Synthesis of Two Stereoisomers of Potentially Bioactive 13,19,20-Trihydroxy Derivative of Docosahexaenoic Acid

Article abstract of DOI:10.1055/s-0040-1706415

The C16-C22 fragment with the acetylene terminus was constructed through the asymmetric dihydroxylation of the corresponding olefin, while the 15-iodo-olefin corresponding to the C11-C15 part was prepared via the asymmetric transfer hydrogenation of the corresponding acetylene ketone followed by hydrozirconation/iodination. Both pieces were joined by a Sonogashira coupling, and the product was further converted into the title compound via a Wittig reaction with the remaining C1-C10 segment and Boland reduction using Zn with TMSCl.

Full text of DOI:10.1055/s-0040-1706415

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
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N. Ogawa et al.
Letter
Synlett
Synthesis of Two Stereoisomers of Potentially Bioactive 13,19,20-
Trihydroxy Derivative of Docosahexaenoic Acid
Narihito Ogawa*a
Shinsaku Sonea
Song Hongb,c
Yan Lub
Yuichi Kobayashid
Sonogashira coupling
then Zn reduction with TMSCl
Wittig olefination
asymmetric transfer
hydrogenation
AD reaction
OTBS
I
*
+
+
I– Ph3P+
CO2Me
TBDPSO
OH
OTBS
a Department of Applied Chemistry, Meiji University, 1-1-1,
Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan
narihito@meiji.ac.jp
b Neuroscience Center of Excellence, Louisiana State University,
Health Sciences Center, 2020 Gravier St., New Orleans, LA
70112, USA
OH
CO2H
*
OH
OH
c Department of Ophthalmology, Louisiana State University,
Health Sciences Center, New Orleans, LA 70112, USA
d Meiji University, Organization for the Strategic Coordination
of Research and Intellectual Properties, 1-1-1 Higashimita,
Tama-ku, Kawasaki, Kanagawa 214-8571, Japan
Received: 29.06.2020
Accepted after revision: 16.07.2020
Published online: 17.08.2020
oxide hydrolases7b,8 and that 13-hydroxy-19,20-epoxy de-
rivative of DHA is isolated,9 compound 3 is likely produced
by 13-lipoxygenation8e,10,11 of the former and/or by epoxide
hydrolysis of the latter. It was envisaged that, in a similar
way, epoxide hydrolysis of 11-hydroxy-17,18-epoxy-EPA12
and 11-lipoxygenation10,13 of 17,18-dihydroxy-EPA would
produce 4, which have high potential to be bioactive.14
DOI: 10.1055/s-0040-1706415; Art ID: st-2020-u0372-l
Abstract The C16–C22 fragment with the acetylene terminus was
constructed through the asymmetric dihydroxylation of the corre-
sponding olefin, while the 15-iodo-olefin corresponding to the C11–
C15 part was prepared via the asymmetric transfer hydrogenation of
the corresponding acetylene ketone followed by hydrozirconation/io-
dination. Both pieces were joined by a Sonogashira coupling, and the
product was further converted into the title compound via a Wittig re-
action with the remaining C1–C10 segment and Boland reduction us-
ing Zn with TMSCl.
OH
14
22
CO2H
CO2H
CO2H
OH
14,21-dihydroxy-DHA (1)
Key words DHA metabolite, trihydroxylated DHA, organic synthesis,
enyne, Boland reduction, TMSCl, Hansen protocol
14
HO
22
OH
14,22-dihydroxy-DHA (2)
Discovery of new metabolites of docosahexaenoic acid
(DHA) formed by lipoxygenases and/or cytochrome P450
enzyme pathways is an active area of study because most of
the metabolites isolated to date show properties of resolv-
ing and preventing inflammation.1 Recently, we isolated
compound 1, a dihydroxylated metabolite of DHA2 (Figure
1). Interestingly, 1 displayed wound-healing activity, a
unique property for a DHA metabolite.3 Subsequently, the
compound was synthesized, and the structure was deter-
mined.4 Similar properties were then found in new metabo-
lite 2 (‘maresin like’),5 and the structure of 2 was also deter-
mined after organic synthesis as well.6 We then envisaged
that hydroxylated compound 3 would possess similar activ-
ities because of the structural similarity in the positions of
the hydroxylated carbon atoms relative to those in 1 and 2.
Based on the fact that the -epoxide7 (19,20-epoxide) of
DHA is converted into 19,20-dihydroxy-DHA by soluble ep-
OH
19
13
22
OH
OH
13,19,20-trihydroxy-DHA (3)
OH
17
11
20
CO2H
OH
OH
11,17,18-trihydroxy-EPA (4)
Figure 1 Dihydroxy-DHA metabolites with wound-healing activity and
potentially bioactive metabolites of DHA and EPA
Among 3 and 4, we chose 3 as a synthetic target because
it has the same origin (DHA) as 1 and 2, and we hoped that
the method would be applicable to the synthesis of 4. We
established the 19,20-dihydroxy moiety as syn, based on
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
N. Ogawa et al.
Letter
Synlett
the same stereochemistry seen in leukotoxin diol and isole-
ukotoxin diol,15 in which the diol unit is nonconjugated, as
that seen in 3. Consequently, diastereoisomers 3aa and 3ab,
shown in Figure 2, represent different relative stereochem-
istry and would be useful stereoisomers for biological
study. We also hoped that, once the method was estab-
lished, enantiomers of 3aa and 3ab could also be synthe-
sized as well.
phy on silica gel to afford 12 in 35% yield with 86% ee, as
1
determined by H NMR spectroscopy of the derived MTPA
ester. Diol 1219 was protected as TBS ether 13, which pro-
duced 6a in 93% yield after TMS-desilylation with K2CO3.
TMS
MsCl, Et3N
CuI, NaI, Cs2CO3
OMs
OH
THF, 0 °C, 1 h
(each 1.5 equiv)
DMF, rt, 20 h
9
10
OH
OH
OH
TMS
TMS
AD-mix-α, MeSO2NH2
t-BuOH/H2O (1:1)
OH
OH
OH
OH
OH
3aa
3ab
11
12 (86% ee)
35% from 9
Figure 2 Targeted stereoisomers of 3
OTBS
R
TBSCl, imidazole
DMF, rt, 23 h
Retrosynthetic analysis of 3aa indicated acetylene 5aa
to be a key precursor, which could be disconnected to diol
derivative 6a, iodo-olefin 7a, and Wittig reagent 8 (Scheme
1). We expected the asymmetric dihydroxylation (AD)16
and the asymmetric transfer hydrogenation17 to produce
the stereogenic centers in 6a and 7a, respectively. In prac-
tice, the syntheses were successful with high enantioselec-
tivity, as summarized in Schemes 2 and 3. Wittig reagent 8
was prepared by a straightforward method, as delineated in
Scheme 4.
OTBS
K2CO3, MeOH
13, R = TMS
6a, R = H, 93% from 12
rt, 13 h
Scheme 2 Synthesis of diol intermediate 6a
Synthesis of 7a was carried out according to our previ-
ous method.20 In brief, 1,3-propanediol was converted into
alcohol 15 with 96% ee, as determined by HPLC analysis, via
the asymmetric transfer hydrogenation17 of ketone 1421
(Scheme 3). TBDPS protection of the hydroxy group in 15
3aa
Synthesis of 7a
Sonogashira coupling
reduction
RuCl[(R,R)-TsDPEN]·
(p-cymene) (5 mol%)
Wittig olefination
TMS
TMS
OH
OTBS
OTBS
CO2Me
i-PrOH, rt, 30 min
O
OH
15, 96% ee
OH
OH
98%
14
5aa
1) Cp2ZrCl2 (1.2 equiv)
DIBAL-H (1.1 equiv)
THF, 0 °C to rt, 1 h
1) TBDPSCl, imidazole
CH2Cl2, rt, 14 h
OTBS
OTBDPS
asymmetric transfer
hydrogenation
2) K2CO3 (1.5 equiv)
MeOH
AD reaction
OTBS
2) I2 (1.5 equiv), –78 °C, 2 h
16
I
OH
OTBDPS
H
+
17, R = TBS
7a, R = H
I
OR
OTBDPS
PPTS (20 mol%)
MeOH, rt, 13 h
OTBS
6a
7a
80% from 15
+
I– Ph3P+
CO2Me
Synthesis of ent-7a
RuCl[(S,S)-TsDPEN]·
8
1) TBDPSCl
imidazole
Scheme 1 Retrosynthesis of 3aa
TMS
(p-cymene) (5 mol%)
OTBS
14
i-PrOH, rt, 30 min
2) K2CO3, MeOH
OH
93%
Synthesis of 6a was started with mesylation of alcohol
9, which was followed by the CuI-assisted coupling18 with
TMS-acetylene to afford 11 and the SN2′ regioisomer (struc-
ent-15, 98% ee
1) Cp2ZrCl2, DIBAL-H
I
OH
OTBS
1
ture not shown) in a 72:28 ratio, as determined with H
OTBDPS
ent-7a, 74% from ent-15
OTBDPS
ent-16
2) I2
3) PPTS, MeOH
NMR spectroscopy (Scheme 2). Although the mixture was
difficult to separate by chromatography on silica gel, the di-
ols after the AD reaction were separated by chromatogra-
Scheme 3 Synthesis of 7a and ent-7a
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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N. Ogawa et al.
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forded 20, which gave olefin 21 in 81% yield upon reduction
with P-2 Ni24 under hydrogen. Desilylation, iodination, and
the reaction of the resulting iodide with PPh3 proceeded
cleanly to furnish Wittig reagent 8 in a good yield.
1) MsCl (1.5 equiv)
Et3N, Et2O, 0 °C, 1 h
OH
TBDPSO
2) HC C(CH2)2CO2Me (19)
CuI, Cs2CO3, NaI (each 1.5 equiv)
DMF, rt, 19 h
18
Construction of the target compound 3aa began with
the Sonogashira coupling of 7a with 6a (1.1 equiv) to afford
22 in 83% yield (Scheme 5). Oxidation with SO3·pyri-
dine(Py)/Et3N afforded the somewhat unstable aldehyde
23, which was then subjected to a Wittig reaction with the
ylide generated from 8 and NaHMDS in the presence of
HMPA (11 equiv, THF/HMPA = 5:1).25 Olefin 24 was pro-
duced stereoselectively and cleanly, and subsequently,
treated with TBAF to furnish the key intermediate 5aa in
63% yield from alcohol 22. Next, 5aa was subjected to the
Boland reduction of the triple bond under the modified
conditions reported by Hansen,26 who added TMSCl to
Zn(Cu/Ag) in aqueous MeOH. In practice, the reduction was
successful in cleanly affording 25 in 81% yield. By contrast,
an attempted reduction under the standard conditions27
(without TMSCl) caused elimination of the hydroxy group
at C13 and afforded a mixture of 25 and the elimination by-
products in a 73:27 weight ratio.28 A similar elimination re-
action has been reported previously.29 Finally, hydrolysis of
25 produced 3aa in 84% yield.
H2, MeOH, rt, 2 h
TBDPSO
TBDPSO
CO2Me
P-2 Ni (1 equiv), EDA (2 equiv)
20
C
C
1) TBAF, THF, rt, 14 h
2) I2, PPh3, rt, 1 h
8
CO2Me
3) PPh3, MeCN
reflux, 23 h
21
81% from 18
87%
Scheme 4 Synthesis of the Wittig reagent 8
and subsequent deprotection of the TMS group afforded 16,
which was subjected to hydrozirconation with in situ gen-
erated Cp2Zr(H)Cl,22 iodination, and TBS desilylation to give
trans-iodide 17 stereo- and regioselectively in 80% yield. In
a similar manner, ketone 14 was converted into ent-15 with
98% ee, and the subsequent transformations furnished ent-7a.
Wittig reagent 8 was synthesized from alcohol 1823 by
the method delineated in Scheme 4. Thus, mesylation of 18
followed by CuI-assisted coupling18 with acetylene 19 af-
Synthesis of 3aa
OTBS
OTBDPS
CHO
OTBDPS
OH
SO3·Py (3.0 equiv)
Et3N (5.0 equiv)
OTBS
6a (1.1 equiv)
OTBS
OTBS
I
OH
CH2Cl2/DMSO (1:1)
OTBDPS
7a
Pd(PPh3)2Cl2 (10 mol%)
CuI (20 mol%), Et3N
OTBS
OTBS
22
23
83%
OTBDPS
CO2Me
IPh3P
OTBS
TBAF (6 equiv)
8 (2 equiv)
CO2Me
THF
63% from 22
NaHMDS (2.0 equiv), THF/HMPA (5:1)
24
OTBS
OH
Zn(Cu/Ag) (200 equiv)
TMSCl (10 equiv)
OH
OH
OH
CO2R
CO2Me
MeOH/H2O (1:1), rt, 18 h
81%
OH
OH
5aa
2 N LiOH (aq)
MeOH/H2O (1:1)
25, R = Me
3aa, R = H, 84%
OTBS
Synthesis of 3ab
OTBDPS
OH
6a (1.1 equiv)
OTBS
3 steps
66%
OTBS
OH
I
OH
OTBDPS
OH
CO2Me
Pd(PPh3)2Cl2 (10 mol%)
CuI (20 mol%), Et3N
5ab
26
OTBS
OH
76%
ent-7a
OH
Zn(Cu/Ag) (200 equiv)
TMSCl (10 equiv)
CO2R
MeOH/H2O (1:1), rt, 19 h
77%
OH
OH
2 N LiOH (aq)
MeOH/H2O (1:1)
27, R = Me
3ab, R = H, 78%
Scheme 5 Synthesis of 3aa and 3ab
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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N. Ogawa et al.
Letter
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In a similar way, the coupling reaction of ent-7a with 6a
gave 26, which was converted into 5ab in 66% yield. Reduc-
tion of 5ab with Zn/TMSCl proceeded cleanly, and the re-
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1
sulting ester 27 was hydrolyzed to acid 3ab. The H NMR
spectra of 3aa and 3ab were completely superimposed,
whereas some of the olefinic carbons in the 13C NMR spec-
trum were observed at different positions (see the Support-
ing Information).
In summary, we developed a method to produce the ti-
tle triol and successfully performed the syntheses of 3aa
and 3ab through the Boland reduction of enyne 5aa and
5ab with Zn(Cu/Ag), which proceeded cleanly in the pres-
ence of TMSCl.30 The 13C NMR spectra of these products
were found to be useful for determining the relative stereo-
chemistry between the carbon atoms at C13 and syn
C19,C20. Synthesis of the enantiomers of 6a and 7a is un-
doubtedly possible by changing the chirality of the catalysts
and would furnish the enantiomers of 3aa and 3ab. The
asymmetric dihydroxylation reaction of the cis olefin corre-
sponding to 11 produces the anti diol, which is the key in-
termediate for the synthesis of another set of targets with
anti stereochemistry at C19 and C20.
Funding Information
This work was supported by the Japan Society for the Promotion of
Science (JSPS KAKENHI, Grant Number JP15H05904 (Y. K.)). This work
was also supported by the National Institute of Health of The United
States of America (Grant Numbers R01DK087800-07, R01DK087800-
07S1, 1R21AG060430, 1R21AG060430S1, 1R21AG066119, and
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706415.
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TBDPS-oxy group.
remaining solids were washed with H2O, MeOH, acetone, and
Et2O, sequentially. A solution of triol 5aa (129 mg, 0.330 mmol)
in H2O/MeOH (1:1, 20 mL) was added to the above solids. Sub-
sequently, TMSCl (0.410 mL, 3.28 mmol) was added. The
mixture was stirred at rt for 18 h and filtered through a pad of
Celite. The filtrate was concentrated, and the residue was puri-
fied first by chromatography on silica gel (hexane/EtOAc) and
second by recycling HPLC (LC-Forte/R equipped with YMC-Pack
SIL-60, ø 20 × 250 mm, hexane/EtOAc 30:70, 25 mL/min) to
afford methyl ester 25 (104 mg, 81%) as a colorless liquid:
21
Rf = 0.22 (hexane/EtOAc = 1:2); []D –2.3 (c 1.0, CHCl3). IR
(26) Mohamed, Y. M. A.; Hansen, T. V. Tetrahedron 2013, 69, 3872.
(27) Boland, W.; Schroer, N.; Sieler, C. Helv. Chim. Acta 1987, 70,
1025.
(neat): 3480, 1733, 1652, 759 cm–1. 1H NMR (400 MHz, CDCl3): 
= 0.99 (t, J = 7.4 Hz, 3 H), 1.44–1.66 (m, 2 H), 1.77 (br s, 1 H),
2.22–2.52 (m, 10 H), 2.77–2.90 (m, 4 H), 3.40 (dt, J = 8.4, 4.2 Hz,
1 H), 3.53 (q, J = 5.8 Hz, 1 H), 3.68 (s, 3 H), 4.25 (q, J = 6.0 Hz, 1
H), 5.31–5.60 (m, 7 H), 5.77 (dd, J = 15.2, 6.0 Hz, 1 H), 6.16 (t,
J = 11.2 Hz, 1 H), 6.55 (dd, J = 15.2, 11.2 Hz, 1 H). 13C NMR (100
MHz, CDCl3):  = 10.1, 22.9, 25.7, 25.9, 26.6, 32.3, 34.1, 35.4,
51.7, 71.9, 73.5, 75.1, 125.0, 125.3, 127.5, 127.9, 128.0, 128.3,
129.4, 130.8, 131.2, 136.5, 173.8. HRMS (FD): m/z calcd for
(28) Determined by 1H NMR spectroscopy and Rf values (0.60 and
0.33 for the byproduct and 25 (hexane/EtOAc = 1:2).
(29) Dayaker, G.; Durand, T.; Balas, L. Chem. Eur. J. 2014, 20, 2879;
see the Supporting Information on page S35.
(30) To an argon-bubbled suspension of Zn powder (4.30 g, 65.8
mmol) in H2O (20 mL) were added Cu(OAc)2 (436 mg, 2.40
mmol) and, after 20 min, AgNO3 (442 mg, 2.60 mmol). The sus-
pension was stirred for 45 min and filtered by suction, and the
C
23H36O5 [M]+: 392.25627; found: 392.25781.
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