A convergent approach for the total synthesis of the α-glucosidase inhibitor (-)-panaxjapyne-C

Article abstract of DOI:10.1016/j.tetasy.2013.09.017

The stereoselective total synthesis of (-)-panaxjapyne-C was accomplished in a convergent fashion. The synthesis utilizes the readily available enantiomers l-(+)-diethyltartrate and d-(-)-diethyltartrate and involves a Cadiot-Chodkiewicz coupling reaction, and an Ohira-Bestmann reaction as the key steps.

Full text of DOI:10.1016/j.tetasy.2013.09.017

Tetrahedron: Asymmetry 24 (2013) 1524–1530
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A convergent approach for the total synthesis of the
a-glucosidase
inhibitor (ꢀ)-panaxjapyne-C
A. Sathish Reddy, P. Gangadhar, P. Srihari
⇑
Division of Natural Products Chemistry, GCL 1st Floor, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective total synthesis of (ꢀ)-panaxjapyne-C was accomplished in a convergent fashion. The
Received 30 August 2013
Accepted 19 September 2013
Available online 29 October 2013
synthesis utilizes the readily available enantiomers
L
-(+)-diethyltartrate and
D
-(ꢀ)-diethyltartrate and
involves a Cadiot–Chodkiewicz coupling reaction, and an Ohira–Bestmann reaction as the key steps.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
with the control drug acarbose.2 The studies also indicated that the
hydroxyl moieties at C-9 and C-10 and the terminal vinylic group
Polyacetylene compounds continue to attract significant atten-
tion because of their wide range of biological properties such as
cytotoxic, anti-platelet effect, antitumor, anti-inflammatory, anti-
microbial, antiviral, RNA-cleaving, sedative, and enzyme-inhibitory
activities.1 Recent investigations on the extracts from the roots of
Panax japonicus C. A. Meyer var. major resulted in an active fraction
are responsible for decreasing the a-glucosidase inhibitory activity.
Since several diacetylene polyol molecules display a wide range
of biological activities, we became interested in the synthesis of
these diacetylene triol molecules to make them available for further
biological screening. Our recent studies on the synthesis of the
diacetylene tetrol molecules oploxynes A and B (Fig. 1) led us to
revise the absolute stereochemistry of oploxyne B and showed that
both (+)-oploxyne A and (ꢀ)-oploxyne-B displayed cytotoxic activ-
displaying inhibitory activity against baker’s yeast
a-glucosidase
with an IC50 value of 1.02 mg/mL. Further characterizations of
the active fraction resulted in the isolation of three new diacety-
lene triol molecules; panaxjapynes A–C (Fig. 1).2 The structures
of these compounds were elucidated by chemical and spectro-
scopic methods in a relative fashion.2,3 Panaxjapyne A displayed
a higher inhibitory effect than panaxjapyne C and both of these
compounds displayed a significant inhibitory effect in comparison
ity against a human neuroblastoma cell line with an IC50 value 7
and 12 M against the reference sample doxorubicin, which
displayed an IC50 value of 9
lM
l
l
M.4 In continuation of our studies on
the synthesis of diacetylene containing natural products,4,5 we here-
in report the total synthesis of panaxjapyne C utilizing a convergent
approach starting from both enantiomers of diethyl tartrate.
OH
OH
6
5
5
OH
(+)-panaxjapyne A
OH
1
OH
2
(-)-panaxjapyne B
OH
(+)-panaxjapyne C
OH
OH
OMe
OMe OH
6
O
6
6
OH
(-)-oploxyne B
OH
(+)-oploxyne B
5
(+)-oploxyne A
6
4
OH
OH
OH
Figure 1. Examples of diacetylene polyols.
⇑
Corresponding author. Tel.: +91 4027191815; fax: +91 4027160512.
E-mail address: srihari@iict.res.in (P. Srihari).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.09.017

A. Sathish Reddy et al. / Tetrahedron: Asymmetry 24 (2013) 1524–1530
1525
The synthesis began with the oxidation of mono silylated alcohol
12 synthesized from -(+)-diethyltartrate in three transformations,
2. Results and discussion
L
that is, acetonide protection, LiAlH4 reduction, and TBDPS protec-
tion6 to yield the aldehyde, which upon subsequent Wittig reaction
with benzyloxy-n-pentyltriphenyl phosphonium bromide in the
presence of n-BuLi afforded the Wittig product 15 in good yield.
Compound 15 was subjected to one-pot debenzylation and olefin
reduction using Pd(OH)2 to afford alcohol 11. The IBX oxidation7 of
11 followed by treatment with methyl triphenylphosphonium bro-
mide in the presence of t-BuOK afforded olefin 16 in 90% yield. Cleav-
age of silyl ether 16 with TBAF provided alcohol 17, which was
converted into the triflate and then coupled to trimethylsilyl acety-
lene to provide 10. The silver nitrate catalyzed bromination of com-
pound 10 using N-bromosuccinamide produced bromoalkyne 8, the
key fragment with the desired stereochemistry (Scheme 2).
We envisioned that panaxjapyne-C could be obtained from pre-
cursor 7 by deprotection of the PMB and acetonide moieties. The
precursor 7 could in turn be obtained by a coupling reaction be-
tween two key fragments, the bromoalkyne 8 and the free terminal
alkyne
9 under Cadiot–Chodkiewicz conditions (Scheme 1).
Compound 8 can be prepared from compound 10 via silver nitrate
catalyzed bromination. Compound 10 in turn can be synthesized
from L-(+)-diethyltartrate after sequential manipulations through
12 and 11. Alkyne 9 could be prepared from compound 13 via an
oxidation followed by Ohira–Bestmann homologation reaction.
Compound 13 was in turn obtained from 14 in five steps; base
mediated reductive elimination reaction, olefin reduction, TBDPS
deprotection, acetal formation, and regioselective acetal opening
to obtain the primary free alcohol. Compound 14 was easily
The synthesis of the other key fragment 9 is shown in Scheme 3.
Accordingly, commercially available
D
-(ꢀ)-diethyltartrate was
accessed from commercially available
D-(ꢀ)-diethyltartrate.
O
O
5
O
3
5
Br
O
OPMB
OPMB
7
8
9
O
O
O
OH
8
5
TBDPSO
OH
TBDPSO
5
TMS
O
O
O
10
11
12
O
L
-(+)-diethyltartrate
OH
OTBDPS
9
D-(-)-diethyltartrate
I
OPMB
O
14
13
Scheme 1. Retrosynthesis for panaxjapyne C.
O
O
OH
IBX, THF:DMSO, rt
1) 2,2-DMP, PTSA
2) LiAlH4, THF
OH
OEt
TBDPSO
EtO
BnO
P(Ph)3I
O
3
OH
O
3) NaH, TBDPSCl
(82% over three steps)
n-BuLi, THF
12
L-(+)-diethyltartrate
-78 °C-rt, 16 h, 70%
O
O
1) IBX, THF:DMSO, rt
Pd(OH)2, H2
TBDPSO
OH
TBDPSO
O
2) CH3P(Ph)3Br, tBuOK
THF, 0 °C-rt, 8 h, 90%
5
THF, 30 h, 98%
BnO
O
O
11
15
Tf2O, Et3N, CH2Cl2
-78 °C - 30 m
O
TBAF, THF
TBDPSO
HO
5
5
0 °C-rt, 4 h
90%
n-BuLi,
TMS
O
O
THF, -78 °C, 4 h
16
17
70% (for two steps)
O
O
NBS, AgNO3
5
5
acetone, 0 °C- 1 h
80%
Br
O
TMS
O
8
10
Scheme 2. Synthesis of bromoalkyne 8.

1526
A. Sathish Reddy et al. / Tetrahedron: Asymmetry 24 (2013) 1524–1530
O
O
OH
1) 2,2-DMP, PTSA
2) LAH, THF
O
TPP, I2, imidazole
OTBDPS
OEt
OTBDPS
I
EtO
HO
THF, -10 °C - rt
2 h, 90%
3) NaH, TBDPSCl
O
OH
O
O
18
(81% over three steps)
14
OH
22
D-(-)-Diethyltartrate
OH
OH
TBAF, THF
Ni(OAc)2, H2
n-BuLi, THF
OTBDPS
OH
OTBDPS
0 °C- rt, 6 h
95%
-78 °C, 3 h, 80%
NaBH4, ethanol
3 h, 98%
21
19
O
1) MeO(C6H4)CH(OMe)2
OTBDPS
CSA, CH2Cl2
OPMB
OH
1) IBX, THF:DMSO, rt
reflux, 24 h
20
2) X, K2CO3, MeOH
0 °C - rt, 8 h
2) DIBAL-H, CH2Cl2
OPMB
13
9
O
O
-78 °C, 3 h, 80%
(over two steps)
OMe
P
50% over two steps
X=
OMe
N2
Scheme 3. Synthesis of alkyne 9.
converted into alcohol 18 in three steps following standard litera-
ture protocols.6 The mono protected alcohol 18 was converted into
the corresponding iodide8 14 using triphenylphosphine, I2, and
imidazole and subjected to an elimination reaction by treatment
with n-BuLi (2 equiv) at ꢀ78 °C to afford allylic alcohol 19 in 80%
yield.9 Our initial attempts to reduce the double bond in 19 using
Pd/C or Pd(OH)2 were unsuccessful and led to the formation of
undesired ethyl ketone10 20 without the formation of the desired
saturated product 21. However, this problem was successfully
overcome with Ni(OAc)2/NaBH4 to provide 21 in 98% yield.11 Our
initial attempts to protect the secondary alcohol with MPMBr
ended up with a mixture of spots leading to a low yield of the de-
sired product12 which had to be subsequently subjected to silyl
deprotection. Alternatively, compound 18 was first treated with
TBAF to provide diol 22. Diol 22 was then protected with anisalde-
hyde dimethyl acetal in the presence of a catalytic amount of
camphor sulfonic acid and subjected to regioselective ring opening
reaction with DIBAL-H13 to furnish the free primary alcohol 13 in
good yields. Compound 13 was oxidized to the aldehyde and sub-
jected to an Ohira–Bestmann homologation reaction14 to finish the
synthesis of alkyne 9.
The 1H NMR and 13C NMR spectra of the synthesized product were
in full agreement with those of the reported natural product.2
However, the specific rotation of our synthetic product was ob-
served to be ½a 2D5
¼ ꢀ16:0 (c 0.1, MeOH), whereas the specific rota-
ꢁ
tion for the natural product from isolation studies2 and the earlier
synthesis3 was found to be ½a 2D5
¼ þ20:6 (c 0.02, MeOH) and
ꢁ
½
a 2D5
ꢁ
¼ þ17:3 (c 0.2, MeOH), respectively. However, based on the
outcome of our synthesis, we can herein unequivocally assign the
absolute structure of natural product as 3a, the enantiomer of our
synthesized product 3.
3. Conclusion
In conclusion the total synthesis of (ꢀ)-panaxjapyne-C has been
achieved in a convergent fashion utilizing both enantiomers of
diethyltartrate as chirons. Once again, the Cadiot–Chodkiewicz
reaction has been found to be pivotal in generating diacetylene
functionality. The synthesis of other members of the panaxjapynes
is currently in progress in our laboratory.
With both intermediates, alkyne 9 and bromo alkyne 8 in hand,
we proceeded to couple them under Cadiot–Chodkiewicz coupling
conditions.15 Compounds 9 and 8 were coupled using CuCl,
n-BuNH2 to afford precursor compound 7 in good yield. Finally,
the one pot deprotection of PMB as well as the acetonide moiety
in compound 7 with TFA afforded panaxjapyne-C 3 (Scheme 4).
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded in CDCl3 or
mixture of CDCl3 and CCl4 as solvent on 300 MHz or 500 MHz
O
O
CuCl, n-BuNH2, Et2O
NH2OH.HCl, 30 min
5
O
5
Br
O
OPMB
0 °C-rt, 80%
7
9
8
OPMB
OH
OH
TFA, CH2Cl2
5
5
OH
OH
0 °C-rt, 30 h, 80%
ent-3 3a
OH
3
OH
synthesized structure of panaxjapyne C
revised structure of panaxjapyne C
[α]D25 = +20.6 (c 0.02, MeOH)
[α]D25 = -16.0 (c 0.1, MeOH)
Scheme 4. Synthesis of (ꢀ)-panaxjapyne C.

A. Sathish Reddy et al. / Tetrahedron: Asymmetry 24 (2013) 1524–1530
1527
spectrometer at ambient temperature. The coupling constants J are
given in Hz. The chemical shifts are reported in ppm on a scale
downfield from TMS as the internal standard and signal patterns
are indicated as follows: s = singlet, d = doublet, dd = doublet of
doublet, dt = doublet of triplet, t = triplet, q = quartet, qd = quartet
of doublet, m = multiplet, br = broad. FTIR spectra were recorded
on KBr pellets CHCl3/neat (as mentioned) and reported in wave
numbers (cmꢀ1). For low (MS) and high (HRMS) resolution, m/z
ratios are reported as values in atomic mass units. Mass analysis
was done in ESI mode. Optical rotations were measured on Anton
Paar digital polarimeter and the values given are specific rotations.
All reagents were of reagent grade and used without further
purification unless specified otherwise. Solvents for reactions were
distilled prior to use: THF was distilled from Na and benzophenone
ketyl; MeOH from Mg and I2; CH2Cl2 from CaH2. All air- or mois-
ture-sensitive reactions were conducted under a nitrogen or argon
atmosphere in flame-dried or oven-dried glassware with magnetic
stirring. Reactions were monitored by thin-layer chromatography
carried out on silica plates (silica gel 60 F254, Merck) using
UV-light, iodine and anisaldehyde for visualization. Column chro-
matography was carried out using silica gel (60–120 mesh) packed
in glass columns. Technical grade ethyl acetate and petroleum
ether used for column chromatography were distilled prior to use.
filtered over Celite and concentrated under reduced pressure. The
resulting crude product was purified through column chromatog-
raphy to afford compound 11 (4.12 g, 8.76 mmol, 98%) as a color-
less oil. ½a 2D5
ꢁ
¼ ꢀ4:2 (c 1.0, CHCl3). IR [NEAT]: 3451, 2930, 2858,
1633, 1374, 1107, 701, 610, 502 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
d 7.69–7.64 (m, 4H), 7.45–7.34 (m, 6H), 3.98–3.92 (m, 1H), 3.78–
3.68 (m, 3H), 3.63 (t, J = 6.4 Hz, 2H), 1.67–1.45 (m, 5H), 1.43–1.18
(m, 5H), 1.40 (s, 3H), 1.37 (s, 3H), 1.05 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3): d 135.6, 133.2, 133.1, 129.7, 129.6, 127.6, 108.4,
81.1, 78.4, 64.1, 62.8, 33.2, 32.6, 29.4, 27.4, 26.9, 26.8, 26.0, 25.5,
19.2 ppm. MS(ESI): m/z 493 [M+Na]+. HRMS(ESI) m/z calculated
for C28H42O4NaSi 493.27446, found: 493.27328.
4.1.3. tert-Butyl(((4S,5S)-5-(hept-6-en-1-yl)-2,2-dimethyl-1,3-
dioxolan-4-yl)methoxy) diphenylsilane 16
Compound 11 (4.0 g, 8.51 mmol) was dissolved in a solvent
mixture of THF (30 mL) and DMSO (30 mL). To this, IBX was
(3.57 g, 12.76 mmol) added in one portion and the reaction mix-
ture was stirred for 5 h at room temperature. The reaction mixture
was diluted with ice cold water (30 mL) and extracted with CH2Cl2
(5 ꢂ 30 mL). The combined organic layers were washed with satu-
rated NaHCO3 (100 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure to yield the crude aldehyde, which
was directly used for the next step without further purification.
Dry THF (50 mL) was added to a mixture of methyl triphenyl phos-
phonium bromide (7.62 g, 21.36 mmol) and t-BuOK (2.2 g,
19.65 mmol) at 0 °C for 20 min and then stirred for 1 h at room
temperature. During this time, the reaction color changed from
colorless to yellow. Again the reaction was cooled to 0 °C and to
this was added dropwise the aldehyde obtained above and then al-
lowed to stir for 12 h at room temperature. The reaction mixture
was quenched with aq saturated ammonium chloride solution
(10 mL) at 0 °C. The reaction mixture was extracted with ethyl ace-
tate (4 ꢂ 30 mL), dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The resulting crude was purified through
column chromatography to afford compound 16 (3.56 g,
4.1.1. (((4S,5S)-5-((Z)-6-(Benzyloxy)hex-1-en-1-yl)-2,2-dimethyl-
1,3-dioxolan-4-yl)methoxy)(tert-butyl)diphenylsilane 15
Compound 12 (10.0 g, 25 mmol) was dissolved in a solvent mix-
ture of THF (60 mL) and DMSO (60 mL). To this IBX was (10.5 g,
37.5 mmol) added in one portion and stirred for 2 h at room tem-
perature. The reaction mixture was diluted with ice cold water
and extracted with CH2Cl2 (5 ꢂ 40 mL). The combined organic
layers were washed with saturated NaHCO3 (150 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure to
yield the crude aldehyde, which was directly used for next step
without further purification. Benzyloxy-n-pentyltriphenyl phos-
phonium bromide (20.27 g, 37.6 mmol) was dissolved in dry THF
(150 mL) and cooled to ꢀ78 °C. To this n-BuLi (20.41 mL,
32.66 mmol) was added dropwise and stirred for 3 h at ꢀ78 °C.
During this time, the reaction color changed from colorless to brick
red. To this, the crude aldehyde obtained above (dissolved in 30 mL
dry THF) was added dropwise and stirred overnight. After the addi-
tion of aldehyde the reaction color changed from brick red to color-
less. The reaction mixture was quenched with aq saturated
ammonium chloride solution (20 mL) at 0 °C. The reaction mixture
was extracted with ethyl acetate (5 ꢂ 30 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The resulting
crude was purified through column chromatography to afford com-
7.63 mmol, 90%) as a colorless oil. ½a D25
¼ ꢀ9:85 (c 5.0, CHCl3). IR
ꢁ
[NEAT]: 3071, 2931, 2859, 1639, 1465, 1372, 1109, 1082, 822,
703, 608, 505 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.70–7.65 (m,
.
4H), 7.45–7.35 (m, 6H), 5.87–5.74 (m, 1H), 5.03–4.91 (m, 2H),
3.99–3.92 (m, 1H), 3.76–3.68 (m, 3H), 2.08–2.01 (m, 2H), 1.60–
1.46 (m, 3H), 1.44–1.25 (m, 5H), 1.40 (s, 3H), 1.37 (s, 3H), 1.06 (s,
9H) ppm. 13C NMR, (75 MHz, CDCl3): d 138.9, 135.6, 133.2, 133.1,
129.7, 129.6, 127.7, 114.2, 108.3, 81.1, 78.4, 64.1, 33.7, 33.3, 29.1,
28.7, 27.4, 27.0, 26.8, 25.9, 19.2 ppm. MS(ESI): m/z 489 [M+Na]+.
HRMS(ESI) m/z calculated for C29H42O3NaSi 489.27954, found:
489.27781.
pound 15 (9.81 g, 17.58 mmol, 70%) as a colorless oil. ½a D25
¼ þ12:67
ꢁ
(c 0.6, CHCl3). IR [NEAT]: 3068, 2931, 2858, 1656, 1056, 1428, 1217,
4.1.4. ((4S,5S)-5-(Hept-6-en-1-yl)-2,2-dimethyl-1,3-dioxolan-4-
yl)methanol 17
1109, 1070, 822, 702, 606, 504 cmꢀ1 1H NMR, (300 MHz, CDCl3): d
.
7.73–7.65 (m, 4H), 7.44–7.35 (m, 11H), 5.68–5.60 (m, 1H), 5.42–
5.35 (m, 1H), 4.86 (t, J = 8.7 Hz, 1H), 4.47 (s, 2H), 3.83 (dd, J = 11.1,
3.0 Hz, 1H), 3.74–3.63 (m, 2H), 3.42 (t, J = 6.4 Hz, 2H), 2.29–2.17
(m, 1H), 2.11–1.97 (m, 1H), 1.68–1.50 (m, 3H),1.45 (s, 3H), 1.44 (s,
3H), 1.50–1.36 (m, 1H), 1.07 (s, 4H), 1.05 (s, 5H) ppm. 13C NMR
(125 MHz, CDCl3): d 138.5, 135.7, 135.6, 135.5, 135.2, 134.8,
133.3, 133.1, 129.7, 129.6, 129.5, 128.3, 127.6, 127.4, 126.7, 108.8,
81.7, 72.8, 70.1, 62.3, 29.6, 27.6, 27.3, 27.0, 26.8, 26.5, 26.2, 19.2,
19.0 ppm. MS(ESI): m/z 581 [M+Na]+. HRMS(ESI) m/z calculated
for C35H46O4NaSi 581.30576, found: 581.30521.
Compound 16 (3.5 g, 7.51 mmol) was dissolved in anhydrous
THF (30 mL) and cooled to 0 °C. To this tetra n-butyl ammonium
fluoride (12.76 mmol, 12.76 mL, 1 M solution in THF) was added
dropwise and stirred for 3 h. The reaction was quenched with aq.
saturated ammonium chloride solution (20 mL) at 0 °C and
extracted with ethyl acetate (3 ꢂ 30 mL). The organic layer was
separated and dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The resulting crude product was purified
through column chromatography to afford compound 17 (1.71 g,
7.5 mmol, 90%) as a colorless oil. ½a D25
¼ ꢀ22:0 (c 2.7, CHCl3). IR
ꢁ
[NEAT]: 3450, 3075, 2930, 2859, 1640, 1457, 1374, 1102, 910,
4.1.2. 6-((4S,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)hexan-1-ol 11
To compound 15 (5.0 g, 8.96 mmol) dissolved in anhydrous THF
(30 mL) was added Pd(OH)2 (100 mg) and the reaction mixture was
stirred under an H2 atmosphere for 24 h. The reaction mixture was
759, 516 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.87–5.73 (m, 1H),
.
5.03–4.89 (m, 2H), 3.91–3.70 (m, 3H), 3.66–3.57 (m, 1H), 2.08–
2.01 (m, 2H), 1.75 (br s, 1H), 1.62–1.45 (m, 3H), 1.42–1.23 (m,
5H), 1.41 (s, 3H), 1.40 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d
138.9, 114.3, 108.5, 81.5, 76.8, 62.0, 33.6, 33.0, 29.1, 28.7, 27.3,

1528
A. Sathish Reddy et al. / Tetrahedron: Asymmetry 24 (2013) 1524–1530
27.0, 25.8 ppm. MS(ESI): m/z 229 [M+H]+. HRMS(ESI) m/z calcu-
lated for C13H25O3 229.17982, found: 229.17982.
0.18 mmol, 80%) as a colorless oil. ½a D25
¼ ꢀ154:5 (c 1.5, CHCl3).
ꢁ
IR [NEAT]: 2932, 2970, 2859, 1612, 1460, 1513, 1247, 1064, 821,
766, 517 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.31–7.28 (m, 2H),
.
4.1.5. (3-((4S,5S)-5-(Hept-6-en-1-yl)-2,2-dimethyl-1,3-dioxolan-
4-yl)prop-1-yn-1-yl) trimethylsilane 10
6.90–6.85 (m, 2H), 5.87–5.73 (m, 1H), 5.03–4.91 (m, 2H), 4.76–
4.69 (m, 1H), 4.46–4.39 (m, 1H), 4.08–4.00 (m, 1H), 3.85–3.71
(m, 2H), 3.81 (s, 3H), 2.61 (d, J = 5.3 Hz, 2H), 2.08–2.01 (m, 2H),
1.82–1.69 (m, 2H), 1.65–1.47 (m, 3H), 1.45–1.32 (m, 5H), 1.41 (s,
6H), 1.03–0.95 (m, 3H) ppm. 13C NMR (125 MHz, CDCl3): d 159.2,
138.9, 129.7, 129.6, 114.2, 113.7, 108.7, 80.4, 78.4, 78.1, 75.8,
70.4, 70.3, 69.8, 66.8, 55.2, 33.6, 32.8, 29.1, 28.7 (2C), 27.4, 27.0,
25.7, 23.5, 9.6 ppm. MS(ESI): m/z 461 [M+Na]+. HRMS(ESI) m/z cal-
culated for C28H38O4Na 461.26623, found: 461.26483.
To alcohol 17 (0.5 g, 2.19 mmol) dissolved in dry CH2Cl2 (15 mL)
was added triethylamine (0.66 g, 6.57 mmol) at room temperature
and stirred for 5 min. The reaction mixture was cooled to ꢀ78 °C
and trifluoromethane sulfonic anhydride (0.74 g, 2.63 mmol) was
added and stirred for an additional 30 min. The reaction mixture
was quenched with aq saturated ammonium chloride solution
(4 ml) at 0 °C, and extracted with CH2Cl2 (4 ꢂ 5 mL). The organic
layer was separated, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude triflate was puri-
fied through short pad of silica gel and used without further
characterization.
4.1.8. Panaxjapyne-C 3
Compound 7 (0.04 g, 0.09 mmol) was dissolved in 8 mL of dry
CH2Cl2 and cooled to 0 °C. To this, trifluoroacetic acid (0.1 mL)
was added and stirred for 30 h at room temperature. The solvent
was evaporated under reduced pressure and the resulting crude
was purified through column chromatography to afford compound
Next, n-BuLi (1.37 mL, 1.6 M, 2.19 mmol) was added to a solu-
tion of trimethylsilyl acetylene (0.21 g, 2.19 mmol) in dry THF
(7 mL) at 0 °C. The reaction mixture was stirred for 3 h at 0 °C
and cooled to ꢀ78 °C. To this, HMPA (2.35 g, 13.15 mmol) and tri-
flate in dry THF (5 mL) were added and stirred for 3–4 h at ꢀ78 °C.
The reaction mixture was quenched with aq saturated ammonium
chloride (5 mL) at 0 °C, and extracted with ethyl acetate (4 ꢂ 5 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting crude product was purified through column
chromatography to afford compound 10 (0.47 g, 1.52 mmol, 70%)
3 (20 mg, 0.07 mmol, 80%) as colorless oil. ½a D25
¼ ꢀ16:0 (c 0.1,
ꢁ
MeOH). Lit.3
½
a 2D5
ꢁ
¼ ꢀ20:6 (c 0.02, MeOH) IR [NEAT]: 3350, 2931,
2856, 1780, 1639, 1611, 1506, 13336, 1247, 1035, 969, 811, 756,
665 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.87–5.74 (m, 1H), 5.03–
.
4.92 (m, 2H), 4.35 (t, J = 6.4 Hz, 1H), 3.78–3.58 (m, 2H), 2.56 (d,
J = 5.5 Hz, 2H), 2.31 (br s, 2H), 2.08–2.02 (m, 2H), 1.78–1.69 (m,
2H), 1.58–1.20 (m, 8H), 1.01 (t, J = 7.4 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d 138.9, 114.3, 77.3, 77.2, 73.1, 72.1, 69.5, 66.7,
64.0, 33.7, 33.5, 30.7, 29.0, 28.8, 25.4, 25.0, 9.3 ppm. MS(ESI): m/z
301 [M+Na]+. HRMS(ESI) m/z calculated for C17H26O3Na
301.17742, found: 301.17783.
as a colorless oil. ½a D25
ꢁ
¼ ꢀ1:9 (c 1.5, CHCl3). IR [NEAT]: 2923,
2854, 1633, 1436, 1116, 542 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d
5.87–5.74 (m, 1H), 5.02–4.91(m, 2H), 3.92–3.59 (m, 2H), 2.64–
2.47 (m, 2H), 2.08–2.02 (m, 2H), 1.74–1.45 (m, 3H), 1.44–1.25
(m, 5H), 1.39 (s, 6H), 0.15 (s, 9H) ppm. 13C NMR, (75 MHz, CDCl3):
d 139.0, 114.2, 108.2, 80.6, 80.3, 79.4, 78.1, 33.7, 33.1, 29.2, 28.8,
27.5, 27.0, 25.9, 24.0, 0.03 ppm. MS(ESI): m/z 331 [M+Na]+.
4.1.9. tert-Butyl (((4S,5R)-5-(iodomethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)methoxy)diphenylsilane 14
Into a 250 mL round bottom flask, compound 18 (10.0 g,
25 mmol), triphenylphosphine (13.1 g, 50 mmol), and imidazole
(5.1 g, 75 mmol) were added. To this, dry THF (120 mL) was added
and cooled to ꢀ10 °C. Next, I2 (14.0 g, 55 mmol) was added in por-
tion wise and then the ice bath was removed and the reaction was
stirred for 2 h at room temperature. The solvent was removed
through rotavapour and the resulting crude was purified by col-
umn chromatography to afford compound 14 (11.47 g,
4.1.6. (4S,5S)-4-(3-Bromoprop-2-yn-1-yl)-5-(hept-6-en-1-yl)-
2,2-dimethyl-1,3-dioxolane 8
Compound 10 (0.2 g, 0.64 mmol) was dissolved in dry acetone
(10 mL) and cooled to 0 °C. To this N-bromosuccinamide (0.14 g,
0.77 mmol) and a catalytic amount of silver nitrate were added
successively and stirred for 1 h at 0 °C. The solvent was evaporated
under reduced pressure and the resulting residue was diluted with
ethyl acetate and washed with brine solution. The combined or-
ganic layers were dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The resulting crude was purified through
column chromatography to afford compound 8 (0.16 g, 0.5 mmol,
22.49 mmol, 90%) as a colorless oil. ½a D25
¼ þ6:2 (c 5.0, CHCl3). IR
ꢁ
[NEAT]: 3069, 2932, 2858, 1428, 1238, 1110, 1080, 939, 824, 703,
609, 505 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.72–7.66 (m, 4H),
.
7.46–7.33 (m, 6H), 3.99–3.93 (m, 1H), 3.89–3.74 (m, 3H), 3.41–
3.36 (m, 1H), 3.31–3.26 (m, 1H), 1.46 (s, 3H), 1.39 (s, 3H), 1.06 (s,
9H) ppm. 13C NMR (75 MHz, CDCl3): d 135.6, 135.5, 133.0, 132.8,
129.8, 129.7, 109.5, 81.1, 77.5, 64.1, 27.4, 27.3, 26.8, 19.2,
6.8 ppm. MS(ESI): m/z 533 [M+Na]+. HRMS(ESI) m/z calculated for
C23H31O3INaSi 533.09794, found: 533.09827.
80%) as a yellow oil. ½a D25
¼ ꢀ9:1 (c 1.0, CHCl3). IR [NEAT]: 3075,
ꢁ
2986, 2858, 1730, 1640, 1613, 1459, 1244, 1060, 911, 748,
514 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.88–5.74 (m, 1H), 5.03–
.
4.91 (m, 2H), 3.92–3.59 (m, 2H), 2.52 (d, J = 5.3 Hz, 2H), 2.08–
2.02 (m, 2H), 1.68–1.46 (m, 3H), 1.45–1.25 (m, 5H), 1.40 (s, 6H)
ppm. 13C NMR, (75 MHz, CDCl3): d 139.0, 114.3, 108.6, 80.4, 79.3,
78.2, 75.9, 33.7, 33.0, 29.7, 28.7, 27.4, 27.0, 25.8, 23.8 ppm.
4.1.10. (S)-1-((tert-Butyldiphenylsilyl)oxy)but-3-en-2-ol 19
Compound 14 (5.0 g, 9.8 mmol) was dissolved in 50 mL dry THF
and cooled to ꢀ78 °C. To this n-BuLi (12.25 mL, 1.6 M, 19.6 mmol)
was added and stirred for 3 h. The reaction was quenched with aq
saturated ammonium chloride solution (25 mL) and extracted with
ethyl acetate (5 ꢂ 30 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The resulting crude material was purified by column chromatogra-
phy to afford compound 19 (2.55 g, 7.8 mmol, 80%) as a colorless
4.1.7. (4S,5S)-4-(Hept-6-en-1-yl)-5-((S)-6-((4-methoxybenzyl)oxy)-
octa-2,4-diyn-1-yl)-2,2-dimethyl-1,3-dioxolane 7
At first, CuCl (1 mg) was added to 30% n-butylamine solution
(3 mL). After blue coloration occurs, few crystals of hydroxylamine
hydrochloride were added until the blue color disappeared. Next,
alkyne 9 (0.05 g, 0.24 mmol) dissolved in diethyl ether (5 mL)
was added in one portion and immediately cooled to 0 °C. The bro-
mo alkyne 8 (0.06 g, 0.19 mmol) in diethyl ether (5 mL) was added
in one portion and stirred for 30 min. The reaction mixture was ex-
tracted with diethyl ether (5 ꢂ 20 mL) and the combined organic
layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The resulting crude product was purified
through column chromatography to afford compound 7 (0.085 g,
oil. ½a 2D5
ꢁ
¼ ꢀ4:6 (c 3.2, CHCl3). IR [NEAT]: 3447, 3071, 2931, 2858,
1643, 1468, 1427, 1110, 927, 703, 613, 505 cmꢀ1
.
1H NMR
(500 MHz, CDCl3): d 7.67–7.66 (m, 4H), 7.45–7.38 (m, 6H), 5.83–
5.76 (m, 1H), 5.33–5.15 (m, 2H), 4.27–4.22 (m, 1H), 3.71–3.69
(m, 1H), 3.57–3.54 (m, 1H), 2.58 (br s, 1H), 1.07 (s, 9H) ppm. 13C
NMR (75 MHz, CDCl3): d 136.6, 135.5, 133.1, 133.0, 129.8, 127.7,

A. Sathish Reddy et al. / Tetrahedron: Asymmetry 24 (2013) 1524–1530
1529
116.4, 73.0, 67.7, 26.8, 19.2 ppm. MS(ESI): m/z 349 [M+Na]+.
HRMS(ESI) m/z calculated for C20H26O2NaSi 349.15943, found:
349.15832.
4.1.14. (S)-1-Methoxy-4-((pent-1-yn-3-yloxy)methyl)benzene 9
Compound 13 (0.2 g, 1.0 mmol) was dissolved in a solvent mix-
ture of dry THF/dry DMSO (16 mL, 1:1). To this IBX (0.4 g,
1.4 mmol) was added in one portion and stirred for 2 h at room
temperature. The reaction mixture was diluted with ice cold water
(50 mL) and extracted with CH2Cl2 (5 ꢂ 10 mL). The combined or-
ganic layers were washed with saturated NaHCO3 solution (30 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure to yield the crude aldehyde which was used directly for
the alkyne formation.
4.1.11. (S)-1-((tert-Butyldiphenylsilyl)oxy)butan-2-ol 21
Into a 50 mL double neck round bottom flask Ni(OAc)2 (0.4 g,
66 mg per mmol) in 10 mL of ethanol was added and an H2
balloon was fixed. To this, 1 M NaBH4 (1.5 mL) was added and
stirred for 10 min. To this, compound 19 (2.0 g, 6.13 mmol)
was added and stirred for 3 h. The reaction mixture was filtered
through a sintered funnel and the solvent was evaporated under
reduced pressure. The resulting crude product was purified by
column chromatography to afford compound 21 (1.96 g,
The aldehyde obtained above was dissolved in dry methanol
(5 mL). To this Ohira–Bestmann (0.28 g, 1.4 mmol) reagent in
5 mL dry methanol was added and cooled to 0 °C. K2CO3 (0.26 g,
2.0 mmol) was added and the reaction mixture was stirred for
12 h at room temperature. The reaction mixture was filtered and
the filtrate was concentrated. The resulting crude was purified by
silica gel column chromatography to afford compound 9 (0.1 g,
6.0 mmol, 98%) as a colorless oil. ½a D25
¼ þ4:2 (c 2.2, CHCl3). IR
ꢁ
[NEAT]: 3447, 3070, 2932, 2859, 1466, 1110, 772, 703, 611,
505 cmꢀ1 1H NMR (300 MHz, CDCl3):
. d 7.67–7.65 (m, 4H),
7.44–7.36 (m, 6H), 3.68 (m, 2H), 3.52–3.45 (m, 1H), 2.51 (br s,
1H), 1.49–1.41 (m, 1H), 1.32–1.25 (m, 1H), 1.06 (s, 9H), 0,90 (t,
J = 7.5 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): d 135.5, 133.2,
133.1, 129.8, 127.7, 73.3, 67.7, 26.8, 25.7, 19.2, 9.9 ppm. MS(ESI):
m/z 351 [M+Na]+. HRMS(ESI) m/z calculated for C20H28O2NaSi
351.17508, found: 351.17379.
0.5 mmol, 50%) as colorless oil. ½a D25
ꢁ
¼ ꢀ108:3 (c 1.2, CHCl3). Lit.1
½
a 2D5
ꢁ
¼ ꢀ112:2 (c 2.0, CHCl3). IR [NEAT]: 3291, 2967, 2869, 1612,
1513, 1248, 1068, 821, 644, 517 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d 7.30–7.25 (m, 2H), 6.90–6.85 (m, 2H), 4.73 (d, J = 11.3 Hz, 1H),
4.44 (d, J = 11.3 Hz, 1H), 3.99 (td, J = 6.4, 1.9 Hz, 1H), 3.80 (s, 3H),
2.45 (d, J = 2.1 Hz, 1H), 1.81–1.71 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d 159.0, 129.7, 129.3, 113.5,
82.6, 73.7, 69.8, 69.0, 54.8, 28.5, 9.3 ppm. HRMS(ESI) m/z calculated
for C13H16O2Na 227.10425, found: 227.10399.
4.1.12. (S)-Butane-1,2-diol 22
Compound 21 (1.5 g, 4.5 mmol) was dissolved in 20 mL of dry
THF and cooled to 0 °C. To this, tetra n-butylammonium fluoride
(7.7 mL, 7.7 mmol, 1 M solution THF) was added and stirred for
4–6 h at room temperature. The reaction mixture was quenched
with saturated ammonium chloride solution (10 mL) and extracted
with ethyl acetate (4 ꢂ 20 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The resulting crude was purified through column chro-
matography to afford compound 22 (0.26 g, 4.3 mmol, 95%) as a
Acknowledgments
A.S.R. and P.G. thanks CSIR, New Delhi for financial support as
part of XII Five Year plan programme under title ORIGIN (CSC-
0108). A.S.R. thanks CSIR, New Delhi for financial assistance in
the form of a fellowship.
colorless oil. ½a D25
ꢁ
¼ þ2:5 (c 1.0, CHCl3). IR [NEAT]: 3410, 2966,
2880, 1401, 1059, 989, 768, 540 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
References
d 3.67–3.58 (m, 2H), 3.46–3.40 (m, 1H), 3.12 (br s, 2H), 1.51–1.40
(m, 2H), 1.00 (t, J = 7.5 Hz, 3H) ppm. 13C NMR, 75 MHz, CDCl3: d
73.7, 66.5, 26.0, 9.9 ppm.
1. (a) Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006, 45, 1034–
1057; (b) Jung, H. J.; Min, B. S.; Park, J. Y.; Kim, Y. H.; Lee, H. K.; Bae, K. H. J. Nat.
Prod. 2002, 65, 897–901; (c) Bernart, M. W.; Cardelina, J. H., II; Balaschak, M. S.;
Alexander, M. R.; Shoemaker, R. H.; Boyd, M. R. J. Nat. Prod. 1996, 59, 748–753;
(d) Teng, C. M.; Kuo, S. C.; Ko, F. N.; Lee, J. C.; Lee, L. G.; Chen, S. C.; Huang, T. F.
Biochem. Biophys. Acta 1989, 990, 315–320; (e) Seo, Y. W.; Cho, K. W.; Rho, J. R.;
Shin, J. H.; Sim, C. J. Tetrahedron 1998, 54, 447–462; (f) Kobaisy, M.;
Abramowski, Z.; Lermer, L.; Saxena, G.; Hancock, R. E. W.; Towers, G. H. N. J.
Nat. Prod. 1997, 60, 1210–1213; (g) Bernart, M. W.; Cardellina, J. H.; Balaschak,
M. S.; Alexander, M. R.; Shoemaker, R. H.; Boyd, M. R. J. Nat. Prod. 1996, 59, 748–
753; (h) Wang, Y.; Toyota, M.; Krause, F.; Hamburger, M.; Hostettmann, K.
Phytochemistry 1990, 29, 3101–3105; (i) Kobayashi, M.; Mahmud, T.; Tajima,
H.; Wang, W.; Aoki, S.; Naka- gawa, S.; Mayumi, T.; Kitagawa, I. Chem. Pharm.
Bull. 1996, 44, 720–724; (j) Issacs, S.; Kashmann, Y.; Loya, S.; Hizi, A.; Loya, Y.
Tetrahedron 1993, 49, 10435–10438; (k) Cimino, G.; De Giulio, S.; De Rosa, S.; Di
Marzo, V. J. Nat. Prod. 1990, 53, 345–353.
2. Chan, H. H.; Sun, H. D.; Vijaya Bhaskar Reddy, M.; Wu, T.-S. Phytochemistry
2010, 71, 1360–1364.
3. Thakur, P.; Kumaraswamy, B.; Raji Reddy, G.; Bandichhor, R.; Mukkanti, K.
Tetrahedron Lett. 2012, 53, 3703–3705.
4. (a) Yadav, J. S.; Kumaraswamy, B.; Sathish Reddy, A.; Srihari, P.; Janakiram, R.
V.; Kalivendi, S. V. J. Org. Chem. 2011, 76, 2568–2576; (b) Srihari, P.; Sathish
Reddy, A.; Yadav, J. S.; Yedlapudi, D.; Kalivendi, V. S. Tetrahedron Lett. 2013, 54,
5616–5618.
5. Sabitha, G.; Srinivas Reddy, Ch.; Srihari, P.; Yadav, J. S. Synthesis 2003, 2699–
2704.
4.1.13. (S)-2-((4-Methoxybenzyl)oxy)butan-1-ol 13
Into a 50 mL round bottom flask, diol 22 (0.2 g, 3.3 mmol), CSA
(catalytic amount), anisaldehyde dimethyl acetal (0.91 g,
5.0 mmol) and CH2Cl2 (12 mL) were added and refluxed for 20 h.
The reaction mixture was quenched with triethylamine (2 mL).
The solvent was removed with a rotary evaporator and the result-
ing crude acetal was directly utilized for the next reaction without
further purification. The crude acetal (0.5 g) was dissolved in 15 mL
of dry CH2Cl2 and cooled to ꢀ78 °C. To this, diisobutyaluminium
hydride (2.6 mL, 3.6 mmol, and 1.4 M solution in toluene) was
added and stirred for 2 h at ꢀ30 °C. The reaction mixture was
quenched with saturated sodium potassium tartrate solution and
stirred for 6 h at room temperature. The reaction mixture was ex-
tracted with CH2Cl2 (3 ꢂ 10 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The resulting crude was purified by column chromatog-
raphy to afford compound 13 (0.38 g, 1.8 mmol, 80%) as a colorless
oil. ½a 2D5
¼ 6:4 (c 1.5, CHCl3). IR [NEAT]: 3426, 2926, 2875, 1612,
ꢁ
6. (a) Feit, P. W. J. Med. Chem. 1964, 7, 14–17; (b) Toda, F.; Tanaka, K. Tetrahedron
Lett. 1988, 29, 551–554; (c) Roulland, E. Angew. Chem., Int. Ed. 2008, 47, 3762–
3765.
7. (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019–8022; (b)
Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60,
7272–7276.
1586, 1513, 1247, 1034, 820, 516 cmꢀ1. 1H NMR, (300 MHz, CDCl3):
d 7.30–7.26 (m, 2H), 6.90–6.87 (m, 2H), 4.56 (d, J = 11.2 Hz, 1H),
4.46 (d, J = 11.2 Hz, 1H), 3.80 (s, 3H), 3.80–3.72 (m, 1H), 3.70–
3.65 (m, 1H), 3.55–3.39 (m, 1H), 1.97 (br s, 1H), 1.72–1.39
(m, 2H), 0.92 (t, J = 7.5 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3):
8. Garegg, J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980, 2866–2869.
9. (a) Marshall, J. A.; Sedrani, R. J. Org. Chem. 1991, 56, 5496–5498; (b) Paquette, L.
A.; Dong, S.; Parker, G. D. J. Org. Chem. 2007, 72, 7135–7147.
d
159.2, 129.3, 128.6, 113.9, 80.7, 71.1, 64.9, 55.2, 23.5,
9.6 ppm. MS(ESI): m/z 233 [M+Na]+. HRMS(ESI) m/z calculated for
12H18O3Na 233.11482, found: 233.11446.
10. Compound 20 was characterized by 1H NMR spectroscopy.
11. Brown, C. A.; Ahuza, V. K. J. Chem. Soc., Chem. Commun. 1973, 553–554.
C

1530
A. Sathish Reddy et al. / Tetrahedron: Asymmetry 24 (2013) 1524–1530
13. Takano, S.; Akiyama, M.; Sato, S.; Ogasawar, K. Chem. Lett. 1983, 1593–1596.
14. (a) Ohira, S. Synth. Commun. 1989, 19, 561–564; (b) Muller, S.; Liepold, B.; Roth,
G. J.; Bestmann, H. J. Synlett 1996, 521–522.
12. Along with the desired product, TBDPS migrated compound was also formed.
However, the yield was too poor to proceed further.
15. Cadiot, P.; Chodkiewicz, W. Chemistry of Acetylenes In Viehe, H. G., Ed.; Marcel
Dekker: New York, 1969.
OH
OPMB
20%
OTBDPS
OPMB
PMB-Br, NaH
OTBDPS
+
OTBDPS
THF, 0 °C to rt
16 h
20%
21
+ mixture of spots