Stereocontrolled total synthesis of Neuroprotectin D1/Protectin D1 and its aspirin-triggered stereoisomer

Article abstract of DOI:10.1016/j.tetlet.2012.01.032

Neuroprotectin D1/Protectin D1, a potent anti-inflammatory, proresolving, and neuroprotective lipid mediator derived biosynthetically from docosahexaenoic acid, was prepared in an enantiomerically pure form via total organic synthesis. The synthetic strategy is highly stereocontrolled and convergent, featuring epoxide opening of glycidol starting materials for the introduction of the 10(R) and 17(S) hydroxyl groups. The desired alkene Z geometry was secured via the cis-reduction of alkyne precursors, while the conjugated E,E,Z triene was introduced at the end, in order to minimize Z/E isomerization. The same strategy, was also employed for the total synthesis of aspirin-triggered neuroprotectin D1/protectin D1 having the 17(R)-stereochemistry. Synthetic compounds obtained with the reported method were matched with endogenously derived materials, and helped establish their complete stereochemistry.

Full text of DOI:10.1016/j.tetlet.2012.01.032

Tetrahedron Letters 53 (2012) 1695–1698
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereocontrolled total synthesis of Neuroprotectin D1/Protectin D1 and its
aspirin-triggered stereoisomer
Nicos A. Petasis a, , Rong Yang a, Jeremy W. Winkler a, Min Zhu a, Jasim Uddin a,
⇑
Nicolas G. Bazan b, Charles N. Serhan c
a Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089, USA
b Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
c Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine,
Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Neuroprotectin D1/Protectin D1, a potent anti-inflammatory, proresolving, and neuroprotective lipid
mediator derived biosynthetically from docosahexaenoic acid, was prepared in an enantiomerically pure
form via total organic synthesis. The synthetic strategy is highly stereocontrolled and convergent, featur-
ing epoxide opening of glycidol starting materials for the introduction of the 10(R) and 17(S) hydroxyl
groups. The desired alkene Z geometry was secured via the cis-reduction of alkyne precursors, while
the conjugated E,E,Z triene was introduced at the end, in order to minimize Z/E isomerization. The same
strategy, was also employed for the total synthesis of aspirin-triggered neuroprotectin D1/protectin D1
having the 17(R)-stereochemistry. Synthetic compounds obtained with the reported method were
matched with endogenously derived materials, and helped establish their complete stereochemistry.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 2 December 2011
Revised 7 January 2012
Accepted 9 January 2012
Available online 14 January 2012
Keywords:
Neuroprotectin D1/protectin D1
Docosahexaenoic acid
Aspirin
Anti-inflammatory
Total synthesis
Recent investigations on the enzymatic oxygenation pathways
of docosahexaenoic acid (DHA) led to the discovery of several novel
lipid mediators, including the resolvins and protectins, which are
potent endogenous anti-inflammatory and proresolving agents.1
These findings provided the first supporting evidence at the
molecular level for the long-recognized beneficial actions of DHA,
a major omega-3 fatty acid, against several inflammatory2 and
neurodegenerative diseases.3 Since the isolation of such lipid
mediators from biogenic sources typically generates very small
quantities, it is often necessary to produce these molecules in
larger scale in order to unambiguously establish their complete
stereochemistry and to enable the detailed investigation of their
biological actions and their potential use in drug discovery.
Herein, we detail the stereocontrolled total synthesis of a DHA-
derived docosatriene4,5 (Fig. 1), that was initially named neuropro-
tectin D1 (NPD1)6 due to its potent actions in protecting the retina
and the brain from oxidative stress. The same endogenously
produced compound was also shown to have a broader range of
activities in non-neuronal tissues and termed protectin D1
(PD1).7 The biosynthetic conversion of DHA to NPD1/PD1 (1) in-
volves the action of 15-lipoxygenase (15-LO) to form an epoxide
intermediate followed by enzymatic hydrolysis.8
A related enzymatic pathway that was recently elucidated,9 in-
volves the initial oxygenation of DHA by cyclooxygenase-2 (COX-2)
⇑
Corresponding author. Tel.: +1 213 740 6683; fax: +1 213 740 6270.
E-mail address: petasis@usc.edu (N.A. Petasis).
Figure 1. Biosynthesis of NPD1/PD1 and AT-(NPD1/PD1).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.032

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N. A. Petasis et al. / Tetrahedron Letters 53 (2012) 1695–1698
Figure 2. Retrosynthetic analysis of NPD1/PD1.
Figure 4. Synthesis of the key intermediate 5. (a) n-BuLi, BF3ÁEt2O, À78 °C, THF,
77%; (b) TBDPS–Cl, imid., DMAP, rt, CH2Cl2, 97%; (c) CSA, rt, CH2Cl2/MeOH, 81%; (d)
NBS, PPh3, 0 °C, CH2Cl2, 80%; (e) TBSOTf, lutidine, 0 °C, CH2Cl2, 89%; (f) CuI, NaI,
K2CO3, rt, DMF, 75%; (g) CSA, rt, CH2Cl2/MeOH, 88%; (h) H2/Lindlar cat., quinoline, rt,
EtOAc, 68%; (i) DMSO, (COCl)2, Et3N, À78 °C, CH2Cl2, 98%; (j) Ph3P@CHCHO, PhMe,
reflux, 2 h, 90%; (k) CHI3, CrCl2, 0 °C, THF, 67%.
The synthesis of the intermediate 4 is detailed in Figure 3. Lith-
iation of 1-butyne followed by addition to the epoxide of the (S)-
glycidol derivative 7 in the presence of boron trifluoride etherate,
gave the resulting alcohol which was silylated to give the deprotec-
ted diol 10. Selective removal of the primary silyl ether protective
group of 10 with camphorsulfonic acid (CSA) to form 11 and sub-
sequent Lindlar hydrogenation afforded alcohol 12 in high yield.
Swern oxidation of 12 gave aldehyde 13 which was converted to
alkyne 411 via the Corey–Fuchs reaction.12
Figure 3. Synthesis of the key intermediate 4. (a) nBuLi, BF3ÁOEt2, À78 °C, THF, 84%;
(b) TBDPS–Cl, imidazole, DMAP, rt, CH2Cl2, 89%; (c) CSA, rt, CH2Cl2/MeOH, 78%; (d)
H2/Lindlar cat., quinoline, rt, EtOAc, 95%; (e) DMSO, (COCl)2 Et3N, À78 °C, CH2Cl2,
98%; (f) PPh3, CBr4, 0 °C, CH2Cl2,72%; (g) nBuLi, Et2O, 83%.
The synthesis of intermediate 5, shown in Figure 4, began
with a similar lithiation of silylated propargyl alcohol 9 followed
by reaction with the (R)-glycidol derivative 8 to produce alcohol
14. Protection of 14 as the tert-butyldiphenylsilyl ether (TBDPS)
followed by treatment with CSA removed both primary tert-
butyldimethylsilyl (TBS) groups to afford diol 15. Selective
bromination of the propargyl hydroxyl group with N-bromo-suc-
cinimide and triphenylphosphine, followed by silylation with TBS
triflate and lutidine gave bromide 16. Copper-mediated coupling
of 14 with methyl pen-4-ynate 1713 followed by the removal of
the primary TBS group gave alcohol 18. Lindlar hydrogenation
followed by Swern oxidation led to aldehyde 19. Wittig homolo-
in the presence of aspirin (Fig. 1). Under these conditions, COX-2
functions as a lipoxygenase-like enzyme, catalyzing the stereospe-
cific formation of hydroxylated products with a 17R, rather than a
17S stereochemistry. The resulting isomeric lipid mediator was
termed aspirin-triggered NPD1/PD1 or AT-(NPD1/PD1) (2),9 and
its synthesis is also reported herein.
In order to ensure the unambiguous total synthesis of NPD1/
PD1 (1) in enantiomerically pure form, we earlier devised a conver-
gent strategy8,10 by starting with protected glycidol and by gener-
ating all Z-alkenes via the selective reduction of the corresponding
alkynes (Fig. 2). Thus, the synthesis of 1 involved the selective
reduction of dienyne 3, which is generated via the Sonogashira
coupling of alkyne 4 and dienyl iodide 5. The chiral alcohol moie-
ties of both intermediates 4 and 5 were produced via the initial
epoxide opening of a glycidol derivative (7 or 8) with a metallated
1-alkyne (6 or 7). In addition to being highly convergent, this ap-
proach ensures a pre-defined R/S chirality depending on the glyc-
idol enantiomer used, while all C@C bonds adopt the desired Z or
E geometry and limit Z/E isomerization, particularly for the triene
moiety.
gation of 19 to the corresponding
a,b-unsaturated aldehyde 20,
and Takai olefination14,15 gave the key E,E-dienyl iodide interme-
diate 5.16 Small amounts of the isomeric E,Z byproduct was
removed with column chromatography, to afford 5 with greater
isomeric purity.
For the combination of alkyne 4 and dienyl iodide 5 (Fig. 5), we
relied on the palladium-catalyzed Sonogashira coupling reaction
that proceeded in very high yield. Subsequent fluoride-mediated
removal of the two silyl protective groups gave the alkynyl precur-
sor of NPD1/PD1 methyl ester (3).17

N. A. Petasis et al. / Tetrahedron Letters 53 (2012) 1695–1698
1697
alkenes. Addition of excess of this heterogeneous reagent to a solu-
tion of 3 in aqueous methanol, followed by filtration and purifica-
tion by HPLC, afforded NPD1/PD1 methyl ester (21)20 in
a
stereochemically pure form. Hydroxide hydrolysis of 21 and HPLC
purification gave NPD1/PD1 (1)21 as the sodium salt or as the free
acid upon neutralization.
The aspirin-triggered isomer AT-(NPD1/PD1) (2) was synthe-
sized similarly from its methyl ester (24), which was analogously
prepared by reacting 5 with alkyne 22 instead of 4. The 17R-stereo-
chemistry of 22 was secured similarly to the synthesis of 4 (Fig. 3),
by reacting alkyne 6 with the (R)-glycidol derivative 8 rather than
7. Sonogashira coupling of 22 with iodide 5 followed by deprotec-
tion gave the dienyne methyl ester precursor 23,22 which was
selectively reduced to the triene methyl ester 24.23 Hydrolysis of
24 gave AT-(NPD1/PD1) (2).24
The methodology detailed herein was employed in the first to-
tal synthesis of NPD1/PD1 (1)8,10 and served as a means to unam-
biguously establish its complete stereochemical structure. The
synthetic 1 was matched in all respects with material isolated from
peripheral blood mononuclear cells,8 and was also used for the
development of methods for lipidomic analysis via mass spectrom-
etry.25 Several enantiomerically pure stereoisomers of 1, prepared
by analogous synthetic routes, were utilized in detailed matching
studies in comparison with biogenically-derived compounds.
Based on these comparisons, we were able to assign for the first
time the R/S and Z/E stereochemistry of this potent lipid mediator.8
Similarly, we recently employed this approach to firmly establish
the stereochemistry of AT-(NPD1/PD1) (2).9
Synthetic protectins 1 and 2, produced in larger quantities using
the strategy detailed herein, were also employed in several collab-
orative studies aimed at exploring their biological actions and ther-
apeutic potential against inflammation8,9 and neurodegenerative
diseases affecting the retina26,27 or the brain, such as the
Alzheimer’s disease.28 These efforts provide further insights into
the biological roles of these potent lipids, and may lead to a greater
understanding of the important role of DHA and other omega-3
fatty acids in health and disease.
Acknowledgments
This work was supported in part by the National Institutes of
Health Grants P50-DE016191 (C.N.S, N.A.P), RC2-AT005909
(N.G.B., N.A.P., C.N.S), and P01-GM095467 (C.N.S, N.A.P).
N.A.P is an inventor on patents assigned to the University of
Southern California and licensed to Resolvyx Pharmaceuticals.
C.N.S. is an inventor on patents assigned to Brigham and Women’s
Hospital (BWH) and licensed to Resolvyx Pharmaceuticals. N.G.B. is
an inventor on patents assigned to LSU-HSC. N.A.P. and C.N.S. are
co-founders of Resolvyx Pharmaceuticals and own equity in the
company. C.N.S.’ interests were reviewed and are managed by
BWH and Partners HealthCare in accordance with their conflict of
interest policies.
Figure 5. Synthesis of NPD1/PD1 (1) and AT-(NPD1/PD1) (2). (a) Cat. Pd(PPh3)4, CuI,
rt, PhH, 96%; (b) TBAF, THF, rt, 2 h, 65%; (c) Zn(Cu/Ag), MeOH/H2O, 40 °C, 60%; (d)
NaOH, MeOH/H2O, rt, 95%. Insert shows the HPLC chromatogram of the co-elution
of methyl esters 24 (retention time 11.3 min) and 21 (retention time 15.2 min),
using a C18 reverse phase column, eluent of 28% water in methanol, and a UV
detector at 270 nm.
References and notes
1. Serhan, C. N.; Petasis, N. A. Chem. Rev. 2011, 111, 5922–5943. and references
cited there in.
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4. Hong, S.; Gronert, K.; Devchand, P. R.; Moussignac, R.-L.; Serhan, C. N. J. Biol.
Chem. 2003, 278, 14677–14687.
5. Marcheselli, V. L.; Hong, S.; Lukiw, W. J.; Tian, X. H.; Gronert, K.; Musto, A.;
Hardy, M.; Gimenez, J. M.; Chiang, N.; Serhan, C. N.; Bazan, N. G. J. Biol. Chem.
2003, 278, 43807–43817.
6. Mukherjee, P. K.; Marcheselli, V. L.; Serhan, C. N.; Bazan, N. G. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 8491–8496.
The use of Lindlar hydrogenation for the conversion of the E,E-
dienyne system of 3 to the corresponding E,E,Z triene is hampered
by over-reduction and the formation of difficult to remove by-
products. For this key step, we relied on the selective cis-reduction
of the alkyne bond of 3 by using a known Zn(Cu/Ag) reagent18,19
freshly prepared from zinc dust, copper(II) acetate monohydrate
and silver(I) nitrate. Unlike catalytic hydrogenation reactions, this
alkyne reduction method is much more selective and it reduces
alkynes in conjugated systems much faster than other alkynes or
7. 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.

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8. 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.
21. NPD1/PD1 (1): 1H NMR (400 MHz, MeOH-d4):
d 6.52(dd, J = 14.0 Hz and
11.5 Hz, 1H), 6.26(m, 2H), 6.05(dd, J = 11.1 Hz and 11.1 Hz, 1H), 5.75(dd, J = 6.4
and 14.4 Hz, 1H), 5.50–5.30(m, 6H), 4.53(m, 1H), 4.04(m, 1H), 2.82(m, 2H),
2.35(m, 4H), 2.18(m, 4H), 2.05(m, 2H), 0.96(t, J = 7.5 Hz, 3H). 13C NMR (400 Hz,
MeOH-d4): d 174.94, 137.58, 134.32, 134.48, 134.25, 130.71, 130.12, 129.92,
129.65, 127.92, 127.78, 124.84, 123.39, 71.80, 67.68, 35.35, 33.90, 31.54, 25.77,
22.80, 22.61, 14.10. MS (m/z): 137, 153, 163, 188, 206, 217, 245, 261, 279, 297,
315, 323, 341, 359.
9. 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, 976–987.
10. Petasis, N.A.; Uddin, J.; Winkler, J.W.; Yang, R.; Bazan, N.G.; Serhan, C.N. 235th
ACS National Meeting, New Orleans, LA, 2008, Abstract MEDI 038.
11. Compound 4: 1H NMR(400 MHz, CDCl3): d 7.72(m, 4H), 7.37(m, 6H), 5.46(m,
1H), 5.37(m, 1H), 4.31(td, J = 6.6 Hz and 2.1 Hz, 1H), 2.40(m, 2H), 2.33(d,
J = 2.1 Hz, 1H), 1.28(m, 2H), 1.08(s, 9H), 0.88(td, J = 7.0 Hz and 1.8 Hz, 3). 13C
NMR (100 MHz, CDCl3): d 136.0, 135.9, 134.6, 133.8, 133.6, 129.8, 128.6, 128.5,
127.6, 127.4, 84.8, 72.5, 63.6, 36.1, 26.9, 22.4, 14.1.
22. Compound 23: 1H NMR (400 MHz, CDCl3): d 6.57(dd, J = 15.6 Hz and 10.8 Hz,
1H), 6.30(J = 15.8 and 11.4 Hz, 1H), 5.84(dd, J = 15.4 and 5.8 Hz, 1H), 5.70–
5.30(m, 7H), 4.53(m, 1H), 4.24(m, 1H), 3.67(s, 3H), 2.83(m, 2H), 2.09(m,2H),
2.38 (m, 6H), 2.09(m, 2H), 0.98(t, J = 7.5 Hz, 3H). 13C NMR (400 Hz, CDCl3): d
170.65, 141.34, 138.11, 136.01, 131.49, 129.27, 128.94, 128.10, 124.63, 122.65,
110.79, 92.33, 83.96, 71.46, 62.54, 50.89, 35.59, 35.30, 33.92, 25.78, 22.82,
20.82, 14.22.
12. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772.
13. Alkyne 17 was prepared from pent-4-yn-1-ol via Jones oxidation and
esterification with methanol catalyzed by toluenesulfonic acid.
14. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410.
15. For a review see Petasis, N. A. In Science of Synthesis: Alkenes; Meijere, A. d., Ed.;
Thieme-Verlag: Stuttgart, 2009; pp 161–246.
23. AT-(NPD1/PD1) methyl ester (24): 1H NMR (400 MHz, CDCl3):
d 6.51(dd,
J = 14.0 Hz and 11.4 Hz, 1H), 6.26(m, 2H), 6.09(dd, J = 11.0 and 11.0 Hz, 1H),
5.62–5.30(m, 7H), 4.60(m, 1H), 4.23(m, 1H), 3.67(s, 3H), 2.83(m, 2H), 2.44–
2.22(m, 8H), 2.07(m, 2H), 0.96(t, J = 7.5 Hz, 3H). 13C NMR (400 Hz, CDCl3): d
173.64, 136.48, 135.32, 133.78, 133.46, 131.21, 130.32, 130.03, 129.02, 128.02,
127.78, 124.85, 123.49, 71.81, 67.70, 35.37, 33.94, 31.58, 25.79, 22.82, 22.64,
14.10.
16. Compound 5: 1H NMR(400 MHz, CDCl3): d 7.67(m, 4H), 7.38(m, 6H), 6.93(dd,
J = 15.1 Hz and 11.2 Hz, 1H), 6.18(d, J = 14.6 Hz, 1H), 5.90(dd, J = 14.6 Hz and
10.8 Hz, 1H), 5.67(dd, J = 15.1 Hz and 6.4 Hz, 1H), 5.32(m, 4H), 4.20(m, 1H),
2.62(m, 2H), 2.30(m, 6H), 1.09(s, 9H). 13C NMR (100 MHz, CDCl3): d 1743.4,
144.6, 136.5, 135.9, 135.8, 134.0, 133.7, 129.8, 129.7, 129.6, 129.5, 129.2, 127.7,
127.5, 127.4, 124.8, 73.0, 51.5, 35.6, 34.1, 27.0, 25.6, 19.3, 14.1.
24. AT-(NPD1/PD1) (2): 1H NMR (400 MHz, MeOH-d4): d 6.52(dd, J = 14.0 Hz and
11.4 Hz, 1H), 6.26(m, 2H), 6.07(dd, 10.8 and 11.6 Hz), 5.75(dd, J = 6.4 and
14.4 Hz, 1H), 5.50–5.29(m, 6H), 4.58(m, 1H), 4.12(m, 1H), 2.84(m, 2H), 2.35(m,
4H), 2.18(m, 4H), 2.06(m, 2H), 0.96(t, J = 7.5 Hz, 3H). 13C NMR (400 Hz, MeOH-
d4): d 174.94, 137.58, 134.32, 134.48, 134.25, 130.71, 130.12, 129.92, 129.65,
127.92, 127.78, 124.84, 123.39, 71.80, 67.68, 35.35, 33.90, 31.54, 25.77, 22.80,
22.61, 14.10. MS (m/z): 137, 153, 163, 188, 206, 217, 245, 261, 279, 297, 315,
323, 341, 359.
17. Compound 3: 1H NMR (400 MHz, CDCl3): d 6.57(dd, J = 15.6 Hz and 10.8 Hz,
1H), 6.29(dd, J = 15.8 Hz and 11.4 Hz, 1H), 5.83(dd, J = 15.4 Hz and 5.8 Hz, 1H),
5.7–5.3(m, 7H), 4.53(m, 1H), 4.24(m, 1H), 3.67(s, 3H), 2.84(m, 2H), 2.50(m, 2H),
2.38(m, 6H), 2.09(m, 2H), 0.98(t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): d
170.65, 141.34, 138.11, 136.01, 131.49, 129.27, 128.94, 128.10, 124.63, 122.65,
110.79, 92.33, 83.96, 71.46, 62.54, 50.89, 35.59, 35.30, 33.92 25.78, 22.82,
20.80, 14.22.
18. Boland, W.; Schroer, N.; Sieler, C.; Feigel, M. Helv. Chim. Acta 1987, 70, 1025–
1040.
25. Hong, S.; Lu, Y.; Yang, R.; Gotlinger, K. H.; Petasis, N. A.; Serhan, C. N. J. Am. Soc.
Mass. Spectrom. 2007, 18, 128–144.
19. Chemin, D.; Linstrumelle, G. Tetrahedron 1992, 48, 1943–1952.
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Petasis, N. A.; Bazan, N. G. J. Biol. Chem. 2009, 284, 17877–17882.
27. Marcheselli, V. L.; Mukherjee, P. K.; Arita, M.; Hong, S.; Antony, R.; Sheets, K.;
Winkler, J. W.; Petasis, N. A.; Serhan, C. N.; Bazan, N. G. Prostaglandins Leukot.
Essent. Fatty Acids 2010, 82, 27–34.
20. NPD1/PD1 methyl ester (21): 1H NMR (400 MHz, MeOH-d4):
d 6.51(dd,
J = 14.0 Hz and 11.5 Hz, 1H), 6.26(m, 2H), 6.07(dd, J = 11.1 Hz and 11.1 Hz,
1H), 5.50–5.28(m, 7H), 4.90(s, 2H), 5.50–5.60(m, 2H), 4.55(m, 1H), 4.14(m, 1H),
3.65(s, 3H), 2.82(m, 2H), 2.40–2.13(m, 8H), 2.06(m, 2H), 2.07(m, 2H), 0.96(t,
J = 7.5 Hz, 3H). 13C NMR (125 Hz, MeOH-d4): d 174.93, 137.59, 134.56, 134.47,
134.35, 131.01, 130.52, 130.17, 129.92, 128.57, 128.52, 126.14, 124.89, 72.60,
68.18, 36.00, 35.97, 34.45, 26.30, 23.43, 21.312, 14.20.
28. Zhao, Y.; Calon, F.; Julien, C.; Winkler, J. W.; Petasis, N. A.; Lukiw, W. J.; Bazan,
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