Synthesis of Optically Active Maresin 2 and Maresin 2 n-3 DPA

Article abstract of DOI:10.1055/s-0040-1705959

Maresins are among the most potent antiinflammatory lipid metabolites. We report stereoselective syntheses of maresin 2 and maresin 2 _{n-3 DPA}. The anti -diol was constructed through epoxide ring opening of an optically active β,γ-epoxy aldehyde, synthesized in situ by Swern oxidation of the corresponding alcohol. Finally, the target compounds were synthesized through a Sonogashira coupling of a C9-C22 iodide and methyl (Z)-oct-4-en-7-ynoate or methyl oct-7-ynoate, respectively.

Full text of DOI:10.1055/s-0040-1705959

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–D
letter
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N. Ogawa et al.
Letter
Synlett
Synthesis of Optically Active Maresin 2 and Maresin 2n-3 DPA
Narihito Ogawa*a
Takahito Amanoa
Yuichi Kobayashib
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COOMe
COOH
OH
Sonogashira
coupling reaction
8
4
a Department of Applied Chemistry, Meiji University, 1-1-1
Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571,
Japan
Zn reduction
22
I
OH
9
OH
narihito@meiji.ac.jp
maresin 2; cis-double bond at C4–C5
maresin 2n-3 DPA; single bond at C4–C5
b Organization for the Strategic Coordination of Research
and Intellectual Properties, Meiji University, 1-1-1
Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571,
Japan
OH
asymmetric epoxidation
then Swern oxidation
Corresponding Author
Received: 02.09.2020
Accepted after revision: 02.10.2020
Published online: 02.11.2020
sized various lipid mediators by constructing chiral centers
by asymmetric reactions.6 Here, we report stereoselective
syntheses of maresin 2 and maresin 2n-3 DPA by using asym-
metric reactions.
DOI: 10.1055/s-0040-1705959; Art ID: st-2020-u0484-l
Abstract Maresins are among the most potent antiinflammatory lip-
id metabolites. We report stereoselective syntheses of maresin 2 and
maresin 2n-3 DPA. The anti-diol was constructed through epoxide ring
opening of an optically active ,-epoxy aldehyde, synthesized in situ by
Swern oxidation of the corresponding alcohol. Finally, the target com-
pounds were synthesized through a Sonogashira coupling of a C9–C22
iodide and methyl (Z)-oct-4-en-7-ynoate or methyl oct-7-ynoate, re-
spectively.
OH
OH
COOH
maresin 1 (1)
OH
COOH
OH
maresin 2 (2)
Key words maresins, asymmetric synthesis, trienes, Swern oxidation
OH
COOH
Resolvins and protectins, metabolized from polyunsatu-
rated fatty acids, are specialized pro-resolving mediators
(SPMs).1 SPMs have been reported to actively promote the
resolution of inflammation. In 2014, Serhan isolated mares-
in 2 from human macrophages as a metabolite derived from
docosahexaenoic acid (Figure 1).2 This compound shows a
strong antiinflammatory effect at 1 ng per mouse in a
mouse peritonitis model.2 Maresin 2n-3 DPA, possessing a sin-
gle bond at the C4–C5 position of maresin 2, also shows an
antiinflammatory effect.3 Several SPMs are undergoing ini-
tial clinical trials, and maresin 1 has recently been reported
to possess wound-healing activity.4 Consequently, maresin
2 and maresin 2n-3 DPA are also of interest as candidates for
drug-discovery research. However, maresins are available
only in minute amounts from natural sources. In addition,
commercially available maresin 2 is expensive, making it
difficult to obtain sufficient amounts. The groups of Spur
and Hansen have reported syntheses of these compounds
through the chiral-pool method with 2-deoxy-D-ribose as a
starting material.5 However, drug-discovery research re-
quires a flexible synthetic method that can efficiently sup-
ply the desired chiral centers. We have previously synthe-
OH
maresin 2n-3 DPA (3)
Figure 1 Structures of maresins
Scheme 1 outlines our retrosynthetic analysis of mares-
in 2 (2). We planned to construct the triene of 2 by connect-
ing two components, the terminal alkyne 4 and the iodo-
alkene 5, by a Sonogashira coupling reaction, followed by
acetylene reduction.6 The internal cis-olefin 4 would be ob-
tained from -butyrolactone by a Wittig reaction. The vici-
nal diol at C13–C14 would be constructed stereoselectively
by a Sharpless asymmetric epoxidation, followed by an ep-
oxide ring opening of the ,-epoxy aldehyde.
The first step in our synthesis of maresin 2 (2) involved
the preparation of enyne 4 (Scheme 2). Phosphonium salt 9
was synthesized from but-3-yn-1-ol (8) by a previously re-
ported procedure.7 The ring-opening reaction of -butyro-
lactone (10) with Et3N/MeOH generated the corresponding
alcohol, which was then oxidized with sulfur trioxide/pyri-
dine (SO3·py) to yield aldehyde 11. Wittig reaction of 11
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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N. Ogawa et al.
Letter
Synlett
the TBDPS group. As a result, the resulting primary hydroxy
group was protected once again with TBDPSCl to give allylic
alcohol 178 in 51% yield. This was then converted into the
epoxy alcohol 18 by a Sharpless asymmetric epoxida-
tion6c,12 in 75% yield with >99% ee, as determined by 1H
NMR analysis of the MTPA ester derivative. In this reaction,
the enantiomeric purity was improved by kinetic resolution
of 17 (98% ee). Protection of epoxy alcohol 18 followed by
deprotection using DDQ afforded alcohol 19 in 58% yield.
COOH
OH
Sonogashira
coupling reaction
OH
maresin 2 (2)
Wittig reaction
COOMe
TBDPSCl, NaH
4
HO
OH
HO
OTBDPS
85%
Wittig reaction
12
13
I
OH
OH OTBDPS
1) SO3•Py, Et3N, DMSO
PCC
75%
OH
OPMB
5
2) n-BuLi,
PMBO
14
rac-15
65%
asymmetric epoxidation
then Swern oxidation
RuCl[(S,S)-TsDPEN]·
(p-cymene)
O
OTBDPS
OH OTBDPS
I
OPMB
OPMB
OTES
i-PrOH
92%
CHO
IPh3P
(S)-15
16
OTES
6
7
Ti(Oi-Pr)4
L-(+)-DIPT
1) Red-Al
OPMB
OH OTBDPS
Scheme 1 Retrosynthetic analysis of maresin 2 (2)
2) TBDPSCl
imidazole
51%
t-BuOOH
75%
17
with phosphonium salt 9 in the presence of NaHMDS af-
forded the terminal alkyne 48 in 64% yield over the three
steps.
1) TBSOTf
2,6-lutidine
OPMB
OH OTBDPS
OH
TBSO
OTBDPS
2) DDQ
58%
O
O
Next, the iodoolefin 5 was prepared via the epoxy alco-
hol 19. Propane-1,3-diol (12) was converted into the silyl
ether 13 by a reported procedure (Scheme 3).9 Oxidation of
13 by SO3·py was followed by the addition of alkyne 1410 to
the resulting aldehyde to give alcohol rac-15 in 65% yield.
Oxidation of rac-15 followed by asymmetric transfer hydro-
genation11 produced the optically active alcohol (S)-15 in
69% yield with 98% ee, as determined by 1H NMR analysis of
its -methoxy--(trifluoromethyl)phenylacetic (MTPA) es-
ter derivative. Treatment of (S)-15 with Red-Al not only re-
duced the triple bond, but also promoted deprotection of
18
19
Scheme 3 Synthesis of epoxy alcohol 19
Enal 20,8 containing a vicinal diol, was prepared in 69%
yield by oxidation of epoxy alcohol 19 followed by cleavage
of the epoxide ring (Scheme 4). Protection of 20 with TB-
SOTf in the presence of 2,6-lutidine gave the disilyl ether 21
in 83% yield; this was subsequently converted into enyne 22
(76% yield) by treatment with TMSCHN2 and LDA.13 The (E)-
stereoselectivity of the olefin in 22 was >99%, as deter-
mined by 1H NMR spectroscopy. Hydrozirconation of 22
with Cp2Zr(H)Cl, generated in situ from Cp2ZrCl2 and
DIBAL,14 followed by iodination of the resulting vinylzirco-
nium species with I2 produced vinyl iodide 23.8 The TBS and
TBDPS groups in 23 were then replaced by TES groups in a
two-step reaction to produce 24. Swern oxidation15 of 24
occurred regioselectively at the terminal carbon to afford an
aldehyde that, upon Wittig reaction with phosphonium salt
75a followed by desilylation, afforded iodoolefin 58 in 59%
yield over three steps.
1) I2, imidazole, PPh3
OH
PPh3I
2) PPh3
68%
8
9
O
1) Et3N, MeOH
2) SO3•Py, Et3N, DMSO
OHC
COOMe
O
10
11
In the last stage, the synthesis of maresin 2 (2) was com-
pleted, as shown in Scheme 5. Polyene 25 was synthesized
in 61% yield by Sonogashira coupling of the alkyne 4 and io-
doolefin 5.6 Finally, reduction of 25 by Zn(Cu/Ag),6b,c,16 fol-
9, NaHMDS
64% from 10
COOMe
4
Scheme 2 Synthesis of terminal alkyne 4
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

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N. Ogawa et al.
Letter
Synlett
pared from oct-7-yn-1-ol (26) in three steps. Maresin 2n-3
DPA (3) was then synthesized in a two-step reaction by using
the same method as used for 2. The spectral data (NMR and
UV) and []D of 3 were consistent with those reported pre-
viously.5a
O
TBSO
OTBDPS
OH
TBSO
OTBDPS
(COCl)2, DMSO
H
then Et3N
69%
O
OH
20
19
TBSOTf
2,6-lutidine
TMSCHN2
LDA
O
H
TBSO
OTBDPS
1) SO3•Py, DMSO
Et3N
83%
OH
76%
COOMe
OTBS
21
2) NaClO2,
2-methylbut-2-ene
3) TMSCHN2
75%
27
26
Cp2ZrCl2
DIBAL-H
I
TBSO
OTBDPS
TBSO
OTBDPS
then I2
OTBS
22
OTBS
COOMe
I
OH
23
27
Pd(PPh3)4, CuI
81%
I
1) (COCl)2, DMSO
Et3N
OH
TESO
OTES
1) TBAF
5
2) TESCl
imidazole
69% from 22
2) NaHMDS
IPh3P
OTES
COOMe
24
7
1) Zn(Ag/Cu)
OH
3) TBAF
59%
2) 2 N LiOH
65%
I
OH
OH
28
OH
COOH
5
OH
Scheme 4 Synthesis of iodoolefin 5
OH
maresin 2n-3 DPA (3)
COOMe
I
OH
4
Scheme 6 Synthesis of maresin 2n-3 DPA (3)
Pd(PPh3)4, CuI
61%
OH
In conclusion, we have accomplished asymmetric syn-
theses of maresin 2 (2) and maresin 2n-3 DPA (3). Alkyne 4
was synthesized from -butyrolactone (10) and phosphoni-
um salt 7 in three steps. Meanwhile, vicinal diol 20 was
constructed by a Sharpless asymmetric epoxidation and a
Swern oxidation. Diol 20 was then converted into iodoolefin
5 by a multistep reaction. Finally, reaction of 4 with 5 gave
maresin 2 (2) in 22 steps from propane-1,3-diol (12) with a
total yield of 0.79%. We also synthesized 3 by using the
same approach as that described for 2 in 22 steps from 12,
with a total yield of 0.58%. The spectral data for 2 and 3
were consistent with those previously reported.5
5
COOMe
OH
1) Zn(Cu/Ag)
2) 2 N LiOH
63%
OH
25
COOH
OH
OH
maresin 2 (2)
Scheme 5 Synthesis of maresin 2 (2)
Funding Information
This work was supported by Research Project Grant (B) by Institute of
lowed by hydrolysis with aqueous LiOH afforded maresin 2
(2) in 63% yield.17 The spectral data (NMR and UV) of 2 were
in good agreement with those reported previously.5b
Next, maresin 2n-3 DPA (3) was synthesized according to
the method shown in Scheme 6. Alkyne 28 was obtained by
Sonogashira coupling of iodoolefin 5 with alkyne 27, pre-
Science and Technology Meiji University (N.O.).
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iversiyt()
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705959. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
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N. Ogawa et al.
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References and Notes
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.
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CD3OD):  = 0.86 (t, J = 7.4 Hz, 3 H), 1.97 (quin, J = 7.4 Hz, 2 H),
2.02–2.13 (m, 1 H), 2.20–2.33 (m, 5 H), 2.70 (t, J = 6.2 Hz, 2 H),
2.89 (t, J = 6.0 Hz, 2 H), 3.47 (dt, J = 8.4, 5.0 Hz, 1 H), 3.92 (dd, J =
7.0, 5.0 Hz, 1 H), 4.84 (s, 3 H, overlapped with the residue from
CD3OD), 5.15–5.43 (m, 7 H), 5.72 (dd, J = 14.8, 7.0 Hz, 1 H), 5.94
(t, J = 11.0 Hz, 1 H), 6.16 (dd, J = 14.8, 11.0 Hz, 1 H), 6.26 (dd, J =
14.8, 11.0 Hz, 1 H), 6.48 (dd, J = 14.8, 11.0 Hz, 1 H). 13C NMR
(100 MHz, CD3OD):  = 14.7, 21.5, 23.8, 26.6, 27.0, 31.8, 35.0,
75.8, 76.3, 127.1, 128.2, 129.1, 129.5, 129.7, 129.8, 131.0, 131.2,
132.7, 133.6, 133.7, 133.8, 177.1. HRMS (FD): m/z [M+] calcd for
C22H32O4: 360.23006; found: 360.23029. UV (MeOH): max
=
262, 274, 282 nm.
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D