Total synthesis of (-)-corilagin

Article abstract of DOI:10.1021/ja803111z

The synthesis of corilagin was achieved by the integration of the development of the oxidative coupling of the symmetrically protected gallates and the temporarily ring-opened synthetic route for the 3,6-hexahydroxydiphenoyl (HHDP) bridge. This is the fir

Full text of DOI:10.1021/ja803111z

Published on Web 05/28/2008
Total Synthesis of (-)-Corilagin
Hidetoshi Yamada,* Kohei Nagao, Kazutoyo Dokei, Yusuke Kasai, and Naoki Michihata
School of Science and Technology, Kwansei Gakuin UniVersity, Sanda 669-1337, Japan
Received April 27, 2008; E-mail: hidetosh@kwansei.ac.jp
Ellagitannins are a biologically and structurally diverse class of
natural products.1 The structure typically consists of galloyl and
hexahydroxydiphenoyl (HHDP) group(s) esterified to a glucose
(Figure 1), and the structural diversity arises from the number and
location of the ester substituents, modification of the substituents,
oligomerization, and ring-opening of the pyranose. The pyranose
ring of the glucose moiety can even be in the axial-rich conforma-
tion, which is the flipped chair (1C4) or a twist-boat (B) form, when
Figure 1. Structure of corilagin (1).
an HHDP group bridges two discontiguous hydroxy groups. Hence,
the ellagitannins possessing the axial-rich glucose have been termed
Scheme 1. Retrosynthetic Approach to Corilagin (1)a
1
1C4/B-ellagitannins. Corilagin (1), one of the C4/B-ellagitannins,
is the first discovered natural product containing stable axial-rich
glucose. It was isolated from dividivi (Caesalpina coriaria) by
Schmidt and co-workers in 1951.2 The HHDP group bridges the
3- and 6-oxygens of the glucose,3 and its axial chirality is R.4
Recently, a wide range of biological activities has been reported
for 1, for example, the potentiation of ꢀ-lactam antibiotics against
MRSA, antiviral and antimicrobial activities, inhibition of TNF-R
release, antihypertensive effect, and inhibition of a chitin synthase.5
We now describe the synthesis 1, which is also the first total
1
synthesis of a C4/B-ellagitannin.
Two main efforts in the synthesis of 1 were the strategy to build
the 3,6-bridged bis-macrolactone structure, which is holding the
glucose ring in the contra-thermodynamic conformation, and the
development of an efficient synthetic method for the HHDP group.
As the retrosynthetic perspective in scheme 1, we constructed the
bicyclic ring system by synthesizing the floppy bis-macrolactone
ring first then the more rigid six-membered ring (Scheme 1), that
is (i) ring-opening of the pyranose; (ii) preparation of the HHDP
group by coupling of the two gallates on the 3- and 6-oxygens;
and (iii) reconstruction of the pyranose, since the formation of the
bis-macrolactone involving ring-flip of the pyranose was difficult.
Although we once achieved the skeleton by this three-step sequence,
the unattainable complete demethylation of nonamethylcorilagin
(2) prevented the total synthesis.6 Further, difficulty of the iodination
of corresponding tri-O-benzyl- or MOM-protected gallates forced
us to abandon the use of Ullmann coupling for the HHDP-
preparation. Previously, two methods for the HHDP-preparation
have contributed to the total syntheses of ellagitannins.7 One of
them, Feldman’s method, involves the intramolecular oxidative
phenol coupling of diphenylmethylene-protected gallates.8 This
method provides a mixture of regioisomers due to the asymmetry
of the protecting groups, which require subsequent deprotection/
protection steps to afford a single synthetic intermediate.9 Conse-
quently, development of an effective coupling of symmetrically
protected gallates should advance the synthetic approach in ella-
gitannin chemistry.
a This work: R1 ) X ) H, R2 ) Bn, (/) oxidative phenol coupling. Our
previous approach: R1 ) R2 ) CH3, X ) I, (/) Ullmann coupling.6
co-workers for the coupling reactions required for the preparation
of binaphthols.12 In this synthesis, ethylamine or amphetamine were
the most effective compounds for the amine part of the reagent
when the substrate is 2-naphthol. We also found that the use of
primary amines was effective for the intermolecular coupling of 3.
Thus, the coupling of 3 was successful when using not only
ethylamine, but also n-butyl- and n-hexylamines to give the
corresponding dimer in 35, 52, and 49% yield, respectively, along
with the trimer and lager oligomers (Scheme 2). The reaction
conditions could be applied to the intramolecular case with a
digallate 4, in which the four-carbon-linker corresponds to the 3-
to 6-positions of glucose in 1. The yields of the intramolecular
couplings were better than those of the intermolecular cases
providing 5 in 77-85% yield.
The CuCl2 ·amine mediated coupling was applied to 6 to afford
the bridged synthetic intermediate 7 as the sole coupled product
(Scheme 3). The coupling precursor 6 was prepared by the
esterification of the ring-opened 8 (seven steps from D-glucose)6
with 9, followed by the removal of the MOM groups. For the
oxidative intramolecular coupling of 6, the use of n-butylamine
was optimal for constructing the 3,6-HHDP-bridge to afford 7 in
76% yield. In contrast, the operations with ethyl- and n-hexylamines
decreased the yield to 30% and trace, respectively. The coupled
product 7 was a single diastereomer, with the sugar-derived sp3
asymmetries being completely transferred to the axial site. This
To develop an effective synthetic method for the HHDP group,
symmetrically designed methyl 4-O-benzylgallate (3)10 was applied
in the known phenol coupling methods.11 This preliminary inves-
tigation revealed that utilization of the CuCl2 ·amine complex was
promising. This reagent was originally developed by Brussee and
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7566 J. AM. CHEM. SOC. 2008, 130, 7566–7567
10.1021/ja803111z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Coupling of 4-O-Benzylgallates by CuCl2 ·amine
Complex
The subsequent five steps following the synthesis of key
intermediate 7 achieved the total synthesis (Scheme 3). Thus, the
benzyl protection of 7 followed by the cleavage of the PMB group
afforded 10 whose double-bond was then oxidatively cleaved to
reconstruct the pyranose ring providing 11. Introduction of the
galloyl group to the anomeric position afforded 12 (R/ꢀ ) 33/67).
Hydrogenolysis of the ꢀ-isomer 12b cleaved eleven benzyl groups
to provide 1 whose physical and spectral data (optical rotation, 1H
and 13C NMR, IR) were identical with those of the natural corilagin.
In summary, the total synthesis of 1 was achieved by the
integration of the development of the oxidative coupling of the
symmetrically protected gallates and the temporarily ring-opened
synthetic route for the 3,6-HHDP bridge. This first total synthesis
1
of a C4/B-ellagitannin reveals that the combination of the 4-O-
benzyl gallate and the CuCl2 ·amine complex allows efficient
preparation of the HHDP group. Because of the structural resem-
blance in ellagitannins, this new method would be applicable for
the syntheses of the other natural ellagitannins and their artificial
analogues.
Scheme 3. Synthesis of Corilagin (1)a
Acknowledgment. We thank Professor Takashi Yoshida (Mat-
suyama University, Japan) for providing natural corilagin. This work
was partly supported by the Grant-in-Aid for Scientific Research
on Priority Areas (17035086) from MEXT.
Supporting Information Available: Complete ref 11, experimental
procedures, characterization of new compounds, 1H and 13C NMR
spectra for compound 5-7, 9-11, 12ab, and natural and synthetic 1.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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a DDQ ) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMAP ) 4-(N,N-
dimethylamino)pyridine, EDCI ) 1-ethyl-3-(3-dimethylaminopropyl)-car-
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