in vivo, their complete stereochemical characterization re-
quires direct matching with stereochemically pure materi-
als produced via total synthesis. These synthetic efforts
are also essential for elucidating the biological functions of
these molecules.
Our convergent and stereocontrolled synthetic strategy
for RvD3 1 is outlined in Scheme 2. While the structures of
RvD3 and AT-RvD3 were initially deduced by using mass
spectrometry,5 their detailed Z/E geometry and R/S con-
figuration remained to be established. Toward this goal,
and based on the above biosynthetic hypothesis, we first
targeted the total synthesis of the RvD3 isomer shown in
Scheme 1, namely (4S,11R,17S)-trihydroxy-5Z,7E,9E,13-
Z,15E,19Z-docosahexaenoic acid.
Thus, we have recently developed the first total synthesis
that led to the first stereochemical and biological character-
ization for several of these new lipid mediators.1 Some of our
efforts1 with resolvin E1 (RvE1),9 resolvin D1 (RvD1),10
resolvin D2 (RvD2),11 neuroprotectin D1/protectin D1
(NPD1/PD1),12 and maresin 1 (MaR1)13 have been dis-
closed, while additional studies will be reported in due course.
Herein, we detail our synthetic work toward resolvin D3
(RvD3), an important member of the D-series resolvins1,5
with potent pro-resolving properties, such as reduction of
human neutrophil transendothelial migration.5 Notably,
the endogenous production of RvD3 was shown to be
elevated during ischemic injury of the kidney,14 and in a
colitis model with fat-1 transgenic mice15 that produce in-
creased levels of DHA.
Scheme 2. Retrosynthetic Analysis of Resolvin D3
The postulated biosynthesis1,5 of RvD3 from DHA is
summarized in Scheme 1. The first step involves the con-
versionofDHAto(17S)-hydroperoxy DHA (17S-HpDHA)
catalyzed by a lipoxygenase enzyme (LOX), such as 15-LOX.
A second lipoxygenation of this intermediate or its reduced
hydroxy product (17S-HDHA) leads to a new hydroperox-
ide at the C-4 position, which is converted enzymatically to
the 4S,5S epoxide that undergoes enzymatic hydrolysis to
form RvD3 1.
Scheme 1. Biosynthesis of Resolvin D3 and AT-Resolvin D3
In order to prevent Z/E isomerization, our aim was to
follow a synthetic route allowing for the sensitive triene
and diene moieties to be formed in the final steps of the
(9) (a) Arita, M.; Bianchini, F.; Aliberti, J.; Sher, A.; Chiang, N.;
Hong, S.; Yang, R.; Petasis, N. A.; Serhan, C. N. J. Exp. Med. 2005, 201,
713. (b) Petasis, N. A. U.S. Patent 6,949,664, 2005. (c) Arita, M.; Oh, S. F.;
Chonan, T.; Hong, S.; Elangovan, S.; Sun, Y. -P.; Uddin, J.; Petasis, N. A.;
Serhan, C. N. J. Biol. Chem. 2006, 281, 22847.
(10) (a) 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. (b) Kasuga, K.; Yang, R.; Porter, T. F.; Agrawal, N.;
Petasis, N. A.; Irimia, D.; Toner, M.; Serhan, C. N. J. Immunol. 2008,
181, 8677. (c) Krishnamoorthy, S.; Recchiuti, A.; Chiang, N.; Yacoubian,
S.;Lee, C. -H.;Yang, R.;Petasis, N. A.;Serhan, C. N.Proc. Natl. Acad. Sci.
U.S.A. 2010, 107, 1660.
(11) (a) Spite, M.; Norling, L. V.; Summers, L.; Yang, R.; Cooper,
D.; Petasis, N. A.; Flower, R. J.; Perretti, M.; Serhan, C. N. Nature 2009,
461, 1287. (b) Petasis, N. A.; Winkler, J. W.; Nagengast, E. S.; Uddin, J.;
Serhan, C. N. 237th ACS National Meeting Salt Lake City, UT, 2009,
Abstract Medi-056.
(12) (a) 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. (b) Serhan, C. N.; Fredman, G.; Yang, R.; Karamnov, S.; Belayev,
L. S.; Bazan, N. G.; Zhu, M.; Winkler, J. W.; Petasis, N. A. Chem. Biol.
2011, 18, 976. (c) Petasis, N. A.; Yang, R.; Winkler, J. W.; Zhu, M.;
Uddin, J.; Bazan, N. G.; Serhan, C. N. Tetrahedron Lett. 2012, 53, 1695.
(13) (a) Serhan, C. N.; Dalli, J.; Karamnov, S.; Choi, A.; Park, C. -K.;
Xu, Z. -Z.; Ji, R.-R.; Zhu, M.; Petasis, N. A. FASEBJ. 2012, 26, 1755. (b)
Zhu, M.; Serhan, C. N.; Petasis, N. A. 243rd ACS National Meeting San
Diego, CA, 2012, Abstract Biol-225.
(14) Duffield, J. S.; Hong, S.; Vaidya, V. S.; Lu, Y.; Fredman, G.;
Serhan, C. N.; Bonventre, J. V. J. Immunol. 2006, 177, 5902.
(15) Hudert, C. A.; Weylandt, K. H.; Lu, Y.; Wang, J.; Hong, S.;
Dignass, A.; Serhan, C. N.; Kang, J. X. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 11276.
A related biosynthetic pathway1,5 involves the initial
oxygenation of DHA with COX-2 in the presence of
aspirin to form the (17R)-hydroperoxy DHA (17R-
HpDHA) and its reduced hydroxy product 17R-HDHA.
Similar lipoxygenation and furthertransformation of these
17R metabolites lead to the (17R)-epimer of RvD3, named
aspirin-triggered RvD3 or AT-RvD3 2.1,5
B
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