Total synthesis of the potent anti-inflammatory lipid mediator Protectin D1

Article abstract of DOI:10.1016/j.tetlet.2014.09.007

The total synthesis of the potent anti-inflammatory lipid mediator Protectin D1 derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C10 and C17 were obtained via a chiral pool strategy from (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane and 3,4-O-isopropylidene-2-deoxy-d-ribose, respectively. Wittig reactions, Takai olefination, Pd⁰/Cu^ISonogashira coupling, and Zn(Cu/Ag) reduction completed the total synthesis of Protectin D1.

Full text of DOI:10.1016/j.tetlet.2014.09.007

Tetrahedron Letters 55 (2014) 6011–6015
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of the potent anti-inflammatory lipid mediator
Protectin D1
⇑
Ana R. Rodriguez, Bernd W. Spur
Department of Cell Biology, Rowan University-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 the potent anti-inflammatory lipid mediator Protectin D1 derived from docosahex-
aenoic acid, has been achieved. The chiral hydroxy-groups at C10 and C17 were obtained via a chiral pool
Received 12 August 2014
Accepted 3 September 2014
Available online 16 September 2014
strategy from (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane and 3,4-O-isopropylidene-2-deoxy-D-
ribose, respectively. Wittig reactions, Takai olefination, Pd0/CuI Sonogashira coupling, and Zn(Cu/Ag)
reduction completed the total synthesis of Protectin D1.
Keywords:
Protectin D1/Neuroprotectin D1
Total synthesis
Ó 2014 Elsevier Ltd. All rights reserved.
Inflammation resolution
Wittig reaction
Takai olefination
Sonogashira coupling
The health benefit of eicosapentaenoic and docosahexaenoic
acids in inflammatory diseases is well documented.1 We reported
neuroprotective lipid mediator; therefore Protectin D1 could be a
lead molecule to be evaluated for the treatment of Alzheimer’s
disease and other neurological disorders.16 The limited availability
from natural sources requires its preparation by total synthesis to
produce sufficient amounts for biological and pharmacological
testings.
earlier that dietary enrichment with these
x-3 fatty acids in
humans impairs in vitro neutrophil and monocyte leukotriene
generation and neutrophil function.2 These studies were later
broadened to include auto-immune diseases such as rheumatoid
arthritis and asthma.3,4 The groundbreaking work by Serhan and
collaborators revealed that the biologically active compounds in
the resolution of inflammation were enzymatically formed di-
and tri-hydroxylated products of eicosapentaenoic and docosahex-
aenoic acids, the Resolvins.5–10
In 2004, Serhan and collaborators discovered a novel docosa-
noid mediator of inflammation resolution in the brain named
Neuroprotectin D1 (NPD1) also known as Protectin D1
(PD1).11,12 The complete stereochemical structure of Protectin
D1 was later on established as (4Z,7Z,10R,11E,13E,15Z,17S,19Z)-
10,17-dihydroxy-4,7,11,13,15,19-docosahexaenoic acid.13 This
product is formed in vivo from docosahexaenoic acid via S-selec-
tive 17-lipoxygenation to the hydroperoxide intermediate that
undergoes epoxide formation followed by enzymatic hydrolysis
(Fig. 1). Protectin D1 is rapidly formed in response to oxidative
stress in the brain and protects against resulting damage.14 With
respect to Alzheimer’s disease pathogenesis, Protectin D1 regu-
lates the b-amyloid secretion and improves neuronal survival.15
Interestingly Alzheimer’s patients are not capable to produce this
A strategy for the synthesis of Protectin D1 was first outlined by
Petasis and collaborators.13 A total synthesis of Protectin D1 was
later reported by Ogawa and Kobayashi.17 The key features of
Kobayashi’s strategy encompass the Suzuki coupling between the
C13–C22 vinyl borane and the C1–C12 vinyl iodide. The chiral cen-
ters were obtained via a Sharpless kinetic resolution. The first total
synthesis of the aspirin-triggered Protectin D1 (AT-PD1) was
reported by Petasis and collaborators.18,19 In their synthesis the
chiral centers were derived from chiral glycidol derivatives via
epoxide opening with acetylenes under Yamaguchi conditions.
Recently Hansen and collaborators reported an interesting total
synthesis of Protectin D1 using a stereocontrolled Evans-aldol
reaction with Nagao’s chiral auxiliary.20 However the b-hydroxy-
aldehyde key intermediate is extremely prone to elimination. Balas
and collaborators prepared the 10S-epimer of Protectin D1
constructing first the conjugated triene system followed by Wittig
reactions.21 They observed, similar to Hansen, that their b-
hydroxy-aldehyde intermediate easily eliminated the OTBS group
during the final Wittig reaction.
As part of our continuing interest in the field of anti-inflamma-
tory lipid mediators and in view of its promising biological profile
we decided to undertake the total synthesis of Protectin D1.
⇑
Corresponding author. Tel.: +1 856 566 7016; fax: +1 856 566 6195.
E-mail address: spurbw@rowan.edu (B.W. Spur).
http://dx.doi.org/10.1016/j.tetlet.2014.09.007
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6012
A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 55 (2014) 6011–6015
Figure 1. Biosynthesis of Protectin D1.
In this Letter, we wish to report a different synthetic strategy
Scheme 1. c-Butyrolactone (7) was converted to the hydroxy-
toward the total synthesis of Protectin D1 (1). As shown in the
retrosynthetic approach (Fig. 2) Protectin D1 (1) has been prepared
from the two key intermediates 2 and 3. The chiral center at C10
was obtained from commercial (4R)-4-(2-hydroxyethyl)-2,
2-dimethyl-1,3-dioxolane (6) and 3,4-O-isopropylidene-2-deoxy-
methyl ester 8 by treatment with 2 equiv of triethylamine in meth-
anol containing a small amount of water.23,24 Without the addition
of water no reaction occurred. Compound 8 was oxidized to
aldehyde 9 using PCC in CH2Cl2 in the presence of NaOAc.25 Wittig
reaction of aldehyde
9 with the silyloxy-substituted ylide
D
-ribose (4) was used as the source of chirality for C17. Wittig reac-
generated in situ from phosphonium salt 10 gave, after acidic
work-up, the Z-alkene ester 14.26 In the second route commercial
phosphonium salt 11 was transformed to the crystalline methyl
ester 12 with 2,2-dimethoxypropane/CH3OH/10% TMSCl in
quantitative yield.27 The phosphonium salt 12 was converted to
its ylide with NaHMDS in THF and then reacted with aldehyde
tions, Takai olefination, Sonogashira coupling, and Zn(Cu/Ag)
reduction provided Protectin D1 (1).
The phosphonium salt 5, a key intermediate in our synthesis of
compound 3, was previously reported in the literature.22 Herein we
report two short alternative routes toward 5 as outlined in
Figure 2. Retrosynthetic approach to Protectin D1.

A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 55 (2014) 6011–6015
6013
Scheme 1. Reagents and conditions: (a) Et3N, CH3OH, cat. H2O, 85%; (b) PCC, NaOAc, CH2Cl2, 80%; (c) 2,2-dimethoxypropane, cat. TMSCl, CH3OH, rt, 99%; (d) 10, KHMDS, THF,
0 °C to rt, TMSCl, 0 °C, 9, ꢀ78 °C to rt then 1 N HCl, 0 °C to rt, 45%; (d0) NaHMDS, THF, ꢀ78 °C to 0 °C then 1 N HCl, 0 °C to rt, 57%; (e) I2, Ph3P, imidazole, i-Pr2EtN, CH3CN, ether
75%; (f) Ph3P, CH3CN, 70 °C, 88%.
Scheme 2. Reagents and conditions: (a) Ref. 29; (b) NaHMDS, THF, ꢀ78 °C, 42%; (c) CuCl2ꢁ2H2O, CH3CN, 0 °C to rt, 92%; (d) TBSCl, imidazole, DMAP, DMF, 0 °C to rt, 81%; (e)
HFꢁpy, THF, 0 °C to rt, 60%; (f) Dess–Martin periodinane, CH2Cl2, rt, 88%; (g) Ph3P@CHACHO, toluene, 90 °C, 89%; (h) CrCl2, CHI3, THF, 0 °C, 52%.
13 to give, after acidic work up, the Z-alkene ester 14. Compound
14 was converted into iodide 15 by the method of Samuelsson28
and transformed to the crystalline phosphonium salt 5 with PPh3
in CH3CN at 70 °C in 88% yield.
The synthesis of the C1–C14 key intermediate 3 from commer-
cial (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (6) is
outlined in Scheme 2. The alcohol 6 was converted to the aldehyde
16 using the Swern reagent in good yield.29 Z-selective Wittig

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A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 55 (2014) 6011–6015
Scheme 3. Reagents and conditions: (a) CH3(CH2)2P+Ph3Brꢀ, NaHMDS, ether, ꢀ78 °C to 0 °C, 60%; (b) I2, Ph3P, imidazole, toluene, 60 °C, 90%; (c) LDA, THF, ꢀ78 °C, 72%.
Scheme 4. Reagents and conditions: (a) Pd(PPh3)4, CuI, piperidine, benzene, rt, 76%; (b) TBAF, THF, 0 °C to rt, 82%; (c) Zn(Cu/Ag), CH3OH, H2O, 40–45 °C, 47%; (d) 1 N LiOH,
CH3OH, H2O, 0 °C, then satd NaH2PO4, 89%.
reaction between 16 and the ylide generated from the phospho-
nium salt 5 using NaHMDS produced 17, no trace of the E-isomer
was detected. The isopropylidene protective group was cleaved
with CuCl2ꢁ2H2O in CH3CN to give 18 in 92% isolated yield.30 The
free hydroxyl groups were silylated using TBSCl, imidazole, DMAP
in DMF to give 19. Attempts to convert 19 directly into 21 by selec-
tive oxidation using quinolinium fluorochromate resulted in the
full recovery of 19.31 Therefore the primary TBS group of 19 was
first selectively deprotected with excess HFꢁpy in THF to give 20
which was then converted to the aldehyde 21 in 88% by Dess Mar-
tin oxidation in CH2Cl2.32,33 Wittig homologation of the aldehyde
21 with (triphenylphosphoranylidene)acetaldehyde in toluene at
90 °C gave enal 22 that was converted to the key intermediate 3
by a modified Takai reaction.34,35
approaches have been described in the literature for the selective
cis-reduction of the triple bond in 26 to give Protectin D1 methyl
ester (27): a modified Lindlar reduction20 and the Boland reduction
with Zn(Cu/Ag) alloy.18 The modified Lindlar reduction was ham-
pered in our hands by simultaneous over-reduction. We therefore
employed the Boland reduction with freshly prepared Zn(Cu/
Ag)41,42 in CH3OH/H2O at 40–45 °C for 60 min to produce Protectin
D1 methyl ester (27) along with
D15-trans-Protectin D1 methyl
ester in an average ratio of 65:35. The products could be easily sep-
arated by flash chromatography using triethylamine-deactivated
silica.43 When the reaction was performed in CD3OD/D2O the
15,16-dideuterio-Protectin D1 methyl ester was cleanly produced.
Mild hydrolysis of the methyl ester 27 with 1 N LiOH in CH3OH/
H2O at 0 °C under argon gave, after acidification with satd NaH2PO4
(pH 3) in the presence of ethyl acetate, Protectin D1 (1) in 89%
yield. All spectroscopic data were in agreement with those
reported in the literature.18,20,44
In summary, a concise total synthesis of Protectin D1 has been
achieved,44 making this anti-inflammatory lipid mediator from
docosahexaenoic acid available for further biological and pharma-
cological testing. The synthesis of other specialized pro-resolving
mediators (SPM) will be reported in due course.
The C15–C22 fragment 2 was obtained in three steps from 3,4-
O-isopropylidene-2-deoxy-D
-ribose (4)36 as outlined in Scheme 3.
Wittig reaction of 4 with 2.5 equiv of phosphorane generated from
n-propyl triphenylphosphonium bromide and NaHMDS in ether at
ꢀ78 °C gave the cis-olefination product 23.37 Using the method of
Samuelsson,28 23 was converted into the iodide 24 with triphenyl-
phosphine, imidazole, and iodine in toluene at 60 °C in 90% yield.38
The isopropylidene iodide 24 was converted directly into the key
intermediate 2 using 7 equiv of LDA in THF at ꢀ78 °C.
The total synthesis of Protectin D1 was completed as shown in
Scheme 4. Modified Sonogashira coupling35,39 of 3 in the presence
of Pd(PPh3)4,40 CuI, and piperidine in benzene with a very slow
addition of the acetylene 2 gave the TBS-mono-protected triple
bond precursor of Protectin D1 methyl ester (25). Cleavage of the
TBS protective group with TBAF in THF gave 26.18,20 Two
Acknowledgments
Financial support of this research by the DOD (AS073084P1);
NJCBIR, the Governor’s Council on Autism, and the Office of
Patent
& Licensing UMDNJ–UMDNJ Foundation is gratefully
acknowledged.

A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 55 (2014) 6011–6015
6015
300 MHz): d 7.9–7.6 (m, 15H), 5.7–5.6 (m, 1H), 5.4–5.2 (m, 1H), 3.7–3.6 (m,
2H), 3.6 (s, 3H), 2.5–2.3 (m, 2H), 2.3–2.2 (br t, J = 6.7 Hz, 2H), 2.2–2.0 (m, 2H);
13C NMR (CDCl3, 75.5 MHz): d 173.28, 135.13 (d, J = 3.1 Hz, 3C), 133.69 (d,
J = 9.9 Hz, 6C), 130.54 (d, J = 12.5 Hz, 6C), 130.27, 127.45 (d, J = 15.4 Hz), 117.46
(d, J = 85.3 Hz, 3C), 51.47, 33.25, 23.18 (d, J = 48.7 Hz), 22.60, 20.38 (d,
J = 3.1 Hz). Mp 114–115 °C. Compound 17: 1H NMR (CDCl3, 300 MHz): d 5.6–
5.2 (m, 4H), 4.2–4.1 (m, 1H), 4.0 (dd, J = 7.8, 6.3 Hz , 1H), 3.7 (s, 3H), 3.6–3.5 (dd,
J = 7.8, 6.9 Hz, 1H), 2.8 (m, 2H), 2.5–2.2 (m, 6H), 1.4–1.3 (2 s, 6H); 13C NMR
(CDCl3, 75.5 MHz): d 173.44, 130.52, 129.02, 128.07, 124.57, 108.94, 75.54,
69.02, 51.49, 33.98, 31.54, 26.88, 25.76, 25.63, 22.82. Compound 18: 1H NMR
(CDCl3, 300 MHz): d 5.6–5.3 (m, 4H), 3.8–3.7 (m, 2H), 3.7 (s, 3H), 3.5 (dd,
J = 10.8, 6.6 Hz, 1H), 2.9–2.7 (m, 2H), 2.4–2.2 (m, 6H); 13C NMR (CDCl3,
75.5 MHz): d 173.69, 131.10, 129.02, 128.10, 124.98, 71.79, 66.22, 51.56, 33.96,
31.43, 25.74, 22.87. Compound 19: 1H NMR (CDCl3, 300 MHz): d 5.6–5.2 (m,
4H), 3.7–3.6 (m, 1H), 3.6 (s, 3H), 3.5–3.4 (dd, J = 9.9, 5.4 Hz, 1H ABsystem), 3.4
(dd, J = 9.9, 6.0 Hz, 1H ABsystem), 2.8–2.7 (m, 2H), 2.4–2.1 (m, 6H), 0.87 (s, 9H),
0.85 (s, 9H), 0.031 (s, 6H), 0.023 (s, 3H), 0.020 (s, 3H); 13C NMR (CDCl3,
75.5 MHz): d 173.47, 129.58, 129.28, 127.71, 126.43, 73.21, 67.05, 51.45, 34.08,
32.28, 25.98 (3C), 25.90 (3C), 25.75, 22.84, 18.36, 18.14, ꢀ4.39, ꢀ4.65, ꢀ5.32,
ꢀ5.37. Compound 20: 1H NMR (CDCl3, 300 MHz): d 5.6–5.3 (m, 4H), 3.8–3.7
(m, 1H), 3.6 (s, 3H), 3.6–3.5 (dd, J = 11.1, 3.9 Hz , 1H ABsystem), 3.5–3.4 (dd,
J = 11.1, 5.4 Hz , 1H ABsystem), 2.8 (m, 2H), 2.4–2.2 (m, 6H), 0.88 (s, 9H), 0.073
(s, 6H); 13C NMR (CDCl3, 75.5 MHz): d 173.54, 130.03, 129.19, 127.99, 125.41,
72.72, 66.00, 51.50, 34.00, 32.03, 25.83 (3C), 25.72, 22.84, 18.08, ꢀ4.44, ꢀ4.66.
Compound 22: 1H NMR (CDCl3, 300 MHz): d 9.5 (d, J = 7.8 Hz, 1H), 6.8 (dd,
J = 15.6, 4.5 Hz, 1H), 6.3–6.2 (ddd, J = 15.6, 8.1, 1.5 Hz, 1H), 5.6–5.3 (m, 4H),
4.5–4.4 (m, 1H), 3.6 (s, 3H), 2.8–2.7 (m, 2H), 2.4–2.2 (m, 6H), 0.88 (s, 9H), 0.052
(s, 3H), 0.020 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 193.39, 173.42, 159.17,
130.92, 130.75, 128.88, 128.18, 124.35, 71.52, 51.50, 35.35, 33.93, 25.77 (4C),
22.82, 18.16, ꢀ4.73, ꢀ4.83. Compound 3: 1H NMR (CDCl3, 300 MHz): d 7.1–6.9
(dd, J = 14.1, 10.8 Hz, 1H), 6.3–6.2 (d, J = 14.1 Hz, 1H), 6.1–6.0 (br dd, J = 15.3,
10.8 Hz, 1H), 5.8–5.6 (dd, J = 15.3, 5.7 Hz, 1H), 5.4–5.2 (m, 4H), 4.2–4.0 (m, 1H),
3.6 (s, 3H), 2.8–2.7 (m, 2H), 2.4–2.2 (m, 6H), 0.87 (s, 9H), 0.024 (s, 3H), 0.002 (s,
3H). Compound 24: 1H NMR (CDCl3, 300 MHz): d 5.6–5.4 (dtt, J = 10.8, 7.5,
1.5 Hz, 1H), 5.4–5.3 (dtt, J = 10.8, 7.2, 1.5 Hz, 1H), 4.4–4.3 (m, 1H), 4.2–4.1 (td,
J = 7.2, 5.7 Hz, 1H), 3.2–3.1 (m, 2H), 2.3 (br t, J = 7.2 Hz, 2H), 2.1–2.0 (br 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 134.44, 123.63, 108.52, 78.30, 77.69, 28.36, 27.45, 25.68, 20.86,
14.00, 3.66. Compound 2: 1H NMR (CDCl3, 300 MHz): d 5.7–5.5 (dtt, J = 10.8,
7.5, 1.5 Hz, 1H), 5.5–5.3 (dtt, J = 10.8, 7.5, 1.5 Hz, 1H), 4.4–4.3 (m, 1H), 2.5–2.4
(m, 2H), 2.4 (d, J = 2.1 Hz, 1H), 2.1–2.0 (br quint, J = 7.5 Hz, 2H), 1.9 (d,
J = 5.7 Hz, 1H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d 136.13,
122.43, 84.56, 72.90, 61.88, 35.47, 20.79, 14.14. Compound 25: 1H NMR (C6D6,
300 MHz): d 6.6 (dd, J = 15.6, 10.8 Hz, 1H), 6.2 (dd, J = 15.0, 10.8 Hz, 1H), 5.7–
5.2 (m, 8H), 4.4–4.3 (br qd, J = 6.3, 1.8 Hz, 1H), 4.1 (br q, J = 6.3 Hz, 1H), 3.3 (s,
3H), 2.8–2.7 (m, 2H), 2.5–2.4 (br t, J = 6.3 Hz, 2H), 2.4–2.2 (m, 4H), 2.2–2.1 (t,
J = 7.5 Hz, 2H), 2.0–1.8 (m, 2H), 1.5–1.4 (d, J = 6.3 Hz, 1H), 0.98 (s, 9H), 0.9–0.8
(t, J = 7.5 Hz, 3H), 0.068 (s, 3H), 0.043 (s, 3H); 13C NMR (C6D6, 75.5 MHz): d
172.69, 141.68, 139.65, 135.18, 130.14, 129.39, 128.95, (one carbon overlaps
with C6D6 signal), 125.88, 123.73, 111.07, 93.65, 84.20, 73.10, 62.78, 50.95,
36.62, 36.14, 34.01, 26.16, 26.06 (3C), 23.14, 21.05, 18.41, 14.30, ꢀ4.27, ꢀ4.61.
Compound 26: 1H NMR (C6D6, 300 MHz): d 6.6 (dd, J = 15.6, 10.8 Hz, 1H), 6.2–
6.1 (br dd, J = 15.3, 10.8 Hz, 1H), 5.6–5.2 (m, 8H), 4.4–4.3 (m, 1H), 3.9 (m, 1H),
3.3 (s, 3H), 2.8–2.7 (m, 2H), 2.5–2.4 (m, 2H), 2.3–2.2 (m, 2H), 2.2–2.0 (m, 4H),
2.0–1.8 (m, 2H), 0.9–0.8 (t, J = 7.5 Hz, 3H); 13C NMR (C6D6, 75.5 MHz): d 172.84,
141.74, 139.03, 135.20, 131.04, 129.24, 129.08, (one carbon overlaps with C6D6
signal), 125.39, 123.72, 111.10, 93.64, 84.21, 71.40, 62.79, 50.99, 36.13, 35.67,
33.96, 26.08, 23.11, 21.04, 14.30. Compound 27: 1H NMR (CD3OD, 300 MHz): d
6.5 (dd, J = 14.1, 11.1 Hz, 1H), 6.3–6.2 (m, 2H), 6.1 (t, J = 11.1 Hz, 1H), 5.8–5.7
(dd, J = 14.4, 6.3 Hz, 1H), 5.5–5.3 (m, 7H), 4.6–4.5 (m, 1H), 4.1 (q, J = 6.3 Hz, 1H),
3.6 (s, 3H), 2.9–2.7 (m, 2H), 2.5–2.1 (m, 8H), 2.1–2.0 (m, 2H), 1.0–0.9 (t,
J = 7.5 Hz, 3H); 13C NMR (CD3OD, 75.5 MHz): d 175.46, 137.93, 134.94, 134.81,
134.77, 131.40, 130.92, 130.57, 130.31, 128.92 (2C), 126.50, 125.24, 72.98,
68.56, 52.14, 36.35, 36.30, 34.84, 26.68, 23.79, 21.68, 14.59; UV (EtOH) kmax
References and notes
1. De Caterina, R. N. Eng. J. Med. 2011, 364, 2439–2450.
2. Lee, T. H.; Hoover, R. L.; Williams, J. D.; Sperling, R. I.; Ravalese, J.; Spur, B. W.;
Robinson, D. R.; Corey, E. J.; Lewis, R. A.; Austen, K. F. N. Eng. J. Med. 1985, 312,
1217–1224.
3. Sperling, R. I.; Weinblatt, M.; Robin, J. L.; Ravalese, J.; Hoover, R. L.; House, F.;
Coblyn, J. S.; Fraser, P. A.; Spur, B. W.; Robinson, D. R.; Lewis, R. A.; Austen, K. F.
Arthritis Rheum. 1987, 30, 988–997.
4. Arm, J. P.; Horton, C. E.; Spur, B. W.; Mencia-Huerta, J. M.; Lee, T. H. Am. Rev.
Respir. Dis. 1989, 139, 1395–1400.
5. Serhan, C. N.; Hong, S.; Gronert, K.; Colgan, S. P.; Devchand, P. R.; Mirick, G.;
Moussignac, R. L. J. Exp. Med. 2002, 196, 1025–1037.
6. Serhan, C. N.; Yang, R.; Martinod, K.; Kasuga, K.; Pillai, P. S.; Porter, T. F.; Oh, S.
F.; Spite, M. J. Exp. Med. 2009, 206, 15–23.
7. Chiang, N.; Fredman, G.; Backhed, F.; Oh, S. F.; Vickery, T.; Schmidt, B. A.;
Serhan, C. N. Nature 2012, 484, 524–528.
8. Xu, Z. Z.; Zhang, L.; Liu, T.; Park, J. Y.; Berta, T.; Yang, R.; Serhan, C. N.; Ji, R. R.
Nat. Med. 2010, 16, 592–597.
9. Xu, Z. Z.; Ji, R. R. Br. J. Pharm. 2011, 164, 274–277.
10. Rogerio, A. P.; Haworth, O.; Croze, R.; Oh, S. F.; Uddin, M.; Carlo, T.; Pfeffer, M.
A.; Priluck, R.; Serhan, C. N.; Levy, B. D. J. Immunol. 2012, 189, 1983–1991.
11. Mukherjee, P. K.; Marcheselli, V. L.; Serhan, C. N.; Bazan, N. G. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 8491–8496.
12. Ariel, A.; Li, P.-L.; Wang, W.; Tang, W.-X.; Fredman, G.; Hong, S.; Gotlinger, K.
H.; Serhan, C. N. J. Biol. Chem. 2005, 280, 43079–43086.
13. Serhan, C. N.; Gotlinger, K.; Hong, S.; Lu, Y.; Siegelman, J.; Baer, T.; Yang, R.;
Colgan, S. P.; Petasis, N. A. J. Immunol. 2006, 176, 1848–1859.
14. Wang, X.; Zhu, M.; Hjorth, E.; Cortes-Toro, V.; Eyjolfsdottir, H.; Graff, C.;
Eriksdotter, M.; Nennesmo, I.; Palmblad, J.; Sambamurti, K.; Fitzgerald, J. M.;
Serhan, C. N.; Granholm, A.-C.; Schultzberg, M. Alzheimers Dement. 2014, in
press, http://dx.doi.org/10.1016/j.jalz.2013.12.024.
15. Lukiw, W. J.; Cui, J.-G.; Marcheselli, V. L.; Bodker, M.; Botkjaer, A.; Gotlinger, K.;
Serhan, C. N.; Bazan, N. G. J. Clin. Invest. 2005, 115, 2774–2783.
16. Serhan, C. N. Nature 2014, 510, 92–101.
17. Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2011, 52, 3001–3004.
18. Petasis, N. A.; Yang, R.; Winkler, J. W.; Zhu, M.; Uddin, J.; Bazan, N. G.; Serhan, C.
N. Tetrahedron Lett. 2012, 53, 1695–1698.
19. Serhan, C. N.; Petasis, N. A. Chem. Rev. 2011, 111, 5922–5943.
20. Aursnes, M.; Tungen, J. E.; Vik, A.; Dalli, J.; Hansen, T. V. Org. Biomol. Chem.
2014, 12, 432–437.
21. Dayaker, G.; Durand, T.; Balas, L. Chem. Eur. J. 2014, 20, 2879–2887.
22. Delorme, D.; Girard, Y.; Rokach, J. J. Org. Chem. 1989, 54, 3635–3640.
23. Corey, E. J.; Hashimoto, S.-I. Tetrahedron Lett. 1981, 22, 299–302.
24. Spur, B.; Crea, A.; Peters, W.; Koenig, W. Tetrahedron Lett. 1983, 24, 1755–1758.
25. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647–2650.
26. Couturier, M.; Dory, Y. L.; Rouillard, F.; Deslongchamps, P. Tetrahedron 1998, 54,
1529–1562.
27. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron Lett. 1998, 39,
8563–8566.
28. Gareg, P. J.; Samuelson, B. J. Chem. Soc., Perkin Trans. I 1980, 2866–2869.
29. Dias, L. C.; Meira, P. R. R. J. Org. Chem. 2005, 70, 4762–4773.
30. Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K. Tetrahedron Lett.
1998, 39, 3091–3092.
31. Chandrasekhar, S.; Mohanty, P. K.; Takhi, M. J. Org. Chem. 1997, 62, 2628–2629.
32. Towada, R.; Kurashina, Y.; Kuwahara, S. Tetrahedron Lett. 2013, 54, 6878–6881.
33. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
34. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410.
35. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2012, 53, 4169–4172.
36. Corey, E. J.; Marfat, A.; Munroe, J.; Kim, K. S.; Hopkins, P. B.; Brion, F.
Tetrahedron Lett. 1981, 22, 1077–1080.
37. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717–8720.
38. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2012, 53, 6990–6994.
39. Alami, M.; Crousse, B.; Linstrumelle, G.; Mambu, L.; Larchevêque, M.
Tetrahedron: Asymmetry 1997, 8, 2949–2958.
262, 271, 282 nm; HPLC-UV: Zorbax SB-C18, 1.8
lm, 50 ꢂ 2.1 mm, 271 nm,
H2O/CH3OH (0.1% formic acid) 50:50–30:70, 0.2 mL/min, tR = 20.0 min; HPLC/
40. Tetrakis(triphenylphosphine)palladium(0) 99% (99.9%-Pd) from Strem
Chemicals, catalog # 46-2150, was used.
41. Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. Helv. Chim. Acta 1987, 70, 1025–
1040.
42. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2001, 42, 6057–6060.
43. Flash chromatography purification: triethylamine-deactivated silica gel 60
MS (m/z): 397.2 [MꢀNa]+.
D
15-trans-Protectin D1 methyl ester: 1H NMR
(CDCl3, 300 MHz): d 6.3–6.1 (m, 4H), 5.8–5.7 (m, 2H), 5.6–5.3 (m, 6H), 4.3–4.1
(m, 2H), 3.6 (s, 3H), 2.9–2.7 (m, 2H), 2.4–2.2 (m, 8H), 2.1–2.0 (m, 2H), 1.0–0.9 (t,
J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d 173.65, 135.81, 135.68, 135.41,
132.27, 132.19, 131.17, 130.38, 130.31, 129.03, 128.02, 124.90, 123.54, 71.89,
71.85, 51.62, 35.36, 35.20, 33.93, 25.78, 22.79, 20.73, 14.21; UV (EtOH) kmax
(40–63
lm), 25–35% ethyl acetate in hexane.
261, 270, 281 nm; HPLC-UV: Zorbax SB-C18, 1.8
lm, 50 ꢂ 2.1 mm, 271 nm,
44. Satisfactory spectroscopic data were obtained for all compounds. Selected physical
H2O/CH3OH (0.1% formic acid) 50:50–30:70, 0.2 mL/min, tR = 18.4 min; HPLC/
MS (m/z): 397.2 [MꢀNa]+. Protectin D1 (1): 1H NMR (CD3OD, 300 MHz): d 6.5
(dd, J = 14.1, 11.1 Hz, 1H), 6.4–6.2 (m, 2H), 6.1 (t, J = 11.1 Hz, 1H), 5.8–5.7 (dd,
J = 14.4, 6.3 Hz, 1H), 5.5–5.3 (m, 7H), 4.6–4.5 (m, 1H), 4.2–4.1 (m, 1H), 2.9–2.7
(m, 2H), 2.4–2.1 (m, 8H), 2.1–2.0 (m, 2H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR
(CD3OD, 75.5 MHz): d 176.99, 137.95, 134.95, 134.81, 134.73, 131.39, 130.98,
130.58, 130.14, 129.17, 128.89, 126.48, 125.27, 72.98, 68.55, 36.37, 36.32,
35.00, 26.70, 23.88, 21.69, 14.58; UV (EtOH) kmax 262, 271, 282 nm; HPLC-UV:
data: Compound 8: 1H NMR (CDCl3, 300 MHz):
d 3.6 (s, 3H), 3.7–3.6 (t,
J = 6.2 Hz, 2H), 2.4 (t, J = 7.2 Hz, 2H), 1.9–1.8 (m, 2H); 13C NMR (CDCl3,
75.5 MHz): d 174.29, 61.92, 51.58, 30.74, 27.71. Compound 9: 1H NMR (CDCl3,
300 MHz): d 9.8 (s, 1H), 3.6 (s, 3H), 2.8–2.7 (t, J = 6.6 Hz, 2H), 2.6 (t, J = 6.6 Hz,
2H); 13C NMR (CDCl3, 75.5 MHz):
d 199.72, 172.63, 51.84, 38.54, 26.38.
Compound 14: 1H NMR (CDCl3, 300 MHz): d 5.5–5.4 (m, 2H), 3.7–3.6 (s and m,
5H), 2.4–2.3 (m, 6H); 13C NMR (CDCl3, 75.5 MHz): d 173.58, 130.54, 127.14,
62.09, 51.48, 33.82, 30.77, 22.77. Compound 15: 1H NMR (CDCl3, 300 MHz): d
5.6–5.4 (m, 1H), 5.4–5.3 (m, 1H), 3.6 (s, 3H), 3.1 (t, J = 7.2 Hz, 2H), 2.7–2.6 (br q,
J = 7.2 Hz, 2H), 2.4–2.3 (m, 4H); 13C NMR (CDCl3, 75.5 MHz): d 173.31, 130.07,
129.43, 51.52, 33.81, 31.34, 22.97, 4.93. Compound 5: 1H NMR (CDCl3,
Zorbax SB-C18, 1.8
lm, 50 ꢂ 2.1 mm, 271 nm, H2O/CH3OH (0.1% formic acid)
50:50–30:70, 0.2 mL/min, tR = 16.6 min; HPLC/MS (m/z): 359.2 [MꢀH]ꢀ.