A direct synthesis of racemic 1,3,4,5-tetragalloylapiitol

Article abstract of DOI:10.1055/s-0029-1217123

A direct and flexible synthesis of racemic 1,3,4,5-tetragalloylapiitol is described.

Full text of DOI:10.1055/s-0029-1217123

SHORT PAPER
389
A Direct Synthesis of Racemic 1,3,4,5-Tetragalloylapiitol
S
ynthesis of Racem
e
ic 1,3,4,5-
o
T
etragalloyl
r
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Fax +1(515)2940105; E-mail: gakraus@iastate.edu
Received 7 August 2009; revised 13 October 2009
OH
OH
OH
Abstract: A direct and flexible synthesis of racemic 1,3,4,5-tetra-
galloylapiitol is described.
O
HO
O
Key words: apiitol, HIV, osmium tetroxide, deprotection
HO
O
OH
OH
O
O
HO
OH
Plant derived natural products are increasingly being in-
vestigated as leads for pharmaceutical development. Us-
ing bioactivity-guided fractionation of plants reported to
be useful as folk medicines, valuable bioactive com-
pounds have been discovered.1 As part of a screening
campaign to find natural products that actively inhibit
RNase H activity, natural product extracts were screened
by a group at the National Institutes of Health.2 They iso-
lated and determined the structure of a new compound
from an extract of the plant Hylodendron gabunensis
Taub. (Fabaceae). The compound was the tetragallate es-
ter of apiitol, a rare carbohydrate.2 This compound exhib-
its potent activity against HIV RNase H. The apiitol
derivative inhibited HIV-1, HIV-2, and human RNase H
with IC50 values of 0.24, 0.13, and 1.5 mM, respectively.
Significantly, it did not show inhibition of E. coli RNase
H at 10 mM. Recently, Patel and Argade reported3 a ten-
step synthesis of racemic 1,3,4,5-tetragalloylapiitol (1)
(Figure 1).
O
O
O
HO
OH
OH
OH
1
Figure 1 1,3,4,5-Tetragalloylapiitol (1)
Herein, we report a direct synthesis of 1,3,4,5-tetragalloyl-
apiitol (1). Commercially available 1,3-dihydroxyacetone
dimer 2 was readily protected as the bis-TBS ether using
TBSCl and imidazole in DMF as shown in Scheme 1.4
After the addition of vinylmagnesium bromide (THF,
–30 °C), the benzyl group was introduced using sodium
hydride and benzyl bromide. The benzyl group was cho-
sen as the protecting group, since the gallic acid phenols
also had to be protected and it would be convenient to re-
move all of the protecting groups at one time at the end of
the synthesis. Additionally, the benzyl group is not subject
OH
OH
TBSO
TBSO
1. TBSCl, imidazole
MgBr
O
1. NaH, BnBr, TBAI
OH
OBn
2.
O
HO
HO
2. OsO4, Me4NO
42%
65%
OTBS
OH
OTBS
OH
4
3
2
O
BnO
BnO
Cl
OBn
83%
O
Ar
TBSO
O
O
OBn
Ar
1. HF⋅pyr
H2, Pd/C
25%
OBn
O
Ar
O
O
1
O
2.
O
O
OTBS
BnO
BnO
O
O
O
O
Cl
(4 equiv)
Ar
OBn
Ar
Ar = 3,4,5-(BnO)3C6H2
Ar
62% over 2 steps
5
6
Scheme 1 Synthesis of 1 from dihydroxyacetone dimer
SYNTHESIS 2010, No. 3, pp 0389–0391
x
x
.
x
x
.2
0
0
9
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1217123; Art ID: M04709SS
© Georg Thieme Verlag Stuttgart · New York

390
G. A. Kraus, A. Kempema
SHORT PAPER
O
Ar
O
O
O
TBSO
O
BnO
BnO
BnO
BnO
OH
OH
OH
TBSO
OH
OsO4
Me4NO
Ar
O
O
Ar
OH
HF⋅pyr
OBn
DCC
OBn
DCC
O
O
O
O
O
O
OTBS
O
OTBS
48%
89%
Ar
Ar
Ar
3
7
8
Ar = 3,4,5-(BnO)3C6H2
Scheme 2 Alternate synthesis of 1
4-tert-Butyldimethylsilyloxy-3-(tert-butyldimethylsilyloxy-
methyl)but-1-en-3-ol (3)
to protecting group translocation under basic conditions
as sometimes happens with an ester protecting group or a
silyl ether protecting group.5 Moreover, the benzyl group
will enhance the solubility of polyhydroxy intermediates
in organic solutions. The resulting benzyl ether was hy-
droxylated using catalytic osmium tetroxide and tetrame-
thylammonium N-oxide in aqueous acetone in high yield.
The resulting diol 4 was treated with the tribenzyl ether of
galloyl chloride6 to form the bis-galloylated material 5 in
83% yield. Removal of the silyl ether protecting groups
with HF·pyridine7 followed by a second galloylation gave
the protected material 6 in 19% yield over seven steps.
Removal of the benzyl groups afforded a polar material
To a stirred solution of dihydroxyacetone dimer 2 (4.000 g, 22.20
mmol) in DMF (30 mL) were added imidazole (7.558 g, 111.0
mmol) and tert-butyldimethylsilyl chloride (16.73 g, 111.0 mmol)
at 0 °C. The mixture was stirred at r.t. for 1 h and then H2O (30 mL)
was added at 0 °C. The mixture was extracted with EtOAc (3 × 20
mL) and the combined organic extracts were washed with brine (30
mL), dried (MgSO4), filtered, and concentrated. The residue was
purified by flash column chromatography (hexanes) to give the pro-
tected intermediate (12.56 g, 89%) as a colorless oil. To a stirred so-
lution of vinylmagnesium bromide (1 M in THF; 9.41 mL, 9.41
mmol) in THF (15 mL) was added the above protected intermediate
(1.000 g, 3.138 mmol) in THF (10 mL) dropwise at –30 °C. The
mixture was stirred at –30 °C for 3 h and then treated with sat. aq
that was purified by recrystallization from toluene–ethyl NH4Cl (20 mL). The mixture was extracted with EtOAc (3 × 10
acetate. The 1H and 13C NMR spectra of our synthetic ma-
mL) and the combined organic extracts were washed with brine (10
mL), dried (MgSO4), filtered, and concentrated. The residue was
purified by flash column chromatography over silica gel (hexanes–
terial were identical to that of the natural product 1.
In an alternate synthetic route to tetragalloylapiitol (1), the
known intermediate alcohol 83 was prepared by hydroxy-
lation of 3 using osmium tetroxide, followed by the acyla-
tion using 3 equivalents of tri-O-benzylgallic acid and
DCC. This gave the diacylated product as the main prod-
uct 7 in 48% yield (Scheme 2). The mono- and bis-galloyl-
ated products proved difficult to separate because of their
surprisingly similar polarity. Since both of the compounds
could in principle be converted to 8 by desilylation and
acylation, the mixture was treated with HF–pyridine and
acylated. Alcohol 8 was produced in 89% yield over two
steps, which had been quantitatively debenzylated to 1.3
EtOAc, 10:1) to give 3 (0.794 g, 73%) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.06 (s, 12 H), 0.90 (s, 18 H), 2.71
(s, 1 H), 3.54 (dd, J = 29.7, 9.3 Hz, 4 H), 5.19 (dd, J = 11.1, 1.8 Hz,
1 H), 5.42 (dd, J = 17.4, 1.8 Hz, 1 H), 5.96 (dd, J = 17.5, 10.8 Hz, 1
H).
13C NMR (100 MHz, CDCl3): d = –5.24, 18.5, 26.1, 65.9, 75.0,
114.9, 138.7.
MS (ESI): m/z calcd for C17H38O3Si2 (M+): 347; found: 347.
3-Benzyloxy-4-tert-butyldimethylsilyloxy-3-(tert-butyldimeth-
ylsilyloxymethyl)butane-1,2-diol (4)
To a suspension of NaH (60% dispersion in mineral oil; 0.243 g,
6.07 mmol) in THF (20 mL) was added a solution of alcohol 3
(1.915 g, 5.522 mmol) in THF (10 mL) at 0 °C. The mixture was
stirred at 0 °C for 20 min. Bu4NI (204 mg, 0.552 mmol) and benzyl
bromide (0.72 mL, 6.1 mmol) were added. The mixture was al-
lowed to warm to r.t. and was stirred for 18 h. The reaction was
quenched with sat. aq NH4Cl (20 mL) and diluted with EtOAc (20
mL). After extraction with EtOAc (3 × 10 mL), the combined or-
ganic extracts were washed with brine (20 mL), dried (MgSO4), fil-
tered, and concentrated. The residue was purified by flash
chromatography over silica gel (hexanes) to give the intermediate
benzyl ether (1.665 g, 69%) as a colorless oil. A solution of the in-
termediate benzyl ether (1.401 g, 3.207 mmol), trimethylamine
N-oxide dihydrate (0.713 g, 6.41 mmol), and OsO4 (0.160 mmol,
4.07 mL of a 100 mg/10 mL stock solution) in acetone (90 mL) and
H2O (45 mL) was stirred at r.t. for 7 h. The reaction was quenched
with sat. aq Na2SO3 (100 mL), stirred for 0.5 h, concentrated, and
extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were washed with brine (50 mL), dried (MgSO4), filtered, and con-
centrated. The residue was purified by flash chromatography over
silica gel (hexanes–EtOAc, 5:1) to give 4 (0.911 g, 61%) as a color-
less oil.
The synthesis of tetragalloylapiitol described by us is
direct and flexible. It will be possible to prepare other
galloyl-substituted apiitols using our route. For example,
the deprotection of the bis-galloylated intermediate 5 will
provide a bis-galloylapiitol. The biological evaluation of
selected derivatives will be reported in the future.
Commercially available dihydroxyacetone dimer, imidazole,
TBSCl, vinylmagnesium bromide solution (1 M in THF), NaH
(60% dispersion in mineral oil), TBAI, BnBr, TMNO·2H2O, OsO4,
DMAP, DCC, HF·pyridine, and Pd/C were used. THF was dried
over sodium. NMR experiments were performed with either a
Varian 300 MHz or a 400 MHz instrument. LRMS were performed
with a Shimaduzu LC–MS 2010 mass spectrometer. Standard grade
silica gel (60 Å) was used for flash column chromatography. All re-
actions were performed under an argon atmosphere. Thin-layer
chromatography was performed using commercially prepared 60
mesh silica gel plates (Whatman K6F), and visualization was effect-
ed with short wavelength UV light (254 nm).
Synthesis 2010, No. 3, 389–391 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Racemic 1,3,4,5-Tetragalloylapiitol
391
1H NMR (300 MHz, CDCl3): d = 0.10 (s, 12 H), 0.92 (s, 18 H), 2.87
(m, 1 H), 3.27 (d, J = 29.7, 9.3 Hz, 1 H), 3.91 (m, 7 H), 4.71 (dd,
J = 17.4, 1.8 Hz, 2 H), 7.32 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = –5.44, 18.3, 26.0, 62.6, 63.0, 63.1,
66.1, 72.9, 80.0, 127.6, 128.5, 139.1.
MS (ESI): m/z calcd for C24H46O5Si2 + Na (M + Na)+: 493; found:
493.
mmol of a 100 mg/10 mL stock solution) in acetone (80 mL) and
H2O (40 mL) was stirred at r.t. for 7 h. The reaction was quenched
with sat. aq Na2SO3 (100 mL) and stirred for 0.5 h, concentrated,
and extracted with CH2Cl2 (3 × 50 mL). The combined organic lay-
ers were washed with brine (50 mL), dried (MgSO4), filtered, and
concentrated. The residue was purified by flash chromatography
over silica gel (hexanes–EtOAc) to give (0.9052 g, 55%) as a color-
less oil. To a solution of the diol (0.401 g, 1.053 mmol) was added
3,4,5-tris(benzyloxy)benzoic acid (0.401 g, 1.053 mmol), DCC
(0.861 g, 4.21 mmol), and DMAP (0.283 g, 2.32 mmol) in CH2Cl2
(20 mL). The solution was refluxed for 2 h. The solvent was evap-
orated and chromatography of the residue over silica gel (hexanes–
EtOAc, 5:1) furnished 7 (1.035 g, 80%) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.11 (s, 12 H), 0.89 (s, 18 H), 2.89
(m, 1 H), 3.62–4.74 (m, 4 H), 4.98–5.10 (m, 14 H), 6.05 (dd, J = 96,
2.4 Hz, 1 H), 7.27–7.38 (m, 34 H).
13C NMR (100 MHz, CDCl3): d = –5.3, 18.4, 26.0, 60.6, 63.4, 63.3,
64.2, 71.2, 71.3, 73.2, 75.3, 75.3, 109.1, 109.4, 125.1, 125.3, 127.7,
127.9, 128.1, 128.3, 128.6, 128.7, 136.7, 136.8, 137.6, 137.7, 142.5,
142.9, 152.6, 152.7, 165.6, 166.1.
3-Benzyloxy-4-tert-butyldimethylsilyloxy-3-(tert-butyldimeth-
ylsilyloxymethyl)butane-1,2-diyl Bis[3,4,5-tris(benzyloxy)ben-
zoate] (5)
To a solution of diol 4 (0.456 g, 0.972 mmol) and DMAP (0.475 g,
3.89 mmol) in CH2Cl2 (40 mL) was added 3,4,5-tris(benzyl-
oxy)benzoyl chloride (1.784 g, 3.886 mmol). The mixture was
stirred at r.t. for 8 h. The solvent was evaporated and chromatogra-
phy of the residue over silica gel (hexanes, EtOAc, 10:1) to give 5
(1.094 g, 83%) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.10 (s, 12 H), 0.94 (s, 18 H),
3.83–4.08 (m, 4 H), 4.81–5.13 (m, 16 H), 6.05 (dd, J = 8.6, 3.6 Hz,
1 H), 7.27–7.39 (m, 39 H).
13C NMR (100 MHz, CDCl3): d = –5.4, 18.4, 26.1, 61.6, 62.5, 66.3,
71.1, 71.2, 72.7, 75.2, 75.3, 80.6, 109.0, 109.3, 109.3, 125.2, 125.3,
127.5, 127.8, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 136.6, 136.8,
137.6, 137.7, 139.1, 142.3, 142.8, 152.6, 152.7, 165.4, 166.1.
MS (ESI): m/z calcd for C73H84O13Si2 +Na (M + Na)+: 1248; found:
1248.
3-Hydroxy-3-[3,4,5-tris(benzyloxy)benzoyloxymethyl]butane-
1,2,4-triyl Tris[3,4,5-tris(benzyloxy)benzoate] (8)
MS (ESI): m/z calcd for C80H90O13Si2 + Na (M + Na)+: 1339; found:
1339.
A solution of bis-TBS protected alcohol 7 (0.160 g, 0.130 mmol) in
anhyd THF (2.0 mL) and pyridine (2.0 mL) was cooled to 0 °C, and
HF·pyridine (0.67 mL) was added. The mixture was warmed to r.t.
and stirred for 18 h. The mixture was then diluted with EtOAc (2
mL) and washed with 10% aq CuSO4 (2 mL). The aqueous phase
was extracted with EtOAc (3 × 2 mL) and the combined organics
were washed with sat. aq NaHCO3 (10 mL) and dried (MgSO4). The
solvent was removed in vacuo to afford a yellow oil. To the ob-
tained intermediate diol (0.130 mmol) was added 3,4,5-tris(benzyl-
oxy)benzoic acid (0.172 g, 0.391 mmol), DCC (0.106 g, 0.521
mmol), and DMAP (0.035 g, 0.286 mmol) in CH2Cl2 (5 mL). The
solution was refluxed for 2 h. The solvent was evaporated and chro-
matography of the residue over silica gel (CH2Cl2–EtOAc, 10:1)
furnished 8 (0.213 g, 89% over 2 steps) as a colorless oil. Charac-
terization matched perfectly with literature values.3
3-Benzyloxy-3-[3,4,5-tris(benzyloxy)benzoyloxymethyl]butane-
1,2,4-triyl Tris[3,4,5-tris(benzyloxy)benzoate] (6)
To a solution of 5 (0.459 g, 0.350 mmol) in anhyd THF (6 mL) and
pyridine (6 mL) cooled to 0 °C was added HF·pyridine (2.0 mL).
The mixture was warmed to r.t. and stirred for 18 h. The mixture
was then diluted with EtOAc (5 mL) and washed with 10% aq
CuSO4 (5 mL). The aqueous phase was extracted with EtOAc (3 × 5
mL) and the combined organics were washed with sat. aq NaHCO3
(10 mL) and dried (MgSO4). The solvent was removed in vacuo to
afford a yellow oil. To a solution of the obtained intermediate diol
(0.350 mmol) and DMAP (0.228 g, 1.86 mmol) in CH2Cl2 (20 mL)
was added 3,4,5-tris(benzyloxy)benzoyl chloride (0.855 g, 1.86
mmol). The mixture was stirred at r.t. for 8 h. The solvent was evap-
orated and chromatography of the residue over silica gel (CH2Cl2–
EtOAc, 10:1) gave 6 (0.554 g, 86% over 2 steps) as a colorless oil.
Acknowledgment
1H NMR (300 MHz, CDCl3): d = 4.39–5.16 (m, 32 H), 6.17 (dd,
J = 7.0, 3.0 Hz, 1 H), 7.26–7.43 (m, 73 H).
We thank the GAANN program for partial support of this work.
13C NMR (100 MHz, CDCl3): d = 62.1, 63.1, 63.3, 66.5, 71.2, 71.3,
71.7, 75.3, 78.6, 109.0, 109.1, 109.3, 124.3, 124.4, 124.7, 127.5,
127.6, 127.7, 127.9, 128.2, 128.3, 128.4, 128.6, 128.7, 136.5, 136.6,
136.7, 136.8, 137.5, 137.6, 137.7, 137.8, 142.7, 142.8, 143.0, 143.2,
151.0, 152.7, 152.8, 165.2, 165.4, 165.6, 165.9.
References
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Fridlender, B. Trends Biotechnol. 2002, 20, 522.
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MS (ESI): m/z calcd for C124H106O21 (M+): 1933; found: 1933.
1,3,4,5-Tetragalloylapiitol (1)
A suspension of benzyl-protected tetragalloylapiitol 6 (0.249 g,
0.129 mmol), 10% Pd/C (25 mg) in anhyd THF (15 mL) was stirred
at 40 °C under H2 for 16 h. The mixture was cooled and filtered
through Celite, and the filtrate was evaporated. The residue was
crystallized from toluene–EtOAc. Compound 1 (26 mg, 26%) was
obtained as colorless crystals. Characterization matched perfectly
with literature values.2
(5) Furegati, S.; White, A. J. P.; Miller, A. D. Synlett 2005,
2385.
(6) Ren, Y.; Himmeldirk, K.; Chen, X. J. Med. Chem. 2006, 49,
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4-tert-Butyldimethylsilyloxy-3-(tert-butyldimethylsilyloxy-
methyl)-3-hydroxybutane-1,2-diyl Bis[3,4,5-tris(benzyl-
oxy)benzoate] (7)
To a solution of olefin 3 (1.500 g, 4.326 mmol), trimethylamine
N-oxide dihydrate (0.962 g, 8.65 mmol), and OsO4 (4.40 mL, 0.216
Synthesis 2010, No. 3, 389–391 © Thieme Stuttgart · New York