Reaction of 1-Trimethylsilyl-1,2-epoxy-3-alkanols with Alkynes and Application to the Synthesis of 18-HEPE

Article abstract of DOI:10.1055/s-0037-1610194

A reaction of epoxy alcohols (anti and/or syn isomers) derived from (E)-TMS-CH=CHCH(OH)R with TMS-C≡CLi in THF/HMPA stereoselectively afforded (E)-TMS-C≡C-CH=CHCH(OH)R. The (E) stereochemistry was independent of the anti / syn stereochemistry, but the syn

Full text of DOI:10.1055/s-0037-1610194

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
Y. Nanba et al.
Letter
Synlett
Reaction of 1-Trimethylsilyl-1,2-epoxy-3-alkanols with Alkynes
and Application to the Synthesis of 18-HEPE
Yutaro Nanba
TMS
O
Masao Morita
TMS
C
C
Li
1) TBSCl
TMS
Yuichi Kobayashi*
THF/HMPA, rt
2) K2CO3, MeOH
OH
OH
Department of Bioengineering, Tokyo Institute
of Technology, Box B-52, Nagatsuta-cho 4259,
Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
CO2Me
CO2H
Br
OTBS
via Castro–Stephenes coupling
OH
(18R)-HEPE
Received: 27.04.2018
Accepted after revision: 04.06.2018
Published online: 29.06.2018
coupling,6 Wittig reaction,7 and others.8 Herein, we report a
study of this transformation and its application to the syn-
thesis of 18-hydroxyeicosapentaenoic acid (18-HEPE) (5) in
its R and S forms.9
DOI: 10.1055/s-0037-1610194; Art ID: st-2018-u0263-l
Abstract A reaction of epoxy alcohols (anti and/or syn isomers)
derived from (E)-TMS-CH=CHCH(OH)R with TMS-C≡CLi in THF/HMPA
stereoselectively afforded (E)-TMS-C≡C-CH=CHCH(OH)R. The (E) stereo-
chemistry was independent of the anti/syn stereochemistry, but the syn
isomers showed higher reactivity than the anti isomers. The reaction
was applied to the synthesis of (18R)- and (18S)-HEPE.
R2
R2
C
C
H (2), n-BuLi
O
R1
TMS
R1
*
*
*
*
additive
OH
OH
1
3
Scheme 1 Present study
Key words alkynes, epoxide ring opening, silicon, stereoselective syn-
thesis, Castro–Stephens coupling, eicosapentaenoic acid
Biochemical oxidation of eicosapentaenoic acid (EPA)
(4) catalyzed by aspirin-treated COX-2 and by cytochrome
P450 produces 18-HEPE (5) in optically active forms (Figure
1).10 Several biological properties, including anti-inflamma-
tory activity, have been reported.9b,10 Soybean lipoxygenase
(sLOX) was used to convert 18-HEPE into RvE3.9c
The epoxide ring opening of epoxysilane by nucleo-
philes at a carbon bearing a silyl group (known as the
Hudrlik reaction), and the subsequent Peterson olefination,
is a potentially useful combination that affords nucleophile-
containing olefins in a stereoselective manner.1 Alkyl, alke-
nyl, and aryl Grignard reagents/Cu catalysts, and organo-
copper reagents with or without BF3·OEt2, have been inten-
sively studied as reagents for that reaction.2 As regards
alkynyl species, the formation of enynes was reported only
by Negishi, who used epoxysilanes derived from 1-TMS-1-
alkenes (TMS: trimethylsilyl) and alkynyl lithiums.2c It is
particularly noteworthy that this two-step conversion took
place through a one-pot reaction. In contrast, the first step
of the epoxide ring opening was reported using alkynyl-
aluminum reagents.3 Although the above-mentioned epoxy-
silanes were structurally simple substrates,2c we envisaged
the combination of epoxy alcohol 1 with 1-alkynes 2 (R1 =
any alkyl; R2 = TMS, alkyl, aryl, etc.) as delineated in Scheme
1. The resulting enynyl alcohols 3 would be intermediates
for the synthesis of metabolites of unsaturated fatty acids.
Previously, 3 (R1 = TMS, H) and their derivatives have been
synthesized by several methods, including the reduction of
ynenones,4 reduction of diynyl alcohols,5 Sonogashira
CO2H
CO2H
OH
EPA (4)
18-HEPE (5)
Figure 1 EPA and 18-HEPE
An anti/syn mixture of 1a in a ratio of 37:68 was
subjected to an anion derived from TMS-acetylene 2a and
n-BuLi in THF at rt for 14 hours. However, the reaction was
incomplete and the anti isomer of 1a was recovered
(Table 1, entry 1). Reactions attempted at higher tempera-
tures of 40–45 °C (entry not shown) or in THF/DMPU (entry
2) resulted in the recovery of 1a (anti), affording a mixture
of 3a and 1a (anti) in ratios of 70:30 and 67:33. These re-
sults indicate that the syn isomer of 1a was more reactive
than the anti isomer; thus, the reaction conditions for con-
version of the less reactive anti isomer were intensively ex-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
Y. Nanba et al.
Letter
Synlett
Table 1 Exploration of Reaction Conditions
TMS
O
TMS
C
C
H (2a), n-BuLi
*
TMS
C5H11
C5H11
OH
*
THF, additive
OH
1a (anti and/or syn)
3a
Entry
anti/syn
2a (equiv)
n-BuLi (equiv)
Additive (equiv)
Temp. (°C)
Time (h)
Yield (%) of 3a
3a/1a (anti)a
1
2
3
4
5
6
7
37:63
37:63
100:0
100:0
100:0
4.5
4.5
4.5
9
4
4
4
8
8
4
4
–
rt
rt
rt
rt
rt
rt
0
14
4
48
64:36
67:33
40:60
50:50
91:9
DMPU (9)
HMPA (9)
HMPA (9)
HMPA (18)
–
n.d.b
n.d.b
n.d.b
60
5
4
9
3
0:100
0:100
4.5
4.5
4
59
100:0
100:0
HMPA (9)
4
65
a Determined by 1H NMR.
b Not determined.
A: slowly reacting anti isomer
Li
The conditions optimized above were applied to reac-
O
H
O
Li
O
tions of other epoxy alcohols with acetylenes as shown in
Scheme 3. A stereoisomeric mixture of 1b (anti/syn =
40:60) was converted into 3b in 75% yield, with complete
conversion of the less reactive anti isomer. Similarly, the
pure anti isomers 1c and 1d afforded 3c and 3d in 69 and
64% yield, respectively. The latter result would be useful for
planning a synthesis of metabolites possessing the same
side chain, as described in the following paragraph. An
anti/syn mixture of 1e also afforded 3e in 50% yield. Unlike
TMS-acetylene 2a, 1-heptyne (2b), selected as a represen-
tative 1-alkyne, was less reactive, affording 3f in 75% yield
after 20 hours, whereas phenylacetylene (2c) showed a
similar reactivity to TMS-acetylene (2a).
SiMe3
O
TMS
H
C5H11
SiMe3
C5H11
H
SiMe3
Li
B: swiftly reacting syn isomer
O
H
O
Li
O
SiMe3
O
TMS
C5H11
H
C5H11
SiMe3
H
SiMe3
The above products 3a–d could be converted into meta-
bolites of fatty acids: for example, 3a to 15-HETE, and 8,15-
dihydroxyl-ARA; 3b to resolvins E1, E2, 18-hydroxy-EPA
(18-HEPE), and 20-hydroxy-DHA; 3c to resolvins D4, D5,
and 17-hydroxy-DHA; and 3d to 12-hydroxy-EPA, and 14-
hydroxy-DHA. Among these targets, (18R)- and (18S)-HEPE
[(R)- and (S)-5] were chosen for the present investigation,
and the results are described below.
Epoxy alcohol (R)-1b (anti) with 99% ee and allylic alco-
hol (S)-8 with >99% ee, shown in Scheme 4, were obtained
by Sharpless asymmetric epoxidation of racemic (E)-1-
(trimethylsilyl)pent-1-en-3-ol (see the Supporting Infor-
mation).12 As with the synthesis of racemic 3b (anti/syn)
from 1b (Scheme 3), (R)-1b (anti) was converted into enyne
(R)-3b in 73% yield with >99% ee as determined by the
derived MTPA ester. The enyne was transformed into (R)-7
in 88% yield by protection with TBSCl, followed by proto-
desilylation of the resulting (R)-6 with K2CO3 in MeOH. In
the synthesis of (S)-7, epoxidation of (S)-8 with m-CPBA
afforded epoxy alcohol (S)-1b as a 40:60 mixture of anti/syn
isomers. Without separation, the mixture was converted
Scheme 2 Plausible transition states A and B for the epoxide opening
plored to find that the use of HMPA as a co-solvent with
THF promoted the reaction. However, the reaction re-
mained incomplete (entry 3). Increasing the quantity of the
acetylide anion was partially effective (entry 4), and adding
more HMPA drove the reaction to near completion, giving
3a in 60% yield (entry 5).11
The difference in reactivity of the anti and syn stereo-
isomers of 1a is understood by assuming transition states A
and B (Scheme 2), in which chelation of a lithium cation
(Li+) to the epoxy oxygen atom fixes the conformation and
partially activates the epoxide C–O bond for the reaction.
Between A and B, the epoxide ring opening of A is probably
prevented by steric hindrance from the C5H11 group, and
addition of HMPA prompted the reaction by increasing the
nucleophilicity of the anion. In accordance with this mech-
anism, the TBS ether of 1a was slightly reactive under simi-
lar conditions, giving the corresponding enyne in 21% yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
Y. Nanba et al.
Letter
Synlett
TMS
O
2a (6.5 equiv), n-BuLi (6 equiv)
TMS
THF, HMPA (12 equiv), rt, 3 h
75%
OH
OH
1b (anti/syn = 40:60)
3b
TMS
O
as above
69%
TMS
OH
OH
3c
1c (anti)
TMS
O
as above
64%
TMS
OH
OH
3d
1d (anti)
TMS
O
as above
50%
TMS
OTBS
OTBS
OH
OH
1e (anti/syn = 37:63)
3e
C5H11
C
C
H (2b) (9 equiv)
C5H11
O
n-BuLi (8 equiv)
TMS
C5H1
C5H11
OH
THF, HMPA (18 equiv), rt, 20 h
75%
OH
1a (anti)
3f
Ph
C
C
H (2c) (10 equiv)
Ph
n-BuLi (9 equiv)
C5H11
OH
1a (anti)
THF, HMPA (19 equiv), rt, 3 h
77%
3g
Scheme 3 Further examples of the enyne synthesis
Synthesis of (R)-7
TMS
H
O
2a/n-BuLi (6 equiv)
K2CO3 (1.5 equiv)
MeOH, 87%
TMS
THF, HMPA (12 equiv), rt, 4 h
73%
OH
OR
OTBS
(R)-1b (anti)
(R)-3b, R = H
(R)-7
TBSCl, imid.
99% ee
(R)-6, R = TBS
88%
Synthesis of (S)-7
TMS
O
m-CPBA
2a/n-BuLi (6 equiv)
TMS
TMS
NaHCO3
83%
THF, HMPA (12 equiv), rt, 4 h
73%
OH
OH
OH
(S)-8, >99% ee
(S)-1b
(anti/syn = 40:60)
(S)-3b
H
1) TBSCl, imid.
2) K2CO3, MeOH
83%
OTBS
(S)-7
Scheme 4 Synthesis of enantiomeric enynes (R)- and (S)-8
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
Y. Nanba et al.
Letter
Synlett
Synthesis of (18R)-HEPE
CO2Me
CO2Me
OTBS
CuI (2 equiv), NaI (2 equiv),
Cs2CO3 (1.5 equiv)
H2, P-2 Ni (1.2 equiv)
+
(R)-7
(1.06 equiv)
Br
(CH2NH2)2 (2.2 equiv), EtOH
62%
DMF, rt, 7 h
63%
9 (1 equiv)
(R)-10
CO2Me
CO2Me
OTBS
Zn (excess), Cu(OAc)2, AgNO3
+
MeOH, H2O
89%
OTBS
(R)-11
OTBS
4:1
(R)-11
(R)-12
55% (2 steps)
CO2Me
CO2H
aqueous LiOH
TBAF (3 equiv)
67%
THF, MeOH
OH
OH
56%
(R)-13
(18R)-HEPE [(R)-5]
Synthesis of (18S)-HEPE
CO2H
OH
CO2Me
OTBS
as above
CuI, NaI, Cs2CO3
9
+
(S)-7
DMF, rt, 7 h
64%
(S)-10
(18S)-HEPE [(S)-5]
Scheme 5 Synthesis of 18R- and 18S-HEPE
into the (S)-enantiomer of enyne (S)-7. Previously, (S)-7 or
its (R)-isomers and derivatives have been synthesized
through asymmetric reduction,4a optical resolution,4b and
biosynthesis8d using a fungus, and the presented methods
will be complementary to these methods.
Funding Information
This work was supported by JSPS KAKENHI Grant Number
JP15H05904.
)(
The Castro–Stephens coupling13 of (R)-7 (1.06 equiv)
with propargylic bromide 914 (1.0 equiv) using CuI (2
equiv), NaI (2 equiv), and Cs2CO3 (1.5 equiv) in DMF at rt for
seven hours gave (R)-10 in 63% yield (Scheme 5).15 Semi-
hydrogenation of (R)-10 under hydrogen by using P-2 nickel
and ethylene diamine (EDA) gave a mixture of (R)-11 and
(R)-12 in a ratio of 4:1. Without separation, the mixture
was treated with freshly prepared Zn(Cu/Ag) to afford (R)-
11 in 55% yield from (S)-10, which gave alcohol (R)-13 in
67% yield upon desilylation. Finally, hydrolysis produced
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610194.
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References and Notes
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2263.
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1
(18R)-HEPE [(R)-5] in 56% yield. The H and 13C NMR spec-
tra were consistent with those reported by Inoue.9c Similar-
ly, the coupling of 9 and (R)-7 afforded (S)-10, which was
converted to (18S)-HEPE [(S)-5].
In summary, the transformation of 1-trimethylsilyl-1,2-
epoxy-3-alkanols with 1-alkynes to the corresponding
enynyl alcohols was studied. The anti and syn stereo-
isomers had different reactivity; less reactive anti isomers
underwent the reaction using excess alkynes in THF/HMPA.
The reaction was applied to the synthesis of (18R)- and
(18S)-HEPE.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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Letter
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1.20–1.66 (m, 9 H), 4.08–4.22 (m, 1 H), 5.72 (dd, J = 15.9 Hz, 1.5
Hz, 1 H), 6.20 (dd, J = 15.9, 6.3 Hz, 1 H) ppm. 13C–APT NMR (75
MHz, CDCl3): δ = –0.05 (+), 14.1 (+), 22.6 (–), 25.0 (–), 31.8 (–),
36.9 (–), 72.3 (+), 95.1 (–), 103.2 (–), 109.8 (+), 147.0 (+) ppm.
HRMS (FAB+): m/z [M + Na]+ calcd for C13H24OSiNa: 247.1494;
found: 247.1490.
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Chem. Commun. 2017, 53, 1813. (b) Li, C.; Xu, W.; Vadivel, S. K.;
Fan, P.; Makriyannis, A. J. Med. Chem. 2005, 48, 6423.
(15) Castro–Stephens coupling of rac-7 (1.2 equiv) with Z-allylic
bromide i (1 equiv) using CuI (2 equiv), NaI (2 equiv), and K2CO3
(1.5 equiv) at rt in DMF gave a mixture of rac-12 and the regio-
isomer ii in a 3:1 ratio (1H NMR), which were hardly separated
by chromatography on silica gel (Scheme 6). The mixture was
converted into 18-HEPE and the regioisomer by a sequence of
reactions: 1) TBAF; 2) Zn (Cu/Ag); 3) LiOH; an attempted sepa-
ration at each step was hardly successful.
CO2Me
CuI (2 equiv), NaI (2 equiv),
K2CO3 (1.5 equiv)
+
rac-7
DMF, rt, 8 h
63%
Br
i (1 equiv)
(1.2 equiv)
(11) To an ice-cold solution of 2a (0.40 mL, 2.89 mmol) and n-BuLi
(1.55 M in hexane, 1.60 mL, 2.48 mmol) in THF (0.1 mL) were
added HMPA (0.95 mL, 5.44 mmol) and a solution of 1a (anti)
(65 mg, 0.30 mmol) in THF (0.2 mL). After being stirred at rt for
3 h, the solution was diluted with saturated NH4Cl. The mixture
was extracted with EtOAc and the crude product was purified
by chromatography on silica gel (hexane/EtOAc) to afford enyne
rac-3a (41 mg, 60%). Liquid, Rf = 0.43 (hexane/EtOAc 9:1). 1H
NMR (300 MHz, CDCl3): δ = 0.19 (s, 9 H), 0.88 (t, J = 6.9 Hz, 3 H),
OTBS
CO2Me
OTBS
+
rac-12
ii
3:1
Scheme 6 An unsuccessful result
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E