First total synthesis of the anti-inflammatory lipid mediator Resolvin D6

Article abstract of DOI:10.1016/j.tetlet.2011.11.003

The first total synthesis of Resolvin D6, an endogenous lipid mediator of resolution of inflammation derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C4 and C17 were generated via an asymmetric Noyori transfer hydrogenation and a Sharpless catalytic asymmetric epoxidation, respectively. A mild copper catalyzed coupling of cis-1,4-dibromo-2-butene with TMS-acetylene generated the C7-C14 fragment. Pd⁰/Cu^I Sonogashira couplings and Zn(Cu/Ag) reduction completed the synthesis of Resolvin D6.

Full text of DOI:10.1016/j.tetlet.2011.11.003

Tetrahedron Letters 53 (2012) 86–89
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
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First total synthesis of the anti-inflammatory lipid mediator Resolvin D6
⇑
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 first total synthesis of Resolvin D6, an endogenous lipid mediator of resolution of inflammation
derived from docosahexaenoic acid, has been achieved. The chiral hydroxy-groups at C4 and C17 were
generated via an asymmetric Noyori transfer hydrogenation and a Sharpless catalytic asymmetric epox-
idation, respectively. A mild copper catalyzed coupling of cis-1,4-dibromo-2-butene with TMS-acetylene
generated the C7–C14 fragment. Pd0/CuI Sonogashira couplings and Zn(Cu/Ag) reduction completed the
synthesis of Resolvin D6.
Received 20 October 2011
Revised 1 November 2011
Accepted 2 November 2011
Available online 7 November 2011
Keywords:
Resolvin D6
Ó 2011 Elsevier Ltd. All rights reserved.
Total synthesis
Inflammation resolution
Asymmetric transfer hydrogenation
Asymmetric epoxidation
The health benefits of
x
-3 fatty acids are well documented,1
genation of 7 in i-PrOH produced the chiral intermediate 8 with
>95% ee as determined by chiral HPLC (Chiracel OF, hexane/i-PrOH
95:5).22,23 TMS desilylation of 8 with KFꢀ2H2O in DMF in the pres-
ence of a catalytic amount of 18-crown-6 gave cleanly the terminal
acetylene 9. Protection of 9 with TBSCl in DMF produced the silyl
ether 10. Free radical addition with excess tributyltin hydride at
130 °C in the presence of a catalytic amount AIBN produced the
trans-vinyl tin compound 11 in 63% combined yield (three-steps).
The key intermediate 2 was obtained from 11 by reaction with
iodine in ether at 0 °C (93% yield).
The C15–C22 chiral fragment 3 was prepared from propargyl
alcohol (12) and 1-bromo-2-pentyne (13) according to the method
of Eiter et al. (CuI, DBU, and HMPA) to afford 2,5-octadiyn-1-ol (14)
as outlined in Scheme 2.24 Selective reduction of the propargylic
triple bond with LiAlH4 in ether afforded (E)-2-octen-5-yn-1-ol
(15) in 70% yield. Sharpless cat. AE of 15 gave the crystalline epoxy
alcohol 16. Recrystallization from hexane/ethyl acetate at 4 °C gave
16 with >98% ee, as determined by Chiral HPLC (Chiracel OD, hex-
ane/i-PrOH 95:5).25–27 Lindlar reduction of 16 in hexane afforded
crystalline 17. Using the method of Samuelson,28 17 was converted
to the iodo epoxide 18. The crucial step to transform the 1-iodo-
2,3-epoxide 18 into (1E,3S,5Z)-1-iodo-1,5-octadien-3-ol (19) was
achieved following Nakata’s protocol (NaHMDS in DMF at
ꢁ60 °C).29,30 Standard protection of 19 with TBSCl in DMF gave
the second key intermediate 3 in 67% yield.
including their effects on neutrophil function and leukotriene gen-
eration in humans.2 In 2002, Serhan et al. discovered that the enzy-
matic metabolism of the two major
x-3 fatty acids of fish oil
(docosahexaenoic and eicosapentaenoic acids) produced the
Resolvins (resolution phase interaction products) in vivo.3 These
x
-3 fatty acid metabolites are powerful anti-inflammatory and
immunoregulatory lipid mediators. The protective role in chronic
inflammatory diseases as well as sepsis is currently explored.4–11
Their low availability from natural sources prompted us to pre-
pare the Resolvins by total synthesis in order to evaluate their bio-
logical and pharmacological properties. We have previously
reported the total syntheses of Resolvins D2 and D5.12,13 Later on
syntheses of Resolvins E1 and E2, Protectin D1 and Maresin have
been described.14–20
In this communication, we wish to report the first total synthe-
sis of Resolvin D6 [RvD6; (4S,5E,7Z,10Z,13Z,15E,17S,19Z)-4,17-
dihydroxy-5,7,10,13,15,19-docosahexaenoic acid; (1)]. As shown
in Figure 1, RvD6 was prepared from the key intermediates 2, 3,
and 4. The chiral center at C4 was obtained via Noyori transfer
hydrogenation, using the Ru[(S,S)-TsDPEN](p-cymene) catalyst,
whereas the chiral center at C17 was prepared via Sharpless asym-
metric epoxidation.
The fragment C1–C6 was prepared from commercial methyl 4-
chloro-4-oxobutyrate (5) and bis(trimethylsilyl)acetylene (6) as
outlined in Scheme 1. Alkynylation using 10% InBr3 in CH2Cl2 affor-
ded the intermediate 7 in 94% yield.21 Asymmetric transfer hydro-
The synthesis of the C7–C14 fragment 4 was accomplished in
two-steps as outlined in Scheme 3. According to the method of
Bieber et al.31 CuI catalyzed coupling of freshly distilled cis-1,4-di-
bromo-2-butene (20)32 with excess trimethylsilyl acetylene (21) in
DMF at room temperature gave 22 in 34% isolated yield. The 1H
⇑
Corresponding author. Tel.: +1 856 566 7016; fax: +1 856 566 6195.
E-mail address: spurbw@umdnj.edu (B.W. Spur).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.003

A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 86–89
87
Figure 1.
Scheme 1. Reagents and conditions: (a) 10% InBr3, CH2Cl2, 0 °C to rt; (b) Ru[(S,S)-TsDPEN](p-cymene), i-PrOH, rt; (c) KFꢀ2H2O, 18-crown-6, DMF, rt; (d) TBSCl, imidazole, DMF,
0 °C to rt; (e) (Bu)3SnH, AIBN, 130 °C; and (f) I2, ether, 0 °C.
0
Scheme 2. Reagents and conditions: (a) DBU, CuI, HMPA, THF; (b) LiAlH4, ether, 0 °C to rt; (c) L(+)DMT, Ti(OiPr)4, TBHP, molecular sieves 4 ÅA, CH2Cl2; (d) H2, Lindlar cat., Et3N,
hexane; (e) I2, Ph3P, imidazole, i-Pr2EtN, CH3CN, ether; (f) NaHMDS, DMF, ꢁ60 °C; and (g) TBSCl, imidazole, DMF.
Scheme 3. Reagents and conditions: (a) CuI, Na2SO3, K2CO3, DMF, rt; (b) AgNO3, CH3OH, H2O, NaCN, 0 °C.
NMR indicated only minimal amount of trans-isomer present.
Silver catalyzed monodesilylation of 22 with 2 equiv of AgNO3 in
CH3OH/H2O at 0 °C followed by treatment with NaCN and extrac-
tive work-up with hexane/ethyl acetate gave 4.33,34 It should be
noted that 1 equiv of AgNO3 was not sufficient and produced a
mixture of starting material and 4 in a ratio of 1:1.
produced compound 23.35 Desilylation using AgNO3 followed by
NaCN work-up gave 24, that was used without further purification
in the second Sonogashira coupling with 2 to give the diacetylene
precursor of RvD6 methyl ester (25).
The synthesis was completed as outlined in Scheme 5 via depro-
tection of the TBS groups of compound 25 with catalytic HCl, gen-
erated in situ from acetyl chloride in absolute methanol at 0 °C, to
give 26. Zn(Cu/Ag) reduction of 26 in CH3OH/H2O at 50 °C (24 h)
The skeleton of RvD6 was obtained from the key intermediates
2, 3, and 4 as outlined in Scheme 4. Pd0/CuI coupling of 3 with 4

88
A. R. Rodriguez, B. W. Spur / Tetrahedron Letters 53 (2012) 86–89
Scheme 4. Reagents and conditions: (a) Pd(PPh3)4, CuI, n-PrNH2, benzene, rt; (b) AgNO3, CH3OH, H2O, NaCN, 0 °C.
Scheme 5. Reagents and conditions: (a) MeCOCl, CH3OH, 0 °C to rt; (b) Zn(Cu/Ag), CH3OH, H2O, 50 °C; and (c) 1 N LiOH, H2O, THF, 0 °C, then H+ (NaH2PO4 saturated).
13. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2005, 46, 3623–3627.
gave RvD6 methyl ester (27).36,37 Mild alkaline hydrolysis of 27
with LiOH in H2O/THF at 0 °C followed by acidification with sat.
NaH2PO4 in the presence of ethyl acetate gave RvD6 (1).
In summary, a concise total synthesis of RvD6 has been
achieved,38 making this anti-inflammatory lipid mediator from
docosahexaenoic acid available for further biological testing. The
synthesis of other Resolvins, Maresin, and Neuroprotectin D1 will
be reported in due course.
14. Petasis, N. A. U.S. Pat. Appl. Publ. 2005, 20050228047, and 2009 20090291916.
15. Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2009, 50, 6079–6082.
16. Kosaki, Y.; Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2010, 51, 1856–1859.
17. Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2011, 52, 3001–3004.
18. Ogawa, S.; Urabe, D.; Yokokura, Y.; Arai, H.; Arita, M.; Inoue, M. Org. Lett. 2009,
11, 3602–3605.
19. Sasaki, K.; Urabe, D.; Arai, H.; Arita, M.; Inoue, M. Chem. Asian J. 2011, 6, 534–
543.
20. 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.
21. Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Parimala, G. Synthesis (Stuttg) 2003, 15,
2390–2394.
Acknowledgments
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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.
25. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.
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1. Massaro, M.; Scoditti, E.; Carluccio, M. A.; Campana, M. C.; De Caterina, R. Cell.
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89
3.7 (s, 3H), 2.6–2.4 (m, 2H), 2.3 (br s, 1H), 2.1–1.9 (m, 2H), 0.13 (s, 9H); 13C NMR
(CDCl3, 75.5 MHz): d 173.95, 105.73, 90.05, 61.86, 51.68, 32.41, 29.71, ꢁ0.20
(3C). Compound 9: 1H NMR (CDCl3, 300 MHz): d 4.5–4.4 (dt, J = 6.0, 2.1 Hz, 1H),
3.7 (s, 3H), 2.7–2.4 (m, 2H), 2.5–2.4 (d, J = 2.1 Hz, 1H), 2.1–2.0 (m, 2H); 13C NMR
148.80, 134.24, 123.62, 75.66, 75.08, 35.57, 25.81 (3C), 20.73, 18.21, 14.18,
ꢁ4.63, ꢁ4.83. Compound 20: 1H NMR (CDCl3, 300 MHz): d 6.0–5.8 (m, 2H),
4.1–3.9 (m, 4H); 13C NMR (CDCl3, 75.5 MHz):
d 129.31 (2C), 24.26 (2C).
Compound 22: 1H NMR (CDCl3, 300 MHz): d 5.6–5.4 (m, 2H), 3.0–2.9 (m, 4H),
0.1 (s, 18H); 13C NMR (CDCl3, 75.5 MHz): d 126.08 (2C), 104.32 (2C), 84.85 (2C),
18.44 (2C), 0.06 (6C). Compound 4: 1H NMR (CDCl3, 300 MHz): d 5.6–5.4 (m,
2H), 3.0–2.9 (m, 4H), 2.0 (t, J = 2.7 Hz, 1H), 0.1 (s, 9H); 13C NMR (CDCl3,
75.5 MHz): d 126.25, 125.76, 104.08, 84.90, 81.90, 68.42, 18.37, 16.91, 0.03
(3C). Compound 23: 1H NMR (CDCl3, 300 MHz): d 6.1–6.0 (dd, J = 15.9, 5.1 Hz,
1H), 5.7–5.5 (m, 3H), 5.5–5.2 (m, 2H), 4.2–4.0 (m, 1H), 3.1–2.9 (m, 4H), 2.3–2.1
(m, 2H), 2.1–1.9 (br quint, J = 7.5 Hz,, 2H), 0.93 (t, J = 7.5 Hz, 3H), 0.87 (s, 9H),
0.13 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 145.15,
133.85, 126.34, 125.87, 124.23, 109.11, 104.36, 87.56, 84.85, 78.99, 72.69,
36.03, 25.89 (3C), 20.75, 18.40, 18.23, 17.96, 14.09, 0.06 (3C), ꢁ4.52, ꢁ4.76.
Compound 26: 1H NMR (CDCl3, 300 MHz): d 6.1–5.9 (2dd, J = 15.7, 6.0 Hz, 2H),
5.8–5.5 (m, 5H), 5.4–5.2 (m, 1H), 4.2–4.1 (m, 2H), 3.6 (s, 3H), 3.1–3.0 (m, 4H),
2.4 (m, 2H), 2.3 (br t, J = 6.9 Hz, 2H), 2.1–2.0 (br quint, J = 7.5 Hz, 2H), 2.0–1.7
(m, 2H), 0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d 174.24, 144.05,
143.79, 135.65, 126.15, 125.97, 123.24, 110.80, 110.32, 88.52, 88.16, 78.63,
78.47, 71.63, 71.30, 51.70, 34.96, 31.60, 29.87, 20.72, 17.85, 17.82, 14.11.
Compound 27: 1H NMR (CD3CN, 300 MHz): d 6.7–6.5 (m, 2H), 6.1–5.9 (br t,
J = 11.1 Hz 2H), 5.8–5.7 (dd, J = 15.3, 6.0 Hz, 1H), 5.7–5.6 (dd, J = 15.3, 6.3 Hz,
1H), 5.6–5.3 (m, 6H), 4.2–4.1 (m, 2H), 3.6 (s, 3H), 3.1–2.9 (m, 4H), 2.4 (dt,
J = 7.5, 1.2 Hz, 2H), 2.3–2.2 (br t, J = 6.9 Hz, 2H), 2.1 (quint, J = 7.5 Hz, 2H), 1.9–
1.7 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR (CD3CN, 75.5 MHz): d 174.22,
137.56, 137.21, 133.94, 130.04, 129.80, 128.66, 128.56, 128.40, 128.35, 125.31,
125.13, 124.98, 71.87, 71.08, 51.36, 35.59, 32.64, 30.13, 26.24 (2C), 20.81,
13.88. Compound 1: 1H NMR (CD3CN, 300 MHz): d 6.7–6.5 (br dd, J = 15.3,
11.1 Hz, 2H), 6.1–6.0 (br t, J = 11.1 Hz, 2H), 5.8–5.6 (m, 2H), 5.6–5.3 (m, 6H),
4.2–4.1 (q, J = 6.3 Hz, 2H), 3.1–2.9 (m, 4H), 2.4 (t, J = 7.5, 1.2 Hz, 2H), 2.3–2.2 (br
t, J = 6.9 Hz, 2H), 2.3–2.1 (br s, 2H), 2.1 (quint, J = 7.5 Hz, 2H), 1.9–1.7 (m, 2H),
0.98 (t, J = 7.5 Hz, 3H); 13C NMR (CD3CN, 75.5 MHz): d 174.85, 137.79, 137.48,
134.26, 130.36, 130.13, 128.95, 128.86, 128.69 (2C), 125.65, 125.41, 125.33,
72.19, 71.46, 35.89, 32.82, 30.26, 26.55 (2C), 21.11, 14.18. UV (EtOH) kmax
232 nm. HPLC/API-ES/MS (m/z): 383.5 [M+Na+]+.
(CDCl3, 75.5 MHz):
d 173.86, 84.06, 73.37, 61.36, 51.68, 32.40, 29.65.
Compound 10: 1H NMR (CDCl3, 300 MHz): d 4.4 (dt, J = 6.0, 1.8 Hz, 1H), 3.6
(s, 3H), 2.5–2.4 (t, J = 7.6, 2H), 2.4 (d, J = 1.8 Hz, 1H), 2.1–1.9 (m, 2H), 0.9 (s, 9H),
0.1 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 173.61, 84.67, 72.58,
61.61, 51.48, 33.41, 29.40, 25.71 (3C), 18.14, ꢁ4.69, ꢁ5.18. Compound 11: 1H
NMR (CDCl3, 300 MHz): d 6.1–6.0 (d, J = 19.2 Hz, 1H), 6.0–5.8 (dd, J = 19.2,
5.7 Hz, 1H), 4.1 (m, 1H), 3.6 (s, 3H), 2.4–2.3 (br t, J = 7.5 Hz, 2H), 1.9–1.7 (m,
2H), 1.5–1.4 (quint, J = 7.5 Hz, 6H), 1.4–1.2 (hex, J = 7.5 Hz, 6H), 0.9 (s, 9H), 1.0–
0.8 (m, 15H), 0.01 (s, 3H), 0.005 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 174.16,
150.96, 127.87, 75.44, 51.30, 32.91, 29.74, 29.14 (3C), 27.21 (3C), 25.93 (3C),
18.27, 13.58 (3C), 9.60 (3C), ꢁ4.31, ꢁ4.83. Compound 2: 1H NMR (CDCl3,
300 MHz): d 6.5–6.4 (dd, J = 14.4, 5.7 Hz, 1H), 6.2 (dd, J = 14.4, 1.5 Hz, 1H), 4.2–
4.1 (m, 1H), 3.6 (s, 3H), 2.4–2.3 (t, J = 7.5 Hz, 2H), 1.9–1.7 (m, 2H), 0.9 (s, 9H),
0.01 (s, 3H), 0.001 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 173.77, 148.32, 76.41,
73.85, 51.55, 32.13, 29.02, 25.78 (3C), 18.15, ꢁ4.61, ꢁ5.02. Compound 15: 1H
NMR (CDCl3, 300 MHz): d 6.0–5.8 (dtt, J = 15.0, 5.7, 1.8 Hz, 1H), 5.7–5.6 (dtt,
J = 15.0, 5.4, 1.5 Hz, 1H), 4.1 (m, 2H), 2.9 (m, 2H), 2.2–2.1 (qt, J = 7.5, 2.4 Hz, 2H),
1.1 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d 130.28, 127.32, 84.07,
76.01, 63.13, 21.68, 14.15, 12.37. Compound 16: 1H NMR (CDCl3, 300 MHz): d
3.9 (dd, J = 12.6, 2.1 Hz, 1H), 3.6 (dd, J = 12.6, 4.2 Hz, 1H), 3.1 (m, 2H), 2.6–2.5
(ddt, J = 17.4, 4.2, 2.4 Hz, 1H), 2.5–2.4 (ddt, J = 17.4, 4.8, 2.4 Hz, 1H), 2.2–2.1 (qt,
J = 7.5, 2.4 Hz, 2H), 2.1(br s, 1H), 1.1 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3,
75.5 MHz): d 84.18, 73.27, 61.26, 57.83, 53.61, 21.67, 13.96, 12.31. Compound
17: 1H NMR (CDCl3, 300 MHz): d 5.6–5.4 (dtt, J = 10.8, 7.2, 1.5 Hz, 1H), 5.4–5.2
(dtt, J = 10.8, 7.5, 1.5 Hz, 1H), 3.9 (dd, J = 12.6, 2.4 Hz, 1H), 3.6 (dd, J = 12.6,
4.2 Hz, 1H), 3.0–2.9 (m, 2H), 2.5–2.2 (m, 2H), 2.1–1.9 (m, 2H), 1.9–1.8 (br s, 1H),
0.95 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d 134.92, 122.36, 61.75,
57.95, 55.29, 29.23, 20.66, 14.06. Compound 3: 1H-NMR (CDCl3, 300 MHz): d
6.5 (dd, J = 14.4, 5.7 Hz, 1H), 6.2 (d, J = 14.4 Hz, 1H), 5.5 (m, 1H), 5.3 (m, 1H), 4.1
(br q, J = 6.0 Hz, 1H), 2.2 (m, 2H), 2.0 (br quint, J = 7.5 Hz, 2H), 0.94 (t, J = 7.5 Hz,
3H), 0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H). 13C NMR (CDCl3, 75.5 MHz): d