Total syntheses of (+)- and (-)-1,3,4,5-tetragalloylapiitol and revision of absolute configuration of naturally occurring (-)-1,3,4,5-tetragalloylapiitol

Article abstract of DOI:10.1016/j.tet.2011.08.088

The total syntheses of (+)- and (-)-1,3,4,5-tetragalloylapiitol were achieved in seven steps from d- and l-ribose, respectively. By comparing the optical rotations of both enantiomers with those of the natural product, the absolute configuration at C-3 in

Full text of DOI:10.1016/j.tet.2011.08.088

Tetrahedron 67 (2011) 8293e8299
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total syntheses of (þ)- and (ꢀ)-1,3,4,5-tetragalloylapiitol and revision of absolute
configuration of naturally occurring (ꢀ)-1,3,4,5-tetragalloylapiitol
,
a
b
b
a
Masaru Kojima a , Yutaka Nakamura , Shoji Akai , Ken-ichi Sato , Seiji Takeuchi
*
a Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan
b Material and Life Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2011
Received in revised form 29 August 2011
Accepted 29 August 2011
Available online 3 September 2011
The total syntheses of (þ)- and (ꢀ)-1,3,4,5-tetragalloylapiitol were achieved in seven steps from
D- and L-
ribose, respectively. By comparing the optical rotations of both enantiomers with those of the natural
product, the absolute configuration at C-3 in the naturally occurring 1,3,4,5-tetragalloylapiitol has been
revised to R. The absolute configurations at C-3 in the synthetic (þ)- and (ꢀ)-1,3,4,5-tetragalloylapiitol
were further confirmed by the circular dichroism exciton chirality method.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Absolute configuration
2,3-O-Benzylidene-D-apiitol
1,3,4,5-Tetragalloylapiitol
Circular dichroism exciton chirality method
1. Introduction
The biological activities of polygalloyl and hexahydrox-
ydiphenoyl glucoses have generated considerable interest because
of their anti-HIV, antidiabetic, antiviral, antimicrobial, and antihy-
pertensive effects.1 1,3,4,5-Tetragalloylapiitol (1) was isolated from
the aqueous extract of Hylodendron gabunensis by screening for
substances that possess HIV ribonuclease H (RNase H) inhibitory
activity.2 Because RNase H is known to participate in the specific
hydrolyzation of an RNA strand in an RNA/DNA heteroduplex3 and
is known to be critical for the growth of HIV, activity that counters
this enzyme could be an attractive feature of novel drugs for HIV
chemotherapy.4 In addition, the secondary metabolite 1 was shown
to inhibit HIV-1, HIV-2, and human RNase H in vitro at the micro-
molar level. The intriguing structure and characteristic biological
activity of 1 have stimulated interest in the synthetic community.
The structure of 1 consists of four gallic acids (3) and apiitol (2), and
the acids are connected to the hydroxyl groups at C-1, C-3, C-4, and
C-5 of the sugar via ester linkages (Fig. 1). The absolute configura-
tion of 1 was originally assigned as S by comparing the optical ro-
tation of the compound, which was obtained through the
hydrolysis of the natural product (1) under basic conditions, with
Fig. 1. Structures of 1,3,4,5-tetragalloylapiitol (1), D-apiitol (2), and gallic acid (3).
Recently, Argade’s6 and Kraus’s7 groups reported independently
the total synthesis of racemic 1,3,4,5-tetragalloylapiitol from in-
expensive and commercially available citraconic anhydride and 1,3-
dihydroxy acetone dimer, respectively, using hydroxylation with
osmium tetroxide as a key step. More recently, Argade’s group also
reported the chemoenzymatic total synthesis of (ꢀ)-1 via lipase-
catalyzed resolution.8 However, it has not been demonstrated
that of authentic D
-apiitol.5
* Corresponding author. Fax: þ81 025 25 5021; e-mail address: masaru@nu-
pals.ac.jp (M. Kojima).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.088

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M. Kojima et al. / Tetrahedron 67 (2011) 8293e8299
that the absolute configuration of the synthesized product (ꢀ)-1 is
unambiguously S. That is, the optical rotation of the synthetic in-
termediate, 2-(R)-hydroxy-3-methylenesuccinic acid dimethyl es-
D
-apiitol (½a 2D6
ꢁ
ꢀ4.0 (c 0.8, MeOH))5 by Kitajima’s group. We next
examined an esterification of 8 using 3,4,5-tris(benzyloxy)benzoyl
chloride14 (Table 1). However, the esterification of 8 with acyl
chloride (4.4 equiv) in the presence of a catalytic amount of DMAP
(0.2 equiv) in pyridine at room temperature gave the desired tet-
raester 9 in 8% yield and triester 9015 in 68% yield (entry 1). When
the reaction was carried out at 60 ꢂC, 9 and 90 were obtained in 26%
and 71% yields, respectively (entry 2). To achieve the complete
ter (½a 2D5
ꢀ19.7 (c 0.68, EtOH)) differed in magnitude from the
ꢁ
published value (½a D
ꢁ
ꢀ11 (c 1.0, EtOH)9a and ½a D25
ꢀ10 (c 1.77,
ꢁ
EtOH)9b). Moreover, Argade’s group accomplished the total syn-
thesis of 1 (½a 2D5
ꢀ23.6 (c 0.03, MeOH)) through the reductive re-
ꢁ
moval of benzyl groups on the aromatic rings of its precursor (½a D25
ꢁ
þ26.5 (c 0.11, CHCl3)). However, an incomprehensible change in the
sign of the optical rotation was not observed upon the synthesis of 1
by hydrogenolysis of the same dextrorotatory precursor in a pre-
liminary examination of our work. Therefore, we decided to un-
dertake the total synthesis of optically active 1 to confirm the
absolute configuration at C-3 and to further investigate its bi-
ological activity.
conversion of intermediate 90 to the corresponding tetraester 9,
D-
apiitol 8 was reacted with an excess amount of acyl chloride
(8.0 equiv) at 60 ꢂC. As a result, the desired tetraester 9 was suc-
cessfully obtained in 90% yield (entry 3). The spectroscopic data for
tetraester 9 agreed well with previously reported data except in the
assignments of H-1 and H-10. The careful analysis of the 1He1H
COSY spectrum of 9 indicated that all the protons were assigned.
In our previous paper, we reported a simple synthetic route for
The optical rotation (½a D26
þ15.9 (c 1.00, CHCl3)) and melting point
ꢁ
2,3-O-benzylidene-3-C-(hydroxymethyl)-
from
-ribose (Scheme 1).10 The key step in this synthesis is the
selective introduction of the hydroxymethyl group at the C-2 of
ribose by the aldol reaction of 2,3-O-benzylidene- -ribose with an
D
-erythrofuranose
(6)
(159.2e160.9 ꢂC) of 9, however, differed in magnitude from the
L
published values (½a D25
ꢁ
þ26.5 (c 0.11, CHCl3) and mp 130e131 ꢂC).8
L-
Finally, the debenzylation of the precursor 9 gave the target com-
pound (S)-1 in quantitative yield.
L
excess of formaldehyde. Because the functional groups of the
branched-chain sugar derivative can be selectively protected and
chemically modified, these compounds are often used as chiral
building blocks for the asymmetric syntheses of promising bi-
ologically active natural and unnatural products.11,12 These in-
teresting works prompted us to employ 2,3-O-benzylidene-3-C-
Synthetic (S)-1 was isolated as a pale yellow solid by re-
crystallization from toluene/EtOAc. Although the 1H and 13C NMR
spectra of the synthetic (S)-1 were identical to those of the natural
product, its optical rotation (½a D20
ꢁ
þ20.3 (c 1.0, MeOH)16) was di-
ametrically opposed to the published values (natural (S)-1: ½a D20
ꢁ
ꢀ18.6 (c 0.1, MeOH),4 synthetic (S)-1: ½a 2D5
ꢁ
ꢀ23.6 (c 0.03, MeOH)8).
(hydroxymethyl)-
D-erythrofuranose, which possesses the same
In addition, the 1H, 13C NMR spectra, and optical rotation of syn-
thetic (S)-1 that was obtained by 10% PdeC-catalyzed hydro-
genolysis of 9 according to Argade’s procedure were also identical
to those of synthetic (S)-1 by Pd(OH)2-catalyzed hydrogenolysis.
configuration as the naturally occurring 1,3,4,5-tetragalloylapiitol
(1), as the chiral synthon for the expeditious synthesis of opti-
cally pure 1.
Scheme 1. Synthesis of 2,3-O-benzylidene-3-C-(hydroxymethyl)-D-erythrofuranose 6.
Herein, we describe the total synthesis of the originally pro-
posed structure of (S)-1 from -ribose and show that the absolute
configuration at C-3, which is the only chiral center of naturally
occurring 1,3,4,5-tetragalloylapiitol, was incorrectly assigned in the
original literature. Furthermore, the enantiomer (R)-1 was pre-
Since our
(S)-1 by alkaline hydrolysis according to Gustafson’s reaction con-
ditions gave data fully consistent with those reported for -apiitol
by Kitajima’s group, it was undoubtedly established that the es-
terification, hydrogenolysis, and hydrolysis proceeded without in-
version of the configuration of C-3. Therefore, these experimental
results suggest that our synthetic (þ)-1 is actually the enantiomer
of naturally occurring 1,3,4,5-tetragalloyapiitol and that correct
absolute configuration at C-3 in the natural product should be re-
vised to R.
D
-apiitol 8 that was recovered from the precursor 917 and
L
D
pared using the same synthetic route from D-ribose to confirm the
correct absolute configuration of the natural 1,3,4,5-
tetragalloylapiitol. The stereochemistry of synthetic (þ)- and
(ꢀ)-1 was confirmed through the application of a dibenzoate chi-
rality method for acyclic alcohols.13a,b
2. Results and discussion
2.2. Total synthesis of (R)-1,3,4,5-tetragalloylapiitol
2.1. Total synthesis of (S)-1,3,4,5-tetragalloylapiitol
To confirm the revised structure, we employed the above-
described route to achieve the first total synthesis of (R)-1 start-
As shown in Scheme 2, 2,3-O-benzylidene-3-C-(hydrox-
ing from -ribose (Scheme 3). The resulting synthetic (R)-1 had an
D
ymethyl)-
D
-erythrofuranose 6, which was easily prepared on
optical rotation of ½a D15
ꢀ20.5 (c 1.03, MeOH), and the spectroscopic
ꢁ
a multigram scale from
L
-ribose in three steps according to pre-
data were identical to those of the natural product.3 Moreover, the
(R)-synthetic intermediates showed diametrically opposite optical
rotations and identical physical data to those of the corresponding
(S)-intermediates. Based on these results, we concluded that the
absolute configuration of the 1,3,4,5-tetragalloylapiitol isolated by
Gustafson is R.
viously reported procedures (Scheme 1),10 was converted to the
erythritol 7 in 97% yield with NaBH4. The hydrogenolysis of 7 was
carried out using Pd(OH)2. The reaction proceeded smoothly to give
a
D
-apiitol 8 in quantitative yield. The synthetic
ꢀ6.9 (c 0.54, MeOH)) gave data consistent with those reported for
D
-apiitol 8 (½a 2D5
ꢁ

M. Kojima et al. / Tetrahedron 67 (2011) 8293e8299
8295
Scheme 2. Synthesis of 1,3,4,5-tetragalloylapiitol (S)-1.
Table 1
Esterification of D-apiitol 8
negative exciton chirality are shown in Fig. 3. Compound (S)-16
exhibited a CD spectrum very similar to those of the compounds
reported by Uzawa,13a Harada,13b Sakamoto,13d Ami,13e and Oguri,13f
while enantiomer (R)-16 showed the opposite positive exciton
chirality. The stereochemistry around the chiral centers of the
compounds shown in Fig. 3 is the same, although the R,S-nomen-
clatures are different. Therefore, the spectroscopic results strongly
suggest that the stereochemistry of the chiral center of (S)-16 is
actually the (S)-configuration.
Entry Reagents and condition
Isolated yield(%)
9
90
1
2
3
3,4,5-Tris(benzyloxy)benzoyl chloride (4.4 equiv.)
DMAP (2.0 equiv) Py, rt, 48 h
8
68
3,4,5-Tris(benzyloxy)benzoyl chloride (4.4 equiv.) 26
71
Py, 60 ꢂC, 48 h
3,4,5-Tris(benzyloxy)benzoyl chloride (8.0 equiv.) 90
Py, 60 ꢂC, 12 h
d
The configurations at the chiral centers of -apiitol 8, tetraester
D
9, and tetragalloylapiitol (þ)-1 are the same as that of tetra-O-
benzoate (S)-16 because, as we have already demonstrated above,
the esterification and hydrogenolysis reaction conditions do not
affect the configuration during these reactions.
2.3. Further corroboration of absolute configurations at C-3
of tetragalloylapiitol (D)-1 and (L)-1
To confirm the configurations of (þ)-1 and (ꢀ)-1 determined
above, we also attempted to clarify the absolute configurations of
the synthesized apiitol 8 and 14 by application of the circular
dicroism (CD) exciton chirality method.13a,b Apiitol 8 and 14 were
reacted with benzoyl chloride in pyridine to give tetra-O-benzoate
(S)-16 and (R)-16 in 99% and quantitative yields, respectively
(Scheme 4).18 As shown in Fig. 2, the CD spectrum of (S)-16
3. Conclusion
The total synthesis of the previously proposed structure of (S)-
1,3,4,5-tetragalloylapiitol was accomplished from L-ribose in seven
steps. The optical rotations of the synthesized product (S)-1 and the
natural product exhibited the opposite signs. These results sug-
gested that the absolute configuration at C-3 in the natural product
should be revised to R. The correct absolute stereochemistry was
further confirmed through the first total synthesis of the enantio-
exhibited a negative peak (
and a positive peak (
D
3
ꢀ1.2) at a long wavelength (241 nm)
D
3
þ4.3) at a short wavelength (227 nm),
which indicated a negative exciton chirality in the stable confor-
mation of (S)-16. Typical acyclic 1,2-di-O-benzoates that exhibit
mer of (S)-1 from inexpensive D-ribose and the analysis of the CD

8296
M. Kojima et al. / Tetrahedron 67 (2011) 8293e8299
Scheme 3. Total synthesis of 1,3,4,5-tetragalloylapiitol (R)-1 from D-ribose.
the biological activities of (R)- and (S)-1 will be reported in the near
future. To demonstrate the versatility of the 3-C-(hydroxymethyl)-
erythrofuranose derivatives 6 and 12 as chiral synthons, the syn-
theses of other bioactive compounds are also underway.
4. Experimental section
4.1. General
Melting points were measured using a Yanaco Model MP-J3
micro-melting point apparatus, and these values are uncorrected.
IR spectra were recorded using a JASCO FT/IR-460 spectrometer
using KBr pellets or liquid film on NaCl. 1H and 13C NMR spectra
were measured using a Bruker Avance DPX-250 spectrometer. J
values were recorded in hertz, and the abbreviations used were s
(singlet), d (doublet), t (triplet), m (multiplet), and br (broad).
Scheme 4. Syntheses of tetra-O-benzoates (S)-16 and (R)-16.
spectra of both compounds. A comparison of the optical rotations
and the CD spectra of tetra-O-benzoate (S)-16 and (R)-16 with those
published in the literature confirmed that our determination of
their absolute configurations at C-3 was correct. The evaluation of
Chemical shifts are expressed in
d values relative to the internal
standard TMS or the deuterated solvent. Thin-layer chromatogra-
phy (TLC) was carried out on Merck Silica gel 60 F254 plates. Flash
column chromatography was carried out on silica gel 60 N
(spherical, neutral) (40e100
mm, Kanto). Specific rotations were
measured in 1.0-dm tubes using a PerkineElmer 241 polarimeter in
CHCl3, CH3OH, or pyridine. CD spectra were measured in CH3OH (1-
cm quartz cell) at 25 ꢂC using a JASCO J-820 spectropolarimeter.
ESI-TOF mass spectra were recorded using a JEOL JMS-T100LC
AccuTOF mass spectrometer.
4.2. Total synthesis of (S)-1,3,4,5-tetragalloylapiitol
4.2.1. [(5S)-2-Phenyl-1,3-dioxolane-4,4,5-triyl]trimethanol
(7). To
a solution of 6 (350 mg, 1.48 mmol) in MeOH (3.0 mL) was cau-
tiously added sodium borohydride (67 mg, 1.78 mmol) in small
portions. After stirring for 30 min at room temperature, the re-
action mixture was quenched with saturated aq NH4Cl solution
(3.0 mL). After the solvent was evaporated, the remaining aqueous
solution was extracted with EtOAc (5.0 mLꢃ5). The combined or-
ganic layer was dried over Na2SO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography (EtOAc)
to give
7 (353 mg, 97% yield) as colorless prisms: mp:
Fig. 2. CD spectra of compounds (S)-16 and (R)-16 in MeOH.
108.4e109.4 ꢂC (hexane-EtOAc); ½a 1D3
ꢀ3.7 (c 1.0, MeOH); Rf¼0.20
ꢁ

M. Kojima et al. / Tetrahedron 67 (2011) 8293e8299
8297
Fig. 3. Structures of acyclic 1,2-di-O-benzoates exhibited a negative first and positive second Cotton effects in the CD spectra.
(EtOAc); IR (KBr, disk): 3287, 749, 699 cmꢀ1
;
1H NMR (250 MHz,
1H NMR (250 MHz, C5D5N):
d 7.85, 7.81, 7.79, 7.78 (each s, 8H, ArH),
CDCl3): 7.46e7.35 (m, 5H, ArH), 5.83 (s, 1H, PhCH), 4.11 (t,
d
6.43 (dd, J3,4a¼2.5 Hz, J3,4b¼8.0 Hz, 1H, H-3), 5.30 (dd, J4a,3¼2.5 Hz,
J4a,4b¼12.0 Hz,1H, H-4a), 5.11, 4.87 (each d, J¼11.5 Hz, 2H, H-1), 5.06
(dd, J4b,3¼8.0 Hz, J4b,4a¼12.0 Hz, 1H, H-4b), 4.97, 4.90 (each d,
J3,4¼5.9 Hz, 1H, H-3), 3.94 (d, J4,3¼5.9 Hz, 2H, H-4), 3.84, 3.78 (each
d, J¼11.9 Hz, 2H, H-1), 3.80, 3.74 (each d, J¼11.6 Hz, 2H, H-10), 3.32
(br s, 2H, eOHꢃ2), 3.01 (br s, 1H, eOH); 13C NMR (63 MHz, CDCl3):
J¼11.7 Hz, 2H, H-10); 13C NMR (63 MHz, C5D5N):
d 166.9, 166.7,
d
136.3, 129.7, 128.4, 126.7, 102.6, 83.3, 80.9, 63.5, 61.4, 59.9; ESI-
166.6, 166.2, 147.3, 147.2, 140.99, 140.97, 140.92, 120.63, 120.56,
120.45, 110.2, 74.2, 72.6, 65.33, 65.25, 63.6; ESI-HRMS calcd for
C33H28O21Na m/z [MþNa]þ: 783.1021. Found: 783.1056.
HRMS calcd for C12H16O5Na m/z [MþNa]þ: 263.0895. Found:
263.0870.
4.2.2. (3S)-2-Hydroxymethylbutane-1,2,3,4-tetrol (8) [
D-apiitol]. To
4.3. Total synthesis of (R)-1,3,4,5-tetragalloylapiitol
a solution of 7 (200 mg, 0.832 mmol) in MeOH (20 mL) was added
palladium hydroxide on carbon (palladium 20 wt % on carbon). The
suspension was stirred for 24 h at room temperature under H2 gas.
The mixture was filtered through Celite, and the filtrate was con-
centrated. The residue was loadedonto an octadecyl silica gel column
and eluted successively with water and MeOH. The water fraction
4.3.1. 2,3-O-Benzylidene-
a/b-D-ribofuranose (10). To a suspension of
D-ribose (10.0 g, 66.6 mmol), freshlydistilled benzaldehyde (27.0 mL,
266.4 mmol), and CuSO4 (20 g) in dry DMF (30 mL) was added
camphor sulfonic acid (7.7 g, 33.3 mmol). After stirring for 48 h at
room temperature under argon, the reaction mixture was quenched
with triethylamine (30 mL) and diluted with CH2Cl2 (70 mL), after
which 20 g of Celite was added to the mixture. After stirring for
15 min, the suspension was filtered through Celite. The filter cake
was washed with CH2Cl2 (20 mLꢃ3), and the filtrate was concen-
trated in vacuo. The residue was purified by silica gel column chro-
matography (hexane/acetone¼5:1 then 3:2 v/v) to give 10 (5.18 g,
was concentrated to give -apiitol 8 (127 mg, quant.) as a colorless
D
syrup. ½a 2D5
ꢁ
ꢀ6.9 (c 0.54, MeOH) [lit. ½a D26
ꢁ
ꢀ4.0 (c 0.8, MeOH)5];
Rf¼0.31 (CHCl3/MeOH/H2O¼10:10:1 v/v). The 1H and 13C NMR data
for synthetic 8 agreed well with previously reported values.4,5
4.2.3. (3S)-2-Hydroxy-2-[3,4,5-tris(benzyloxy)benzoyloxymethyl]bu-
tane-1,3,4-triyl tris[3,4,5-tris(benzyloxy)benzoate] (9). To a solution
of 8 (5.4 mg, 0.0355 mmol) in pyridine (1 mL) was added 3,4,5-
tris(benzyloxy)benzoyl chloride (130 mg, 0.2839 mmol) at room
temperature. After stirring for 12 h at 60 ꢂC, the reaction mixture was
quenched with MeOH (0.1 mL). The solvent was evaporated and the
residue was coevaporated with toluene (5 mLꢃ3). The residue was
purified by silica gel column chromatography (toluene/EtOAc¼14:1
then 4:1 v/v) to give 9 (59.1 mg, 90% yield) as colorless needles: mp:
33% yield,
a
/
b
¼1:10) as colorless needles: mp 124.8e125.9 ꢂC
(hexane/EtOAc) [lit. 123e124 ꢂC (benzene)19]; ½a 1D7
ꢀ22.7 (c 1.02,
ꢁ
CHCl3) [lit. ½a 2D0
ꢁ
ꢀ22.4 (c 1.4, CHCl3)14]; Rf¼0.26 (hexane/EtOAc¼1:1
v/v); IR (KBr, disk): 3303, 2937, 767, 697 cmꢀ1; 1H NMR (250 MHz,
CDCl3, selected b-anomer signal): d 7.53e7.36 (m, 5H, ArH), 5.77 (s,
1H, PhCH), 5.56 (br d, J1,OH¼3.5 Hz, 1H, H-1), 4.91 (d, J3,2¼6.2 Hz, 1H,
H-3), 4.68 (d, J2,3¼6.2 Hz, 1H, H-2), 4.64, 3.46 (each br s, 2H, OHꢃ2),
4.57 (t, J4,5¼2.5 Hz, 1H, H-4), 3.77 (m, 2H, H-5); 13C NMR (63 MHz,
159.2e160.9 ꢂC (hexane/EtOAc) [lit. 130e131 ꢂC]; ½a 2D6
ꢁ
þ15.9 (c 1.0,
CDCl3, selected b-anomer signal): d 135.8, 129.9, 128.4, 126.9, 105.8,
CHCl3) [lit.
½
a 2D5
ꢁ
þ26.5 (c 0.11, CHCl3)8]; Rf¼0.51 (toluene/
102.7, 87.54, 87.48, 82.6, 63.6; ESI-HRMS calcd for C12H14O5Na m/z
acetone¼10:1 v/v); IR (KBr, disk): 3421, 3030, 2868, 1719, 730,
[MþNa]þ: 261.0739. Found: 261.0723.
694 cmꢀ1; 1H NMR (250 MHz, CDCl3):
d 7.42e7.18 (m, 68H, ArH), 5.89
(dd, J3,4a¼3.4 Hz, J3,4b¼7.6 Hz, 1H, H-3), 5.16e4.87 (m, 24H,
PhCH2ꢃ12), 5.01 (dd, J4a,3¼3.4 Hz, J4a,4b¼12.4 Hz,1H, H-4a), 4.70, 4.49
(each d, J¼11.9 Hz, 2H, H-1), 4.65 (dd, J4b,3¼7.6 Hz, J4b,4a¼12.2 Hz,1H,
H-4b), 4.58, 4.44 (each d, J¼11.9Hz, 2H, H-10), 3.31 (brs,1H, eOH); 13C
4.3.2. 2,3-O-Benzylidene-2-C-(hydroxymethyl)-a/b-D-ribofuranose
(11). To a solution of 10 (4.6 g,19.3 mmol) and potassium carbonate
(3.74 g, 27.0 mmol) in MeOH (69.0 mL) was added a 37% aq form-
aldehyde solution (41.0 mL). After stirring for 8 h at 85 ꢂC, the re-
action mixture was neutralized with 1 M aq HCl solution and
concentrated. The remaining aqueous solution was extracted with
CH2Cl2 (20 mLꢃ5), and the combined organic layer was dried over
Na2SO4, filtered, and concentrated. The residue was purified by
silica gel column chromatography (hexane/acetone¼1:1 v/v) to
NMR (63 MHz, CDCl3):
d 166.2, 166.1, 165.7, 165.1, 152.66, 152.64,
152.62, 152.56, 143.2, 143.03, 143.01, 142.7, 137.45, 137.43, 137.42,
137.36, 136.62, 136.59, 136.5, 136.4, 128.50, 128.49, 128.45, 128.39,
128.38, 128.31, 128.15, 128.10, 127.98, 127.87, 127.81, 127.63, 127.54,
127.48,127.47,124.5, 124.1, 124.0,123.9,109.4,109.2,108.9, 75.1, 75.0,
74.4, 72.4, 71.19, 71.14, 71.03, 65.5, 65.4, 62.7; ESI-HRMS calcd for
C117H100O21Na m/z [MþNa]þ: 1863.6655. Found: 1863.6660.
give 12 (4.5 g, 88% yield,
a
/
b
¼1:3) as colorless needles: mp
145.1e146.7 ꢂC (EtOH); ½a 1D8
ꢁ
ꢀ16.3 (c 1.01, MeOH); Rf¼0.26 (hex-
ane/acetone¼1:1 v/v); IR (KBr, disk): 3331, 2929, 2887, 769,
4.2.4. (S)-(þ)-1,3,4,5-Tetragalloylapiitol ((S)-1). To a solution of 9
(112 mg, 0.061 mmol) in THF/MeOH/H2O (22 mL, 20:1:1 v/v) was
added palladium hydroxide on carbon (palladium 20 wt % on car-
bon). The suspension was stirred for 13 h at room temperature
under H2 gas. The mixture was filtered through Celite, and the fil-
trate was concentrated. After the residue was dissolved with EtOAc,
the resulting precipitate was filtered off, and the filtrate was con-
centrated. The crude crystals were recrystallized from toluene/
EtOAc to give (S)-1 (46 mg, 99% yield) as a pale yellow solid: mp:
695 cmꢀ1
; b-anomer signal):
1H NMR (250 MHz, CD3OD, selected
d
7.64e7.35 (m, 5H, ArH), 6.06 (s, 1H, PhCH), 5.36 (s, 1H, H-1), 4.70
(s, 1H, H-3), 4.31 (t, J4,5¼5.3 Hz, 1H, H-4), 3.94 (s, 2H,H-6), 3.68 (2H,
d, J5,4¼5.3 Hz, H-5); 13C NMR (63 MHz, CD3OD, selected
b-anomer
signal): d 138.7, 130.6, 129.2, 128.1, 107.7, 104.2, 96.3, 88.4, 85.8, 64.1,
62.5; ESI-HRMS calcd for C13H16O6Na m/z [MþNa]þ: 291.0845.
Found: 291.0867.
4.3.3. 2,3-O-Benzylidene-3-C-(hydroxymethyl)-a/b-L-erythrofur-
anose (12). To a solution of 11 (3.7 g, 13.8 mmol) in MeOH (60.0 mL)
was cautiously added sodium borohydride (1.6 g, 41.5 mmol) in
>300 ꢂC (toluene/EtOAc); ½a 2D0
ꢁ
þ20.3 (c 1.0, MeOH); Rf¼0.39
(CHCl3/MeOH/H2O¼10:10:3 v/v); IR (KBr, disk): 3379, 1701 cmꢀ1
;

8298
M. Kojima et al. / Tetrahedron 67 (2011) 8293e8299
small portions. After stirring for 30 min at room temperature, the
reaction mixture was cooled to 0 ꢂC and then neutralized to pH 7
with a 1 M aq HCl solution. To this mixture was then added a so-
lution of sodium periodate (5.9 g, 27.6 mmol) in H2O (45.0 mL), and
the reaction mixture was stirred for an additional 1 h at room
temperature. After the solvent was evaporated, the remaining
aqueous solution was extracted with EtOAc (20 mLꢃ3). The com-
bined organic layer was dried over Na2SO4, filtered, and concen-
trated. The residue was purified by silica gel column
chromatography (hexane/EtOAc¼3:2 v/v) to give 12 (2.4 g, 73%
employing 15 (200 mg, 0.109 mmol) and palladium hydroxide on
carbon (palladium 20 wt % on carbon) to afford the pure compound
(R)-1 (82 mg, 99% yield) as a pale yellow solid: mp: >300 ꢂC (tol-
uene/EtOAc); ½a D15
ꢀ20.5 (c 1.03, MeOH); Rf¼0.39 (CHCl3/MeOH/
ꢁ
H2O¼10:10:3 v/v); IR (KBr, disk): 3367, 1700 cmꢀ1
;
1H NMR
(250 MHz, C5D5N): d 7.84, 7.81, 7.79, 7.77 (each s, 8H, ArH), 6.43 (dd,
J3,4a¼2.6 Hz, J3,4b¼8.2 Hz, 1H, H-3), 5.30 (dd, J4a,3¼2.6 Hz,
J4a,4b¼11.8 Hz,1H, H-4a), 5.10, 4.87 (each d, J¼11.5 Hz, 2H, H-1), 5.06
(dd, J4b,3¼8.2 Hz, J4b,4a¼11.8 Hz, 1H, H-4b), 4.97, 4.91 (each d,
J¼11.7 Hz, 2H, H-10); 13C NMR (63 MHz, C5D5N):
d 166.9, 166.7,
yield,
a
/b
¼1:10) as a colorless syrup: ½a D17
ꢁ
þ35.9 (c 1.05, CHCl3);
166.6, 166.2, 147.3, 147.2, 140.99, 140.98, 140.92, 120.63, 120.56,
120.46, 110.2, 74.2, 72.6, 65.34, 65.29, 63.6; ESI-HRMS calcd for
C33H28O21Na m/z [MþNa]þ: 783.1021. Found: 783.1014.
Rf¼0.56 (hexane/acetone¼3:2 v/v); IR (NaCl, neat): 3409, 2939,
; b-anomer sig-
760, 699 cmꢀ1 1H NMR (250 MHz, CDCl3, selected
nal): 7.53e7.34 (m, 5H, ArH), 5.89 (s, 1H, PhCH), 5.53 (s, 1H, H-1),
d
4.44 (s, 1H, H-2), 4.12, 4.06 (each d, J¼10.3 Hz, 2H, H-4), 3.91, 3.85
Acknowledgements
(each d, J¼11.7 Hz, 2H, H-5), 3.75, 2.84 (each br s, 2H, OHꢃ2); 13C
NMR (63 MHz, CDCl3, selected b-anomer signal): d 136.0, 129.9,
We wish to thank Ms Y. Yamazaki for technical assistance.
128.4, 127.0, 106.2, 101.2, 91.9, 87.3, 73.3, 63.1. ESI-HRMS calcd for
C12H14O5Na m/z [MþNa]þ: 261.0739. Found: 261.0735.
References and notes
4.3.4. [(5R)-2-Phenyl-1,3-dioxolane-4,4,5-triyl]trimethanol
(13). This compound was prepared according to the procedure
described for 7, employing 12 (1.0 g, 4.20 mmol) and sodium bo-
rohydride (191 mg, 5.04 mmol) to afford the pure compound 13
(1.01 g, quant.) as colorless needles: mp: 81.5e82.6 ꢂC (hexane-
1. (a) Bokesch, H. R.; Wamiru, A.; Le Grice, S. F. J.; Beutler, J. A.; McKee, T. C.;
McMahon, J. B. J. Nat. Prod. 2008, 71, 1634; (b) Yamada, H.; Nagao, K.; Dokei, K.;
Kasai, Y.; Michihata, N. J. Am. Chem. Soc. 2008, 130, 7566; (c) Ren, Y.; Himmel-
dirk, K.; Chen, X. J. Med. Chem. 2006, 49, 2829; (d) Baumgartner, R. R.; Stein-
mann, D.; Heiss, E. H.; Atanasov, A. G.; Ganzera, M.; Stuppner, H.; Dirsch, V. M. J.
Nat. Prod. 2010, 73, 1578.
2. 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.
3. (a) Kohlstaedt, L. A.; Wang, J.; Friedman, J. M.; Rice, P. A.; Steitz, T. A. Science
1992, 256, 1783; (b) Arnold, E.; Jacobo-Molina, A.; Nanni, R. G.; Williams, R. L.;
Lu, X.; Ding, J. Nature 1992, 357, 85.
EtOAc); ½a 1D3
ꢁ
þ1.8 (c 1.0, MeOH); Rf¼0.20 (EtOAc); IR (KBr, disk):
3323, 764, 700 cmꢀ1
;
1H NMR (250 MHz, CDCl3):
d
7.41e7.27 (m,
5H, ArH), 5.73 (s, 1H, PhCH), 4.02 (t, J3,4¼6.0 Hz, 1H, H-3), 3.82 (d,
J4,3¼5.9 Hz, 2H, H-4), 3.75e3.60 (m, 4H, H-1 and 10); 13C NMR
4. Klumpp, K.; Mirzadegan, T. Curr. Pharm. Des. 2006, 12, 1909.
5. Kitajima, J.; Suzuki, N.; Ishikawa, T.; Tanaka, Y. Chem. Pharm. Bull. 1998, 46, 1583.
6. Patel, R. M.; Argade, N. P. Synthesis 2009, 3, 372.
(63 MHz, CDCl3):
d 136.5, 129.7, 128.4, 126.7, 102.6, 83.3, 81.0, 63.5,
61.5, 60.0; ESI-HRMS calcd for C12H16O5Na m/z [MþNa]þ: 263.0895.
7. Kraus, G. A.; Kempema, A. Synthesis 2010, 3, 389.
Found: 263.0891.
8. Batwal, R. U.; Patel, R. M.; Argade, N. P. Tetrahedron: Asymmetry 2011, 22, 173.
9. (a) Guindon, Y.; Bencheqroun, M.; Bouzide, A. J. Am. Chem. Soc. 2005, 127, 554;
(b) Papageorgiou, C.; Benezra, C. Tetrahedron Lett. 1984, 25, 1303.
10. Kojima, M.; Nakamura, Y.; Nakamura, A.; Takeuchi, S. Tetrahedron Lett. 2009, 50,
939.
11. (a) Koumbis, A. E.; Kotoulas, S. S.; Gallos, J. K. Tetrahedron 2007, 63, 2235; (b)
Koumbis, A. E.; Kaitaidis, A. D.; Kotoulas, S. S. Tetrahedron Lett. 2006, 47, 8479;
(c) Gallos, J. K.; Stathakis, C. I.; Kotoulas, S. S.; Koumbis, A. E. J. Org. Chem. 2005,
70, 6884; (d) Koumbis, A. E.; Kaitaidis, A. D.; Dieti, K. M.; Vikentiou, M. G.;
Kotoulas, S. S. Tetrahedron Lett. 2003, 44, 2513; (e) Ho, P.-T.; Wong, S. Can. J.
Chem. 1985, 63, 2221; (f) Ho, P.-T. Can. J. Chem. 1980, 58, 858.
4.3.5. (3R)-2-Hydroxymethylbutane-1,2,3,4-tetrol (14) [L-apiitol]. -
This compound was prepared according to the procedure described
for 8, employing 13 (200 mg, 0.109 mmol) and palladium hydroxide
on carbon (palladium 20 wt % on carbon) to afford the pure com-
pound 14 (126.5 mg, quant.) as a colorless syrup: ½a D26
þ7.4 (c 1.0,
ꢁ
MeOH) [lit. ½a 2D6
ꢁ
þ4.3 (c 1.2, MeOH)5]; Rf¼0.31 (CHCl3/MeOH/
H2O¼10:10:1 v/v): The 1H and 13C NMR data for synthetic 14 agreed
well with previously reported values.4,5
12. Totokotsopoulos, S. M.; Koumbis, A. E.; Gallos, J. K. Tetrahedron 2008, 64, 3998;
(b) Kim, M. J.; Jeong, L. S.; Kim, J. H.; Shim, J. H.; Chung, S. Y.; Lee, S. K.; Chun, M.
W. Nucleosides, Nucleotides Nucleic Acids 2004, 23, 715.
4.3.6. (3R)-2-Hydroxy-2-[3,4,5-tris(benzyloxy)benzoyloxymethyl]bu-
tane-1,3,4-triyl tris[3,4,5-tris(benzyloxy)benzoate] (15). This com-
pound was prepared according to the procedure described for 9,
employing 14 (5.7 mg, 0.0375 mmol), 3,4,5-tris(benzyloxy)benzoyl
chloride (138 mg, 0.300 mmol), and pyridine (1.0 mL) to afford the
pure compound 15 (61.3 mg, 89% yield) as colorless needles: mp:
13. (a) Uzawa, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1990, 55, 116; (b)
Harada, N.; Saito, A.; Ono, H.; Uda, H.; Jacek, G.; Krystyna, G. The 33rd Sym-
posium on the Chemistry of Natural Products; Osaka, Japan, October 1991,
Symposium Papers, p 464; (c) Kim, K. H.; Choi, S. U.; Lee, K. R. Chem. Lett. 2009,
38, 894; (d) Sakamoto, I.; Ichimura, K.; Ohrui, H. Biosci. Biotechnol. Biochem.
2000, 64, 1915; (e) Ami, E.; Kishimoto, H.; Ohrui, H.; Meguro, H. Biosci. Bio-
technol. Biochem. 1997, 61, 2019; (f) Oguri, H.; Hishiyam, S.; Sato, O.; Oishi, T.;
Hirama, M.; Murata, M.; Yasumoto, T.; Harada, N. Tetrahedron 1997, 53, 3057.
14. Doda, K.; Minato, T.; Noguchi-Yoshida, T.; Suganuma, M.; Hashimoto, Y. Bioorg.
Med. Chem. 2008, 16, 7975.
158.9e160.1 ꢂC (hexane/EtOAc); ½a 2D6
ꢀ15.1 (c 1.0, CHCl3); Rf¼0.51
ꢁ
(toluene/acetone¼10:1 v/v); IR (KBr, disk): 3423, 3031, 2869, 1717,
731, 694 cmꢀ1 1H NMR (250 MHz, CDCl3):
; d 7.42e7.18 (m, 68H,
15. (3S)-2,3-Dihydroxy-2-[3,4,5-tris(benzyloxy)benzoyloxymethyl]butane-1,4-diyl bis
[3,4,5-tris(benzyloxy)benzoate] (90). mp: 108.4e109.5 ꢂC (colorless needles,
ArH), 5.88 (dd, J3,4a¼3.4 Hz, J3,4b¼7.6 Hz, 1H, H-3), 5.16e4.87 (m,
24H, PhCH2ꢃ12), 5.01 (dd, J4a,3¼3.4 Hz, J4a,4b¼12.1 Hz, 1H, H-4a),
4.70, 4.49 (each d, J¼11.9 Hz, 2H, H-1), 4.65 (dd, J4b,3¼7.6 Hz,
J4b,4a¼12.2 Hz, 1H, H-4b), 4.58, 4.44 (each d, J¼11.8 Hz, 2H, H-10),
hexane/EtOAc); ½a D15
ꢁ
ꢀ2.7 (c 1.0, CHCl3); Rf¼0.29 (toluene/acetone 10:1 v/v); IR
1H NMR (250 MHz, CDCl3):
(KBr, disk): 3452, 3031, 2857, 1712, 734, 695 cmꢀ1
;
d
7.39e7.18 (m, 51H, ArH), 5.09e5.00 (m, 18H, PhCH2ꢃ9), 4.85 (dd, J4a,3¼3.9 Hz,
J4a,4b¼11.8 Hz, 1H, H-4a), 4.61e4.54 (dd, 1H, H-4b, overlapped with H-1 and 10
signals), 4.60, 4.49 (each d, J¼11.9 Hz, 2H, H-1), 4.56 (s, 2H, H-10), 4.08 (br ddd,
J3,4a¼4.0 Hz, J3,4b¼5.8 Hz, J3, OH¼4.8 Hz, 1H, H-3), 3.20 (br s, 1H, eOH), 3.07 (br
3.30 (br s, 1H, eOH); 13C NMR (63 MHz, CDCl3):
d 166.2, 166.1, 165.7,
d, JOH3¼4.9 Hz, 1H, eOH); 13C NMR (63 MHz, CDCl3):
d 166.5, 166.4, 166.1, 152.
165.2, 152.68, 152.65, 152.64, 152.57, 143.3, 143.07, 143.05, 142.7,
137.46, 137.45, 137.40, 137.38, 136.63, 136.61, 136.5, 136.4, 128.50,
128.49, 128.45, 128.39, 128.38, 128.31, 128.15, 128.10, 127.98, 127.87,
127.81, 127.64, 127.54, 127.49, 127.47, 124.5, 124.1, 124.0, 123.9, 109.4,
109.3, 109.0, 75.13, 75.05, 74.4, 72.4, 71.21, 71.17, 71.05, 65.5, 65.4,
62.7; ESI-HRMS calcd for C117H100O21Na m/z [MþNa]þ: 1863.6655.
Found: 1863.6615.
59, 152.57, 142.96, 142.92, 142.8, 137.39, 137.37, 137.35, 136.6, 128.48, 128.41, 128.
40, 128.37, 128.13, 127.97, 127.88, 127.72, 127.53, 127.47, 127.46, 124.4, 124.1, 109.
26, 109.22, 109.19, 75.1, 74.5, 71.2, 65.3, 65.2; ESI-HRMS calcd for C89H78O17Na
m/z [MþNa]þ: 1441.5137. Found: 1441.5106.
16. In the cases of low concentration, the optical rotations were ½a D25
þ19.8 (c 0.1,
ꢁ
MeOH) and ½a 1D8
þ20.0 (c 0.03, MeOH).
ꢁ
17. Since the precursor
9 bearing four nonpolar 3,4,5-tris(benzyloxy)benzoyl
groups was insoluble in 2 N NaOH/MeOH (1:1), the alkaline hydrolysis of 9 was
carried out in 2 N NaOH/MeOH/THF (1:1:1).
18. (3S)-2-Hydroxy-2-(benzoyloxymethyl)butane-1,3,4-triyltrisbenzoate ((S)-16). To
a solution of 8 (35 mg, 0.23 mmol) in pyridine (2.0 mL) was added dropwise
4.3.7. (R)-(ꢀ)-1,3,4,5-Tetragalloylapiitol ((R)-1). This compound
was prepared according to the procedure described for (S)-1,
benzoyl chloride (159 m
L, 1.38 mmol) at 0 ꢂC. After stirring for 12 h at room

M. Kojima et al. / Tetrahedron 67 (2011) 8293e8299
8299
temperature, the reaction mixture was quenched with a saturated aq NaHCO3
solution (20 mL). The aqueous layer was extracted with CH2Cl2 (10 mLꢃ3), and
the combined organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated. The residue was purified by silica gel column chromatog-
raphy (hexane/EtOAc¼4: 1 v/v) to give 16 (130 mg, 99% yield) as a colorless
1637. (3R)-2-Hydroxy-2-(benzoyloxymethyl)butane-1,3,4-triyltrisbenzoate ((R)-
16) This compound was prepared according to the procedure described for (S)-
16, employing 14 (35 mg, 0.230 mmol), benzoyl chloride (159 mL, 1.380 mmol),
and pyridine (1 mL) to afford the pure compound (R)-16 (131 mg, quant.) as
a colorless amorphous powder: ½a D26
ꢁ
ꢀ23.0 (c 1.0, CHCl3); CD (MeOH, c 0.
þ1.3); Rf¼0.41 (hexane/EtOAc¼3:2
1H NMR (250 MHz, CDCl3):
8.
06e7.33 (m, 20H, ArH), 5.96 (dd, J34a¼3.3 Hz, J34b¼7.4 Hz, 1H, H-3), 4.99 (dd,
J4a,3¼3.3 Hz, J4a 4b¼12.1 Hz, 1H, H-4a), 4.79, 4.67 (each d, J¼11.9 Hz, 2H, H-1), 4.
77 (dd, J4b,3¼7.4 Hz, J4b,4a¼12.0 Hz, 1H, H-4b), 4.71, 4.61 (each d, J¼12.0 Hz, 2H,
H-10), 3.54 (br s, 1H, eOH); 13C NMR (63 MHz, CDCl3):
166.7, 166.2, 165.5, 133.
amorphous powder. ½a D20
ꢁ
þ22.7 (c 1.01, CHCl3); CD (MeOH, c 0.018
ꢀ1.2); Rf¼0.41 (hexane/EtOAc¼3:2 v/v); IR (NaCl,
1H NMR (250 MHz, CDCl3):
8.05e7.32 (m,
m
mol/mL)
018 mmol/mL) lext 227 nm (D 3 e3.6), 241 (D 3
lext 227 nm (
D
3
þ3.5), 241 (
D
3
v/v); IR (NaCl, neat): 3461, 1725, 1267, 707 cmꢀ1
;
d
neat): 3470, 1725, 1268, 709 cmꢀ1
;
d
20H, ArH), 5.97 (dd, J3,4a¼3.3 Hz, J3,4b¼7.4 Hz, 1H, H-3), 5.00 (dd, J4a,3¼3.3 Hz,
J4a,4b¼12.1 Hz, 1H, H-4a), 4.79, 4.68 (each d, J¼11.8 Hz, 2H, H-1), 4.77 (dd,
J4b,3¼7.5 Hz, J4b,4a¼11.9 Hz, 1H, H-4b), 4.71, 4.62 (each d, J¼12.0 Hz, 2H, H-10), 3.
,
d
63 (br s, 1H, eOH); 13C NMR (63 MHz, CDCl3):
d
166.6, 166.2, 165.5, 133.5, 133.1,
5, 133.1, 129.82, 129.79, 129.7, 129.4, 129.17, 129.12, 129.06, 128.5, 128.4, 74.4, 72.
3, 65.5, 65.4, 62.9.
19. Wood, H. B., Jr.; Diehl, H. W.; Fletcher, H. G., Jr. J. Am. Chem. Soc. 1956, 78, 4715.
129.80, 129.78, 129.6, 129.4, 129.15, 129.11, 129.05, 128.5, 128.4, 74.3, 72.3, 65.5,
65.4, 62.9; ESI-HRMS calcd for C33H28O9Na m/z [MþNa]þ: 591.1631. Found: 591.