Synthesis of maresin 1 and (7S)-isomer

Article abstract of DOI:10.1016/j.tetlet.2014.03.065

Maresin 1 (with the 7R carbon) and (7S)-maresin 1 were synthesized stereoselectively. The conjugated triene system was constructed by Pd-catalyzed coupling of the trans cis-dienylborane (the C10-C22 part) with the trans vinyl iodide corresponding to the C

Full text of DOI:10.1016/j.tetlet.2014.03.065

Tetrahedron Letters 55 (2014) 2738–2741
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of maresin 1 and (7S)-isomer
⇑
Narihito Ogawa, Toshifumi Tojo, Yuichi Kobayashi
Department of Bioengineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Maresin 1 (with the 7R carbon) and (7S)-maresin 1 were synthesized stereoselectively. The conjugated
triene system was constructed by Pd-catalyzed coupling of the trans cis-dienylborane (the C10–C22 part)
with the trans vinyl iodide corresponding to the C1–C9 part. The stereogenic centers at C7 and C14 were
created by Ru-catalyzed asymmetric reduction of ketone and asymmetric epoxidation/kinetic resolution
of the racemic alcohol, respectively.
Received 30 December 2013
Revised 9 March 2014
Accepted 13 March 2014
Available online 20 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Maresin 1
Stereoselective synthesis
Suzuki–Miyaura coupling
Lipid mediator
Docosahexaenoic acid
Maresin 1 is a metabolite of DHA by macrophage1 and is a
potent mediator that inhibits PMN infiltration, stimulates macro-
phage phagocytosis of apoptotic cells, and controls pain. These
properties are similar to resolvins E1 and E2.2,3 The structure
including the olefin geometry and the absolute configuration of
the chiral carbons has been determined as depicted in Figure 1
(1a).2 Previously, two syntheses of maresin 1 have been reported.
Asymmetric addition of alkyne to aldehyde and Julia–Kocienski
olefination were the key reactions in constructing the C14 chiral
carbon and the conjugated triene unit; however, these reactions
suffer from low stereoselectivity.4a Sonogashira coupling gave the
dehydro-derivative of the conjugated triene, and the acetylene part
was reduced to cis olefin by using Zn(Cu/Ag) followed by HPLC sep-
aration.4b Although the full structure, including the chiral carbons,
is unambiguously determined, the 7S isomer shows comparable
activity in blocking neutrophil infiltration in the acute peritonitis
model, suggesting that further study is necessary to establish the
biochemical properties of maresin 1.4a However, availability is lim-
ited to the abovementioned syntheses and commercial supply is
extremely expensive.5 Therefore, we investigated the synthesis of
maresin 1 (1a) and its (7S)-isomer (1b) and described the results
herein.
Figure 1. Structures of Maresin 1 and (7S)-maresin 1.
with an acetylene (an ethyne equivalent) and subsequent
hydroboration. For the synthesis of 4, two methods consisting of
the Stork–Wittig reaction of 5 and Peterson elimination of the
dibromide derived from aldehyde 6 were planned. The use of
(S)-3 should furnish the (7S)-isomer 1b.
Results of the Stork–Wittig8 approach to iodide 4a (X = I,
R = TBDPS) are summarized in Scheme 2. Methyl ester 8 was
synthesized from malic acid according to the procedure reported
in the literature9 and converted to aldehyde 5 (R = TBDPS) by
reduction with DIBAL followed by TPAP-catalyzed oxidation of
the resulting alcohol in 80% yield. The key Stork–Wittig reaction
was initiated by adding the aldehyde to the ylide prepared from
[Ph3PCH2I]+Iꢀ and KHMDS in THF/HMPA at ꢀ100 °C and the reac-
tion temperature was gradually raised to 0 °C to afford 9, which
afforded iodide 4a upon deprotection of the TBS group followed
by oxidation. The cis selectivity of this iodide synthesized several
times was ca. 90% on average and 94% at maximum.10 The trans
isomer was not separated by routine chromatography at this stage
Based on a successful strategy for the synthesis of the resolv-
ins,6 we envisaged a Suzuki–Miyaura coupling7 of vinylborane 2
with iodide (R)-3 for the synthesis of 1a as delineated in Scheme 1.
Borane 2 was in turn conceived to be synthesized from the cis ole-
fin aldehyde 4 by Wittig reaction followed by Sonogashira coupling
⇑
Corresponding author. Tel./fax: +81 45 924 5789.
E-mail address: ykobayas@bio.titech.ac.jp (Y. Kobayashi).
http://dx.doi.org/10.1016/j.tetlet.2014.03.065
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

N. Ogawa et al. / Tetrahedron Letters 55 (2014) 2738–2741
2739
Scheme 1. Retrosynthetic analysis of maresin 1. Use of the enantiomer of (R)-3 should produce (7S)-maresin 1 (1b).
epoxidation to afford a mixture of 11 (98% ee)13 and the epoxide
12. These products were separated easily by routine chromatogra-
phy on silica gel. Bromination of alcohol 11 (equivalent to 6) at
ꢀ78 °C followed by Peterson elimination with TBAF afforded cis bro-
mide 13. The 1H NMR signals corresponding to the trans isomer
were not observed at the expected region. The alcohol part of 13
was protected as TBS ether in 63% yield from 11 (3 steps), and DIBAL
reduction of the ether 14 at ꢀ78 °C afforded aldehyde 4b cleanly.
Further transformation of 4b to the intermediate 18, which is the
precursor of the vinylborane 2, is summarized in Scheme 3. Alde-
hyde 4b was subjected to the Wittig reaction with the ylide derived
from 1514 and NaHMDS in THF to afford 16 in 71% yield. Sonogashira
coupling of 16 with TMS-acetylene (17) under standard conditions
followed by desilylation produced enyne 18, which was shown to
be highly clean by 1H and 13C NMR spectroscopy, proving exclusive
formation of the cis olefin at C16.
Synthesis of the C1–C9 intermediate (R)-3 was accomplished by
the method delineated in Scheme 4. Ketone 19 was prepared from
propane-1,3-diol in four steps and subjected to the Ru-catalyzed
asymmetric reduction in i-PrOH.15 The alcohol (R)-20 (98% ee)13 ob-
tained in 96% yield was transformed to (R)-21 in two steps as indi-
cated. Hydrozirconation of (R)-21 with Cp2Zr(H)Cl generated in situ
from Cp2ZrCl2 and DIBAL16 followed by iodination of the resulting
vinylzirconium species with I2 produced vinyliodide (R)-22, which
upon deprotection of the TBS group under slightly acidic conditions
afforded the intermediary alcohol (R)-7 in 58% from (R)-20. Oxida-
tion of (R)-7 was followed by Wittig reaction of the resulting alde-
hyde with the ylide derived from Brꢀ[Ph3P(CH2)3CO2H]+ and
afforded (R)-23 in 73% yield after methylation with CH2N2. Finally,
Scheme 2. Synthesis of iodide 4a through Stork–Wittig reaction.
or at later stages of the conversion, leading to the borane interme-
diate 2 (scheme not shown). Therefore, we investigated a second
route through 6.
As delineated in Scheme 3, synthesis of 4b (X = Br, R = TBS) began
with the addition of enolate derived from CH3CO2-n-Bu to aldehyde
1011 according to a previously reported method.12 The resulting
racemic alcohol was subjected to kinetic resolution/asymmetric
Scheme 3. Synthesis of bromide 4b through Peterson elimination, and further transformation to 18, the precursor of 2.

2740
N. Ogawa et al. / Tetrahedron Letters 55 (2014) 2738–2741
Scheme 4. Synthesis of the intermediates (R)- and (S)-3. (a) Ru cat. = Ru[(R,R)-TsDPEN](p-cymene) or the (S,S)-isomer.
deprotection of the TBDPS ether afforded alcohol (R)-3 in good yield.
The Z selectivity of this Wittig reaction was determined to be 95% by
1H NMR spectroscopy, and the selectivity in the repeated reaction
was ca. 90–95%. Fortunately, the purity was improved by prepara-
tive HPLC for the final stage of the synthesis.
As shown in Scheme 5, hydroboration of enyne 18 with freshly
prepared Sia2BH gave vinylborane
2 (R = TBS) in THF (0 °C,
30 min). The coupling reaction of iodide (R)-3 (1 equiv) with 2
(1.5 equiv) was set up in the presence of Pd(PPh3)4 (10 mol %) and
2 N NaOH (10 equiv) in THF and H2O (14:1) and conducted at rt for
1 h to prevent hydrolysis. The crude product 24 was passed through
a short column of silica gel to eliminate most of the reagent resi-
due.17 Desilylation of 24 with TBAF afforded diol 25, and the spectral
data (1H and 13C NMR in CDCl3 and in CD3CN; UV)18 were consistent
with those previously reported.4b Finally, hydrolysis furnished
maresin 1 (1a) in 68% yield. The spectral data (NMR and UV) and
[a]
were again consistent with those reported.4a,b Similarly, (7S)-
D
maresin 1 (1b) was synthesized through 26 in an overall yield com-
parable to that of 1a. Spectroscopic data and [a]D are attached in the
ref18 and copies of the spectra are attached to the Supplementary
material.
In summary, maresin 1 and (7S)-maresin 1 were synthesized in
a highly stereoselective manner in 13.5% and 16.6% yields, respec-
tively, over 12 steps from ketone 19. The method presented herein
complements those reported previously; these methods will be
useful for the synthesis of structural analogues for biochemical
studies, such as structure–activity relationships.
Acknowledgments
Plasticizer-free silica gel was kindly provided by Fuji Silysia,
Japan. This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture, Japan.
Supplementary data
Supplementary data (1H NMR, 13C-APT NMR, (and UV) of 18,
(R)-20, (R)-3, 25, 1a, 26, 1b) associated with this article can be
Scheme 5. Final stage of maresins 1 synthesis.

N. Ogawa et al. / Tetrahedron Letters 55 (2014) 2738–2741
2741
the above triene in THF (5 mL) was added TBAF (1.0 M in THF, 0.10 mL,
0.10 mmol). The mixture was stirred at room temperature for 7 h, and diluted
with McIlvaine’s phosphate buffer (pH 5.0). The resulting mixture was
extracted with CH2Cl2 three times. The combined extracts were washed with
brine, dried over MgSO4, and concentrated. The residue was purified by
chromatography on silica gel (Fiji Silysia, BW-200, Et2O) to give alcohol 25
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2014.03.065.
References and notes
(15.9 mg, 57% over 2 steps); ½a D20
ꢀ31 (c 0.23, CHCl3); UV (EtOH) kmax 262, 271,
ꢁ
1. (a) 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; (b) Dalli, J.; Zhu, M.; Vlasenko, N.
A.; Deng, B.; Haeggström, J. Z.; Petasis, N. A.; Serhan, C. N. FASEB J. 2013, 27,
2573–2583; (c) Marcon, R.; Bento, A. F.; Dutra, R. C.; Bicca, M. A.; Leite, D. F. P.;
Calixto, J. B. J. Immunol. 2013, 191, 4288–4298.
2. Serhan, C. N.; Dalli, J.; Karamnov, S.; Choi, A.; Park, C.-K.; Xu, Z.-Z.; Ji, R.-R.; Zhu,
M.; Petasis, N. A. FASEB J. 2012, 26, 1755–1765.
3. (a) Li, Y.; Dalli, J.; Chiang, N.; Baron, R. M.; Quintana, C.; Serhan, C. N. Immunity
2013, 39, 885–898; (b) Lee, C. H. Arch. Pharm. Res. 2012, 35, 3–7; (c) Stables, M.
J.; Gilroy, D. W. Prog. Lipid Res. 2011, 50, 35–51.
282 nm; 1H NMR (300 MHz, CDCl3) d 0.97 (t, J = 7.5 Hz, 3H), 1.6–1.9 (br s, 2H),
2.07 (quint, J = 7.5 Hz, 2H), 2.22–2.51 (m, 8H), 2.82 (t, J = 7 Hz, 2H), 3.67 (s, 3H),
4.24 (q, J = 6.5 Hz, 1H), 4.62 (dt, J = 8, 6.5 Hz, 1H), 5.24–5.62 (m, 7H), 5.79 (dd,
J = 14, 6.5 Hz, 1H), 6.10 (t, J = 11 Hz, 1H), 6.24 (dd, J = 14, 11 Hz, 1H), 6.33 (dd,
J = 14, 11 Hz, 1H), 6.51 (dd, J = 14, 12 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.3
(+), 20.7 (ꢀ), 22.8 (ꢀ), 25.8 (ꢀ), 33.7 (ꢀ), 35.4 (ꢀ), 35.5 (ꢀ), 51.8 (+), 67.7 (+),
71.7 (+), 124.5 (+), 126.2 (+), 126.8 (+), 127.7 (+), 130.20 (+), 130.24 (+), 131.2
(+), 131.8 (+), 132.3 (+), 133.4 (+), 134.0 (+), 136.7 (+), 173.8 (ꢀ); 1H NMR
(300 MHz, CD3CN) d 0.90 (t, J = 7.5 Hz, 3H), 2.02 (quint, J = 7.5 Hz, 2H), 2.08–
2.36 (m, 8H), 2.74 (t, J = 6.5 Hz, 2H), 2.86 (d, J = 4.5 Hz, 1H), 2.92 (d, J = 4.5 Hz,
1H), 3.56 (s, 3H), 4.06 (quint, J = 6 Hz, 1H), 4.43–4.55 (m, 1H), 5.20–5.46 (m,
7H), 5.70 (dd, J = 14, 6.5 Hz, 1H), 5.99 (t, J = 11 Hz, 1H), 6.13–6.28 (m, 2H), 6.40–
6.58 (m, 1H); 13C NMR (75 MHz, CD3CN) d 14.6 (+), 21.1 (ꢀ), 23.6 (ꢀ), 26.3 (ꢀ),
34.3 (ꢀ), 36.0 (ꢀ), 36.2 (ꢀ), 51.9 (+), 67.9 (+), 72.1 (+), 126.3 (+), 127.6 (+), 128.0
(+), 128.7 (+), 129.7 (+), 130.3 (+), 130.8 (+), 131.0 (+), 132.6 (+), 134.4 (+), 135.5
(+), 138.5 (+), 174.3 (ꢀ); HRMS (FAB) calcd for C23H34O4 374.2457 [M+], found
374.2465.
4. (a) Sasaki, K.; Urabe, D.; Arai, H.; Arita, M.; Inoue, M. Chem. Asian J. 2011, 6,
534–543; (b) Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2012, 53, 4169–
4172.
5. Available from Cayman Chemical and Cayman Europe.
6. (a) Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2009, 50, 6079–6082; (b) Kosaki,
Y.; Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2010, 51, 1856–1859; (c) Ogawa,
N.; Kobayashi, Y. Tetrahedron Lett. 2011, 52, 3001–3004.
7. (a) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem. Soc. 1985,
107, 972–980; (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
8. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173–2174.
Maresin 1 (1a): To a solution of 25 (7.6 mg, 0.0203 mmol) in MeOH (1 mL) was
added aqueous 1 N LiOH (1.0 mL, 1.0 mmol). The mixture was stirred at room
temperature for 2 h and diluted with McIlvaine’s phosphate buffer (pH 5.0).
The resulting mixture was extracted with Et2O approximately 5 times. The
combined extracts were washed with brine, dried over MgSO4, and
concentrated. The residue was purified by chromatography on silica gel (Fiji
9. Álvarez, C.; Pérez, M.; Zúñiga, A.; Gómez, G.; Fall, Y. Synthesis 2010, 22, 3883–
3890.
10. The Z/E ratios obtained with NaHMDS at temperatures (in 10:1 THF/HMPA):
75:25, ꢀ78 °C; 90:10, ꢀ100 °C.
Silysia, BW-200, Et2O) to give maresin 1 (1a) (5.0 mg, 68%); ½a D20
ꢀ25 (c 0.18,
ꢁ
11. Jung, M. E.; Gaede, B. Tetrahedron 1979, 35, 621–625.
MeOH); cf. lit.4a
½
a 2D2
ꢁ
ꢀ31 (c 0.19, MeOH); UV (EtOH) kmax 260, 271, 281 nm; 1
H
12. Kobayashi, Y.; Yoshida, S.; Nakayama, Y. Eur. J. Org. Chem. 2001, 1873–1881.
13. Determined by 1H NMR of the derived MTPA ester.
NMR (300 MHz, CD3OD) d 0.96 (t, J = 7.5 Hz, 3H), 2.07 (quint, J = 7.5 Hz, 2H),
2.16–2.45 (m, 8H), 2.79 (t, J = 6.0 Hz, 2H), 4.07–4.18 (m, 1H), 4.51–4.62 (m, 1H),
5.22–5.54 (m, 7H), 5.74 (dd, J = 14, 6.5 Hz, 1H), 6.07 (t, J = 11 Hz, 1H), 6.17–6.36
(m, 2H), 6.44–6.60 (m, 1H); 13C NMR (75 MHz, CD3OD) d 14.7, 21.5, 24.0, 26.6,
34.9, 36.2, 36.5, 68.5, 73.0, 126.1, 127.5, 128.2, 128.9, 130.6, 131.1, 131.3,
14. Prepared from leaf alcohol (EtCH@ CH(CH2)2OH) quantitatively by iodination
(I2, PPh3, imidazole) followed by reaction with Ph3P in MeCN (reflux). The
literature procedure [(1) TsCl, (2) NaI, (3) PPh3], in our hand, suffered from low
reproducibility in yield (a) Kojima, K.; Koyama, K.; Amemiya, S. Tetrahedron
1985, 41, 4449–4462; (b) Kim, S.; Lawson, J. A.; Praticò, D.; FitzGerald, G. A.;
Rokach, J. Tetrahedron Lett. 2002, 43, 2801–2805.
15. Hartmann, O.; Kalesse, M. Org. Lett. 2012, 14, 3064–3067.
16. Preparation of Cp2Zr(H)Cl from Cp2ZrCl2 and DIBAL: (a) Huang, Z.; Negishi, E.
Org. Lett. 2006, 8, 3675–3678; (b) Kiyotsuka, Y.; Igarashi, J.; Kobayashi, Y.
Tetrahedron Lett. 2002, 43, 2725–2729.
17. Coupling of the TBDPS ether of (S)-3, that is, (S)-23, with 2 (R = TBS) gave a
mixture of the coupling product and the reagent residue. Because these
products were less polar with similar Rf values on TLC, separation of the
products were partially successful.
18. Methyl ester 25: To an ice-cold solution of enyne 18 (33.2 mg, 0.109 mmol) in
THF (5 mL) was added freshly prepared Sia2BH (0.50 M in THF, 0.29 mL,
0.145 mmol). The solution was stirred at 0 °C for 30 min, and aqueous 2 N
131.4, 132.8, 134.8, 135.0, 138.0, 177.0; HRMS (FAB) calcd for
C22H31O4
359.2222 [(MꢀH)+], found 359.2222.
Methyl ester 26: ½a D22
ꢁ
ꢀ14 (c 0.19, CHCl3); UV (EtOH) kmax 262, 271, 282 nm; 1
H
NMR (300 MHz, CDCl3) d 0.97 (t, J = 7.5 Hz, 3H), 1.5–1.7 (br s, 1H), 1.9–2.1 (br s,
1H), 2.07 (quint, J = 7.5 Hz, 2H), 2.16–2.50 (m, 8H), 2.82 (t, J = 7 Hz, 2H), 3.67 (s,
3H), 4.24 (q, J = 6 Hz, 1H), 4.62 (q, J = 7, 1H), 5.24–5.62 (m, 7H), 5.79 (dd, J = 14,
6 Hz, 1H), 6.10 (t, J = 11.5 Hz, 1H), 6.26 (dd, J = 14, 11 Hz, 1H), 6.32 (dd, J = 14,
11 Hz, 1H), 6.51 (dd, J = 14, 11 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 14.3 (+),
20.7 (ꢀ), 22.8 (ꢀ), 25.8 (ꢀ), 33.7 (ꢀ), 35.4 (ꢀ), 35.5 (ꢀ), 51.8 (+), 67.7 (+), 71.7
(+), 124.5 (+), 126.2 (+), 126.8 (+), 127.7 (+), 130.20 (+), 130.24 (+), 131.2 (+),
131.8 (+), 132.3 (+), 133.4 (+), 134.0 (+), 136.7 (+), 173.8 (ꢀ); HRMS (FAB) calcd
for C23H34O4 374.2457 [M+], found 374.2459.
(7S)-Maresin 1 (1b): ½a D20
ꢁ
ꢀ21 (c 0.18, MeOH); cf. lit.4a a 2D2
½ ꢁ ꢀ23 (c 0.18, MeOH);
UV (EtOH) kmax 260, 271, 281 nm; 1H NMR (300 MHz, CD3OD) d 0.96 (t,
J = 7.5 Hz, 3H), 2.07 (quint, J = 7.5 Hz, 2H), 2.15–2.47 (m, 8H), 2.79 (t, J = 6.0 Hz,
2H), 4.12 (q, J = 6.5 Hz, 1H), 4.51–4.63 (m, 1H), 5.15–5.56 (m, 7H), 5.74 (dd,
J = 14, 6.5 Hz, 1H), 6.07 (t, J = 11 Hz, 1H), 6.16–6.37 (m, 2 H), 6.42–6.60 (m, 1H);
13C NMR (75 MHz, CD3OD) d 14.7 (+), 21.5 (ꢀ), 24.1 (ꢀ), 26.6 (ꢀ), 34.9 (ꢀ), 36.2
(ꢀ), 36.5 (ꢀ), 68.5 (+), 73.0 (+), 126.1 (+), 127.5 (+), 128.2 (+), 128.9 (+), 130.6
(+), 131.1 (+), 131.3 (+), 131.4 (+), 132.8 (+), 134.8 (+), 135.0 (+), 138.0 (+), 177.2
(–); HRMS (FAB) calcd for C22H31O4 359.2222 [(MꢀH)+], found 359.2222.
NaOH (0.36 mL, 0.727 mmol) and
a solution of iodide (R)-3 (22.5 mg,
0.0727 mmol) in THF (1 mL) were added. Argon was bubbled into the
reaction mixture for 15 min and then Pd(PPh3)4 (8.4 mg, 0.00727 mmol) was
added. The mixture was stirred at room temperature for 1 h, and diluted with
saturated NH4Cl. The resulting mixture was extracted with EtOAc twice. The
combined extracts were washed with brine, dried over MgSO4, and
concentrated to afford a residue, which was purified by chromatography on
silica gel (Fiji Silysia, BW-200, hexane/EtOAc) to give triene 24. To a solution of