Total synthesis of (+)-davidiin

Article abstract of DOI:10.1002/anie.201203305

Quite strained: The total synthesis of (+)-davidiin, an ellagitannin with more substituents in axial than in equatorial positions, requires a conformational lock of the glucose, induced by steric repulsion between adjacent bulky silyloxy groups. This conformational lock played a pivotal role in 1) the β-selective formation of the glycosyl ester at the anomeric position, 2) the formation of the 1,6-HHDP bridge, and 3) the complete control of axial chirality in the aryl-aryl coupling. Copyright

Full text of DOI:10.1002/anie.201203305

Angewandte
Chemie
DOI: 10.1002/anie.201203305
Natural Product Synthesis
Total Synthesis of (+)-Davidiin**
Yusuke Kasai, Naoki Michihata, Hidehisa Nishimura, Tsukasa Hirokane, and
Hidetoshi Yamada*
Nature occasionally presents us with unusual chemical
structures. Although thermodynamic effects regulate the
conformation of d-glucopyranose to a C1 form with more
conformation. Based on 1H NMR data, Haslam and co-
workers established that the conformation of the glucopyr-
anose ring is of a skew-boat type.[2,3] The axial chirality of the
HHDP group was predicted to be S by circular dichroism.[2]
A synthetic approach to axial-rich ellagitannins still
remains undeveloped. The only previously synthesized
axial-rich ellagitannin is corilagin (5; Scheme 1),[7] although
total syntheses of more than a dozen other ellagitannins have
been achieved to supply natural ellagitannins and systemati-
cally designed analogues in pure form.[8–10] Herein, we
describe the total synthesis of compound 1. In this synthesis,
a conformational lock of the glucose to an axial-rich form,
induced by steric repulsion between adjacent bulky silyloxy
groups, played a pivotal role in 1) the b-selective formation of
the glycosyl ester at the anomeric position, 2) the formation of
the 1,6-HHDP bridge, and 3) the complete control of axial
chirality in the formation of the HHDP group.
4
substituents in an equatorial than in an axial position
1
(equatorial-rich form), nature allows the existence of a C4
or a twist-boat conformation with more substituents in an
axial than in an equatorial position (axial-rich) of glucose
through the introduction of a bridge. This peculiar structure
sporadically appears in ellagitannins, a structurally and
biologically diverse class of hydrolysable tannins.[1] Ellagitan-
1
nins with C4 and twist-boat conformers are designated as
axial-rich ellagitannins in this communication; (+)-davidiin
(1) is a typical example.
A challenging problem had to be solved before a success-
ful synthetic route toward 1 could be developed. The
formation of the 1,6-HHDP bridge with simultaneous con-
formational inversion of the pyranose ring into the thermo-
dynamically unfavorable axial-rich form was impossible. This
problem became evident during an attempt to carry out the
intramolecular aryl–aryl coupling of 2 [Eq. (1)], that is, the
desired product 3 was not produced by treatment of 2 with
(+)-Davidiin (1) was isolated from Davidia involucrata
(Dove tree) by Haslam and co-workers.[2,3] Subsequently,
Okuda and co-workers isolated 1 from Acer saccharum
(Sugar Maple).[4] The compound inhibits the binding of
a ligand to a m-opioid receptor.[5] Structurally, 1 has an (S)-
hexahydroxydiphenoyl (HHDP)[6] group, which forms an
intramolecular bridge between the 1-b- and the 6-oxygen
atoms of d-glucopyranose. The existence of the bridge keeps
the glucose ring in the thermodynamically unfavorable
CuCl2/nBuNH2, a reagent combination that effectively cou-
pled 4-O-benzylated gallates intramolecularly.[7,11] We
encountered a similar problem in the synthesis of 5,[12] and
overcame it by using a temporary-ring-opening strategy
(Scheme 1),[7] in which the flexible conformation of digallate
4 allowed the two galloyl groups to get in close proximity to
each other, and thus their intramolecular coupling. After the
formation of the 3,6-HHDP bridge, reconstruction of the
pyranose ring furnished the HHDP-bridged glucopyranose
moiety of 5. However, we were not able to apply this concept
to the formation of the 1,6-HHDP structure of 1, because one
of the “arms” of the bridge is in the anomeric position.
Accordingly, to allow the two galloyl groups to get in close
[*] Dr. Y. Kasai, N. Michihata, H. Nishimura, T. Hirokane,
Prof. Dr. H. Yamada
School of Science and Technology, Kwansei Gakuin University
2-1 Gakuen, Sanda 669-1337 (Japan)
E-mail: hidetosh@kwansei.ac.jp
[**] We thank Prof. Tsutomu Hatano (Okayama University (Japan)) for
identification of natural davidiin. We also thank Dr. Yasuko
Okamoto (Tokushima Bunri University) for the recording of FAB
mass spectra. Kakenhi and a SUNBOR grant partially supported this
work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203305.
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formation of the glycosyl ester with tri-TIPS ether 9.[15,16] This
“glycosyl donor” 9 would be derived from known, conforma-
tionally locked compound 10.[15]
The synthesis commenced with the reductive removal of
the pivaloyl ester of 10 with iBu2AlH (Scheme 3). The
acylation of the resulting alcohol 11 with acid chloride 12
furnished the “glycosyl donor” 9. Treatment of 9 with MeOTf
and 4 ꢀ molecular sieves in the presence of carboxylic acid 8
as the nucleophile provided b-13 in 83% yield as a single
diastereomer. The stereochemistry at the anomeric center of
b-13 was confirmed by 1H NMR analysis after desilylation to
return the pyranose ring to the 4C1 conformation, followed by
acetylation of the resulting triols.
Scheme 1. Synthetic route toward 5.
proximity to each other, the conformation of the glucopyr-
anose should be locked into an axial-rich form.
The strategy for the total synthesis of 1 is outlined in
Scheme 2. The retrosynthetic analysis started with the dis-
connection of the three galloyl groups of 1, which would be
acylated in the final stage of the synthesis. To form the 1,6-
HHDP group of 6, the aryl–aryl bond was disconnected.
Because this disconnection removed the foundation of the
axial-rich conformation, we applied the conformational-lock
strategy on the basis of steric repulsion of the adjacent bulky
silyl groups to overcome the problem,[13] as in tri-TIPS ether 7.
This strategy has recently been applied to obtain anomeric
stereoselectivity in glycosylation reactions.[14–16] The aryl–aryl
coupling was expected to occur with CuCl2/nBuNH2 as the
oxidizing agent.[7] For digallate 7, the gallate at the anomeric
position was disconnected because the axially-oriented bulky
silyloxy group would have hindered the approach of protected
gallic acid 8 on the a face, thus allowing the b-selective
Scheme 3. Stereoselective synthesis of b-13.
The excellent b selectivity of the glycosyl ester formation
is noteworthy. Although b-selective galloylation is possible
when the glucopyranose is in an equatorial-rich conforma-
tion,[17] realization of b selectivity has been difficult with axial-
rich glucopyranose, with the anomeric hydroxy group of the
carbohydrate moiety as the nucleophile and protected gallate
as the electrophile.[7,12] The solution to this problem was the
inversion of the electrophilic/nucleophilic roles to achieve
b selectivity with the axial-rich conformer.
The coupling precursor 7 was obtained quantitatively by
aminolysis of the acetyl groups of b-13 (Scheme 4) through
the application of Nomuraꢁs reaction conditions,[18] employing
hydrazine monohydrate. The galloyl esters remained intact.
In the 1H NMR spectra, the 3JH–H coupling constants between
À
the protons on the pyranose ring of 7 were H1 H2: 2.6 Hz,
À
À
À
H2 H3: 0 Hz, H3 H4: 0 Hz, H4 H5: 2.3 Hz. These small
coupling constants showed that 7 maintained an axial-rich
form, thus indicating the robustness of the conformational
lock, because the adjacent silyloxy groups on the pyranose
kept the ring in the axial-rich conformation, even when two
protected gallates were in the 1- and 6-positions.
The 1,6-HHDP moiety embedded in the 12-membered
bislactone ring could be formed by intramolecular coupling of
4-O-benzylated gallates of 7 with CuCl2/nBuNH2 as oxidizing
agent in MeOH to afford 14 in 75% yield (Scheme 4), thus
Scheme 2. Retrosynthetic analysis of davidiin (1).
2
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Finally, hydrogenolytic removal of the fifteen benzyl groups
gave davidiin (1). Compounds 15, 6, 17, and 1 were all single
diastereomers, thus indicating that the axial chirality
remained intact during the conversion. The spectroscopic
data of synthetically obtained 1 were identical to those of the
naturally occurring 1.[3,4]
In summary, we have accomplished the first total synthesis
of (+)-davidiin (1). The synthesis was concise, proceeded in
nine steps and gave the product in 19% overall yield from
known carbohydrate 10. In this work, a conformational lock
to the axial-rich form enabled 1) the b-stereoselective for-
mation of the glycosyl ester, 2) the formation of the 1,6-
HHDP bridge, and 3) the complete control of the axial
chirality of the HHDP group. In addition, this synthesis
expands the scope of conformationally locked carbohydrates,
applications of which have to date focused on glycosylation
chemistry. This work also constitutes the first total synthesis
of a 1,6-HHDP-bridged ellagitannin. Because of the many
known similar naturally occurring ellagitannins, the confor-
mational-lock strategy could become a general method to
axial-rich natural ellagitannins and artificial analogues.
Received: April 30, 2012
Published online: && &&, &&&&
Keywords: carbohydrates · medium-sized rings ·
.
natural products · phenols · total synthesis
Scheme 4. Synthesis of 1.
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groups in 15 furnished 2,3,4-triol 6, in which the conformation
of the pyranose ring remained almost unchanged, according
1
to the H NMR analysis. Acylation of the 2,3,4-triol with tri-
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Natural Product Synthesis
Quite strained: The total synthesis of
(+)-davidiin, an ellagitannin with more
substituents in axial than in equatorial
position, requires a conformational lock
of the glucose, induced by steric repul-
sion between adjacent bulky silyloxy
groups. This conformational lock played
a pivotal role in 1) the b-selective forma-
tion of the glycosyl ester at the anomeric
position, 2) the formation of the 1,6-
HHDP bridge, and 3) the complete con-
trol of axial chirality in the aryl–aryl
coupling.
Y. Kasai, N. Michihata, H. Nishimura,
T. Hirokane, H. Yamada*
&&&& — &&&&
Total Synthesis of (+)-Davidiin
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!