Enantioselective Synthesis of 7(S)-Hydroxydocosahexaenoic Acid, a Possible Endogenous Ligand for PPARα

Article abstract of DOI:10.1021/acs.joc.0c01770

We report the first total synthesis of the polyunsaturated fatty acid 7-hydroxydocosahexaenoic acid (7-HDHA) in racemic form and the enantioselective synthesis of 7-(S)-HDHA. Both syntheses follow a convergent approach that unites the C1-C9 and C10-C22 fragments using Sonogashira coupling and Boland reduction as key steps. These syntheses enabled the unambiguous characterization of this natural product for the first time and helped establish 7(S)-HDHA as a possible endogenous ligand for peroxisome proliferator-activated receptor alpha.

Full text of DOI:10.1021/acs.joc.0c01770

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Article
Enantioselective Synthesis of 7(S)-Hydroxydocosahexaenoic
Acid, a Brain-Specific Endogenous Ligand for PPAR#
Minhao Zhang, Ashik Sayyad, Anmol Dhesi, and Arturo Orellana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01770 • Publication Date (Web): 20 Sep 2020
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The Journal of Organic Chemistry
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Enantioselective Synthesis of 7(S)-Hydroxydocosahexaenoic Acid, a
Brain-Specific Endogenous Ligand for PPAR
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Minhao Zhang, Ashik A. Sayyad, Anmol Dhesi and Arturo Orellana*
Department of Chemistry, York University, 4700 Keele Street. Toronto ON, M3J 1P3, Canada.
aorellan@yorku.ca
Supporting Information Placeholder
ABSTRACT: We report the first total synthesis of the polyunsaturated fatty acid 7-hydroxydocosahexaenoic acid (7-HDHA) in
racemic form, and the enantioselective synthesis of 7-(S)-HDHA. Both
syntheses follow a convergent approach that unites the C1-C9 and C10-C22
fragments using a Sonogashira coupling and a Boland reduction as key steps.
These syntheses enabled the unambiguous characterization of this natural
product for the first time, and helped establish 7(S)-HDHA as the
endogenous ligand for peroxisome proliferator-activated receptor alpha (PPAR) in the brain.
INTRODUCTION
Oxidative metabolites of polyunsaturated fatty acids (PUFAs),
such as docosahexaenoic acid (DHA), have become attractive
leads for the development of new therapeutics, primarily due to
their anti-inflammatory effects.1,2 Congeners of this family of
natural products arise through progressive oxidation of the
weak bis-allylic C-H bonds (BD = 72.7 kcal/mol),2a resulting in
the simultaneous installation of hydroxyl groups and double
bond conjugation. Representative examples3 of this family, with
increasing oxidation states, include 7-HDHA (2), maresin 1 (3)
and resolvin D1 (4) (Figure 1).
Besides exerting regulatory effects on metabolism and
inflammation, PUFAs are also implicated in signalling
pathways in the brain.4 It has been shown that activation of the
peroxisome proliferator-activated receptor alpha (PPAR in
adult hippocampal neural stem cells promotes neurogenesis.5
Therefore, the identification of high affinity brain-specific
ligands for PPAR could serve as a lead for the development of
treatment for neurodegenerative diseases such as Alzheimer’s.
A recent study identified 7-HDHA as a selective, brain-specific
endogenous ligand for PPAR,6 however, structural assignment
of 7-HDHA relied on HPLC-MS-MS and therefore remained
inconclusive. In addition, the limited supply, prohibitive cost
and questionable purity of commercial 7-HDHA prevented
follow-up studies. To alleviate this supply problem, we
embarked on the first synthesis of rac-7-HDHA and
enantiopure 7(S)-HDHA. These syntheses enabled the
unambiguous identification of 7(S)-HDHA as a potent and
selective ligand for brain PPAR and serve as a possible
starting point for the development of therapeutics for
neurodegenerative diseases.
Figure 1. Docosahexaenoic acid (DHA, 1) and some of its
oxidation products, 7-HDHA (2) maresin 1 (3) and resolvin D1 (4)
are biologically active metabolites with therapeutic potential.
RESULTS AND DISCUSSION
The synthetic challenge posed by 7–HDHA consists primarily
of establishing the conjugated trans,cis-diene at C8–C11, the
allylic hydroxyl function at C7, and the skipped tetraene
spanning C10 to C20 (Scheme 1). An additional concern in this
synthesis is the three doubly allylic methylene groups (at C12,
C15 and C18), which render the target and some intermediates
sensitive to oxidation. Retrosynthetic disconnection of 7–
HDHA about the C9–C10 sigma bond results in two fragments
of similar complexity, which can be joined in the forward sense
through a Sonogashira cross-coupling of a trans-alkenyl iodide
and a terminal alkyne, and cis-selective semi-hydrogenation of
the resulting conjugated enyne.
Scheme 1. Retrosynthetic analysis of 7-HDHA
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providing the silyl-protected tetraalkyne 19 in good yield. The
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selective hydrogenation of skipped polyalkynes to the
corresponding skipped alkenes characteristic of poly-
unsaturated fatty acids, remains very challenging.12 Commonly
used methods, such as hydrogenation with Lindlar’s catalyst
and the Rosenmund reduction provided no conversion in our
hands. Luckily, the P-2 nickel system13 furnished the desired
all-cis skipped triene in a modest 26% yield, supplying
sufficient material to continue with the synthesis. Removal of
the trimethylsilyl group was achieved under standard conditions
to furnish alkyne 6.
Our first-pass racemic synthesis of 7–HDHA began with the
preparation of the C1–C9 fragment 5 (Scheme 2). Formylation
of commercially available TIPS-mono-protected acetylene 7 by
deprotonation with n-BuLi and quenching with DMF provided
aldehyde 8 in quantitative yield. Installation of acetal protected
aldehyde at the C5 position and the secondary alcohol at the C7
position in 10 was achieved by addition of Grignard 97 to
aldehyde 8 in 83% yield. Removal of the acetylenic silyl
protecting group by treatment with TBAF, and protection of the
propargylic alcohol furnished acetal 11 in high yield. Protection
of the alcohol became necessary because all attempts to remove
the acetal group at C5 in compound 10 inevitably led to
elimination (not shown). Regioselective hydrozirconation8
followed by an iodine quench provided 12, with the required
trans-alkenyl iodide at the eventual C8–C9 position.
Unexpectedly, removal of the acetal moiety in 12 proved
challenging using standard methods and largely resulted in
decomposition. The required aldehyde 13 could be revealed
using palladium as a mild Lewis acid9 in the presence of
acetone. Although uncommon, the use of Pd(II) for acetal
deprotection provided a high yield of the product (based on
recovered starting material), while the use of other Lewis acids
(e.g. FeCl3) resulted in significant decomposition. Wittig
reaction with the unstabilized ylide10 derived from 14 provided
the C4–C5 cis-alkene 5 as expected.
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Scheme 3. Synthesis of C10-C22 fragment 6.
To complete the synthesis, we united the C1–C9 and the C10–
C22 fragments using a Sonogashira coupling14 (Scheme 4). The
critical step in this final sequence involved stereoselective semi-
reduction of the conjugated enyne 20 spanning C8–C11. We
elected to use Boland’s method15 over others, such as the
Lindlar reduction, because it reliably provides the cis-
configured semi-reduction product. Addition of dioxane to the
usual solvent mixture consisting of MeOH and water was
necessary to solubilize the highly lipophilic substrate.
Interestingly, we found that the progress of this reaction stopped
periodically, however activity could be rescued by spiking the
reaction mixture with a few drops of aqueous 1M HCl every
24h. Finally, removal of the TBDPS protecting group using
TBAF, and hydrolysis of the ethyl ester provided the desired (±)
7–HDHA 2. To the best of our knowledge this is the first
synthesis of this natural product. Curiously, no spectral data for
this compound has been reported and we therefore fully
characterized this synthetic sample using an array of NMR
techniques, confirming its structure (See SI for full assignment
and details).
Scheme 2. Synthesis of C1-C9 fragment 5.
Scheme 4. Cross-coupling of fragments 5 and 6, and
completion of the total synthesis of (±)7–HDHA.
Preparation of the C10–C22 fragment 6 began with the copper
mediated coupling of tosylated 2-pentyn-1-ol 15 with
propargylic alcohol 16,11 giving the intermediate alcohol in
74% yield (Scheme 3). This alcohol was then converted to the
corresponding bromide 17 which was then coupled with the
commercially available skipped diyne 18 in a similar manner,
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Chiral HPLC separation of (±)-7-HDHA into individual
enantiomers identified 7(S)–HDHA as the endogenous ligand
for PPAR and therefore this became our next target.6 Our first
synthesis of (±)-7-HDHA revealed a number of problems with
the preparation of the C1-C9 fragment 5, prompting a revised
approach. The unanticipated use of a Pd(II) catalyst in high
loads to reveal the C5 aldehyde, and the stoichiometric use of
Schwartz’s reagent were of particular concern. Furthermore, the
propensity of the C7 alcohol to undergo elimination prompted
us to seek an alternative approach to the installation of this
group. These issues were readily addressed with a new strategy
that also allowed the enantioselective synthesis of 7(S)–HDHA.
The synthesis began with a titanium mediated16 Nagao-Fujita
acetate aldol reaction17 between (R)–acetyl thiazolidinethione
21 and β-iodoacrolein 22,18 providing aldol 23 as the major
adduct19 in 68% yield and with greater than 9:1
diastereoselectivity (Scheme 5). It is worth noting that a
particular challenge with this reaction is the instability of trans-
iodoacrolein 22, which decomposes readily when neat. TIPS-
protection of the secondary alcohol in 23 furnished silyl ether
24, and reductive cleavage of the chiral auxiliary with DIBAL-
H provided aldehyde 25 in 88% overall yield. Wittig reaction
between aldehyde 25 and the phosphorane derived from 14 as
before (c.f. Scheme 2) gave the cis-alkene 26 in good yield and
greater than 5:1 selectivity for the desired geometric isomer.
The presumptive minor trans-isomer (not shown) was separated
to avoid complications at a later stage. Completion of the
synthesis consisted of Sonogashira coupling of 6 and 26,
Boland reduction, and deprotections as before (c.f. Scheme 4),
to furnish 7(S)-HDHA for the first time.
CONCLUSIONS
We have completed the first total synthesis of the
polyunsaturated fatty acid 7-HDHA in racemic and
enantioselective forms using a convergent approach. Our
racemic synthesis proved to have some liabilities but
nevertheless enabled the identification of the active enantiomer,
allowed full characterization of this low-abundance natural
product for the first time, and provided insights for the eventual
enantioselective synthesis of 7(S)-HDHA. Our enantioselective
approach provided sufficient amounts of 7(S)-HDHA for
further biological studies.
EXPERIMENTAL SECTION
General. All reactions were conducted in flame or oven-dried
glassware under an atmosphere of argon using anhydrous
solvents unless specified otherwise. Tetrahydrofuran (THF),
diethylether (Et2O), dichloromethane (DCM) and toluene were
dried using an INERT® PureSolv solvent purification system.
Commercial reagents were used as received. Thin-layer
chromatography was performed on SiliCycle® silica gel 60
F254 plates. Visualization was carried out using UV light (254
nm) and/or KMnO4, (NH4)2Ce(NO3)6, vanillin, or anisaldehyde
stains. Flash column chromatography20 was carried out using
SiliCycle® SilaFlash® silica gel (230–400 mesh, 40-63 μ, 60º
A pore size). Hexanes (ACS grade) and ethyl acetate (ACS
grade) were used as received. 1H–NMR and 13C–NMR spectra
were recorded on a Bruker 400 AV, Bruker DRX 600 or Bruker
300 AV spectrometer in chloroform-d (99.8 % deuterated).
Spectra recorded using chloroform were calibrated to 7.26 ppm
1H and 77.16 ppm 13C. Chemical shifts (δ) are reported in ppm
and multiplicities are indicated by s (singlet), d (doublet), t
(triplet), q (quartet), p (quintet), sext (sextet), sept (septet), td
(triplet of doublets), dt (doublet of triplets), dd (doublet of
doublets), ddt (doublet of doublet of triplets),21 dddd (doublet
of doublet of doublet of doublets),21 m (multiplet) and br
Scheme 5. Enantioselective synthesis of 7(S)-HDHA.
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(broad). Coupling constants J are reported in Hertz (Hz). three hours. The reaction mixture was then concentrated under
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Infrared (IR) spectra were recorded as thin films (neat) using
AlphaPlatinum ATR, Bruker, diamond crystal FT-IR
instrument. High-resolution mass spectroscopy (HRMS) was
performed on a JEOL AccuTOF Plus 4G model JMS-T 1000LP
mass spectrometer equipped with a Direct Analysis in Real
Time (DART) ion source; or an Agilent 6538 Q-TOF mass
spectrometer equipped with an Agilent 1200 HPLC and a ESI
ion source. Structural assignments were made with additional
information from COSY, HSQC, HMBC, TOCSY, and
NOESY experiments
vacuum and the resulting residue was dissolved in 30 mL of
ethyl acetate. This organic phase was then washed with 30 mL
of brine and dried over MgSO4, filtered and concentrated under
reduced pressure. The residual oil was purified by flash
chromatography using ethyl acetate and hexane (50:50) as
eluent to afford the intermediate alcohol (not shown) as a
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colourless oil (217.13 mg, 91% yield). The H-NMR and 13C-
NMR data is in accordance with that previously reported.23 1H-
NMR (300 MHz, CDCl3), δ 5.16 (dd, J = 4.86 Hz, 4.68 Hz, 1H),
4.67 (m, 1H), 4.05-3.87 (m, 4H), 3.07 (d, J = 5.34 Hz, 1H), 2.48
(d, J = 2.22 Hz, 1H), 2.22-2.04 (m, 2H); 13C{H}-NMR (75
MHz, CDCl3), δ 102.5, 83.9, 73.2, 65.0, 58.9, 40.5; IR υ = 3405,
2966, 2891, 2891, 2185, 1411, 1303, 1134, 1065, 1019 cm-1.
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1-(triisopropylsilyl)-1-propynal (8). A 200 mL round-bottom
flask was charged with 7 (5.00 g, 27.42 mmol, 1.0 equiv.) in 30
mL of dry Et2O and equipped with a stir bar. The solution was
cooled to 0 C and n–BuLi (1.6 M in hexane, 18.85 mL, 30.16
mmol, 1.1 equiv.) was added dropwise to it, the reaction was
allowed to stir at 0 C for 30 min. DMF (8.5 mL, 109.7 mmol,
4.0 equiv.) in 20 mL of Et2O was then added dropwise to the
reaction mixture at 0 C. The reaction stirring was continued at
0 C for two hours and finally quenched at 0 C by slow addition
of 1M HCl until a slightly acidic pH (5–6) was reached. After
an hour of stirring at room temperature, the organic phase was
separated, and the aqueous phase was extracted with 150 mL of
ether. The organic layers were combined, washed with 100 mL
of brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The residual oil was purified by flash
chromatography using ethyl acetate and hexane (10:90) as
eluent to afford 8 as a pale-yellow oil (5.73 g, 99% yield). The
1H-NMR and 13C-NMR data is in accordance with that
previously reported in the literature.22 1H-NMR (400 MHz,
CDCl3) δ 9.21 (s, 1H), 1.13-1.09 (m, 21H); 13C{H}-NMR (100
MHz, CDCl3) δ 176.8, 104.6, 101.1, 18.5, 11.1.
Step 2: A 25 mL round-bottom flask equipped with a stir bar
was charged with the aforementioned alcohol (214.0 mg, 1.51
mmol, 1.0 equiv.), imidazole (257.3 mg, 3.78 mmol, 2.5 equiv.)
and 5 mL of DMF. TBDPSCl (496.23 mg, 1.81 mmol, 1.2
equiv.) in 2 mL of DMF was then added to the reaction mixture
dropwise at room temperature and the reaction was stirred
overnight. Next, the mixture was diluted with 15 mL of Et2O,
and 10 mL of water was added. The organic phase was
separated, and the aqueous phase was extracted with ether (3 x
20 mL). The organic layers were combined, washed with 35 mL
of brine, dried over MgSO4, filtered, and concentrated under
vacuum. The residual oil was purified by flash column
chromatography using ethyl acetate and hexane (20:80) as
eluent to afford alkyne 11 as a colourless oil (570.20 mg, 99%
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yield); H-NMR (600 MHz, CDCl3), δ 7.75 (d, J = 6.72 Hz,
2H), 7.70 (d, J = 7.35 Hz, 2H), 7.44-7.36 (m, 6H), 5.02 (t, J =
5.1 Hz, 1H), 4.57 (td, J = 6.78 Hz, 1.92 Hz, 1H), 3.88-3.74 (m,
4H), 2.32 (d, J = 1.92 Hz, 1H), 2.10-2.03 (m, 2H), 1.08 (s, 9H);
13C{H}-NMR (150 MHz, CDCl3), δ 136.2, 136.1, 133.5, 129.9,
129.8, 127.7, 127.5, 101.7, 84.3, 73.5, 64.9, 64.8, 60.7, 42.9,
27.1, 19.4; HRMS (DART) m/z: [M+H]+ calcd for C23H29O3Si
381.1880; found 381.1885; IR υ = 2957, 2929, 2889, 2556,
1463, 1421, 1361, 1138, 1086, 1058 cm-1.
1-(1,3-dioxolan-2-yl)-4-(triisopropylsilyl)but-3-yn-2-ol (10).
A 200 mL round-bottom flask equipped with a condenser and a
stir bar was charged with Mg turnings (458.5 mg, 19.00 mmol,
4.0 equiv.) and 20 mL of THF, which was followed by the
addition of 2-(bromomethyl)-1,3-dioxolane (1.59 g, 9.5 mmol,
2.0 equiv.) and a small crystal of I2. The reaction mixture was
stirred for two hours at room temperature, then aldehyde 8 (1.0
g, 4.75 mmol, 1.0 equiv.) in 5 mL of THF was added dropwise
to the Grignard reagent 9. The reaction mixture was stirred at
room temperature overnight and then cooled to 0 C. Water (20
mL) were added dropwise to the reaction, followed by the
addition of saturated aq. NH4Cl. The organic phase was
separated and the aqueous phase was extracted with ether (3 x
25 mL). The organic layers were combined and washed with 50
mL of brine and dried over MgSO4, filtered and concentrated
under vacuum. The residual oil was purified by flash column
chromatography using ethyl acetate and hexane (30:70) as
eluent to afford 10 as a colourless oil (1.18 g, 83% yield). 1H-
NMR (300 MHz, CDCl3), δ 5.17 (dd, J = 5.43 Hz, 4.41 Hz, 1H),
4.66 (m, 1H), 4.03-3.86 (m, 4H), 2.89 (d, J = 4.89 Hz, 1H),
2.21-2.02 (m, 2H), 1.07-1.05 (m, 20H); 13C{H}-NMR (75
MHz, CDCl3), δ 107.6, 102.7, 85.8, 64.9, 59.6, 41.1, 18.7, 11.2;
HRMS (DART) m/z: [M+NH4]+ calcd for C16H34O3SiN
316.2302; found 316.2310; IR υ = 3454, 2892, 2867, 2149,
1462, 1368, 1255, 1072 cm-1.
(E)-((1-(1,3-dioxolan-2-yl)-4-iodobut-3-en-2-yl)oxy)(tert-
butyl)diphenylsilane (12). A 25 mL round-bottom flask
equipped with a magnetic stir bar was charged with Cp2ZrCl2
(602.16 mg, 2.06 mmol, 2.0 equiv.) and 2.5 mL of THF, and
resulting solution was cooled to 0 C. A DIBAL-H solution (1.0
M in toluene, 1.85 mL, 1.85 mmol, 1.8 equiv.) was added
dropwise into the reaction flask. The reaction was stirred for 30
minutes and then a solution of alkyne 11 (392.2 mg, 1.03 mmol,
1.0 equiv. in 1.5 mL of THF) was added dropwise to the
reaction mixture at 0 C. After one hour of stirring, the reaction
was cooled to 78 C and a solution of I2 (522.85 mg, 2.06
mmol, 2.0 equiv. in 1.5 mL of THF) was added dropwise very
slowly to the reaction mixture. After 20 minutes, the reaction
was quenched with 1 M HCl. The organic phase was separated,
and the aqueous phase was extracted with ether (3 x 20 mL).
The organic layers were combined, washed successively with
saturated aq. Na2S2O3 (30 mL), NaHCO3 (30 mL) and brine (30
mL), dried over MgSO4, filtered, and concentrated under
vacuum. The residual oil was purified by flash column
chromatography using ethyl acetate and hexane (5:95) as eluent
to afford alkenyl iodide 12 as a colourless oil (485.5 mg, 93%
yield). 1H-NMR (400 MHz, CDCl3), δ 7.66-7.61 (m, 4H), 7.43-
7.36 (m, 6H), 6.48 (dd, J = 14.44 Hz, 7.40 Hz, 1H), 5.88 (dd, J
=14.24 Hz, 0.84 Hz, 1H), 4.87 (t, J = 5.16 Hz, 1H), 4.31 (q, J =
6.56 Hz, 1H), 3.87-3.72 (m, 4H), 1.92 (m, 1H), 1.80 (m, 1H),
1.05 (s, 9H); 13C{H}-NMR (100 MHz, CDCl3), δ 147.6, 135.9,
((1-(1,3-dioxolan-2-yl)but-3-yn-2-yl)oxy)(tert-
butyl)diphenylsilane (11). Step 1: A 50 mL round-bottom
flask equipped with a magnetic stir bar was charged with
alcohol 10 (500.0 mg, 1.68 mmol, 1.0 equiv.) in 20 mL of THF.
TBAF (483.3 mg, 1.85 mmol, 1.1 equiv.) was then added
portion-wise. The mixture was stirred at room temperature for
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was sequentially washed with saturated NaHCO3 and brine,
133.6, 129.8, 127.6, 101.5, 77.9, 73.0, 64.7, 64.6, 41.7, 26.9,
19.4; HRMS (ESI) m/z: [M+Na]+ calcd for C23H29IO3SiNa
531.0823; found 531.0816; IR υ = 2958, 2941, 2886, 1607,
1471, 1427, 1137, 1110, 947 cm-1.
dried over MgSO4, filtered and concentrated under reduced
pressure to afford 15 as a pale-yellow oil (2.51 g, 89% yield),
no further purification was needed. The 1H-NMR and 13C-NMR
data is in accordance with that previously reported in the
literature.25 1H-NMR (400 MHz, CDCl3), δ 7.82 (d, J = 8.28
Hz, 2H), 7.34 (d, J = 8.22 Hz, 2H), 4.70 (t, J = 2.16 Hz, 2H),
2.45 (s, 3H), 2.12-2.06 (m, 2H), 1.02 (t, J = 7.52 Hz, 3H);
13C{H}-NMR (100 MHz, CDCl3), δ 144.99, 133.60, 129.86,
128.29, 91.90, 71.35, 58.89, 21.78, 13.30, 12.49.
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(E)-3-((tert-butyldiphenylsilyl)oxy)-5-iodopent-4-enal (13).
A 50 mL round-bottom equipped with a magnetic stirring bar
was charged with 20 mL of acetone. Acetal 12 (50.00 mg, 0.1
mmol, 1.0 equiv.) was then added to the flask and stirred for 5
min followed by the addition of PdCl2(MeCN)2 (2.60 mg, 0.01
mmol, 0.10 equiv.). The reaction mixture was stirred at room
temperature, in the dark for two days. The solvent was then
removed using rotary evaporator, and the residual mixture was
dissolved in 5 mL of Et2O, dried over MgSO4, filtered and
concentrated under reduced pressure. The residual oil was
purified by flash chromatography using hexane and toluene
(10:90) as eluent to afford 13 as a colourless oil (22.75 mg,
49%, 98% brsm), whereas 25 mg (50%) of starting material 12
was recovered. 1H-NMR (300 MHz, CDCl3), δ 9.67 (t, J = 2.19
Hz, 1H), 7.65-7.60 (m, 4H), 7.45-7.37 (m, 6H), 6.54 (dd, J =
14.48 Hz, 6.57 Hz, 1H), 6.12 (dd, J = 14.46 Hz, 0.99 Hz, 1H),
4.58 (q, J = 5.73 Hz, 1H), 2.59-2.44 (m, 2H), 1.05 (s, 9H);
13C{H}-NMR (75 MHz, CDCl3), δ 200.3, 146.4, 135.9, 133.1,
130.2, 127.9, 78.7, 71.8, 50.4, 27.0, 19.4; HRMS (DART) m/z:
[M+NH4]+ calcd for C21H29IO2SiN 482.1006; found 482.1005;
IR υ = 3070, 2957, 2930, 2857, 1724, 1607, 1427, 1361, 1104,
1071, 997 cm-1.
1-bromoocta-2,5-diyne (17). Step 1: In a 100 mL round-
bottom flask equipped with a magnetic stirring bar, 15 (2.51 g,
10.53 mmol, 1.0 equiv.) was dissolved in 25 mL of DMF, and
to this solution was added CuI (2.01 g, 10.53 mmol, 1.0 equiv.),
K2CO3 (2.18 g, 15.80 mmol, 1.5 equiv.) and TBAI (3.89 g,
10.53 mmol, 1.0 equiv.). The reaction mixture was cooled to 0
C and propargyl alcohol 16 (708.6 mg, 12.64 mmol, 1.2 equiv.)
was added dropwise. The reaction mixture was brought to room
temperature and stirred overnight. Next, the reaction mixture
was cooled to 0 C, 20 mL of cold water and 150 mL of
saturated aq. NH4Cl were added sequentially. The mixture was
extracted with Et2O (3 x 50 mL). The organic layers were
combined, washed with 50 mL of brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residual
oil was purified by flash chromatography using ethyl acetate
and hexane (30:70) as eluent to afford intermediate propargylic
alcohol (not shown) as a yellow oil (816.20 mg, 74% yield).
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Ethyl (4Z,8E)-7-((tert-butyldiphenylsilyl)oxy)-9-iodonona-
4,8-dienoate (5). A 25 mL round-bottom flask equipped with a
magnetic stirring bar was charged with Wittig salt 1424 (667.73
mg, 1.46 mmol, 4.3 equiv.) in 3 mL of THF, which was then
cooled to -78 C. A KHMDS solution (0.5 M in toluene, 2.72
mL, 1.36 mmol, 4.0 equiv.) was added dropwise in the reaction
mixture, resulting in a yellow suspension. After one hour of
stirring at -78 C, a solution of aldehyde 13 (106.0 mg, 0.34
mmol, 1.0 equiv.) in 3 mL of THF was then added dropwise
(very slowly) to the reaction mixture. The reaction mixture was
stirred for an hour at -78 C and quenched by dropwise addition
of sat. aq. NH4Cl and diluted with Et2O. The organic phase was
separated and the aqueous phase was extracted with ether (35
mL x 3). The organic layers were combined, washed with 50
mL of brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The residual oil was purified by flash
chromatography using ethyl acetate and hexane (5:95) as eluent
to afford 5 as a colourless oil (110.84 mg, 58% yield). The
geometry of the newly installed double bond was confirmed
using a homo-decoupling experiment (see Figure S8 in the
Supporting Information) ; 1H-NMR (400 MHz, CDCl3), δ 7.67-
7.61 (m, 4H), 7.44-7.35 (m, 6H), 6.47 (dd, J = 14.40 Hz, 6.56
Hz, 1H), 5.98 (dd, J = 14.40 Hz, 1.04 Hz, 1H), 5.42-5.28 (m,
2H), 4.14-4.08 (m, 3H), 2.28-2.16 (m, 6H), 1.25 (t, J = 7.12 Hz,
3H), 1.06 (s, 9H); 13C{H}-NMR (100 MHz, CDCl3), δ 173.2,
147.9, 136.0, 133.9, 133.6, 130.4, 129.9, 127.7, 125.4, 75.7,
60.5, 35.2, 34.3, 27.1, 22.9, 19.5, 14.0; HRMS (DART) m/z:
[M+NH4]+ calcd for C27H39IO3SiN 580.1738; found 580.1732;
IR υ = 2958, 2930, 2857, 1734, 1606, 1427, 1362, 1161, 1105,
1076, 941 cm-1.
1
The H-NMR and 13C-NMR data is in accordance with that
previously reported in the literature.26 1H-NMR (400 MHz,
CDCl3), δ 4.27 (m, 2H), 3.19 (m, 2H), 2.18 (m, 2H), 1.12 (t, J =
2.16 Hz, 3H); 13C{H}-NMR (100 MHz, CDCl3), δ 82.6, 80.9,
78.5, 72.8, 51.4, 13.9, 12.4, 9.9.
Step 2: A 100 mL round-bottom flask equipped with a magnetic
stirring bar was charged with the above intermediate alcohol
(1.00 g, 8.19 mmol, 1.0 equiv.) and CBr4 (2.99 g, 9.01 mmol,
1.1 equiv.) in 20 mL of DCM. A solution of PPh3 (2.36 g, 9.01
mmol, 1.1 equiv.) in 10 mL of DCM was then added dropwise
to the reaction mixture. After stirring overnight at room
temperature, the solvent was removed by using a rotary
evaporator, and the residual mixture was purified directly using
flash chromatography with ethyl acetate and hexane (5:95) as
eluent to afford 17 as a pale-yellow oil (1.27 g, 84% yield). The
1H-NMR and 13C-NMR data is in accordance with that
previously reported in the literature.27 1H-NMR (600 MHz,
CDCl3), δ 3.92 (m, 2H), 3.21 (m, 2H), 2.17 (m, 2H), 1.12 (td, J
= 7.44 Hz, 1.67 Hz, 3H); 13C{H}-NMR (150 MHz, CDCl3), δ
82.8, 82.2, 75.4, 72.3, 14.9, 13.9, 12.5, 12.5, 10.2; IR υ = 2976,
2936, 2232, 1713, 1691, 1592, 1453, 1411, 1320, 1209, 1124
cm-1.
Trimethyl(trideca-1,4,7,10-tetrayn-1-yl)silane (19). In a 200
mL round-bottom flask, bromide 17 (1.29 g, 6.87 mmol, 1.0
equiv.) was dissolved in 60 mL of DMF. To this solution was
added CuI (1.99 g, 10.46 mmol, 1.5 equiv.), K2CO3 (1.93 g,
13.94 mmol, 2.0 equiv.), and NaI (1.57 g, 10.46 mmol, 1.5
equiv.). The reaction mixture was cooled to 0 C and alkyne 18
(1.23 g, 9.06 mmol, 1.3 equiv.) was added dropwise. The
reaction mixture was brought to room temperature and stirred
overnight. Next, the reaction mixture was cooled to 0 C, 20 mL
of cold water and 150 mL of saturated aq. NH4Cl were added
sequentially. The mixture was extracted with Et2O (3 x 50 mL).
The organic layers were combined, washed with brine, dried
over MgSO4, filtered and concentrated under reduced pressure
to afford 19 as a red oil (1.43 g, 85% yield). The compound 19
Pent-2-yn-1-yl 4-methylbenzenesulfonate (15) In a 100 mL
round-bottom flask, 2-pentynol (1.00 g, 11.89 mmol, 1.0
equiv.) was dissolved in 25 mL Et2O. Tosyl chloride (2.83 g,
14.86 mmol, 1.25 equiv.) and potassium hydroxide (3.34 g,
59.45 mmol, 5.0 equiv.) were then added into the solution. After
the mixture was stirred at room temperature overnight, 20 mL
Et2O was added into the reaction mixture. The reaction mixture
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The Journal of Organic Chemistry
Page 6 of 10
was unstable on silica gel and therefore used in the next step
by flash chromatography using ethyl acetate and hexane (5:95)
immediately without further purification. Crude 1H-NMR (300
MHz, CDCl3), δ 3.22 - 3.13 (m, 6H), 2.22 – 2.13 (m, 2H), 1.12
(t, J = 7.50 Hz, 3H), 0.9 (s, 9H).
as eluent to afford 20 as a colourless oil (69.9 mg, 96% yield);
1H-NMR (400 MHz, CDCl3), δ 7.68 – 7.61 (m, 4H), 7.43 – 7.34
(m, 6H), 6.01 (dd, J = 15.84 Hz, 5.74 Hz, 1H), 5.54 (dd, J =
15.83 Hz, 1.51 Hz, 1H), 5.50 – 5.26 (m, 8H), 4.20 (m, 1H), 4.10
(q, J = 7.13 Hz, 2H), 3.09 – 3.08 (m, 2H), 2.86 – 2.80 (m, 4H),
2.28 – 2.04 (m, 8H), 1.24 (t, J = 7.13 Hz, 3H), 1.06 (s, 9H), 0.98
(t, J = 7.53 Hz, 3H); 13C{H}-NMR (150 MHz, CDCl3), δ 173.
2, 144.0, 136.0, 136.0, 134.3, 133.8, 132.3, 130.0, 129.8, 129.8,
129.1, 127.7, 127.7, 127.4, 127.1, 125.8, 124.7, 110.0, 88.6,
78.7, 73.2, 60.4, 35.6, 34.2, 29.9, 27.2, 25.7, 22.9, 20.7, 18.5,
18.1, 14.4; HRMS (DART) m/z: [M+H]+ calcd for C40H53O3Si
609.3758; found 609.3761; IR υ = 3013, 2960, 2857, 1736,
1471, 1427, 1369, 1157, 1110, 1070, 955 cm-1.
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(4Z,7Z,10Z)-trideca-4,7,10-trien-1-yne (6). Step 1: A 125 mL
round-bottomed flask equipped with a magnetic stirring bar was
charged with Ni(OAc)2.4H2O (301.1 mg, 1.21 mmol, 0.20
equiv.). The flask was purged with H2 gas three times by
vacuum-H2 cycle and 20 mL of 95% EtOH (all EtOH was
freshly degassed by three freeze-pump-thaw cycles) was
introduced into the flask under constant supply of H2 gas. A
solution of NaBH4 (45.77 mg, 1.21 mmol, 0.20 equiv.) in 5 mL
of 95% EtOH was added dropwise (reaction mixture turns
black). After 30 minutes of stirring, ethylenediamine (109.4 mg,
1.82 mmol, 0.40 equiv.) in 1 mL of 95% EtOH was then added
into the reaction mixture and a solution of compound 19 (1.46
g, 6.07 mmol, 1.0 equiv.) in 2 mL of 95% EtOH was introduced
into the reaction mixture dropwise. The reaction flask was then
sealed and equipped with an H2 balloon and stirred overnight.
The reaction mixture was filtered through a pad of Celite and
rinsed with 20 mL of ether. The filtrate was concentrated under
reduced pressure, and purified by flash chromatography with
pentane as eluent to afford the skipped alkene intermediate (not
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()7-HDHA (2). Step 1: Alkylne Semi-reduction 3.0 g of Zn
dust was purified by washing sequentially with 1 M HCl twice,
distilled water, EtOH, and Et2O (the wash solutions were
removed each time by filtration). The purified zinc dust was
transferred into a 100 mL round-bottomed flask that was
equipped with a magnetic stirring bar. Distilled water (30 ml)
was added, and 300 mg of Cu(OAc)2·H2O was added to the
vigorously stirred suspension. After 15 minutes of stirring, 300
mg of AgNO3 was added to the suspension. After another 30
minutes stirring, the water was filtered off under strict argon
atmosphere, the wet Zn(Cu/Ag) cake was washed sequentially
with acetone and Et2O, the solvents were removed each time by
filtration. The fresh Zn(Cu/Ag) was then dried under vacuum.
1
shown) as a colourless oil (388.50 mg, 26% yield); H-NMR
(600 MHz, CDCl3), δ 5.48-5.29 (m, 6H), 3.02 (d, J = 4.74 Hz,
2H), 2.84-2.79 (m, 4H), 2.06 (m, 2H), 0.98 (t, J = 7.56 Hz, 3H),
0.15 (s, 9H); 13C{H}-NMR (150 MHz, CDCl3), δ 132.3, 130.0,
129.1, 127.4, 127.1, 124.4, 105.2, 84.5, 25.7, 25.7, 20.7, 18.6,
14.4, 0.2; the intact protonated molecular ion (M+H+) is not
observed by DART, nor is the molecular ion (M+) observed in
the EI spectrum, thus no HRMS data is obtained for this
compound; IR υ = 3012, 2962, 2176, 1442, 1249, 1028, 841
cm-1.
The fresh Zn(Cu/Ag) was then transferred to a 100 mL argon-
filled round-bottom flask and 50 mL of MeOH: H2O (1:1) was
added into the flask. A solution of compound 20 (150.0 mg,
0.25 mmol) in 1.5 mL of dioxane was added to the suspension
of Zn(Cu/Ag). The reaction mixture was stirred at 45 C (oil
bath heating) for 6 hours, then 0.2 mL of 1 M HCl was added
to the reaction mixture. After stirring overnight, another 0.2 mL
of 1 M HCl was added to the reaction as progress of the reaction
was found to have stalled (Aliquots were taken to check the
consumption of 20 by 1H-NMR). Until the reaction reached full
conversion, 0.2 mL of 1 M HCl was added to the reaction
mixture every 16 to 24 hours. After completion, the reaction
mixture was filtered through Celite, the cake was thoroughly
rinsed with 50 mL of MeOH and then 100 mL of Et2O. The
filtrate was concentrated under reduced pressure until most of
the organic solvent was removed. The residual mixture was
diluted with 100 mL of Et2O, the organic layer was washed with
water, then brine (50 mL x 2), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residual oil was
purified by flash chromatography using ethyl acetate and
hexane (5:95) as eluent to afford cis-olefin intermediate (not
Step 2: A 25 mL round-bottomed flask equipped with a
magnetic stirring bar was charged with 5 mL of THF/MeOH
(1:1), the skipped alkene intermediate obtained from step 1
(100.0 mg, 0.41 mmol, 1.0 equiv.), and K2CO3 (170.0 mg, 1.23
mmol, 3.0 equiv.). After the reaction mixture was stirred at
room temperature for three hours, it was filtered through a pad
of Celite. The filtrate was concentrated under reduced pressure,
and purified directly by flash chromatography with pentane as
eluent to afford 6 as a colourless oil (48.8 mg, 68% yield). 1H-
NMR (600 MHz, CDCl3), δ 5.55-5.30 (m, 6H), 3.00 (m, 2H),
2.88-2.82 (m, 4H), 2.10 (pentet, J = 7.57 Hz, 2H), 2.01 (t, J =
2.72 Hz, 1H), 1.00 (t, J = 7.54 Hz, 3H); 13C{H}-NMR (150
MHz, CDCl3), δ 132.4, 130.4, 129.3, 127.3, 127.1, 124.2, 82.8,
68.3, 25.8, 20.8, 17.1, 14.5; HRMS (DART) m/z: [M+H]+ calcd
for C13H19 175.1481; found 175.1480; IR υ = 3307, 3012, 2963,
2930, 2119, 1651, 1461, 1403, 1393, 1260, 1079, 1018, 910 cm-
1
shown) as a colourless oil (154.1 mg, 100% yield). H-NMR
1
.
(600 MHz, CDCl3), δ 7.69 – 7.64 (m, 4H), 7.42 – 7.33 (m, 6H),
6.22 (dd, J = 15.11 Hz, 11.09 Hz, 1H), 5.89 (t, J = 10.82 Hz,
1H), 5.61 (dd, J = 15.12 Hz, 6.54 Hz, 1H), 5.41 – 5.28 (m, 9H),
4.23 (m, 1H), 4.11 (q, J = 7.14 Hz, 2H), 2.83 – 2.78 (m, 6H),
2.32 – 2.28 (m, 1H), 2.25 – 2.22 (m, 3H), 2.20 – 2.16 (m, 2H),
2.05 (m, 2H), 1.24 (t, J = 7.22 Hz, 3H), 1.07 (s, 9H), 0.97 (t, J
= 7.53 Hz, 3H); 13C{H}-NMR (150 MHz, CDCl3), δ 173. 2,
136.1, 136.1, 135.9, 134.5, 134.2, 132.2, 129.7, 129.7, 129.6,
128.8, 128.6, 128.3, 127.9, 127.6, 127.5, 127.2, 126.4, 125.4,
73.9, 60.4, 36.1, 34.3, 29.8, 27.2, 26.1, 25.8, 25.7, 23.0, 20.7,
19.5, 14.4; HRMS (DART) m/z: [M+H]+ calcd for C40H55O3Si
611.3915; found 611.3918; IR crystal υ = 3070, 3012, 2960,
2930, 2856, 1736, 1462, 1390, 1175, 1157, 1110 cm-1.
Ethyl (4Z,8E,13Z,16Z,19Z)-7-((tert-butyldiphenylsilyl)oxy)
docosa-4,8,13,16,19-pentaen-10-ynoate (20). To a 10 mL
round-bottomed flask equipped with a magnetic stirring bar was
added 2 mL of freshly-distilled diisopropylamine, compound 5
(67.51 mg, 0.12 mmol, 1.0 equiv.) and Pd(PPh3)4 (13.87 mg,
0.012 mmol, 0.10 equiv.). The resulting solution was stirred for
30 minutes, then CuI (11.43 mg, 0.06 mmol, 0.50 equiv.) and 6
(30.0 mg, 0.16 mmol, 1.3 equiv.) were added. After stirring
overnight at room temperature, the reaction mixture was diluted
with Et2O, followed by addition of saturated aq. NH4Cl. The
aqueous layer was extracted with Et2O (15 mL x 3). The organic
layers were combined, washed with 25 mL of brine, dried over
MgSO4, filtered, and concentrated. The residual oil was purified
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The Journal of Organic Chemistry
Step 2: TBAF Deprotection A 25 mL round-bottom flask DCM (12 mL) was added to the reaction mixture via syringe
1
equipped with a magnetic stirring bar was charged with the
above cis-olefin intermediate (130.0 mg, 0.21 mmol, 1.0
equiv.) in 10 mL of THF. A solution of TBAF (1M in THF, 0.24
mL, 0.23 mmol, 1.1 equiv.) was added to the reaction mixture
dropwise and stirred at room temperature overnight. Next, the
reaction mixture was quenched by the addition of water, the
aqueous layer was separated and extracted with ethyl acetate
(25 mL x 3). The organic phase was then washed with 25 mL
of brine, and dried over MgSO4, filtered, and concentrated
under reduced pressure. The residual oil was purified by flash
chromatography using ethyl acetate and hexane (15:85) as
eluent to afford intermediate alcohol (not shown) as a colourless
oil (61.4 mg, 78% yield); 1H-NMR (700 MHz, CDCl3), δ 6.56
(dd, J = 15.07 Hz, 11.23 Hz, 1H), 6.02 – 5.99 (m, 1H), 5.73 (dd,
J = 14.71 Hz, 6.44 Hz, 1H), 5.55 – 5.46 (m, 2H), 5.43 – 5.36
(m, 6H), 5.34 – 5.30 (m, 1H), 4.24 (m, 1H), 4.13 (q, J = 7.21
Hz, 2H), 2.97 (m, 2H), 2.85 (m, 2H), 2.81 (m, 2H), 2.42 – 2.33
(m, 6H), 2.08 (m, 2H), 1.25 (t, J = 7.03 Hz, 3H), 0.98 (t, J = 7.54
Hz, 3H); 13C{H}-NMR (150 MHz, CDCl3), δ 173.4, 135.9,
132.2, 131.2, 130.5, 128.8, 128.2, 127.9, 127.8, 127.2, 126.3,
125.6, 72.0, 60.6, 35.6, 34.1, 26.3, 25.8, 25.7, 23.0, 20.7, 14.4,
14.4; HRMS (DART) m/z: [M+NH4]+ calcd for C24H40O3N
390.3002; found 390.3002; IR υ = 3433, 2968, 2942, 2252,
1735, 1647, 1446, 1418, 1375, 1180, 1038, 918 cm-1.
pump over 30 min. After 30 min of stirring at –78 C the
reaction was quenched by the dropwise addition of H2O (50 ml).
The flask was removed from the cooling bath and the system
was allowed to warm to 23 C while the mixture was rapidly
stirring. The biphasic mixture was transferred to a separatory
funnel and the layers were separated. The aqueous layer was
extracted with DCM (2 × 50 mL). The combined organic layers
were washed with brine (2 × 20 mL) and then dried over
Na2SO4. The dried solution was filtered and the filtrate was
concentrated. The crude residue was purified by flash
chromatography (silica gel, eluent: EtOAc:hexanes = 1 : 9) to
afford β-hydroxyl amide 23 (2.23 g, 68%) as a yellow solid.
(The dr ratio was found to be 9:1 in favour of desired product
23 from crude 1H NMR. The minor isomer was separated using
gravity column chromatography using EtOAc:hexanes = 10:90
to ensure proper separation. 1H NMR (400 MHz, CDCl3) δ 6.62
(dd, J = 14.5, 5.3 Hz, 1H), 6.48 (dd, J = 14.5, 1.4 Hz, 1H), 5.14
(ddd, J = 7.7, 6.3, 1.1 Hz, 1H), 4.70–4.56 (m, 1H), 3.68 (dd, J
= 17.6, 3.1 Hz, 1H), 3.54 (dd, J = 11.5, 8.0 Hz, 1H), 3.29 (dd, J
= 17.6, 8.6 Hz, 1H), 3.05 (dd, J = 11.5, 1.1 Hz, 2H), 2.35 (dq, J
= 13.6, 6.8 Hz, 1H), 1.07 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 7.0
Hz, 3H); 13C{H}-NMR (101 MHz, CDCl3) δ 203.2, 171.9,
145.9, 78.4, 71.5, 70.6, 44.4, 30.9, 30.9, 19.2, 17.9; HRMS
(ESI) m/z: [M+H]+ Calcd for C11H17INO2S2 385.9740; found
385.9732; IR υ = 2960, 2925, 1697, 1684, 1538, 1387, 1278,
1254, 1169, 1092, 1041 cm-1.
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Step 3: Ester Hydrolysis In 10 mL round-bottomed flask
equipped with magnetic stir bar, the alcohol intermediate from
Step 2 (41.0 mg, 0.11 mmol, 1.0 equiv.) was dissolved in 3 mL
of H2O: THF (1:1) and LiOH.H2O (39.5mg, 1.65 mmol, 15.0
equiv.) was then added to the flask. The reaction was stirred at
room temperature overnight. The reaction mixture was then
cooled to 0 C and acidified by dropwise addition of 1 M HCl
until pH = 5. The aqueous layer was then extracted with ethyl
acetate (3 x 10 mL), and the combined organics were then
washed over 15 mL of brine, and dried over MgSO4, filtered,
and concentrated. The residual oil was purified by flash
chromatography using ethyl acetate and hexane (50:50) as
eluent to afford ()7–HDHA (2) as a colourless oil (30.4 mg,
80% yield); 1H-NMR (700 MHz, CDCl3), δ 6.55 (dd, J = 15.13
Hz, 11.06 Hz, 1H), 6.00 (t, J = 10.86 Hz, 1H), 5.72 (dd, J =
15.16 Hz, 6.41 Hz, 1H), 5.53 (m, 1H), 5.48 (m, 1H), 5.43 – 5.35
(m, 6H), 5.32 (m, 1H), 4.25 (m, 1H), 2.97 (t, J = 6.93 Hz, 2H),
2.85 (t, J = 6.41 Hz, 2H), 2.81 (t, J = 6.51 Hz, 2H), 2.45 – 2.33
(m, 6H), 2.09 – 2.06 (m, 2H), 0.97 (t, J = 7.84 Hz, 3H), the
carboxylic acid proton was not observed in this spectrum;
13C{H}-NMR (176 MHz, CDCl3), δ 177.7, 135.6, 132.2, 130.9,
130.6, 128.8, 128.1, 127.9, 127.7, 127.1, 126.5, 125.7, 72.1,
35.5, 33.6, 26.2, 25.8, 25.7, 22.7, 20.7, 14.4; HRMS (DART)
m/z: [M-H]-calcd for C22H31O3 343.2268; found 343.2278; IR υ
= 3617, 3005, 2943, 2310, 2292, 1733, 1652, 1437, 1418, 1375,
1038, 918 cm-1.
(S,E)-5-iodo-1-((R)-4-isopropyl-2-thioxothiazolidin-3-yl)-3-
((triisopropylsilyl)oxy)pent-4-en-1-one (24). A solution of
alcohol 23 (1.0 g, 2.6 mmol, 1.0 equiv.) in anhydrous DCM (10
mL) was cooled to 0 C, which was followed by dropwise
addition of 2, 6-lutidine (0.52 mL, 5.2 mmol, 2.0 equiv.) and
then TIPSOTf (0.76 mL, 3.9 mmol, 1.5 equiv.). After stirring
for two hours, the reaction mixture was quenched with 25 mL
of cold water at 0 C and extracted with dichloromethane (3 x
25 mL). The organic layer was washed with water (2 x 25 mL),
dried over anhydrous Na2SO4 and concentrated. The crude
product was purified by silica gel column chromatography (8%
ethyl acetate/hexanes) to give 1.4 g of desired product 24 as a
colourless oil in quantitative yield. 1H-NMR (400 MHz,
CDCl3) δ 6.66 (dd, J = 14.5, 6.8 Hz, 1H), 6.38 (d, J = 14.5 Hz,
1H), 5.07 (ddd, J = 7.8, 6.2, 1.3 Hz, 1H), 4.81 (q, J = 6.5 Hz,
1H), 3.62 (dd, J = 16.9, 6.4 Hz, 1H), 3.52 – 3.35 (m, 2H), 3.02
(dd, J = 11.5, 1.3 Hz, 1H), 2.41 – 2.28 (m, J = 6.8 Hz, 1H), 1.11
– 0.99 (m, 24H), 0.97 (d, J = 7.0 Hz, 3H); 13C{H}-NMR (101
MHz, CDCl3) δ 202.9, 170.7, 148.2, 77.8, 72.4, 71.7, 46.3, 30.9,
30.8, 19.3, 18.2, 18.1, 17.9, 12.5; HRMS (ESI) m/z: [M+H]+
Calcd for C20H37INO2S2Si 542.1074; found 542.1064; IR υ =
2960, 2942, 2865, 1696, 1607, 1464, 1361, 1254, 1173, 1153,
1093, 1038, 882 cm-1.
(S,E)-5-iodo-3-((triisopropylsilyl)oxy)pent-4-enal (25). Ester
24 (1.4 g, 2.58 mmol, 1.0 equiv.) was dissolved in 50 mL of
DCM and cooled to 0 C. To this solution was added 2.84 mL
(2.84 mmol, 1.1 equiv.) of DIBAL (1M in DCM) dropwise, and
the reaction was stirred for 0.5 h at 0 C. The reaction was
quenched by the addition of saturated solution of K-Na tartrate
in water (20 mL) at 0 C and kept standing for 1 h to separate
the two layers. After the layers were separated, the aqueous
layer was washed with DCM (2 x 30 mL) and the combined
organic layers were dried over Na2SO4 and concentrated in
vacuo and purified by chromatography (15% ethyl
acetate/hexanes) over silica gel to afford 869 mg of 25 as
colorless oil in 88% yield. 1H-NMR (400 MHz, CDCl3) δ 9.79
(S,E)-3-hydroxy-5-iodo-1-((R)-4-isopropyl-2-
thioxothiazolidin-3-yl)pent-4-en-1-one (23). To a 100 mL
round-bottom flask containing 21 (1.89 g, 9.31 mmol, 1.1
equiv.) was added 36 mL of DCM, the resulting yellow solution
was cooled to –78 C. TiCl4 (1.00 M in DCM, 10.2 mL, 10.2
mmol, 1.2 equiv.) was added dropwise to the reaction mixture,
resulting in a deep yellow solution. After five minutes of
stirring, DIPEA (1.77 mL, 10.2 mmol, and 1.2 equiv.) was
added carefully using a syringe pump over 30 min, and the
resulting deep red solution was stirred for two hours at –78 C.
A solution of aldehyde 22 (1.54 g, 8.46 mmol, 1.0 equiv.) in
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(t, J = 2.1 Hz, 1H), 6.63 (dd, J = 14.5, 6.2 Hz, 1H), 6.42 (dd, J
2052, 1734, 1698, 1647, 1558, 1504, 1457, 1437, 1082, 1042
cm-1.
1
2
3
4
5
6
7
8
= 14.5, 1.2 Hz, 1H), 4.73 (qd, J = 5.9, 1.2 Hz, 1H), 2.69 – 2.60
(m, 2H), 1.04 (d, J = 4.4 Hz, 21H); 13C{H}-NMR (101 MHz,
CDCl3) δ 200.6, 147.6, 77.8, 71.3, 51.1, 18.1, 18.1, 12.4;
HRMS (ESI) m/z: [M+Na]+ Calcd for C14H27IO2SiNa
405.0723; found 405.0717; IR υ = 2942, 2865, 2724, 1724,
1607, 1462, 1164, 1106, 947 cm-1.
Ethyl (S,4Z,8E,10Z,13Z,16Z,19Z)-7-((triisopropylsilyl)oxy)
docosa-4,8,10,13,16,19-hexaenoate (28). 3.0 g of Zn dust was
purified by washing sequentially with 1 M HCl twice, distilled
water, EtOH, and Et2O (the wash solutions were removed each
time by filtration). The purified zinc dust was transferred into a
100 mL round-bottomed flask that was equipped with a
magnetic stirring bar and filled with argon. Distilled water (30
mL) was added, and 300 mg of Cu(OAc)2·H2O was added to
the vigorously stirred suspension. After 15 minutes of stirring,
300 mg of AgNO3 was added to the suspension. After another
30 minutes stirring, the water was filtered off under strict argon
atmosphere, the wet Zn(Cu/Ag) cake was washed sequentially
with acetone and Et2O, the solvents were removed each time by
filtration. The fresh Zn(Cu/Ag) was then dried under vacuum.
Ethyl (S,4Z,8E)-9-iodo-7-((triisopropylsilyl)oxy)nona-4,8-
dienoate (26). A 25 mL round-bottom oven-dried flask was
equipped with a magnetic stirring bar and charged with Wittig
salt 14 (1.23 g, 2.62 mmol, 2.0 equiv.) in 10 mL of THF was
introduced into the flask, which was then cooled to -78 C. A
solution of KHMDS (0.5 M in toluene, 3.92 mL, 1.96 mmol,
1.5 equiv.) was added dropwise into the flask, resulting in a
yellow suspension. After 1 hour of stirring at -78 C, compound
25 (500.0 mg, 1.31 mmol, 1.0 equiv.) in 10 mL of THF was
added dropwise (very slowly) to the reaction mixture. After one
hour stirring at -78 C, the reaction was quenched by addition
of saturated aq. NH4Cl solution (20 mL) and diluted with Et2O
(25 mL). The organic phase was separated, and the aqueous
phase was extracted with ether (25 mL x 2). The combined
organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residual
oil was purified by flash chromatography using ethyl acetate
and hexane (5:95) as eluent to afford the major isomer 26 as a
colourless oil (452.0 mg, 72% yield). The identity of compound
26 was assigned by analogy to compound 5, which differs only
in the nature of the silyl protecting group. 1H-NMR (400 MHz,
CDCl3) δ 6.52 (dd, J = 14.4, 6.4 Hz, 1H), 6.21 (dd, J = 14.4, 1.1
Hz, 1H), 5.49 – 5.35 (m, 2H), 4.28 – 4.18 (m, 1H), 4.12 (q, J =
7.1 Hz, 2H), 2.40 – 2.23 (m, 6H), 1.25 (t, J = 7.1 Hz, 3H), 1.04
(d, J = 3.0 Hz, 21H); 13C{H}-NMR (101 MHz, CDCl3) δ 173.2,
148.9, 130.3, 125.6, 76.2, 75.2, 60.5, 35.9, 34.3, 23.2, 18.2,
18.1, 14.4, 12.5; HRMS (ESI) m/z: [M+H]+ Calcd for
C20H38IO3Si 481.1619; found 481.1629; IR υ = 2942, 2865,
1735, 1606, 1462, 1370, 1248, 1162, 1087, 1064, 943 cm-1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The fresh Zn(Cu/Ag) was then transferred to a 100 mL argon-
filled round-bottom flask. 50 mL of MeOH: H2O (1:1) was
added into the flask. Compound 27 (150.0 mg, 0.25 mmol) in
1.5 mL of dioxane was added to the suspension of Zn(Cu/Ag).
The reaction mixture was stirred at 45 C (oil bath heating) for
six hours, then 0.2 mL of 1 M HCl was added to the reaction
mixture. After stirring overnight, another 0.2 mL of 1 M HCl
was added to the reaction. Aliquots were taken to check the
consumption of 27 by 1H-NMR. Until the reaction reached full
conversion, 0.2 mL of 1 M HCl was added to the reaction
mixture every 16 to 24 hours. After completion, the reaction
mixture was filtered through Celite, the cake was thoroughly
rinsed with 50 mL of MeOH and then 50 mL of Et2O. The
filtrate was concentrated under reduced pressure until most of
the organic solvent was removed. The residual mixture was
diluted with Et2O, the organic layer was washed with water,
then brine (25 mL x 2), dried over MgSO4, filtered and
concentrated under reduced pressure. The residual oil was
purified by flash chromatography using ethyl acetate and
hexane (5:95) as eluent to afford 28 as a colourless oil (124.0
mg, 82% yield). 1H-NMR (400 MHz, CDCl3) δ 6.52 – 6.40 (m,
1H), 6.06 – 5.92 (m, 1H), 5.66 (dd, J = 15.2, 6.4 Hz, 1H), 5.49
– 5.28 (m, 9H), 4.33 (q, J = 6.2 Hz, 1H), 4.12 (q, J = 7.1 Hz,
2H), 2.95 (ddd, J = 7.5, 4.8, 2.5 Hz, 2H), 2.88 – 2.74 (m, 4H),
2.42– 2.25 (m, 6H), 2.13–2.07 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H),
1.06 (q, J = 2.2 Hz, 21H), 0.97 (t, J = 7.5 Hz, 3H); 13C{H}-
NMR (101 MHz, CDCl3) δ 173.1, 136.9, 132.0, 129.4, 129.4,
128.6, 128.5, 128.2, 127.8, 127.0, 126.5, 124.5, 72.9, 60.3, 36.6,
34.2, 26.0, 25.6, 25.5, 23.1, 20.6, 18.1, 18.1, 14.3, 12.4; HRMS
(ESI) m/z: [M+H]+ Calcd for C33H57IO3Si 529.4067; found
529.4071; IR υ = 3031, 2925, 2865, 1738, 1699, 1647, 1558,
1463, 1372, 1246, 1158, 1084, 1063 cm-1.
Ethyl
(S,4Z,8E,14Z,17Z,20Z)-7-
((triisopropylsilyl)oxy)tricosa-4,8,14,17,20-pentaen-10-
ynoate (27). A 10 mL round-bottomed flask was equipped with
a magnetic stir bar and charged with 2 mL of freshly-distilled
diisopropylamine, 26 (250.0 mg, 0.52 mmol, 1.0 equiv.) and
Pd(PPh3)4 (60.1 mg, 0.052 mmol, 0.10 equiv.) were added to
the flask. The resulting solution was stirred for 30 minutes.
Next, CuI (49.5 mg, 0.26 mmol, 50 mol %) and 6 (117.5 mg,
0.62 mmol, 1.2 equiv.) were added. After stirring overnight at
room temperature, the mixture was diluted with Et2O, followed
by addition of saturated aq. NH4Cl. The aqueous layer was
extracted with Et2O (20 mL x 3). The organic layers were
combined, washed with brine, dried over MgSO4, filtered, and
concentrated. The residual oil was purified by flash
chromatography using ethyl acetate and hexane (5:95) as eluent
to afford 27 as a colourless oil (234 mg, 83% yield). 1H-NMR
(400 MHz, CDCl3) δ 6.01 (dd, J = 15.9, 5.9 Hz, 1H), 5.62 (dq,
J = 15.9, 2.0 Hz, 1H), 5.51 – 5.24 (m, 8H), 4.34 – 4.22 (m, 1H),
4.12 (q, J = 7.1 Hz, 2H), 3.08 (dd, J = 5.2, 2.3 Hz, 2H), 2.81 (dt,
J = 13.5, 6.1 Hz, 4H), 2.42 – 2.22 (m, 6H), 2.13 – 2.01 (m, 2H),
1.24 (t, J = 7.1 Hz, 3H), 1.04 (d, J = 2.9 Hz, 21H), 0.97 (t, J =
7.5 Hz, 3H); 13C{H}-NMR (101 MHz, CDCl3) δ 173.3, 145.0,
132.3, 129.8, 129.8, 129.1, 127.4, 127.1, 126.1, 124.7, 109.6,
88.5, 78.7, 72.7, 60.4, 36.3, 34.33, 25.7, 23.2, 20.7, 18.2, 18.1,
14.4, 12.5; HRMS (ESI) m/z: [M+H]+ Calcd for C33H55O3Si
527.3907; found 527.3915; IR υ = 2957, 2925, 2854, 2225,
Ethyl (S,4Z,8E,10Z,13Z,16Z,19Z)-7-hydroxydocosa-4,8,10,
13,16,19-hexaenoate (29). A 25 mL round-bottom flask was
equipped with a magnetic stirring bar, and charged with 28
(130.0 mg, 0.21 mmol, 1.0 equiv.) in 10 mL of THF, TBAF (1M
in THF, 0.24 mL, 0.23 mmol, 1.1 equiv.) was then added to the
solution drop-wise. The mixture was stirred at 0 C for three
hours. Next, the reaction was quenched by the addition of water,
the aqueous layer was separated and extracted with ethyl acetate
(3 x 20 mL). The organic phase was then washed over brine,
and dried over MgSO4, filtered, and concentrated under reduced
pressure. The residual oil was purified by flash chromatography
using ethyl acetate and hexane (15:85) as eluent to afford 29 as
1
a colourless oil (77.8 mg, 78% yield). H-NMR (400 MHz,
CDCl3) δ 6.56 (dd, J = 15.2, 11.0 Hz, 1H), 6.02–5.99 (m, 1H),
5.73 (dd, J = 15.2, 6.3 Hz, 1H), 5.58 – 5.27 (m, 8H), 4.25–4.20
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The Journal of Organic Chemistry
We thank the Natural Sciences and Engineering Research Council
(m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.98–2.95 (m, 2H), 2.83 (dt,
1
2
3
4
5
6
7
8
of Canada for support of this work through a Discovery grant. We
also thank Dr. Howard Hunter of York University for assistance
with NMR experiments.
J = 16.1, 6.1 Hz, 4H), 2.47 – 2.27 (m, 6H), 2.11–2.03 (m, 2H),
1.94 (d, J = 4.1 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.97 (t, J =
7.5 Hz, 3H); 13C{H}-NMR (101 MHz, CDCl3) δ 173.4, 135.9,
135.7, 132.2, 131.2, 130.5, 130.4, 128.8, 128.2, 127.9, 127.9,
127.8, 127.2, 126.3, 125.6, 77.4, 77.1, 72.0, 60.6, 35.6, 34.1,
26.3, 26.2, 25.8, 25.7, 23.0, 20.7, 14.4, 14.4; HRMS (ESI) m/z:
[M+H]+ Calcd for C24H37O3 373.2727: found 373.2737; IR υ
=3433, 2969, 2942, 2251, 1735, 1647, 1446, 1418, 1375, 1180,
1038 cm-1.
REFERENCES
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7(S)-HDHA (2). In a 10 mL round-bottomed flask, 29 (70.0
mg, 0.19 mmol, 1.0 equiv.) was dissolved in 3 mL of H2O:THF
(1:1), LiOH.H2O (39.5 mg, 0.94 mmol, 5.0 equiv.) was then
added to the flask. The reaction was stirred at room temperature
for six hours. The reaction mixture was then cooled to 0 C, 1
M HCl was then added dropwise until the aqueous layer was
acidified to pH around 5. The aqueous layer was extracted with
ethyl acetate (15 mL x 4). The organic phase was then washed
over brine, and dried over MgSO4, filtered and concentrated.
The residual oil was purified by flash chromatography using
ethyl acetate and hexane (50:50) as eluent to afford 7(S)–HDHA
(2) as colourless oil (45.3 mg, 70% yield). Chiral HPLC
indicates that only 7(S)-HDHA is present in the sample without
the other enantiomer. The chiral HPLC was performed on a
Chiralpak-IA column (Amylose tris 3,5-dimethylphenyl-
carbamate, 250 × 4.6 mm, Chiral Technologies Europe) and
eluted with an isocratic elution of 45% mobile phase A (H2O
containing 0.1% formic acid), 55% mobile phase B (acetonitrile
containing 0.1% formic acid). The temperatures of the column
and sample compartments were maintained at 20 °C and 4 °C,
respectively. Data were acquired at a wavelength of 230 nm
using a DAD detector. 1H-NMR (400 MHz, CDCl3) δ 6.55 (dd,
J = 15.2, 11.0 Hz, 1H), 6.03 – 5.97 (m, 1H), 5.72 (dd, J = 15.2,
6.4 Hz, 1H), 5.55 – 5.27 (m, 8H), 4.26-4.19 (m, 1H), 2.98 (t, J
= 6.7 Hz, 2H), 2.98 (t, J = 6.7 Hz, 2H), 2.93 – 2.80 (m, 4H),
2.43 – 2.34 (m, 6H), 2.09 – 2.06 (m, 2H), 0.98 (t, J = 7.5 Hz,
3H); 13C{H}-NMR (101 MHz, CDCl3) δ 177.3, 135.7, 132.3,
130.8, 130.6, 128.8, 128.1, 127.9, 127.7, 127.2, 126.6, 125.7,
72.1, 35.5, 33.5, 26.3, 25.8, 25.7, 22.7, 20.7, 14.4; HRMS (ESI)
m/z: [M+Na]+ Calcd for C22H32O3Na 367.2234; found
367.2244; IR υ = 3617, 3005, 2943, 2310, 2292, 1733, 1652,
1437, 1418, 1375, 1038, 918 cm-1.
10
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
COSY and HMBC Correlation tables of (±) 7-HDHA, spectral data
of all synthesized compounds, and chiral HPLC data of 7(S)-
HDHA and 7(R)-HDHA.
AUTHOR INFORMATION
Corresponding Author
* aorellan@yorku.ca.
ORCID ID
0000-0002-8372-2222
ACKNOWLEDGMENT
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Page 10 of 10
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