Stereocontrolled synthesis of resolvin D1

Article abstract of DOI:10.1039/C8OB03128B

We studied the synthesis of RvD1, a pro-resolving mediator. The intermediate containing vic-diol and enal functional groups was prepared via the oxidation of the γ,δ-epoxy alcohol followed by the epoxide ring opening in one pot. The C11-aldehyde in the resulting enal was converted to the trans iodo-olefin by reaction with TMSC(N₂)Li and subsequent hydrozirconation using in situ generated Cp₂Zr(H)Cl followed by iodination. The trans enynyl alcohol was synthesized by the reaction of the TMS-containing epoxy alcohol with lithium TMS-acetylide. Finally, two fragments were joined by the Sonogashira coupling, and the triple bond was reduced to afford RvD1 stereoselectively.

Full text of DOI:10.1039/C8OB03128B

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Stereocontrolled synthesis of resolvin D1†
Cite this: DOI: 10.1039/c8ob03128b Masao Morita, Shangze Wu and Yuichi Kobayashi
*
We studied the synthesis of RvD1, a pro-resolving mediator. The intermediate containing vic-diol and enal
functional groups was prepared via the oxidation of the γ,δ-epoxy alcohol followed by the epoxide ring
opening in one pot. The C11-aldehyde in the resulting enal was converted to the trans iodo-olefin by
reaction with TMSC(N )Li and subsequent hydrozirconation using in situ generated Cp Zr(H)Cl followed
Received 17th December 2018,
Accepted 29th January 2019
2
2
by iodination. The trans enynyl alcohol was synthesized by the reaction of the TMS-containing epoxy
alcohol with lithium TMS-acetylide. Finally, two fragments were joined by the Sonogashira coupling, and
the triple bond was reduced to afford RvD1 stereoselectively.
DOI: 10.1039/c8ob03128b
rsc.li/obc
intermediate was derived from the 2-deoxy-D-ribose deriva-
Introduction
3
,7
tive,
while the latter monohydroxy part was prepared by
Resolvin D1 (RvD1) is a metabolite of docosahexaenoic acid several methods. Consequently, we quested for a synthesis of a
DHA), which is produced through oxidations by 15-lipoxygen- dihydroxy intermediate by a method that does not rely on a
(
1
ase (LOX) and 5-LOX (Fig. 1). The stereochemistry of the conju- chiral pool, and studied the construction of the tetraene with
gated olefins is determined by H NMR analysis, and the chir- the C12–C13 bond formation. We felt that a method developed
1
2
ality of hydroxy-bearing carbons is established by an organic along this line would expand the synthetic variation in design-
2,3
synthesis that is shortly communicated. Previous biochemical ing analogues of RvD1 for SAR studies.
studies have indicated that RvD1 promotes the anti-inflamma- We have reported several transformations of epoxy alcohols 1,
4
11
tory and pro-resolution processes. Similar activity has been including those that produce enynes 2 and monohydroxy enols
3
12
found in other tetraene triol metabolites, including RvD2 and 3 (Scheme 1). These transformations have been key steps in
lipoxins derived from DHA and arachidonic acid, respectively. the synthesis of lipoxygenase and/or CYP-catalyzed metabolites
Consequently, certain quantities of RvD1 and the other metab- of polyunsaturated fatty acids.
5
11–13
We also established the oxi-
olites are indispensable for further biological studies that will dative conversion of epoxy alcohol 4 to dihydroxy enols 5 via the
evaluate their contribution to the biological events and to find a epoxide ring opening, which was triggered by the resulting alde-
14
new biological function. The structure–activity relationship hyde group. With these transformations and transition metal-
SAR) would be a necessary option. Presently, RvD1 is commer- catalyzed coupling reactions in mind, two retrosyntheses of
(
6
cially available, but relatively expensive. In contrast, biochemi- RvD1 were envisaged as depicted in Scheme 2. Dienyl borane 6
cal synthesis from 17S-hydroxy-DHA by human PMN produces and iodo-diene 9 were the intermediates in the first set of the
2
limited quantities of much less than one mg, whereas the retrosynthesis based on the Suzuki–Miyaura coupling, and dihy-
7
organic synthesis is reported without the experimental details.
droxy and monohydroxy enal derivatives 8 and 10 were selected
RvD1 consists of vic-dihydroxy and monohydroxy moieties, as reasonable precursors of these intermediates. In the second
7
which are connected to the conjugated tetraene. In the pre- retrosynthesis, the reported dehydro-RvD1 (11) was discon-
2
,3,7
15
vious syntheses,
C1–C14 dihydroxy dien-yne and C15– nected at the C12–C13 bond to generate intermediates 12 and
C22 monohydroxy iodo-olefin were coupled to each other by 13. As a precursor of 12, aldehyde 8 was envisaged by the Takai
the Sonogashira coupling and the resulting dehydro-RvD1 was
8
semi-hydrogenated with Zn(Cu/Ag). A similar coupling using
dien-yne and iodo-olefin has been utilized in the synthesis of
9
a,b
10
RvD2
and lipoxin A4. The dihydroxy part in the C1–C14
Department of Biotechnology, Tokyo Institute of Technology, B-52, Nagatsuta-cho
4259, Midori-ku, Yokohama 226-8501, Japan. E-mail: ykobayas@bio.titech.ac.jp
†
Electronic supplementary information (ESI) available: Synthesis of imtermedi-
1
13
ates and copies of H and C spectra of all new compounds. See DOI: 10.1039/
c8ob03128b
Fig. 1 Resolvins possessing the conjugated tetraene structure.
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developed for the synthesis of the one methylene long ana-
1
4
logue. However, the conversion was unexpectedly affected by
the oxygen atom at the near position, and the synthesis was
improved as summarized in Scheme 3. Amide 16 derived from
β-lactone 14 was converted to ketone 18 upon reaction with the
lithium acetylide derived from 17 and n-BuLi in a good yield.
The asymmetric transfer hydrogenation of 18 with RuCl[(S,S)-
1
7
TsDPEN](p-cymene), abbreviated as Ru(S,S) in the scheme,
resulted in the production of propargylic alcohol 19 with 94%
ee (HPLC analysis of the derived benzoate) in 90% yield.
Reduction of 19 to trans allylic alcohol with Red-Al proceeded
with unexpected deprotection of the TBS group, and the regio-
selective silylation of the resulting diol 20 with TBSCl afforded
Scheme 1 Synthesis of intermediates 2, 3 and 5.
21a in 61% yield over two steps.
To secure high anti stereoselectivity in the subsequent
16
epoxidation, the Sharpless asymmetric epoxidation was
reaction, but somewhat low stereoselectivity and the use of
excess CrCl led us to develop an alternative method. On the
1
8
applied to 21a with Ti(O-i-Pr) /L-(+)-DIPT (1 equiv.); however,
4
2
the epoxidation proceeded marginally, and 21a was recovered
even after a longer period of time (21 h) than the standard. It
is likely that the coordination of the electron-rich TBS-oxygen
to the Ti atom in the Ti-allylic alcohol complex is dominant,
and hence, t-BuOOH was dislodged from the Ti atom. In the
literature, allylic alcohols possessing the Bn, alkyl or TBDPS
groups at the same distance from the allylic moiety were com-
other hand, the transformation of 1 to 2 was already applied to
the synthesis of the TMS-acetylene derivative of enynyl alcohol
11
1
3. Thus, the synthesis of functional group-rich 8 and efficient
conversion of 8 to 12 were key points of the synthesis. In prac-
tice, the first approach was unsuccessful at the last stage,
whereas the second one afforded RvD1 stereoselectively. Herein,
we report the results of these syntheses.
1
9
4
patible with the Ti(O-i-Pr) /L-(+)-DIPT complex. The use of
the Bn group for the present synthesis was, however, con-
sidered to be inadequate for the further transformation, and
hence the bulky TBDPS ether 21b that was prepared from diol
Results and discussion
The synthesis of dienal aldehyde 8, the common intermediate 20 and TBDPSCl was subjected to the epoxidation, which took
in the two retrosyntheses, was studied by applying the method place smoothly and was completed in a reasonable time of 4 h.
Scheme 2 Two retrosyntheses of RvD1.
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a
Scheme 3 Synthesis of the enal intermediate. Ru(S,S): Ru[(S,S)-TsDPEN](p-cymene).
Epoxy alcohol 22b isolated in 77% yield was diastereochemi- enyne 26 in 89% yield (Scheme 4(A)). Deprotection of the
1
13
cally homogeneous as judged by H and C NMR spectroscopy TBDPS group was attempted with TBAF·AcOH, which is
2
1
and enantiomerically highly pure (>99% ee) as a consequence known as the TBDPS group-selective desilylation reagent.
of the kinetic resolution between 21b and ent-21b in a ratio of However, the deprotection of the TBS group(s) took place
7 : 3, which was the composition of “94% ee of 21b”. competitively. Previously, the prim-TBS-oxy group among
Protection of 22b with TBSOTf followed by the deprotection of prim- and sec-TBS-oxy groups was selectively removed with
9
1
3a–e,14
the PMB group afforded alcohol 23 in 70% yield. The Swern PPTS in the alcoholic solvent.
Consequently, all the
oxidation of 23 gave trans enal 25 as the sole product in 83% silyl groups were removed with TBAF, and the resulting triol
yield via the epoxide ring opening of 24. Finally, silylation with was reprotected with TBSOTf to afford tri-TBS ether 27.
TBSOTf gave TBS ether 8 in a good yield.
Finally, 27 was converted to vinyl borane 6 by hydroboration
The synthesis of vinyl borane 6 was commenced with the with (Sia) BH for the Suzuki–Miyaura coupling with iodo-
2
2
0
reaction of aldehyde 8 with TMSC(Li)N
2
to afford trans diene 9.
Scheme 4 Synthesis of the two C5–C12 intermediates 6 and 12 for the synthesis of RvD1.
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Iodo-diene 9, the other partner for the Suzuki–Miyaura
Construction of the entire structure was also attempted by
coupling, was synthesized by the method delineated in changing the sequence of the reactions (Scheme 7). Thus, TBS
Scheme 5(A). Epoxy alcohol 30 with >99% ee was obtained by ether 27 prepared in Scheme 4 was converted to aldehyde 37
the Sharpless asymmetric epoxidation of the corresponding in 54% yield by prim-site selective TBS deprotection with PPTS
1
3c,22
racemic allylic alcohol
and converted to aldehyde 31 in in MeOH/CH Cl followed by the Swern oxidation. The Wittig
2 2
1
2
4
7% yield according to the published procedure. The Stork– olefination with 7/NaHMDS under the conditions applied to
Wittig reaction was run at an initial temp. of −90 °C to 35 proceeded as expected to afford enyne 38 in 81% yield.
2
3
afford iodo-diene 9 with a Z/E ratio of 91 : 9, and pure 9 was Hydroboration of 38 with (Sia) BH generated vinyl borane 39.
2
obtained in 60% yield by preparative HPLC.
Unfortunately, the Suzuki–Miyaura coupling with iodide 9
The Pd-catalyzed coupling of vinyl borane 6 with iodide 9 under the above conditions (KOH in aq. THF) did not produce
1.5 equiv.) and KOH in aq. THF was conducted with 0.25 36. Attempts with NaOH and LiOH in aq. THF also proved
(
equiv. of Pd(PPh
tetraene 33 in 39% yield (Scheme 6). Since isomerization of
3
)
4
, which was higher than normal to afford unsuccessful.
We next investigated the second strategy, in which the
the cis olefin in the tetraene moiety was a concern, the regio- Sonogashira coupling was utilized to afford the dehydro-RvD1
selective TBS deprotection of tetraene 33 with PPTS in MeOH/ structure (Scheme 2). The first step of the investigation was the
2 2 2
CH Cl (1 : 1) was instead halted before the complete con- construction of the iodo-diene moiety. To avoid the CrCl -
1
6
sumption of 33, affording alcohol 34 in 41% and recovered 33 mediated reaction of aldehyde 8 by the reasons mentioned
in 31% yield. Subsequently, the Swern oxidation of alcohol 34 above, acetylene 26 derived from aldehyde 8 (Scheme 4(A)) was
gave aldehyde 35 in 43% yield. Unfortunately, the Wittig reac- subjected to hydrozirconation with Cp
2
Zr(H)Cl, prepared
2
4
tion of 35 with the ylide derived from 7 and NaHMDS did not in situ from Cp ZrCl and DIBAL, and the subsequent iodina-
2
2
afford 36, but instead led to destruction of 35.
tion to afford 28 in 75% yield (Scheme 4(B)). The conversion
Scheme 5 Synthesis of the two C13–C22 intermediates 9 and 13 for the synthesis of RvD1.
Scheme 6 Attempted synthesis of RvD1.
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Scheme 7 Another attempted synthesis of RvD1.
Scheme 8 Synthesis of RvD1.
was stereospecific, and a 67% yield over two steps from 8 RvD1 were consistent with those reported in ref. 7, and the
1
3
would be acceptable. All the silyl groups were then removed
C–APT NMR spectrum (APT: attached proton test) was in
with TBAF, and the resulting triol was re-silylated with TBSOTf accordance with the structure.
to afford 29 in 79% yield. Finally, regioselective desilylation
with PPTS in MeOH/CH Cl (1 : 1) at rt for 3 h gave 12 in 50%
2
2
yield.
Synthesis of the other intermediate 13 was accomplished in
9% yield by the Hudrlick–Peterson reaction of epoxide 30 Two syntheses of RvD1 were studied. The first attempt via the
Conclusions
5
1
1
with lithium acetylide according to the literature procedure
Suzuki–Miyaura coupling was unsuccessful, whereas the second
followed by TMS-deprotection of trans enyne 32 with K
MeOH (Scheme 5(B)).
2
CO
3
in synthesis via the Sonogashira coupling of iodo-diene 41 and
enyne 13 afforded RvD1. The anti vic-diol moiety with the olefin
The first step in the final stage of the synthesis (Scheme 8) in aldehyde 8 was constructed via the anti selective epoxidation
was the Swern oxidation of 12 to furnish aldehyde 40, which of 21b and the subsequent Swern oxidation of the epoxy alcohol
upon the Wittig reaction with 7/NaHMDS gave olefin 41 in 23 followed by the epoxide ring opening of the resulting epoxy
7
3% yield from alcohol 12. The Sonogashira coupling of 41 aldehyde 24. Furthermore, the conversion of the aldehyde
with enyne 13 proceeded as expected, and the TBS desilylation group in 8 to the trans iodo-olefin of 28 was accomplished
of the coupling product 42 with TBAF afforded triol 43 in 78% stereoselectively without the use of the Cr reagent.
yield from 41. The Boland reduction of 43 required excess
9
c
Zn(Cu/Ag) as reported in the synthesis of RvD2 and 15-epi-
1
0c
LXA4,
but proceeded stereoselectively. Filtration of the
Experimental
General methods
mixture with Zn was easy operation, and subsequent purifi-
cation by chromatography on silica gel gave the methyl ester
2
5
1
13
4
4
of RvD1 in 93% yield. Finally, hydrolysis of the ester furn- The H (300 and 400 MHz) and C NMR (75 and 100 MHz)
1
13
ished RvD1 stereoselectively. The H and C NMR spectra of spectroscopic data were recorded in CDCl3 or CD OD with
3
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Me
4
Si (δ = 0 ppm), the centerline of the CDCl
3
triplet (δ = on silica gel (toluene/EtOAc = 50 : 1) to afford 18 (1.39 g, 91%):
7
7.1 ppm) or residual protonated solvent as an internal stan- colorless oil; R = 0.63 (hexane/EtOAc = 3 : 1); IR (neat) 2211,
f
dard. Signal patterns are indicated as br s (broad singlet), 1676, 1514, 1250, 1100, 835, 778 cm−
1 1
;
H NMR (400 MHz,
3
s (singlet), d (doublet), t (triplet), q (quartet), quint. (quintet) CDCl ) δ 0.06 (s, 6 H), 0.87 (s, 9 H), 2.65 (t, J = 7.0 Hz, 2 H),
and m (multiplet). Coupling constants (J) are given in Hertz 2.73 (t, J = 6.2 Hz, 2 H), 3.60 (t, J = 7.0 Hz, 2 H), 3.81 (s, 3 H),
(
(
Hz). Chemical shifts of carbons are accompanied by minus 3.95 (t, J = 6.2 Hz, 2 H), 4.48 (s, 2 H), 6.88 (d, J = 8.8 Hz, 2 H),
for C and CH ) and plus (for CH and CH ) signs of the 7.26 (d, J = 8.8 Hz, 2 H); C–APT NMR (100 MHz, CDCl )
2 3 3
1
3
attached proton test (APT) experiment. High-resolution mass δ −5.4 (+), 18.2 (−), 20.5 (−), 25.8 (+), 48.5 (−), 55.2 (+), 58.4
spectroscopy (HRMS) was performed with a double-focusing (−), 66.8 (−), 72.8 (−), 81.5 (−), 91.0 (−), 113.9 (+), 129.4 (+),
+
mass spectrometer. The solvents that were distilled prior to 129.7 (−), 159.3 (−), 186.3 (−); HRMS (FAB ) calcd for
+
use are THF (from Na/benzophenone) and CH Cl (from C H O Si [(M–H) ] 375.1992, found 375.1989.
2
2
21 31 4
2
CaH ). After extraction of the products, the extracts were con-
(
S)-1-[(tert-Butyldimethylsilyl)oxy]-7-[(4-methoxybenzyl)oxy]
hept-4-yn-3-ol (19)
mixture of RuCl(p-cymene)[(S,S)-TsDPEN] (85 mg,
.134 mmol) and KOH (ca. 97 mg, 1.7 mmol) in CH Cl (5 mL)
was stirred at rt for 5 min. The mixture was washed with H O
centrated by using an evaporator and then residues were puri-
fied by chromatography on silica gel (Kanto, spherical silica
gel 60N).
A
0
2
2
3
-[(tert-Butyldimethylsilyl)oxy]-N-methoxy-
2
N-methylpropanamide (16)
(
×6). The CH
2
Cl
2
solution was transformed to another flask.
, decanted, and concentrated
To an ice-cold solution of (MeO)MeNH·HCl (2.93 g, The solution was dried over CaH
0.0 mmol) in MeCN (50 mL) was added Me AlCl (1.0 M in in vacuo to afford a purple solid, to which a solution of ketone
2
3
2
hexane, 60 mL, 60.0 mmol), and the cooling bath was 18 (1.00 g, 2.66 mmol) in i-PrOH (21 mL) was added. After 1 h
removed. After 1 h of stirring at rt, a solution of lactone 14 of stirring at rt, organic solvents were removed by evaporation.
(
1.50 g, 20.8 mmol) in MeCN (5 mL) was added to the solution. The residue was purified by chromatography on silica gel
After 18 h of stirring at rt, the reaction was quenched by (hexane/EtOAc = 3 : 1) to afford alcohol 19 (0.908 g, 90%):
adding 1 N HCl solution. The mixture was extracted with colorless oil; R = 0.51 (hexane/EtOAc = 3 : 1); 94.2% ee deter-
CH Cl (×5). The combined organic extracts were dried mined by HPLC of the derived benzoate [Daicel Chiralcel
f
2
2
−
1
(
MgSO
4
) and concentered in vacuo. The residue was purified by OD-H; hexane/i-PrOH = 99 : 1, 1 mL min , 35 °C; t
R
(min) =
); IR (neat)
H NMR (400 MHz,
) δ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.90 (s, 9 H), 1.78–1.89 (m,
added imidazole (4.25 g, 62.4 mmol) and TBSCl (4.70 g, 1 H), 1.91–2.00 (m, 1 H), 2.52 (td, J = 7.3 Hz, 2.0 Hz, 2 H), 3.38
1.2 mmol). After 1 h of stirring at rt, the solution was diluted (d, J = 5.6 Hz, 1 H), 3.55 (t, J = 7.2 Hz, 2 H), 3.76–3.84 (m, 1 H),
with saturated NaHCO solution, and the mixture was 3.79 (s, 3 H), 3.97–4.04 (m, 1 H), 4.47 (s, 2 H), 4.56–4.62 (m,
extracted with CH Cl (×2). The combined organic extracts 1 H), 6.87 (d, J = 8.8 Hz, 2 H), 7.26 (d, J = 8.8 Hz, 2 H); C–APT
were dried (MgSO ), and concentrated in vacuo. The residue NMR (100 MHz, CDCl ) δ −5.5 (+), 18.2 (−), 20.1 (−), 25.9 (+),
2
0
chromatography on silica gel (hexane/EtOAc = 3 : 1) to afford 10.6 (minor), 11.5 (major)]; [α] −13 (c 1.72, CHCl
3
D
−
1 1
amide 15.
To a solution of the above amide in CH
3429, 1613, 1514, 1250, 835, 777 cm
(20 mL) were CDCl
;
2
Cl
2
3
3
3
1
3
2
2
4
3
was purified by chromatography on silica gel (hexane/EtOAc = 39.1 (−), 55.2 (+), 61.0 (−), 61.6 (+), 68.1 (−), 72.6 (−), 81.8 (−),
+
9
: 1) to afford 16 (2.81 g, 55% over two steps): colorless oil; 81.9 (−), 113.8 (+), 129.3 (+), 130.1 (−), 159.2 (−); HRMS (FAB )
+
R = 0.29 (hexane/EtOAc = 20 : 1); IR (neat) 1667, 1096, 836, calcd for C H O SiNa [(M + Na) ] 401.2124, found 401.2131.
f
21 34 4
78 cm− ; H NMR (400 MHz, CDCl
1 1
7
9
3
) δ 0.06 (s, 6 H), 0.88 (s,
(
S,E)-1-[(tert-Butyldiphenylsilyl)oxy]-7-[(4-methoxybenzyl)oxy]
hept-4-en-3-ol (21b)
8.3 (−), 25.9 (+), 31.9 (+), 35.1 (−), 59.3 (−), 61.3 (+), 172.4 (−). To an ice-cold solution of alcohol 19 (850 mg, 2.25 mmol) in
The H and C NMR spectra were identical to those reported toluene (3 mL) was added Red-Al (3.60 M in toluene, 1.88 mL,
in ref. 26. 6.77 mmol). After 1 h of stirring at rt, the reaction was
quenched by adding H O (5 mL) and Celite (850 mg). The
H), 2.67 (t, J = 6.6 Hz, 2 H), 3.18 (s, 3 H), 3.69 (s, 3 H), 3.94 (t,
1
3
J = 6.6 Hz, 2 H); C–APT NMR (100 MHz, CDCl ) δ −5.4 (+),
1
3
1
13
2
1
-[(tert-Butyldimethylsilyl)oxy]-7-[(4-methoxybenzyl)oxy]hept-4-
resulting mixture was filtered through a pad of Celite. The fil-
trate was concentrated to afford diol 20 and was semi-purified
yn-3-one (18)
To a solution of alkyne 17 (1.54 g, 8.10 mmol) in THF (10 mL) by chromatography on silica gel (MeOH/EtOAc = 1 : 19) for the
was added n-BuLi (1.55 M in hexane, 4.82 mL, 7.47 mmol) at next reaction: R = 0.29 (EtOAc).
78 °C. The solution was stirred at −78 °C for 1 h. A solution To an ice-cold solution of the above diol in CH Cl (10 mL)
f
−
2
2
of amide 16 (1.00 g, 4.04 mmol) in THF (5 mL) was added to were added imidazole (460 mg, 6.75 mmol) and TBDPSCl
the solution, and the cooling bath was removed. After 15 min (618 mg, 2.25 mmol). After 30 min of stirring at rt, the solution
of stirring at rt, the reaction was quenched by adding saturated was diluted with saturated NaHCO solution, and the mixture
3
NH
The combined organic extracts were dried (MgSO
centered in vacuo. The residue was purified by chromatography purified by chromatography on silica gel (hexane/EtOAc = 3 : 1)
4
2 2
Cl solution. The mixture was extracted with EtOAc (×3). was extracted with CH Cl (×3). The combined organic extracts
4
) and con- were dried (MgSO ), and concentrated in vacuo. The residue was
4
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to afford allylic alcohol 21b (650 mg, 57% over two steps): mixture was extracted with CH
2
Cl
2
(×2). The combined organic
2
0
colorless oil; R = 0.37 (hexane/EtOAc = 4 : 1); [α] +6 (c 0.77, extracts were dried (MgSO ) and concentrated in vacuo. The
f
D
4
−
1 1
CHCl
400 MHz, CDCl
J = 6.8 Hz, 2 H), 3.14 (d, J = 2.0 Hz, 1 H), 3.53 (t, J = 7.0 Hz, 98%): colorless oil; R = 0.86 (hexane/EtOAc = 19 : 1); [α] −14
3
); IR (neat) 3445, 1513, 1248, 1111, 704 cm ; H NMR residue was purified by chromatography on silica gel (hexane/
(
3
) δ 1.10 (s, 9 H), 1.75–1.90 (m, 2 H), 2.40 (q, EtOAc = 9 : 1) to afford the corresponding silyl ether (11.6 g,
2
0
f
D
); IR (neat) 1514, 1249, 1111, 836 cm− ; H NMR
) δ 0.01 (s, 3 H), 0.03 (s, 3 H), 0.84 (s, 9 H),
.6 Hz, 1 H), 6.92 (d, J = 7.2 Hz, 2 H), 7.31 (d, J = 7.2 Hz, 2 H), 1.04 (s, 9 H), 1.66–1.76 (m, 2 H), 1.80–1.94 (m, 2 H), 2.70 (dd,
1 1
2
(
6
7
(
5
(
1
H), 3.85 (s, 3 H), 3.84–3.95 (m, 2 H), 4.40–4.47 (m, 1 H), 4.49 (c 0.76, CHCl
3
s, 2 H), 5.62 (dd, J = 15.4 Hz, 4.8 Hz, 1 H), 5.76 (dt, J = 15.4 Hz, (400 MHz, CDCl
3
1
3
.41–7.51 (m, 6 H), 7.70–7.74 (m, 4 H);
) δ 19.1 (−), 26.9 (+), 32.8 (−), 38.8 (−), 2 H), 3.74–3.83 (m, 2 H), 3.79 (s, 3 H), 4.43 (s, 2 H), 6.86 (d, J =
5.3 (+), 62.6 (−), 69.5 (−), 71.7 (+), 72.6 (−), 113.8 (+), 127.5 8.8 Hz, 2 H), 7.25 (d, J = 8.8 Hz, 2 H), 7.34–7.44 (m, 6 H),
C–APT NMR J = 4.4 Hz, 2.0 Hz, 1 H), 2.97–3.02 (m, 1 H), 3.54 (t, J = 5.8 Hz,
100 MHz, CDCl
3
1
3
+), 127.8 (+), 129.3 (+), 129.4 (+), 129.9 (+), 130.5 (−), 133.1 (−), 7.64–7.68 (m, 4 H); C–APT NMR (100 MHz, CDCl
33.2 (−), 134.5 (+), 135.6 (+), 159.2 (−); HRMS (FAB ) calcd for −4.4 (+), 18.2 (−), 19.2 (−), 25.8 (+), 26.9 (+), 32.3 (−), 38.0 (−),
C H O Si [(M–H) ] 503.2618, found 503.2625.
3
) δ −5.0 (+),
+
+
53.9 (+), 55.3 (+), 60.1 (−), 61.1 (+), 66.8 (−), 68.1 (+), 72.8 (−),
3
1
39 4
1
1
13.8 (+), 127.6 (+), 129.3 (+), 129.6 (+), 130.4 (−), 133.8 (−),
35.6 (+), 159.2 (−).
To a mixture of the above PMB ether (11.6 g, 18.3 mmol) in
(
S)-3-[(tert-Butyldiphenylsilyl)oxy]-1-[(2S,3S)-3-
[2-((4-methoxybenzyl)oxy)ethyl]oxiran-2-yl]propan-1-ol (22b)
4 2 2
To an ice-cold solution of Ti(O-i-Pr) (0.174 mL, 0.594 mmol) CH Cl (100 mL) and phosphate buffer solution (pH 6.8,
in CH
2
Cl
2
(1 mL) was added L-(+)-DIPT (0.149 mL, 100 mL) was added DDQ (6.24 g, 27.5 mmol). The mixture was
0
.713 mmol). After 10 min of stirring at 0 °C, the solution was stirred at rt for 2 h and diluted with saturated NaHCO solu-
3
cooled to −30 °C and a solution of allylic alcohol 21b (300 mg, tion. The mixture was extracted with CH
.594 mmol) in CH Cl (1 mL) was added. The solution was bined organic extracts were dried (MgSO
stirred at −30 °C for 20 min. To this solution was added in vacuo. The residue was purified by chromatography on silica
t-BuOOH (2.05 M in CH Cl , 0.58 mL, 1.19 mmol) at −30 °C gel (toluene/EtOAc = 19 : 1) to afford alcohol 23 (6.69 g, 71%):
dropwise. The solution was stirred at −18 °C for 4 h, and then colorless oil; R
Me S (1.0 mL, 14 mmol), 10% tartaric acid (20 mL), and NaF (c 0.37, CHCl ); IR (neat) 3445, 1111, 1089, 836, 702 cm ; H
2
Cl
2
(×3), and the com-
0
2
2
4
) and concentrated
2
2
2
1
f
= 0.80 (toluene/EtOAc = 19 : 1); [α]D −16
−
1 1
2
3
(
500 mg, 12 mml) were added. The resulting mixture was NMR (400 MHz, CDCl
stirred at rt for 15 min. The mixture was extracted with CH Cl 9 H), 1.05 (s, 9 H), 1.64–1.78 (m, 2 H), 1.82–2.00 (m, 2 H), 2.78
×3). The combined organic layers were concentrated in vacuo (dd, J = 4.6 Hz, 2.0 Hz, 1 H), 2.99–3.04 (m, 1 H), 3.71–3.83 (m,
3
) δ 0.02 (s, 3 H), 0.04 (s, 3 H), 0.84 (s,
2
2
(
13
to give a residue, to which were added Et
2
O (10 mL) and 2 N 5 H), 7.35–7.46 (m, 6 H), 7.64–7.69 (m, 4 H); C–APT NMR
) δ −5.0 (+), −4.4 (+), 18.1 (−), 19.2 (−), 25.8
mixture was extracted with Et O (×3). The combined organic (+), 26.9 (+), 34.0 (−), 37.9 (−), 54.6 (+), 59.8 (−), 60.0 (−), 60.5
NaOH (10 mL, 20 mmol). After 40 min of stirring at rt, the (100 MHz, CDCl
3
2
extracts were dried (MgSO ) and concentered in vacuo. The (+), 68.3 (+), 127.7 (+), 129.6 (+), 133.8 (−), 135.6 (+); HRMS
4
+
+
47 4 2
residue was purified by chromatography on silica gel (hexane/ (FAB ) calcd for C29H O Si [(M + H) ] 515.3013, found
EtOAc = 3 : 1) to afford epoxide alcohol 22b (239 mg, 77%): 515.2994.
1
9
R
(
9.9% ee by H NMR spectroscopy of the derived MTPA ester;
2
0
(4R,5S,E)-4,5-Bis[(tert-butyldimethylsilyl)oxy]-7-
[(tert-butyldiphenylsilyl)oxy]hept-2-enal (8)
f
D
3
= 0.49 (hexane/EtOAc = 3 : 1); [α] −13 (c 0.99, CHCl ); IR
neat) 3464, 1613, 1513, 1248 cm ; H NMR (400 MHz, CDCl )
−
1 1
3
δ 1.06 (s, 9 H), 1.73–1.98 (m, 4 H), 2.82 (dd, J = 4.4 Hz, 2.4 Hz, To a solution of (COCl)
1
2
2
(1.11 mL, 14.3 mmol) in CH
H), 3.05 (d, J = 2.0 Hz, 1 H), 3.13 (ddd, J = 6.6 Hz, 4.6 Hz, (30 mL) was slowly added DMSO (1.85 mL, 26.0 mmol) at
.4 Hz, 1 H), 3.58 (t, J = 6.4 Hz, 2 H), 3.78 (s, 3 H), 3.81–3.95 −78 °C. The solution was stirred at −78 °C for 5 min. A solu-
Cl (10 mL) was
.37–7.48 (m, 6 H), 7.65–7.70 (m, 4 H); C–APT NMR added to the solution at −78 °C. After additional 15 min of
2 2
Cl
(
7
m, 3 H), 6.87 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H), tion of alcohol 23 (6.69 g, 13.0 mmol) in CH
2
2
1
3
(
100 MHz, CDCl ) δ 19.1 (−), 26.9 (+), 32.3 (−), 35.4 (−), 53.9 stirring at −78 °C, Et N (18.2 mL, 130 mmol) was added, and
3
3
(
(
1
5
+), 55.3 (+), 60.7 (+), 62.3 (−), 66.8 (−), 69.3 (+), 72.8 (−), 113.8 then the ice bath was removed. After stirring of 10 min at rt,
+), 127.8 (+), 129.4 (+), 130.0 (+), 130.3 (−), 133.1 (−), 135.5 (+), the reaction was quenched by adding saturated NaHCO solu-
59.2 (−); HRMS (FAB ) calcd for C H O SiNa [(M + Na) ] tion, and the resulting mixture was extracted with CH Cl (×3).
3
+
+
3
1
40
5
2
2
43.2543, found 543.2548.
4
The combined organic extracts were dried (MgSO ) and con-
centrated in vacuo. The residue was purified by chromato-
graphy on silica gel (hexane/EtOAc = 9 : 1) to afford aldehyde
2
-[(2S,3R)-3-((S)-2,2,3,3,10,10-Hexamethyl-9,9-diphenyl-4,8-
dioxa-3,9-disilaundecan-5-yl)oxiran-2-yl]ethan-1-ol (23)
2
5 (5.54 g, 83%): pale yellow oil; R
f
= 0.20 (hexane/EtOAc =
); IR (neat) 3465, 1693, 1111, 837,
CH Cl (100 mL) were added 2,6-lutidine (6.50 mL, 703 cm− ; H NMR (400 MHz, CDCl ) δ 0.04 (s, 3 H), 0.08 (s, 3
2
0
To an ice-cold solution of alcohol 22b (9.70 g, 18.6 mmol) in 9 : 1); [α] +22 (c 0.86, CHCl
3
D
1
1
2
2
3
5
5.8 mmol) and TBSOTf (6.83 mL, 29.7 mmol). The cooling H), 0.87 (s, 9 H), 1.05 (s, 9 H), 1.58–1.67 (m, 1 H), 1.79–1.88
bath was removed. The solution was stirred at rt for 30 min (m, 1 H), 3.22 (d, J = 3.6 Hz, 1 H), 3.70 (ddd, J = 10.9 Hz,
and diluted with saturated NaHCO3 solution. The resulting 7.3 Hz, 3.9 Hz, 1 H), 3.81 (ddd, J = 10.9 Hz, 6.4 Hz, 4.4 Hz,
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+
1
1
1
1
H), 3.98 (q, J = 5.3 Hz, 1 H), 4.43–4.48 (m, 1 H), 6.38 (ddd, J = 134.0 (−), 135.6 (+) 145.7 (+); HRMS (FAB ) calcd for
+
5.6 Hz, 8.0 Hz, 1.6 Hz, 1 H), 6.81 (dd, J = 15.6 Hz, 4.4 Hz, C H O Si Na [(M + Na) ] 645.3592, found 645.3597.
3
6
58
3
3
H), 7.35–7.47 (m, 6 H), 7.62–7.68 (m, 4 H), 9.57 (d, J = 8.0 Hz,
1
3
(5R,6S)-6-[(tert-Butyldimethylsilyl)oxy]-5-[(1E,3E)-4-iodobuta-
,3-dien-1-yl]-2,2,3,3,11,11-hexamethyl-10,10-diphenyl-4,9-
H); C–APT NMR (100 MHz, CDCl ) δ −4.6 (+), −4.5 (+), 18.0
3
1
(−), 19.1 (−), 25.8 (+), 26.8 (+), 35.4 (−), 59.9 (−), 72.4 (+), 74.2
+), 127.8 (+), 129.8 (+), 132.0 (+), 133.0 (−), 135.5 (+) 155.4 (+),
dioxa-3,10-disiladodecane (28)
(
1
93.5 (+).
To an ice-cold solution of bis(cyclopentadienyl)zirconium
dichloride (70.4 mg, 0.241 mmol) in THF (0.5 mL) was added
To a solution of alcohol 25 (5.54 g, 10.8 mmol) in CH Cl
2
2
(20 mL) were added 2,6-lutidine (3.77 mL, 32.4 mmol) and DIBAL (1.03 M in hexane, 0.23 mL, 0.24 mmol), and then the
TBSOTf (3.72 mL, 16.5 mmol). The solution was stirred at rt ice bath was removed. After 20 min of stirring at rt, the suspen-
for 30 min and diluted with saturated NaHCO solution. The sion was cooled to −78 °C. A solution of alkyne 26 (50.0 mg,
3
resulting mixture was extracted with CH
2
2
Cl (×2). The com- 0.0802 mmol) in THF (1 mL) was added, and then the ice bath
bined organic extracts were dried (MgSO
4
) and concentrated was removed. After 1 h of stirring at rt, the solution was cooled
in vacuo to leave a residual oil, which was purified by chromato- to −78 °C. A solution of iodide (46.7 mg, 0.184 mmol) in THF
graphy on silica gel (hexane/EtOAc = 9 : 1) to afford silyl ether 8 (1.5 mL) was added at −78 °C, and then the ice bath was
(
f
6.20 g, 92%): colorless oil; R = 0.63 (hexane/EtOAc = 50 : 1); removed. After 20 min of stirring at rt, the reaction was
2
0
−1
[
α] −3 (c 0.33, CHCl ); IR (neat) 1696, 1111, 836, 776 cm
;
quenched by adding 10% aqueous Na S O (5 mL), and the
2 2 3
D
3
1
H NMR (400 MHz, CDCl
3
) δ 0.025 (s, 3 H), 0.028 (s, 3 H), 0.06 resulting mixture was extracted with EtOAc (×2). The combined
) and concentrated in vacuo.
.62–1.75 (m, 2 H), 3.67–3.76 (m, 2 H), 3.97–4.03 (m, 1 H), The residue was purified by chromatography on silica gel
.31–4.35 (m, 1 H), 6.24 (dd, J = 15.8 Hz, 8.0 Hz, 1 H), 6.83 (dd, (hexane/toluene = 9 : 1) to afford iodide 28 (45.3 mg, 75%):
(s, 3 H), 0.07 (s, 3 H), 0.82 (s, 9 H), 0.91 (s, 9 H), 1.04 (s, 9 H), organic extracts were dried (MgSO
4
1
4
2
1
J = 15.8 Hz, 5.0 Hz, 1 H), 7.32–7.46 (m, 6 H), 7.58–7.68 (m, 4 pale yellow oil; R = 0.57 (hexane/toluene = 9 : 1); [α]D −19
H), 9.55 (d, J = 8.0 Hz, 1 H); C–APT NMR (100 MHz, CDCl3) (c 1.06, CHCl ); IR (neat) 1471, 1254, 1106, 835, 776 cm ; H
f
1
3
−1 1
3
δ −4.8 (+), −4.7 (+), −4.6 (+), −3.9 (+), 18.2 (−), 18.3 (−), 19.2 NMR (400 MHz, CDCl
3
) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.05 (s,
(
−), 25.9 (+), 26.9 (+), 36.8 (−), 60.3 (−), 73.4 (+), 76.5 (+), 127.7 3 H), 0.06 (s, 3 H), 0.83 (s, 9 H), 0.89 (s, 9 H), 1.05 (s, 9 H),
(
+), 129.7 (+), 132.3 (+), 133.7 (−), 135.5 (+) 157.4 (+), 193.5 (+); 1.54–1.80 (m, 2 H), 3.66–3.77 (m, 3 H), 3.86 (dt, J = 7.0 Hz,
+
+
HRMS (FAB ) calcd for C35
H
58
O
4
Si
3
Na [(M + Na) ] 649.3541, 3.8 Hz, 1 H), 3.98–4.01 (m, 1 H), 5.68 (dd, J = 15.5 Hz, 6.4 Hz,
found 649.3512.
1 H), 6.04 (dd, J = 15.5 Hz, 11.0 Hz, 1 H), 6.26 (d, J = 14.3 Hz,
1
7
−
2
1
H), 7.00 (dd, J = 14.3 Hz, 11.0 Hz, 1 H), 7.34–7.46 (m, 6 H),
1
3
.62–7.68 (m, 4 H); C–APT NMR (75 MHz, CDCl
3
) δ −4.8 (+),
(
5R,6S)-5-[(E)-But-1-en-3-yn-1-yl]-6-[(tert-butyldimethylsilyl)
4.7 (+), −4.3 (+), −4.0 (+), 18.2 (−), 18.3 (−), 19.2 (−), 26.0 (+),
oxy]-2,2,3,3,11,11-hexamethyl-10,10-diphenyl-4,9-dioxa-3,10-
disiladodecane (26)
6.9 (+), 36.5 (−), 60.6 (−), 73.3 (+), 77.2 (+), 78.6 (+), 127.6 (+),
29.5 (+), 130.8 (+), 133.9 (−), 135.2 (+), 135.6 (+), 144.8 (+);
+
+
To an ice-cold solution of i-Pr
THF (50 mL) was added n-BuLi (1.55 M in hexane, 6.45 mL, 749.2746.
0.0 mmol). After 20 min of stirring, the solution was cooled
to −78 °C. TMSCHN (2.0 M in Et O, 5.0 mL, 10.0 mmol) was
added at −78 °C. After 15 min of stirring at −78 °C, aldehyde 8
5.57 g, 8.88 mmol) in THF (1 mL) was added, and then the To a solution of 28 (135.6 mg, 0.181 mmol) in THF (1 mL) was
2 58 3 3
NH (1.02 mL, 10.9 mmol) in HRMS (FAB ) calcd for C36H O Si I [(M–H) ] 749.2739, found
1
(
5
3S,4R,5E,7E)-3,4-Bis[(tert-butyldimethylsilyl)oxy]-8-iodoocta-
,7-dien-1-ol (12)
2
2
(
cooling bath was removed. After 15 min of stirring at rt, the added TBAF (1.0 M in THF, 0.91 mL, 0.91 mmol) dropwise at
reaction was quenched by adding saturated NH Cl solution, rt. After 2 h, the reaction was quenched by adding NH Cl
4
4
and the resulting mixture was extracted with EtOAc (×2). The (194 mg 3.62 mmol). After removal of the solvent, the residue
combined organic extracts were dried (MgSO ) and concen- was purified by chromatography on silica gel (hexane/EtOAc =
trated in vacuo. The residue was purified by chromatography 9 : 1 to MeOH/EtOAc = 1 : 20) to afford the corresponding triol:
on silica gel (hexane/EtOAc = 19 : 1) to afford alkyne 26 (4.91 g, = 0.29 (EtOAc). To a solution of the above triol in CH Cl
= 0.69 (hexane/EtOAc = 49 : 1); [α] −18 (3 mL) were added 2,6-lutidine (0.21 mL, 1.81 mmol) and
4
R
f
2
2
2
1
8
(
9%): colorless oil; R
f
D
−
1 1
c 1.02, CHCl ); IR (neat) 3311, 1255, 1111, 836, 776 cm ; H TBSOTf (0.208 mL, 0.905 mmol) at 0 °C. The solution was
3
NMR (400 MHz, CDCl
3
) δ 0.01 (s, 3 H), 0.03 (s, 3 H), 0.05 (s, stirred for 15 min and diluted with saturated NaHCO
3
solu-
3
1
3
H), 0.06 (s, 3 H), 0.83 (s, 9 H), 0.89 (s, 9 H), 1.04 (s, 9 H), tion. The resulting mixture was extracted with CH Cl (×3). The
2
2
.58–1.76 (m, 2 H), 2.88 (d, J = 2.0 Hz, 1 H), 3.66–3.76 (m, 2 H), combined organic extracts were dried (MgSO ) and concen-
4
.86 (dt, J = 7.6 Hz, 3.8 Hz, 1 H), 4.02–4.07 (m, 1 H), 5.60 (dt, trated in vacuo to leave a residual oil, which was purified by
J = 16.0 Hz, 2.0 Hz, 1 H), 6.22 (dd, J = 16.0 Hz, 6.0 Hz, 1 H), chromatography on silica gel (hexane/toluene = 9 : 1) to afford
1
3
7
.33–7.45 (m, 6 H), 7.62–7.67 (m, 4 H);
100 MHz, CDCl ) δ −4.8 (+), −4.6 (+), −4.4 (+), −4.0 (+), 18.2 EtOAc = 50 : 1); [α] −15 (c 0.74, CHCl
−), 18.3 (−), 19.2 (−), 26.0 (+), 26.9 (+), 36.4 (−), 60.6 (−), 73.2 1097, 835, 776 cm− ; H NMR (400 MHz, CDCl
+), 77.2 (+), 77.6 (−), 82.0 (−), 109.7 (+), 127.6 (+), 129.6 (+), 0.02 (s, 6 H), 0.05 (s, 6 H), 0.87 (s, 9 H), 0.88 (s, 9 H), 0.89 (s,
C–APT NMR silyl ether 29 (89.5 mg, 79%): pale yellow oil; R = 0.86 (hexane/
f
2
1
(
(
(
3
3
); IR (neat) 1471, 1255,
) δ 0.01 (s, 6 H),
D
1
1
3
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9
1
6
1
H), 1.55–1.75 (m, 2 H), 3.60–3.72 (m, 2 H), 3.75–3.80 (m, Methyl (4Z,7S,8R,9E,11E)-7,8-bis[(tert-butyldimethylsilyl)oxy]-
H), 4.00 (dd, J = 6.5 Hz, 3.0 Hz, 1 H), 5.70 (dd, J = 15.4 Hz, 12-iodododeca-4,9,11-trienoate (41)
.5 Hz, 1 H), 6.06 (dd, J = 15.4 Hz, 10.4 Hz, 1 H), 6.27 (d, J =
2 2 2
To a solution of (COCl) (0.093 mL 1.08 mmol) in CH Cl
1
3
4.6 Hz, 1 H), 7.02 (dd, J = 14.6 Hz, 10.4 Hz, 1 H); C–APT
(
5 mL) was slowly added DMSO (0.115 mL, 1.63 mmol) at
NMR (75 MHz, CDCl ) δ −5.3 (+), −4.8 (+), −4.6 (+), −4.3 (+),
−
3
−
CH
78 °C. A solution of alcohol 12 (278 mg, 0.542 mmol) in
Cl (2 mL) was added to the solution at −78 °C. After
additional 15 min of stirring at −78 °C, NEt3 (0.755 mL,
.42 mmol) was added, and then the ice bath was removed.
4.0 (+), 18.2 (−), 18.25 (−), 18.33 (−), 25.9 (+), 26.0 (+), 36.7
2
2
(
−), 60.0 (−), 73.3 (+), 77.2 (+), 78.5 (+), 130.8 (+), 135.2 (+),
1
44.9 (+).
5
2 2
To a solution of 29 (89.5 mg, 0.144 mmol) in CH Cl (2 mL)
The solution was stirred for 5 min at rt. The reaction was
quenched by adding saturated NaHCO3 solution, and the
and MeOH (2 mL) was added PPTS (40 mg, 0.159 mmol) at rt.
After 3 h of stirring, the reaction was quenched by adding satu-
2 2
mixture was extracted with CH Cl (×3). The combined organic
rated NaHCO
CH Cl (×3). The combined organic extracts were dried
MgSO ) and concentrated in vacuo. The residue was purified
3
solution. The mixture was extracted with
extracts were dried (MgSO ) and concentrated in vacuo to
4
2
2
afford crude aldehyde 40, which was passed through a short
silica gel column for the next reaction: R = 0.62 (hexane/
f
(
4
by chromatography on silica gel (hexane/EtOAc = 9 : 1) to
afford alcohol 12 (36.3 mg, 50%): pale yellow oil; R = 0.43
hexane/EtOAc = 9 : 1); [α] −8 (c 0.91, CHCl ); IR (neat) 3365,
EtOAc = 9 : 1).
f
To a solution of phosphonium salt 7 (1.08 g, 2.43 mmol) in
2
0
(
D
3
THF (3 mL) was added NaHMDS (1.0 M in THF, 1.94 mL,
−
1 1
1
3
255, 1100, 836, 776 cm ; H NMR (400 MHz, CDCl ) δ 0.02
1
.94 mmol) at rt. After 30 min of stirring, the mixture was
cooled to −78 °C. A solution of the above aldehyde 40 in THF
3 mL) was added to the mixture, and the cooling bath was
(s, 3 H), 0.04 (s, 3 H), 0.06 (s, 3 H), 0.07 (s, 3 H), 0.87 (s, 9 H),
0
3
6
7
.88 (s, 9 H), 1.68–1.88 (m, 2 H), 2.51 (br s, H), 3.68–3.84 (m,
H), 4.06–4.12 (m, 1 H), 5.66 (dd, J = 15.2 Hz, 6.8 Hz, 1 H),
.08 (dd, J = 15.2 Hz, 10.8 Hz, 1 H), 6.32 (d, J = 14.4 Hz, 1 H),
.00 (dd, J = 14.4 Hz, 10.8 Hz, 1 H); C–APT NMR (100 MHz,
) δ −4.7 (+), −4.2 (+), 18.1 (−), 18.2 (−), 25.86 (+), 25.92
+), 34.8 (−), 59.0 (−), 74.3 (+), 76.6 (+), 79.4 (+), 131.4 (+), 134.9
(
removed. After 5 min of stirring at 0 °C, the reaction was
quenched by adding saturated NH Cl solution. The mixture
4
1
3
was extracted with EtOAc (×2). The combined organic extracts
CDCl
(
3
were dried (MgSO ) and concentered in vacuo. The residue was
4
purified by chromatography on silica gel (hexane/EtOAc =
+
+
(+), 144.5 (+); HRMS (FAB ) calcd for C H O Si I [(M + H) ]
20 42 3 2
5
0 : 1) to afford 41 (234 mg, 73% over two steps): pale yellow
5
13.1717, found 513.1716.
20
oil; R = 0.57 (hexane/EtOAc = 20 : 1); [α] +0.9 (c 1.71, CHCl3);
f
D
IR (neat) 1742, 1462, 1254, 982 cm−
1
;
1
H NMR (400 MHz,
(
S,3E,7Z)-Deca-3,7-dien-1-yn-5-ol (13)
To an ice-cold solution of trimethysilyacetylene (1.26 mL,
.10 mmol) in THF (2 mL) was added n-BuLi (1.55 M in
hexane, 5.42 mL, 8.39 mmol). After 30 min of stirring, HMPA
2.92 mL, 16.8 mmol) and epoxide 30 (>99% ee, 300 mg,
CDCl ) δ −0.01 (s, 3 H), 0.02 (s, 6 H), 0.03 (s, 3 H), 0.86 (s, 9 H),
3
0.88 (s, 9 H), 2.13–2.40 (m, 6 H), 3.58–3.64 (m, 1 H), 3.67 (s,
3 H), 3.94–3.98 (m, 1 H), 5.35–5.53 (m, 2 H), 5.70 (dd, J =
15.4 Hz, 7.2 Hz, 1 H), 6.05 (dd, J = 15.4 Hz, 10.8 Hz, 1 H), 6.29
9
(
(
d, J = 14.5 Hz, 1 H), 7.02 (dd, J = 14.5 Hz, 10.8 Hz, 1 H);
1
.40 mmol) in THF (1 mL) were added, and then the ice bath 13
C–APT NMR (75 MHz, CDCl ) δ −4.7 (+), −4.4 (+), −4.2 (+),
3
was removed. After 4 h of stirring at rt, the reaction was
quenched by adding saturated NH Cl solution, and the result-
ing mixture was extracted with EtOAc (×2). The combined
organic extracts were dried (MgSO ) and concentrated in vacuo.
The residue was purified by chromatography on silica gel
1
7
8.1 (−), 18.2 (−), 23.1 (−), 25.9 (+), 31.5 (−), 33.9 (−), 51.6 (+),
4
6.2 (+), 76.4 (+), 78.8 (+), 127.5 (+), 129.0 (+), 131.1 (+), 135.2
+
(
+), 144.8 (+), 173.5 (−); HRMS (FAB ) calcd for C H O Si I
2
5
46
4
2
+
4
[(M–H) ] 593.1979, found 593.1994.
(
hexane/EtOAc = 9 : 1) to afford enyne 32.
To a solution of enyne 32 in MeOH (2 mL) was added
Methyl (4Z,7S,8R,9E,11E,15E,17S,19Z)-7,8,17-trihydroxydocosa-
,9,11,15,19-pentaen-13-ynoate (43)
4
K
1
2
CO
3
(180 mg, 1.28 mmol) at rt. The solution was stirred for
Cl solution. The resulting To a solution of iodide 41 (130 mg, 0.219 mmol) and alkyne 13
h and diluted with saturated NH
4
mixture was extracted with EtOAc (×3). The combined organic (42.8 mg, 0.285 mmol) in t-BuNH2 (2 mL) were added Pd
extracts were dried (MgSO ) and concentrated in vacuo to leave (PPh (13 mg, 0.011 mmol) and CuI (4 mg, 0.022 mmol).
4
3 4
)
a residual oil, which was purified by chromatography on silica After 15 min of stirring at rt, the mixture was diluted with satu-
gel (hexane/EtOAc = 7 : 1) to afford alkyne 13 (125 mg, 59% rated NH Cl solution. The mixture was extracted with EtOAc
4
over two steps): colorless oil; R
f
= 0.40 (hexane/EtOAc = 5 : 1); (×2). The combined organic extracts were dried (MgSO
4
) and
concentrated in vacuo to afford coupling product 42, which
H NMR (400 MHz, CDCl ) δ 0.97 (s, J = 7.6 Hz, 3 H), 1.81 (br s, was passed through a short silica gel column for the next
2
1
−1
[
3
α] −29 (c 0.84, CHCl ); IR (neat) 3366, 3297, 2096, 958 cm ;
D
1
3
1
1
1
5
H), 2.02–2.12 (m, 2 H), 2.29–2.36 (m, 2 H), 2.88 (d, J = 2.0 Hz reaction.
H), 4.16–4.25 (m, 1 H), 5.28–5.37 (m, 1 H), 5.56–5.64 (m,
To an ice-cold solution of the above product in THF
H), 5.72 (dt, J = 15.9 Hz, 2.0 Hz, 1 H), 6.28 (dd, J = 15.9 Hz, (10 mL) was added TBAF (1.0 M in THF, 2.19 mL, 2.19 mmol)
1
3
3
.2 Hz, 1 H); C–APT NMR (75 MHz, CDCl ) δ 14.1 (+), 20.7 dropwise at rt. After 2 h of stirring, the reaction was quenched
(
−), 34.7 (−), 71.3 (+), 77.9 (−), 81.6 (−), 108.8 (+), 123.0 (+), by adding MacIlvaine’s phosphate buffer (pH 5.0, 30 mL). The
1
35.9 (+), 146.8 (+).
mixture was extracted with Et O (×4). The combined organic
2
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4 2
extracts were dried (MgSO ) and concentrated in vacuo. The ified by chromatography on silica gel (Et O/MeOH = 20 : 1) to
residue was purified by chromatography on silica gel (hexane/ afford RvD1 (11.5 mg, 42%), which was further purified by
EtOAc = 1 : 2) to afford the mixture. The mixture was further using a recycling HPLC (LC-Forte/R equipped with YMC-Pack
−
1
2 f
purified by using a recycling HPLC (LC-Forte/R equipped with SIL-60, Et O/MeOH = 9 : 1, 25 mL min ): pale yellow oil; R =
−
1
1
YMC-Pack SIL-60, hexane/EtOAc = 1 : 2, 25 mL min ) to give 0.23 (EtOAc/hexane = 2 : 1); H NMR (400 MHz, CD OD) δ 0.93
3
triol 43 (67.0 mg, 78% over two steps): pale yellow oil; R
f
= 0.46 (t, J = 7.6 Hz, 3 H), 1.98–2.08 (m, 2 H), 2.12–2.38 (m, 11 H),
); H NMR 3.51 (dt, J = 8.0 Hz, 4.8 Hz, 1 H), 3.96–4.01 (m, 1 H), 4.10–4.17
400 MHz, CDCl ) δ 0.97 (t, J = 7.4 Hz, 3 H), 1.81 (br s, 1 H), (m, 1 H), 5.30–5.56 (m, 4 H), 5.70 (dd, J = 15.0 Hz, 6.2 Hz, 1 H),
2
1
1
(
hexane/EtOAc = 1 : 2); [α] −61 (c 1.45, CHCl
3
D
(
3
2
1
5
.06 (quint, J = 7.4 Hz, 2 H), 2.13–2.53 (m, 9 H), 2.62 (br s, 5.83 (dd, J = 15.2 Hz, 7.0 Hz, 1 H), 5.92–6.04 (m, 2 H), 6.26 (dd,
H), 3.66 (s, 3 H), 3.66–3.77 (m, 1 H), 4.18–4.27 (m, 2 H), J = 14.4 Hz, 10.8 Hz, 1 H), 6.36 (dd, J = 15.2 Hz, 10.8 Hz, 1 H),
1
3
.29–5.38 (m, 1 H), 5.43–5.53 (m, 2 H), 5.55–5.64 (m, 1 H), 5.74 6.67–6.78 (m, 2 H); C–APT NMR (75 MHz, CD OD) δ 14.8 (+),
3
(dd, J = 15.6 Hz, 2.0 Hz, 1 H), 5.83–5.92 (m, 2 H), 6.16 (dd, J = 22.0 (−), 24.4 (−), 32.2 (−), 35.2 (−), 36.5 (−), 73.4 (+), 76.1 (+),
1
6.0 Hz, 5.6 Hz, 1 H), 6.37 (dd, J = 15.4 Hz, 11.2 Hz, 1 H), 6.59 76.6 (+), 125.8 (+), 126.9 (+), 128.6 (+), 129.5 (+), 130.5 (+), 130.8
1
3
(dd, J = 15.6 Hz, 11.2 Hz, 1 H); C–APT NMR (100 MHz, (+), 131.1 (+), 133.8 (+), 134.8 (+), 134.9 (+), 135.0 (+), 138.5 (+),
+
+
3
32 5
CDCl ) δ 14.2 (+), 20.7 (−), 22.6 (−), 30.0 (−), 33.5 (−), 34.8 (−), 177.5 (−); HRMS (FAB ) calcd for C22H O Na [(M + Na) ]
1
13
5
1
1
1.7 (+), 71.6 (+), 73.9 (+), 74.7 (+), 89.5 (−), 90.6 (−), 110.0 (+), 399.2147, found 399.2153. The H and C NMR spectra were
12.0 (+), 123.1 (+), 126.8 (+), 130.8 (+), 131.7 (+), 133.6 (+), identical to those reported in ref. 7.
+
35.6 (+), 140.7 (+), 144.9 (+), 174.0 (−); HRMS (FAB ) calcd for
+
C
23
H
31
O
5
[(M–H) ] 387.2171, found 387.2170.
Conflicts of interest
Methyl (4Z,7S,8R,9E,11E,13Z,15E,17S,19Z)-7,8,17-
trihydroxydocosa-4,9,11,13,15,19-hexaenoate (44)
There are no conflicts to declare.
To a slurry of Zn (5.0 g, 77 mmol) in H O (30 mL) were added
2
Cu(OAc)
.97 mmol). The mixture was stirred at rt for 1 h and filtered
using a Hirsch funnel. The remaining Zn solids were washed
with H O (30 mL), MeOH (30 mL), acetone (30 mL), and Et
40 mL). The activated Zn solids were transformed to MeOH/
H O (1 : 1, 30 mL). A solution of alkyne 43 (32.3 mg,
2
(500 mg, 2.75 mmol) and AgNO
3
(505 mg,
Acknowledgements
2
This work was supported by JSPS KAKENHI Grant Number
JP15H05904.
2
2
O
(
2
0
.083 mmol) in MeOH (10 mL) was added to the suspension of
Notes and references
activated Zn. After 5 h of stirring at rt, the mixture was filtered
through a pad of Celite, and washed with EtOAc. The com-
bined organic extracts were dried (MgSO
vacuo. The residue was purified by chromatography on silica
gel (hexane/EtOAc = 1 : 1) to afford tetraene 44 (30.1 mg,
1 A. Ariel and C. N. Serhan, Trends Immunol., 2007, 28, 176.
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4
) and concentrated in
2
5
1
9
3%): pale yellow oil; R
f
= 0.29 (hexane/EtOAc = 1 : 1); H NMR
3 C. N. Serhan and N. A. Petasis, Chem. Rev., 2011, 111, 5922.
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(400 MHz, CD OD) δ 0.94 (t, J = 7.6 Hz, 3 H), 1.98–2.08 (m,
3
2 H), 2.12–2.40 (m, 11 H), 3.52 (dt, J = 8.4 Hz, 4.8 Hz, 1 H),
3.62 (s, 3 H), 3.97–4.02 (m, 1 H), 4.15 (q, J = 6.3 Hz, 1 H),
5.30–5.56 (m, 4 H), 5.72 (dd, J = 15.0 Hz, 6.3 Hz, 1 H), 5.84 (dd,
J = 15.0 Hz, 7.0 Hz, 1 H), 5.93–6.04 (m, 2 H), 6.27 (dd, J =
1
6
2
7
4.4 Hz, 10.8 Hz, 1 H), 6.37 (dd, J = 15.0 Hz, 10.8 Hz, 1 H),
.67–6.78 (m, 2 H); C–APT NMR (75 MHz, CD OD) δ 14.8 (+),
3
2.0 (−), 24.3 (−), 32.1 (−), 35.0 (−), 36.5 (−), 52.4 (+), 73.4 (+),
6.1 (+), 76.5 (+), 125.7 (+), 126.9 (+), 128.8 (+), 129.5 (+), 130.6
1
3
(
+), 130.8 (+), 133.8 (+), 134.8 (+), 135.0 (+), 138.6 (+), 175.7 (−);
6 Available from Cayman.
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+
+
HRMS (FAB ) calcd for C H O Na [(M + Na) ] 413.2304,
found 413.2316.
2
3
34 5
8
W. Boland, N. Schroer and C. Sieler, Helv. Chim. Acta, 1987,
0, 1025.
Resolvin D1
7
To a solution of ester 44 (28.1 mg, 0.072 mmol) in MeOH
0.7 mL) and THF (0.7 mL) was added 1 N LiOH (0.35 mL,
.35 mmol). After 5 h of stirring at rt, McIlvaine’s phosphate
buffer (pH 5.0, 20 mL) was added. The resulting mixture was
extracted with Et O (×5). The combined organic extracts were
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(
0
2
dried (MgSO ) and concentrated in vacuo. The residue was pur-
4
Org. Biomol. Chem.
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Organic & Biomolecular Chemistry
Paper
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1
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