Total Synthesis of the Antidiabetic (Type 2) Lipid Mediator Protectin DX/PDX

Article abstract of DOI:10.1021/acs.joc.8b01973

The first total synthesis of a lipid mediator derived from natural ?-3-fatty acid docosahexaenoic acid (DHA), 10S,17S-diHDHA (also referred to as protectin DX/PDX), was achieved in a convergent route (29 steps). The two chiral hydroxyl groups at C-10 and

Full text of DOI:10.1021/acs.joc.8b01973

Article
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Total Synthesis of the Antidiabetic (Type 2) Lipid Mediator Protectin
DX/PDX
Jean-Yves Sanceau,* Rene
Maltais,† Donald Poirier,†,‡ and Andre Marette§
́ ́ ́
,
†
†
Organic Synthesis Service, Medicinal Chemistry Platform, Centre Hospitalier Universitaire (CHU) de Queb
́
ec-Research Center,
Queb
́
ec, QC, G1V 4G2, Canada
‡
Department of Molecular Medicine, Faculty of Medicine, Universite
́
Laval, Queb
́
ec, QC, G1V 0A6, Canada
́
ec, QC G1V 4G5, Canada
§
Department of Medicine, Queb
́
ec Heart and Lung Institute, Laval Hospital, Queb
*
S Supporting Information
ABSTRACT: The first total synthesis of a lipid mediator derived from natural ω-3-fatty acid docosahexaenoic acid (DHA),
0S,17S-diHDHA (also referred to as protectin DX/PDX), was achieved in a convergent route (29 steps). The two chiral
1
hydroxyl groups at C-10 and C-17 were derived from readily available (S)-1,2,4-butanetriol and (R)-glycidol, respectively. The
two stereodefined E-double bonds were generated by a Takai olefination, and the skipped diene side chain was introduced with
a stereocontrolled Wittig olefination. Importantly, the sensitive conjugated E,Z,E-triene intermediate was generated by a Boland
reduction of the central triple bond of a E,E-dienyne. Overall, this synthetic strategy should allow the preparation of a larger
quantity of PDX, which is inaccessible via previously reported biosynthetic approaches.
INTRODUCTION
■
(
Eicosapentaenoic acid (EPA) and docosahexaenoic acid
DHA) are the most physiologically important members of
the natural ω-3 fatty acid class, being key precursors in the
biosynthesis of hydroxylated metabolites that mediate
resolution of inflammation process. Such lipid mediators
(
LMs) are divided to E-series and D-series resolvins (RvDs),
1
,2
protectins (PDs), and maresins (MaRs).
The founding
member of the PDs is protectin D1 (1), or PD1, also known as
neuroprotectin D1 (NPD1). PD1 is derived from DHA
through the action of 15-LOX, a lipoxygenase, followed by
enzymatic hydrolysis. Its molecular structure is characterized
by the presence of two alcohol groups and a conjugated triene
Figure 1. Structure of protectin D1 (PD1) and its structural isomer
protectin DX (PDX).
3
system possessing one cis olefin (Figure 1). PD1 (1) has
7
attracted significant attention from both synthetic chemists and
biologists, owing to its interesting biochemical activities such
as anti-inflammatory, immunoregulatory, and neuroprotective
PDX. Interestingly, its structure differs from PD1 only by
having an E,Z,E-geometry instead of the E,E,Z-geometry unit
and with a (10S) instead of (10R)-configuration (Figure 1).
PDX and PD1 both exert immunoresolving action, but PDX,
4
properties.
4e
In 2002, Hong et al. reported an additional protectin
unlike PD1, is less potent as a pro-resolving agonist. In
addition, PDX inhibited the human platelet aggregation
resulting from a biosynthesis through the sequential actions of
8
9
5
responses, the replication of the influenza virus, and
two lipoxygenases on DHA. The structure of this new double-
1
0
6
conferred protection against sepsis in mice. PDX also
reversed the fibrotic process in mice with lung fibrosis.
oxygenated product was partially elucidated by Butovich in
11
2
005, but its complete stereochemistry was established in 2006
4e
as 10S,17S-diHDA (2). In 2009, Guichardant and co-workers
also reported the exact structural and configurational assign-
ment of 10S,17S-diHDA (2) and named it protectin DX or
Received: August 1, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01973
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 2. Retrosynthetic analysis of Protectin DX (PDX, 2).
As another promising property, Marette and co-workers
recently investigated the glucoregulatory activity of PDX,
which is distinct from its antiaggregatory and anti-inflamma-
treatment of type 2 diabetes. Furthermore, a total synthesis will
also provide the opportunity to obtain non-natural stereo-
isomers, as well as isotopically labeled materials. We thus
herein describe our effort toward the development of a
successful PDX total synthetic route.
1
2
tory actions. They showed the in vitro and in vivo efficacy of
PDX at submicromolar concentrations for release of the
prototypic myokine interleukin-6 (IL-6) for activation of AMP-
activated kinase (AMPK) and for the prevention of lipid-
induced and obesity-linked insulin resistance in mouse models.
Overall, these findings suggest that PDX might be a potential
tool for alleviating type 2 diabetes through both anti-
inflammatory and insulin-sensitizing actions. Interestingly, in
the same biological tests, PD1 was ineffective at inducing IL-6
release from skeletal muscle cells.
RESULTS AND DISCUSSION
■
As for an E,E,Z-triene system, we suspected that the internal
conjugated E,Z,E-triene of PDX (2) (Figure 1) could be
sensitive to isomerization by means of heating, light, or acid to
the corresponding more stable E,E,E-triene. For this reason, in
all the strategies described to access to dihydroxylated-E,E,Z-
docosatrienes, the conjugated E,E,Z-triene was built at a very
late stage. Careful manipulations were also required regarding
the skipped diene of the polar chain, which is potentially prone
to oxidation and isomerization. Among the reported
approaches to E,E,Z-docosatrienes, we were interested in
Several total syntheses of docosatrienes having three
conjugated double bonds with a characteristic E,E,Z geometry
1
3
have already been achieved and recently reviewed. However,
only a few examples of syntheses of polyenes similar to PDX
bearing a triene system with the isomeric E,Z,E geometry
17
18
14
those reported by the Balas and Hansen teams. Briefly, the
key intermediate, a E,E-dienyne aldehyde, was assembled from
two smaller fragments and subsequently elongated through a
Wittig reaction. Finally, a semihydrogenation under Boland
conditions of the alkyne portion of a E,E-dienyne afforded the
highly sensitive E,E,Z-triene unit. This convergent approach
could be applied to the synthesis of 2 with suitable
modifications to the building blocks. Furthermore, flexibility
of this strategy is amenable, especially for potential
modifications of the polar head chain. Thus, inspired by the
precedents in literature, we dissected the structure of 2 in three
flanked with two carbinols have been published. In fact, it has
been mentioned in the literature that PDX has been obtained
15
by total synthesis, but there is no details reported to date.
Unlike many other docosatrienes, this complex compound is
produced from enzymatic synthesis. Unfortunately, its
commercial availability is very limited and expensive, being
16
offered only in microgram quantities. For those reasons, and
considering its potential therapeutic activity, we therefore
investigated the total synthesis of PDX. An efficient synthesis
will offer quantities allowing for further investigations into the
underlying mechanisms of action of PDX, particularly in
B
DOI: 10.1021/acs.joc.8b01973
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The Journal of Organic Chemistry
Article
a
Scheme 1. Synthesis of C13−C22 Fragment 7
a
Reagents and conditions: (a) ref 19; (b) phosphonium 4, t-BuOK, THF, 0 °C, 96%; (c) CrCl , CHI , THF−dioxane, room temperature, 54%; (d)
2
3
TMS-acetylene, Pd(PPh ) Cl , CuI, (i-Pr) NH, THF, room temperature, 100%; (e) K CO , MeOH, room temperature, 95%.
3
2
2
2
2
3
a
Scheme 2. Synthesis of C1−C7 Fragment 15
a
Reagents and conditions: (a) Ph P·HBr neat, 180-190 °C, 94% ; (b) NaHMDS, THF, 0 °C; (c) KHCO , MeI, DMF, room temperature, 51%
3
3
(from 10); (d) TBAF, THF, room temperature, 90%; (e) I , Ph P, imidazole, 0 °C, THF, 92%; (f) Ph P, toluene, reflux, 96%.
2
3
3
fragments (C13−C22, C8−C12, and C1−C7) as shown in our
retrosynthetic approach plan (Figure 2).
the terminal conjugated (S)-dienyne 7 (95% yield) in a
stereochemically pure form.
We initiated our synthesis by the stereoselective preparation
of C13−C22 chiral fragment (compound 7) as outlined in
Scheme 1. (S)-Enyne 7 was obtained from (S)-aldehyde 3,
itself prepared from commercial (R)-glycidol, following
As depicted in Scheme 2, the C1−C7 fragment (a
phosphonium salt 15) was prepared from known propanalde-
22
hyde derivative 10. A Wittig reaction with the readily
available (3-carboxypropyl)triphenylphosphonium bromide
(9) and aldehyde 10 furnished the desired (Z)-olefin 11
19
standard manipulations reported by Winkler et al. Overall,
S)-aldehyde 3 was synthesized in a stereochemically pure
1
(
(100% isomeric purity by H NMR), which was directly
form in six steps and in a 40% yield from (R)-glycidol. We
sought to prove that (S)-enyne 7 could directly arise from a
Wittig olefination of (S)-aldehyde 3 using the phosphorus
ylide derived from (trimethylsilylpropargyl)-
converted into the corresponding methyl ester 12 (KHCO3,
MeI in DMF) in 51% yield. Cleavage of the silyl ether with
TBAF afforded in 90% yield the alcohol 13, which was then
transformed uneventfully into the desired phosphonium salt 15
via iodide 14 (88%, two steps).
20
triphenylphosphonium bromide (4) (known as Yates salt).
Thus, generating the ylide by treatment of the salt 4 with n-
BuLi and condensation with the (S)-aldehyde 3 afforded the
The C8−C12 fragment, (S)-vinyl iodide 8 (Scheme 3), was
prepared in four steps (overall 36% yield) from commercially
1
17
desired (E)-enyne 6 together with its (Z)-regioisomer. H
available (S)-1,2,4-butanetriol, as described by Balas’s group.
NMR analysis showed a ratio of 80:20 (E/Z), but we have
observed that this E/Z ratio could be increased to 85:15 by
using potassium tert-butoxide as a base. Disappointingly, we
found that both regioisomers were not separable by flash
chromatography at this time, even after deprotection of a
trimethylsilyl group or at a later stage in the synthesis. For this
reason, we abandoned the direct Wittig reaction and opted for
a two-step preparation involving a Sonogashira reaction with
As a key step, these authors selectively protected the 1,3-diol
functionality of (S)-1,2,4-butanetriol as a stable six-membered
di-tert-butylsilylene ketal.
The first C13−C22 and second C18−C12 fragments were
assembled as outlined in Scheme 3. Conjugated (S)-alkyne 7
and (S)-vinylic iodide 8 were thus coupled via a Sonogashira
reaction (Pd(PPh ) PdCl , (i-Pr) NH, CuI) to quantitatively
3
2
2
2
afford the tris-protected (S,S)-trienyne 16. Manipulations of
the protecting group were required to ensure selective
oxidation of the primary alcohol. First, both the TBDPS and
silylene groups were removed in the presence of TBAF to yield
triol 17 in 72% yield. Selective tritylation of the primary
alcohol with chlorotriphenylmethane (Et N, DMAP, CH Cl )
(
S)-(E)-vinyl iodide 5. Employing conditions developed by
21
Furstner and co-workers, iodide 5 was obtained as a unique
(
E)-regioisomer by a Takai olefination in 54% yield.
Finally, coupling of 5 with TMS-acetylene under Sonoga-
shira conditions (Pd(PPh ) Cl , (i-Pr) NH, CuI) cleanly
3
2
2
2
3
2
2
produced quantitatively the TMS-protected (S)-dienyne 6.
Removal of the TMS group with K CO in methanol afforded
followed by protection of the two residual hydroxyls of 17 as
TBDPS ethers (chloro-tert-butyldiphenylsilane, Et N, CH Cl )
2
3
3
2
2
C
DOI: 10.1021/acs.joc.8b01973
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The Journal of Organic Chemistry
Article
a
Scheme 3. Fragment Assembly (Synthesis of Intermediate 22)
a
Reagents and conditions: (a) Pd(PPh ) Cl , CuI, (i-Pr) NH, benzene, room temperature, 100%; (b) TBAF, THF, room temperature, 72%; (c)
3
2
2
2
trityl chloride, Et N, DMAP, CH Cl , room temperature; (d) TBDPS-Cl, imidazole, DMAP, CH Cl , room temperature, 80% (from 17); (e) CSA,
3
2
2
2
2
CH Cl −MeOH, 0 °C, 80%; (f) Dess−Martin periodinane, CH Cl , room temperature, 80%; (g) NaHMDS, THF−HMPA, −78 to 0 °C, 75%.
2
2
2
2
provided the fully protected triol 19. Chemoselective cleavage
methanol, and chlorotrimethylsilane leading E,Z,E triene 24
in 51% yield. Careful analysis of the H NMR spectrum of the
1
of the trityl ether in acidic conditions (CSA, CH Cl ) gave the
2
2
bis-protected triol 20 (80% overall yield from trienyne 17).
Oxidation of primary alcohol was achieved using Dess−Martin
reagent in CH Cl giving a 80% yield of 21. Interestingly, we
crude material revealed the presence of a byproduct (∼5%,
1
estimated by H NMR analysis) that we suspect to be the
E,E,E regioisomer of PDX (2). Indeed, we observed a broad
2
2
17
obtained a higher yield than those reported in the literature
signal at 6.25 ppm that could correspond to those of vinylic
25
when this oxidation was performed on a similar substrate
having full TBDMS protection. The sensitive protected β-
hydroxy aldehyde 21, which is prone to elimination of the
OTBDPS group, was immediately reacted with the ylide
generated from phosphonium 15 and NaHMDS in THF at
protons of an all E-conjugated triene.
The final saponification of ester 24 was accomplished with
an excess of LiOH in diluted aqueous methanol−THF at 0 °C,
followed by acidification with NaH PO to provide PDX (2) in
2
4
77% yield after chromatography on deactivated silica gel (96%
HPLC purity). The chromatographic behavior in LC−MS/MS
of commercial PDX (from the Cayman Chemical Company)
and synthetic PDX (2) were found to be identical (Figure 3).
In fact, the multiple reaction monitoring (MRM) chromato-
1
7
−
78 °C in the presence of HMPA. Under these conditions,
the Wittig reaction proceeds with a high (Z)-selectivity
(
>95%) to give a 75% yield of 22.
The synthesis of PDX was completed as outlined in Scheme
4
via deprotection of the TBDPS groups of E,E-enynene 22
gram gave a peak at t = 14.20 min (Figure 3A), while the
R
with TBAF to give diol 23 (80% yield, 96% HPLC purity).
To achieve the crucial chemoselective reduction of the
central triple bond of 23, we chose to use zinc-activated by
copper(II) acetate and silver(I) nitrate (Zn (Cu/Ag)) in
aqueous methanol according to a modified Boland proce-
MRM chromatogram of synthetic PDX (2) gave also a major
peak at t = 14.21 min (Figure 3B). These results confirmed
R
that synthetic PDX (2) matched perfectly with natural PDX.
1
13
Furthermore, our H and C NMR and UV−vis absorption
spectral data of 2 were in perfect agreement with those
2
3
6,7
dure. These conditions have proven to be more efficient to
previously published.
reduce alkyne in conjugated polyunsaturated systems over
In summary, the above results represent the first total
synthesis of PDX (2). This complex molecule was prepared by
a convergent approach in 29 steps, which favorably compares
24
other hydrogenation catalysts. Thus, conjugated E,E-enynene
3 was treated in the dark with Zn(Cu/Ag), aqueous
2
D
DOI: 10.1021/acs.joc.8b01973
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The Journal of Organic Chemistry
Article
Billerica, MA) at 400 MHz for H NMR and 100.6 MHz for 13C
a
1
(
Scheme 4. Completion of the Synthesis of PDX (2)
NMR. Spectra are referenced relative to the central residual proton
1
solvent resonance in H NMR (CDCl δ = 7.26 ppm, MeOH-d δ =
3
4
3
.31 ppm and DMSO-d δ = 2.50 ppm) and to the central carbon
6
1
3
solvent resonance in C NMR (CDCl δ = 77.0 ppm, MeOH-d δ =
3
4
4
9.0 ppm and DMSO-d δ = 39.4 ppm). High-performance liquid
6
chromatography (HPLC) analyses for chemical purities were
performed on a Shimadzu Prominence instrument (Kyoto, Japan)
using a diode array detector (PDA) and an Altima C18 analytical
reversed-phase column (5 μm, 4.6 × 250 mm), applying the
conditions as stated (wavelength detection and solvent gradient).
Low-resolution mass spectra (LRMS) were recorded on a Shimadzu
Prominence instrument (Kyoto, Japan) equipped with a Shimadzu
LCMS-2020 mass spectrometer and an APCI probe. ESI-TOF
HRMS, APCI-TOF HRMS, or APPI-TOF HRMS spectra were
provided by Pierre Audet at the Laval University Chemistry
Department (Queb
comparison assays with natural PDX (2) was performed by Jocelyn
Trottier (Bioanalytical Services-CHU de Quebec Research Center) as
́
ec, QC, Canada). LC−MS/MS analysis for
́
12a
previously reported.
Preparation of (2S,4Z)-2-(tert-Butyldiphenylsilyloxy)hept-4-enal
3). Aldehyde 3, which was prepared in seven steps from commercially
(
available (R)-glycidol, was obtained in a 40% overall yield as a
1
9a
1
colorless oil as previously reported.
H NMR data were in full
19a
21
agreement with those reported in the literature: [α] +13 (c 0.23,
D
1
CHCl ); H NMR (400 MHz, CDCl ) δ 9.55 (s, 1H, H ), 7.67−7.62
3
3
1
(
1
1
m, 4H), 7.45−7.26 (m, 6H), 5.59−5.42 (m,1H, H ), 5.40−5.31 (m,
5
H, H ), 4.04 (qd, 1H, J = 6.5, 1.7 Hz, H ), 2.45 (m, 1H), 2.34 (m,
4
2
1
3
1
H), 1.91 (m, 2H), 1.11 (s, 9H), 0.88 (t, 3H, J = 7.5 Hz); C{ H}
NMR (100.6 MHz, CDCl ) δ 203.4, 135.8, 135.7, 134.9, 133.3, 132.9,
3
1
30.1, 130.0, 127.8, 127.7, 122.0, 77.8, 31.0, 26.9, 20.6, 20.5, 14.0.
Preparation of (3E)-Enyne 7 (C13−C22 Fragment). (3S,1E,5Z)-3-
(tert-Butyldiphenylsilyloxy)-1-iodoocta-1,5-diene (5). Iodo vinylic
a
Reagents and conditions: (a) TBAF, THF, room temperature, 80%;
compound 5 was prepared using a Takai olefination following the
previously described Furstner’s procedure. A 250 mL flask was
21
(
b) Zn(Cu/Ag), MeOH−H O, room temperature, 51% (c) LiOH,
2
MeOH−THF−H O, 5 °C, 77%.
2
charged with commercially CrCl (5 g, 40.6 mmol). The solid was
2
dried using a heat gun under high vacuum. After being cooled to
room temperature under argon, the flask was protected from light
with an aluminum foil, and then dry THF (7 mL) and dry dioxane
with other previously reported syntheses of docosatrienes,
where at least 26 steps were necessary, no matter the targets
and chosen strategies. The configuration of the two
asymmetric carbons was secured by the chiron approach
using traditional chiral precursors ((R)-glycidol and (S)-1,2,4-
butanetriol). Since the stereochemistry of the six double bonds
was highly controlled, particularly the Boland semireduction,
this work opens an access to the preparation of larger amounts
of PDX (2).
(40 mL) were added followed at 0 °C by CHI (8 g, 20.3 mmol). The
3
initial dark-green mixture was stirred at room temperature for 2 h
until it had turned brown. Aldehyde 3 (2 g, 5.1 mmol) in dioxane (5
mL) was added and the mixture stirred for 2 h. The reaction mixture
was quenched with a saturated aqueous solution of NH Cl, and the
4
aqueous phase was extracted with Et O. The combined organic phase
2
was washed successively with a saturated aqueous solution of Na S O
2
2
3
and brine solution, dried over Na SO , filtered, and evaporated under
2
4
reduced pressure. Purification of the residue by flash chromatography
on deactivated silica gel with hexanes afforded iodide 5 as a light
EXPERIMENTAL SECTION
1
yellow oil (1.4 g, 54%): H NMR data were in full agreement with
■
1
9
21
1
General Experimental Procedure. Reagents and solvents were
obtained from commercial suppliers (Sigma-Aldrich, Strem, Combi-
blocks, Alfa Aesar) and used without further purification unless
otherwise mentioned. Optical rotations of commercial (R)-glycidol
and (S)-1,2,4-butanetriol were checked before use. Natural PDX, used
as a standard reference, was purchased from Cayman Chemical
Company. All reactions that were moisture and air-sensitive were
carried out in flame-dried glassware and under an argon atmosphere.
Reaction progress was monitored by thin-layer chromatography using
EMD silica gel 60 F254 aluminum plates. The spots were visualized
with UV light (254 nm), followed by staining with cerium ammonium
molybdate (CAM) solution or potassium permanganate, and then
heated on a hot plate. Silicycle R10030B 230−400 mesh silica gel
those reported in the literature: [α]
NMR (400 MHz, CDCl ) δ 7.72−7.66 (m, 4H,) 7.51−7.41 (m, 6H),
6.56 (dd, 1H, J = 14.4, 6.5 Hz, H ), 6.15 (dd, 1H, J = 14.4, 1.1 Hz,
), 5.45−5.38 (m, 1H, H ), 5.30−5.24 (m, 1H, H ), 4.24 (qd, 1H, J
D
−41 (c 0.33, CHCl
3
); H
3
2
H
1
6
5
= 6.6, 1.2 Hz, H ), 2.32−2.18 (m, 2H), 1.91−1.84 (m, 2H), 1.07 (s,
9H), 0.87 (t, 3H, J = 7.5 Hz, H ); C{ H} NMR (100.6 MHz,
3
1
3
1
8
CDCl ) δ 147.9, 135.9, 135.7, 134.4, 133.8, 133.5, 129.8, 129.6, 123.0,
3
75.7, 35.1, 26.9, 20.6, 19.3, 14.2.
(5S,3E,7Z)-5-(tert-Butyldiphenylsilyloxy)-1-(trimethylsilyl)deca-
3,7-dien-1-yne (6). Method A: To a cooled (salt−ice mixture)
solution of TMS-propargyl triphenylphosphonium bromide (4)
(prepared by reaction of TMS-propargyl bromide and triphenylphos-
20
phine in refluxing toluene) (668 mg, 1.47 mmol) in THF (5 mL)
was added potassium tert-butoxide (183 mg, 1.63 mmol). The mixture
was stirred under argon for 30 min. Aldehyde 3 (360 mg, 0.98 mmol)
was added in THF (2 mL), and the mixture was stirred for 1 h before
(
Quebec, QC, Canada) was used for flash chromatography. When
́
indicated, deactivated silica gel was prepared by mixing silica gel (100
g) with water (46 mL) and stirring the mixture on a rotavapor for 2 h
without applying vacuum. Optical rotations were measured on a
JASCO DIP-370 digital polarimeter (Easton, MD) using a cylindrical
glass cell (50 mm length). Nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker Avance 400 digital spectrometer
being quenched by the addition of a saturated solution of NH Cl. The
4
resulting mixture was extracted with EtOAc, washed with brine, dried
over Na SO , filtered, and evaporated under reduce pressure.
2
4
Purification on silica gel with hexanes afforded TMS-dienyne 6
E
DOI: 10.1021/acs.joc.8b01973
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The Journal of Organic Chemistry
Article
Figure 3. Comparison of LC−MS/MS profiles. Multiple reaction monitoring chromatograms for selected ion pair m/z 359−206 of PDX (2) from
Cayman Chemical Company (A) and synthetic compound (B).
2
1
(
390 mg, 96%) as a mixture of (E/Z)-isomers (85:15 ratio based on
chloroform solution at room temperature: [α] −34 (c 0.2, CHCl );
D
3
1
1
1
H NMR analysis). For the (E)-isomer: see below (method B) for H
data. For the (Z)-isomer: H NMR (400 MHz, CDCl ) δ 7.69−7.60
H NMR (400 MHz, CDCl ) δ 7.72−7.61 (m, 4H), 7.44−7.34 (m,
3
1
6H), 6.20 (dd, 1H, J = 15.9, 5.3 Hz, H ), 5.88−5.80 (m, 1H,, H ),
3
4
6
(
(
m, 4H), 7.45−7. 32 (m, 6H), 5.93 (dd, 1H, J = 11.1, 8.9 Hz), 5.80
5.67 (dd, 1H, J = 15.9, 1.5 Hz, H ), 5.62−5.71 (m, 1H, H ), 4.22
3
5
m, 3H), 4.80 (m, 1H), 2.30 (m, 1H), 2.20 (m, 1H), 1.88 (m, 2H),
(tdd, 1H, J = 6.4, 5.3, 1.3 Hz, H ), 2.30−2.16 (m, 1H), 2.16−2.05 (m,
4
1
.11 (s, 9H), 0.89 (t, 3H,, J = 7.4 Hz), 0.04 (s, 9Η). Method B: A
Schlenk tube was charged with iodovinyle 5 (1.4 g, 2.94 mmol), THF
20 mL), and (i-Pr) NH (20 mL). Argon was bubbled through the
1H), 1.77−1.71 (m, 2H), 1.06 (s, 9H), 0.82 (t, 3H, J = 7.5 Hz, H ),
1
0
1
3
1
0.18 (s, 9Η); C{ H} NMR (100.6 MHz, CDCl ) δ 146.5, 135.9,
3
(
135.8, 134.2, 134.1, 133.5, 129.8, 129.7 129.6, 127.6, 123.1, 123.0,
2
mixture for 5 min, and then dichlorobis(triphenylphosphine)
palladium II (206 mg, 0.294 mmol) and copper(I) iodide (112 mg,
109.1, 103.7, 94.4, 73.0, 35.3, 27.0, 20.5, 19.3, 14.0, −0.1; HRMS
+
(APPI-TOF) m/z 461.2690 [M + H] calcd for C H OSi , found
2
9
41
2
0.59 mmol) were added followed by the addition of TMS-acetylene
461.2701.
(
0.84 mL, 5.9 mmol). The tube was sealed, and the resulting black
(5S,3E,7Z)-5-(tert-Butyldiphenylsilyloxy)deca-3,7-dien-1-yne (7).
To a solution of TMS-protected dienyne 6 (1.2 g, 2.7 mmol) in
MeOH (25 mL) was added K CO (46 mg, 0.33 mmol) at 0 °C. The
mixture was stirred for 18 h. After filtration on a pad of Celite and
washing with EtOAc, the filtrate was concentrated under vacuum. The
oily residue was purified by flash chromatography on silica gel via
gradient elution (98/2 hexanes−CH Cl to 90/10 hexanes−CH Cl )
to yield (3E)-dienyne 6 as a dark yellow oil (1.2 g, 100%). We have
observed that pure compound 6 can easily lose its TMS group in
2
3
reaction mixture was allowed to warm to room temperature and
stirred for 2 h. Water was added, and then the aqueous phase was
extracted with CH Cl and the combined organic phase was washed
2
2
2
2
2
2
with brine, dried over Na SO , and concentrated under vacuum. The
2
4
F
DOI: 10.1021/acs.joc.8b01973
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
oily residue purified by flash chromatography on silica gel via gradient
elution (98/2 hexanes−CH Cl to 90/10 hexanes−CH Cl ) to yield
2H), 3.67 (s, 3H), 3.61 (m, 2H), 2.36 (m, 4H), 2.28 (m, 2H), 0.88 (s,
9Η), 0.05 (s, 6Η).
Methyl (4Z)-7-Hydroxyhept-4-enoate (13). To an ice-cooled
solution of ester 12 (2.9 g, 10.6 mmol) in dry THF (20 mL) was
added TBAF (1 M solution in THF, 12 mL, 12 mmol). The reaction
mixture was stirred for 1 h at room temperature before it was
quenched by the addition of phosphate buffer (pH = 7). Brine and
2
2
2
2
2
1
terminal (3E)-dienyne 7 as a yellow oil (950 mg, 95%). [α] −22 (c
D
1
0
7
.4, CHCl ); H NMR (400 MHz, CDCl ) δ 7.69−7.61 (m, 4H,),
3
3
.45−7.34 (m, 6H), 6.21 (dd, 1H, J = 15.9, 5.4 Hz, H ), 5.58 (dt, 1H,
4
J = 15.9, 2.1 Hz, H ), 5.61−5.34 (m, 1H, H ), 5.21−5.15 (m, 1H,
3
7
H ), 4.21 (dtd, 1H, J = 8.4, 5.4, 2.1 Hz, H ), 2.84 (d, 1H, J = 2.1 Hz,
6
5
H ), 2.25−2.09 (m, 2H, H ), 1.80−1.73 (p, 2H, J = 7.5 Hz, H ), 1.07
CH
extracted with CH
with brine, dried over Na
2
Cl
2
were added and the layers separated. The aqueous phase was
Cl , and the combined organic phase was washed
SO , and concentrated under vacuum. The
1
6
9
1
3
1
(
s, 9H), 0.83 (t, 3H, J = 7.5 Hz, H ); C{ H} NMR (100.6 MHz,
2
2
1
0
CDCl ) δ 147.2, 135.9, 135.7, 134.3, 134.0, 133.5, 129.8, 129.6, 127.6,
2
4
3
oily residue was purified by flash chromatography on silica gel (80/20
1
23.0, 108.2, 82.1, 76.7, 73.0, 35.3, 27.0, 20.5, 19.3, 14.1; HRMS
+
hexanes-EtOAc) to yield hydroxyl ester 13 as a pale yellow oil (1.51 g,
(APPI-TOF) m/z 389.2295 [M + H] calcd for C H OSi, found
26 33
1
9
0%). H NMR data were in full agreement with those reported in the
3
89.2295.
17a,18,27
1
literature:
H NMR (400 MHz, CDCl ) δ 5.58−5.40 (m, 2H),
Preparation of (3S,4E)-1,3-Di-tert-butylsilenyldioxy-5-iodopent-
-ene (8: C8−C12 Fragment). (4E)-1,3-Di-tert-butylsilylene ketal 8
3
4
3.69 (s, 3H), 3.60 (t, 2H, J = 6.0 Hz), 2.44−2.35 (m, 6H), 1.8 (bs,
was prepared in four steps and 36% overall yield from commercially
available (S)-1,2,4-butanetriol, as previously reported.
data were in full agreement with those reported in literature. [α]
+
=
1H).
1
7a
1
H NMR
Methyl (4Z)-7-Iodohept-4-enoate (14). Iodoester 14 was prepared
17a,18,27
1
7a
21
as previously reported.
To an ice-cooled solution of alcohol 13
D
1
(
930 mg, 5.9 mmol) in dry CH Cl (15 mL), protected against light
6.5 (c 0.2, CHCl ); H NMR (400 MHz, CDCl ) δ 6.54 (dd, 1H, J
14.2, 4.4 Hz, H ), 6.37 (dd, 1H, J = 14.2, 1.5 Hz, H ), 4.55 (tdd,
2
2
3
3
with aluminum foil, were added while stirring, successively imidazole
5
4
(
(
1.2 g, 17.7 mmol), triphenylphosphine (2.3 g, 8.9 mmol), and iodine
2.25 g, 8.9 mmol). The mixture was stirred for 2 h and then diluted
1
H, J = 11.0, 4.2, 1.8 Hz, H ), 4.12 (dd, 1H, J = 4.6, 2.6 Hz, H ), 4.09
3
1
(
d, 1H, J = 2.1 Hz, H ), 1.91−1.79 (m, 1H, H ), 1.76−1.65 (m, 1H,
1
2
1
3
1
with CH Cl . The organic phase was successively washed with an
H ), 1.02 (s, 9H), 1.00 (s, 9Η); C{ H} NMR (100.6 MHz, CDCl )
δ 147.8, 76.2, 76.0, 63.8, 36.1, 27.3, 27.1, 19.9.
2 2
2
3
saturated aqueous solution of Na S O and a brine solution, dried
2
2
3
over Na SO , filtered, and evaporated under reduced pressure.
Preparation of Phosphonium Iodide 15 (C1−C7 Fragment). (3-
2
4
Purification of the residue by flash chromatography on silica gel
90/10 hexanes−CH Cl ) afforded iodide 14 (1.45 g, 92%) as a
Carboxypropyl)triphenylphosphonium Bromide (9). Phosphonium
26
(
salt 9 was prepared as previously reported. A flask was charged with
γ-butyrolactone (5 g, 58 mmol) and triphenylphosphine hydro-
bromide (18.1 g, 52.7 mmol) and then preheated at 180−190 °C in a
graphite bath under an argon atmosphere. After 10 min, all of the
solids had melted, and the resulting liquid then became solid again.
After 2 h at 180−190 °C, the mixture was cooled to room
temperature and triturated with toluene. The solid was collected by
filtration and washed with toluene. Upon drying under vacuum in the
presence of phosphorus pentoxide, phosphonium salt 9 was recovered
2
2
1
slightly yellow oil. H NMR data were in full agreement with those
reported in the literature:
17a,18,27
1
H NMR (400 MHz, CDCl ) δ
3
5
7
.53−5.43 (m, 1H), 5.41−5.30 (m, 1H), 3.65 (s, 3H), 3.14 (t, 2H, J =
.1 Hz), 2.63 (q, 2H, J = 7.1 Hz), 2.32- 2.23 (m, 4H).
(
3Z)-(7-Carbomethoxyhept-3-enyl)triphenylphosphonium Io-
dide (15). Phosphonium salt 15 was prepared as previously
reported.
17a,18
To a solution of iodo ester 14 (973 mg, 3.6 mmol)
in acetonitrile (20 mL) was added while stirring triphenylphosphine
(1.14 g, 4.35 mmol). The mixture was heated under reflux and under
argon for 10 h. After the mixture was cooled to room temperature, the
solvent was evaporated under vacuum and the residue taken up with
hexanes. To remove residual triphenylphosphine, the white
suspension was vigorously stirred for 1 h and then filtered. The
white solid was washed with hexanes and air-dried to yield the
phosphonium salt 15 (1.8 g, 96%). This material was kept under
vacuum and protected from light in a dryer containing phosphorus
1
as a white powder (21.4 g, 94%). H NMR data were consistent with
26
1
those previously described:
H NMR (400 MHz, DMSO-d ) δ
6
1
2.31 (bs, 1H,), 7.91−7.74 (m, 15H), 3.58 (m, 2H), 2.49 (m, 2H),
1.70 (m, 2Η).
3
-(tert-Butydimethylsilyloxy)propanal (10). Aldehyde 10 was
prepared in two steps in 83% overall yield from commercially
22
available 1,3-propanediol as previously reported. It was obtained as
a crude liquid which was used in the next step without any further
1
pentoxide as dehydrating agent. H NMR data were in full agreement
1
purification. H NMR data were in full agreement with those reported
17a
1
22
1
with those reported in the literature:
H NMR (400 MHz, DMSO-
in the literature: H NMR (400 MHz, CDCl ) δ 9.81 (bs, 1H), 3.90
3
d ) δ 7.90−7.74 (m, 15H), 5.41 (m, 2H), 3.61 (m, 2H), 3.54 (s, 3H),
6
(
t, 2H, J = 6 Hz), 2.60 (m, 2H), 0.89 (s, 9Η), 0.07 (s, 6Η).
13
1
2
.49 (m, 4H), 2.11 (m, 2Η); C{ H} NMR (100.6 MHz, DMSO-d )
6
Methyl (4Z)-7-(tert-Butyldimethylsilyloxy)hept-4-enoate (12). A
4
3
δ 172.7, 134.9 (d, J = 2.8 Hz), 133.6 (d, J = 10.2 Hz), 130.2 (d,
CP
CP
suspension of (3-carboxypropyl)triphenylphosphonium bromide (9)
2.8 g, 6.5 mmol) in dry THF (45 mL) was cooled under argon at
78 °C and treated with a solution of 1 M NaHMDS in THF (13
2
1
JCP = 11.6 Hz), 127.7, 127.5, 118.3 (d, J = 85 Hz), 51.3, 32.8, 22.2,
CP
(
−
1
2
20.0 (d, J = 49.4 Hz), 19.7 (d, J = 3.1 Hz).
CP CP
Preparation of Conjugated-(4E,8E)-Trienyne 22.
3S,10S,4E,8E,12Z)-10-(tert-Butyldiphenylsilyloxy)-1,3-((di-tert-
mL, 13 mmol). The mixture which turned yellow-orange was
gradually warmed to 0 °C and stirred for 20 min at this temperature.
After being cooled again to −78 °C, a solution of freshly prepared 3-
(
butyl)silenyldioxy)pentadeca-4,8,12-trien-6-yne (16). A solution of
acetylenic compound 7 (950 mg, 2.45 mmol) in degassed benzene (5
mL) was added to a stirred mixture of vinyl iodide 8 (750 mg, 2.04
mmol), dichlorobis(triphenylphosphine)palladium(II) (172 mg, 0.2
mmol), and copper(I) iodide (91 mg, 0.48 mmol) in benzene (10
(tert-butydimethylsilyloxy)propanal (10) (940 mg, 5 mmol) in THF
(5 mL) was added dropwise to the orange ylide solution. The mixture
was allowed to warm to 0 °C gradually and was stirred at that
temperature for 2 h. The mixture was then quenched by addition of a
mL) under argon. (i-Pr) NH (15 mL) was added and the reaction
2
saturated aqueous solution of NaH PO and extracted by Et O. The
2
4
2
mixture stirred at room temperature for 10 h. After this delay, the
reaction mixture was filtered through a pad of Celite and washed with
hexanes. The filtrate was concentrated and purified by flash
chromatography on silica gel via gradient elution (99/1 hexanes−
CH Cl to 80/20 hexanes−CH Cl ) to afford compound 16 as a pale
combined organic phases were washed with brine, dried over Na SO ,
2
4
filtered, and evaporated. The crude oil, which contains the desired Z-
alcene 11 (1.1 g, 100% isomeric purity, ∼90% chemical purity) was
dissolved in dry DMF (40 mL). MeI (0.95 mL, 15 mmol) was added
2
2
2
2
2
1
1
followed by KHCO (3 g, 30 mmol), and the resulting suspension was
brown oil (1.2 g, ∼100%). [α]
−50 (c 0.18, CHCl ); H NMR
3
D
3
stirred at room temperature for 12 h. Water was added, and the
(400 MHz, CDCl ) δ 7.70−7.61 (m, 4H), 7.44−7.33 (m, 6H), 6.12
3
aqueous phase was extracted with Et O. The combined organic phase
(dd, 1H, J = 15.5, 4.1 Hz, H ), 6.09 (dd, 1H, J = 15.7, 5.6 Hz, H ),
2
4
9
was washed with brine, dried over Na SO , filtered, and evaporated.
5.95 (dd, 1H, J = 15.8, 1.5 Hz), 5.72 (dd, 1H, J = 15.8, 2.0 Hz), 5.38−
2
4
The crude oil was purified by flash chromatography on silica gel (95/
5.34 (m, 1H, H ), 5.22−5.16 (m, 1H, H ), 4.66 (dtt, 1H, J = 11.0,
1
3
12
5
hexanes−EtOAc) to yield pure (Z)-ester 12 as an colorless oil (0.7
4.2, 1.5 Hz, H ), 4.21 (dtd, 1H, J = 8.4, 5.4, 2.1 Hz, H ), 4.13−4.08
3
10
1
g, 51% from aldehyde 10): H NMR (400 MHz, CDCl ) δ 5.43 (m,
(m, 2H, H ), 2.24−2.20 (m, 1H), 2.18−2.10 (m, 1H), 1.88−1.67 (m,
3
1
G
DOI: 10.1021/acs.joc.8b01973
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
3
1
4
H), 1.06, 1.03, and 1.00 (3s, 27H), 0.82 (t, 3H, J = 7.5 Hz, H );
C{ H} NMR (100.6 MHz, CDCl ) δ 144.8, 144.7, 144.2, 135.9,
3
1
5
13
1
C{ H} NMR (100.6 MHz, CDCl ) δ 145.0, 144.6, 135.9, 134.1,
135.8, 135.7, 134.1, 134.0, 133.6, 128.7, 129.6, 129.5, 128.6, 127.7,
127.5, 127.4, 127.3, 126.8, 123.2, 109.6, 109.4, 88.1, 88.2, 86.4, 73.2,
71.6, 59.8, 38.0, 35.5, 27.0, 26.9, 20.5, 19.3, 19.2, 14.1; HRMS (APPI-
3
1
7
34.0, 133.6, 129.7, 129.6, 127.5, 123.2, 109.3, 108.5, 88.7, 87.9, 73.4,
3.2, 64.0, 36.4, 35.5, 27.3, 27.1, 27.0, 20.5, 20.0, 19.3, 14.1; HRMS
APPI-TOF) m/z 629.3841 [M + H] calcd for C H O Si , found
+
+
(
TOF) m/z 968.5014 [M] calcd for C H O Si , found 968.5045.
3
9
57
3
2
66 72
3
2
6
29.3843.
3S,10S,4E,8E,12Z)-Pentadeca-4,8,12-trien-6-yne-1,3,10-triol
17). To an ice-cooled solution of (4E,8E)-trienyne 16 (1.2 g, 2
(3S,10S,4E,8E,12Z)-3,10-Bis(tert-butyldiphenylsilyloxy)-
pentadeca-4,8,12-trien-6-yn-1-ol (20). A solution of tris-protected
diol 19 (1.15 g, 1.17 mmol) in CH Cl (10 mL) and MeOH (10 mL)
(
(
2
2
mmol) in THF (20 mL) was added TBAF (1 M in THF, 9 mL, 9
mmol). After being stirred for 10 min, the reaction mixture was then
warmed to room temperature and stirred for an additional 2 h. After
was cooled to 0 °C, and camphor-10-sulfonic acid (200 mg, 0.87
mmol) was added in portions. The mixture was stirred at 0−5 °C for
30 min and then warmed to room temperature. After being stirred for
2 h at this temperature, the reaction was neutralized with a saturated
this time, it was partitioned between Et O and water, and the layers
2
were separated. The organic layer was washed with brine, dried over
aqueous solution of NaHCO . MeOH was evaporated, and the
3
Na SO , filtered and evaporated. Purification of the residue by flash
residue extracted with CH Cl . The organic layers were combined,
2
4
2
2
chromatography on silica gel (60/40 hexanes−acetone) afforded triol
washed with brine, dried over Na SO , filtered, and evaporated under
2 4
2
1
1
7 (360 mg, 72%) as a light yellow oil: [α] −32 (c 0.18, CHCl );
reduced pressure. Purification of the residue by flash chromatography
on silica gel via gradient elution (99/1 hexanes−EtOAc to 80/20
hexanes−EtOAc afforded bis-protected triol 20 (700 mg, 80%) as a
D
3
1
H NMR (400 MHz, CDCl ) δ 6.16 (dd, 1H, J = 15.8, 5.8 Hz, H ),
3
4
6
1
5
.15 (dd, 1H, J = 15.7, 5.4 Hz, H ), 5.90 (d, 1H, J = 15.8 Hz), 5.87 (d,
9
2
1
1
H, J = 15.8 Hz), 5.66−5.56 (dt, 1H, J = 10.5, 7.5 Hz, H ), 5.36−
viscous oil: [α]
−96 (c 0.24, CHCl ); H NMR (400 MHz,
1
3
D
3
.32 (dt, 1H, J = 10.8, 6.9 Hz, H ), 4.48 (dt, 1H, J = 7.7, 4.5 Hz,
CDCl ) δ 7.70−7.62 (m 8H,), 7.44−7.35 (m, 12H), 6.10 (dd, 1H, J =
15.5 Hz, 6.0 Hz, H ), 6.06 (dd 1H,, J = 16.2, 6.5 Hz, H ), 5.71 (dd,
1
2
3
H ), 4.21 (q, 1H, J = 5.8 Hz, H ), 3.93−3.81 (m, 2H, H ), 2.60 (bs,
10
3
1
4
9
1
1
H, OH), 2.32 (t, 2H, J = 6.9 Hz, H ), 2.06 (p, 2H, J = 7.4 Hz, H ),
1H, J = 15.8, 1.5 Hz), 5.65 (dd, 1H, J = 15.8, 1.5 Hz), 5.39−5.30 (m,
1
1
14
.92−1.72 (m, 2H, H ), 1.60 (bs, 2H, OH), 0.97 (t, 3H, J = 7.5 Hz,
1H, H ), 5.22−5.16 (m, 1H, H ), 4.46 (qd, 1H, J = 4.9, 1.5 Hz, H ),
2
13
12
3
13
1
H ); C{ H} NMR (100.6 MHz, MeOH-d ) δ 146.8, 146.4, 134.9,
4.21 (dtd,1H, J = 7.0, 5.0, 1.5 Hz, H ), 3.74−3.66 (m, 1H, H ),
15
4
10
1
1
25.1, 110.6, 110.4, 88.9, 88.8, 72.7, 70.0, 59.6, 40.5, 35.8, 21.6, 14.5;
3.63−3.57 (m, 1H, H ), 3.49 (d, 1H, J = 5.6 Hz, OH), 2.25−2.04 (m,
1
+
HRMS (ESI-TOF) m/z 249.1485 [M + H] calcd for C H O ,
2H), 1.80−1.72 (m, 2H), 1.70−1.60 (m, 2H), 1.08 (s, 9H), 1.07 (s,
1
5
21
3
1
3
1
found 249.1481.
3S,10S,4E,8E,12Z)-1-O-(Triphenylmethyl)pentadeca-4,8,12-
trien-6-yne-1,3,10-triol (18). To an ice-cooled solution of triol 17
360 mg, 1.44 mmol), Et N (0.9 mL, 6.2 mmol), and DMAP (5 mg)
9H), 0.83 (t, 3H, J = 7.5 Hz, H ); C{ H} NMR (100.6 MHz,
15
(
CDCl ) δ 145.2, 144.1, 135.9, 135.8, 134.1, 134.0, 133.6, 133.5, 133.1,
3
129.9, 129.8, 129.7, 127.7, 127.6, 127.5, 123.2, 110.1, 109.3, 88.7,
87.7, 73.2, 72.1, 59.2, 35.4, 30.3, 27.1, 27.0, 19.3, 19.2, 14.1; molecule
apolar, no ion detected by ESI or APCI mass spectrometry.
(
3
in CH Cl (100 mL) was added chlorotriphenylmethane (691 mg,
2
2
2
.48 mmol). The reaction mixture was then warmed to room
(3S,10S,4E,8E,12Z)-3,10-Bis(tert-butyldiphenylsilyloxy)-
pentadeca-4,8,12-trien-6-ynal (21). Dess−Martin periodinane (18
mg, 0.041 mmol) was added to an ice-cooled solution of alcohol 20
(20 mg, 0.027 mmol) in CH Cl (2 mL). The solution was warmed to
temperature and stirred for an additional 2 h. After this time, it was
partitioned between Et O and water, and the layers were separated.
2
The organic layer was washed with brine, dried over Na SO , filtered,
2
4
2
2
and evaporated. Crude material (∼800 mg) was used directly in the
next step without any purification. A pure sample of monoprotected
triol 18 was obtained by flash chromatography (80/20 hexanes/
room temperature and stirred for 2 h. The reaction was quenched by
adding a solution of Na S O containing some Et N (0.1 mL). The
mixture was vigorously stirred for 30 min to destroy any excess of
2
2
3
3
2
1
EtOAc) and used for characterization: [α] −8.8 (c 0.28, CHCl );
oxidizing reagent. Solid Na SO was added and the mixture filtered
D
3
2
4
1
H NMR (400 MHz, CDCl ) δ 7.45−7.42 (m, 5H), 7.41−7.22 (m,
through a pad of deactivated silica gel. Elution with 99/1 pentane−
3
21
1
5
5
4
2
7
0H), 6.14 (dd, 1H, J = 15.7, 5.6 Hz), 6.05 (dd, 1H, J = 15.7, 5.3 Hz),
.85 (dd, 1H, J = 15.8, 1.8 Hz), 5.82 (dd, 1H, J = 15.8, 1.8 Hz), 5.63−
.57 (m, 1H), 5.37−5.31 (m, 1H), 4.42−4.39 (m, 1H, H ), 4.25−
Et O yielded aldehyde 21 (16 mg, 80%) as a pale yellow oil: [α]
2 D
1
−105 (c 0.1, acetone); H NMR (400 MHz, CDCl ) δ 9.64 (t, 1H, J
3
= 2.3 Hz, H ), 7.69−7.61 (m, 8H) 7.44−7.35 (m, 12H,), 6.12 (dd,
1
0
1
.06 (m, 1H, H ), 3.37−3.33 (m, 1H, H ), 3.01−3.32 (m, 1H, H ),
1H, J = 15.8, 5.8 Hz) 6.10 (d, 1H, J = 15.7 Hz), 5.76 (dd, 1H, J =
15.8, 1.5 Hz), 5.70 (d, 1H, J = 15.8, 1.5 Hz), 5.38−5.33 (m, 1H),
5.21−5.16 (m, 1H), 4.69 (m, 1H), 4.21 (m, 1H), 2.47 (ddd, 1H, J =
3
1
1
.96 (d, 1H, J = 4.0 Hz, OH), 2.20−2.24 (m, 1H), 2.33 (dd, 2H, J =
.1, 6.4 Hz, H ), 2.07 (p, 2H, J = 7.4 Hz, H ), 1.90−1.76 (m, 2H,
10
14
H ), 1.67 (d, 1H, J = 4.3 Hz, OH), 0.97 (t, 3H, J = 7.6 Hz, H );
7.6, 5.0, 2.1 Hz, H ), 2.22−2.10 (m, 2H), 1.78−1.72 (m, 2H), 1.07 (s,
2
15
2
13
1
13
1
C{ H} NMR (100.6 MHz, CDCl ) δ 144.9, 144.5, 143.6, 135.8,
18H), 0.83 (t, 3H, J = 7.5 Hz, H ); C{ H} NMR (100.6 MHz,
3
15
1
7
28.5, 128.3, 127.9, 127.1, 123.1, 110.0, 109.6, 88.3, 87.9, 87.4, 71.5,
1.1, 61.6, 36.3, 34.9, 20.7, 14.1; no molecular ion obtained by ESI,
CDCl ) δ 200.5, 145.4, 142.9, 135.9, 135.8, 134.1, 134.0, 132.9, 130.0,
3
129.9, 129.7, 129.6, 127.8, 127.7, 127.5, 110.8, 109.2, 89.4, 87.3, 73.2,
69.2, 55.1, 50.6, 35.6, 35.4, 30.9, 27.0, 26.9, 20.5, 19.4, 14.0; molecule
apolar and unstable, no ion detected by ESI or APCI mass
spectrometry.
APPI, or APCI mass spectrometry.
3S,10S,4E,8E,12Z)-3,10-Bis(tert-Butyldiphenylsilyloxy)-1-O-
triphenylmethyl)pentadeca-4,8,12-trien-6-yne-1,3,10-triol (19). A
(
(
solution of crude monoprotected triol 18 (∼ 800 mg, 1.44 mmol),
Methyl (10S,17S,4Z,7Z,11E,15E,19Z)-10,17-Bis(tert-
butyldiphenylsilyloxy)docosa-4,7,11,15,19-penten-13-ynoate (22).
Prior to starting the reaction, phosphonium salt 15 was coevaporated
twice with toluene. A flamed dried flask was charged with
phosphonium salt 15 (647 mg, 1.2 mmol), THF (6 mL), and
HMPA (0.6 mL) under argon. The mixture was cooled to −78 °C. A
solution of NaHMDS (1 M in THF, 1 mL, 1 mmol) was added
dropwise and the mixture stirred for 1 h at −78 °C. The color of the
reaction mixture changed during this period, passing from dark-
yellowish to dark orange. Freshly prepared aldehyde 21 (445 mg, 0.58
mmol) in THF (1 mL) was added and the cooling bath replaced by
an ice bath. The mixture was slowly warmed to 0−5 °C with further
stirring for 1 h and then quenched with an aqueous solution of
saturated NaH PO . The resulting solution was extracted with EtOAc,
imidazole (476 mg, 7 mmol), and DMAP (10 mg) in CH Cl (5 mL)
2
2
was cooled to 0 °C, and chloro-tert-butyldiphenylsilane (0.92 mL, 3.5
mmol) was added. The reaction was stirred for 10 h at room
temperature. After this time, the reaction mixture was diluted with
CH Cl , washed with a 10% aqueous HCl solution and then brine,
2
2
and finally dried over Na SO . Filtration, concentration, and
2
4
purification of the residue by flash chromatography on silica gel via
gradient elution (99/1 hexanes−CH Cl to 95/5 hexanes−CH Cl )
2
2
2
2
afforded tris-protected triol 19 (1.15 g, 80% from triol 17) as a
viscous oil: [α]21 −57 (c 0.18, CHCl ); H NMR (400 MHz,
1
D
3
CDCl ) δ 7.69−7.52 (m, 8H), 7.44−6.99 (m, 27H), 6.05 (dd, 1H, J =
5.7, 5.6 Hz), 5.97 (dd, 1H, J = 15.8, 6.4 Hz), 5.68 (d, 1H, J = 15.8
3
1
Hz), 5.46 (d, 1H, J = 16.3 Hz), 5.39−5.30 (m, 1H), 5.26−5.17 (m,
2
4
1
2
2
H), 4.40 (q, 1H, J = 5.6 Hz), 4.23−4.19 (m, 1H), 3.02−2.95 (m,
washed with brine, dried over Na SO , filtered, and evaporated under
2 4
H, H ), 2.23−2.03 (m, 2H), 1.80−1.70 (m, 2H), 1.70−1.49 (m,
reduced pressure. Purification of the residue by flash chromatography
1
H), 1.07 (s, 9H), 1.00 (s, 9H), 0.84 (t, 3H, J = 7.6 Hz, H );
on deactivated silica gel (98/2 pentane−Et O) afforded ester (7Z)-22
1
5
2
H
DOI: 10.1021/acs.joc.8b01973
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
372 mg, 75%) as a pale yellow oil: [α]21D −68 (c 0.19, acetone); H
1
(10S,17S,4Z,7Z,11E,13Z,15E,19Z)-10,17-Dihydroxydocosa-4,7,-
(
NMR (400 MHz, CDCl ) δ 7.68 (d, 2H, J = 6.6 Hz), 7.63 (d, 2H, J =
11,13,15,19-hexenoic Acid (2: PDX). PDX-methyl ester (24) (10 mg,
3
7
(
1
(
.1 Hz), 7.57−7.26 (m, 16H), 6.09 (dd, 1H, J = 15.8, 6.1 Hz), 6.08
dd, 1H, J = 14.2, 6.0 Hz), 5.73 (d, 1H, J = 15.8 Hz), 5.72 (d, 1H, J =
5.8 Hz), 5.69−5.16 (m, 6H, H , H , H , H , H , H ), 4.27−4.19
0.026 mmol) was dissolved in a 2:2:1 mixture of THF−MeOH−H O
2
(0.5 mL), and the solution was degassed with argon. After being
cooled at 5 °C, solid LiOH (34 mg, 0.8 mmol) was added, and the
mixture was degassed again. After 3 h of stirring at 5 °C, the reaction
4
5
7
8
19
20
m, 2H, H , H ), 3.66 (s, 3H, CO CH ), 2.56 (t, 2H, J = 5.7 Hz,
10 17 2 3
H ), 2.35−2.30 (m, 4H, H , H ), 2.30−2.08 (m, 4H, H , H ), 1.76
was neutralized with an aqueous solution of saturated NaH
PO ,
2 4
6
2
3
9
18
followed by an extraction with Et O. The combined organic phase
(
p, 2H, J = 7.4 Hz, H ), 1.07 (s, 18H), 0.83 (t, 3H, J = 7.4 Hz, H );
2
2
1
22
13
1
was washed with brine, dried over Na SO , filtered, and evaporated
C{ H} NMR (100.6 MHz, CDCl ) δ 173.4, 144.9, 144.6, 135.9,
2
4
3
under vacuum without any heating. The residue was purified by flash
chromatography on deactivated silica gel via gradient elution (95/5
hexanes−acetone to 70:30 hexanes−acetone) to give PDX (2) (7.4
mg, 77%) as a pale yellow oil. PDX (2) was known to be sensitive
when exposed to light and air. A concentrated solution of PDX (2) in
MeOH was found to decompose quickly thus it was kept in dilute
1
1
3
35.9, 134.1, 133.7, 133.6, 130.0, 129.8, 129.7, 129.6, 129.2, 127.7,
27.5, 124.6, 123.3, 109.7, 109.5, 88.3, 88.1, 73.2, 73.1, 51.5, 35.6,
5.5, 34.0, 27.0, 26.9, 22.7, 20.5, 19.3, 14.0; molecule apolar, no ion
detected by ESI or APCI mass spectrometry.
-Preparation of Methyl Ester 24 and PDX (2). Methyl
10S,17S,4Z,7Z,11E,15E,19Z)-10,17-Dihydroxydocosa-4,7,11,15,19-
7
(
pentene-13-ynoate (23). Pentaenyne 22 (372 mg, 0.438 mmol) was
treated with TBAF (1 M solution in THF, 5 mL), and the reaction
mixture was then stirred at room temperature for 2 h. After this time,
it was partitioned between EtOAc and an aqueous solution of
saturated NaH PO , and the layers were separated. The organic layer
EtOH solution (0.01%) in a vial protected from light under argon at
1
−80 °C: H NMR (400 MHz, MeOH-d
) δ 6.75−6.69 (m, 2H, H12
,
4
H
15), 5.97 (dt, 2H, J = 10.1, 8.1 Hz, H13, H14), 5.74 (dd, 1H, J = 15.3,
6.4 Hz, H11 or H16), 5.71 (dd, 1H, J = 15.0, 6.4 Hz, H11 or H16),
5.50−5.32 (m, 6H, H
, H
, H
, H
, H19, H20), 4.20−4.15 (m, 2H, H10
,
,
2
4
4
5
7
8
was successively washed with water and brine solutions, dried over
Na SO , filtered, and evaporated under reduced pressure. Purification
of the residue by flash chromatography on deactivated silica gel via
gradient elution (95/5 pentane−Et O to 75/25 pentane−Et O)
afforded diol 23 (140 mg, 80%) as a light yellow oil: [α] +17 (c
H
H
17), 2.83 (bt, 2H, J = 5.4 Hz, H
6
), 2.39−2.12 (m, 8H, H , H , H
2
3
9
18), 2.07 (p, 2H, J = 7.4 Hz, H21), 0.95 (t, 3H, J = 7.5 Hz, H22);
2
4
1
3
1
C{ H} NMR (100.6 MHz, MeOH-d ) δ 136.7, 136.6, 135.7, 133.3,
4
130.0, 129.5, 128.7, 128.5, 127.8, 125.1, 125.0, 124.7, 124.0, 71.7,
71.6, 34.9, 34.8, 33.6, 29 4, 25.3, 22.5, 20.2, 13.1; MS (APCI neg) m/z
2
2
2
1
D
1
0
1
1
.2, MeOH); H NMR (400 MHz, MeOH-d ) δ 6.08 (dd, 1H, J =
5.6, 3.4 Hz), 6.06 (dd, 1H, J = 15.5, 3.5 Hz), 5.79 (dd, 1H, J = 15.8,
.7 Hz), 5.78 (dd, 1H, J = 15.8, 1.5 Hz), 5.52−5.32 (m, 6H, H , H ,
(intensity) 359 [M − H] (100), 341 [M − H − H
analysis, mobile phase MeOH−H O from 70:30 to 85:15 (30 min)
and 100:0 (5 min), flow (1.0 mL/min), UV detector at 266 nm, t
2
O] (16). HPLC
4
2
=
4
5
R
H , H , H , H ), 4.16−4.02 (m, 2H, H , H ), 3.65 (s, 3H,
13.49 min, 96% purity. LC−MS/MS analysis for comparison assay
7
8
19
20
10
17
CO CH ), 2.83 (bt, 2H, J = 5.5 Hz, H ), 2.38−2.36 (m, 4H, H2, H3),
with natural material (for the analytical procedures see ref 12a), t
14.20 min for PDX (2) from the Cayman Chemical Company, t
R
R
=
=
2
3
6
2
.35−2.27 (m, 4H, H , H ), 2.05 (m, 2H, H ), 0.96 (t, 3H, J = 7.6
9
18
21
13
1
Hz, H ); C{ H} NMR (100.6 MHz, MeOH-d ) δ 175.3, 146.4,
14.21 min for synthetic PDX (2); UV−vis (MeOH) λmax 269 nm
(shoulders at 258 and 280 nm).
22
4
1
1
3
46.3, 136.3, 135.0, 131.2, 130.9, 130.2, 129.9, 129.8, 129.0, 126.5,
26.2, 125.6, 125.1, 110.7, 110.6, 88.9, 88.8, 72.6, 72.5, 52.1, 36.0,
5.9, 34.8, 30.9, 28.9, 26.7, 23.8, 21.6, 14.5; MS (APCI neg) m/z
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01973.
■
(
intensity) 371 [M − H] (25), 353 [M − H − H O] (25), 335 [M −
2
*
S
H − 2H O] (100). HPLC analysis; mobile phase MeOH−H O from
2
2
7
0:30 to 85:15 (15 min) and 100:0 (5 min), flow (1.0 mL/min), UV
detector at 265 nm, t = 13.5 min, 96% purity.
R
Methyl (10S,17S,4Z,7Z,11E,13Z,15E,19Z)-10,17-Dihydroxydoco-
sa-4,7,11,13,15,19-hexenoate, (24: PDX-methyl Ester). A 10 mL
Schlenk tube was charged with freshly prepared activated Zn(Cu/
NMR spectra of 3, 5−8, 12, 13, 15-23, PDX-methyl
ester (24), and PDX (2); HPLC chromatograms of
PDX-methyl ester (24) and PDX (2); UV−vis
absorption spectrum of PDX (2) (PDF)
23,24
Ag)
(20% suspension in a 1:1 mixture of MeOH−H O, 6.5 mL).
2
Argon was bubbled through the mixture, and then TMSCl (100 μL)
was added. A solution of conjugated alkyne 23 (35 mg, 0.094 mmol)
in MeOH (4 mL) was added 5 min later, and the black suspension
was purged again for 5 min and then the tube was sealed. After
vigorous stirring at room temperature for 16 h in the dark, the black
slurry was filtered through a pad of Celite and thoroughly washed
AUTHOR INFORMATION
Corresponding Author
*Tel: +1 418 654 2296. Fax: +1 418 654 2298. E-mail: jean-
yves.sanceau@crchudequebec.ulaval.ca.
■
with Et O. The solvents were evaporated under vacuum in the dark
2
and without heating. The residue was purified by flash chromatog-
raphy on deactivated silica gel via gradient elution (95/5 pentane−
Et O to 70/30 pentane−Et O) giving PDX-methyl ester 24 (18 mg,
ORCID
Jean-Yves Sancea
́
u: 0000-0003-4340-7284
Maltais: 0000-0002-0394-1653
Donald Poirier: 0000-0002-7751-3184
2
2
Rene
́
5
1%) as a pale yellow oil. This material was found to decompose at
room temperature when exposed to light and air (allylic oxidation);
thus, it was kept in a vial protected from light under argon at −80 °C:
Notes
2
1
1
[
6
α] +6 (c 0.02, MeOH); H NMR (400 MHz, MeOH-d ) δ 6.78−
D
4
The authors declare no competing financial interest.
.66 (m, 2H, H , H ), 5.96 (dt, 2H, J = 10.2, 8.5 Hz, H , H ), 5.74
12 15 13 14
(
dd, 1H, J = 15.1, 6.4 Hz, H11 or H ), 5.70 (dd, 1H, J = 15.1, 6.4 Hz,
16
ACKNOWLEDGMENTS
This research was supported by a Pfizer/CIHR Research Chair
H11 or H ), 5.52−5.32 (m, 6H, H , H , H , H , H , H ), 4.16−4.02
■
16
4
5
7
8
19
20
(
m, 2H, H , H ), 3.65 (s, 3H, CO CH ), 2.82 (bt, 2H, J = 5.7 Hz,
10 17 2 3
H ), 2.38−2.26 (m, 8H, H , H , H , H ), 2.05 (p, 2H, J = 7.6 Hz,
H ), 0.96 (t, 3H, J = 7.6 Hz, H ); C{ H} NMR (100.6 MHz,
6
2
3
9
18
to Andre
́
Marette on the pathogenesis of insulin resistance and
1
3
1
21
22
cardiovascular complications. We are grateful to Marie-Claude
Trottier and Sophie Boutin (Medicinal Chemistry Platform-
MeOH-d ) δ 173.9, 137.7, 136.6, 134.6, 133.2, 130.0, 129.5, 129.2,
1
7
(
(
MeOH-H O from 70:30 to 85:15 (15 min) and 100:0 (5 min), flow
(
4
28.9, 128.6, 128.5, 127.5, 125.4, 125.2, 125.1, 125.0, 124.5, 124.0,
1.7, 71.6, 50.6, 34.9, 34.8, 33.4, 28.1,25.2, 22.4, 20.2, 13.1; MS
CHU de Queb
́
ec Research Center) for recording NMR spectra
ec
and Jocelyn Trottier (Bioanalytical Services-CHU de Queb
́
APCI pos) m/z (intensity) 375 [M + H] (5), 357 [M + H − H O]
2
Research Center) for performing LC−MS/MS analysis (for
comparison assay with natural PDX). We also thank Dr.
Olivier Barbier for taking part in important discussions.
100), 339 [M + H − 2H O] (100). HPLC analysis; mobile phase
2
2
1.0 mL/min), UV detector at 270 nm, t = 15.8 min, 93% purity.
R
I
DOI: 10.1021/acs.joc.8b01973
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
PDX). An overview on the dihydroxy-docosatrienes described to
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DOI: 10.1021/acs.joc.8b01973
J. Org. Chem. XXXX, XXX, XXX−XXX