Total Synthesis of Four Stereoisomers of (4Z,7Z,10Z,12E,16Z,18E)-14,20-Dihydroxy-4,7,10,12,16,18-docosahexaenoic Acid and Their Anti-inflammatory Activities

Article abstract of DOI:10.1021/acs.joc.5b01461

A novel anti-inflammatory lipid mediator, (4Z,7Z,10Z,12E,14S,16Z,18E,20R)-14,20-dihydroxy-4,7,10,12,16,18-docosahexaenoic acid (1aa), and its three C14,C20 stereoisomers (1ab,ba,bb) were synthesized in a convergent fashion. The carbon backbone of the target compounds was assembled from seven simple fragments by employing two Sonogashira coupling and three S_N2 alkynylation reactions. The thus constructed four internal alkynes were chemoselectively reduced to the corresponding (Z)-alkenes by applying a newly developed stepwise protocol: (i) hydrogenation of the three alkynes using Lindlar catalyst and (ii) formation of the dicobalt hexacarbonyl complex from the remaining alkyne and subsequent reductive decomplexation. The synthetic preparation of the stereochemically defined four isomers 1aa,ab,ba,bb permitted determination of the absolute structure of the isolated natural product to be 1aa. Biological testing of the four synthetic 14,20-dihydroxydocosahexaenoic acids disclosed similar anti-inflammatory activities of the non-natural isomers (1ab,ba,bb) and the natural form (1aa).

Full text of DOI:10.1021/acs.joc.5b01461

Article
pubs.acs.org/joc
Total Synthesis of Four Stereoisomers of
(4Z,7Z,10Z,12E,16Z,18E)‑14,20-Dihydroxy-4,7,10,12,16,18-
docosahexaenoic Acid and Their Anti-inflammatory Activities
Tomomi Goto,†,‡ Daisuke Urabe,† Koji Masuda,†,‡ Yosuke Isobe,†,§ Makoto Arita,†,§
and Masayuki Inoue*,†
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Pharmaceutical Research Center, Shionogi & Co. Ltd., Futaba-cho, Toyonaka, Osaka 561-0825, Japan
§Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa
230-0045, Japan
S
* Supporting Information
ABSTRACT: A novel anti-inflammatory lipid mediator, (4Z,7Z,10Z,12E,14S,16Z,18E,20R)-14,20-dihydroxy-4,7,10,12,16,18-
docosahexaenoic acid (1aa), and its three C14,C20 stereoisomers (1ab,ba,bb) were synthesized in a convergent fashion. The
carbon backbone of the target compounds was assembled from seven simple fragments by employing two Sonogashira coupling
and three SN2 alkynylation reactions. The thus constructed four internal alkynes were chemoselectively reduced to the
corresponding (Z)-alkenes by applying a newly developed stepwise protocol: (i) hydrogenation of the three alkynes using Lindlar
catalyst and (ii) formation of the dicobalt hexacarbonyl complex from the remaining alkyne and subsequent reductive
decomplexation. The synthetic preparation of the stereochemically defined four isomers 1aa,ab,ba,bb permitted determination of
the absolute structure of the isolated natural product to be 1aa. Biological testing of the four synthetic 14,20-
dihydroxydocosahexaenoic acids disclosed similar anti-inflammatory activities of the non-natural isomers (1ab,ba,bb) and the
natural form (1aa).
INTRODUCTION
■
Endogenous lipid mediators control acute or innate inflamma-
tory response toward microorganisms or tissue injury and play
an important role in the active resolution phase of inflammation
for protecting organs from collateral damage.1 Metabolites of
omega-3 polyunsaturated fatty acids (e.g., docosahexaenoic acid
(DHA)) have attracted significant attention as lipid mediators,
as they exhibit in vivo anti-inflammatory activities (Figure 1).2,3
Maresin 14 is a representative lipid mediator, and its intriguing
structural features, such as a (E,E,Z)-triene and two allylic
hydroxy groups, are biosynthetically constructed from DHA.
The structure determination of these biologically important
Figure 1. Structures of DHA and anti-inflammatory active lipid
lipid mediators has been highly challenging. Whereas UV
spectroscopic and LC-MS/MS analyses are effective in
deducing planar structures of lipid mediators, stereochemical
assignments of the double bonds and hydroxy groups by
detailed NMR analyses have been hampered due to the scarce
availability of lipid mediators from natural sources. Accordingly,
practical preparation of all the stereoisomers by stereoselective
total synthesis is necessary in order to establish the absolute
structure of the lipid mediators.5,6
mediators and the possible biosynthetic pathway of maresin 1 and 1
from DHA.
Recently, we identified a novel anti-inflammatory metabolite
of DHA (1; Figure 1), produced by eosinophils during the
resolution phase of a mouse acute inflammation model.7
Received: June 27, 2015
© XXXX American Chemical Society
A
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Biological tests revealed that nanomolar concentrations of 1
inhibited infiltration of polymorphonuclear (PMN) leukocytes
in a zymosan-induced mouse peritonitis model. The planar
the four internal alkynes as surrogates of the requisite (Z)-
alkenes of 1. Compound 2 was dissected into the halves 3 and
4. In the synthetic direction, Sonogashira coupling between
C12−C22 vinyl iodide 3 and the copper alkynide of triyne 4
was envisioned to furnish the carboskeleton of 2. C12−C22
vinyl iodide 3 could be synthesized by SN2 alkynylation of the
lithium alkynide of 5 and TES-protected glycidol 6 and
subsequent vinyl iodide formation with iodoform. The four
stereoisomers 3aa,ab,ba,bb of 3 could be synthesized in
enantiopure form by combining the enantiomeric pairs 5a/5b
and 6a/6b. Chiral 5a/5b was to be prepared through two-
carbon elongation by Sonogashira coupling between 7 and 8
and subsequent asymmetric reduction of the C20-ketone. On
the other hand, achiral triyne 4 could be synthesized from 9 by
sequential SN2 alkynylation of the copper acetylides generated
from 10 and 11.
The synthesis began with preparation of enantiomers 5a,b
from 7 (Scheme 2). Compound 7 was obtained as an
inseparable mixture with 7′ (7:7′ = 3.5:1) by AlCl3-promoted
acylation of 12 with propionyl chloride.8 The mixture was
subjected to Sonogashira coupling using TMS-acetylene 8, CuI,
and Pd(PPh3)4 to produce the C16−C22 carbon chain 13.9
The chiral complex of BH3·SMe2 and (S)-2-butyl-CBS-
oxazaborolidine 14a in turn induced the asymmetric reduction
s t r u c t u r e o f
1 w a s t e n t a t i v e l y a s s i g n e d a s
(4Z,7Z,10Z,12E,16Z,18E)-14,20-dihydroxy-4,7,10,12,16,18-do-
cosahexaenoic acid from UV and LS-MS/MS analysis of the
minute amount of sample available. E regiochemistries at C12
and C18 were also suggested from the biogenetic oxidation
pathway of 1. Additionally, the C14 configuration of 1 was
speculated to be S, because biosynthetic production of both 1
and maresin 1 was shown to involve 12/15-lipoxygenase
(LOX)-promoted oxidation of DHA to 14S-hydroperoxydoco-
sahexaenoic acid.4a,7
We set about unambiguously establishing the absolute
structure of naturally occurring 1 by synthesizing the four
possible stereoisomers at the C14- and C20-hydroxy groups.
Here we report the detailed stereoselective total synthesis of
the four stereoisomers of 1, (14S,20R)-, (14S,20S)-,
(14R,20R)-, and (14R,20S)-14,20-dihydroxydocosahexaenoic
acids (1aa,ab,ba,bb; Scheme 1). HPLC analysis of the natural
Scheme 1. Synthetic Plan of the Four Stereoisomers of 1
Scheme 2. Synthesis of C16−C22 Fragments 5a,b through
Asymmetric Reduction and Determination of the Absolute
a
Stereochemistry of the C20 Position
and synthetic compounds established the absolute structure of
natural 1 to be 1aa with the 14S,20R configuration.
Furthermore, a structure−activity relationship (SAR) study of
the four isomers disclosed similar anti-inflammatory activities of
the synthesized natural (1aa) and non-natural compounds
(1ab,ba,bb).
RESULTS AND DISCUSSION
■
To establish a unified synthetic route to the four stereoisomers
of 14,20-dihydroxydocosahexaenoic acid (1aa,ab,ba,bb), we
designed a convergent strategy using two chiral fragments (5a/
5b, 6a/6b), three achiral fragments (9−11), and iodoform
(Scheme 1). 14,20-Dihydroxydocosahexaenoic acid (1) was
first retrosynthetically converted to tetrayne 2, which possesses
a
The values on the lowermost structure are the differences (Δδ) in 1H
chemical shifts between 17a and 17a′ (Δδ = δ(17a) − δ(17a′)) in
CDCl3.
B
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of the C20-ketone of 13 to produce the optically active 15a in
96% ee.10,11 Protection of the C20-hydroxy group of 15a as its
TBS ether, followed by removal of the C16-TMS group under
basic conditions, afforded the requisite C16−C22 fragment
(20R)-5a. Alternative use of (R)-2-butyl-CBS-oxazaborolidine
14b in the reduction of 13 led to 15b (96% ee), which was
converted to the C16−C22 fragment (20S)-5b using the above
two-step protocol. The C20 absolute configurations of 5a,b
were established by application of the modified Mosher method
to 15a.12 Namely, 15a was transformed to (S)-MTPA ester 17a
Scheme 3. Synthesis of Four C12−C22 Fragments
3aa,ab,ba,bb
1
and (R)-MTPA ester 17a′. The difference in the H NMR
chemical shifts between 17a and 17a′ confirmed the 20R-
configuration of 15a.
Parts A and B of Scheme 3 show the synthesis of the four
C12−C22 fragments 3aa,ab,ba,bb. The lithium alkynides,
which were prepared from (20R)-5a and (20S)-5b using n-
BuLi, reacted with TES-protected glycidol (14S)-6a13 in the
presence of BF3·OEt2, resulting in formation of (14S,20R)-18aa
and (14S,20S)-18ab, respectively.14 The obtained 18aa,ab were
transformed to aldehydes 20aa,ab, respectively, by the
following three steps: (i) TBS protection of the C14-hydroxy
group, (ii) chemoselective removal of the TES group, and (iii)
Dess−Martin oxidation15 of the resulting C13-primary alcohol.
Next, treatment of aldehydes 20aa,ab with CHI3 and CrCl216 in
THF and 1,4-dioxane17 resulted in formation of the (E)-vinyl
iodide of C12−C22 fragments (14S,20R)-3aa and (14S,20S)-
3ab, respectively.18 The stereoisomers (14R,20R)-3ba and
(14R,20S)-3bb were synthesized by following the same five-
step transformation from TES-protected glycidol (14R)-6b.
C1−C11 fragment 4 was synthesized from the known 919
and 1020 through two Cu-mediated SN2 alkynylations (Scheme
4). The copper alkynide was formed from C1−C5 alkyne 10 by
21
the action of CuI and Cs2CO3 and attached on C6 of
propargyl tosylate 9 to produce C1−C9 diyne 21. The C9-
hydroxy group of 21 was then converted to the corresponding
bromide by treatment with CBr4 and (PPh2CH2)2.22 The
second SN2 alkynylation between 22 and ethynylcopper,
derived from ethynylmagnesium bromide 11′ and CuCl,
furnished C1−C11 triyne 4.
Next, the entire carbon backbone of 1 was assembled by
Sonogashira coupling between the four stereoisomeric C12−
C22 fragments and the C1−C11 fragment (Scheme 5).
Compounds 3aa,ab,ba,bb were separately subjected to C1−
C11 fragment 4 (1.2−1.5 equiv) and CuI in the presence of
catalytic Pd(PPh3)4, delivering tetraynes 2aa,ba,ab,bb, respec-
tively. Hence, a series of C−C bond formations using metal
alkynides successfully transformed the simple fragments into
the functionalized carbon structure of 1 bearing the four triple
bonds.
The most challenging task in the synthesis of 1 was reduction
of the four alkynes to the corresponding Z-alkenes, because the
chemoselective reductions should be realized without over-
reduction of the C12−C13 and C18−C19 (E)-alkenes and the
generating (Z)-alkenes (Scheme 6). To achieve the requisite
conversion, reagents and conditions were tuned using 2aa as
the substrate. Lindlar reduction23 of 2aa in the presence of
quinoline in hexane at room temperature resulted in generation
of a mixture of desired hexaene 23aa (30% yield) and over-
reduced products.24 Contamination of 23aa with the over-
reduced byproducts at this stage was found to be problematic.
Purification of the final product 1aa was not possible using
various chromatographic methods when the contaminated 23aa
was subjected to the last three steps.25 Thus, further efforts to
produce pure 23aa were pursued. Optimization of the amount
of Lindlar catalyst (300 wt %), quinoline (12 equiv), reaction
time (100 min), and temperature (0 °C) allowed selective
reduction of three (C4−C5, C7−C8, and C10−C11) of the
C
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four alkynes to generate pure 24aa. Consequently, the C16−
C17 alkyne, sterically protected by the neighboring bulky C14-
TBS ether, was more resistant to hydrogenation than the other
three triple bonds. Indeed, reduction of the remaining C16−
C17 alkyne of 24aa with Lindlar catalyst under more forceful
conditions only produced a mixture of 23aa and over-reduced
products, while the alternative use of Cu/Ag-activated Zn in
MeOH26 with 24aa did not induce the requisite reduction.
A more powerful yet chemoselective method was required to
obtain pure 23aa from 24aa. Numerous unsuccessful attempts
to hydrogenate 24aa led us to note the mechanistically distinct
reductive protocol reported by Isobe and co-workers.27,28 They
demonstrated that treatment of alkyne dicobalt hexacarbonyl
complexes with n-Bu3SnH at elevated temperature afforded the
corresponding (Z)-alkenes. This protocol was indeed applicable
to transformation of 24aa to 23aa (Table 1). The alkyne
Scheme 4. Synthesis of C1−C11 Triyne 4
Scheme 5. Assembly of the Carbon Backbone of 1
a
Table 1. Synthesis of Hexaene 23aa by Isobe Reduction
entry
reductant
additive
temp, °C yield, %
b
1
2
3
4
n-Bu3SnH
none
65
0
41
86
94
18
48
n-Bu3SnH
N-methylmorpholine oxide
N-methylmorpholine oxide
N-methylmorpholine oxide
N-methylmorpholine oxide
Ph3SnH
0
c
(TMS)3SiH
NaH2PO2·H2O
0
d
b
5
0
a
Conditions: 25aa (1 equiv), reductant (15 equiv), additive (10
b
1
equiv), toluene (10 mM), 0 °C. Yield was calculated by H NMR
analysis of a mixture of 23aa, 24aa, and over-reduced compounds.
c
Yield was calculated by 1H NMR analysis of a mixture of 23aa, 24aa,
d
and hydrosilylated products. Methoxyethanol was used as a solvent.
dicobalt hexacarbonyl complex 25aa was first prepared by
treatment of 24aa with Co2(CO)8 and then was submitted to
the original conditions (n-Bu3SnH (10 equiv), 65 °C, toluene,
entry 1),27 leading to hexaene 23aa in 41% yield. Despite
generation of 23aa, the reaction suffered from decomposition
and over-reduction. Thus, milder reaction conditions needed to
be realized by accelerating the reductive decomplexation step.
N-Methylmorpholine oxide is known to increase the rate of
the Pauson−Khand reaction of an alkyne dicobalt hexacarbonyl
complex.29 It is widely accepted that reaction between an amine
oxide and cobalt-coordinating carbon monoxide generates a
coordinately unsaturated cobalt species, which triggers the
Pauson−Khand reaction at low temperature.30 Accordingly, we
speculated that N-methylmorpholine oxide would strongly
promote the reductive decomplexation of 25aa through
Scheme 6. Chemoselective Reduction of Tetrayne 2aa to
Monoyne 24aa
D
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decarbonylation of the complex.31 When N-methylmorpholine
oxide (10 equiv) was added to the reaction mixture (Table 1,
entry 2), the reaction of 25aa proceeded at 0 °C to afford pure
23aa in 86% yield. Importantly, no decomposition of 23aa/
24aa or over-reduction was observed under these conditions.
Screening of the reductants clarified that n-Bu3SnH and
Ph3SnH (entries 2 and 3) were superior to (TMS)3SiH and
NaH2PO2·H2O32 (entries 4 and 5). Because residual Ph3SnH
could not be separated from 23aa, entry 2 was chosen as the
optimized conditions for synthesis of pure hexaene 23aa.
Thus, a combination of the Lindlar reduction and modified
Isobe reaction successfully converted tetrayne 2aa to pure
hexaene 23aa by the intermediacy of monoyne 24aa. It is
noteworthy that direct application of tetrayne 2aa to the Co-
complexation/decomplexation protocol was much less effective
(Scheme 7). Although complex 26aa was smoothly formed
Scheme 8. Total Synthesis of (14S,20R)-1aa and (14S,20S)-
1ab
Scheme 7. Attempted Isobe Reduction of 2aa
from 2aa and Co2(CO)8, reductive decomplexation of 26aa
using n-Bu3SnH and N-methylmorpholine oxide produced
23aa in only poor yield along with the over-reduced products.
The observed byproducts were attributable to reduction of the
less sterically shielded olefins by in situ generated cobalt
hydride species.33
As with 2aa, the optimized Lindlar and Isobe reductions were
applied to stereoisomer tetrayne 2ab (Scheme 8). Hydro-
genation of tetrayne 2ab produced monoyne 24ab, which was
then converted to the alkyne dicobalt hexacarbonyl complex
and treated with n-Bu3SnH and N-methylmorpholine oxide to
provide 23ab. Total synthesis of 1aa/1ab was completed from
the obtained hexaene 23aa/23ab in three steps.5 Specifically,
the cyclic acetal of hexaene 23aa and 23ab was selectively
removed in the presence of acid-sensitive TBS ethers under
Kita−Fujioka conditions (TMSOTf and 2,6-lutidine; aqueous
workup), leading to 27aa,ab, respectively.34 After oxidation of
aldehydes 27aa,ab to the carboxylic acids 28aa,ab with NaClO2,
removal of the two TBS groups with TBAF delivered
2ba and 2bb. Hence, the total synthesis of all the stereoisomers
of (4Z,7Z,10Z,12E,16Z,18E)-14,20-dihydroxy-4,7,10,12,16,18-
docosahexaenoic acid was accomplished. HPLC analysis of
DHA-derived natural 1 and the synthetic 1aa,ab,ba,bb
established the absolute structure of natural 1 to be
(14S,20R)-1aa.7,35
We evaluated the anti-inflammatory activity of synthetic
(14S,20R)-1aa, (14S,20S)-1ab, (14R,20R)-1ba, and (14R,20S)-
1bb using an in vivo inflammation model (Figure 2).36
Zymosan A, a glucan from the yeast cell wall, was used to
induce acute peritonitis in mice. Intravenous administration of
the four compounds at a concentration as low as 1 ng
significantly blocked the infiltration of PMN leucocytes at 2 h
in the inflamed peritoneal cavity. Importantly, all of the artificial
isomers 1ab,ba,bb displayed the same level of anti-inflamma-
tory activity as the natural form (1aa), indicating the
inconsequential nature of the stereochemistries of the two
hydroxy groups of (4Z,7Z,10Z,12E,16Z,18E)-14,20-dihydroxy-
1
(14S,20R)-1aa and (14S,20S)-1ab, respectively. The H−1H
coupling constants confirmed no geometric isomerization from
the (E,Z)-diene to the more stable (E,E)-diene under this series
of reaction conditions. As shown in Scheme 9, two other
stereoisomers of 1aa, (14R,20R)-1ba and (14R,20S)-1bb, were
also synthesized by application of the same 6-step sequence to
E
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Scheme 9. Total Synthesis of (14R,20R)-1ba and (14R,20S)-
1bb
Figure 2. Bioassay of synthetic 1aa,ab,ba,bb. The compounds (1 ng)
were injected intravenously through the tail vein, followed by
peritoneal injection of zymosan A (1 mg/mL). After 2 h, peritoneal
lavages were collected and the number of PMN leucocytes was
counted. Values represent mean SE, n ≥ 3 (*P < 0.05, **P < 0.01),
versus vehicle control.
C10−C11) and modified Isobe reduction of the remaining
C16−C17 alkyne. Construction of the (Z)-alkene from the
sterically shielded alkyne by combining Co-complexation and
reductive decomplexation should have wider application for the
chemoselective preparation of various (Z)-alkenes beyond this
target. Further studies toward functional analysis of 1aa and the
non-natural isomers are currently underway in our laboratory.
EXPERIMENTAL SECTION
■
General Methods. All reactions sensitive to air or moisture were
carried out under an argon atmosphere in dry solvents, unless
otherwise noted. THF, CH2Cl2, and toluene were purified by a Glass
Contour solvent dispensing system. Et3N and piperidine were purified
by distillation over CaH2. BF3·OEt2 was purified by distillation over
P2O5. All other reagents were used as supplied. Analytical thin-layer
chromatography (TLC) was performed using precoated TLC glass
plates (silica gel 60 F254, 0.25 mm). Flash chromatography was
performed using silica gel (spherical, neutral, 40−50 μm; granular,
neutral, 32−53 μm; spherical, carboxylic acid supported (Chromator-
ex-ACD COOH), 45−75 μm). Medium-pressure liquid chromatog-
raphy was carried out by using a system equipped with prepacked silica
gel 40 μm (45 g (26 × 150 mm) or 120 g (46 × 130 mm)). Optical
rotations were measured using the sodium D line. Infrared (IR)
spectra were recorded as a thin film on a NaCl disk using an FT/IR
spectrometer. 1H and 13C NMR spectra were recorded on 400 or 500
MHz and 100 or 150 MHz spectrometers, respectively. Chemical shifts
were reported in ppm on the δ scale relative to residual CHCl3 for 1H
NMR (δ 7.26), CDCl3 for 13C NMR (δ 77.0), C6HD5 for 1H NMR (δ
4,7,10,12,16,18-docosahexaenoic acid for potent anti-inflamma-
tory activity.
CONCLUSION
■
We established a unified route to the four stereoisomers of the
new lipid mediator 1, (14S,20R)-1aa, (14S,20S)-1ab,
(14R,20R)-1ba, and (14R,20S)-1bb, from the six simple
fragments 6−11 and iodoform in 16 longest linear steps and
19 overall steps. These total syntheses allowed the absolute
structure of the naturally occurring 1 to be determined as 1aa,
and the anti-inflammatory activities of all four stereoisomers
were shown to be equipotent for the first time. The key features
of the synthesis route include (i) enantioselective reduction of
the C20-ketone with chiral 2-butyl-CBS-oxazaborolidines for
the synthesis of C16−C22 fragments 5a,b, (ii) construction of
the carbon backbone of 1 by employing two Sonogashira
couplings and three SN2 alkynylations, and (iii) chemoselective
formation of the four (Z)-alkenes by stepwise reduction using
Lindlar reduction of the three alkynes (C4−C5, C7−C8, and
1
7.16), C6D6 for 13C NMR (δ 128.06), CD2HOD for H NMR (δ
3.31), and CD3OD for 13C NMR (δ 49.0) as internal references. Signal
patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad peak. High-resolution mass spectra
were measured on ESI-TOF and DART-TOF mass spectrometers.
(E)-7-(Trimethylsilyl)hept-4-en-6-yn-3-one (13). A solution of
propionyl chloride (1.86 g, 20.1 mmol) in CH2Cl2 (30 mL) and a
solution of 12 (3.00 g, 16.8 mmol) in CH2Cl2 (30 mL) were
successively added to a solution of AlCl3 (2.69 g, 20.2 mmol) in
CH2Cl2 (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for
30 min and at room temperature for 1 h, and then saturated aqueous
NH4Cl (70 mL) was added. The resultant mixture was extracted with
CH2Cl2 (50 mL × 3), and the combined organic layers were dried
over Na2SO4, filtered, and concentrated. The residue was purified by
medium-pressure liquid chromatography on silica gel (45 g, pentane to
pentane/Et2O 16/1) to afford a 3.5/1 mixture of bromide 7 and
F
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chloride 7′ along with pentane and Et2O (3.05 g), which was used in
the next reaction without further purification due to the volatility of 7.
Pd(PPh3)4 (528 mg, 0.457 mmol), CuI (174 mg, 0.916 mmol),
Et3N (5.3 mL, 38 mmol), and (trimethylsilyl)acetylene 8 (4.3 mL, 30
mmol) were successively added to a solution of the above 3.5/1
mixture of 7 and 7′ at room temperature. The reaction mixture was
stirred at room temperature for 2.5 h. After the reaction mixture was
cooled to 0 °C, saturated aqueous NH4Cl (50 mL) was added. The
resultant mixture was extracted with Et2O (50 mL × 3), and the
combined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash column
chromatography on silica gel (120 g, pentane to pentane/Et2O 16/1)
to afford 13 (2.74 g, 11.2 mmol, a 5/1.5/1 mixture of ketone 13, Et2O,
and pentane). The yield of 13 was determined to be 67% over two
K2CO3 (980 mg, 7.10 mmol) was added to a solution of the above
crude TBS ether 16a in MeOH (45 mL) at room temperature. The
reaction mixture was stirred at room temperature for 1.5 h. After the
reaction mixture was cooled to 0 °C, Et2O (50 mL) and saturated
aqueous NH4Cl (60 mL) were successively added. The resultant
mixture was extracted with Et2O (100 and 50 mL), and the combined
organic layers were washed with H2O (50 mL) and brine (50 mL),
dried over Na2SO4, filtered, and concentrated. The residue was
purified three times by flash column chromatography on silica gel (40
g, hexane to hexane/EtOAc 25/1; 30 g, hexane/EtOAc 100/1 to 50/1;
30 g, hexane to hexane/EtOAc 100/1) to afford C16−C22 fragment
24
5a (718 mg, 3.21 mmol) in 68% over two steps: colorless oil; [α]D
1
+19 (c 0.16, CHCl3); H NMR (400 MHz, CDCl3) δ 6.23 (dd, J =
16.0, 6.0 Hz, 1H), 5.65 (ddd, J = 16.0, 2.3, 1.8 Hz, 1H), 4.12 (dtd, J =
6.0, 6.0, 1.8 Hz, 1H), 2.86 (d, J = 2.3 Hz, 1H), 1.52 (m, 2H), 0.90 (s,
9H), 0.88 (t, J = 7.3 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 148.3, 107.6, 82.2, 77.2, 73.3, 30.5, 25.8 (×3),
18.2, 9.2, −4.6, −4.9; IR (neat) ν 3427, 2956, 2930, 2858, 2221, 1471,
1463, 1362, 1255 cm−1. Anal. Calcd for C13H24OSi: C, 69.58; H, 10.78.
Found: C, 69.42; H, 10.48.
1
steps by the H NMR analysis of the mixture. For characterization of
13, the residual solvents of the above mixture were completely
1
removed: colorless oil; H NMR (400 MHz, CDCl3) δ 6.64 (d, J =
16.0 Hz, 1H), 6.53 (d, J = 16.0 Hz, 1H), 2.56 (q, J = 7.3 Hz, 2H), 1.10
(t, J = 7.3 Hz, 3H), 0.21 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
199.4, 137.7, 122.4, 105.5, 101.9, 34.3, 7.8, −0.5 (×3); IR (neat) ν
2962, 2940, 2902, 1692, 1677, 1596, 1252, 1081, 1020 cm−1; HRMS
(ESI) calcd for C10H16OSiNa 203.0863 [M + Na]+, found 203.0864.
(R,E)-7-(Trimethylsilyl)hept-4-en-6-yn-3-ol (15a). BH3·Me2S
(1.5 mL, 16 mmol) was added to a solution of (S)-2-butyl-CBS-
oxazaborolidine 14a (1.0 M solution in toluene, 14 mL, 14 mmol) in
toluene (46 mL) at room temperature. The mixture was stirred at
room temperature for 30 min. After the mixture was cooled to −78 °C,
a solution of 13 (2.42 g, 7.41 mmol, a 27/53/1 mixture of 13, pentane
and Et2O) in toluene (23 mL) was added over 35 min. The reaction
mixture was stirred at −78 °C for 1 h, and then 0.4 M aqueous HCl
(60 mL) was added. The mixture was filtered through a pad of Celite
with Et2O, and the filtrate was extracted with Et2O (100 and 50 mL).
The combined organic layers were washed with saturated aqueous
NaHCO3 (50 mL), H2O (50 mL), and brine (50 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified by
medium-pressure liquid chromatography on silica gel (120 g, hexane
to hexane/EtOAc 5/1) to afford 15a (868 mg, 4.77 mmol) in 64%
yield. The enantiopurity of 15a was determined to be 96% ee by the
1H NMR analysis of the corresponding MTPA ester: colorless oil;
[α]D28 −4.2 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.20 (dd,
J = 16.0, 6.0 Hz, 1H), 5.73 (dd, J = 16.0, 1.4 Hz, 1H), 4.09 (m, 1H),
1.57 (qd, J = 7.3, 6.0 Hz, 2H), 1.46 (d, J = 4.6 Hz, 1H), 0.94 (t, J = 7.3
Hz, 3H), 0.19 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 146.5, 110.0,
103.1, 95.1, 73.5, 29.8, 9.5, −0.12 (×3); IR (neat) ν 3357, 2962, 2935,
2877, 2155, 2130, 1457, 1250 cm−1; HRMS (DART) calcd for
C10H19OSi 183.1200 [M + H]+, found 183.1208.
C16−C22 Fragment 5b. According to the synthetic procedure of
5a, 5b (1.73 g, 7.72 mmol) was synthesized from 15b (1.71 g, 9.40
mmol) in 82% yield over two steps by using TBSCl (2.84 g, 18.8
mmol) and imidazole (2.55 g, 37.5 mmol) in DMF (100 mL) for the
first step and K2CO3 (1.94 g, 14.1 mmol) in MeOH (100 mL) for the
second. Purification was performed twice by medium-pressure liquid
chromatography on silica gel (120 g, hexane to hexane/EtOAc 30/1 to
20/1; 45 g, hexane to hexane/EtOAc 30/1 to 20/1): colorless oil;
24
[α]D −18 (c 1.3, CHCl3). Anal. Calcd for C13H24OSi: C, 69.58; H,
10.78. Found: C, 69.39; H, 10.48. The other analytical data of 5b were
identical with those of 5a.
(S)-MTPA Ester 17a. (R)-MTPACl (12 μL, 64 μmol) was added
to a solution of 15a (3.0 mg, 16 μmol), Et3N (16 μL, 0.12 mmol), and
DMAP (10 mg, 82 μmol) in CH2Cl2 (1.0 mL) at room temperature.
The reaction mixture was stirred at room temperature for 20 min, and
then H2O (5 mL) was added. The resultant mixture was extracted with
EtOAc (5 mL × 3), and the combined organic layers were washed
with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash column
chromatography on silica gel (1 g, hexane/EtOAc 20/1) to afford
(S)-MTPA ester 17a (4.9 mg, 13 μmol) in 81% yield: colorless oil; 1H
NMR (CDCl3) δ 7.51−7.48 (m, 2H), 7.42−7.36 (m, 3H), 6.02 (dd, J
= 16.0, 7.3 Hz, 1H), 5.70 (d, J = 16.0 Hz, 1H), 5.40 (dt, J = 7.3, 6.4
Hz, 1H), 3.55 (s, 3H), 1.80−1.67 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H),
0.19 (s, 9H).
(R)-MTPA Ester 17a′. According to the synthetic procedure of
17a, (R)-MTPA ester 17a′ (4.1 mg, 11 μmol) was synthesized from
15a (2.6 mg, 14 μmol) in 79% yield by using (S)-MTPACl (5.5 μL, 29
μmol), Et3N (10 μL, 0.12 mmol), and DMAP (4.4 mg, 36 μmol) in
CH2Cl2 (0.7 mL). The residue was purified by flash column
chromatography on silica gel (1 g, hexane/EtOAc 20/1): colorless
oil; 1H NMR (CDCl3) δ 7.51−7.48 (m, 2H), 7.42−7.38 (m, 3H), 6.10
(dd, J = 16.0, 6.8 Hz, 1H), 5.79 (d, J = 16.0 Hz, 1H), 5.42 (td, J = 6.8,
6.8 Hz, 1H), 3.54 (s, 3H), 1.75−1.55 (m, 2H), 0.83 (t, J = 7.3 Hz,
3H), 0.19 (9H, s).
Alcohol 18aa. n-BuLi (1.6 M in hexane, 2.0 mL, 3.2 mmol) was
added to a solution of C16−C22 fragment 5a (714 mg, 3.19 mmol) in
THF (25 mL) at −78 °C over 10 min. The mixture was stirred at −78
°C for 10 min, warmed to 0 °C, and stirred for 30 min. After the
mixture was cooled to −78 °C, BF3·OEt2 (0.36 mL, 2.9 mmol) and a
solution of glycidol derivative 6a (503 mg, 2.68 mmol) in THF (6.0
mL) were successively added. The reaction mixture was stirred at −78
°C for 1 h and warmed to −40 °C over 3 h, and then saturated
aqueous NH4Cl (30 mL) was added. The resultant mixture was
extracted with Et2O (30 mL × 3), and the combined organic layers
were washed with H2O (30 mL) and brine (30 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified twice by
medium-pressure liquid chromatography on silica gel (45 g, hexane to
hexane/EtOAc 9/1) and flash column chromatography on silica gel
(30 g, hexane to hexane/EtOAc 9/1) to afford alcohol 18aa (707 mg,
(S,E)-7-(Trimethylsilyl)hept-4-en-6-yn-3-ol (15b). According to
the synthetic procedure of 15a, 15b (965 mg, 5.30 mmol) was
synthesized from 13 (2.82 g, 8.65 mmol, a 27/53/1 mixture of 13,
pentane, and Et2O) in 65% yield by using (R)-2-butyl-CBS-
oxazaborolidine 14b (1.0 M solution in toluene, 16.3 mL, 16.3
mmol) and BH3·Me2S (1.8 mL, 18 mmol) in toluene (83 mL).
Purification was performed twice by medium-pressure liquid
chromatography on silica gel (120 g, hexane to hexane/EtOAc 6/1;
45 g, hexane to hexane/EtOAc 6/1). The enantiopurity of 15b was
determined to be 96% ee by the 1H NMR analysis of the
30
corresponding MTPA ester: colorless oil; [α]D +4.3 (c 0.84,
CHCl3). Anal. Calcd for C10H18OSi: C, 65.87; H, 9.95. Found: C,
66.04; H, 9.71. The other analytical data of 15b were identical with
those of 15a.
C16−C22 Fragment 5a. TBSCl (1.43 g, 9.49 mmol) was added to
a solution of alcohol 15a (864 mg, 4.75 mmol) and imidazole (1.29 g,
20.0 mmol) in DMF (47 mL) at 0 °C. The reaction mixture was
warmed to room temperature and stirred for 6 h, and then H2O (100
mL) was added. The resultant solution was extracted with Et2O (60
and 40 mL), and the combined organic layers were washed with H2O
(50 mL) and brine (50 mL), dried over Na2SO4, filtered, and
concentrated to afford the crude TBS ether 16a, which was used in the
next reaction without further purification.
G
DOI: 10.1021/acs.joc.5b01461
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The Journal of Organic Chemistry
Article
1.71 mmol) in 64% yield: colorless oil; [α]D28 +31 (c 1.3, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 6.04 (dd, J = 16.0, 6.0 Hz, 1H), 5.61 (dtd,
J = 16.0, 1.8, 1.8 Hz, 1H), 4.08 (dtd, J = 6.0, 6.0, 1.8 Hz, 1H), 3.81 (m,
1H), 3.72 (dd, J = 10.0, 4.1 Hz, 1H), 3.62 (dd, J = 10.0, 5.9 Hz, 1H),
2.60−2.50 (m, 2H), 1.50 (qd, J = 7.8, 6.0 Hz, 2H), 0.97 (t, J = 8.2 Hz,
9H), 0.90 (s, 9H), 0.86 (t, J = 7.8 Hz, 3H), 0.63 (q, J = 8.2 H, 6H),
0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.6,
108.7, 85.8, 80.8, 73.6, 70.4, 65.4, 30.7, 25.8 (×3), 24.1, 18.2, 9.3, 6.7
(×3), 4.3 (×3), −4.6, −4.9; IR (neat) ν 3566, 2956, 2926, 2852, 1956,
1478, 1255 cm−1; HRMS (ESI) calcd for C22H44O3Si2Na 435.2721 [M
+ Na]+, found 435.2726.
mg, 1.12 mmol) in 66% over two steps: colorless oil; [α]D21 +21 (c 1.2,
CHCl3); H NMR (400 MHz, CDCl3) δ 6.02 (dd, J = 16.0, 6.0 Hz,
1
1H), 5.60 (dtd, J = 16.0, 1.8, 1.4 Hz, 1H), 4.07 (tdd, J = 6.4, 6.0, 1.4
Hz, 1H), 3.91 (m, 1H), 3.68 (dd, J = 11.4, 3.7 Hz, 1H), 3.58 (dd, J =
11.4, 5.0 Hz, 1H), 2.53 (ddd, J = 17.0, 6.9, 1.8 Hz, 1H), 2.42 (ddd, J =
17.0, 6.4, 1.8 Hz, 1H), 1.50 (qd, J = 7.3, 6.4 Hz, 2H), 0.91 (s, 9H),
0.90 (s, 9H), 0.86 (t, J = 7.3 Hz, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.04
(s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.8, 109.1,
86.7, 81.0, 74.0, 72.0, 66.2, 31.0, 26.2 (×3), 26.1 (×3), 25.1, 18.5, 18.4,
9.6, −4.21, −4.24, −4.5, −4.6; IR (neat) ν 3449, 2955, 2929, 2857,
1471, 1461, 1362, 1255, 1113 cm−1; HRMS (ESI) calcd for
C22H44O3Si2Na 435.2721 [M + Na]+, found 435.2709.
Alcohol 18ab. According to the synthetic procedure of 18aa, 18ab
(791 mg, 1.92 mmol) was synthesized from C16−C22 fragment 5b
(833 mg, 3.72 mmol) and glycidol derivative 6a (596 mg, 3.17 mmol)
in 61% yield by using n-BuLi (1.6 M in hexane, 2.5 mL, 4.0 mmol) and
BF3·OEt2 (0.41 mL, 3.3 mmol) in THF (31 mL). Purification was
performed by medium-pressure liquid chromatography on silica gel
Alcohol 19ab. According to the synthetic procedure of 19aa, 19ab
(453 mg, 1.10 mmol) was synthesized from alcohol 18ab (780 mg,
1.89 mmol) in 58% yield over two steps by using Et3N (0.66 mL, 4.7
mmol) and TBSOTf (0.48 mL, 2.1 mmol) in CH2Cl2 (19 mL) for the
first step, and PPTS (40 mg, 0.16 mmol) in a mixture of MeOH (16
mL) and THF (2.6 mL) for the second. Purification was performed by
flash column chromatography on silica gel (30 g, hexane to hexane/
EtOAc 20/1) for the first step, and on silica gel (20 g, hexane to
25
(45 g, hexane to hexane/EtOAc 9/1): colorless oil; [α]D −5.9 (c
0.98, CHCl3); HRMS (ESI) calcd for C22H44O3Si2Na 435.2721 [M +
Na]+, found 435.2716. The other analytical data of 18ab were identical
with those of 18ba.
25
hexane/EtOAc 9/1) for the second: colorless oil; [α]D −17 (c 1.1,
Alcohol 18ba. According to the synthetic procedure of 18aa, 18ba
(760 mg, 1.84 mmol) was synthesized from C16−C22 fragment 5a
(610 mg, 2.72 mmol) and glycidol derivative 6b (436 mg, 2.32 mmol)
in 79% yield by using n-BuLi (1.6 M in hexane, 1.8 mL, 2.9 mmol) and
BF3·OEt2 (0.30 mL, 2.4 mmol) in THF (26 mL). Purification was
performed by flash column chromatography on silica gel (40 g, hexane
CHCl3); HRMS (ESI) calcd for C22H44O3Si2Na 435.2721 [M + Na]+,
found 435.2721. The other analytical data of 19ab were identical with
those of 19ba.
Alcohol 19ba. According to the synthetic procedure of 19aa, 19ba
(427 mg, 1.04 mmol) was synthesized from alcohol 18ba (676 mg,
1.64 mmol) in 63% yield over two steps by using Et3N (0.58 mL, 4.2
mmol) and TBSOTf (0.42 mL, 1.8 mmol) in CH2Cl2 (16 mL) for the
first step, and PPTS (37 mg, 0.15 mmol) in a mixture of MeOH (15
mL) and THF (2.5 mL) for the second. Purification was performed by
flash column chromatography on silica gel (30 g, hexane to hexane/
EtOAc 9/1) for the first step, and twice on silica gel (30 g, hexane to
hexane/EtOAc 9/1; 30 g, hexane/EtOAc 9/1) for the second:
colorless oil; [α]D31 +17 (c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 6.01 (dd, J = 16.0, 6.0 Hz, 1H), 5.60 (ddt, J = 16.0, 2.3, 1.4 Hz, 1H),
4.07 (tdd, J = 6.0, 6.0, 1.4 Hz, 1H), 3.91 (m, 1H), 3.68 (ddd, J = 11.4,
6.0, 3.7 Hz, 1H), 3.58 (ddd, J = 11.4, 6.0, 5.0 Hz, 1H), 2.53 (ddd, J =
16.9, 7.3, 2.3 Hz, 1H), 2.47 (ddd, J = 16.9, 6.0, 2.3 Hz, 1H), 1.87 (t, J =
6.0 Hz, 1H), 1.50 (qd, J = 7.8, 6.0 Hz, 2H), 0.904 (s, 9H), 0.895 (s,
9H), 0.86 (t, J = 7.8 Hz, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.04 (s, 3H),
0.03 (s, 3H,); 13C NMR (100 MHz, CDCl3) δ −4.9, −4.8, −4.6, −4.5,
9.3, 18.1, 18.2, 24.8, 25.77 (×3), 25.84 (×3), 30.7, 65.9, 71.7, 73.6,
80.7, 86.4, 108.8, 145.5; IR (neat) ν 3434, 2956, 2929, 2857, 2221,
1634, 1472, 1464, 1362, 1255 cm−1; HRMS (ESI) calcd for
C22H44O3Si2Na 435.2721 [M + Na]+, found 435.2744.
30
1
to hexane/EtOAc 9/1): colorless oil; [α]D +6.2 (c 1.2, CHCl3); H
NMR (400 MHz, CDCl3) δ 6.03 (dd, J = 16.0, 6.0 Hz, 1H), 5.61 (dtd,
J = 16.0, 2.3, 1.4 Hz, 1H), 4.08 (dtd, J = 6.0, 5.5, 1.4 Hz, 1H), 3.81 (m,
1H), 3.72 (dd, J = 10.0, 4.1 Hz, 1H), 3.62 (dd, J = 10.0, 6.0 Hz, 1H),
2.60−2.50 (m, 2H), 1.50 (qd, J = 7.3, 5.5 Hz, 2H), 0.97 (t, J = 7.8 Hz,
9H), 0.90 (s, 9H), 0.86 (t, J = 7.3 Hz, 3H), 0.63 (q, J = 7.8 Hz, 6H),
0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.6,
108.7, 85.8, 80.8, 73.6, 70.4, 65.3, 30.7, 25.8 (×3), 24.1, 18.2, 9.3, 6.7
(×3), 4.3 (×3), −4.5, −4.9; IR (neat) ν 3429, 2956, 2931, 2877, 1463,
1362, 1255 cm−1; HRMS (ESI) calcd for C22H44O3Si2Na 435.2721 [M
+ Na]+, found 435.2744.
Alcohol 18bb. According to the synthetic procedure of 18aa, 18bb
(777 mg, 1.88 mmol) was synthesized from C16−C22 fragment 5b
(867 mg, 3.87 mmol) and glycidol derivative 6b (624 mg, 3.32 mmol)
in 57% yield by using n-BuLi (1.6 M in hexane, 2.6 mL, 4.2 mmol) and
BF3·OEt2 (0.43 mL, 3.5 mmol) in THF (37 mL). Purification was
performed by medium-pressure liquid chromatography on silica gel
(45 g, hexane to hexane/EtOAc 20/1): colorless oil; [α]D24 −32 (c 1.1,
CHCl3); HRMS (ESI) calcd for C22H44O3Si2Na 435.2721 [M + Na]+,
found 435.2713. The other analytical data of 18bb were identical with
those of 18aa.
Alcohol 19aa. TBSOTf (0.43 mL, 1.9 mmol) was added to a
solution of alcohol 18aa (704 mg, 1.70 mmol) and Et3N (0.60 mL, 4.3
mmol) in CH2Cl2 (17 mL) at 0 °C. The reaction mixture was warmed
to room temperature and stirred for 30 min, and then saturated
aqueous NaHCO3 (30 mL) was added. The resultant mixture was
extracted with Et2O (50 and 20 mL), and the combined organic layers
were washed with H2O (30 mL) and brine (30 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel (30 g, hexane to hexane/EtOAc
9/1) to afford the crude TBS ether, which was used in the next
reaction without further purification.
PPTS (37 mg, 0.15 mmol) was added to a solution of the above
crude TBS ether in a mixture of MeOH (15 mL) and THF (2.5 mL)
at room temperature. The reaction mixture was stirred at room
temperature for 15 min. After the reaction mixture was cooled to 0 °C,
saturated aqueous NaHCO3 (30 mL) was added. The resultant
mixture was extracted with Et2O (50 and 20 mL), and the combined
organic layers were washed with H2O (20 mL) and brine (30 mL),
dried over Na2SO4, filtered, and concentrated. The residue was
purified three times by flash column chromatography on silica gel (30
g, hexane to hexane/EtOAc 9/1; 20 g, hexane to hexane/EtOAc 9/1;
20 g, hexane to hexane/EtOAc 20/1) to afford TBS ether 19aa (463
Alcohol 19bb. According to the synthetic procedure of 19aa, 19bb
(480 mg, 1.16 mmol) was synthesized from alcohol 18bb (766 mg,
1.86 mmol) in 62% yield over two steps by using Et3N (0.65 mL, 4.7
mmol) and TBSOTf (0.47 mL, 2.0 mmol) in CH2Cl2 (19 mL) for the
first step, and PPTS (41 mg, 0.16 mmol) in a mixture of MeOH (16
mL) and THF (2.6 mL) for the second. Purification was performed by
flash column chromatography on silica gel (30 g, hexane to hexane/
EtOAc 9/1) for the first step and twice on silica gel (30 g, hexane to
hexane/EtOAc 20/1; 10 g, hexane to hexane/EtOAc 9/1) for the
23
second: colorless oil; [α]D −20 (c 1.2, CHCl3); HRMS (ESI) calcd
for C22H44O3Si2Na 435.2721 [M + Na]+, found 435.2738. The other
analytical data of 19bb were identical with those of 19aa.
Aldehyde 20aa. Dess−Martin periodinane (693 mg, 1.63 mmol)
was added to a suspension mixture of alcohol 19aa (449 mg, 1.09
mmol) and NaHCO3 (887 mg, 10.6 mmol) in CH2Cl2 (23 mL) at 0
°C. The mixture was warmed to room temperature and stirred for 5 h,
and then H2O (50 mL) was added. The resultant mixture was
extracted with Et2O (50 and 30 mL × 2), and the combined organic
layers were washed with H2O (30 mL) and brine (30 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel (40 g, hexane to hexane/EtOAc
20/1) to afford aldehyde 20aa (343 mg, 0.835 mmol) in 77% yield:
29
colorless oil; [α]D −3.4 (c 1.2, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 9.65 (d, J = 1.4 Hz, 1H), 6.04 (dd, J = 16.0, 5.5 Hz, 1H),
5.60 (br d, J = 16.0 Hz, 1H), 4.13 (ddd, J = 7.8, 5.0, 1.4 Hz, 1H), 4.07
H
DOI: 10.1021/acs.joc.5b01461
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The Journal of Organic Chemistry
Article
(td, J = 6.0, 5.5 Hz, 1H), 2.71 (ddd, J = 16.9, 5.0, 1.8 Hz, 1H), 2.57
(ddd, J = 16.9, 7.8, 1.8 Hz, 1H), 1.50 (qd, J = 7.3, 6.0 Hz, 2H), 0.93 (s,
9H), 0.89 (s, 9H), 0.86 (t, J = 7.3 Hz, 3H), 0.13 (s, 6H), 0.04 (s, 3H),
0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.2, 145.9, 108.6,
85.0, 81.2, 76.2, 73.6, 30.7, 25.8 (×3), 25.7 (×3), 24.1, 18.23, 18.22,
9.3, −4.6, −4.78, −4.82, −4.9; IR (neat) ν 2956, 2930, 2858, 1741,
1472, 1464, 1362, 1255 cm−1; HRMS (ESI) calcd for C23H46O4Si2Na
465.2827 [M + MeOH + Na]+, found 465.2819.
1.88 mmol) and CrCl2 (687 mg, 5.58 mmol) in a mixture of THF (1.1
mL) and 1,4-dioxane (15.5 mL). Purification was performed three
times by flash column chromatography on silica gel (30 g, hexane/
EtOAc 20/1; 30 g, hexane to hexane/EtOAc 20/1; 30 g, hexane/
23
CH2Cl2 100/1 to 20/1): colorless oil; [α]D +25 (c 1.1, CHCl3);
HRMS (ESI) calcd for C23H43IO2Si2Na 557.1738 [M + Na]+, found
557.1728. The other analytical data of 3ab were identical with those of
3ba.
Aldehyde 20ab. According to the synthetic procedure of 20aa,
20ab (393 mg, 0.956 mmol) was synthesized from alcohol 19ab (437
mg, 1.06 mmol) in 90% yield by using NaHCO3 (861 mg, 10.3 mmol)
and Dess−Martin periodinane (677 mg, 1.60 mmol) in CH2Cl2 (22
mL). Purification was performed by flash column chromatography on
C12−C22 Fragment 3ba. According to the synthetic procedure
of 3aa, 3ba (270 mg, 0.505 mmol) was synthesized from aldehyde
20ba (342 mg, 0.832 mmol) in 61% yield by using iodoform (657 mg,
1.67 mmol) and CrCl2 (615 mg, 5.00 mmol) in a mixture of THF (1.0
mL) and 1,4-dioxane (14 mL). Purification was performed three times
by flash column chromatography on silica gel (40 g, hexane/EtOAc
20/1; 30 g, hexane/EtOAc 20/1; 30 g, hexane/EtOAc 20/1): colorless
25
silica gel (40 g, hexane to hexane/EtOAc 9/1): colorless oil; [α]D
−52 (c 1.2, CHCl3); HRMS (ESI) calcd for C23H46O4Si2Na 465.2827
[M + MeOH + Na]+, found 465.2832. The other analytical data of
20ab were identical with those of 20ba.
31
1
oil; [α]D −16 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 6.64
(ddd, J = 14.6, 5.5 Hz, 1H), 6.33 (dd, J = 14.6, 1.4 Hz, 1H), 6.03 (dd, J
= 16.0, 6.0 Hz, 1H), 5.61 (dd, J = 16.0, 1.4 Hz, 1H), 4.24 (td, J = 6.9,
5.5 Hz, 1H), 4.08 (dt, J = 6.0, 6.0 Hz, 1H), 2.49 (ddd, J = 16.9, 6.9, 1.8
Hz, 1H), 2.42 (ddd, J = 16.9, 6.9, 1.8 Hz, 1H), 1.50 (qd, J = 7.8, 6.0
Hz, 2H), 0.899 (s, 9H), 0.896 (s, 9H), 0.87 (t, J = 7.8 Hz, 3H), 0.09 (s,
3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 147.6, 145.7, 108.8, 86.1, 81.0, 76.7, 74.0, 73.7, 30.7, 28.8,
25.9 (×3), 25.7 (×3), 18.23, 18.19, 9.3, −4.5, −4.7, −4.86, −4.89; IR
(neat) ν 2956, 2929, 2857, 1607, 1463, 1362, 1255, 1090 cm−1; HRMS
(ESI) calcd for C23H43IO2Si2Na 557.1738 [M + Na]+, found 557.1754.
C12−C22 Fragment 3bb. According to the synthetic procedure
of 3aa, 3bb (213 mg, 0.391 mmol) was synthesized from aldehyde
20bb (370 mg, 0.900 mmol) in 43% yield by using iodoform (571 mg,
1.45 mmol) and CrCl2 (657 mg, 5.34 mmol) in a mixture of THF (1.1
mL) and 1,4-dioxane (15 mL). Purification was performed by flash
column chromatography on silica gel (40 g, hexane to hexane/CH2Cl2
Aldehyde 20ba. According to the synthetic procedure of 20aa,
20ba (352 mg, 0.856 mmol) was synthesized from alcohol 19ba (418
mg, 1.01 mmol) in 85% yield by using NaHCO3 (818 mg, 10.8 mmol)
and Dess−Martin periodinane (645 mg, 1.52 mmol) in CH2Cl2 (21
mL). Purification was performed by flash column chromatography on
31
silica gel (40 g, hexane to hexane/EtOAc 20/1): colorless oil; [α]D
1
+47 (c 1.1, CHCl3); H NMR (400 MHz, CDCl3) δ 9.65 (d, J = 1.0
Hz, 1H), 6.04 (dd, J = 16.0, 6.0 Hz, 1H), 5.60 (dd, J = 16.0, 1.8 Hz,
1H), 4.13 (ddd, J = 7.8, 5.0, 1.0 Hz, 1H), 4.08 (td, J = 6.0, 6.0 Hz, 1H),
2.71 (ddd, J = 17.0, 5.0, 1.8 Hz, 1H), 2.57 (ddd, J = 17.0, 7.8, 1.8 Hz,
1H), 1.50 (qd, J = 7.3, 6.0 Hz, 2H), 0.93 (s, 9H), 0.90 (s, 9H), 0.86 (t,
J = 7.3 Hz, 3H), 0.136 (s, 3H), 0.132 (s, 3H), 0.04 (s, 3H), 0.03 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 202.2, 146.0, 108.6, 85.0, 81.2,
76.2, 73.6, 30.7, 25.8 (×3), 25.7 (×3), 24.1, 18.2 (×2), 9.3, −4.6,
−4.78, −4.82, −4.9; IR (neat) ν 2956, 2930, 2858, 1741, 1472, 1464,
1362, 1255 1117 cm−1; HRMS (ESI) calcd for C23H46O4Si2Na
465.2827 [M + MeOH + Na]+, found 465.2851.
22
20/1 to 12/1): colorless oil; [α]D −50 (c 0.77, CHCl3); HRMS
(ESI) calcd for C23H43IO2Si2Na 557.1738 [M + Na]+, found 557.1719.
The other analytical data of 3bb were identical with those of 3aa.
Triyne 4. A mixture of CuI (833 mg, 4.37 mmol), NaI (650 mg,
4.34 mmol), and Cs2CO3 (1.41 g, 4.32 mmol) was dried at 95 °C in
vacuo. After the mixture was cooled to 0 °C, a solution of alcohol 9
(548 mg, 4.35 mmol) in DMF (4.0 mL) was added. The mixture was
stirred at 0 °C for 5 min, and then a solution of alkyne 10 (1.18 g, 4.91
mmol) in DMF (4.8 mL) was added. The reaction mixture was
warmed to room temperature and stirred for 16 h, and then saturated
aqueous NH4Cl (20 mL) was added. The resultant solution was
filtered through a pad of Celite with Et2O, and the filtrate was
extracted with Et2O (30 and 20 mL × 2). The combined organic layers
were washed with H2O (30 mL) and brine (30 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified by
medium-pressure liquid chromatography on silica gel (45 g, hexane/
EtOAc 9/1 to 3/2) to afford the crude diyne 21, which was used in the
next reaction without further purification.
Aldehyde 20bb. According to the synthetic procedure of 20aa,
20bb (378 mg, 0.920 mmol) was synthesized from alcohol 19bb (472
mg, 1.15 mmol) in 80% yield by using NaHCO3 (904 mg, 10.8 mmol)
and Dess-Martin periodinane (1.20 g, 2.83 mmol) in CH2Cl2 (24 mL).
Purification was performed twice by flash column chromatography on
silica gel (40 g, hexane to hexane/EtOAc 9/1; 30 g, hexane to hexane/
22
EtOAc 9/1): colorless oil; [α]D +12 (c 1.2, CHCl3); HRMS (ESI)
calcd for C23H46O4Si2Na 465.2827 [M + MeOH + Na]+, found
465.2825. The other analytical data of 20bb were identical with those
of 20aa.
C12−C22 Fragment 3aa. Iodoform (644 mg, 1.63 mmol) and a
solution of aldehyde 20aa (334 mg, 0.813 mmol) in 1,4-dioxane (13.5
mL) were successively added to a suspension of CrCl2 (600 mg, 4.88
mmol) in THF (0.98 mL) at room temperature. The reaction mixture
was stirred at room temperature for 15 h, and then Et2O (40 mL) and
H2O (20 mL) were successively added. The resultant mixture was
extracted with Et2O (50 and 30 mL), and the combined organic layers
were washed with H2O (30 mL) and brine (30 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified twice by
flash column chromatography on silica gel (40 g, hexane to hexane/
EtOAc 20/1; 40 g, hexane/EtOAc 20/1) to afford 3aa (297 mg, 0.555
DIPHOS (1.48 g, 3.72 mmol) and CBr4 (827 mg, 2.49 mmol) were
successively added to a solution of the above crude 21 in CH2Cl2 (12
mL) to 0 °C. The reaction mixture was stirred at 0 °C for 15 min and
then was directly subjected to medium-pressure liquid chromatog-
raphy on silica gel (45 g, hexane/EtOAc 20/1 to 8/1) to afford
bromide 22, which was immediately used in the next reaction.
CuCl (181 mg, 1.83 mmol) was dried at 90 °C in vacuo, and then
THF (25 mL) was added. Ethynylmagnesium bromide (11′; 0.5 M in
THF, 27 mL, 14 mmol) was added to the suspension at room
temperature. The mixture was stirred for 10 min at room temperature,
and then a solution of the above bromide 22 in THF (30 mL) was
added. The reaction mixture was stirred at room temperature for 14 h,
and then saturated aqueous NH4Cl (50 mL) was added. The resultant
solution was filtered through a pad of Celite, and the filtrate was
extracted with EtOAc (50 and 30 mL). The combined organic layers
were washed with H2O (30 mL) and brine (30 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel (40 g, hexane/EtOAc 20/1 to 9/
1) to afford triyne 4 (228 mg, 1.04 mmol) in 24% yield over three
steps. Triyne 4 was immediately used in the next reaction due to its
31
1
mmol) in 68% yield: colorless oil; [α]D +47 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3) δ 6.64 (dd, J = 14.8, 5.5 Hz, 1H), 6.33 (dd, J
= 14.8, 1.4 Hz, 1H), 6.03 (dd, J = 16.0, 6.0 Hz, 1H), 5.61 (ddt, J =
16.0, 2.3, 1.8 Hz, 1H), 4.24 (td, J = 6.9, 5.5, 1.4 Hz, 1H), 4.08 (td, J =
6.0, 6.0 Hz, 1H), 2.49 (ddd, J = 16.9, 6.9, 2.3 Hz, 1H), 2.42 (ddd, J =
16.9, 6.9, 2.3 Hz, 1H), 1.50 (qd, J = 7.3, 6.0 Hz, 2H), 0.899 (s, 9H),
0.896 (s, 9H), 0.87 (t, J = 7.8 Hz, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.05
(s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.6, 145.7,
108.8, 86.1, 81.1, 76.7, 74.0, 73.6, 30.7, 28.8, 25.9 (×3), 25.7 (×3),
18.22, 18.19, 9.3, −4.5, −4.7, −4.86, −4.89; IR (neat) ν 2956, 2929,
2857, 1607, 1471, 1463, 1362, 1255, 1092 cm−1; HRMS (ESI) calcd
for C23H43IO2Si2Na 557.1738 [M + Na]+, found 557.1733.
C12−C22 Fragment 3ab. According to the synthetic procedure
of 3aa, 3ab (218 mg, 0.407 mmol) was synthesized from aldehyde
20ab (384 mg, 0.934 mmol) in 44% yield by using iodoform (739 mg,
I
DOI: 10.1021/acs.joc.5b01461
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
instability in air: yellow oil; 1H NMR (400 MHz, CDCl3) δ 4.96 (t, J =
4.6 Hz, 1H), 4.00−3.91 (m, 2H), 3.91−3.82 (m, 2H), 3.17 (dt, J = 2.7,
2.3 Hz, 2H), 3.13 (tt, J = 2.3, 2.3 Hz, 2H), 2.30 (tt, J = 7.2, 2.3 Hz,
2H), 2.06 (t, J = 2.7 Hz, 1H), 1.85 (td, J = 7.3, 4.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 103.2, 79.7, 78.1, 75.5, 73.9, 73.4, 68.7, 64.9
(×2), 32.9, 13.6, 9.7, 9.6; IR (neat) ν 3287, 2887, 1413, 1317, 1138,
1038 cm−1.
(3.0 mL) was stirred 0 °C for 1 h under an H2 atmosphere (1 atm).
Then Lindlar catalyst (39 mg) was added. The reaction mixture was
stirred at 0 °C for a further 40 min under an H2 atmosphere and was
filtered through a pad of Celite with hexane. The filtrate was
concentrated, and the residue was purified by flash column
chromatography on silica gel (4 g, hexane to hexane/EtOAc 9/1)
and twice on Chromatorex-ACD (10 g, hexane/EtOAc 500/1 to 300/
1; 8 g, hexane/EtOAc 500/1 to 200/1) to afford alkyne 24aa (18.1
Tetrayne 2aa. Pd(PPh3)4 (92 mg, 80 μmol), CuI (32 mg, 0.17
mmol), a solution of C12−C22 fragment 3aa (278 mg, 0.520 mmol)
in benzene (4.5 mL), and piperidine (0.16 mL, 1.6 mmol) were
successively added to a solution of 4 (157 mg, 0.777 mmol) in
benzene (14 mL) at room temperature. The reaction mixture was
stirred at room temperature for 15 h, and then Et2O (10 mL) and
saturated aqueous NH4Cl (40 mL) were successively added. The
resultant mixture was extracted with Et2O (30 and 10 mL), and the
combined organic layers were washed with H2O (20 mL) and brine
(20 mL), dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography on silica gel (30 g,
hexane/EtOAc 15/1) to afford tetrayne 2aa (223 mg, 0.366 mmol) in
70% yield. Tetrayne 2aa was immediately used in the next reaction due
27
mg, 29.4 μmol) in 55% yield: colorless oil; [α]D +41 (c 0.81,
1
CHCl3); H NMR (400 MHz, C6D6) δ 6.74 (dd, J = 15.6, 11.4 Hz,
1H), 6.19 (dd, J = 15.6, 6.0 Hz, 1H), 6.02 (dd, J = 11.4, 11.4 Hz, 1H),
5.86 (ddt, J = 15.6, 1.4, 1.4 Hz, 1H), 5.77 (dd, J = 15.6, 6.0 Hz, 1H),
5.50−5.47 (m, 5H), 4.84 (t, J = 4.6 Hz, 1H), 4.38 (dt, J = 6.4, 6.0 Hz,
1H), 3.93 (dt, J = 6.0, 6.0 Hz, 1H), 3.60−3.52 (m, 2H), 3.42−3.35 (m,
2H), 2.99 (t, J = 6.4 Hz, 2H), 2.87 (m, 2H), 2.59 (ddd, J = 16.9, 7.3,
2.3 Hz, 1H), 2.45 (ddd, J = 16.9, 5.9, 2.3 Hz, 1H), 2.31 (m, 2H), 1.81
(m, 2H), 1.43 (m, 2H), 1.04 (s, 9H), 0.97 (s, 9H), 0.83 (t, J = 7.3 Hz,
3H), 0.16 (s, 3H), 0.12 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 145.2, 135.6, 129.9, 129.2, 128.6, 128.3, 128.0,
127.6, 124.7, 109.0, 104.1, 87.3, 80.4, 73.7, 72.0, 64.9 (×2), 33.7, 30.7,
29.6, 26.0, 25.83 (×3), 25.80 (×3), 25.5, 21.9, 18.3, 18.2, 9.3, −4.5,
−4.6, −4.8, −4.9; IR (neat) ν 2961, 2926, 2855, 1733, 1457, 1260,
1029 cm−1; HRMS (ESI) calcd for C36H62O4Si2Na 637.4079 [M +
Na]+, found 637.4094.
Alkyne 24ab. According to the synthetic procedure of 24aa, 24ab
(87.8 mg, 0.143 mmol) was synthesized from 2ab (86.9 mg, 0.143
mmol) in 100% yield by using Lindlar catalyst (180 mg) and quinoline
(0.20 mL, 1.4 mmol) in hexane (8.8 mL). Purification was performed
by flash column chromatography on silica gel (10 g, hexane/EtOAc
30/1): colorless oil; [α]D19 +16 (c 1.4, CHCl3); HRMS (ESI) calcd for
C36H62O4Si2Na 637.4079 [M + Na]+, found 637.4083. The other
analytical data of 24ab were identical with those of 24ba.
1
to its instability in air: pale yellow oil; H NMR (400 MHz, C6D6) δ
6.20 (dd, J = 15.6, 5.5 Hz, 1H), 6.16 (dd, J = 15.6, 5.5 Hz, 1H), 5.87−
5.78 (m, 2H), 4.87 (t, J = 5.0 Hz, 1H), 4.16 (td, J = 6.0, 5.5 Hz, 1H),
3.91 (td, J = 6.0, 5.5 Hz, 1H), 3.47−3.38 (m, 2H), 3.33−3.25 (m, 2H),
2.94 (s, 2H), 2.85 (br s, 2H), 2.41 (dd, J = 16.0, 6.9 Hz, 1H), 2.30 (dd,
J = 16.0, 6.4 Hz, 1H), 2.28 (br t, J = 7.8 Hz, 2H), 1.86 (td, J = 7.8, 5.0
Hz, 2H), 1.42 (qd, J = 7.3, 6.0 Hz, 2H), 0.97 (s, 9H), 0.95 (s, 9H),
0.83 (t, J = 7.3 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.00
(s, 3H); 13C NMR (100 MHz, C6D6) δ 145.6, 144.8, 110.1, 109.9,
103.4, 87.5, 85.2, 81.2, 80.1, 79.1, 75.8, 74.5, 74.4, 74.1, 71.9, 64.8
(×2), 33.6, 31.1, 29.5, 26.1 (×3), 26.0 (×3), 18.43, 18.41, 14.0, 10.5,
9.9, 9.5, −4.3, −4.5, −4.71, −4.73; HRMS (ESI) calcd for
C36H56O4Si2Na 631.3609 [M + Na]+, found 631.3587.
Alkyne 24ba. According to the synthetic procedure of 24aa, 24ba
(34.0 mg, 55.3 μmol) was synthesized from 2ba (61.7 mg, 0.101
mmol) in 55% yield by using Lindlar catalyst (500 mg) and quinoline
(0.14 mL, 1.2 mmol) in hexane (6.2 mL). Purification was performed
by flash column chromatography on silica gel (4 g, hexane to hexane/
EtOAc 30/1 to 20/1) and three times on Chromatorex-ACD (20 g,
hexane/EtOAc 300/1 to 100/1; 15 g, hexane/EtOAc 300/1 to 100/1;
15 g, hexane/EtOAc 300/1 to 100/1): colorless oil; [α]D24 −20 (c 1.7,
Tetrayne 2ab. According to the synthetic procedure of 2aa, 2ab
(175 mg, 0.287 mmol) was synthesized from 3ab (218 mg, 0.407
mmol) and 4 (98 mg, 0.49 mmol) in 71% yield by using Pd(PPh3)4
(69 mg, 60 μmol), CuI (23 mg, 0.12 mmol), and piperidine (0.12 mL,
1.6 mmol) in benzene (14 mL). Purification was performed by flash
column chromatography on silica gel (30 g, hexane to hexane/EtOAc
1
15/1): pale yellow oil; H NMR (400 MHz, C6D6) δ 6.20 (dd, J =
1
15.1, 5.0 Hz, 1H), 6.16 (dd, J = 15.6, 5.5 Hz, 1H), 5.88−5.78 (m, 2H),
4.87 (t, J = 5.0 Hz, 1H), 4.16 (dt, J = 6.0, 6.0 Hz, 1H), 3.92 (dt, J = 6.0,
6.0 Hz, 1H), 3.47−3.38 (m, 2H), 3.33−3.27 (m, 2H), 2.94 (d, J = 2.3
Hz, 2H), 2.85 (tt, J = 2.3, 2.3 Hz, 2H), 2.42 (ddd, J = 16.5, 6.9, 1.8 Hz,
1H), 2.30 (ddd, J = 16.5, 6.0, 1.8 Hz, 1H), 2.28 (tt, J = 7.3, 2.3 Hz,
2H), 1.86 (td, J = 7.3, 5.0 Hz, 2H), 1.41 (qd, J = 7.3, 6.0 Hz, 2H), 0.97
(s, 9H), 0.95 (s, 9H), 0.83 (t, J = 7.3 Hz, 3H), 0.06 (s, 3H), 0.05 (s,
3H), 0.03 (s, 3H) 0.00 (3H, s); 13C NMR (100 MHz, C6D6) δ 145.6,
144.8, 110.1, 109.9, 103.4, 87.5, 85.2, 81.2, 80.1, 79.1, 75.8, 74.5, 74.4,
74.1, 71.9, 64.8 (×2), 33.6, 31.1, 29.5, 26.1 (×3), 26.0 (×3), 18.43,
18.42, 14.0, 10.5, 9.9, 9.5, −4.3, −4.5, −4.72, −4.74.
CHCl3); H NMR (400 MHz, C6D6) δ 6.75 (dd, J = 15.6, 11.4 Hz,
1H), 6.19 (dd, J = 15.6, 6.0 Hz, 1H), 6.02 (dd, J = 11.4, 11.4 Hz, 1H),
5.86 (ddt, J = 15.6, 1.4, 1.4 Hz, 1H), 5.77 (dd, J = 15.6, 6.0 Hz, 1H),
5.50−5.47 (m, 5H), 4.84 (t, J = 4.6 Hz, 1H), 4.38 (dt, J = 6.4, 6.0 Hz,
1H), 3.93 (dt, J = 6.0, 6.0 Hz, 1H), 3.60−3.52 (m, 2H), 3.42−3.35 (m,
2H), 3.00 (t, J = 6.4 Hz, 2H), 2.87 (m, 2H), 2.59 (ddd, J = 16.9, 7.3,
2.3 Hz, 1H), 2.45 (ddd, J = 16.9, 5.9, 2.3 Hz, 1H), 2.31 (m, 2H), 1.81
(m, 2H), 1.43 (m, 2H), 1.04 (s, 9H), 0.97 (s, 9H), 0.84 (t, J = 7.3 Hz,
3H), 0.17 (s, 3H), 0.12 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 145.2, 135.6, 129.9, 129.2, 128.6, 128.3, 128.0,
127.7, 124.7, 109.0, 104.1, 87.3, 80.4, 73.7, 72.0, 64.9 (×2), 33.7, 30.7,
29.6, 26.0, 25.84 (×3), 25.81 (×3), 25.6, 21.9, 18.3, 18.2, 9.3, −4.5,
−4.6, −4.8, −4.9; IR (neat) ν 2956, 2928, 2856, 1472, 1255, 1136
cm−1; HRMS (ESI) calcd for C36H62O4Si2Na 637.4079 [M + Na]+,
found 637.4080.
Tetrayne 2ba. According to the synthetic procedure of 2aa, 2ba
(174 mg, 0.286 mmol) was synthesized from 3ba (218 mg, 0.407
mmol) and 4 (127 mg, 0.629 mmol) in 70% yield by using Pd(PPh3)4
(74 mg, 64 μmol), CuI (23 mg, 0.12 mmol), and piperidine (0.12 mL,
1.6 mmol) in benzene (14.5 mL). Purification was performed by flash
column chromatography on silica gel (15 g, hexane to hexane/EtOAc
15/1): pale yellow oil; HRMS (ESI) calcd for C36H56O4Si2Na
Allkyne 24bb. According to the synthetic procedure of 24aa, 24bb
(51.7 mg, 84.1 μmol) was synthesized from 2bb (68.4 mg, 0.112
mmol) in 75% yield by using Lindlar catalyst (173 mg) and quinoline
(0.16 mL, 1.4 mmol) in hexane (7.0 mL). Purification was performed
by flash column chromatography on silica gel (10 g, hexane to hexane/
EtOAc 20/1) and twice on Chromatorex-ACD (20 g, hexane/EtOAc
500/1 to 100/1; 15 g, hexane/EtOAc 300/1 to 100/1): colorless oil;
1
631.3609 [M + Na]+, found 631.3613. The H NMR spectrum of
2ba was identical with that of 2ab.
Tetrayne 2bb. According to the synthetic procedure of 2aa, 2bb
(144 mg, 0.236 mmol) was synthesized from 3bb (203 mg, 0.380
mmol) and 4 (93 mg, 0.460 mmol) in 62% yield by using Pd(PPh3)4
(65 mg, 56 μmol), CuI (22 mg, 0.12 mmol), and piperidine (0.12 mL,
1.20 mmol) in benzene (13 mL). Purification was performed by flash
column chromatography on silica gel (30 g, hexane to hexane/EtOAc
21
[α]D −43 (c 0.69, CHCl3).. The other analytical data of 24bb were
identical with those of 24aa.
Complex 25aa. Co2(CO)8 (69 mg, 0.20 mmol) was added to a
solution of 24aa (31.1 mg, 50.5 mmol) in CH2Cl2 (4.5 mL) at 0 °C.
The reaction mixture was warmed to room temperature, stirred for 2
h, and then concentrated. The residue was directly subjected to flash
column chromatography on silica gel (8 g, hexane to hexane/EtOAc
20/1) to afford 25aa (42.2 mg, 46.8 mol) in 93% yield: brown oil; 1H
1
15/1): pale yellow oil. The H NMR spectrum of 2bb was identical
with that of 2aa.
Alkyne 24aa. A suspension of tetrayne 2aa (32.4 mg, 53.2 μmol),
quinoline (75 μL, 0.64 mmol), and Lindlar catalyst (65 mg) in hexane
J
DOI: 10.1021/acs.joc.5b01461
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The Journal of Organic Chemistry
Article
NMR (400 MHz, CDCl3) δ 6.62 (d, J = 15.6 Hz, 1H), 6.58 (dd, J =
15.6, 11.5 Hz, 1H), 6.00 (dd, J = 11.5, 11.5 Hz, 1H), 5.99 (dd, J = 15.6,
6.0 Hz, 1H), 5.74 (dd, J = 15.6, 6.0 Hz, 1H), 5.47−5.30 (m, 5H), 4.87
(t, J = 4.6 Hz, 1H), 4.44 (td, J = 6.0, 5.0 Hz, 1H), 4.13 (td, J = 6.4, 6.0
Hz, 1H), 4.01−3.91 (m, 2H), 3.90−3.80 (m, 2H), 3.26−3.15 (m, 2H),
3.00−2.89 (m, 2H), 2.82 (t, J = 6.4 Hz, 2H), 2.20 (td, J = 7.3, 7.3 Hz,
2H), 1.72 (m, 2H), 1.54 (m, 2H), 0.93 (s, 9H), 0.90 (s, 9H), 0.89 (t, J
= 7.8 Hz, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 140.4, 135.3, 130.5, 129.2, 128.7,
128.3, 128.0, 127.6, 126.4, 125.9, 104.1, 93.8, 74.4, 73.6, 64.9 (×2),
44.0, 33.7, 31.0, 26.0, 25.9 (×3), 25.8 (×3), 25.5, 21.9, 18.34, 18.26,
9.6, −4.46, 4.54, −4.8, some of the 13C peaks were missing due to
broadening of the spectrum; IR (neat) ν 2956, 2930, 2858, 2088,
(ESI) calcd for C36H64O4Si2Na 639.4235 [M + Na]+, found 639.4233.
The H NMR spectrum of 23aa was identical with that of 23bb.
1
Hexaene 23ab. According to the synthetic procedure of 23aa,
23ab (47.2 mg, 76.6 μmol) was synthesized from 25ab (80.2 mg, 89.1
μmol) in 86% yield by using n-Bu3SnH (0.34 mL, 1.3 mmol) and N-
methylmorpholine oxide (101 mg, 0.86 mmol) in toluene (45 mL).
Purification was performed twice by flash column chromatography on
silica gel (10 g, hexane to hexane/EtOAc 20/1; 8 g, hexane to hexane/
EtOAc 20/1): colorless oil; [α]D22 +21 (c 0.96, CHCl3); HRMS (ESI)
calcd for C36H64O4Si2Na 639.4235 [M + Na]+, found 639.4246. The
other analytical data of 23ab were identical with those of 23ba.
Hexaene 23ba. According to the synthetic procedure of 23aa,
23ba (24.5 mg, 39.7 μmol) was synthesized from 25ba (41.3 mg, 45.9
μmol) in 86% yield by using n-Bu3SnH (0.19 mL, 0.71 mmol) and N-
methylmorpholine oxide (54 mg, 0.46 mmol) in toluene (40 mL).
Purification was performed by flash column chromatography (a
column consecutively packed with silica gel 3 g and 10% (w/w) KF in
silica gel 1 g, hexane to hexane/EtOAc 20/1): colorless oil; [α]D23 −24
2048, 2018, 1255, 1061 cm−1
; HRMS (ESI) calcd for
C42H62Co2O10Si2Na 923.2438 [M + Na]+, found 923.2457.
Complex 25ab. According to the synthetic procedure of 25aa,
25ab (80.2 mg, 89.1 μmol) was synthesized from 24ab (54.2 mg, 88.1
μmol) in 99% yield by using Co2(CO)8 (119 mg, 0.348 mmol) in
CH2Cl2 (6.0 mL). Purification was performed by flash column
chromatography on silica gel (8 g, hexane to hexane/EtOAc 20/1):
brown oil; HRMS (ESI) calcd for C42H62Co2O10Si2Na 923.2438 [M +
1
(c 0.85, CHCl3); H NMR (400 MHz, CDCl3) δ 6.48 (dd, J = 15.6,
11.4 Hz, 1H), 6.38 (dd, J = 15.6, 11.0 Hz, 1H), 6.04 (dd, J = 11.4, 11.0
Hz, 1H), 5.98 (dd, J = 11.0, 11.0 Hz, 1H), 5.66 (dd, J = 15.6, 6.0 Hz,
1H), 5.62 (dd, J = 15.6, 6.0 Hz, 1H), 5.48−5.32 (m, 6H), 4.87 (t, J =
5.0 Hz, 1H), 4.22 (td, J = 6.0, 6.0 Hz, 1H), 4.07 (dt, J = 6.4, 6.0 Hz,
1H), 4.02−3.91 (m, 2H), 3.90−3.80 (m, 2H), 2.95 (t, J = 6.4 Hz, 2H),
2.83 (t, J = 6.4 Hz, 2H), 2.40 (m, 2H), 2.21 (td, J = 8.2, 6.9 Hz, 2H),
1.72 (m, 2H), 1.52 (m, 2H), 0.90 (s, 18H), 0.87 (t, J = 7.3 Hz, 3H),
0.05 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 137.2, 136.6, 129.8, 129.5, 129.1, 128.6, 128.3, 128.2, 127.7, 127.0,
124.7, 124.5, 104.1, 74.5, 72.9, 64.8 (×2), 36.8, 33.7, 31.1, 26.0, 25.90
(×3), 25.86 (×3), 25.6, 21.9, 18.3, 18.2, 9.7, −4.3, −4.4, −4.7, −4.8; IR
(neat) ν 2956, 2927, 2856, 1471, 1462, 1362, 1255 cm−1; HRMS
(ESI) calcd for C36H64O4Si2Na 639.4235 [M + Na]+, found 639.4247.
Hexaene 23bb. According to the synthetic procedure of 23aa,
23bb (52.4 mg, 84.9 μmol) was synthesized from 25bb (92.0 mg,
0.102 mmol) in 83% yield by using n-Bu3SnH (0.40 mL, 1.50 mmol)
and N-methylmorpholine oxide (119 mg, 1.02 mmol) in toluene (50
mL). Purification was performed twice by flash column chromatog-
raphy on silica gel (5 g, hexane to hexane/EtOAc 20/1; 10 g, hexane
to hexane/EtOAc 20/1): colorless oil; [α]D21 −10 (c 1.1, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 6.48 (dd, J = 15.6, 11.4 Hz, 1H), 6.38 (dd,
J = 15.6, 11.0 Hz, 1H), 6.04 (dd, J = 11.4, 11.0 Hz, 1H), 5.98 (dd, J =
11.0, 11.0 Hz, 1H), 5.66 (dd, J = 15.6, 6.0 Hz, 1H), 5.62 (dd, J = 15.6,
6.0 Hz, 1H), 5.48−5.32 (m, 6H), 4.87 (t, J = 5.0 Hz, 1H), 4.22 (td, J =
6.0, 6.0 Hz, 1H), 4.07 (dt, J = 6.4, 6.0 Hz, 1H), 4.02−3.91 (m, 2H),
3.90−3.80 (m, 2H), 2.94 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.4 Hz, 2H),
2.40 (m, 2H), 2.21 (td, J = 8.2, 6.9 Hz, 2H), 1.72 (m, 2H), 1.52 (m,
2H), 0.90 (s, 18H), 0.87 (t, J = 7.3 Hz, 3H), 0.07 (s, 3H), 0.05 (s, 3H),
0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 137.2,
136.6, 129.8, 129.5, 129.2, 128.6, 128.3, 128.2, 127.7, 126.9, 124.6,
124.5, 104.1, 74.4, 72.9, 64.9 (×2), 36.8, 33.7, 31.1, 26.0, 25.90 (×3),
25.87 (×3), 25.6, 21.9, 18.3, 18.2, 9.7, −4.3, −4.4, −4.7, −4.8; HRMS
(ESI) calcd for C36H64O4Si2Na 639.4235 [M + Na]+, found 639.4240.
(14S,20R)-1aa. TMSOTf (0.15 mL, 0.83 mmol) was added to a
solution of 23aa (34.1 mg, 55.3 μmol) and 2,6-lutidine (0.15 mL, 1.3
mmol) in CH2Cl2 (3.5 mL) at −10 °C. The reaction mixture was
stirred at −10 °C for 45 min, and then H2O (1.0 mL) was added. The
resultant mixture was warmed to room temperature and stirred for 30
min. Then the mixture was extracted with EtOAc (8 mL × 2), and the
combined organic layers were washed with aqueous 0.1 M HCl (4
mL), H2O (4 mL), and brine (4 mL), dried over Na2SO4, filtered, and
concentrated. The residue was purified by flash column chromatog-
raphy on silica gel (4 g, hexane to hexane/EtOAc 20/1) to afford the
crude aldehyde 27aa, which was used in the next reaction without
1
Na]+, found 923.2507. The H NMR spectrum of 25ab was identical
with that of cobalt complex 25ba.
Complex 25ba. According to the synthetic procedure of 25aa,
25ba (41.3 mg, 45.9 μmol) was synthesized from 24ba (30.5 mg, 49.6
μmol) in 92% yield by using Co2(CO)8 (69 mg, 0.20 mmol) in
CH2Cl2 (4.4 mL). Purification was performed by flash column
chromatography on silica gel (4 g, hexane to hexane/EtOAc 20/1):
brown oil; 1H NMR (400 MHz, CDCl3) δ 6.62 (d, J = 15.6 Hz, 1H),
6.59 (dd, J = 15.6, 11.5 Hz, 1H), 6.00 (dd, J = 11.5, 11.5 Hz, 1H), 5.99
(dd, J = 15.6, 6.0 Hz, 1H), 5.75 (dd, J = 15.6, 6.0 Hz, 1H), 5.47−5.30
(m, 5H), 4.87 (t, J = 4.6 Hz, 1H), 4.44 (td, J = 6.0, 5.0 Hz, 1H), 4.13
(td, J = 6.4, 6.0 Hz, 1H), 4.01−3.91 (m, 2H), 3.90−3.80 (m, 2H),
3.26−3.15 (m, 2H), 3.00−2.89 (m, 2H), 2.81 (t, J = 6.4 Hz, 2H), 2.20
(td, J = 7.3, 7.3 Hz, 2H), 1.72 (m, 2H), 1.54 (m, 2H), 0.93 (s, 9H),
0.90 (s, 9H), 0.88 (t, J = 7.8 Hz, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.07
(s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.7, 140.5,
135.3, 130.4, 129.2, 128.7, 128.3, 128.0, 127.6, 126.4, 125.8, 104.1,
93.7, 91.8, 74.3, 73.5, 64.9 (×2), 44.0, 33.7, 31.0, 26.0, 25.9 (×3), 25.8
(×3), 25.5, 21.9, 18.33, 18.26, 9.6, −4.5, −4.6, −4.78, −4.80, some of
the 13C peaks were missing due to broadening of the spectrum; IR
(neat) ν 2955, 2929, 2857, 2088, 2048, 2018, 1472, 1255, 1062 cm−1;
HRMS (ESI) calcd for C42H62Co2O10Si2Na 923.2438 [M + Na]+,
found 923.2425.
Complex 25bb. According to the synthetic procedure of 25aa,
25bb (92.0 mg, 0.102 mmol) was synthesized from 24bb (66.0 mg,
0.107 mmol) in 95% yield by using Co2(CO)8 (149 mg, 0.436 mmol)
in CH2Cl2 (10 mL). Purification was performed by flash column
chromatography on silica gel (10 g, hexane to hexane/EtOAc 20/1):
brown oil; HRMS (ESI) calcd for C42H62Co2O10Si2Na 923.2438 [M +
1
Na]+, found 923.2449. The H NMR spectrum of 25bb was identical
with that of complex 25aa.
Complex 26aa. Co2(CO)8 (213 mg, 0.623 mmol) was added to a
solution of 2aa (38.3 mg, 62.8 μmol) in CH2Cl2 (5.0 mL) at 0 °C. The
reaction mixture was warmed to room temperature, stirred for 4 h, and
then concentrated. The residue was directly subjected to flash column
chromatography on silica gel (10 g, hexane to hexane/EtOAc 20/1) to
afford 26aa (104 mg, 59.4 μmol) in 94% yield: brown oil. Because
1
signals in the H NMR spectrum of 26aa were broad, the formation
was confirmed by the MS analysis: LRMS (ESI) calcd for
C60H56Co8O28Si2Na 1774.7 [M + Na]+, found 1774.7.
Hexaene 23aa. n-Bu3SnH (0.19 mL, 0.71 mmol) and N-
methylmorpholine oxide (55 mg, 0.47 mmol) were successively
added to a solution of 25aa (42.2 mg, 46.9 μmol) in toluene (45 mL)
at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h under air
and was directly subjected to flash column chromatography (a column
consecutively packed with silica gel 4 g and 10% (w/w) KF in silica gel
4 g, hexane to hexane/EtOAc 20/1) to afford 23aa (25.2 mg, 40.8
1
further purification. Aldehyde 27aa: H NMR (400 MHz, CDCl3) δ
9.77 (s, 1H), 6.47 (dd, J = 15.1, 11.0 Hz, 1H), 6.38 (dd, J = 15.1, 11.0
Hz, 1H), 6.04 (dd, J = 11.0, 11.0 Hz, 1H), 5.91 (dd, J = 11.0, 11.0 Hz,
1H), 5.67 (dd, J = 15.1, 6.0 Hz, 1H), 5.62 (dd, J = 15.1, 6.4 Hz, 1H),
5.46−5.30 (m, 6H), 4.23 (q, J = 6.0 Hz, 2H), 4.07 (dt, J = 6.4, 6.0 Hz,
2H), 2.95 (t, J = 6.4 Hz, 2H), 2.84 (t, J = 5.9 Hz, 2H), 2.50 (t, J = 6.8
Hz, 2H), 2.40 (m, 4H), 1.50 (m, 2H), 0.90 (s, 18H), 0.87 (t, J = 7.3
27
mmol) in 87% yield: colorless oil; [α]D +10 (c 0.93, CHCl3); IR
(neat) ν 2955, 2928, 2856, 1471, 1463, 1361, 1255 cm−1; HRMS
K
DOI: 10.1021/acs.joc.5b01461
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz, 3H), 0.05 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 201.9, 137.2, 136.7, 129.8, 129.3, 129.2, 128.3, 128.2,
128.0, 127.7, 126.9, 124.5, 124.3, 74.4, 72.9, 43.7, 36.8, 31.1, 26.1,
25.90 (×3), 25.87 (×3), 25.6, 20.1, 18.3, 18.2, 9.7, −4.3, −4.4, −4.7,
−4.8.
UV (MeOH) λmax 236 nm (ε 2.60 × 104). The other analytical data of
1ab were identical with those of 1ba.
(14R,20R)-1ba. According to the synthetic procedure of 1aa, 1ba
(5.60 mg, 15.6 μmol) was synthesized from 23ba (40.7 mg, 66.0
μmol) in 24% yield over three steps by using TMSOTf (0.18 mL, 0.99
mmol) and 2,6-lutidine (0.18 mL, 1.5 mmol) in CH2Cl2 (4.2 mL) for
the first step, NaClO2 (80% purity, 68 mg, 0.60 mmol) and NaH2PO4·
2H2O (99 mg, 0.64 mmol) in a 1/1/1 mixture of t-BuOH, 2-methyl-2-
butene, and H2O (4.5 mL) for the second, and TBAF (1.0 M in THF,
0.66 mL, 0.66 mmol) in THF (4.2 mL) for the third. Purification was
performed by flash column chromatography on silica gel (4 g, hexane/
EtOAc 4/1 to 3/1) for the second step and by flash column
chromatography on silica gel (4 g, hexane/EtOAc/AcOH 40/60/0.05
to 50/50/0.05 to 40/60/0.05) and HPLC (Inertsil ODS-4, MeOH/
H2O/AcOH 7/3/0.1 3 mL/min, tR = 33 min) for the third. Aldehyde
27ba: 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 6.47 (dd, J = 15.1,
11.0 Hz, 1H), 6.38 (dd, J = 15.1, 11.0 Hz, 1H), 6.04 (dd, J = 11.0, 11.0
Hz, 1H), 5.91 (dd, J = 11.0, 11.0 Hz, 1H), 5.67 (dd, J = 15.1, 6.0 Hz,
1H), 5.62 (dd, J = 15.1, 6.4 Hz, 1H), 5.46−5.30 (m, 6H), 4.23 (m,
2H), 4.07 (dt, J = 6.4, 6.0 Hz, 2H), 2.95 (t, J = 6.4 Hz. 2H), 2.84 (t, J =
5.9 Hz, 2H), 2.50 (t, J = 6.8 Hz, 2H), 2.40 (m, 4H), 1.50 (m, 2H),
0.90 (s, 18H), 0.87 (t, J = 7.3 Hz, 3H), 0.05 (s, 6H), 0.04 (s, 3H), 0.03
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.9, 137.2, 136.7, 129.8,
129.3, 129.2, 128.3, 128.2, 128.0, 127.4, 127.0, 124.6, 124.4, 74.5, 72.8,
43.7, 36.8, 31.1, 26.0, 25.91 (×3), 25.86 (×3), 25.6, 20.1, 18.3, 18.2,
A solution of NaClO2 (80% purity, 55 mg, 0.49 mmol) and
NaH2PO4·2H2O (80 mg, 0.52 mmol) in H2O (1.5 mL) was added to a
solution of the above crude aldehyde 27aa in a mixture of t-BuOH (1.5
mL) and 2-methyl-2-butene (1.5 mL) at 0 °C. The reaction mixture
was warmed to room temperature and stirred for 1 h. Then the
mixture was extracted with EtOAc (8 mL × 2), and the combined
organic layers were washed with H2O (4 mL) and brine (4 mL), dried
over anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash column chromatography on silica gel (4 g, hexane/
EtOAc 4/1 to 3/1) to afford the crude carboxylic acid 28aa, which was
used in the next reaction without further purification. Carboxylic acid
28aa: 1H NMR (400 MHz, CDCl3) δ 6.47 (dd, J = 15.1, 11.0 Hz, 1H),
6.38 (dd, J = 15.1, 11.0 Hz, 1H), 6.04 (dd, J = 11.0, 11.0 Hz, 1H), 5.98
(dd, J = 11.0, 11.0 Hz, 1H), 5.67 (dd, J = 15.1, 6.0 Hz, 1H), 5.62 (dd, J
= 15.1, 6.4 Hz, 1H), 5.46−5.30 (m, 6H), 4.23 (dt, J = 6.0, 6.0 Hz, 2H),
4.07 (dt, J = 6.4, 6.4 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.84 (t, J = 6.0
Hz, 2H), 2.42−2.35 (m, 6H), 1.55−1.44 (m, 2H), 0.90 (s, 18H), 0.87
(t, J = 7.3 Hz, 3H), 0.05 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 137.2, 136.6, 129.8, 129.5, 129.3, 128.3 (×2),
128.0, 127.6, 126.9, 124.6, 124.4, 74.4, 72.9, 36.8, 33.9, 31.1, 26.0,
25.91 (×3), 25.87 (×3), 25.6, 22.5, 18.3, 18.2, 9.7, −4.3, −4.4, −4.7,
−4.8, the C1 peak was missing due to broadening of the spectrum;
HRMS (ESI) calcd for C34H59O4Si2 587.3957 [M − H]−, found
587.3951.
1
9.7, −4.3, −4.4, −4.7, −4.8. Carboxylic acid 28ba: H NMR (400
MHz, CDCl3) δ 6.47 (dd, J = 15.1, 11.0 Hz, 1H), 6.38 (dd, J = 15.1,
11.0 Hz, 1H), 6.04 (d, J = 11.0, 11.0 Hz, 1H), 5.98 (dd, J = 11.0, 11.0
Hz, 1H), 5.67 (dd, J = 15.1, 6.0 Hz, 1H), 5.62 (dd, J = 15.1, 6.4 Hz,
1H), 5.46−5.30 (m, 6H), 4.23 (dt, J = 6.0, 6.0 Hz, 2H), 4.07 (dt, J =
6.4, 6.4 Hz, 2H), 2.95 (t, J = 6.4 Hz, 2H), 2.84 (t, J = 6.0 Hz, 2H),
2.42−2.35 (m, 6H), 1.55−1.44 (m, 2H), 0.90 (s, 18H), 0.86 (t, J = 7.3
Hz, 3H), 0.05 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 137.2, 136.6, 129.8, 129.5, 129.3, 128.3, 128.2, 128.0,
127.6, 127.0, 124.7, 124.4, 74.5, 72.9, 36.8, 33.9, 31.1, 26.0, 25.91 (×3),
25.87 (×3), 25.6, 22.5, 18.3, 18.2, 9.7, −4.3, −4.4, −4.7, −4.8, the C1
peak was missing due to broadening of the spectrum; HRMS (ESI)
calcd for C34H59O4Si2 587.3957 [M − H]−, found 587.3974.
TBAF (1.0 M in THF, 0.55 mL, 0.55 mmol) was added to a
solution of the above crude carboxylic acid 28aa in THF (3.5 mL) at 0
°C. The reaction mixture was warmed to room temperature and
stirred for 18 h, and then saturated aqueous NH4Cl (4 mL) and 0.1 M
HCl (10 mL) were successively added. The resultant mixture was
extracted with EtOAc (10 and 5 mL), and the combined organic layers
were washed with H2O (5 mL) and brine (5 mL), dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash column
chromatography on silica gel (4 g, hexane/EtOAc/AcOH 40/60/0.05
to 50/50/0.05 to 40/60/0.05) to afford the crude (14S,20R)-1aa.
Then the crude 1aa was further purified by HPLC (Inertsil ODS-4,
MeOH/H2O/AcOH 7/3/0.1 3 mL/min, tR = 40 min) to afford 1aa
(10.0 mg, 27.8 μmol) in 50% over three steps. (14S,20R)-1aa: pale
27
(14R,20R)-1ba: pale yellow oil; [α]D −16 (c 0.28, MeOH); 1H
NMR (400 MHz, CD3OD) δ 6.58 (dd, J = 15.6, 11.0 Hz, 1H), 6.51
(ddt, J = 15.1, 11.0. 1.4 Hz, 1H), 6.08 (dd, J = 11.0, 11.0 Hz, 1H), 5.98
(dd, J = 11.0, 11.0 Hz, 1H), 5.69 (dd, J = 15.5, 6.4 Hz, 1H), 5.66 (dd, J
= 15.5, 6.4 Hz, 1H), 5.50−5.32 (m, 6H), 4.18 (dt, J = 6.4, 6.4 Hz, 1H),
4.01 (dt, J = 6.4, 6.4 Hz, 1H), 2.98 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 5.5
Hz, 2H), 2.52−2.27 (m, 6H), 1.53 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H);
13C NMR (100 MHz, CD3OD) δ 137.8, 137.1, 131.1, 130.8, 130.1,
129.6, 129.4, 129.3, 128.7, 128.1, 126.6, 126.5, 74.7, 73.1, 36.7, 31.2,
27.0, 26.5, 10.2, the C1, C2, and C3 peaks were missing due to
broadening of the spectrum; IR (neat) ν 3380, 3011, 2958, 2925,
2855, 1713, 1556, 1415, 1260 cm−1; HRMS (ESI) calcd for C22H31O4
359.2228 [M − H]−, found 359.2243.
18
yellow oil; [α]D −28 (c 0.42, MeOH); 1H NMR (400 MHz,
CD3OD) δ 6.57 (dd, J = 15.1, 11.0 Hz, 1H), 6.50 (dd, J = 15.1, 11.0
Hz, 1H), 6.08 (dd, J = 11.0, 11.0 Hz, 1H), 5.98 (dd, J = 11.0, 11.0 Hz,
1H), 5.69 (dd, J = 15.1, 6.9 Hz, 1H), 5.65 (dd, J = 15.1, 6.9 Hz, 1H),
5.50−5.32 (m, 6H), 4.18 (dt, J = 6.4, 6.4 Hz, 1H), 4.01 (dt, J = 6.4, 6.4
Hz, 1H), 2.98 (t, J = 6.4 Hz, 2H), 2.87 (m, 2H), 2.52−2.27 (m, 6H),
1.53 (m, 2H), 0.91 (t, J = 7.8 Hz, 3H); 13C NMR (100 MHz,
CD3OD) δ 137.8, 137.2, 131.1, 130.8, 130.2, 129.7, 129.5, 129.3,
128.7, 128.1, 126.7, 126.5, 74.8, 73.1, 36.8, 31.2, 27.0, 26.6, 10.2, the
C1, C2, and C3 peaks were missing due to broadening of the
spectrum; IR (neat) ν 3348, 3010, 2956, 2923, 2851, 1726, 1451,
1389, 1274 cm−1; HRMS (ESI) calcd for C22H31O4 359.2228 [M −
H]−, found 359.2222; UV (MeOH) λmax 237 nm (ε 2.82 × 104).
(14S,20S)-1ab. According to the synthetic procedure of 1aa, 1ab
(8.64 mg, 24.1 μmol) was synthesized from 23ab (47.2 mg, 76.4
μmol) in 32% yield over three steps by using TMSOTf (0.21 mL, 1.2
mmol) and 2,6-lutidine (0.20 mL, 1.7 mmol) in CH2Cl2 (4.7 mL) for
the first step, NaClO2 (80% purity, 76 mg, 0.67 mmol) and NaH2PO4·
2H2O (113 mg, 0.73 mmol) in a 1/1/1 mixture of t-BuOH, 2-methyl-
2-butene, and H2O (6.0 mL) for the second, and TBAF (1.0 M in
THF, 0.76 mL, 0.76 mmol) in THF (5.0 mL) for the third.
Purification was performed by flash column chromatography on
Chromatorex-ACD (8 g, hexane/EtOAc 4/1 to 3/1 to 3/2) for the
second step and by flash column chromatography on silica gel (6 g,
hexane/EtOAc/AcOH 40/60/0.05 to 30/70/0.05) and HPLC
(Inertsil ODS-4, MeOH/H2O/AcOH 7/3/0.1 3 mL/min, tR = 36
(14R,20S)-1bb. According to the synthetic procedure of 1aa, 1bb
(4.59 mg, 12.8 μmol) was synthesized from 23bb (22.0 mg, 35.6
μmol) in 36% yield over three steps by using TMSOTf (95 μL, 0.52
mmol) and 2,6-lutidine (95 μL, 0.82 mmol) in CH2Cl2 (2.2 mL) for
the first step, NaClO2 (80% purity, 35 mg, 0.31 mmol) and NaH2PO4·
2H2O (54 mg, 0.35 mmol) in a 1/1/1 mixture of t-BuOH, 2-methyl-2-
butene, and H2O (3.0 mL) for the second, and TBAF (1.0 M in THF,
0.36 mL, 0.36 mmol) in THF (2.3 mL) for the third. Purification was
performed by flash column chromatography on Chromatorex-ACD (4
g, hexane/EtOAc 4/1 to 3/1) for the second step and by flash column
chromatography on silica gel (4 g, hexane/EtOAc/AcOH 50/50/0.05
to 40/60/0.05) and HPLC (Inertsil ODS-4, MeOH/H2O/AcOH 7/
3/0.1 3 mL/min, tR = 42 min) for the third: pale yellow oil; [α]D17 +22
(c 0.21, MeOH); HRMS (ESI) calcd for C22H31O4 359.2228 [M −
H]−, found 359.2224. The other analytical data of 1bb were identical
with those of 1aa.
Bioassay. Peritonitis was induced as described in ref 36. Synthetic
1aa,ab,ba,bb (each 1 ng) were injected intravenously through the tail
vein followed by peritoneal injection of zymosan A (1 mg/mL). After
19
min) for the third: pale yellow oil; [α]D +13 (c 0.41, MeOH);
HRMS (ESI) calcd for C22H31O4 359.2228 [M-H]−, found 359.2223;
L
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2 h, peritoneal lavages were collected, PMN leucocyte numbers were
counted, cell viability was determined using Trypan blue exclusion,
and differential cell counts were monitored by Wright−Giemsa
staining.
2005, 46, 3623. Resolvin D6: (n) Rodriguez, A. R.; Spur, B. W.
Tetrahedron Lett. 2012, 53, 86. For a review on syntheses of
eicosanoids, see: (o) Nicolaou, K. C.; Ramphal, J. Y.; Petasis, N. A.;
Serhan, C. N. Angew. Chem., Int. Ed. Engl. 1991, 30, 1100.
(7) Yokokura, Y.; Isobe, Y.; Matsueda, S.; Iwamoto, R.; Goto, T.;
Yoshioka, T.; Urabe, D.; Inoue, M.; Arai, H.; Arita, M. J. Biochem.
2014, 156, 315.
Statistical Analysis. Results are expressed as means
SE.
Differences between two groups were tested by the Student t test.
Multiple comparisons were analyzed using ANOVA followed by the
Tukey test. Significance levels of P < 0.05 and P < 0.01 were used.
(8) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A. Tetrahedron
2000, 56, 327.
ASSOCIATED CONTENT
* Supporting Information
Figures giving NMR spectra for all isolated compounds. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b01461.
(9) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. For a review on Sonogashira coupling reactions, see:
(b) Marsden, J. A.; Haley, M. M. In Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A., Diederich, F., Ed.; Wiley-VCH, Weinheim,
Germany, 2004; Vol. 1, pp 317.
■
S
(10) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-
P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925. (c) Corey, E. J.;
Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611.
AUTHOR INFORMATION
Corresponding Author
*E-mail for M.I.: inoue@mol.f.u-tokyo.ac.jp.
Notes
■
(11) The enantiopurity of 15a,b was determined by 1H NMR
analyses of the corresponding MTPA esters.
(12) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
The authors declare no competing financial interest.
(13) Glycidol derivatives 6a/6b were synthesized from the
commercially available (R)-/(S)-glycidols (98% ee), respectively,
according to the literature. See: Mori, Y.; Asai, M.; Okumura, A.;
Furukawa, H. Tetrahedron 1995, 51, 5299.
(14) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(16) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(17) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(18) Epimerization of the C14-hydroxy group was not observed
during the vinyl iodide formation. The configurational stability of the
similar α-siloxy aldehydes was reported previously. See: (a) Nicolaou,
K. C.; Zipkin, R. E.; Dolle, R. E.; Harris, B. D. J. Am. Chem. Soc. 1984,
106, 3548. (b) Taffer, I. M.; Zipkin, R. E. Tetrahedron Lett. 1987, 28,
6543.
ACKNOWLEDGMENTS
■
This research was financially supported by the Funding
Program for a Grant-in-Aid for Scientific Research (A)
(JSPS) to M.I. and for Scientific Research (C) (JSPS) and on
Innovative Areas (MEXT) to D.U. We are grateful to Prof.
Minoru Isobe (National Tsing Hua University) and Dr. Akinari
Hamajima (Chiba University) for the crucial suggestion to use
amine oxides in the reductive decomplexation of alkyne
dicobalt hexacarbonyl complexes.
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N
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