Total synthesis, structural elucidation, and structure-cytotoxic activity relationship of (-)-gummiferol

Article abstract of DOI:10.1021/jo302665c

A highly stereoselective and stereodivergent synthesis of two possible diastereomers of (-)-gummiferol was achieved, wherein the stepwise epoxidation and Cadiot-Chodkiewicz reaction were utilized for the construction of the diepoxide moiety and triacetylene part, respectively. Detailed comparison of their ¹H and ¹³C NMR data and specific rotation with those of the natural product unambiguously elucidated the absolute stereostructure of gummiferol. In addition, the cytotoxic activity of the synthesized gummiferol, its stereoisomers, and its truncated analogues was evaluated, which clearly indicates that (1) the absolute configuration of the diepoxide moiety has little influence on the cytotoxic activity against human cancer cells and (2) the triacetylene unit is the crucial structural element required for exerting the cytotoxic activity.

Full text of DOI:10.1021/jo302665c

Article
pubs.acs.org/joc
Total Synthesis, Structural Elucidation, and Structure−Cytotoxic
Activity Relationship of (−)-Gummiferol
Hiroyoshi Takamura,*,† Hiroko Wada,† Nan Lu,† Osamu Ohno,‡ Kiyotake Suenaga,‡ and Isao Kadota*,†
†Department of Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku,
Okayama 700-8530, Japan
‡Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa
223-8522, Japan
S
* Supporting Information
ABSTRACT: A highly stereoselective and stereodivergent synthesis of two possible diastereomers of (−)-gummiferol was
achieved, wherein the stepwise epoxidation and Cadiot−Chodkiewicz reaction were utilized for the construction of the diepoxide
moiety and triacetylene part, respectively. Detailed comparison of their 1H and 13C NMR data and specific rotation with those of
the natural product unambiguously elucidated the absolute stereostructure of gummiferol. In addition, the cytotoxic activity of
the synthesized gummiferol, its stereoisomers, and its truncated analogues was evaluated, which clearly indicates that (1) the
absolute configuration of the diepoxide moiety has little influence on the cytotoxic activity against human cancer cells and (2) the
triacetylene unit is the crucial structural element required for exerting the cytotoxic activity.
urations at the C8/C9 and C10/C11 two epoxide moieties
were inferred from the observation of small coupling constants
INTRODUCTION
■
Conjugated acetylenes are common structural units found in a
large number of natural products, many of which exhibit the
potent and diverse biological activities such as antibacterial,1
antiparasitic,2 and insecticidal.3 These polyacetylenes also show
HIV-1 integrase-inhibitory effect4 and cytotoxicity toward a
wide range of cell lines.5
3
(3J8,9 and J10,11 = 2.0 Hz). However, the stereostructure of
gummiferol, that is, the absolute configuration of the two
contiguous epoxide moieties, was not clarified. Therefore, we
embarked on the synthetic study of (−)-gummiferol toward the
structural elucidation.7 In 2011, as a preliminary communica-
tion, we reported the stereoselective total synthesis of two
possible diastereomers of (−)-gummiferol, which has culmi-
nated in the stereochemical elucidation of this natural product.8
In this article, we describe the details of our total synthesis of
(−)-gummiferol including the examination of Cadiot−
Chodkiewicz reaction for the efficient introduction of the
conjugated triacetylene moiety. Furthermore, we also report the
synthesis of the structurally simplified analogues of gummiferol
and a growth-inhibitory activity of the synthesized gummiferol,
its stereoisomers, and its truncated analogues against human
cancer cells.
In 1995, Wall and co-workers isolated (−)-gummiferol as a
new conjugated acetylenic compound from the 50% MeOH/
CHCl3 extract of the leaves of Adenia gummifera collected in
Mazowe, Zimbabwe, by the cytotoxicity-guided fractionation.6
The cytotoxicity of gummiferol was evaluated by using 13
mammalian cancer cell lines, which revealed that this molecule
exhibited the strong cytotoxicity against P388 murine leukemia
cell line (ED50 = 0.03 μg/mL) and U373 human glioma cell
line (ED50 = 0.05 μg/mL). The planar structure of gummiferol,
which has featured the conjugated triacetylene unit and its
neighboring diepoxide moiety, was determined by the analyses
of HRMS, IR, UV, and NMR measurements including H−1H
COSY, HMQC, and HMBC (Figure 1). The trans-config-
1
RESULTS AND DISCUSSION
■
Synthetic Strategy of 5a and 5b. Toward the structural
determination of (−)-gummiferol, we initially envisioned the
stereoselective and stereodivergent synthesis9 of two possible
diastereomers of this natural product, 5a and 5b, as depicted in
Scheme 1. We planned to introduce the stereochemistries at
Received: December 7, 2012
Figure 1. Planar structure of (−)-gummiferol.
© XXXX American Chemical Society
A
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Scheme 1. Synthetic Strategy of 5a and 5b
the C8 to C11 positions by utilizing the stepwise epoxidation.
Thus, stereoselective epoxidation of allylic alcohol 1 and
subsequent carbon elongation would give epoxide 2. The same
procedure, which includes the stereodiversification step, would
be applied to the allylic alcohol 2 to afford diepoxides 3a and
3b, respectively. The conjugated triacetylene unit could be
constructed by Cadiot−Chodkiewicz coupling10 through a
combination of the bromoacetylenes 3a and 3b and diacetylene
4 to provide the target molecules 5a and 5b, respectively.
Stereoselective Synthesis of syn-Diepoxide 5a. First,
we investigated the stereoselective synthesis of the syn-
diepoxide 5a. Sharpless asymmetric epoxidation11 with
(+)-diisopropyl tartrate (DIPT) was applied to the known
dienol 612 to yield epoxy alcohol 7a as a single stereoisomer
(Scheme 2). The optical purity of 7a was determined by the 1H
NMR comparison between its derivatized (R)-MTPA ester and
the (R)-MTPA ester prepared from the racemic epoxy alcohol,
which was synthesized by epoxidation of 6 with m-CPBA. The
epoxy alcohol 7a was derivatized for the unambiguous
configurational determination. Thus, 7a was subjected to the
Red-Al reduction in THF, wherein the corresponding 1,3-diol
was expected to be obtained,13 to produce 1,2-diol 8 as the sole
product. The plausible rationale of this outcome of the
regioselective epoxide opening is the C−O bond activation at
the C11 position by the neighboring π-orbital. Selective
protection of the primary hydroxy group of 8 provided
TBDPS ether 9. Treatment of the secondary alcohol 9 with
MTPACl/Et3N/DMAP afforded MTPA esters (S)- and (R)-
10, respectively. The modified Mosher method14 was utilized to
elucidate the stereochemistry at the C10 position. Thus, the
1H−1H COSY spectra of (S)- and (R)-10 were analyzed, and
the ΔδS−R values were calculated (Figure 2). The signs at the
Figure 2. Chemical shift differences (ΔδS−R) of (S)- and (R)-10. R =
MTPA. MTPA = α-methoxy-β-(trifluoromethyl)phenylacetyl.
left side of the C10 position were negative, and those at the
right side were positive. Therefore, the absolute stereo-
chemistry of 10 was elucidated to be 10R, which led to the
configurational assignment of 7a.
Scheme 2. Synthesis of 7a and Its Derivatization for the
Structural Elucidation
We next carried out the stereoselective introduction of the
8,9-epoxide moiety and its stereochemical assignment. Parikh−
Doering oxidation15 of 7a and subsequent two-carbon
elongation under the Masamune−Roush conditions16 afforded
α,β-unsaturated ester 11 in 80% yield in two steps (Scheme 3).
The ester 11 was transformed to alcohol 12 through the
corresponding aldehyde by the stepwise DIBAL-H reduction,
wherein 1.1 equiv of the reagent was used in each step because
the epoxide opening was observed as a side reaction in the case
of 2.2 equiv. The second epoxidation was carried out under the
Sharpless conditions11 with (+)-DIPT to yield syn-diepoxide
13a in 80% yield as a single diastereomer. The configurational
establishment of the resulting 8,9-epoxide moiety of 13a was
performed by the derivatization and the modified Mosher
method.14 Thus, the double bond of 13a was reduced with
diimide, in order to decrease the reactivity at the C11 position
in the next Red-Al reduction, to provide alkane 14. Chemo- and
regioselective reduction of the 8,9-epoxide moiety of 14 with
Red-Al13 produced the desired 1,3-diol. The primary alcohol
was selectively protected to give TBDPS ether 15. The
secondary alcohol 15 was converted to MTPA esters (S)-
and (R)-16 quantitatively by the standard conditions. In the
B
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Scheme 3. Synthesis of 13a and Its Derivatization for the
Structural Elucidation
Scheme 4. Synthesis of 18a
examined the Cadiot−Chodkiewicz reaction10 between 18a and
diacetylene 19 (Table 1).20 When we treated 18a (1.0 equiv)
Table 1. Cadiot−Chodkiewicz Coupling between 18a and 19
a
entry
conditions
yield (%)
1
2
3
4
CuI, (Ph3P)2PdCl2, pyrrolidine, rt
0
20
40
67
CuCl, NH2OH·HCl, EtNH2, MeOH, rt
CuCl, NH2OH·HCl, EtNH2, MeOH, 0 °C
CuCl, NH2OH·HCl, EtNH2, MeOH, −78 °C
a
Isolated yield in two steps.
observed ΔδS−R values of the (S)- and (R)-16, the signs at the
left side of the C9 position proved to be positive, and those at
the right side were elucidated to be negative (Figure 3).
Therefore, the absolute configuration at the C9 position of 16
was assigned to be R, which culminated in the structural
determination of the 8,9-epoxide moiety of 13a.
and 19 (1.1 equiv) with CuI/(Ph3P)2PdCl2 in pyrrolidine
according to Alami protocol,21 the reaction yielded the complex
mixture (entry 1). The use of CuCl/NH2OH·HCl/EtNH2 at
room temperature gave the desired cross-coupling product
(entry 2).22 Treatment of the resulting allylic alcohol with
Ac2O/pyridine/DMAP and purification by silica gel column
chromatography afforded acetate 20a in 20% yield in two steps.
Although the desired product 20a was obtained, we observed
the formation of several byproducts in the first step. Therefore,
we carried out the Cadiot−Chodkiewicz reaction at 0 °C to
provide 20a in 40% yield (entry 3). The chemical yield of 20a
could be improved to 67% by lowering the reaction
temperature to −78 °C (entry 4). It is noteworthy that the
reactive propargylic and vinylic epoxides as well as the free
allylic alcohol of 18a could be tolerated under the reaction
conditions. Finally, deprotection of the TBS moiety of 20a with
HF·pyr produced the syn-diepoxide 5a, quantitatively (Scheme
5).
Figure 3. Chemical shift differences (ΔδS−R) of (S)- and (R)-16. R =
MTPA.
Transformation of the alcohol 13a to the coupling precursor
18a is described in Scheme 4. Parikh−Doering oxidation15 of
13a afforded the corresponding aldehyde. The initial attempt to
convert the aldehyde to dibromoalkene 17 under the standard
Corey−Fuchs conditions17 provided a mixture of products
because of the epoxide opening side reaction.18 After the
detailed investigation, it was proven that the addition of Et3N
was effective and the dibromoalkene 17 was obtained as the
sole product.19 Removal of the TBS group and dehydrobromi-
nation were carried out simultaneously with an excess amount
of TBAF to afford the bromoacetylene 18a.19b We next
Stereoselective Synthesis of anti-Diepoxide 5b. Next,
we examined the stereoselective synthesis of the anti-diepoxide
5b by using a transformation similar to that toward 5a. The
allylic alcohol 12 was subjected to the Sharpless asymmetric
epoxidation11 with (−)-DIPT to give epoxy alcohol 13b in 81%
yield as the sole product (Scheme 6). The diastereomeric purity
C
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1
Scheme 5. Synthesis of 5a
Table 2. H NMR Chemical Shifts and Their Deviations of
Natural (−)-Gummiferol and the Synthetic Products 5a and
a
5b
b
c
c
d
d
position
natural
5a
5b
Δ(δN−δ5a)
Δ(δN−δ5b)
1
8
9
4.34
3.46
3.35
3.04
3.39
5.49
6.05
4.58
2.09
4.36
3.44
3.34
3.02
3.38
5.49
6.04
4.59
2.08
4.36
3.43
3.27
2.92
3.35
5.48
6.04
4.58
2.08
−0.02
+0.02
+0.01
+0.02
+0.01
0.00
−0.02
+0.03
+0.08
+0.12
+0.04
+0.01
+0.01
0.00
10
11
12
13
+0.01
−0.01
+0.01
14
14-COCH3
+0.01
a
Chemical shifts are reported in parts per million with reference to
Scheme 6. Synthesis of 5b
b
c
tetramethylsilane. Data from ref 6. Recorded at 500 MHz. Recorded
at 400 MHz. δN, δ5a, and δ5b are chemical shifts of the natural product
d
and the synthetic products 5a and 5b, respectively.
Table 3. 13C NMR Chemical Shifts and Their Deviations of
Natural (−)-Gummiferol and the Synthetic Products 5a and
a
5b
b
c
c
d
d
position
natural
5a
5b
Δ(δN−δ5a)
Δ(δN−δ5b)
1
2
3
4
5
6
7
8
9
51.3
77.2
70.1
62.4
62.8
69.0
73.9
43.1
57.5
56.2
55.2
129.4
130.5
63.6
170.8
20.9
51.5
77.2
70.4
62.6
62.7
69.0
74.0
43.1
57.5
56.2
55.1
129.3
130.4
63.5
170.4
20.9
51.5
77.2
70.4
62.8
62.6
69.2
73.7
43.5
58.7
57.1
55.9
129.1
130.5
63.5
170.4
20.9
−0.2
0.0
−0.2
0.0
−0.3
−0.2
+0.1
0.0
−0.3
−0.4
+0.2
−0.2
+0.2
−0.4
−1.2
−0.9
−0.7
+0.3
0.0
−0.1
0.0
0.0
10
0.0
11
+0.1
+0.1
+0.1
+0.1
+0.4
0.0
12
13
14
+0.1
+0.4
0.0
14-COCH3
14-COCH3
a
Chemical shifts are reported in parts per million with reference to
b
c
tetramethylsilane. Data from ref 6. Recorded at 125 MHz. Recorded
at 100 MHz. δN, δ5a, and δ5b are chemical shifts of the natural product
d
and the synthetic products 5a and 5b, respectively.
1
of 13b was judged by the H and 13C NMR data, which
deviated obviously from those of 13a. Parikh−Doering
oxidation,15 dibromo-olefination utilizing Corey−Fuchs proto-
col in the presence of Et3N,17,19 and TBS deprotection/
dehydrobromination afforded allylic alcohol 18b in 57% yield in
three steps. The bromoacetylene 18b was reacted with
diacetylene 19 under the optimized conditions of Cadiot−
Chodkiewicz reaction10 to form the desired coupling product.
Acetylation of the resulting allylic alcohol provided acetate 20b
in 48% yield from 18b. Finally, desilylation of 20b was
performed to produce the anti-diepoxide 5b.
Structural Elucidation of (−)-Gummiferol. With two
possible diastereomers of (−)-gummiferol in hand, we next
submitted these two synthetic products to the detailed 2D
NMR analysis. Tables 2 and 3 describe chemical shifts and their
deviations of natural gummiferol6 and the synthesized
diepoxides 5a and 5b in the 1H and 13C NMR spectra,
respectively. The 1H and 13C NMR data of 5a were in excellent
agreement with those of natural gummiferol. On the other
hand, the 1H and 13C NMR data of the synthetic anti-diepoxide
5b were clearly different from those of the natural product. It
was proven that there were the critical differences in the
chemical shifts at the C9 and C10 positions between natural
gummiferol and the synthetic 5b: Δ(δN−δ5b) = +0.08 (H-9),
+0.12 (H-10), −1.2 (C-9), −0.9 (C-10). The measured specific
28
rotation of the synthetic adduct 5a, [α]D −62.5 (c 0.07,
CH3OH), was consistent with the reported value of natural
(−)-gummiferol, [α]D −170 (c 0.2, CH3OH).6,23 Therefore,
25
the absolute configuration of (−)-gummiferol was elucidated to
be that depicted in 5a.
Synthesis of 5c and 5b. Having elucidated the absolute
configuration of (−)-gummiferol by the chemical synthesis of
two possible diastereomers 5a and 5b, we next turned our
attention to the structure−activity relationship of gummiferol.
First, we decided to elucidate the influence on the biological
activity by the stereostructure of the diepoxide moiety.
Therefore, in addition to the diepoxides 5a and 5b, their
enantiomers 5c and 5d were also synthesized through the
common synthetic intermediate 7b, which was obtained by the
D
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Scheme 7. Synthesis of 5c and 5d
Sharpless epoxidation11 with (−)-DIPT of 6, as shown in
Scheme 7.
Scheme 9. Synthesis of 26
Synthesis of Analogues. We next tried to synthesize the
structurally simplified analogues corresponding to the diep-
oxide and triacetylene moieties. Synthesis of the truncated
diepoxide analogue 22 is described in Scheme 8. Protection of
Scheme 8. Synthesis of 22
deprotection of 28 with HF·pyr proceeded smoothly to give the
second truncated triacetylene analogue 29, which is the two-
carbon elongated diacetylene analogue of 26. Investigation on
the synthesis of 33 was also commenced from the allylic alcohol
6. Chemoselective epoxidation of 6 took place with mCPBA to
provide epoxy alcohol 30 in 78% yield as the racemate. The
epoxy alcohol 30 was converted to the third structurally
simplified triacetylene analogue 33, which is the monoepoxi-
dized compound of 29, through 31 and 32 as the synthetic
intermediates by using the similar sequence to that toward 29.
Evaluation of the Cytotoxicity of (−)-Gummiferol, Its
Stereoisomers, and Its Analogues. With (−)-gummiferol
(5a), its stereoisomers 5b−5d, and its truncated analogues 22,
26, 29, and 33 in hand, we evaluated the growth-inhibitory
activity of these compounds by using the MTT assay with
HL60 human leukemia cells and HeLa S3 human cervical
cancer cells. The cells were treated in 96-well plates with
various concentrations of the compounds for 72 h. The results
are shown in Table 4. Interestingly, (−)-gummiferol (5a) and
its stereoisomers 5b−5d exhibited the similar activity without
the epoxy alcohol 13a, which is the synthetic intermediate
toward (−)-gummiferol (5a), as the PMB ether, removal of the
TBS protective group, and acetylation of the resulting alcohol
gave acetate 21. Oxidative deprotection of the PMB moiety
with DDQ afforded the structurally simplified diepoxide
analogue 22 in 81% yield.
Next, we investigated the synthesis of the truncated
triacetylene analogues 26, 29, and 33 on the basis of the
Cadiot−Chodkiewicz cross-coupling.10 Dibromo-olefination of
the known aldehyde 2312 under the modified Corey−Fuchs
conditions17,19 followed by deprotection of the TBS group and
dehydrobromination with TBAF provided bromoacetylene 24
(Scheme 9). The bromoacetylene 24 was coupled with the
diacetylene 19 to yield the desired triacetylene. Treatment of
the resulting alcohol with Ac2O/pyr/DMAP gave acetate 25 in
63% yield in four steps. The TBS group was removed with
HF·pyr to produce the first structurally simplified triacetylene
analogue 26. The other two truncated triacetylene analogues 29
and 33 were also synthesized, as depicted in Scheme 10.
Parikh−Doering oxidation15 of the dienol 6 afforded dienal 27
in 89% yield. The aldehyde 27 was transformed to triacetylene
28 by the following four-step sequence: (1) one-carbon
elongation with CBr4/PPh3 in the presence of Et3N,17,19 (2)
TBS removal and dehydrobromination in one-pot, (3) Cadiot−
Chodkiewicz coupling10 of the corresponding bromoalkyne
with 19, and (4) acetylation of the resulting alcohol. The final
regard to the stereostructure of the diepoxide moiety (IC50
=
1.22−3.61 μM for HL60 cells and 6.76−19.1 μM for HeLa S3
cells). The structurally simplified diepoxide analogue 22 was
inactive against both HL60 and HeLa S3 cells (IC50 >100 μM).
On the other hand, the truncated triacetylene analogue 26
retained the growth-inhibitory activity (IC50 = 12.3 μM for
HL60 cells and 31.6 μM for HeLa S3 cells). The cytotoxic
activity of the other two triacetylene analogues 29 and 33
E
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Scheme 10. Synthesis of 29 and 33
the modified Mosher method. The Cadiot−Chodkiewicz
reactions between the bromoacetylenes and the diacetylene
were efficiently applied to the construction of the triacetylene
unit. The detailed comparison of the synthetic 5a and 5b and
Table 4. Growth-Inhibitory Activity of (−)-Gummiferol, Its
Stereoisomers, and Its Structural Analogues against Human
a
Cancer Cells
compounds
HL60
1.22
HeLa S3
1
the natural product in the H and 13C NMR data and specific
5a
5b
5c
5d
22
26
29
33
25
28
32
6.76
8.61
rotation revealed the absolute configuration of (−)-gummiferol
to be that shown in 5a.
1.62
1.23
3.61
6.68
Besides 5a and 5b, their enantiomers 5c and 5d were also
synthesized for elucidating the stereostructure−activity rela-
tionship of gummiferol. Moreover, its skeletal analogues 22, 25,
26, 28, 29, 32, and 33 were synthesized as the structurally
simplified diepoxide and triacetylene analogues, respectively.
The growth-inhibitory activity of these synthetic products
against HL60 and HeLa S3 cells was evaluated, establishing that
(1) the stereostructure of the diepoxide unit has little effect on
the cytotoxic activity and (2) the presence of the triacetylene
moiety is crucial for the cytotoxic activity.
19.1
>100
12.3
>100
31.6
4.63
4.75
4.48
22.4
17.4
19.3
19.4
7.40
50.9
20.6
a
IC50 values in μM.
EXPERIMENTAL SECTION
proved to be slightly increased in comparison with that of 26.
Furthermore, to elucidate the influence on the cytotoxic activity
by the propargylic alcohol moieties of 26, 29, and 33, we
evaluated the growth-inhibitory activity of the TBS ethers 25,
28, and 32, and it was found that these compounds also
exhibited the cytotoxic activity against both HL60 and HeLa S3
cells. These results revealed the following two points
concerning the structure−activity relationship: (1) The stereo-
chemistry of the diepoxide moiety has little influence on the
growth-inhibitory activity. (2) The triacetylene unit is essential
for exerting the growth inhibition.
■
Epoxy Alcohol 7a. To a suspension of powdered MS4Å (400 mg)
in CH2Cl2 (40 mL) were added (+)-DIPT (0.27 mL, 1.32 mmol),
Ti(Oi-Pr)4 (0.26 mL, 0.877 mmol), and TBHP (ca. 6.0 M solution in
2,2,4-trimethylpentane, 2.9 mL, 17.4 mmol) at −25 °C. The mixture
was stirred at the same temperature for 30 min, and a solution of allylic
alcohol 6 (2.00 g, 8.77 mmol) in CH2Cl2 (5.0 mL + 3.0 mL + 2.0 mL)
was added. After the resulting mixture was stirred at −25 °C for 4 h,
the reaction was quenched with 3 M aqueous NaOH. The mixture was
stirred at room temperature for 1 h. The mixture was filtered through a
Celite pad and washed with EtOAc. The mixture was washed with
H2O and brine and then dried over Na2SO4. Concentration and
column chromatography (hexane/EtOAc = 6:1) gave epoxy alcohol 7a
(901 mg, 42%) as a light yellow oil and allylic alcohol 6 (816 mg, 41%
CONCLUSION
■
25
recovery). Epoxy alcohol 7a: Rf = 0.39 (hexane/EtOAc = 1:1); [α]D
First, we have synthesized two possible diastereomers of
(−)-gummiferol, 5a and 5b, in a highly stereoselective and
stereodivergent manner. In the synthetic route, two contiguous
epoxide parts were stereoselectively introduced by the
Sharpless asymmetric epoxidation conditions. The resulting
stereochemistries of the synthetic products in the epoxidation
steps were unambiguously determined by the derivatization and
−27.1 (c 0.10, CHCl3); IR (neat) 3434, 2954, 2928 cm−1; H NMR
1
(400 MHz, CDCl3) δ 6.03 (dt, J = 15.4, 4.4 Hz, 1 H), 5.50 (ddt, J =
15.4, 8.0, 2.0 Hz, 1 H), 4.20 (dd, J = 4.4, 2.0 Hz, 2 H), 3.96 (ddd, J =
12.7, 5.4, 2.4 Hz, 1 H), 3.70 (ddd, J = 12.7, 7.8, 3.9 Hz, 1 H), 3.44 (dd,
J = 8.0, 2.4 Hz, 1 H), 3.09 (dt, J = 3.9, 2.4 Hz, 1 H), 1.60 (dd, J = 7.8,
5.4 Hz, 1 H), 0.92 (s, 9 H), 0.08 (s, 6 H); 13C NMR (100 MHz,
CDCl3) δ 135.5, 125.9, 62.8, 61.2, 60.0, 55.3, 26.0, 18.6, −5.2, −5.2;
F
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HRMS (ESI−TOF) calcd for C12H24O3SiNa [M + Na]+ 267.1393,
found 267.1385.
= 10:1, 5:1) gave the corresponding aldehyde (865 mg), which was
used for the next reaction without further purification.
TBDPS Ether 9. To a solution of epoxy alcohol 7a (50.0 mg, 0.205
mmol) in THF (2.0 mL) was added Red-Al (65% in toluene, 0.31 mL,
1.00 mmol) at −40 °C. After the mixture was stirred at 0 °C for 5 h,
the reaction was quenched with saturated aqueous sodium potassium
tartrate. The mixture was diluted with EtOAc and washed with H2O
and brine and then dried over Na2SO4. Concentration and column
chromatography (hexane/EtOAc = 4:1, 2:1) gave diol 8 (40.5 mg),
which was used for the next reaction without further purification.
To a solution of diol 8 obtained above (40.5 mg) in CH2Cl2 (1.5
mL) were added DMAP (32.6 mg, 0.237 mmol), imidazole (32.2 mg,
0.474 mmol), and TBDPSCl (82 μL, 0.316 mmol) at 0 °C. After the
mixture was stirred at room temperature for 1 h, the reaction was
quenched with saturated aqueous NH4Cl. The mixture was diluted
with EtOAc, washed with H2O and brine and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 25:1,
10:1, 4:1) gave TBDPS ether 9 (61.9 mg, 65% in two steps) as a
To a solution of (EtO)2P(O)CH2CO2Et (1.6 mL, 7.12 mmol) in
CH3CN (27 mL) were added DIPEA (1.8 mL, 10.7 mmol), LiCl (602
mg, 14.2 mmol), and the aldehyde obtained above (865 mg) in
CH3CN (5.0 mL + 3.0 mL + 1.0 mL) at 0 °C. After the mixture was
stirred at room temperature for 30 min, the reaction was quenched
with saturated aqueous NH4Cl. The mixture was diluted with Et2O,
washed with H2O and brine, and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 20:1)
gave α,β-unsaturated ester 11 (1.02 g, 80% in two steps) as a colorless
22
oil: Rf = 0.63 (hexane/EtOAc = 4:1); [α]D −43.2 (c 1.00, CHCl3);
IR (neat) 2955, 2930, 1723, 1657 cm−1; 1H NMR (400 MHz, CDCl3)
δ 6.70 (dd, J = 15.6, 6.8 Hz, 1 H), 6.13 (d, J = 15.6 Hz, 1 H), 6.03 (dt,
J = 15.3, 4.4 Hz, 1 H), 5.50 (ddt, J = 15.3, 7.7, 1.9 Hz, 1 H), 4.22−4.17
(m, 4 H), 3.38−3.32 (m, 2 H), 1.29 (t, J = 7.1 Hz, 3 H), 0.91 (s, 9 H),
0.07 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 165.5, 143.7, 135.8,
125.3, 123.7, 62.7, 60.7, 60.6, 58.2, 26.0, 18.4, 14.3, −5.2, −5.2; HRMS
(ESI−TOF) calcd for C16H28O4SiNa [M + Na]+ 335.1655, found
335.1648.
22
yellow oil: Rf = 0.67 (hexane/EtOAc = 4:1); [α]D +1.2 (c 0.77,
1
CHCl3); IR (neat) 3412, 2956, 2930 cm−1; H NMR (400 MHz,
CDCl3) δ 7.67−7.65 (m, 4 H), 7.44−7.37 (m, 6 H), 5.67−5.56 (m, 2
H), 4.10 (d, J = 3.7 Hz, 2 H), 3.78−3.75 (m, 1 H), 3.67 (dd, J = 10.2,
3.9 Hz, 1 H), 3.54 (dd, J = 10.2, 6.8 Hz, 1 H), 2.43 (br s, 1 H), 2.23 (t,
J = 6.4 Hz, 2 H), 1.07 (s, 9 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR
(100 MHz, CDCl3) δ 135.4, 133.1, 132.2, 129.7, 127.7, 126.2, 71.5,
67.4, 63.7, 36.1, 26.9, 26.0, 19.3, 18.5, −5.0; HRMS (ESI−TOF) calcd
for C28H44O3Si2Na [M + Na]+ 507.2727, found 507.2733.
Allylic Alcohol 12. To a solution of α,β-unsaturated ester 11 (18.4
mg, 59.0 μmol) in CH2Cl2 (1.0 mL) was added DIBAL-H (1.03 M
solution in hexane, 63 μL, 64.9 μmol) at −78 °C. After the mixture
was stirred at the same temperature for 10 min, the reaction was
quenched with MeOH. The mixture was filtered through a Celite pad
and washed with EtOAc. Concentration and column chromatography
(hexane/EtOAc = 20:1, 10:1, 4:1) gave the corresponding aldehyde
(16.4 mg), which was used for the next reaction without further
purification.
MTPA Ester (S)-10. To a solution of alcohol 9 (2.8 mg, 5.77 μmol)
in CH2Cl2 (0.2 mL) were added DMAP (1.4 mg, 11.5 μmol), Et3N
(1.1 μL, 8.00 μmol), and (R)-MTPACl (1.3 μL, 6.93 μmol) at 0 °C.
After the mixture was stirred for 10 min at the same temperature, the
reaction was quenched with saturated aqueous NH4Cl. The mixture
was diluted with Et2O, washed with H2O and brine, and then dried
over Na2SO4. Concentration and column chromatography (hexane/
EtOAc = 45:1) gave MTPA ester (S)-10 (4.0 mg, 99%) as a colorless
To a solution of the aldehyde obtained above (16.4 mg) in CH2Cl2
(1.0 mL) was added DIBAL-H (1.03 M solution in hexane, 63 μL,
64.9 μmol) at −78 °C. After the mixture was stirred at the same
temperature for 10 min, the reaction was quenched with MeOH. The
mixture was filtered through a Celite pad and washed with EtOAc.
Concentration and column chromatography (hexane/EtOAc = 10:1,
4:1) gave allylic alcohol 12 (12.7 mg, 80% in two cycles) as a colorless
23
oil: Rf = 0.45 (hexane/EtOAc = 10:1); [α]D −7.7 (c 0.19, CHCl3);
1
25
IR (neat) 2954, 2928, 1748 cm−1; H NMR (400 MHz, CDCl3) δ
oil: Rf = 0.35 (hexane/EtOAc = 2:1); [α]D −32.1 (c 0.87, CHCl3);
7.65−7.32 (m, 15 H), 5.64−5.52 (m, 2 H, H-12 and H-13), 5.25−5.20
(m, 1 H, H-10), 4.06 (d, J = 4.4 Hz, 2 H, H2-14), 3.74−3.66 (m, 2 H,
H2-9), 3.54 (s, 3 H), 2.55−2.41 (m, 2 H, H2-11), 1.01 (s, 9 H), 0.89 (s,
9 H), 0.04 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 166.0, 135.5,
135.4, 133.4, 133.0, 132.8, 132.2, 129.7, 129.5, 129.4, 128.2, 127.6,
127.6, 127.4, 124.2, 77.2, 76.8, 64.0, 63.4, 55.5, 33.5, 26.8, 26.0, 19.2,
18.5, −5.2; HRMS (ESI−TOF) calcd for C38H51F3O5Si2Na [M +
Na]+ 723.3125, found 723.3130.
IR (neat) 3409, 2954, 2929, 1692 cm−1; 1H NMR (400 MHz, CDCl3)
δ 6.08 (dt, J = 15.4, 4.4 Hz, 1 H), 6.00 (dt, J = 15.4, 4.4 Hz, 1 H),
5.54−5.46 (m, 2 H), 4.20−4.17 (m, 4 H), 3.29−3.27 (m, 2 H), 1.36
(br s, 1 H), 0.91 (s, 9 H), 0.08 (s, 6 H); 13C NMR (100 MHz, CDCl3)
δ 134.8, 134.2, 128.0, 126.1, 62.8, 62.7, 59.9, 59.6, 26.0, 18.4, −5.2;
HRMS (ESI−TOF) calcd for C14H26O3SiNa [M + Na]+ 293.1549,
found 293.1545.
Epoxy Alcohol 13a. To a suspension of powdered MS4Å (130
mg) in CH2Cl2 (10 mL) were added (+)-DIPT (0.17 mL, 0.843
mmol), Ti(Oi-Pr)4 (0.17 mL, 0.562 mmol), and TBHP (ca. 6.0 M
solution in 2,2,4-trimethylpentane, 1.8 mL, 10.8 mmol) at −30 °C.
The mixture was stirred at the same temperature for 30 min, and a
solution of allylic alcohol 12 (151 mg, 0.558 mmol) in CH2Cl2 (3.0
mL + 1.0 mL + 1.0 mL) was added at −40 °C. After the resulting
mixture was stirred at −40 °C for 17 h and at −30 °C for further 8 h,
the reaction was quenched with saturated aqueous sodium potassium
tartrate. The mixture was filtered through a Celite pad and washed
with EtOAc. The mixture was washed with H2O and brine and then
dried over Na2SO4. After the concentration, the mixture was diluted
with Et2O and 3 M aqueous NaOH was added to the mixture. The
mixture was stirred at 0 °C for 30 min. The mixture was diluted with
EtOAc, washed with H2O and brine, and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 4:1)
gave epoxy alcohol 13a (127 mg, 80%) as a colorless oil: Rf = 0.42
(hexane/EtOAc = 1:1); [α]D20 −61.2 (c 0.98, CHCl3); IR (neat) 3435,
MTPA Ester (R)-10. To a solution of the alcohol 9 (2.8 mg, 5.77
μmol) in CH2Cl2 (0.2 mL) were added DMAP (1.4 mg, 11.5 μmol),
Et3N (1.1 μL, 8.00 μmol), and (S)-MTPACl (1.3 μL, 6.93 μmol) at 0
°C. After the mixture was stirred for 10 min at the same temperature,
the reaction was quenched with saturated aqueous NH4Cl. The
mixture was diluted with Et2O, washed with H2O and brine, and then
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 45:1) gave MTPA ester (R)-10 (4.1 mg, quant) as a
colorless oil: Rf = 0.45 (hexane/EtOAc = 10:1); [α]D26 +26.7 (c 0.72,
1
CHCl3); IR (neat) 2954, 2930, 1749 cm−1; H NMR (400 MHz,
CDCl3) δ 7.65−7.29 (m, 15 H), 5.53−5.39 (m, 2 H, H-12 and H-13),
5.27−5.20 (m, 1 H, H-10), 4.01−3.98 (m, 2 H, H2-14), 3.77 (dd, J =
5.6, 2.2 Hz, 2 H, H2-9), 3.55 (s, 3 H), 2.35 (t, J = 6.3 Hz, 2 H, H2-11),
1.04 (s, 9 H), 0.88 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz,
CDCl3) δ 166.0, 135.5, 135.4, 133.3, 133.0, 132.8, 132.4, 129.8, 129.8,
129.4, 128.6, 128.3, 127.7, 127.4, 124.0, 77.2, 76.8, 64.4, 63.4, 55.5,
33.3, 26.8, 26.0, 19.3, 18.4, −5.1; HRMS (ESI−TOF) calcd for
C38H51F3O5Si2Na [M + Na]+ 723.3125, found 723.3135.
1
2954, 2929 cm−1; H NMR (400 MHz, CDCl3) δ 6.04 (dt, J = 15.6,
α,β-Unsaturated Ester 11. To a solution of alcohol 7a (998 mg,
4.09 mmol) in CH2Cl2 (40 mL) and DMSO (13 mL) were added
Et3N (1.3 mL, 12.3 mmol) and SO3·pyr (1.30 g, 8.18 mmol) at 0 °C.
The mixture was stirred at room temperature for 2 h. The mixture was
diluted with EtOAc, washed with H2O and brine, and then dried over
Na2SO4. Concentration and column chromatography (hexane/EtOAc
4.4 Hz, 1 H), 5.46 (ddt, J = 15.6, 7.8, 2.0 Hz, 1 H), 4.19 (dd, J = 4.4,
2.0 Hz, 2 H), 3.96 (ddd, J = 12.7, 4.4, 2.2 Hz, 1 H), 3.70 (ddd, J =
12.7, 7.8, 3.6 Hz, 1 H), 3.39 (dd, J = 7.8, 2.0 Hz, 1 H), 3.17 (dt, J = 3.6,
2.2 Hz, 1 H), 3.07 (dd, J = 4.4, 2.2 Hz, 1 H), 2.92 (dd, J = 4.4, 2.0 Hz,
1 H), 1.82 (br s, 1 H), 0.90 (s, 9 H), 0.07 (s, 6 H); 13C NMR (100
MHz, CDCl3) δ 135.8, 125.4, 62.7, 60.5, 57.9, 55.7, 55.5, 53.3, 25.9,
G
dx.doi.org/10.1021/jo302665c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
18.4, −5.2; HRMS (ESI−TOF) calcd for C14H26O4SiNa [M + Na]+
309.1498, found 309.1496.
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 10:1) gave MTPA ester (R)-16 (2.0 mg, quant) as a
27
Alkane 14. To a mixture of alkene 13a (10.0 mg, 34.9 μmol),
pyridine (0.54 mL, 5.58 mmol), and KO2CNNCO2K (542 mg, 2.79
mmol) in MeOH (2.0 mL) was added AcOH (0.32 mL, 5.58 mmol) at
40 °C. After the mixture was stirred at the same temperature for 6 h,
the reaction was quenched with saturated aqueous NH4Cl. The
mixture was diluted with EtOAc and washed with saturated aqueous
NH4Cl, saturated aqueous NaHCO3, and brine. The organic layer was
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 4:1) gave alkane 14 (9.6 mg, 95%) as a yellow oil:
colorless oil: Rf = 0.41 (hexane/EtOAc = 7:1); [α]D +28.0 (c 0.23,
1
CHCl3); IR (neat) 2954, 2929, 1752 cm−1; H NMR (400 MHz,
CDCl3) δ 7.73−7.70 (m, 1 H), 7.64−7.60 (m, 4 H), 7.53−7.51 (m, 1
H), 7.45−7.29 (m, 9 H), 5.20−5.15 (m, 1 H, H-9), 3.66−3.56 (m, 4
H, H2-7 and H2-14), 3.57 (s, 3 H), 2.93 (dd, J = 7.3, 2.0 Hz, 1 H, H-
10), 2.91−2.89 (m, 1 H, H-11), 1.93−1.80 (m, 2 H, H2-8), 1.66−1.51
(m, 4 H, H2-12 and H2-13), 1.05 (s, 9 H), 0.89 (s, 9 H), 0.05 (s, 6 H);
13C NMR (100 MHz, CDCl3) δ 165.7, 135.5, 135.4, 134.7, 133.4,
133.3, 132.3, 129.7, 129.4, 128.3, 127.7, 127.2, 77.2, 74.5, 62.4, 59.2,
58.5, 57.1, 55.6, 34.0, 29.1, 28.2, 26.9, 26.0, 19.2, 18.4, −5.2; HRMS
(ESI−TOF) calcd for C40H55F3O6Si2Na [M + Na]+ 767.3387, found
767.3381.
Bromoacetylene 18a. To a solution of alcohol 13a (18.6 mg, 64.9
μmol) in CH2Cl2 (1.0 mL) and DMSO (0.3 mL) were added Et3N
(45 μL, 0.325 mmol) and SO3·pyr (41.3 mg, 0.260 mmol) at 0 °C.
The mixture was stirred at room temperature for 2 h. The mixture was
diluted with EtOAc, washed with H2O and brine, and then dried over
Na2SO4. Concentration and column chromatography (hexane/EtOAc
= 10:1, 5:1) gave the corresponding aldehyde (15.1 mg), which was
used for the next reaction without further purification.
To a solution of CBr4 (70.3 mg, 0.212 mmol) in CH2Cl2 (1.5 mL)
was added PPh3 (111 mg, 0.425 mmol) at 0 °C. The mixture was
stirred at the same temperature for 15 min, and Et3N (59 μL, 0.425
mmol) was added to the resulting mixture at 0 °C. After the mixture
was stirred at the same temperature for 5 min, the aldehyde obtained
above (15.1 mg) in CH2Cl2 (0.6 mL + 0.4 mL) was added at −78 °C.
The mixture was stirred at the same temperature for 1 h. The reaction
was quenched with saturated aqueous NaHCO3. The mixture was
diluted with EtOAc, washed with H2O and brine, and then dried over
Na2SO4. Concentration and column chromatography (hexane/EtOAc
= 30:1, 20:1) gave dibromoalkene 17 (22.4 mg), which was used for
the next reaction without further purification.
22
Rf = 0.60 (hexane/EtOAc = 1:1); [α]D −34.9 (c 0.20, CHCl3); IR
(neat) 3435, 2954, 2928 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.99−
3.96 (m, 1 H), 3.71−3.69 (m, 3 H), 3.16 (dt, J = 4.4, 2.2 Hz, 1 H),
3.04 (dd, J = 4.6, 2.2 Hz, 1 H), 3.00−2.97 (m, 1 H), 2.76 (dd, J = 4.6,
2.2 Hz, 1 H), 1.74−1.57 (m, 5 H), 0.89 (s, 9 H), 0.05 (s, 6 H); 13C
NMR (100 MHz, CDCl3) δ 62.4, 60.6, 56.2, 55.9, 55.7, 53.7, 29.1,
28.2, 26.0, 18.4, −5.2; HRMS (ESI−TOF) calcd for C14H28O4SiNa
[M + Na]+ 311.1655, found 311.1653.
TBDPS Ether 15. To a solution of epoxy alcohol 14 (12.0 mg, 41.5
μmol) in THF (0.6 mL) was added Red-Al (65% in toluene, 62 μL,
0.208 mmol) at −40 °C. After the mixture was allowed to warm to
−10 °C for 2 h, the reaction was quenched with saturated aqueous
sodium potassium tartrate. The mixture was diluted with EtOAc,
washed with H2O and brine, and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 1:1)
gave the corresponding diol (11.0 mg), which was used for the next
reaction without further purification.
To a solution of the diol obtained above (11.0 mg) in CH2Cl2 (0.5
mL) were added DMAP (5.4 mg, 44.0 μmol), imidazole (3.0 mg, 44.0
μmol), and TBDPSCl (7.6 μL, 29.3 μmol) at 0 °C. After the mixture
was stirred at room temperature for 7 h, the reaction was quenched
with saturated aqueous NH4Cl. The mixture was diluted with EtOAc,
washed with H2O and brine, and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 10:1)
gave TBDPS ether 15 (12.1 mg, 55% in two steps) as a colorless oil: Rf
= 0.57 (hexane/EtOAc = 4:1); [α]D24 −3.2 (c 0.33, CHCl3); IR (neat)
3419, 2954, 2929 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68−7.65 (m,
4 H), 7.46−7.37 (m, 6 H), 3.93−3.80 (m, 3 H), 3.67−3.60 (m, 2 H),
2.99−2.96 (m, 1 H), 2.78 (dd, J = 4.6, 2.2 Hz, 1 H), 2.63 (d, J = 4.6
Hz, 1 H), 1.85−1.75 (m, 2 H), 1.67−1.58 (m, 4 H), 1.05 (s, 9 H), 0.89
(s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 135.5, 135.5,
129.7, 127.7, 69.6, 62.6, 61.6, 61.5, 55.9, 36.2, 29.8, 29.2, 28.3, 26.9,
26.0, 19.2, −5.2; HRMS (ESI−TOF) calcd for C30H48O4Si2Na [M +
Na]+ 551.2989, found 551.2988.
To a solution of dibromoalkene 17 obtained above (22.4 mg) in
THF (0.5 mL) was added TBAF (1.0 M solution in THF, 0.20 mL,
0.200 mmol) at 0 °C. The mixture was stirred at room temperature for
1 h. Concentration and column chromatography (hexane/EtOAc =
4:1) gave bromoacetylene 18a (11.1 mg, 70% in three steps) as a
24
colorless amorphous solid: Rf = 0.23 (hexane/EtOAc = 1:1); [α]D
−89.9 (c 0.90, CHCl3); IR (neat) 3354, 3012, 2949, 2225, 1644 cm−1;
1H NMR (400 MHz, CDCl3) δ 6.12 (dt, J = 15.6, 5.0 Hz, 1 H), 5.46
(ddt, J = 15.6, 7.8, 1.7 Hz, 1 H), 4.20−4.18 (m, 2 H), 3.40 (dd, J = 7.8,
2.0 Hz, 1 H), 3.38 (d, J = 2.0 Hz, 1 H), 3.27 (dd, J = 3.4, 2.0 Hz, 1 H),
2.99 (dd, J = 3.4, 2.0 Hz, 1 H), 1.55 (br s, 1 H); 13C NMR (100 MHz,
CDCl3) δ 135.7, 126.5, 75.8, 62.5, 57.0, 56.5, 55.3, 45.4, 43.6; HRMS
(ESI−TOF) calcd for C9H9BrO3Na [M + Na]+ 268.9613, found
268.9611.
MTPA Ester (S)-16. To a solution of alcohol 15 (1.7 mg, 3.21
μmol) in CH2Cl2 (0.2 mL) were added DMAP (0.8 mg, 6.42 μmol),
Et3N (0.6 μL, 4.50 μmol), and (R)-MTPACl (0.7 μL, 3.85 μmol) at 0
°C. After the mixture was stirred for 10 min at the same temperature,
the reaction was quenched with saturated aqueous NH4Cl. The
mixture was diluted with Et2O, washed with H2O and brine, and then
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 10:1) gave MTPA ester (S)-16 (2.5 mg, quant) as a
Acetate 20a. To a solution of EtNH2 (70% aqueous solution, 0.5
mL) in MeOH (0.7 mL) was added CuCl (2.0 mg, 19.9 μmol) at
room temperature that resulted in the formation of a blue solution. To
the resulting mixture was added NH2OH·HCl (8.3 mg, 0.119 mmol)
at room temperature to discharge the blue color. The resulting
colorless solution indicated the presence of Cu(I) salt. To the resulting
mixture was added diacetylene 19 (8.5 mg, 43.7 μmol) in MeOH (0.3
mL + 0.2 mL) at room temperature, and the mixture was stirred at the
same temperature for 20 min that resulted in the formation of a yellow
suspension. To the resulting mixture was added bromoacetylene 18a
(10.1 mg, 39.7 μmol) in MeOH (0.3 mL + 0.2 mL) at −78 °C, and
the mixture was stirred at the same temperature for 20 min. The
mixture was diluted with Et2O, washed with H2O and brine, and then
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 2:1) gave the corresponding triacetylene (9.9 mg),
which was used for the next reaction without further purification.
To a solution of the alcohol obtained above (9.9 mg) in CH2Cl2
(0.5 mL) were added pyridine (12 μL, 0.149 mmol), Ac2O (10 μL,
0.106 mmol), and DMAP (1.0 mg, 8.19 μmol) at 0 °C. The mixture
was stirred at the same temperature for 20 min. The mixture was
diluted with Et2O, washed with H2O and brine, and then dried over
Na2SO4. Concentration and column chromatography (hexane/EtOAc
24
colorless oil: Rf = 0.41 (hexane/EtOAc = 7:1); [α]D −14.3 (c 0.23,
1
CHCl3); IR (neat) 2953, 2929, 1751 cm−1; H NMR (400 MHz,
CDCl3) δ 7.65−7.62 (m, 4 H), 7.54−7.52 (m, 2 H), 7.39−7.35 (m, 9
H), 5.27−5.22 (m, 1 H, H-9), 3.75−3.70 (m, 2 H, H2-7), 3.61−3.56
(m, 2 H, H2-14), 3.47 (s, 3 H), 2.88 (dd, J = 6.5, 2.1 Hz, 1 H, H-10),
2.79−2.76 (m, 1 H, H-11), 2.07−1.88 (m, 2 H, H2-8), 1.61−1.51 (m,
4 H, H2-12 and H2-13), 1.06 (s, 9 H), 0.89 (s, 9 H), 0.05 (s, 6 H); 13
C
NMR (100 MHz, CDCl3) δ 165.7, 135.4, 135.4, 133.3, 133.2, 132.1,
130.0, 129.5, 128.3, 127.7, 127.4, 77.2, 73.8, 62.4, 59.4, 58.4, 56.4, 55.4,
33.8, 29.1, 28.2, 26.9, 26.0, 19.2, 18.4, −5.2; HRMS (ESI−TOF) calcd
for C40H55F3O6Si2Na [M + Na]+ 767.3387, found 767.3378.
MTPA Ester (R)-16. To a solution of alcohol 15 (1.3 mg, 2.45
μmol) in CH2Cl2 (0.2 mL) were added DMAP (0.6 mg, 4.90 μmol),
Et3N (0.5 μL, 3.43 μmol), and (S)-MTPACl (0.6 μL, 2.94 μmol) at 0
°C. After the mixture was stirred for 10 min at the same temperature,
the reaction was quenched with saturated aqueous NH4Cl. The
mixture was diluted with Et2O, washed with H2O and brine, and then
H
dx.doi.org/10.1021/jo302665c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
= 7:1) gave acetate 20a (10.6 mg, 67% in two steps) as a yellow oil: Rf
mixture was stirred at the same temperature for 2 h. The reaction was
quenched with saturated aqueous NaHCO3. The mixture was diluted
with EtOAc, washed with H2O and brine, and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 30:1,
20:1) gave the corresponding dibromoalkene (18.0 mg), which was
used for the next reaction without further purification.
25
= 0.63 (hexane/EtOAc = 2:1); [α]D −77.7 (c 0.30, CHCl3); IR
1
(neat) 2954, 2930, 2216, 1740 cm−1; H NMR (400 MHz, CDCl3) δ
6.04 (dt, J = 15.6, 5.9 Hz, 1 H), 5.48 (ddd, J = 15.6, 7.8, 1.2 Hz, 1 H),
4.58 (dd, J = 5.9, 1.2 Hz, 2 H), 4.39 (s, 2 H), 3.44 (d, J = 2.0 Hz, 1 H),
3.38 (dd, J = 7.8, 2.0 Hz, 1 H), 3.33 (dd, J = 3.2, 2.0 Hz, 1 H), 3.01
(dd, J = 3.2, 2.0 Hz, 1 H), 2.08 (s, 3 H), 0.90 (s, 9 H), 0.12 (s, 6 H);
13C NMR (100 MHz, CDCl3) δ 170.4, 130.4, 129.3, 77.8, 73.6, 69.5,
69.1, 63.5, 63.1, 62.0, 57.5, 56.2, 55.1, 52.1, 43.1, 25.8, 20.9, 18.3, −5.1;
HRMS (ESI−TOF) calcd for C22H28O5SiNa [M + Na]+ 423.1604,
found 423.1613.
To a solution of the dibromoalkene obtained above (18.0 mg) in
THF (0.4 mL) was added TBAF (1.0 M solution in THF, 0.16 mL,
0.160 mmol) at 0 °C. The mixture was stirred at room temperature for
30 min. Concentration and column chromatography (hexane/EtOAc
= 2:1) gave bromoacetylene 18b (8.1 mg, 57% in three steps) as a
21
Diepoxide 5a. To a solution of TBS ether 20a (1.2 mg, 2.99
μmol) in THF (0.2 mL) was added HF·pyr (5.0 μL) at 0 °C. After the
mixture was stirred at the same temperature for 40 min, HF·pyr (2.0
μL) was added. The mixture was stirred at 0 °C for further 2 h. The
reaction was quenched with saturated aqueous NaHCO3, and the
mixture was diluted with Et2O. The mixture was washed with saturated
aqueous NaHCO3, H2O, and brine and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 5:1)
gave diepoxide 5a (1.6 mg, quant) as a light yellow amorphous solid:
colorless amorphous solid: Rf = 0.24 (hexane/EtOAc = 2:1); [α]D
−9.0 (c 0.62, CHCl3); IR (neat) 3354, 3006, 2949, 2224, 1633 cm−1;
1H NMR (400 MHz, CDCl3) δ 6.12 (dt, J = 15.6, 5.1 Hz, 1 H), 5.45
(ddt, J = 15.6, 7.8, 1.7 Hz, 1 H), 4.19 (dd, J = 5.1, 1.7 Hz, 2 H), 3.40−
3.34 (m, 2 H), 3.22 (dd, J = 4.4, 2.0 Hz, 1 H), 2.91 (dd, J = 4.4, 2.0 Hz,
1 H), 1.58 (br s, 1 H); 13C NMR (100 MHz, CDCl3) δ 135.8, 126.2,
75.5, 62.4, 58.1, 57.2, 56.1, 45.7, 44.1; HRMS (ESI−TOF) calcd for
C9H9BrO3Na [M + Na]+ 268.9613, found 268.9617.
Acetate 20b. To a solution of EtNH2 (70% aqueous solution, 0.4
mL) in MeOH (0.7 mL) was added CuCl (1.6 mg, 16.3 μmol) at
room temperature that resulted in the formation of a blue solution. To
the resulting mixture was added NH2OH·HCl (6.8 mg, 97.8 μmol) at
room temperature to discharge the blue color. The resulting colorless
solution indicated the presence of Cu(I) salt. To the resulting mixture
was added diacetylene 19 (6.9 mg, 35.9 μmol) in MeOH (0.2 mL +
0.2 mL) at room temperature, and the mixture was stirred at the same
temperature for 10 min that resulted in the formation of a yellow
suspension. To the resulting mixture was added bromoacetylene 18b
(8.0 mg, 32.6 μmol) in MeOH (0.2 mL + 0.2 mL) at −78 °C, and the
mixture was stirred at the same temperature for 20 min. The mixture
was diluted with Et2O, washed with H2O and brine, and then dried
over Na2SO4. Concentration and column chromatography (hexane/
EtOAc = 3:1) gave the corresponding triacetylene (5.5 mg), which was
used for the next reaction without further purification.
28
Rf = 0.40 (hexane/EtOAc = 1:1); [α]D −62.5 (c 0.07, CH3OH); IR
1
(neat) 3410, 3015, 2925, 1707 cm−1; H NMR (400 MHz, CDCl3) δ
6.04 (dt, J = 15.6, 5.6 Hz, 1 H), 5.49 (ddt, J = 15.6, 7.8, 1.4 Hz, 1 H),
4.59 (dd, J = 5.6, 1.4 Hz, 2 H), 4.36 (d, J = 5.8 Hz, 2 H), 3.44 (d, J =
2.0 Hz, 1 H), 3.38 (dd, J = 7.8, 2.0 Hz, 1 H), 3.34 (dd, J = 3.2, 2.0 Hz,
1 H), 3.02 (dd, J = 3.2, 2.0 Hz, 1 H), 2.08 (s, 3 H), 1.69 (t, J = 5.8 Hz,
1 H); 13C NMR (100 MHz, CDCl3) δ 170.4, 130.4, 129.3, 77.2, 74.0,
70.4, 69.0, 63.5, 62.7, 62.6, 57.5, 56.2, 55.1, 51.5, 43.1, 20.9; HRMS
(ESI−TOF) calcd for C16H14O5Na [M + Na]+ 309.0739, found
309.0731.
Epoxy Alcohol 13b. To a suspension of powdered MS4Å (20 mg)
in CH2Cl2 (1.0 mL) were added (−)-DIPT (22 μL, 0.110 mmol),
Ti(Oi-Pr)4 (22 μL, 73.2 μmol), and TBHP (ca. 6.0 M solution in
2,2,4-trimethylpentane, 0.23 mL, 1.38 mmol) at −30 °C. The mixture
was stirred at the same temperature for 30 min, and a solution of allylic
alcohol 12 (19.8 mg, 73.2 μmol) in CH2Cl2 (0.8 mL + 0.2 mL) was
added at −40 °C. After the resulting mixture was stirred at −40 °C for
8 h and at −30 °C for further 8 h, the reaction was quenched with
saturated aqueous sodium potassium tartrate. The mixture was filtered
through a Celite pad and washed with EtOAc. The mixture was
washed with H2O and brine and then dried over Na2SO4. After the
concentration, the mixture was diluted with Et2O and 3 M aqueous
NaOH was added to the mixture. The mixture was stirred at 0 °C for
30 min. The mixture was diluted with EtOAc, washed with H2O and
brine, and then dried over Na2SO4. Concentration and column
chromatography (hexane/EtOAc = 4:1) gave epoxy alcohol 13b (17.0
To a solution of the alcohol obtained above (5.5 mg) in CH2Cl2
(0.5 mL) were added pyridine (12 μL, 0.149 mmol), Ac2O (10 μL,
0.106 mmol), and DMAP (0.8 mg, 6.55 μmol) at 0 °C. The mixture
was stirred at the same temperature for 20 min. The mixture was
diluted with Et2O, washed with H2O and brine, and then dried over
Na2SO4. Concentration and column chromatography (hexane/EtOAc
= 8:1) gave acetate 20b (6.3 mg, 48% in two steps) as a colorless oil:
23
Rf = 0.57 (hexane/EtOAc = 1:1); [α]D −1.5 (c 0.44, CHCl3); IR
1
(neat) 2954, 2929, 2217, 1741 cm−1; H NMR (400 MHz, CDCl3) δ
6.04 (dt, J = 15.6, 5.8 Hz, 1 H), 5.47 (ddt, J = 15.6, 7.6, 1.4 Hz, 1 H),
4.58 (dd, J = 5.8, 1.4 Hz, 2 H), 4.39 (s, 2 H), 3.42 (d, J = 2.0 Hz, 1 H),
3.35 (dd, J = 7.6, 2.0 Hz, 1 H), 3.26 (dd, J = 4.1, 2.0 Hz, 1 H), 2.92
(dd, J = 4.1, 2.0 Hz, 1 H), 2.08 (s, 3 H), 0.90 (s, 9 H), 0.12 (s, 6 H);
13C NMR (100 MHz, CDCl3) δ 170.4, 130.5, 129.1, 77.8, 73.3, 69.5,
69.4, 63.4, 63.2, 62.0, 58.7, 57.1, 55.8, 52.1, 43.5, 25.8, 20.9, 18.3, −5.1;
HRMS (ESI−TOF) calcd for C22H28O5SiNa [M + Na]+ 423.1604,
found 423.1610.
22
mg, 81%) as a colorless oil: Rf = 0.34 (hexane/EtOAc = 1:1); [α]D
−2.7 (c 1.14, CHCl3); IR (neat) 3435, 2954, 2929 cm−1; H NMR
1
(400 MHz, CDCl3) δ 6.01 (dt, J = 15.6, 4.2 Hz, 1 H), 5.43 (ddt, J =
15.6, 7.9, 2.0 Hz, 1 H), 4.17 (dd, J = 4.2, 2.0 Hz, 2 H), 3.95−3.92 (m,
1 H), 3.67−3.64 (m, 1 H), 3.34 (dd, J = 7.9, 2.2 Hz, 1 H), 3.13 (dt, J =
4.2, 2.2 Hz, 1 H), 3.04 (dd, J = 4.4, 2.2 Hz, 1 H), 2.91 (dd, J = 4.4, 2.2
Hz, 1 H), 1.76 (br s, 1 H), 0.88 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100
MHz, CDCl3) δ 135.8, 125.2, 62.7, 60.8, 58.0, 56.5, 56.5, 53.7, 26.0,
18.4, −5.2; HRMS (ESI−TOF) calcd for C14H26O4SiNa [M + Na]+
309.1498, found 309.1490.
Diepoxide 5b. To a solution of TBS ether 20b (5.0 mg, 12.4
μmol) in THF (2.5 mL) was added HF·pyr (5.0 μL) at 0 °C. After the
mixture was stirred at the same temperature for 2 h, HF·pyr (2.0 μL)
was added. The mixture was stirred at 0 °C for further 2 h. The
reaction was quenched with saturated aqueous NaHCO3, and the
mixture was diluted with Et2O. The mixture was washed with saturated
aqueous NaHCO3, H2O, and brine and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 20:1,
7:1) gave diepoxide 5b (2.4 mg, 68%) as a light yellow amorphous
Bromoacetylene 18b. To a solution of alcohol 13b (16.6 mg,
57.9 μmol) in CH2Cl2 (1.0 mL) and DMSO (0.3 mL) were added
Et3N (40 μL, 0.289 mmol) and SO3·pyr (36.7 mg, 0.231 mmol) at 0
°C. The mixture was stirred at room temperature for 2 h. The mixture
was diluted with EtOAc, washed with H2O and brine, and then dried
over Na2SO4. Concentration and column chromatography (hexane/
EtOAc = 7:1) gave the corresponding aldehyde (11.6 mg), which was
used for the next reaction without further purification.
23
solid: Rf = 0.43 (hexane/EtOAc = 1:1); [α]D +32.0 (c 0.12,
1
CH3OH); IR (neat) 3448, 2920, 2214, 1711 cm−1; H NMR (400
MHz, CDCl3) δ 6.04 (dt, J = 15.6, 5.8 Hz, 1 H), 5.48 (ddt, J = 15.6,
7.8, 1.5 Hz, 1 H), 4.58 (dd, J = 5.8, 1.5 Hz, 2 H), 4.36 (d, J = 6.1 Hz, 2
H), 3.43 (d, J = 2.0 Hz, 1 H), 3.35 (dd, J = 7.8, 2.0 Hz, 1 H), 3.27 (dd,
J = 4.2, 2.0 Hz, 1 H), 2.92 (dd, J = 4.2, 2.0 Hz, 1 H), 2.08 (s, 3 H), 1.67
(br t, J = 6.1 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 170.4, 130.5,
129.1, 77.2, 73.7, 70.4, 69.2, 63.5, 62.8, 62.6, 58.7, 57.1, 55.9, 51.5,
To a solution of CBr4 (51.0 mg, 0.155 mmol) in CH2Cl2 (1.5 mL)
was added PPh3 (81 mg, 0.310 mmol) at 0 °C. The mixture was stirred
at the same temperature for 15 min, and Et3N (43 μL, 0.310 mmol)
was added to the resulting mixture at 0 °C. After the mixture was
stirred at the same temperature for 5 min, the aldehyde obtained above
(11.6 mg) in CH2Cl2 (0.3 mL + 0.2 mL) was added at −78 °C. The
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Article
43.5, 20.9; HRMS (ESI−TOF) calcd for C16H14O5Na [M + Na]+
309.0739, found 309.0743.
mixture was stirred at the same temperature for 15 min, and Et3N
(0.13 mL, 0.902 mmol) was added to the resulting mixture at 0 °C.
After the mixture was stirred at the same temperature for 5 min,
aldehyde 23 (22.6 mg, 0.113 mmol) in CH2Cl2 (0.3 mL + 0.2 mL) was
added at −78 °C. The mixture was stirred at the same temperature for
1 h. The reaction was quenched with saturated aqueous NaHCO3. The
mixture was diluted with EtOAc, washed with H2O and brine, and
then dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 50:1) gave the corresponding dibromoalkene (39.2
mg), which was used for the next reaction without further purification.
To a solution of the dibromoalkene obtained above (39.2 mg) in
THF (2.0 mL) was added TBAF (1.0 M solution in THF, 0.44 mL,
0.440 mmol) at room temperature. The mixture was stirred at 45 °C
for 18 h and diluted with Et2O. The mixture was washed with
saturated aqueous NH4Cl, H2O, and brine and then dried over
Na2SO4. Concentration gave the mixture of the corresponding TBS-
deprotected dibromoalkene and bromoacetylene 24 (36.3 mg). The
same procedure was repeated twice to give bromocetylene 24 (17.3
mg), which was used for the next reaction without further purification.
To a solution of EtNH2 (70% aqueous solution, 0.9 mL) in MeOH
(1.5 mL) was added CuCl (5.3 mg, 54.0 μmol) at room temperature
that resulted in the formation of a blue solution. To the resulting
mixture was added NH2OH·HCl (22.5 mg, 0.324 mmol) at room
temperature to discharge the blue color. The resulting colorless
solution indicated the presence of Cu(I) salt. To the resulting mixture
was added diacetylene 19 (73.4 mg, 0.378 mmol) in MeOH (0.4 mL +
0.4 mL) at room temperature, and the mixture was stirred at the same
temperature for 10 min that resulted in the formation of a yellow
suspension. To the resulting mixture was added bromoacetylene 24
(17.3 mg, 0.108 mmol) in MeOH (0.4 mL + 0.4 mL) at −78 °C, and
the mixture was stirred at the same temperature for 30 min. The
mixture was allowed to warm to room temperature for 3 h. The
mixture was diluted with Et2O, washed with H2O and brine, and then
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 4:1) gave the corresponding triacetylene (20.5 mg),
which was used for the next reaction without further purification.
To a solution of the alcohol obtained above (20.5 mg) in CH2Cl2
(3.0 mL) were added pyridine (45 μL, 0.335 mmol), Ac2O (40 μL,
0.424 mmol), and DMAP (1.0 mg, 8.19 μmol) at 0 °C. The mixture
was stirred at the same temperature for 20 min. The mixture was
diluted with Et2O, washed with H2O and brine, and then dried over
Na2SO4. Concentration and column chromatography (hexane/EtOAc
= 20:1) gave acetate 25 (22.5 mg, 63% in four steps) as a yellow oil: Rf
= 0.69 (hexane/EtOAc = 2:1); IR (neat) 2953, 2929, 2860, 2173, 1746
cm−1; 1H NMR (400 MHz, CDCl3) δ 6.37 (dt, J = 16.1, 5.4 Hz, 1 H),
5.78 (dt, J = 16.1, 1.7 Hz, 1 H), 4.63 (dd, J = 5.4, 1.7 Hz, 2 H), 4.40 (s,
2 H), 2.09 (s, 3 H), 0.90 (s, 9 H), 0.12 (s, 6 H); 13C NMR (100 MHz,
CDCl3) δ 170.1, 141.7, 111.0, 79.0, 75.5, 74.5, 69.8, 66.4, 63.4, 62.6,
52.2, 25.8, 20.8, 18.3, 5.1; HRMS (ESI−TOF) calcd for C18H24O3SiNa
[M + Na]+ 339.1393, found 339.1388.
Epoxy Alcohol 7b: Light yellow oil; [α]D29 +25.7 (c 1.21, CHCl3);
HRMS (ESI−TOF) calcd for C12H24O3SiNa [M + Na]+ 267.1393,
found 267.1396; IR, 1H NMR, and 13C NMR spectra were identical to
those of epoxy alcohol 7a.
Diepoxide 5c: Light yellow amorphous solid; [α]D25 +76.0 (c 0.03,
CH3OH); HRMS (ESI−TOF) calcd for C16H14O5Na [M + Na]+
1
309.0739, found 309.0743; IR, H NMR, and 13C NMR spectra were
identical to those of diepoxide 5a.
23
Diepoxide 5d: Light yellow amorphous solid; [α]D −32.0 (c
0.12, CH3OH); HRMS (ESI−TOF) calcd for C16H14O5Na [M + Na]+
1
309.0739, found 309.0739; IR, H NMR, and 13C NMR spectra were
identical to those of diepoxide 5b.
Acetate 21. To a suspension of NaH (60% dispersion in oil, 9.5
mg, 0.197 mmol, washed with hexane in advance) in THF (1.0 mL)
was added alcohol 13a (16.2 mg, 56.4 μmol) in THF (0.7 mL + 0.3
mL) at 0 °C. To the mixture were added PMBCl (23 μL, 0.169 mmol)
and TBAI (10.3 mg, 28.0 μmol) at the same temperature. After the
mixture was stirred for 12 h at room temperature, the reaction was
quenched with saturated aqueous NH4Cl and the mixture was diluted
with EtOAc. The mixture was washed with H2O and brine and then
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 10:1, 8:1) gave the corresponding PMB ether (19.7
mg), which was used for the next reaction without further purification.
To a solution of the TBS ether obtained above (19.7 mg) in THF
(0.5 mL) was added TBAF (1.0 M solution in THF, 97 μL, 97.0
μmol) at 0 °C. The mixture was stirred for 3 h at the same
temperature. The mixture was diluted with EtOAc, washed with H2O
and brine, and then dried over Na2SO4. Concentration and column
chromatography (hexane/EtOAc = 1:1) gave the corresponding
alcohol (12.6 mg), which was used for the next reaction without
further purification.
To a solution of the alcohol obtained above (12.6 mg) in CH2Cl2
(0.8 mL) were added pyridine (4.5 μL, 56.1 μmol), Ac2O (4.9 μL, 51.8
μmol), and DMAP (0.8 mg, 6.55 μmol) at 0 °C. The mixture was
stirred at the same temperature for 20 min. The mixture was diluted
with Et2O, washed with H2O and brine, and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 5:1,
3:1) gave acetate 21 (13.9 mg, 74% in three steps) as a colorless oil: Rf
31
= 0.36 (hexane/EtOAc = 2:1); [α]D −42.7 (c 0.66, CHCl3); IR
1
(neat) 3000, 2934, 1735 cm−1; H NMR (400 MHz, CDCl3) δ 7.25
(d, J = 8.3 Hz, 2 H), 6.88 (d, J = 8.3 Hz, 2 H), 6.02 (dt, J = 15.6, 5.8
Hz, 1 H), 5.50 (ddt, J = 15.6, 7.8, 1.5 Hz, 1 H), 4.58 (dd, J = 5.8, 1.5
Hz, 2 H), 4.49 (d, J = 4.2 Hz, 2 H), 3.80 (s, 3H), 3.71 (dd, J = 11.7, 2.0
Hz, 1 H), 3.52 (dd, J = 11.7, 4.0 Hz, 1 H), 3.37 (dd, J = 7.8, 2.0 Hz, 1
H), 3.18 (dt, J = 4.2, 2.0 Hz, 1 H), 2.96 (dd, J = 4.4, 2.0 Hz, 1 H), 2.91
(dd, J = 4.4, 2.0 Hz, 1 H), 2.08 (s, 3 H); 13C NMR (100 MHz, CDCl3)
δ 170.4, 159.3, 130.0, 129.8, 129.7, 129.3, 113.8, 73.1, 68.8, 63.6, 57.9,
55.3, 54.9, 54.6, 53.5, 20.9; HRMS (ESI−TOF) calcd for C18H22O6Na
[M + Na]+ 357.1314, found 357.1312.
Alcohol 26. To a solution of TBS ether 25 (22.5 mg, 71.1 μmol) in
THF (2.0 mL) was added HF·pyr (0.10 mL) at 0 °C. After the mixture
was stirred at the same temperature for 1 h, HF·pyr (0.10 mL) was
added. The mixture was stirred at 0 °C for further 2 h. The reaction
was quenched with saturated aqueous NaHCO3, and the mixture was
diluted with Et2O. The mixture was washed with H2O and brine and
then dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 5:1, 3:1) gave alcohol 26 (12.6 mg, 88%) as a
yellow oil: Rf = 0.37 (hexane/EtOAc = 2:1); IR (neat) 3418, 2925,
Alcohol 22. To a solution of PMB ether 21 (11.0 mg, 32.9 μmol)
in CH2Cl2 (1.0 mL) and H2O (30 μL) was added DDQ (14.9 mg,
65.8 μmol) at 0 °C. The mixture was stirred at the same temperature
for 2 h and at room temperature for 1 h. The mixture was diluted with
EtOAc. The mixture was washed with saturated aqueous Na2SO3,
saturated aqueous NaHCO3, H2O, and brine and then dried over
Na2SO4. Concentration and column chromatography (hexane/EtOAc
= 2:1) gave alcohol 22 (5.7 mg, 81%) as a colorless oil: Rf = 0.21
(hexane/EtOAc = 1:1); [α]D28 −62.0 (c 0.25, CHCl3); IR (neat) 3457,
1
2187, 1740 cm−1; H NMR (400 MHz, CDCl3) δ 6.39 (dt, J = 16.1,
1
2925, 1736 cm−1; H NMR (400 MHz, CDCl3) δ 6.04 (dt, J = 15.6,
5.6 Hz, 1 H), 5.78 (dt, J = 16.1, 2.0 Hz, 1 H), 4.64 (dd, J = 5.6, 2.0 Hz,
2 H), 4.37 (s, 2 H), 2.09 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
170.2, 141.9, 110.8, 78.1, 75.4, 74.9, 70.7, 66.0, 63.4, 63.2, 51.6, 20.8;
HRMS (ESI−TOF) calcd for C12H10O3Na [M + Na]+ 225.0528,
found 225.0519.
Dienal 27. To a solution of dienol 6 (24.2 mg, 0.106 mmol) in
CH2Cl2 (1.5 mL) and DMSO (0.5 mL) were added Et3N (80 μL,
0.578 mmol) and SO3·pyr (76.4 mg, 0.481 mmol) at 0 °C. The
mixture was stirred at room temperature for 2 h. The mixture was
diluted with EtOAc, washed with H2O and brine, and then dried over
5.9 Hz, 1 H), 5.51 (ddt, J = 15.6, 7.6, 1.2 Hz, 1 H), 4.59 (dd, J = 5.9,
1.2 Hz, 2 H), 3.97 (dd, J = 13.0, 2.2 Hz, 1 H), 3.72 (dd, J = 13.0, 3.4
Hz, 1 H), 3.39 (dd, J = 7.6, 2.0 Hz, 1 H), 3.18 (dt, J = 3.4, 2.2 Hz, 1
H), 3.10 (dd, J = 4.4, 2.2 Hz, 1 H), 2.94 (dd, J = 4.4, 2.0 Hz, 1 H), 2.08
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ 170.4, 129.9, 129.9, 63.6,
60.5, 57.8, 55.8, 54.9, 53.1, 20.9; HRMS (ESI−TOF) calcd for
C10H14O5Na [M + Na]+ 237.0739, found 237.0734.
Acetate 25. To a solution of CBr4 (150 mg, 0.451 mmol) in
CH2Cl2 (1.0 mL) was added PPh3 (237 mg, 0.902 mmol) at 0 °C. The
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Na2SO4. Concentration and column chromatography (hexane/EtOAc
then dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 3:1) gave alcohol 29 (6.4 mg, 86%) as a yellow oil:
Rf = 0.52 (hexane/EtOAc = 1:1); IR (neat) 3508, 2912, 2173, 1715
= 10:1) gave dienal 27 (24.2 mg, 89%) as a colorless oil: Rf = 0.54
1
(hexane/EtOAc = 4:1); IR (neat) 2954, 2929, 1685, 1646 cm−1; H
1
cm−1; H NMR (400 MHz, CDCl3) δ 6.78 (dd, J = 15.6, 11.0 Hz, 1
NMR (400 MHz, CDCl3) δ 9.55 (d, J = 8.0 Hz, 1 H), 7.12 (dd, J =
15.3, 11.0 Hz, 1 H), 6.58−6.51 (m, 1 H), 6.31 (dt, J = 15.1, 4.4 Hz, 1
H), 6.08 (dd, J = 15.3, 8.0 Hz, 1 H), 4.33 (dd, J = 4.4, 1.5 Hz, 2 H),
0.93 (s, 9 H), 0.09 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 193.6,
151.4, 144.2, 131.1, 127.0, 62.9, 25.9, 18.4, −5.3; HRMS (ESI−TOF)
calcd for C12H22O2SiNa [M + Na]+ 249.1287, found 249.1283.
Acetate 28. To a solution of CBr4 (142 mg, 0.428 mmol) in
CH2Cl2 (1.5 mL) was added PPh3 (225 mg, 0.856 mmol) at 0 °C. The
mixture was stirred at the same temperature for 15 min, and Et3N
(0.12 mL, 0.856 mmol) was added to the resulting mixture at 0 °C.
After the mixture was stirred at the same temperature for 5 min,
aldehyde 27 (24.2 mg, 0.107 mmol) in CH2Cl2 (0.3 mL + 0.2 mL) was
added at −78 °C. The mixture was stirred at the same temperature for
1 h. The reaction was quenched with saturated aqueous NaHCO3. The
mixture was diluted with EtOAc, washed with H2O and brine, and
then dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 50:1, 30:1) gave the corresponding dibromoalkene
(39.7 mg), which was used for the next reaction without further
purification.
To a solution of the dibromoalkene obtained above (39.7 mg) in
THF (2.0 mL) was added TBAF (1.0 M solution in THF, 0.42 mL,
0.420 mmol) at room temperature. The mixture was stirred at 45 °C
for 20 h and diluted with Et2O. The mixture was washed with
saturated aqueous NH4Cl, H2O, and brine, and then dried over
Na2SO4. Concentration gave the mixture of the corresponding TBS-
deprotected dibromoalkene and TBS-deprotected bromoacetylene
(42.3 mg). The same procedure was repeated once to give the
corresponding TBS-deprotected bromocetylene (31.3 mg), which was
used for the next reaction without further purification.
H), 6.33 (dd, J = 15.3, 11.0 Hz, 1 H), 5.94 (dt, J = 15.3, 6.1 Hz, 1 H),
5.66 (d, J = 15.6 Hz, 1 H), 4.64 (d, J = 6.1 Hz, 1 H), 4.38 (s, 2 H), 2.09
(s, 3 H); 13C NMR (100 MHz, CDCl3) δ 170.5, 145.3, 131.9, 131.8,
110.1, 78.6, 77.2, 70.9, 67.0, 64.1, 63.9, 63.5, 51.6, 20.9; HRMS (ESI−
TOF) calcd for C14H12O3Na [M + Na]+ 251.0684, found 251.0689.
Epoxy Alcohol 30. To a solution of allylic alcohol 6 (297 mg, 1.30
mmol) in CH2Cl2 (17 mL) were added NaHCO3 (179 mg, 2.13
mmol) and mCPBA (69−75%, 306 mg, 1.22−1.33 mmol) at 0 °C.
The mixture was stirred at room temperature for 5 h. The mixture was
diluted with EtOAc, washed with saturated aqueous NaHCO3, H2O,
and brine, and then dried over Na2SO4. Concentration and column
chromatography (hexane/EtOAc = 4:1) gave epoxy alcohol 30 (243
mg, 78%) as a light yellow oil: HRMS (ESI−TOF) calcd for
1
C12H24O3SiNa [M + Na]+ 267.1393, found 267.1396; IR, H NMR,
and 13C NMR spectra were identical to those of epoxy alcohol 7a.
Aldehyde 31. To a solution of alcohol 30 (15.7 mg, 64.1 μmol) in
CH2Cl2 (0.6 mL) and DMSO (0.2 mL) were added Et3N (45 μL,
0.321 mmol) and SO3·pyr (40.7 mg, 0.256 mmol) at 0 °C. The
mixture was stirred at room temperature for 2 h. The mixture was
diluted with EtOAc, washed with H2O and brine, and then dried over
Na2SO4. Concentration and column chromatography (hexane/EtOAc
= 8:1) gave aldehyde 31 (14.0 mg, 90%) as a colorless oil: Rf = 0.57
(hexane/EtOAc = 1:1); IR (neat) 3439, 2954, 2929, 1730, 1692 cm−1;
1H NMR (400 MHz, CDCl3) δ 9.07 (d, J = 6.1 Hz, 1 H), 6.12 (dt, J =
15.6, 4.2 Hz, 1 H), 5.49 (ddt, J = 15.6, 7.8, 2.0 Hz, 1 H), 4.21 (dd, J =
4.2, 2.0 Hz, 2 H), 3.68 (dd, J = 7.8, 2.0 Hz, 1 H), 3.30 (dd, J = 6.1, 2.0
Hz, 1 H), 0.91 (s, 9 H), 0.07 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ
197.1, 137.4, 123.3, 62.5, 60.8, 56.2, 25.9, 18.4, −5.3; HRMS (ESI−
TOF) calcd for C13H26O4SiNa [M + Na]+ 297.1498, found 297.1500.
Acetate 32. To a solution of CBr4 (75.3 mg, 0.227 mmol) in
CH2Cl2 (0.8 mL) was added PPh3 (119 mg, 0.454 mmol) at 0 °C. The
mixture was stirred at the same temperature for 15 min, and Et3N (63
μL, 0.454 mmol) was added to the resulting mixture at 0 °C. After the
mixture was stirred at the same temperature for 5 min, aldehyde 31
(13.7 mg, 56.7 μmol) in CH2Cl2 (0.3 mL + 0.2 mL) was added at −78
°C. The mixture was stirred at the same temperature for 1 h. The
reaction was quenched with saturated aqueous NaHCO3. The mixture
was diluted with EtOAc, washed with H2O and brine, and then dried
over Na2SO4. Concentration and column chromatography (hexane/
EtOAc = 20:1) gave the corresponding dibromoalkene (21.7 mg),
which was used for the next reaction without further purification.
To a solution of the dibromoalkene obtained above (21.7 mg) in
THF (0.7 mL) was added TBAF (1.0 M solution in THF, 0.22 mL,
0.220 mmol) at 0 °C. The mixture was stirred at room temperature for
1 h. The mixture was diluted with EtOAc, washed with H2O and brine,
and then dried over Na2SO4. Concentration and column chromatog-
raphy (hexane/EtOAc = 3:1) gave the corresponding bromoacetylene
(9.7 mg), which was used for the next reaction without further
purification.
To a solution of EtNH2 (70% aqueous solution, 1.3 mL) in MeOH
(3.0 mL) was added CuCl (5.1 mg, 52.0 μmol) at room temperature
that resulted in the formation of a blue solution. To the resulting
mixture was added NH2OH·HCl (21.7 mg, 0.312 mmol) at room
temperature to discharge the blue color. The resulting colorless
solution indicated the presence of Cu(I) salt. To the resulting mixture
was added diacetylene 19 (70.7 mg, 0.364 mmol) in MeOH (0.7 mL +
0.3 mL) at room temperature, and the mixture was stirred at the same
temperature for 10 min that resulted in the formation of a yellow
suspension. To the resulting mixture was added the bromoacetylene
obtained above (31.3 mg) in MeOH (0.7 mL + 0.3 mL) at −78 °C,
and the mixture was stirred at the same temperature for 30 min. The
mixture was allowed to warm to room temperature for 3 h. The
mixture was diluted with Et2O, washed with H2O and brine, and then
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 5:1) gave the corresponding triacetylene (18.8 mg),
which was used for the next reaction without further purification.
To a solution of the alcohol obtained above (18.8 mg) in CH2Cl2
(2.0 mL) were added pyridine (24 μL, 0.179 mmol), Ac2O (20 μL,
0.212 mmol), and DMAP (1.0 mg, 8.19 μmol) at 0 °C. The mixture
was stirred at the same temperature for 20 min. The mixture was
diluted with Et2O, washed with H2O and brine, and then dried over
Na2SO4. Concentration and column chromatography (hexane/EtOAc
= 20:1) gave acetate 28 (20.5 mg, 56% in four steps) as a yellow oil: Rf
= 0.60 (hexane/EtOAc = 2:1); IR (neat) 2954, 2929, 2173, 1744
To a solution of EtNH2 (70% aqueous solution, 0.6 mL) in MeOH
(1.0 mL) was added CuCl (2.4 mg, 24.0 μmol) at room temperature
that resulted in the formation of a blue solution. To the resulting
mixture was added NH2OH·HCl (10.0 mg, 0.144 mmol) at room
temperature to discharge the blue color. The resulting colorless
solution indicated the presence of Cu(I) salt. To the resulting mixture
was added diacetylene 19 (10.2 mg, 52.7 μmol) in MeOH (0.2 mL +
0.2 mL) at room temperature, and the mixture was stirred at the same
temperature for 10 min that resulted in the formation of a yellow
suspension. To the resulting mixture was added the bromoacetylene
obtained above (9.7 mg) in MeOH (0.2 mL + 0.2 mL) at −78 °C, and
the mixture was stirred at the same temperature for 30 min. The
mixture was diluted with Et2O, washed with H2O and brine, and then
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc = 3:1) gave the corresponding triacetylene (11.1 mg),
which was used for the next reaction without further purification.
1
cm−1; H NMR (400 MHz, CDCl3) δ 6.77 (dd, J = 15.4, 10.8 Hz, 1
H), 6.33 (dd, J = 15.1, 10.8 Hz, 1 H), 5.93 (dt, J = 15.1, 6.0 Hz, 1 H),
5.66 (d, J = 15.4 Hz, 1 H), 4.64 (d, J = 6.0 Hz, 2 H), 4.41 (s, 2 H), 2.09
(s, 3 H), 0.91 (s, 9 H), 0.13 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ
170.4, 145.1, 131.9, 131.6, 110.2, 79.5, 76.3, 70.0, 67.4, 64.1, 63.9, 62.9,
52.3, 25.8, 20.9, 18.3, −5.1; HRMS (ESI−TOF) calcd for
C20H26O3SiNa [M + Na]+ 365.1549, found 365.1549.
Alcohol 29. To a solution of TBS ether 28 (11.2 mg, 32.7 μmol) in
THF (1.2 mL) was added HF·pyr (40 μL) at 0 °C. After the mixture
was stirred at the same temperature for 2 h, HF·pyr (50 μL) was
added. The mixture was stirred at 0 °C for further 1 h. The reaction
was quenched with saturated aqueous NaHCO3, and the mixture was
diluted with Et2O. The mixture was washed with H2O and brine and
K
dx.doi.org/10.1021/jo302665c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
To a solution of the alcohol obtained above (11.1 mg) in CH2Cl2
(0.6 mL) were added pyridine (3.7 μL, 45.5 μmol), Ac2O (4.0 μL, 42.0
μmol), and DMAP (0.8 mg, 6.55 μmol) at 0 °C. The mixture was
stirred at the same temperature for 20 min. The mixture was diluted
with Et2O, washed with H2O and brine, and then dried over Na2SO4.
Concentration and column chromatography (hexane/EtOAc = 8:1)
gave acetate 32 (11.8 mg, 58% in four steps) as a yellow oil: Rf = 0.63
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(hexane/EtOAc = 2:1); IR (neat) 2954, 2930, 2216, 1745 cm−1; H
NMR (400 MHz, CDCl3) δ 6.07 (dt, J = 15.6, 5.6 Hz, 1 H), 5.46 (ddt,
J = 15.6, 7.3, 1.2 Hz, 1 H), 4.58 (br d, J = 5.6 Hz, 2 H), 4.39 (s, 2 H),
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4:1) gave alcohol 33 (7.3 mg, 91%) as a yellow oil: Rf = 0.82 (hexane/
EtOAc = 1:1); IR (neat) 3436, 2925, 2214, 1738 cm−1; 1H NMR (400
MHz, CDCl3) δ 6.08 (dt, J = 15.6, 5.6 Hz, 1 H), 5.46 (ddt, J = 15.6,
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Cell Growth-Inhibitory Activity. HL60 cells were cultured at 37
°C with 5% CO2 in RPMI (Nissui, Tokyo, Japan) supplemented with
10% heat-inactivated fetal bovine serum (FBS; Sigma-Aldrich Co., St.
Louis, MO), 100 units/mL penicillin, 100 μg/mL streptomycin, 0.25
μg/mL amphotericin, 300 μg/mL L-glutamine, and 2.25 mg/mL
NaHCO3. HeLa S3 cells were cultured at 37 °C with 5% CO2 in MEM
(Nissui) supplemented with 10% heat-inactivated FBS, 100 units/mL
penicillin, 100 μg/mL streptomycin, 0.25 μg/mL amphotericin, 300
μg/mL L-glutamine, and 2.25 mg/mL NaHCO3. HL60 cells were
seeded at 1 × 104 cells/well in 96-well plates (Iwaki, Tokyo, Japan).
HeLa S3 cells were seeded at 4 × 103 cells/well in 96-well plates and
cultured overnight. Various concentrations of compounds were then
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for new compounds and
1H−1H COSY, HMQC, and HMBC spectra for compounds 5a
and 5b. This material is available free of charge via the Internet
at http://pubs.acs.org.
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AUTHOR INFORMATION
■
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(23) The optical purity of the synthetic 5a was unambiguously
determined at the stage of 7a.
̈
Corresponding Author
*E-mail: takamura@cc.okayama-u.ac.jp, kadota-i@cc.okayama-
u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Division of Instrumental Analysis, Okayama
University, for the NMR measurements. This work was
supported by a Grant-in-Aid for Scientific Research (No.
24710250) from Japan Society for the Promotion of Science
(JSPS).
L
dx.doi.org/10.1021/jo302665c | J. Org. Chem. XXXX, XXX, XXX−XXX