Ellagitannin chemistry. The first total synthesis of a dimeric ellagitannin, coriariin A [6]

Full text of DOI:10.1021/ja001013f

7396
J. Am. Chem. Soc. 2000, 122, 7396-7397
synthesis and subsequent dimerization chemistry of the related
HHDP-containing putative coriariin A precursor 5 proved prob-
lematic and eventually this approach was abandoned. The hope
that a second-generation approach featuring a three-component
coupling with the dehydrodigalloyl ether diacid 4 and 2 equiv of
the tellimagrandin trichloroacetimidate 7 was buoyed by the
observation that the model trichloroacetimidate 8 coupled smoothly
with the tribenzyl ether of gallic acid 13 to furnish the key
â-anomeric linkage in the pentagalloylglucose product 9. How-
ever, implementation of this plan again was frustrated by a lack
of correspondence between the model compounds and the coriariin
A system, as the combination of 8 with 4 did not afford any
dimeric ellagitannin product. Consequently, a third-generation
approach to this dimeric ellagitannin was devised (Scheme 1).
This final strategy utilized galloyl orthoquinone dimerization
chemistry, inspired by the presumed biosynthesis, to assemble
the dehydrodigalloyl ether diacid 47 but then relied on early
attachment of this diaryl ether linker unit to the two glucose cores
3. In this approach, the more electron releasing and less sterically
encumbered O(2) and O(3) TBS ethers of 3 are employed to
enhance the prospects for efficient execution of the Schmidt
trichloroacetimidate acylation chemistry.8 Conversion of all of
the glucose protecting groups in 2 into the appropriately func-
tionalized galloyl esters then sets the stage for the second key
step in this synthesis, the penultimate Pb(OAc)4-mediated double
oxidative cyclization of this octagalloylated coriariin A precursor.
Ellagitannin Chemistry. The First Total Synthesis of
a Dimeric Ellagitannin, Coriariin A
Ken S. Feldman* and Michael D. Lawlor
Department of Chemistry
The PennsylVania State UniVersity
UniVersity Park, PennsylVania 16802
ReceiVed March 22, 2000
The ellagitannins comprise a vast family of secondary plant
metabolites whose likely biogenesis derives from the various
combinations and permutations of oxidative coupling between and
among their polygalloylated glucose cores.1 One subfamily of note
includes the structurally (but not phylogenetically!) related dimeric
ellagitannins agrimoniin, coriariin A (1), and gemin A, which
are characterized by carbon-coupled glucose-bound galloyl esters
(cf. 1, (S)-hexahydroxydiphenoyl, HHDP) and a C-O linkage
between the anomeric galloyl units.2 These species demonstrate
very promising tumor remissive properties against several murine
xenograft tumor lines.3 Circumstantial evidence implicates a host-
mediated immunostimulatory response rather than direct cyto-
toxicity in the tumoricidal activity for at least two of these species,
agrimoniin3c,d and coriariin A,4 and suggests that further mech-
anism-of-action studies are warranted. Organic synthesis can
contribute to these studies by providing pure and homogeneous
ellagitannin5 as well as structural analogues. In this vein, the
development of methodology that enables assembly of members
of this class of ellagitannins is described. These studies culminate
in the first total synthesis of a dimeric ellagitannin, coriariin A
(1).
Prior success in implementing a biomimetic strategy for
monomeric ellagitannin synthesis suggested that an approach to
these more complex dimeric targets might also benefit from
consideration of their biosynthesis.6 Absent any data on this point,
speculation that in vivo dimerization of an oxidatively activated
tellimagrandin II derivative (cf. 5) guided the design of the initial
synthesis strategy. Dimerization of the simple model system 6 to
furnish a dehydrogalloyl ether-containing ellagitannin-gallotannin
hybrid gave further support to this plan.7 Unfortunately, the
The route to coriariin A (1) commences with the synthesis of
the tetraprotected glucopyranosyl alcohol 3 from the known diol
10,6b Scheme 2. Conversion of this free alcohol to the R-trichlo-
roacetimidate 11 permits testing of the critical bis acylation
reaction with known diacid 4. Simply refluxing 2 equiv of 11
with the diacid 4 in benzene furnishes the requisite diglucopy-
ranosyl dehydrodigalloyl diester 2 in good yield and free of
anomeric stereoisomers. The facility of this acylation stands in
sharp contrast to the failed attempts with the related O(2),O(3)-
digalloylated glucopyranosyl trichloroacetimidate 8, an observa-
tion reminiscent of the results derived from the arming/disarming
glucopyranosyl etherification protocols established by Fraser-Reid
et al.9 Electronic influences on trichloroacetimidate acylation
chemistry have not been explored systematically, and the results
with 8/11 suggest that reactivity may be responsive to the electron
demand of the O(2) substituent. Much of the remaining synthesis
involves orchestration of protecting group removal, as three
distinct sets of hydroxyl moieties must be revealed in the
appropriate sequence. In particular, the use of TBAF buffered
with HOAc was crucial for maintaining the integrity of the
sensitive dehydrodigallyl ester bonds during the desilylation of
2.10 Other common desilylation protocols (unbuffered TBAF,
(1) See (a) Haslam, E. Practical Polyphenolics; Cambridge University
Press: Cambridge, 1998. (b) Feldman, K. S.; Sahasrabudhe, K.; Quideau, S.;
Hunter, K. L.; Lawlor, M. D. Plant Polyphenols 2: Chemistry, Biology,
Pharmacology, Ecology; Kluwer Academic/Plenum Publishers: New York,
1999. (c) Okuda, T.; Yoshida, T.; Hatano, T. In Progress in the Chemistry of
Organic Natural Products; Herz, W., Kirby, G. W., Moore, R. E., Steglich,
W., Tamm, Ch., Eds.; Springer-Verlag: New York, 1995; Vol. 66, pp 1-117
and references therein.
(2) (a) Miyamoto, K.; Koshiura, R.; Ikeya, Y.; Taguchi, H. Chem. Pharm.
Bull. 1985, 33, 3977. (b) Hatano, T.; Hattori, S.; Okuda, T. Chem. Pharm.
Bull. 1986, 34, 4092. (c) Yoshida, Y.; Memon, M. U.; Shingu, T.; Okuda, T.
J. Chem. Soc., Perkin Trans 1 1985, 315.
(3) (a) Miyamoto, K.; Kishi, N.; Koshiura, R. Jpn. J. Pharmacol. 1987,
43, 187. (b) Miyamoto, K.; Kishi, N.; Koshiura, R.; Yoshida, T.; Hatano, T.;
Okuda, T. Chem. Pharm. Bull. 1987, 35, 814. (c) Miyamoto, K.; Murayama,
T.; Nomura, M.; Hatano, T.; Yoshida, T.; Furukawa, T.; Koshiura, R.; Okuda,
T. Anticancer Res. 1993, 13, 37. (d) Murayama, T.; Kishi, N.; Koshiura, R.;
Takagi, K.; Furukawa, T.; Miyamoto, K. Anticancer Res. 1992, 12, 1471. (e)
Miyamoto, K.; Nomura, M.; Murayama, T.; Furukawa, T.; Hatano, T.;
Yoshida, T.; Koshiura, R.; Okuda, T. Biol. Pharm. Bull. 1993, 16, 379.
(4) Feldman, K. S.; Sahasrabudhe, K.; Smith, R. S.; Scheuchenzuber, W.
J. Biorg. Med. Chem. Lett. 1999, 9, 985.
(5) Ellagitannins are invariably isolated as complex mixtures from their
plant sources. A lack of crystallinity and ready decomposition during isolation
and separation can make acquisition of substantial quantities of pure material
challenging. See (a) Okuda, T.; Yoshida, T.; Hatano, T. J. Nat. Prod. 1989,
52, 1. (b) Okuda, T.; Yoshida, T.; Hatano Heterocycles 1990, 30, 1195. (c)
Yoshida, T.; Hatano, T.; Kuwajima, T.; Okuda, T. Hetrocycles 1992, 33, 463.
(6) (a) Feldman, K. S.; Ensel. S, M. J. Am. Chem. Soc. 1994, 116, 3357.
(b) Feldman, K. S.; Sambandam, A. J. Org. Chem. 1995, 60, 8171. (c)
Feldman, K. S.; Smith, R. S. J. Org. Chem. 1996, 61, 2606.
(8) (a) Schmidt, R. R.; Michel, J. J. Carbohydr. Chem. 1985, 4, 141. (b)
Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19, 731. (c)
Schmidt, R. R.; Jung, K.-H. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997.
(9) Fraser-Reid, B.; Madsen, R. I. In PreparatiVe Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997.
(7) Feldman, K. S.; Sahasrabudhe, K. J. Org. Chem. 1999, 64, 209.
(10) Otera, J.; Niibo, Y.; Nozaki, H. Tetrahedron Lett. 1992, 33, 3655.
10.1021/ja001013f CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/14/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7397
Scheme 1
Scheme 3
Scheme 2
from these earlier studies, the double oxidative cyclization of this
tetraphenolic substrate afforded a complex mixture of regioiso-
meric bis (S)-HHDP containing products, a point of no conse-
quence for the coriariin A effort. Hydrogenolysis of all of the
benzyl and diphenyl ketal protecting groups furnished coriariin
A (1) in excellent yield as an off-white solid following trituration
with Et2O and hexane. The equivalence of this synthetic material
and the natural product was ascertained by comparison of its 1H
NMR, 13C NMR, CD, and mass spectra with those reported for
coriariin A, and by direct comparison of the 1H NMR spectra of
synthetic and natural material (kindly provided by Professor T.
Yoshida, Okayama University).
In summary, a stereo- and regioselective synthesis of the
naturally occurring dimeric ellagitannin coriariin A (1) was
accomplished in 11 steps from known diol 10. Highlights of the
synthesis include the bis acylation of an electron-rich glucopy-
ranosyl trichloroacetimidate with a sensitive dehydrodigalloyl
diacid, and the double oxidative cyclization of a octagalloyl
substrate. This latter transformation establishes the utility of this
Wessely oxidation-based methodology in the synthesis of dimeric
ellagitannins bearing hydrolytically sensitive dehydrodigalloyl
ether linking units.
TAS-F, HF, HF‚pyridine) led to partial or complete anomeric ester
hydrolysis. Galloylation of the liberated hydroxyls proceeded
efficiently using Keck’s modification11a of the Steglich esterifi-
cation protocol11b to furnish the hexaester 14.
Continuation of the synthesis of coriariin A required exchange
of the acetal moieties in 14 for protected versions of the Pb(IV)-
sensitive galloyl units provided by 16. Desilylation of the phenolic
protecting groups within the octagalloyl dimeric species 17 again
required HOAc buffering to preserve the anomeric ester linkages.
The derived tetragalloylphenol 18 was subjected to Wessely
oxidation,12 as per the conditions established in earlier digalloyl-
to-HHDP transformations,6 with gratifying results. As anticipated
Acknowledgment. Support from the NIH (GM35727) is appreciated.
We thank Dr. K. Sahasrabudhe for her contributions in exploring the
chemistry of 5 and 7.
Supporting Information Available: Experimental procedures, spec-
tral data (1H and 13C NMR, IR, LRMS, HRMS, or elemental analysis)
for 1, 2, 3, 11, 12, 14, 15, 17, and 18, and copies of the 1H and 13C NMR
spectra for 1 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) (a) Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394. (b) Neises,
B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.
(12) Bubb, W. A.; Sternhell, S. Tetrahedron Lett. 1970, 4499.
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