First total synthesis of pro-resolving and tissue-regenerative resolvin sulfido-conjugates

Article abstract of DOI:10.1016/j.tetlet.2017.03.041

The first total synthesis of the pro-resolving and tissue-regenerative resolvin sulfido-conjugates: 7S,8R,17S-RCTR1, 7S,8R,17S-RCTR2 and 7S,8R,17S-RCTR3, derived from docosahexaenoic acid, has been achieved. Two synthetic approaches are described. Chiral

Full text of DOI:10.1016/j.tetlet.2017.03.041

Accepted Manuscript
First total synthesis of pro-resolving and tissue-regenerative resolvin sulfido-
conjugates
Ana R. Rodriguez, Bernd W. Spur
PII:
S0040-4039(17)30336-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.041
TETL 48742
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 February 2017
10 March 2017
13 March 2017
Please cite this article as: Rodriguez, A.R., Spur, B.W., First total synthesis of pro-resolving and tissue-regenerative
resolvin sulfido-conjugates, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.03.041
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First total synthesis of pro-resolving and
tissue-regenerative resolvin sulfido-
conjugates
Ana R. Rodriguez, Bernd W. Spur

1
Tetrahedron Letters
journal homepage: www.els evier.com
First total synthesis of pro-resolving and tissue-regenerative resolvin sulfido-
conjugates
Ana R. Rodriguez and Bernd W. Spur∗
Department of Cell Biology, Rowan University- SOM, Stratford, NJ 08084, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
The first total synthesis of the pro-resolving and tissue-regenerative resolvin sulfido-conjugates:
7S,8R,17S-RCTR1, 7S,8R,17S-RCTR2 and 7S,8R,17S-RCTR3, derived from docosahexaenoic
acid, has been achieved. Two synthetic approaches are described. Chiral centers 7S and 8R were
introduced in both approaches via a chiral pool strategy starting from 2-deoxy-D-ribose. The 17S
chiral center was introduced either by a chiral pool strategy or by an enzymatic hydroxylation
with lipoxidase. Wittig reactions, selective epoxide formation and epoxide opening with
glutathione, L-cysteinylglycine and L-cysteine respectively, were the key steps in the synthesis.
Received in revised form
Accepted
Available online
Keywords:
Resolvin sulfido-conjugates
Total synthesis
2009 Elsevier Ltd. All rights reserved
.
Inflammation resolution
Tissue-regeneration
Lipoxidase
Chiral pool
———
∗ Corresponding author. Tel.: +1-856-566-7016; fax: +1-856-566-6195; e-mail: spurbw@rowan.edu

2
Tetrahedron Letters
Inflammation is a response to tissue damage and/ or
infection. If acute inflammation is self-limited and achieves
resolution this is a protective mechanism,1,2 but uncontrolled
inflammation is the underlining course of chronic diseases. It is
known that ω-3 polyunsaturated fatty acids found in fish-oil,
mainly docosahexaenoic acid (DHA) and eicosapentaenoic acid
(EPA), have anti-inflammatory and anti-infective activities in
humans.3-6 The pioneering work by Serhan and co-workers have
identified in self-resolving exudates during the resolution phase
of inflammation powerful lipid mediators derived from ω-3
polyunsaturated fatty acids that are produced by lipoxygenase
enzymes.7-12 Those products are among the so called specialized
pro-resolving mediators (SPMs) and they include the resolvins,
protectins and maresins.
Figure 1. Structures of the maresin, protectin and resolvin sulfido-conjugates.
Recently, Serhan and co-workers investigated self-resolving
exudates in E. coli infected mice, human spleen and blood of
sepsis patients, and discovered the novel anti-inflammatory, pro-
resolving and tissue regenerative sulfido-conjugates of maresin
(MCTRs), protectin (PCTRs) and resolvin (RCTRs) (Figure
1).13,14 These compounds promote pathogen clearance, wound
healing, tissue repair and regeneration. The rapidly increasing
bacterial resistance towards currently used antibiotics requires
new approaches to combat infections. These novel SPMs could
provide a different way to treat infections utilizing the immune
system.
The proposed biosynthesis of the resolvin sulfido-conjugates
by Serhan and co-workers is based on the identified precursor
and its products formed as shown in Figure 2.14 DHA undergoes
two subsequent enzymatic lipoxygenations in C-17 and C-7
followed by an enzymatic conversion to an allylic epoxide to
Figure 2. Proposed biosynthesis of 7S,8R,17S-RCTR1 (1), 7S,8R,17S-
RCTR2 (2) and 7S,8R,17S-RCTR3 (3) from DHA.14
In this letter we wish to report the first total synthesis of the
resolvin sulfido-conjugated mediators 7S,8R,17S-RCTR1
[(4Z,7S,8R,9E,11E,13Z,15E,17S,19Z)-8-glutathionyl-7,17-
dihydroxy-4,9,11,13,15,19-docosahexaenoic
7S,8R,17S-RCTR2 [(4Z,7S,8R,9E,11E,13Z,15E,17S,19Z)-8-
cysteinylglycinyl-7,17-dihydroxy-4,9,11,13,15,19-
docosahexaenoic acid (2)] and 7S,8R,17S-RCTR3
acid
(1)],
produce (4Z,7S,8S,9E,11E,13Z,15E,17S,19Z)-7,8-epoxy-17-
hydroperoxy-4,9,11,13,15,19-docosahexaenoic acid. This
[(4Z,7S,8R,9E,11E,13Z,15E,17S,19Z)-8-cysteinyl-7,17-
product is converted enzymatically by a glutathione S-transferase
to give the 7S,8R,17S-resolvin glutathione conjugate in tissue
regeneration (RCTR1). Similar to the maresin and protectin
sulfido-conjugates, the epoxide opening by the thiopeptides
follows an SN2 mechanism comparable to the peptido-
leukotrienes.15-20 RCTR1 is further metabolized by a γ-glutamyl
transpeptidase to RCTR2 and finally by a dipeptidase to
RCTR3.14
Based on the reported biological properties and due to the
limited availability from natural sources these SPMs have to be
prepared by total synthesis to make them available for further
biological and pharmacological evaluation. We have reported the
first total synthesis of the maresin and protectin sulfido-
conjugates (MCTR1, MCTR2, MCTR3, PCTR1, PCTR2 and
PCTR3).15,16 A synthesis of PCTR1 was later reported by Hansen
and co-workers.17
dihydroxy-4,9,11,13,15,19-docosahexaenoic acid (3)]. As shown
in the retrosynthetic scheme (Figure 3) compounds 1, 2, 3 have
been prepared via two different strategies. The chiral epoxy
esters 4 and 5 were the key intermediate in each synthesis. The
peptide moiety of these sulfido-conjugates was introduced by
epoxide opening with glutathione, L-cysteinylglycine and L-
cysteine. Chiral centers at C7 and C8 were generated in both
approaches from epoxide 6 using a chiral pool strategy starting
from 2-deoxy-D-ribose. The introduction of the chiral center at
C17 was what differentiated both approaches. One used an
enzymatic reaction with lipoxidase once the skeleton of the
molecule was already built and the other used the chiral synthon
8 prepared from D-(-)-arabinose.

3
Figure 3. Two retrosynthetic approaches to 7S,8R,17S-RCTR1 (1), 7S,8R,17S-RCTR2 (2) and 7S,8R,17S-RCTR3 (3).
chiral epoxy alcohol 14 in 52% isolated yield. In this reaction a
terminal epoxide is first formed that undergoes epoxide
transposition under the basic condition similar as described by
Rokach.23,24 The epoxy alcohol 14 was cleanly transformed into
the epoxy aldehyde 15 using Dess-Martin oxidation in CH2Cl2.25
Four-carbon homologation of aldehyde 15 with recrystallized
(2E)-4-triphenylphosphoranylidene-2-butenal (16) 26,27 in CH2Cl2
at rt for 18 h followed by treatment with catalytic iodine in
benzene afforded the E,E-dienal 6.
The required phosphonium salt 7 was prepared in 2 steps
from the easily available (Z,Z)-3,6-nonadien-1-ol (17) (Scheme
2).28 17 was converted to the tosylate 18 with excess tosyl
chloride in high yield and then reacted with
3 equiv
triphenylphosphine in a small amount of acetonitrile under reflux
to give the crystalline phosphonium tosylate 7 as described by
Taber and collaborator.29
Scheme 1. Reagents and conditions: (a) 10, KHMDS, THF, -78 °C to -15
°C, 58%; (b) TsCl, pyridine, 0 °C to rt, 82%; (c) CH3COCl, CH3OH, 0 °C to
rt, 95%; (d) NaOMe, Na2SO4, CH3OH, rt, 52%; (e) Dess-Martin, NaHCO3,
CH2Cl2 , rt; (f) 16, CH2Cl2, rt; (g) cat. I2, benzene, rt, 34% (over three steps).
Scheme 2. Reagents and conditions: (a) TsCl, pyridine, CH2Cl2, 0 °C to rt,
78%; (b) Ph3P, CH3CN, reflux, 80%.
The synthesis of the C1-C13 key intermediate 6 was
achieved in 7 steps starting from the readily available 3,4-O-
isopropylidene-2-deoxy-D-ribose (9)21 (Scheme 1). Cis-selective
Wittig reaction of 9 with 2 equiv of the phosphorane generated
from (Methoxycarbonylpropyl)triphenylphosphonium bromide
(10) and KHMDS in THF gave the isopropylidene ester 11.22 The
free primary hydroxy-group was converted to the tosylate with
tosyl chloride in pyridine in good yield. Cleavage of the
isopropylidene protective group in 12 with HCl generated in situ
from acetyl chloride in CH3OH at 0 ºC to rt gave 13 in 95%
yield. Treatment of the tosylate 13 with 5 equiv of NaOMe in
CH3OH in the presence of Na2SO4 at rt afforded the desired
Wittig reaction of 6 with the ylide prepared in situ from the
phosphonium tosylate 729 with n-BuLi at –78 ºC in THF afforded
the key epoxy ester 4 in 64% isolated yield (Scheme 3).
Compound 4 was characterized by 1H NMR, 13C NMR, COSY,
HSQC, and UV.30 The conversion of epoxy ester 4 to
(4Z,7S,8R,9E,11E,13Z,16Z,19Z)-8-glutathionyl-7-hydroxy-
4,9,11,13,16,19-docosahexaenoic acid (19) was achieved in two
steps as described in Scheme 3.15,16 Reaction of 4 with 3 equiv of
glutathione in CH3OH/triethylamine/H2O gave the intermediate
monomethyl ester that was hydrolyzed with 1 N LiOH in H2O for

4
Tetrahedron Letters
30 min affording crude 19. Compound 19 was purified by HPLC
[Zorbax SB-C18 250 × 21.2 mm, 280 nm, CH3OH/H2O (0.1%
NH4OAc, pH 5.6, 0.05% EDTA disodium) 64/36]. The fraction
containing 19 was desalted using a reversed phase C–18 cartridge
to give pure 19.
Scheme 3. Reagents and conditions: (a) n-BuLi, THF, –78 °C to –30 °C, 64%; (b) Glutathione, Et3N, H2O, CH3OH, rt; (c) L-
Cysteinylglycine, Et3N, H2O, CH3OH, rt; (d) L-Cysteine methyl ester hydrochloride, Et3N, H2O, CH3OH, rt; (e) 1 N LiOH, H2O, 0 °C
to rt, 29% 19, 51% 20 and 31% 21 (over two steps after HPLC purification and desalting); (f) lipoxidase from soybean, 0.1 M
Phosphate buffer pH 8.5, rt; (g) TCEP-HCl, rt, 23% 1, 52% 2 and 56% 3 (over two steps after HPLC purification and desalting).
Using the same conditions as described for 19, compound 4
was reacted with L-cysteinylglycine to obtain after mild
hydrolysis (4Z,7S,8R,9E,11E,13Z,16Z,19Z)-8-cysteinylglycinyl-
7-hydroxy-4,9,11,13,16,19-docosahexaenoic acid (20) (Scheme
3). Compound 20 was purified by HPLC [Zorbax SB-C18 250 ×
21.2 mm, 280 nm, CH3OH/H2O (0.1% NH4OAc, pH 5.6, 0.05%
EDTA disodium) 65/35]. Compound 4 was reacted with L-
cysteine methyl ester hydrochloride to give after mild hydrolysis
(4Z,7S,8R,9E,11E,13Z,16Z,19Z)-8-cysteinyl-7-hydroxy-
[Zorbax SB-C18 250 × 21.2 mm, 309 nm, CH3OH/H2O (0.1%
NH4OAc, pH 5.6, 0.05% EDTA disodium) 57/43] and desalting
gave pure 7S,8R,17S-RCTR1 (1). Compounds 20 and 21 were
converted to 7S,8R,17S-RCTR2 (2) and 7S,8R,17S-RCTR3 (3)39
respectively using similar conditions. H NMR, COSY, UV, and
HPLC/UV/MS analyses were consistent with the structures of 1,
2 and 3.30
1
4,9,11,13,16,19-docosahexaenoic acid (21) using the same steps
as described for 19. Compound 21 was purified by HPLC
[Zorbax SB-C18 250 × 21.2 mm, 280 nm, CH3OH/H2O (0.1%
NH4OAc, pH 5.6, 0.05% EDTA disodium) 67/33]. The 1H NMR,
COSY, UV, and HPLC/UV/MS analysis were consistent with the
structures of 19, 20 and 21.30
The introduction of the 17S-hydroxy group was achieved by
an enzymatic reaction with lipoxidase from soybean followed by
reduction of the intermediate 17S-hydroperoxide. The same
enzyme was previously used in the synthesis of Lipoxin A, B and
the peptido-lipoxins.31-37 The standard conditions for this
transformation, borate buffer pH 9, lipoxidase and sodium
borohydride reduction resulted in a slow and incomplete reaction
of 19 to 7S,8R,17S-RCTR1 (1). The best results were obtained
using phosphate buffer pH 8.5, Fluka lipoxidase and the water
soluble
reducing
agent
tris(2-carboxyethyl)phosphine
Scheme 4. Reagents and conditions: (a) H5IO6, Et2O, THF, 0 °C to rt, 84%;
(b) 24, n-BuLi, THF, –78 °C to 0 °C, 81%; (c) H5IO6, Et2O, THF, rt, 76%; (d)
27, NaHMDS, THF, –78 °C to rt, 85%; (e) DIBAL-H, CH2Cl2, –78 °C to –20
°C, 88%; (f) CBr4, Ph3P, CH2Cl2, 0 °C to rt; (g) Ph3P, CH2Cl2, 0 °C to rt, 87%
(over two steps).
hydrochloride (TCEP-HCl).38 Compound 19 was cleanly
converted to 7S,8R,17S-RCTR1 (1) as evidenced by the
bathochromic shift from 281 nm to 308 nm,32 and the
HPLC/UV/MS analysis of crude 1. Purification by HPLC

5
In our second approach the 17S-hydroxy group was
introduced using the chiral phosphonium salt 8. As shown in
Scheme 4 compound 8 was prepared starting from compound 22
readily available from D-(-)-arabinose in four steps.40-42 Cleavage
of the dithioacetal group in 22 using the Rokach protocol,43,44
with periodic acid dihydrate in THF/Ether for 5 min produced the
aldehyde 23 after filtration through celite. Wittig reaction of 23
with the ylide prepared from n-propyl triphenylphosphonium
bromide (24) and n-BuLi in THF at -78 ºC gave intermediate 25.
Deprotection of the isopropylidene group and oxidative diol
cleavage of 25 occurs smoothly with periodic acid dihydrate in
THF/Ether at rt for 18 h to give the aldehyde 26.45 Horner–
Wadsworth–Emmons reaction of 26 with 27 gave the α,β-
unsaturated ester 28. Compound 28 was reduced to the allyl
alcohol 29 by DIBAL-H in CH2Cl2 and converted to the labile
bromide 30 with CBr4/triphenylphosphine in CH2Cl2. Reaction of
compound 30 with 5 equiv triphenylphosphine in CH2Cl2
followed by flash chromatography gave the crystalline
phosphonium bromide 8.
The phosphorane of 8 was generated with 1.0 equiv n-BuLi
in THF at -100 ºC46-48 and reacted with 1 equiv of aldehyde 6 to
give the protected RCTR precursor 5 and its 13E-isomer in a 1:1
ratio in only moderate yield (Scheme 5). The use of different
bases and temperatures resulted in lower yields. 5 could be easily
separated from the 13E-isomer by straight phase HPLC [Altex
Ultrasphere-Si 250 × 10 mm, 325 nm, Hexane/Et3N 99/1].
1
Compound 5 was characterized by H NMR, 13C NMR, COSY,
HSQC, and UV.30
Scheme 5. Reagents and conditions: (a) n-BuLi, THF, –100 °C to –40 °C, 24% (after HPLC purification); (b) Glutathione, Et3N, H2O,
CH3OH, rt; (c) L-Cysteinylglycine, Et3N, H2O, CH3OH, rt; (d) L-Cysteine, Et3N, H2O, CH3OH, rt; (e) TBAF, CH3COOH, THF, 0 °C to rt;
(f) 1 N LiOH, H2O, 0 °C to rt, 61% 1, 60% 2, 64% 3 (over three steps).
The conversion of 5 to 7S,8R,17S-RCTR1 (1), 7S,8R,17S-
RCTR2 (2) and 7S,8R,17S-RCTR3 (3) required reaction with
glutathione, L-cysteinylglycine and L-cysteine respectively
followed by TBDPS cleavage and ester hydrolysis. Reaction of 5
with 10 equiv of glutathione in CH3OH/triethylamine/H2O gave
the intermediate monomethyl ester 31 that was purified by
reversed phase C–18 cartridge to remove excess glutathione. The
TBDPS-group was cleaved using excess TBAF/acetic acid (1:1)46
followed by mild hydrolysis of the methyl ester with 1N LiOH in
H2O to give after HPLC purification and desalting 7S,8R,17S-
RCTR1 (1). Compounds 2 and 3 were prepared from 5 similar as
described for 1. Co-injections of 7S,8R,17S-RCTR1 (1),
7S,8R,17S-RCTR2 (2) and 7S,8R,17S-RCTR3 (3) prepared from
both routes were analyzed by HPLC/UV/MS and found to be
identical.
biological and pharmacological testing. The synthesis of other
specialized pro-resolving mediators (SPMs) will be reported in
due course.
Acknowledgments
Financial support of this research in part by the NJHF and
NJCBIR is gratefully acknowledged.
References and notes
1. Serhan, C. N. FASEB J. 2017 doi: 10.1096/fj.201601222R. [Epub
ahead of print].
2. Serhan, C. N. Nature 2014, 510, 92–101.
3. De Caterina, R. N. Engl. J. Med. 2011, 364, 2439–2450.
4. 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. Engl. J. Med. 1985, 312, 1217–1224.
5. Sperling, R. I.; Weinblatt, M.; Robin, J. L.; Ravalese, J.; Hoover,
R. L.; House, F.; Coblyn, J. S.; Fraser., P. A.; Spur, B. W.;
In summary we have developed two synthetic routes for the
synthesis of 7S,8R,17S-RCTR1 (1), 7S,8R,17S-RCTR2 (2) and
7S,8R,17S-RCTR3 (3)30 that makes these pro-resolving and tissue
regenerative resolvin sulfido-conjugates available for further

6
Tetrahedron Letters
Robinson, D. R.; Lewis, R. A.; Austen, K. F. Arthritis Rheum.
1987, 30, 988–997.
61.51 (CH2), 57.78 (CH), 54.98 (CH), 51.61 (CH3), 33.80 (CH2),
29.17 (CH2), 22.84 (CH2). Rf 0.34 (hexane/EtOAc 1:1).
Compound 15: 1H NMR (CDCl3, 300 MHz): δ 9.0 (d, J = 6.0 Hz,
1H), 5.6–5.3 (m, 2H), 3.7 (s, 3H), 3.3–3.2 (td, J = 5.1, 1.8 Hz,
1H), 3.2–3.1 (dd, J = 6.0, 1.8 Hz, 1H), 2.5 (ddd, J = 5.7, 5.1, 1.8
=
6. Mil-Homens, D.; Bernardes, N.; Fialho, A. M. FEMS Microbiol.
Lett. 2012, 328, 61–69.
7. Serhan, C. N.; Petasis, N. A. Chem. Rev. 2011, 111, 5922–5943.
8. 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.
Hz, 2H), 2.4–2.3 (m, 4H). Rf
= 0.49 (hexane/EtOAc 7:3).
Compound 6: 1H NMR (CDCl3, 300 MHz): δ 9.6–9.5 (d, J = 7.8
Hz, 1H), 7.1–7.0 (dd, J = 15.3, 11.1 Hz, 1H), 6.6 (dd, J = 15.3,
11.1 Hz, 1H), 6.2–6.1 (dd, J = 15.3, 7.8 Hz, 1H), 6.0–5.9 (dd, J =
15.3, 7.5 Hz, 1H), 5.6–5.4 (m, 2H), 3.7 (s, 3H), 3.3–3.2 (dd, J =
7.5, 2.1 Hz, 1H), 3.0–2.9 (td, J = 5.1, 2.1 Hz, 1H), 2.5–2.3 (m,
6H); 13C NMR (CDCl3, 75.5 MHz): δ 193.59 (CH), 173.38 (C),
149.97 (CH), 141.08 (CH), 132.19 (CH), 131.19 (CH), 131.00
(CH), 124.14 (CH), 60.55 (CH), 56.71 (CH), 51.62 (CH3), 33.73
(CH2), 29.52 (CH2), 22.85 (CH2). Rf = 0.38 (hexane/EtOAc 7:3).
Compound 18: 1H NMR (CDCl3, 300 MHz): δ 7.8–7.7 (d, J = 8.4
Hz, 2H), 7.3 (d, J = 8.4 Hz, 2H), 5.5–5.3 (m, 2H), 5.3–5.1 (m,
2H), 4.0 (t, J = 7.0 Hz, 2H), 2.8–2.7 (br t, J = 7.2 Hz, 2H), 2.5–2.3
(m, 2H), 2.4 (s, 3H), 2.1–1.9 (m, 2H), 0.9 (t, J = 7.5 Hz, 3H); 13C
NMR (CDCl3, 75.5 MHz): δ 144.68 (C), 133.08 (C), 132.31 (CH),
132.00 (CH), 129.77 (2C, CH), 127.86 (2C, CH), 126.33 (CH),
122.92 (CH), 69.59 (CH2), 27.02 (CH2), 25.50 (CH2), 21.60
(CH3), 20.48 (CH2), 14.17 (CH3). Rf = 0.65 (hexane/EtOAc 8:2).
Compound 7: 1H NMR (CDCl3, 300 MHz): δ 7.9–7.6 (m, 17H),
7.1–7.0 (d, J = 7.8 Hz, 2H), 5.6–5.4 (m, 1H), 5.4–5.2 (m, 2H),
5.2–5.0 (m, 1H), 3.8–3.6 (m, 2H), 2.5–2.4 (br t, J = 7.2 Hz, 2H),
2.5–2.3 (m, 2H), 2.3 (s, 3H), 1.9–1.8 (m, 2H), 0.9 (t, J = 7.5 Hz,
3H); 13C NMR (CDCl3, 75.5 MHz): δ 144.58 (C), 138.34 (C),
134.84 (d, J = 2.9 Hz, 3C, CH), 133.70 (d, J = 9.8 Hz, 6C, CH),
132.22 (CH), 130.40 (d, J = 12.7 Hz, 6C, CH), 130.28 (CH),
128.24 (2C, CH), 126.64 (d, J = 14.4 Hz, CH), 126.29 (CH),
126.21 (2C, CH), 118.51 (d, J = 85.3 Hz, 3C, C), 25.40 (CH2),
21.99 (d, J = 48.9 Hz, CH2), 21.28 (CH3), 20.47 (CH2), 20.35 (d,
J = 4.0 Hz, CH2), 14.16 (CH3). Rf = 0.45 (CH2Cl2/CH3OH 9:1).
Compound 4: 1H NMR (C6D6, 300 MHz): δ 6.6–6.4 (dd, J = 14.4,
11.7 Hz, 1H), 6.4–6.3 (dd, J = 15.3, 10.8 Hz, 1H), 6.2–6.0 (dd, J =
14.4, 10.8 Hz, 1H), 6.1–6.0 (t, J = 11.7 Hz, 1H), 5.5–5.2 (m, 8H),
3.3 (s, 3H), 3.0 (dd, J = 7.5, 1.8 Hz, 1H), 3.0–2.8 (br t, J = 6.6 Hz,
2H), 2.8–2.7 (br t, J = 5.7 Hz, 2H), 2.7–2.6 (td, J = 5.1, 1.8 Hz,
1H), 2.3–1.9 (m, 8H), 0.9 (t, J = 7.5 Hz, 3H). 13C NMR (C6D6,
75.5 MHz): δ 172.64 (C), 134.07 (CH), 132.32 (CH), 132.22
(CH), 131.33 (CH), 131.07 (CH), 130.86 (CH), 129.26 (CH),
129.08 (CH), 128.73 (CH), (1CH under the C6D6 signals), 127.26
(CH), 125.21 (CH), 60.00 (CH), 57.61 (CH), 50.98 (CH3), 33.84
(CH2), 30.00 (CH2), 26.54 (CH2), 25.90 (CH2), 23.12 (CH2),
20.88 (CH2), 14.40 (CH3). UV (Hexane/Et3N 9.9/0.1) λmax 270,
280, 292 nm. Rf = 0.83 (hexane/EtOAc/Et3N 8:2:0.1). Compound
19: 1H NMR (CD3OD, 300 MHz): δ 6.6 (dd, J = 13.6, 11.1 Hz,
1H), 6.3–6.2 (m, 2H), 6.0 (t, J = 11.1 Hz, 1H), 5.7 (dd, J = 13.8,
9.9 Hz, 1H), 5.5–5.2 (m, 7H), 4.6–4.5 (dd, J = 9.3, 5.1 Hz, 1H),
3.9–3.7 (2d ABsystem, J = 17.4 Hz, 2H), 3.7 (m, 1H), 3.7–3.6 (t, J
= 6.0 Hz, 1H), 3.4 (dd, J = 9.9, 4.2 Hz, 1H), 3.1–2.9 (m, 2H), 3.0–
2.9 (dd, J = 14.1, 5.1 Hz, 1H), 2.9–2.8 (br t, J = 6.0 Hz, 2H), 2.7
(dd, J = 14.1, 9.3 Hz, 1H), 2.6–2.5 (m, 2H), 2.4–2.0 (m, 10H),
0.95 (t, J = 7.5 Hz, 3H). UV (CH3OH) λmax 272, 281, 292 nm.
HPLC/UV: Zorbax SB-C18, 1.8 µm, 50 x 2.1 mm, 280 nm,
9. 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.
10. Chiang, N.; Fredman, G.; Backhed, F.; Oh, S. F.; Vickery, T.;
Schmidt, B. A.; Serhan, C. N. Nature 2012, 484, 524–528.
11. 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.
12. Dalli, J.; Colas, R. A.; Quintana, C.; Barragan-Bradford, D.;
Hurwitz, S.; Levy, B. D.; Choi, A. M.; Serhan, C. N.; Baron, R.
M. Crit. Care Med. 2017, 45, 58–68.
13. Dalli, J.; Chiang, N.; Serhan, C. N. Proc. Natl. Acad. Sci. USA
2014, 111, E4753–E4761.
14. Dalli, J.; Ramon, S.; Norris, P. C.; Colas, R. A.; Serhan, C. N.
FASEB J. 2015, 29, 2120–2136.
15. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2015, 56, 3936–
3940.
16. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2015, 56, 5811–
5815.
17. Ramon, S.; Dalli, J.; Sanger, J. M.; Winkler, J. W.; Aursnes, M.;
Tungen, J. E.; Hansen, T. V.; Serhan, C. N. Am. J. Pathol. 2016,
186, 962–973.
18. Dalli, J.; Sanger, J. M.; Rodriguez, A. R.; Chiang, N.; Spur, B. W.;
Serhan, C. N. PLoS One 2016, 11(2):e0149319.
19. Dalli, J.; Vlasakov, I.; Riley I. R.; Rodriguez, A. R.; Spur, B. W.;
Petasis, N. A.; Chiang, N.; Serhan, C. N. Proc. Natl. Acad. Sci.
USA 2016, 113, 12232–12237.
20. Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.;
Samuelsson, B.; Hammarstrom, S. J. Am. Chem. Soc. 1980, 102,
1436–1439.
21. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2015, 56, 256–
259.
22. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2014, 55, 6011–
6015.
23. Zamboni, R.; Milette, S.; Rokach, J. Tetrahedron Lett. 1983, 24,
4899–4902.
24. Zamboni, R.; Milette, S.; Rokach, J. Tetrahedron Lett. 1984, 25,
5835–5838.
25. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–
7287.
26. Berenguer, M. J.; Castells, J.; Galard, R. M.; Moreno-Manas, M.
Tetrahedron Lett. 1971, 12, 495–496.
27. Ernest, I; Main, A. J.; Menasse, R. Tetrahedron Lett. 1982, 23,
167–170.
28. de la Torre, A.; Lee, Y. Y.; Mazzoni, A.; Guy, A.; Bultel-Ponce,
V.; Durand, T.; Oger, C.; Lee, J. C.-Y.; Galano, J. M. Chem. Eur.
J. 2015, 21, 2442–2446.
29. Taber, D. F.; You, K. J. Org. Chem. 1995, 60, 139–142.
30. Satisfactory spectroscopic data were obtained for all compounds.
Selected physical data: Compound 12: 1H NMR (CDCl3, 300
MHz): δ 7.8 (d, J = 7.8 Hz, 2H), 7.4–7.3 (d, J = 7.8 Hz, 2H), 5.5–
5.3 (m, 2H), 4.2 (q, J = 6.0 Hz, 1H), 4.1 (dt, J = 7.6, 6.0 Hz, 1H),
4.0 (dd, J = 9.9, 6.0 Hz, 1H), 3.9 (dd, J = 9.9, 6.0 Hz, 1H), 3.7 (s,
3H), 2.4 (s, 3H), 2.4–2.2 (m, 6H), 1.3 (s, 3H), 1.3 (s, 3H); 13C
NMR (CDCl3, 75.5 MHz): δ 173.39 (C), 145.02 (C), 132.57 (C),
130.41 (CH), 129.89 (2C, CH), 128.03 (2C, CH), 125.76 (CH),
108.76 (C), 76.50 (CH), 74.63 (CH), 67.91 (CH2), 51.59 (CH3),
33.66 (CH2), 27.82 (CH3), 27.01 (CH2), 25.30 (CH3), 22.90
(CH2), 21.65 (CH3). Rf = 0.63 (hexane/EtOAc 6:4). Compound
13: 1H NMR (CDCl3, 300 MHz): δ 7.8 (d, J = 7.8 Hz, 2H), 7.4–7.3
(d, J = 7.8 Hz, 2H), 5.6–5.4 (m, 2H), 4.3 (dd, J = 10.5, 3.3 Hz,
1H), 4.1 (dd, J = 10.5, 6.6 Hz, 1H), 3.8–3.7 (m, 1H), 3.7–3.5 (m,
1H), 3.7 (s, 3H), 2.6 (d, J = 2.1 Hz, 1H), 2.6 (d, J = 3.3 Hz, 1H),
2.4 (s, 3H), 2.4–2.2 (m, 6H); 13C NMR (CDCl3, 75.5 MHz): δ
174.06 (C), 145.09 (C), 132.50 (C), 131.67 (CH), 129.95 (2C,
CH), 128.00 (2C, CH), 126.08 (CH), 72.03 (CH), 71.64 (CH2),
71.05 (CH), 51.77 (CH3), 33.24 (CH2), 30.91 (CH2), 22.46
(CH2), 21.66 (CH3). Rf = 0.20 (hexane/EtOAc 6:4). Compound
14: 1H NMR (CDCl3, 300 MHz): δ 5.6–5.4 (m, 2H), 3.9 (ddd, J =
12.6, 5.4, 2.7 Hz, 1H), 3.7 (s, 3H), 3.7–3.6 (m, 1H), 3.0–2.9 (m,
2H), 2.4–2.3 (m, 6H), 1.7–1.6 (dd, J = 6.9, 5.4 Hz, 1H); 13C NMR
(CDCl3, 75.5 MHz): δ 173.46 (C), 130.78 (CH), 124.67 (CH),
CH3OH/H2O (0.1% formic acid) 35:65–70:30, 0.2 mL/min, tR
=
12.7 min; HPLC/MS (m/z): 648.2 [M-H] –. Compound 20: 1H
NMR (CD3OD, 300 MHz): δ 6.7–6.5 (dd, J = 13.8, 11.1 Hz, 1H),
6.4–6.2 (m, 2H), 6.1–6.0 (t, J = 11.1 Hz, 1H), 5.7 (dd, J = 14.1,
10.2 Hz, 1H), 5.6–5.2 (m, 7H), 4.0 (d, J = 17.1 Hz, 1H), 3.9–3.8
(dd, J = 7.8, 6.0 Hz, 1H), 3.8–3.7 (m, 1H), 3.6 (d, J = 17.1 Hz,
1H), 3.5–3.4 (dd, J = 10.2, 3.6 Hz, 1H), 3.1–2.7 (m, 6H), 2.4–2.2
(m, 6H), 2.1–2.0 (br quint, J = 7.5 Hz, 2H), 0.95 (t, J = 7.5 Hz,
3H). UV (CH3OH) λmax 272, 281, 292 nm. HPLC/UV: Zorbax SB-
C18, 1.8 µm, 50 x 2.1 mm, 280 nm, CH3OH/H2O (0.1% formic
acid) 35:65–70:30, 0.2 mL/min, tR = 11.5 min; HPLC/MS (m/z):
519.2 [M-H] –. Compound 21: 1H NMR (CD3OD, 300 MHz): δ 6.6
(dd, J = 14.4, 10.8 Hz, 1H), 6.4–6.2 (m, 2H), 6.1–6.0 (t, J = 10.8
Hz, 1H), 5.7 (dd, J = 14.4, 10.2 Hz, 1H), 5.5–5.2 (m, 7H), 3.8 (m,
1H), 3.7–3.6 (dd, J = 10.2, 3.3 Hz, 1H), 3.5–3.4 (dd, J = 10.2, 3.3
Hz, 1H), 3.1 (dd, J = 14.7, 3.3 Hz, 1H), 3.0–2.7 (m, 4H), 2.8–2.7
(dd, J = 14.7, 10.2 Hz, 1H), 2.4–2.2 (m, 6H), 2.2–2.0 (br quint, J =
7.5 Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H). UV (CH3OH) λmax 272, 281,
292 nm. HPLC/UV: Zorbax SB-C18, 1.8 µm, 50 x 2.1 mm, 280
nm, CH3OH/H2O (0.1% formic acid) 35:65–70:30, 0.2 mL/min, tR
= 13.9 min; HPLC/MS (m/z): 462.2 [M-H] –. 7S,8R,17S-RCTR1
(1): 1H NMR (CD3OD, 300 MHz): δ 6.9–6.7 (m, 2H), 6.4–6.2 (m,

7
2H), 6.1–5.9 (m, 2H), 5.8–5.6 (m, 2H), 5.5–5.3 (m, 4H), 4.6–4.5
(dd, J = 9.6, 4.8 Hz, 1H), 4.2–4.1 (m, 1H), 3.8–3.7 (2d ABsystem,
J = 17.4 Hz, 2H), 3.8–3.6 (m, 1H), 3.6 (t, J = 6.3 Hz, 1H), 3.4 (dd,
J = 10.2, 4.2 Hz, 1H), 3.0–2.9 (dd, J = 14.1, 4.8 Hz, 1H), 2.8–2.6
(dd, J = 14.1, 9.6 Hz, 1H), 2.6–2.5 (m, 2H), 2.4–2.2 (m, 8H), 2.2–
2.1 (q, J = 6.3 Hz, 2H), 2.1–2.0 (m, 2H), 0.96 (t, J = 7.5 Hz, 3H).
UV (CH3OH) λmax 295, 308, 323 nm. HPLC/UV: Zorbax SB-C18,
1.8 µm, 50 x 2.1 mm, 309 nm, CH3OH/H2O (0.1% formic acid)
35:65–70:30, 0.2 mL/min, tR = 9.9 min; HPLC/MS (m/z): 664.2
[M-H] –. 7S,8R,17S-RCTR2 (2): 1H NMR (CD3OD, 300 MHz): δ
6.9–6.7 (m, 2H), 6.4–6.2 (m, 2H), 6.1–5.9 (m, 2H), 5.8–5.6 (m,
2H), 5.6–5.3 (m, 4H), 4.2–4.1 (m, 1H), 4.0–3.9 (d, J = 17.1 Hz,
1H), 3.9–3.8 (dd, J = 8.1, 6.0 Hz, 1H), 3.8–3.7 (m, 1H), 3.7–3.6
(d, J = 17.1 Hz, 1H), 3.5–3.4 (dd, J = 10.2, 3.6 Hz, 1H), 3.0–2.8
(dd, J = 14.1, 6.0 Hz, 1H), 2.8–2.7 (dd, J = 14.1, 8.1 Hz, 1H), 2.4–
2.2 (m, 8H), 2.1–2.0 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H). UV
(CH3OH/H2O 7/3) λmax 295, 308, 323 nm. HPLC/UV: Zorbax SB-
C18, 1.8 µm, 50 x 2.1 mm, 309 nm, CH3OH/H2O (0.1% formic
acid) 35:65–70:30, 0.2 mL/min, tR = 9.4 min; HPLC/MS (m/z):
535.2 [M-H] –. 7S,8R,17S-RCTR3 (3): 1H NMR (CD3OD, 300
MHz): δ 6.9–6.7 (m, 2H), 6.4–6.2 (m, 2H), 6.1–5.9 (m, 2H), 5.8–
5.6 (m, 2H), 5.6–5.3 (m, 4H), 4.2–4.1 (m, 1H), 3.8 (td, J = 6.6,
3.6 Hz, 1H), 3.7–3.6 (dd, J = 10.2, 3.3 Hz, 1H), 3.5–3.4 (dd, J =
10.2, 3.6 Hz, 1H), 3.1 (dd, J = 14.7, 3.3 Hz, 1H), 2.8–2.7 (dd, J =
14.7, 10.2 Hz, 1H), 2.4–2.2 (m, 8H), 2.1–2.0 (m, 2H), 0.95 (t, J =
7.5 Hz, 3H). UV (CH3OH/H2O 7/3) λmax 295, 308, 323 nm.
HPLC/UV: Zorbax SB-C18, 1.8 µm, 50 x 2.1 mm, 309 nm,
= 0.88 (hexane/EtOAc 9:1). Compound 8: 1H NMR (CDCl3, 300
MHz): δ 7.9–7.7 (m, 9H), 7.7–7.6 (m, 6H), 7.6–7.4 (m, 4H), 7.4–
7.2 (m, 6H), 6.2 (dt, J = 15.3, 4.6 Hz, 1H), 5.6–5.4 (m, 1H), 5.3–
5.1 (m, 1H), 5.0–4.8 (td, J = 15.3, 7.2 Hz, 1H), 4.9–4.8 (m, 1H),
4.7–4.5 (td, J = 15.3, 7.2 Hz, 1H), 4.3–4.1 (m, 1H), 2.2–1.8 (m,
2H), 1.7–1.5 (m, 2H), 0.9 (s, 9H), 0.7 (t, J = 7.5 Hz, 3H); 13C
NMR (CDCl3, 75.5 MHz): δ 143.75 (d, J = 13.3 Hz, CH), 135.75
(2C, CH), 135.62 (2C, CH), 134.85 (d, J = 2.9 Hz, 3C, CH),
134.17 (CH), 133.99 (d, J = 9.8 Hz, 6C, CH), 133.85 (C), 133.40
(C), 130.27 (d, J = 12.1 Hz, 6C, CH), 129.74 (CH), 129.71 (CH),
127.65 (2C, CH), 127.57 (2C, CH), 122.93 (CH), 118.28 (d, J =
85.4 Hz, 3C, C), 113.66 (d, J = 9.2 Hz, CH), 72.47 (d, J = 1.7 Hz,
CH), 34.86 (d, J = 3.4 Hz, CH2), 27.42 (d, J = 49.5 Hz, CH2),
26.95 (3C, CH3), 20.50 (CH2), 19.30 (C), 14.09 (CH3). Rf = 0.46
(CH2Cl2/CH3OH 9:1). Compound 5: 1H NMR (C6D6, 300 MHz): δ
7.9–7.7 (m, 4H), 7.3–7.2 (m, 6H), 6.7–6.5 (m, 2H), 6.4–6.2 (dd, J
= 15.0, 10.8 Hz, 1H), 6.1–6.0 (dd, J = 15.0, 10.8 Hz, 1H), 6.0–5.8
(m, 2H), 5.8–5.6 (dd, J = 15.0, 6.6 Hz, 1H), 5.5–5.2 (m, 5H), 4.5–
4.3 (m, 1H), 3.3 (s, 3H), 3.0 (dd, J = 7.8, 1.8 Hz, 1H), 2.9–2.8 (td,
J = 5.1, 1.8 Hz, 1H), 2.5–2.3 (m, 2H), 2.3–2.0 (m, 6H), 2.0–1.8
(m, 2H), 1.2 (s, 9H), 0.8 (t, J = 7.5 Hz, 3H). 13C NMR (C6D6, 75.5
MHz): δ 172.64 (C), 137.52 (CH), 136.38 (2C, CH), 136.34 (2C,
CH), 134.55 (C), 134.41 (C), 134.06 (CH), 133.97 (CH), 132.65
(CH), 131.70 (CH), 130.88 (CH), 130.01 (2C, CH), 129.98 (CH),
129.45 (CH), 129.01 (CH), (4CH under the C6D6 signals), 126.03
(CH), 125.19 (CH), 124.36 (CH), 74.52 (CH), 60.06 (CH), 57.65
(CH), 50.98 (CH3), 36.36 (CH2), 33.84 (CH2), 30.00 (CH2),
27.27 (3C, CH3), 23.12 (CH2), 21.00 (CH2), 19.62 (C), 14.32
(CH3). UV (Hexane/Et3N 10/0.1) λmax 296, 309, 324 nm.
CH3OH/H2O (0.1% formic acid) 35:65–70:30, 0.2 mL/min, tR
=
10.1 min; HPLC/MS (m/z): 478.1 [M-H] –. Compound 25: 1H
NMR (CDCl3, 300 MHz): δ 7.8–7.6 (m, 4H), 7.5–7.3 (m, 6H),
5.4–5.2 (m, 2H), 4.1–4.0 (m, 1H), 3.9 (t, J = 7.5 Hz, 1H), 3.9–3.8
(m, 1H), 3.8 (t, J = 7.5 Hz, 1H), 2.3–2.1 (m, 1H), 2.1–2.0 (m, 1H),
1.8 (br quint, J = 7.5 Hz, 2H), 1.3 (s, 3H), 1.3 (s, 3H), 1.0 (s, 9H),
0.8 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): δ 136.04
(2C, CH), 135.97 (2C, CH), 134.10 (C), 134.03 (CH), 133.60 (C),
129.66 (CH), 129.64 (CH), 127.53 (2C, CH), 127.50 (2C, CH),
123.50 (CH), 108.73 (C), 77.76 (CH), 73.06 (CH), 66.00 (CH2),
31.96 (CH2), 27.00 (3C, CH3), 26.46 (CH3), 25.36 (CH3), 20.49
(CH2), 19.43 (C), 14.04 (CH3). Rf = 0.74 (hexane/EtOAc 9:1).
Compound 26: 1H NMR (CDCl3, 300 MHz): δ 9.6–9.5 (d, J = 1.5
Hz, 1H), 7.7–7.6 (m, 4H), 7.5–7.3 (m, 6H), 5.5–5.4 (m, 1H), 5.4–
5.2 (m, 1H), 4.1–4.0 (td, J = 6.0, 1.5 Hz, 1H), 2.5–2.2 (m, 2H),
2.0–1.8 (br quint, J = 7.5 Hz, 2H), 1.1 (s, 9H), 0.9 (t, J = 7.5 Hz,
3H); 13C NMR (CDCl3, 75.5 MHz): δ 203.43 (CH), 135.78 (4C,
CH), 134.94 (CH), 133.04 (C), 132.92 (C), 130.01 (CH), 129.97
(CH), 127.79 (2C, CH), 127.73 (2C, CH), 121.99 (CH), 77.75
(CH), 30.96 (CH2), 26.88 (3C, CH3), 20.56 (CH2), 19.31 (C),
13.98 (CH3). Rf = 0.44 (hexane/EtOAc 9.5:0.5). Compound 28:
1H NMR (CDCl3, 300 MHz): δ 7.7–7.5 (m, 4H), 7.5–7.2 (m, 6H),
7.0–6.8 (dd, J = 15.6, 5.1 Hz, 1H), 6.0–5.9 (dd, J = 15.6, 1.8 Hz,
1H), 5.4–5.3 (m, 1H), 5.2–5.1 (m, 1H), 4.4–4.3 (m, 1H), 3.7 (s,
3H), 2.3–2.0 (m, 2H), 1.8–1.6 (br quint, J = 7.5 Hz, 2H), 1.1 (s,
9H), 0.8 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): δ
167.00 (C), 150.19 (CH), 135.85 (2C, CH), 135.79 (2C, CH),
134.60 (CH), 133.79 (C), 133.29 (C), 129.79 (CH), 129.76 (CH),
127.62 (4C, CH), 122.59 (CH), 119.74 (CH), 72.26 (CH), 51.49
(CH3), 34.97 (CH2), 26.98 (3C, CH3), 20.50 (CH2), 19.33 (C),
14.00 (CH3). Rf = 0.27 (hexane/EtOAc 9.5:0.5). Compound 29:
1H NMR (CDCl3, 300 MHz): δ 7.7–7.6 (m, 4H), 7.5–7.3 (m, 6H),
5.6 (ddt, J = 15.3, 6.3, 1.2 Hz, 1H), 5.5–5.2 (m, 3H), 4.2–4.1 (m,
1H), 3.9 (m, 2H), 2.4–2.1 (m, 2H), 1.9–1.8 (br quint, J = 7.5 Hz,
2H), 1.0 (s, 9H), 0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5
MHz): δ 136.03 (2C, CH), 135.93 (2C, CH), 134.43 (C), 134.18
(C), 134.18 (CH), 133.65 (CH), 129.59 (CH), 129.50 (CH), 129.20
(CH), 127.49 (2C, CH), 127.35 (2C, CH), 124.01 (CH), 73.57
(CH), 63.08 (CH2), 35.77 (CH2), 26.99 (3C, CH3), 20.61 (CH2),
31. Corey, E .J.; Su, W. Tetrahedron Lett. 1985, 26, 281–284.
32. Adams, J.; Fitzsimmons, B. J.; Girard, Y.; Leblanc, Y.; Evans, J.
F.; Rokach, J. J. Am. Chem. Soc. 1985, 107, 464–469.
33. Corey, E .J.; Mehrotra, M. M.; Su, W. Tetrahedron Lett. 1985, 26,
1919–1922.
34. Corey, E. J.; Su, W.; Cleaver, M. B. Tetrahedron Lett. 1989, 30,
4181–4184.
35. Murphy, R.C.; Hammarstrom, S.; Samuelsson, B. Proc. Natl.
Acad. Sci. USA 1979, 76, 4275–4279.
36. Orning, L.; Hammarstrom, S. FEBS Lett. 1983, 153, 253–256.
37. Steinhilber, D.; Roth, H. J. FEBS Lett. 1989, 255, 143–148.
38. Itoh, T.; Saito, T.; Yamamoto, Y.; Ishida, H.; Yamamoto, K.
Bioorg. Med. Chem. Lett. 2016, 26, 343–345.
39. To a 0.1 M solution of phosphate buffer pH 8.5 (10 ml) containing
lipoxidase from soybean (Fluka cat. # 62340, EEC No. 2328531,
10.8 U/mg) (2 mg) was added at rt and with stirring compound 21
(0.6 mg, 1.29x10-3 mmol) dissolved in CH3OH (20 µl) and H2O
(180 µl). An aliquot was taken immediately to analyze the starting
material (21) by UV showing λmax at 281 nm. After 1 min the
bathochromic shift from 281 nm to 310 nm indicated that the
reaction was completed. The solution was purged with argon and
TCEP-HCl (3 mg, 0.01 mmol) was added. After stirring for 1 min
the reaction mixture was passed through a reversed phase C–18
cartridge, washed with H2O and compound
3 eluted with
CH3OH:H2O (7:3). Purification by HPLC [Zorbax SB-C18 250 ×
21.2 mm, 309 nm, CH3OH/H2O (0.1% NH4OAc, pH 5.6, 0.05%
EDTA disodium) 60/40] and desalting gave pure 7S,8R,17S-
RCTR3 (3) (0.35 mg, 56%).
40. Wong, M. Y. H.; Gray, G. R. J. Am. Chem. Soc. 1978, 100, 3548–
3553.
41. Chang, C.-T.; Jacobo, S. H.; Powell, W. S.; Lawson, J. A.;
FitzGerald, G. A; Pratico, D.; Rokach, J. Tetrahedron Lett. 2005,
46, 6325–6328.
42. Patel, P.; Gore, V.; Powell, W. S.; Rokach, J. Bioorg. Med. Chem.
Lett. 2011, 21, 1987–1990.
43. Shi, X.-X.; Khanapure, S. P.; Rokach, J. Tetrahedron Lett. 1996,
37, 4331–4334.
44. Khanapure, S. P.; Powell, W. S.; Rokach, J. J. Org. Chem. 1998,
63, 8976–8982.
19.29 (C), 14.15 (CH3). Rf
= 0.20 (hexane/EtOAc 9:1).
Compound 30: 1H NMR (CDCl3, 300 MHz): δ 7.7–7.6 (m, 4H),
7.5–7.3 (m, 6H), 5.8–5.6 (m, 2H), 5.4–5.3 (m, 1H), 5.3–5.1 (m,
1H), 4.2–4.1 (m, 1H), 3.9–3.8 (d, J = 6.9 Hz, 2H), 2.3–2.1 (m,
2H), 1.8 (br quint, J = 7.5 Hz, 2H), 1.1 (s, 9H), 0.8 (t, J = 7.5 Hz,
3H); 13C NMR (CDCl3, 75.5 MHz): δ 137.55 (CH), 135.92 (2C,
CH), 135.90 (2C, CH), 134.06 (C), 133.95 (CH), 133.78 (C),
129.65 (CH), 129.57 (CH), 127.53 (2C, CH), 127.47 (2C, CH),
126.18 (CH), 123.46 (CH), 72.83 (CH), 35.55 (CH2), 32.42
(CH2), 27.01 (3C, CH3), 20.56 (CH2), 19.29 (C), 14.12 (CH3). Rf
45. Winkler, J. W.; Uddin, J.; Serhan, C. N.; Petasis, N. A. Org. Lett.
2013, 15 (7), 1424-1427.
46. Adams, J.; Fitzsimmons, B. J.; Rokach, J. Tetrahedron Lett. 1984,
25, 4713–4716.
47. Corey, E. J.; Mehrotra. M. M. Tetrahedron Lett. 1986, 27, 5173–
5176.
48. Gravier-Pelletier, C.; Dumas, J.; Le Merrer, Y.; Depezay, J. C.
Tetrahedron Lett. 1991, 32, 1165–1168.

8
Tetrahedron Letters
Highlights
•
The first total synthesis of pro-resolving and tissue-
regenerative resolvin sulfido conjugates has been
achieved.
•
•
•
Chiral centers at C-7 and C-8 were obtained using a
chiral pool strategy starting from 2-deoxy-D-ribose.
The chiral center at C-17 was generated by an enzymatic
hydroxylation with lipoxidase in the first approach.
The chiral center at C-17 was obtained using a chiral pool
strategy starting from D-(-)-arabinose in the second approach.