A conventional approach to the total synthesis of (-)-varitriol

Article abstract of DOI:10.1016/j.tetasy.2012.10.010

The stereoselective total synthesis of (-)-varitriol has been achieved starting from commercially available d-(-)-ribose and o-anisic acid. A Mitsunobu reaction, Julia-Kocienski olefination, and one pot reduction of both ester and iodo functionalities with superhydride are the key reactions involved in this synthesis.

Full text of DOI:10.1016/j.tetasy.2012.10.010

Tetrahedron: Asymmetry 23 (2012) 1584–1587
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A conventional approach to the total synthesis of (ꢀ)-varitriol
⇑
K. Vamshikrishna, P. Srihari
Division of Natural Products Chemistry, 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:
Received 27 September 2012
Accepted 15 October 2012
The stereoselective total synthesis of (ꢀ)-varitriol has been achieved starting from commercially avail-
able
D
-(ꢀ)-ribose and o-anisic acid. A Mitsunobu reaction, Julia–Kocienski olefination, and one pot reduc-
tion of both ester and iodo functionalities with superhydride are the key reactions involved in this
synthesis.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of (+)-varitriol and the C60-epimer;8 herein we report the
total synthesis of its enantiomer (ꢀ)-varitriol.
Natural products from marine-derived fungi show a pronounced
degree of structural diversity and have been found to display inter-
esting biological and pharmacological properties. This feature has
attracted significant interest from synthetic chemists and the phar-
maceutical industry.1 (+)-Varitriol 1, a novel low molecular weight
natural product isolated by Malmstrom et al.2 from a marine derived
strain of fungus Emericella variecolor displayed lower potency to-
ward leukemia, ovarian, and colon cell lines with GI50 values ranging
from 2.52 ꢁ 10ꢀ5 to 9.59 ꢁ 10ꢀ5 M and an increased potency toward
renal, CNS, and breast cancer cell lines with GI50 values ranging from
1.63–2.44 ꢁ 10ꢀ7 M. Since the mode of action of varitriol has not yet
been fully established,3 it is necessary to further investigate and elu-
cidate the mechanism of action. Toward the end, several chemists
have taken up the total synthesis4,5 and analogue synthesis6 of varit-
riol for further investigation. The absolute structure of (+)-varitriol
was initially determined after accomplishing the total synthesis of
its enantiomer (ꢀ)-varitriol 10 (Fig. 1) and later followed by natural
(+)-varitriol synthesis. As part of an academic exercise, we have ini-
tiated a program to synthesize both enantiomers of the potentially
active natural products.7 We have recently accomplished the total
The first synthesis of (ꢀ)-varitriol was reported by Jennings
et al.4a which resulted in the reassignment of the absolute struc-
ture of natural varitriol; this was followed by Taylor4b et al. who
used Horner-Wadsworth-Emmons (HWE) and Ramberg Backlund
reactions. Several syntheses have since been reported for the syn-
thesis of both natural5 and unnatural analogues6 of varitriol.
2. Results and discussion
Our synthetic approach to (ꢀ)-varitriol is depicted in Scheme 1.
The target molecule can be obtained from the intermediate 2
involving a four step sequence, that is, deprotection of the silyl
group, iodination of the resulting alcohol, and a one pot reduction
of the ester and iodide functionalities with super hydride, followed
by isopropylidene deprotection. Compound 2 can be obtained via a
coupling reaction of sulfone 3 and aromatic aldehyde 4 by Julia–
Kocienski olefination reaction. Sulfone 3 was synthesized from
alcohol five involving a Mitsunobu reaction followed by an oxida-
tion reaction. Alcohol 5 in turn was readily accessible from
ribose in five steps. The aromatic aldehyde 4 was synthesized from
commercially available o-anisic acid in four steps.
D-(ꢀ)-
The synthesis of sulfone 3 started with
Scheme 2. Alcohol 5 [which we had synthesized earlier from
D
-(ꢀ)-ribose as shown in
D
-(ꢀ)-
O
O
ribose involving five steps8] was treated with 1-phenyl-1H-tetra-
zole-5-thiol, triphenylphosphine, diisopropyl azodicarboxylate in
THF (Mitsunobu conditions) to provide sulfide 6 in 84% yield.9 Sul-
fide 6 upon oxidation with H2O2 in the presence of a catalytic
amount of ammonium molybdate in EtOH furnished the sulfone
OH
HO
O
O
3 in 70% good yield10
.
The other key aromatic fragment 4 was synthesized as shown in
Scheme 3. O-Anisic acid was converted into compound 7 following
earlier known procedures8 in two steps amidation through acid
chloride formation, and finally formylation. Amide 7 was then sub-
jected to acidic hydrolysis to give the hemi acetal 8, which upon
exposure to diazomethane yielded aldehyde 4.
HO
OH
HO
OH
1'
(+)-varitriol 1
(−)-varitriol
(natural)
Figure 1. Structures of natural and unnatural varitriols.
⇑
Corresponding author. Tel.: +91 4027191815; fax: +91 4027160512.
E-mail address: srihari@iict.res.in (P. Srihari).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.10.010

K. Vamshikrishna, P. Srihari / Tetrahedron: Asymmetry 23 (2012) 1584–1587
1585
O
O
O
O
O
O
O
N
N
OH
O
O
O
O
N
OTBS
O
O
S
N
O
O
OTBS
CHO
O
O
O
4
OTBS
LHMDS, DME
-78 oC -rt, 2 h, 76%
O
O
HO
OH
O
O
O
9
3
2
1'
(-)-varitriol
cis-isomer 9a
O
O
OTBS
O
O
(inseparable
N
N
diastereomers)
O
S
O
COOH
O
N
O
CHO
N
I2, TPP
imidazole
O
OH
Ph
O
O
TBAF, THF
0 oC-rt, 1 h
95%
O
O-anisic acid
3
4
CH2Cl2, 0°C-rt
2 h, 75%
O
O
10
OTBS
OH
O
HO
cis-isomer 10a
O
O
O
O
OH
OH
O
O
HO
OH
O
O
super hydride
I
O
5
D-(-)-Ribose
THF, -78 oC -rt,
2 h, 85%
O
Scheme 1. Retrosynthesis of (ꢀ)-varitriol.
O
O
O
OH
OTBS
OH
11
2
O
O
OH
O
PTSH
DIAD, TPP
ref: 8
OH
THF
oC-rt, 2 h
HO
OH
O
O
0
1N HCl, THF
rt, 2 h, 65%
yield: 84%
O
D-(-)-Ribose
5
N
N
N
N
O
S
N
HO
(-)-varitriol
OH
N
OTBS
OTBS
O
S
(NH4)6Mo7O24.4H2O
30% H2O2
N
N
O
O
O
1'
EtOH
rt, 12 h
yield: 70%
Scheme 4. Synthesis of (ꢀ)-varitriol 10.
O
O
O
in 75% yield.12 Compound 11 with both ester and halide function-
alities then underwent reduction with LiEt3BH (super hydride) to
provide the alcohol 2. Finally, compound 2 upon isopropylidene
deprotection with 1 N Hcl yielded the target product (ꢀ)-varitriol
1’. The analytical data of this synthesized product were found to
be identical to those previously reported.4a
6
3
Scheme 2. Synthesis of sulfone 3.
O
O
10% HCl
CONEt2
COOH
ref: 8
reflux, 24 h
65%
3. Conclusion
CHO
o-anisic acid
7
In conclusion, we have accomplished the total synthesis of
O
O
unnatural (ꢀ)-varitriol. The furanoside part was synthesized from
O
O
readily available inexpensive
D
-(ꢀ)-ribose while the aromatic part
CH2N2
O
was obtained from o-anisic acid. The one pot reduction of the two
functionalities (ester and alkyl halide) has been achieved with
super hydride. The present strategy could be further explored for
the synthesis of other analogues to screen their biological activity
and is currently being investigated in our laboratory.
O
THF;diethyl ether (1:1)
CHO
0
oC, 0.5 h
OH
yield: 95%
8
4
Scheme 3. Synthesis of Aromatic aldehyde 4.
4. Experimental
4.1. General
Treatment of 3 and 4 with lithium hexamethyl disilazane in THF
provided the desired coupling product 9 along with its other dia-
stereomer (cis-isomer 9a) in
a 65:35 ratio in 76% yield
(Scheme 4).11 Desilylation of 9 with TBAF provided primary alcohol
10. Alcohol 10 was converted into the corresponding iodide 11
upon treatment with I2, TPP, and imidazole at room temperature
Column chromatography was performed using silica gel 60-120
mesh. All solvents were dried and distilled prior to use. IR spectra
were recorded on a Perkin–Elmer Infrared spectrophotometer as

1586
K. Vamshikrishna, P. Srihari / Tetrahedron: Asymmetry 23 (2012) 1584–1587
KBr wafers or neat or in CHCl3 as a thin film. 1H, and 13C NMR spec-
tra were recorded on a Bruker Avance 300 or Varian Inova 500 MHz
instrument using TMS as an internal standard. Mass spectra were
recorded on Micro mass VG 7070H mass spectrometer for EI, VG
Autospec mass spectrometer for FABMS, and micromass Quatro
LC triple quadrupole mass spectrometer for ESI analysis. Syringe
and septa techniques were used for moisture free reactions.
KOH (1.06 g, 18.93 mmol, 5 equiv) in EtOH (15 mL) at room tem-
perature; the reaction mixture was immediately distilled off until
the reaction mixture turned yellowish to colorless, which resulted
in a yellowish liquid containing CH2N2 in diethyl ether (40 mL).
This freshly generated CH2N2 solution (20 mL) was added dropwise
to the compound 8 (0.6 g, 3.8 mmol, 1 equiv) in THF:diethylether
(1:1) (10 mL) at 0 °C over 20 min, and the reaction mixture was
stirred at same temperature for 1 h. After complete consumption
of the starting material, which was monitored by TLC, the reaction
mixture was concentrated under reduced pressure to give 4 as a
light yellowish oil Rf 0.30 (hexane-EtOAc, 20:80) (0.7 g, 95%); IR
4.2. Procedures and analytical data
4.2.1. 5-(((3aR,4R,6R,6aR)-6-((tert-Butyldimethylsilyloxy) methyl)-
2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylthio)-
1-phenyl-1H-tetrazole 6
tmax (KBr): 2955, 1738, 1698, 1472, 1268 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 9.96 (s, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.46 (d,
J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 3.97 (s, 3H), 3.89 (s, 3H);
13C NMR (75 MHz, CDCl3): d 190.3, 167.2, 156.5, 134.1, 131.0,
123.2, 116.9, 56.2, 52.7; ESIMS: m/z 217 [M+Na]+.
To a solution of compound 5 (3.0 g, 9.4 mmol, 1 equiv) and tri-
phenyl phosphine (3.7 g, 14.2 mmol, 1.5 equiv), 1-phenyl-1H-tet-
razole-5-thiol (2.5 g, 14.3 mmol, 1.5 equiv) was added dry THF
(30 mL). The reaction mixture was then cooled to 0 °C and diiso-
propyl azo dicarboxylate (2.89 mL, 14.1 mmol, 1.5 equiv) was
added dropwise to the reaction mixture at 0 °C over 10 min. The
reaction mixture was stirred at same temperature for 20 min, then
allowed to warm to room temperature and stirred at the same
temperature for 2 h. After complete consumption of the starting
material (monitored by TLC), the reaction mixture was concen-
trated under reduced pressure, and purified by column chromatog-
raphy Rf 0.40 (hexane-EtOAc, 90:10) to give 6 (3.8 g, 84%) as a
4.2.4. Methyl 2-((E)-2-((3aS,4S,6R,6aR)-6-(hydroxymethyl)-2,2-
dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)vinyl)-6-meth-
oxybenzoate 10
To a solution of compound 4 (0.68 g, 3.52 mmol, 1 equiv) and
compound 3 (1.44 g, 2.82 mmol, 0.8 equiv) in 1.2-dimethoxy eth-
ane (20 mL) was added dropwise 1 M LiHMDS (5.28 mL, 1.5 equiv)
at ꢀ78 °C over 15 min, then the reaction mixture was allowed to
warm to room temperature over 1 h, and stirred at the same tem-
perature for 12 h. After the reaction mixture was quenched with
saturated aq NH4Cl (20 mL), the reaction mixture was diluted with
EtOAc (20 mL). The organic layer was separated and the aqueous
layer was extracted with EtOAc (2 ꢁ 10 mL). The combined organic
layer was washed with brine (10 mL), dried over anhydrous
Na2SO4, concentrated under reduced pressure, and purified on col-
umn chromatography Rf 0.70 (hexane-EtOAc, 80:20) to give a mix-
ture of inseparable diastereomers 9 and 9a in a 65:35 ratio (LCMS)
(1.02 g, 76%) as a yellow oil.
colorless oil; ½a D25
ꢂ
¼ ꢀ34:2 (c 1.9, CHCl3); IR tmax (Neat): 2931,
1382, 1251, 1079, 837 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.61–
7.52 (m, 5H), 4.70 (dd, J = 3.0, 6.0 Hz, 1H), 4.51 (dd, J = 4.5, 6.8 Hz,
1H), 4.34–4.29 (m, 1H), 4.12 (q, J = 2.3, 5.3 Hz, 1H), 3.79–3.59 (m,
4H), 1.51 (s, 3H), 1.33 (s, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.04 (s,
3H); 13C NMR (75 MHz, CDCl3): d 153.9, 133.6, 130.0, 129.7,
123.8, 113.8, 85.3, 84.2, 82.9, 82.1, 63.7, 36.2, 27.3, 25.9, 25.5,
18.3, ꢀ5.4, ꢀ5.6; ESIMS: m/z 479 [M+H]+; HRESIMS: m/z
479.2164 [M+H]+ (calcd for C22H35N4O4SiS: m/z 479.2148).
To the solution of the inseparable diastereomeric mixture 9 and
9a (1.02 g, 2.13 mmol, 1 equiv) in dry THF (10 mL) was added
dropwise a 1.0 M TBAF solution in THF (3.19 mL, 1.5 equiv) over
10 min. at 0 °C. The reaction mixture was then allowed to warm
to room temperature while stirring for 2 h. After complete con-
sumption of the starting material, the reaction mixture was
quenched with saturated aq. NH4Cl (5 mL), and diluted with EtOAc
(10 mL) and water (10 mL). The organic layer was separated and
the aqueous layer was extracted with EtOAc (2 ꢁ 10 mL). The com-
bined organic layer was washed with brine (10 mL), dried over
anhydrous Na2SO4, and the solvent was removed under reduced
pressure to give crude material, which was purified by column
chromatography Rf 0.30 (hexane-EtOAc, 60:40) to give separable
diastereomers 10 and 10a (0.73 g, 95%) as a colorless oil; 10:
4.2.2. 5-(((3aR,4R,6R,6aR)-6-((tert-Butyldimethylsilyloxy)methyl)-
2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylsul-
fonyl)-1-phenyl-1H-tetrazole 3
To a solution of ammonium molybdate tetrahydrate (1.96 g,
1.59 mmol, 0.2 equiv), in EtOH (20 mL) was added dropwise 30%
H2O2 (7.94 mL, 79.5 mmol, 10 equiv) at 0 °C over 5 min and the reac-
tion mixture was stirred at room temperature for 15 min; immedi-
ately the reaction mixture turned into a light yellow color. To this
compound 6 (3.8 g, 7.95 mmol, 1 equiv) in EtOH was added drop-
wise at 0 °C over 10 min. The reaction mixture was allowed to warm
to room temperature and stirred at room temperature for 12 h, after
which the reaction mixture was quenched by the addition of solid
Na2SO3 (20.0 g) portionwise at room temperature. The reaction mix-
ture was then stirred at room temperature until the yellow color
turned white, then the reaction mixture filtered on a pad of Celite,
dried over anhydrous Na2SO4, concentrated under reduced pressure,
and purified by column chromatography Rf 0.40 (hexane-EtOAc,
90:10) to give 3 (2.8 g, 70%) as a white solid; mp 82–84 °C.
½
a 2D5
ꢂ
¼ ꢀ19:5 (c 2.2, CHCl3); IR tmax (Neat): 3456, 2940, 1730,
1472, 1272, 1074 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.31 (t,
;
J = 8.4 Hz, 1H) 7.11 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.67
(d, J = 15.9 Hz, 1H), 6.22 (dd, J = 5.6, 15.9 Hz, 1H), 4.69–4.67 (m,
1H), 4.53–4.49 (m, 2H), 4.14–4.12 (m, 1H), 3.91 (s, 3H), 3.86–
3.83 (m, 1H), 3.83 (s, 3H), 3.70 (dd, J = 4.7, 7.5 Hz, 1H), 2.02 (br s,
1H), 1.57 (s, 3H) 1.35 (s, 3H); 13C NMR (75 MHz, CDCl3): d 168.4,
156.5, 135.2, 130.5, 130.3, 128.4, 122.6, 117.9, 114.6, 110.2, 85.2,
85.1, 84.6, 81.6, 62.9, 55.9, 52.4, 27.3, 25.3; ESIMS: m/z 387
[M+Na]+; HRESIMS: m/z 387.1432 [M+Na]+ (calcd for C19H24O7Na:
m/z 387.1419).
½
a 2D5
ꢂ
¼ ꢀ46:7 (c 3.1, CHCl3); IR tmax (Neat): 2931, 1352, 1256,
1081, 838 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.64–7.55 (m, 5H),
;
4.65 (d, J = 5.9 Hz, 1H), 4.54–4.53 (m, 1H), 4.49–4.45 (m, 1H), 4.21
(dd, J = 8.9, 14.8 Hz, 1H), 4.15 (br s, 1H), 3.85 (dd, J = 3.9, 14.8 Hz,
1H), 3.60–3.51 (m, 2H), 1.49 (s, 3H), 1.32 (s, 3H), 0.92 (s, 9H), 0.13
(s, 3H), 0.11 (s, 3H); 13C NMR (75 MHz, CDCl3): d 153.7, 133.1,
131.3, 129.3, 125.7, 113.7, 85.8, 84.6, 82.2, 79.9, 64.0, 59.6, 27.1,
25.9, 25.3, 18.4, ꢀ5.4, ꢀ5.7; ESIMS: m/z 511 [M+H]+; HRESIMS: m/z
511.2032 [M+H]+ (calcd for C22H35 N4O6SiS: m/z 511.2046).
4.2.5. Methyl 2-((E)-2-((3aS,4S,6S,6aS)-6-(iodomethyl)-2,2-
dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)vinyl)-6-meth-
oxybenzoate 11
4.2.3. Methyl 2-formyl-6-methoxybenzoate 4
To a solution of compound 10 (0.26 g, 0.72 mmol, 1 equiv), tri-
phenyl phosphine (0.37 g, 1.44 mmol, 2 equiv) and imidazole
(0.14 g, 2.17 mmol, 3 equiv) in dry CH2Cl2 (8 mL) was added
To
a solution of N-methyl-N-nitrosotoluene-p-sulfonamide
(3.25 g, 15.19 mmol, 4 equiv), in diethyl ether (40 mL) was added

K. Vamshikrishna, P. Srihari / Tetrahedron: Asymmetry 23 (2012) 1584–1587
1587
molecular I2 (0.40 g, 1.59 mmol, 2.2 equiv) at 0 °C. The reaction
mixture was then stirred at the same temperature for 15 min, after
which the reaction mixture was allowed to warm to room temper-
ature, and stirred at room temperature for 2 h. After completion of
the reaction (monitored by TLC) the reaction mixture was
quenched with a saturated aq. Na2S2O3 ꢃ5H2O solution. The organic
layer was separated and the aqueous layer was extracted with
CH2Cl2 (2 ꢁ 10 mL). The combined organic layer was washed with
brine (5 mL), and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure to give a crude material, which
was purified by column chromatography Rf 0.80 (hexane-EtOAc,
(5 mL) and dried over anhydrous Na2SO4. The solvent was evapo-
rated under reduced pressure to give a crude product, which was
purified by column chromatography Rf 0.30 (hexane-EtOAc,
20:80) to give (ꢀ)-varitriol 10 (0.013 g, 65%) as a white solid; mp
102–104 °C, ½a 2D5
ꢂ
¼ ꢀ29:2 (c 0.7, MeOH); lit.4a
½ ꢂ ¼ ꢀ18:2 (c
a rDt
0.0033 g mlꢀ1, MeOH); IR tmax (KBr): 3405, 2926, 1469, 1249,
1094 cmꢀ1 1H NMR (300 MHz, acetone-d6): d 7.22 (t, J = 7.9 Hz,
;
1H), 7.15 (br s, 1H), 7.11 (d, J = 5.5, Hz, 1H), 6.89 (d, J = 8.1 Hz,
1H), 6.20 (dd, J = 6.6, 15.9 Hz, 1H), 4.70 (br s, 2H), 4.30-4.27 (m,
1H), 3.92–3.88 (m, 1H), 3.85–3.78 (m, 1H), 3.82 (s, 3H), 3.70–
3.67 (m, 1H), 1.26 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, acetone-
d6): d 159.9, 139.9, 133.4, 130.3, 130.2, 128.9, 120.3, 111.6, 86.3,
80.9, 78.1, 77.4, 57.0, 56.4, 20.5; ESIMS: m/z 303 [M+Na]+; HRE-
SIMS: m/z 303.1197 [M+Na]+ (calcd for C15H20O5Na: m/z
303.1208).
60:40) to give 11 (0.25 g, 75%) as a colorless oil; ½a D25
¼ ꢀ39:6 (c
ꢂ
6.3, CHCl3); IR tmax (Neat): 2927, 1731, 1467, 1269, 1075 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.30 (t, J = 8.3 Hz, 1H) 7.12 (d,
J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 15.9 Hz, 1H),
6.23 (dd, J = 5.3, 15.9 Hz, 1H), 4.58–4.51 (m, 3H), 4.04-4.00 (m,
1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.37–3.27 (m, 2H), 1.56 (s, 3H),
1.34 (s, 3H); 13C NMR (75 MHz, CDCl3): d 168.2, 156.4, 135.0,
130.4, 130.0, 128.6, 122.8, 117.9, 114.7, 110.2, 85.2, 85.1, 85.0,
83.0, 55.9, 52.4, 27.2, 25.4, 6.9; ESIMS: m/z 475 [M+H]+; HRESIMS:
m/z 475.0634 [M+H]+ (calcd for C19H24O6I: m/z 475.0617).
Acknowledgments
VK thanks the CSIR, New Delhi for financial assistance. PSH
thanks the Department of Science & Technology (DST) for financial
assistance under SERC FAST Track Scheme no. SR/FT/CS-036/2009,
GAP-0284. The authors thank Dr. J. S. Yadav, CSIR Bhatnagar fellow
for his kind encouragement.
4.2.6. (2-Methoxy-6-((E)-2-((3aS,4S,6R,6aR)-2,2,6-trimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)vinyl)phenyl)methanol 2
To a solution of compound 11 (0.10 g, 0.21 mmol, 1 equiv) in
dry THF (3 mL) was added 1 M LiEt3BH (1.68 mL, 8 equiv) in THF
at ꢀ78 °C, over 10 min; then the reaction mixture was allowed to
warm to room temperature. After complete consumption of the
starting material, the reaction mixture was quenched with satu-
rated NaHCO3 (10 mL) at 0 °C followed by 30% H2O2 (3 mL) at
0 °C. The reaction mixture was then allowed to warm to room tem-
perature and stirred at the same temperature for 5 h. The organic
layer was separated and the aqueous layer was extracted with
EtOAc (2 ꢁ 5 mL). The combined organic layer was washed with
brine (5 mL), dried over anhydrous Na2SO4, and concentrated un-
der reduced pressure to give the product which was purified by
column chromatography Rf 0.35 (hexane-EtOAc, 50:50) to give 2
References
1. (a) Blunt, W. J.; Copp, R. B.; Munro, G. H. M.; Northcote, T. P.; Prinsep, R. M. J.
Nat. Prod. Rep. 2011, 28, 196–268; (b) Simmons, L. T.; Andrianasolo, E.; McPhail,
K.; Flatt, P.; Gerwick, H. W. Mol. Cancer Ther. 2005, 4, 333–342; (c) Faulkner, D. J.
Nat. Prod. Rep. 2000, 17, 7–55.
2. Malmstrom, J.; Christophersen, C.; Barrero, A. F.; Oltra, J. E.; Justicia, J.; Rosales,
A. J. Nat. Prod. 2002, 65, 364–367.
3. Mayer, A. M. S.; Gustafson, K. R. Eur. J. Cancer 2004, 40, 2676–2704.
4. (a) Clemens, R. T.; Jennings, M. P. Chem. Commun. 2006, 2720–2721; (b)
McAllister, G. D.; Robinson, J. E.; Taylor, R. J. K. Tetrahedron 2007, 63, 12123–
12130.
5. (a) Kumar, V.; Shaw, A. K. J. Org. Chem. 2008, 73, 7526–7531; (b) Palik, M.;
Karlubikova, O.; Lasikova, A.; Kozisek, J.; Gracza, T. Eur. J. Org. Chem. 2009, 709–
715; (c) Brichacek, M.; Batory, L. A.; McGrath, N. A.; Njardarson, J. T.
Tetrahedron 2010, 66, 4832–4840; (d) Palík, M.; Karlubíková, O.; Lackovicová,
D.; Lásiková, A.; Gracza, T. Tetrahedron 2010, 66, 5244–5249; (e) Srinivas, B.;
Sridhar, R.; Rama Rao, K. Tetrahedron 2010, 66, 8527–8535; (f) Ghosh, S.;
Pradhan, T. K. J. Org. Chem. 2010, 75, 2107–2110; (g) Palik, M.; Karlubikova, O.;
Lasikova, A.; Kozisek, J.; Gracza, T. Synthesis 2010, 3449–3452; (h) Zeng, J.;
Seenuvasan, V.; Xiang, S.; Liu, X.-W. Org. Lett. 2011, 13, 42–45; (i) Ghosal, P.;
Sharma, D.; Kumar, B.; Meena, S.; Sinha, S.; Shaw, A. K. Org. Biomol. Chem. 2011,
7372–7383; (j) Nagarapu, L.; Paparaju, V.; Satyender, A.; Rajasheker, B.
Tetrahedron Lett. 2011, 52, 7075–7078; (k) Sun, T.; Deutsch, C.; Krause, N.
Org. Biomol. Chem. 2012, 9, 7372–7383.
6. (a) Nagarapu, L.; Paparaju, V.; Satyender, A. Bioorg. Med. Chem. Lett. 2008, 18,
2351–2354; (b) Senthilmurugan, A.; Aidhen, I. S. Eur. J. Org. Chem. 2010, 3, 555–
564; (c) Caletkova, O.; Lasikova, A.; Hajduch, M.; Dzubak, P.; Gracza, T. ARKIVOC
2012, 365–383.
7. (a) Srihari, P.; Sridhar, Y. Eur. J. Org. Chem. 2011, 6690–6697; (b) Mehta, G.;
Ramesh, S.; Srihari, P. Tetrahedron Lett. 2012, 53, 829–832; For few other
contributions on the total synthesis of natural products see (c) Srihari, P.;
Mahankali, B.; Rajendraprasad, K. Tetrahedron Lett. 2012, 53, 56–58; (d) Srihari,
P.; Satyanarayana, K.; Ganganna, B.; Yadav, J. S. J. Org. Chem. 2011, 76, 1922–
1925; (e) Srihari, P.; Kumaraswamy, B.; Shankar, P.; Ravishashidhar, V.; Yadav,
J. S. Tetrahedron Lett. 2010, 51, 6174–6176.
(0.057 g, 85%) as a colorless oil; ½a D25
ꢂ
¼ ꢀ36:6 (c 1.5, CHCl3); IR tmax
(Neat): 3452, 2932, 1579, 1467, 1262, 1077 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): d 7.23 (t, J = 7.9 Hz, 1H) 7.09–7.04 (m, 2H),
6.82 (d, J = 8.9 Hz, 1H), 6.15 (dd, J = 6.9, 15.9 Hz, 1H), 4.78 (s, 2H),
4.54 (dd, J = 4.9, 6.9 Hz, 1H), 4.45 (t, J = 5.9 Hz, 1H), 4.33 (dd,
J = 3.9, 5.9 Hz, 1H), 4.04 (qt, J = 5.9, 10.9 Hz, 1H), 3.86 (s, 3H), 1.57
(s, 3H), 1.36 (d, J = 6.9 Hz, 3H), 1.35 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 158.0, 137.3, 130.7, 129.4, 128.8, 126.4, 119.3, 115.0,
119.7, 86.3, 85.5, 84.8, 80.3, 56.8, 55.6, 27.4, 25.5, 19.1; ESIMS:
m/z 343 [M+Na]+; HRESIMS: m/z 343.1512 [M+Na]+ (calcd for
C18H24O5Na: m/z 343.1521).
4.2.7. (2S,3R,4S,5R,E)-2-(2-(Hydroxymethyl)-3-methoxystyryl)-
5-methyl-tetrahydrofuran-3,4-diol 10
To a solution of compound 2 (0.025 g, 0.078 mmol, 1 equiv) in
THF (3 mL) was added 1N HCl (3 mL) and then the reaction mixture
was stirred at room temperature for 3 h. After complete conversion
of the starting material, the reaction mixture was quenched with
solid NaHCO3 (2.0 g), diluted with EtOAc (5 mL), and the organic
layer was separated. The aqueous layer was extracted with EtOAc
(2 ꢁ 5 mL) and the combined organic layer was washed with brine
8. Vamshikrishna, K.; Srihari, P. Tetrahedron 2012, 68, 1540–1546.
9. Mitsunobu, O. Synthesis 1981, 1–28.
10. (a) Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V. Synthesis 1996, 285–
296; (b) Blakemore, P. R.; Kocienski, P. J.; Marzcak, S.; Wicha, J. Synthesis 1999,
1209–1215.
11. (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26–28;
(b) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365–366.
12. Garegg, P. J.; Samuelson, B. J. Chem. Soc. Perkin Trans. 1 1980, 2866–2869.