Chemoenzymatic total synthesis of potent HIV RNase H inhibitor (-)-1,3,4,5-tetragalloylapiitol

Article abstract of DOI:10.1016/j.tetasy.2010.11.032

Starting from racemic dimethyl 2-acetoxy-3-methylenesuccinate, the chemoenzymatic facile total synthesis of (-)-1,3,4,5-tetragalloylapiitol has been demonstrated via an efficient lipase catalyzed resolution followed by a DIBAL reduction-double gallyolatio

Full text of DOI:10.1016/j.tetasy.2010.11.032

Tetrahedron: Asymmetry 22 (2011) 173–177
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemoenzymatic total synthesis of potent HIV RNase H inhibitor
(ꢀ)-1,3,4,5-tetragalloylapiitol
Ramesh U. Batwal, Ramesh M. Patel, Narshinha P. Argade
⇑
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from racemic dimethyl 2-acetoxy-3-methylenesuccinate, the chemoenzymatic facile total syn-
thesis of (ꢀ)-1,3,4,5-tetragalloylapiitol has been demonstrated via an efficient lipase catalyzed resolution
followed by a DIBAL reduction–double gallyolation, osmium tetroxide dihydroxylation–double gallyola-
tion, and reductive global O-benzyl deprotection pathway.
Received 24 November 2010
Accepted 26 November 2010
Available online 12 January 2011
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
started our synthesis with the selenium dioxide allylic oxidation
of dimethyl itaconate 2 and obtained the desired product ( )-4,
Polygalloylated sugars have recently been isolated as bioactive
natural products and they possess anti-HIV, antiviral, antitumor
and antidiabetic activities (Fig. 1).1–3 HIV-1 RNase H is an attrac-
tive molecular target for the development of new anti-HIV agents
as potential chemotherapeutics.4–6 Gustafson et al. isolated a new
potent HIV RNase H inhibitor (ꢀ)-1,3,4,5-tetragalloylapiitol 1a
from an extract of the plant Hylodendron gabunensis.1 The struc-
tural features revealed that the natural products (ꢀ)-apiitol7
and gallic acid could be the biogenetic precursors of 1a. Starting
from citraconic anhydride, we designed the pentahydroxy sugar
apiitol and reported the first total synthesis of ( )-1,3,4,5-tetrag-
alloylapiitol 1a.8 Very recently, Kraus and Kempema also
accomplished a flexible racemic synthesis of 1a using the 1,3-
dihydroxyacetone dimer as the starting material.9 The chemoen-
but only in 37% yield (Scheme 1). All our attempts to further im-
prove the yield were ineffective and under the forced reaction con-
ditions, we always ended up with the formation of decomposed
materials and polymeric gums. Even the use of a catalytic amount
of SeO2 and t-BuOOH at room temperature for the conversion of 2
to ( )-4 was not effective and the starting material remained unre-
acted. Finally starting from dimethyl tartarate 3, the required pre-
cursor ( )-4 was synthesized in three steps with very good overall
yield by using the known Baylis–Hillman reaction between the
methyl 2-oxoacetate and methyl acrylate, followed by an O-acyla-
tion step.13
On the basis of the higher acidity of the methine proton in
(ꢀ)-4 and the anticipated propensity for racemization, an enzy-
matic resolution of ( )-4 appeared more appropriate. Hence sys-
tematic studies on the biphasic hydrolytic enzymatic resolution
of ( )-4 using the promising enzymes Pig pancreas lipase (PPL),
Candida cylindracea lipase (CCL), and Pseudomonas cepacia lipase
(Amano PS) for the preparation of enantiomerically pure (ꢀ)-4
were planned.12–14 The enzyme PPL was ineffective in recognizing
our racemic substrate 4, while we obtained very low enantiomeric
excess when using the enzyme CCL (Table 1, entry 4). Fortunately,
the readily available and relatively inexpensive enzyme Amano PS,
which is specific for the secondary alcohols, better recognized our
starting material ( )-4. The Amano PS catalyzed resolutions of ( )-4
at 25 °C and 35 °C were found to be slow (Table 1, entries 5 and 6).
The same Amano PS catalyzed biphasic resolution of ( )-4 at 50 °C
furnished the desired unhydrolyzed enantiomerically pure (ꢀ)-4 in
42% yield with 97% ee (by chiral HPLC) in 84 h (Table 1, entry 7). In
the above mentioned enzymatic resolution the hydrolyzed alcohol
(+)-5 was obtained in 58% yield, but with only 53% ee. The same
reaction at about 40% conversion also provided the product (+)-5
in very good yield with 87% ee (by chiral HPLC).15 We can infer that
both the multifunctional enantiomerically pure products (ꢀ)-4 and
zymatic synthesis provides
a powerful approach and new
opportunities for accessing chemical diversity.10 In continuation
of our studies on both cyclic anhydrides and derivatives to bioac-
tive natural and unnatural products,11 and efficient enzymatic
resolutions,12 starting from ( )-dimethyl 2-acetoxy-3-methylene-
succinate 4, we herein report our results on the first total
synthesis of enantiomerically pure (ꢀ)-1a (Schemes 1 and 2).
2. Results and discussions
We reasoned that ( )-dimethyl 2-acetoxy-3-methylenesucci-
nate 4 could be a potential precursor for the chemoenzymatic total
synthesis of (ꢀ)-1,3,4,5-tetragalloylapiitol 1a via lipase catalyzed
resolution followed by reduction of two ester units and the conse-
quent carbon–carbon double bond dihydroxylation route. We
⇑
Corresponding author. Tel.: +91 20 25902333; fax: +91 20 25902629.
E-mail address: np.argade@ncl.res.in (N.P. Argade).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.032

174
R. U. Batwal et al. / Tetrahedron: Asymmetry 22 (2011) 173–177
OH
OH
O
OH
O
O
OH
OH
O
(S)
HO
HO
OH
OH
O
O
O
OH
O
HO
OH
OH
1,3,4,5-Tetragalloylapiitol 1a
(anti-HIV)1
OH
HO
OH
HO
OH
OH
HO
OH
O
HO
O
O
OH
O
O
OH
OH
O
O
O
O
O
O
O
OH
O
O
O
HO
O
O
O
OH
HO
OH
OH
HO
OH
HO
HO
OH
OH
OH
HO
Sanguiin H-5 1b
(antiviral/antitumor)2
1,2,3,4,6-Penta-O-galloyl-D-glucopyranose 1c
(antidiabetic)3
Figure 1. Recently isolated bioactive natural products with the polygalloylated sugar architectures.1–3
O
O
O
OH
OH
MeO
MeO
MeO
MeO
MeO
MeO
SeO2, AcOH
3-steps (56%)
(ref. 13)
reflux, 5 h (37%)
OAc
O
O
O
Dimethyl
Dimethyl
( )-4
tartarate 3
itaconate 2
Scheme 1. Synthesis of ( )-dimethyl 2-acetoxy-3-methylenesuccinate 4.
O
O
O
O
O
ArOCO
ArOCO
MeO
MeO
HO
HO
MeO
MeO
MeO
MeO
HCl (2 M)
DIBAL
ArCOOH
TBDMSCl
THF, -78 oC
EDCI
MeOH
(90%)
Imidazole
OTBDMS
OAc
OTBDMS
OH
OTBDMS
(95%)
(96%)
(73%)
H
H
H
H
H
O
(-)-8
(-)-7
(+)-6
(-)-5 (~100% ee)
(-)-4 (97% ee)
OH
OH
OH
OH
Ar'OCO
Ar'OCO
OCOAr'
H2, Pd/C
(~100%)
ArCOOH ArOCO
OCOAr
OCOAr
ArOCO
ArOCO
OH
ArOCO
ArOCO
OH
TBAF
OsO4
EDCI
ArOCO
THF
NMO
OCOAr'
(90%)
OH
(92%)
OTBDMS
H
(68%)
H
H
H
(_)-Tetragalloylapiitol 1a
(Ar' = 3,4,5-trihydroxyphenyl)
(+)-11
10
9
(8-11: Ar = 3,4,5-tribenzyloxyphenyl, 9/10: diastereomeric mixture with a ~3:2 ratio)
Scheme 2. Total synthesis of (ꢀ)-1,3,4,5-tetragalloylapiitol from (R)-dimethyl 2-hydroxy-3-methylenesuccinate.

R. U. Batwal et al. / Tetrahedron: Asymmetry 22 (2011) 173–177
175
Table 1
from enantiomerically pure (ꢀ)-dimethyl 2-acetoxy-3-methylene-
succinate 4 the (ꢀ)-1,3,4,5-tetragalloylapiitol 1a was obtained in
8-steps with 34% overall yield.
Lipase catalyzed resolution of ( )-4
O
O
O
pet ether: benzene:
phosphate buffer
MeO
MeO
MeO
MeO
MeO
MeO
+
R
S
pH 7 (2:1:2)
3. Conclusion
OAc
OAc
OH
H
H
O
O
O
In conclusion, we have accomplished a straightforward chemo-
enzymatic total synthesis of the naturally occurring potent anti-
HIV compound (ꢀ)-1,3,4,5-tetragalloylapiitol in very good overall
yield. In the present synthesis an efficient enzymatic resolution
for the preparation of enantiomerically pure dimethyl acetoxyitac-
onate, DIBAL reduction of two different ester functions, and very
clean simultaneous deprotections of the twelve benzyl groups
were the key steps. In our present synthesis the stepwise double
gallyolation demanded one extra step and was essential for the
smooth handling of the intermediate compounds. We feel that
the use of dimethyl itaconate/tartarate for the synthesis of a sugar
moiety is noteworthy.
( )-4
(-)-4
(+)-5
Entry
Enzyme
Temp/timea
(ꢀ)-4:% yield/ee
1
2
3
4
5
6
7
PPL
PPL
CCL
CCL
Amano PS
Amano PS
Amano PS
25 °C, 48 h
35 °C, 48 h
25 °C, 48 h
35 °C, 48 h
25 °C, 96 h
35 °C, 8 days
50 °C, 84 h
NRb
NR
NR
57/25
83/NDc
44/95d
42/97d
a
b
c
Reactions were monitored by HPLC.
NR: no reaction.
ND: not determined.
d
Chiral HPLC, the (+)-5 was obtained in 58% yield with only 53% ee.
4. Experimental
4.1. General
(+)-5 would serve as important building blocks for the total syn-
thesis of several desired bioactive natural and unnatural products.
The enantiomerically pure (ꢀ)-dimethyl 2-acetoxy-3-methyl-
enesuccinate 4 on acid catalyzed methanolysis delivered the de-
sired alcohol (ꢀ)-5 in 90% yield with ꢁ100% ee (by chiral HPLC),
which on treatment with TBDMSCl gave the corresponding silyl
ether (+)-6 in 96% yield (Scheme 2). To avoid the foreseen difficulty
of possible intramolecular cyclization upon dihydroxylation to
Melting points are uncorrected. The 1H NMR spectra were re-
corded on 200 MHz NMR spectrometer, 400 MHz NMR spectrome-
ter, and 500 MHz NMR spectrometer using TMS as an internal
standard. The 13C NMR spectra were recorded on 200 NMR spec-
trometer (50 MHz), 400 NMR spectrometer (100 MHz), and 500
NMR spectrometer (125 MHz). Mass spectra were taken on MS-
TOF mass spectrometer. The IR spectra were recorded on an FT-
IR spectrometer. Elemental analyses were taken at NCL. HRMS
(ESI) were taken on mass spectrometer at IICT, Hyderabad. Column
chromatographic separations were carried out on silica gel (60–
120 mesh). Commercially available TBDMCl, DIBAL, EDCI, DMAP,
aqueous solution of NMO (60%), OsO4, TBAF solution in THF
(1.0 M), and Pd on charcoal (10 wt %) were used. 3,4,5-Tris(benzyl-
oxy)benzoic acid was prepared using the known procedure.17
form the c-lactone, we first considered the reduction of both the
ester moieties in (+)-6 to the corresponding primary alcohols.
The DIBAL (6.00 equiv) reduction of diester (+)-6 at ꢀ78 °C exclu-
sively provided the expected diol (ꢀ)-7 in 73% yield. At this stage
we decided to carry out the double gallyolation of diol (ꢀ)-7 rather
than the immediate dihydroxylation of the carbon–carbon double
bond to form the corresponding tetrol for two obvious reasons;
(i) to keep the polarity of our intermediate compounds under con-
trol for convenient column chromatographic purifications and (ii)
to avoid any plausible intramolecular shuffling of our TBDMS pro-
tecting group.16 The N-ethyl N0-(3-dimethylpropyl)carbodiimide
(EDCI) induced dehydrative double coupling of diol (ꢀ)-7 with
the triple benzyl protected gallic acid17 to furnish the required
diester (ꢀ)-8 in 95% yield. The osmium tetroxide induced dihydr-
oxylation of the carbon–carbon double bond in compound (ꢀ)-8
in the presence of N-methylmorpholine N-oxide (NMO) as the
oxidizing agent yielded a diastereomeric mixture of the desired
diol 9 in 68% yield with a ꢁ3:2 ratio (by NMR). The TBAF-
deprotection of silyl ether 9 provided the expected diastereomeric
mixture of triol 10 in 92% yield. It should be noted that triol 10
contains free the 1°, 2°, and 3° alcohol units, but we did not notice
any intramolecular acyl migration under our reaction conditions.16
The second EDCI induced selective dehydrative double coupling of
1° and 2° alcohol units in triol 10 with the tri-benzyl protected
gallic acid yielded the required enantiomerically pure dodecaben-
zyl protected tetraester (+)-11 in 90% yield. The final product 1a is
very polar in nature as it contains the free 12-phenolic and an
alcoholic hydroxyl groups. Hence, we decided to check the
enantiomeric purity of the penultimate step product (+)-11; all
attempts to resolve a sample of ( )-11 from our earlier racemic
synthesis8 on suitable chiral columns were unsuccessful. Finally,
hydrogenolysis using palladium on charcoal was used for the
global deprotection of benzyl groups in (+)-11 to obtain the desired
natural product (ꢀ)-1a in ꢁ100% yield. The analytical and
spectroscopic data obtained for (ꢀ)-1,3,4,5-tetragalloylapiitol 1a
were in complete agreement with the reported data.1,8 Starting
4.2. ( )-Dimethyl 2-acetoxy-3-methylenesuccinate 4
To a stirred solution of dimethyl itaconate (2.00 g, 12.66 mmol)
in glacial acetic acid (25 mL) was added SeO2 (1.55 g, 13.92 mmol)
and the reaction mixture was refluxed for 5 h. The deposited sele-
nium metal was filtered off and the residue was washed with ace-
tic acid (5 mL). The filtrate was concentrated in vacuo and the
residue obtained was dissolved in ethyl acetate (30 mL). The or-
ganic layer was washed with saturated NaHCO3 solution, water,
and brine and dried over Na2SO4. Concentration of the organic
layer in vacuo followed by silica gel column chromatographic puri-
fication of the resulting residue using 15% ethyl acetate/petroleum
ether as an eluent afforded pure product ( )-4 as a colorless oil
(1.01 g, 37%). 1H NMR (CDCl3, 200 MHz) d 2.18 (s, 3H), 3.77 (s,
3H), 3.82 (s, 3H), 6.00 (s, 1H), 6.02 (s, 1H), 6.51 (s, 1H); 13C NMR
(CDCl3, 50 MHz) d 20.6, 52.3, 52.7, 70.2, 130.7, 134.6, 164.8,
168.3, 169.6; ESIMS (m/z) 217 [M+H]+, 239 [M+Na]+, 255 [M+K]+;
IR (CHCl3) mmax 1755, 1747, 1732, 1638 cmꢀ1
.
4.3. (R)-Dimethyl 2-acetoxy-3-methylenesuccinate 4
To a stirred solution of acetate ( )-4 (1.00 g, 4.63 mmol) in a
mixture of petroleum ether and benzene (15 mL, 1:2) were succes-
sively added the phosphate buffer (pH 7, 10 mL) and enzyme Ama-
no PS (100 mg). The resulting reaction mixture was stirred at 50 °C
for 84 h, with monitoring the reaction progress by chiral HPLC. The

176
R. U. Batwal et al. / Tetrahedron: Asymmetry 22 (2011) 173–177
reaction mixture was filtered through Celite bed and washed with
ethyl acetate (50 mL). The organic layer was washed with water
and brine and dried over Na2SO4. The concentration of the organic
layer in vacuo followed by silica gel column chromatographic puri-
fication of the resulting residue using 15% ethyl acetate/petroleum
ether as an eluent afforded pure product (ꢀ)-4 as a colorless oil
purification of the resulting residue using 40% ethyl acetate/
petroleum ether as an eluent afforded pure product (ꢀ)-7 as a
colorless oil (206 mg, 73%). ½a D25
ꢂ
¼ ꢀ7:0 (c 0.16, EtOH); 1H NMR
(CDCl3, 200 MHz) d 0.07 (s, 3H), 0.10 (s, 3H), 0.91 (s, 9H), 2.46
(br s, 2H), 3.54–3.70 (m, 2H), 4.10 (d, J = 12 Hz, 1H), 4.21 (d,
J = 12 Hz, 1H), 4.34 (t, J = 6 Hz, 1H), 5.18 (br s, 1H), 5.20 (br s,
1H); 13C NMR (CDCl3, 50 MHz) d ꢀ5.1, ꢀ4.8, 18.1, 25.7, 63.1,
66.5, 75.2, 114.2, 148.1; ESIMS (m/z) 255 [M+Na]+; HRMS (ESI)
calcd for C11H24O3NaSi 255.1392, found 255.1383; IR (CHCl3) mmax
(421 mg, 42% yield, 97% ee). ½a D25
ꢂ
¼ ꢀ49:9 (c 0.50, EtOH); 1H
NMR (CDCl3, 200 MHz) d 2.18 (s, 3H), 3.77 (s, 3H), 3.82 (s, 3H),
6.00 (s, 1H), 6.02 (s, 1H), 6.51 (s, 1H); 13C NMR (CDCl3, 50 MHz) d
20.6, 52.3, 52.7, 70.2, 130.7, 134.6, 164.8, 168.3, 169.6; ESIMS (m/
z) 217 [M+H]+, 239 [M+Na]+, 255 [M+K]+; IR (CHCl3) mmax 1755,
1747, 1732, 1638 cmꢀ1. In the aforementioned enzymatic resolu-
tion the hydrolyzed opposite isomer (+)-5 was obtained in 58%
yield with only 53% ee. HPLC conditions: column: Kromasil 5-Cellu-
Coat (250 ꢃ 4.6 mm), wavelength: 220 nm, flow rate: 0.5 mL/min,
retention time: 19.8 min (+)-isomer, 25.2 min (ꢀ)-isomer.
3456, 1652 cmꢀ1
.
4.7. (R)-2-((tert-Butyldimethylsilyl)oxy)-3-methylenebutane-
1,4-diyl bis(3,4,5-tris(benzyloxy)benzoate) 8
To
a
stirred solution of mixture of diol (ꢀ)-7 (150 mg,
0.65 mmol), 3,4,5-tris(benzyloxy)benzoic acid (tribenzylgallic acid)
(626 mg, 1.42 mmol), and a catalytic amount of DMAP in dichloro-
methane (10 mL) at room temperature was added dropwise a solu-
tion of EDCI (371 mg, 1.94 mmol) in dichloromethane (3 mL). The
reaction mixture was stirred for a further 3 h and then quenched
with water (10 mL). The reaction mixture was extracted with
dichloromethane (2 ꢃ 25 mL) and the combined organic layer
was washed with water and brine and dried over Na2SO4. The con-
centration of the organic layer in vacuo followed by silica gel col-
umn chromatographic purification of the resulting residue using
15% ethyl acetate/petroleum ether as an eluent afforded pure prod-
4.4. (R)-Dimethyl 2-hydroxy-3-methylenesuccinate 5
To a stirred solution of acetate (ꢀ)-4 (400 mg, 1.85 mmol) in
methanol (10 mL) at 0 °C was added 2 M HCl (10 mL) and the reac-
tion mixture was further stirred for 2 h. The reaction mixture was
concentrated in vacuo and the residue obtained was diluted with
ethyl acetate (20 mL). The organic layer was washed with water
and brine and dried over Na2SO4. The concentration of the organic
layer in vacuo followed by silica gel column chromatographic puri-
fication of the resulting residue using 25% ethyl acetate/petroleum
ether as an eluent afforded pure product (ꢀ)-5 as a colorless oil
uct (ꢀ)-8 as a white solid (662 mg, 95%). Mp 59–61 °C; ½a D25
¼ ꢀ4:2
ꢂ
(290 mg, 90%). ½a D25
ꢂ
¼ ꢀ19:7 (c 0.68, EtOH); 1H NMR (CDCl3,
(c 0.34, CHCl3); 1H NMR (CDCl3, 200 MHz) d 0.08 (s, 3H), 0.10 (s,
3H), 0.91 (s, 9H), 4.38 (d, J = 6 Hz, 2H), 4.62 (t, J = 6 Hz, 1H), 4.80–
5.00 (m, 2H), 5.05 (s, 4H), 5.09 (s, 8H), 5.34 (s, 1H), 5.40 (s, 1H),
7.15–7.45 (m, 34H); 13C NMR (CDCl3, 50 MHz) d ꢀ4.9, ꢀ4.8, 18.1,
25.7, 64.4, 68.2, 71.04, 71.06, 72.3, 75.1, 108.9, 117.1, 125.0,
127.46, 127.49, 127.86, 127.94, 128.1, 128.4, 128.5, 136.56,
136.62, 137.4, 142.36, 142.41, 143.4, 152.49, 152.53, 165.7,
165.9; ESIMS (m/z) 1100 [M+Na]+; IR (CHCl3) mmax 1716,
1590 cmꢀ1. Anal. Calcd for C67H68O11Si: C, 74.70; H, 6.36. Found:
C, 74.37; H, 5.84.
200 MHz) d 3.58 (br s, 1H), 3.79 (s, 6H), 4.88 (br s, 1H), 5.97 (s,
1H), 6.39 (s, 1H); 13C NMR (CDCl3, 50 MHz) d 52.1, 53.0, 71.2,
129.2, 137.8, 165.6, 172.7; ESIMS (m/z) 175 [M+H]+, 197
[M+Na]+; IR (CHCl3) mmax 3503, 1746, 1726, 1636 cmꢀ1
.
4.5. (R)-Dimethyl 2-((tert-butyldimethylsilyl)oxy)-3-
methylenesuccinate 6
To a stirred solution of alcohol (ꢀ)-5 (250 mg, 1.44 mmol) in
dichloromethane (10 mL) at 0 °C were added imidazole (108 mg,
1.58 mmol) and TBDMSCl (239 mg, 1.58 mmol). The reaction mix-
ture was allowed to return to room temperature and stirred for a
further 6 h. The reaction mixture was concentrated in vacuo and
the residue obtained was diluted with ethyl acetate (20 mL). The
organic layer was washed with water and brine and dried over
Na2SO4. The concentration of the organic layer in vacuo followed
by silica gel column chromatographic purification of the resulting
residue using 5% ethyl acetate/petroleum ether as an eluent affor-
4.8. 3-((tert-Butyldimethylsilyl)oxy)-2-hydroxy-2-(hydroxy-
methyl)butane-1,4-diyl bis(3,4,5-tris(benzyloxy)benzoate) 9
[diastereomeric mixture (3:2)]
To a stirred solution of diester (ꢀ)-8 (600 mg, 0.56 mmol) and
an aqueous solution of NMO (60%, 3 mL) in t-butanol (10 mL) at
room temperature was added OsO4 solution in t-butanol
(0.22 mL, 1 M, 0.22 mmol) and the reaction mixture was further
stirred for 6 h. The reaction was quenched with a saturated solu-
tion of sodium sulfite and concentrated in vacuo. The obtained res-
idue was diluted with ethyl acetate (25 mL) and washed with
water and brine and dried over Na2SO4. The concentration of the
organic layer in vacuo followed by silica gel column chromato-
graphic purification of the resulting residue using 35% ethyl ace-
ded pure product (+)-6 as
a colorless oil (397 mg, 96%).
½
a 2D5
ꢂ
¼ þ23:9 (c 0.60, EtOH); 1H NMR (CDCl3, 200 MHz) d 0.10 (s,
3H), 0.13 (s, 3H), 0.91 (s, 9H), 3.72 (s, 3H), 3.78 (s, 3H), 5.08 (dd,
J = 2 and 2 Hz, 1H), 6.07 (dd, J = 2 and 2 Hz, 1H), 6.38 (dd, J = 2
and 2 Hz, 1H); 13C NMR (CDCl3, 50 MHz) d ꢀ5.4, ꢀ5.2, 18.3, 25.6,
52.0, 52.3, 70.9, 126.4, 138.7, 165.9, 171.2; ESIMS (m/z) 289
[M+H]+, 311 [M+Na]+; IR (CHCl3) mmax 1759, 1736, 1686 cmꢀ1
.
tate/petroleum ether as an eluent afforded product
9 as a
4.6. (R)-2-((tert-Butyldimethylsilyl)oxy)-3-methylenebutane-
1,4-diol 7
colorless oil (421 mg, 68%). 1H NMR (CDCl3, 400 MHz) d 0.07–
0.13 (m, 12H), 0.92 (s, 18H), 2.42 (br s, 4H), 3.65–3.83 (m, 4H),
4.05–4.10 (m, 2H), 4.35–4.70 (m, 8H), 5.02–5.15 (m, 24H), 7.20–
7.45 (m, 68H); 13C NMR (CDCl3, 100 MHz) d ꢀ5.6, 18.2, 25.8,
64.1, 64.3, 64.9, 65.0, 65.4, 65.9, 71.06, 71.12, 72.5, 74.0, 74.3,
75.1, 108.96, 109.01, 109.07, 109.10, 124.3, 124.6, 124.68, 124.71,
127.4, 127.5, 127.9, 127.96, 127.98, 128.2, 128.5, 136.6, 137.32,
137.34, 142.4, 142.57, 142.62, 152.5, 152.6, 166.1, 166.25, 166.31,
166.6; ESIMS (m/z) 1134 [M+Na]+; IR (CHCl3) mmax 3463, 1716,
1590 cmꢀ1. Anal. Calcd for C67H70O13Si: C, 72.41; H, 6.35. Found:
C, 72.11; H, 6.78.
To a stirred solution of diester (+)-6 (350 mg, 1.22 mmol) in THF
(10 mL) at ꢀ78 °C was dropwise added a DIBAL solution in toluene
(1 M, 7.30 mL, 7.30 mmol) and the reaction mixture was stirred for
2 h at the same temperature. The reaction was quenched with
saturated NH4Cl solution and then concentrated in vacuo. The ob-
tained residue was diluted with ethyl acetate (20 mL) and washed
with brine and dried over Na2SO4. The concentration of the organic
layer in vacuo followed by silica gel column chromatographic

R. U. Batwal et al. / Tetrahedron: Asymmetry 22 (2011) 173–177
177
4.9. 2,3-Dihydroxy-2-(hydroxymethyl)butane-1,4-diyl bis(3,4,5-
tris(benzyloxy)benzoate) 10 [diastereomeric mixture (3:2)]
was added 10% Pd/C (50 mg) and the reaction mixture was sub-
jected to hydrogenation at 65-psi hydrogen pressure for 8 h. The
reaction mixture was filtered through a Celite bed and washed
with methanol. The concentration of the filtrate in vacuo followed
by silica gel column chromatographic purification of the resulting
residue using methanol/chloroform (3:1) as an eluent furnished
pure product (ꢀ)-1a as a pale purple solid (185 mg, ꢁ100%). The
analytically pure sample was obtained by reversed-phase C18 HPLC
(Grace Denali id 4 ꢃ 250 mm) with an isocratic elution from 30%
To a stirred solution of diol 9 (400 mg, 0.36 mmol) in THF
(10 mL) at 0 °C was added TBAF solution in THF (1 M, 0.43 mL,
0.43 mmol) and the reaction mixture was further stirred at the
same temperature for 20 min. The reaction was then quenched
with saturated solution of NH4Cl and concentrated in vacuo. The
residue obtained was diluted with ethyl acetate (25 mL) and the
organic layer was washed with brine and dried over Na2SO4. The
concentration of the organic layer in vacuo followed by silica gel
column chromatographic purification of the resulting residue using
65% ethyl acetate/petroleum ether as an eluent afforded product
10 as a colorless oil (330 mg, 92%). 1H NMR (CDCl3, 200 MHz) d
3.22 (br s, 4H), 3.56–3.90 (m, 4H), 4.00–4.12 (m, 2H), 4.35–4.70
(m, 8H), 4.92–5.00 (m, 2H), 5.00–5.15 (m, 24H), 7.15–7.45 (m,
68H); 13C NMR (CDCl3, 125 MHz) d 63.6, 64.1, 65.1, 65.3, 65.65,
65.69, 71.20, 71.24, 72.1, 72.2, 74.3, 74.8, 75.12, 75.14, 109.2,
109.25, 109.33, 109.4, 127.46, 127.48, 127.5, 127.6, 127.95,
127.97, 128.0, 128.1, 128.2, 128.3, 128.4, 128.46, 128.48, 128.50,
128.53, 136.56, 136.59, 137.31, 137.33, 152.58, 152.61, 166.5,
166.56, 166.58, 166.7; ESIMS (m/z) 1020 [M+Na]+; IR (CHCl3) mmax
3462, 1716, 1590 cmꢀ1. Anal. Calcd for C61H56O13: C, 73.48; H, 5.66.
Found: C, 73.08; H, 5.33.
aqueous MeOH. Mp >300 °C; ½a D25
ꢂ
¼ ꢀ23:6 (c 0.03, MeOH); 1H
NMR (C5D5N, 400 MHz)
d 4.88 (d, J = 12 Hz, 1H), 4.92 (d,
J = 12 Hz, 1H), 4.98 (d, J = 12 Hz, 1H), 5.06 (dd, J = 12 and 8 Hz,
1H), 5.12 (d, J = 12 Hz, 1H), 5.31 (br d, J = 12 Hz, 1H), 6.45 (dd,
J = 8 and 4 Hz, 1H), 7.80 (s, 2H), 7.82 (s, 2H), 7.84 (s, 2H), 7.87 (s,
2H); 13C NMR (C5D5N, 100 MHz) d 63.8, 65.5, 72.7, 74.3, 110.3,
120.5, 120.66, 120.71, 141.1, 141.2, 147.4, 147.5, 166.4, 166.8,
166.9, 167.1; ESIMS (m/z) 759 [M–H]ꢀ (calcd for C33H27O21); IR
(Nujol) mmax 3432, 1742, 1682 cmꢀ1
.
Acknowledgments
R.U.B. and R.M.P. respectively thank UGC and CSIR, New Del-
hi, for the award of research fellowships. N.P.A. thanks the
Department of Science and Technology, New Delhi, for financial
support. We thank Dr. S. S. Kunte from NCL, Pune, for the HPLC
data.
4.10. (S)-3-Hydroxy-3-(((3,4,5-tris(benzyloxy)benzoyl)oxy)
methyl)butane-1,2,4-triyl tris(3,4,5-tris(benzyloxy)benzoate) 11
To a stirred solution of a mixture of triol 10 (300 mg, 0.30 mmol),
3,4,5-tris(benzyloxy)benzoic acid (tribenzylgallic acid) (291 mg,
0.66 mmol), and DMAP (4 mg, 0.03 mmol) in dichloromethane
(15 mL) was added dropwise a solution of EDCI (172 mg, 0.90 mmol)
in dichloromethane (5 mL) at room temperature. The reaction mix-
ture was stirred for 5 h and then quenched with water (15 mL). The
reaction mixture was extracted with dichloromethane (2 ꢃ 30 mL).
The combined organic layer was washed with water and brine and
dried over Na2SO4. The concentration of organic layer in vacuo fol-
lowed by silica gel column chromatographic purification of the
resulting residue using 40% ethyl acetate/petroleum ether as an
eluent afforded pure product (+)-11 as a white solid (499 mg, 90%).
References
1. Takada, K.; Bermingham, A.; O’Keefe, B. R.; Wamiru, A.; Beutler, J. A.; Le
Grice, S. F. J.; Lloyd, J.; Gustafson, K. R.; McMahon, J. B. J. Nat. Prod. 2007,
70, 1647.
2. Su, X.; Surry, D. S.; Spandl, R. J.; Spring, D. R. Org. Lett. 2008, 10, 2593. and
references cited therein.
3. Baumgartner, R. R.; Steinmann, D.; Heiss, E. H.; Atanasov, A. G.; Ganzera, M.;
Stuppner, H.; Dirsch, V. M. J. Nat. Prod. 2010, 73, 1578. and 1742.
4. Kohlstaedt, L. A.; Wang, J.; Friedman, J. M.; Rice, P. A.; Steitz, T. A. Science 1992,
256, 1783.
5. Arnold, E.; Jacobo-Molina, A.; Nanni, R. G.; Williams, R. L.; Lu, X.; Ding, J.; Clark,
A. D., Jr.; Zhang, A.; Ferris, A. L.; Clark, P.; Hizi, A.; Hughes, S. H. Nature 1992,
357, 85.
6. Imamichi, T. Curr. Pharm. Des. 2004, 10, 4039.
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8. Patel, R. M.; Argade, N. P. Synthesis 2009, 372.
9. Kraus, G. A.; Kempema, A. Synthesis 2010, 389.
10. Mortison, J. D.; Sherman, D. H. J. Org. Chem. 2010, 75, 7041. and references cited
therein.
11. (a) Singh, M.; Argade, N. P. J. Org. Chem. 2010, 75, 3121; (b) Kshirsagar, U. A.;
Puranik, V. G.; Argade, N. P. J. Org. Chem. 2010, 75, 2702; (c) Haval, K. P.; Argade,
N. P. J. Org. Chem. 2008, 73, 6936; (d) Patel, R. M.; Argade, N. P. J. Org. Chem.
2007, 72, 4900; (e) Mondal, M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007,
72, 2068; (f) Baag, M. M.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2007, 72,
1009. and references cited therein 11a–f.
12. (a) Gogoi, S.; Argade, N. P. Tetrahedron: Asymmetry 2006, 17, 927; (b) Easwar, S.;
Argade, N. P. Tetrahedron: Asymmetry 2003, 14, 333; (c) Easwar, S.; Desai, S. B.;
Argade, N. P.; Ganesh, K. N. Tetrahedron: Asymmetry 2002, 13, 1367; (d) Desai, S.
B.; Argade, N. P.; Ganesh, K. N. J. Org. Chem. 1999, 64, 8105; (e) Desai, S. B.;
Argade, N. P.; Ganesh, K. N. J. Org. Chem. 1996, 61, 6730. and references cited
therein 12a–e.
Mp 130–131 °C; ½a D25
ꢂ
¼ þ26:5 (c 0.11, CHCl3); 1H NMR (CDCl3,
500 MHz) d 3.42 (br s, 1H), 4.46 (dd, J = 25 and 15 Hz, 2H), 4.58
(d, J = 10 Hz, 1H), 4.62–4.68 (m, 1H), 4.70 (d, J = 10 Hz,1H), 4.87–
5.15 (m, 25H), 5.87–5.93 (m, 1H), 7.15–7.45 (m, 68H); 13C NMR
(CDCl3, 125 MHz) d 62.7, 65.4, 65.5, 70.9, 71.0, 71.1, 72.3, 74.3,
75.0, 75.1, 108.8, 109.1, 109.3, 123.9, 123.95, 124.03, 124.4, 127.4,
127.46, 127.52, 127.6, 127.8, 127.9, 127.96, 127.98, 128.09, 128.14,
128.3, 128.39, 128.40, 128.45, 128.47, 128.5, 136.3, 136.4, 136.5,
136.6, 137.3, 137.37, 137.38, 142.5, 142.8, 142.9, 143.1, 152.5,
152.56, 152.58, 152.61, 165.1, 165.7, 166.1, 166.2; ESIMS (m/z)
1859 [M+NH3]+, 1865 [M+Na]+, 1881 [M+K]+; IR (CHCl3)
1724, 1589, 1215 cmꢀ1
mmax 3447,
.
4.11. (S)-3-Hydroxy-3-(((3,4,5-trihydroxybenzoyl)oxy)methyl)-
butane-1,2,4-triyl tris(3,4,5-trihydroxybenzoate) 1a [(ꢀ)-
tetragalloylapiitol]
13. Guindon, Y.; Bencheqroun, M.; Bouzide, A. J. Am. Chem. Soc. 2005, 127, 554.
14. Papageorgiou, C.; Benezra, C. Tetrahedron Lett. 1984, 25, 1303.
15. Lipase Candida rugosa recognizes the corresponding (R)-isomer.13
16. (a) Wuts, P. G. M.; Bigelow, S. S. J. Org. Chem. 1988, 53, 5023; (b) Crich, D.;
Ritchie, T. J. Carbohydr. Res. 1990, 197, 324; (c) Friesen, R. W.; Daljeet, A. K.
Tetrahedron Lett. 1990, 31, 6133.
To a stirred solution of (+)-11 (450 mg, 0.24 mmol) in a mixture
of ethyl acetate and methanol (20 mL, 1:1) at room temperature
17. Ren, Y.; Himmeldirk, K.; Chen, X. J. Med. Chem. 2006, 49, 2829.