Total synthesis and bioactivities of two proposed structures of maresin

Article abstract of DOI:10.1002/asia.201000494

Maresin is a potent anti-inflammatory lipid mediator derived from docosahexaenoic acid (DHA). A highly convergent total synthesis of two proposed structures of C7-epimeric maresins from the four known fragments was achieved in 17 steps. The three key coupling reactions were the BF₃-mediated alkyne attack on the epoxide, chiral titanium complex-promoted enantioselective alkyne addition to the aldehyde, and a Julia-Kocienski olefination. The two synthesized diastereomers were found to be comparably active in blocking neutrophil infiltration in the acute peritonitis model. Copyright

Full text of DOI:10.1002/asia.201000494

FULL PAPERS
DOI: 10.1002/asia.201000494
Total Synthesis and Bioactivities of Two Proposed Structures of Maresin
Kenji Sasaki, Daisuke Urabe, Hiroyuki Arai, Makoto Arita, and Masayuki Inoue*[a]
Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday
Abstract: Maresin is a potent anti-inflammatory lipid mediator derived from doco-
sahexaenoic acid (DHA). A highly convergent total synthesis of two proposed
structures of C7-epimeric maresins from the four known fragments was achieved
Keywords: biological activity · fatty
in 17 steps. The three key coupling reactions were the BF3-mediated alkyne attack
acids · inflammation · olefination ·
on the epoxide, chiral titanium complex-promoted enantioselective alkyne addi-
total synthesis
tion to the aldehyde, and a Julia–Kocienski olefination. The two synthesized dia-
stereomers were found to be comparably active in blocking neutrophil infiltration
in the acute peritonitis model.
Introduction
Endogenous lipid mediators play key roles in local control-
ling and programming of the acute innate inflammatory re-
sponse and its resolution as an active biosynthetic process.[1]
During resolution, specific fatty-acid-derived mediators, in-
cluding resolvin E1[2] and protectin D1 (Figure 1), are gener-
ated within resolving exudates.[3] Serhan and co-workers
demonstrated that these mediators are biosynthesized from
omega-3 fatty acids, eicosapentanoic acid (EPA) or docosa-
hexaenoic acid (DHA), and display potent multilevel anti-
inflammatory and proresolving action.[4] More recently, mar-
esin (1) was isolated from macrophages[5] as a novel lipid
mediator generated from DHA, and was shown to exhibit
activity equipotent to resolvin E1 and protectin D1. Accord-
ingly, these anti-inflammatory molecules are expected to
open new avenues in the development of treatment strat-
egies for inflammatory diseases.
Figure 1. Structures of bioactive omega-3-polyunsaturated fatty acids.
The 1,8-dihydroxy groups and conjugated trienes are highlighted in gray.
Maresin 1 is thought to be biosynthesized through a series
of enzymatic reactions (Scheme 1): enantioselective hydro-
peroxydation of DHA at C14, epoxidation from (14S)-hy-
droperoxide 2, and hydrolysis of 3. Based on the postulated
biosynthetic route and the MS/MS analyses of maresin and
analogous molecules, 1 was proposed to have the (7,14S)-di-
[a] Dr. K. Sasaki, Dr. D. Urabe, Prof. Dr. H. Arai, Prof. Dr. M. Arita,
hydroxy-(8E,10E,12Z)-conjugated triene substructure shown
in Figure 1. The absolute stereochemistry of the C14-OH of
the structure originates from 2, although that of the C7-OH
remains unestablished. Interestingly, the 1,8-dihydroxy
groups and the conjugated triene are also found in the struc-
tures of both resolvin E1 and protectin D1, thereby suggest-
ing the importance of these particular structural patterns for
Prof. Dr. M. Inoue
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5841-0568
E-mail: inoue@mol.f.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000494.
534
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Chem. Asian J. 2011, 6, 534 – 543

(S)-4 were to be readily derived from the (S)- and (R)-glyci-
dol derivatives 5,[9] respectively, through alkynylation with
6,[10] followed by cis-hydrogenation of the C4-triple bond.
On the other hand, the C9–22 fragment 7 was planned to be
prepared from enantioselective alkynylation of b,g-unsatu-
rated aldehyde 9[11] with enyne 8[12] and subsequent partial
reduction of the triple bond. This concise and flexible syn-
thetic route should provide access not only to (7R)-1 and
(7S)-1, but also to a variety of hydroxy and olefinic stereo-
isomers for future biological and SAR studies.
C1–8 fragments (R)-4 and (S)-4 were synthesized from
the para-methoxybenzyl (PMB)-protected (S)- and (R)-gly-
cidol 5, respectively (Scheme 3). Lithium acetylide, generat-
ed from 6, attacked the epoxide group of (S)-5 and (R)-5 by
the action of BF3·OEt2,[13] and led to the formation of homo-
propargyl alcohols (R)-10 and (S)-10, respectively. The sec-
ondary hydroxy group of 10 was then protected as its TBS
ether to afford 11. Carefully controlled partial hydrogena-
tion of the triple bond of 11 was realized by using either
Lindlar’s catalyst[14] or Pd/BaSO4 in EtOAc, and subsequent
oxidative removal of the PMB group of 12 with DDQ pro-
Scheme 1. Proposed biosynthesis of maresin (see Ref. [5]).
bioactivity. Herein, we report the total synthesis of the two
proposed structures of C7-epimeric maresins (7R)-1 and
(7S)-1,[6,7] and their anti-inflammatory activities have been
evaluated.
Results and Discussion
Four readily available fragments (5, 6, 8, and 9, Scheme 2)
were designed to be employed for the convergent total syn-
theses of the highly unsaturated molecules (7R)-1 and (7S)-
1. The chemically unstable (E,E,Z)-triene unit of 1 was to
be introduced at the last stage of the synthesis, and there-
ꢀ
fore 1 was retrosynthetically disconnected at the C8 9 bond.
In the synthetic direction, the Julia–Kocienski olefination[8]
of 7 with (R)-4 and (S)-4 would lead to (7R)-1 and (7S)-1,
respectively, in a stereoselective fashion. Both (R)-4 and
Scheme 3. Syntheses of the two C1–8 fragments. Reagents and condi-
tions: a) nBuLi, BF3·OEt2, THF, ꢀ788C!RT, 6 (2.2 equiv). b) TBSCl,
imidazole, DMF, RT. c) H2, Lindlar’s cat., EtOAc, RT. d) H2, Pd/BaSO4,
EtOAc, RT. e) DDQ, CH2Cl2, 08C. f) (COCl)2, DMSO, Et3N, CHCl2,
ꢀ788C!RT. THF=tetrahydrofuran; TBSCl=tert-butyldimethylsilyl
chloride; DMF=N,N-dimethylformamide; DDQ=2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone; DMSO=dimethylsulfoxide.
Scheme 2. Synthetic plan of the two proposed structures of maresin.
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M. Inoue et al.
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vided 13. Stereochemistries of the cis-olefins of the obtained
(R)-13 and (S)-13 were confirmed from their coupling con-
stants (J4ꢀ5 =11.0 Hz). Then, Swern oxidation of the primary
alcohols (R)-13 and (S)-13 smoothly provided aldehydes
(R)-4 and (S)-4, respectively.[15]
Synthesis of the C9–22 fragment 7 is illustrated in
Scheme 4. The known aldehyde 9 was routinely prepared
from diyne 14[16] in two steps. The two triple bonds of 14
Figure 2. Determination of the absolute stereochemistry at C14. The
numbers in bold are the difference (Dd) in the 1H chemical shifts be-
tween 17a and 17b (Dd=d (17a)-d (17b)) in CD3OD. MTPA=2-me-
thoxy-2-phenyl-2-(trifluoromethyl)acetyl.
were reduced to the two cis-double bonds in 15 (J16ꢀ17
=
10.5 Hz and J19ꢀ20 =11.0 Hz), and the primary alcohol of 15
was oxidized to aldehyde 9[10] by using o-iodoxybenzoic acid
(IBX).[17] The enantioselective coupling reaction between 8
and 9 was challenging, this was mainly due to the chemical
instability of b,g-unsaturated aldehyde 9 towards both basic
and acidic conditions. Lewis acid-mediated asymmetric alky-
nylation[18] of 9 typically resulted in decomposition of 9.
After many unsuccessful attempts, we found that the Ti-
and 17b were calculated in order to determine the (S)-ste-
reochemistry of the C14-alcohol. This structural assignment
unambiguously demonstrated that the (R)-BINOL-based
catalyst installed the desired (14S)-stereocenter in the reac-
tion from 8 to 16.
A
Chemoselective hydrogenation of the triple bond of 16
(97% ee) into the double bond without reducing the other
three olefins was achieved by treating 16 with copper/silver-
activated zinc in methanol and water,[23] thereby affording
tetraene 18 (Scheme 4). Silylation of the resultant secondary
alcohol 18 using TBSOTf and Et3N was followed by the
site-selective TBAF-promoted deprotection of bis-TBS
ether 19, which then led to 20. To prepare for the Julia–Ko-
cienski olefination,[8] sulfone 7 was synthesized from 20 in
two steps: the primary hydroxy group of 20 was displaced
by 2-mercaptobenzothiazole[24] under Mitsunobu condi-
tions[25] to generate sulfide 21, and the selective S-oxidation
of 21 in the presence of the four potentially reactive olefins
was accomplished by using ammonium molybdate[26] to de-
liver the C9–22 fragment 7.
enantioselective reaction.[19] Enyne 8 was treated with Et2Zn
to prepare the corresponding alkynyl zinc compound, which
was then added to aldehyde 9 in the presence of TiACTHUNRGTNEUNG(OiPr)4
and (R)-BINOL; this gave rise to propargyl alcohol 16 in an
enantioselective fashion (69% ee). Despite the modest
enantioselectivity, introduction of the C14-stereochemistry
through this coupling chemistry greatly simplified the over-
all synthetic strategy.
To increase the enantiomeric excess, the secondary alco-
hol 16 (69% ee) was subjected to an enzymatic kinetic reso-
lution by using lipase AK in vinylacetate, and this delivered
enantiomerically pure alcohol 16 (97% ee) in 52% yield,
along with the acetate in 30% yield.[20,21] The absolute ste-
reochemistry of C14 was determined by the modified
Mosher method, after 16 was derivatized to the correspond-
ing (S)-MTPA 17a and (R)-MTPA 17b esters (Figure 2).[22]
The most problematic reaction in our synthesis was the
Julia–Kocienski coupling of the two highly unsaturated frag-
ments, 4 and 7 (Scheme 5). The C9-conjugated anion, gener-
The differences in the H-chemical shifts (Dd) between 17a
Scheme 4. Synthesis of the C9–22 fragment. Reaction conditions: a) H2, Pd/BaSO4, pyridine, DMF, RT, 80% yield. b) IBX, THF/DMSO, RT. c) 8
(4 equiv), Et2Zn (4 equiv), Ti(OiPr)4 (1 equiv), (R)-BINOL (0.4 equiv), Et2O, RT; 63% yield over 2 steps. d) Lipase AK, vinylacetate, 558C, 52% yield.
AHCTUNGTRENNUNG
e) Zn, MeOH/H2O (1:1), RT, 94% yield. f) TBSOTf, Et3N, CH2Cl2, ꢀ788C!RT, 91% yield. g) TBAF, THF, ꢀ108C, 92% yield. h) 2-mercaptobenzothia-
zole, DIAD, PPh3, THF, RT, 93% yield. i) H2O2, EtOH, RT, 72% yield. TBSOTf=tert-butyldimethylsilyl trifluoromethanesulfonate; TBAF=tetra-n-bu-
tylammonium fluoride; DIAD=azodicarboxylic diisopropylate.
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Chem. Asian J. 2011, 6, 534 – 543

Total Synthesis of Maresin
Scheme 5. Total syntheses of the two proposed structures of maresin. Reaction conditions: a) P4-tBu, CH3CN, ꢀ408C. b) TMSOTf, lutidine, CH2Cl2,
ꢀ208C, H2O, RT. c) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH/H2O (1:1), RT. d) TBAF, THF, RT.
ated by deprotonation of 7 with typical bases (e.g., nBuLi,
KNACHTUNGTRENNUNG(TMS)2), underwent facile C12-olefin isomerization prior
to slow nucleophilic attack on aldehyde 4; this resulted in
the formation of adduct 22 in low yield as a mixture of ste-
reoisomers at C8 and C12. Changing the sulfone moiety of 7
to the 1-phenyl-1H-tetrazol-5-yl, 1-tert-butyl-1H-tetrazol-5-yl
or 3,5-bis(trifluoromethyl)phenyl sulfones did not improve
the yield or stereoselectivity. After extensive optimization,
the highly reactive “naked” anion, generated from 7 by
using phosphazene base P4-tBu in MeCN,[27] underwent
facile addition to (R)-4 or (S)-4, thereby resulting in 22 as a
mixture of C8-stereoisomers (8E/8Z=3:2) in approximately
60% yield. HPLC purification of the obtained coupling ad-
ducts from (R)-4 and (S)-4 yielded pure (7R,8E)-22 (22%
based on 7) and (7S,8E)-22 (23% based on 7), respectively.
Finally, the chemically sensitive hexaenes (7R,8E)-22 and
(7S,8E)-22 were converted to the proposed structures of
maresin through three steps. Kitaꢁs conditions effective-
ly[6b,28] removed the cyclic acetal moiety of 22 in the pres-
ence of the acid-labile allylic TBS ethers and the triene, thus
giving rise to the aldehyde; NaClO2-mediated oxidation of
which gave carboxylic acid 23. Desilylation of (7R)-23 and
(7S)-23 with TBAF delivered the targeted (7R)-1 and (7S)-
Figure 3. 1H-1H coupling constants of the conjugated triene unit of (7R)-1
and (7S)-1.
1
1, respectively. Intriguingly, the H and 13C NMR spectra of
(7R)-1 and (7S)-1 in CD3OD were identical, while their re-
tention times on an ODS HPLC were different (t
RACHTUNGTRNE(NUNG 7R-1)=
12.4 min, tRA
CHTUNGTRENNUNG
unstable (8E,10E,12Z)-conjugated triene units of both (7R)-
1
1 and (7S)-1 was confirmed by the H–1H coupling constants
shown in Figure 3.
Next, we evaluated the biological activity of synthetic
(7R)-1 and (7S)-1 by using an in vivo inflammation model
(Figure 4). Zymosan A, a glucan from the yeast cell wall,
was used to induce acute peritonitis in mice. Intravenous ad-
ministration of (7R)-1 and (7S)-1 as low as 1.0 and 10 ng sig-
nificantly blocked neutrophil infiltration after 2 h in the in-
flamed peritoneal cavity in a comparable manner.[5]
Figure 4. Synthetic (7R)-1 and (7S)-1 reduced neutrophil infiltration in
zymosan-induced peritonitis. Maresin or vehicle alone was injected into
the mouse followed by zymosan A injection. At 2 h, peritoneal lavages
were collected and cells were enumerated.
Chem. Asian J. 2011, 6, 534 – 543
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M. Inoue et al.
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The resulting mixture was extracted twice with EtOAc. Combined organ-
ic layers were washed with H2O and brine, dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by flash chromatog-
raphy on silica gel (hexane/EtOAc 10:0 to 20:1) to afford (R)-11
(447 mg, 1.03 mmol) in 94% yield: colorless oil; ½aꢁ2D0 =ꢀ0.6 (c=0.48,
Conclusions
The convergent total synthesis of two proposed structures of
maresin ((7R)-1 and (7S)-1) was achieved in 17 steps from
the four fragments 5, 6, 8, and 9. BF3-mediated alkyne
attack on the epoxide, chiral titanium complex-promoted
enantioselective alkyne addition to the aldehyde, and Julia–
Kocienski olefination were the three key coupling reactions.
Intriguingly, both synthetic (7R)-1 and (7S)-1 were found to
exhibit comparable anti-inflammatory properties in blocking
neutrophil infiltration. As the highly convergent and flexible
strategy developed here would enable the synthesis of a va-
riety of hydroxy and olefinic stereoisomers, further studies
will focus on the preparation of other isomers of maresin
and detailed biological analysis of these synthesized com-
pounds.
CHCl3); IR (neat): n˜ =2931, 2857, 1513, 1248, 1123, 1038 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): d=0.06 (3H, s, CH3 of TBS), 0.08 (3H, s, CH3 of
TBS), 0.88 (9H, s, tBu of TBS), 1.82 (2H, td, J=7.5, 4.6 Hz, CH2-CH2-
CH), 2.25–2.32 (3H, m, CHAHB-CC, CH2-CC), 2.37–2.44 (1H, m,
CHAHB-CC), 3.41 (1H, dd, J=10.3, 5.7 Hz, CHAHB-OPMB), 3.47 (1H,
dd, J=10.3, 4.6 Hz, CHAHB-OPMB), 3.80 (3H, s, OCH3), 3.83–3.96 (5H,
m, O-CH2CH2-O, CH-OTBS), 4.46 (2H, s, CH2-C6H5-OCH3), 4.95 (1H, t,
J=4.6 Hz, O-CH-O), 6.87 (2H, d, J=9.2 Hz, aromatic H), 7.25 ppm (2H,
d, J=9.2 Hz, aromatic H); 13C NMR (125 MHz, CDCl3): d=ꢀ4.7, ꢀ4.6,
13.7, 18.1, 25.0, 25.8, 33.2, 55.2, 64.9, 70.8, 73.0, 73.5, 80.5, 103.3, 113.7,
129.1, 130.5, 159.1 ppm; HRMS (FAB) calcd for C24H38O5SiCs 567.1543
[M+Cs]+, found 567.1553.
cis-olefin (R)-12: Lindlar catalyst (176 mg) was added to a mixture of
(R)-11 (352 mg, 0.81 mmol) and quinoline (20 mL) in EtOAc (32 mL).
The mixture was vigorously stirred at room temperature for 1 h under an
atmospher of H2 (1 atom, balloon). The reaction mixture was filtered
through a pad of Celite with EtOAc. The filtrate was concentrated in
vacuo to give the crude (R)-12 (352 mg, 0.805 mmol), which was used for
the next reaction without further purification. A portion of crude (R)-12
was purified by flash column chromatography to give the pure (R)-12:
½aꢁ1D7 =ꢀ0.1 (c=0.25, CHCl3); IR (neat): n˜ =2952, 2928, 2856, 1613, 1514,
Experimental Section
All reactions sensitive to air or moisture were carried out under an at-
mosphere of argon or in dry or freshly distilled solvents under anhydrous
conditions, unless otherwise noted. All other reagents were used as sup-
plied unless otherwise noted. Analytical thin-layer chromatography
(TLC) was performed using E. Merck Silica gel 60 F254 pre-coated
plates. Column chromatography was performed using 100–210 mm Silica
Gel 60N (Kanto Chemical Co., Inc.) and flash column chromatography
was performed using 50–60 mm Silica Gel 60 (Kanto Chemical Co., Inc.).
1H and 13C NMR spectra were recorded on a JEOL JNM-ECX-500,
JNM-ECA-500, or a JNM-ECS-400 spectrometer. Chemical shifts were
reported in ppm on the d scale relative to residual CHCl3 (d=7.26 for
1H NMR and d=77.0 for 13C NMR), C6HD5 (d=7.16 for 1H NMR), and
CD2HOD (d=3.30 for 1H NMR and d=49.0 for 13C NMR) as an inter-
nal reference. Signal patterns are indicated as s=singlet; d=doublet;
m=multiple. Infrared (IR) spectra were recorded on a Perkin–Elmer
Spectrum BX FT-IR spectrometer, or a JASCO FT/IR-4100 spectrome-
ter. High-resolution mass spectra were measured on a JEOL JMS-700 or
a Bruker microTOFII. Optical rotations were recorded on a JASCO
DIP-370 Polarimeter or a JASCO DIP-1000 Digital Polarimeter.
1249, 1132, 1037 cmꢀ1 1H NMR (500 MHz, CDCl3): d=0.04 (3H, s, CH3
;
of TBS), 0.05 (3H, s, CH3 of TBS), 0.87 (9H, s, tBu of TBS), 1.70 (2H,
td, J=7.4, 4.6 Hz, CH2-CH2-CH), 2.12–2.34 (4H, m, CH2-C=C-CH2), 3.35
(2H, d, J=5.8 Hz, CH2-OPMB), 3.81 (3H, s, OCH3), 3.82–3.98 (5H, m,
O-CH2CH2-O, CH-OTBS), 4.44 (2H, s, CH2-C6H5-OCH3), 4.85 (1H, t,
J=4.6 Hz, O-CH-O), 5.43 (1H, dd, J=10.9, 5.8 Hz, CHA =CHB), 5.47
(1H, dd, J=10.9, 6.3 Hz, CHA =CHB), 6.86 (2H, d, J=8.6 Hz, aromatic
H), 7.25 ppm (2H, d, J=9.2 Hz, aromatic H); 13C NMR (125 MHz,
CDCl3): d=ꢀ4.7, ꢀ4.5, 18.1, 22.0, 25.0, 25.8, 32.5, 33.7, 55.2, 64.8, 71.5,
72.9, 74.1, 104.1, 113.6, 126.2, 129.1, 130.5, 159.0 ppm; HRMS (FAB)
calcd for C24H40O5SiCs 569.1699 [M+Cs]+, found 569.1700.
Alcohol (R)-13: DDQ (187 mg, 0.82 mmol) was added to a mixture of
(R)-12 (240 mg, 0.55 mmol) in CH2Cl2 (5.5 mL) and phosphate buffer
(pH 7, 0.55 mL) at 08C. After being stirred for 1 h at 08C, MgSO4
(200 mg) was added to the reaction mixture, and the resulting mixture
was filtered through a pad of Celite with EtOAc. The filtrate was concen-
trated, and purified by flash chromatography on silica gel (hexane/
EtOAc 10:0 to 8:1) to afford (R)-13 (143 mg, 0.451 mmol) in 82% yield:
colorless oil; ½aꢁ2D3 =ꢀ22 (c=0.42, CHCl3); IR (neat): n˜ =3447, 2953,
Alcohol (R)-10: nBuLi (1.6m in hexane, 2.6 mL, 4.1 mmol) was added to
a solution of 6 (770 mg, 4.53 mmol, a 1.77:1 mixture of 6 and benzene) in
THF (4.5 mL) at ꢀ788C. After the solution was stirred for 5 min,
BF3·OEt2 (0.51 mL, 4.1 mmol) was added to the mixture. Then, a solution
of 5 (0.40 g, 2.1 mmol) in THF (2.4 mL) was added to the mixture at
ꢀ788C, and the reaction mixture was allowed to warm to room tempera-
ture over 2 h. The reaction was quenched with saturated aqueous NH4Cl,
and the resulting solution was extracted twice with Et2O. Combined or-
ganic layers were washed with H2O and brine, dried over anhydrous
Na2SO4, filtered, and concentrated. Flash chromatography on silica gel
(hexane/EtOAc 10:1 to 4:1) afforded (R)-10 (491 mg, 1.53 mmol) in 74%
yield: pale yellow viscous oil; ½aꢁ1D9 =ꢀ5.1 (c=0.6, CHCl3); IR (neat): n˜ =
2857, 1472, 1254, 1102, 1040 cmꢀ1 1H NMR (400 MHz, CDCl3): d=0.088
;
(3H, s, CH3 of TBS), 0.091 (3H, s, CH3 of TBS), 0.90 (9H, s, tBu of
TBS), 1.71 (2H, td, J=7.5, 5.2 Hz, CH2-CH2-CH), 1.89 (1H, brs, OH),
2.18 (2H, br dt, J=7.4, 7.4 Hz, C=C-CH2-CH2-), 2.28 (2H, dd, J=7.4,
7.4 Hz, TBSOCH-CH2), 3.43 (1H, dd, J=11.5, 5.2 Hz, CHAHB-OH), 3.53
(1H, dd, J=11.5, 4.0 Hz, CHAHB-OH), 3.73–3.79 (1H, m, CH-OTBS),
3.82–3.98 (4H, m, OCH2CH2O), 4.86 (1H, t, J=5.2 Hz, O-CH-O), 5.39
(1H, dt, J=11.0, 7.5 Hz, TBSOCHCH=CH), 5.48 ppm (1H, dt, J=11.0,
7.4 Hz, TBSOCHCH=CH); 13C NMR (100 MHz, CDCl3): d=ꢀ4.7, ꢀ4.5,
18.1, 22.0, 25.8, 31.8, 33.6, 64.9, 65.8, 72.6, 104.0, 125.4, 131.1 ppm; HRMS
(FAB) calcd for C16H32O4SiCs 449.1124 [M+Cs]+, found 449.1126.
1
3445, 2883, 1611, 1513, 1247, 1034 cmꢀ1; H NMR (500 MHz, CDCl3): d=
1.83 (2H, td, J=7.5, 4.6 Hz, CH2-CH2-CH), 2.28 (2H, tt, J=7.5, 2.9 Hz,
CH2-CH2-CH), 2.38 (2H, dt, J=5.7, 2.9 Hz, HOCHCH2-), 2.50 (1H, brs,
OH), 3.44 (1H, dd, J=9.8, 6.9 Hz, CHAHB-OPMB), 3.54 (1H, dd, J=9.8,
4.0 Hz, CHAHB-OPMB), 3.79 (3H, s, OCH3), 3.82–3.96 (5H, m, O-
CH2CH2-O, CH-OH), 4.48 (2H, s, CH2-C6H5-OCH3), 4.93 (1H, t, J=
4.6 Hz, O-CH-O), 6.87 (2H, d, J=9.2 Hz, aromatic H), 7.25 ppm (2H, d,
J=9.2 Hz, aromatic H); 13C NMR (125 MHz, CDCl3): d=13.6, 23.9, 33.0,
55.2, 64.9, 69.0, 72.6, 73.0, 81.7, 103.4, 113.7, 129.3, 130.0, 159.2 ppm;
HRMS (FAB) calcd for C18H24O5Cs 453.0678 [M+Cs]+, found 453.0683.
Aldehyde (R)-14: Dimethyl sulfoxide (40 mL, 570 mmol) in CH2Cl2
(0.6 mL) was added to a solution of (COCl)2 (24 mL, 280 mmol) in CH2Cl2
(0.6 mL) at ꢀ788C. After 15 min at ꢀ788C, a solution of (R)-13 (30 mg,
95 mmol) in CH2Cl2 (0.7 mL) was added to the solution. After the reac-
tion mixture was stirred for 10 min at ꢀ788C, Et3N (132 mL, 948 mmol)
was added, and the solution was allowed to warm to 108C over 40 min.
The reaction was then quenched with saturated aqueous NH4Cl. The re-
sulting mixture was extracted twice with EtOAc, the combined organic
layers were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated to give (R)-14 (35 mg) as a pale yellow oil, which was
used for the next reaction without further purification.
TBS ether (R)-11: tert-Butyldimethylsilyl chloride (494 mg, 3.28 mmol)
was added to a mixture of (R)-10 (350 mg, 1.09 mmol) and imidazole
(446 mg, 6.55 mmol) in DMF (5.5 mL) at 08C. The reaction mixture was
stirred for 12 h at room temperature and then poured into ice-cold water.
538
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 534 – 543

Total Synthesis of Maresin
Alcohol (S)-10: Following the same procedure for synthesis of (R)-10,
(S)-10 (1.06 g, 3.31 mmol) was synthesized in 64% yield by treating 6
(1.93 g, 11.3 mmol, as a 1.77:1 mixture of 6 and benzene) with (R)-5
(1.00 g, 5.15 mmol); ½aꢁ2D4 =+5.1 (c=1.1, CHCl3); IR (neat): n˜ =3466,
CDCl3): d=0.97 (3H, t, J=7.3 Hz, CH2-CH3), 2.07 (2H, dq, J=7.8,
7.3 Hz, CH2-CH3), 2.35 (2H, dt, J=7.8, 6.4 Hz, HOCH2-CH2-), 2.82 (2H,
t, J=6.9 Hz, CH=CH-CH2-CH=CH), 3.65 (2H, t, J=6.4 Hz, HOCH2),
5.30 (1H, dtt, J=11.0, 7.3, 1.4 Hz, CH=CH-CH2-CH=CH), 5.35–5.43
(2H, m, CH=CH-CH2-CH=CH), 5.54 ppm (1H, dtt, J=10.5, 7.8, 0.9 Hz,
CH=CH-CH2-CH=CH); 13C NMR (100 MHz, CDCl3): d=14.2, 20.5,
25.6, 30.7, 62.2, 125.3, 126.8, 131.5, 132.2 ppm; HRMS (FAB) calcd for
C9H17O 141.1279 [M+H]+, found 141.1279.
1
2887, 1612, 1514, 1249, 1132, 1036 cmꢀ1; H NMR (500 MHz, CDCl3): d=
1.83 (2H, td, J=7.5, 4.6 Hz, CH2-CH2-CH), 2.28 (2H, brt, J=7.5 Hz,
CH2-CH2-CH), 2.38 (2H, br d, J=5.7 Hz, HOCHCH2-), 2.61 (1H, d, J=
4.1 Hz, OH), 3.44 (1H, dd, J=9.7, 6.9 Hz, CHAHB-OPMB), 3.54 (1H, dd,
J=9.7, 4.0 Hz, CHAHB-OPMB), 3.79 (3H, s, OCH3), 3.82–3.96 (5H, m,
O-CH2CH2-O, CH-OH), 4.48 (2H, s, CH2-C6H5-OCH3), 4.93 (1H, t, J=
4.6 Hz, O-CH-O), 6.87 (2H, d, J=8.6 Hz, aromatic H), 7.25 ppm (2H, d,
J=8.6 Hz, aromatic H); 13C NMR (125 MHz, CDCl3): d=13.7, 23.9, 33.0,
55.2, 64.9, 69.0, 72.6, 73.0, 81.7, 103.4, 113.8, 129.4, 130.0, 159.2 ppm;
HRMS (FAB) calcd for C18H24O5Cs 453.0678 [M+Cs]+, found 453.0685.
Propargyl alcohol 16: IBX (3.2 g, 11.4 mmol) was added to a solution of
15 (920 mg, 5.7 mmol, a 3.4:1 mixture of 15 and Et2O) in THF (22.8 mL)
and DMSO (5.7 mL) at 08C. The suspension was stirred for 5 h at room
temperature. The mixture was filtered through a pad of Celite with Et2O,
and the filtrate was washed with saturated aqueous Na2S2O3·5H2O, satu-
rated aqueous NaHCO3, H2O and brine, and dried over anhydrous
Na2SO4. The residue was filtered, concentrated in vacuo (80 mmHg,
378C) to afford 9 (900 mg) as a pale yellow oil, which was used for the
next reaction without purification. A mixture of Et2Zn (1.1m toluene,
20.7 mL, 22.8 mmol) and 8 (4.48 g, 22.8 mmol) were refluxed for 3 h.
After the solution was cooled to room temperature, (R)-BINOL (653 mg,
TBS ether (S)-11: Following the same procedure for synthesis of (R)-11,
(S)-11 (900 mg, 2.07 mmol) was synthesized from (S)-10 (700 mg,
2.19 mmol) in 94% yield; ½aꢁD17 =+1.1 (c=0.58, CHCl3); IR (neat): n˜ =
1
2929, 2855, 1514, 1249, 1124, 1038 cmꢀ1; H NMR (500 MHz, CDCl3): d=
0.06 (3H, s, CH3 of TBS), 0.08 (3H, s, CH3 of TBS), 0.88 (9H, s, tBu of
TBS), 1.82 (2H, td, J=7.5, 4.6 Hz, CH2-CH2-CH), 2.24–2.31 (3H, m,
CHAHB-CC, CH2-CC), 2.37–2.43 (1H, m, CHAHB-CC), 3.41 (1H, dd, J=
10.3, 5.7 Hz, CHAHB-OPMB), 3.47 (1H, dd, J=10.3, 4.6 Hz, CHAHB-
OPMB), 3.80 (3H, s, OCH3), 3.83–3.97 (5H, m, O-CH2CH2-O, CH-
OTBS), 4.47 (2H, s, CH2-C6H5-OCH3), 4.95 (1H, t, J=4.6 Hz, O-CH-O),
6.87 (2H, d, J=8.6 Hz, aromatic H), 7.25 ppm (2H, d, J=8.6 Hz, aromat-
ic H); 13C NMR (125 MHz, CDCl3): d=ꢀ4.6, 13.7, 18.2, 25.0, 25.8, 33.2,
55.2, 64.9, 70.8, 73.0, 73.5, 80.5, 103.3, 113.7, 129.2, 130.5, 159.0 ppm;
HRMS (FAB) calcd for C24H38O5SiCs 567.1543 [M+Cs]+, found
567.1533.
2.28 mmol), Et2O (25 mL) and TiACHTUNTRGNE(UNG OiPr)4 (1.7 mL, 5.7 mmol) were added
sequentially. The reaction mixture was stirred for 1 h, and then a solution
of crude 9 in Et2O (51 mL) was added to the mixture. After being stirred
for 4 h at room temperature, the reaction mixture was quenched with sa-
turated aqueous NH4Cl. The resulting suspension was filtered through a
pad of Celite with Et2O. The filtrate was washed with brine and concen-
trated. The residue was purified by flash chromatography on silica gel
(hexane/EtOAc 100:0 to 20:1) to afford 16 (1.2 g, 3.6 mmol) in 63%
yield. The optical purity of 16 was determined as 69% ee from the inte-
gration of the 1H NMR spectrum after derivatization into the corre-
sponding MTPA ester.
Alcohol (S)-13: Pd/BaSO4 (5%, 50 mg) was added to a solution of (S)-11
(100 mg, 0.230 mmol) and pyridine (18 mL, 0.23 mmol) in EtOAc
(9.2 mL). The mixture was vigorously stirred for 1 h under an atmosphere
of H2 (1 atm, balloon) at room temperature. The residue was filtered
through a pad of Celite with EtOAc. The filtrate was concentrated in
vacuo to give crude (S)-12, which was then used for the next reaction
without further purification. DDQ (58 mg, 0.26 mmol) was added to a so-
lution of the crude (S)-12 in CH2Cl2 (1.7 mL) and phosphate buffer
(pH 7, 70 mL) at 08C. The reaction mixture was stirred for 1 h and al-
lowed to warm to room temperature. MgSO4 (200 mg) was added to the
reaction mixture, and the resulting mixture was filtered through a pad of
Celite with EtOAc. The filtrate was concentrated, and purified by flash
chromatography on silica gel (hexane/EtOAc 1:0 to 50:1 to 10: 1 to 5:1)
to afford (S)-13 (48 mg, 0.15 mmol) in 66% yield over 2 steps: colorless
oil; ½aꢁ2D8 =+22 (c=0.47, CHCl3); IR (neat): n˜ =3481, 2953, 2929, 2857,
Kinetic resolution of propargyl alcohol 16: A mixture of 16 (1.1 g,
3.3 mmol, 69% ee) and lipase AK (1.1 g) in vinylacetate (16.4 mL) was
stirred at 558C for 22 h. The suspension was filtered through a pad of
Celite with hexane, and the filtrate was concentrated in vacuo. The resi-
due was purified by flash chromatography on silica gel (hexane/AcOEt
100:0 to 30:1) to afford 16 (576 mg, 1.72 mmol) in 52% yield, and the
corresponding acetate in 30% yield (368 mg, 0.98 mmol). The optical
purity of 16 was determined as 97% ee from the integration of 1H NMR
after derivatization into the corresponding MTPA ester: ½aꢁ1D7 =ꢀ19 (c=
0.41, CHCl3); IR (neat): n˜ =3358, 2957, 1463, 1376, 1256, 1130 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=0.06 (6H, s, CH3 of TBS), 0.90 (9H, s,
tBu of TBS), 0.96 (3H, t, J=7.5 Hz, CH2-CH3), 1.99 (1H, brs, OH), 2.06
(2H, dq, J=7.5, 7.4 Hz, CH2-CH3) 2.52 (2H, br dd, J=6.9, 6.9 Hz, HOC-
CH2-), 2.83 (2H, dd, J=6.9, 6.9 Hz, C=CH-CH2-CH=C), 4.21–4.23 (2H,
m, CH2-OTBS), 4.52 (1H, t, J=6.3 Hz, CH-OH), 5.27–5.32 (1H, m, CH=
CH-Et), 5.36–5.42 (1H, m, CH=CH-Et), 5.47–5.52 (1H, m, CH2-CH=
CH-CH2-CH=C), 5.56–5.62 (1H, m, CH2-CH=CH-CH2-CH=C), 5.77
(1H, dd, J=16.0, 2.3 Hz, CH=CH-CC), 6.19 ppm (1H, dt, J=16.0,
4.0 Hz, CH=CH-CC); 13C NMR (125 MHz, CDCl3): d=ꢀ5.4, 14.2, 18.3,
20.5, 25.7, 25.8, 35.7, 62.4, 62.8, 83.3, 89.8, 108.0, 123.7, 126.7, 132.2, 132.3,
142.8 ppm; HRMS (FAB) calcd for C20H34O2SiCs 467.1382 [M+Cs]+,
found 467.1385.
1
1472, 1254, 1103, 1041 cmꢀ1; H NMR (400 MHz, CDCl3): d=0.08 (3H, s,
CH3 of TBS), 0.09 (3H, s, CH3 of TBS), 0.89 (9H, s, tBu of TBS), 1.71
(2H, dt, J=7.3, 5.0 Hz, CH2-CH2-CH), 2.18 (2H, dt, J=7.8, 7.3 Hz, C=C-
CH2-CH2-), 2.28 (2H, dd, J=6.9, 6.9 Hz, TBSOCH-CH2), 3.43 (1H, dd,
J=10.6, 5.0 Hz, CHAHB-OH), 3.52 (1H, dd, J=10.6, 3.2 Hz, CHAHB-
OH), 3.73–3.79 (1H, m, CH-OTBS), 3.82–3.98 (4H, m, OCH2CH2O),
4.85 (1H, t, J=5.0 Hz, O-CH-O), 5.39 (1H, dt, J=11.0, 7.3 Hz,
TBSOCHCH=CH), 5.48 ppm (1H, dt, J=11.0, 7.8 Hz, TBSOCHCH=
CH); 13C NMR (100 MHz, CDCl3): d=ꢀ4.7, ꢀ4.5, 18.1, 22.0, 25.8, 31.8,
33.6, 64.8, 65.8, 72.6, 104.0, 125.4, 131.1 ppm; HRMS (FAB) calcd for
C16H32O4SiCs 449.1124 [M+Cs]+, found 449.1118.
(S)-MTPA derivatives 17a: A mixture of propargyl alcohol 16 (1.6 mg,
4.8 mmol), (R)-MTPACl (2 mL, 10 mmol), and Et3N (3 mL, 20 mmol) in
CH2Cl2 (0.1 mL) was stirred for 1 h at room temperature. Then a catalyt-
ic amount of DMAP was added. After being stirred for 1 h, the reaction
mixture was directly subjected to flash chromatography on silica gel
(hexane/EtOAc 5:1) to afford (S)-MTPA derivatives 17a (2.6 mg,
4.7 mmol) in 98% yield: colorless oil; 1H NMR (400 MHz, CD3OD): d=
0.082 (6H, s, CH3 of TBS), 0.920 (9H, s, tBu of TBS), 0.945 (3H, t, J=
7.8 Hz, CH2-CH3), 2.030 (2H, dq, J=7.8 Hz, CH2-CH3), 2.541 (1H, dd,
J=14.2, 6.4 Hz, CHAHB-CHOMTPA), 2.604 (1H, dd, J=13.7, 6.8 Hz,
CHAHB-CHOMTPA), 2.650 (1H, ddd, J=15.1, 7.3, 7.3 Hz, C=CH-
CHAHB-CH=C), 2.727 (1H, ddd, J=15.6, 7.3, 7.3 Hz, C=CH-CHAHB-
CH=C), 3.566 (3H, s, OMe), 4.253 (2H, dd, J=4.1, 2.3 Hz, CH2-OTBS),
5.204 (1H, dtt, J=11, 7.3, 1.4 Hz, CH=CH-CH2CH3), 5.309 (1H, ddt, J=
11, 7.3, 1.4 Hz, MTPAOCHCH2-CH=CH), 5.354 (1H, ddt, J=11, 7.3,
1.4 Hz, CH=CH-CH2CH3), 5.456 (1H, dtt, J=11, 7.3, 1.4 Hz,
Aldehyde (S)-4 was synthesized from (S)-13 (15 mg, 47 mmol) by using
the same procedure for synthesis of (R)-4 and then used for the next re-
action without further purification.
Diene 15:
A mixture of 14 (3.5 g, 26 mmol), pyridine (10.4 mL,
128 mmol) and 5% Pd-BaSO4 (1.75 g) in DMF (257 mL) was vigorously
stirred for 1 h under an atmosphere of H2 (1 atm, balloon) at room tem-
perature. Then 5% Pd-BaSO4 (1.75 g) was added to the reaction mixture,
and the mixture was stirred for an additional 2 h. The suspension was fil-
tered through a pad of Celite with EtOAc, and the filtrate was washed
with H2O and brine, dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by flash chromatography on
silica gel (hexane/EtOAc 5:1 to 2:1) to afford 14 (3.3 g, 21 mmol, as a
3.4:1 mixture of 14 and Et2O) in 80% yield: 1H NMR (400 MHz,
Chem. Asian J. 2011, 6, 534 – 543
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
539

M. Inoue et al.
FULL PAPERS
MTPAOCHCH2-CH=CH), 5.682 (1H, td, J=6.4, 1.4 Hz, CH-OMTPA),
5.781 (1H, ddt, J=16, 1.8, 1.8 Hz, TBSOCH2-CH=CH), 6.257 (1H, ddd,
J=16, 4.1 Hz, TBSOCH2-CH=CH), 7.37–7.44 (3H, m, aromatic H), 7.50–
7.54 ppm (2H, m, aromatic H).
5.43 (5H, m, CH=CH-CHOTBS, CH=CH-CH2-CH=CH), 5.76 (1H, dt,
J=14.9, 4.6 Hz, CH=CH-CH2OTBS), 5.96 (1H, dd, J=11.5, 11.5 Hz,
CH=CH-CH=CH-CH2OTBS), 6.45–6.51 ppm (1H, m, CH=CH-
CH2OTBS); 13C NMR (125 MHz, CDCl3): d=ꢀ5.2, ꢀ4.8, ꢀ4.4, 14.3,
18.2, 18.4, 20.5, 25.8, 25.9, 36.4, 63.3, 68.8, 124.4, 125.5, 127.1, 127.2, 129.9,
131.9, 134.0, 134.4 ppm; HRMS (FAB) calcd for C26H51O2Si2 451.3428
[M+H]+, found 451.3409.
(R)-MTPA derivatives 17b: Following the same procedure for synthesis
of (S)-MTPA 17a, (R)-MTPA 17b was synthesized from propargyl alco-
hol 16 (1.8 mg, 5.4 mmol) with (S)-MTPACl (2 mL, 10 mmol) in 87%
yield: colorless oil; 1H NMR (400 MHz, CD3OD): d=0.085 (6H, s, CH3
of TBS), 0.924 (9H, s, tBu of TBS), 0.945 (3H, t, J=7.3 Hz, CH2-CH3),
2.048 (2H, dq, J=7.3 Hz, CH2-CH3), 2.603 (1H, dd, J=14.6, 6.9 Hz,
CHAHB-CHOMTPA), 2.678 (1H, dd, J=15.1, 7.3 Hz, CHAHB-CHOMT-
PA), 2.795 (1H, dd, J=7.3, 7.3 Hz, C=CH-CH2-CH=C), 3.531 (3H, s,
OMe), 4.250 (2H, dd, J=4.1, 2.3 Hz, CH2-OTBS), 5.267 (1H, dtt, J=11,
7.3, 1.8 Hz, CH=CH-CH2CH3), 5.33–5.48 (2H, m, MTPAOCHCH2-CH=
CH, CH=CH-CH2CH3), 5.549 (1H, dt, J=11, 7.3 Hz, MTPAOCHCH2-
CH=CH-), 5.648 (1H, td, J=7.3, 1.4 Hz, CH-OMTPA), 5.749 (1H, ddt,
J=16, 2.3, 2.3 Hz, TBSOCH2-CH=CH), 6.222 (1H, ddd, J=16, 4.6 Hz,
TBSOCH2-CH=CH), 7.36–7.43 (3H, m, aromatic H), 7.48–7.53 ppm (2H,
m, aromatic H).
Preparation of activated zinc:[23c] Nitrogen gas was bubbled through a
suspension of Zn (12.0 g, 18.3 mmol) in H2O (60 mL) for 30 min. Cu-
ACHTUNGTRENNUNG(OAc)2·2H2O (1.13 g, 6.24 mmol) was added to the suspension, and the
resulting mixture was stirred for 30 min. Then AgNO3 (1.24 g,
7.34 mmol) was added and the resulting mixture was stirred for 1 h. The
suspension was filtered through a pad of Celite and the cake was washed
with H2O (2ꢂ25 mL), MeOH (2ꢂ25 mL), acetone (2ꢂ25 mL), and Et2O
(2ꢂ25 mL), and suspended in a mixture of H2O/MeOH (1:1, 30 mL).
Alcohol 20: TBAF (1.0m in THF, 4.2 mL, 4.2 mmol) was added to a solu-
tion of 19 (474 mg, 1.05 mmol) in THF (10 mL) at ꢀ108C. After being
stirred for 50 min, the reaction mixture was quenched with saturated
aqueous NH4Cl. The resulting solution was extracted twice with EtOAc.
Combined organic layers were washed with H2O and brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was purified
by flash chromatography on silica gel (hexane/EtOAc 100:0 to 20:1) to
afford 20 (324 mg, 0.96 mmol) in 92% yield: colorless oil; ½aꢁ1D8 =+5.6
(c=0.41, CHCl3); IR (neat): n˜ =3308, 2957, 2929, 1254, 1081 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=0.02 (3H, s, CH3 of TBS), 0.04 (3H, s,
CH3 of TBS), 0.87 (9H, s, tBu of TBS), 0.96 (3H, t, J=7.5 Hz, CH2-
CH3), 2.06 (2H, br dq, J=6.9, 6.9, CH2-CH3), 2.21 (1H, ddd, J=13.7, 6.3,
6.3 Hz, TBSOCH-CHAHB-), 2.35 (1H, ddd, J=13.8, 6.9, 6.9 Hz,
TBSOCH-CHAHB-), 2.77 (2H, dd, J=6.9, 6.9 Hz, C=CH-CH2-CH=C),
4.21 (2H, br s, CH2OH), 4.57 (1H, dt, J=8.6, 6.9 Hz, CHOTBS), 5.27–
5.45 (5H, m, CH=CH-CHOTBS, CH=CH-CH2-CH=CH), 5.83 (1H, dt,
J=14.9, 5.8 Hz, CH=CH-CH2OH), 5.95 (1H, dd, J=11.5, 11.5 Hz, CH=
CH-CH=CH-CH2OH), 6.47 ppm (1H, ddd, J=14.9, 11.5, 1.1 Hz, CH=
CH-CH=CH-CH2OH); 13C NMR (125 MHz, CDCl3): d=ꢀ4.7, ꢀ4.3,
14.3, 18.2, 20.5, 25.7, 25.8, 36.3, 63.3, 68.8, 125.4, 126.2, 126.8, 127.1, 130.0,
131.9, 133.3, 135.4 ppm; HRMS (FAB) calcd for C20H36O2SiCs 469.1539
[M+Cs]+, found 469.1531.
Allylic alcohol 18: A solution of 16 (500 mg, 1.49 mmol) in MeOH
(5 mL) was added to a suspension of the activated Zn in a mixture of
H2O/MeOH (1:1, 10 mL). After being stirred at room temperature for
22 h, the reaction mixture was filtered through a pad of Celite and the
cake was washed with a mixture of hexane/EtOAc (1:1). The filtrate was
separated and the organic layer was washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated. The residue was purified by
flash chromatography on silica gel (hexane/EtOAc 100:0 to 20:1) to
afford 18 (470 mg, 1.39 mmol) in 94% yield: yellow oil; ½aꢁ2D5 =ꢀ42 (c=
0.68, CHCl3); IR (neat): n˜ =3360, 2957, 2930, 2857, 1463, 1255,
Sulfide 21: A mixture of 2-mercaptobenzthiazole (58 mg, 0.35 mmol),
Ph3P (121 mg, 0.46 mmol), and 20 (78 mg, 0.23 mmol) in THF (2.3 mL)
was stirred at room temperature for 5 min, and then DIAD (1.9m tolu-
ene, 240 mL, 0.46 mmol) was added. After being stirred for 1 h at room
temperature, the reaction mixture was poured into ice-cold water. The re-
sulting solution was extracted twice with EtOAc. Combined organic
layers were washed with H2O and brine, dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by flash chromatog-
raphy on silica gel (hexane/EtOAc 100:0 to 20:1) to afford 21 (104 mg,
0.21 mmol) in 93% yield: colorless oil; ½aꢁ2D2 =ꢀ2.4 (c=0.55, CHCl3); IR
1049 cmꢀ1 1H NMR (500 MHz, CDCl3): d=0.07 (6H, s, CH3 of TBS),
;
0.91 (9H, s, tBu of TBS), 0.96 (3H, t, J=7.5 Hz, CH2-CH3), 2.06 (2H, dq,
J=7.4, 7.4 Hz, CH2-CH3), 2.26 (1H, ddd, J=14.4, 6.9, 6.9 Hz, HOCH-
CHAHB-), 2.42 (1H, ddd, J=14.4, 6.9, 6.9 Hz, HOCH-CHAHB-), 2.80
(2H, dd, J=6.9, 6.9 Hz, C=CH-CH2-CH=C), 4.22 (2H, dd, J=4.6,
1.2 Hz, CH2-OTBS), 4.61 (1H, dt, J=8.1, 6.9 Hz, CH-OH), 5.25–5.31
(1H, m, CH=CH-CH2-CH=CH), 5.36–5.42 (3H, m, CH=CH-CHOH,
CH=CH-CH2-CH=CH), 5.50–5.55 (1H, m, CH=CH-CH2-CH=CH), 5.80
(1H, dt, J=14.9, 4.6 Hz, CH=CH-CH2OTBS), 6.07 (1H, dd, J=10.9,
10.9 Hz, CH=CH-CH=CH-CH2OTBS), 6.50–6.55 ppm (1H, m, CH=CH-
CH2OTBS); 13C NMR (125 MHz, CDCl3): d=ꢀ5.3, 14.2, 18.4, 20.5, 25.7,
25.9, 35.3, 63.3, 67.6, 124.3, 124.5, 126.8, 129.6, 131.5, 132.1, 132.4,
134.9 ppm; HRMS (FAB) calcd for C20H36O2SiCs 469.1539 [M+Cs]+,
found 469.1542.
(neat): n˜ =2956, 2928, 1461, 1428, 1254, 1077, 996 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): d=0.00 (3H, s, CH3 of TBS), 0.03 (3H, s, CH3 of
TBS), 0.88 (9H, s, tBu of TBS), 0.99 (3H, t, J=7.5 Hz, CH2-CH3), 2.08
(2H, dq, J=7.5, 7.5 Hz, CH2-CH3), 2.22 (1H, ddd, J=13.2, 6.3, 6.3 Hz,
TBSOCH-CHAHB-), 2.35 (1H, ddd, J=13.2, 6.9, 6.9 Hz, TBSOCH-
CHAHB-), 2.78 (2H, dd, J=6.9, 6.9 Hz, C=CH-CH2-CH=C), 4.07 (1H,
dd, J=14.3, 7.5 Hz, CHAHB-S-), 4.11 (1H, dd, J=14.3, 7.5 Hz, CHAHB-S-
), 4.56 (1H, dt, J=8.0, 6.9 Hz, CHOTBS), 5.27–5.45 (5H, m, CH=CH-
CHOTBS, CH=CH-CH2-CH=CH), 5.88 (1H, dt, J=14.9, 7.5 Hz, CH=
CH-CH2-S-), 5.95 (1H, dd, J=11.5, 11.5 Hz, CH=CH-CH=CH-CH2-S-),
6.61 (1H, ddd, J=14.9, 11.5, 1.1 Hz CH=CH-CH2-S-), 7.32 (1H, dd, J=
8.0, 8.0 Hz, aromatic H), 7.44 (1H, dd, J=8.0, 8.0 Hz, aromatic H), 7.77
(1H, d, J=8.0 Hz, aromatic H), 7.90 ppm (1H, d, J=8.0 Hz, aromatic
H); 13C NMR (125 MHz, CDCl3): d=ꢀ4.8, ꢀ4.4, 14.3, 18.1, 20.6, 25.7,
25.8, 35.7, 36.3, 68.8, 120.9, 121.6, 124.3, 125.2, 126.0, 126.5, 127.1, 128.2,
129.5, 130.1, 131.9, 135.3, 135.8, 153.1, 166.0 ppm; HRMS (FAB) calcd
for C27H40NOS2Si 486.2321 [M+H]+, found 486.2320.
Bis-TBS ether 19: TBSOTf (440 mL, 2.50 mmol) was added to a solution
of 18 (420 mg, 1.25 mmol) and Et3N (700 mL, 70 mmol) in CH2Cl2
(12.5 mL) at ꢀ788C. After being stirred at ꢀ788C for 10 min and then
warmed to room temperature for 2 h, the reaction mixture was poured
into ice-cold water. The resulting solution was extracted twice with
EtOAc. Combined organic layers were washed with H2O and brine, dried
over anhydrous Na2SO4, filtered, and concentrated. The residue was puri-
fied by flash chromatography on silica gel (hexane/EtOAc 100:0 to 40:1)
to afford 19 (515 mg, 1.14 mmol) in 91% yield: colorless oil; ½aꢁ2D8 =ꢀ2.8
Sulfone 7: H2O2 (30% in H2O, 220 mL, 2.10 mmol) was added to a solu-
tion of 21 (104 mg, 0.21 mmol) and Mo7ACHTUNGTRNEUNG(NH4)6O24·4H2O (79 mg,
64 mmol) in EtOH (4.2 mL) at room temperature. After being stirred for
3 h, the reaction mixture was cooled to 08C, and saturated aqueous
Na2S2O3 was added to the mixture. The resulting mixture was extracted
twice with EtOAc. Combined organic layers were washed with H2O and
brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resi-
due was purified by flash chromatography on silica gel (hexane/EtOAc
100:0 to 20:1) to afford 7 (80 mg, 0.15 mmol) in 72% yield: off-white
waxy solid; m.p. 53–558C; ½aꢁD18 =ꢀ8.1 (c=0.85, CHCl3); IR (neat): n˜ =
(c=0.77, CHCl3); IR (neat): n˜ =2956, 2929, 2857, 1471, 1254, 1077 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d=0.02 (3H, s, CH3 of TBS), 0.04 (3H, s,
CH3 of TBS), 0.075 (3H, s, CH3 of TBS), 0.079 (3H, s, CH3 of TBS), 0.87
(9H, s, tBu of TBS), 0.92 (9H, s, tBu of TBS), 0.96 (3H, t, J=7.5 Hz,
CH2-CH3), 2.06 (2H, dq, J=7.5, 7.5 Hz, CH2-CH3), 2.20 (1H, dt, J=13.7,
6.3 Hz, TBSOCH-CHAHB-), 2.35 (1H, dt, J=13.7, 6.9 Hz, TBSOCH-
CHAHB-), 2.77 (2H, t, J=6.9 Hz, C=CH-CH2-CH=C), 4.24 (2H, dd, J=
4.6, 1.2 Hz, CH2-OTBS), 4.58 (1H, dt, J=8.6, 6.9 Hz, CHOTBS), 5.26–
2956, 2928, 2855, 1472, 1335, 1146, 1080 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d=ꢀ0.18 (3H, s, CH3 of TBS), ꢀ0.14 (3H, s, CH3 of TBS), 0.78
540
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 534 – 543

Total Synthesis of Maresin
(9H, s, tBu of TBS), 0.96 (3H, t, J=7.5 Hz, CH2-CH3), 2.00–2.07 (3H, m,
CH2-CH3, TBSOCH-CHAHB-), 2.18 (1H, dt, J=14.3, 6.9 Hz, TBSOCH-
CHAHB-), 2.68 (2H, dd, J=6.9, 6.9 Hz, C=CH-CH2-CH=C), 4.25–4.36
(3H, m, CH2-SO2-, CHOTBS), 5.13–5.40 (4H, m, CH=CH-CH2-CH=
CH), 5.42 (1H, dd, J=10.9, 9.2 Hz, CH=CH-CHOTBS), 5.67 (1H, dt, J=
15.5, 8.0 Hz, CH=CH-CH2-SO2-), 5.89 (1H, dd, J=11.5, 10.9 Hz, CH=
CH-CH=CH-CH2-SO2-), 6.45 (1H, dd, J=15.5, 11.5 Hz CH=CH-CH2-
SO2-), 7.58 (1H, dd, J=8.0, 8.0 Hz, aromatic H), 7.63 (1H, dd, J=8.0,
8.0 Hz, aromatic H), 7.99 (1H, d, J=8.0 Hz, aromatic H), 8.23 ppm (1H,
d, J=8.0 Hz, aromatic H); 13C NMR (125 MHz, CDCl3): d=ꢀ5.0, ꢀ4.6,
14.3, 18.0, 20.5, 25.7, 36.0, 58.5, 68.6, 99.9, 117.7, 122.3, 124.8, 125.4, 125.8,
127.0, 127.7, 128.0, 130.2, 132.0, 135.4, 136.9, 137.9, 152.6, 165.3 ppm;
HRMS (FAB) calcd for C27H40NO3S2Si 518.2219 [M+H]+, found
518.2225.
solution of the crude aldehyde in a mixture of 2-methyl-2-butene
(0.6 mL) and tBuOH (0.6 mL) at 08C. After being stirred at room tem-
perature for 1 h, the reaction mixture was diluted with H2O (2 mL) and
EtOAc (5 mL). The separated organic layer was washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated. The residue was puri-
fied by flash chromatography on silica gel (hexane/EtOAc/AcOH 10:0:0
to 20:1:0 to 10:1:0.01) to afford (7R)-23 (6.0 mg, 0.010 mmol) in 76%
yield over 2 steps: a colorless oil; ½aꢁ2D0 =ꢀ15 (c=0.27, CHCl3); IR (neat):
n˜ =2929, 2856, 1712, 1254, 1076 cmꢀ1 1H NMR (500 MHz, C6D6): d=
;
0.090 (3H, s, CH3 of TBS), 0.093 (3H, s, CH3 of TBS), 0.12 (3H, s, CH3
of TBS), 0.13 (3H, s, CH3 of TBS), 0.93 (3H, t, J=7.3 Hz, H-22), 1.007
(9H, s, tBu of TBS), 1.013 (9H, s, tBu of TBS), 2.03 (2H, qd, J=7.3,
5.5 Hz, H-21), 2.09 (2H, t, J=7.3 Hz, H-2), 2.20–2.60 (6H, m, H-3, H-6,
and H-15), 2.85 (2H, dd, J=5.5, 5.5 Hz, H-18), 4.17 (1H, dt, J=5.9,
5.9 Hz, H-7), 4.74 (1H, br dt, J=8.2, 8.2 Hz, H-14), 5.30–5.63 (7H, m, H-
4, H-5, H-13, H-16, H-17, H-19 and H-20), 5.68 (1H, dd, J=15.1, 6.4 Hz,
H-8), 5.98 (1H, dd, J=11.4, 11.4 Hz, H-12), 6.15 (1H, dd, J=14.7,
11.0 Hz, H-10), 6.34 (1H, dd, J=15.6, 11.0 Hz, H-9), 6.65 ppm (1H, dd,
J=15.1, 11.4 Hz, H-11); 13C NMR (125 MHz, CDCl3): d=ꢀ4.78, ꢀ4.4,
ꢀ4.3, 14.3, 18.2, 18.3, 20.6, 22.7, 25.7, 25.8, 25.9, 33.6, 36.2, 36.4, 69.0, 72.8,
125.5, 127.2, 127.4, 127.15, 127.14, 127.7, 129.0, 129.4, 129.9, 131.9, 133.4,
135.0, 137.3, 177.7 ppm; HRMS (ESI) calcd for C34H59O4Si2 587.3952
[MꢀH]ꢀ, found 587.3947.
Triene (7R,8E)-22: P4-tBu (1.0m in hexane, 70 mL, 70 mmol) was added to
the mixture of 7 (30 mg, 58 mmol) and the crude (R)-4 (35 mg) in CH3CN
(2.3 mL) at ꢀ408C. The mixture was stirred for 5 min at ꢀ408C, and
then allowed to warm to room temperature for 2 h. The reaction was
quenched with saturated aqueous NH4Cl, and the resulting solution was
extracted with Et2O. The organic layer was washed with H2O and brine,
dried over anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by flash chromatography on silica gel (hexane/EtOAc 100:0
to 40:1) to afford (7R)-22 along with other stereoisomers (20 mg,
32 mmol) in 56% yield. The mixture was further purified by HPLC (In-
ertsil, SIL 100 A, 250ꢂ10 mm, UV 254 nm, hexane/EtOAc 95:5,
3.0 mLminꢀ1) to give (7R,8E)-22 (8.3 mg, 0.013 mmol, tR =17.2 min) in
22% yield and (7R,8Z)-22 (5.1 mg, 8.3 mmol, tR =14.5 min) in 14% yield:
(7R,8E)-22: ½aꢁ1D7 =ꢀ15 (c=0.42, CHCl3); IR (neat): n˜ =2955, 2929, 2856,
7R,14S-dihydroxydocosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid (7R)-1:
TBAF (1.0m in THF, 0.09 mL, 90 mmol) was added to a solution of (7R)-
23 (5.3 mg, 9.0 mmol) in THF (0.9 mL) at 08C. After being stirred at
room temperature for 11 h, the reaction mixture was quenched with satu-
rated aqueous NH4Cl. The resulting solution was extracted with Et2O.
The organic layer was washed with aqueous HCl (0.1N), H2O, and brine,
and concentrated in vacuo. The residue was purified by flash chromatog-
raphy on silica gel (hexane/EtOAc/AcOH 1:1:0 to 1:5:0.01) to afford
(7R)-1 (3.8 mg, 0.011 mmol) in 99% yield: pale yellow oil; HPLC analy-
sis: l-column2 ODS (CERI) (3 mm, 4.6ꢂ150 mm), UV 270 nm,
1
1472, 1254, 1073 cmꢀ1; H NMR (400 MHz, C6D6): d=0.09 (3H, s, CH3 of
TBS), 0.10 (3H, s, CH3 of TBS), 0.12 (6H, s, CH3 of TBS), 0.93 (3H, t,
J=7.3 Hz, H-22), 1.01 (18H, s, tBu of TBS), 1.81 (2H, td, J=7.8, 5.0 Hz,
H-2), 2.03 (2H, br dq, J=6.8, 6.8 Hz, H-21), 2.25–2.60 (6H, m, H-3, H-6,
and H-15), 2.85 (2H, dd, J=5.5, 5.5 Hz, H-18), 3.35–3.42 (2H, m,
OCHAHBCHAHBO), 3.49–3.56 (2H, m, OCHAHBCHAHBO), 4.20 (1H,
dt, J=6.4, 6.4 Hz, H-7), 4.74 (1H, dt, J=7.8, 6.9 Hz, H-14), 4.84 (1H, t,
J=5.0 Hz, H-1), 5.39–5.65 (7H, m, H-4, H-5, H-13, H-16, H-17, H-19,
and H-20), 5.71 (1H, dd, J=15.6, 6.4 Hz, H-8), 5.97 (1H, dd, J=11.4,
11.4 Hz, H-12), 6.14 (1H, dd, J=14.6, 11.0 Hz, H-10), 6.35 (1H, dd, J=
15.1, 11.0 Hz, H-9), 6.63 ppm (1H, dd, J=14.6, 11.9 Hz, H-11); 13C NMR
(125 MHz, CDCl3): d=ꢀ4.8, ꢀ4.4, 14.3, 18.2, 18.3, 20.6, 22.1, 25.7, 25.8,
25.9, 33.7, 36.2, 36.4, 64.9, 69.0, 72.9, 104.1, 125.5, 126.0, 127.1, 127.3,
1.0 mLminꢀ1
, KH2PO4 buffer (pH 3.0, 25 mm)/CH3CN 55:45, tR =
12.4 min; ½aꢁ2D2 =ꢀ31 (c=0.19, MeOH); IR (neat): n˜ =3327, 2923, 1713,
1399, 1264, 996 cmꢀ1 1H NMR (500 MHz, CD3OD): d=0.96 (3H, t, J=
;
7.5 Hz, H-22), 2.07 (2H, dq, J=7.5, 7.5 Hz, H-21), 2.19–2.42 (8H, m, H-
2, H-3, H-6, and H-15), 2.79 (2H, dd, J=6.9, 6.9 Hz, H-18), 4.12 (1H, dt,
J=6.9, 5.2 Hz, H-7), 4.57 (1H, dt, J=9.8, 7.4 Hz, H-14), 5.26–5.47 (7H,
m, H-4, H-5, H-13, H-16, H-17, H-19 and H-20), 5.75 (1H, dd, J=14.9,
6.9 Hz, H-8), 6.07 (1H, dd, J=11.4, 11.4 Hz, H-12), 6.24 (1H, dd, J=
14.3, 10.9 Hz, H-10), 6.28 (1H, dd, J=14.9, 10.9, 1.1 Hz, H-9), 6.51 ppm
(1H, br dd, J=13.8, 12.0, Hz, H-11); 13C NMR (125 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, 177.1 ppm; HRMS
(FAB) calcd for C22H31O4 359.2222 [MꢀH]ꢀ, found 359.2220.
127.8, 129.3, 129.9, 130.6, 131.9, 133.5, 134.9, 137.5 ppm; HRMS (EI)
26
calcd for C36H64O4Si2 616.4343 [M]+, found 616.4352. (7R,8Z)-22: ½aꢁD
=
ꢀ5.7 (c=0.090, CHCl3); IR (neat): n˜ =2956, 2928, 2856, 1462, 1254,
1074 cmꢀ1; H NMR (500 MHz, C6D6): d=0.10 (3H, s, CH3 of TBS), 0.11
1
(3H, s, CH3 of TBS), 0.12 (3H, s, CH3 of TBS), 0.13 (3H, s, CH3 of
TBS), 0.92 (3H, t, J=7.5 Hz, H-22), 1.006 (9H, s, tBu of TBS), 1.009
(9H, s, tBu of TBS), 1.81 (2H, td, J=8.0, 5.0 Hz, H-2), 2.02 (2H, qd, J=
7.5, 5.7 Hz, H-21), 2.26–2.55 (6H, m, H-3, H-6 and H-15), 2.84 (2H, dd,
J=6.3, 6.3 Hz, H-18), 3.36–3.42 (2H, m, OCHAHBCHAHBO), 3.52–3.56
(2H, m, OCHAHBCHAHBO), 4.72 (1H, dt, J=7.5, 7.5 Hz, H-7 or H-14),
4.73 (1H, dt, J=7.4, 7.4 Hz, H-7 or H-14), 4.84 (1H, t, J=5.0 Hz, H-1),
5.42–5.65 (8H, m, H-4, H-5, H-8, H-13, H-16, H-17, H-19, and H-20),
5.99 (1H, dd, J=11.4, 11.4 Hz, H-9 or H-12), 6.04 (1H, dd, J=11.4,
11.4 Hz, H-9 or H-12), 6.59 (1H, dd, J=14.9, 11.4 Hz, H-10 or H-11),
6.64 ppm (1H, dd, J=14.9, 11.4 Hz, H-10 or H-11); 13C NMR (100 MHz,
CDCl3): d=ꢀ4.7, ꢀ4.3, 14.3, 18.2, 20.6, 22.2, 25.78, 25.84, 25.9, 29.7, 33.7,
36.3, 36.4, 64.9, 69.03, 69.04, 104.1, 125.5, 126.0, 127.1, 127.65, 127.69,
128.8, 128.9, 130.0, 130.6, 131.9, 135.7, 135.8 ppm; HRMS (ESI) calcd for
C36H64O4Si2Na 639.4241 [M+Na]+, found 639.4244.
Triene (7S,8E)-22: Following the same procedure for synthesis of triene
(7R,8E)-22, triene (7S,8E)-22 (4.1 mg, 6.6 mmol) and (7S,8Z)-22 were syn-
thesized from 7 (15 mg, 29 mmol) and the crude (S)-4 in 63% combined
yield. The obtained compounds were further purified by using the same
HPLC procedure for (7R)-22. ((7S,8Z)-22: tR =14.7 min (23% yield),
(7S,8E)-22: tR =13.0 min (18% yield)): (7S,8E)-22: ½aꢁ1D7 =+18 (c=0.40,
CHCl3); IR (neat): n˜ =2955, 2928, 2856, 1471, 1254, 1069 cmꢀ1 1H NMR
;
(500 MHz, C6D6): d=0.09 (3H, s, CH3 of TBS), 0.10 (3H, s, CH3 of
TBS), 0.13 (3H, s, CH3 of TBS), 0.14 (3H, s, CH3 of TBS), 0.93 (3H, t,
J=7.4 Hz, H-22), 1.01 (18H, s, tBu of TBS), 1.79–1.83 (2H, m, H-2), 2.02
(2H, dq, J=7.5 Hz, H-21), 2.28–2.54 (6H, m, H-3, H-6 and H-15), 2.84
(2H, dd, J=5.8, 5.8 Hz, H-18), 3.35–3.41 (2H, m, OCHAHBCHAHBO),
3.50–3.57 (2H, m, OCHAHBCHAHBO), 4.19 (1H, dt, J=6.3, 6.3 Hz, H-7),
4.73 (1H, dt, J=8.0, 6.9 Hz, H-14), 4.83 (1H, t, J=5.2 Hz, H-1), 5.40–
5.64 (7H, m, H-4, H-5, H-13, H-16, H-17, H-19 and H-20), 5.70 (1H, dd,
J=15.5, 6.3 Hz, H-8), 5.96 (1H, dd, J=11.4, 11.4 Hz, H-12), 6.13 (1H,
dd, J=14.9, 10.9 Hz, H-10), 6.34 (1H, dd, J=15.5, 10.9 Hz, H-9),
6.63 ppm (1H, dd, J=14.3, 11.4 Hz, H-11); 13C NMR (125 MHz, CDCl3):
d=ꢀ4.8, ꢀ4.4, ꢀ4.3, 14.3, 18.2, 18.3, 20.6, 22.1, 25.7, 25.8, 25.9, 33.7, 36.2,
36.4, 64.9, 68.9, 72.9, 104.1, 125.5, 126.0, 127.1, 127.3, 127.8, 129.3, 130.0,
130.5, 131.9, 133.4, 134.9, 137.4 ppm; HRMS (FAB) calcd for
C36H64O4Si2Cs 749.3398 [M+Cs]+, found 749.3392. (7S,8Z)-22: ½aꢁ2D6 =+27
(c=0.13, CHCl3); IR (neat): n˜ =2956, 2929, 2856, 1472, 1256, 1073,
Carboxylic acid (7R)-23: TMSOTf (37 mL, 0.20 mmol) was added to a so-
lution of (7R)-22 (8.3 mg, 14 mmol) and 2,6-lutidine (35 mL, 0.30 mmol) in
CH2Cl2 (1.3 mL) at ꢀ208C. After 1 h at ꢀ208C, H2O was added to the
reaction mixture. The solution was stirred at room temperature for an ad-
ditional 1 h, and diluted with CH2Cl2. The separated organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated to give the crude aldehyde, which was used for the next reaction
without further purification. A solution of NaClO2 (11 mg, 0.12 mmol)
and NaH2PO4·4H2O (20 mg, 0.13 mmol) in H2O (0.6 mL) was added to a
Chem. Asian J. 2011, 6, 534 – 543
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
541

M. Inoue et al.
FULL PAPERS
836 cmꢀ1
;
1H NMR (500 MHz, C6D6): d=0.08 (3H, s, CH3 of TBS), 0.10
[1] a) C. N. Serhan, N. Chiang, T. E. Van Dyke, Nat. Rev. Immunol.
2008, 8, 349–361; b) C. N. Serhan, N. Chiang, Br. J. Pharmacol.
2008, 153, S200–S215.
[2] M. Arita, F. Bianchini, J. Aliberti, A. Sher, N. Chiang, S. Hong, R.
Yang, N. A. Petasis, C. N. Serhan, J. Exp. Med. 2005, 201, 713–722.
[3] C. N. Serhan, K. Gotlinger, S. Hong, Y. Lu, J. Siegelman, T. Baer, R.
Yang, S. P. Colgan, N. A. Petasis, J. Immunol. 2006, 176, 1848–1859.
[4] J. M. Schwab, N. Chiang, M. Arita, C. N. Serhan, Nature 2007, 447,
869.
[5] C. N. Serhan, R. Yang, K. Martinod, K. Kasuga, P. S. Pillai, T. F.
Porter, S. F. Oh, M. Spite, J. Exp. Med. 2009, 206, 15–23.
[6] For total syntheses of other anti-inflammatory lipid mediators. Re-
solvin E1: a) N. Ogawa, Y. Kobayashi, Tetrahedron Lett. 2009, 50,
6079–6082; see also Ref. 2; Resolvin E2: b) S. Ogawa, D. Urabe, Y.
Yokokura, H. Arai, M. Arita, M. Inoue, Org. Lett. 2009, 11, 3602–
3605; c) Y. Kosaki, N. Ogawa, Y. Kobayashi, Tetrahedron Lett. 2010,
51, 1856–1859; Resolvin D2: d) A. R. Rodrꢃguez, B. W. Spur, Tetra-
hedron Lett. 2004, 45, 8717–8720; Resolvin D5: e) A. R. Rodrꢃguez,
B. W. Spur, Tetrahedron Lett. 2005, 46, 3623–3627; Protectin D1: see
Ref. 3.
(3H, s, CH3 of TBS), 0.13 (6H, s, CH3 of TBS), 0.92 (3H, t, J=7.5 Hz,
H-22), 1.00 (9H, s, tBu of TBS), 1.01 (9H, s, tBu of TBS), 1.81 (2H, td,
J=7.5, 4.5 Hz, H-2), 2.02 (2H, qd, J=7.5, 5.0 Hz, H-21), 2.25–2.55 (6H,
m, H-3, H-6 and H-15), 2.84 (2H, dd, J=6.5, 6.5 Hz, H-18), 3.36–3.42
(2H, m, OCHAHBCHAHBO), 3.50–3.58 (2H, m, OCHAHBCHAHBO), 4.72
(1H, dt, J=7.0, 7.0 Hz, H-7 or H-14), 4.73 (1H, dt, J=7.0, 7.0 Hz, H-7 or
H-14), 4.84 (1H, t, J=4.5 Hz, H-1), 5.38–5.63 (8H, m, H-4, H-5, H-8, H-
13, H-16, H-17, H-19 and H-20), 5.98 (1H, dd, J=10.5, 10.5 Hz, H-9 or
H12), 6.04 (1H, dd, J=10.5, 10.5 Hz, H-9 or H12), 6.59 (1H, dd, J=15.0,
11.0 Hz, H-10 or H-11), 6.64 ppm (1H, dd, J=14.5, 10.0 Hz, H-10 or H-
11); 13C NMR (100 MHz, CDCl3): d=ꢀ4.7, ꢀ4.4, ꢀ4.3, 14.3, 18.2, 20.6,
22.2, 25.78, 25.84, 25.9, 29.7, 33.7, 36.3, 36.4, 64.9, 68.98, 69.01, 104.1,
125.5, 126.0, 127.1, 127.67, 127.73, 128.8, 128.9, 130.0, 130.6, 131.9, 135.7,
135.8 ppm; HRMS (ESI) calcd for C36H64O4Si2Na 639.4241 [M+Na]+,
found 639.4231.
Carboxylic acid (7S)-23: Following the same procedure for synthesis of
(7R)-23, (7S)-23 (5.9 mg, 10 mmol) was synthesized from (7S,8E)-22
(8.0 mg, 13.0 mmol) in 77% yield over 2 steps: ½aꢁ2D0 =+16 (c=0.30,
CHCl3); IR (neat): n˜ =2956, 2928, 2856, 1712, 1471, 1254, 1076 cmꢀ1
;
1H NMR (500 MHz, C6D6): d=0.09 (3H, s, CH3 of TBS), 0.10 (3H, s,
CH3 of TBS), 0.13 (3H, s, CH3 of TBS), 0.14 (3H, s, CH3 of TBS), 0.94
(3H, t, J=7.5 Hz, H-22), 1.01 (9H, s, tBu of TBS), 1.02 (9H, s, tBu of
TBS), 2.00–2.06 (2H, m, H-21), 2.10 (2H, t, J=7.5 Hz, H-2), 2.19–2.40
(5H, m, H-3, H-6, and H-15a), 2.52 (1H, ddd. J=14.3, 6.9, 6.9 Hz, H-
15b), 2.84 (2H, dd, J=6.3, 6.3 Hz, H-18), 4.16 (1H, dt, J=6.3, 6.3 Hz, H-
7), 4.74 (1H, dt, J=8.6, 6.9 Hz, H-14), 5.32–5.37 (1H, m, H-4), 5.40–5.47
(2H, m, H-19 and H-20), 5.49–5.62 (4H, m, H-5, H-13, H-16 and H-17),
5.68 (1H, dd, J=15.5, 6.5 Hz, H-8), 5.98 (1H, dd, J=11.5, 11.5 Hz, H-
12), 6.15 (1H, dd, J=14.9, 11.5 Hz, H-10), 6.34 (1H, dd, J=15.5, 11.5 Hz,
H-9), 6.65 ppm (1H, dd, J=14.9, 12.0 Hz, H-11); 13C NMR (125 MHz,
CDCl3): d=ꢀ4.8, ꢀ4.4, ꢀ4.3, 14.3, 18.2, 18.3, 20.6, 22.7, 25.7, 25.8, 25.9,
33.7, 36.2, 36.3, 68.9, 72.8, 125.5, 127.1, 127.2, 127.5, 127.8, 128.9, 129.5,
130.0, 131.9, 133.3, 135.0, 137.2, 178.0 ppm; HRMS (FAB) calcd for
C34H59O4Si2 587.3952 [MꢀH]ꢀ, found 587.3947.
[7] For a review on syntheses of eicosanoids, see: K. C. Nicolaou, J. Y.
Ramphal, N. A. Petasis, C. N. Serhan, Angew. Chem. 1991, 103,
1119–1136; Angew. Chem. Int. Ed. Engl. 1991, 30, 1100–1116.
[8] For reviews of the modified Julia olefination, see: a) P. R. Blake-
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[15] The configurational stability of the similar a-siloxy aldehydes was
reported previously, see: a) K. C. Nicolaou, R. E. Zipkin, R. E.
Dolle, B. D. Harris, J. Am. Chem. Soc. 1984, 106, 3548–3551;
b) I. M. Taffer, R. E. Zipkin, Tetrahedron Lett. 1987, 28, 6543–6544.
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Carreira, Acc. Chem. Res. 2000, 33, 373–381; b) L. Pu, Tetrahedron
2003, 59, 9873–9886; c) P. G. Cozzi, R. Hilgraf, N. Zimmermann,
Eur. J. Org. Chem. 2004, 4095–4105.
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4143–4146.
[20] The optical purity of 16 was determined from the integration of the
1H NMR spectrum of the corresponding MTPA ester.
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licky, J. W. Reed, Chem. Soc. Rev. 2009, 38, 3117–3132; H. Akita,
Heterocycles 2009, 78, 1667–1713.
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7S,14S-dihydroxydocosa-4Z,8E,10E,12Z,1Z,19Z-hexaenoic acid (7S)-1:
Following the same procedure for synthesis of (7R)-1, (7S)-1 (3.5 mg,
9.7 mmol) was synthesized from (7S)-23 (5.9 mg, 10 mmol) in 97% yield:
colorless oil; HPLC analysis: l-column2 ODS (CERI) (3 mm, 4.6ꢂ
150 mm), UV 270 nm, 1.0 mLminꢀ1, 25 mm KH2PO4 buffer (pH 3.0)/
CH3CN 55:45, tR =11.6 min; ½aꢁD22 =ꢀ23 (c=0.18, MeOH); IR (neat): n˜ =
3304, 3011, 2962, 2923, 1713, 1400, 1264, 996 cmꢀ1 1H NMR (500 MHz,
;
CD3OD): d=0.96 (3H, t, J=7.5 Hz, H-22), 2.08 (2H, dq, J=7.5, 7.5 Hz,
H-21), 2.19–2.42 (8H, m, H-2, H-3, H-6, and H-15), 2.79 (2H, dd, J=6.9,
6.9 Hz, H-18), 4.12 (2H, dt, J=6.9, 6.3 Hz, H-7), 4.57 (1H, dt, J=8.6,
6.9 Hz, H-14), 5.26–5.47 (7H, m, H-4, H-5, H-13, H-16, H-17, H-19 and
H-20), 5.75 (1H, dd, J=14.9, 6.9 Hz, H-8), 6.07 (1H, dd, J=11.5,
11.5 Hz, H-12), 6.24 (1H, dd, J=14.3, 10.9 Hz, H-10), 6.28 (1H, dd, J=
14.9, 10.9, 1.2 Hz, H-9), 6.51 ppm (1H, br dd, J=13.8, 11.5, Hz, H-11);
13C NMR (125 MHz, CD3OD): d=14.7, 21.5, 24.2, 26.6, 35.2, 36.2, 36.5,
68.5, 73.0, 126.1, 127.4, 128.2, 128.9, 130.6, 131.2, 131.3, 131.4, 132.8,
134.8, 135.0, 138.0, 178.6 ppm; HRMS (FAB) calcd for C22H31O4 359.2222
[MꢀH], found 359.2227.
Bioassay: Murine peritonitis was carried out by using 7- to 8-week year
old C57BL/6 male mice (CLEA Japan). Maresin or vehicle alone was in-
jected into the tail vein, followed by 1 mL of zymosan A (1 mgmLꢀ1
;
Sigma–Aldrich) injected into the peritoneum. After 2 h, peritoneal lavag-
es were collected and the cells were enumerated with light microscopy.
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32, 1175–1178.
[25] O. Mitsunobu, Synthesis 1981, 1.
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1140–1142.
Acknowledgements
[27] a) R. Schwesinger, C. Hasenfratz, H. Schlemper, L. Walz, E.-M.
Peters, K. Peters, H. G. von Schnering, Angew. Chem. 1993, 105,
1420–1422; Angew. Chem. Int. Ed. Engl. 1993, 32, 1361–1363;
b) D. A. Alonso, M. Fuensanta, C. Nꢆjera, M. Varea, J. Org. Chem.
This work was supported by a Grant-in-Aid for Young Scientists (S)
(JSPS) to M.I. and PRESTO from the Japan Science and Technology
Agency (JST) to M.A. We thank Michiko Kamio (The University of
Tokyo) for technical assistance.
542
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 534 – 543

Total Synthesis of Maresin
2005, 70, 6404–6416; c) D. A. Alonso, M. Fuensanta, E. Gꢇmez-
Bengoa, C. Nꢆjera, Eur. J. Org. Chem. 2008, 2915–2922.
from the Cayman Chemical Company. See Supporting Information
for details.
[28] H. Fujioka, T. Okitsu, Y. Sawama, N. Murata, R. Li, Y. Kita, J. Am.
Chem. Soc. 2006, 128, 5930–5938.
Received: July 17, 2010
Published online: November 24, 2010
[29] 1H NMR spectrum and the retention time on the ODS HPLC of the
synthesized (7S)-1 were identical with those of the purchased (7S)-1
Chem. Asian J. 2011, 6, 534 – 543
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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