Synthesis of 8-HEPE and 10-HDoHE in both (R)- and (S)-Forms via Wittig Reactions with COOH-Ylides

Article abstract of DOI:10.1055/s-0037-1611976

Wittig reactions using carboxy (CO ₂ H) ylides derived from a carboxylic phosphonium salt and NaN(TMS) ₂ (NaHMDS) in a 1:1 ratio were applied to the synthesis of 8-HEPE and 10-HDoHE, which are metabolites of eicosapentaenoic acid and

Full text of DOI:10.1055/s-0037-1611976

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
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Y. Suganuma et al.
Letter
Synlett
Synthesis of 8-HEPE and 10-HDoHE in both (R)- and (S)-Forms via
Wittig Reactions with COOH-Ylides
CO2H
Yuta Suganuma
Shun Saito
Br– Ph3P+
NaN(TMS)2
(1 equiv per Wittig reagent)
Yuichi Kobayashi*
–
–
CO2H (not CO2
)
+
OTBS
OH
*
Ph3P
(carboxy ylide)
CHO
CO2H
Department of Bioengineering, Tokyo Institute of Technology,
Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501,
Japan
*
THF/HMPA
Bu4NF
ykobayas@bio.titech.ac.jp
(R)- and (S)-enantiomer
(8R)- and (8S)-HEPE
OH
*
Similarly,
CO2H
(10R)- and (10S)-HDoHE
Received: 18.11.2018
Accepted after revision: 12.12.2018
Published online: 10.01.2019
poxygenase produces (10S)-HDoHE in minute quantities.4
However, racemic forms of 8-HEPE and 10-HDoHE are com-
mercially available. Herein, we present syntheses of 8-HEPE
(1) and 10-HDoHE (2) in both the (R)- and (S)-forms.
DOI: 10.1055/s-0037-1611976; Art ID: st-2018-u0754-l
Abstract Wittig reactions using carboxy (CO2H) ylides derived from a
carboxylic phosphonium salt and NaN(TMS)2 (NaHMDS) in a 1:1 ratio
were applied to the synthesis of 8-HEPE and 10-HDoHE, which are me-
tabolites of eicosapentaenoic acid and docosahexaenoic acid, respec-
tively. The attempted Wittig reaction of 3-(TBS-oxy)pentadeca-
4E,6Z,9Z,12Z-tetraenal with the carboxy ylide (2 equiv) derived from
Br– Ph3P+(CH2)4CO2H and NaHMDS (1:1) competed with the elimination
of the TBS-oxy group at C3 to give a mixture of the Wittig product and
the elimination product in 45–50% and 30–40% yields, respectively. The
elimination was suppressed completely by using three equiv of the car-
boxy ylides in THF/HMPA (7–8:1), and the subsequent desilylation gave
8-HEPE in (R)- and (S)-forms. Similarly, both enantiomers of 10-HDoHE
were synthesized.
OH
*
OH
CO2H
CO2H
*
Me20
Me22
10-HDoHE (10-HDHA) (2)
8-HEPE (1)
Figure 1 Two targets of the present study
CO2H
OTBS
Br– Ph3P+
(4a)
CHO
*
TBS ether of 1
NaHMDS
(R)- and (S)-3
Br– Ph3P+
CO2H (4b)
Key words lipoxygenase metabolite, 10-HDoHE, 8-HEPE, Wittig reac-
TBS ether of 2
tion, carboxy phosphonium salt
NaHMDS
Scheme 1 Synthesis of 8-HEPE and 10-HDoHE using 4a and 4b
In the preceding paper, we reported that the one equiv
of NaN(TMS)2 (NaHMDS) is sufficient to generate ylides
from carboxy (CO2H) phosphonium salts of the form
[Ph3PCH2-alk-CO2H]+ X– for use in Wittig reactions and that
the carboxy ylides can be reacted to give Z-olefinic acids
stereoselectively. To demonstrate the utility of these ylides
in organic synthesis, we selected 8-HEPE (1) and 10-HDoHE
(2) as specific synthetic targets (Figure 1). These com-
pounds are metabolites of eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) in mammals1 and marine
creatures.2 The former enhances adipogenesis and glucose
uptake.2a In a previously reported synthesis of (8R)-HEPE, a
protected hydroxymethyl group was used as a precursor to
the carboxy moiety, and the (R)-chirality was derived from
mannitol.3 However, no access to the (S)-isomer was indi-
cated. As for 10-HDoHE, no organic synthesis has been pub-
lished, whereas biochemical oxidation of DHA by potato li-
Scheme 1 shows the key intermediate 3 in the (R)- and
(S)-forms and the Wittig reactions with carboxy ylides de-
rived from 4a and 4b with NaHMDS for the synthesis of the
selected targets. Since competition between the Wittig re-
action and the elimination of the β-siloxy group from alde-
hyde 3 was an issue, 3-alkoxy-3-phenylpropanals 5–8 were
used in a preliminary study of the Wittig reactions with
4c/NaHMDS to secure suitable reaction conditions (Table
1). The TBS derivative 6 afforded a mixture of olefin 10 and
the elimination product 13 in an 80:20 ratio as expected,
and the former was isolated in 56% yield with 95% Z-selec-
tivity (Table 1, entry 4). TES- and TBDPS-oxy aldehydes 5
and 7 also underwent the elimination and produced 13 in
32% and 11% relative yields (Table 1, entries 1 and 6). The
methoxy derivative 8 also afforded a mixture of olefin 12
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
Y. Suganuma et al.
Letter
Synlett
and byproduct 13 in a 79:21 ratio (Table 1, entry 7), where-
as the α-ethoxyethyl ether gave a mixture of unidentified
products. Similar Z-selectivity (93%) and reactivity were ob-
served in the reaction of 3-phenylbutanal (14) to afford 15
in 64% yield (Scheme 2, eq. 1).
75% yield (Table 1, entry 3). Similarly, TBS-oxy aldehyde 6
afforded 10 exclusively under the improved conditions (Ta-
ble 1, entry 5, cf. entry 4).
The above method using carboxy ylides was applied to
the construction of the Δ5 olefin group of 8-HEPE (1), and
the Δ4 and Δ7 olefin groups of 10-HDoHE (2). Synthesis of
the common aldehydes (R)- and (S)-3 commenced with
conversion of β-propiolactone (17) to amide 18, which
upon reaction with TMS-acetylene/n-BuLi afforded ketone
19 in 87% yield (Scheme 3). The asymmetric transfer hydro-
genation6 gave (R)-20 with 97% ee as determined by chiral
HPLC. Subsequently, Red-Al reduction followed by TBS pro-
tection of the resulting diol afforded (R)-21 in 67% yield.
Transformation of (R)-21 to aldehyde (R)-23 was conducted
in three steps consisting of the epoxidation, the epoxide
ring opening with Et2AlCN,7 and DIBAL reduction. The Wit-
tig olefination with phosphonium salt 248 under the stan-
dard conditions for alkyl ylides afforded (R)-25 with high Z-
stereoselectivity, and the TBS group on the primary carbon
was removed with PPTS in EtOH (46% over two steps). Fi-
nally, Swern oxidation of the resulting alcohol (R)-26 af-
forded (R)-3 in 67% yield. In a similar manner, alcohol (S)-20
was derived from ketone 19 and converted into (S)-3
(Scheme 3).
4c/NaHMDS (1:1)
Me
Me
(2 equiv)
CHO
(1)
Ph
Ph
CO2H
15, 64%, Z/E = 93:7
THF, –90 to 0 °C, 3 h
14
4c/NaHMDS (1:1)
(2 equiv)
(2)
13
+
13
Ph
CO2H
16, 48%, Z/E = 62:38
THF, –90 to 0 °C, 3 h
37%
Scheme 2 Wittig reactions using aldehydes 14 and 13
These results clearly indicated that the reactivity and
selectivity were marginally influenced by the oxygen atom
in the silyloxy substituent. Interestingly, the possible Wittig
product of aldehyde 13 with 4c was not detected by 1H
NMR spectroscopy (S/N ratio, >95:5),5 indicating the lower
reactivity of 13 than that of the silyloxy aldehydes. In fact,
an independent reaction of 13 with 4c/NaHMDS (1:1) un-
der the same reaction conditions proceeded slowly to afford
a mixture of diene 16 (Z/E = 62:38) and unreacted 13 in 48%
and 37% yields, respectively (Scheme 2, eq. 2).
To identify reaction conditions that suppress the elimi-
nation, various were tested with TES-oxy aldehyde 5, which
underwent the elimination most easily among the silyloxy
aldehydes (Table 1, entry 1, cf. entries 4 and 6). The use of
HMPA as a co-solvent with THF was effective to some ex-
tent (Table 1, entry 2), and further elaboration using three
equiv of the reagent in THF/HMPA afforded 9 exclusively in
The Wittig reaction of (R)-3 with the carboxy ylide de-
rived from 4a/NaHMDS (1:1) in THF/HMPA (7:1) according
to the procedure in Table 1, entry 5 afforded (R)-27 as the
sole product in 84% yield (Scheme 4), whereas the ylide in
THF under the conditions in Table 1, entry 4 gave a mixture
of (R)-27 and the unsaturated aldehyde 28 in 45–50% and
30–40% yields, respectively, as observed over several runs.
Finally, desilylation of (R)-27 with TBAF afforded (8R)-HEPE
Table 1 Wittig Reactions of β-Alkoxyaldehydes with 4ca
Br– Ph3P+
CO2H (4c)/NaHMDS
(2 or 3 equiv)
OR
OR
CHO
CHO
Ph
Ph
CO2H
+
Ph
THF or THF/HMPA (7~8:1)
9–12
13
5–8
Entry
R
Aldehyde
Solvent
Product
Yield (%)
Z/Eb
92:8
Product /13
1
TES
5
5
5
6
6
7
8
THF
9
9
56
NDd
75
56
70
56
61
68:32
77:23
>95:5f
80:20
>95:5f
89:11
79:21
2
TES
THF/HMPAc
THF/HMPAc
THF
NDd
92:8
95:5
94:6
92:8
93:7
3e
4
TES
9
TBS
TBS
TBDPS
Me
10
10
11
12
5e
6
THF/HMPAc
THF
7
THF
a Carried out with the ylide derived from 4c (2 equiv) and NaHMDS (2 equiv) at –90 to 0 °C for 3 h unless otherwise noted.
b Ratios of peak heights in the 13C NMR spectrum.
c 7–8:1.
d Not determined.
e Three equiv of 4c/NaHMDS (1:1).
f S/N ratio of 1H NMR spectrum = ca. 95:5. The aldehyde proton of 13 was not seen in the 1H NMR spectrum.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

C
Y. Suganuma et al.
Letter
Synlett
Synthesis of (R)-3
TMS
(3 equiv)
O
OTBS
1) Me2AlCl (4 equiv)
MeNH(OMe)·HCl (2 equiv)
O
OTBS
O
O
(R,R)-Ru (3.5 mol%)a
i-PrOH, r.t., 3 h
93%
n-BuLi (2.5 equiv)
MeO
N
Et2O, –78 to –20 °C, 1 h
87%
2) TBSCl, imid., DMF, r.t., 3 h
49%
TMS
Me
17
19
18
1) Red-Al (3 equiv)
Et2O, r.t., 5 h
OH OTBS
1) m-CPBA, NaHCO3
r.t., 24 h
TBSO
OTBS
TBSO
OTBS
DIBAL (2 equiv)
toluene, –78 to 0 °C
60%
TMS
NC
2) TBSCl, imid.
2) Et2AlCN, r.t., 3 h
62%
TMS
(R)-22
(R)-20, 97% ee
67%
(R)-21
P+Ph3 I–
OTBS
OR
OTBS
CHO
TBSO
OTBS
24 (1.8 equiv)
(COCl)2, DMSO
OHC
NaHMDS (1.4 equiv), THF
–78 to 0 °C, 3 h
then Et3N
67%
(R)-23
(R)-25, R = TBS
(R)-26, R = H
(R)-3
PPTS (1 equiv)
EtOH, 0 °C, 23 h
46% (two steps)
Synthesis of (S)-3
OTBS
CHO
OH OTBS
(S,S)-Ru (3 mol%)
i-PrOH, r.t., overnight
92%
19
as above
TMS
(S)-20, 97% ee
(S)-3
Scheme 3 Synthesis of the key aldehyde. a RuCl[(R,R)-TsDPEN](p-cymene).
((R)-1) in 84% yield. The 1H NMR spectral data of the prod-
uct were consistent with the reported data.2d The 13C-APT
NMR and UV spectra further supported the structure. The
1H NMR spectrum of the derived methyl ester (with CH2N2)
was consistent with the reported data.2c The high chemical
purity of (R)-1 was confirmed by these NMR spectra. Enan-
tiomeric purity of (R)-1 was 97% ee as determined by chiral
HPLC of the derived methyl ester (CH2N2), and the ee indi-
cated that no isomerization occurred during synthesis.9 In a
similar manner, aldehyde (S)-3 was converted into (8S)-
HEPE ((S)-1) (97% ee) in 73% yield over two steps.
Synthesis of (R)-1
CO2H
Br– Ph3P+
4a (3 equiv)
NaHMDS (3 equiv)
(R)-3
THF/HMPA (7:1), –90 to 0 °C, 3 h
84%
OR
CO2H
CHO
28
TBAF (5 equiv)
THF, 0 °C to r.t.
(R)-27, R = TBS
(R)-1, R = H, 97% ee
84%
In the synthesis of (10R)-HDoHE ((R)-2), two intermedi-
ates 30 and (R)-33 were prepared by the carboxy ylide Wit-
tig reaction, as delineated in Scheme 5. Although the elimi-
nation of the TBS-oxy group from aldehyde 29 was possible,
a small-scale Wittig reaction of 29 (ca. 100 mg) with two
equiv of 4c (ca. 400 mg)/NaHMDS (1:1) in THF/HMPA pro-
duced 30 in 64% yield. Since the yield was similar to that
(70%) for the Wittig reaction of aldehyde 6 with 4c/NaH-
MDS in Table 1, entry 5, we concluded that the elimination
to produce CH2=CHCHO was negligible. The reaction could
be performed with an increased quantity (11 g) and a re-
duced equivalency (1.5 equiv) of 4c to give 30 in 62% with
97% Z-selectivity, as presented in Scheme 5 (the first step).
Then, 30 was converted in four steps into the carboxy phos-
phonium salt 4b. Subsequently, the Wittig reaction of (R)-3
with the carboxy ylide derived from 4b afforded (R)-33 ste-
reoselectively in 84% yield. Finally, desilylation with TBAF
furnished (10R)-HDoHE ((R)-2) with 97% ee (according to
Synthesis of (S)-1
OR
CO2H
4a/NaHMDS (1:1) (3 equiv)
(S)-3
THF/HMPA (5:1)
–90 to 0 °C, 3 h
TBAF
THF
(S)-27, R = TBS
(S)-1, R = H, 97% ee
81%
90%
Scheme 4 Synthesis of (8R)- and (8S)-HEPE
chiral HPLC analysis of the methyl ester) in good yield. The
1H NMR and 13C-APT NMR spectra, UV spectrum, and HRMS
data were consistent with the structure. Furthermore, the
1H NMR spectrum of the derived methyl ester (CH2N2) was
consistent with the reported data.2b Synthesis of (10S)-
HDoHE ((S)-2) from (S)-3 was also completed (Scheme 5).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
Y. Suganuma et al.
Letter
Synlett
HDoHE. This method would be applicable for the synthesis
of structurally similar metabolites such as monohydroxy-
ARA, -EPA, and -DHA, and their dihydroxy derivatives that
include maresin 1, protectin D1, and resolvin D5, which are
anti-inflammatory and pro-resolving mediators.11
Synthesis of phosphonium salt 4b
Br– Ph3P+
4c (1.5 equiv)
CO2H
OTBS
CHO
R1O
CO2R2
NaHMDS (1.5 equiv)
THF/HMPA (6:1)
–90 to 0 °C, 3 h
29
30, R1 = TBS, R2 = H
Z/E = 97:3
p-TsOH (cat.)
THF, MeOH
31, R1 = H, R2 = Me
62%
82%
Funding Information
1) CBr4, PPh3
X
CO2H
2) LiOH aqueous
88%
This work was supported by JSPS KAKENHI Grant Number
PPh3
MeCN
32, X = Br
JP15H05904.
J
S
P
S
K
A
K
E
N
H
I
Grant(J
P
1
5
H
0
5
9
0
4)
4b, X = Ph3P+ Br–
81%
Acknowledgment
Synthesis of (R)-2
OTBS
3,6-Nonadienol was gifted by Zeon Corporation, Jpn.
CHO
4b/NaHMDS (1:1) (3 equiv)
THF/HMPA (7:1)
–90 to 0 °C, 3 h
84%
Supporting Information
(R)-3
OR
Supporting information for this article is available online at
CO2H
https://doi.org/10.1055/s-0037-1611976.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
TBAF (5 equiv)
THF, 0 °C to r.t.
(R)-33, R = TBS
(R)-2, R = H, 97% ee
References and Notes
94%
Synthesis of (S)-2
(1) (a) Hong, S.; Lu, Y.; Yang, R.; Gotlinger, K. H.; Petasis, N. A.;
Serhan, C. N. J. Am. Soc. Mass Spectrom. 2007, 18, 128.
(b) Morgan, L. T.; Thomas, C. P.; Kühn, H.; O’Donnell, V. B. Bio-
chem. J. 2010, 431, 141. (c) Sanaki, T.; Inaba, Y.; Fujiwara, T.;
Yoshioka, T.; Matsushima, K.; Minagawa, K.; Higashino, K.;
Nakano, T.; Numata, Y. Rapid Commun. Mass Spectrom. 2016, 30,
751. (d) Schuchardt, J. P.; Ostermann, A. I.; Stork, L.; Fritzsch, S.;
Kohrs, H.; Greupner, T.; Hahn, A.; Schebb, N. H. Prostaglandins
Leukot. Essent. Fatty Acids 2017, 121, 76.
OH
4b/NaHMDS (1:1) (3 equiv)
CO2H
(S)-3
THF/HMPA (5:1)
–90 to 0 °C, 3 h
TBAF
THF
(S)-33, R = TBS
(S)-2, R = H, 97% ee
77%
86%
Scheme 5 Synthesis of (10R)- and (10S)-HDoHE (2)
(2) (a) Yamada, H.; Oshiro, E.; Kikuchi, S.; Hakozaki, M.; Takahashi,
H.; Kimura, K. J. Lipid Res. 2014, 55, 895. (b) Mancini, I.;
Guerriero, A.; Guella, G.; Bakken, T.; Zibrowius, H.; Pietra, F.
Helv. Chim. Acta 1999, 82, 677. (c) Guerriero, A.; D’Ambrosio, M.;
Pietra, F. Helv. Chim. Acta 1988, 71, 1094. (d) D'Auria, M. V.;
Minale, L.; Riccio, R.; Uriarte, E. Experientia 1988, 44, 719.
(3) Shing, T. K. M.; Gibson, K. H.; Wiley, J. R.; Watt, C. I. F. Tetrahe-
dron Lett. 1994, 35, 1067.
(4) Butovich, I. A.; Hamberg, M.; Rådmark, O. Lipids 2005, 40, 249.
(5) Signal-to-noise (S/N) ratios of 1H NMR and 13C NMR spectra are
ca. 95% and ca. 97%, respectively.
(6) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738.
The reasonable yield of 30 obtained using 1.5 equiv of
4c prompted us to study a similar reaction of 29 with phos-
phonium salt 4a, which is one carbon longer than 4c. As de-
lineated in Scheme 6, olefinic acid 34 with 97% Z-selectivity
was obtained in 63% yield using 1.5 equiv of the reagent.
Exposure of 34 to acidic MeOH gave hydroxy methyl ester
35, which has been used as a component in the synthesis of
fatty acid metabolites.10,11
CO2H
Br– Ph3P+
(4a) (1.5 equiv)
NaHMDS (1.5 equiv)
CO2R2
(7) Ogawa, N.; Kobayashi, Y. Tetrahedron Lett. 2009, 50, 6079.
(8) de la Torre, A.; Lee, Y. Y.; Mazzoni, A.; Guy, A.; Bultel-Poncé, V.;
Durand, T.; Oger, C.; Lee, J. C.-Y.; Galano, J.-M. Chem. Eur. J. 2015,
21, 2442.
R1O
29
THF/HMPA (7:1)
–90 to 0 °C, 3 h
34, R1 = TBS, R2 = H
Z/E = 97:3
p-TsOH (cat.)
THF, MeOH
35, R1 = H, R2 = Me
63%
71%
21
(9) Since the observed specific rotation of (R)-1 ([α]D +6 (c 1.58,
CHCl3)) was inconsistent with the reported data for 86% ee11
([α]D24 +33.4 (c 2.1, CHCl3)), the reported 1H NMR analysis of the
MTPA ester derived from the methyl ester of (R)-1 was applied
to our sample to determine ca. 96.6% ee of (R)-1 (δ = 6.50–6.62
(m) and 6.60–6.69 (dd) ppm). Since accurate calculation was
prevented by the slight overlap of the signals, the methyl ester
was subjected to chiral HPLC analysis to establish 96.9% ee. In
addition, the Δδ values between the (S)- and (R)-MTPA esters of
the methyl ester indicated the (R)-chirality. The results are pre-
sented in the ESI.
Scheme 6 Preparation of 35 for the synthesis of fatty acid metabolites
In summary, the Wittig reactions of aldehydes possess-
ing a silyloxy group at the β-position with carboxy (CO2H)
ylides proceeded smoothly without the elimination of the
silyloxy group by using a carboxy ylide (3 equiv) in
THF/HMPA (7–8:1).12 The method was successfully applied
for the synthesis of both enantiomers of 8-HEPE and 10-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
Y. Suganuma et al.
Letter
Synlett
(10) (a) Taber, D. F.; Hoerrner, R. S. J. Org. Chem. 1992, 57, 441.
(b) Sandri, J.; Viala, J. J. Org. Chem. 1995, 60, 6627. (c) Han, X.;
Crane, S. N.; Corey, E. J. Org. Lett. 2000, 2, 3437. (d) Christiansen,
M. A.; Andrus, M. B. Tetrahedron Lett. 2012, 53, 4805.
was purified by chromatography on silica gel to give olefin (R)-
27 (102 mg, 84%) as the sole product: liquid; Rf = 0.21 (hex-
ane/EtOAc, 4:1); [α]D –21 (c 0.86, CHCl3). IR (neat): 1710,
20
1255, 836, 776 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.04 (s, 3 H),
0.05 (s, 3 H), 0.90 (s, 9 H), 0.97 (t, J = 7.5 Hz, 3 H), 1.69 (quint., J =
7.5 Hz, 2 H), 2.08 (quint., J = 7.5 Hz, 2 H), 2.09 (q, J = 7.5 Hz, 2 H),
2.25 (t, J = 6.0 Hz, 1 H), 2.22–2.31 (m, 2 H), 2.81 (t, J = 6.0 Hz, 2
H), 2.95 (t, J = 6.0 Hz, 2 H), 4.20 (q, J = 6.0 Hz, 1 H), 5.25–5.51 (m,
7 H), 5.66 (dd, J = 15.0, 6.0 Hz, 1 H), 5.98 (t, J = 11.1 Hz, 1 H), 6.48
(dd, J = 15.0, 11.1 Hz, 1 H), 10.2–11.2 (br s, 1 H) ppm. 13C-APT
NMR (75 MHz, CDCl3): δ = –4.7 (+), –4.4 (+), 14.3 (+), 18.3 (–),
20.6 (–), 24.5 (–), 25.6 (–), 25.9 (+), 26.1 (–), 26.7 (–), 33.5 (–),
36.4 (–), 73.0 (+), 124.4 (+), 126.8 (+), 127.0 (+), 127.6 (+), 128.2
(+), 128.9 (+), 129.5 (+), 130.2 (+), 132.1 (+), 136.7 (+), 180.3 (+)
ppm. HRMS (FAB+): m/z calcd for C26H43O3Si [(M – H)+]:
431.2981; found: 431.2990.
(11) (a) Balas, L.; Durand, T. Prog. Lipid Res. 2016, 61, 1. (b) Serhan, C.
N.; Petasis, N. A. Chem. Rev. 2011, 111, 5922. (c) Seki, H.; Tani, Y.;
Arita, M. Prostaglandins Other Lipid Mediators 2009, 89, 126.
(12) To an ice-cold suspension of 4a (374 mg, 0.844 mmol, 3 equiv)
in THF (2.4 mL) and HMPA (0.5 mL) was added NaHMDS (1.0 M
in THF, 0.843 mL, 0.843 mmol, 3 equiv). The resulting reddish-
orange mixture was stirred at 0 °C for 1 h and cooled to –90 °C.
A solution of aldehyde (R)-3 (98 mg, 0.281 mmol, 1 equiv) in
THF (0.7 mL) and HMPA (0.1 mL) was added to the mixture
dropwise. After 1 h, the mixture was warmed to 0 °C over 2 h
before addition of saturated NH4Cl. The resulting mixture was
extracted with EtOAc three times. The combined extracts were
dried over MgSO4 and concentrated to afford a residue, which
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E