Total synthesis of resolvin E1

Article abstract of DOI:10.1016/j.tetlet.2009.08.061

Resolvin E1 (RvE1), which is an endogenous mediator to resolve inflammation, was synthesized by Wittig reaction between the C15-C20 aldehyde and the C10-C14 phosphonium salt possessing the vinyl iodo moiety followed by Suzuki-Miyaura coupling of the resul

Full text of DOI:10.1016/j.tetlet.2009.08.061

Tetrahedron Letters 50 (2009) 6079–6082
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Tetrahedron Letters
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Total synthesis of resolvin E1
*
Narihito Ogawa, Yuichi Kobayashi
Department of Biomolecular Engineering, Tokyo Institute of Technology, 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 E1 (RvE1), which is an endogenous mediator to resolve inflammation, was synthesized by Wittig
reaction between the C15–C20 aldehyde and the C10–C14 phosphonium salt possessing the vinyl iodo
moiety followed by Suzuki–Miyaura coupling of the resulting vinyl iodide with the vinyl borane of the
C1–C9 part, which was derived from the corresponding acetylene by hydroboration. The C5 and C18 chi-
Received 18 July 2009
Revised 19 August 2009
Accepted 20 August 2009
Available online 23 August 2009
ral centers in these parts were created by the kinetic resolution of the racemic
using the asymmetric epoxidation, while that of the C10–C14 part was constructed by the asymmetric
hydrogen transfer reaction of the corresponding -TMS acetylene ketone.
Ó 2009 Elsevier Ltd. All rights reserved.
c-TMS allylic alcohols
c
Resolvin E1 (RvE1) is a metabolite of eicosapentaenoic acid
(EPA) produced by aspirin-modified lipoxygenase.1,2 At nanomolar
levels, RvE1 suppresses inflammatory actions such as PMNL migra-
tion/infiltration and IL-12 production through binding to the spe-
cific receptor (ChemR23). These counter regulatory responses in
inflammation strongly suggest that RvE1 is a natural endogenous
regulator of the immune system against inflammation. In contrast
to such a promising pharmaceutical property, the availability of
RvE1 in the natural sources is limited to at most microgram levels,3
and thus total synthesis of RvE1 is urgently required. The structure
of RvE1 (1) is similar to that of LTB4 (2), which, in contrast, induces
inflammation intensively (Fig. 1).4 The structural similarity implies
that the (6Z,8E,10E)-triene unit of 1 is prone to isomerize to the
chemically more stable (6E)-triene. On the other hand, the similar-
ity suggests an idea that the established strategies for the synthesis
of 25–9 would be applicable for construction of the triene unit of 1.
In fact, the semi-hydrogenation strategy8 with the corresponding
bis-acetylene derivative is stated in a journal with a brief summary
of the synthesis (Fig. 2 of Ref. 2b), whereas experimental details are
available from a patent.10 In brief, semi-hydrogenation was, as ex-
pected, halted at 60% conversion and the product, the methyl ester
of 1, was purified by using reverse phase HPLC though hydrolysis
to RvE1 is not mentioned.10
while iodide 4 was disconnected to Wittig reagent 5 and aldehyde
6. Herein, we report the synthesis of vinyl iodide 4 and the
construction of 1.
Synthesis of the C15–C20 intermediate 6 is delineated in Scheme
2. Propargylic alcohol 7 was prepared by addition of TMS–C„C–Li to
EtCHO and subjected to reduction with Red-Al to afford the racemic
allylic alcohol rac-8 with the trans olefin stereoselectively in high
yield. Kinetic resolution of rac-8 using asymmetric epoxidation12,13
with t-BuOOH using Ti(O-i-Pr)4/
D
-(À)-DIPT complex (1 equiv) at
À20 °C for 24 h delivered a mixture of epoxy alcohol 9 and alcohol
(S)-8, which was separated by chromatography on silica gel. Enan-
tiomeric purity of the products 9 and (S)-8 isolated in 45% and 46%
yields were 99% and 98% ee, respectively, by 1H NMR spectroscopy
of the derived MTPA esters. Epoxide ring opening of 9 with Et2AlCN
took place smoothly and the resulting Et2Al complex of 10 under-
went syn-elimination under the reaction conditions, thus accom-
plishing the Peterson olefination reaction in one pot to afford 11 as
a sole product.14,15 Due to an expectation of a TBS ether of 11 being
highly volatile, the hydroxyl group was protected with heavy
TBDPSCltoaffordtheTBDPSether 12, whichuponreductionwithDI-
BAL furnished the key intermediate 6 in high yield. Alcohol (S)-8
obtained above by the kinetic resolution of rac-8 was converted to
In our consideration, the strategy using Suzuki–Miyaura
coupling, which was developed by us,9 was chosen since the
construction of the conjugated triene unit of 2 is stereoselective
to allow easy purification by chromatography on silica gel. For
the synthesis of 1, vinyl borane 3 and vinyl iodide 4 were the
requisite coupling partners as disclosed in Scheme 1. Borane 3 is
prepared by hydroboration of the corresponding acetylene,9,11
OH
OH
CO2H
CO2H
6
OH
15
10
OH
Resolvin E1 (RvE1) (1)
OH
Leukotriene B4 (LTB4) (2)
* Corresponding author. Tel./fax: +81 45 924 5789.
E-mail address: ykobayas@bio.titech.ac.jp (Y. Kobayashi).
Figure 1. Structures of RvE1 and LTB4.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.061

6080
N. Ogawa, Y. Kobayashi / Tetrahedron Letters 50 (2009) 6079–6082
OH
O
TMS
TMS
CO2H
OH OPMB
15
+
OH
t-BuOOH
TMS
20
9
OH OPMB
rac-14
Ti(O-i-Pr)4
D-(–)-DIPT
10
Suzuki
coupling
OH
RvE1 (1)
OH OPMB
(R)-14
–20 ºC, 24 h
15 and/or (R)-14
OTBS
5
CO2Me
OH
I
Scheme 3. An attempted synthesis of the C10–C14 intermediate 5.
+
OH
9
B(Sia)2
4
TMS
Ru cat. (3 mol %)a
SO3•Py, DMSO
3
rac-14
i-PrOH, rt
89%
Et3N, CH2Cl2
83%
O
OPMB
16
OR
15
OHC
I
14
+
1) TBDPSCl
imid.
10
OR P+Ph3•I–
TMS
OPMB
6
5
2) K2CO3
MeOH
OH OPMB
OTBDPS
Scheme 1. Retrosynthetic analysis of RvE1. R in 5 and 6 = TBDPS.
(R)-14, > 98% ee
17
100%
1) DDQ, wet CH2Cl2
2) TsCl, Et3N, DMAP
the intermediate 6 as shown in the scheme. Thus, epoxidation of (S)-
8 with t-BuOOH using Ti(O-i-Pr)4/L-(+)-DIPT produced ent-9, which
upon Mitsunobuinversionfollowedby hydrolysis afforded 13 in 72%
yield from (S)-8. Finally, the above three-step conversion including
the Peterson olefination with Et2AlCN was applied to 13, furnishing
6 in good yield. The combined overall yield from rac-8 through 9 and
(S)-8 was 58%.
Investigated next was synthesis of the Wittig reagent 5, for
which we envisioned similar transformation through kinetic reso-
lution/epoxidation of racemic allylic alcohol rac-14.16 However,
Bu3SnH, Pd cat.
CH2Cl2, rt
OPMB
X
3) NaI
58%
OTBDPS
18, X = Bu3Sn
19, X = I
79% from 17
I2
I
I
PPh3
EtOH
5
OTBDPS
20
100%
epoxidation with t-BuOOH and Ti(O-i-Pr)4/
D
-(À)-DIPT gave a mix-
ture of products containing a small quantity of the allylic alcohol
and the epoxy alcohol by 1H NMR spectroscopy and TLC analysis
(Scheme 3).17 Next, another synthesis involving asymmetric reduc-
tion of ketone 16 was investigated (Scheme 4). Racemic alcohol
rac-14 was oxidized to ketone 16 in 83% yield. Asymmetric reduc-
Scheme 4. Synthesis of the C10–C14 intermediate 5. aRu cat. = Ru[(R,R)-TsDPEN](p-
cymene).
tion was carried out with Ru[(R,R)-TsDPEN](p-cymene)18 as a cata-
lyst in i-PrOH to give (R)-14, which had >98% ee by 1H NMR
OH
OH
OH
Red-Al
t-BuOOH (1.5 equiv)
OH
TMS-C C-H
O
EtCHO
+
TMS
TMS
TMS
Et2O
94%
Ti(O-i-Pr)4 / D-(–)-DIPT
(1 equiv)
n-BuLi
80%
TMS
(S)-8
46%, 98% ee
9
7
rac-8
45%, 99% ee
–20 ºC, 24 h
NC
TMS
OH
Et2AlCN
OR
DAIBAL-H
15
OTBDPS
20
9
NC
OHC
benzene
rt, 14 h
toluene, –78 °C
OH
10
6
11, R = H
12, R = TBDPS
74% from 9
97%
TBDPSCl
imid., DMF
1) p-NO2C6H4COOH
DIAD, PPh3
1) Et2AlCN, benzene
OH
O
OH
t-BuOOH (1.5 equiv)
O
6
(S)-8
TMS
TMS
2) TBDPSCl
imidazole, DMF
3) DIBAL-H
Ti(O-i-Pr)4 / L-(+)-DIPT
(1 equiv)
2) 2 N NaOH
MeOH, THF
ent-9, 85%
13
85%
77%
Scheme 2. Synthesis of the C15–C20 intermediate 6.

N. Ogawa, Y. Kobayashi / Tetrahedron Letters 50 (2009) 6079–6082
6081
spectroscopy of the derived MTPA ester. The hydroxyl group of (R)-
14 was protected as the TBDPS ether and the TMS group was re-
moved by using K2CO3 in MeOH to produce acetylene 17 quantita-
tively. Palladium-catalyzed hydrostannation19 with Bu3SnH at
room temperature proceeded cleanly to afford the trans stannyl
olefin 18 stereoselectively in good yield, and subsequent exposure
to I2 gave iodide 19 in 79% yield from 17. Note that AIBN-catalyzed
hydrostannation under refluxing toluene gave 18 with several
minor products in our hand. Three-step transformation of 19 given
in the scheme was successful in affording di-iodide 20, which upon
reaction with PPh3 in hot EtOH produced the Wittig reagent 5 in
58% yield from 19.
consistent with those published.10,21 The spectra in CDCl3 given
in Ref. 20 also support the structure.
Similarly, the (6E)-isomer of 1 was synthesized (Scheme is not
shown). With the 1H NMR spectrum of the isomer in hand, the pur-
ity of 1 we have synthesized above was calculated to be more than
92%.22 The decreased stereoselectivity might be due to the chemi-
cal instability of the conjugated triene unit as mentioned in the
introduction. We believe that the purity would be sufficient for
the biological study of RvE1 (1).
Acknowledgment
An anion derived from 5 and NaHMDS was subjected to Wittig
reaction with aldehyde 6 (0.67 equiv) between À78 °C and room
temperature for 13 h to afford diene 21, which upon desilylation
with Bu4NF afforded the intermediate 4 (Scheme 5). Although
the 1H NMR spectrum of 21 suffered from broadening the signals,
that of alcohol 4 was quite sharp in establishing stereoselective
production of the desired (14Z,16E)-diene part (d 5.3–6.7 ppm).20
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan.
References and notes
1. (a) Serhan, C. N. Prostaglandins Leukotrienes Essent. Fatty Acids 2008, 79, 157–
163; (b) Serhan, C. N.; Chiang, N.; Van Dyke, T. E. Nat. Rev. Immun. 2008, 8, 349–
361; (c) Serhan, C. N.; Gotlinger, K.; Hong, S.; Arita, M. Prostaglandins Other Lipid
Mediat. 2004, 73, 155–172.
Suzuki–Miyaura coupling of
4 with the borane reagent 3
(1.5 equiv), generated in situ from the corresponding acetylene
and Sia2BH in THF, was carried out with Pd(PPh3)4 (5 mol %) and
excess LiOH (12 equiv) in aqueous THF at 40 °C. During the cou-
pling reaction, the methyl ester part of the product underwent
hydrolysis to afford acid 22. Chromatography of the crude acid
on silica gel was, however, contaminated with minor unidentified
products probably derived from the reagents. The mixture was
subjected to desilylation with Bu4NF in THF to furnish RvE1 (1).
Unfortunately, chromatographic purification of crude 1 on silica
gel was unsuccessful, giving a mixture of 1 and a small quantity
of by-products. We then repeated the coupling reaction with NaOH
in place of LiOH to produce the methyl ester 23, which was isolated
cleanly by chromatography on silica gel. Finally, desilylation with
Bu4NF furnished 1, which was free of the by-product(s). For confir-
mation of the structure, 1 was converted to the methyl ester with
CH2N2, and its 1H and 13C NMR spectra in C6D6 were found to be
2. (a) Schwab, J. M.; Chiang, N.; Arita, M.; Serhan, C. N. Nature 2007, 447, 869–874;
(b) Arita, M.; Bianchini, F.; Aliberti, J.; Sher, A.; Chiang, N.; Hong, S.; Yang, R.;
Petasis, N. A.; Serhan, C. N. J. Exp. Med. 2005, 201, 713–722.
3. Masoodi, M.; Mir, A. A.; Petasis, N. A.; Serhan, C. N.; Nicolaou, A. Rapid Commun.
Mass Spectrom. 2008, 22, 75–83.
4. Recent reviews of TLB4: (a) Tsuji, F.; Horiuchi, M.; Enomoto, H.; Aono, H. Curr.
Top. Pharmacol. 2005, 9, 71–79; (b) Toda, A.; Yokomizo, T.; Shimizu, T.
Prostaglandins Other Lipid Mediat. 2002, 68–69, 575–585; (c) Yokomizo, T.;
Izumi, T.; Shimizu, T. Arch. Biochem. Biophys. 2001, 385, 231–241.
5. (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
141; (b) Sato, F.; Kobayashi, Y. Synlett 1992, 849–857.
6. (a) Corey, E. J.; Marfat, A.; Goto, G.; Brion, F. J. Am. Chem. Soc. 1980, 102, 7984–
7985; (b) Guindon, Y.; Zamboni, R.; Lau, C.-K.; Rokach, J. Tetrahedron Lett. 1982,
23, 739–742; (c) Zamboni, R.; Rokach, J. Tetrahedron Lett. 1982, 23, 2631–2634.
7. Corey, E. J.; Marfat, A.; Munroe, J.; Kim, K. S.; Hopkins, P. B.; Brion, F.
Tetrahedron Lett. 1981, 22, 1077–1080.
8. Nicolaou, K. C.; Zipkin, R. E.; Dolle, R. E.; Harris, B. D. J. Am. Chem. Soc. 1984, 106,
3548–3551.
9. Kobayashi, Y.; Shimazaki, T.; Taguchi, H.; Sato, F. J. Org. Chem. 1990, 55, 5324–
5335.
10. Petasis, N. A. U.S. Patent Appl. Publ. (2005), US 2005228047 A1 20051013;
Chem. Abstr. 2005, 143, 386846.
1) NaHMDS, THF
I
11. Nakayama, Y.; Kumar, G. B.; Kobayashi, Y. J. Org. Chem. 2000, 65, 707–715.
12. (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.
OR
0 ºC, 1 h
5
2) aldehyde 6
–78 ºC to rt, 13 h
OR
13. Kitano, Y.; Matsumoto, T.; Sato, F. Tetrahedron 1988, 44, 4073–4086.
14. Another possible synthesis of 11 is kinetic resolution of the corresponding
21, R = TBDPS
4, R = H
Bu4NF
racemic
Urabe, H.; Kobayashi, Y.; Sato, F. Tetrahedron Lett. 1991, 32, 2045–2048.
15. Other syntheses of optically active -cyanoallylic alcohols: (a) Ono, T.;
c-cyanoallylic alcohol, which would be proceed slowly: Yamakawa, I.;
82% from 5
c
Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J.; Wakabayashi, S. J. Am. Chem.
Soc. 1984, 106, 7890–7893; (b) Tanikaga, R.; Hosoya, K.; Kaji, A. Chem. Lett.
1987, 16, 829–832; (c) Kitano, Y.; Matsumoto, T.; Wakasa, T.; Okamoto, S.;
Shimazaki, T.; Kobayashi, Y.; Sato, F.; Miyaji, K.; Arai, K. Tetrahedron Lett. 1987,
28, 6351–6354; (d) Abe, H.; Nitta, H.; Mori, A.; Inoue, S. Chem. Lett. 1992, 21,
2443–2446; (e) Baeza, A.; Casas, J.; Nájera, C.; Sansano, J. M. J. Org. Chem. 2006,
71, 3837–3848; (f) Hagiwara, H.; Isobe, K.; Numamae, A.; Hoshi, T.; Suzuki, T.
Synlett 2006, 1601–1603.
OTBS
CO2R
B(Sia)2
(3)
OH
Pd(PPh3)4 cat., aq. THF
with
OH
2 N LiOH, 40 °C, 24 h
or
2 N NaOH, rt, 6 h
16. Prepared from propane-1,3-diol by a sequence of following reactions: (1)
PMBCl, NaH, DMF, 70%; (2) SO3ÁPy; (3) TMS-acetylene, n-BuLi, 85% over two
steps; (4) Red-Al, Et2O–toluene, 97%.
17. The PMB-oxy group seems responsible for the unexpected result since the
compound with the benzyl-oxy group undergoes epoxidation without any
event.13 Epoxidation with other catalysts such as Ti(O-i-Pr)4 and VO(acac)2 also
gave a mixture.
22, R = H
with LiOH
23, R = Me, 100%
with NaOH
OH
18. Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119,
8738–8739.
CO2H
Bu4NF, THF
rt, 24 h
19. Zhang, H. X.; Guibé, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857–1867.
20. Compound 4: 1H NMR (300 MHz, CDCl3) d 0.94 (t, J = 7.5 Hz, 3H), 1.59 (d of
quint, J = 2.5, 7 Hz, 2H), 1.65–1.84 (br s, 1H), 1.85–2.04 (br s, 1H), 2.46 (t,
J = 7 Hz, 2H), 4.03–4.25 (m, 2H), 5.43 (dt, J = 11, 7 Hz, 1H), 5.75 (dd, J = 15,
6.5 Hz, 1H), 6.19 (t, J = 11 Hz, 1H), 6.39 (dd, J = 14, 1 Hz, 1H), 6.47 (dd, J = 15,
11 Hz, 1H), 6.60 (dd, J = 14, 6 Hz, 1H). RvE1 (1): 1H NMR (500 MHz, CDCl3) d
0.93 (t, J = 7.5 Hz, 3H), 1.1–2.3 (m, 10H), 2.41 (t, J = 7 Hz, 2H), 2.49 (t, J = 7 Hz,
2H), 4.12 (q, J = 6.5 Hz, 1H), 4.25–4.34 (m, 1H), 4.59–4.66 (m, 1H), 5.43 (dd,
J = 11, 10 Hz, 1H), 5.48 (dt, J = 11, 7 Hz, 1H), 5.72 (dd, J = 15, 6.5 Hz, 1H), 5.79
OH
< 55% from 4
96% from 23
OH
RvE1 (1)
Scheme 5. Synthesis of RvE1.

6082
N. Ogawa, Y. Kobayashi / Tetrahedron Letters 50 (2009) 6079–6082
(dd, J = 15, 6.5 Hz, 1H), 6.09 (t, J = 11 Hz, 1H), 6.16 (t, J = 11 Hz, 1H), 6.23 (dd,
2.12 (t, J = 7.5 Hz, 2H), 2.38–2.54 (m, 2H), 3.33 (s, 3H), 3.94 (q, J = 6 Hz, 1H),
4.12 (q, J = 6 Hz, 1H), 4.45–4.52 (m, 1H), 5.39 (t, J = 10.5 Hz, 1H), 5.47 (dt, J = 11,
8 Hz, 1H), 5.62 (dd, J = 15, 6 Hz, 1H), 5.67 (dd, J = 15, 6 Hz, 1H), 6.00 (t,
J = 10.5 Hz, 1H), 6.11–6.20 (m, 2H), 6.34 (dd, J = 15, 11 Hz, 1H), 6.55 (dd, J = 15,
11 Hz, 1H), 6.62 (dd, J = 15, 11 Hz, 1H); 13C NMR (75 MHz) d 9.9, 21.2, 30.6,
33.8, 36.2, 37.1, 51.0, 67.6, 71.9, 73.5, 125.3, 126.9, 128.4 (overlapped with
C6D6), 129.7, 130.4, 131.1, 134.1, 134.9, 137.1, 137.8, 173.5. The 1H and 13C
NMR spectra were identical with those reported.10
J = 15, 11 Hz, 1H), 6.31 (dd, J = 15, 11 Hz, 1H), 6.45–6.54 (m, 2H). Methyl ester
of RvE1 in CDCl3: 1H NMR (500 MHz) d 0.93 (t, J = 7 Hz, 3H), 1.19–1.94 (m, 6H),
1.8–2.0 (br s, 3H), 2.34 (t, J = 6.5 Hz, 2H), 2.43–2.55 (m, 2H), 3.67 (s, 3H), 4.11
(q, J = 6.5 Hz, 1H), 4.27 (q, J = 6.5 Hz, 1H), 4.56–4.62 (m, 1H), 5.43 (t, J = 11 Hz,
1H), 5.46 (dt, J = 11, 8 Hz, 1H), 5.73 (dd, J = 15, 6.5 Hz, 1H), 5.79 (dd, J = 15,
6.5 Hz, 1H), 6.09 (t, J = 11 Hz, 1H), 6.16 (t, J = 11 Hz, 1H), 6.23 (dd, J = 15, 11 Hz,
1H), 6.32 (dd, J = 15, 11 Hz, 1H), 6.45–6.56 (m, 2H); 13C NMR (75 MHz) d 9.8,
20.9, 30.2, 33.9, 35.8, 36.8, 51.7, 67.7, 71.9, 74.1, 125.5, 126.7, 127.8, 130.2,
21. The 1H NMR spectrum of the free acid (RvE1) is not given in Ref. 10.
22. On the other hand, purity of the methyl ester over the (6E)-isomer was ca. 85%.
130.6, 131.1, 133.9, 134.0, 136.5, 137.2, 174.1. Methyl ester of RvE1 in C6D6: 1
NMR (500 MHz) d 0.89 (t, J = 7.5 Hz, 3H), 1.08–1.82 (m, 6H), 1.8–2.3 (br s, 3H),
H