Seven-Step Stereodivergent Total Syntheses of Punicafolin and Macaranganin

Article abstract of DOI:10.1021/jacs.0c10714

The first total syntheses of punicafolin (1) and macaranganin (2) were achieved in seven steps, respectively, from commercial α-d-glucose. The characteristic features of the synthesis are (1) sequential site-selective introduction of the adequate galloyl groups into unprotected d-glucose by a catalyst-controlled manner and (2) stereodivergent construction of the 3,6-HHDP bridge by oxidative phenol coupling of a common intermediate via a ring-flipping process of the glucose core. Because no protective groups were used for glucose throughout the process, extremely short-step total syntheses of natural glycosides 1 and 2 (MW 938) were performed.

Full text of DOI:10.1021/jacs.0c10714

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Seven-Step Stereodivergent Total Syntheses of Punicafolin and
Macaranganin
Hiromitsu Shibayama, Yoshihiro Ueda,* Takashi Tanaka, and Takeo Kawabata*
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ABSTRACT: The first total syntheses of punicafolin (1) and
macaranganin (2) were achieved in seven steps, respectively, from
commercial α-D-glucose. The characteristic features of the synthesis
are (1) sequential site-selective introduction of the adequate galloyl
groups into unprotected D-glucose by a catalyst-controlled manner
and (2) stereodivergent construction of the 3,6-HHDP bridge by
oxidative phenol coupling of a common intermediate via a ring-
flipping process of the glucose core. Because no protective groups
were used for glucose throughout the process, extremely short-step
total syntheses of natural glycosides 1 and 2 (MW 938) were
performed.
Yamada and co-workers reported the first example for the
construction of a 3,6-HHDP-bridged glucose skeleton via a
ring-opened glucose derivative in 2004.5c The strategy was
INTRODUCTION
■
Ellagitannins constitute one of the major classes of hydro-
lyzable tannins. More than 500 natural products of this
ellagitannin family have been structurally characterized,
exhibiting a variety of biological activities including antiox-
idative, anticancer, and antiviral activities.1 The structures are
basically composed of a central sugar core, typically D-glucose,
to which are esterified gallic acid (3,4,5-trihydroxybenzoic
acid) and hexahydroxydiphenoic (HHDP) acid. Punicafolin
(1) and macaranganin (2) (Scheme 1a) have been isolated
from the leaves of Punica granatum in 1985 and Macaranga
tanarius (L.) MUELL. et ARG. in 1990, respectively, by
Nishioka and co-workers.2,3 They are characterized by a 3,6-
HHDP group bridged between C(3)−OH and C(6)−OH of
the glucose core. Construction of the 3,6-HHDP group has
been a synthetic challenge because a less stable axial-rich
1
successfully applied to the first total synthesis of a C4/B-
ellagitannin, corilagin, in 2008 (Scheme 1b, route A).8
Recently, Ikeuchi, Yamada, and co-workers reported an
improved synthesis of corilagin via a conformationally fixed
intermediate (Scheme 1b, route B).9 In these precedents, use
of a ring-opened pyranose derivative or a conformationally
fixed pyranose derivative seemed essential for the construction
of the 3,6-HHDP group. For straightforward total synthesis,
direct formation of the 3,6-HHDP group from a stable chair
4C1 conformation with all equatorial substituents seems to be
more desirable. The potential was demonstrated also by
Yamada’s group.10 The regiochemical profile of oxidative
phenol coupling of penta-(4-O-benzyl)galloylglucose 6 was
investigated (Scheme 1c). They carefully isolated the 3,6-
HHDP derivative, and the structure was unambiguously
clarified to be 7. Although the formation of 7 was only in a
trace amount, this study demonstrated that the direct
1
conformer such as C4 conformer of the pyranose ring is
required for the formation.4,5 Natural glycosides 1 and 2 have
the same molecular formula and are stereoisomeric to each
other concerning the chiral axis of the HHDP group. They
show different biological activities depending on the chirality
of the 3,6-HHDP groups. Glycoside 1 with an R-HHDP group
exhibits inhibitory activity of invasion of HT1080 fibrosarcoma
cells (IC50 = 4.2 μM),6 while 2 with an S-HHDP group acts as
a strong inhibitor of prolyl endopeptidase (IC50 = 43 nM).7
Thus, stereodivergent construction of the HHDP groups is an
important additional challenge. Here, we report the first total
syntheses of 1 and 2 in seven steps, respectively, from D-
glucose via sequential site-selective introduction of galloyl
groups into unprotected D-glucose without employing any
protective groups for hydroxy groups of glucose (Scheme 1a).
1
formation of the 3,6-HHDP glucose derivative with the C4
conformation is possible via the ring-flipping process of the
4
glucose derivative with a stable C1 conformation.
Received: October 16, 2020
Published: January 14, 2021
https://dx.doi.org/10.1021/jacs.0c10714
J. Am. Chem. Soc. 2021, 143, 1428−1434
© 2021 American Chemical Society
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a
Scheme 1. Structure and Synthetic Strategy for Ellagitannins with a 3,6-HHDP Group
a
(a) This work: Retrosynthetic analysis for total syntheses of punicafolin (1) and macaranganin (2). (b) Yamada’s total synthesis of corilagin. (c)
Regiochemical profile of oxidative phenol coupling of penta-(4-O-benzyl)galloylglucose derivative 6 reported by Yamada’s group. (d)
Conformational analysis of glucose (β-Glc) and the perbenzoylated derivative (β-PBG).
Inspired by Yamada’s pioneering studies, we planned a total
synthesis of 1 and 2. The retrosynthetic analysis is shown in
Scheme 1a. We envisaged that stereodivergent oxidative
phenol coupling between the 3- and 6-galloyl groups of 3
process from its stable 4C1 conformer is the most
straightforward route to 1 and 2 (step 4: key step). Control
of the stereochemistry of the oxidative phenol coupling might
be achieved by a proper choice of chiral amines in the presence
of Cu(II) as the oxidant. The plausibility of the all-axial
1
with an unstable C4 conformation generated via a ring-flip
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Scheme 2. Total Syntheses of Punicafolin (1) and Macaranganin (2)
conformer of 3 seemed to be of critical importance to realize
the construction of the 3,6-HHDP group. The ring-flip process
of 3 was estimated by a DFT calculation. Conformational
analysis of β-pentabenzoylglucose (β-PBG) as a model of 3
was performed with comparison with that of β-glucose (β-Glc)
(Scheme 1d). The optimized geometries of β-PBG and β-Glc
were obtained by conformational searches with molecular
mechanics (OPLS force field, MCMM) and the subsequent
optimization by a DFT calculation at the M06-2X/6-311+
+G(2d,2p)//M06-2X/6-31G(d) level (For details, see Figures
S1 and S27). In both cases, the 4C1 conformer was found to be
challenge because chiral pyrrolidinopyridines (PPYs) with
various side chains have been shown to promote site-selective
acylation of glucose derivatives with intrinsic site-selectivity
depending on the side chains for molecular recognition.12c,d
The strategy for preparation of digallate 5 has already been
established by our group13 via a stereo- and site-selective SN2-
type Mitsunobu glycosylation14 of gallic acid derivative G1 with
unprotected α-D-glucose as a glycosyl donor followed by
catalyst-controlled site-selective introduction of the second
galloyl group G1.12a−c,13
1
the most stable and the flipped-chair C4 conformer was the
RESULTS AND DISCUSSION
most stable among axial-rich conformers. The energy differ-
■
4
1
ence between C1 and C4 conformers of β-Glc was evaluated
to be 6.5 kcal/mol, while that of β-PBG was estimated to be
only 1.0 kcal/mol. The origin of the relative preference of the
all-axial conformer of β-PBG rather than that of β-Glc seemed
to be resulting from the stronger orbital interaction between
the nonbonding orbital of the ring oxygen with the σ* orbital
of the electron withdrawing C(1)−OBz bond (stronger
anomeric effect),11 which was suggested by natural bond
orbital (NBO) analysis (for detailed analysis, see Figure S2).
These results suggested that axial-rich conformations of 3
essential for the oxidative phenol coupling could exist to some
extent via the ring-flip process of the stable 4C1 conformer (the
conformational analysis of β-PBG based on Boltzmann
distribution analysis indicates the ratio between β-PBG (4C1)
and β-PBG (1C4) to be 30:1; for details, see Figure S4).
We then planned site-selective preparation of 3 from D-
glucose without employing any protective groups for glucose.
Galloyl groups G2 required for the oxidative phenol coupling
were planned to be introduced at C(3)−OH and C(6)−OH.
Because the rational precursor for 3 is to be 1,2,4-trigallate 4,
another key step must be site-selective introduction of galloyl
group G1 at C(2)−OH into the known intermediate, 1,4-
digallate 5 (step 2). We envisaged that use of our catalyst
library for site-selective acylation might be effective for this
Actual synthesis was commenced with α-D-glucose and O-
MOM-protected gallic acid derivative 8 via a known two-step
procedure13 to give 1,4-digallate 11 in 64% yield from α-D-
glucose (Scheme 2). The first key step concerning site-
selective introduction of the same galloyl group, 8, into the
C(2)−OH of 11 with three free hydroxy groups was
investigated (Scheme 1a, step 2, Table 1). We first examined
DMAP-catalyzed acylation of 11 with gallic acid anhydride
derivative 10 to assess the inherent reactivity of 11 toward
galloylation. Treatment of 11 with 10 in the presence of
DMAP (10 mol %) and diisopropylethylamine (DIPEA) in
CHCl3 at −20 °C gave the desired 2-O-acylate 12 and 3-O-
acylate 13 in 44 and 36% yield, respectively, with the primary
C(6)−OH intact (0% formation of 14) (entry 1). The
relatively higher reactivity of the C(2)−OH and the C(3)−
OH toward acylation in the presence of the primary C(6)−OH
was also observed in total synthesis of cercidinin A.15
Furthermore, the lack of the reactivity of the free C(6)−OH
in the glucose core in DMAP-catalyzed acylation of a natural
cardiac glycoside, lanatoside C, was observed (0% acylation),
where the C(6)−OH was suggested to form a strong
intramolecular hydrogen bond (2.9 Å for O−H−O distance)
by molecular modeling.12b We suppose that the intramolecular
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that of C2 (entries 6 and 7). The yield of the desired C(2)-
acylate 12 was low (13−22%) in both cases, while the
promising site-selectivity (79%) was observed in the reaction
with C3. We further examined a newly developed catalyst, C5
with a 3-benzothiophenyl group instead of the 3-indolyl group
of C2. Site-selective introduction of the galloly group at C(2)−
OH was achieved with C5 in 42% yield with 75% selectivity
(entry 8). Finally, use of 2.2 equiv of anhydride 10 in the
presence of C5 afforded the desired 2-O-acylate 12 with
moderately acceptable yield and selectivity (entry 9, 51% yield,
78% selectivity). The rationale of the C(2)−OH selectivity in
C5-catalyzed acylation was totally unclear at this moment.
With the desired 1,2,4-trigallate 12 in hand, 1,2,3,4,6-
pentagallate 15 (Scheme 2), the precursor for the key step
(step 4 in Scheme 1a: stereodivergent oxidative phenol
coupling), was prepared. Condensation of 12 with gallic acid
derivative 8′ (protected G2 in Scheme 1a) followed by
hydrogenolysis gave 15 in 72% yield. Construction of the 3,6-
HHDP bridge by oxidative phenol coupling of 15 via the
presumed ring-flip process of the pyranose core was examined.
Treatment of 15 under the standard conditions for oxidative
phenol coupling (CuCl2 (3.0 equiv)/n-BuNH2 (20 equiv)/
CHCl3/MeOH (1/1))8,17 gave no HHDP-bridged products;
instead, decomposition of 15 by solvolysis and/or aminolysis
was observed (Table S1, entry 1). We then examined sparteine
in place of n-BuNH2 according to Quideau’s achievement.
Recently, Quideau, Deffieux, and co-workers reported
(−)-sparteine/Cu(II)-mediated oxidative phenol coupling for
the construction of a nonahydroxytriphenoyl (NHTP) group
toward total synthesis of a C-glucoside ellagitannin, (−)-vesca-
lin.18 Treatment of 15 with CuCl2 (3.0 equiv) and
(+)-sparteine (10 equiv) in CHCl3/MeOH (1/1) at rt for
30 min afforded the desired 3,6-HHDP-bridged product 16
with R configuration in 60% yield as a single diastereomer
(Scheme 2). Use of smaller amounts (5.0 equiv) of
(+)-sparteine resulted in the reduced yield (29%) with
complete stereocontrol of the HHDP group formation
(Table S1, entry 7). The 1C4 conformation of 16 was
Table 1. Catalyst Screening for the C(2)−OH-Selective
Introduction of the Third Galloyl Group into 1,4-Digallate
11
recovery
(%)
site-selectivity (%) for
yield (%)
13 14
C(2)−OH acylation
entry catalyst
12
11
12/(12 + 13 + 14)
1
2
3
4
5
6
7
8
9
DMAP
C1
C2
ent-C1
ent-C2
C3
C4
C5
C5
44
32
23
37
21
22
13
42
51
36
20
9
37
19
5
7
10
13
0
4
1
3
3
1
4
4
1
10
24
48
13
36
49
37
30
10
55
57
70
48
49
79
54
75
78
a
a
Acid anhydride 10 (2.2 equiv) and DIPEA (3.0 equiv) were used.
3
suggested by comparison of the chemical shifts and JHH of
1
the pyranose moiety in the H NMR spectra of 16 with those
of 15 (see the Supporting Information). Use of (−)-sparteine
for the oxidative phenol coupling of 15 resulted in complete
reversal of stereochemistry for the construction of the 3,6-
HHDP group. On treatment of 15 with CuCl2 (3.0 equiv) and
(−)-sparteine (10 equiv) in CHCl3/MeOH (1/1) at rt for 30
min, the desired product 17 with an (S)-3,6-HHDP group was
obtained in 26% yield as a single diastereomer. The recovery of
15 was only ∼10% in this transformation. The major reason of
the poor material balance seemed to be resulting from
solvolysis and aminolysis of 17 and/or the related derivatives.
Although the yields are not satisfactory, this is the first
successful example of stereodivergent construction of the
HHDP groups from a common precursor among the reported
syntheses of ellagitannins.19 Deprotection of the MOM groups
of 16 and 17 under the hydrogenation conditions15,20 afforded
1 and 2 in 56 and 42% yield, respectively (cf. The MOM group
remained intact during the transformation of 12 to 15 via
hydrogenation conditions in THF. Use of alcoholic solvents is
indispensable for the removal of acid-labile groups under
hydrogenation conditions.15,20). Thus, the first total syntheses
of 1 and 2 were achieved in overall seven steps, respectively,
from D-glucose (nine steps from gallic acid) without using
protective groups for hydroxy groups of glucose. Two
hydrogen bond could be, at least in some part, responsible for
the reduced reactivity of the free C(6)−OH.
We then examined a catalyst mini-library including C1−C5,
ent-C1, and ent-C2, which were expected to be able to control
the site-selectivity of acylation of polyol compounds
irrespective of the inherent reactivity of the substrate polyols
(Table 1).16 Catalyst C1 was first examined because it was
shown to be extremely effective for site-selective acylation of D-
glucose derivatives.12c Treatment of 11 with anhydride 10 in
the presence of 10 mol % of C1 gave the desired 2-O-acylate
12 and 3-O-acylate 13 in 32 and 20% yield, respectively, with
24% recovery of 11 (57% site-selectivity for C(2)−OH
acylation, entry 2). Since the site-selectivity was not improved,
its diastereomeric catalysts C2, ent-C1, and ent-C2 were
examined (entries 2−4). The highest site-selectivity (70%) was
obtained by C2 with R,S,S,R configuration, although the yield
was low (23%, entry 2). We then examined catalysts C3 and
C4 possessing β-naphthylalanine- and valine-derived side
chains, respectively, with the same R,S,S,R configuration as
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organocatalysts, C1 and C5, played a pivotal role for site-
selective introduction of galloyl groups, which could avoid the
use of the protective groups.
suggested to be the most stable structure of 2. The former was
shown to be more stable than the latter by 1.8 kcal/mol. The
preference of the (R)-3,6-HHDP bridge with the glucose core
was compatible with the observation of exclusive formation of
the (R)-3,6-HHDP-bridged glucose derivatives during the total
synthesis of corilagin and mallotusinin.8,9 Thermal equilibrium
between 16 and 17 was also examined. Treatment of 16 in d6-
DMSO (2 mg/mL) at 130 °C for 30 min gave >99% recovery
without any formation of 17. Partial decomposition was
observed on the same treatment of 17 without formation of 16
(data not shown). Thus, thermal equilibrium between 16 and
17 was not observed in the absence of Cu(II).22,23 Based on all
of these results, it was evident that more stable 16 with an (R)-
HHDP group was converted exclusively to less stable 17 with
an (S)-HHDP group by treatment with a (−)-sparteine/
Cu(II) system under the thermodynamically controlled
conditions. We then examined the effects of (−)-sparteine/
Cu(II) on the equilibrium process between the (R)- and (S)-
3,6-HHDP groups by DFT calculations using the simplified
model (Figure 2). The model was constructed with (S)- and
To get insights into the unprecedented stereodivergent
oxidative phenol coupling, we examined whether the stereo-
chemical outcome was determined by a kinetically or
thermodynamically controlled manner. The stereochemically
pure isomer 16 with an (R)-HHDP group was treated under
the conditions with (−)-sparteine/Cu(II), which were
employed for the conversion from 15 to 17, to give 17 with
an (S)-HHDP group as a single diastereomer in 66% yield
(Scheme 3). Alternatively, 16 with an (R)-HHDP was
Scheme 3. Influence of the Chirality of Sparteine on the
Interconversion between Atropisomers 16 and 17
obtained as a single diastereomer in 40% yield on treatment
of 17 under the conditions with (+)-sparteine/Cu(II) that
were employed for the conversion from 15 to 16. Thus,
generation of axial chirality in the HHDP group was found to
be totally governed by thermodynamic control depending on
the chiral ligands.17b,c,21 We then investigated the relative
stability of the (R)- and (S)-3,6-HHDP-bridged glucose core.
DFT calculation was performed to assess the most stable
structure and the relative stability of punicafolin (1) and
macaranganin (2) (Figure 1). The most stable structure of 1
with an R-HHDP group was shown to contain an all-axially
substituted glucose core with 1C4 conformation, while a
5
strained skew boat glucose core with S1 conformation was
Figure 2. Most stable structures of Cu(II)-(−)-sparteine-(S)-HHDP
(A) and Cu(II)-(−)-sparteine-(R)-HHDP (B) as models for Cu(II)-
17-(−)-sparteine and Cu(II)-16-(−)-sparteine, respectively, and the
relative stability calculated by DFT at the M06/SDD(Cu)/6-311+
+G(2d,2p)//M06/LanL2DZ(Cu)/6-31G(d,p) level of theory.
(R)-HHDP derivatives. The most stable structures of Cu(II)-
(−)-sparteine-HHDP (A) and Cu(II)-(−)-sparteine-(R)-
HHDP (B) are shown, respectively, in Figure 2. Complex A
was found to be more stable than B by 4.1 kcal/mol due to the
lack of unfavorable steric interactions (for the detail, see
Figures S3 and S56). Based on these results, matched
complexation between 17 and Cu(II)/(−)-sparteine was
assumed to be the origin of its higher stability than the
mismatched complexation between 16 and Cu(II)/(−)-spar-
teine.24
In conclusion, the first total syntheses of punicafolin (1) and
macaranganin (2) were achieved in seven steps, respectively,
from D-glucose, an abundant cheap natural source. The
prominent features of the synthesis are sequential site-selective
introduction of the adequate galloyl groups into the requisite
hydroxy groups of D-glucose and stereodivergent construction
of the 3,6-HHDP bridge from a common intermediate via a
flipping process of the pyranose ring to the less stable axial-rich
conformer. Because no protective groups were used for glucose
throughout the process, extremely-short-step total syntheses of
Figure 1. Most stable structures of punicafolin (1) and macaranganin
(2) and the relatve stability calculated by DFT at the M06-2X/6-311+
+G(2d,2p)//M06-2X/6-31G(d) level in acetone (PCM).
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(4) For example, the 1C4 conformer of β-D-glucose was suggested to
be much less stable than the C1 conformer. See: (a) Appell, M.;
natural glycosides were achieved. Since structural diversity of
ellagitannins stems from regiochemistry of galloyl groups and
the HHDP groups, the present strategy based on site-selective
introduction of galloyl groups would provide a powerful
strategy for total synthesis of a variety of natural and unnatural
ellagitannins of biological interests.
4
Strati, G.; Willett, J. L.; Momany, F. A. B3LYP/6-311++G** study of
4
1
α- and β-D-glucopyranose and 1,5-anhydro-D-glucitol: C1 and C4
chairs, 3,OB and B3,O boats, and skew-boat conformations. Carbohydr.
Res. 2004, 339, 537−551. (b) Csonka, G. I.; Elias, K.; Csizmadia, I. G.
Relative stability of 1C4 and 4C1 chair forms of β-D-glucose: a density
functional study. Chem. Phys. Lett. 1996, 257, 49−60. (c) Dowd, M.
K.; French, A. D.; Reilly, P. J. Modeling of aldopyranosyl ring
puckering with MM3 (92). Carbohydr. Res. 1994, 264, 1−19.
ASSOCIATED CONTENT
* Supporting Information
■
sı
́
(5) (a) Pouysegu, L.; Deffieux, D.; Malik, G.; Natangelo, A.;
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10714.
Quideau, S. Synthesis of ellagitannin natural products. Nat. Prod. Rep.
2011, 28, 853−874. (b) Su, X.; Thomas, G. L.; Galloway, R. J. D.;
Surry, D. S.; Spandl, R. J.; Spring, D. R. Synthesis of biaryl-containing
medium-ring systems by organocuprate oxidation: applications in the
total synthesis of ellagitannin natural products. Synthesis 2009, 2009,
3880−3896. (c) Ikeda, Y.; Nagao, K.; Tanigakiuchi, K.; Tokumaru,
G.; Tsuchiya, H.; Yamada, H. The first construction of a 3,6-bredged
ellagitannin skeleton with 1C4/B glucose core; synthesis of non-
amethylcorilagin. Tetrahedron Lett. 2004, 45, 487−489.
Experimental details, additional experiment, compound
characterization, spectra, and calculation data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Yoshihiro Ueda − Institute for Chemical Research, Kyoto
University, Kyoto 611-0011, Japan; orcid.org/0000-
0002-5485-2722; Email: ueda@fos.kuicr.kyoto-u.ac.jp
Takeo Kawabata − Institute for Chemical Research, Kyoto
University, Kyoto 611-0011, Japan; orcid.org/0000-
0002-9959-0420; Email: kawabata@scl.kyoto-u.ac.jp
(6) Tanimura, S.; Kadomoto, R.; Tanaka, T.; Zhang, Y.; Kouno, I.;
Kohno, M. Suppression of tumor cell invasiveness by hydrolysable
tannins (plant polyphenols) via the inhibition of matrix metal-
loproteinase-2/-9 activity. Biochem. Biophys. Res. Commun. 2005, 330,
1306−1313.
(7) Lee, S.; Jun, M.; Choi, J.; Yang, E.; Hur, J.; Bae, K.; Seong, Y.;
Huh, T.; Song, K. Plant phenolics as prolyl endopeptidase inhibitors.
Arch. Pharmacal Res. 2007, 30, 827−833.
(8) Yamada, H.; Nagao, K.; Dokei, K.; Kasai, Y.; Michihata, N. Total
synthesis of (−)-corilagin. J. Am. Chem. Soc. 2008, 130, 7566−7567.
(9) Yamashita, K.; Kume, Y.; Ashibe, S.; Puspita, C. A. D.; Tanigawa,
K.; Michihata, N.; Wakamori, S.; Ikeuchi, K.; Yamada, H. Total
synthesis of mallotusinin. Chem. - Eur. J. 2020, 26, 16408−16421.
(10) Ashibe, S.; Ikeuchi, K.; Kume, Y.; Wakamori, S.; Ueno, Y.;
Iwashita, T.; Yamada, H. Non-enzymatic oxidation of a pentagalloyl-
glucose analogue into members of the ellagitannin family. Angew.
Chem., Int. Ed. 2017, 56, 15402−15406.
Authors
Hiromitsu Shibayama − Institute for Chemical Research,
Kyoto University, Kyoto 611-0011, Japan
Takashi Tanaka − Graduate School of Biomedical Sciences,
Nagasaki University, Nagasaki 852-8521, Japan;
orcid.org/0000-0001-7762-7432
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10714
Notes
(11) (a) Hettikankanamalage, A. A.; Lassfolk, R.; Ekholm, F. S.;
Leino, R.; Crich, D. Mechanisms of stereodirecting participation and
ester migration from near and far in glycosylation and related
reactions. Chem. Rev. 2020, 120, 7104−7151. (b) Kleinpeter, E.;
Taddei, F.; Wacker, P. Electronic and steric substituent influences on
the conformational equilibria of cyclohexyl esters: The anomeric
effect is not anomalous! Chem. - Eur. J. 2003, 9, 1360−1368.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
No. JP26221301 (to T.K.) and JP18H04405 (Middle
Molecular Strategy) (to Y.U.). T.K. acknowledges the financial
support from the Kobayashi Foundation. Y.U. acknowledges
the financial support from the Naito Foundation.
̈
(c) Lichtenthaler, F. W.; Ronninger, S.; Kreis, U. Tetra-O-acetyl-β-D-
glucopyranosyl chloride: occurrence of gg and gt rotamers in the
crystal and correlation between conformation at C-6 and anomeric
stabilization. Liebigs Ann. Chem. 1990, 1990, 1001−1006. (d) Kirby,
A. J. The anomeric effect and related stereoelectronic effects at oxygen;
Springer: Berlin, New York, 1983.
DEDICATION
■
In memory of the late Professor Hidetoshi Yamada.
(12) (a) Ueda, Y.; Furuta, T.; Kawabata, T. Final-stage site-selective
acylation for the total syntheses of multifidosides A−C. Angew. Chem.,
Int. Ed. 2015, 54, 11966−11970. (b) Ueda, Y.; Mishiro, K.; Yoshida,
K.; Furuta, T.; Kawabata, T. Regioselective diversification of a cardiac
glycoside, lanatoside C, by organocatalysis. J. Org. Chem. 2012, 77,
7850−7857. (c) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata,
T.; Schedel, H. A catalytic one-step process for the chemo- and
regioselective acylation of carbohydrates. J. Am. Chem. Soc. 2007, 129,
12890−12895. (d) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata,
T.; Uruno, Y.; Stragies, S. Regioselective acylation of octyl β-D-
glucopyranoside by chiral 4-pyrrolidinopyridine analogues. Synthesis
2008, 2008, 747−753.
(13) (a) Takeuchi, H.; Mishiro, K.; Ueda, Y.; Fujimori, Y.; Furuta,
T.; Kawabata, T. Total synthesis of ellagitannins through
regioselective sequential functionalization of unprotected glucose.
Angew. Chem., Int. Ed. 2015, 54, 6177−6180. (b) Takeuchi, H.; Ueda,
Y.; Furuta, F.; Kawabata, T. Total synthesis of ellagitannins via
sequential site-selective functionalization of unprotected D-glucose.
Chem. Pharm. Bull. 2017, 65, 25−32.
REFERENCES
■
́
(1) (a) Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouysege, L.
Plant polyphenols: chemical properties, biological activities, and
synthesis. Angew. Chem., Int. Ed. 2011, 50, 586−621. (b) Yoshida, T.;
Hatano, T.; Ito, H.; Okuda, T. Structural diversity and antimicrobial
activities of ellagitannins. In chemistry and biology of ellagitannins: an
underestimated class of bioactive plant polyphenols; Quideau, S., Ed.;
World Wcientific Publishing Co. Pte. Ltd.: Singapore, 2009; pp 55−
93. (c) Haslam, E.; Cai, Y. Plant polyphenols (vegetable tannins):
gallic acid metabolism. Nat. Prod. Rep. 1994, 11, 41−66.
(2) Tanaka, T.; Nonaka, G.; Nishioka, I. Punicafolin, an ellagitannin
from the leaves of Punica granatum. Phytochemistry 1985, 24, 2075−
2078.
(3) Lin, J.; Nonaka, G.; Nishioka, I. Tannins and related compounds.
XCIV. Isolation and characterization of seven new hydrolysable
tannins from the leaves of Macaranga tanarius (L.) MUELL. et Arg.
Chem. Pharm. Bull. 1990, 38, 1218−1223.
1433
https://dx.doi.org/10.1021/jacs.0c10714
J. Am. Chem. Soc. 2021, 143, 1428−1434

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(14) Takeuchi, H.; Fujimori, Y.; Ueda, Y.; Shibayama, H.; Nagaishi,
M.; Yoshimura, T.; Sasamori, T.; Tokitoh, N.; Furuta, T.; Kawabata,
T. Solvent-dependent mechanism and stereochemistry of Mitsunobu
glycosylation with unprotected pyranoses. Org. Lett. 2020, 22, 4754−
4759.
(15) Shibayama, H.; Ueda, Y.; Kawabata, T. Total synthesis of
cercidinin A via a sequential site-selective acylation strategy. Chem.
Lett. 2020, 49, 182−185.
(16) Ueda, Y.; Kawabata, T. Organocatalytic site-selective acylation
of carbohydrates and polyol compounds. Top. Curr. Chem. 2015, 372,
203−231.
́
(17) (a) Malik, G.; Natangelo, A.; Charris, J.; Laurent Pouysegu, L.;
Manfredini, S.; Cavagnat, D.; Buffeteau, T.; Deffieux, D.; Quideau, S.
Synthetic studies toward C-glucosidic ellagitannins: A biomimetic
total synthesis of 5-O-desgalloylepipunicacortein A. Chem. - Eur. J.
2012, 18, 9063. (b) Brussee, J.; Groenendijk, J. L. G.; te Koppele, J.
M.; Jansen, A. C. A. On the mechanism of the formation of S(−)-
(1,1′-binaphthalene)-2,2′-diol via copper(II)amine complexes. Tetra-
hedron 1985, 41, 3313−3319. (c) Feringa, B.; Wynberg, H.
Biomimetic asymmetric oxidative coupling of phenols. Bioorg. Chem.
1978, 7, 397−408. (d) Feringa, B.; Wynberg, H. Oxidative phenol
coupling with cupric-amine complexes. Tetrahedron Lett. 1977, 18,
4447−4450.
́
(18) Richieu, A.; Peixoto, P. A.; Pouysegu, L.; Deffieux, D.; Quideau,
S. Bioinspired total synthesis of (−)-vescalin: a nonahydroxytriphe-
noylated C-glucosidic ellagitannin. Angew. Chem., Int. Ed. 2017, 56,
13833−13837.
(19) For example, total syntheses of an ellagitannin with R-4,6-
HHDP group was performed via a totally different strategy from the
corresponding ellagitannin with S-4,6-HHDP group. See: (a) Ikeuchi,
K.; Ueji, T.; Matsumoto, S.; Wakamori, S.; Yamada, H. First total
synthesis of neostrictinin. Eur. J. Org. Chem. 2020, 2020, 2077−2085.
(b) Michihata, M.; Kaneko, Y.; Kasai, Y.; Tanigawa, K.; Hirokane, T.;
Higasa, S.; Yamada, H. High-yield total synthesis of (−)-strictinin
through intramolecular coupling of gallates. J. Org. Chem. 2013, 78,
4319−4328.
(20) Deprotection of TES and THP groups under Pd/C-catalyzed
hydrogenation conditions has been reported. (a) Sajiki, H.; Ikawa, T.;
Hirota, K. Significant supplier-dependent disparity in catalyst activity
of commercial Pd/C toward the cleavage of triethylsilyl ether.
Tetrahedron Lett. 2003, 44, 7407−7410. (b) Kaisalo, L. H.; Hase, T.
A. Cleavage of the THP protecting group under Pd/C-catalyzed
hydrogenation conditions. Tetrahedron Lett. 2001, 42, 7699−7701.
(21) (a) Tsubaki, K.; Miura, M.; Morikawa, H.; Tanaka, H.;
Kawabata, T.; Furuta, T.; Tanaka, K.; Fuji, K. J. Am. Chem. Soc. 2003,
125, 16200−16201. (b) Tsubaki, K.; Tanaka, H.; Takaishi, K.; Miura,
M.; Morikawa, H.; Furuta, T.; Tanaka, K.; Fuji, K.; Sasamori, T.;
Norihiro Tokitoh, N.; Kawabata, T. Bottom-up synthesis of optically
active oligonaphthalenes: Three different pathways for controlling
axial chirality1. J. Org. Chem. 2006, 71, 6579−6587.
(22) Atropisomerism of 2,2′-dihydroxy-1,1′-binaphthyl derivatives
was reported to readily take place at 0 °C to rt in the presence of
Cu(II). See refs 17b, 21b, and 24a.
(23) In the presence of n-BuNH2/Cu(II), transformation of less
stable 17 to more stable 16 was observed in 12% yield with 52%
recovery of 17, while no atropisomerization of 16 to 17 was observed
under the identical conditions. For the details, see Scheme S1.
(24) (a) Zhang, Y.; Yeung, S.-M.; Wu, H.; Heller, D. P.; Wu, C.;
Wulff, W. D. Highly enantioselective deracemization of linear and
vaulted biaryl ligands. Org. Lett. 2003, 5, 1813−1816. (b) Smrcina,
M.; Polakova, J.; Vyskocil, S.; Kocovsky, P. Synthesis of enantiomeri-
cally pure binaphthyl derivatives. Mechanism of the enantioselective,
oxidative coupling of naphthols and designing a catalytic cycle. J. Org.
Chem. 1993, 58, 4534−4358. (c) Smrcina, M.; Lorenc, M.; Hanus, V.;
Sedmera, P.; Kocovsky, P. Synthesis of enantiomerically pure 2,2′-
dihydroxy-1,1′-binaphthyl, 2,2′-diamino-1,1′-binaphthyl, and 2-
amino-2′-hydroxy-1,1′-binaphthyl. Comparison of processes operat-
ing as diastereoselective crystallization and as second order
asymmetric transformation. J. Org. Chem. 1992, 57, 1917−1920.
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