Total synthesis of resolvin E2

Article abstract of DOI:10.1016/j.tetlet.2010.01.109

Resolvin E2 (2) was synthesized stereoselectively using the C1-8 and C15-20 aldehydes 6 and 9, which were connected to the C9-14 fragment by using Wittig reactions. The aldehyde 6 was prepared from the γ-silyl alcohol (S)-20 by a sequence of reactions involving ozonolysis, oxidation with NaIO₄, and the Wittig reaction of the resulting aldehyde with Ph₃P{double bond, long}CHCHO, whereas the aldehyde 9 was synthesized from the corresponding γ-silyl alcohol through epoxidation, reaction with Et₂AlCN, and reduction with DIBAL-H.

Full text of DOI:10.1016/j.tetlet.2010.01.109

Tetrahedron Letters 51 (2010) 1856–1859
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of resolvin E2
*
Yusuke Kosaki, Narihito Ogawa, Yuichi Kobayashi
Department of Biomolecular Engineering, Tokyo Institute of Technology, Box B52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Resolvin E2 (2) was synthesized stereoselectively using the C1–8 and C15–20 aldehydes 6 and 9,
which were connected to the C9–14 fragment by using Wittig reactions. The aldehyde 6 was prepared
Received 9 December 2009
Revised 24 January 2010
Accepted 29 January 2010
Available online 6 February 2010
from the
c-silyl alcohol (S)-20 by a sequence of reactions involving ozonolysis, oxidation with NaIO4,
and the Wittig reaction of the resulting aldehyde with Ph3P@CHCHO, whereas the aldehyde 9 was syn-
thesized from the corresponding
reduction with DIBAL-H.
c
-silyl alcohol through epoxidation, reaction with Et2AlCN, and
Ó 2010 Elsevier Ltd. All rights reserved.
During the study aimed at finding compounds that promote
resolution of inflammation, a number of metabolites of the -3
ura coupling reaction.3 Then, we chose RvE2 (2) as a new target.
Quite recently, Inoue published the synthesis of 2 by connecting
the C1–10 and C13–20 bromides to acetylene followed by Lindlar
reduction.4 The hydroxyl groups involved in these bromides were
constructed with 6–7:1 diastereoselectivities from 87% ee of the
cyclobutene lactone. Consequently, the connection of these bro-
mides of the somewhat low ee should produce the diastereoiso-
mers. However, separation of the diastereoisomers is not
x
fatty acids such as eicosapentaenoic acid (EPA) and docosahexa-
enoic acid (DHA) have been isolated.1,2 Among them, resolvins E1
and E2 (RvE1 and RvE2, respectively) carry potent counterregula-
tory and anti-inflammatory properties (Fig. 1). Since these com-
pounds are available only in at most microgram quantities by
enzymatic transformation of the
x-3 fatty acids, development
of chemical synthesis has been an urgent subject in organic syn-
thesis. RvE1 and RvE2 possess allylic alcohol moieties, which are
conjugated to the stereodefined olefin(s). In general, the hydroxyl
group and the cis olefin in the conjugated allylic alcohol moiety
are chemically unstable so that transformations at the latter
stage should be carried out under mild conditions. Recently, we
succeeded in the synthesis of RvE1 (1) by using the Suzuki–Miya-
OH
CO2H
OH
8
9
Wittig
14 15
Resolvin E2 (RvE2) (2)
OH
OH
CO2H
CO2H
OH
Wittig disconnection
OH
OTBS
X1
OTBDPS
OH
CO2Me
+
OHC
Resolvin E2 (RvE2) (2)
Resolvin E1 (RvE1) (1)
6
5
OH
OH
CO2H
Wittig disconnection
CO2H
OH
X1
OTBS
OH
CO2Me
OHC
5(S),12(S)-diHETE (3)
5(S),15(S)-diHETE (4)
X2
8
7
OTBDPS
Figure 1. RvE1 and RvE2 derived from EPA and diHETEs derived from ARA.
+
OHC
9
* Corresponding author. Tel./fax: +81 45 924 5789.
E-mail address: ykobayas@bio.titech.ac.jp (Y. Kobayashi).
Scheme 1. Disconnection of RvE2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.109

Y. Kosaki et al. / Tetrahedron Letters 51 (2010) 1856–1859
1857
OR1
R2
OR1
9
1) TBDPSCl
imid.
TBDPSO
HO
Me3Si
OHC
R2
*
Br–
2) PPh3, MeCN
70 °C
PPh3
Br
10
9 and 6
22
23
74%
For 9 (ref. 3): (1) kinetic resolution/epoxidation; (2) Et 2AlCN; (3) DIBAL-H
For 6: see the present text
OTBDPS
aN(TMS)2
then
Scheme 2. An approach to unsaturated aldehydes.
OPMB
OPMB
OHC
(24)
25
OTBS
THF, –78 °C to 0 °C, 3.5 h
100%
1) BF3·OEt2
R
RO
O
O
O
2) TBSCl, imid.
O
OTBDPS
11, R = H
PPh3, MeCN
1) DDQ, CH2Cl2/H2O
PhNCO
1) NaIO4,
13, R = CH=CH2
14, R = CO2Me
12, R = PhN(H)CO
RuCl3 (cat.)
2) CH2N2
I
70 °C, 16 h
96%
2) TsCl, Et3N, DMAP
3) NaI, acetone, 50 °C
26
78%
OTBS
CO2Me
CO2Me
OTBDPS
HO
OH
9
15
MeONa
MeOH
NaIO4
I–
PPh3
+
14
THF/H2O
OH
27 (= 7, X1 = OTBDPS, X2 = Ph3P+ I–)
TBSO
Scheme 5. Synthesis of the C9–14 intermediate 27.
OH
16
aldehydes 6 and 9. Among these aldehydes the latter was synthe-
sized from the corresponding racemic -TMS allylic alcohols via (1)
OTBS
c
the kinetic resolution10 using the Sharpless asymmetric epoxida-
tion;11 (2) reaction with Et2AlCN;3 (3) reduction of the resulting
CN group with DIBAL-H (Scheme 2). This transformation would
be an attractive approach to the former aldehyde 6. However, the
ester group is incompatible with DIBAL-H and probably with
Et2AlCN, and the requirement of a synthetic equivalent to the ester
group led us to choose an alternative construction of 6 from 812 by
using Wittig reaction.13 Herein, we describe the synthesis of 8 by a
new sequence of reactions and transformed to RvE2 (2).
+
OHC
CO2Me
CO2Me
OHC
8
17
Scheme 3. An approach to aldehyde 8.
mentioned. Regarding the separation, our preliminary study re-
vealed that a mixture of RvE2 and the diastereoisomers derived
from the racemic parts by using the present method (vide infra)
was little separated by routine chromatography on silica gel.
Consequently, we chose reactions that deliver chiral alcohols
with quite high ee.
Similar structures to the conjugated dienyl alcohol moiety of 2
are seen in diHETEs such as 5(S),12(S)- and 5(S),15(S)-diHETEs (3
and 4), derivatives of arachidonic acid (ARA),5,6 which have been
the target compounds in the 1980–1990s.7 However, we found
that the previous syntheses of the intermediates and further con-
structions to diHETEs8,9 are hardly applicable to 2 due to the struc-
tural difference. Instead, we planed to use Wittig reaction to
construct the three cis olefins present in 2. Scheme 1 shows the
In our first attempt to prepare 8, epoxy alcohol 11 prepared by
the Sharpless asymmetric epoxidation of the corresponding allylic
alcohol according to the literature procedure14 was converted to
carbamate 12 (Scheme 3). BF3ꢀOEt2-assisted transformation of 12
at ꢁ18 °C for 2 h proceeded cleanly and the subsequent protection
with TBSCl afforded carbonate 13 in 66% yield. RuCl3-catalyzed oxi-
dation of 13 with NaIO4 followed by esterification with CH2N2 pro-
duced 14 in 92% yield. Unfortunately, exposure of carbonate 14 to
NaOMe (0.5 equiv) in MeOH at room temperature for 20 h resulted
in the production of 15 and 16 as the major and minor products.
Without separation, the mixture was subjected to oxidation with
NaIO4 to produce aldehydes 8 and 17 in a 1:4 ratio by 1H NMR
Wittig disconnection at the two olefins, giving
a,b-unsaturated
t-BuOOH
OH
OR
O3, EtOAc, –78 °C
Ti(O-i-Pr)4 / D-(–)-DIPT
CO2Me
CO2Me
TMS
TMS
O
O
O
then
kinetic resolution
39%
PPh3 (1.5 equiv)
–78 °C to rt, 20 min
(S)-19, R = H
20, R = TBS
rac-19
TBSCl
imid.
18
100%
OTBS
OTBS
OTBS
NaIO4 (1.6 equiv)
h3P=CHCHO (1.2 equiv)
OHC
CO2Me
CO2Me
CO2Me
OHC
OHC
THF/H2O (8 : 1)
0 °C to rt, 3 h
PhH, reflux, 17 h
92%
OTMS
8, 92% from 20
6
21
Scheme 4. Synthesis of the unsaturated aldehyde 6.

1858
Y. Kosaki et al. / Tetrahedron Letters 51 (2010) 1856–1859
OR
OTBDPS
NaN(TMS)2
1) TsCl, Et3N, DMAP
9
OTBDPS
I–
PPh3
OTBDPS
then
2) NaI, acetone, 50 °C
90%
14
OHC
(9)
27
28, R = TBDPS
29, R = H
Bu4NF
THF
THF, –78 °C to 0 °C, 3 h
90% from 9
NaN(TMS)2
PPh3, MeCN
90%
Ph3P
I–
OTBDPS
I
OTBDPS
then
OHC
OTBS
CO2Me
30
31
(6)
(= 5, X1 = Ph3P+ I–)
DMPU, –78 °C to –40 °C, 3.5 h
OTBS
OH
CO2Me
OTBDPS
CO2H
OH
Bu4NF (5 equiv)
THF, rt, 26 h
87%
32
RvE2 (2)
51% from 6
Scheme 6. Synthesis of RvE2 (2).
spectroscopy (65%). Use of smaller quantities of NaOMe at lower
temperatures (0 °C to rt) for shorter reaction times resulted in an
incomplete conversion of carbonate 14, whereas reaction did not
proceed with MeOMgBr in MeOH.
between 31 (1.5 equiv) and 6 (1 equiv) was conducted at temper-
atures between ꢁ78 °C and ꢁ40 °C to give 32 as the sole product
in 51% yield based on 6 after chromatography.19 Finally, reaction
of 32 with Bu4NF at room temperature for 26 h gave RvE2 (2) in
87% yield. The 1H and 13C NMR spectra and the specific rotation
We then investigated another preparation of 8. According to the
procedure published15 glutaric anhydride (18) was converted to
rac-19, which was subjected to the asymmetric epoxidation to give
(S)-19 (99% ee by 1H NMR of the MTPA derivative). Protection with
TBSCl as usual afforded 20 quantitatively (Scheme 4). Ozonolysis of
the vinyl silane moiety of 20 at ꢁ78 °C in EtOAc followed by reduc-
tive workup with PPh3 produced aldehyde 21. In contrast, workup
with Me2S produced a mixture of products. Ozonolysis of the vinyl
silanes was reported by Büchi and Wüest16 and applied to the syn-
thesis of artemisinin.17 Recently, Tomooka and co-workers shed
light on this class of ozone oxidation and they have successfully
were in accordance with those reported: ½a D21
ꢁ4 (c 0.056, MeOH);
ꢂ
lit.4
½
a 2D4
ꢂ
ꢁ2.1 (c 0.25, MeOH).
In conclusion, we have developed an efficient method to syn-
thesize RvE2 (2) in which the cis olefins are constructed stereose-
lectively.20 The asymmetric carbons with the hydroxyl groups at
C5 and C18 were constructed in enantiomerically highly pure
forms (generally >95% ee) by the epoxidation/kinetic resolution
of the
the ozonolysis of the
c
-silylallylic alcohols using the Sharpless epoxidation. In
-silylallylic alcohol to -alkoxyaldehyde,
c
a
reductive workup with PPh3 was found to be the choice.
isolated the anti-peroxide intermediates in a reaction of chiral c-si-
lyl allylic alcohol derivatives.18 Accordingly, product 21 should be
the anti isomer as depicted, though the determination was unnec-
essary for the further transformation. Oxidation of 21 was carried
out with NaIO4 in THF and H2O (8:1), under which deprotection
of the TMS group and the oxidative cleavage of the resulting
hydroxyaldehyde took place smoothly to produce aldehyde 8 in
92% yield from 20. Finally, Wittig reaction with Ph3P@CHCHO in
refluxing benzene produced the key aldehyde 6 in 92% yield.
Scheme 5 shows our synthesis of 27, the C9–14 part of 2. Phos-
phonium salt 23 was prepared from commercial bromoalcohol 22
in two steps and converted to the Wittig anion, to which aldehyde
24 was added to afford 25 as a sole stereoisomer quantitatively.
The PMB (p-MeOC6H4CH2) was removed and the resulting alcohol
was converted to iodide 26 in 78% yield. Finally, reaction with PPh3
in hot MeCN gave the phosphonium salt 27 in 96% yield.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan.
Supplementary data
Supplementary data (the 1H and 13C NMR spectra of 2) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.01.109.
References and notes
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11, 3602–3605.
An anion was generated from the Wittig salt 27 using
NaN(TMS)2 at 0 °C for 30 min and subjected to reaction with alde-
hyde 9, which had been synthesized from the corresponding the c-
TMS allylic alcohol with the R configuration (>99% ee).3 The reac-
tion was carried out at ꢁ78 °C for 2 h and then at temperatures
slowly raised to 0 °C over 1 h, producing cis olefin 28 exclusively.19
The silyl protective group at the primary hydroxyl group was selec-
tively removed with Bu4NF (1 equiv) at 0 °C to rt for 3 h, and the
resulting alcohol 29 was changed to iodide 30, which was con-
verted to the Wittig salt 31 in good yield. Finally, Wittig reaction
5. 5,12-diHETE: (a) Borgeat, P.; Fruteau de Laclos, B.; Picard, S.; Drapeau, J.;
Vallerand, P.; Corey, E. J. Prostaglandins 1982, 23, 713–724; (b) Lee, T. H.;
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1984, 259, 2383–2389.

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1859
6. 5,15-diHETE: (a) Maas, R. L.; Turk, J.; Oates, J. A.; Brash, A. R. J. Biol. Chem. 1982,
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the corresponding MTPA ester, thus confirming no racemization. The
transformation was applied to that delineated in Scheme 6.
Et
I– / NaN(TMS)2
Et
OR
PPh3
7. (a) Rokach, J.; Guindon, Y.; Young, R. N.; Adams, J.; Atkinson, J. G. In The Total
Synthesis of Natural Products; ApSimon, J., Ed.; Wiley: New York, 1988; Vol. 7, p
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3339–3342; (b) Adams, J.; Leblanc, Y.; Rokach, J. Tetrahedron Lett. 1984, 25,
1227–1230.
3
93%
Bu4NF
88%
i, R = TBDPS
ii, R = H
20. Spectral data of the intermediates. Aldehyde 6: ½a D21
ꢂ
+16 (c 0.91, CHCl3); 1H NMR
9. 5,15-diHETE: Nicolaou, K. C.; Webber, S. E. J. Am. Chem. Soc. 1984, 106, 5734–
5736.
(300 MHz, CDCl3) d 0.03 (s, 3H), 0.07 (s, 3H), 0.91 (s, 9H), 1.46–1.78 (m, 4H),
2.34 (t, J = 7 Hz, 2H), 3.68 (s, 3H), 4.41–4.49 (m, 1H), 6.28 (ddd, J = 15, 8, 1.5 Hz,
1H), 6.79 (dd, J = 15, 4.5 Hz, 1H), 9.58 (d, J = 8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d ꢁ4.9 (+), ꢁ4.6 (+), 20.2 (ꢁ), 25.8 (+), 33.8 (ꢁ), 36.3 (ꢁ), 51.6 (+), 71.2
10. Kitano, Y.; Matsumoto, T.; Sato, F. Tetrahedron 1988, 44, 4073–4086.
11. (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K.
B. J. Am. Chem. Soc. 1981, 103, 6237–6240; (b) Gao, Y.; Klunder, J. M.; Hanson, R.
M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–
5780.
12. Similar compounds which possess the alkoxy or acyloxy group instead of the
TBSO group have been synthesized: (a) Guidon, Y.; Zamboni, R.; Lau, C.-K.;
Rokach, J. Tetrahedron Lett. 1982, 23, 739–742; (b) Spur, B.; Crea, A.; Peters, W.
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5324–5335.
(+), 131.0 (+), 159.5 (+), 173.7 (ꢁ), 193.6 (+). Alcohol 29: ½a D21
ꢂ
+34 (c 0.83,
CHCl3); 1H NMR (300 MHz, CDCl3) d 0.79 (t, J = 7.5, 3H), 1.07 (s, 9H), 1.40–1.61
(m, 2H), 2.30 (dt, J = 7, 7 Hz, 2H), 2.82 (dd, J = 7, 7 Hz, 2H), 3.62 (t, J = 7 Hz, 2H),
4.17 (ddd, J = 6, 6, 6 Hz, 1H), 5.28 (dt, J = 11, 7 Hz, 1H), 5.34–5.55 (m, 2H), 5.61
(dd, J = 15, 6 Hz, 1H), 5.90 (dd, J = 11, 11 Hz, 1H), 6.20 (dd, J = 15, 11 Hz, 1H),
7.30–7.45 (m, 6H), 7.61–7.74 (m, 4H); 13C NMR (75 MHz, CDCl3) d 9.0 (+), 19.5
(ꢁ), 26.2 (ꢁ), 27.1 (+), 30.7 (ꢁ), 30.8 (ꢁ), 62.2 (ꢁ), 75.2 (+), 125.1 (+), 125.9 (+),
127.4 (+), 127.5 (+), 128.5 (+), 129.0 (+), 129.5 (+), 129.6 (+), 130.8 (+), 134.4
(ꢁ), 134.6 (ꢁ), 136.0 (+), 136.1 (+), 136.3 (+). Salt 31: 1H NMR (300 MHz, CDCl3)
d 0.78 (t, J = 7.5 Hz, 3H), 1.04 (s, 9H), 1.40–1.62 (m, 2H), 2.35–2.54 (m, 2H), 2.55
(dd, J = 7.5, 7.5 Hz, 2H), 3.62–3.86 (m, 2H), 4.13 (q, J = 6 Hz, 1H), 5.10 (dt, J = 11,
7.5 Hz, 1H), 5.27–5.40 (m, 1H), 5.54–5.69 (m, 2H), 5.84 (dd, J = 11, 11 Hz, 1H),
6.01 (dd, J = 15, 11 Hz, 1H), 7.26–7.44 (m, 6H), 7.59–7.87 (m, 19H). Methyl ester
32: ½a 2D4
ꢂ
+30 (c 0.84, CHCl3); 1H NMR (300 MHz, CDCl3) d 0.02 (s, 3H), 0.05 (s,
3H), 0.79 (t, J = 7.5, 3H), 0.89 (s, 9H), 1.07 (s, 9H), 1.41–1.79 (m, 6H), 2.31 (t,
J = 7.5 Hz, 2H), 2.81 (dd, J = 6.5, 6.5 Hz, 2H), 2.91 (dd, J = 6.5, 6.5 Hz, 2H), 3.65 (s,
3H), 4.08–4.24 (m, 2H), 5.19–5.51 (m, 4H), 5.60 (dd, J = 15, 6.5 Hz, 1H), 5.63
(dd, J = 15, 6.5 Hz, 1H), 5.90 (dd, J = 11, 11 Hz, 1H), 5.97 (dd, J = 11, 11 Hz, 1H),
6.18 (dd, J = 15, 11 Hz, 1H), 6.44 (dd, J = 15, 11 Hz, 1H), 7.29–7.45 (m, 6H),
7.62–7.73 (m, 4H); 13C NMR (75 MHz, CDCl3) d ꢁ4.7 (+), ꢁ4.2 (+), 9.1 (+), 18.3
(ꢁ), 19.5 (ꢁ), 20.8 (ꢁ), 25.9 (+), 26.0 (ꢁ), 26.1 (ꢁ), 27.1 (+), 30.7 (ꢁ), 34.1 (ꢁ),
37.7 (ꢁ), 51.5 (+), 72.8 (+), 75.3 (+), 124.5 (+), 125.2 (+), 127.4 (+), 127.5 (+),
128.1 (+), 128.31 (+), 128.33 (+), 128.5 (+), 129.1 (+), 129.4 (+), 129.5 (+), 129.6
(+), 134.4 (ꢁ), 134.6 (ꢁ), 136.0 (ꢁ), 136.1 (ꢁ), 136.2 (ꢁ), 137.0 (ꢁ), 174.1 (ꢁ).
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19. A model transformation of epoxy alcohol 3 (76% ee) to olefin i (ꢁ78 to 0 °C, 3 h
then rt, overnight) afforded ii, which was 76% ee by 1H NMR spectroscopy of