Ellagitannin Chemistry. the First Synthesis of Dehydrohexahydroxydiphenoate Esters from Oxidative Coupling of Unetherified Methyl Gallate

Article abstract of DOI:10.1021/jo971354k

A simple o-chloranil-mediated oxidative dimerization of methyl gallate in anhydrous ether furnishes a dimethyl dehydrohexahydroxydiphenoate (DHHDP) product as a pale yellow precipitate in good yield. This methyl gallate dehydrodimer rapidly rearranges in acetone to give a mixture of two additional DHHDP regioisomers. One of these species corresponds to the isomer of the dehydro-hexahydroxydiphenoyl group commonly observed in dehydroellagitannin natural products. Sodium dithionite-mediated reduction of the initially formed dimethyl dehydrohexahydroxydiphenoate and/ or its derived regioisomers efficiently furnishes dimethyl hexahydroxydiphenoate (HHDP). Addition of N-(carbobenzyloxy)-L-cysteine benzyl ester to dimethyl dehydrohexahydroxydiphenoate(s) in THF solution produces two diastereomeric 3-S-cysteinyl derivatives of dimethyl hexahydroxydiphenoate.

Full text of DOI:10.1021/jo971354k

J . Org. Chem. 1997, 62, 8809-8813
8809
Ella gita n n in Ch em istr y. Th e F ir st Syn th esis of
Deh yd r oh exa h yd r oxyd ip h en oa te Ester s fr om Oxid a tive Cou p lin g
of Un eth er ified Meth yl Ga lla te
Ste´phane Quideau† and Ken S. Feldman*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
Received J uly 23, 1997X
A simple o-chloranil-mediated oxidative dimerization of methyl gallate in anhydrous ether furnishes
a dimethyl dehydrohexahydroxydiphenoate (DHHDP) product as a pale yellow precipitate in good
yield. This methyl gallate dehydrodimer rapidly rearranges in acetone to give a mixture of two
additional DHHDP regioisomers. One of these species corresponds to the isomer of the dehydro-
hexahydroxydiphenoyl group commonly observed in dehydroellagitannin natural products. Sodium
dithionite-mediated reduction of the initially formed dimethyl dehydrohexahydroxydiphenoate and/
or its derived regioisomers efficiently furnishes dimethyl hexahydroxydiphenoate (HHDP). Addition
of N-(carbobenzyloxy)-L-cysteine benzyl ester to dimethyl dehydrohexahydroxydiphenoate(s) in THF
solution produces two diastereomeric 3-S-cysteinyl derivatives of dimethyl hexahydroxydiphenoate.
Progress in the synthesis of bioactive ellagitannin plant
secondary metabolites depends upon the development of
reliable methodologies for the facile preparation of their
characteristic galloyl-derived biaryl and diaryl ether acyl
groups.1,2 Novel approaches for synthesizing hexahy-
droxydiphenoyl (HHDP) and dehydrodigalloyl units have
recently been developed1,3 and successfully applied to the
total synthesis of several naturally occurring ellagitan-
nins.4 Access to dehydrohexahydroxydiphenoyl (DH-
HDP) units and DHHDP-containing ellagitannins, ex-
4
emplified by the C1-glucopyranosyl-containing geraniin
(1),5 remains a challenge. Current art is defined by
Schmidt’s 30-year-old report on the preparation of a
DHHDP phenazine derivative via a multistep procedure
from ellagic acid.6
The chemical details of the biogenesis of ellagitannin
HHDP and DHHDP esters are still under active investi-
gation.1a,2 Although these two units differ only by their
membered ring hemiketals,1,5,7 whereas only the six-
membered ring is observed for other DHHDP-containing
ellagitannins.8 A requirement for glucose-free DHHDP
and HHDP units in our ongoing chemical studies of
ellagitannin natural products led us to revisit the oxida-
tion of methyl gallate (2) for preparing unprotected
versions of these compounds in a concise and efficient
manner. The results obtained bear on strategies for
dehydroellagitannin chemical synthesis and also on
hypotheses advanced for their biosynthesis.
oxidation level, it is not clear if the former precedes the
latter during biosynthesis. Thus, oxidation of a glucose-
bound HHDP unit could afford a DHHDP product, but
it is also possible that the DHHDP functionality can
emerge directly from the oxidative dimerization of glucose-
bound galloyl rings (vide infra). In aqueous acetone
solution, the DHHDP unit of geraniin-type ellagitannins
exists as a mixture of the two possible five- and six-
† Current address: Department of Chemistry and Biochemistry,
Texas Tech University, Lubbock, TX 79409-1061.
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) (a) Quideau, S.; Feldman, K. S. Chem. Rev. (Washington, D.C.)
1996, 96, 475 and references therein. (b) Nelson, T. D.; Meyers, A. I.
J . Org. Chem. 1994, 59, 2577. (c) Lipshutz, B. H.; Liu, Z.-P.; Kayser,
F. Tetrahedron Lett. 1994, 35, 5567.
Resu lts a n d Discu ssion
The value of o-chloranil in the clean oxidation of galloyl
monoethers has been the subject of previous reports from
this laboratory.3,9 In the current study, this mild and
selective oxidant is equally successful in furnishing good
yields of characterizable oxidative dimerization products
from unetherified methyl gallate (2). This observation
(2) Okuda, T.; Yoshida, T.; Hatano, T. Prog. Chem. Org. Nat. Prod.
1995, 66, 1.
(3) Feldman, K. S.; Quideau, S.; Appel, H. M. J . Org. Chem. 1996,
61, 6656.
(4) (a) Feldman, K. S.; Ensel, S. M.; Minard, R. D. J . Am. Chem.
Soc. 1994, 116, 1742. (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.
(5) (a) Okuda, T.; Yoshida, T.; Hatano, T. J . Chem. Soc., Perkin
Trans. 1 1982, 9. (b) Okuda, T.; Yoshida, T.; Hatano, T. Tetrahedron
Lett. 1980, 21, 2561. (c) Okuda, T.; Nayeshiro, H.; Seno, K. Tetrahedron
Lett. 1977, 4421. (d) Okuda, T.; Yoshida, T.; Nayeshiro, H. Chem.
Pharm. Bull. 1977, 25, 1862. (e) Okuda, T.; Yoshida, T.; Nayeshiro,
H. Tetrahedron Lett. 1976, 3721. (f) Haddock, E. A.; Gupta, R. K.;
Haslam, E. J . Chem. Soc., Perkin Trans. 1 1982, 2535.
(6) Schmidt, O. T.; Wieder, G. Liebigs Ann. Chem. 1967, 706, 198.
(7) (a) Okuda, T.; Hatano, T.; Nitta, H.; Fujii, R. Tetrahedron Lett.
1980, 21, 4361. (b) Yazaki, K.; Hatano, T.; Okuda, T. J . Chem. Soc.,
Perkin Trans. 1 1989, 2289.
(8) (a) Yoshida, T.; Arioka, H.; Fujita, T.; Chen, X.-M.; Okuda, T.
Phytochemistry 1994, 37, 863. (b) Okuda, T.; Hatano, T.; Yasui, T.
Heterocycles 1981, 16, 1321. (c) Nonaka, G.-i.; Matsumoto, Y.; Nishioka,
I. Chem. Pharm. Bull. 1981, 29, 1184.
(9) Quideau, S.; Feldman, K. S.; Appel, H. M. J . Org. Chem. 1995,
60, 4982.
S0022-3263(97)01354-6 CCC: $14.00 © 1997 American Chemical Society

8810 J . Org. Chem., Vol. 62, No. 25, 1997
Quideau and Feldman
Sch em e 1a
Sch em e 2a
a
Reaction conditions: (a) o-phenylenediamine, AcOH-CH3CN;
(b) CH2N2, Et2O; (c) H2O-MeOH, reflux; (d) Na2S2O4, H2-THF,
0 °C; (e) MeI, NaH, DMF.
to afford a known compound, dimethyl hexahydroxy-
diphenoate (11). Several reducing agents (H2, Pd/C;5f
Zn-Cu; Na2S2O4)8c were tried under various experimen-
tal conditions. The sodium dithionite (Na2S2O4)-mediated
reduction was found to be superior in providing 11 in high
yield and with relatively good purity. Ellagic acid was
not detected; it was readily obtained, however, as an off-
white precipitate upon trituration of 11 with aqueous
acetone at rt. The only byproduct, methyl gallate (2),
which presumably resulted from reductive cleavage of
transient intermediate 4, was typically detected in
5-15% yield by 1H NMR analysis. The propensity of
hydroxyorthoquinone-derived dimers to undergo ready
dissociation into their quinonoid monomeric form is
documented.12b Permethylation of 11 furnished 12 in
good yield. This two-step procedure for the synthesis of
11 from commercially available methyl gallate compares
favorably with previously reported routes to HHDP
derivatives.10j,q,13
a
E ) CO2CH3.
stands in stark contrast to the many previous attempts
at gallate ester (or acid) oxidation with a host of chemical
and biochemical oxidants. These oxidation attempts
invariably delivered ellagic acid and/or purpurogallin
derivatives with only occasional HHDP ester formation
in modest yield.10 Thus, treatment of an equimolar
amount of o-chloranil in Et2O at -40 °C with 2, and
allowing the reddish solution to warm slowly to rt,
furnished a pale yellow precipitate in a reproducible 64%
yield. Mass spectrometric, combustion, and rapid NMR
analyses indicated that this solid was a dimer of the
hydroxyorthoquinone 3, but a combination of derivati-
zations and careful NMR study was necessary to unveil
its structure (Scheme 1).
The pale yellow solid compound was first converted to
its phenazine derivative 8 in order to verify its quinonoid
nature (Scheme 2).5f,11 The phenazine 8 was further
transformed into a known permethylated derivative 95d,6
and bislactonized to form 105d,f,11a in order to determine
unambiguously the regiochemistry of phenazine forma-
tion. Most importantly, the pale yellow solid was reduced
The structural elucidation of the first-formed precipi-
tate 5 and its rearrangement products 6 and 7 com-
1
menced with H and 13C NMR analyses that, in the case
of 5, had to be performed immediately after preparation
of the sample at a concentration g0.3 M to record
(12) (a) Musso, H. Angew. Chem., Int. Ed. Engl. 1963, 2, 723. (b)
Critchlow, A.; Halslam, E.; Haworth, R. D.; Tinker, P. B.; Waldron,
N. M. Tetrahedron 1967, 23, 2829. (c) Perkin, A. G.; Steven, A. B. J .
Chem. Soc. 1906, 802. (d) Teuber, H.-J .; Steinmetz, G. Chem. Ber. 1965,
98, 666. (e) Teuber, H.-J .; Heinrich, P.; Dietrich, M. Liebigs Ann. Chem.
1966, 696, 64. The pyrogallol-derived orthoquinone i dimerizes as
shown to furnish the “head-to-tail” dimer ii, a distinct regioisomer of
the “head-to-head” structure of galloyl orthoquinone dimer 6. The
assignment of connectivity shown in 6 is preferred over an alternative
iii since no three-bond HMBC response between the hydroxyl protons
OH-5/5′ at 5.86 ppm and the protonated carbons C-1/1′ was observed,
as would be expected for iii.
(10) (a) Lo¨we, J . F. F. F. Z. Chem. 1868, 4, 603. (b) Ernst, F.;
Zwenger, C. Annalen 1871, 159, 32. (c) Perkin, A. G.; Nierenstein, M.
J . Chem. Soc. 1905, 87, 1412. (d) Perkin, A. G. J . Chem. Soc. 1906,
89, 251. (e) Erdtman, H. Svensk Kem. Tidskr. 1935, 47, 223. (f) Mayer,
W. Annalen 1952, 578, 34. (g) Hathway, D. E. J . Chem. Soc. 1957,
519. (h) J urd, L. J . Am. Chem. Soc. 1959, 81, 4606. (i) Pastuska, G.
Naturwissenschaften 1961, 48, 457. (j) Mayer, W.; Hoffmann, E. H.;
Lo¨sch, N.; Wolf, H.; Wolter, B.; Schilling G. Annalen 1984, 929. (k)
Zeng, W.; Heur, Y.-H.; Kinstle, T. H.; Stoner, G. D. Labeled Cmpd.
1991, 29, 657. (l) Hathway, D. E. Biochem. J . 1957, 67, 445. (m) Flaig,
W.; Haider, K. Planta Med. 1961, 9, 123. (n) Kamel, M. Y.; Saleh, N.
A.; Ghazy, A. M. Phytochemistry 1977, 16, 521. (o) Pospisil, F.;
Cvikrova´, M.; Hrubcova´, M. Biochem. Plantar. (Praha) 1983, 25, 373.
(p) Gross, G. In Plant Polyphenols. Synthesis, Properties, Significance;
Hemingway, R. W., Laks, P. E., Eds.; Plenum Press: New York, 1992;
pp 43-60. (q) Gupta, R. K.; Al-Shafi, S. M. K.; Layden, K.; Haslam, E.
J . Chem. Soc., Perkin Trans. 1 1982, 2525.
(11) (a) Schmidt, O. T.; Schanz, R.; Eckert, R.; Wurmb, R. Liebigs
Ann. Chem. 1967, 706, 131. (b) Schmidt, O. T.; Schanz, R.; R., W.;
Groebke, W. Liebigs Ann. Chem. 1967, 706, 154. (c) Schmidt, O. T.;
Schulz, J .; Wurmb, R. Liebigs Ann. Chem. 1967, 706, 169.

Ellagitannin Chemistry
Ta ble 1: HMBC Da ta for Com p ou n d s 5-7a
J . Org. Chem., Vol. 62, No. 25, 1997 8811
Sch em e 3
proton
HMBC
5
H-1
H-1′
H-3
C-2, C-3, C-5, C-6, C-7, C-1′(?), C-2′
C-1, C-2, C-2′(?), C-6′, C-7′
C-1, C-5, C-7
H-3′
OH-4′
OH-5
C-5 (w), C-1′, C-4′, C-5′, C-7′(w)
C-3′, C-4′, C-5′
C-4, C-5, C-6, C-2′
6
7
H-1/1′
H-3/3′
OH-5/5′
C-1/1′, C-2/2′, C-3/3′, C-5/5′, C-6/6′, C-7/7′
C-1/1′, C-2/2′, C-5/5′, C-7/7′
C-4/4′, C-5/5′, C-6/6′
H-1
H-3
H-3′
OH-4′
OH-5
OH-5′
C-2, C-3, C-5, C-6, C-7, C-1′, C-2′, C-6′
C-1, C-2 (w), C-5, C-7
C-1′, C-2′ (w), C-7′, C-4′, C-5′
C-3′, C-4′, C-5′
C-4, C-5, C-6
C-4′, C-5′, C-6′
a
Chemical shift assignments are given in the Experimental
Section; ? ) ambiguous, w ) weak intensity.
B in 4 followed by (2) intramolecular addition of the
resulting phenol (OH-6′) to the central carbonyl carbon
C-5 (Scheme 1). The regiochemistry of hemiketalization
(phenol addition to C-5 vs C-6) is determined unambigu-
ously from observation of three-bond HMBC responses
between H-3 and C-5 and between OH-5 and C-4/C-6.
Compound 7 corresponds to the nonhydrated form of the
six-membered ring hemiketal DHHDP ester group con-
tained in ellagitannin natural products (e.g., 1). HMBC
data for compounds 5-7 are given in Table 1.
Alternative mechanisms to the simple two-step conver-
sion of putative intermediate orthoquinone 3 to dimer 5
can be envisioned. For example, it is possible that dimer
5 is formed via a direct one-step Diels-Alder-type cy-
cloaddition of one molecule of (protonated?) 3 acting as
a dipolar (cationic?) five-carbon 4π component with the
alkene (2π) of a second molecule of 3. In addition,
nascent orthoquinone 3 may be trapped by nucleophilic
phenol 2 to furnish intermediate dimethyl HHDP 11 after
aromatization. This species could undergo subsequent
o-chloranil-mediated oxidation to deliver 5 via an unob-
served orthoquinone derivative of 11, a process in accord
with earlier speculation by Schmidt.6 At present, no
basis to distinguish between these three hypotheses
exists.
The electrophilicity of the DHHDP unit of ellagitannin
natural products may be relevant to their expression of
biological activity. Tanaka et al. have shown that thiol
nucleophiles such as cysteine methyl ester and glu-
tathione add to the DHHDP ester groups of 1 to give
dihydro-1,4-thiazine derivatives and various rearranged
sulfide derivatives, respectively.15 In every case, initial
thiol addition occurs at the C-3 carbon (cf. 1) of the
DHHDP unit. The yellow solid 5 was combined with
N-(carbobenzyloxy)-L-cysteine benzyl ester (13)3 in THF
solution to afford, probably via an intermediate of type
14, a 1:1 diastereomeric mixture of the rearomatized
adducts 15a :15b in good yield (Scheme 3). This type of
C-3 sulfur-bearing HHDP unit has not been reported by
Tanaka et al.,15 but it might be relevant to dehydroella-
gitannin-mediated covalent modification of proteins in
vivo.
relatively clean spectra. The detection and assignment
of the nonoxygenated aliphatic quaternary carbon (C-2′
at 53.0 ppm) by 13C and DEPT NMR analyses was key
to the elucidation of this structure. A delayed 1H-1H
COSY experiment14 was run to confirm the assigment of
the pair of allylic coupled protons H-1/H-3 (4J ≈ 1.0 Hz).
H-1′ is vicinally coupled with H-1, but no correlation was
observed with H-3′. These observations and HMQC/
HMBC data (Table 1) are all in agreement with structure
5. This dimer plausibly arises from an intramolecular
direct (2′ f 5) or conjugate (5′ f 2) addition of a ring B
enol to the cyclohexenetrione unit of 4 (Scheme 1).
Dimer 5 in acetone-d6 was rapidly converted into the
symmetrical dimer 6, which slowly (ca. 7 days) equili-
brated to a ca. 1:1 mixture of 6 and 7 upon storage at
-10 °C. This equilibration is much more rapid at rt and
gives rise to 1:2 to 1:4 mixtures of 6 and 7 after ca. 24 h.
Although extensive degradation to unidentified products
accompanies this isomerization, 6:7 mixtures are typi-
cally stable long enough to permit complete NMR char-
acterization.
The symmetrical nature of structure 6 was apparent
from the number of signals in both the 1H and 13C
spectra. The presence of tertiary alcoholic carbons R to
two ketone carbonyls (C-5/5′) was indicated by a reso-
nance at 96.0 ppm. This compound likely results from a
direct enol/carbonyl coupling within 4 to form the C-5/
C-5′ bond of the tricyclic core (Scheme 1). Similar
compounds have been observed as products of the oxida-
tive dimerization of various pyrogallols.12
The assignment of structure 7 depended upon the
observation of two phenolic hydroxyl protons (OH-4′ and
OH-5′) resonating at 8.47 and 8.70 ppm, respectively, as
well as the observation of one hemiketal hydroxyl proton
OH-5 resonating at 7.36 ppm. The allylic proton H-1
(5.90 ppm) exhibits diagnostic HMBC responses with the
vinylic carbon C-3 (130.4 ppm), the hemiketal carbon C-5
(98.2 ppm), the carbonyl carbon C-6 (195.3 ppm), and,
more importantly, three aromatic carbons (ring B) reso-
nating at 113.7 ppm (C-1′), 121.8 ppm (C-2′), and 143.4
ppm (oxygenated C-6′). Compound 7 is the third DHHDP
species observed in acetone-d6 solution, and its formation
can be rationalized via (1) initial aromatization of ring
In summary, methyl gallate (2) can be oxidized by
o-chloranil to furnish dehydroellagitannin-related di-
methyl dehydrohexahydroxydiphenoates. Their clean
(13) (a) Schmidt, O. T.; Voigt, H.; Puff, W.; Ko¨ster, R. Liebigs Ann.
Chem. 1954, 586, 165. (b) Schmidt, O. T., Demmler, M. Liebigs Ann.
Chem. 1954, 586, 179. (c) Itoh, T.; Chika, J .-i.; Shirakami, S.; Ito, H.;
Yoshida, T.; Kubo, Y.; Uenishi, J .-i. J . Org. Chem. 1996, 61, 3700.
(14) Bax, A.; Freeman, R. J . Magn. Reson. 1981, 44, 542.
(15) (a) Tanaka, T.; Fujisaki, H.; Nonaka, G.-I.; Nishioka, I. Chem.
Pharm. Bull. 1992, 40, 2937. (b) Tanaka, T.; Fujisaki, H.; Nonaka,
G.-i.; Nishioka, I. Heterocycles 1992, 33, 375. (c) Tanaka, T.; Kouno,
I.; Nonaka, G.-i. Chem. Pharm. Bull. 1996, 44, 34.

8812 J . Org. Chem., Vol. 62, No. 25, 1997
Quideau and Feldman
7: 1H NMR (CD3COCD3) δ 3.77 (s, MeO-7), 3.91 (s, MeO-
7′), 5.90 (s, H-1), 6.96 (s, H-3), 7.14 (s, H-3′), 7.36 (s, OH-5),
8.47 (s, OH-4′), 8.70 (s, OH-5′); 13C NMR (CD3COCD3) δ 195.3
(C-6), 189.3 (C-4), 167.3 (C-7′), 164.8 (C-7), 147.8 (C-2), 146.8
(C-4′) 143.4 (C-6′), 137.8 (C-5′), 130.4 (C-3), 121.8 (C-2′), 114.2
(C-3′), 113.7 (C-1′), 98.2 (C-5), 53.5 (MeO-7), 52.4 (MeO-7′), 46.8
(C-1).
reduction by sodium dithionite offers a convenient and
reproducible two-step synthesis of dimethyl hexahy-
droxydiphenoate, a C-C-coupled biaryl acyl unit requi-
site for ellagitannin synthesis. This study provides
support for a dehydroellagitannin biosynthesis hypoth-
esis featuring galloyl-derived orthoquinones, as opposed
to phenoxy radicals and even perhaps phenoxonium
ions,16 in galloyl oxidative coupling. In addition, DHHDP
esters are masked quinonoid electrophiles that can be
efficiently trapped by a cysteinyl nucleophile to furnish
3-S-cysteinyl-HHDP units. This thiol addition reaction
may be involved in the covalent modification of proteins
by dehydroellagitannins, thus mediating the biological
activity of these DHHDP-containing natural products.
Meth yl 4-Hyd r oxy-3-[4,5,6-tr ih yd r oxy-2-(m eth oxyca r -
b on yl)p h en yl]p h en a zin e-2-ca r b oxyla t e (8). Solid di-
methyl dehydrohexahydroxydiphenoate 5 (107 mg, 0.29 mmol)
was dissolved in CH3CN (4 mL) and treated with a solution of
o-phenylenediamine (48 mg, 0.44 mmol) in glacial AcOH (2
mL) for 15 h at rt.5f The resulting orangeish precipitate was
collected by filtration, triturated with water, recollected by
filtration, and extensively washed with Et2O to give 8 (94 mg,
73%) as a yellow solid: mp 402 °C dec; IR (KBr) 3400-3000,
1729, 1617 cm-1; 1H NMR (CD3COCD3 + 2 drops CD3SOCD3)
δ 3.43 (s, 3 H), 3.67 (s, 3 H), 7.21 (s, 1 H), 7.96-7.99 (m, 2 H),
8.24 (s, 1 H), 8.27-8.31 (m, 2 H); 13C NMR (CD3COCD3) δ
167.43, 167.37, 151.0, 145.2, 144.9, 144.5, 143.3, 142.8, 137.8,
137.6, 136.5, 132.3, 131.9, 130.7, 130.1, 122.1, 121.8, 119.2,
118.5, 110.7, 52.3, 51.4; EIMS m/z (relative intensity) 436 (M+,
46); HRMS (EI) calcd for C22H16O8N2 436.0907, found 436.0921.
Exp er im en ta l Section
Tetrahydrofuran (THF) and diethyl ether (Et2O) were
purified by distillation from sodium/benzophenone under Ar
immediately before use. Moisture- and oxygen-sensitive reac-
tions were carried out in flame-dried glassware under Ar.
Solvents for chromatography (Et2O, EtOAc, CH2Cl2, hexane)
were distilled from CaH2 prior to use. Evaporations were
conducted under reduced pressure at temperatures less than
45 °C unless otherwise noted. Column chromatography was
carried out under positive pressure using 32-63 µm silica gel
and the indicated solvents. Melting points are uncorrected.
One- and two-dimensional NMR spectra of samples in the
indicated solvent were run at either 300 or 500 MHz (1H).
Carbon multiplicities were determined by DEPT90 and
DEPT135 experiments.17 Correlation information was ob-
tained with inverse-detected short-range (one bond) 1H-13C
HMQC18 and long-range (two and three bonds) 1H-13C
HMBC19 correlative experiments and with delayed 1H-1H
correlative experiments14 using a fixed delay of 200 ms.
Chemical impact mass spectra (CIMS) were obtained with
isobutane as the reagent gas, and electron impact mass spectra
(EIMS) were obtained at 50-70 eV. FAB high-resolution mass
spectra were obtained from the mass spectrometry laboratory
at the University of Texas at Austin. Combustion analyses
were performed by Galbraith Laboratories, Knoxville, TN. 1H
and 13C NMR spectra are provided in the Supporting Informa-
tion to establish purity for those compounds that were not
subject to combustion analyses.
Meth yl 4-Meth oxy-3-[4,5,6-tr im eth oxy-2-(m eth oxyca r -
bon yl)ph en yl]ph en azin e-2-car boxylate (9). Phenolic phena-
zine 8 (28 mg, 0.06 mmol) in MeOH (1 mL) was treated with
an excess of ethereal diazomethane for 12 h, after which time
the resulting yellow solution was evaporated to dryness. The
residue was purified by preparative TLC, eluting with CH2Cl2-
MeOH (20:1), to afford 95d,6 (28 mg, 90%) as a yellow oil, which
was crystallized from MeOH-H2O to furnish small yellow
needles: mp 156-158 °C (lit.6 mp 158-159 °C); IR (KBr) 1728
cm-1; 1H NMR (CDCl3) δ 3.56 (s, 3 H), 3.66 (s, 3 H), 3.77 (s, 3
H), 3.98 (s, 3 H), 4.00 (s, 6 H), 7.48 (s, 1 H), 7.85-7.91 (m, 2
H), 8.25-8.36 (m, 2 H), 8.75 (s, 1 H); 13C NMR (CDCl3) δ 166.7,
166.5, 152.54, 152.46, 151.2, 145.6, 143.8, 143.4, 142.9, 139.7,
133.9, 131.2, 130.9, 130.2, 129.7, 129.6, 127.8, 125.9, 124.4,
109.0, 62.3, 60.8, 60.7, 56.0, 52.4, 51.8; EIMS m/z (relative
intensity) 492 (M+, 61); HRMS (FAB) calcd for C26H24O8N2
493.1611, found 493.1617.
P h en a zin e Bis-la cton e 10. Phenolic phenazine 8 (37 mg,
0.09 mmol) in 1:1 MeOH-H2O (3 mL) was refluxed for 12 h,
after which time the resulting reddish brown precipitate was
collected by filtration, washed with H2O and then Et2O to
furnish 32 mg of 105d,f,11a as a brick red solid in quantitative
yield: mp >400 °C (lit.5d mp >360 °C); IR (KBr) 3422, 1762,
Dim eth yl Deh yd r oh exa h yd r oxyd ip h en oa tes 5-7.
A
solution of methyl gallate (2) (2.08 g, 11.3 mmol) in Et2O (250
mL) was added dropwise under Ar to a stirred -40 °C cooled
solution of o-chloranil (3.05 g, 12.4 mmol) in Et2O (50 mL).
After completion of the addition, the reaction mixture was
allowed to warm slowly to rt over 2 h. A yellowish solid
precipitated out of the mixture. Stirring was continued for 1
h, after which time the solid was collected by filtration and
washed extensively with cold Et2O to give 5 (1.32 gm, 64%) as
a pale yellow solid: mp 210 °C dec; IR (KBr) 3345, 1782, 1728,
1
1734 cm-1; H NMR (CF3COOD) δ 8.10 (s, 1 H), 8.45 (t, J )
7.5 Hz, 1 H), 8.64 (t, J ) 7.5 Hz, 1 H), 8.73 (d, J ) 8.7 Hz, 1
H), 8.82 (d, J ) 8.7 Hz, 1 H), 9.63 (s, 1 H); 13C NMR
(CF3COOD) δ 163.0, 161.7, 153.4, 147.3, 144.7, 144.1, 142.0,
139.5, 138.7, 137.6, 136.2, 132.8, 132.7, 125.8, 124.4, 123.3,
121.8, 116.0, 113.5; FABMS m/z (relative intensity) 373 (MH+,
61); HRMS (FAB) calcd for C20H8O6N2 373.0461, found 373.0461.
Dim eth yl 4,4′,5,5′,6,6′-Hexah ydr oxy-2,2′-diph en oate (11).
Solid dimethyl dehydrohexahydroxydiphenoate (5) (280 mg,
0.77 mmol) was dissolved in THF (12 mL). The resulting
solution was cooled to 0 °C (ice-water bath), and sodium
dithionite (268 mg, 1.54 mmol) was added. The reaction
mixture was stirred for 30 min, after which time it was poured
over ice-cold water (20 mL), extracted with EtOAc (2 × 20 mL),
washed with brine, dried over Na2SO4, filtered, and evaporated
at rt to furnish crude 11 (262 mg) as a beige solid. 1H NMR
analysis indicated the presence of about 15% of methyl gallate
(2); 5-15% of 2 was typically observed in repeated runs.
Further purification by silica gel column chromatography,
eluting with EtOAc:AcOH (100:1), afforded 1110j,13b (223 mg,
79%) as an off-white solid: mp 258 °C (lit.10j mp 210 °C dec);
1
1682 cm-1; H NMR (CD3COCD3) δ 3.73 (s, MeO-7′), 3.87 (s,
MeO-7), 4.61 (dd, J ) 7.8, 0.9 Hz, H-1), 4.68 (d, J ) 7.8 Hz,
H-1′), 6.32 (s, OH-5), 6.43 (s, H-3′), 6.88 (d, J ) 1.1 Hz, H-3),
8.50 (s, OH-4′); 13C NMR (CD3COCD3) δ 196.9 (C-6), 195.3 (C-
4), 191.4 (C-6′), 176.7 (C-5′), 171.0 (C-7′), 164.4 (C-7), 153.7
(C-2), 151.0 (C-4′), 132.3 (C-3), 119.4 (C-3′), 96.8 (C-5), 53.9
(MeO-7), 53.6 (MeO-7′), 53.4 (C-1′), 53.0 (C-2′), 50.2 (C-1);
CIMS m/z (relative intensity) 367 ([MH + 2]+, 2), 365 (MH+,
3). Anal. Calcd for C16H12O10: C, 52.76; H, 3.32. Found: C,
52.50; H, 3.48.
6: 1H NMR (CD3COCD3) δ 3.95 (s, MeO-7/7′), 4.36 (s, H-1/
1′), 5.86 (s, OH-5/5′), 7.02 (s, H-3/3′); 13C NMR (CD3COCD3) δ
196.2 (C-6/6′), 190.3 (C-4/4′), 164.3 (C-7/7′), 146.6 (c-2/2′), 133.4
(C-3/3′), 96.0 (C-5/5′), 54.0 (MeO-7/7′), 53.2 (C-1/1′).
1
IR (Nujol) 1727 cm-1; H NMR (CD3COCD3) δ 3.46 (s, 6 H),
7.12 (s, 2 H), 7.66 (bs, 6 H); 13C NMR (CD3COCD3) δ 167.4,
144.6, 144.5, 137.6, 122.6, 118.7, 110.7, 51.3; CIMS m/z
(relative intensity) 367 (MH+, 3).
(16) (a) Haslam, E.; Cai, Y. Nat. Prod. Rep. 1994, 41. (b) Waters,
W. A. J . Chem. Soc. B 1971, 2026.
(17) Doddrell, D. M.; Pegg, D. T.; Bendall, M. R. J . Magn. Reson.
1982, 48, 323.
(18) Bax, A.; Subramanian, S. J . Magn. Reson. 1986, 67, 565.
(19) Bax, A.; Summers, M. F. J . Am. Chem. Soc. 1986, 108, 2093.
Dim eth yl 4,4′,5,5′,6,6′-Hexam eth oxy-2,2′-diph en oate (12).
Compound 11 (50 mg) was permethylated according to Itoh’s

Ellagitannin Chemistry
J . Org. Chem., Vol. 62, No. 25, 1997 8813
procedure to furnish 1213c,20 as a yellowish beige syrup in 59%
yield: IR (CCl4) 1731 cm-1; 1H NMR (CDCl3) δ 3.60 (s, 12 H),
3.94 (s, 6 H), 3.95 (s, 6 H), 7.37 (s, 2 H); 13C NMR (CDCl3) δ
166.9, 152.0, 151.1, 145.3, 126.5, 124.9, 108.8, 60.7, 60.5, 55.9,
51.8; CIMS m/z (relative intensity) 450 (M+, 42); HRMS (FAB)
calcd for C22H26O10 450.1526, found 450.1525.
5.19 (m, 8 H), 6.92 (d, J ) 7.8 Hz, 2 H), 7.074 (s, 1 H), 7.077
(s, 1 H), 7.27-7.36 (m, 20 H), 7.7-8.3 (bs, 12 H); 13C NMR
(CD3COCD3) δ 171.5/171.3, 169.1/168.9, 167.3/167.2, 157.2/
156.9, 147.3, 146.4/146.3, 145.4, 145.3, 145.1, 137.9, 137.54/
137.46, 136.8/136.7, 134.4/134.3, 133.7/133.6, 129.3, 129.2,
128.9, 128.8, 128.6, 123.4/123.3, 115.8/115.6, 115.4/115.2, 110.8
(2), 106.0/105.8, 67.5/67.4, 67.0/66.9, 54.9/54.8, 51.8/51.7, 51.6
(2), 38.7/37.7; FABMS m/z (relative intensity) 710 (MH+, 100);
HRMS (FAB) calcd for C34H31O14NS 710.1543, found 710.1554.
Dim eth yl 3-N-(Car boben zyloxy)-S-cystein yl-4,4′,5,5′,6,6′-
h exah ydr oxy-2,2′-diph en oate Ben zyl Ester s (15a/b). Solid
dimethyl dehydrohexahydroxydiphenoate (5) (179 mg, 0.49
mmol) was dissolved in THF (10 mL) and added dropwise at
rt over 1 h to a solution of N-(carbobenzyloxy)-L-cysteine benzyl
ester 13 (170 mg, 0.49 mmol).3 Evaporation of the solvent
afforded a dark yellow oil, which was purified by column
chromatography, eluting with light petroleum-EtOAc-AcOH
(1:2:0.02), to give 15a :15b (215 mg, 62%) in a 1:1 ratio as an
Ack n ow led gm en t. This work was supported by the
NIH under the auspices of GM 35727.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 6-8, 11, 12, and 15a /b (12 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
1
amorphous pale yellow solid: IR (KBr) 3394, 1708 cm-1; H
NMR (CD3COCD3) δ 3.07-3.40 (m, 4 H), 3.37 (s, 3 H), 3.38 (s,
3 H), 3.43 (s, 3 H), 3.45 (s, 3 H), 4.38-4.49 (m, 2 H), 5.00-
(20) (a) Schmidt, O. T.; Demmler, K. Liebigs Ann. Chem. 1952, 576,
85. (b) Herzig, J .; Polak, J . Monatsch. Chem. 1908, 29, 263.
J O971354K