Stereoselective total synthesis of (+)-oploxyne A, (-)-oploxyne B, and their C-10 epimers and structure revision of natural oploxyne B

Article abstract of DOI:10.1021/jo102445h

The first total synthesis of recently isolated diacetylene alcohols oploxyne A, oploxyne B, and their C-10 epimers was accomplished. The structure of natural oploxyne B has been revised. The key steps involved are base-induced double elimination of a carbohydrate-derived β-alkoxy chloride to generate the chiral acetylenic alcohol and Cadiot-Chodkiewicz cross-coupling reaction. The target compounds displayed potent cytotoxicity against neuroblastoma and prostate cancer cell lines.

Full text of DOI:10.1021/jo102445h

ARTICLE
pubs.acs.org/joc
Stereoselective Total Synthesis of (þ)-Oploxyne A, (-)-Oploxyne B,
and Their C-10 Epimers and Structure Revision of Natural Oploxyne B
J. S. Yadav,*,†,‡ Kumaraswamy Boyapelly,† Sathish Reddy Alugubelli,† Srihari Pabbaraja,†
Janakiram R Vangala,§ and Shasi V Kalivendi*,§
†Organic Division-I, Indian Institute of Chemical Technology, CSIR, Hyderabad-500 607, India
‡King Saud University, Riyadh-11451, Saudi Arabia
§Chemical Biology, Indian Institute of Chemical Technology, CSIR, Hyderabad-500 607, India
S Supporting Information
b
ABSTRACT: The first total synthesis of recently isolated diacetylene alcohols
oploxyne A, oploxyne B, and their C-10 epimers was accomplished. The structure
of natural oploxyne B has been revised. The key steps involved are base-induced
double elimination of a carbohydrate-derived β-alkoxy chloride to generate the
chiral acetylenic alcohol and Cadiot-Chodkiewicz cross-coupling reaction. The
target compounds displayed potent cytotoxicity against neuroblastoma and
prostate cancer cell lines.
’ INTRODUCTION
give the key intermediate 9. The intermediate 9 can be easily
maneuvered to synthesize the final targets involving two steps:
tosylation to obtain 7, one-pot PMB cleavage, acetonide deprotec-
tion, and epoxide formation to yield the target oploxyne A or
methylation of 9 to obtain methyl ether 8 followed by PMB and
acetonide deprotection to yield oploxyne B 4. While the fragment
10 can be obtained from readily available sugar D-mannitol, the
other key fragment 11 could be obtained from D-ribose (Scheme 1).
Polyacetylene containing molecules attract significant atten-
tion due to their impressive biological properties such as anti-
tumor, antiinflammatory, antimicrobial, antiviral, cytotoxic, and
phytotoxic activities.1 For example, the diacetylene panaxydol 1
(Figure 1) displayed antiproliferative effects against malignant
cells2 and panaxytriol 2, obtained from Red ginseng, was found to
show inhibitory activity against MK-1 cells with IC50 8.5 ng/mL
and suppress the growth of B16 melanoma cells in mice.3
Recently, investigations on the inhibitors for the formation of
NO and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-
induced murine macrophage RAW 267.7 cells resulted in isola-
tion of two new diynes oploxynes A and B from the CH2Cl2
extract of the stem of Oplopanax elatus.4 The structures of
oploxyne A 3 and oploxyne B 4 were established based on
NMR spectroscopy through chiral derivatization. Oploxyne A
was found to display inhibition of NO and PGE2 production with
an IC50 of 1.90 ( 0.28 and 3.08 ( 0.37 mg/mL. In continuation
to our program toward the development of new protocols and
their applications in the total synthesis of biologically potent
natural products,5 we herein describe the first total synthesis of
oploxyne A, oploxyne B, and their C-10 epimers 5 and 6, wherein
a strategy that allows facile access to all four molecules (3-6) has
been employed. These target compounds when screened against
cancer cell lines were found to display potent cytotoxicity.
We initially focused on the total synthesis of oploxynes A and B
and also accomplished the total synthesis of their C-10 epimers.
Retrosynthetically, oploxyne A and oploxyne B were envisaged to be
obtained in a convergent fashion wherein two fragments 10 and 11
are coupled together by Cadiot-Chodkiewicz cross-coupling to
’ RESULTS AND DISCUSSION
Our synthesis of fragment 10 is delineated in Scheme 2, which
departs from the prior work at the readily available secondary
alcohol 12 obtained from D-mannitol.6 PMB protection of
compound 12 yielded the corresponding PMB ether 13,
which was treated with 1 M HCl to obtain the diol 14. The diol
14 upon treatment with NaIO4 yielded the corresponding
aldehyde,7 which was converted to alkyne 16 by employing
Ohira-Bestmann reagent 15.8 The free terminal acetylene was
converted to the key intermediate bromo alkyne 10 by using
NBS and catalytic silver nitrate in 98% yield (Scheme 2).
For the synthesis of fragment 11, we started with the mixture
of esters 18 and 19 synthesized from D-ribose following the
known procedures.9 The mixture of esters 18 and 19 was reduced
to a mixture of aldehydes 20 and 21 and subjected to a Wittig
reaction with n-pentyltriphenylphosphonium bromide in the
presence of NaNH2 to afford diastereomers 22 and 23 in
68.5:31.5 ratio (diastereomers 22, 23 were in turn a mixture of
Received: December 10, 2010
Published: March 17, 2011
r
2011 American Chemical Society
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synthesis of oploxynes A and B, whereas the minor isomer 23 can
be used for the synthesis of C-10 epimers of oploxynes A and B.
Reduction of 22 with Pd/C afforded 24, which was thoroughly
characterized by 2D NMR studies for the anti relation of C2 and
C5 protons (for NOESY correlations see the Supporting In-
formation). The free hydroxyl group in 24 was converted to
chloride 25 in the presence of TPP and cat. imidazole at reflux in
CCl4. Compound 25, a β-alkoxy chloride, was subjected to our
protocol of base-induced elimination reaction to provide the
chiral propargylic alcohol.5a,b Thus, compound 25 when treated
with LiNH2 in NH3 afforded the chiral acetylenic alcohol 11
(Scheme 3). Compound 11 was cross-coupled with alkynyl
bromide 10 under Cadiot-Chodkiewicz conditions to yield
diyne 9.10 Tosylation of 9 with p-toluenesulfonyl chloride
afforded tosylate 7, which was converted to the target molecule
oploxyne A 3 upon exposure to TFA followed by base (N,N0-
diisopropylethylamine)-induced epoxide formation.11
Synthesis of oploxyne B started with methylation of 9 to yield 8,
albeit low yields resulted either with methyl iodide and NaH
(35%) or Meerwein’s salt in the presence of proton sponge
(36%).12 For the scheme to be amenable for large-scale synthesis,
we also proceeded alternatively for product 8 starting from 11 by
O-methylation with NaH and methyl iodide followed by coupling
with 10 (Scheme 4) in good yields. Compound 26 was cross-
coupled with alkynyl bromide 10 under Cadiot-Chodkiewicz
conditions to yield the precursor intermediate 8 for the synthesis
of oploxyne B. One-pot PMB and acetonide deprotection was
achieved by exposing 8toTFAfor 36h to yield oploxyneB 4. Thus
the total syntheses of oploxynes A and B were accomplished. The
spectroscopic data of the synthesized compounds oploxyne A 3
(Table 1) and oploxyne B 4 (Table 2) were found to be identical
with those of the isolated natural products. However, surprisingly
in the case of oploxyne B, the optical rotation for the synthetic
product was found to be with opposite sign, i.e., [R]D -12.0
(c 0.28, MeOH) instead of [R]D þ11.7 (c 0.06, MeOH) as
reported for natural material. Upon comparison of the 2D NOESY
spectrum of the acetonide product4 from isolated compound and
our synthetic product 8a, similar NOE correlations were observed
as noticed previously4 (see Figure 2). As both the synthetic
compound and isolated product (from the previous paper)
displayed similar NOE correlations, it presents stronger evidence
for the possibility of the synthetic and isolated oploxyne B to be
the enantiomers. Having all the experimental evidence (for
oploxyne A and a similar strategy applied for synthesis of oploxyne
B), wecametothe conclusionthatYanget al. have misassigned the
structure of oploxyne B formulated as 4 after its isolation and
Figure 1. Diacetylene hydroxyl compounds.
Scheme 1. Retrosynthesis
Scheme 2. Synthesis of Fragment 10
1
characterization through Mosher’s ester H NMR spectroscopic
experiments. We herein revise the structural configuration of
natural oploxyne B as compound 4a (ent-4).
After completion of the total synthesis of (þ)-oploxyne A and
(-)-oploxyne B, we proceeded further with the minor isomer 23
for the synthesis of their C-10 epimers. Accordingly, compound
23 was subjected to a similar sequence of reactions such as
reduction of olefin to yield 27, chlorination of alcohol to yield
chloride 28, and then base-induced elimination to afford acet-
ylenic alcohol 29 (Scheme 5).
Alcohol 29 can be utilized directly for the synthesis of C-10
epimers of (þ)-oploxyne A and (-)-oploxyne B. Compound 29
on cross-coupling with 10 provided 30, which on treatment with
tosyl chloride in the presence of diisopropylethylamine and
DMAP provided 31. Compound 31 on exposure to TFA
followed by treatment with diisopropylethylamine provided
1
geometrical isomers (E,Z mixture as observed from H NMR
spectroscopy)). The major compound 22 can be utilized for the
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Scheme 3. Synthesis of (þ)-Oploxyne A
Scheme 4. Synthesis of Oploxyne B
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5 (Scheme 5). Similarly, for the synthesis of 6, we proceeded with
methylation of the free secondary hydroxyl group in compound
30. Since the yield for methylation was low, compound 32 was
also synthesized from 29 by methylation with methyl iodide and
sodium hydride followed by cross-coupling with 10 in overall
79% yield. Exposure of 32 to TFA for 36 h led to the deprotection
of isopropylidene moiety and PMB ether cleavage to yield the
C-10 epimer of (-)-oploxyne B 6 (Scheme 6).
Table 1. Comparison of 1H and 13C NMR Data for Natural, Synthetic Oploxyne A 3 and Its C-10 Epimer 5
isolated
synthesized 3
C-10 epimer 5
H mult [J (Hz)]
13C NMR CDCl3,
125 MHz
H mult [J (Hz)]
13C NMR CDCl3,
75 MHz
H mult [J (Hz)]
13C NMR CDCl3,
75 MHz
position
CDCl3, 500 MHz
CDCl3, 300 MHz
CDCl3, 300 Hz
1
2
1.03 t (7.5)
9.3 CH3
30.6 CH2
64.0 CH
81.0 C
1.02 t (7.4)
1.83-1.68
4.43-4.33
9.3
1.01 t (7.5)
1.82-1.65
4.65 d (3.0)
9.3
1.76 m
30.5
64.0
80.9
68.7
70.3
77.4
60.7
58.0
58.1
27.5
26.5
29.4
29.1
31.7
22.6
14.1
30.5
64.0
80.7
68.6
70.4
75.7
61.5
56.3
59.2
29.1
25.8
31.1
29.2
31.7
22.6
14.0
3
4.40 br dt (6.0, 6.0)
4
5
68.7 C
6
70.3 C
7
77.4 C
8
4.36 br dd (7.5, 3.5)
3.16 dd (7.5, 4.0)
60.7 CH
58.0 CH
58.1 CH
27.5 CH2
26.5 CH2
29.4 CH2
29.2 CH2
31.8 CH2
22.6 CH2
14.1 CH3
4.43-4.33
3.16 dd (7.4, 4.0)
3.10-3.01
1.67-1.57
1.57-1.43
1.42-1.18
1.42-1.18
1.42-1.18
1.42-1.18
0.89 t (7.0)
2.19 br s
4.38 t (6.4)
3.10 td (5.6, 2.3)
3.02 dd (3.4, 2.4)
1.64-1.52
1.52-1.38
1.37-1.19
1.37-1.19
1.37-1.19
1.37-1.19
0.88 t (7.0)
2.10 br s
9
10
11
12
13
14
15
16
17
3-OH
8-OH
3.07 br ddd (7.0,5.5,4.0)
1.64 m
1.51 m
1.35 m
1.29 m
1.29 m
1.29 m
0.89 t (7.0)
2.19 br d (6.0)
2.50 br d (3.5)
2.50 br s
2.50 br s
Table 2. Comparison of 1H and 13C NMR Data for Natural, Synthetic Oploxyne B 4 and Its C-10 Epimer 6
isolated
synthesized 4
C-10 epimer 6
H mult [J (Hz)]
13C NMR CDCl3,
125 MHz
H mult [J (Hz)]
13C NMR CDCl3,
75 MHz
H mult [J (Hz)]
13C NMR CDCl3,
75 MHz
position
CDCl3, 500 MHz
CDCl3, 300 MHz
CDCl3, 500 MHz
1
1.04 t (7.5)
1.77 m
9.5 CH3
30.8 CH2
64.3 CH
80.7 C
1.02 t (7.8)
1.80-1.71
4.39 t (6.8)
9.3
1.02 t (7.8)
1.80-1.68
4.38 t (6.9)
9.3
2
30.5
64.0
80.5
68.7
70.4
77.6
65.3
73.2
81.3
29.3
25.0
29.7
29.2
31.7
22.6
14.0
30.5
63.9
80.4
68.8
70.7
77.4
65.1
74.4
82.1
29.8
24.3
29.9
29.3
31.8
22.6
14.1
3
4
4.40 dt (6.0, 6.0)
5
69.0 C
6
70.7 C
7
77.8 C
8
4.53 dd (9.0, 4.5)
65.7 CH
73.1 CH
81.7 CH
29.4 CH2
25.2 CH2
30.0 CH2
29.3 CH2
32.0 CH2
22.9 CH2
14.3 CH3
4.52 d (4.9)
3.65 t (3.9)
3.61-3.55
1.68-1.57
1.36-1.24
1.36-1.24
1.36-1.24
1.36-1.24
1.36-1.24
0.89 t (7.8)
2.89-2.36 br s
2.89-2.36 br s
2.89-2.36 br s
3.44 s
4.67 d (3.9)
9
3.66 ddd (8.5, 4.5, 3.5)
3.61 ddd (7.5, 5.0, 3.5)
1.64 m
3.73-3.68
10
3.35-3.29
11
1.80-1.68, 1.67-1.57
12
13
1.31 m
1.35-1.22
1.35-1.22
1.35-1.22
1.35-1.22
0.89 t (6.9)
2.54 br s
14
1.31 m
15
1.30 m
16
1.31 m
17
0.90 t (7.0)
1.85 d (6.0)
3.41 d (9.0)
2.68 d (8.5)
3.44 s
3-OH
8-OH
9-OH
OCH3
3.90-3.79
3.79-3.64
3.39 s
57.5 CH3
57.4
57.9
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Since several diacetylene containing molecules are found to
display potent biological activities, and we had the new natural
products in ample amounts, we were interested in investigating
their cytotoxic properties. All four target molecules 3-6 along
with other intermediate compounds such as 7, 8, 9, 11, 26, 29, 30,
32, and 33 were screened for cytotoxicity employing MTT assay
against four different cancer cell lines,13 viz., A549 (lung cancer),
MCF-7 (breast), DU-145 (prostate), and SK-N-SH (neuro-
blastoma), using doxorubicin as a reference sample (see the
Supporting Information). Interestingly, compounds 3 (IC50 of 7
μM) and 5 (IC50 of 12 μM) werefoundtobebetter than or similar
to doxorubicin (IC50 of 9 μM) against the human neuroblastoma
cell line, while compound 4 was found to be effective against the
human prostate cancer cell line with an IC50 value of 17 μM.
temperature. The coupling constant J is given in Hz. The chemical shifts
are reported in ppm on scale downfield from TMS as internal standard
and signal patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; m, multiplet; br, broad peak. FTIR spectra were recorded in
CHCl3. Optical rotations were measured on a digital polarimeter, using a
1 mL cell with a 1 dm path length. For low (MS) and high (HRMS)
resolution, m/z ratios are reported as values in atomic mass units. Mass
analysis was done in either APCI mode or EI mode. All reagents and
solvents were reagent grade and were used without further purification
unless specified otherwise. Technical grade ethyl acetate and petroleum
ether used for column chromatography were distilled prior to use.
Tetrahydrofuran (THF) and diethyl ether (Et2O), when used as solvent
for reactions, were freshly distilled from sodium benzophenone ketyl
radical. Column chromatography was carried out with silica gel (60-120
mesh or 100-200 mesh) packed in glass columns. All reactions were
performed under an atmosphere of nitrogen in flame-dried or oven-dried
glassware with magnetic stirring.
’ CONCLUSIONS
In conclusion, the first total synthesis of diacetylene molecules
(þ)-oploxyne A, (-)-oploxyne B, and their C-10 epimers has
been accomplished. Two compounds 3 and 5 were found to
display potent activity similar to that of doxorubicin. Our total
synthesis has led to the structural revision of oploxyne B. The
strategy with readily available raw materials and simple experi-
mental procedures merits its use toward scaling up of the
materials for their further availability toward biological screening.
(R)-2-[(S)-1-(4-Methoxybenzyloxy)propyl ]-1,4-dioxaspiro
[4.5]decane (13). To a well-stirred suspension of freshly activated
(washed with anhydrous hexane) NaH (1.5 g, 37.5 mmol, 60% disper-
sion in mineral oil) in anhydrous THF (20 mL) was added a solution of
Scheme 6. Synthesis of C-10 Epimer of (-)-Oploxyne B 6
’ EXPERIMENTAL SECTION
General Methods. 1H NMR and 13C NMR spectra were recorded
in CDCl3 solvent on 200, 300, or 500 MHz spectrometers at ambient
Figure 2. Key NOE correlations in the NOESY spectra of 8a in CDCl3.
Scheme 5. Synthesis of C-10 Epimer of (þ)-Oploxyne A 5
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alcohol 12 (5.0 g, 25 mmol) in THF (50 mL) at 0 °C. After 30 min,
p-methoxybenzyl bromide (5.53 g, 27.5 mmol) was added and the
reaction mixture was stirred at room temperature for 6 h. The reaction
was quenched with ice pieces and extracted with Et2O (3 ꢀ 100 mL).
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (60-120 mesh, 2%
EtOAc/hexane) to afford compound 13 (7.2 g, 90% yield) as a colorless
oil. [R]29D þ16.4 (c 1, CHCl3); IR (CHCl3) 2935, 2862, 1613, 1513,
1248, 1101 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 2H),
6.96-6.83 (m, 2H), 4.59-4.45 (m, 2H), 4.12-3.97 (m, 1H), 3.93-
3.85 (m, 1H), 3.83-3.77 (m, 4H), 3.54-3.43 (m, 1H), 1.96-1.78 (m,
1H), 1.70-1.49 (m, 9H), 1.50-1.26 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 159.1, 130.8, 129.4, 113.7, 109.4, 79.9,
72.2, 71.4, 66.1, 55.2, 41.9, 36.3, 34.9, 25.2, 24.0, 23.8, 9.2; MS (ESI) m/z
343 [M þ Na]þ; HRMS (ESI) m/z calcd for C19H28NaO4 343.1880,
found 343.1876.
compound 10 (677 mg, 98% yield) as a yellow oil. [R]30 -107.5
D
(c 0.9, CHCl3); IR (CHCl3) 2967, 2936, 2874, 2837, 2205, 1612, 1513,
1249, 1036 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.32-7.24 (m, 2H),
6.91-6.85 (m, 2H), 4.72 (d, J = 11.3 Hz, 1H), 4.43 (d, J = 11.3 Hz, 1H),
4.01 (t, J = 6.8 Hz, 1H), 3.81 (s, 3H), 1.81-1.68 (m, 2H), 0.99 (t, J = 7.5
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 129.8, 129.6, 113.8, 79.4,
70.4, 70.3, 55.2, 45.0, 28.8, 9.3.
Ethyl 2-{(3aS,4R,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethy
ltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}acetate (18) and Ethyl
2-{(3aS,4S,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetra
hydrofuro[3,4-d][1,3]dioxol-4-yl}acetate (19). A solution of
2,3-O-isopropylidene-D-ribose 17 (2.0 g, 10.5 mmol) and (carbetho
xymethylene)triphenylphosphorane (9.1 g, 26.3 mmol) in CH3CN
(50 mL) was refluxed for 4 days. Examination of the reaction mixture
by TLC showed the absence of starting material and the formation of
two products. The solvent was removed under reduced pressure, then
the residue was purified by column chromatography on silica gel (100-200
mesh, 10% EtOAc/hexane) to afford compound 19 (340 mg, 12%; this
material was utilized for data purpose) followed by a mixture of 19 and 20
(2R,3S)-3-(4-Methoxybenzyloxy)pentane-1,2-diol 14. A so-
lution of cyclohexylideneacetal 13 (4 g, 12.5 mmol) in 60 mL of 1:1
CH3CN/1 M HCl was stirred at room temperature for 3 h. The reaction
was quenched with solid sodium bicarbonate (until neutralization) at
room temperature. The CH3CN in the reaction mixture was removed
under vacuum. Then, it was diluted with ethyl acetate (30 mL) and the
aqueous layer was further extracted with ethyl acetate (3 ꢀ 60 mL). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (60-120 mesh, 40% EtOAc/
hexane) to afford the compound 14 (2.7, 90% yield). [R]28D þ13.7 (c 2.7,
CHCl3); IR(CHCl3) 3372, 2964, 2936, 2878, 1612, 1514, 1248, 1080 cm-
(2.2 g, 80% yield) as a colorless oil. Analytical data of compound 19: [R]29
D
-6.5 (c 1.25, CHCl3); IR (CHCl3) 2987, 2939, 1734, 1373, 1213,
1
1078 cm-1; H NMR (300 MHz, CDCl3) δ 4.73 (dd, J = 6.8, 3.8 Hz,
1H), 4.54 (dd, J= 6.8, 4.3 Hz, 1H), 4.29-4.21 (m, 1H), 4.16 (q, J= 6.8, 11.3
Hz, 2H), 4.07 (q, J = 6.8, 3.8 Hz, 1H), 3.80 (dd, J = 12.1, 3.0 Hz, 1H), 3.65
(dd, J = 12.1, 3.0 Hz, 1H), 2.73 (dd, J = 15.8, 5.3 Hz, 1H), 2.61 (dd, J = 15.8,
6.0 Hz, 1H), 1.53 (s, 3H), 1.34 (s, 3H), 1.26 (t, J = 6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 170.7, 114.2, 84.6, 83.9, 81.4, 80.6, 62.5, 60.7, 37.8,
27.4, 25.3, 14.0; MS (ESI) m/z 261 [M þ H] þ; HRMS (ESI) m/z calcd
for C12H20O6Na 283.1157, found 283.1166.
2-{(3aS,4R,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetra
hydrofuro[3,4-d][1,3]dioxol-4-yl}acetaldehyde (20) and 2-
{(3aS,4S,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetrahy
drofuro[3,4-d][1,3]dioxol-4-yl}acetaldehyde (21). Diisobuty-
laluminium hydride (21.9 mL, 30.7 mmol, 20% in hexane) was added
to a mixture of esters (4.0 g, 15.3 mmol) in CH2Cl2 (40 mL) at -78 °C
and the solution was stirred for 5 h. The reaction was quenched with aq
saturated sodium-potasium tartarate (10 mL) and extracted with
CH2Cl2 (3 ꢀ 100 mL). The combined organic layer was dried over
Na2SO4 and concentrated under reduced pressure, then the residue was
passed through a short pad of silica gel (60-120 mesh, 50% EtOAc/
hexane) to afford the mixture of compounds 20 and 21 (3.1 g, 95%
yield) which were directly used for further reaction.
{(3aR,4R,6R,6aS)-6-(Hept-2-enyl)-2,2-dimethyltetrahydro
furo[3,4-d][1,3]dioxol-4-yl}methanol (22) and {(3aR,4R,6S,
6aS)-6-(Hept-2-enyl)-2,2-dimethyltetrahydrofuro[3,4-d]-
[1,3]dioxol-4-yl}methanol (23). A solution of n-pentyltriphenyl-
phosphonium bromide (47.8 g, 115.7 mmol) in THF (200 mL) and
NaNH2 (4.1 g, 106.5 mmol) was refluxed for 4 h. Then the reaction was
cooled to -78 °C and to this a mixture of aldehydes 20 and 21 (10 g,
46.3 mmol) in THF (60 mL) was added then the solution was stirred for
3 h at room teperature. The reaction was quenched with aq saturated
ammonium chloride solution (10 mL). The aqueous layer was extracted
with ethyl actate (3 ꢀ 100 mL) and the combined organic layer was
dried over anhydrous Na2SO4 and concentrated under reduced pres-
sure. The crude product was purified by column chromatography on
silica gel (60-120 mesh, 10% EtOAc/hexane) to afford 23 (2.9 g, 23%
yield) comprised of a mixture of E and Z isomers and 22 (6.2 g, 50%
yield) comprised of a mixture of E and Z isomers.
1; H NMR (300 MHz, CDCl3) δ 7.23-7.14 (m, 2H), 6.84-6.77 (m,
1
2H), 4.53-4.39 (m, 2H), 3.78-3.74 (m, 3H), 3.62 (s, 3H), 3.43-3.30 (m,
1H), 3.20 (br s, 1H), 1.72-1.46 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 159.2, 130.4, 129.4, 113.8, 81.3, 72.4, 72.0, 63.5,
55.0, 23.0, 9.6; MS (ESI) m/z 241 [M þ H] þ; HRMS (ESI) m/z calcd for
C13H20O4Na 263.1254, found 263.1250.
(S)-1-Methoxy-4-[(pent-1-yn-3-yloxy)methyl]benzene 16.
NaIO4 (3.4 g, 16.2 mmol) was added to a solution of diol 14 (2.6 g, 10.8
mmol) in 60% CH3CN/H2O (30 mL) at 0 °C. Then the reaction was
stirred at room temperature for 1 h. The reaction mixture was extracted
with ethyl acetate (3 ꢀ 60 mL). The combined organic layer was dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The
resulting aldehyde was dissolved in dry methanol and K2CO3 (4.4 g, 31.7
mmol) and to this was added Ohira-Bestmann reagent 15 (2.5 g, 13.2
mmol) at rt, then the mixture was stirred for 10 h. The reaction mixture
was extracted with diethyl ether (3 ꢀ 40 mL). The combined organic
layer was dried over anhydrous Na2SO4 and concentrated under
reduced pressure and the residue was purified by silica gel chromatography
(60-120 mesh, 1-2% EtOAc/hexane) to afford the compound 16 (1.9 g,
86% yield) as a colorless oil. [R]30D -112.2 (c 2.0, CHCl3); IR (CHCl3)
1
3306, 2926, 2956, 2853, 2129, 1613, 1514, 1248, 1068 cm-1; H NMR
(300 MHz, CDCl3) δ 7.27-7.15 (m, 2H), 6.87-6.75 (m, 2H), 4.67 (d, J =
11.3 Hz, 1H), 4.38 (d, J = 11.3 Hz, 1H), 3.92 (dt, J = 1.8, 6.4 Hz, 1H), 3.73
(s, 3H), 2.39 (d, J = 1.8 Hz, 1H), 1.75-1.63 (m, 2H), 0.93 (t, J = 7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 129.9, 129.6, 113.7, 82.8, 73.7,
70.1, 69.3, 55.2, 28.7, 9.6; MS (EI) m/z 204.
(S)-1-[(1-Bromopent-1-yn-3-yloxy)methyl]-4-methoxy-
benzene (10). Compound 16 (500 mg, 2.4 mmol) was dissolved in
acetone (8 mL). NBS (523 mg, 2.9 mmol) and silver nitrate (83 mg, 0.49
mmol) were added to this solution. The reaction mixture was stirred at
room temperature for 1 h. The reaction mixture was cooled to 0 °C,
mixed with cold water, and extracted with Et2O (3 ꢀ 15 mL). The
combined organic layer was dried over anhydrous Na2SO4 and con-
centrated under reduced pressure, then the residue was purified by silica
gel chromatography (60-120 mesh, 1% EtOAc/hexane) to afford
{(3aR,4R,6R,6aS)-6-Heptyl-2,2-dimethyltetrahydrofuro-
[3,4-d][1,3]dioxol-4-yl}methanol (24). To a solution of compound
22 (3.0 g, 11.1 mmol) in methanol (30 mL) was added 10% Pd/C (100
mg) and the mixture was stirred for 4 h under hydrogen atmosphere at
55 psi pressure. After filtering the catalyst and solvent evaporation, the
resulting residue was chromatographed on silica gel (60-120 mesh,
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ARTICLE
10% EtOAc/hexane) to afford compound 24 (2.96 g, 98%) as a colorless
oil. [R]31D -2.5 (c 2, CHCl3); IR (CHCl3) 3450, 2929, 2856, 1638, 1210,
1086 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.66-4.55 (m, 2H), 4.11
(t, J = 6.2 Hz, 1H), 3.85 (ddd, J = 10.2, 6.8, 3.6 Hz, 1H), 3.57 (d, J = 6.2Hz,
2H), 1.99 (br s, 1H), 1.70 (q, J = 14.5, 7.4 Hz, 2H), 1.49 (s, 3H), 1.45-
1.35 (m, 2H), 1.33 (s, 3H), 1.32-1.20 (m, 8H), 0.87 (t, J = 7.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 112.4, 83.9, 82.3, 81.6, 80.9, 61.5, 31.8,
29.7, 29.1, 29.0, 26.3, 26.2, 25.1, 22.6, 14.1; MS (ESI) m/z 295 [M þ Na]
þ; HRMS (ESI) m/z calcd for C15H29O4 273.2060, found 273.2068.
(3aS,4S,6R,6aS)-4-(Chloromethyl)-6-heptyl-2,2-dimethy-
ltetrahydrofuro[3,4-d][1,3]dioxole (25). To a stirred solution of
compound 24 (3.0 g, 11.0 mmol) in CCl4 (50 mL) was added TPP (4.3 g,
16.5 mmol) followed by a catalytic amount of imidazole and the resulting
reaction mixture was refluxed for 4 h. The reaction mixture was then
cooled to 0 °C, diluted with hexane, and filtered through Celite. After
evaporation of the solvent under reduced pressure, the crude product was
purified by column chromatography on silica gel (60-120 mesh, 10%
Et2O/hexane) to afford compound 25 (2.72 g, 88% yield) as a colorless
oil. [R]32D -11.6 (c 2.8, CHCl3); IR (CHCl3) 2928, 2857, 1443, 1372,
1218, 772 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.77 (dd, J = 6.0, 1.1 Hz,
1H), 4.65 (dd, J = 6.0, 3.8 Hz, 1H), 4.22 (t, J = 6.4 Hz, 1H), 3.93 (ddd, J =
10.4, 6.8, 3.8 Hz, 1H), 3.58-3.42 (m, 2H), 1.69 (q, J = 14.5, 7.2 Hz, 2H),
1.50 (s, 3H), 1.35 (s, 3H), 1.34-1.22 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 112.5, 83.5, 83.3, 82.0, 81.7, 43.4, 31.7,
29.6, 29.1, 29.0, 26.3, 26.1, 25.1, 22.6, 14.1; MS(ESI)m/z279 [M þ Na-
Cl] þ; HRMS (ESI) m/z calcd for C15H28ClO3 291.1721, found
291.1735 and calcd 293.1697, found 293.1694.
(R)-1-{(4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl}
octan-1-ol (11). To a freshly distilled ammonia (20 mL) in a 100 mL
two-necked round-bottomed flask fitted with a coldfinger condenser was
added freshly cut lithium metal pieces (0.6 g, 86.2 mmol) at -33 °C and
the resulting gray suspension was stirred for 30 min. To this reaction
mixture was added chloro compound 25 (2.5 g, 8.6 mmol) in anhydrous
THF (15 mL) over a period of 20 min. After being stirred at -33 °C for
5 h, the reaction was quenched by the portion wise addition of solid
NH4Cl and then ammonia was allowed to evaporate. The reaction
mixture was diluted with water (30mL) and extracted with Et2O (3 ꢀ
30 mL). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica gel (60-
120 mesh, 10% EtOAc/hexane) to afford compound 11 (1.86 g, 85%) as a
colorless oil. [R]29D þ47 (c 1.2, CHCl3); IR (CHCl3) 3508, 3310, 2986,
2928, 2857, 2113, 1458, 1381, 1372, 1228, 1073 cm-1; 1H NMR (300
MHz, CDCl3) δ 4.74 (dd, J = 5.7, 2.4 Hz, 1H), 4.01-3.85 (m, 2H), 2.56
(d, J = 2.4 Hz, 1H), 2.28 (brs, 1H), 1.57 (s, 3H), 1.55-1.40 (m, 3H), 1.37
(s, 3H), 1.36-1.18 (m, 9H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 110.4, 81.0, 79.5, 75.9, 71.2, 66.9, 32.7, 31.7, 29.3, 29.1, 27.4,
25.9, 25.2, 22.6, 14.0; MS (ESI) m/z 277 [M þ Na]þ; HRMS (ESI) m/z
calcd for C15H26O3Na 277.1774, found 277.1762.
[M þ Na] þ; HRMS (ESI) m/z calcd for C27H40O6N 474.2850, found
474.2860.
R )-1-{ ( 4R,5R )-5-[ (S)-5-( 4-Methoxybenzyloxy)hepta-1,3-
diynyl]-2,2-dimethyl-1,3-dioxolan-4-yl}octyl 4-Methylben-
zenesulfonate (7). Diisopropylethylamine (0.24 mL, 1.4 mmol)
was added to a solution of compound 9 (160 mg, 0.35 mmol) in
CH2Cl2 (8 mL) at 0 °C and the mixture was stirred for 20 min at room
temperature. Then the reaction mixture was cooled to 0 °C, and to this
p-toluenesulfonylchloride (133.8 mg, 0.7 mmol) and DMAP (51.4 mg,
0.42 mmol) were added and the reaction was stirred at room tempera-
ture for 36 h. Then the solvent was removed under reduced pressure and
the residue was purified by silica gel chromatography by eluting with 5%
EtOAc/hexane to afford compound 7 (181.5, 85% yield). [R]30
-
D
101.8 (c 2.6, CHCl3); IR (CHCl3) 2955, 2925, 2853, 2064,1639, 1513,
1175 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.87-7.80 (m, 2H), 7.35-
7.24 (m, 4H), 6.93-6.83 (m, 2H), 4.91-4.82 (m, 1H), 4.78-4.67 (m,
2H), 4.44 (d, J = 11.3, 1H), 4.11-3.99 (m, 2H), 3.81 (s, 3H), 2.43 (s,
3H), 1.87-1.72 (m, 2H), 1.72-1.65 (m, 1H), 1.64 (s, 3H), 1.57-1.40
(m, 2H), 1.29 (s, 3H), 1.28-1.17 (m, 9H), 1.02 (t, J = 7.5 Hz, 3H), 0.87
(t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3, 144.0, 134.9,
129.6, 129.5, 129.0, 128.2, 113.8, 111.0, 82.7, 80.2, 78.8, 73.6, 72.1, 70.6,
69.8, 69.2, 67.2, 55.2, 31.7, 31.4, 29.1, 29.0, 28.6, 27.3, 25.7, 24.4, 22.6,
21.5, 14.0, 9.6; MS (ESI) m/z 628 [M þ NH4]þ; HRMS (ESI) m/z
calcd for for C35H50NO7S 628.3303, found 628.3280.
(þ)-Oploxyne A (3). A solution of compound 7 (70 mg, 0.11
mmol) in CH2Cl2 (8 mL) and trifluoroacetic acid (0.1 mL) was stirred
at room temperature for 42 h. Diisopropylethylamine (0.6 mL) was
introduced o basify the reaction mixture, which was then stirred for 8 h at
room temperature. The solution was concentrated under reduced
pressure and the resulting residue was purified by silica gel column
chromatography (60-120 mesh, 20% EtOAc/hexane) to afford oplox-
yne A 3 (22.6 mg, 71% yield) as a colorless oil. [R]30 þ33.3 (c 0.9,
D
CHCl3), [R]23 þ126.6 (c 0.15, MeOH), lit.4 [R]25 þ123.4 (c 0.4,
D
D
MeOH); IR (CHCl3) 3432, 2956, 2925, 2854, 2252, 2144, 1247 cm-1
;
MS (ESI) m/z 301 [M þ Na] þ; HRMS (ESI) m/z calcd for
C17H30NO3 296.2220, found 296.2207.
(4R,5S)-4-Ethynyl-5-[(R)-1-methoxyoctyl]-2,2-dimethyl-
1,3-dioxolane (26). To a sirred suspension of NaH (71 mg, 1.77
mmol) in anhydrous THF (3 mL) at 0 °C, was added compound 11
(0.3 g, 1.18 mmol) in anhydrous THF (5 mL) slowly with a syringe over a
periodof5 min. Afterstirring at0 °C for15min, CH3I (0.1 mL, 1.5mmol)
was added and themixture was furtherstirredat room temperature for 1 h.
After quenching the reaction with ice pieces, the reaction mixture was
extracted with Et2O (3 ꢀ 10 mL) and the combined organic layers were
washed with brine and dried on anhydrous Na2SO4. After removing the
solvent under reduced pressure, crude residue was purified by column
chromatography on silica gel (60-120 mesh, 5% Et2O/hexane) to afford
compound 26 (0.29 g, 94%) as a colorless oil. [R]29 þ37.5 (c 1.5,
D
CHCl3); IR (CHCl3) 3310, 2929, 2857, 2112, 1456, 1380, 1228,
1107 cm-1; 1H NMR (200 MHz, CDCl3) δ 4.64 (dd, J = 4.9, 2.0 Hz,
1H), 4.02 (dd, J = 8.8, 5.8 Hz, 1H), 3.51 (s, 3H), 3.50-3.46 (m, 1H), 2.50
(d, J = 2.0 Hz, 1H), 1.57 (s, 3H), 1.55-1.37 (m, 4H), 1.36 (s, 3H), 1.35-
1.06 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
110.8, 81.1, 80.5, 80.2, 75.2, 67.2, 58.7, 31.8, 30.8, 29.5, 29.1, 27.7, 26.2,
24.7, 22.6, 14.0; MS (ESI) m/z 291 [M þ Na]þ; HRMS (ESI) m/z calcd
for C16H28O3Na 291.1931, found 291.1928.
(R)-1-{(4S,5R)-5-[(S)-5-(4-Methoxybenzyloxy)hepta-1,3-
diynyl]-2,2-dimethyl-1,3-dioxolan-4-yl}octan-1-ol (9). Com-
pound 9 was prepared according to the procedure described for compound
8 starting from compounds 11 (150 mg, 0.6 mmol) and 10 (183 mg, 0.65
mmol). The crude product was purified by column chromatography on
silica gel (60-120 mesh, 5% EtOAc/hexane) to afford compound 9 (257
mg, 94% yield). [R]30D -40.4 (c 2.3, CHCl3); IR (CHCl3) 3467, 2926,
2854, 2230, 2142,1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.31-7.25
(m, 2H), 6.91-6.86 (m, 2H), 4.82 (d, J = 5.3 Hz, 1H), 4.71 (d, J = 11.3 Hz,
1H), 4.42 (d, J= 11.3 Hz, 1H), 4.05 (t, J = 6.8 Hz, 1H), 4.00-3.87 (m, 2H),
3.81 (s, 3H), 2.06 (br s, 1H), 1.83-1.68 (m, 2H), 1.58 (s, 3H), 1.56-1.39
(m, 3H), 1.38 (s, 3H), 1.37-1.22 (m, 9H), 0.99 (t, J = 6.8 Hz, 3H), 0.87
(t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3, 129.6 (2C),
113.8, 110.7, 81.5, 79.8, 74.2, 71.9, 71.3, 70.5, 69.8, 69.4, 67.6, 55.2, 32.8,
31.8, 29.3, 29.2, 28.6, 27.6, 25.9, 25.2, 22.6, 14.1, 9.6; MS (ESI) m/z 479
(4R,5S)-4-[(S)-5-(4-Methoxybenzyloxy)hepta-1,3-diynyl]-
5-[(R)-1-methoxyoctyl]-2,2-dimethyl-1,3-dioxolane (8). CuCl
(1.84 mg, 0.02 mmol) was added to a 30% n-BuNH2 (3 mL) aqueous
solution at room temperature to result in the formation of a blue
solution. A few crystals of hydroxylamine hydrochloride were added to
discharge the blue color. The resulting colorless solution indicated the
presence of Cu(I) salt. To this solution was added alkyne 26 (250 mg,
0.93 mmol) in Et2O (2 mL) at room temperature to result in the
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ARTICLE
formation of a yellow acetylide suspension that was immediately cooled
with an ice-water mixture. To this mixture bromoalkyne 10 (210 mg,
0.7 mmol) was added at once and the ice bath was removed. More
crystals of hydroxylamine hydrochloride were added throughout the
reaction as necessary to prevent the solution from turning blue or green.
After 30 min, additional bromoalkyne 10 (79 mg, 0.28 mmol) was
added. At this point the reaction was completed according to TLC. The
product was repeatedly extracted with Et2O (4 ꢀ 20 mL), dried over
Na2SO4, and concentrated under reduced pressure. The crude product
was purified by column chromatography on silica gel (60-120 mesh, 1%
EtOAc/hexane) to afford compound 8 (392 mg, 90%). [R]30D -37.2
(c 0.75, CHCl3); IR (CHCl3) 2928, 2856, 2228, 2143, 1612, 1513, 1463,
1249, 1228, 1105 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.34-7.23 (m,
2H), 6.92-6.84 (m, 2H), 4.76-4.69 (m, 2H), 4.43 (d, J = 11.3 Hz, 1H),
4.05 (dd, J = 8.3, 6.2 Hz, 2H), 3.81 (s, 3H), 3.53 (s, 3H), 3.52-3.48
(m, 1H), 1.83-1.70 (m, 2H), 1.59 (s, 3H), 1.58-1.53 (m, 2H), 1.51-
1.41 (m, 1H), 1.37 (s, 3H), 1.36-1.20 (m, 9H), 1.00 (t, J = 7.4 Hz, 3H),
0.88 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3, 129.6,
113.8, 111.0 (2C), 81.6, 80.4, 79.4, 75.0, 71.2, 70.5, 69.8, 69.6, 67.8, 58.8,
55.3, 31.8, 31.1, 29.7, 29.2, 28.7, 27.8, 26.1, 24.8, 22.6, 14.1, 9.7; MS
(ESI) m/z 488 [M þ NH4]þ; HRMS (ESI) m/z calcd for C29H42O5Na
493.2929, found 493.2937.
29.1, 27.3, 25.4, 25.36, 22.6, 14.0; MS (ESI) m/z 273 [M þ H]þ; HRMS
(ESI) m/z calcd for C15H28O4Na 295.1885, found 295.1876.
(3aS,4S,6S,6aS)-4-(Chloromethyl)-6-heptyl-2,2-dimethy
ltetrahydrofuro[3,4-d][1,3]dioxole (28). Compound 28 was pre-
pared according to the procedure described for compound 25 starting from
compound 27 (2.2 g, 8.5 mmol). Purification by silica gel chromatography
(60-120 mesh, 10% Et2O/hexane) afforded compound 28 (2.4 g, 90% yield)
as a colorless oil. [R]32D -14.4 (c 2, CHCl3); IR (CHCl3) 2955, 2928, 2857,
1639, 1381, 1212, 1080 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.52 (dd, J =
7.0, 4.1 Hz, 1H), 4.25 (dd, J = 7.0, 4.9 Hz, 1H), 4.05 (q, J = 9.4, 4.3 Hz, 1H),
3.80 (q, J = 11.7, 6.6 Hz, 1H), 3.64-3.50 (m, 2H), 1.63-1.51 (m, 2H), 1.49
(s, 3H), 1.44-1.35 (m, 2H), 1.30 (s, 3H), 1.30-1.23 (m, 8H), 0.88 (t, J=7.0
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 114.5, 85.0, 84.7, 82.9, 82,8, 44.5,
33.7, 31.9, 29.6, 29.3, 27.5, 25.6, 25.5, 22.7, 14.2; MS (ESI) m/z 279 [M þ Na
-Cl] þ;HRMS(ESI) m/zcalcd for C15H28O3Cl 291.1721, found 291.1736.
(S)-1-[(4S,5R)-5-Ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]o
ctan-1-ol (29). Compound 29 was prepared according to the procedure
described for compound 11 starting from compound 28 (2.2 g, 7.6 mmol).
Purification by silica gel (60-120 mesh, 10% EtOAc/hexane) afforded
compound 29 (1.8 g, 93% yield) as a colorless oil. [R]33 þ7.5
D
(c 2, CHCl3); IR (CHCl3) 3450, 3310, 2986, 2926, 2857, 2112, 1636,
1458, 1371, 1228, 1067 cm-1; 1H NMR (300 MHz, CDCl3) δ4.81 (dd, J=
5.3, 2.3 Hz, 1H), 3.88-3.82 (m, 2H), 2.56 (d, J = 2.3 Hz, 1H), 2.14 (br s,
1H), 1.82-1.68 (m, 1H), 1.60-1-52 (m, 1H), 1.49 (s, 3H), 1.47-1.36
(m, 2H), 1.32 (s, 3H), 1.31-1.25 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 110.7, 80.7, 80.5, 76.0, 71.3, 68.1, 34.0, 31þ.9,
(-)-Oploxyne B (4). Trifluoroacetic acid (0.07 mL) was added to a
solution of compound 8 (60 mg, 0.13 mmol) in CH2Cl2 (10 mL) at 0 °C
and the mixture was stirred for 36 h at room temperature. The reaction
mixture was concentrated under reduced pressure, and the resulting residue
was purified by column chromatography on silica gel (60-120 mesh, 20%
29.7, 29.3, 27.6, 26.0, 25.2, 22.7, 14.2; MS (ESI) m/z 255 [M þ H]
HRMS (ESI) m/z calcd for C15H26O3Na 277.1779, found 277.1789.
;
EtOAc/hexane) to afford oploxyne B (4) (35.8 mg, 89% yield). [R]29
-
D
12.0 (c 0.28, MeOH), lit.4 [R]25D þ11.7 (c 0.06, MeOH); IR (CHCl3)
3389, 2925, 2855, 2250, 2140, 1496, 1463, 1081 cm-1; MS (ESI) m/z 333
[M þ Na]þ; HRMS (ESI) m/z calcd for C18H30O4Na, 333.2036, found
333.2040.
(S)-1-{(4S,5R)-5-[(S)-5-(4-Methoxybenzyloxy)hepta-1,3-
diynyl]-2,2-dimethyl-1,3-dioxolan-4-yl}octan-1-ol (30). Com-
pound 30 was prepared according to the procedure described for compound
8 starting from compounds 29 (200 mg, 0.79 mmol) and 10 (244 mg, 0.86
mmol). Purification by silica gel (60-120 mesh, 5% EtOAc/hexane) afforded
(S)-7-{(4R,5S)-5-[(R)-1-Methoxyoctyl]-2,2-dimethyl-1,3-
dioxolan-4-yl}hepta-4,6-diyn-3-ol (8a). To a solution of 8
(50 mg, 0.10 mmol) in CH2Cl2 (10 mL) at 0 °C were added aqueous
NaH2PO4/Na2HPO4 (pH 7), buffer (3 mL), and DDQ (97 mg, 0.42
mmol). The reaction was allowed to warm to room temperature. After 10
h at room temperature, the reaction mixture was filtered through a Celite
pad, and the layers were separated. The aqueous layer was extracted with
CH2Cl2 (2 ꢀ 10 mL), and the combined organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure, then the
residue was purified on silica gel chromatography (60-120 mesh, 7%
EtOAc/hexane) to afford the compound 8a (33 mg, 89% yield) as a
yellow oil. [R]33D þ23 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ
4.70 (d, J = 5.1 Hz, 1H), 4.42-4.36 (m, 1H), 4.05 (dd, J = 8.8, 5.8 Hz,
1H), 3.51 (s, 3H), 3.50-3.44 (m, 1H), 1.93 (br s, 1H), 1.79-1.71 (m,
2H), 1.56 (s, 3H), 1.52-1.38(m, 2H), 1.36 (s, 3H), 1.35-1.24 (m, 10H),
1.03 (t, J = 7.3 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 111.0, 81.6, 80.5, 80.4, 75.7, 71.0, 68.8, 67.8, 64.0, 58.8, 31.8,
31.0, 30.6, 29.7, 29.6, 29.2, 27.8, 26.1, 24.7, 22.6, 14.1, 9.3; MS (ESI) m/z
373 [M þ Na] þ; HRMS (ESI) m/z calcd for C21H34O4Na 373.2349,
found 373.2332.
compound 30 (330 mg, 92%) as a colorless oil. [R]29 -58.5 (c 0.4,
D
CHCl3); IR (CHCl3) 3450, 2929, 2857, 2156, 2240, 1612, 1514, 1249, 1226,
1067 cm-1; 1H NMR (300 MHz, CDCl3) δ7.32-7.24 (m, 2H), 6.92-6.85
(m, 2H), 4.96 (dd, J = 4.7, 2.6 Hz, 1H), 4.71 (d, J = 11.3 Hz, 1H), 4.42 (d,
J = 11.3 Hz, 1H), 4.05 (t, J = 6.4 Hz, 1H), 3.97-3.87 (m, 2H), 3.81 (s, 3H),
1.86-1.69 (m, 4H), 1.54 (s, 3H), 1.53-1.40 (m, 1H), 1.36 (s, 3H), 1.35-
1.22 (m, 9H), 0.99 (t, J= 7.5 Hz, 3H), 0.88 (t, J= 7.0 Hz, 3H); 13CNMR(75
MHz, CDCl3) δ 159.3, 129.6, 129.6, 113.8, 110.9, 81.0, 79.8, 75.0, 71.8, 71.3,
70.5, 69.8, 69.4, 68.9, 55.2, 34.2, 31.8, 29.6, 29.2, 28.6, 27.6, 25.9, 25.1, 22.6,
14.0, 9.6; MS (ESI) m/z 474 [M þ NH4] þ; HRMS (ESI) m/z calcd for
C28H40O5Na 479.2773, found 479.2771.
(S)-1-{(4R,5R)-5-[(S)-5-(4-Methoxybenzyloxy)hepta-1,3-
diynyl]-2,2-dimethyl-1,3-dioxolan-4-yl}octyl 4-Methylben-
zenesulfonate (31). Compound 31 was prepared according to the
procedure described for compound 7 starting from compound 30 (152 mg,
0.33 mmol). Purification by silica gel column chromatography (60-120
mesh, 5% EtOAc/hexane) afforded the compound 31 (187 mg, 92% yield)
as a colorless oil. [R]32D -32 (c 1.75, CHCl3); IR (CHCl3) 2925, 2854,
2235, 2154, 1638, 1176 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.93-7.78
(m, 2H), 7.39-7.21 (m, 4H), 6.94-6.81 (m, 2H), 4.89-4.82 (m, 2H),
4.74 (d, J = 11.3 Hz, 1H), 4.44 (d, J = 11.3 Hz, 1H), 4.33 (dd, J = 11.3, 6.0
Hz, 1H), 4.07 (dd, J = 12.8, 6.0 Hz, 1H), 3.80 (s, 3H), 2.42 (s, 3H), 1.85-
1.62 (m, 4H), 1.50 (s, 3H), 1.32 (s, 3H), 1.31-1.07 (m, 10 H), 1.01 (t, J =
7.5 Hz, 3H), 0.85 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3,
144.7, 134.0, 129.6, 129.5, 127.8, 124.6, 113.7, 110.6, 81.6, 80.0, 78.2, 73.7,
72.8, 70.4, 69.7, 69.4, 68.1, 55.2, 31.6, 30.4, 29.0, 28.6, 26.8, 25.3, 24.0, 22.6,
21.5, 14.0, 9.6; MS (ESI) m/z633 [M þ Na] þ;HRMS(ESI) m/zcalcd for
C35H50O7NS 628.3307, found 628.3278.
{(3aR,4R,6S,6aS)-6-Heptyl-2,2-dimethyltetrahydrofuro-
[3,4-d][1,3]dioxol-4-yl}methanol (27). Compound 27 was pre-
pared according to the procedure described for compound 24 starting
from compound 23 (2.5 g, 9.3 mmol). Purification by silica gel (60-120
mesh, 10% EtOAc/hexane) afforded compound 27 (2.4 g, 98% yield) as
a colorless oil. [R]31 -3.6 (c 1.5, CHCl3); IR (CHCl3) 3453, 2928,
D
1
2858, 1458, 1381, 1212, 1077 cm-1; H NMR (300 MHz, CDCl3) δ
4.58 (dd, J = 7.0, 4.5 Hz, 1H), 4.27 (dd, J = 7.0, 5.3 Hz, 1H), 3.94 (q, J =
7.9, 4.3 Hz, 1H), 3.88-3.76 (m, 2H), 3.65 (dd, J = 11.7, 4.0 Hz, 1H),
2.07 (br s, 1H), 1.63-1.54 (m, 2H), 1.52 (s, 3H), 1.46-1.34 (m, 2H),
1.33 (s, 3H), 1.32-1.20 (m, 8H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 114.6, 85.0, 84.5, 83.8, 81.3, 62,7, 33.6, 31.7, 29.4,
C-10 Epimer of (þ)-Oploxyne A (5). A solution of compound 31
(90 mg, 0.15 mmol) in CH2Cl2 (5 mL) and trifluoroacetic acid (0.1 mL)
was stirred at room temperature for 42 h. Diisopropylethylamine (0.6 mL)
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ARTICLE
was introduced to basify the reaction mixture and the solution was stirred for
8 h at room tempeature. The solution was then concentrated under reduced
pressure and the resulting residue was purified by silica gel column
chromatography (60-120 mesh, 20% EtOAc/hexane) to afford oploxyne
A C-10 epimer 5 (30.7 mg, 75%) as a colorless oil. [R]27D þ2.0 (c 0.45,
MeOH); IR (CHCl3) 3435, 2959, 2928, 2856, 2252, 2144, 1463 cm-1; MS
(ESI) m/z 296 [M þ NH4]þ; HRMS (ESI) m/z calcd for C17H30O3N
296.2220, found 296.2211.
J.S.Y acknowledges partial support by King Saud University for
Global Reasearch Network for Organic Synthesis (GRNOS).
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(4R,5S)-4-[(S)-5-(4-Methoxybenzyloxy)hepta-1,3-diynyl]-5-
((S)-1-methoxyoctyl)-2,2-dimethyl-1,3-dioxolane (32). Com-
pound 32 was prepared according to the procedure described for
compound 8 starting from compounds 33 (60 mg, 0.22 mmol) and 10
(69 mg, 0.24 mmol). Purification by silica gel column chromatrography (60-
120 mesh, 1% EtOAc/hexane) afforded compound 32 (96 mg, 91% yield) as
a colorless oil. [R]29D -66.2 (c 0.7, CHCl3); IR (CHCl3) 2956, 2923, 2318,
1458, 1371, 1228, 1101 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.41-7.22
(m,2H), 6.92-6.85 (m, 2H), 4.94 (d, J = 6.0 Hz, 1H), 4.73 (dd, J = 11.3, 9.1
Hz, 1H), 4.43 (dd, J = 11.3, 6.8 Hz, 1H), 4.10 -3.96 (m, 2H), 3.81 (s, 3H),
3.61-3.53 (m, 1H), 3.41 (s, 3H), 1.83-1.71 (m, 2H), 1.58 (s, 3H), 1.57-
1.36 (m, 3H), 1.34 (s, 3H), 1.33-1.23 (m, 9H), 0.99 (t, J= 6.0 Hz, 3H), 0.89
(t, J= 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ159.3, 129.7, 113.8 (2C),
110.6, 79.8, 79.0, 78.9, 75.9, 71.1, 70.5, 69.8 (2C), 69.5, 57.6, 55.3, 31.8, 31.5,
30.6, 29.7, 29.3, 28.7, 27.6, 25.9, 22.7, 14.0, 9.6; MS (ESI) m/z470 [M þ Na]
þ; HRMS (ESI) m/z calcd for C29H42O5Na 493.2929, found 493.2928.
(4R,5S)-4-Ethynyl-5-[(S)-1-methoxyoctyl]-2,2-dimethyl-1,3-
dioxolane (33). A similar procedure was followed as described for
compound 26 starting from compound 29 (200 mg, 0.78 mmol). Purifica-
tion by silica gel column chromatography (60-120 mesh, 5% Et2O/hexane)
afforded compound 33 (183 mg, 87%) as a colorless oil. [R]28D þ 6.8 (c
0.7, CHCl3); IR (CHCl3) 2986, 2929, 2857,2113, 1458, 1228 cm-1; 1H
NMR (300 MHz, CDCl3) δ 4.79 (dd, J = 5.3, 2.3 Hz, 1H), 3.89 (dd, J = 5.3,
8.3 Hz, 1H), 3.59-3.52 (m, 1H), 3.35 (s, 3H), 2.46 (d, J = 2.3 Hz, 1H),
1.81-1.67 (m, 1H), 1.63-1.52 (m, 1H), 1.50 (s, 3H), 1.48-1.33 (m, 4H),
1.32 (s, 3H), 1.31-1.23 (m, 6H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 110.3, 81.0, 79.7, 78.5, 75.2, 68.8, 57.4, 31.8, 30.5, 29.9,
29.2, 27.5, 26.0, 23.9, 22.6, 14.0; MS (ESI) m/z 291 [M þ Na]þ; HRMS
(ESI) m/z calcd for C16H28O3Na 291.1931, found 291.1918.
(6) Yadav, J. S.; Reddy, P. M. K.; Reddy, P. V. Tetrahedron Lett. 2007,
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G. J.; Liepold, B.; Muller, S. J.; Bestmann, H. J. Synthesis 2004, 59–62.
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(12) A significant amount of byproduct was formed. On the basis of
1H NMR, we came to the conclusion that we end up with a byproduct
tetrahydrofuran structure having an ene yne bond along with the desired
protected methoxy ether in minor amounts.
C-10 Epimer (-)-Oploxyne B (6). Trifluoroacetic acid (0.07 mL)
was added to a solution of compound 32 (55 mg, 0.12 mmol) in CH2Cl2
(10 mL) at 0 °C and the solution was stirred for 36 h at room temperature.
The reaction mixture was concentrated under reduced pressure, and the
resulting residue was purified by column chromatography on silica gel (60-
120 mesh, 30% EtOAc/hexane) to afford compound 6 (31.0 mg, 86%
yield) as a semi solid. [R]30D þ6.3 (c 2.2, CHCl3); IR (CHCl3) 3453, 2955,
2924, 2852, 2253, 2152, 2064, 1247 cm-1; MS (ESI) m/z 333 [M þ Na]þ;
HRMS (ESI) m/z calcd for C18H30O4Na 333.2036, found 333.2034.
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’ ASSOCIATED CONTENT
S
Supporting Information. Biological experimental de-
b
tails, screening data, and 1H NMR and 13C NMR spectra of all
the new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: yadavpub@iict.res.in and kalivendi@iict.res.in. Phone:
þ914027193030 and þ914027191814. Fax: þ914027160387.
’ ACKNOWLEDGMENT
B.K.S. and A.S.R. thank CSIR, New Delhi and J.R.V. thanks
ICMR, New Delhi for financial assistance in the form of fellowships.
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