Catalytic asymmetric synthesis of Leukotriene B4

Article abstract of DOI:10.1016/j.tetasy.2017.09.013

Leukotriene B₄ 1 was prepared from two chiral synthons 8 and 14. The chiral secondary alcohols of 8 and 14 were constructed by BINOL/Ti(OiPr)₄ catalyzed enantioselective alkynylzinc addition to aldehydes.

Full text of DOI:10.1016/j.tetasy.2017.09.013

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic asymmetric synthesis of Leukotriene B4
Pengfei Yang, Jiangchun Zhong, Kaijie Ji, Jingwei Yin, Shuoning Li, Siyuan Wei, Yun Zhou, Lifeng Wang,
⇑
Min Wang, Qinghua Bian
Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Leukotriene B4 1 was prepared from two chiral synthons 8 and 14. The chiral secondary alcohols of 8 and
Received 25 July 2017
Revised 14 August 2017
Accepted 12 September 2017
Available online xxxx
1
4 were constructed by BINOL/Ti(OiPr)
4
catalyzed enantioselective alkynylzinc addition to aldehydes.
Ó 2017 Elsevier Ltd. All rights reserved.
1
. Introduction
involved chiral borane catalyzed asymmatric reduction of an acet-
9
ylenic ketone, enzymatic enantioselective reduction of a ketone or
1
0
Arachidonic acid is released from membrane phospholipids
upon cell stimulation and converted to leukotrienes via the 5-
lipoxygenase pathway.1 Leukotriene B
1 (Fig. 1) gained special
hydrolysis of an ester, Sharpless catalytic asymmetric epoxida-
1
1
tion, stereocontrolled acetate–aldol reaction with Nagao’s chiral
12
4
auxiliary, the kinetic resolution of the racemic alcohol or TES-gly-
1
3
interest because it is a lipid mediator of inflammation and immune
cidol, and the derivation from chiral materials D-(+)-2-deoxyri-
responses, and has a number of biological activities.2 Leukotriene
bose,
The significant biological functions and the need for a better
supply of Leukotriene B prompted us to embark on more efficient
and convenient synthetic approaches. Herein, we report an alter-
native and efficient synthesis of Leukotriene B . The chiral sec-
ondary alcohols of Leukotriene were introduced using
enantioselective alkynylation of aldehydes with BINOL ligand and
Ti(OiPr) as catalysts.
D-mannitol, or L-glutamic acid.
14
B
4
activates inflammatory cells and the transcription factor PPAR
a
that regulates the oxidative degradation of fatty acids and their
4
3
derivatives. Leukotriene B
4
also enhances alveolar macrophages
anti-fungal activity. Newer results demonstrated that Leukotriene
could serve as a potential biomarker of rheumatioid arthritis
4
4
B
4
B
4
5
and microbial invasion of the aminotic cavity.
4
OH
OH
2. Results and discussion
COOH
4
As depicted by the retrosynthetic analysis of Leukotriene B 1 in
4
Figure 2, the target molecule Leukotriene B 1 could be obtained
1
from two chiral synthons 8 and 14 via coupling, reduction with
Zn(Cu/Ag), and saponification with LiOH. Chiral chlorotriene alco-
hol 8 could be prepared by desilylation, coupling and reduction
from TMS enynic alcohol 4, which could be synthesized from the
enantioselective addition of trimethylsilyacetylene to olefinic alde-
4
Figure 1. The structures of Leukotriene B 1.
4
Leukotriene B was first obtained by incubation of arachidonic
acid with rabbit peritoneal polymorphonuclear leukocytes, and
4
hyde 3 with (S)-BINOL and Ti(OiPr) as catalysts. We envisioned
its structure was elucidated as (5S,12R)-5,12-dihydroxyicosa-
that the (R)-BINOL/Ti(OiPr) catalyzed enantioselective alkynylzinc
4
6
,8,10,14-tetraenoic acid in 1979.6 Recently, de Campos Soares
addition to formyl ester 11 would provide TMS alkynol ester 12,
and subsequent desilylation could afford the key intermediate 14.
Our approach started from the synthesis of chiral chlorotriene
alcohol 8 (Scheme 1). Oxidation of olefinic alcohol 2 with Dess–
et al. reported that Paracoccidioides brasiliensis could produce Leu-
7
kotriene B
4
using endogenous arachidonic acid. The original syn-
from 2-deoxyribose and D-mannose
thesis of Leukotriene B
4
assigned the stereochemistry of the three conjugated double bonds
Martin periodinane (DMP) gave the desired olefinic aldehyde 3 in
8
as (6Z,8E,10E). The main strategies of the previous synthesis
15
6
4
0% yield. Using (S)-BINOL and Ti(OiPr) as catalysts, the reaction
of olefinic aldehyde 3 with alkynylzinc reagent, prepared in situ
from trimethylsilylacetylene and diethylzinc, led to TMS enynic
alcohol 4 in 64% yield and with 86% ee. The governing precedents
⇑
Corresponding author. Tel.: +86 010 62731356; fax: +86 010 62820325.
E-mail address: bianqinghua@cau.edu.cn (Q. Bian).
1
6
https://doi.org/10.1016/j.tetasy.2017.09.013
957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
0
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2
P. Yang et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
configuration of 12 was confirmed as (S).16 Recrystallization of
3,5-dinitrobenzoate 13 derived from the chiral alcohol 12
OH
OH
COOH
1
7
improved the enantiomeric excess from 80% to 97%. Exposure
2 3
to K CO
converted 13 into alkynol ester 14 in 74% yield.1
7,18
1
OH
Dess-Martin
periodinane
O
O
COOMe
COOMe
HCl, CH OH
3
HO
Cl
COOMe
8
OH
14
12
refluxed
90% yield
CH Cl , rt
0% yield
2
2
1
0
8
9
OH
TMS
O
TMS, (R)-BINOL, ZnEt
Ti(OiPr) , HMPA, CH Cl , rt
83% yield, 80% ee
2
COOMe
4
2
2
11
4
TMS
OH
TMS
3,5-dinitrobenzoyl chloride
O
Et N, CH Cl , 0 oC to rt
TMS
TMS
COOMe
CHO
COOMe
3
2
2
3
11
1.
OH
90% yield
1
2
TMS
Figure 2. Retrosynthetic analysis of Leukotriene B
4
K
2
CO
OH, rt
74% yield
3
COOMe
COOMe
CH
3
OAr
Ar = 3,5-dinitrobenzoyl
recryt. 60% yield, 97% ee
OH
Dess-Martin
1
3
14
periodinane
OH
CHO
CH Cl , rt
2 2
2
60% yield
3
Scheme 2. Synthesis of alkynol ester 14.
OH
TMS, (S)-BINOL, ZnEt
2
With key intermediates 8 and 14 in hand, the target molecule
Leukotriene B 1 was synthesized (Scheme 3). In the presence of
Pd(PPh and CuI, the reaction of chlorotriene alcohol 8 with alky-
nol ester 14 gave the coupling product 15. Using Zn metal, acti-
vated by AgNO and Cu(OAc) , the reduction of triple bond in
enynol ester 15 to cis double bond was achieved and provided ester
Ti(OiPr)
4 2 2
, HMPA, CH Cl , rt
4
TMS
TMS
6
4% yield, 86% ee
4
OAr
3 4
)
3,5-dinitrobenzoyl chloride
22
Et N, CH Cl
3
2
2
,
0 oC to rt
3
2
5
Ar = 3,5-dinitrobenzoyl
recryst. 68% yield, 98% ee
9
0% yield
2
3
1
6 in 60% yield. Final saponification of 16 with LiOH furnished
OH
Cl
24,25
K
2
CO
3
Leukotriene B
{[
value {[
1 in 78% yield.
The specific rotation of 1
Cl
Pd(PPh
4
2
1
CH
3
OH, rt
a]
D
3
= +10.9 (c 0.76, CHCl )} was consistent with the literature
3
)
4
, CuI, Et
benzene, rt
0% yield
3
N
2
0
10 a
8
7% yield
6
a
]
= +12.6 (c 0.46, CHCl
3
)},
while its NMR spectrum
D
6
8
was identical to the natural one.
OH
LiAlH
THF, -20 oC
5% yield
4
8
7
Cl
OH
OH
COOMe
Cl
8
OH
Pd(PPh
14
Cl
Scheme 1. Synthesis of chlorotriene alcohol 8.
8
3
)
4
, CuI, piperidine
benzene, rt
40% yield
OH
Zn(Cu/Ag)
MeOH/H O (1:1), rt
of Pu’s enantioselective alkynylation of unsaturated aldehydes
(R)-configuration.16 a,16 c
COOMe
2
favored
its
absolute
Slow
60% yield
OH
recrystallization of 3,5-dinitrobenzoate 5 derived from 4 and 3,5-
1
5
dinitrobenzoyl chloride, improved the ee to 98%.17 Subsequent
LiOH, 0 oC to rt
OH
OH
in situ desilylation and methanolysis of 5 using K
2
CO
which was coupled with
E)-1,2-dichloroethene in the presence of Pd(PPh and CuI to fur-
nish chloro enynic alcohol 7 in 80% yield. The treatment of 7 with
LiAlH resulted in the generation of a new trans double bond, and
chlorotriene alcohol 8 was obtained in 85% yield.
3
and MeOH
THF/CH OH/ H O (2:2:1)
3
2
COOMe
afforded enynic alcohol 6 in 87% yield,1
7,18
7
8% yield
OH
(
3 4
)
OH
19
16
COOH
4
2
0
1
The preparation of chiral subunit 14 was next studied
Scheme 2). An acid-induced methanolysis of lactone 9 afforded
(
4
Scheme 3. Synthesis of Leukotriene B 1.
21
the corresponding hydroxyl ester 10, followed by oxidation with
DMP produced formyl ester 11 in 80% yield.1 With the addition
5 b
of hexamethylphosphoramide, the (R)-BINOL/Ti(OiPr)
4
catalyzed
3. Conclusion
enantioselective alkynylzinc addition to formyl ester 11 was
conducted smoothly, and generated TMS alkynol ester 12 in 83%
yield and with 80% ee. According to the governing precedents
of Pu’s enantioselective alkynylation of aldehydes, the absolute
In conclusion, we have achieved an alternative and efficient
synthesis of Leukotriene B , which is short and convergent in 4%
total yield over 9 steps (longest linear sequence). The key steps
1
6
4
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P. Yang et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
of our strategy involved Pu’s asymmetric alkynylation of aldehyde,
coupling of terminal alkyne with chloro olefin, and reduction of tri-
1.0 mL/min, 220 nm), major (R)-enantiomer t
r
= 38.64 min; minor
1
8.5
1
(S)-enantiomer t
r
= 44.37 min. [
a]
D
= +7.4 (c 0.43, CHCl
3
).
H
ple bond to cis double bond with Zn(Cu/Ag). Moreover, the Leuko-
3
NMR (300 MHz, CDCl ) d 5.63 (dt, J = 10.9, 7.3 Hz, 1H), 5.46 (dt,
triene B
4
synthesized herein is valuable for the development of
J = 10.9, 7.3 Hz, 1H), 4.42–4.36 (m, 1H), 2.51–2.43 (m, 2H), 2.12–
2.05 (m, 2H), 1.97 (d, J = 5.8 Hz, 1H), 1.42–1.30 (m, 6H), 0.90 (t,
biomarkers of rheumatioid arthritis and microbial invasion of the
aminotic cavity.
1
3
J = 6.8 Hz, 3H), 0.18 (s, 9H). C NMR (75 MHz, CDCl
3
) d 134.3,
1
23.2, 106.3, 89.4, 62.4, 35.6, 31.5, 29.3, 27.5, 22.5, 14.0, À0.2;
+
HRMS (ESI) m/z 239.1844 [M+H] (calcd for C14H27OSi, 239.1826).
4
4
. Experimental
4
.4. (R,Z)-1-Trimethylsilyl-3-(3,5-dinitrobenzoyloxy)undec-5-
.1. General
en-1-yne 5
Unless otherwise stated, all reactions were carried out under an
To
.8 mmol) in anhydrous CH
0.576 g, 5.7 mmol) and 3,5-dinitrobenzoyl chloride (1.063 g,
.6 mmol) sequentially at 0 °C. The reaction mixture was warmed
to room temperature and stirred for 12 h. After being quenched
with water (10 mL), the organic phase was separated and the aque-
a
stirred solution of TMS enynic alcohol
4 (0.916 g,
argon atmosphere. Solvents were dried and distilled according to
standard procedures. All reagents were purchased commercially
and used directly, unless otherwise mentioned. Melting points
were collected on a STUART-SMP3 Melt-Temp apparatus without
correction. Optical rotations were measured on a PERKIN ELEMER
3
(
4
2
Cl (20 mL) were added Et
2
3
N
1
13
3
41 Polarimeter. H and C NMR spectra were recorded on a Bru-
ker DP-X300 MHz spectrometer, and chemical shifts (d) were
reported in ppm with tetramethylsilane (TMS) and CDCl as inter-
ous phase was extracted with CH
organic layers were washed with brine (3 Â 30 mL), dried over
anhydrous Na SO , and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatogra-
phy (petroleum ether/CH Cl 1:1) to obtain 3,5-dinitrobenzoate 5
1.479 g, 90% yield) as a white solid. The product 5 was recrystal-
lized three times from n–hexane-diethyl ether (5:1), and afforded
(1.011 g, 68% yield, 98% ee) as white crystals. mp 70.2–70.6 °C.
2
Cl
2
(3 Â 20 mL). The combined
3
2
4
nal standards. High resolution Mass spectra were collected on a
Waters LCT Premier instrument with an ESI mass spectrometer.
Enantiomeric excesses (ee) were determined on an Agilent 1200
HPLC system with a Daicel Chiralcel AD-H or OD-H chiral-phase
column and elution with n–hexane and 2-propanol.
2
2
(
5
Enantiomeric excess was determined by HPLC with a Daicel Chiral-
cel OD-H column (10% 2-propanol in n–hexane, 1.0 mL/min,
4
.2. (Z)-Non-3-enal 3
2
r
54 nm), major (R)-enantiomer t = 9.44 min; minor (S)-enan-
To a stirred solution of Dess–Martin periodinane (16.600 g,
18.5
1
tiomer t
r
= 10.13 min. [
300 MHz, CDCl ) d 9.21 (t, J = 2.1 Hz, 1H), 9.15 (d, J = 2.1 Hz, 2H),
.67 (t, J = 6.6 Hz, 1H), 5.59 (dt, J = 10.7, 7.3 Hz, 1H), 5.42 (dt,
a]
D
3
= +23.5 (c 0.65, CHCl ). H NMR
3
(
9.1 mmol) in dry CH
4.290 g, 30.2 mmol) in CH
2
Cl
2
(280 mL) was added olefinic alcohol 2
Cl (45 mL) at room temperature under
(
5
3
2
2
an argon atmosphere. After stirring for 2 h at the same tempera-
ture, the reaction mixture was diluted with petroleum ether
J = 10.7, 7.3 Hz, 1H), 2.77–2.65 (m, 2H), 2.11–2.04 (m, 2H), 1.34–
13
1
(
1
.23 (m, 6H), 0.84 (t, J = 6.7 Hz, 3H), 0.17 (s, 9H).
75 MHz, CDCl ) d 161.4, 148.7, 134.6, 133.7, 129.6, 122.4, 122.0,
00.8, 92.3, 66.6, 33.0, 31.5, 29.2, 27.5, 22.5, 13.9, À0.4; HRMS
C NMR
(
600 mL). The resulting mixture was cooled to À30 °C, and filtered
3
through a Celite pad. The filtrate was dried over anhydrous Na SO
2
4
,
and concentrated under reduced pressure. The crude product was
+
(
28 6 2
ESI) m/z 455.1626 [M+Na] (calcd for C21H O N NaSi, 455.1609).
distilled under reduced pressure to afford olefinic aldehyde 3
1
(
9
3
2.541 g, 60% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) d
4
.5. (R,Z)-Undec-5-en-1-yn-3-ol 6
.66 (t, J = 2.0 Hz, 1H), 5.75–5.66 (m, 1H), 5.58–5.49 (m, 1H),
.20–3.17 (m, 2H), 2.08–1.99 (m, 2H), 1.37–1.27 (m, 6H), 0.88 (t,
To
a
cooled solution of 3,5-dinitrobenzoate
5
(1.000 g,
CO
1
3
J = 6.8 Hz, 3H). C NMR (75 MHz, CDCl
3
) d 199.6, 135.5, 117.9,
2
.3 mmol) in MeOH (11 mL) was added anhydrous
K
2
3
4
+
2.5, 31.4, 28.9, 27.5, 22.4, 13.9; HRMS (ESI) m/z 141.1273 [M
(
0.959 g, 6.9 mmol) at room temperature. The reaction mixture
+
H] (calcd for C
9
H17O, 141.1274).
was stirred for 12 h at the same temperature, and quenched with
water (10 mL). After MeOH was evaporated under reduced pres-
sure, the residue was extracted with CH Cl (3 Â 12 mL). The com-
4
.3. (R,Z)-1-(Trimethylsilyl)undec-5-en-1-yn-3-ol 4
2
2
bined organic phases were washed with brine (30 mL), dried over
anhydrous Na SO , and concentrated under reduced pressure.
To a stirred solution of (S)-BINOL (0.680 g, 2.4 mmol) in dry
Cl (96 mL) were added trimethylsilylacetylene (3.31 mL,
2
4
CH
2
2
The crude product was purified by silica gel chromatography (pet-
2
4.0 mmol) and hexamethylphosphoramide (2.150 g, 12.0 mmol)
at room temperature under an argon atmosphere. Next, Et Zn
16 mL, 1.5 M in toluene, 24.0 mmol) was added slowly via a syr-
inge, and the resulting mixture was stirred for 20 h at the same
temperature. Next, Ti(OiPr) (1.710 g, 6.0 mmol) was added slowly,
roleum ether/ethyl acetate 5:1) to afford enynic alcohol 6 (0.333 g,
2
1
= +28.1 (c 1.5, CHCl3). 1H NMR
2
87% yield) as a colorless oil. [
a]
D
(
(300 MHz, CDCl ) d 5.67–5.58 (m, 1H), 5.51–5.42 (m, 1H), 4.42–
3
4.35 (m, 1H), 2.51–2.45 (m, 3H), 2.09–2.03 (m, 3H), 1.38–1.25
1
3
4
(m, 6H), 0.87 (t, J = 6.8 Hz, 3H). C NMR (75 MHz, CDCl ) d 134.5,
3
and the mixture was stirred for another 1 h. After the addition of
olefinic aldehyde 3 (0.840 g, 6.0 mmol), the reaction mixture was
maintained for 4 h at room temperature. The reaction mixture
was then cooled to 0 °C, and quenched with water (20 mL). The
resulting mixture was filtered, and the organic phase was sepa-
rated from the filtrate. The organic layer was washed with brine
122.9, 84.5, 72.9, 61.8, 35.5, 31.5, 29.2, 27.4, 22.5, 14.0; HRMS
(ESI) m/z 189.1231 [M+Na] (calcd for C11H18ONa, 189.1250).
+
4.6. (R,1E,7Z)-1-Chlorotrideca-1,7-dien-3-yn-5-ol 7
At first, CuI (0.057 g, 0.3 mmol), Pd(PPh ) (0.173 g, 0.15 mmol),
3 4
(
3 Â 100 mL), dried over anhydrous Na
2
SO
4
, and concentrated
(E)-1,2-dichloroethene (1.1 mL, 15 mmol), and anhydrous benzene
(3 mL) were placed sequentially in a 10-mL Schlenk tube at room
under reduced pressure. The crude product was purified by silica
gel column chromatography (petroleum ether/ethyl acetate 10:1)
to obtain TMS enynic alcohol 4 (0.916 g, 64% yield, 86% ee) as a pale
yellow oil. Enantiomeric excess was determined by HPLC with a
Daicel Chiralcel OD-H column (5% 2-propanol in n-hexane,
temperature under an argon atmosphere. Enynic alcohol
6
(0.249 g, 1.5 mmol) and Et N (2 mL, 15 mmol) were then added,
3
and the reaction was carried out overnight at the same
temperature. After the reaction was quenched with saturated
Please cite this article in press as: Yang, P.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.013

4
P. Yang et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
NH
4
Cl solution (4 mL), the organic phase was separated and the
O (3 Â 5 mL). The combined
organic layers were dried over anhydrous Na SO , and concen-
4.10. (S)-Methyl 5-hydroxy-7-(trimethylsilyl)hept-6-ynoate 12
aqueous phase was extracted with Et
2
2
4
To a stirred solution of (R)-BINOL (0.680 g, 2.4 mmol) in dry CH
(96 mL) were added trimethylsilylacetylene (3.31 mL,
24.0 mmol) and hexamethylphosphoramide (2.15 g, 12.0 mmol) at
room temperature under an argon atmosphere. Next, Et Zn
2
-
trated under reduced pressure. The crude product was purified
by silica gel column chromatography (petroleum ether/ethyl acet-
ate 20:1) to furnish chloro enynic alcohol 7 (0.272 g, 80% yield) as a
Cl
2
2
1
8.5
1
pale yellow oil. [
CDCl ) d 6.53 (d, J = 13.7 Hz, 1H), 5.94 (dd, J = 13.7, 1.8 Hz, 1H),
.63 (dt, J = 10.9, 7.3 Hz, 1H), 5.42 (dt, J = 10.9, 7.3 Hz, 1H), 4.49
dt, J = 6.1, 4.4 Hz, 1H), 2.51–2.47 (m, 2H), 2.09–2.03 (m, 2H),
a]
D
= +26.0 (c 0.23, CHCl
3
). H NMR (300 MHz,
(16 mL, 1.5 M in toluene, 24.0 mmol) was added slowly via a syr-
inge, and the resulting mixture was stirred for 20 h at the same tem-
perature. Ti(OiPr) (1.710 g, 6.0 mmol) was then added slowly, and
4
3
5
(
the mixture was stirred for another 1 h. After the addition of formyl
ester 11 (0.780 g, 6.0 mmol), the reaction mixture was maintained
for 4 h at room temperature. The reaction mixture was then cooled
to 0 °C, and quenched with water (20 mL). The resulting mixture
was filtered, and the organic phase was separated from the filtrate.
The organic layer was washed with brine (3 Â 100 mL), dried over
1
.94 (d, J = 6.0 Hz, 1H), 1.38–1.28 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H).
1
3
C NMR (75 MHz, CDCl
2.4, 35.5, 31.5, 29.3, 27.5, 22.5, 14.0; HRMS (ESI) m/z 249.1039
3
) d 134.7, 130.8, 122.9, 113.2, 92.4, 79.9,
6
+
[
M+Na] (calcd for C13
H19OClNa, 249.1017).
4
.7. (R,1E,3E,7Z)-1-Chlorotrideca-1,3,7-trien-5-ol 8
2 4
anhydrous Na SO , and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography
(petroleum ether/ethyl acetate 10:1) to obtain TMS alkynol ester
12 (1.137 g, 83% yield, 80% ee) as a pale yellow oil. Slow recrystal-
lization of 3,5-dinitrobenzoate 13 derived from 12 from n–hex-
ane-diethyl ether (5:1) improved optical purity to 97% ee.
Enantiomeric excess was determined by HPLC with a Daicel Chiral-
cel AD-H column (5% 2-propanol in n–hexane, 1.0 mL/min, 220 nm),
To a stirred suspension of LiAlH
1 mL) was added chloro enynic alcohol 7 (0.114 g, 0.5 mmol) in
4
(0.038 g, 1.0 mmol) in dry THF
(
THF (1 mL) at À20 °C under an argon atmosphere. The reaction
mixture was stirred for 12 h at the same temperature, followed
by quenching with MeOH (1 mL) and water (1.5 mL). Next, Et
15 mL) was added and diluted the mixture. The organic phase
2
O
(
was separated and the aqueous phase was extracted with Et
2
O
major (S)-enantiomer
r
t = 31.36 min; minor (R)-enantiomer
2
1
1
(
3 Â 3 mL). The combined organic layers were dried over anhy-
t
r
= 35.21 min. [
a
]
D
= À0.7 (c 1.1, CHCl
3 3
). H NMR (300 MHz, CDCl )
drous Na SO , and concentrated under reduced pressure. The crude
2
4
d 4.39–4.33 (m, 1H), 3.66 (s, 3H), 2.39–2.34 (m, 2H), 2.06 (d,
1
3
product was purified by silica gel column chromatography (petro-
J = 5.4 Hz, 1H), 1.85–1.67 (m, 4H), 0.15 (s, 9H). C NMR (75 MHz,
leum ether/ethyl acetate 20:1) to give chlorotriene alcohol 8
CDCl ) d 173.9, 106.4, 89.6, 62.3, 51.5, 36.9, 33.5, 20.5, À0.2; HRMS
3
21
+
(
0.097 g, 85% yield) as a pale yellow oil. [
a
]
D
= +12.3 (c 0.59,
) d 6.44 (dd, J = 13.2, 11.0 Hz,
H), 6.22–6.17 (m, 2H), 5.73 (dd, J = 15.3, 6.0 Hz, 1H), 5.60–5.53
m, 1H), 5.39–5.33 (m, 1H), 4.20–4.17 (m, 1H), 2.36–2.29 (m,
(ESI) m/z 229.1248 [M+H] (calcd for C11
21 3
H O Si, 229.1255).
1
3 3
CHCl ). H NMR (300 MHz, CDCl
1
(
4.11.
(S)-Methyl
7-trimethylsilyl-5-(3,5-dinitrobenzoyloxy)
hept-6-ynoate 13
2
6
1
1
2
H), 2.07–1.99 (m, 2H), 1.77 (d, J = 4.0 Hz, 1H), 1.34–1.26 (m,
H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl
) d 136.4,
34.1, 132.9, 126.0, 123.8, 121.0, 71.5, 35.3, 31.5, 29.2, 27.4, 22.5,
4.0; HRMS (ESI) m/z 229.1348 [M+H] (calcd for C13H22OCl,
29.1354).
3
According to the similar procedure for synthesis of 3,5-dini-
trobenzoate 5, TMS alkynol ester 12 (1.137 g, 4.9 mmol) and 3,5-
dinitrobenzoyl chloride (1.378 g, 6.0 mmol) furnished 3,5-dini-
trobenzoate 13 (1.863 g, 90% yield). The product 13 was recrystal-
lized three times from n-hexane-diethyl ether (5:1), and afforded
13 (1.117 g, 60% yield) as white crystals. mp 86.5–86.8 °C.
+
4
.8. Methyl 5-hydroxypentanoate 10
1
8.5
1
[
a
]
D
= À17.3 (c 0.60, CHCl
3 3
). H NMR (300 MHz, CDCl ) d 9.26
To a solution of lactone 9 (3.850 g, 38.5 mmol) in MeOH (40 mL)
(t, J = 2.1 Hz, 1H), 9.20 (d, J = 2.1 Hz, 2H), 5.73 (t, J = 6.4 Hz, 1H),
3.71 (s, 3H), 2.45 (t, J = 7.2 Hz, 2H), 2.05–1.99 (m, 2H), 1.94–1.86
(m, 2H), 0.21 (s, 9H). C NMR (75 MHz, CDCl
was added concentrated HCl (four drops) at room temperature. The
reaction mixture was then heated at reflux for 16 h. After being
cooled to room temperature, the reaction was quenched with sat-
1
3
3
) d 173.2, 161.5,
148.7, 133.6, 129.6, 122.5, 100.5, 92.7, 66.7, 51.6, 34.1, 33.2, 20.4,
+
urated NaHCO
3
solution (10 mL), after which MeOH was evapo-
À0.4; HRMS (ESI) m/z 445.1038 [M+Na] (calcd for C18
22 2 8
H N NaO -
rated under reduced pressure, and the residue was dissolved in
ethyl acetate (300 mL). The solution was washed with brine
Si, 445.1038).
(
40 mL), dried over anhydrous Na
2
SO
4
, and concentrated under
4.12. (S)-Methyl 5-hydroxyhept-6-ynoate 14
reduced pressure. The crude product was purified by silica gel col-
umn chromatography (petroleum ether/ethyl acetate 20:1) to
According to the similar procedure for synthesis of enynic alco-
hol 6, 3,5-dinitrobenzoate 13 (1.091 g, 2.6 mmol) and anhydrous
1
afford hydroxyl ester 10 (4.579 g, 90% yield) as a colorless oil.
NMR (300 MHz, CDCl
J = 7.2 Hz, 2H), 1.75–1.69 (m, 2H), 1.65–1.58 (m, 3H). C NMR
75 MHz, CDCl ) d 174.1, 62.2, 51.5, 33.6, 32.0, 21.1; HRMS (ESI)
m/z 133.0864 [M+H] (calcd for C
H
3
) d 3.68 (s, 3H), 3.65–3.63 (m, 2H), 2.36 (t,
K
2
CO
yield) as a yellow oil. [
(300 MHz, CDCl ) d 4.45–4.41 (m, 1H), 3.70 (s, 3H), 2.49 (d,
J = 2.1 Hz, 1H), 2.40 (t, J = 7.0 Hz, 2H), 1.97 (d, J = 5.5 Hz, 1H),
3
(1.071 g, 7.7 mmol) afforded alkynol ester 14 (0.300 g, 74%
13
18.5
1
a
]
D
= À3.1 (c 0.26, CHCl
3
). H NMR
(
3
3
+
6
13 3
H O , 133.0859).
1
3
1
.90–1.74 (m, 4H). C NMR (75 MHz, CDCl
61.7, 51.6, 36.8, 33.5, 20.4; HRMS (ESI) m/z 157.0864 [M+H] (calcd
for C , 157.0859).
3
) d 173.9, 84.5, 73.1,
+
4
.9. Methyl 5-oxopentanoate 11
According to the similar procedure for synthesis of olefinic alde-
8 13 3
H O
hyde 3, hydroxyl ester 10 (4.000 g, 30.28 mmol) and Dess–Martin
4.13. (5S,8E,10E,12R,14Z)-Methyl 5,12-dihydroxyicosa-8,10,14-
periodinane (16.680 g, 39.2 mmol) afforded formyl ester 11
trien-6-ynoate 15
1
(
3.153 g, 80% yield) as a colorless oil. H NMR (300 MHz, CDCl
3
) d
9
2
.74 (t, J = 1.3 Hz, 1H), 3.64 (s, 3H), 2.51 (td, J = 7.2, 1.3 Hz, 2H),
To a stirred solution of chloro triene alcohol 8 (116 mg,
0.5 mmol) in anhydrous benzene (2 mL), was added Pd(PPh )
3 4
.35 (t, J = 7.3 Hz, 2H), 1.94–1.89 (m, 2H). 13C NMR (75 MHz, CDCl
)
3
d 201.3, 173.2, 51.5, 42.8, 32.8, 17.2; HRMS (ESI) m/z 131.0705 [M
(116 mg, 0.1 mmol) at room temperature under an argon
atmosphere. The resulting mixture was stirred for 30 min at the
+
6 11 3
+H] (calcd for C H O , 131.0703).
Please cite this article in press as: Yang, P.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.09.013

P. Yang et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
same temperature, piperidine (0.426 g, 5.0 mmol) and CuI
organic layers were washed with brine (10 mL), dried over anhy-
drous Na SO , and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography (CH Cl
1 (14.9 mg, 78% yield) as a
(
(
38.0 mg, 0.2 mmol) were added. The solution of alkynol ester 14
118 mg, 0.75 mmol) in anhydrous benzene (4 mL) was then
2
4
2
2
/
injected via a syringe. After stirring overnight at room temperature,
the reaction was quenched with saturated NH Cl solution (4 mL).
The mixture was diluted with Et O (5 mL), and the organic phase
was separated. The aqueous phase was extracted with Et
3 Â 5 mL). The combined organic layers were dried over anhy-
drous Na SO , and concentrated under reduced pressure. The crude
product was purified by silica gel chromatography (petroleum
MeOH 90:10) to afford Leukotriene B
4
2
1
10a
20
4
pale yellow oil. [
3 3
0.46, CHCl ). H NMR (300 MHz, CDCl ) d 6.34 (dd, J = 25.2,
a
]
D
= +10.9 (c 0.76, CHCl
3
); Lit
D
[a] = +12.6 (c
1
2
2
O
12.6 Hz, 1 H, 1H), 6.19–6.06 (m, 2H), 5.98 (dd, J = 23.4, 12.3 Hz,
1H), 5.65 (dd, J = 14.4, 6.2 Hz, 1H), 5.48–5.40 (m, 1H), 5.26 (dt,
J = 11.0, 8.8 Hz, 2H), 4.51–4.47 (m, 1H), 4.13–4.06 (m, 1H), 2.25–
2.07 (m, 4H), 1.95–1.88 (m, 2H), 1.61–1.41 (m, 4H), 1.25–1.13
(
2
4
1
3
ether/Et
pale yellow oil. [
CDCl
2
O 1:1) to obtain enynol ester 15 (70 mg, 40% yield) as a
3
(m, 8H), 0.76 (t, J = 6.7 Hz, 3H). C NMR (75 MHz, CDCl ) d 171.3,
2
7.7
1
a
]
D
= À2.0 (c 0.20, MeOH). H NMR (300 MHz,
137.6, 135.1, 134.0, 131.6, 129.8, 128.2, 126.6, 123.9, 71.9, 71.8,
3
)
d 6.58 (dd, J = 15.6, 10.9 Hz, 1H), 6.30 (dd, J = 15.4,
35.3, 31.5, 29.4, 29.3, 28.6, 27.4, 22.5, 18.5, 14.0; HRMS (ESI) m/z
–
1
5
3
1
0.8 Hz, 1H), 5.85 (dd, J = 15.2, 5.9 Hz, 1H), 5.65–5.56 (m, 2H),
.42–5.33 (m, 1H), 4.56–4.51 (m, 1H), 4.27–4.23 (m, 1H), 3.70 (s,
H), 2.43–2.32 (m, 4H), 2.07–2.02 (m, 2H), 1.97 (br s, 1H), 1.83–
.79 (m, 4H), 1.74 (br s, 1H), 1.37–1.31 (m, 6H), 0.90 (t,
335.2227 [MÀH] (calcd for C20
31 4
H O , 335.2228).
Acknowledgments
1
3
J = 6.7 Hz, 3H). C NMR (75 MHz, CDCl
3
) d 173.8, 141.5, 138.3,
34.2, 129.2, 123.8, 110.6, 92.3, 84.2, 71.6, 62.6, 51.6, 37.1, 35.3,
3.6, 31.5, 29.3, 27.4, 22.5, 20.6, 14.0; HRMS (ESI) m/z 349.2381
We appreciate the National Key Research and Development
Program of China (No. 2017YFD0201404 and 2015BAK45B01),
National Training Program of Innovation and Entrepreneurship
for Undergraduates (201710019245 and 201710019237), and Bei-
jing Training Program of Innovation and Entrepreneurship for
Undergraduates (2017bj089) for the financial support.
1
3
+
[
33 4
M+H] (calcd for C21H O , 349.2373).
4
.14.
(5S,6Z,8E,10E,12R,14Z)-Methyl
5,12-dihydroxyicosa-
6
,8,10,14-tetraenoate 16
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7
2
7.9
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1
993, 58, 3516–3520.
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5
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1
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1
1
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4
H34NaO , 373.2349).
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