Total synthesis of (±)-1,3,4,5-tetragalloylapiitol

Article abstract of DOI:10.1055/s-0028-1083310

Starting from citraconic anhydride, the first total synthesis of (±)-1,3,4,5-tetragalloylapiitol has been demonstrated via a stepwise route involving generation of an apiitol derivative followed by benzoylation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083310

372
SHORT PAPER
Total Synthesis of ( )-1,3,4,5-Tetragalloylapiitol
Total
Synthesis
o
a
f
(
)-1,3,4,
m
5-Tetragalloylapiito
e
l
sh M. Patel, Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
Fax +91(20)25902624; E-mail: np.argade@ncl.res.in
Received 29 September 2008; revised 7 October 2008
OH
Abstract: Starting from citraconic anhydride, the first total synthe-
sis of ( )-1,3,4,5-tetragalloylapiitol has been demonstrated via a
stepwise route involving generation of an apiitol derivative fol-
lowed by benzoylation.
HO
OH
OH
OH
s
O
HO
OH
OH
O
s
Key words: allylic hydroxylation, osmium tetroxide, natural prod-
ucts, ( )-1,3,4,5-tetragalloylapiitol
O
OH
OH
O
2
HO
OH
OH
O
O
O
HO
O
HIV-1 RNase H is an attractive molecular target for the
OH
O
HO
HO
development of new anti-HIV agents as potential chemo-
OH
therapeutics.1–3 Very recently, Gustafson et al. isolated a
HO
OH
new potent HIV RNase H inhibitor, (–)-1,3,4,5-tetragal-
loylapiitol (1) from an extract of the plant Hylodendron
gabunensis.4 The structural features revealed that the nat-
ural products (–)-apiitol (2)5 and gallic acid (3) could be
biogenetic precursors of 1 (Figure 1).
OH
OH
1
3
Figure 1 The natural products (–)-1,3,4,5-tetragalloylapiitol (1),
(–)-apiitol (2) and gallic acid (3)
We reasoned that citraconic anhydride (4) would be a suit-
able precursor for the pentahydroxy sugar, apiitol. One of
the hydroxy groups can be generated by allylic hydroxy-
lation of the methyl group, two further hydroxy units can
be introduced by osmium tetroxide dihydroxylation of the
carbon–carbon double bond and finally, the last two hy-
droxy groups can be installed by reduction of the two car-
bonyl groups. In this context, we herein report our studies
on the synthesis of ( )-1 (Scheme 1).
Dimethyl bromomethylfumarate (5)6 obtained from citra-
conic anhydride (4) in two steps, on refluxing with sodium
acetate in acetic acid underwent a smooth chemoselective
allylic nucleophilic substitution reaction with the weakly
nucleophilic carboxylate anion to yield dimethyl 2-(acet-
oxymethylfumarate) (6) in 92% yield. The osmium
tetroxide induced dihydroxylation of the carbon–carbon
double bond in 6, in the presence of N-methylmorpholine
N-oxide (NMO) as the oxidizing agent, furnished the diol
O
O
O
O
O
i
ii
iii
iv
MeO
Br
MeO
OAc
MeO
OAc
MeO
OAc
HO
HO
O
O
O
OMe
OMe
OMe
(ref. 6)
OMe
O
O
O
O
O
4
5
( )-8
6
( )-7
v
OH
OH
OH
OH
vii Ar'OCO
OCOAr'
OCOAr'
vi HO
ix
viii
Ar'OCO
OCOAr'
OCOAr'
Ar'OCO
Ar'OCO
OCOAr'
OCOAr'
O
( )-1
O
O
O
HO
9
12
11
10
Ar' = 3,4,5-tribenzyloxyphenyl
Scheme 1 Reagents, conditions and yields: (i) (a) MeOH, H+/H2SO4, reflux, 8 h, (b) NBS (1.5 equiv), AIBN, CCl4, reflux, 8 h (90% over
2 steps); (ii) AcOH, NaOAc, reflux, 8 h (92%); (iii) OsO4, NMO, t-BuOH, r.t., 6 h (72%); (iv) Me2C(OMe)2, PTSA, 4 Å MS, benzene, reflux,
1.5 h (94%); (v) LAH (3.0 equiv), THF, r.t., 8 h (94%); (vi) Ar¢COOH (4.5 equiv), EDC (6.0 equiv), DMAP, CH2Cl2, reflux, 2 h (96%); (vii)
TFA (aq, 90% soln), r.t., 10 min (91%); (viii) Ar¢COOH (1.50 equiv), EDC (2.0 equiv), DMAP, CH2Cl2, reflux, 2 h (96%); (ix) H2, 10%
Pd/C, EtOAc, MeOH, r.t., 6 h (quant.).
SYNTHESIS 2009, No. 3, pp 0372–0374
x
x
.
x
x
.2
0
0
9
Advanced online publication: 09.01.2009
DOI: 10.1055/s-0028-1083310; Art ID: Z22008SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Total Synthesis of ( )-1,3,4,5-Tetragalloylapiitol
373
ring at 25 °C. The reaction mixture was cooled to 10 °C and a solu-
tion of OsO4 in t-BuOH (0.1 M, 0.63 mL, 0.13 mmol) was added
with stirring. The reaction mixture was stirred at 10 °C for 6 h and
then quenched by the addition of solid Na2SO3 (2.00 g). Stirring was
continued for 45 min after which the reaction mixture was extracted
with EtOAc (3 × 25 mL). The combined organic layer was washed
with H2O (20 mL) and brine (30 mL) and dried over Na2SO4. Con-
centration of the organic layer in vacuo followed by silica gel col-
umn chromatographic purification of the resulting residue (EtOAc–
PE, 2:3) furnished pure ( )-7 as a dense oil; yield: 4.51 g (72%).
IR (CHCl3): 3499, 3481, 1801, 1747, 1643 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.06 (s, 3 H), 3.62 (br d, J = 8 Hz,
1 H), 3.87 (s, 6 H), 4.00 (br s, 1 H), 4.36–4.49 (m, 3 H).
13C NMR (50 MHz, CDCl3): d = 20.5, 53.1, 53.5, 65.5, 72.6, 79.0,
170.3, 170.8, 171.5.
( )-7 in 72% yield. Protection of the cis-diol 7 as ketal ( )-
8 (94%), followed by lithium aluminum hydride reduction
gave the crystalline triol 9 in 94% yield. The conversion
of triol 9 into the sugar apiitol (2) is known in the litera-
ture.5 We envisaged the higher propensity of apiitol for in-
tramolecular dehydrative cyclizations. Therefore, we first
transformed triol 9 into the triester 10 using 3,4,5-tris(ben-
zyloxy)benzoic acid7 and N-ethyl-N'-(3-dimethylamino-
propyl)carbodiimide (EDC) as the dehydrating agent, in
96% yield. Aqueous TFA-induced chemoselective cleav-
age of ketal 10 gave the desired diol 11 in 91% yield. As
before, EDC-induced regioselective dehydrative coupling
of the secondary alcohol group of 11 with 3,4,5-tris(ben-
zyloxy)benzoic acid yielded tetraester 12 in 96% yield.
Finally, catalytic hydrogenation using palladium on char-
coal was used for very clean removal of all twelve benzyl
protecting groups to afford the desired natural product
( )-1 in quantitative yield. The analytical and spectral data
obtained for ( )-1,3,4,5-tetragalloylapiitol (1) were in
complete agreement with the reported data.4 Starting from
citraconic anhydride (4), racemic 1 was obtained in ten
steps in 44% overall yield.
Anal. Calcd for C9H14O8: C, 43.21; H, 5.64. Found: C, 43.30; H,
5.69.
Dimethyl 4-(Acetoxymethyl)-2,2-dimethyl-1,3-dioxolane-4,5-
dicarboxylate [( )-8]
To a solution of diol ( )-7 (4.00 g, 16.00 mmol) in benzene (50 mL)
was added Me2C(OMe)2 (3.33 g, 32.00 mmol) and PTSA (0.004 g,
0.02 mmol) and the stirred reaction mixture was refluxed for 1 h us-
ing a Dean–Stark apparatus containing freshly activated 4 Å MS (5
g). The reaction mixture was concentrated in vacuo and silica gel
column chromatographic purification of the resulting residue
(EtOAc–PE, 3:7) afforded ( )-8 as a thick oil; yield: 4.36 g (94%).
IR (CHCl3): 1751, 1749, 1735, 1215 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.45 (s, 3 H), 1.58 (s, 3 H), 2.03
(s, 3 H), 3.79 (s, 3 H), 3.83 (s, 3 H), 4.34 (s, 2 H), 5.07 (s, 1 H).
In summary, we have accomplished a straightforward
synthesis of the potent anti-HIV compound ( )-1,3,4,5-
tetragalloylapiitol in high yield. The use of an anhydride
for preparing a sugar derivative is noteworthy.8
Melting points were determined using a Mel-Temp apparatus
(Barnstead International) and are uncorrected. The 1H NMR spectra
were recorded on a Bruker AC 200 NMR spectrometer using TMS
as an internal standard. The 13C NMR spectra were recorded on a
Bruker AC 200 NMR spectrometer (at 50 MHz). The IR spectra
were recorded on a Shimadzu FT-IR 8300 spectrometer. Column
chromatographic separations were carried out on ACME silica gel
(60–120 mesh). Commercially available citraconic anhydride,
OsO4, NMO, Me2C(OMe)2, TFA, EDC, LAH, DMAP and NBS
were used. 3,4,5-Tris(benzyloxy)benzoic acid was prepared using a
known procedure.7 THF was dried over LAH. Petroleum ether (PE)
refers to the fraction boiling in the 60–80 °C range.
13C NMR (50 MHz, CDCl3): d = 20.5, 25.6, 27.1, 52.5, 53.2, 63.5,
77.9, 83.7, 113.1, 167.9, 169.9, 170.0.
Anal. Calcd for C12H18O8: C, 49.65; H, 6.25. Found: C, 49.52; H,
6.33.
(2,2-Dimethyl-1,3-dioxolane-4,4,5-triyl)trimethanol (9)
To a stirred slurry of LAH (1.38 g, 36.00 mmol) in THF (60 mL) at
0 °C, a solution of ( )-8 (3.50 g, 12.00 mmol) in THF (40 mL) was
added dropwise and the reaction mixture was allowed to warm to r.t.
After stirring for 8 h at 25 °C, the reaction mixture was cooled to
0 °C and quenched very slowly with a few drops of a sat. aq soln of
Na2SO4. The reaction mixture was filtered through Celite®. Concen-
tration of the filtrate in vacuo afforded triol 9 as a white solid; yield:
2.32 g (94%); mp 86–88 °C.
Dimethyl 2-(Acetoxymethyl)fumarate (6)
A stirred solution of 5 (7.11 g, 30 mmol) and NaOAc (4.92 g, 60
mmol) in AcOH (80 mL) was refluxed for 8 h. The reaction mixture
was allowed to reach 25 °C and was concentrated in vacuo. The res-
idue was dissolved in EtOAc (50 mL) and the organic layer was
washed with a 5% aq soln of NaHCO3 (25 mL) and brine (25 mL)
and dried over Na2SO4. Concentration of the organic layer in vacuo
followed by silica gel column chromatographic purification of the
resulting residue (EtOAc–PE, 1:9) afforded pure 6 as a thick oil;
yield: 5.97 g (92%).
IR (CHCl3): 1735, 1732, 1729, 1653 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.05 (s, 3 H), 3.82 (s, 3 H), 3.85
(s, 3 H), 5.22 (s, 2 H), 6.94 (s, 1 H).
IR (CHCl3): 3400–3300 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.41 (s, 3 H), 1.46 (s, 3 H), 1.76
(br s, 1 H), 2.54 (br s, 1 H), 2.95 (br s, 1 H), 3.70 (q, J = 12 Hz, 2
H), 3.78 (s, 2 H), 3.93 (d, J = 6 Hz, 2 H), 4.14 (t, J = 6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 26.5, 28.3, 60.0, 62.1, 64.8, 78.8,
83.3, 108.5.
Anal. Calcd for C8H16O5: C, 49.99; H, 8.39. Found: C, 50.07; H,
8.41.
(2,2-Dimethyl-1,3-dioxolane-4,4,5-triyl)tris(methyl-
ene)tris[3,4,5-tris(benzyloxy)benzoate] (10)
13C NMR (50 MHz, CDCl3): d = 20.5, 52.1, 52.7, 57.7, 130.9,
A suspension of triol 9 (0.48 g, 2.50 mmol), 3,4,5-tris(benzyl-
oxy)benzoic acid (4.95 g, 11.25 mmol), EDC (2.87 g, 15.00 mmol)
and DMAP (1.01 g, 8.25 mmol) in CH2Cl2 (40 mL) was refluxed for
2 h. The reaction mixture was concentrated in vacuo and the residue
was treated with H2O (50 mL) and extracted with EtOAc (3 × 25
mL). The combined organic layer was washed with H2O (50 mL)
and brine (50 mL) and dried over Na2SO4. Concentration of the or-
ganic layer in vacuo followed by silica gel column chromatographic
139.8, 164.9, 165.6, 170.2.
Anal. Calcd for C9H12O6: C, 50.00; H, 5.59. Found: C, 50.08; H,
5.47.
Dimethyl 2-(Acetoxymethyl)-2,3-dihydroxysuccinate [( )-7]
To a stirred solution of alkene 6 (5.41 g, 25 mmol) in t-BuOH (30
mL) was added a solution of NMO in H2O (60%, 15 mL) with stir-
Synthesis 2009, No. 3, 372–374 © Thieme Stuttgart · New York

374
R. M. Patel, N. P. Argade
SHORT PAPER
purification of the resulting residue (EtOAc–PE, 3:7) afforded pure
product 10 as a white solid; yield: 3.51 g (96%); mp 75–76 °C.
IR (CHCl3): 1719, 1653, 1215 cm–1.
13C NMR (50 MHz, CDCl3): d = 62.7, 65.5, 70.8, 70.9, 72.2, 74.1,
74.9, 75.0, 108.6, 108.9, 109.1, 109.5, 123.86, 123.90, 124.0, 124.3,
127.36, 127.39, 127.44, 127.6, 127.8, 127.9, 128.0, 128.1, 128.2,
128.35, 128.37, 136.2, 136.3, 136.4, 136.5, 137.2, 137.3, 142.4,
142.6, 142.7, 142.9, 152.40, 152.44, 152.47, 152.51, 165.1, 165.7,
166.0, 166.1.
1H NMR (200 MHz, CDCl3): d = 1.48 (s, 3 H), 1.55 (s, 3 H), 4.40–
4.66 (m, 6 H), 4.77 (dd, J = 10, 4 Hz, 1 H), 4.96–5.07 (m, 16 H),
5.09 (s, 2 H), 7.10–7.45 (m, 51 H).
13C NMR (50 MHz, CDCl3): d = 26.3, 28.1, 70.9, 70.94, 75.0, 77.1,
81.0, 108.68, 108.75, 108.84, 109.9, 124.1, 124.2, 127.41, 127.46,
127.52, 127.9, 128.06, 128.09, 128.12, 128.35, 128.41, 128.5,
136.45, 136.51, 137.29, 137.34, 137.4, 142.4, 142.56, 142.60,
152.44, 152.49, 152.52, 165.2, 165.5, 165.6.
Anal. Calcd for C117H100O21: C, 76.29; H, 5.47. Found: C, 76.18; H,
5.55.
3-Hydroxy-3-[(3,4,5-trihydroxybenzoyloxy)methyl]butane-
1,2,4-triyl Tris(3,4,5-trihydroxybenzoate) [( )-1,3,4,5-Tetra-
galloylapiitol, ( )-1]
To a stirred solution of 12 (1.23 g, 0.67 mmol) in EtOAc (10 mL)
and MeOH (10 mL) at 25 °C, 10% Pd/C (50 mg) was added and the
reaction mixture was subjected to hydrogenation at 65 psi hydrogen
pressure for 6 h. The reaction mixture was filtered through Celite®.
Concentration of the filtrate in vacuo followed by silica gel column
chromatographic purification of the resulting residue (MeOH–
CHCl3, 3:1) furnished pure ( )-1 as a pale yellow solid; yield: 508
mg (quant.); mp > 300 °C (for tabulated 1H and 13C NMR data, see
reference 4).
Anal. Calcd for C92H82O17: C, 75.70; H, 5.66. Found: C, 75.66; H,
5.48.
2,3-Dihydroxy-2-{[3,4,5-tris(benzyloxy)benzoyloxy]methyl}bu-
tane-1,4-diyl Bis[3,4,5- tris(benzyloxy)benzoate] (11)
Compound 10 (2.00 g, 1.37 mmol) was dissolved in TFA (aq, 90%
soln, 8 mL) and the resulting mixture was stirred for 10 min at
10 °C. The reaction mixture was evaporated and to the residue was
added toluene (15 mL). Concentration in vacuo followed by silica
gel column chromatographic purification of the resulting residue
(EtOAc–PE, 1:4) furnished pure product 11 as a white solid; yield:
1.77 g (91%); mp 96–98 °C.
Anal. Calcd for C33H28O21: C, 52.11; H, 3.71. Found: C, 52.02; H,
3.65.
IR (CHCl3): 3506, 3423, 1734, 1719, 1703 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.80–4.10 (m, 2 H), 4.30–4.70 (m,
5 H), 4.80–5.10 (m, 18 H), 7.00–7.40 (m, 51 H).
13C NMR (50 MHz, CDCl3): d = 65.1, 65.2, 65.3, 71.0, 74.4, 75.1,
77.2, 108.93, 108.98, 109.02, 124.1, 124.3, 127.4, 127.5, 127.7,
127.9, 128.0, 128.1, 128.3, 128.4, 128.5, 128.6, 136.5, 137.3, 142.6,
142.68, 142.72, 152.47, 152.50, 166.0, 166.35, 166.43.
Acknowledgment
R.M.P. thanks CSIR, New Delhi, for the award of a research fel-
lowship.
References
(1) Kohlstaedt, L. A.; Wang, J.; Friedman, J. M.; Rice, P. A.;
Steitz, T. A. Science 1992, 256, 1783.
Anal. Calcd for C89H78O17: C, 75.30; H, 5.54. Found: C, 75.41; H,
5.63.
(2) 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.
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(4) 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.
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1984, 133, 235.
(6) Kar, A.; Argade, N. P. J. Org. Chem. 2002, 67, 7131.
(7) Ren, Y.; Himmeldirk, K.; Chen, X. J. Med. Chem. 2006, 49,
2829.
(8) For a recent synthesis of an analogous natural product,
sanguiin H-5, see: Su, X.; Surry, D. S.; Spandl, R. J.; Spring,
D. R. Org. Lett. 2008, 10, 2593.
3-Hydroxy-3-{[(3,4,5-tris(benzyloxy)benzoyloxy]methyl}bu-
tane-1,2,4-triyl Tris[3,4,5- tris(benzyloxy)benzoate] (12)
A suspension of diol 11 (1.42 g, 1.00 mmol), 3,4,5-tris(benzyl-
oxy)benzoic acid (0.66 g, 1.50 mmol), EDC (0.38 g, 2.00 mmol)
and DMAP (0.13 mg, 1.10 mmol) in CH2Cl2 (10 mL) was refluxed
for 2 h. The reaction mixture was concentrated in vacuo and the res-
idue was diluted with H2O (25 mL) and extracted with EtOAc (3 ×
25 mL). The combined organic layer was washed with H2O (25 mL)
and brine (25 mL) and dried over Na2SO4. The organic layer was
concentrated in vacuo and silica gel column chromatographic puri-
fication of the resulting residue (EtOAc–PE, 1:4) afforded pure
product 12 as a white solid; yield: 1.77 g (96%); mp 130–131 °C.
IR (CHCl3): 3447, 1724, 1589, 1215 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.20–4.70 (m, 6 H), 4.60–5.10 (m,
24 H), 5.80 (t, J = 6 Hz, 1 H), 7.00–7.40 (m, 68 H).
Synthesis 2009, No. 3, 372–374 © Thieme Stuttgart · New York