First total synthesis of the anti-inflammatory and pro-resolving lipid mediator 16(R),17(S)-diHDHA

Article abstract of DOI:10.1016/j.tetlet.2018.02.029

The first total synthesis of the anti-inflammatory and pro-resolving lipid mediator 16(R),17(S)-diHDHA, derived from docosahexaenoic acid (DHA), and its 16-epimer have been achieved. Two synthetic approaches are described for the synthesis of 16(R),17(S)-diHDHA. The first strategy started from DHA and used an enzymatic reaction, a vanadium catalyzed allylic epoxidation and a base-promoted epoxide isomerization. The second approach utilized a chiral pool strategy starting from 2-deoxy-D-ribose to establish the chiral centers; Wittig reactions, mild acetonide cleavage and ester hydrolysis were the key steps in the synthesis.

Full text of DOI:10.1016/j.tetlet.2018.02.029

Accepted Manuscript
First total synthesis of the anti-inflammatory and pro-resolving lipid mediator
16(R),17(S)-diHDHA
Ana R. Rodriguez, Bernd W. Spur
PII:
S0040-4039(18)30199-0
https://doi.org/10.1016/j.tetlet.2018.02.029
TETL 49714
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 January 2018
3 February 2018
12 February 2018
Please cite this article as: Rodriguez, A.R., Spur, B.W., First total synthesis of the anti-inflammatory and pro-
resolving lipid mediator 16(R),17(S)-diHDHA, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.02.029
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First total synthesis of the anti-inflammatory and pro-resolving lipid mediator
16(R),17(S)-diHDHA
Dedicated to Professor E. J. Corey on the occasion of his 90th birthday
Ana R. Rodriguez and Bernd W. Spur
Department of Cell Biology and Neuroscience, Rowan University- SOM, Stratford, NJ 08084, USA
ARTICLE INFO
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
16(R),17(S)-diHDHA
Total synthesis
Inflammation resolution
Base-promoted epoxide isomerization
Lipoxidase
Chiral pool
———
 Corresponding author. Tel.: +1-856-566-7016; fax: +1-856-566-6195; e-mail: spurbw@rowan.edu

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Tetrahedron Letters
ABSTRACT
The first total synthesis of the anti-inflammatory and pro-resolving lipid mediator 16(R),17(S)-diHDHA , derived from docosahexaenoic acid (DHA),
and its 16-epimer have been achieved. Two synthetic approaches are described for the synthesis of 16(R),17(S)-diHDHA . The first strategy started
from DHA and used an enzymatic reaction, a vanadium catalyzed allylic epoxidation and a base-promoted epoxide isomerization. The second approach
utilized a chiral pool strategy starting from 2-deoxy-D-ribose to establish the chiral centers; Wittig reactions, mild acetonide cleavage and ester
hydrolysis were the key steps in the synthesis.
Inflammation is a response to tissue damage and/ or infection. Acute inflammation that is self-limited and achieves resolution is a
protective mechanism,1,2 but uncontrolled inflammation is the underlining course of chronic diseases including autoimmune diseases,
cancer, diabetes, asthma and neurological diseases such as Alzheimer’s and Parkinson disease.3 It is well documented that ω-3 fatty
acids mainly found in fish oil have anti-inflammatory properties and help with the resolution of inflammation.4-6 The pioneering work
by Serhan and collaborators revealed that these ω-3 poly-unsaturated fatty acids are converted at the side of inflammation by
lipoxygenase enzymes to potent lipid mediators that are responsible for the resolution of inflammation.7,8
Several families of pro-resolving lipid mediators have been identified and collectively named specialized pro-resolving mediators
(SPMs): lipoxins derived from arachidonic acid, resolvins of the E-type derived from eicosapentaenoic acid (EPA), resolvins of the D-
type, maresins, protectins and their sulfido-conjugates derived from docosahexaenoic acid (DHA) and the more recently uncovered
metabolites from n-3 docosapentaenoic acid (n-3 DPA).9-16
Figure 1. Proposed biosynthesis of 10R,17S-Protectin D1, 16(R),17(S)-diHDHA and PCTRs.
The proposed biosynthesis of the protectins is outlined in figure 1.17 DHA is converted by the 15-lipoxidase to 17(S)-hydroperoxy-
docosahexaenoic acid [17(S)-HpDHA] that undergoes enzymatic conversion to the allylic epoxide 16(S),17(S)-epoxy-docosahexaenoic
acid. This intermediate undergoes enzymatic hydrolysis to 10(R),17(S)-protectin D1 (PD1) whereas a soluble epoxide hydrolase gives
the 16(R),17(S)-diHDHA. The same 16(S),17(S)-epoxy-docosahexaenoic acid intermediate can be converted by a glutathione S-
transferase via a SN2 mechanism to the Protectin conjugate in tissue regeneration (PCTR).18-20 Due to the growing interest to study the
biological and pharmacological properties of these mediators combined with the limited availability from natural sources these products
have to be prepared by chemical synthesis. We have recently reported the total synthesis of PD121 and the PCTRs.19 In the current
publication we wish to report the total synthesis of 16(R),17(S)-diHDHA [(4Z,7Z,10Z,12E,14E,16R,17S,19Z)-16,17-dihydroxy-
4,7,10,12,14,19-docosahexaenoic acid (1)].
As shown in the retrosynthetic scheme (Figure 2) we have prepared 16(R),17(S)-diHDHA via two different strategies. In the first
approach we used an enzymatic-chemical route starting from DHA (3). In the second approach we employed a chiral pool strategy
starting from 2-deoxy-D-ribose. The key intermediates 4 and 5 were used to produce the 16(R),17(S)-diHDHA skeleton.

Figure 2. Two retrosynthetic approaches to 16(R),17(S)-diHDHA.
As shown in Scheme 1 DHA (3) was reacted with lipoxidase from soybean in borate buffer pH 9 in the presence of O2 followed by
reduction with Ph3P to obtain 17(S)-hydroxy-docosahexaenoic acid [17(S)-HDHA] (2) with > 97.2% ee as determined by chiral-HPLC
(racemic 17-HDHA was prepared from 2 by Dess-Martin oxidation followed by NaBH4 reduction in ethanol).22 Esterification of 2 with
trimethylsilyldiazomethane in CH3OH/toluene afforded compound 11 in 85% isolated yield22 that was submitted to allylic epoxidation
with TBHP in the presence of a catalytic amount of vanadyl acetylacetonate to afford a mixture of erythro and threo epoxy-alcohols 12
and 13 in the proportion of 77/23 respectively.23 It should be mentioned that excess TBHP had to be avoided to minimize diepoxidation.
The separation of the epoxides 12 and 13 was easily achieved by flash chromatography in the presence of 1% Et3N providing a
convenient access to 16(R),17(S)-diHDHA (1) and its 16-epi-isomer 16 respectively. Compounds 12 (erythro) and 13 (threo) had the
1
characteristic H-1H coupling constants between the epoxide and the alcohol (J16,17 = 3.0 Hz for 12 and 4.5 Hz for 13).23,24 Mild
hydrolysis of the methyl ester in compound 12 with 1N LiOH in THF/CH3OH/H2O 4/1/1 followed by acidification with sat. NaH2PO4
in the presence of ethyl acetate afforded erythro 15(S),16(S)-epoxy-17(S)-HDHA (14) that was submitted to a base-promoted epoxide
isomerization, modified from the procedures reported by the groups of Falck and Corey.25-28 The best results were obtained by adding 5
equiv of KHMDS in toluene to 14 in THF at 0 ºC affording 16(R),17(S)-diHDHA (1). The geometry of the 10Z,12E,14E-triene in 1
(J10,11 = 11.1, J12,13 = 14.4 Hz and J14,15 = 15.0 Hz) was confirmed by the 1H-1H coupling constants.24 The 1H NMR, 13C NMR, UV and
HPLC/UV/MS analysis were consistent with the structures of 1.24 In a similar manner threo-13 was converted to 16(S),17(S)-diHDHA
(16).24

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Tetrahedron Letters
Scheme 1. Reagents and conditions: (a) lipoxidase from soybean, O2, 0.1 M borate buffer pH 9, 0 C then citric acid, hexane/EtOAc 1/1; (b) Ph3P,
hexane/EtOAc 1/1, 0 C to 4 C, > 97.2% ee, 70% (over two steps); (c) TMSCHN2, CH3OH/Toluene 1/1, 0 C to rt, 85%; (d) TBHP, cat. VO(acac)2, CH2Cl2, –
15 C, 54%; (e) chromatographic separation: 77% erythro, 23% threo; (f) 1 N LiOH, THF/CH3OH/H2O 4/1/1, 0 C to rt, then sat. NaH2PO4; (g) KHMDS
(toluene), THF, 0 C, 47% of 1 (over two steps from erythro-12) and 48% of 16 (over two steps from threo-13).
In the second strategy the key intermediate 4 was prepared from compound 17 (Scheme 2). We had previously reported the
synthesis of 17 from the intermediates 6 and 7.19 The free hydroxy group in compound 17 was converted to its tosylate with 3 equiv of
tosyl chloride in CH2Cl2 in the presence of pyridine to afford 18, which was then transformed to the phosphonium salt 4 with
triphenylphosphine in acetonitrile at reflux in 84% yield.
Scheme 2. Reagents and conditions: (a) p-TsCl, pyridine, CH2Cl2, 0 C to rt, 87%; (b) Ph3P, CH3CN, reflux, 84%.
The C11–C22 chiral fragment 5 was obtained in 4 steps from 3,4-O-isopropylidene-2-deoxy-D-ribose (9) (Scheme 3).29 Wittig
reaction of 9 with 2.5 equiv of the ylide generated in situ from n-propyltriphenylphosphonium bromide (10) with n-BuLi (2.5 equiv) in
THF in the presence of HMPA at –78 ºC produced 19 in 76% yield.30 Compound 19 was converted to the aldehyde 20 by oxidation with
PCC in CH2Cl2.31 Four-carbon homologation of the aldehyde 20 with recrystallized (2E)-4-triphenylphosphoranylidene-2-butenal (8)32,33
in CH2Cl2 followed by treatment with catalytic iodine in benzene afforded the E,E-dienal 5 in 35% yield (2-steps).

Scheme 3. Reagents and conditions: (a) 10, n-BuLi, HMPA, THF, –78 C to 0 C, 76%; (b) PCC, NaOAc, CH2Cl2, rt, 71%; (c) 8, CH2Cl2, rt, 39%; (d) I2,
benzene, rt, 91%; (e) 4, KHMDS, THF, –78 C to 0 C, 52%; (f) PTSA, CH3OH, 0 C, 43%; (g) 1 N LiOH, CH3OH/H2O 3/1, 0 C, then sat. NaH2PO4, 96%.
Wittig reaction of the phosphorane prepared in situ from the phosphonium tosylate 4 with KHMDS at –78ºC in THF with the
dienal 5 gave the isopropylidene protected 16(R),17(S)-diHDHA methyl ester (21) in 52% yield based on recovered aldehyde 5
(Scheme 3). The geometry of the 12E,14E-diene unit in 5 (J12,13 = 15.3 Hz and J14,15 = 15.3 Hz) and the 10Z,12E,14E-triene in 21 (J10,11
= 10.8 Hz, J12,13 = 14.4 Hz and J14,15 = 15.0 Hz) were confirmed by the 1H-1H coupling constants.24 The isopropylidene protective group
was cleaved with p-toluenesulfonic acid in CH3OH at 0 ºC to give 16(R),17(S)-diHDHA methyl ester (22). Mild hydrolysis of 22 with 1
N LiOH in CH3OH/H2O at 0 ºC under argon followed by acidification with sat. NaH2PO4 (pH 3) in the presence of ethyl acetate,
afforded 16(R),17(S)-diHDHA (1) in 96% yield. Co-injection of 16(R),17(S)-diHDHA (1) prepared from both routes were analyzed by
HPLC/UV/MS and found to be identical.
In summary we have developed two routes for the synthesis of 16(R),17(S)-diHDHA (1),24 making this anti-inflammatory and pro-
resolving lipid mediator from docosahexaenoic acid available for further biological and pharmacological testing. The synthesis of the
epimeric 16(S),17(S)-diHDHA (16)24 has also been accomplished. 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
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Serhan CN. FASEB J. 2017;31:1273–1288.
Serhan CN. Nature. 2014;510:92–101.
Serhan CN, Chiang N, Dalli J. Mol Aspects Med. 2017. In press. doi.org/10.1016/j.mam.2017.08.002.
De Caterina R. N Engl J Med. 2011;364:2439–2450.
Lee TH, Hoover RL, Williams JD, Sperling RI, Ravalese J, Spur BW, Robinson DR, Corey EJ, Lewis RA, Austen KF. N Engl J Med.
1985;312:1217–1224.
6.
Sperling RI, Weinblatt M, Robin JL, Ravalese J, Hoover RL, House F, Coblyn JS, Fraser PA, Spur BW, Robinson DR, Lewis RA, Austen KF.
Arthritis Rheum. 1987;30:988–997.
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Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, Moussignac RL. J Exp Med. 2002;196:1025–1037.
Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. J Biol Chem. 2003;278:14677–14687.
Serhan CN, Hamberg M, Samuelsson B. Proc Natl Acad Sci USA. 1984;81:5335–5339.
10. Serhan CN, Gotlinger K, Hong S, Arita M. Prostaglandins Other Lipid Mediat. 2004;73:155–172.
11. Serhan CN, Gotlinger K, Hong S, Lu Y, Siegelman J, Baer T, Yang R, Colgan SP, Petasis NA. J Immunol. 2006;176:1848–1859.
12. Dalli J, Colas RA, Serhan CN. Sci Rep. 2013;3:1940.
13. Dalli J, Ramon S, Norris PC, Colas RA, Serhan CN. FASEB J. 2015;29:2120–2136.
14. Dalli J, Sanger JM, Rodriguez AR, Chiang N, Spur BW, Serhan CN. PLoS One 2016;11(2):e0149319.
15. Dalli J, Vlasakov I, Riley IR, Rodriguez AR, Spur BW, Petasis NA, Chiang N, Serhan CN. Proc Natl Acad Sci USA. 2016;113:12232–12237.
16. Vik A, Dalli J, Hansen TV. Bioorg Med Chem Lett. 2017;27:2259–2266.
17. Serhan CN, Dalli J, Colas RA, Winkler JW, Chiang N. Biochim Biophys Acta. 2015;1851:397–413.
18. Aursnes M, Tungen JE, Colas RA, Vlasakov I, Dalli J, Serhan CN, Hansen TV. J Nat Prod. 2015;78:2924–2931.
19. Rodriguez AR, Spur BW. Tetrahedron Lett. 2015;56:5811–5815.
20. Ramon S, Dalli J, Sanger JM, Winkler JW, Aursnes M, Tungen JE, Hansen TV, Serhan CN. Am J Pathol. 2016;186:962–973.
21. Rodriguez AR, Spur BW. Tetrahedron Lett. 2014;55:6011–6015.
22. Itoh T, Saito T, Yamamoto Y, Ishida H, Yamamoto K. Bioorg Med Chem Lett. 2016;26:343–345.
23. Mihelich ED. Tetrahedron Lett. 1979;204729–4732.
24. Satisfactory spectroscopic data were obtained for all compounds. Selected physical data: Compound 2: 1H NMR (CDCl3, 300 MHz):  6.6–6.5 (ddt, J
= 15.3, 11.1, 1.2 Hz, 1H), 6.0 (br t, J = 11.1 Hz, 1H), 5.7 (dd, J = 15.3, 6.0 Hz, 1H), 5.6–5.5 (dtt, J = 10.8, 7.2, 1.5 Hz, 1H), 5.5–5.3 (m, 8H), 4.3–4.2
(m, 1H), 3.0–2.9 (m, 2H), 2.9–2.7 (m, 4H), 2.4–2.2 (m, 6H), 2.1–2.0 (m, 2H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz):  178.09,
135.44, 135.12, 130.26, 129.44, 128.48, 128.10, 128.06, 128.01, 127.66 (2C), 125.50, 123.63, 72.08, 35.20, 33.92, 26.10, 25.67, 25.61, 22.62, 20.70,
14.09; [α]D20= +13.3 (c 0.3, EtOH) {[α]D24= +13.1 (c 0.55, EtOH)};22 Chiracel OD, 5 µm, 250 x 4.6 mm, 236 nm, Hexane/i-PrOH (0.05% formic acid)
95:5, 0.6 mL/min, tR = 15.0 min. Compound 11: 1H NMR (CDCl3, 300 MHz):  6.6–6.4 (ddt, J = 15.3, 11.1, 1.2 Hz, 1H), 6.0 (br t, J = 11.1 Hz, 1H),
5.7 (dd, J = 15.3, 6.0 Hz, 1H), 5.6–5.5 (dtt, J = 10.8, 7.2, 1.5 Hz, 1H), 5.5–5.2 (m, 8H), 4.3–4.1 (m, 1H), 3.7 (s, 3H), 3.0–2.9 (m, 2H), 2.9–2.7 (m, 4H),
2.4–2.2 (m, 6H), 2.1–2.0 (m, 2H), 1.8-1.7 (d, J = 4.2 Hz, 1H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz):  173.62, 135.76, 135.27,

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Tetrahedron Letters
130.22, 129.30, 128.49, 128.12 (2C), 128.02, 127.88, 127.69, 125.38, 123.71, 72.00, 51.59, 35.27, 33.99, 26.11, 25.66, 25.59, 22.79, 20.74, 14.19;
[α]D20= +10.9 (c 1.5, benzene); Chiracel OD, 5 µm, 250 x 4.6 mm, 236 nm, Hexane/i-PrOH 95:5, 0.6 mL/min, tR = 13.8 min. Compound 12: 1H NMR
(CDCl3, 300 MHz):  5.8–5.6 (dt, J = 10.8, 7.5 Hz, 1H), 5.6–5.5 (ddt, J = 10.8, 7.2, 1.2 Hz, 1H), 5.5–5.3 (m, 7H), 5.2–5.0 (ddt, J = 10.8, 9.0, 1.5 Hz,
1H), 3.9–3.8 (m, 1H), 3.7 (dd, J = 9.0, 2.1 Hz, 1H), 3.7–3.6 (s, 3H), 3.1–2.9 (m, 2H), 3.0–2.9 (dd, J = 3.0, 2.1 Hz, 1H), 2.9–2.7 (m, 4H), 2.4–2.3 (m,
6H), 2.1–2.0 (m, 3H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz):  173.64, 135.15, 134.86, 129.24, 128.98, 128.30, 127.91 (2C),
127.19, 126.50, 123.07, 68.41, 61.79, 51.59, 50.74, 33.98, 31.39, 26.10, 25.66, 25.59, 22.79, 20.66, 14.14; [α]D20= +18.3 (c 0.48, benzene). Compound
13: 1H NMR (CDCl3, 300 MHz):  5.8–5.6 (dt, J = 11.1, 7.5 Hz, 1H), 5.6–5.5 (ddt, J = 10.8, 7.5, 1.5 Hz, 1H), 5.5–5.3 (m, 7H), 5.2–5.0 (ddt, J = 11.1,
9.0, 1.5 Hz, 1H), 3.8–3.6 (s and m, 5H), 3.1–2.9 (m, 2H), 3.0–2.9 (dd, J = 4.5, 2.4 Hz, 1H), 2.9–2.7 (m, 4H), 2.4–2.3 (m, 6H), 2.2–2.0 (m, 2H), 2.0–
1.9 (d, J = 6.6 Hz, 1H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz):  173.61, 135.33, 134.93, 129.21, 128.98, 128.30, 127.95, 127.89,
127.19, 126.38, 122.99, 70.28, 62.23, 52.02, 51.59, 33.98, 32.59, 26.09, 25.66, 25.59, 22.79, 20.66, 14.15; [α]D20= +5.6 (c 0.29, benzene). 16(R),17(S)-
diHDHA (1): 1H NMR (CD3OD, 300 MHz):  6.7–6.5 (dd, J = 14.4, 11.1 Hz, 1H), 6.4–6.2 (m, 2H), 6.1–6.0 (br t, J = 11.1 Hz, 1H), 5.9–5.7 (dd, J =
15.0, 7.2 Hz, 1H), 5.5–5.3 (m, 7H), 4.1–3.9 (m, 1H), 3.6–3.5 (dt, J = 8.1, 4.8 Hz, 1H), 3.0–2.9 (m, 2H), 2.9–2.8 (m, 2H), 2.5–2.2 (m, 5H), 2.2–2.0 (m,
3H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CD3OD, 75.5 MHz):  176.57, 134.38, 133.85, 133.81, 133.67, 131.20, 129.89, 129.82, 129.59 (2C),
129.09, 128.64, 126.31, 76.29, 75.98, 35.36, 31.84, 27.08, 26.51, 24.49, 21.68, 14.58. UV (EtOH) λmax 264, 274, 285 nm; HPLC-UV: Zorbax SB-C18,
–
1.8 µm, 50 x 2.1 mm, 274 nm, H2O/CH3OH (0.1% formic acid) 50:50–30:70, 0.2 mL/min, tR = 18.4 min; HPLC/MS (m/z): 359.3 [M-H]
.
16(S),17(S)-diHDHA (16): 1H NMR (CD3OD, 300 MHz):  6.7–6.5 (dd, J = 14.4, 11.1 Hz, 1H), 6.4–6.2 (m, 2H), 6.1–6.0 (br t, J = 11.1 Hz, 1H), 5.8–
5.7 (dd, J = 15.0, 6.9 Hz, 1H), 5.5–5.3 (m, 7H), 4.1–3.9 (m, 1H), 3.5–3.4 (dt, J = 7.8, 5.0 Hz, 1H), 3.0–2.9 (m, 2H), 2.9–2.8 (m, 2H), 2.5–2.2 (m, 5H),
2.2–2.0 (m, 3H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CD3OD, 75.5 MHz):  176.25, 134.36, 134.30, 133.72, 133.48, 131.27, 129.86, 129.80,
129.60, 129.56, 129.22, 128.63, 126.26, 76.14, 75.88, 35.82, 31.71, 27.09, 26.52, 24.25, 21.64, 14.57. UV (EtOH) λmax 264, 274, 285 nm; HPLC-UV:
Zorbax SB-C18, 1.8 µm, 50 x 2.1 mm, 274 nm, H2O/CH3OH (0.1% formic acid) 50:50–30:70, 0.2 mL/min, tR = 19.9 min; HPLC/MS (m/z): 359.2 [M-
H] –. Compound 18: 1H NMR (CDCl3, 300 MHz):  7.8–7.7 (d, J = 8.5 Hz, 2H), 7.4–7.3 (d, J = 8.5 Hz, 2H), 5.5–5.3 (ddt, J = 10.5, 7.3, 1.5 Hz, 1H),
5.4–5.2 (m, 3H), 4.0 (t, J = 6.9 Hz, 2H), 3.7–3.6 (s, 3H), 2.8–2.7 (m, 2H), 2.5–2.3 (m, 6H), 2.4 (s, 3H); 13C NMR (CDCl3, 75.5 MHz):  173.46,
1
144.69, 133.11, 131.49, 129.79 (2C), 128.66, 128.21, 127.88 (2C), 123.37, 69.56, 51.55, 33.87, 27.06, 25.58, 22.73, 21.61. Compound 4: H NMR
(CDCl3, 300 MHz):  7.9–7.6 (m, 17H), 7.1–7.0 (d, J = 7.8 Hz, 2H), 5.6–5.4 (m, 1H), 5.4–5.1 (m, 3H), 3.8–3.6 (m, 2H), 3.6 (s, 3H), 2.5 (br t, J = 6.7
Hz, 2H), 2.5–2.3 (m, 2H), 2.3 (s, 3H), 2.3–2.1 (m, 4H); 13C NMR (CDCl3, 75.5 MHz):  173.44, 144.60, 138.26, 134.88 (d, J = 2.9 Hz, 3C), 133.64
(d, J = 9.8 Hz, 6C), 130.40 (d, J = 12.1 Hz, 6C), 129.82, 128.52, 128.18 (2C), 128.13, 126.81 (d, J = 14.9 Hz, 1C), 126.17 (2C), 118.35 (d, J = 85.8
Hz, 3C), 51.52, 33.71, 25.40, 22.66, 21.95 (d, J = 48.9 Hz, 1C), 21.23, 20.33 (d, J = 3.5 Hz, 1C). Compound 20: 1H NMR (CDCl3, 300 MHz):  9.7–
9.6 (d, J = 3.0 Hz, 1H), 5.6–5.4 (dtt, J = 10.8, 7.5, 1.5 Hz, 1H), 5.4–5.2 (dtt, J = 10.8, 7.2, 1.5 Hz, 1H), 4.4–4.3 (m, 1H), 4.3–4.2 (dd, J = 7.2, 3.0 Hz,
1H), 2.4–2.2 (m, 2H), 2.1–1.9 (m, 2H), 1.6 (s, 3H), 1.4 (s, 3H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz):  201.64, 135.02, 122.89,
1
110.55, 81.91, 78.41, 27.76, 27.43, 25.19, 20.78, 13.90. Compound 5: H NMR (CDCl3, 300 MHz):  9.6–9.5 (d, J = 8.1 Hz, 1H), 7.2–7.0 (dd, J =
15.3, 11.1 Hz, 1H), 6.6–6.4 (dd, J = 15.3, 11.1 Hz, 1H), 6.3–6.1 (m, 2H), 5.6–5.4 (dtt, J = 10.8, 7.2, 1.5 Hz, 1H), 5.4–5.2 (dtt, J = 10.8, 7.2, 1.5 Hz,
1H), 4.7–4.6 (m, 1H), 4.3–4.2 (dt, J = 7.5, 6.3 Hz, 1H), 2.4–2.1 (m, 2H), 2.1–1.9 (m, 2H), 1.5 (s, 3H), 1.4 (s, 3H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C
NMR (CDCl3, 75.5 MHz):  193.63, 150.54, 140.13, 134.43, 132.27, 130.16, 123.44, 108.85, 78.33, 78.04, 28.69, 28.01, 25.43, 20.84, 14.05.
Compound 21: 1H NMR (CDCl3, 300 MHz):  6.6–6.4 (dd, J = 14.4, 10.8 Hz, 1H), 6.4–6.3 (dd, J = 15.0, 10.8 Hz, 1H), 6.3–6.1 (dd, J = 14.4, 10.8 Hz,
1H), 6.1–6.0 (br t, J = 10.8 Hz, 1H), 5.9–5.8 (dd, J = 15.0, 7.8 Hz, 1H), 5.5–5.2 (m, 7H), 4.6–4.5 (m, 1H), 4.2–4.1 (dt, J = 8.1, 6.0 Hz, 1H), 3.7–3.6 (s,
3H), 3.0–2.9 (m, 2H), 2.9–2.7 (m, 2H), 2.4–2.3 (m, 4H), 2.3–2.1 (m, 2H), 2.1–1.9 (m, 2H), 1.5 (s, 3H), 1.4 (s, 3H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C
NMR (CDCl3, 75.5 MHz):  173.54, 134.01, 133.71, 131.94, 130.89, 129.18, 128.88, 128.68, 128.60, 128.50, 127.98, 127.64, 124.11, 108.21, 79.11,
78.52, 51.56, 33.98, 28.75, 28.19, 26.21, 25.59, 25.57, 22.80, 20.79, 14.12. 16(R),17(S)-diHDHA methyl ester (22): 1H NMR (CDCl3, 300 MHz): 
6.6–6.5 (dd, J = 14.7, 11.1 Hz, 1H), 6.5–6.3 (dd, J = 14.7, 10.8 Hz, 1H), 6.3–6.1 (dd, J = 14.7, 10.8 Hz, 1H), 6.1–6.0 (br t, J = 11.1 Hz, 1H), 5.8–5.7
(dd, J = 14.7, 7.2 Hz, 1H), 5.6–5.5 (dtt, J = 10.5, 7.2, 1.5 Hz, 1H), 5.5–5.3 (m, 6H), 4.3–4.1 (m, 1H), 3.8–3.6 (m, 1H), 3.6 (s, 3H), 3.0–2.9 (m, 2H),
2.9–2.7 (m, 2H), 2.4–2.3 (m, 4H), 2.3–2.1 (m, 2H), 2.1–1.9 (m, 2H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz):  173.63, 135.27,
133.26, 131.95, 130.88, 130.68, 129.18, 128.68, 128.53, 128.49, 127.94, 127.60, 124.06, 74.93, 73.95, 51.60, 33.98, 29.99, 26.24, 25.60, 22.81, 20.72,
14.21.
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Highlights
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First total synthesis of 16(R),17(S)-diHDHA and its 16-epimer have been achieved
Two synthetic approaches described: enzymatic-chemical and a chiral pool strategy
Key steps: lipoxidase, allylic epoxidation and base-promoted epoxide isomerization
Chiral centers were stablished from 2-deoxy-D-ribose in the second approach

8
Tetrahedron Letters
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First total synthesis of the anti-inflammatory and
pro-resolving lipid mediator 16(R),17(S)-
diHDHA
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Ana R. Rodriguez, Bernd W. Spur