
using the method of Samuelson with I2, Ph3P, and imidazole in tol-
uene at 60 °C in 82% yield.32,33 Base induced deprotonation-elimi-
nation of 17 with 7 equiv LDA at ꢀ78 °C in THF produced directly
the key intermediate 3 in 53% isolated yield.33,34
The total synthesis of Maresin 1 (1) was completed as shown in
Scheme 3. Sonogashira coupling of the two key fragments 2 and 3
with a catalytic amount of Pd(PPh3)4,35 CuI, and piperidine in ben-
zene at room temperature gave the mono-TES-protected acetylene
precursor of Maresin 1 (18).36–38 Mild desilylation with a catalytic
iden-acetaldehyde in benzene at 70 °C gave the
a,b-unsaturated
aldehyde 14 that was converted into the key intermediate 2 by
the Takai olefination (CrCl2/CHI3) in THF at 0 °C (69% yield).29
The C12–C22 chiral fragment 3 was obtained in 4 steps from
2-deoxy-D-ribose (5) as outlined in Scheme 2. Isopropylidene
protection of 5 with 2-methoxypropene in the presence of a cata-
lytic amount of PPTS in ethyl acetate gave 3,4-O-isopropylidene-2-
deoxy-D
-ribose (15) in 50% yield.30 Wittig reaction of 15 with

A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 4169–4172
4171
Scheme 2. Reagents and conditions: (a) 2-methoxypropene, PPTS, EtOAc, 0 °C to rt, 50%; (b) (Z)-CH3CH2CH@CH(CH2)2P+Ph3I-, BuLi, THF, ꢀ78 °C to 0 °C, 81%; (c) I2, Ph3P,
imidazole, toluene, 60 °C, 82%; (d) LDA, THF, ꢀ78 °C, 53%.
Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, CuI, piperidine, benzene, rt, 81%; (b) PPTS, CH3OH, 0 °C, 96%; (c) Zn(Cu/Ag), CH3OH, H2O, 40–45 °C, 66%; (d) 1 N LiOH,
CH3OH, H2O, 0 °C, then satd. NaH2PO4, 77%.
amount of PPTS in CH3OH at 0 °C gave the acetylene precursor of
Maresin 1 methyl ester (19) in high yield. Attempts to reduce the
conjugated triple bond with deactivated Lindlar catalyst produced
only over-reduced products. The reduction of the conjugated triple
bond with freshly prepared Zn(Cu/Ag) in CH3OH/H2O (1:1) at 40–
45 °C (16 h) produced Maresin 1 methyl ester (20)39,40 that was
purified by HPLC.41 Mild alkaline hydrolysis of 20 with 1 N LiOH
in CH3OH/H2O (1:1) at 0 °C followed by acidification with sat.
NaH2PO4 in the presence of ethyl acetate gave natural Maresin 1
(1) (77%). The 1H and 13C NMR spectra were in accordance with
those reported by Inoue.16 HPLC analysis revealed that the synthe-
sized 1 co-eluted with an authentic sample of Maresin 1 (Cayman
Chemical Company).42
Financial support of this research by the DOD (AS073084P1);
the Governor’s Council on Autism, and the Office of Patent &
Licensing UMDNJ-UMDNJ Foundation is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
143.
References and notes
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In summary, a concise total synthesis of Maresin 1 has been
achieved,42 making this anti-inflammatory lipid mediator from
docosahexaenoic acid available for further biological and pharma-
cological testing. The synthesis of other Resolvins and Neuropro-
tectin D1 will be reported in due course.
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Acknowledgments
We thank Dr. T. Peter Stein and Margaret D. Schluter for the
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51.61, 33.78, 22.98, 14.77. Compound 4: 1H NMR (CDCl3, 300 MHz): d 3.7 (s,
3H), 3.1–3.0 (m, 1H), 2.8–2.7 (dd, J = 4.8, 3.9 Hz, 1H), 2.7–2.6 (dd, J = 4.8, 2.7 Hz,
1H), 2.6–2.3 (m, 6H); 13C NMR (CDCl3, 75.5 MHz): d 172.42, 80.59, 75.07, 51.60,
50.03, 46.25, 33.57, 22.38, 14.65. Compound 11: ½a D25
ꢂ
= +2.6 (c 1, CHCl3). 1H
NMR (CDCl3, 300 MHz): d 3.8–3.7 (quint, J = 5.7 Hz, 1H), 3.7 (s, 3H), 3.6–3.4 (2
dd ABsystem, J = 9.9, 5.7 Hz, 2H), 2.6–2.4 (m, 4H), 2.5–2.3 (ddt ABsystem,
J = 16.5, 5.7, 1.8 Hz, 1H), 2.3–2.1 (ddt ABsystem, J = 16.5, 6.0, 2.1 Hz, 1H), 1.0–
0.9 (2 t, J = 7.8 Hz, 18H), 0.7–0.5 (2 q, J = 7.8 Hz, 12H); 13C NMR (CDCl3,
75.5 MHz): d 172.49, 79.37, 78.07, 72.26, 66.28, 51.60, 33.72, 24.58, 14.82, 6.77
(3C), 6.69 (3C), 4.98 (3C), 4.41 (3C). Compound 12: 1H NMR (CDCl3, 300 MHz): d
5.6–5.3 (m, 2H), 3.7–3.6 (m, 1H), 3.6 (s, 3H), 3.5–3.4 (dd ABsystem, J = 9.9,
5.7 Hz, 1H), 3.4–3.3 (dd ABsystem, J = 9.9, 6.3 Hz, 1H), 2.6–2.1 (m, 6H), 1.0–0.9
(2 t, J = 8.1 Hz, 18H), 0.7–0.5 (2 q, J = 7.8 Hz, 12H); 13C NMR (CDCl3, 75.5 MHz):
d 173.59, 129.18, 127.34, 73.02, 66.63, 51.45, 34.07, 32.19, 22.97, 6.85 (3C),
6.74 (3C), 5.01 (3C), 4.41 (3C). Compound 14: 1H NMR (CDCl3, 300 MHz): d 9.6–
9.5 (d, J = 8.1 Hz, 1H), 6.8–6.7 (dd, J = 15.6, 4.5 Hz, 1H), 6.4–6.2 (ddd, J = 15.6,
8.1, 1.5 Hz, 1H), 5.5–5.3 (m, 2H), 4.5–4.3 (m, 1H), 3.6 (s, 3H), 2.4–2.2 (m, 6H),
0.9 (t, J = 7.8 Hz, 9H), 0.6 (q, J = 7.8 Hz, 6H); 13C NMR (CDCl3, 75.5 MHz): d
193.44, 173.32, 159.12, 130.93, 130.64, 125.37, 71.35, 51.52, 35.37, 33.79,
22.97, 6.74 (3C), 4.84 (3C). Compound 2: 1H NMR (C6D6, 300 MHz): d 7.0–6.9
(dd, J = 14.4, 10.8 Hz, 1H), 6.1–5.9 (m, 2H), 5.7–5.4 (m, 3H), 4.2–4.0 (m, 1H), 3.4
(s, 3H), 2.5–2.2 (m, 6H), 1.1 (t, J = 7.8 Hz, 9H), 0.7 (q, J = 7.8 Hz, 6H); 13C NMR
(C6D6, 75.5 MHz): d 173.15, 145.40, 138.33, 130.61, 129.85, 127.22, 79.51,
73.03, 51.46, 36.91, 34.44, 23.82, 7.55 (3C), 5.84 (3C). Compound 16: 1H NMR
(CDCl3, 300 MHz): d 5.6–5.2 (m, 4H), 4.3–4.1 (m, 2H), 3.7–3.5 (m, 2H), 2.8–2.7
(br t, J = 7.0 Hz, 2H), 2.5–2.2 (m, 2H), 2.1–1.9 (quint, J = 7.5 Hz, 2H), 2.0–1.9 (br
t, J = 6.0 Hz, 1H), 1.5 (s, 3H), 1.3 (s, 3H), 0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3,
75.5 MHz): d 132.27, 130.86, 126.57, 124.78, 108.18, 77.82, 76.70, 61.68, 28.09,
27.43, 25.77, 25.38, 20.54, 14.17. Compound 17: 1H NMR (CDCl3, 300 MHz): d
5.6–5.2 (m, 4H), 4.4–4.2 (m, 1H), 4.2–4.0 (m, 1H), 3.2–3.1 (m, 2H), 2.8 (br t,
J = 7.0 Hz, 2H), 2.4–2.3 (br t, J = 6.5 Hz, 2H), 2.1–2.0 (quint, J = 7.5 Hz, 2H), 1.5 (s,
3H), 1.3 (s, 3H), 1.0 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d 132.32,
130.98, 126.51, 124.50, 108.53, 78.26, 77.55, 28.35, 27.55, 25.84, 25.66, 20.59,
14.19, 3.56. Compound 3: ½a D20
ꢂ
= ꢀ31.7 (c 1, CHCl3). 1H NMR (CDCl3, 300 MHz):
d 5.7–5.2 (m, 4H), 4.5–4.3 (qd, J = 6.3, 2.1 Hz, 1H), 2.9–2.7 (m, 2H), 2.6–2.4 (m,
2H), 2.4 (d, J = 2.1 Hz, 1H), 2.1–2.0 (m, 2H), 1.9 (d, J = 6.3 Hz, 1H), 0.9 (t,
J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d 132.58, 132.35, 126.65, 123.35,
84.46, 73.00, 61.80, 35.55, 25.79, 20.58, 14.17. Compound 19: 1H NMR (C6D6,
300 MHz): d 6.8–6.6 (dd, J = 15.3, 11.1 Hz, 1H), 6.4–6.2 (dd, J = 15.3, 11.1 Hz,
1H), 5.8–5.6 (m, 4H), 5.6–5.4 (m, 4H), 4.5 (td, J = 6.3, 1.8 Hz, 1H), 4.1–4.0 (br q,
J = 6.3 Hz, 1H), 3.4 (s, 3H), 2.9 (br t, J = 5.7 Hz, 2H), 2.6 (br t, J = 6.3 Hz, 2H), 2.4–
2.0 (m, 8H), 1.0 (t, J = 7.5 Hz, 3H); 13C NMR (C6D6, 75.5 MHz): d 173.47, 142.31,
139.70, 132.71, 132.37, 131.43, 129.52, 127.84, 127.06, 125.11, 111.50, 94.00,
84.82, 71.77, 63.23, 51.54, 36.74, 36.06, 34.22, 26.62, 23.57, 21.36, 14.86. UV
(EtOH) kmax 267, 279 nm. Compound 20: 1H NMR (CD3CN, 300 MHz): d 6.6–6.4
(m, 1H), 6.3–6.2 (m, 2H), 6.1–5.9 (t, J = 11.1 Hz, 1H), 5.8–5.6 (dd, J = 14.1,
6.3 Hz, 1H), 5.5–5.2 (m, 7H), 4.6–4.4 (m, 1H), 4.2–4.0 (m, 1H), 3.6 (s, 3H), 2.9 (d,
J = 4.5 Hz, 1H), 2.8 (d, J = 4.5 Hz, 1H), 2.8–2.7 (br t, J = 6.4 Hz, 2H), 2.4–2.1 (m,
8H), 2.1–2.0 (quint, J = 7.5 Hz, 2H), 0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CD3CN,
75.5 MHz): d 173.88, 138.17, 135.15, 134.12, 132.34, 130.69, 130.47, 130.05,
129.42, 128.36, 127.73, 127.21, 125.96, 71.76, 67.66, 51.53, 36.00, 35.73, 34.05,
26.01, 23.27, 20.80, 14.17. UV (EtOH) kmax 262, 271, 282 nm. Compound 1: 1H
36. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–4470.
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41. HPLC [Zorbax SB-C18, 21.2 mm ꢁ 25 cm, 271 nm, CH3OH/H2O 70/30, 10 mL/
min, tR (E, E, E-isomer) = 61 min, tR (E, E, Z-isomer, 20) = 77 min].
42. Satisfactory spectroscopic data were obtained for all compounds. Selected physical
data: Compound 8: 1H NMR (CDCl3, 300 MHz): d 5.9–5.7 (ddt, J = 17.1, 9.9,
5.4 Hz, 1H), 5.3–5.2 (dq, J = 17.1, 1.8 Hz, 1H), 5.1–5.0 (dq, J = 9.9, 1.8 Hz, 1H),
3.8–3.7 (m, 2H), 3.0–2.8 (m, 2H), 2.4–2.2 (tt, J = 6.9, 2.4 Hz, 2H), 1.8–1.7 (quint,
NMR (CD3OD, 300 MHz):
d 6.7–6.5 (m, 1H), 6.4–6.2 (m, 2H), 6.1–6.0 (t,
J = 11.1 Hz, 1H), 5.8–5.7 (dd, J = 14.1, 6.6 Hz, 1H), 5.6–5.2 (m, 7H), 4.6–4.5 (m,
1H), 4.2–4.1 (br q, J = 6.6 Hz, 1H), 2.8 (br t, J = 6.3 Hz, 2H), 2.5–2.2 (m, 8H), 2.2–
2.0 (quint, J = 7.5 Hz, 2H), 1.0 (t, J = 7.5 Hz, 3H). 13C NMR (CD3OD, 75.5 MHz): d
C1 not observed, 138.00, 134.95, 134.84, 132.81, 131.40, 131.35, 131.15,
130.58, 128.90, 128.20, 127.42, 126.12, 72.96, 68.57, 36.53, 36.29, 35.15, 26.64,
24.17, 21.48, 14.59. UV (EtOH) kmax 262, 271, 282 nm. HPLC-UV: Hypersil-ODS,
100 ꢁ 2.1 mm, 271 nm, CH3OH/H2O (0.1% formic acid) 50/50 to 70/30, 0.2 mL/
J = 6.9 Hz, 2H); 13C NMR (CDCl3, 75.5 MHz):
d 133.19, 115.71, 81.84, (C5
overlaps with CDCl3 signals), 62.00, 31.58, 23.08, 15.43. Compound 9: 1H NMR
(CDCl3, 300 MHz): d 5.9–5.7 (ddt, J = 17.1, 9.9, 5.1 Hz, 1H), 5.3–5.2 (dq, J = 17.1,
1.8 Hz, 1H), 5.1–5.0 (dq, J = 9.9, 1.8 Hz, 1H), 3.7 (s, 3H), 2.9–2.8 (m, 2H), 2.5–2.4
(m, 4H); 13C NMR (CDCl3, 75.5 MHz): d 172.45, 133.00, 115.66, 80.60, 77.50,
min, tR = 17.2 min [synthesized
1 co-eluted with an authentic sample of
Maresin 1 (Cayman Chemical Company)]. HPLC/MS/MS (m/z): 359.3 [MꢀH]ꢀ.