Total synthesis of Resolvin D1, a potent anti-inflammatory lipid mediator

Article abstract of DOI:10.1016/j.tetlet.2012.10.059

The total synthesis of Resolvin D1, a potent endogenous anti-inflammatory lipid mediator derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C7, C8 and C17 were obtained via a chiral pool strategy from 2-deoxy-d-ribose. Witt

Full text of DOI:10.1016/j.tetlet.2012.10.059

Tetrahedron Letters 53 (2012) 6990–6994
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of Resolvin D1, a potent anti-inflammatory lipid mediator
⇑
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 Resolvin D1, a potent endogenous anti-inflammatory lipid mediator derived from
docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C7, C8 and C17 were obtained via
Received 20 September 2012
Revised 9 October 2012
Accepted 15 October 2012
Available online 23 October 2012
0
I
a chiral pool strategy from 2-deoxy-
coupling and Zn(Cu/Ag) cis-reduction completed the total synthesis of Resolvin D1.
Ó 2012 Elsevier Ltd. All rights reserved.
D-ribose. Wittig reactions followed by a modified Pd /Cu Sonogashira
Keywords:
Resolvin D1
Total synthesis
Inflammation resolution
Chiral pool synthesis
Sonogashira coupling
The health benefits of the
and eicosapentaenoic acid in a variety of human diseases such as
x
-3 fatty acids, docosahexaenoic acid
The biosynthesis of Resolvin D1 is shown in Figure 1. Resolvin
D1 is formed in vivo from docosahexaenoic acid via lipoxygenation
asthma, rheumatoid arthritis and cardiovascular diseases are well
2
at C17 and C7. Elimination of H O forms the 7S,8S-epoxide inter-
documented in the literature.1 The effects of these
x-3 fatty acids
–3
mediate that undergoes enzymatic epoxide opening to produce
the 7S,8R,17S-trihydroxy-docosahexaenoic acid (Resolvin D1).1
In order to explore the full potential of these Resolvins they
have to be prepared by total syntheses since the availability from
2,13
on neutrophil function were explored in healthy volunteers in or-
der to establish a biochemical mechanism of the observed effects
4
in humans. In 2002 Serhan and collaborators could show for the
1
4–27
first time that the enzymatic conversion of these polyunsaturated
fatty acids by different lipoxygenase enzymes led to a series of
natural sources is limited to microgram quantities.
As part of our studies on the total syntheses of lipid mediators
of resolution we wish to report a convergent total synthesis of
Resolvin D1 [RvD1; (4Z,7S,8R,9E,11E,13Z,15E,17S,19Z)-7,8,17-tri-
hydroxy-4,9,11,13,15,19-docosahexaenoic acid (1)]. As shown in
the retrosynthetic scheme (Fig. 2) 3,4-O-isopropylidene-2-deoxy-
highly potent anti-inflammatory lipid mediators named Resolvins
5
(
resolution phase interaction products). Later on they discovered
the Neuroprotectins and Maresin 1 (macrophage mediator in
6
,7
resolving inflammation).
These novel pro-resolving lipids are
generated at the side of injury and they participate actively in
the resolution of inflammation. It has been reported that Resolvin
D1 attenuates inflammatory pain under a variety of conditions
D-ribose was used as the source of chirality for C7, C8 and C17.
Wittig reactions and Sonogashira coupling followed by cis-selec-
tive Zn(Cu/Ag) reduction produced Resolvin D1 (1).
8
,9
including arthritic pain. In addition Resolvin D1 promotes the
resolution of allergic airway responses.10 Recently Chiang and col-
laborators reported that bacterial infections contribute to the
active resolution of acute inflammation.11 They identified Resolvin
D1 (RvD1) among others in self-resolving Escherichia coli exudates.
In human macrophages RvD1 promotes phagocytosis of E. coli and
as a result Resolvin D1 accelerated the resolution to enhance sur-
vival towards gram-positive and gram-negative bacteria and low-
ered the requirement of concurrent antibiotic treatment.11 These
findings offer a potential new strategy to overcome the problems
associated with antibiotic resistance towards bacteria.
The synthesis of the C1–C14 key intermediate 3 was achieved in
5 steps starting from the readily available 3,4-O-isopropylidene-2-
2
8
deoxy-
with 2.2 equiv of the phosphorane generated from (methoxycar-
bonylpropyl)triphenylphosphonium bromide (6) and KN(TMS) in
THF gave the isopropylidene ester 9. Dess Martin oxidation of 9
D-ribose (2) (Scheme 1). cis-Selective Wittig reaction of 2
2
2
9
in CH
2 2
Cl produced the aldehyde 10 in 84% yield. The use of
30
PCC in the presence of sodium acetate gave slightly lower yields.
The aldehyde 10 was converted into 11 in 2 steps. Wittig reaction
of 10 with the phosphorane generated from the corresponding
3
1
phosphonium bromide 7 and n-BuLi in THF followed by catalytic
iodine isomerization in benzene at rt gave the trans, trans-diene 11
in a high yield. A small amount of the remaining 9-cis-isomer could
be easily removed by flash chromatography. Cleavage of the termi-
nal TMS-group with potassium fluoride dihydrate in DMF in the
⇑
Corresponding author. Tel.: +1 856 566 7016; fax: +1 856 566 6195.
E-mail address: spurbw@umdnj.edu (B.W. Spur).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.059

A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 6990–6994
6991
Figure 1. Biosynthesis of Resolvin D1.
Figure 2. Retrosynthetic approach to Resolvin D1.
presence of a catalytic amount of 18-crown-6 gave the key inter-
mediate 3 in 88% yield.32
from the phosphonium bromide 8 and NaN(TMS)
2
in ether at
14
À78 °C gave the cis-olefination product 5. Using the method of
Samuelsson, 5 was converted into the iodide 12 with triphenyl-
phosphine, imidazole and iodine in toluene at 60 °C in 82%
The C15–C22 fragment 4 was obtained in 3 steps from 3,4-O-
isopropylidene-2-deoxy-D-ribose (2) as outlined in Scheme 2.
3
3–35
Wittig reaction of 2 with 2.5 equiv of the phosphorane generated
yield.
The isopropylidene iodide 12 was converted into the

6
992
A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 6990–6994
Scheme 1. Reagents and conditions: (a) 6, KN(TMS)
rt, 87%; (e) KFÁ2H O, 18-crown-6, DMF, rt, 88%.
2
, THF, À70 °C to rt, 43%; (b) Dess–Martin periodinane, CH
Cl
2 2
, rt, 84%; (c) 7, n-BuLi, THF, À78 to 0 °C, 80%; (d) I
2
, benzene,
2
trans-iodovinyl alcohol 4 using 4 equiv of LDA in THF at À78 °C.
This reaction also produced the propargyl alcohol 13 that was sep-
arated by flash chromatography. The cis-iodovinyl alcohol isomer
of 4 was not observed. This new strategy is the shortest approach
The total synthesis of Resolvin D1 was completed as shown in
3
6,37
Scheme 3. Modified Sonogashira coupling
of 4 in the presence
3
8
3 4
of Pd(PPh ) ,
CuI and piperidine in benzene with a very slow
addition of the acetylene 3 gave the isopropylidene protected acet-
1
5
39
to alcohol 4, previously used in our syntheses of Resolvin D5 and
ylene precursor of Resolvin D1 methyl ester (14) in 86% yield.
2
2
Resolvin D6.
Under these conditions no dimerization of acetylene 3 was
Scheme 2. Reagents and conditions: (a) 8, NaN(TMS)
2
, Et
2
O, À78 °C to rt, 60%; (b) I
2
, Ph
3
P, imidazole, toluene, 60 °C, 82%; (c) LDA, THF, À78 °C, 40% (4).
3 4 3 3 3 2
Scheme 3. Reagents and conditions: (a) Pd(PPh ) , CuI, piperidine, benzene, rt, 86%; (b) CH COCl cat, CH OH, 0 °C, 90%; (c) Zn(Cu/Ag), CH OH, H O, 50 °C, 5 h, 67%; (d) 1 N
LiOH, CH OH, H O, 0 °C, then sat. NaH PO , 94%.
3
2
2
4

A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 6990–6994
6993
detected. Mild cleavage of the isopropylidene protective group
with a catalytic amount of acetyl chloride in CH OH at 0 °C gave
5. The cis-selective reduction of the conjugated triple bond was
31. Nicolaou, K. C.; Veale, C. A.; Webber, S. E.; Katerinopoulos, H. J. Am. Chem. Soc.
985, 107, 7515–7518.
1
3
3
3
2. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2001, 42, 6057–6060.
3. Gareg, P. J.; Samuelson, B. J. Chem. Soc., Perkin Trans. I 1980, 2866–2869.
1
40
achieved with freshly prepared Zn(Cu/Ag) in CH
3 2
OH/H O at
34. Kang, S.-K.; Lee, D.-H.; Lee, J.-M. Synlett 1990, 591–593.
35. Kang, S.-K.; Cho, I.-H. Tetrahedron Lett. 1989, 30, 743–746.
36. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–4470.
37. Alami, M.; Crousse, B.; Linstrumelle, G.; Mambu, L.; Larchevêque, M.
Tetrahedron: Asymmetry 1997, 8, 2949–2958.
5
0 °C to produce Resolvin D1 methyl ester (16) in 67% yield after
4
1,42
HPLC purification.
1
Mild hydrolysis of the methyl ester 16 with
O at 0 °C under argon gave after acidification
N LiOH in CH
3
OH/H
2
3
3
8. Tetrakis(triphenylphosphine)palladium(0) 99% (99.9%-Pd) from Strem
Chemicals, catalog # 46-2150, was used.
with sat. NaH
2 4
PO in the presence of ethyl acetate Resolvin D1 (1)
in 94% yield. HPLC analysis showed that the synthetic 1 co-eluted
9. In
a flame dried flask under argon CuI (5.2 mg, 0.027 mmol) and
with an authentic sample of Resolvin D1 (Cayman Chemical
tetrakis(triphenylphosphine)palladium(0) (15.8 mg, 0.014 mmol) were added
followed by a solution of 4 (69 mg, 0.27 mmol) in benzene (2 ml). The solution
4
3
Company).
In summary, a short and concise total synthesis of Resolvin D1
was alternatively evacuated and flushed with argon and then piperidine (54
ll,
0.55 mmol) was added. The flask was protected from light and a solution of 3
4
3
from 3,4-O-isopropylidene-2-deoxy-
D
-ribose has been achieved,
(75 mg, 0.25 mmol) in benzene (2.2 ml), previously saturated with argon, was
added over a period of 2 h with a syringe pump. The reaction mixture was
stirred for two additional hours and then quenched by the addition of a
making this important lipid mediator of resolution available for fur-
ther biological and pharmacological testing. The synthesis of other
Resolvins and Neuroprotectin D1 will be reported in due course.
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.
saturated solution of NH
4
Cl. The resulting suspension was extracted with ether
and the organic layer was washed with NH Cl, NaCl and dried over Na SO .
4
2
4
Concentration followed by flash chromatography purification (silica gel,
hexane/EtOAc 85:15 ? 80:20) afforded 92 mg (86%) of 14.
4
4
4
0. Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. Helv. Chim. Acta 1987, 70, 1025–
1040.
1. HPLC [Zorbax SB-C18, 21.2 mm  25 cm, 325 nm, CH
3 2
OH/H O 63/37, 10 mL/
min, tR(RvD1-Me) = 65 min].
Acknowledgment
2. When the reaction was performed in CD
Resolvin D1 methyl ester was cleanly produced.
43. Satisfactory spectroscopic data were obtained for all compounds. Selected
physical data: Compound 9: 1H NMR (CDCl
, 300 MHz): d 5.5–5.4 (m, 2H),
.2–4.1 (m, 2H), 3.7–3.6 (m, 2H), 3.6 (s, 3H), 2.5–2.2 (m, 6H), 1.8 (br s, 1H), 1.4
s, 3H), 1.3 (s, 3H); 13C NMR (CDCl
, 75.5 MHz): d 173.45, 130.14, 126.37,
108.21, 77.78, 76.66, 61.69, 51.52, 33.78, 28.06, 27.45, 25.37, 23.01. Compound
3 2
OD/D O the 13,14-dideuterio-
We thank Dr. T. Peter Stein and Margaret D. Schluter for the
HPLC/MS/MS analysis.
3
4
(
3
References and notes
1
1
2
(
1
0: H NMR (CDCl
H), 4.4–4.3 (m, 1H), 4.3 (dd, J = 7.2, 3.0 Hz, 1H), 3.6 (s, 3H), 2.4–2.2 (m, 6H), 1.6
, 75.5 MHz): d 201.65, 173.34, 130.88,
25.32, 110.61,1 81.91, 78.23, 51.51, 33.63, 27.86, 27.43, 25.19, 22.98.
, 300 MHz): d 6.7–6.5 (dd, J = 15.6, 10.8 Hz,
H), 6.4–6.2 (dd, J = 15.0, 10.8 Hz, 1H), 5.8–5.7 (dd, J = 15.0, 7.8 Hz, 1H), 5.7–5.6
d, J = 15.6 Hz, 1H), 5.5–5.3 (m, 2H), 4.6–4.5 (m, 1H), 4.2–4.1 (dt, J = 8.4, 5.8 Hz,
H), 3.6 (s, 3H), 2.4–2.0 (m, 6H), 1.5 (s, 3H), 1.3 (s, 3H), 0.2 (s, 9H); 13C NMR
CDCl , 75.5 MHz): d C1 not observed, 141.54, 132.23, 131.85, 129.96, 126.36,
12.16, 108.50, 104.08, 97.86, 78.60, 78.30, 51.51, 33.85, 28.87, 28.10, 25.50,
3
, 300 MHz): d 9.7–9.6 (dd, J = 3.0, 0.6 Hz, 1H), 5.6–5.4 (m,
1
.
.
Arm, J. P.; Horton, C. E.; Spur, B. W.; Mencia-Huerta, J. M.; Lee, T. H. Am. Rev.
Respir. Dis. 1989, 139, 1395–1400.
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.
s, 3H), 1.4 (s, 3H); 13C NMR (CDCl
3
2
Compound 11: H NMR (CDCl
3
1
(
1
(
1
2
3
4
.
.
De Caterina, R. N. Eng. J. Med. 2011, 364, 2439–2450.
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,
3
1
217–1224.
1
3.04, À0.12 (3C). Compound 3: H NMR (CDCl
3
, 300 MHz): d 6.7–6.6 (dd,
5.
6.
7.
8.
9.
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.
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Serhan, C. N.; Dalli, J.; Karamnov, S.; Choi, A.; Park, C. K.; Xu, Z. Z.; Ji, R. R.; Zhu,
M.; Petasis, N. A. FASEB J. 2012, 26, 1755–1765.
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.
J = 15.6, 10.8 Hz, 1H), 6.4–6.2 (ddt, J = 15.0, 10.8, 0.9 Hz, 1H), 5.8–5.7 (dd,
J = 15.0, 7.8 Hz, 1H), 5.6 (br dd, J = 15.6, 2.4 Hz, 1H), 5.5–5.3 (m, 2H), 4.6–4.5 (m,
1
2
H), 4.2–4.1 (dt, J = 8.1, 6.0 Hz, 1H), 3.6 (s, 3H), 3.1–3.0 (d, J = 2.4 Hz, 1H), 2.4–
.1 (m, 6H), 1.5 (s, 3H), 1.3 (s, 3H); 13C NMR (CDCl
3
, 75.5 MHz): d C1 not
observed, 142.28, 132.40, 131.88, 130.01, 126.48, 111.11, 108.59, 82.71, 79.88,
8.63, 78.45, 51.39, 33.94, 29.02, 28.12, 25.53, 23.16. Compound 12: 1H NMR
CDCl , 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
(
3
7
2
3
1
.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,
Xu, Z. Z.; Ji, R. R. Br. J. Pharm. 2011, 164, 274–277.
H), 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,
1
1
1
0. 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.
1. Chiang, N.; Fredman, G.; Backhed, F.; Oh, S. F.; Vickery, T.; Schmidt, B. A.;
Serhan, C. N. Nature 2012, 484, 524–528.
2. Sun, Y. P.; Oh, S. F.; Uddin, J.; Yang, R.; Gotlinger, K.; Campbell, E.; Colgan, S. P.;
Petasis, N. A.; Serhan, C. N. J. Biol. Chem. 2007, 282, 9323–9334.
H), 1.0 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl
, 75.5 MHz): d 134.44, 123.63,
3
1
08.52, 78.30, 77.69, 28.36, 27.45, 25.68, 20.86, 14.00, 3.66. Compound 4:
H
NMR (CDCl
3
, 300 MHz): d 6.6–6.5 (dd, J = 14.4, 6.0 Hz, 1H), 6.4–6.3 (dd, J = 14.4,
1
1
2
1
.5 Hz, 1H), 5.7–5.5 (dtt, J = 10.8, 7.5, 1.5 Hz, 1H), 5.4–5.2 (dtt, J = 10.8, 7.5,
.5 Hz, 1H), 4.2–4.0 (m, 1H), 2.4–2.2 (m, 2H), 2.1–2.0 (quint d, J = 7.5, 1.5 Hz,
H), 1.7–1.6 (br s, 1H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl
, 75.5 MHz): d
3
1
13. Serhan, C. N.; Petasis, N. A. Chem. Rev. 2011, 111, 5922–5943.
14. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717–8720.
15. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2005, 46, 3623–3627.
16. Ogawa, S.; Urabe, D.; Yokokura, Y.; Arai, H.; Arita, M.; Inoue, M. Org. Lett. 2009,
47.90, 136.07, 122.74, 77.08, 73.91, 34.64, 20.75, 14.14. Compound 13:
, 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),
H
NMR (CDCl
3
2
3
2
1
1
5
2
3
1
7
.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,
H); 13C NMR (CDCl
, 75.5 MHz): d 136.13, 122.43, 84.56, 72.90, 61.88, 35.47,
0.79, 14.14. Compound 14: H NMR (CDCl
11, 3602–3605.
1
1
1
7. Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2009, 50, 6079–6082.
8. Kosaki, Y.; Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2010, 51, 1856–1859.
9. Sasaki, K.; Urabe, D.; Arai, H.; Arita, M.; Inoue, M. Chem. Asian J. 2011, 6, 534–
3
1
3
, 300 MHz): d 6.6–6.5 (dd, J = 15.3,
0.8 Hz, 1H), 6.4–6.2 (dd, J = 15.3, 10.8 Hz, 1H), 6.2–6.1 (dd, J = 15.9, 5.7 Hz,
H), 5.9–5.7 (m, 3H), 5.6–5.5 (dtt, J = 10.8, 7.2, 1.5 Hz, 1H), 5.5–5.4 (m, 2H),
.4–5.2 (dtt, J = 10.8, 7.2, 1.5 Hz, 1H), 4.6–4.5 (br t, J = 6.9 Hz, 1H), 4.2–4.1 (m,
H), 3.6 (s, 3H), 2.4–2.0 (m, 10H), 1.5 (s, 3H), 1.3 (s, 3H), 1.0–0.9 (t, J = 7.5 Hz,
5
43.
2
0. Allard, M.; Barnes, K.; Chen, X.; Cheung, Y.-Y.; Duffy, B.; Heap, C.; Inthavongsay,
J.; Johnson, M.; Krishnamoorthy, R.; Manley, C.; Steffke, S.; Varughese, D.;
Wang, R.; Wang, Y.; Schwartz, C. E. Tetrahedron Lett. 2011, 52, 2623–2626.
1. Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2011, 52, 3001–3004.
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N. Tetrahedron Lett. 2012, 53, 1695–1698.
H); 13C NMR (CDCl
3
, 75.5 MHz): d 173.40, 144.91, 140.36, 135.79, 132.45,
31.34, 129.92, 126.37, 123.10, 112.31, 110.04, 108.47, 90.73, 89.41, 78.66,
2
2
2
8.30, 71.56, 51.50, 34.97, 33.84, 28.87, 28.09, 25.49, 23.03, 20.72, 14.11.
1
Compound 15: H NMR (CDCl
3
, 300 MHz): d 6.7–6.5 (dd, J = 15.3, 10.8 Hz, 1H),
6
3
7
2
1
9
.4–6.3 (dd, J = 15.3, 10.8 Hz, 1H), 6.2–6.1 (dd, J = 15.9, 5.7 Hz, 1H), 5.9–5.7 (m,
H), 5.7–5.5 (dtt, J = 10.8, 7.2, 1.5 Hz, 1H), 5.5–5.4 (m, 2H), 5.4–5.2 (dtt, J = 10.8,
.2, 1.5 Hz, 1H), 4.3–4.1 (m, 2H), 3.8–3.6 (dt, J = 9.0, 3.9 Hz, 1H), 3.6 (s, 3H), 2.5–
2
2
4. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2012, 53, 1912–1915.
5. Isobe, Y.; Arita, M.; Matsueda, S.; Iwamoto, R.; Fujihara, T.; Nakanishi, H.;
Taguchi, R.; Masuda, K.; Sasaki, K.; Urabe, D.; Inoue, M.; Arai, H. J. Biol. Chem.
.0 (m, 10H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl
3
, 75.5 MHz): d 173.73,
44.87, 140.60, 135.83, 133.59, 131.81, 131.08, 126.67, 123.13, 112.13, 110.14,
2
012, 287, 10525–10534.
6. Urabe, D.; Todoroki, H.; Masuda, K.; Inoue, M. Tetrahedron 2012, 68, 3210–
219.
0.64, 89.49, 74.75, 73.91, 71.63, 51.61, 35.03, 33.59, 30.12, 22.75, 20.75, 14.10.
2
1
Compound 16: H NMR (CD
3
CN, 300 MHz): d 6.9–6.7 (m, 2H), 6.5–6.3 (m, 2H),
3
6
1
1
.1–6.0 (m, 2H), 5.9–5.7 (m, 2H), 5.6–5.3 (m, 4H), 4.3–4.1 (m, 1H), 4.1–4.0 (m,
2
2
7. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2012, 53, 4169–4172.
8. Corey, E. J.; Marfat, A.; Munroe, J.; Kim, K. S.; Hopkins, P. B.; Brion, F.
Tetrahedron Lett. 1981, 22, 1077–1080.
H), 3.6 (s, 3H), 3.6–3.5 (m, 1H), 3.1 (d, J = 4.8 Hz, 1H), 3.0–2.9 (d, J = 4.5 Hz,
H), 2.9–2.8 (d, J = 5.1 Hz, 1H), 2.4–2.0 (m, 10H), 1.0 (t, J = 7.5 Hz, 3H); 13C NMR
(
3
CD CN, 75.5 MHz): d C1 not observed, 138.77, 134.55, 134.17, 133.92, 132.19,
2
3
9. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
0. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647–2650.
130.15, 129.84, 129.66, 128.45, 128.06, 125.41, 125.24, 75.32, 74.87, 72.04,

6
994
A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 6990–6994
5
3
1.54, 35.70, 34.08, 30.98, 23.28, 20.98, 14.06. Compound 1: 1H NMR (CD
00 MHz): d 6.8–6.6 (m, 2H), 6.5–6.2 (m, 2H), 6.1–5.9 (m, 2H), 5.9–5.8 (dd,
J = 14.7, 6.7 Hz, 1H), 5.8–5.7 (dd, J = 15.0, 6.6 Hz, 1H), 5.6–5.3 (m, 4H), 4.2–4.1
m, 1H), 4.1–3.9 (m, 1H), 3.6–3.5 (m, 1H), 2.4–2.1 (m, 8H), 2.1–2.0 (quint,
3
OD,
129.19, 128.32, 126.61, 125.47, 76.27, 75.86, 73.13, 36.27, 34.95, 31.89, 24.06,
21.65, 14.46. UV (EtOH) kmax 289, 302, 317 nm. HPLC–UV: Hypersil-ODS,
100 Â 2.1 mm, 301 nm, CH
3
OH/H
2
O (0.1% formic acid) 45/55 to 70/30, 0.2 mL/
co-eluted with an authentic sample
(
min, tR = 21.4 min [synthesized
1
1
3
J = 7.5 Hz, 2H), 1.0–0.9 (t, J = 7.5 Hz, 3H); C NMR (CD
observed, 138.29, 134.69, 134.57, 134.47, 133.44, 130.78, 130.46, 130.24,
3
OD, 75.5 MHz): d C1 not
of Resolvin D1 (Cayman Chemical Company)]. HPLC/MS/MS (m/z): 375.3
À
[MÀH] .