Total syntheses of four possible stereoisomers of resolvin E3

Article abstract of DOI:10.1016/j.tet.2012.02.045

Resolvin E3, 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid, is a potent anti-inflammatory lipid mediator. To determine the stereochemistries of the C17- and C18-hydroxy groups of resolvin E3 and to supply a sufficient amount of material for futu

Full text of DOI:10.1016/j.tet.2012.02.045

Tetrahedron 68 (2012) 3210e3219
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Total syntheses of four possible stereoisomers of resolvin E3
,
Daisuke Urabe a, Hidenori Todoroki a, Koji Masuda b, Masayuki Inoue a
*
a Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
b Shionogi & Co. Ltd., Discovery Research Laboratories, Sagisu, Fukushima-ku, Osaka 541-0045, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 January 2012
Received in revised form 14 February 2012
Accepted 17 February 2012
Available online 23 February 2012
Resolvin E3, 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid, is a potent anti-inflammatory lipid
mediator. To determine the stereochemistries of the C17- and C18-hydroxy groups of resolvin E3 and to
supply a sufficient amount of material for future biological studies, we developed a highly convergent
and practical route to its four possible stereoisomers. The key reactions employed here were the Hor-
nereWadswortheEmmons coupling, the two copper(I)-mediated reactions between the alkynes and the
propargyl tosylates, and the simultaneous reduction of the three triple bonds to the three Z-olefins.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Resolvin
Lipid mediators
Eicosapentaenoic acid
Total synthesis
Convergent strategy
1. Introduction
we report the highly convergent total syntheses of (17R,18R)-,
(17S,18S)-, (17S,18R)-, and (17R,18S)-resolvin E3.
Resolvins are a family of lipid mediators generated during
the spontaneous resolution phase of acute inflammation.1 Resol-
vins E12 and E2,3 which were isolated from human poly-
morphonuclear leukocytes by Serhan, are formed by biosynthetic
oxidation of eicosapentaenoic acid (EPA, Fig. 1) via a common
precursor, 18-hydroxyeicosapentaenoic acid (18-HEPE). These E
series resolvins exhibited potent anti-inflammatory activity in
a model of murine peritonitis, and thus show promise as new
therapeutics for treatment of human disease associated aberrant
inflammation.4
Most recently, Arita and co-workers uncovered a novel array of
18-HEPE-derived metabolites from human eosinophils.5 Among
those, 17,18-dihydroxylated compound 1, designated as resolvin E3,
was found to display potent anti-inflammatory action by limiting
polymorphonuclear infiltration in zymosan-induced peritonitis.
The planar structure of resolvin E3 was determined by 1H NMR
analysis to be 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic
acid. However, the stereochemistries of the two hydroxy groups of
1 have not been elucidated due mainly to its limited supply from
the eosinophils. To unambiguously establish the absolute stereo-
structure of 1 and to supply a sufficient amount of material for
future biological studies, we developed an efficient and practical
synthetic route to all the four possible stereoisomers of 1.6,7 Here
Fig. 1. Structures of EPA, 18-HEPE, and resolvins E1, E2, and E3.
2. Results and discussion
2.1. Synthetic plan of resolvin E3
The four isomers of resolvin E3 (1aed) were retrosynthetically
dissected into the four known compounds 5, 7, 8, and 9 (Scheme 1).
To unveil the geometrically unstable conjugated triene of 1
* Corresponding author. Tel.: þ81 3 5841 1354; fax: þ81 3 5841 0568; e-mail
address: inoue@mol.f.u-tokyo.ac.jp (M. Inoue).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.045

D. Urabe et al. / Tetrahedron 68 (2012) 3210e3219
3211
together with the 5Z,8Z-diene moiety at the last stage of the syn-
thesis, 13E,15E-dien-5,8,11-triyne 2 was designed as the first key
intermediate. In the synthetic direction, the three alkynes of 2 were
to be stereoselectively reduced to the three Z-olefins of 1 in a single
step. Compound 2 was in turn to be constructed by applying two
copper(I)-mediated SN2 reactions: C6eC7 bond formation between
propargyl tosylate 7 and terminal acetylene 8, followed by C10eC11
bond formation between 3 and 4. Fragment 3 would be synthesized
through HornereWadswortheEmmons (H.W.E.) reaction of phos-
phonate 5 with C16e20 aldehyde 6. We envisioned the preparation
of the four chiral aldehydes 6aed from the same E-olefin 9 through
asymmetric dihydroxylation.
Scheme 2. Syntheses of four chiral aldehydes 6aed.
Scheme 1. Retrosynthesis of resolvin E3.
benzoate enabled inversion of the
a-position of the carbonyl
group,13 resulting in formation of benzoates 13a,b after acidic hy-
drolysis of the sulfates. Then, methanolysis of esters 13a and 13b
afforded diols 10c (98% ee) and 10d (96% ee), which were converted
to enantiomeric aldehydes 6c and 6d, respectively, by a three-step
transformation: TBS protection to 11c,d, DIBAL-H reduction, and
DesseMartin oxidation.
The enantiomeric excesses of the four synthesized diols 10a,
10b, 10c, and 10d were determined to be 99%, 98%, 98%, and
96%, respectively, by the simple protocol developed by James
(Fig. 2).14 Diols 10aed were separately treated in CDCl3 with 2-
2.2. Syntheses of the four chiral aldehydes
Preparation of the four enantiomerically pure aldehydes 6aed
started with the Sharpless asymmetric dihydroxylation8 of
methyl 2E-pentenoate 9 (Scheme 2). Application of (DHQD)2PHAL
and (DHQ)2PHAL to 9 as chiral ligands under the osmylation
conditions provided enantiomeric diols 10a and 10b in enantio-
pure forms (vide infra).9 After protection of diols 10a and 10b as
their bis-TBS ethers 11a and 11b, respectively, reduction of their
methyl esters with DIBAL-H and oxidation of the resulting pri-
mary alcohols with DesseMartin periodinane10 led to aldehydes
6a and 6b.
Alternatively, epimeric aldehydes 6c and 6d were synthesized
from chiral diols 10a and 10b, respectively, via stereochemical in-
version at the C17-hydroxyl groups.9c,11 First, sulfates 12a,b were
prepared by treatment of the corresponding alcohols 10a,b with
thionyl chloride and subsequent oxidation with RuO4.12 Regio- and
stereoselective opening of cyclic sulfates 12a,b using ammonium
formylphenyl boronic acid in the presence of enantiopure (S)-a-
methylbenzylamine, resulting in smooth formation of the corre-
sponding diastereomeric iminoboronate esters 14aed. The imine
protons (N]CH) and benzylic protons (NCHPh) of pseudo enan-
tiomeric 14a and 14b, and a-methyne protons (MeO2CCH) of 14c
and 14d displayed large chemical shift differences in their 1H NMR
spectra, and their integrations consequently enabled accurate
quantification of the enantiomeric excess of the parent diols
10aed.

3212
D. Urabe et al. / Tetrahedron 68 (2012) 3210e3219
is noteworthy that this coupling method using a combination of
copper(I) and a weak base minimized both undesired SN20-type
reaction of the acetylide at C8 and base-induced isomerization of
the methylene-bridged 5,8,11-triyne. Chemoselective hydrogena-
tion of the obtained triynes 2a,b using Lindlar catalyst21 in the
presence of quinoline constructed the two Z-olefins and the un-
stable 11Z,13E,15E-triene structures of 17a,b in a single step. Finally,
pentaenes 17a,b were converted into 1a,b by following the three-
step protocol previously developed for our total syntheses of the
lipid mediators.6 Selective hydrolysis of the cyclic acetals of 17a and
17b was attained in the presence of the TBS ethers by applying
Kita’s conditions,22 providing the corresponding aldehydes. Then,
NaClO2 oxidation of the aldehydes into the carboxylic acids and
subsequent desilylation with TBAF delivered (17R,18R)-resolvin E3
1a and (17S,18S)-resolvin E3 1b.
Fig. 2. Determination of enantiopurity of diols 10aed.
2.3. Synthesis of C1e10 fragment
C1e10 fragment 4 was synthesized in two steps from known
compounds (Scheme 3). Treatment of terminal alkyne 815 with CuI
in the presence of Cs2CO3 and NaI16 led to the requisite acetylenic
copper species, which regioselectively attacked at C7 of tosylate 7,17
leading to diyne 15. To prepare for the C10-alkynylation, the
remaining hydroxy group of 15 was transformed to the corre-
sponding tosylate 4 using TsCl and K2CO3 in the presence of
Me3N$HCl.18 To our advantage, the undesirable nucleophilic chlo-
rination of 4 was not observed under this Tanabe conditions.
Scheme 3. Synthesis of C1e10 fragment 4.
2.4. Total syntheses of the four stereoisomers of resolvin E3
Having synthesized the requisite fragments, we shifted our fo-
cus to the convergent assembly of the four isomers of resolvin E3
(1aed). Scheme 4 illustrates the total synthesis of a pair of enan-
tiomers 1a and 1b from the corresponding aldehydes 6a and 6b.
Phosphonate 519 and aldehydes 6a,b were coupled by the H.W.E.
reaction using n-BuLi as a base to generate a mixture of stereo-
isomers (E/Z¼2.5:1).20 The adducts were subjected to I2-induced
isomerization (E/Z¼15:1), giving rise to the pure 13E,15E-dien-11-
ynes 16a,b after separation from the minute amount of the 15Z-
isomer. For the last coupling reaction, the TMS groups of 16a,b were
removed using K2CO3 and MeOH to give C11e20 fragments 3a,b.
The reagent mixture of CuI, NaI, and Cs2CO316 effectively promoted
the SN2-type alkylation of C11e20 fragments 3a,b with C1e10
propargyl tosylate 4, leading to 13E,15E-dien-5,8,11-triynes 2a,b. It
Scheme 4. Total synthesis of (17R,18R)- and (17S,18S)-resolvin E3.

D. Urabe et al. / Tetrahedron 68 (2012) 3210e3219
3213
Next, the established convergent strategy was applied to the
3. Conclusion
total synthesis of (17S,18R)-resolvin E3 1c and (17R,18S)-resolvin E3
1d, the other pair of enantiomers (Scheme 5). The H.W.E. reaction of
phosphonate 5 with aldehydes 6c and 6d provided the coupling
products (E/Z¼1.2:1), the newly formed olefins of which were
isomerized by treatment with iodine to afford 16c and 16d, re-
spectively, as a 10:1 inseparable E/Z mixture. Desilylation of 16c,d
was followed by the copper(I)-mediated coupling with tosylate 4,
resulting in formation of 2c,d (E/Z¼8.5:1). The Lindlar reduction of
the three triple bonds of 2c,d at the last stage successfully con-
structed the three Z-olefins, and the geometrically pure 17c,d were
isolated by separation of the 15Z-isomer. Finally, pentaenes 17c and
17d were transformed into 1c and 1d, respectively, by the three
functional group manipulations. The geometries of the 11Z,13E,15E-
triene structures of all resolvin E3s 1a, 1b (Scheme 4), 1c and 1d
(Scheme 5) were confirmed based on the 1H-1H coupling constants.
Stereoselective total syntheses of (17R,18R)-, (17S,18S)-,
(17S,18R)-, and (17R,18S)-resolvin E3 (1aed) were achieved in
a highly convergent fashion from the corresponding four chiral
aldehydes 6aed. The HornereWadswortheEmmons coupling at
C15 and the two copper(I)-mediated SN2 reactions at C7 and C10
efficiently assembled the four simple substructures, and the late
stage partial reduction greatly simplified the overall route to the
target compounds. Further studies will focus on the absolute
structure determination of resolvin E3 and detailed biological
analysis of the natural resolvin E3 and its stereoisomers.
4. Experimental section
4.1. General
All reactions sensitive to air or moisture were carried out under
argon atmosphere in dry or freshly distilled solvents under anhy-
drous conditions, unless otherwise noted. All other reagents were
used as supplied unless otherwise noted. Analytical thin-layer
chromatography (TLC) was performed using E. Merck Silica gel 60
F254 pre-coated plates. Flash column chromatography was per-
formed using 50e60 mm Silica Gel 60 (Kanto Chemical Co., Inc.).
High performance liquid chromatography (HPLC) experiments
were equipped with a JASCO HPLC system (pump: JASCO PU-2086
Plus x2, detector: JASCO MX-2080-32, degasser: ERC Inc. ERC3325,
data analysis by JASCO ChromNAV 1.5.2.). 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 parts per
million on the
d
scale relative to residual CHCl3 (
d
¼7.26 for 1H NMR
and
d
¼77.0 for 13C NMR), C6H6
(
d
¼7.16 for 1H NMR), and CD2HOD
(d
¼3.31 for 1H NMR and
d
¼49.0 for 13C NMR) as an internal refer-
ence. Signal patterns are indicated as s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet. The numbering of compounds corresponds
to that of natural product. Optical rotations were recorded on
a JASCO DIP-1000 Digital Polarimeter. Infrared (IR) spectra were
recorded on a JASCO FT/IR-4100 spectrometer. High resolution
mass spectra were measured on a Bruker microTOFII. Melting
points were measured on a Yanaco MP-S3 micro melting point
apparatus or a Yanaco MP-J3 micro melting point apparatus, and
are uncorrected.
4.1.1. Diol 10a. A mixture of methanesulfonamide (2.7 g,
28.4 mmol), K3Fe(CN)6 (28.1 g, 85.4 mmol), K2CO3 (11.8 g,
85.5 mmol), OsO4 (1.8 mL, 0,29 mmol, 0.16 M solution in H2O), and
(DHQD)2PHAL (222 mg, 0.285 mmol) in t-BuOH (95 mL) and water
(100 mL) was stirred for 10 min at 0 ꢀC. A solution of ester 9 (4.0 g,
35.1 mmol) in t-BuOH (5 mL) was added to the mixture in one
portion. The reaction mixture was stirred for 24 h at 0 ꢀC, and
saturated aqueous Na2S2O3 (200 ml), solid NaCl, and EtOAc
(100 mL) were successively added. The resultant mixture was
stirred at room temperature for additional 1 h. After separation of
the organic layer, the aqueous layer was extracted with EtOAc
(50 mLꢁ7). Combined organic layers were dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by flash chro-
matography on silica gel (75 g, pentane/ether 1:1 to 1:2 to 1:4) to
afford diol 10a (3.05 g, 20.5 mmol) in 58% yield. The enantiopurity
of diol 10a was determined to be 99% ee by following the James’
25
protocol:14 pale yellow oil; [
a
]
9.3 (c 0.13, CHCl3); IR (neat) n
D
3422, 1737, 1637, 1458, 1284, 1226, 1141 cme1
;
1H NMR (500 MHz,
CDCl3)
d
1.01 (3H, t, J¼7.5 Hz, eCH2CH3), 1.63 (2H, dq, J¼7.3, 7.3 Hz,
eCHCH2CH3), 2.20 (1H, d, J¼8.7 Hz, OH), 3.21 (1H, d, J¼5.5 Hz, OH),
3.79e3.83 (1H, m, HOCHCH2CH3), 3.81 (s, 3H, OMe), 4.12e4.14
Scheme 5. Total synthesis of (17S,18R)- and (17R,18S)-resolvin E3.
(1H, m, COCHOH); 13C NMR (125 MHz, CDCl3)
d 10.1, 26.8, 52.8,

3214
D. Urabe et al. / Tetrahedron 68 (2012) 3210e3219
72.6, 73.9, 174.1; HRMS (ESI) calcd for C6H12NaO4 171.0628
2886, 2858, 1738, 1472, 1256, 1115 cmꢂ1; 1H NMR (400 MHz, CDCl3)
(MþNaþ), found 171.0628.
d
0.04 (3H, s, CH3 of TBS), 0.07 (6H, s, CH3 of TBSꢁ2), 0.08 (3H, s, CH3
of TBS), 0.91 (3H, m, eCH2CH3), 0.89 (9H, s, t-Bu of TBS), 0.92 (9H, s,
t-Bu of TBS), 1.36 (1H, dqd, J¼15.1, 7.3, 7.3 Hz, eCHCHAHBCH3), 1.76
(1H, dqd, J¼14.7, 7.8, 5.6 Hz, eCHCHAHBCH3), 3.79 (1H, td, J¼7.7,
4.1 Hz, eCHCH(OTBS)CH2e), 4.01 (1H, d, J¼4.1 Hz, COCH(OTBS)
4.1.2. Diol 10b. A mixture of methansulfonamide (2.7 g,
28.4 mmol), K3Fe(CN)6 (28.1 g, 85.4 mmol), K2CO3 (11.8 g,
85.5 mmol), OsO4 (1.8 mL, 0.29 mmol, 0.16 M solution in H2O), and
(DHQ)2PHAL (222 mg, 0.285 mmol) in t-BuOH (95 mL) and water
(100 mL) was stirred for 10 min at 0 ꢀC. A solution of ester 9 (4.0 g,
35.1 mmol) in t-BuOH (5 mL) was added to the mixture in one
portion. The reaction mixture was stirred for 24 h at 0 ꢀC, and
saturated aqueous Na2S2O3 (200 ml), solid NaCl, and EtOAc
(100 mL) were successively added. The resultant mixture was stir-
red at room temperature for additional 1 h. After separation of the
organic layer, the aqueous phase was extracted with EtOAc
(50 mLꢁ7). Combined organic layers were dried over Na2SO4, fil-
tered, and concentrated. The residue was purified by flash chro-
matography on silica gel (75 g, pentane/ether 1:1 to 1:2 to 1:4) to
afford diol 10b (3.76 g, 25.4 mmol) in 72% yield. The enantiopurity
CHe), 9.76 (1H ,s, eCHO); 13C NMR (100 MHz, CDCl3)
d
ꢂ5.2, ꢂ4.60,
ꢂ4.58, ꢂ4.52, 10.5, 18.0, 18.2, 25.6, 25.70, 25.72, 76.0, 79.9, 203.8;
HRMS (ESI) calcd for C17H38NaO3Si2 369.2252 (MþNaþ), found
369.2247.
4.1.5. Aldehyde 6b. According to the synthetic procedure of 6a, 6b
(182 mg, 0.52 mmol) was synthesized from 10b (120 mg,
0.81 mmol) in 64% yield over three steps by using TBSCl (440 mg,
2.90 mmol) and imidazole (440 mg, 6.47 mmol) in DMF for the first
step, DIBAL-H (1.1 mL,1.5 M in toluene,1.65 mmol) in CH2Cl2 (8 mL)
for the second step, Dess-Martin periodinane (420 mg, 0.99 mmol)
and NaHCO3 (273 mg, 3.25 mmol) in CH2Cl2 (7 mL) for the third
was determined to be 98% ee by following the James’ protocol:14
step, and purification on silica gel (10 g, hexane/EtOAc 25:1): col-
17
25
pale yellow oil; [
a]
ꢂ7.0 (c 0.93, CHCl3); HRMS (ESI) calcd for
orless oil;
[
a
]
D
ꢂ52 (c 0.12, CHCl3); HRMS (ESI) calcd for
D
C6H12NaO4 171.0628 (MþNaþ), found 171.0634; IR, 1H NMR, and 13
NMR spectra were identical with those of diol 10a.
C
C17H38NaO3Si2 369.2252 (MþNaþ), found 369.2246; IR, 1H NMR,
and 13C NMR spectra were identical with those of aldehyde 6a.
4.1.3. Bis-TBS ether 11a. TBSCl (1.14 g, 7.59 mmol) was added to
a solution of diol 10a (276 mg, 1.86 mmol) and imidazole (1.01 g,
14.9 mmol) in DMF (19 mL). After being stirred at room tempera-
ture for 13 h, the reaction mixture was cooled to 0 ꢀC. Then, H2O
(20 mL) was added to the mixture. The resultant mixture was
extracted with hexane (10 mLꢁ3). Combined organic layers were
washed with brine (30 mL), dried over Na2SO4, filtered, and con-
centrated. The residue was purified by flash chromatography on
silica gel (25 g, hexane/EtOAc 50:1 to 15:1) to afford bis-TBS ether
4.1.6. Sulfate 12a. To a solution of diol 10a (705 mg, 4.76 mmol)
and Et3N (4.0 mL, 29 mmol) in CH2Cl2 (15 mL) was added SOCl2
(710 m
L, 9.7 mmol) dropwise at 0 ꢀC. After being stirred at 0 ꢀC for
30 min, the reaction mixture was quenched with H2O (30 mL). After
separation of the organic layer, the aqueous layer was extracted
with CH2Cl2 (20 mLꢁ2). Combined organic layers were dried over
Na2SO4, filtered, and concentrated to give sulfite, which was used
for the next reaction without further purification.
RuCl3$nH2O (5.6 mg) was added to a solution of the crude sulfite
in a mixture of CH3CN (10 mL) and CCl4 (10 mL), and the resulting
mixture was cooled to 0 ꢀC. Then, a solution of NaIO4 (2.35 g,
11.0 mmol) in H2O (20 mL) was added to the mixture. The mixture
was stirred for 40 min at room temperature and additional
RuCl3$nH2O (32 mg) was added. The reaction mixture was stirred
for additional 30 min, and 2-propanol (5 mL) was added. After
being diluted with 0.1 N HCl (100 mL), the mixture was extracted
with CH2Cl2 (70 mLꢁ1, 20 mLꢁ2). Combined organic layers were
washed with saturated aqueous NaHCO3 (50 mL) and brine
(50 mL), dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography on silica gel (50 g,
hexane/EtOAc 1:2 to 1:3) to afford sulfate 12a (779 mg, 3.71 mmol)
11a (489 mg, 1.30 mmol) in 70% yield: colorless oil; [a]
20 5.3 (c 1.4,
D
CHCl3); IR (neat)
(400 MHz, CDCl3)
n
d
2954, 2930, 2858, 1759, 1255 cmꢂ1
;
1H NMR
0.027 (3H, s, CH3 of TBS), 0.033 (3H, s, CH3 of
TBS), 0.04 (3H, s, CH3 of TBS), 0.06 (3H, s, CH3 of TBS), 0.87 (9H, s, t-
Bu of TBS), 0.89 (3H, t, J¼7.4 Hz, eCH2CH3), 0.90 (9H ,s, t-Bu of TBS),
1.38 (1H, ddq, 1H, J¼15.1, 7.4, 7.4 Hz, eCHCHAHBCH3), 1.75 (1H, dqd,
J¼15.1, 7.4, 6.0 Hz, eCHCHAHBCH3), 3.69 (3H, s, OMe), 3.76 (1H, ddd,
J¼7.4, 6.0, 4.1 Hz, eCH(TBSO)CHCH2CH3), 4.19 (1H, d, J¼4.1 Hz,
COCH(OTBS)CHe); 13C NMR (100 MHz, CDCl3)
d
ꢂ5.2, ꢂ4.9, ꢂ4.5,
ꢂ4.4, 10.3, 18.0, 18.3, 25.4, 25.7, 25.8, 51.4, 74.6, 75.9, 172.8; HRMS
(ESI) calcd for C18H40NaO4Si2 399.2357 (MþNaþ), found 399.2374.
4.1.4. Aldehyde 6a. To a solution of bis-TBS ether 11a (478 mg,
1.27 mmol) in CH2Cl2 (13 mL) was added DIBAL-H (1.8 mL, 1.5 M in
toluene, 2.7 mmol) dropwise at 0 ꢀC. After being stirred for 10 min,
the reaction mixture was quenched with saturated aqueous po-
tassium sodium tartrate (10 mL) at 0 ꢀC. Then, the resulting mixture
was allowed to warm to room temperature and stirred for 30 min.
After separation of the organic layer, the aqueous layer was
extracted with CH2Cl2 (20 mLꢁ3). Combined organic layers were
washed with brine (30 mL), dried over Na2SO4, filtered, and con-
centrated to give crude alcohol, which was used for the next re-
action without further purification.
in 78% yield over two steps: colorless oil; [
(neat)
2980,1771,1751,1394,1209,1050 cmꢂ1; 1H NMR (400 MHz,
CDCl3)
a]
26 46 (c 0.35, CHCl3); IR
D
n
d
1.13 (3H, t, J¼7.3 Hz, eCH2CH3), 1.98e2.09 (2H, m,
eCHCH2CH3), 3.90 (3H, s, OMe), 4.88e4.93 (2H, m, eCHeꢁ2); 13C
NMR (100 MHz, CDCl3) d 9.1, 26.3, 53.7, 79.4, 85.1, 165.4; HRMS (ESI)
calcd for C6H10O6SNa 233.0090 (MþNaþ), found 233.0097.
4.1.7. Sulfate 12b. According to the synthetic procedure of 12a, 12b
(863 mg, 4.11 mmol) was synthesized from 10b (796 mg,
5.38 mmol) in 76% yield over two steps by using SOCl2 (800 mL,
11.0 mmol) and Et3N (4.5 mL, 32 mmol) in CH2Cl2 (15 mL) for the
first step, RuCl3$nH2O (56 mg) and NaIO4 (2.86 g, 13.4 mmol) in
a mixture of CH3CN (10 mL), CCl4 (10 mL), and H2O (20 mL) for the
second step, and purification on silica gel (45 g, hexane/EtOAc 1:1
DesseMartin periodinane (1.15 g, 2.70 mmol) was added to
a solution of the crude alcohol and NaHCO3 (460 mg, 5.48 mmol) in
CH2Cl2 (11 mL) at room temperature. After being stirred at room
temperature for 1 h, the reaction mixture was quenched with H2O
(10 mL). The resultant suspension was filtered through a pad of
cotton and the filtrate was extracted with CH2Cl2 (15 mLꢁ3).
Combined organic layers were washed with brine (20 mL), dried
over Na2SO4, filtered, and concentrated. The residue was purified by
flash chromatography on silica gel (10 g, hexane/EtOAc 30:1) to
afford aldehyde 6a (320 mg, 0.92 mmol) in 72% yield over two
to 3:1): colorless oil; [
a
]
27 ꢂ42 (c 0.55, CHCl3); HRMS (ESI) calcd for
D
C6H10O6SNa 233.0090 (MþNaþ), found 233.0095; IR, 1H NMR, and
13C NMR spectra were identical with those of sulfate 12a.
4.1.8. Benzoate 13a. A solution of sulfate 12a (475 mg, 2.26 mmol)
and NH4OBz (629 mg, 4.52 mmol) in DMF (7.8 mL) was stirred at
room temperature for 1 h. DMF was azeotropically removed with
toluene, then the residue was diluted with Et2O (27 mL) and 20%
steps: colorless oil; [a] n 2956, 2931,
25 58 (c 0.22, CHCl3); IR (neat)
D

D. Urabe et al. / Tetrahedron 68 (2012) 3210e3219
3215
aqueous H2SO4 (4.5 mL) at 0 ꢀC. The mixture was stirred at room
temperature for 12 h, and H2O (30 mL) was added. The resulting
mixture was extracted with EtOAc (20 mLꢁ3), and combined or-
ganic layers were washed with saturated aqueous NaHCO3 (30 mL)
and brine (30 mL), dried over Na2SO4, filtered, and concentrated.
The residue was purified by flash column chromatography on silica
gel (45 g, hexane/EtOAc 9:1 to 2:1). The crude product was further
purified by flash column chromatography on silica gel (45 g, hex-
ane/EtOAc 5:1 to 3:1) to afford benzoate 13a (501 mg,1.99 mmol) in
d 0.02 (3H, s, CH3 of TBS), 0.041 (3H, s, CH3 of TBS), 0.045 (3H, s, CH3
of TBS), 0.054 (3H, s, CH3 of TBS), 0.86 (9H, s, t-Bu of TBS), 0.87 (3H,
t, J¼7.8 Hz, eCH2CH3), 0.89 (9H, s, t-Bu of TBS), 1.51e1.72 (2H, m,
eCHCH2CH3), 3.69 (3H, s, OMe), 3.88 (1H, dt, J¼6.0, 5.0 Hz,
eCHCH(OTBS)CH2e), 4.09 (1H, d, J¼6.0 Hz, COCH(OTBS)CHe);
13C NMR (100 MHz, CDCl3)
d
ꢂ5.3, ꢂ5.1, ꢂ4.8, ꢂ4.5, 8.3, 18.0, 18.2,
25.4, 25.6, 25.8, 51.5, 75.1, 75.2, 173.0; HRMS (ESI) calcd for
C18H40O4Si2Na 399.2357 (MþNaþ), found 399.2373.
88% yield over two steps: colorless oil; [
(neat)
CDCl3)
eCHCH2CH3), 2.43 (1H, br s, OH), 3.79 (3H, s, OMe), 4.07e4.12 (1H,
m, eCHeCH(OH)CH2e), 5.29 (1H, d, J¼4.6 Hz, COCH(OBz)eCHe),
7.46 (2H, dddd, J¼8.0, 7.5, 1.7, 1.7 Hz, aromatic), 7.59 (1H, tt, J¼8.0,
1.7 Hz, aromatic), 8.08 (2H, dd, J¼8.0, 1.7 Hz, aromatic); 13C NMR
a
]
27 ꢂ3.9 (c 0.45, CHCl3); IR
4.1.13. Bis-TBS ether 11d. According to the synthetic procedure of
11a, 11d (976 mg, 2.59 mmol) was synthesized from 10d (384 mg,
2.59 mmol) in 100% yield by using TBSCl (1.56 g, 10.4 mmol) and
imidazole (1.41 g, 20.7 mmol) in DMF (13 mL) and purification on
D
d
3504, 2963, 1727, 1447, 1277, 1114 cmꢂ1; 1H NMR (500 MHz,
d
1.05 (3H, t, J¼7.5 Hz, eCH2CH3), 1.67e1.74 (2H, m,
silica gel (20 g, hexane/Et2O 100:0 to 5:1): colorless oil; [
a
]
24 ꢂ11 (c
D
0.57, CHCl3); HRMS (ESI) calcd for C18H40O4Si2Na 399.2357
(MþNaþ), found 399.2359; IR, 1H NMR, and 13C NMR spectra were
identical with those of bis-TBS ether 11c.
(125 MHz, CDCl3)
d 9.9, 25.7, 52.5, 72.7, 75.5, 128.5, 129.1, 129.9,
133.5, 165.7, 169.0; HRMS (ESI) calcd for C13H16O5Na 275.0890
(MþNaþ), found 275.0901.
4.1.14. Aldehyde 6c. According to the synthetic procedure of 6a, 6c
(105 mg, 0.303 mmol) was synthesized from 11c (153 mg,
0.406 mmol) in 75% yield over two steps by using DIBALeH (1.0 mL,
1.0 M in hexane, 1.0 mmol) in CH2Cl2 (5 mL) for the first step,
DesseMartin periodinane (269 mg, 0.634 mmol) and NaHCO3
(290 mg, 3.45 mmol) in CH2Cl2 (5 mL) for the second step, and
4.1.9. Benzoate 13b. According to the synthetic procedure of 13a,
13b (855 mg, 3.39 mmol) was synthesized from 12b (820 mg,
3.90 mmol) in 87% yield over two steps by using NH4OBz (1.09 g,
7.84 mmol) in DMF (7.8 mL) for the first step, 20% aqueous H2SO4
(7.8 mL) in Et2O (48 mL) for the second step, and purification on
purification on silica gel (10 g, hexane/EtOAc 100:1 to 50:1): col-
26
25
silica gel (30 g, hexane/EtOAc 7:1 to 2:1): colorless oil; [
a
]
3.7 (c
orless oil; [
a
]
0.37 (c 0.31, CHCl3); IR (neat)
n
2956, 2933, 2859,
D
D
0.28, CHCl3); HRMS (ESI) calcd for C13H16O5Na 275.0890 (MþNaþ),
found 275.0889; IR, 1H NMR, and 13C NMR spectra were identical
with those of benzoate 13a.
1739, 1468, 1255, 1114 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 0.06 (3H,
s, CH3 of TBS), 0.070 (3H, s, CH3 of TBS), 0.074 (6H, s, CH3 of TBSꢁ2),
0.87 (9H, s, t-Bu of TBS), 0.87 (3H, t, J¼7.8 Hz, eCH2CH3), 0.91 (9H,
s, t-Bu of TBS), 1.53e1.66 (2H, m, eCHCH2CH3), 3.83 (1H, td,
J¼5.9, 3.7 Hz, eCHCH(OTBS)CH2e), 3.89 (1H, dd, J¼3.7, 1.8 Hz,
COCH(OTBS)CHe), 9.60 (1H, d, J¼1.8 Hz, CHO); 13C NMR (100 MHz,
4.1.10. Diol 10c. A mixture of benzoate 13a (475 mg, 1.88 mmol)
and K2CO3 (143 mg, 1.04 mmol) in MeOH (20 mL) was stirred at
room temperature for 1 h. Then, brine (20 mL) and 1 M HCl (2 mL)
were successively added. The resulting mixture was extracted with
CH2Cl2 (15 mLꢁ7), and combined organic layers were dried over
Na2SO4, filtered, and concentrated. The residue was purified by
flash column chromatography on silica gel (45 g, hexane/EtOAc 1:1
to 1:2) to afford diol 10c (152 mg, 1.03 mmol) in 55% yield. The
enantiopurity was determined to be 98% ee by following the James’
CDCl3)
d
ꢂ4.9, ꢂ4.7, ꢂ4.5, 9.4,18.1,18.3, 25.78, 25.81, 26.2, 76.5, 80.3,
203.7; HRMS (ESI) calcd for C17H38O3Si2Na 369.2252 (MþNaþ),
found 369.2265.
4.1.15. Aldehyde 6d. According to the synthetic procedure of 6a, 6d
(68 mg, 0.196 mmol) was synthesized from 11d (100 mg,
0.265 mmol) in 74% yield over two steps by using DIBALeH (530 mL,
1.0 M in hexane, 0.53 mmol) in CH2Cl2 (2.7 mL) for the first step,
DesseMartin periodinane (197 mg, 0.465 mmol) and NaHCO3
(390 mg, 4.64 mmol) in CH2Cl2 (2.3 mL) for the second step, and
protocol:14 white solid; mp¼50e50.5 ꢀC (as needles recrystallized
28
from hexane/EtOAc); [
a
]
ꢂ25 (c 0.21, CHCl3); IR (neat)
n 3394,
D
2964, 1737, 1446, 1222, 1127, 1088 cmꢂ1; 1H NMR (400 MHz, CDCl3)
0.98 (3H, t, J¼7.3 Hz, eCH2CH3), 1.42e1.60 (2H, m, eCHCH2CH3),
d
purification on silica gel (12 g, hexane/EtOAc 100:0 to 99:1 to 98:2
26
3.74e3.79 (1H, m, eCHeCH(OH)eCH2e), 3.79 (s, 3H, OMe), 4.24
to 97:3 to 96:4 to 95:5): colorless oil; [
a
]
D
0.39 (c 0.62, CHCl3);
(1H, d, J¼3.7 Hz, COCH(OH)CHe); 13C NMR (100 MHz, CDCl3)
d
10.2,
HRMS (ESI) calcd for C17H38O3Si2Na 369.2252 (MþNaþ), found
369.2255; IR, 1H NMR, and 13C NMR spectra were identical with
those of aldehyde 6c.
24.8, 52.5, 73.8, 74.7, 173.3; HRMS (ESI) calcd for C6H12O4Na
171.0628 (MþNaþ), found 171.0632.
4.1.11. Diol 10d. According to the synthetic procedure of 10c, 10d
(394 mg, 2.66 mmol) was synthesized from 11b (810 mg,
3.21 mmol) in 83% yield by using K2CO3 (244 mg, 1.77 mmol) in
MeOH (53 mL) and purification on silica gel (45 g, hexane/EtOAc
1:1 to 1:2). The enantiopurity was determined to be 96% ee by
4.1.16. Tosylate 4. A solution of tosylate 7 (265 mg, 1.10 mmol) in
DMF (1.5 mL) was added to
a suspension of NaI (74 mg,
0.49 mmol), CuI (96 mg, 0.50 mmol), Cs2CO3 (164 mg, 0.50 mmol),
and alkyne 8 (70 mg, 0.50 mmol) in DMF (3.5 mL) at 0 ꢀC. The
resulting mixture was stirred at room temperature for 18 h, and
poured into saturated aqueous NH4Cl (5 mL). After H2O (15 mL)
was added, the solution was extracted with EtOAc (10 mLꢁ3).
Combined organic layers were washed with H2O (20 mL) and brine
(20 mL), dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography on silica gel (6 g,
hexane/EtOAc 5:1 to 3:1 to 2:1 to 1:1) to afford propargyl alcohol
15, which was used in the next reaction without further
purification.
Tosyl chloride (181 mg, 0.95 mmol) was added to a suspension
of the crude propargyl alcohol 15, K2CO3 (132 mg, 0.96 mmol), and
Me3N$HCl (5.6 mg, 0.058 mmol) in CH2Cl2 (4 mL) at 0 ꢀC. The re-
action mixture was stirred at room temperature for 58 h, and di-
luted with Et2O. The resulting solution was filtrated through a pad
using the James’ protocol:14 white solid; mp¼46e47 ꢀC (as nee-
20
dles recrystallized from hexane/EtOAc); [
a
]
24 (c 0.10, CHCl3);
D
HRMS (ESI) calcd for C6H12O4Na 171.0628 (MþNaþ), found
171.0625; IR, 1H NMR, and 13C NMR spectra were identical with
those of diol 10c.
4.1.12. Bis-TBS ether 11c. According to the synthetic procedure of
11a, 11c (290 mg, 0.77 mmol) was synthesized from 10c (127 mg,
0.86 mmol) in 90% yield by using TBSCl (516 mg, 3.43 mmol) and
imidazole (469 mg, 6.90 mmol) in DMF (4.3 mL) and purification
on silica gel (12 g, hexane/EtOAc 1:0 to 50:1 to 30:1 to 15:1): col-
26
orless oil; [
a
]
10 (c 0.53, CHCl3); IR (neat) n 2956, 2935, 2892,
D
2859,1755,1468,1366,1255,1122 cmꢂ1; 1H NMR (400 MHz, CDCl3)

3216
D. Urabe et al. / Tetrahedron 68 (2012) 3210e3219
of Celite with Et2O. The filtrate was concentrated and purified by
flash column chromatography on silica gel (6 g, hexane/EtOAc 4:1)
to afford tosylate 4 (95 mg, 0.26 mmol) in 52% yield over two steps:
(105 mg, 0.303 mmol) by using 5 (136 mg, 0.633 mmol) and n-BuLi
(270 L, 1.6 M in hexane, 0.43 mmol) in THF (3 mL).
The mixture was subjected to the isomerization according to
the synthetic procedure of 16a by treatment with I2 (0.8 mg,
3 mmol) in benzene (3 mL) to give 16c as a 10:1 E/Z mixture. The
mixture was purified by a flash chromatography on silica gel (20 g,
hexane/CH2Cl2 100:1 to 50:1 to 20:1) to afford 16c as a 10:1 E/Z
m
yellow oil; IR (neat)
n
2952, 3884, 1365, 1180, 943 cmꢂ1; HRMS (ESI-
TOF), calcd for C19H22O5SNa 385.1080 (MþNaþ), found 385.1076; 1H
NMR (500 MHz, CDCl3)
d
1.56e1.62 (2H, m, eCH2CH2CH2e), 1.73
(2H, m, eCH2CH2CHe), 2.18 (2H, tt, J¼6.8, 2.3 Hz, CCeCH2CH2e),
2.43 (3H, s, Me of Ts), 3.01 (2H, tt, J¼2.3, 2.3 Hz, eCCeCH2eCCe),
3.81e3.84 (2H, m, acetal), 3.92e3.95 (2H, m, acetal), 4.67 (2H, t,
J¼2.3 Hz, TsOCH2eCCe), 4.84 (1H, t, J¼4.5 Hz, eCH2CHe), 7.33 (2H,
d, J¼8.5 Hz, aromatic), 7.79 (2H, d, J¼8.5 Hz, aromatic); 13C NMR
mixture (127 mg, 0.27 mmol) in 89% over two steps: colorless oil;
25
[
a
]
16 (c 0.10, CHCl3); IR (neat)
n
2958, 2929, 2891, 2858, 2161,
D
2122, 1472, 1252, 1108, 838 cmꢂ1
isomer)
;
1H NMR (400 MHz, CDCl3, E
d
ꢂ0.01 (3H, s, CH3 of TBS), 0.00 (3H, s, CH3 of TBS), 0.02
(125 MHz, CDCl3)
d
9.8, 18.5, 21.6, 23.0, 32.8, 58.2, 64.8, 71.8, 72.7,
(3H, s, CH3 of TBS), 0.03 (3H, s, CH3 of TBS), 0.19 (9H, s, TMS),
0.86e0.89 (3H, m, eCH2CH3 ), 0.87 (9H, s, t-Bu of TBS), 0.88 (9H, s,
t-Bu of TBS), 1.43e1.58 (2H, m, eCHCH2CH3), 3.51 (1H, dt, J¼5.5,
5.5 Hz, eCHCH(OTBS)CH2e), 3.98 (1H, dd, J¼7.3, 5.5 Hz, eCH]
CHCH(OTBS)CHe), 5.57 (1H, d, J¼16.0 Hz, TMSCCeCH]CHe), 5.78
(1H, dd, J¼16.0, 7.3 Hz, eCH]CHCH(OTBS)CHe), 6.15 (1H, dd,
J¼16.0, 11.0 Hz, eC]CHeCH]CHCH(OTBS)e), 6.66 (1H, dd, J¼16.0
11.0 Hz, eCCeCH]CHeCH]CHe); 13C NMR (125 MHz, CDCl3, E
80.8, 84.5, 104.1, 128.1, 129.7, 133.1, 144.9.
4.1.17. Dienyne 16a. n-BuLi (780 mL, 1.6 M in hexane, 1.25 mmol)
was added dropwise to a solution of phosphonate 5 (330 mg,
1.53 mmol) in THF (7 mL) at ꢂ78 ꢀC. The mixture was stirred at 0 ꢀC
for 10 min and cooled to ꢂ78 ꢀC. To the mixture a solution of al-
dehyde 6a (310 mg, 0.893 mmol) in THF (3 ml) was added. The
reaction mixture was allowed to warm to room temperature. After
being stirred for 1 h, the reaction mixture was quenched with
saturated aqueous NH4Cl (10 mL). The resulting mixture was
extracted with EtOAc (20 mLꢁ3), and combined organic layers
were washed with brine (30 mL), dried over Na2SO4, filtered, and
concentrated. Filtration of the residue through short column of
silica gel with a mixture of hexane/EtOAc (15:1) afforded dienyne
16a as a 2.5:1 E/Z mixture, which was used for the next reaction
without further purification.
isomer)
d
ꢂ4.8, ꢂ4.5, ꢂ4.10, ꢂ4.07, 0.1, 9.1, 18.16, 18.22, 25.90,
25.94, 26.05, 75.9, 77.1, 96.9, 104.5, 110.4, 130.3, 138.4, 142.4;
HRMS (ESI) calcd for C25H50O2NaSi3 489.3011 (MþNaþ), found
489.3009.
4.1.20. Dienyne 16d. According to the synthetic procedure of 16a,
a 10:1 E/Z mixture of 16d (132 mg, 0.284 mmol) was synthesized
from 6d (102 mg, 0.295 mmol) in 96% yield over two steps by
using phosphonate 5 (103 mg, 0.479 mmol) and n-BuLi (260
1.6 M in hexane, 0.42 mmol) in THF (3 mL) for the first step, I2
(0.8 mg, 3 mol) in benzene (3 mL) for the second step, and pu-
rification by a flash chromatography on silica gel (20 g, hexane/
mL,
A mixture of the crude 16a and I2 (2.0 mg, 7.9 mmol) in benzene
(9 mL) was stirred for 1 h at room temperature, and the reaction
mixture was quenched with saturated aqueous Na2S2O3$5H2O
(10 mL). The resulting mixture was extracted with EtOAc
(10 mLꢁ3). Combined organic layers were washed with brine
(15 mL), dried over Na2SO4, filtered, and concentrated to give crude
16a as a 15:1 E/Z mixture. The residue was purified by flash chro-
matography on silica gel (15 g, hexane/CH2Cl2 30:1) to afford 16a
m
24
CH2Cl2 100:1 to 50:1 to 20:1): colorless oil; [
a
]
ꢂ10 (c 0.10,
D
CHCl3); HRMS (ESI) calcd for C25H50O2NaSi3 489.3011 (MþNaþ),
found 489.3022; IR, 1H NMR, and 13C NMR spectra were identical
with those of 16c.
(344 mg, 0.74 mmol) in 83% over two steps: colorless oil; [
0.29, CHCl3); IR (neat) 2957, 2930, 2896, 2858, 2165, 2120, 1639,
1472, 1362, 1252, 1110 cmꢂ1; 1H NMR (400 MHz, CDCl3)
0.02 (3H,
a
]
25 86 (c
4.1.21. Terminal alkyne 3a. A mixture of 16a (335 mg, 0.717 mmol)
and K2CO3 (297 mg, 2.15 mmol) in MeOH (7 ml) was stirred for
30 min at room temperature and diluted with H2O (10 mL) and
EtOAc (10 mL). After separation of the organic layer, the aqueous
layer was extracted with EtOAc (10 mLꢁ2), and combined organic
layers were washed with brine (20 mL), dried over Na2SO4, filtered,
and concentrated. The residue was filtered through a pad of silica
D
n
d
s, CH3 of TBS), 0.04 (3H, s, CH3 of TBS), 0.05 (3H, s, CH3 of TBS), 0.06
(3H, s, CH3 of TBS), 0.18 (9H, s, TMS), 0.85 (3H, t, J¼7.4 Hz,
eCH2CH3), 0.89 (9H, s, t-Bu of TBS), 0.90 (9H, s, t-Bu of TBS), 1.16
(1H, dqd, J¼14.2, 8.7, 7.4 Hz, eCHCHAHBCH3), 1.58 (1H, dqd, J¼14.2,
7.4, 3.6 Hz, eCHCHAHBCH3), 3.49 (1H, ddd, J¼8.7, 5.0, 3.6 Hz,
eCHCH(OTBS)CH2e), 4.20 (1H, dd, J¼5.0, 4.6 Hz, eCH]
CHCH(OTBS)eCHe), 5.55 (1H, d, J¼15.6 Hz, TMSCCeCH]CHe),
5.94 (1H, dd, J¼15.6, 4.6 Hz, eCH]CHCH(OTBS)e), 6.25 (1H, ddd,
J¼15.6, 11.0, 0.9 Hz, CH]CHeCH]CHCH(OTBS)e), 6.68 (1H, dd,
J¼15.6, 11.0 Hz, TMSCCeCH]CHe); 13C NMR (100 MHz, CDCl3)
gel (5 g, hexane/EtOAc 20:1) to afford terminal alkyne 3a (278 mg,
25
0.70 mmol) in 98% yield: yellow oil; [
(neat)
1H NMR (400 MHz, CDCl3)
a
]
D
109 (c 0.71, CHCl3); IR
n
3314, 2956, 2930, 2858, 2362, 1472, 1463, 1257, 1110 cmꢂ1
0.03 (3H, s, CH3 of TBS), 0.05 (3H, s, CH3
;
d
of TBS), 0.06 (3H, s, CH3 of TBS), 0.07 (3H, s, CH3 of TBS), 0.87 (3H, t,
J¼7.3 Hz, eCH2CH3), 0.90 (9H, s, t-Bu of TBS), 0.91 (9H, s, t-Bu of
TBS), 1.16 (1H, dqd, J¼14.2, 9.2, 7.3 Hz, eCHCHAHBCH3), 1.61 (1H,
dqd, J¼14.2, 7.3, 3.2 Hz, eCHCHAHBCH3), 2.99 (1H, d, J¼2.3 Hz,
HeCCe), 3.50 (1H, ddd, J¼9.2, 5.0, 3.2 Hz, eCHCH(OTBS)CH2e),
4.22 (1H, dd, J¼4.6, 3.2 Hz, eCH]CHeCH(OTBS)CHe), 5.51 (1H, dd,
J¼15.6, 2.3 Hz, HCCeCH]CHe), 5.97 (1H, dd, J¼15.6, 4.6 Hz, eCH]
CHeCH(OTBS)e), 6.28 (1H, ddd, J¼15.6, 11.0, 1.8 Hz, eCCeCH]
CHeCH]CHe), 6.71 (1H, dd, J¼15.6, 11.0 Hz, eCCeCH]CHeCH]
d
ꢂ4.9, ꢂ4.7, ꢂ4.6, ꢂ4.3, ꢂ0.1, 10.8, 18.0, 18.2, 24.0, 25.80, 25.83,
74.9, 77.1, 96.5, 104.6, 109.7, 129.1, 136.9, 142.9; HRMS (ESI) calcd for
C25H50NaO2Si3 489.3011 (MþNaþ), found 489.2994.
4.1.18. Dienyne 16b. According to the synthetic procedure of 16a,
16b (193 mg, 0.41 mmol) was synthesized from 6b (172 mg,
0.50 mmol) in 82% yield over two steps by using phosphonate 5
(185 mg, 0.86 mmol) and n-BuLi (440
mL, 1.6 M in hexane,
CHe),; 13C NMR (100 MHz, CDCl3)
18.0, 18.2, 24.0, 25.80, 25.83, 74.8, 77.1, 78.9, 83.1, 108.6, 128.8, 137.1,
143.4; HRMS (ESI) calcd for C22H42NaO2Si2 417.2616 (MþNaþ),
found 417.2625.
d
ꢂ4.84, ꢂ4.76, ꢂ4.6, ꢂ4.3, 10.8,
0.70 mmol) in THF (2 mL) for the first step, I2 (1.2 mg, 4.7
mmol) in
benzene (5 mL) for the second step, and purification on silica gel
(15 g, hexane/CH2Cl2 30:1): colorless oil; [
a
]
D
25 ꢂ86 (c 0.43, CHCl3);
HRMS (ESI) calcd for C25H50NaO2Si3 489.3011 (MþNaþ), found
489.3013; IR, 1H NMR, and 13C NMR spectra were identical with
those of 16a.
4.1.22. Terminal alkyne 3b. According to the synthetic procedure of
3a, 3b (154 mg, 0.390 mmol) was synthesized from 16b (183 mg,
0.392 mmol) in 99% yield by using K2CO3 (168 mg, 1.22 mmol) in
MeOH (5 mL) and filtration through a pad of silica gel (5 g, hexane/
4.1.19. Dienyne 16c. According to the synthetic procedure of 16a,
a crude dienyne was synthesized as a 1.2:1 E/Z mixture from 6c
EtOAc 10:1): yellow oil; [
a
]
D
25 ꢂ100 (c 0.69, CHCl3); HRMS (ESI) calcd

D. Urabe et al. / Tetrahedron 68 (2012) 3210e3219
3217
for C22H42NaO2Si2 417.2616 (MþNaþ), found 417.2599; IR, 1H NMR,
and 13C NMR spectra were identical with those of 3a.
0.13 mmol), NaI (19 mg, 0.13 mmol), and Cs2CO3 (41 mg,
0.13 mmol) in DMF (0.4 mL) and purification on silica gel (8 g,
25
hexane/EtOAc 20:1): pale yellow oil; [
a
]
ꢂ51 (c 0.25, CHCl3);
D
4.1.23. Terminal alkyne 3c. According to the synthetic procedure of
3a, 3c (90 mg, 0.23 mmol, a 8.5:1 E/Z mixture) was synthesized
from 16c (130 mg, 0.279 mmol, a 10:1 E/Z mixture) in 82% yield by
using K2CO3 (210 mg, 1.52 mmol) in MeOH (5 mL), and purification
HRMS (ESI) calcd for C34H56NaO4Si2 607.3609 (MþNaþ), found
607.3613; IR, 1H NMR, and 13C NMR spectra were identical with
those of triyne 2a.
on silica gel (20 g, hexane/EtOAc 50:1 to 20:1): yellow oil; [
0.43, CHCl3); IR (neat) 3313, 2956, 2932, 2887, 2858, 2098, 1469,
1362, 1254, 1108 cmꢂ1; 1H NMR (500 MHz, CDCl3, E isomer)
0.00
a]
24 11 (c
4.1.27. Triyne 2c. According to the synthetic procedure of 2a, 2c
(58 mg, 0.099 mmol, a 8.5:1 E/Z mixture) was synthesized from 3c
(99 mg, 0.25 mmol, a 8.5:1 E/Z mixture) in 40% yield by using 4
(109 mg, 0.30 mmol), CuI (48 mg, 0.25 mmol), NaI (38 mg,
0.25 mmol), and Cs2CO3 (82 mg, 0.25 mmol) in DMF (1.3 mL) and
D
n
d
(3H, s, CH3 of TBS), 0.01 (3H, s, CH3 of TBS), 0.03 (3H, s, CH3 of TBS),
0.05 (3H, s, CH3 of TBS), 0.87 (9H, s, t-Bu of TBS), 0.88 (3H, t,
J¼7.4 Hz, eCH2CH3), 0.88 (9H, s, t-Bu of TBS), 1.44e1.59 (2H, m,
eCHCH2CH3), 3.01 (1H, d, J¼2.3 Hz, HeCCe), 3.51 (1H, dt, J¼5.2,
5.2 Hz, eCHCH(OTBS)CH2e), 4.00 (1H, dd, J¼6.9, 5.2 Hz, eCH]
CHeCH(OTBS)CHe), 5.53 (1H, dd, J¼16.1, 2.3 Hz, HCCeCH]CHe),
5.80 (1H, dd, J¼15.5, 6.9 Hz, eCH]CHeCH(OTBS)e), 6.17 (1H, dd,
J¼15.5, 11.5 Hz, eCCeCH]CHeCH]CHe), 6.66 (1H, dd, J¼16.1,
11.5 Hz, eCCeCH]CHeCH]CHe); 13C NMR (125 MHz, CDCl3, E
purification on silica gel (12 g, hexane/EtOAc 1:0 to 100:1 to 50:1 to
26
25:1 to 10:1): yellow oil; [
a
]
D
8.9 (c 0.37, CHCl3); IR (neat) n 2953,
2935, 2887, 2860, 1468, 1253, 1106 cmꢂ1; 1H NMR (500 MHz, CDCl3,
E isomer)
ꢂ0.01 (3H, s, CH3 of TBS), 0.00 (3H, s, CH3 of TBS), 0.02
d
(3H, s, CH3 of TBS), 0.03 (3H, s, CH3 of TBS), 0.86 (9H, s, t-Bu of TBS),
0.87 (9H, s, t-Bu of TBS), 0.86e0.88 (3H, m, H20), 1.45e1.67 (4H, m,
H3 and H19), 1.74e1.78 (2H, m, H2), 2.23 (2H, tt, J¼7.5, 2.3 Hz, H4),
3.14 (2H, tt, J¼2.3, 2.3 Hz, H7), 3.30e3.32 (2H, m, H10), 3.50 (1H, dt,
J¼5.7, 5.7 Hz, H18), 3.83e3.87 (2H, m, acetal), 3.95e3.99 (3H, m,
H17 and acetal), 4.87 (1H, t, J¼4.6 Hz, H1), 5.53 (1H, br d, J¼16.1 Hz,
H13), 5.73 (1H, dd, J¼15.5, 6.9 Hz, H16), 6.13 (1H, dd, J¼15.5,
10.9 Hz, H15), 6.55 (1H, dd, J¼16.1, 10.9 Hz, H14); 13C NMR
isomer)
d
ꢂ4.8, ꢂ4.5, ꢂ4.1, 9.1, 18,15, 18.23, 25.91, 25.94, 26.0, 75.9,
77.2, 79.3, 83.0, 109.3, 129.9, 138.7, 143.1; HRMS (ESI) calcd for
C22H42O2NaSi2 417.2616 (MþNaþ), found 417.2618.
4.1.24. Terminal alkyne 3d. According to the synthetic procedure of
3a, 3d (93 mg, 0.24 mmol, a 8.5:1 E/Z mixture) was synthesized
from 16d (127 mg, 0.273 mmol, a 10:1 E/Z mixture) in 88% yield by
(100 MHz, C6D6, E isomer)
d
ꢂ4.6, ꢂ4.3, ꢂ3.84, ꢂ3.76, 9.4, 9.9, 10.6,
18.43, 18.48, 18.9 , 23.7, 26.19, 26.22, 26.4, 33.4, 64.8 (two peaks),
74.3, 74.7, 75.9, 76.5, 77.4, 80.4, 80.6, 87.0, 104.5, 111.7, 131.2, 137.4,
141.2; HRMS (ESI) calcd for C34H56O4NaSi2 607.3609 (MþNaþ),
found 607.3608.
using K2CO3 (193 mg, 1.44 mmol) in MeOH (5 mL) and purification
25
on silica gel (5 g, hexane/EtOAc 50:1 to 20:1): pale yellow oil; [a]
D
ꢂ5.6 (c 0.10, CHCl3); HRMS (ESI) calcd for C22H42O2Si2Na 417.2616
(MþNaþ), found 417.2602; IR, 1H NMR, and 13C NMR spectra were
identical with those of 3c.
4.1.28. Triyne 2d. According to the synthetic procedure of 2a, 2d
(90 mg, 0.15 mmol, a 8.5:1 E/Z mixture) was synthesized from 3d
(93 mg, 0.24 mmol, a 8.5:1 E/Z mixture) in 64% yield by using 4
(88 mg, 0.24 mmol), CuI (53 mg, 0.28 mmol), NaI (54 mg,
0.36 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in DMF (2 mL), and
4.1.25. Triyne 2a. A mixture of CuI (46 mg, 0.24 mmol), NaI (36 mg,
0.24 mmol), and Cs2CO3 (78 mg, 0.24 mmol) was dried in vacuo
with stirring at 90 ꢀC for 1 h. Then, a solution of 3a (95 mg,
0.24 mmol) in DMF (3.9 mL) was added to the mixture at 0 ꢀC. After
the resulting mixture was stirred for 3 min, a solution of freshly
prepared tosylate 4 (94 mg, 0.26 mmol) in DMF (0.9 ml) was
added. The reaction mixture was stirred at room temperature for
19 h in the dark, and quenched with saturated aqueous NH4Cl
(10 mL). The mixture was extracted with EtOAc (15 mLꢁ1,
10 mLꢁ2) and combined organic layers were washed with brine
(20 mL), dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash chromatography on silica gel (25 g, hexane/
EtOAc 20:1). The impure fractions were re-purified by flash chro-
purification on silica gel (10 g, hexane/EtOAc 7:1 to 3:1 to 1:1):
25
yellow oil; [
a
]
D
ꢂ6.5 (c 0.13, CHCl3); HRMS (ESI) calcd for
C34H56O4NaSi2 607.3609 (MþNaþ), found 607.3608; IR, 1H NMR,
and 13C NMR spectra were identical with those of triyne 2c.
4.1.29. Pentaene 17a. A mixture of triyne 2a (26 mg, 0.044 mmol),
Lindlar catalyst (78 mg, 300 wt %), and quinoline (62 mL,
0.53 mmol) in hexane (4.4 mL) was stirred at room temperature
under hydrogen atmosphere (1 atm) for 15 min. Additional Lindlar
catalyst (100e300 wt %) was added in every 15e30 min to the
reaction mixture until partially reduced products were dis-
appeared on TLC (4000 wt % of Lindlar catalyst was added in total).
The reaction mixture was filtered through a pad of Celite with
EtOAc (5 mLꢁ3). The filtrate was concentrated. The residue was
purified with flash chromatography on silica gel (3 g, hexane/
matography on silica gel (8 g, hexane/EtOAc 20:1). Triyne 2a (total
25
93 mg, 0.16 mmol) was obtained in 67% yield: pale yellow oil; [
48 (c 0.23, CHCl3); IR (neat)
1108 cmꢂ1 1H NMR (400 MHz, CDCl3)
a]
D
n
2955, 2928, 2857, 1471, 1462, 1256,
0.02 (3H, s, CH3 of TBS),
;
d
0.03 (3H, s, CH3 of TBS), 0.06 (6H, s, CH3 of TBS), 0.86 (3H, t,
J¼7.8 Hz, H20), 0.89 (18H, s, t-Bu of TBS), 1.16 (1H, dqd, J¼16.0, 7.8,
7.8 Hz, H19a), 1.53e1.67 (3H, m, H3 and H19b), 1.75 (2H, dt, J¼5.0,
5.0 Hz, H2), 2.22 (2H, tt, J¼6.4, 2.3 Hz, H4), 3.13 (2H, m, H7), 3.29
(2H, d, J¼2.3 Hz, H10), 3.48 (1H, ddd, J¼8.2, 4.6, 3.7 Hz, H18),
3.83e3.98 (4H, m, acetal), 4.19 (1H, dd, J¼4.6, 4.6 Hz, H17), 4.87
(1H, t, J¼5.0 Hz, H1), 5.50 (1H, d, J¼15.6 Hz, H13), 5.89 (1H, dd,
J¼15.1, 4.6 Hz, H16), 6.24 (1H, dd, J¼15.1,11.0 Hz, H15), 6.59 (1H, dd,
EtOAc 50:1) to afford pentaene 17a (14 mg, 0.024 mmol) in 55%
25
yield: pale yellow oil; [
a
]
62 (c 0.12, CHCl3); IR (neat) n 2954,
D
2926, 2857, 1471, 1463, 1256, 1108 cmꢂ1; 1H NMR (400 MHz, CDCl3)
0.047 (3H, s, CH3 of TBS), 0.052 (3H, s, CH3 of TBS), 0.06 (3H, s, CH3
d
of TBS), 0.07 (3H, s, CH3 of TBS), 0.87 (3H, t, J¼7.4 Hz, H20), 0.90
(9H, s, t-Bu of TBS), 0.91 (9H, s, t-Bu of TBS), 1.16e1.25 (1H, m,
H19a), 1.46e1.70 (5H, m, H2, H3 and H19b), 2.12 (2H, dt, J¼6.8,
6.8 Hz, H4), 2.82 (2H, dd, J¼5.6, 5.6 Hz, H7), 2.97 (2H, dd, J¼6.0,
6.0 Hz, H10), 3.49 (1H, ddd, J¼9.6, 4.8, 4.8 Hz, H18), 3.82e3.98 (4H,
m, acetal), 4.21 (1H, dd, J¼5.2, 5.2 Hz, H17), 4.85 (1H, t, J¼4.8 Hz,
H1), 5.34e5.41 (5H, m, H5, H6, H8, H9, and H11), 5.84 (1H, dd,
J¼14.8, 4.8 Hz, H16), 6.03 (1H, dd, J¼11.0, 11.0 Hz, H12), 6.24 (1H,
dd, J¼14.4, 11.6 Hz, H14), 6.28 (1H, ddd, J¼14.8, 11.6, 1.2 Hz, H15),
6.43 (1H, dd, J¼14.4, 11.0 Hz, H13); 13C NMR (125 MHz, CDCl3)
J¼15.6, 11.0 Hz, H14); 13C NMR (125 MHz, CDCl3)
ꢂ4.8, ꢂ4.7, ꢂ4.6,
d
ꢂ4.3, 9.8, 10.6, 10.8, 18.0, 18.1, 18.6, 23.1, 24.0, 25.80, 25.83, 32.9,
64.8(ꢁ2), 74.0, 74.2, 74.9, 75.2, 77.1, 80.0, 80.2, 85.5, 104.2, 109.7,
129.1, 136.0, 141.7; HRMS (ESI) calcd for C34H56NaO4Si2 607.3609
(MþNaþ), found 607.3591.
4.1.26. Triyne 2b. According to the synthetic procedure of 2a, 2b
(42 mg, 0.072 mmol) was synthesized from 3b (50 mg, 0.13 mmol)
in 55% yield by using tosylate 4 (55 mg, 0.15 mmol), CuI (24 mg,
d
ꢂ4.8, ꢂ4.6, ꢂ4.3, 10.8, 18.1, 18.2, 23.96, 24.01, 25.7, 25.9, 26.2,
27.0, 33.4, 64.8 (ꢁ2), 75.1, 77.3, 104.5, 126.7, 127.7, 128.1, 128.7,

3218
D. Urabe et al. / Tetrahedron 68 (2012) 3210e3219
129.0, 129.6, 129.8, 130.1, 133.1, 133.7; HRMS (ESI) calcd for
was stirred at room temperature for 2.5 h, additional TBAF (50
0.05 mmol) was added. After the reaction mixture was stirred at
room temperature for 1.5 h, additional TBAF (100 l, 0.1 mmol) was
ml,
C34H62NaO4Si2 613.4079 (MþNaþ), found 613.4082.
m
4.1.30. Pentaene 17b. According to the synthetic procedure of 17a,
17b (20 mg, 0.034 mmol) was synthesized from 2b (23 mg,
0.039 mmol) in 87% yield by using Lindlar catalyst (900 wt % in
added again. After being stirred for additional 30 min, the reaction
mixture was quenched with saturated aqueous NH4Cl (3 mL). The
resulting mixture was extracted with EtOAc (10 mLꢁ4), and com-
bined organic layers were dried over Na2SO4, filtered, and con-
centrated. The residue was purified by flash chromatography on
silica gel (1 g, hexane/EtOAc/AcOH 1:1:0.05) to afford (17R,18R)-
resolvin E3 1a along with a small amount of its 11E isomer. This
mixture was further purified with HPLC (Inertsil ODS-3, CH3CN/
H2O/AcOH 50:50:0.05, 3 mL/min, tR¼26 min) to afford (17R,18R)-
Resolvin E3 (1a) (5.5 mg, 0.016 mmol) in 43% yield over three steps:
total) and quinoline (55
mL, 0.47 mmol) in hexane (4 mL) under H2
atmosphere and purification on silica gel (3 g, hexane/EtOAc 50:1):
25
pale yellow oil; [
a
]
D
ꢂ78 (c 0.12, CHCl3); HRMS (ESI) calcd for
C34H62NaO4Si2 613.4079 (MþNaþ), found 613.4098; IR, 1H NMR,
and 13C NMR spectra were identical with those of pentaene 17a.
4.1.31. Pentaene 17c. According to the synthetic procedure of 17a,
17c (14 mg, 0.024 mmol) was synthesized from 2c (31 mg,
0.053 mmol, a 8.5:1 E/Z mixture) in 45% yield by using Lindlar
clear oil; [
a
]
D
25 34 (c 0.16, MeOH); IR (neat)
n
3427, 3014, 2931, 1707,
1407, 1260, 995 cme1
;
1H NMR (500 MHz, CD3OD)
d
0.97 (3H, t,
catalyst (1080 wt % in total) and quinoline (73
hexane (5.3 mL) under H2 atmosphere and purification on silica gel
m
L, 0.64 mmol) in
J¼7.5 Hz, H20), 1.36 (1H, ddq, J¼14.0, 9.0, 7.5 Hz, H19a), 1.58 (1H,
dqd, J¼14.0, 7.5, 3.5 Hz, H19b), 1.67 (2H, tt, J¼7.5, 7.5 Hz, H3), 2.13
(2H, td, J¼7.5, 7.0 Hz, H4), 2.29 (2H, t, J¼7.5 Hz, H2), 2.85 (2H, dd,
J¼6.0, 6.0 Hz, H7), 2.99 (2H, dd, J¼6.0, 6.0 Hz, H10), 3.34 (1H, ddd,
J¼9.0, 7.0, 3.5 Hz, H18), 3.97 (1H, dd, J¼7.0, 7.0 Hz, H17), 5.35e5.42
(5H, m, H5, H6, H8, H9, and H11), 5.74 (1H, dd, J¼15.0, 7.0 Hz, H16),
6.04 (1H, dd, J¼11.5, 11.5 Hz, H12), 6.24 (1H, dd, J¼15.0, 11.0 Hz,
H14), 6.37 (1H, dd, J¼15.0, 11.0 Hz, H15), 6.58 (1H, dd, J¼15.0,
27
(4 g, hexane/EtOAc 1:0 to 100:1): colorless oil; [
CHCl3); IR (neat)
3013, 2943, 2862, 1464, 1254, 1105, 1059 cmꢂ1
1H NMR (500 MHz, CDCl3)
0.01 (3H, s, CH3 of TBS), 0.02 (3H, s, CH3
a]
2.5 (c 0.7,
D
n
;
d
of TBS), 0.03 (3H, s, CH3 of TBS), 0.05 (3H, s, CH3 of TBS), 0.86e0.90
(21H, m, t-Bu of TBSꢁ2 and H20), 1.45e1.57 (4H, m, H3 and H19),
1.66e1.70 (2H, m, H2), 2.12 (2H, dt, J¼6.9, 6.9 Hz, H4), 2.82 (2H, dd,
J¼5.8, 5.8 Hz, H7), 2.97 (2H, dd, J¼5.7, 5.7 Hz, H10), 3.51 (1H, td,
J¼5.8, 5.2 Hz, H18), 3.83e3.86 (2H, m, acetal), 3.95e3.98 (2H, m,
acetal), 3.99 (1H, dd, J¼7.5, 5.2 Hz, H17), 4.86 (1H, t, J¼4.6 Hz, H1),
5.34e5.42 (5H, m, H5, H6, H8, H9, and H11), 5.66 (1H, dd, J¼14.3,
7.5 Hz, H16), 6.04 (1H, dd, J¼11.5, 10.9 Hz, H12), 6.14 (2H, m, H14
and H15), 6.45 (1H, dd, J¼14.9, 10.9 Hz, H13); 13C NMR (125 MHz,
11.5 Hz, H13); 13C NMR (100 MHz, CD3OD)
d 10.6, 26.2, 26.55, 26.59,
27.1, 27.7, 34.8, 76.6, 77.3, 128.6, 129.2, 129.66, 129.71, 129.8, 130.2,
131.2, 133.4, 133.7, 134.4, 179.5 (deduced from HMBC correlation
with H2); HRMS (ESI) calcd for C20H30NaO4 357.2036 (MþNaþ),
found 357.2029.
CDCl3)
d
ꢂ4.7, ꢂ4.5, ꢂ4.1, ꢂ4.0, 9.3, 18.19, 18.25, 24.0, 25.7, 25.96,
4.1.34. (17S,18S)-Resolvin E3 (1b). According to the synthetic pro-
cedure of 1a, 1b (3.7 mg, 0.011 mmol) was synthesized from 17b
(20 mg, 0.034 mmol) in 33% yield over three steps by using TMSOTf
25.97, 26.02, 26.2, 27.0, 33.4, 64.8 (two peaks), 76.5, 77.4, 104.5,
127.2, 127.6, 128.1, 128.7, 128.9, 129.8, 130.0, 131.5, 132.8, 135.3;
HRMS (ESI) calcd for C34H62O4Si2Na 613.4079 (MþNaþ), found
613.4081.
(90 mL, 0.5 mmol) and 2,6-lutidine (90 mL, 0.77 mmol) in CH2Cl2
(1 mL) and H2O (2 mL) for the first step, NaClO2 (28 mg, 0.31 mmol)
and NaH2PO4$H2O (53 mg, 0.30 mmol) in a mixture of H2O
(0.4 mL), t-BuOH (0.4 mL), and 2-methyl-2-butene (0.4 mL) for the
4.1.32. Pentaene 17d. According to the synthetic procedure of 17a,
17d (16 mg, 0.027 mmol) was synthesized from 2d (19 mg,
0.032 mmol, a 8.5:1 E/Z mixture) in 84% yield by using Lindlar
catalyst (450 wt % in total) and quinoline (46
hexane (3.3 mL) under H2 atmosphere and purification on silica gel
second step, TBAF (80 mL, 1 M in THF, 0.08 mmol) in THF (1 mL) for
the third step, and purification on HPLC (Inertsil ODS-3, CH3CN/
mL, 0.33 mmol) in
H2O/AcOH 50:50:0.05, 3 mL/min, tR¼26 min): clear oil; [
a]
25 ꢂ33 (c
D
0.24, MeOH); HRMS (ESI) calcd for C20H30NaO4 357.2036 (MþNaþ),
found 357.2048; IR, 1H NMR, and 13C NMR spectra were identical
with those of (17R,18R)-resolvin E3 (1a).
25
(8 g, hexane/EtOAc 99:1 to 50:1 to 33:1 to 24:1): colorless oil; [a]
D
ꢂ4.3 (c 0.11, CHCl3); HRMS (ESI) calcd for C34H62O4Si2Na 613.4079
(MþNaþ), found 613.4080; IR, 1H NMR, and 13C NMR spectra were
identical with those of pentaene 17c.
4.1.35. (17S,18R)-Resolvin E3 (1c). According to the synthetic pro-
cedure of 1a, 1c (3.5 mg, 0.010 mmol) was synthesized from 17c
(14 mg, 0.024 mmol) in 44% yield over three steps by using TMSOTf
4.1.33. (17R,18R)-Resolvin E3 (1a). To a solution of pentaene 17a
(22 mg, 0.037 mmol) and 2,6-lutidine (95
mL, 0.82 mmol) in CH2Cl2
(110 mL, 0.61 mmol) and 2,6-lutidine (110 mL, 0.95 mmol) in CH2Cl2
(1.4 mL), was added TMSOTf (100 L, 0.55 mmol) dropwise at
m
(3.6 mL) and H2O (3 mL) for the first step, NaClO2 (19 mg,
0.21 mmol) and NaH2PO4$H2O (35 mg, 0.20 mmol) in a mixture of
H2O (1.5 mL), t-BuOH (1.5 mL), and 2-methyl-2-butene (1.5 mL) for
the second step, TBAF (0.14 mL, 1 M in THF, 0.14 mmol) in THF
(1 mL) for the third step, and purification on HPLC (Inertsil ODS-3,
CH3CN/H2O/AcOH 50:50:0.05, 3 mL/min, tR¼24 min): colorless oil;
ꢂ20 ꢀC. The reaction mixture was stirred for 1 h at ꢂ20 ꢀC and then
H2O (1.4 mL) was added. After being stirred at room temperature
for 1 h, the reaction mixture was extracted with CH2Cl2 (5 mLꢁ3).
Combined organic layers were washed with brine (10 mL), dried
over Na2SO4, filtered, and concentrated to afford crude aldehyde,
which was used for the next reaction without further purification.
A suspension of the crude aldehyde, NaH2PO4$2H2O (56 mg,
0.31 mmol), and NaClO2 (29 mg, 0.32 mmol) in a mixture of H2O
(0.5 mL), t-BuOH (0.5 mL), and 2-methyl-2-butene (0.5 mL) was
stirred at room temperature for 1 h, and then diluted with H2O
(3 mL) and EtOAc (3 mL). The resulting mixture was extracted with
EtOAc (10 mLꢁ3) and combined organic layers were dried over
Na2SO4, filtered, and concentrated. The residue was roughly puri-
fied by flash chromatography on silica gel (3 g, hexane/EtOAc/AcOH
10:1:0.05) to afford crude carboxylic acid, which was used for the
next reaction without further purification.
[a
]
27 ꢂ7.5 (c 0.18, MeOH); IR (neat)
n
3404, 3013, 2963, 2930, 2878,
0.98 (3H,
D
1712, 1401, 1240, 995 cmꢂ1; 1H NMR (500 MHz, CD3OD)
d
t, J¼7.5 Hz, H20), 1.38 (1H, ddq, J¼14.3, 9.2, 7.5 Hz, H19a), 1.60 (1H,
dqd, J¼14.3, 7.5, 4.3 Hz, H19b), 1.67 (2H, tt, J¼7.5, 7.5 Hz, H3), 2.14
(2H, dt, J¼7.5, 7.5 Hz, H4), 2.29 (2H, t, J¼7.5 Hz, H2), 2.85 (2H, dd,
J¼5.8, 5.8 Hz, H7), 2.99 (2H, dd, J¼6.3, 6.3 Hz, H10), 3.41 (1H, ddd,
J¼9.2, 5.2, 4.0 Hz, H18), 3.98 (1H, dd, J¼7.5, 5.2 Hz, H17), 5.35e5.43
(5H, m, H5, H6, H8, H9, and H11), 5.81 (1H, dd, J¼15.5, 7.5 Hz, H16),
6.04 (1H, dd, J¼11.5, 11.5 Hz, H12), 6.25 (1H, dd, J¼15.5, 10.9 Hz,
H14), 6.36 (1H, dd, J¼15.5, 10.9 Hz, H15), 6.58 (1H, dd, J¼15.5,
11.5 Hz, H13); 13C NMR (125 MHz, CD3OD)
d 10.6, 26.1, 26.6, 26.7,
TBAF (110
m
l, 1 M in THF, 0.11 mmol) was added to a solution of
27.1, 27.6, 34.6, 76.5, 77.3, 128.6, 129.0, 129.6, 129.7, 129.8, 130.2,
131.1, 133.4, 133.9, 134.2, 177.8 (deduced from HMBC correlation
the crude carboxylic acid in THF (1.2 mL). After the reaction mixture

D. Urabe et al. / Tetrahedron 68 (2012) 3210e3219
3219
with H2); HRMS (ESI) calcd for C20H30O4Na 357.2036 (MþNaþ),
3602e3605; Maresin: (b) Sasaki, K.; Urabe, D.; Arai, H.; Arita, M.; Inoue, M.
Chem. Asian J. 2011, 6, 534e543.
found 357.2037.
7. Total syntheses of resolvins from other laboratories. Resolvin E1: (a) Ogawa, N.;
Kobayashi, Y. Tetrahedron Lett. 2009, 50, 6079e6082; (b) Allard, M.; Barnes, K.;
Chen, X.; Cheung, Y.-Y.; Duffy, B.; Heap, C.; Inthavongsay, J.; Johnson, M.;
Krishnamoorthy, R.; Manley, C.; Steffke, S.; Varughese, D.; Wang, R.; Wang, Y.;
Schwartz, C. E. Tetrahedron Lett. 2011, 52, 2623e2626; Resolvin E2: (c) Kosaki,
Y.; Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2010, 51, 1856e1859; Resolvin D2:
(d) Rodríguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717e8720; Re-
solvin D5: (e) Rodríguez, A. R.; Spur, B. W. Tetrahedron Lett. 2005, 46,
3623e3627; For a review of syntheses of eicosanoids, see: (f) Nicolaou, K. C.;
Ramphal, J. Y.; Petasis, N. A.; Serhan, C. N. Angew. Chem., Int. Ed. Engl. 1991, 30,
1100e1116.
8. (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.;
Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org.
Chem. 1992, 57, 2768e2771; For a review on asymmetric dihydroxylation, see:
(b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483e2547.
4.1.36. (17R,18S)-Resolvin E3 (1d). According to the synthetic pro-
cedure of 1a, 1d (2.2 mg, 6.6
(8.4 mg, 0.014 mmol) in 47% yield over three steps by using TMSOTf
(64 L, 0.35 mmol) and 2,6-lutidine (61 L, 0.52 mmol) in CH2Cl2
mmol) was synthesized from 17d
m
m
(2.1 mL) and H2O (2 mL) for the first step, NaClO2 (12 mg,
0.13 mmol) and NaH2PO4$H2O (20 mg, 0.11 mmol) in a mixture of
H2O (0.7 mL), t-BuOH (0.7 mL), and 2-methyl-2-butene (0.7 mL) for
the second step, TBAF (0.10 mL, 1 M in THF, 0.10 mmol) in THF
(1 mL) for the third step, and purification on HPLC (Inertsil ODS-3,
CH3CN/H2O/AcOH 50:50:0.05, 3 mL/min, tR¼24 min): colorless oil;
[a]
27 7.7 (c 0.15, MeOH); HRMS (ESI) calcd for C20H30O4Na 357.2036
D
9. (a) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yamaguchi, S.; Mukaiyama, T.;
Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am. Chem. Soc. 2002, 124,
12078e12079; (b) Kandula, S. R. V.; Kumar, P. Tetrahedron: Asymmetry 2005, 16,
(MþNaþ), found 357.2033; IR, 1H NMR, and 13C NMR spectra were
identical with those of (17S,18R)-resolvin E3 (1c).
ꢀ
3268e3274; (c) Carda, M.; Murga, J.; Falomir, E.; Gonzalez, F.; Marco, J. A.
Tetrahedron 2000, 56, 677e683.
Acknowledgements
10. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277e7287.
11. Diols 10c and 10d were previously synthesized using other methods, see: (a)
Dixon, D. J.; Ley, S. V.; Polara, A.; Sheppard, T. Org. Lett. 2001, 3, 3749e3752; (b)
Ley, S. V.; Dixon, D. J.; Guy, R. T.; Palomero, M. A.; Polara, A.; Rodríguez, F.;
Sheppard, T. D. Org. Biomol. Chem. 2004, 2, 3618e3627.
12. (a) Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K. Synthesis 1993, 65e66; (b)
Durand, S.; Parrain, J.-L.; Santelli, M. Synthesis 1998, 1015e1018; (c) Kandula, S.
V.; Kumar, P. Tetrahedron Lett. 2003, 44, 1957e1958.
This work was supported financially by Funding Program for
Next Generation World-Leading Researchers (JSPS) to M.I. and
a Grant-in-Aid for Young Scientists (B) (JSPS) to D.U.
Supplementary data
13. (a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538e7539; (b) Kim, B.
M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655e658; (c) Allevi, P.; Tarocco,
G.; Longo, A.; Anastasia, M.; Cajone, F. Tetrahedron: Asymmetry 1997, 8,
1315e1325; For reviews on cyclic sulfites and sulfates chemistry, see: (d)
Lohray, B. B. Synthesis 1992, 1035e1052; (e) Byun, H.-S.; He, L.; Bittman, R.
Tetrahedron 2000, 56, 7051e7091.
1H and 13C NMR spectra of all newly synthesized compound.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.02.045.
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14. Kelly, A. M.; Perez-Fuertes, Y.; Fossey, J. S.; Yeste, S. L.; Bull, S. D.; James, T. D.
Nat. Protoc. 2008, 3, 215e219.
15. Fox, M. E.; Marino, J. P., Jr.; Overman, L. E. J. Am. Chem. Soc. 1999, 121,
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