Total synthesis of (+)-varitriol and (+)-6′-epi-varitriol

Article abstract of DOI:10.1016/j.tet.2011.12.008

Total synthesis of (+)-varitriol and its C6′-epimer have been achieved starting from commercially available d-(-)-ribose and o-anisic acid. The key steps involved are Corey Chaykovsky reaction, triethylamine mediated epimerization, and an olefin cross-met

Full text of DOI:10.1016/j.tet.2011.12.008

Tetrahedron 68 (2012) 1540e1546
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (þ)-varitriol and (þ)-60-epi-varitriol
*
K. Vamshikrishna, P. Srihari
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Total synthesis of (þ)-varitriol and its C60-epimer have been achieved starting from commercially
Article history:
Received 20 October 2011
Received in revised form 1 December 2011
Accepted 5 December 2011
Available online 9 December 2011
available
D
-(ꢀ)-ribose and o-anisic acid. The key steps involved are Corey Chaykovsky reaction, trie-
thylamine mediated epimerization, and an olefin cross-metathesis.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Corey Chaykovsky reaction
Epimerization
Cross-metathesis
Wittig reaction
1. Introduction
O
O
Natural products from marine sources continue to attract sig-
nificant attention by both biologists and chemists due to their in-
teresting biological properties and scarce availability for further
elucidation toward their activities.1 (þ)-varitriol 1, a novel low
molecular weight natural product has been recently isolated from
a marine derived strain of fungus Emericella variecolor by Malm-
strom et al.2 Though this compound did not inhibit growth of
bacteria and yeast at 100 mg/mL concentration, it displayed sig-
nificant cytotoxic activity against variety of tumor cell lines and
showed increased potency toward renal, CNS, and breast cancer cell
lines with GI50 values ranging from 1.63 to 2.44ꢁ10ꢀ7 M and lower
potency toward leukemia, ovarian, and colon cell lines with GI50
values ranging from 2.52ꢁ10ꢀ5 to 9.59ꢁ10ꢀ5 M. As the mode of
action of varitriol has not yet been established3 it becomes neces-
sary to further investigate and elucidate the mechanism of action
by this molecule. This feature along with interesting preliminary
biological property and simple structure have attracted several
chemists to take up the total synthesis4,5 and the analogue syn-
thesis6 of varitriol. The absolute structure of (þ)-varitriol was ini-
tially determined after accomplishing the total synthesis of its
enantiomer (ꢀ)-varitriol 10 and later followed by the natural
(þ)-varitriol synthesis (Fig. 1).
OH
HO
O
O
HO
OH
HO
OH
(-)-Varitriol 1'
(+)-Varitriol 1
(Natural)
Fig. 1. Structures of natural and unnatural varitriols.
group involving HornereWadswortheEmmons (HWE) and Ram-
berg Backlund reactions.
The first total synthesis of natural (þ)-varitriol 1, was achieved
by Shaw and Kumar,5a utilizing olefin cross-metathesis to link the
carbohydrate part obtained from methyl a,D-mannopyranoside and
aromatic moiety prepared using Stille cross coupling reaction as
key step. Several other publications have followed for the total
synthesis of natural varitriol5bej and their analogues.6
In continuation of our programme on total synthesis of recently
isolated biologically active natural products,7 here in we report our
strategy for total synthesis of (þ)-varitriol and its C60-epimer. Our
synthetic approach to (þ)-varitriol relies on coupling of sugar olefin
(carbohydrate part) 3 with appropriately derivatized styrene (aro-
matic part) 4 via an olefin cross-metathesis reaction to give in-
termediate 2, which upon ester reduction and acetonide
deprotection gives the target molecule (Scheme 1). While the sugar
The inaugural synthesis started with (ꢀ)-varitriol by Jennings
and Clemens4a involving an olefin cross-metathesis and Suzu-
kieMiyaura reaction as key steps and was followed by Taylor4b
* Corresponding author. Tel.: þ91 4027191815; fax: þ91 4027160512; e-mail
addresses: srihari@iict.res.in, sriharipabbaraja@yahoo.com (P. Srihari).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.008

K. Vamshikrishna, P. Srihari / Tetrahedron 68 (2012) 1540e1546
1541
olefin 3 can be obtained from commercially available
D
(ꢀ)-ribose
OH
OTBS
i) H2SO4, acetone
rt, 5 h, 82.5%
ii) imidazole
through sequence of reactions involving an epimerization, Corey
Chaykovsky reaction etc., the aromatic part 4 is synthesized from
commercially available o-anisic acid in four steps.
O
OH
O
OH
TMSOI, BuOK
t
DMSO:THF (1:1)
TBDMSCl, CH2Cl2
HO
OH
0 oC-rt, 2 h, 56%
O
O
0 oC-rt, 8 h, 79%
D-(-)-Ribose
6
O
O
O
i) (COCl)2, CH2Cl2
DMSO, Et3N,
OTBS
OH
OTBS
OH
1'
O
O
OH
O
O
-78 oC, 2.5 h
ii) Et3N, 24 h
O
O
6'
2'
O
O
i
O
O
CH2Cl2: PrOH (1;1)
3'
4'
5'
OH
Then NaBH4
in MeOH:Et2O (1:1)
70% brsm
7
HO
5
O
2
(+)-Varitriol1
OTBS
O
OTBS
I
I2, TPP
imidazole
O
O
O
O
O
n
Bu3SnH, AIBN
COOH
O
benzene, reflux
2 h, 94%
toluene, reflux
2 h, 92%
O
O
3
O
O
O
O
O
O
O
4
8
9
O-Anisic acid
OH
i) (COCl)2,
O
CH2Cl2, DMSO,
OH
OTBS
OH
Et3N, -78 oC, 2 h
TBAF, THF
0 oC-rt, 1 h
O
O
OH
OH
ii) PPh3CH3I,
O
O
10
t
BuOK, THF
98%
0 oC-rt, 5 h
66%
HO
O
O
3
5
D(-)-Ribose
Scheme 1. Retrosynthesis for (þ)-varitriol.
Scheme 2. Synthesis of 3.
The lactol 13 was subjected to one carbon Wittig olefination re-
action using methyltriphenylphosphonium iodide and potassium
tert-butoxide and then treated with excess of MeI to provide the
aryl olefin 4 in 65% yield.
2. Results and discussion
Synthesis of sugar olefin 3 started with
D
-(ꢀ)-ribose as shown in
Scheme 2.
D-(ꢀ)-Ribose was protected with isopropylidene and was
followed by primary alcohol protection by tert-butyldimethylsilyl
chloride to the corresponding tert-butyldimethylsilyl ether 6.8b
Corey Chaykovsky reaction8 of lactol 6 with trimethylsulfoxonium
iodide and potassium tert-butoxide in DMSO provided homolo-
gated alcohol 7. While compound 7 can be directly utilized for total
synthesis of 60-epi-varitriol, epimerization of the newly generated
carbinol group can lead to total synthesis of natural (þ)-varitriol.
The alcohol 7 upon oxidation under Swern conditions9 provided
aldehyde and was then exposed to several bases, such as DBU,
i) (COCl)2, CH2Cl2
O
O
DMF
COOH
0 oC-rt, 12 h
CONEt2
11
ii) Et2NH, 96%
O
s-BuLi,TMEDA(1:1)
10% HCl
CONEt2
CHO
KtOBu, NaH, LDA, NaHMDS toward epimerization at
a-center
reflux, 24 h
65%
DMF, THF
-78 oC-rt, 70%
without any success as the reaction ended up either with starting
material or undesired self Aldol product. Finally, epimerization10
was achieved with triethylamine and was followed by reduction
of aldehyde functionality with NaBH4 in MeOH to give alcohol 5.11
The alcohol 5 was converted to corresponding iodide 8 upon
treatment with I2, TPP, and imidazole at reflux condition, and was
further reduced to alkane 9 with nBu3SnH and AIBN.12 Desilylation
of 9 with TBAF provided primary alcohol 10, which was oxidized to
corresponding aldehyde under Swern condition and then subjected
to one carbon Wittig homologation reaction with methyl-
triphenylphosphonium iodide and potassium tert-butoxide to
provide the carbohydrate part (sugar olefin) 3 in 66% overall yield
for last two steps (Scheme 2).
The synthetic strategy for aromatic part is given in Scheme 3.
The commercially available o-anisic acid was converted to amide 11
on treatment with oxalyl chloride in presence of catalytic amount
of DMF, followed by quenching with Et2NH. ortho Formylation13
with DMF in presence of sBuLi and TMEDA provided aryl alde-
hyde 12, which on hydrolysis with 10% HCl gave lactone acetal 13.
12
i) PPh3CH3I,
O
O
O
O
t
BuOK, THF
0 oC-rt, 5 h
O
O
ii) Excess MeI
65%
OH
4
13
Scheme 3. Synthesis of 4.
With the two key intermediates 3 and 4 in hand, the stage was
set for coupling them toward total synthesis of (þ)-varitriol
(Scheme 4). Thus, treatment of 3 and 4 in presence of Grubbs’ II
generation catalyst4a,5a,14 provided cross-coupled product 2, which
was subjected to reduction with DIBAL-H to provide alcohol 14.
Finally isopropylidene deprotection with 1 N HCl provided the
natural product (þ)-varitriol. The spectroscopic analytical data was
found to be similar with that of the earlier synthesized product5a
and isolated natural product.2

1542
K. Vamshikrishna, P. Srihari / Tetrahedron 68 (2012) 1540e1546
O
O
O
O
O
Grubbs II
O
O
O
DIBAL-H
CH2Cl2, -78 oC - 0 C,
2 h, 76%
generation catalyst
o
CH2Cl2, reflux,12 h
56%
O
O
3
O
4
O
O
O
2
OH
OH
1N HCl
O
O
THF
rt, 2 h
58%
O
O
14
HO
(+)-Varitriol
OH
(+)-1
.
Scheme 4. Synthesis of (þ)-varitriol.
With enough material of compound 7 in hand, we explored the
total synthesis of 60-epi-varitriol. Thus, iodination of alcohol 7 with
I2, TPP, and imidazole in toluene at reflux temperature furnished
corresponding iodide 15 in good yield. The iodide 15 was reduced
with nBu3SnH in presence of catalytic amount of AIBN to provide 16.
The compound 16 on desilylation with TBAF yielded the corre-
sponding alcohol 17. The alcohol 17 was oxidized to aldehyde under
Swern conditions and subjected to one carbon Wittig olefination
reaction with methyltriphenylphosphonium iodide and potassium
tert-butoxide in THF to yield the olefin 18. Further cross coupling of
compound 18 with 4 using Grubbs II generation catalyst provided
19. The ester 19 upon reduction with DIBAL-H followed by iso-
propylidene deprotection with 1 N HCl provided the (þ)-60-epi-
varitriol (Scheme 5).
other analogues to screen their biological activity and is being cur-
rently investigated in our laboratory.
4. Experimental
4.1. General
Column chromatography was performed using silica gel
60e120 mesh. All the solvents were dried and distilled prior to use.
IR spectra were recorded on a PerkineElmer Infrared spectropho-
tometer as KBr wafers or neat or in CHCl3 as a thin film. 1H, 13C NMR
were recorded on a Bruker Avance 300 or Varian Unity 400 MHz or
Varian Inova 500 MHz instrument using TMS as an internal stan-
dard. Mass spectra were recorded on Micromass VG 7070H mass
OTBS
OH
OTBS
OTBS
OH
I
I2, TPP
imidazole
O
O
O
O
n
Bu3SnH, AIBN
TBAF
benzene
reflux, 2 h
90%
toluene
THF
O
O
O
O
O
O
0 oC-rt, 1 h
95%
O
O
refulx, 2 h
96%
16
17
15
7
O
O
O
O
O
i) (COCl)2,
OH
O
O
CH2Cl2, DMSO,
i) DIBAL-H, CH2Cl2
-78 oC - 0 oC, 2 h
O
Et3N, -78 oC, 2.5 h
4
O
O
ii) PPh3CH3I,
Grubbs II
ii) 1N HCl, THF
rt, 2 h, overall yield 58%
t
O
O
generation catalyst
BuOK, THF
0 oC-rt, 5 h
68%
CH2Cl2 reflux,12 h
62%
HO
OH
19 O
O
20
(+)-6'-epi-Varitriol
18
Scheme 5. Synthesis of 60-epi-varitriol.
3. Conclusion
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.
In summary, we have accomplished the total synthesis of natural
(þ)-varitriol and its 60-epimer involving a convergent approach. The
furanoside part was synthesized from readily available cheap ma-
terial
D
(ꢀ)-ribose and the aromatic part was obtained from o-anisic
4.2. Procedures and analytical data
acid. The keyreactions include Grubbs’ cross-metathesis reaction for
coupling two fragments, a Corey Chaykovsky reaction for homolo-
gation of lactol system and an epimerization step to get the 2,5-syn
geometry. This strategy can be further explored for the synthesis of
4.2.1. (3aR,6R,6aR)-6-((tert-Butyldimethylsilyloxy)methyl)-2,2-
dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (6). To a stirred sus-
pension of
D-ribose (5.0 g, 33.3 mmol) in acetone (50 mL) was

K. Vamshikrishna, P. Srihari / Tetrahedron 68 (2012) 1540e1546
1543
added drop wise concd H2SO4 (0.3 mL) at room temperature and
the reaction mixture was stirred at room temperature for 2.5 h. The
mixture was neutralized with solid NaHCO3 (10 g), filtered, and
dried over anhydrous Na2SO4, the solvent was evaporated under
reduced pressure to give crude material, which was purified by
silica gel column chromatography (hexane/EtOAc 65:35) to afford
acetonide protected lactol as colorless syrup (5.2 g, 82.5%). To this
compound (5.2 g, 27.4 mmol, 1 equiv) in anhydrous CH2Cl2 (52 mL)
was added imidazole (2.41 g, 35.5 mmol, 1.3 equiv) at a time at
room temperature. The mixture was stirred at room temperature
for 20 min after which the reaction mixture was cooled to 0 ꢂC, and
to this was added TBDMSCl (4.5 g, 30.1 mmol, 1.1 equiv) portion
wise. The reaction mixture was allowed to warm to room tem-
perature and stirred for 4 h. Water (40 mL) was added to the re-
action mixture and the organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (2ꢁ30 mL). The combined
organic layer was washed with brine (30 mL), and dried over an-
hydrous Na2SO4, solvent was removed under reduced pressure to
give crude material, which was purified by column chromatogra-
phy Rf: 0.90 (hexane/EtOAc, 95:5) to give 6 (6.6 g, 79% yield) as
layer was separated, aqueous layer was extracted with CH2Cl2
(2ꢁ30 mL), combined organic layer was washed with brine
(30 mL), dried over anhydrous Na2SO4, solvent was removed under
reduced pressure to give crude material, which was purified by
flash column chromatography (hexane/EtOAc, 90:10) to give the
i
aldehyde (2.6 g, 87.2%) as yellow oil, to this PrOH, CH2Cl2 (50 mL,
60 mL), and Et3N (3.6 mL, 26.2 mmol, 3.2 equiv) were added, after
reaction mixture was stirred at room temperature for 24 h, reaction
mixture was concentrated and to the reaction mixture diethyl ether
and MeOH (60 mL, 60 mL) was added. The reaction mixture was
cooled to 0 ꢂC and to this was added NaBH4 (0.63 g, 16.5 mmol,
2 equiv) in portion wise over 10 min. Solvent was removed under
reduced pressure and diluted with water (20 mL) and EtOAc
(20 mL). The organic layer was separated, aqueous layer was
extracted with EtOAc (2ꢁ40 mL), combined organic layer was
washed with brine, and dried over anhydrous Na2SO4, solvent was
removed under reduced pressure to give crude material, which was
purified by column chromatography Rf 0.55 (hexane/EtOAc, 90:10)
to give 5 (1.05 g, 35%) as yellow oil (70% w.r.t. recovered starting
material); ½a 2D0
ꢃ
þ10.89 (c 0.56, CHCl3); IR nmax (Neat): 3458, 2935,
yellow oil; ½a 2D0
ꢃ
ꢀ16.84 (c 1.36, CHCl3); IR nmax (KBr): 3360, 2936,
2862, 1465, 1254, 1079 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
2860, 1471, 1261, 1068 cmꢀ1
d
;
1H NMR (300 MHz, CDCl3þCCl4):
d 4.77e4.70 (m, 2H), 4.22e4.20 (m, 1H), 4.08e4.05 (m, 1H),
5.27 (d, J¼11.9 Hz, 1H), 4.76 (d, J¼11.7 Hz, 1H), 4.69 (d, J¼5.9 Hz,
3.92e3.75 (m, 3H), 3.61 (t, J¼9.6 Hz, 1H), 3.03 (d, J¼9.6 Hz, 1H), 1.54
1H), 4.49 (d, J¼6.0 Hz,1H), 4.35 (br s,1H), 3.79e3.71 (m, 2H),1.47 (s,
(s, 3H), 1.36 (s, 3H), 0.92 (s, 9H), 0.10 (s, 6H); 13C NMR (75 MHz,
3H), 1.31 (s, 3H), 0.92 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H); 13C NMR
CDCl3): d 113.1, 85.5, 84.8, 82.7, 81.0, 63.8, 63.7, 27.5, 25.9, 25.5, 18.4,
(75 MHz, CDCl3):
d
112.0,103.4, 87.6, 86.9, 81.7, 64.8, 26.4, 25.7, 24.9,
ꢀ5.5, ꢀ5.6; ESIMS: m/z 341 [MþNa]þ; HRESIMS: m/z 341.1762
18.2, ꢀ5.6, ꢀ5.7; ESIMS: m/z 322 [MþNH4]þ; HRESIMS: m/z
[MþNa]þ (calcd for C15H30O5NaSi: m/z 341.1760).
327.1589 [MþNa]þ (calcd for C14H28O5NaSi: m/z 327.1603).
4.2.4. tert-Butyl(((3aR,4R,6R,6aR)-6-(iodomethyl)-2,2-dimethyl-tet-
rahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)dimethylsilane (8). To
the solution of compound 5 (1.0 g, 3.14 mmol, 1 equiv) in dry tol-
uene (10 mL) was added imidazole (0.64 g, 9.41 mmol, 3 equiv),
TPP (1.65 g, 6.29 mmol, 2 equiv) at room temperature followed by I2
(1.76 g, 6.91 mmol, 2.2 equiv). Then reaction mixture was refluxed
at 110 ꢂC for 2 h. After complete conversion of starting material,
mixture was allowed to cool to room temperature water (10 mL)
was added to the reaction mixture and diluted with EtOAc (5 mL).
The organic layer was separated; aqueous layer was extracted with
EtOAc (2ꢁ10 mL). Combined organic layer was washed with hypo
(15 mL) followed by brine (15 mL), dried over anhydrous Na2SO4,
solvent was removed under reduced pressure to give crude mate-
rial, which was purified by column chromatography Rf 0.90 (hex-
4.2.2. ((3aS,4R,6R,6aR)-6-((tert-Butyldimethylsilyloxy)methyl)-2,2-
dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (7). To the
mixture of trimethylsulfoxonium iodide (1.31 g, 5.96 mmol,
1.5 equiv) and potassium tert-butoxide (0.67 g, 5.96 mmol,
1.5 equiv) was added dry DMSO (10 mL) at 0 ꢂC then reaction
mixture was stirred at 0 ꢂC for 30 min then at room temperature for
an additional 30 min. To this reaction mixture was added com-
pound 6 (1.2 g, 3.9 mmol,1 equiv) in dry THF (10 mL) at 0 ꢂC and the
reaction mixture was stirred at 0 ꢂC for 30 min and at room tem-
perature for further 30 min. After complete consumption of starting
material, the reaction mixture was quenched with saturated aq
NH4Cl (5 mL). The mixture was diluted with EtOAc (20 mL) and
water (20 mL), organic layer was separated and the aqueous phase
was extracted with EtOAc (2ꢁ15 mL). The combined organic layer
was washed with brine (15 mL), dried over anhydrous Na2SO4, fil-
tered and the solvent was removed under reduced pressure to give
crude material, which was purified by column chromatography
Rf¼0.50 (hexane/EtOAc, 85:15) to give 7 (0.71 g, 56%) as yellow oil;
ane/EtOAc, 95:5) to give 8 (1.24 g, 92%) as transparent syrup; ½a D20
ꢃ
ꢀ3.17 (c 0.60, CHCl3); IR nmax (Neat): 2930, 1465, 1255, 1077,
837 cmꢀ1
;
1H NMR (300 MHz, CDCl3þCCl4) :
d
4.63 (dd, J¼3.0,
6.0 Hz, 1H), 4.41 (dd, J¼3.8, 6.8 Hz, 1H), 4.09 (dd, J¼3.0, 6.8 Hz, 1H),
4.03e3.98 (m, 1H), 3.71 (d, J¼3.8 Hz, 2H), 3.19e3.30 (m, 2H), 1.52 (s,
3H), 1.34 (s, 3H), 0.92 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR
½
a 2D0
1079 cmꢀ1
ꢃ
ꢀ18.46 (c 0.52, CHCl3); IR nmax (Neat): 3475, 2933, 1466, 1256,
;
1H NMR (300 MHz, CDCl3):
d
4.84e4.77 (m, 2H), 4.21
(75 MHz, CDCl3): d 113.5, 85.5, 85.1, 84.7, 82.4, 63.9, 27.3, 25.9, 25.4,
(q, J¼5.5, 9.6 Hz, 1H), 4.14 (t, J¼3.4 Hz, 1H), 3.89e3.78 (m, 2H),
18.3, 6.7, ꢀ5.4, ꢀ5.6; ESIMS: m/z 429 [MþH]þ; HRESIMS: m/z
3.76e3.66 (m, 2H),1.50 (s, 3H), 1.34 (s, 3H), 0.88 (s, 9H), 0.06 (s, 6H);
451.0765 [MþNa]þ (calcd for C15H29O4NaSiI: m/z 451.0777).
13C NMR (75 MHz, CDCl3):
d 112.4, 84.2, 83.3, 82.1, 81.9, 64.9, 62.0,
26.1, 25.8, 24.5, 18.1, ꢀ5.5, ꢀ5.7; ESIMS: m/z 319 [MþH]þ; HRESIMS:
4.2.5. tert-Butyldimethyl(((3aR,4R,6S,6aS)-2,2,6-trimethyl-tetrahy-
drofuro[3,4-d][1,3]dioxol-4-yl)methoxy)silane (9). To the solution of
compound 8 (1.24 g, 2.89 mmol, 1 equiv) in dry benzene (15 mL),
was added mixture of nBu3SnH (1.17 mL, 4.35 mmol, 1.5 equiv) and
AIBN (0.023 g, 0.145 mmol, 5 mol %) in dry benzene slowly drop
wise over 40 min at 80 ꢂC. The reaction mixture was stirred at same
temperature for another 1 h and was allowed to cool to room
temperature and quenched with 10% aq KF solution (40 mL) and
further stirred for 3e4 h. The organic layer was separated; aqueous
layer was extracted with EtOAc (2ꢁ15 mL). The combined organic
layer was washed with brine (15 mL), dried over anhydrous Na2SO4,
solvent was removed under reduced pressure to give crude mate-
rial, which was purified by column chromatography Rf 0.88 (hex-
m/z 341.1762 [MþNa]þ (calcd for C15H30O5NaSi: m/z 341.1760).
4.2.3. ((3aS,4S,6R,6aR)-6-((tert-Butyldimethylsilyloxy)methyl)-2,2-
dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (5). To the
solution of dry DMSO (2.67 mL, 37.7 mmol, 4 equiv) in dry CH2Cl2
(10 mL) was added oxalyl chloride (1.65 mL, 18.8 mmol, 2 equiv) at
ꢀ78 ꢂC drop wise over 15 min and stirred for 20 min at the same
temperature. To this mixture was added compound 7 (3.0 g,
9.4 mmol,1 equiv) dissolved in dry CH2Cl2 (15 mL) added drop wise
over 15 min at ꢀ78 ꢂC and the reaction mixture was stirred at same
temperature for 2 h. The reaction was quenched with Et3N
(7.85 mL, 56.6 mmol, 6 equiv) at ꢀ78 ꢂC, and was allowed to warm
to room temperature, to this water (30 mL) was added, organic
ane/EtOAc, 97:3) to give 9 (0.82 g, 94%) as light yellowish oil; ½a D20
ꢃ

1544
K. Vamshikrishna, P. Srihari / Tetrahedron 68 (2012) 1540e1546
ꢀ2.66 (c 0.64, CHCl3); IR nmax (Neat): 2931, 1465, 1255, 1077 cmꢀ1
;
DMF (1 mL, 13.2 mmol, 0.5 equiv) at room temperature to this
oxalyl chloride (3.4 mL, 39.5 mmol, 1.5 equiv) was added at ꢀ10 ꢂC
drop wise over 10 min. Then reaction mixture was allowed to warm
to room temperature and stirred at room temperature for 12 h
Et2NH (13.5 mL, 131.6 mmol, 5 equiv) was added to the reaction
mixture at 0 ꢂC over 20 min and the reaction mixture was stirred at
30 min at room temperature. The reaction mixture was concen-
trated under reduced pressure to give crude material, which was
purified on column chromatography Rf 0.35 (hexane/EtOAc, 65:35)
to give 11 (5.25 g, 96.5%) as yellowish oil; IR nmax (Neat): 2978, 1627,
1H NMR (300 MHz, CDCl3þCCl4):
4.58 (dd, J¼3.8, 6.6 Hz, 1H), 4.14
d
(t, J¼5.5 Hz, 1H), 3.94e3.89 (m, 2H), 3.75e3.65 (m, 2H), 1.50 (s, 3H),
1.31 (s, 3H), 1.27 (d, J¼6.2 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 113.9, 86.1, 84.4, 82.2, 80.6, 63.7, 27.5, 25.9, 25.5,
19.1, 18.3, ꢀ5.3, ꢀ5.4; ESIMS: m/z 325 [MþNa]þ; HRESIMS: m/z
325.1825 [MþNa]þ (calcd for C15H30O4NaSi: m/z 325.1811).
4.2.6. ((3aR,4R,6S,6aS)-2,2,6-Trimethyl-tetrahydrofuro[3,4-d][1,3]di-
oxol-4-yl)methanol (10). To the solution of compound 9 (0.82 g,
2.72 mmol, 1 equiv) in dry THF (10 mL) was added 1.0 M TBAF so-
lution in THF (4.07 mL, 1.5 equiv) drop wise over 10 min at 0 ꢂC.
Then the reaction mixture was allowed to warm to room temper-
ature while stirring for 2 h. After complete consumption of starting
material, the reaction mixture was quenched with saturated aq
NH4Cl (5 mL), diluted with EtOAc (10 mL), water (10 mL). The or-
ganic layer was separated aqueous layer was extracted with EtOAc
(2ꢁ10 mL). The combined organic layer was washed with brine
(10 mL), dried over anhydrous Na2SO4, solvent was removed under
reduced pressure to give crude material, which was purified by
column chromatography Rf 0.20 (hexane/EtOAc, 60:40) to give 10
1431, 1243, 1018 cmꢀ1; 1H NMR (300 MHz, CDCl3þCCl4):
d 7.32 (dt,
J¼1.7, 7.4 Hz, 1H), 7.19 (dd, J¼1.7, 7.4 Hz, 1H), 6.96 (dt, J¼0.8, 7.4 Hz,
1H), 6.90 (d, J¼8.3 Hz, 1H), 3.81 (s, 3H), 3.59e3.55 (m, 2H), 3.14 (q,
J¼7.2 Hz, 2H), 1.24 (t, J¼7.2 Hz, 3H), 1.03 (t, J¼7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d 168.6, 155.1, 129.7, 127.3, 126.9, 120.6, 110.8, 55.4,
42.7, 38.7, 13.8, 12.8; ESIMS: m/z 230 [MþNa]þ; HRESIMS: m/z
208.1342 [MþH]þ (calcd for C12H18NO2: m/z 208.1337).
4.2.9. N,N-Diethyl-2-formyl-6-methoxybenzamide (12). To the so-
lution of TMEDA (5.41 mL, 36.2 mmol, 1.5 equiv) in anhydrous THF
was added 1.3 M sBuLi (27.9 mL, 1.5 equiv) drop wise at ꢀ78 ꢂC,
reaction mixture was stirred at ꢀ78 ꢂC for 10 min, to this compound
11 (5.0 g, 24.2 mmol, 1 equiv) in dry THF was added drop wise over
20 min, and reaction mixture was stirred at same temperature over
2 h, after reaction mixture was quenched with DMF (7.5 mL,
96.6 mmol, 4 equiv) at ꢀ78 ꢂC then allowed to warm to room
temperature. After complete conversion of starting material, satu-
rated NH4Cl (15 mL), was added to the reaction mixture at 0 ꢂC
diluted with EtOAc and water (30 mL), organic layer was separated,
aqueous layer was extracted with EtOAc (2ꢁ50 mL), combined or-
ganic layer was washed with brine (50 mL), dried over anhydrous
Na2SO4, 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 12 (4.0 g, 70.4%) as yellow oil; IR nmax
a 20
(0.5 g, 98%) as colorless oil; ½ ꢃD þ6.04 (c 0.48, CHCl3); IR nmax
(Neat): 3450, 2982, 1378, 1212, 1076 cmꢀ1 1H NMR (300 MHz,
;
CDCl3þCCl4):
d
4.58 (dd, J¼4.5, 6.8 Hz, 1H), 4.16 (dd, J¼6.0, 7.6 Hz,
1H), 3.96e3.88 (m, 2H), 3.78 (d, J¼12.1 Hz, 1H), 3.64e3.60 (br m,
1H), 1.89 (br s, 1H), 1.50 (s, 3H), 1.31 (s, 3H), 1.30 (d, J¼5.3 Hz, 3H);
13C NMR (75 MHz, CDCl3):
d 114.7, 86.1, 84.2, 81.6, 80.5, 62.6, 27.3,
25.4, 18.8; ESIMS: m/z 186 [MꢀH2]þ; HRESIMS: m/z 211.0954
[MþNa]þ (calcd for C9H16O4Na: m/z 211.0946).
4.2.7. (3aS,4S,6R,6aR)-2,2,4-Trimethyl-6-vinyl-tetrahydrofuro[3,4-d]
[1,3]dioxole (3). To the solution of dry DMSO (1.40 mL, 19.7 mmol,
4 equiv) in dry CH2Cl2 (10 mL) was added oxalyl chloride (0.86 mL,
9.89 mmol, 2 equiv) at ꢀ78 ꢂC drop wise over 15 min and the re-
action mixture was stirred for 20 min at same temperature. To this
was added compound 10 (0.93 g, 4.94 mmol, 1 equiv) in dry CH2Cl2
(10 mL) drop wise over 15 min at ꢀ78 ꢂC, and stirred at same
temperature for 2 h. The reaction mixture was quenched with Et3N
(4.19 mL, 29.6 mmol, 6 equiv) at ꢀ78 ꢂC, and was allowed to warm
to room temperature and quenched with addition of water (15 mL).
The organic layer was separated, aqueous layer was extracted with
CH2Cl2 (2ꢁ20 mL), combined organic layer was washed with brine
(20 mL), dried over anhydrous Na2SO4, solvent was removed under
reduced pressure to give crude material, which was purified by
flash column chromatography (hexane/EtOAc, 95:5) to give the
aldehyde (0.7 g, 76%) as yellow oil. The above aldehyde in dry THF
(3 mL) was added to the mixture of methyltriphenylphosphonium
iodide (3.04 g, 7.52 mmol, 2 equiv) and potassium tert-butoxide
(0.76 g, 6.78 mmol, 1.8 equiv) in dry THF, at 0 ꢂC. The reaction
mixture was allowed to warm to room temperature and stirred at
room temperature for 2 h. Reaction mixture was quenched with
water (2 mL) and diluted with diethyl ether and hexane (1:1)
(40 mL). The white precipitate formed, which was filtered off
through a small pad of Celite and the filtrate was dried over an-
hydrous Na2SO4, solvent was removed under reduced pressure to
give crude material, which was purified by column chromatogra-
phy Rf 0.95 (hexane/EtOAc, 97:3) to give 3 (0.46 g, 65.7%) as light
(Neat): 2977, 1700, 1630, 1469, 1269 cmꢀ1 1H NMR (300 MHz,
;
CDCl3þCCl4) :
d
9.94 (s, 1H), 7.50 (d, J¼7.6 Hz, 1H), 7.42 (t, J¼7.6 Hz,
1H), 7.12 (d, J¼8.3 Hz, 1H), 3.86 (s, 3H), 3.75e3.64 (m, 1H),
3.56e3.47 (m, 1H), 3.09 (q, J¼6.8 Hz, 2H), 1.29 (t, J¼6.8 Hz, 3H), 1.01
(t, J¼7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 190.2, 165.5, 155.2,
133.1, 129.6, 128.4, 120.9, 116.2, 55.6, 42.4, 38.6, 13.3, 12.2; ESIMS:
m/z 236 [MþH]þ; HRESIMS: m/z 258.1111 [MþNa]þ (calcd for
C13H17NO3Na: m/z 258.1106).
4.2.10. 3-Hydroxy-7-methoxyisobenzofuran-1(3H)-one (13). To the
compound 12 (3.0 g), 10% HCl (40 mL) was added and the reaction
mixture was heated at 100 ꢂC for 24 h. After reaction mixture was
allowed to cool to room temperature, the solvent was removed
under reduced pressure to give crude material, which was purified
by silica gel column chromatography Rf 0.95 (MeOH/CHCl3, 95:5) to
give 13 (1.5 g, 65.2%) as white fluffy solid; IR nmax (KBr): 3355, 2969,
1732, 1605, 1487, 1044 cmꢀ1; 1H NMR (300 MHz, DMSO-d6):
d 7.75
(d, J¼8.1 Hz, 1H), 7.63 (t, J¼7.9 Hz, 1H), 7.11 (d, J¼7.6 Hz, 1H), 7.01 (d,
J¼8.3 Hz, 1H), 6.41 (d, J¼7.7 Hz, 1H), 3.98 (s, 3H); 13C NMR (75 MHz,
DMSO-d6):
d 166.1, 157.5, 150.0, 136.8, 115.1, 113.3, 112.7, 96.6, 55.9;
EIMS: m/z 180 [M]þ; HRESIMS: m/z 181.0505 [MþH]þ (calcd for
C9H9O4: m/z 181.0500).
yellowish oil; ½a D20
ꢃ
þ8.59 (c 0.64, CHCl3); IR nmax (Neat): 2927, 1376,
4.2.11. Methyl 2-methoxy-6-vinylbenzoate (4). To the mixture of
methyltriphenylphosphonium iodide (16.8 g, 41.7 mmol, 5 equiv)
and potassium tert-butoxide (4.5 g, 39.9 mmol, 4.8 equiv) was
added dry THF (50 mL) at 0 ꢂC and reaction mixture was allowed to
warm to room temperature while stirring for 1 h. The reaction
mixture was cooled to 0 ꢂC and to this was added compound 13
(1.5 g, 8.33 mmol, 1 equiv) in dry THF (15 mL). The reaction mixture
was allowed to warm to room temperature and further stirred for
5 h. To this reaction mixture methyl iodide (5.18 mL, 83.3 mmol,
1211, 1079 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
5.94e5.83 (m, 1H),
5.36 (dt, J¼1.5, 17.4 Hz, 1H), 5.20 (dd, J¼1.5, 10.6 Hz, 1H) 4.43 (dd,
J¼4.5, 6.8 Hz), 4.29e4.23 (m, 2H), 4.01e3.94 (m, 1H), 1.53 (s, 3H),
1.32, (s, 3H), 1.29 (d, J¼6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d
135.9, 117.3, 114.9, 86.1, 85.3, 84.9, 80.1, 27.3, 25.4, 18.9.
4.2.8. N,N-Diethyl-2-methoxybenzamide (11). To the solution of
o-anisic acid (4.0 g, 26.3 mmol, 1 equiv) in dry CH2Cl2 was added

K. Vamshikrishna, P. Srihari / Tetrahedron 68 (2012) 1540e1546
1545
10 equiv) was added at room temperature and further stirred for
12 h. Reaction mixture was quenched with water (2 mL) and di-
luted with diethyl ether and hexane (1:1) (40 mL). The white pre-
cipitate formed, which was filtered off through a small pad of Celite
and the filtrate was dried over anhydrous Na2SO4, solvent was re-
moved under reduced pressure to give crude material, which was
purified by column chromatography Rf 0.85 (hexane/EtOAc, 95:5) to
give 4 (1.05 g, 65.6%) as yellow oil; IR nmax (Neat): 2950, 1731, 1573,
(5 mL) and the organic layer was separated. The aqueous layer was
extracted with EtOAc (2ꢁ5 mL) and the combined organic layer was
washed with brine (5 mL), dried over anhydrous Na2SO4. The sol-
vent was evaporated under reduced pressure to give crude product,
which was purified by column chromatography Rf 0.30 (hexane/
EtOAc, 20:80) to give (þ)-1 (0.015 g, 58%) as white solid; ½a D20
ꢃ
þ37.00 (c 0.4, MeOH); IR nmax (KBr): 3378, 2924, 1464, 1260,
1090 cmꢀ1; 1H NMR (300 MHz, acetone-d6):
d
7.22 (t, J¼7.9 Hz, 1H),
1468, 1269, 1072 cmꢀ1; 1H NMR (300 MHz, CDCl3þCCl4) :
d
7.28 (t,
7.15 (br s, 1H), 7.11 (d, J¼5.5 Hz, 1H), 6.89 (d, J¼8.1 Hz, 1H), 6.20 (dd,
J¼6.6,15.9 Hz,1H), 4.70 (br s, 2H), 4.30e4.27 (m, 1H), 3.92e3.88 (m,
1H), 3.85e3.78 (m, 1H), 3.82 (s, 3H), 3.70e3.67 (m, 1H), 1.26 (d,
J¼7.9 Hz, 1H), 7.12 (d, J¼7.9 Hz, 1H), 6.79 (d, J¼8.3 Hz, 1H), 6.63 (dd,
J¼10.9, 17.4 Hz, 1H), 5.70 (d, J¼17.4 Hz, 1H), 5.31 (d, J¼10.9 Hz, 1H),
3.89 (s, 3H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
168.3, 156.2,
J¼6.4 Hz, 3H); 13C NMR (75 MHz, acetone-d6þCDCl3):
d 158.7, 138.7,
136.1,133.2,130.3,122.5,117.4,117.1,109.9, 55.8, 52.2; EIMS: m/z 192
[M]þ; HRESIMS: m/z 193.0860 [MþH]þ (calcd for C11H13O3: m/z
193.0864).
132.2, 129.2, 129.1, 127.6, 119.2, 110.4, 85.1, 79.9, 76.9, 76.2, 55.9,
55.5, 19.4; ESIMS: m/z 303 [MþNa]þ; HRESIMS: m/z 303.1231
[MþNa]þ (calcd for C17H19O5Na: m/z 303.1232).
4.2.12. Methyl 2-methoxy-6-((E)-2-((3aR,4R,6S,6aS)-2,2,6-trimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)vinyl)benzoate (2). To the
degassed solution of compound 4 (0.313 g, 1.63 mmol, 1.5 equiv),
and compound 3 (0.2 g, 1.09 mmol, 1 equiv) in dry CH2Cl2 (40 mL)
was added Grubbs II generation catalyst (0.046 g, 0.054 mmol,
0.05 equiv) and the reaction mixture was refluxed for 12 h. The
reaction mixture was concentrated under reduced pressure, puri-
fied by column chromatography Rf 0.40 (hexane/EtOAc, 90:10) to
4.2.15. tert-Butyl(((3aR,4R,6S,6aR)-6-(iodomethyl)-2,2-dimethyl-tet-
rahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)dimethylsilane
(15). Similar procedure was followed as used earlier for the syn-
thesis of 8 to yield 15 (96%) as light yellowish liquid; ½a D20
ꢃ
ꢀ23.65 (c
0.96, CHCl3); IR nmax (Neat): 2932, 1256, 1125, 838 cmꢀ1
;
1H NMR
(500 MHz, CDCl3þCCl4) :
d
4.80 (d, J¼5.9 Hz, 1H), 4.72 (dd, J¼3.6,
5.9 Hz, 1H), 4.39e4.34 (m, 1H), 4.06 (t, J¼2.9 Hz, 1H), 3.70 (dq,
J¼2.9, 10.9, 13.8 Hz, 2H), 3.26 (t, J¼7.9 Hz, 1H), 3.17 (dd, J¼5.9,
8.9 Hz, 1H), 1.48 (s, 3H), 1.35 (s, 3H), 0.91 (s, 9H), 0.08 (s, 3H), 0.07 (s,
give 2 (0.211 g, 56%) as colorless liquid; ½a D20
ꢃ
þ29.82 (c 0.56, CHCl3);
IR nmax (Neat): 2928, 1731, 1467, 1268, 1073 cmꢀ1
;
1H NMR
3H); 13C NMR (75 MHz, CDCl3):
d 112.3, 84.7, 83.4, 83.3, 81.3, 65.1,
(300 MHz, CDCl3):
d
7.30 (t, J¼8.3 Hz,1H), 7.12 (d, J¼7.6 Hz,1H), 6.82
26.2, 25.8, 24.9, 18.1, 0.9, ꢀ5.6, ꢀ5.7; ESIMS: m/z 451 [MþNa]þ;
HRESIMS: m/z 451.0756 [MþNa]þ (calcd for C15H29O4NaSiI: m/z
451.0777).
(d, J¼8.3 Hz, 1H), 6.65 (d, J¼15.9 Hz, 1H), 6.22 (dd, J¼6.0, 15.9 Hz,
1H), 4.51 (dd, J¼4.5, 6.8, Hz, 1H), 4.44e4.40 (m, 1H), 4.32 (dd, J¼4.5,
6.8 Hz, 1H), 4.08e3.99 (m, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 1.56 (s, 3H),
1.34 (d, J¼6.8 Hz, 3H), 1.34 (s, 3H); 13C NMR (75 MHz, CDCl3):
4.2.16. tert-Butyldimethyl(((3aR,4R,6R,6aS)-2,2,6-trimethyl-tetrahy-
drofuro[3,4-d][1,3]dioxol-4-yl)methoxy)silane (16). Similar pro-
cedure was followed as used earlier for the synthesis of 9 to yield in
d
168.2, 156.5, 135.3, 130.7, 130.4, 128.4, 122.9, 118.0, 114.9, 110.1,
86.2, 85.6, 84.5, 80.4, 55.9, 52.3, 27.3, 25.5, 19.1; ESIMS: m/z 371
[MþNa]þ; HRESIMS: m/z 371.1461 [MþNa]þ (calcd for C19H24O6Na:
m/z 371.1470).
16 in 90% yield as colorless liquid; ½a D20
ꢃ
ꢀ6.61 (c 0.56, CHCl3); IR
nmax (Neat): 2934, 1375, 1257, 1087 cmꢀ1
;
1H NMR (300 MHz,
CDCl3þCCl4):
d
4.74 (d, J¼6.0 Hz, 1H) 4.51 (dd, J¼3.8, 6.0 Hz, 1H),
4.2.13. (2-Methoxy-6-((E)-2-((3aR,4R,6S,6aS)-2,2,6-trimethyl-tetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)vinyl)phenyl)methanol (14). To the
solution of compound 2 (0.1 g, 0.25 mmol, 1 equiv) in dry CH2Cl2
(5 mL) was added 1.5 M DIBAL-H (0.48 mL) in toluene drop wise at
ꢀ78 ꢂC over 5 min, reaction mixture was stirred at same temper-
ature for 2 h. The reaction mixture was quenched with saturated
NaeK tartarate solution (5 mL) and was allowed to warm to room
temperature while continuing stirring for 5 h. The organic layer
was separated and aqueous layer was extracted with CH2Cl2
(2ꢁ5 mL), combined organic layer was washed with brine (5 mL),
dried over anhydrous Na2SO4. The solvent was removed under re-
duced pressure to give crude material, which was purified by col-
umn chromatography Rf 0.40 (hexane/EtOAc, 65:35) to give 14
4.16e4.09 (m, 1H), 3.97 (t, J¼3.8 Hz, 1H), 3.66 (d, J¼3.8 Hz, 2H), 1.47
(s, 3H), 1.32 (s, 3H), 1.23 (d, J¼6.8 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H);
13C NMR (75 MHz, CDCl3):
d 111.9, 84.0, 83.4, 82.7, 78.1, 64.6, 26.2,
25.7, 25.0, 18.0, 14.5, ꢀ5.6, ꢀ5.7; ESIMS: m/z 325 [MþNa]þ; HRE-
SIMS: m/z 325.1819 [MþNa]þ (calcd for C15H30O4NaSi: m/z
325.1811).
4.2.17. ((3aR,4R,6R,6aS)-2,2,6-Trimethyl-tetrahydrofuro[3,4-d][1,3]
dioxol-4-yl)methanol (17). Similar procedure was followed as used
earlier for the synthesis of 10 to give 17 in 95% as colorless liquid;
½
a 2D0
1033 cmꢀ1
ꢃ
þ7.12 (c 0.52, CHCl3); IR nmax (Neat): 3445, 2937, 1378, 1210,
;
1H NMR (300 MHz, CDCl3þCCl4):
d 4.59e4.52 (m, 2H)
4.08e4.01 (m, 2H), 3.56 (d, J¼6.0 Hz, 2H), 1.87 (br s,1H), 1.49 (s, 3H),
(0.07 g, 76%) as colorless oil; ½a D20
þ29.77 (c 0.44, CHCl3); IR nmax
ꢃ
1.32 (s, 3H), 1.28 (d, J¼6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
(Neat): 3451, 2926, 1578, 1465, 1261, 1078 cmꢀ1; 1H NMR (500 MHz,
d 112.4, 84.1, 82.7, 82.2, 76.6, 61.7, 26.2, 25.0, 14.1; ESIMS: m/z 186
CDCl3þCCl4):
d
7.18 (t, J¼7.9 Hz, 1H), 7.05 (d, J¼8.9 Hz, 1H), 7.02 (d,
[MꢀH2]þ; HRESIMS: m/z 211.0951 [MþNa]þ (calcd for C9H16O4Na:
m/z 211.0946).
J¼15.8 Hz, 1H), 6.77 (d, J¼7.9 Hz, 1H), 6.12 (dd, J¼5.9, 15.8 Hz, 1H),
4.74 (s, 2H), 4.49e4.48 (m, 1H), 4.41e4.39 (m, 1H), 4.28e4.26 (m,
1H), 4.02e3.96 (m, 1H), 3.87 (s, 3H), 1.55 (s, 3H), 1.35 (d, J¼5.9 Hz,
4.2.18. (3aS,4R,6R,6aR)-2,2,4-Trimethyl-6-vinyl-tetrahydrofuro[3,4-
d][1,3]dioxole (18). Similar procedure was followed as used earlier
for the synthesis of 3 to give 18 in 68% yield as a yellowish liquid;
3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3þCCl4):
d 158.1, 137.7,
131.0, 129.2, 128.7, 126.8, 119.5, 115.0, 109.6, 86.4, 85.8, 84.7, 80.3,
56.8, 55.6, 27.6, 25.7, 19.2; ESIMS: m/z 343 [MþNa]þ; HRESIMS: m/z
343.1509 [MþNa]þ (calcd for C18H24O5Na: m/z 343.1521).
½
a 2D0
1074 cmꢀ1
ꢃ
þ24.11 (c 0.56, CHCl3); IR nmax (Neat): 2928, 1375, 1213,
;
1H NMR (300 MHz, CDCl3þCCl4):
d 5.80e5.69 (m, 1H),
5.28 (d, J¼17.4 Hz,1H), 5.16 (d, J¼10.6 Hz,1H), 4.59 (d, J¼6.2 Hz,1H),
4.2.14. (2R,3S,4R,5S,E)-2-(2-(Hydroxymethyl)-3-methoxystyryl)-5-
methyl-tetrahydrofuran-3,4-diol ((þ)-1). To the solution of com-
pound 14 (0.03 g, 0.094 mmol) in THF (3 mL) was added 1 N HCl
(3 mL) and reaction mixture was stirred at room temperature for
3 h. After complete conversion of starting material, reaction mix-
ture was quenched with solid NaHCO3 (2.0 g), diluted with EtOAc,
4.50e4.47 (m, 2H), 3.93e3.86 (m, 1H) 1.49 (s, 3H), 1.31 (s, 3H), 1.29
(d, J¼6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 135.1, 115.6, 111.9,
85.5, 83.4, 82.2, 75.9, 26.2, 25.2, 13.8.
4.2.19. Methyl 2-methoxy-6-((E)-2-((3aR,4R,6R,6aS)-2,2,6-trimethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)vinyl)benzoate (19). Similar

1546
K. Vamshikrishna, P. Srihari / Tetrahedron 68 (2012) 1540e1546
Flatt, P.; Gerwick, H. W. Mol. Cancer Ther. 2005, 4, 333e342; (c) Faulkner, J. D.
Nat. Prod. Rep. 2000, 17, 7e55.
2. Malmstrom, J.; Christophersen, C.; Barrero, A. F.; Oltra, J. E.; Justicia, J.; Rosales,
procedure was followed as used earlier for the synthesis of 2 to give
19 in 62% yield as sticky liquid; ½a D20
ꢃ
þ34.02 (c 1.12, CHCl3); IR nmax
(Neat): 2931, 1731, 1468, 1268, 1069 cmꢀ1
;
1H NMR (500 MHz
A. J. Nat. Prod. 2002, 65, 364e367.
3. Mayer, A. M. S.; Gustafson, K. R. Eur. J. Cancer 2004, 40, 2676e2704.
4. (a) Clemens, R. T.; Jennings, M. P. Chem. Commun. 2006, 2720e2721; (b)
McAllister, G. D.; Robinson, J. E.; Taylor, R. J. K. Tetrahedron 2007, 63,
12123e12130.
5. (a) Kumar, V.; Shaw, A. K. J. Org. Chem. 2008, 7526e7531; (b) Palik, M.; Kar-
lubikova, O.; Lasikova, A.; Kozisek, J.; Gracza, T. Eur. J. Org. Chem. 2009, 5,
709e715; (c) Brichacek, M.; Batory, L. A.; McGrath, N. A.; Njardarson, J. T. Tet-
CDCl3þCCl4):
d
7.26 (t, J¼7.9 Hz, 1H), 7.03 (d, J¼7.9 Hz, 1H), 6.78 (d,
J¼8.9 Hz, 1H), 6.53 (d, J¼15.8 Hz, 1H), 6.02 (dd, J¼3.9, 15.8 Hz, 1H),
4.64 (d, J¼5.9 Hz, 1H), 4.62 (br s, 1H), 4.51 (dd, J¼3.9, 5.9 Hz, 1H),
3.96e3.92 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 1.50 (s, 3H), 1.32 (s, 3H),
1.31 (d, J¼3.9 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 168.3, 156.4,
135.3, 130.5, 129.5, 127.6, 122.6, 117.9, 112.4, 110.1, 85.8, 83.4, 82.2,
76.4, 55.9, 52.3, 26.2, 25.1, 13.8; ESIMS: m/z 371 [MþNa]þ; HRE-
SIMS: m/z 371.1462 [MþNa]þ (calcd for C19H24O6Na: m/z 371.1470).
ꢀ
ꢀ
rahedron 2010, 66, 4832e4840; (d) Palík, M.; Karlubíkova, O.; Lackovicova, D.;
ꢀ
ꢀ
Lasikova, A.; Gracza, T. Tetrahedron 2010, 66, 5244e5249; (e) Srinivas, B.;
Sridhar, R.; Rama Rao, K. Tetrahedron 2010, 66, 8527e8535; (f) Ghosh, S.;
Pradhan, T. K. J. Org. Chem. 2010, 75, 2107e2110; (g) Palik, M.; Karlubikova, O.;
Lasikova, A.; Kozisek, J.; Gracza, T. Synthesis 2010, 20, 3449e3452; (h) Zeng, J.;
Seenuvasan, V.; Xiang, S.; Liu, X.-W. Org. Lett. 2011, 13, 42e45 While under
consideration of our manuscript, the following publications have appeared; (i)
Ghosal, P.; Sharma, D.; Kumar, B.; Meena, S.; Sinha, S.; Shaw, A. K. Org. Biomol.
Chem. 2011, 9, 7372e7383; (j) Nagarapu, L.; Paparaju, V.; Satyender, A.; Raja-
shaker, B. Tetrahedron Lett. 2011, 52, 7075e7078.
4.2.20. (2R,3S,4R,5R,E)-2-(2-(Hydroxymethyl)-3-methoxystyryl)-5-
methyl-tetrahydrofuran-3,4-diol (20). Compound 20 was prepared
from 19 on reduction of ester moiety with DIBAL-H, following the
similar procedure as given for the synthesis of 14. Acetonide depro-
tection was achieved with 1 N HCl to give 20 as white solid with an
6. (a) Nagarapu, L.; Paparaju, V.; Satyender, A. Bioorg. Med. Chem. Lett. 2008, 18,
2351e2354; (b) Senthilmurugan, A.; Aidhen, I. S. Eur. J. Org. Chem. 2010, 3,
555e564.
overall yield of 58%; ½a D20
þ35.58 (c 0.52, MeOH); IR nmax (KBr): 3440,
ꢃ
3306, 2970, 1580, 1471, 1259 cmꢀ1; 1H NMR (400 MHz, acetone-d6):
7. (a) Srihari, P.; Satyanarayana, K.; Ganganna, B.; Yadav, J. S. J. Org. Chem. 2011, 76,
1922e1925; (b) Yadav, J. S.; Kumaraswamy, B.; Sathish Reddy, A.; Srihari, P.;
Janakiram, R. V.; Kalivendi, S. V. J. Org. Chem. 2011, 76, 2568e2576; (c) Srihari,
P.; Kumarasway, B.; Bhunia, D. C.; Yadav, J. S. Tetrahedron Lett. 2010, 51,
2903e2905; (d) Srihari, P.; Kumaraswamy, B.; Shankar, P.; Ravishashidhar, V.;
Yadav, J. S. Tetrahedron Lett. 2010, 51, 6174e6176; (e) Srihari, P.; Rao, G. M.; Rao,
R. S.; Yadav, J. S. Synthesis 2010, 2407e2412; (f) Srihari, P.; Kumarasway, B.;
Somaiah, R.; Yadav, J. S. Synthesis 2010, 1039e1045; (g) Srihari, P.; Kumar-
aswamy, B.; Rao, G. M.; Yadav, J. S. Tetrahedron: Asymmetry 2010, 21, 106e111;
(h) Srihari, P.; Bhasker, E. V.; Reddy, A. B.; Yadav, J. S. Tetrahedron Lett. 2009, 50,
2420e2424.
d
7.22 (t, J¼7.3 Hz, 1H), 7.13 (d, J¼7.3 Hz, 1H), 7.07 (d, J¼15.9 Hz, 1H),
6.88 (d, J¼7.9 Hz,1H), 6.20 (dd, J¼6.5,15.9 Hz,1H), 4.72e4.70 (m, 2H),
4.33 (t, J¼6.5 Hz, 1H), 4.24e4.18 (m, 1H), 4.07e3.99 (m, 2H), 3.82 (s,
3H), 1.21 (d, J¼6.5 Hz, 3H); 13C NMR (75 MHz, acetone-d6):
d 159.9,
140.2, 134.2, 130.3, 129.9, 128.9, 120.4, 111.6, 84.1, 79.8, 78.1, 74.9, 57.1,
56.5, 16.6; ESIMS: m/z 303 [MþNa]þ; HRESIMS: m/z 303.1198
[MþNa]þ (calcd for C15H20O5Na: m/z 303.1208).
8. (a) Frechou, C.; Dheilly, L.; Beaupere, D.; Uzan, R.; Demailly, G. Tetrahedron Lett.
1992, 33, 5067e5070; (b) Yadav, J. S.; Sreedhar, P.; Bhunia, D. C.; Srihari, P.
Synlett 2007, 992e994; (c) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84,
867e868.
9. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651e1660.
10. Dondoni, A.; Formaglio, P.; Marra, A.; Massi, A. Tetrahedron 2001, 57,
Acknowledgements
V.K. thank CSIR, New Delhi for financial assistance. P.S.H. thank
Department of Science & Technology (DST) for financial assistance
under SERC FAST Track Scheme no. SR/FT/CS-036/2009, GAP-0284.
The authors also thank Dr. J.S. Yadav, Director, IICT for his constant
encouragement and support.
7719e7727.
11. The syn geometry was confirmed based on 2D NMR studies wherein NOESY
correlation was observed for the protons at
Supplementary data).
d 4.07 and 4.22 ppm (see
12. (a) Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron Lett. 1998, 39,
6335e6336; (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102,
4009e4091.
Supplementary data
13. Wacker, D. A.; Varnes, J. G.; Malmstrom, S. E.; Cao, X.; Hung, C.-P.; Ung, T.; Wu,
G.; Zhang, G.; Zuvich, E.; Thomas, M. A.; Keim, W. J.; Cullen, M. J.; Rohrbach, K.
W.; Qu, A.; Narayanan, R.; Rossi, K.; Janovitz, E.; McKeeman, L. L.; Malley, M. F.;
Devenny, J.; Pelleymounter, M. A.; Miller, K. J.; Robl, J. A. J. Med. Chem. 2007, 50,
1365e1379.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.12.008. These data include MOL files and
InChIKeys of the most important compounds described in this article.
14. (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 11360e11370 For other reviews see; (b) Grubbs, R. H. Tetrahedron
2004, 60, 7117e7140; (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4490e4527; (d) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta
2007, 40, 45e52.
References and notes
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Prod. Rep. 2011, 28, 196e268; (b) Simmons, L. T.; Andrianasolo, E.; McPhail, K.;