Galloyl-derived orthoquinones as reactive partners in nucleophilic additions and Diels-Alder dimerizations: A novel route to the dehydrodigalloyl linker unit of agrimoniin-type ellagitannins

Article abstract of DOI:10.1021/jo961043u

Orthochloranil-mediated oxidation of galloyl monoethers furnishes the derived orthoquinones in excellent yield. These reactive electrophiles participate in a variety of nucleophilic addition reactions with heteroatomic and carbanionic partners. In addition, Lewis acid-mediated dimerization of the orthoquinones provides an efficient route to dehydrodigalloyl-type diaryl ether units characteristic of several ellagitannin natural products. The implications for ellagitannin biosynthesis and gallotannin-protein covalent attachment are discussed.

Full text of DOI:10.1021/jo961043u

6656
J . Org. Chem. 1996, 61, 6656-6665
Ga lloyl-Der ived Or th oqu in on es a s Rea ctive P a r tn er s in
Nu cleop h ilic Ad d ition s a n d Diels-Ald er Dim er iza tion s: A Novel
Rou te to th e Deh yd r od iga lloyl Lin k er Un it of Agr im on iin -Typ e
Ella gita n n in s
Ken S. Feldman,*,† Ste´phane Quideau,† and Heidi M. Appel‡
Department of Chemistry and Pesticide Research Laboratory, The Pennsylvania State University,
University Park, Pennsylvania 16802
Received J une 3, 1996X
Orthochloranil-mediated oxidation of galloyl monoethers furnishes the derived orthoquinones in
excellent yield. These reactive electrophiles participate in a variety of nucleophilic addition reactions
with heteroatomic and carbanionic partners. In addition, Lewis acid-mediated dimerization of the
orthoquinones provides an efficient route to dehydrodigalloyl-type diaryl ether units characteristic
of several ellagitannin natural products. The implications for ellagitannin biosynthesis and
gallotannin-protein covalent attachment are discussed.
The structural diversity and pharmaceutical potential
embodied by the extensive gallotannin and ellagitannin1
families of secondary plant metabolites has stimulated
several recent studies in both organic synthesis2 and drug
discovery.3 The relative simplicity of the gallotannin
structural motif, as exemplified by the naturally occur-
ring â-pentagalloylglucose (1, â-PGG), gives way to a
myriad of skeletal possibilities for the ellagitannins as
galloyl rings are joined through oxidative couplings, cf.
agrimoniin (2).4 While no direct evidence yet implicates
â-PGG as the biosynthetic precursor of ellagitannins, this
presumption underscores numerous biosynthetic hypoth-
eses and synthetic strategies. A survey of the more than
500 structurally characterized ellagitannins reveals that
C-C biaryl bond formation is almost exclusively the
province of intramolecular coupling,5 while C-O linkages
between galloyls invariably span either two different
galloylated glucose cores or act as attachment points for
a third galloyl ring to a hexahydroxydiphenyl (HHDP)
unit. Plausible reactive intermediates which have been
postulated to precede galloyl coupling include phenoxo-
nium ions (two-electron oxidation) and/or phenoxy radi-
cals (one-electron oxidation).2a,b,6 The electrophilicity of
phenoxonium ions might also be moderated by deproto-
nation to furnish related orthoquinone intermediates.
Catechol-derived orthoquinones have long been identi-
fied as occupying a central position in the chemistry of
such diverse biological operations as insect cuticle
sclerotization,7a,b melanization,7c-g food browning and
wine ageing,7h-k arene hepatotoxicity,7l brain catechola-
mine aberrant metabolism,7m,n estrogen-mediated car-
cinogenesis,7o,p and poison oak/ivy contact dermatitis in
humans.7q,r In these systems, the electrophilic ortho-
quinone typically scavenges endogenous protein or pep-
tidic nucleophiles leading to a covalent link between the
arene ring and the nucleophilic heteroatom. However,
the role that galloyl-derived orthoquinones might play
in either (1) the expression of biological activity for select
members of the tannin family, or (2) the biosynthesis of
oligomeric ellagitannins has received scant attention. The
reactive and electrophilic character of these orthoquino-
nes can indeed provide a unifying theme to these
otherwise disparate avenues of tannin chemistry. One
particular biological system where galloyl-derived ortho-
quinones may occupy a pivotal position involves gallo-
tannins, LdNPV (Lymantria dispar nuclear polyhedrosis
virus), and gypsy moth (GM) caterpillars.8 The gallo-
tannin-mediated attenuation of infectivity for naturally
occurring LdNPV has ominous implications for manage-
† Department of Chemistry.
‡ Pesticide Research Laboratory.
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) (a) Schmidt, O. T. Fortschr. Chem. Org. Naturstoffe 1956, 13,
70. (b) Haslam, E. Plants polyphenols - Vegetable tannins revisited;
Cambridge University Press: Cambridge, 1989. (c) Okuda, T.; Yoshida,
T.; Hatano, T. Phytochemistry 1993, 32, 507. (d) Quideau, S.; Feldman,
K. S. Chem. Rev. 1996, 96, 475.
(2) (a) Feldman, K. S.; Ensel, S. M. J . Am. Chem. Soc. 1994, 116,
3357. (b) Feldman, K. S.; Ensel, S. M.; Minard, R. D. J . Am. Chem.
Soc. 1994, 116, 1742. (c) Feldman, K. S.; Sambandam, A. J . Org. Chem.
1995, 60, 8171. (d) Feldman, K. S.; Smith, R. S. J . Org. Chem. 1996,
61, 2606. (e) Nelson, T. D.; Meyers, A. I. J . Org. Chem. 1994, 59, 2577.
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S0022-3263(96)01043-2 CCC: $12.00 © 1996 American Chemical Society

Galloyl-Derived Orthoquinones
J . Org. Chem., Vol. 61, No. 19, 1996 6657
Sch em e 1
ment of outbreaks of this significant forest defoliator. The
highly alkaline (pH ) 8-11) and oxidizing (Eh ) +200-
250 mV) GM caterpillar midgut provides a favorable
milieu for ingested polyphenol (e.g., galloyl) oxidation.8
Thus, conversion of galloyl units to orthoquinonoid elec-
trophiles, followed by covalent trapping of nucleophilic
sites on a LdNPV surface envelope protein, might con-
stitute a plausible molecular hypothesis for tannin-
mediated suppression of infectivity. Chemical precedence
for this sequence of events can be gleaned from the work
of Nonaka, who observed that the naturally occurring
(masked) orthoquinone-containing ellagitannin geraniin
combines with the nucleophilic amino acid methyl cys-
teine to furnish a covalent conjugate addition product.9
The biosynthetic construction of the C-O linked de-
hydrodigalloyl moiety (cf. 2) may also proceed through
an electrophilic orthoquinone intermediate 4 and utilize
either a phenolic galloyl nucleophile 3 (e.g., 4 + 3 f 5)
or a second orthoquinone partner via Diels-Alder chem-
istry, 4 + 4 f 6 f 5, Scheme 1. The addition of phenolic
Sch em e 2
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nucleophiles to orthoquinones has been documented,10
while the Diels-Alder route is much more speculative.
Interestingly, Abdul-Hajj et al. have reported the spon-
taneous dimerization of a steroidal orthoquinone to
provide a diaryl ether product and its oxidized mo-
noorthoquinone derivative upon standing at rt for 2 h.7o,11
The mechanistic basis for this transformation is open to
interpretation but might involve chemistry analogous to
that presented in Scheme 1.
In this report we detail and expand upon our initial
studies on the nucleophilic capture of galloyl-derived
orthoquinones.12 Furthermore, we describe the Diels-
Alder dimerization of these species to afford protected
versions of the dehydrodigalloyl linker unit which bridges
the monomer modules in agrimoniin-type ellagitannins.
These studies address the legitimacy of invoking galloyl
orthoquinones as central intermediates in the aforemen-
tioned in vivo chemistry.
Resu lts a n d Discu ssion
The preparation of monoether versions of galloyl ortho-
quinones (Scheme 2) followed from the seminal work of
Horner et al., who described the clean orthochloranil-
mediated oxidative conversion of various catechol deriva-
tives to orthoquinones.13 The galloyl derivative 7 was
explored in Horner’s original study, but isolation of a
pure, monomeric orthoquinone product was not de-
scribed. However, careful control of the reaction condi-
tions permitted acquisition of pure samples of the ortho-
quinones 8 and 11 in excellent yield (see Experimental
Section). The bright yellow powdery solid 8 and the
burgundy solid 11 were obtained as analytically pure
compounds by this procedure. Both solid compounds
were stable indefinitely at room temperature but gradu-
ally decomposed to unidentified materials in solution.
(4) (a) Okuda, T.; Yoshida, T.; Kuwahara, M.; Memon, M. U.; Shingu,
T. J . Chem. Soc., Chem. Commun. 1982, 163. (b) Okuda, T.; Yoshida,
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Miyamoto, K.; Kishi, N.; Koshiura, R. J pn. J . Pharmacol. 1987, 43,
187. (e) Miyamoto, K.; Koshiura, R.; Ikeya, Y.; Taguchi, H. Chem.
Pharm. Bull. 1985, 33, 3977-3981.
(5) For an exception, see J iang, Z.-H.; Tanaka, T.; Kouno, I. J . Chem.
Soc., Chem. Commun. 1995, 1467.
(6) Haslam, E.; Cai, Y. Nat. Prod. Rep. 1994, 41.

6658 J . Org. Chem., Vol. 61, No. 19, 1996
Feldman et al.
The potent orthoquinone electrophiles 8 and 11 were
allowed to react with a range of sulfur, nitrogen, phe-
noxide, and carbon-based nucleophiles in an effort to
define the scope and limitations of the addition process.
The thiol nucleophiles PhSH and cysteines 14a and 14b
all afforded conjugate addition products with the ortho-
quinones 8 and 11 (eq 1). In each pairing, titration of
the thiol in THF or THF:H2O with the orthoquinone in
THF led to immediate discharge of the quinone solution’s
characteristic color and furnished the rearomatized
monoadduct in good yield. This sequence of addition
minimized the opportunity for subsequent oxidation of
the electron-rich products 12, 13, 15-17 by the ortho-
quinones themselves. Hydrogenolysis of the benzyl
protecting groups in 17 liberated the parent-derivatized
amino acid 18. The 1,6-regiochemistry of addition was
assigned by HMBC NMR experiments. Relevant cor-
relations are shown on the structures 13 and 17. This
regiochemical outcome is in complete accord with much
precedent in related orthoquinone/sulfur nucleophile
couplings.7a,d,e,h,k,r One simple rationalization for the
observed regiochemistry of attack might cite the ad-
ditional electrophilic activation of C(6) by the ester moiety
which is absent from C(4) in 8/11.
The addition of nitrogen-based nucleophiles (aniline,
lysine, histidine) to the orthoquinone 11 did not proceed
as smoothly as did the addition of the sulfur species.
Reaction with aniline did not afford any evidence for
conjugate addition, but rather delivered the direct car-
bonyl addition product 20 in modest yield, (eq 2). An
orthoquinone monoimine intermediate 19 presumably
precedes 20 although the reductant of 19 has not been
identified. The regiochemistry of diarylamine 20 was
secured through the NOESY-based correlation shown. In
contrast, the histidine derivative 21 did combine with
orthoquinone 11 at C(6) to furnish small quantities of
the rearomatized conjugate adduct 22. NR-(carbobenzyl-
oxy)lysine did not participate in conjugate addition with
11 to any detectable degree (THF-1 M NaOH), and only
a complex and intractable product mixture resulted.
These disappointing intermolecular amine additions can
be contrasted to the well-known intramolecular cycliza-
tion of dopamine quinones to various indole deriv-
atives.7c,m,n
(7) (a) Sugumaran, M.; Dali, H.; Semensi, V. Arch. Insect Biochem.
Physiol. 1989, 11, 127. (b) Sugumaran, M. Adv. Insect Physiol. 1988,
21, 179. (c) Mason, H. S.; Peterson, E. W. Biochim. Biophys. Acta 1965,
111, 134, and references cited therein. (d) Prota, G.; Scherillo, G.;
Nicolaus, R. A. Gazz. Chim. Ital. 1968, 98, 495. (e) Ito, S.; Prota, G.
Experientia 1977, 33, 1118. (f) Napolitano, A.; Costantini, C.; Crescenzi,
O.; Prota, G. Tetrahedron Lett. 1994, 35, 6365. (g) Thomson, R. H.
Angew. Chem., Int. Ed. Engl. 1974, 13, 305. (h) Cheynier, V.; Trousdale,
E. K.; Singleton, V. L.; Salgues, M. J .; Wylde, R. J . Agric. Food Chem.
1986, 34, 217. (i) Salgues, M.; Cheynier, V.; Gunata, Z.; Wylde, R. J .
Food Sci. 1986, 51, 1191. (j) Walker, J . R. L.; Ferrar, P. H. Chem. Ind.
1995, 836, and references cited therein. (k) Richard, F. C.; Goupy, P.
M.; Nicolas, J . J .; Lacombe, J .-M.; Pavia, A. A. J . Agric. Food Chem.
1991, 39, 841, and references cited therein. (l) Bambal, R. B.; Hanzlik,
R. P. Chem. Res. Toxicol. 1995, 8, 729, and references cited therein.
(m) Pelizzetti, E.; Mentasti, E.; Pramauro, E. J . Chem. Soc., Perkin
Trans. 2 1976, 1651. (n) Tse, D. C. S.; McCreery, R. L.; Adams, R. N.
J . Med. Chem. 1976, 19, 37, and references cited therein. (o) Abul-
Hajj, Y. J .; Tabakovic, K.; Gleason, W. B.; Ojala, W. H. Chem. Res.
Toxicol. 1996, 9, 434. (p) Iverson, S. L.; Shen, L.; Anlar, N.; Bolton, J .
L. Chem. Res. Toxicol. 1996, 9, 492. (q) Byck, J . S.; Dawson, C. R. Anal.
Biochem. 1968, 25, 123. (r) Liberato, D. J .; Byers, V. S.; Dennick, R.
G.; Castagnoli, N. J . Med. Chem. 1981, 24, 28.
(8) (a) Schultz, J . C.; Hunter, M. D.; Appel, H. M. In Plant
Polyphenols. Synthesis, Properties, Significance; Hemingway, R. W.,
Laks, P. E., Eds.; Plenum Press: New York, 1992; p 621. (b) Schultz,
J . C.; Keating, S. T. In Microbial Mediation of Plant-Herbivore
Interactions; Barbosa, P., Krischik, V. A., J ones, C. G., Eds.; Wiley:
New York, 1991; Vol. 16, p 489.
(9) (a) Tanaka, T.; Fujisaki, H.; Nonaka, G.; Nishioka, I. Heterocycles
1992, 33, 375. (b) Tanaka, T.; Fujisaki, H.; Nonaka, G.-I.; Nishioka, I.
Chem. Pharm. Bull. 1992, 40, 2937.
Matters deteriorated further upon attempted addition
of phenol itself or galloyl-based phenols to either ortho-
quinone 8 or 11. No anionic or Lewis acidic experimental
conditions could be devised which permitted isolation of
any characterizable adducts. Rapid decolorization of the
orthoquinone solution was generally observed, and ortho-
quinone precursors 7/10 were isolated in varying amounts.
Enforced intramolecularity was of no avail, as the
phenolic orthoquinone 23 failed to cyclize. Finally, the
presumably more electrophilic bromo orthoquinone 24
provided no advantage in these diaryl ether synthesis
attempts.
(10) (a) Grundmann, C. In Methoden der Organischen Chemie
(Houben-Weyl); Muller, E., Bayer, O., Eds.; Thieme: Stuttgart, 1979;
Vol. VII/3b, part II, 1, and references cited therein. (b) Kutyrev, A. A.
Tetrahedron, 1991, 47, 8043, and references cited therein. (c) Reinaud,
O.; Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1985, 26, 3993.
(11) Tabakovic, K.; Abul-Hajj, Y. J . Chem. Res. Toxicol. 1994, 7, 696.
(12) Quideau, S.; Feldman, K. S.; Appel, H. M. J . Org. Chem. 1995,
60, 4982.
The addition of carbanionic nucleophiles to orthoquino-
nes can proceed to furnish either C-C- or C-O-coupled
products. Enolates favor conjugate addition, as exempli-
fied by the addition of a â-keto ester enolate to a putative
(13) Horner, L.; Teichmann, K.-H.; Weber, K.-H.; Geyer, E. Chem.
Ber. 1965, 98, 1233.

Galloyl-Derived Orthoquinones
J . Org. Chem., Vol. 61, No. 19, 1996 6659
Ta ble 1. Dia r y Eth er s via Oxop h ilic Ar yl Ca r ba n ion
Ad d ition to Or th oqu in on es 8 a n d 11, Eq 3
entry
R
R1
R2
M, T (°C)
MgBr, rt
26:27 yield (%)
a
b
c
d
e
f
Bn
Bn
Me
Me
Me
H
H
2:1
23
55
50
60
75
37
47
9
H
H
H
H
H
H
H
H
H
H
MgBr, -78
3:1
MgBr, -78
1.8:1
5.5:1
MgBr/CuI, -90
MgBr/CeCl3, -90 5.2:1
Me OMe
Me OMe
Me OMe OMe MgBr/CuI, -90
MgBr/CuI, -90
MgBr/CeCl3, -90 1:1
0:1
1:1
g
h
orthoquinone derived from methyl gallate under the
influence of K3Fe(CN)6.14 Grignard reagents, however,
combine with orthoquinones to provide aryl ethers,
presumably through an indirect mechanistic pathway
featuring electron transfer and radical coupling.15 This
latter process might be exploited in the development of
a diaryl ether synthesis from galloyl-derived ortho-
quinone electrophiles and aryl organometallics, (eq 3) and
Table 1.
The last and most successful attempt to synthesize the
dehydrodigalloyl linker unit characteristic of the agri-
moniin-type dimeric ellagitannins from galloyl-derived
orthoquinone precursors utilized hetero-Diels-Alder
dimerization to form the key C-O bond connection.
Simply warming orthoquinone 8 in refluxing benzene
afforded a complex mixture of three (out of a possible
four, 29a -d ) benzodioxene adducts (1H NMR) which
could be further processed by DBU treatment to furnish
the dehydrodigalloyl unit 30a in modest yield after acidic
workup (eq 4). No external reductant was added, and
the endogenous reducing agent has yet to be identified.
Unfortunately, compound sensitivity precluded isolation
and characterization of any pure species between 8 and
30a .
A survey of phenyl-metal species (PhLi, PhMgBr,
PhMgBr/CuI, PhMgBr/CeCl3) in combination with ortho-
quinones 8/11 revealed that the best yields of diaryl ether
products 26/27 attended the Grignard reagent with either
Cu or Ce additives. The assignment of regiochemistry
1
was based on H NMR analysis of the derived permethyl
ethers (see Experimental Section). Moderate regioselec-
tivity with the phenyl organometallics was observed for
the “meta” isomer 26 over the “para” alternative 27 as
might be desired for possible application to dehyrodigal-
loyl construction. Curiously, the presumably more hin-
dered 2,6-dimethoxyphenyl nucleophile (entry h) fur-
nished only the more crowded diaryl ether 27d , albeit in
very low yield. The regiochemical outcome of these
additions might be related to both the stabilities16 of the
putative precursor radical anions 28a and 28b and the
steric demands of bond formation, although the basis for
the unexpected “para” isomer selectivity in entry h
remains obscure. All attempts to add galloyl-derived
organometallics to orthoquinone 8 failed, thus eliminat-
ing this process from consideration as a dehydrodigalloyl
synthesis strategy.
Subsequent optimization studies led to significant
improvements in overall yield and revealed the likely
intervention of a Smiles rearrangement17 to favorably
adjust regiochemistry of the catechol product, Scheme 3.
A survey of Lewis acids/solvents/temperatures converged
18
on the use of B(OAc)3 in CHCl3 at 58 °C for optimum
yield of benzodioxene via [4π + 2π] dimerization of 8. The
intermediates derived from this procedure could be
1
detected by H NMR (∼2:1 of 29a and 29b, unassigned)
but could not be isolated as discrete compounds. Elimi-
nation of the â-phenoxide moieties in 29a /b with NaOAc/
HOAc furnished the isolable orthoquinones 31a /31b as
(14) Wanzlick, H.-W. Chem. Ber. 1959, 92, 3006.
(15) (a) Blomberg, C. Bull. Soc. Chim. Fr. 1972, 2143. (b) Blomberg,
C.; Grootveld, H. H.; Gerner, T. H.; Bickelhaupt, F. J . Organometal.
Chem. 1970, 24, 549-553. (c) Beak, P.; Yamamoto, J .; Upton, C. J . J .
Org. Chem. 1975, 40, 3052. (d) Wege, D. Aust. J . Chem. 1971, 24, 1531.
(16) Methyl gallate: pKa(1) ) 7.85, pKa(2) ) 10.0. Ackermann, G.;
Hesse, D.; Volland, P. Z. Anorg. Allg. Chem. 1970, 377, 92.
(17) (a) Yoshida, T.; Ahmed, A. H. F.; Memon, M. U.; Okuda, T.
Phytochemistry 1993, 33, 197. (b) Yoshida, T.; Maruyama, T.; Nitta,
A.; Okuda, T. Chem. Pharm. Bull. 1992, 40, 1750.

6660 J . Org. Chem., Vol. 61, No. 19, 1996
Feldman et al.
Sch em e 3
rent art (i.e., Ullmann coupling, ∼18%)19 for assembly of
the dehydrodigalloyl linker in usefully protected form.
Exposure of the orthoquinone 8 to either Cu(OAc)2‚H2O
or ZnBr2 produced an entirely different suite of dimeric
adducts (eq 6). Stoichiometric copper acetate mediation
afforded a moderate yield of the all-carbon Diels-Alder
adduct 34 isolated as its hydrate 35. The structural and
exo stereochemical assignment of 35 rests upon the
observation of two hemiketal carbons in the 13C NMR
spectrum (δ 96.9, 97.8) and a mass of 2 × 13 + 18, along
with all the other expected signals. Interestingly, stirring
a solution of orthoquinone 8 with B(OAc)3 at rt furnished
this same Diels-Alder adduct 35 admixed with the
hetero-[4π + 2π]-derived species 29a /b. Warming this
mixture to 58 °C promoted conversion of 35 into 29a /b,
suggesting that the all-carbon dimer might be kinetically
preferred, but the benzodioxene products are thermody-
namic minima. Treatment of 8 with ZnBr2 did not lead
to isolation of any [4π + 2π] addition products, but rather
the HHDP unit 36 was formed in small amounts. The
regiochemistry of 36 was assigned by a delayed H-1H
1
a 2:1 mixture (unassigned) in moderate overall yield from
8. Finally, reduction of this mixture with hydrosulfite
furnished the desired dehydrodigalloyl products 30a /32
as a 2:1 mixture of regioisomers, from which only a single
“meta” isomer 30a was deposited upon crystallization
from wet CH2Cl2 (see Experimental Section). Appar-
ently, Smiles rearrangement-mediated equilibration of
the catechol products during crystallization leads to an
enrichment in isomer 30a over the alternative 32. The
mother liquor, which was enriched in “para” isomer 32
(1H NMR), was evaporated and treated with K2CO3 in
acetone for 10 h at rt to furnish exclusively 30a . Neither
isolation of the intermediate orthoquinones 31a /b nor
eventual crystallization to obtain 30a is necessary, as
washing of the crude elimination products 31a /b with
hydrosulfite solution furnishes the dehydrodigalloyl prod-
ucts 30a /32 directly, while treatment of the ∼2:1 mixture
30a /32 with K2CO3/CH3I in acetone provides only the
single regioisomeric permethylated dehydrodigalloyl unit
30b in good yield.
COSY experiment which revealed the diagnostic five-
bond coupling response shown. The mechanistic subtle-
ties of this transformation, which include the mode of
C-C bond formation (nucleophilic coupling or [4π + 2π]
cycloaddition followed by fragmentation) and source of
reductant for any first-formed mono orthoquinone adduct,
remain obscure. Resubmission experiments showed that
tricycle 35 was not vulnerable to ZnBr2-mediated frag-
mentation.
The benzyl-protected orthoquinone 11 behaved simi-
larly with the important exception that the regioisomeric
benzylated diaryl ethers analogous to 30a /32 could not
be crystallized. However, benzylation of this crude diaryl
ether product mixture was accompanied again by com-
plete equilibration favoring the desired “meta” isomer 33
(eq 5). This regioisomeric preference may be related to
the greater stability of the para alkoxide over the meta
alternative (cf. 28a and 28b, with an aryl group instead
of an oxygen radical). The overall chemical yield of this
four-step sequence (44% from 11 to 33) and the complete
control of regiochemistry compares favorably with cur-
(19) Unpublished results, K. Sahasrabude, Pennsylvania State
University.
(18) The structure of the actual catalytic species in this heteroge-
neous mixture is unknown. Successful Diels-Alder dimerizations
accompanied use of either freshly prepared18a B(OAc)3 (mp 119 °C f
dec, lit. 120 °C) or boron pyroacetate, ((AcO)2B)2O,18b mp 141-146 °C
(lit. 145-147 °C). (a) Kelly, T. R.; Montury, M. Tetrahedon Lett. 1978,
4311. (b) Lalancette, J . M.; Bessette, F.; Cliche, J . M. Can. J . Chem.
1966, 44, 1577.

Galloyl-Derived Orthoquinones
J . Org. Chem., Vol. 61, No. 19, 1996 6661
and extensively washed with cold Et2O to afford 8 (1.48g, 76%)
as a bright yellow powdery solid, mp 122-124 °C (from Et2O-
CH2Cl2). IR (CHCl3) 1727, 1671 cm-1; 1H NMR (CDCl3) δ 3.86
(s, 3 H), 3.94 (s, 3 H), 6.49 (d, J ) 1.5 Hz, 1 H), 6.75 (d, J )
1.5 Hz, 1 H); 13C NMR (CDCl3) δ 179.9, 174.1, 164.8, 153.2,
141.3, 124.2, 106.3, 56.3, 53.4; EIMS m/ z (relative intensity)
196 (M+, 27). Anal. Calcd for C9H8O5: C, 55.11; H, 4.11.
Found: C, 54.71; H, 4.05.
In summary, these studies show that galloyl-derived
orthoquinones are accessible and tractable intermediates
in several biologically relevant bond-forming processes.
These reactive but selective electrophiles function as
expected in nucleophile capture experiments to furnish
good yields of conjugate addition products with thiols, but
are not effective traps for amines. This model work has
implications for the in vivo chemistry hypothesized to
underlie the antiviral activity of tannins against LdNPV.
Specifically, cysteinyl residues on the LdNPV envelope
proteins20 rather than lysyl or histidyl alternatives are
the likely loci for covalent modification by galloyl-derived
orthoquinoid electrophiles in the GM midgut. Experi-
ments to test this premise are ongoing. The successful
demonstration of dehydrodigalloyl preparation through
orthoquinone dimerization bears on both synthesis and
biosynthesis issues. This Diels-Alder-based strategy
provides the most reliable and efficient assembly of this
important ellagitannin linker unit to date and attests to
the feasibility of an operational in vivo orthoquinone
dimerization route for galloyl oxidative coupling in ella-
gitannin genesis.
Ben zyl Ga lla te (9). Benzyl alcohol (2.91 mL, 28.1 mmol),
Et3N (4.28 mL, 30.7 mmol), and DMAP (626 mg, 5.12 mmol)
were successively added to an ice-cold stirring solution of 3,4,5-
triacetoxybenzoyl chloride24 (8.04 g, 25.6 mmol) in dry CH2-
Cl2 (50 mL). The solution was maintained at 0 °C for 30 min
and then allowed to warm up to rt. Stirring was continued
for 4 h, after which time the reaction mixture was poured over
ice-cold H2O, extracted with CH2Cl2, washed several times
with 3% HCl and H2O, dried over Na2SO4, filtered, and
evaporated to give benzyl 3,4,5-triacetoxybenzoate (8.66 g,
88%) as a white solid, mp 106-107 °C (from CH2Cl2-light
1
petroleum). IR (CHCl3) 1769, 1725 cm-1; H NMR (CDCl3) δ
2.28 (s, 6 H), 2.29 (s, 3 H), 5.34 (s, 2 H), 7.32-7.42 (m, 5 H),
7.82 (s, 2 H); 13C NMR (CDCl3) δ 167.6, 166.3, 164.2, 143.4,
138.7, 135.4, 128.5, 128.4, 128.3, 128.2, 122.3, 67.3, 20.5, 20.1;
CIMS m/ z (relative intensity) 387 (MH+, 2), 91 (100). Anal.
Calcd for C20H18O8: C, 62.17; H, 4.70. Found: C, 61.88; H,
4.67.
Deacetylation was performed by treating a solution of benzyl
3,4,5-triacetoxybenzoate (5.42 g, 14.0 mmol) in MeOH-H2O-
CH2Cl2 (5:1:1, 140 mL) with powdered K2CO3 (19.00 g, 137.5
mmol) at 0 °C with vigorous stirring. After formation of a
beige creamy precipitate, the reaction mixture was allowed to
warm up to rt. Stirring was continued for 1 h, after which
time the reaction mixture was cautiously acidified with concd
HCl (20 mL), diluted with EtOAc (100 mL), washed with brine,
dried over Na2SO4, filtered, and evaporated. The resulting oily
residue was purified by column chromatography, eluting with
EtOAc-light petroleum (1:1), to give benzyl gallate (9) (3.05
g, 84%) as a beige solid, which was crystallized from Et2O-
light petroleum to furnish small off-white needles, mp 148 °C.
IR (KBr) 1693 cm-1; 1H NMR (CD3COCD3) δ 5.27 (s, 2 H), 7.15
(s, 2 H), 7.30-7.47 (m, 5 H), 8.15 (bs, 3 H); 13C NMR (CD3-
COCD3) δ 166.5, 146.0, 138.9, 137.7, 129.3, 128.8, 121.6, 109.9,
66.6; CIMS m/ z (relative intensity) 261 (MH+, 36), 91 (100).
Anal. Calcd for C14H12O5: C, 64.61; H, 4.65. Found: C, 64.55;
H, 4.76.
Exp er im en ta l Section
Melting points are uncorrected. Evaporations were con-
ducted under reduced pressure at temperatures less than 45
°C unless otherwise noted. Further elimination of organic
solvents, as well as drying of residues, was accomplished under
high vacuum. Column chromatography was carried out with
32-63 µm silica gel, and preparative thin layer chromatog-
raphy was performed on silica gel 60 F-254 precoated plates
(E. Merck). Solvents for chromatography (Et2O, EtOAc, CH2-
Cl2, hexane) were distilled from CaH2 prior to use. Light
petroleum refers to the fraction boiling in the 40-60 °C range.
Tetrahydrofuran (THF) was purified by distillation from
sodium/benzophenone under N2 immediately before use. Mois-
ture and oxygen sensitive reactions were carried out in flame-
dried glassware under Ar. One- and two-dimensional NMR
spectra of samples in the indicated solvent were run at 300 or
500 MHz (1H). Diagnostic correlation information was ob-
tained with inverse-detected long-range 1H-13C correlative
HMBC experiments21a and delayed 1H-1H correlative
experiments21b using a fixed delay of 250 ms. NOE informa-
tion was obtained with a Hahn-echo NOESY experiment,22
using a mixing time of 1s and a relaxation delay of 4 s. Low
and high resolution mass spectra (EIMS, HRMS) were ob-
tained at 50-70 eV by electron impact. Chemical impact mass
spectra (CIMS) were obtained with isobutane as the reagent
gas, and positive fast atom bombardment mass spectra
(FABMS) were obtained in a 2-nitrophenyl octyl ether matrix.
Combustion analyses were performed by Midwest Microlab,
Ben zyl 3-O-Ben zylga lla te (10). Powdered K2CO3 (10.15
g, 73.5 mmol) and dichlorodiphenylmethane (7.05 mL, 36.7
mmol) were successively added to a solution of benzyl gallate
(8.69 g, 33.4 mmol) in CH3CN (20 mL). This mixture was
stirred at room temperature for 10 h, after which time it was
cautiously poured over ice-cold 3% HCl, extracted with Et2O,
washed with brine, dried over Na2SO4, filtered, and evaporated
to furnish an amber oil. This crude residue was submitted to
column chromatography, eluting with hexane-Et2O (3:1), to
give 12.11 g of a golden foam. This material (3.99 g, 9.41
mmol) was treated with benzyl chloride (1.35 mL, 11.7 mmol),
powdered K2CO3 (1.95 g, 14.1 mmol), and KI (312 mg, 1.88
mmol) in refluxing acetone for 10 h. After cooling to rt, the
reaction mixture was filtered and evaporated to an oily residue.
This residue was dissolved in Et2O, washed sequentially with
H2O, saturated aqueous NaHCO3 and then brine, dried over
Na2SO4, filtered, and evaporated. The resulting crude product
was purified by column chromatography, eluting with light
petroleum-Et2O (2:1), to give the diphenyl ketal of benzyl 3-O-
benzyl gallate (4.01 g, 83%) as a yellow oil which solidified
Indianapolis, IN, or Galbraith Laboratories, Knoxville, TN. 13
NMR spectra are provided in the supporting information to
establish purity for those compounds which were not subject
to combustion analyses.
Meth yl 3-Meth oxy-1,2-d ioxocycloh exa -3,5-d ien e-5-ca r -
boxyla te (8). Methyl 3-O-methylgallate (7) (1.96 g, 9.9 mmol),
prepared from methyl gallate according to the method of
Scheline,23 was dissolved in dry Et2O (100 mL) and added
dropwise over 4 h via a dropping funnel to a stirring solution
of orthochloranil (2.68 g, 10.9 mmol, recrystallized from
benzene) in dry Et2O (50 mL) at -30 °C. The reaction mixture
was kept stirring at -30 °C for 2 h and then stored at -20 °C
for 10 h. The orange precipitate was collected by filtration
C
upon standing, mp 107-109 °C. IR (CHCl3) 1710 cm-1 1H
;
NMR (CDCl3) δ 5.22 (s, 2 H), 5.28 (s, 2 H), 7.30-7.41 (m, 18
H), 7.54-7.57 (m, 4 H); 13C NMR (CDCl3) δ 165.6, 148.4, 142.0,
139.8, 139.5, 136.5, 136.1, 129.3, 128.5, 128.3, 128.14, 128.10,
128.0, 127.6, 126.3, 124.2, 118.5, 112.9, 104.2, 71.7, 66.6; CIMS
m/ z (relative intensity) 515 (MH+, 10), 91 (100); HRMS calcd
for C34H26O5 514.1780, found 514.1780.
(20) (a) Stiles, B.; Burand, J . P.; Meda, M.; Wood, H. A. Appl.
Environ. Microbiol. 1983, 297. (b) Smith, I. R. L.; van Beek, N. A. M.;
Podgwaite, J . D.; Wood, H. A. Gene 1988, 97.
This ketal (3.95 g, 7.7 mmol) was suspended in 80% aqueous
AcOH (100 mL) and heated to reflux for 6 h, after which time
the reaction mixture was cooled down to rt, and then parti-
(21) (a) Bax, A.; Summers, M. F. J . Am. Chem. Soc. 1986, 108, 2093.
(b) Bax, A.; Freeman, R. J . Magn. Reson. 1981, 44, 542.
(22) (a) Bodenhausen, G.; Kogler, H.; Ernst, R. R. J . Magn. Reson.
1984, 58, 370. (b) Davis, D. G. J . Magn. Reson. 1989, 81, 603.
(23) (a) Scheline, R. R. Acta Chem. Scand. 1966, 20, 1182. (b) J urd,
L. J . Am. Chem. Soc. 1959, 81, 4606.
(24) Eisenhauer, H. R.; Link, K. P. J . Am. Chem. Soc. 1953, 75, 2046.

6662 J . Org. Chem., Vol. 61, No. 19, 1996
Feldman et al.
tioned between EtOAc and brine. The organic layer was dried
over Na2SO4, filtered, and evaporated. The resulting brownish
oil was purified by column chromatography, eluting with light
petroleum-EtOAc (3:1), to give 10 (2.49 g, 93%) as amber
crystals, mp 92-94 °C (from Et2O-light petroleum). IR
(CHCl3) 1710 cm-1; 1H NMR (CDCl3) δ 5.11 (s, 2 H), 5.31 (s, 2
H), 5.44 (bs, 1 H), 5.91 (bs, 1 H), 7.33-7.43 (m, 12 H); 13C NMR
(CDCl3) δ 166.2, 145.7, 143.6, 137.3, 136.1, 135.8, 128.7, 128.5,
128.1, 128.0, 121.7, 111.3, 106.4, 71.5, 66.7; CIMS m/ z (relative
intensity) 351 (MH+, 18), 91 (100). Anal. Calcd for C21H18O5:
C, 71.99; H, 5.18. Found: C, 72.55; H, 5.18.
Ben zyl 3-(Ben zyloxy)-1,2-d ioxocycloh exa -3,5-d ien e-5-
ca r boxyla te (11). Prepared from 10 (1.8-3.2 mmolar scale)
in 81-87% as described for 8, burgundy red solid, mp 136-
137 °C. IR (CHCl3) 1724, 1671 cm-1; 1H NMR (CDCl3) δ 5.06
(s, 2 H), 5.31 (s, 2 H), 6.56 (d, J ) 1.5 Hz, 1 H), 6.76 (d, J )
1.5 Hz, 1 H), 7.36-7.41 (m, 10 H); 13C NMR (CDCl3) δ 179.9,
174.2, 164.1, 152.1, 141.4, 134.5, 134.3, 128.9, 128.82, 128.78,
128.7, 128.4, 127.7, 124.4, 107.8, 71.1, 68.3; EIMS m/ z (relative
intensity) 350 ([M + 2]+, 90), 271 (15), 91 (100). Anal. Calcd
for C21H16O5: C, 72.41; H, 4.63. Found: C, 72.06; H, 4.61.
(50 mg, 0.41 mmol)26 were then added to this suspension at 0
°C. This reaction mixture was allowed to warm up to rt and
gently stirred overnight. After filtration through Celite, the
filtrate was successively washed with 1 M H3PO4 and water,
dried over Na2SO4, filtered, and evaporated. The residue was
submitted to column chromatography, eluting with light
petroleum-EtOAc (2:1), to furnish crude N,N′-bis(carboben-
zyloxy)cystine dibenzyl ester which was crystallized from
EtOH as white spherulites (1.18 g, 87%), mp 78 °C (lit.27 mp
79 °C). IR (CHCl3) 3429, 1720, 1506, 1339 cm-1 1H NMR
;
(CDCl3) δ 3.10 (m, 4 H), 4.60-4.70 (m, 2 H) 5.08 (s, 4 H), 5.14
(s, 4), 5.73 (d, J ) 7.7 Hz, 2 H), 7.28-7.36 (m, 20 H); 13C NMR
(CDCl3) δ 170.1, 155.6, 136.0, 134.8, 128.6, 128.51, 128.45,
128.4, 128.2, 128.1, 67.6, 67.1, 53.4, 40.9; EIMS m/ z (relative
intensity) 688 (MH+, 0.1), 91 (100).
The reduction of N,N′-bis(carbobenzyloxy)cystine dibenzyl
ester to white crystalline N-(carbobenzyloxy)cysteine was
accomplished at rt with Zn dust in 80% aqueous AcOH28 (97%),
1
mp 66 °C. IR (CHCl3) 3428, 1720 cm-1; H NMR (CDCl3) δ
1.28 (s, 1 H), 2.97 (m, 1 H), 4.67-4.72 (m, 1 H), 5.10 (s, 2 H),
5.13-5.24 (AB quartet, 2 H), 5.77 (bd, J ) 7.3 Hz, 1 H), 7.29-
7.34 (m, 10 H); 13C NMR (CDCl3) δ 169.8, 155.6, 135.9, 134.9,
128.58, 128.55, 128.5, 128.4, 128.2, 128.0, 67.5, 67.1, 55.2, 27.1;
EIMS m/ z (relative intensity) 345 (MH+, 0.5), 91 (100); HRMS
calcd for C18H19O4NS 345.1035, found 345.1061.
Meth yl 3,4-Dih yd r oxy-5-m eth oxy-2-(p h en ylth io)ben -
zoa te (12). The orthoquinone 8 (50 mg, 0.26 mmol) was
dissolved in dry THF (3 mL) and added via a syringe pump at
rt over 4 h to a stirring solution of thiophenol (28 µL, 0.27
mmol) in dry THF (2 mL). The dark red color of the
orthoquinone solution immediately discharged upon addition.
The reaction mixture was kept stirring at rt for 2 h and then
poured over saturated aqueous Na2S2O3, extracted with Et2O,
washed with brine, dried over Na2SO4, filtered, and evapo-
rated. The resulting oil was purified by column chromatog-
raphy, eluting with CH2Cl2, to give 12 (36 mg, 47%) as a pale
5-(Ben zyloxy)-2-(N-ca r boben zyloxy-S-cystein yl)-3,4-d i-
h yd r oxyben zoic Acid Diben zyl Ester (16). The ortho-
quinone 11 (83 mg, 0.24 mmol) was dissolved in dry THF (4
mL) and added via syringe pump at rt over 4 h to a stirring
solution of the cysteine derivative 14b (165 mg, 0.48 mmol)
in dry THF (4 mL). Discharge of the dark red color of the
orthoquinone solution was observed. Evaporation of the
solvent afforded a pale yellow residue. Purification of this
residue by column chromatography, eluting with light petro-
leum-EtOAc (2:1), furnished 16 (52 mg, 31%) as an oil. IR
(CHCl3) 3693, 3534, 1718 cm-1; 1H NMR (CDCl3) δ 3.17 (dd, J
) 14.0, 6.6 Hz, 1 H), 3.28 (dd, J ) 14.0, 4.1 Hz, 1 H), 4.54 (m,
1 H), 4.94-5.14 (m, 6 H), 5.28 (s, 2 H), 5.94 (bd, J ) 7.6 Hz,
1 H), 7.15 (s, 1 H), 7.25-7.40 (m, 20 H); 13C NMR (CDCl3) δ
170.1, 166.0, 156.1, 146.4, 146.2, 136.9, 136.0, 135.8, 135.7,
134.8, 128.7, 128.55, 128.48, 128.45, 128.4, 128.32, 128.28,
128.1, 128.0, 127.7, 126.4, 112.0, 108.8, 71.3, 67.6, 67.12, 67.09,
54.2, 39.6; EIMS m/ z (relative intensity) 693 (MH+, 0.8), 91
(100); HRMS (FAB) calcd for C39H35O9NS 694.2111, found
694.2106.
yellow amorphous solid. IR (CHCl3) 1724 cm-1 1H NMR
;
(CDCl3) δ 3.79 (s, 3 H), 3.98 (s, 3 H), 6.97 (s, 1 H), 7.06-7.26
(m, 5 H); 13C NMR (90 MHz, CDCl3) δ 166.7, 148.0, 145.6,
136.2, 135.9, 129.1, 127.5, 126.8, 126.1, 109.9, 106.8, 56.4, 52.2;
EIMS m/ z (relative intensity) 306 (M+, 100). Anal. Calcd for
C15H14O5S: C, 58.81; H, 4.61; S, 10.47. Found: C, 58.69; H,
4.69; S, 10.54.
Ben zyl 5-(Ben zyloxy)-3,4-d ih yd r oxy-2-(p h en ylt h io)-
ben zoa te (13). Prepared from 11 (50 mg, 0.14 mmol) in 69%
as described for 12, yellow amorphous solid. IR (CHCl3) 1716
cm-1; 1H NMR (CDCl3) δ 5.17 (s, 2 H), 5.22 (s, 2 H), 7.00-7.42
(m, 16 H); 13C NMR (CDCl3) δ 166.1, 147.1, 145.8, 136.6, 135.8,
135.6, 135.5, 129.0, 128.8, 128.6, 128.4, 128.2, 128.1, 127.9,
127.4, 126.5, 125.9, 109.9, 108.4, 71.4, 67.1; CIMS m/ z (relative
intensity) 459 (MH+, 15), 91 (100). Anal. Calcd for
C27H22O5S: C, 70.72; H, 4.84; S, 7.00. Found: C, 70.59; H,
5.10; S, 6.93.
Meth yl 2-(S-Cystein yl)-3,4-d ih yd r oxy-5-m eth oxyben -
zoa te (15). The orthoquinone 8 (100 mg, 0.51 mmol) was
dissolved in dry THF (10 mL) and added via a syringe pump
at rt over 4 h to a stirring solution of cysteine (60 mg, 0.50
mmol, 0.98 equiv) in H2O-THF (2:1, 5 mL). The solution was
then diluted in CHCl3 (10 mL) and extracted twice with H2O
(3 mL). Lyophilization of the aqueous layer afforded crude
15 as a pink solid which was purified by trituration with
acetone:H2O (9:1) to give 15 (105 mg, 67%) as a white solid,
mp 194-196 °C. IR (KBr) 1684 cm-1; 1H NMR [CD3COCD3-
2 M DCl, (9:1)] δ 3.41 (dd, J ) 14.6, 8.7 Hz, 1 H), 3.64 (dd, J
) 14.6, 4.2 Hz, 1 H), 3.84 (s, 3 H), 3.85 (s, 3 H), 4.11 (dd, J )
8.7, 4.2 Hz, 1 H), 6.96 (s, 1 H); 13C NMR [CD3COCD3-2 M
DCl, (9:1)] δ 169.4, 169.3, 149.4, 148.6, 137.9, 128.2, 109.5,
106.7, 56.5, 52.94, 52.86, 35.45; FABMS m/ z (relative inten-
sity) 318 (MH+, 100), 286 (20). Anal. Calcd for C12H15O7NS:
C, 45.42; H, 4.77; N, 4.41; S, 10.10. Found: C, 45.02; H, 4.83;
N, 4.53; S, 10.09.
Ben zyl 5-(Ben zyloxy)-2-(S-cyst ein yl)-3,4-d ih yd r oxy-
ben zoa te (17). The orthoquinone 11 (64 mg, 0.18 mmol) was
dissolved in dry THF (3 mL) and added via syringe pump at
rt over 4 h to a stirring solution of cysteine (21 mg, 0.17 mmol)
in H2O-THF (2:1, 2 mL). Discharge of the dark red color of
the orthoquinone solution was observed. After 1 h, the
reaction mixture was pale yellow and a white precipitate
started to form. After completion of addition, the precipitate
was collected by filtration and washed with EtOAc to give 43
mg of 17. The filtrate and washings were extracted with H2O,
and the aqueous layer was lyophilized to give an additional
8.5 mg of 17 (62%) as a white solid, mp 184-186 °C. IR (KBr)
1
1723 cm-1; H NMR [CD3COCD3-2 M DCl, (9:1)] δ 3.30 (dd,
J ) 14.7, 9.0 Hz, 1 H), 3.56 (dd, J ) 14.7, 4.1 Hz, 1 H), 4.06
(dd, J ) 9.0, 4.1 Hz, 1 H), 5.15 (s, 2 H), 5.27 (s, 2 H), 7.01 (bs,
1 H), 7.24-7.42 (m, 10 H); 13C NMR [CD3COCD3-2 M DCl,
(9:1)] δ 169.3, 168.2, 148.9, 148.00, 138.3, 137.2, 136.5, 129.2,
129.1, 128.9, 128.8, 128.6, 128.3, 127.8, 109.8, 108.5, 71.1, 67.6,
52.8, 35.7; FABMS m/ z (relative intensity) 470 (MH+, 100);
HRMS (FAB) calcd for C24H23O7NS 470.1273, found 470.1268.
2-(S-Cystein yl)-3,4,5-tr ih yd r oxyben zoic Acid (18). De-
benzylation of 17 (70 mg, 0.15 mmol) in THF-H2O (1:1, 4 mL)
was accomplished by using Pd black (20 mg) under H2
(balloon). A catalytic amount of AcOH was added, and the
mixture was stirred for 4 h at rt. The Pd black was filtered
off, and THF was removed by evaporation at rt. Lyophilization
N-(Ca r boben zyloxy)cystein e Ben zyl Ester (14b). Ben-
zyl alcohol (533 mg, 4.93 mmol) was added to a suspension of
N,N′-bis(carbobenzyloxy)cystine (1.00 g, 1.97 mmol, prepared
in 87% yield from cystine according to the method of Du
Vigneau and Miller)25 in CH2Cl2 (40 mL). Dicyclohexylcarbo-
diimide (854 mg, 4.14 mmol) and 4-(dimethylamino)pyridine
(26) Neises, B.; Andries, T.; Steglich, W. J . Chem. Soc., Chem.
Commun. 1982, 1132.
(27) Zervas, L.; Photaki, I. J . Am. Chem. Soc. 1962, 84, 3887.
(28) Shields, J . E.; Campbell, C. S.; Queener, S. W.; Duckworth, D.
C.; Neuss, N. Helv. Chim. Acta 1984, 67, 870.
(25) (a) Du Vigneau, V.; Miller, G. L. Biochem Prep. 1952, 2, 74. (b)
Ranganathan, S.; J ayaraman, N.; Roy, R. Tetrahedron 1992, 48, 931.

Galloyl-Derived Orthoquinones
J . Org. Chem., Vol. 61, No. 19, 1996 6663
of the aqueous residue afforded 42 mg of 18 (quantitative
yield), mp 164-166 °C dec. IR (KBr) 1654 cm-1; 1H NMR [CD3-
COCD3-2 M DCl, (9:1)] δ 3.26 (dd, J ) 14.7, 9.3 Hz, 1 H),
3.59 (dd, J ) 14.7, 4.0 Hz, 1 H), 4.00 (dd, J ) 9.3, 4.0 Hz, 1
H), 6.93 (s, 1 H); 13C NMR [CD3COCD3-2 M DCl, (9:1)] δ 170.7,
169.6, 149.1, 147.0, 136.8, 128.4, 110.8, 106.9, 52.6, 35.2;
FABMS m/ z (relative intensity) 290 (MH+, 20), 245 (100);
HRMS (FAB) calcd for C10H11O7NS 290.0334, found 290.0333.
Ben zyl 5-An ilin o-3-(ben zyloxy)-4-h ydr oxyben zoate (20).
The orthoquinone 11 (60 mg, 0.14 mmol) was dissolved in dry
THF (3 mL) and added via syringe pump at rt over 3 h to an
ice-cold stirring solution of aniline (20 µL, 0.22 mmol, 1.57
equiv) in dry THF (2 mL). No color discharge was observed.
Stirring was continued for 3 h, after which time the mixture
was evaporated at rt to give a brownish oil. Purification of
this residue was performed by preparative TLC, eluting with
hexane-Et2O (2:1), to give 20 (12.4 mg, 17%) as a brown solid,
mp 130-132 °C (from CHCl3). IR (CHCl3) 1709 cm-1; 1H NMR
(CDCl3) δ 5.16 (s, 2 H), 5.32 (s, 2 H), 5.96 (bs, 1 H), 6.02 (bs,
1 H), 6.97 (bt, J ) 7.3 Hz, 1 H), 7.13 (bd, J ) 8.7Hz, 1 H),
7.27-7.45 (m, 13 H), 7.77 (d, J ) 1.8 Hz, 1 H); 13C NMR
(CDCl3) δ 166.3, 145.4, 142.3, 139.0, 136.3, 136.0, 131.0, 129.4,
128.8, 128.6, 128.5, 128.09, 128.06, 127.9, 121.6, 118.5, 111.6,
106.1, 71.6, 66.4; EIMS m/ z (relative intensity) 425 (M+, 33),
334 (40), 91 (100); HRMS calcd for C27H23O4N 425.1627, found
425.1613.
P r oced u r e B. CuI (5 mg) was added to a solution of 8 or
11 (0.03-0.05 M in THF, 1.0 equiv) cooled at -78 °C or -90
°C. The mixture was stirred for 30 min, and the Grignard
reagent solution (PhMgBr, 3.0 M in Et2O, 2.0 equiv, or
2-MeOPhMgBr, 0.2 M in THF, 2.0 equiv) was added dropwise.
The mixture was then allowed to react and worked-up as
described in procedure A.
P r oced u r e C. Anhydrous CeCl3 (2.0 equiv) was suspended
in dry THF (2.5 mL). The suspension was vigorously stirred
overnight at rt and then cooled down to -78 °C or -90 °C. A
solution of the o-quinone 11 (0.05 M in THF, 1.0 equiv) was
then added, and the mixture was stirred for 30 min, after
which time the Grignard reagent solution (PhMgBr, 3.0 M in
Et2O, 2.0 equiv, or 2-MeOPhMgBr, 0.2 M in THF, 2.0 equiv)
was added dropwise. The mixture was then allowed to react
and worked-up as described in procedure A.
Dia r yl Eth er s 26a a n d 27a . By following general proce-
dures A, B, or C, orthoquinone 8 and PhMgBr were combined
to afford an oily brown residue. Purification of this crude
product by column chromatography, eluting with light petro-
leum-Et2O (3:1), led to 26a and 27a as white solids.
26a : mp 83-85 °C; IR (CHCl3) 1704 cm-1; 1H NMR (CDCl3)
δ 3.84 (s, 3 H), 3.97 (s, 3 H), 6.05 (bs, 1 H), 7.00 (bd, J ) 8.6
Hz, 2 H), 7.09 (bt, J ) 7.6 Hz, 1 H), 7.32 (bt, J ) 8.0 Hz, 2 H),
7.35 (d, J ) 1.7 Hz, 1 H), 7.42 (d, J ) 1.7 Hz, 1 H); 13C NMR
(CDCl3) δ 166.4, 156.9, 147.6, 142.8, 141.8, 129.7, 123.3, 121.5,
117.6, 115.1, 108.2, 56.4, 52.1; CIMS m/ z (relative intensity)
275 (MH+, 100). Anal. Calcd for C15H14O5: C, 65.69; H, 5.14.
Found: C, 65.66; H, 5.29.
Nr-(Ca r boben zyloxy)h istid in e Ben zyl Ester (21). NR-
(Carbobenzyloxy)histidine (735 mg, 2.54 mmol, Aldrich) was
converted to its benzyl ester derivative as described for N,N′-
bis(carbobenzyloxy)cystine dibenzyl ester. After filtration
through Celite, the filtrate was washed with saturated NaH-
CO3, dried over Na2SO4, filtered, and evaporated. The residue
was submitted to column chromatography, eluting with CH2-
Cl2-MeOH (20:1), to furnish 2129 as a white foam (604 mg,
27a : mp 150-152 °C; IR (CHCl3) 1718 cm-1 1H NMR
;
(CDCl3) δ 3.76 (s, 3 H), 3.91 (s, 3 H), 5.75 (bs, 1 H), 6.89 (bd,
J ) 7.9 Hz, 2 H), 7.05 (bt, J ) 7.3 Hz, 1 H), 7.26 (d, J ) 1.8
Hz, 1 H), 7.28 (bt, J ) 7.6 Hz, 2 H), 7.41 (d, J ) 1.8 Hz, 1 H);
13C NMR (CDCl3) δ 166.5, 157.1, 152.4, 149.6, 134.1, 129.6,
127.6, 122.8, 115.0, 110.6, 105.7, 56.2, 52.3; CIMS m/ z (relative
intensity) 275 (MH+, 100). Anal. Calcd for C15H14O5: C, 65.69;
H, 5.14. Found: C, 65.94; H, 5.38.
1
63%). IR (CHCl3) 3463, 1719 cm-1; H NMR (CDCl3) δ 3.10
(m, 2 H), 4.65 (m, 1 H), 5.03-5.19 (m, 2 H), 5.10 (s, 2 H), 6.26
(bd J ) 6.6 Hz, 1 H), 6.56 (s, 1 H), 7.26-7.43 (m, 10 H), 7.48
(s, 1 H); 13C NMR (CDCl3) δ 171.6, 156.2, 136.2, 135.3, 135.2,
133.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 115.8, 66.9, 66.8,
54.1, 29.3; EIMS m/ z (relative intensity) 379 (M+, 10.9), 91
(100); HRMS calcd for C21H21O4N3 379.1532, found 379.1540.
Nτ-[4-(Ben zyloxy)-6-(car boben zyloxy)-2,3-dih ydr oxyph e-
n yl]-Nr-(ca r b ob en zyloxy)h ist id in e Ben zyl E st er (22).
Orthoquinone 8 (100 mg, 0.29 mmol) was dissolved in dry THF
(5 mL) and added via syringe pump at rt over 20 h to a stirring
solution of the histidine derivative 21 (272 mg, 0.72 mmol) in
dry THF (10 mL). Evaporation of the solvent afforded a
Dia r yl Eth er s 26b a n d 27b. By following general proce-
dure A, orthoquinone 11 and PhMgBr were combined to afford
an oily brown residue. Purification of this crude product by
preparative TLC, eluting with CH2Cl2, led to 26b and 27b as
amorphous solids. The regiochemistry of addition was deter-
mined by comparison of the 13C NMR spectra of 26b and 27b
with those of 26a and 27a .
26b: IR (CHCl3) 1710 cm-1 1H NMR (CDCl3) δ 5.18 (s, 2
;
H), 5.27 (s, 2 H), 6.02 (s, 1 H), 6.97 (dt, J ) 7.7, 1.6 Hz, 2 H),
7.08 (bt, J ) 7.4 Hz, 1 H), 7.28-7.45 (m, 13 H), 7.54 (d, J )
1.8 Hz, 1 H); 13C NMR (CDCl3) δ 165.6, 157.0, 146.7, 142.9,
142.5, 136.0, 135.7, 129.7, 128.7, 128.5, 128.2, 128.0, 127.9,
123.2, 121.5, 117.3, 115.9, 110.0, 71.7, 66.6; EIMS m/ z (relative
intensity) 426 (M+, 3.7). Anal. Calcd for C27H22O5: C, 76.04;
H, 5.20. Found: C, 76.09; H, 5.38.
reddish residue which was dissolved in CH2Cl2 (3 mL).
A
precipitate of unidentified material formed upon standing
overnight at rt. Filtration and purification of the mother liquor
by preparative TLC, eluting three times with CH2Cl2-MeOH
(20:1), furnished 22 (33 mg, 16%) as an oil. IR (CHCl3) 3385,
1
1718 cm-1; H NMR [CD3COCD3-CD3SOCD3, (9:1)] δ 2.96-
27b: IR (CHCl3) 1714 cm-1 1H NMR (CDCl3) δ 5.00 (s, 2
;
3.11 (m, signal overlapping with water signal), 4.53-4.59 (m,
1 H), 4.94-5.20 (m, 6 H), 5.25 (s, 2 H), 6.71 (s, 1 H), 7.18 (s, 1
H), 7.21-7.40 (m, 22 H), 7.52 (s, 1 H), 7.54 (s, 1 H); 13C NMR
[CD3COCD3-CD3SOCD3, (9:1)] δ 172.3, 165.6, 156.8, 147.2,
143.9, 140.3, 138.0, 137.7, 137.1, 136.9, 129.14, 129.07, 129.02,
129.00, 128.9, 128.8, 128.61, 128.58, 128.5, 120.4, 120.2, 119.4,
107.6, 71.4, 67.0, 66.9, 66.6, 55.1, ? ; FABMS m/ z (relative
intensity) 728 (MH+, 100); HRMS (FAB) calcd for C42H21O9N3
728.2608, found 728.2607.
H), 5.35 (s, 2 H), 5.70 (s, 1 H), 6.92-7.45 (m, 16 H), 7.47 (d, J
) 1.8 Hz, 1 H); 13C NMR (CDCl3) δ 165.7, 157.3, 151.0, 149.7,
136.0, 135.9, 134.9, 129.6, 128.6, 128.3, 128.2, 127.8, 127.3,
126.9, 123.0, 115.9, 110.8, 107.3, 70.5, 66.9; EIMS m/ z (relative
intensity) 426 (M+, 34). Anal. Calcd for C27H22O5: C, 76.04;
H, 5.20. Found: C, 75.76; H, 5.59.
Dia r yl Eth er s 26c a n d 27c. By following general proce-
dures B or C, orthoquinone 8 and 2-MeOPhMgBr were
combined to afford an oily brown residue. Purification of this
crude product by preparative TLC, eluting with light petro-
leum-Et2O (3:1), led to 26c and 27c as yellow oils.
Dia r yl E t h er s via Oxop h ilic Ad d it ion t o Qu in on oid
Ca r bon yls: P r oced u r e A. A solution of PhMgBr (3.0 M in
Et2O, 2.0 equiv) was added dropwise to a stirring solution of
orthoquinone 8 or 11 (0.03-0.05 M in THF, 1.0 equiv) at the
indicated temperature. The burgundy color of the quinone
solution became light brown upon addition of the Grignard
reagent. The reaction mixture was maintained at the indi-
cated temperature and then allowed to warm up to 0 °C over
ca. 2 h (for the low temperature runs), after which time it
was poured over ice-cold saturated NH4Cl, extracted with
Et2O, washed with brine, dried over Na2SO4, filtered, and
evaporated to give the crude diaryl ethers as oily residues.
26c: IR (CHCl3) 1714 cm-1 1H NMR (CDCl3) δ 3.83 (s, 3
;
H), 3.86 (s, 3 H), 3.97 (s, 3 H), 6.45 (bs, 1 H), 6.89-7.17 (m, 4
H), 7.28 (d, J ) 1.8 Hz, 1 H), 7.39 (d, J ) 1.8 Hz, 1 H); 13C
NMR (CDCl3) δ 166.5, 150.7, 147.5, 145.2, 144.5, 141.2, 125.1,
121.2, 120.4, 113.4, 112.7, 108.1, 56.4, 55.9, 52.0; CIMS m/ z
(relative intensity) 305 (MH+, 100), 273 (38); HRMS calcd for
C16H16O6 304.0947, found 304.0925.
27c: IR (CHCl3) 1716 cm-1 1H NMR (CDCl3) δ 3.85 (s, 3
;
H), 3.90 (s, 3 H), 3.94 (s, 3 H), 6.81-7.08 (m, 4 H), 7.23 (d, J
) 1.9 Hz, 1 H), 7.35 (d, J ) 1.9 Hz, 1 H); 13C NMR (CDCl3) δ
166.5, 152.6, 150.0, 149.3, 146.7, 136.4, 127.4, 124.1, 121.3,
117.7, 112.4, 110.8, 105.4, 56.2, 56.1, 52.2; CIMS m/ z (relative
(29) J a¨ger, G.; Geiger, R.; Siedel, W. Chem. Ber. 1968, 101, 3537.
(30) Mayer, W. Liebigs Ann. Chem. 1952, 578, 34.

6664 J . Org. Chem., Vol. 61, No. 19, 1996
Feldman et al.
intensity) 305 (MH+, 100), 273 (8); HRMS calcd for C16H16O6
304.0947, found 304.0949.
ppm, 7.74/7.40 ppm and 7.80/7.31 ppm, and three sets of two
singlets resonating at 5.60/4.87 ppm, 5.57/5.00 ppm, and 6.97/
5.23 ppm. The reaction mixture was then cooled to rt and
directly treated with DBU (60 µL, 0.40 mmol) for 1 h, after
which time it was poured over ice-cold 3% HCl, extracted with
CH2Cl2, washed with water, dried over Na2SO4, filtered, and
evaporated. The resulting yellow oil was submitted to column
chromatography, eluting with CH2Cl2-MeOH (20:1), to furnish
30a (10 mg, 20%) as the sole regioisomer. Methylation of 30a
with CH3I/K2CO3 in acetone afforded 30b in quantitative yield.
Dia r yl Eth er 27d . 2,6-Dimethoxybromobenzene (166 mg,
0.76 mmol) and Mg turnings (46 mg, 1.89 mmol) were
suspended in dry THF (5 mL) and heated to reflux. A solution
of 1,2-dibromoethane (98 µL, 1.1 mmol) in dry THF (2 mL)
was added dropwise over 2 h to the refluxing reaction mixture.
After cooling down to rt, the resulting pale yellow Grignard
solution was added over 15 min to a -90 °C solution of the
orthoquinone 8 (100 mg, 0.51 mmol) in dry THF (10 mL)
containing 15 mg of CuI. The reaction mixture was main-
tained at -90 °C for 1 h and then allowed to warm up to rt
over 3 h. At that time it was worked-up as described in
procedure A. The resulting oily residue was purified by
preparative TLC, eluting with light petroleum-Et2O (3:1), to
afford 27d (15 mg, 9%) as the sole regioisomer. IR (CHCl3)
1716 cm-1; 1H NMR (CDCl3) δ 3.70 (s, 3 H), 3.80 (s, 6 H), 3.88
(s, 3 H), 6.39 (s, 1 H), 6.60 (d, J ) 8.4 Hz, 2 H), 7.05 (t, J ) 8.4
Hz, 1 H), 7.14 (d, J ) 2.0 Hz, 1 H), 7.32 (d, J ) 2.0 Hz, 1 H);
13C NMR (CDCl3) δ 166.8, 152.3, 151.5, 149.0, 139.0, 135.7,
125.6, 124.4, 110.5, 106.0, 105.4, 56.5, 56.4, 52.1; CIMS m/ z
(relative intensity) 335 (MH+, 100), 303 (15); HRMS calcd for
C17H18O7 334.1052, found 334.1028.
P r oced u r e E. The orthoquinone 8 (85 mg, 0.43 mmol) was
dissolved in CDCl3 (4 mL). B(OAc)3 (81 mg, 0.43 mmol) was
added, and the resulting heterogeneous mixture was heated
1
at 58 °C (oil bath temperature) for 20 h, after which time H
NMR analysis indicated complete conversion of 8 into a 2:1
mixture of tentatively assigned 1,4-dioxenes 29a /b. Diagnostic
1H NMR (CDCl3) signals included two sets of two singlets
resonating at 5.60/6.23 ppm and 5.70/6.16 ppm. The reaction
mixture was then filtered, and the boron-containing pellet was
washed with CH2Cl2. The filtrate and washings were evapo-
rated at rt to give a reddish residue, which was directly treated
with NaOAc (36 mg, 0.44 mmol) in AcOH (2 mL) for 2 h at rt.
This reaction mixture was then partitioned between EtOAc
and water. The EtOAc layer was washed with brine, dried
over Na2SO4, filtered, and evaporated. The resulting light
brown residue was submitted to column chromatography at
-78 °C, eluting with hexane-EtOAc (1:1), to afford the 2:1
regioisomeric mixture 31a /b (51 mg, 60%) as a bright yellow
solid.
This mixture was then treated with Na2S2O4 (113 mg, 0.65
mmol) in THF:H2O (10 mL). This reductive treatment was
performed in a separatory funnel. Discharge of the reaction
mixture’s yellow color was observed upon shaking the reaction
mixture for ca. 2 min. The mixture was then diluted with
EtOAc (20 mL), washed with brine, dried over Na2SO4, filtered,
and evaporated to afford quantitatively an unseparable 2:1
regioisomeric mixture 30a /32 (51 mg) as a crude pale yellow
oil. Four successive crystallizations of this oily mixture (40
mg) from CH2Cl2-H2O furnished 31.7 mg of 30a only (79%)
from 31a /b. Alternatively, direct methylation of the mixture
30a /32 (53 mg from another run) with CH3I/K2CO3 in acetone
afforded 44 mg of 30b only (75%).
Methylations of the diaryl ethers 26a /c, 27a /c/d were
performed on a 0.04-0.08 mmol scale using powdered K2CO3
(2 equiv) and CH3I (2 equiv) in acetone (5 mL) for the purpose
of securing the regiochemistry of addition. After refluxing
overnight, the mixture was cooled to rt, diluted in CH2Cl2,
washed with cold 3% HCl and then H2O, dried over Na2SO4,
filtered, and evaporated to give 37-41, respectively, as yellow
1
oils which were directly analyzed by H NMR.
Deh yd r od iga lla te 30a : white solid, mp 207 °C (from CH2-
1
Cl2-H2O); IR (CHCl3) 3530, 1716 cm-1; H NMR (CD3COCD3)
δ 3.61 (s, 3 H), 3.71 (s, 3 H), 3.89 (s, 3 H), 3.90 (s, 3 H), 6.84
(d, J ) 1.8 Hz, 1 H), 7.10 (s, 1 H), 7.27 (d, J ) 1.8 Hz, 1 H),
8.31 (bs, 2 H), 8.61 (bs, 1 H); 13C NMR (CD3COCD3) δ 166.9,
165.8, 148.9, 147.7, 145.8, 141.7, 140.8, 140.3, 138.5, 120.7,
115.1, 109.4, 108.1, 105.6, 56.7, 56.6, 52.0, 51.9; CIMS m/ z
(relative intensity) 395 (MH+, 25), 199 (100); HRMS calcd for
37: 1H NMR (CDCl3) δ 3.86 (s, 3 H), 3.90 (s, 3 H), 3.94 (s, 3
H), 6.97 (bd, J ) 7.6 Hz, 2 H), 7.08 (bt, J ) 7.4 Hz, 1 H), 7.29-
7.35 (m, 2 H), 7.32 (d, J ) 1.9 Hz, 1 H), 7.43 (d, J ) 1.9 Hz, 1
H).
C
18H18O10 394.0900, found 394.0937.
Deh yd r od iga lla te 30b: off-white solid, mp 113 °C (lit.30
mp 112-113 °C); IR (CHCl3) 1713 cm-1; H NMR (CDCl3) δ
3.73 (s, 3 H), 3.75 (s, 3 H), 3.79 (s, 3 H), 3.91 (s, 3 H), 3.94 (s,
3 H), 3.96 (s, 3 H), 4.05 (s, 3 H), 6.80 (d, J ) 1.8 Hz, 1 H),
7.301 (d, J ) 1.8 Hz, 1 H), 7.304 (s, 1 H); 13C NMR (CDCl3) δ
166.40. 165.2, 153.2, 152.2, 150.3, 147.2, 146.9, 142.1, 141.8,
124.9, 119.3, 108.8, 108.7, 107.1, 61.3, 61.2, 61.1, 56.2 (2), 52.2,
52.1; CIMS m/ z (relative intensity) 436 (M+, 40), 405 (100);
HRMS calcd for C21H24O10 436.1369, found 436.1388.
1
38: 1H NMR (CDCl3) δ 3.83 (s, 6 H), 3.94 (s, 3 H), 6.85 (bd,
J ) 8.6 Hz, 2 H), 7.00 (bt, J ) 7.4 Hz, 1 H), 7.22-7.28 (m, 2
H), 7.38 (s, 2 H).
1
39: H NMR (CDCl3) δ 3.83 (s, 2 × 3 H), 3.94 (s, 3 H), 3.97
(s, 3 H), 6.90-7.15 (m, 4 H), 7.13 (d, J ) 1.9 Hz, 1 H), 7.36 (d,
J ) 1.9 Hz, 1 H).
40: 1H NMR (CDCl3) δ 3.81 (s, 6 H), 3.93 (s, 3 H), 3.95 (s, 3
H), 6.42-6.45 (m, 1 H), 6.71-6.77 (m, 1 H), 6.91-6.98 (m, 2
H), 7.36 (s, 2 H).
Or th oqu in on es 31a /b: amorphous yellow solid; IR (CHCl3)
3455, 1718, 1633 cm-1; 31a : 1H NMR (CDCl3) δ 3.697 (s, 3
H), 3.801 (s, 3 H), 3.909 (s, 3 H), 4.01 (s, 3 H), 5.90 (s, 1 H),
7.40 (d, J ) 1.8 Hz, 1 H), 7.56 (d, J ) 1.8 Hz, 1 H); 13C NMR
(CDCl3) δ 177.47 (2), 166.8, 165.9, 151.6, 149.0, 140.8, 136.7,
134.0, 132.5, 124.5, 111.5, 108.3, 105.3, 56.8, 56.2, 54.3, 52.4;
31b: 1H NMR (CDCl3) δ 3.685 (s, 3 H), 3.812 (s, 3 H), 3.913
(s, 3 H), 3.97 (s, 3 H), 5.77 (s, 1 H), 7.33 (d, J ) 1.8 Hz, 1 H),
7.48 (d, J ) 1.8 Hz, 1 H); 13C NMR (CDCl3) δ 177.50 (2), 167.0,
166.0, 151.6, 148.5, 140.5, 136.7, 134.2, 132.8, 125.5, 112.1,
107.2, 105.4, 56.4, 56.1, 54.2, 53.7; CIMS m/ z (relative
intensity) 393 (MH+, 5), 199 (35); HRMS calcd for C18H16O10
392.0743, found 392.0742.
41: 1H NMR (CDCl3) δ 3.71 (s, 6 H), 3.75 (s, 6 H), 3.90 (s, 3
H), 6.56 (d, J ) 8.4 Hz, 2 H), 6.95 (t, J ) 8.4 Hz, 1 H), 7.29 (s,
2 H).
Deh yd r od iga lla t es via H et er o-Diels-Ald er Dim er -
iza tion s: P r oced u r e D. The orthoquinone 8 (50 mg, 0.26
mmol) was dissolved in benzene-d6 (1 mL). This solution was
1
refluxed for 8 h, after which time H NMR analysis indicated
complete conversion of 8 into a mixture of three out of the four
possible regioisomeric 1,4-dioxene products 29a -d in a 3:2:1
ratio. Degradation of these products upon solvent evaporation
and silica gel chromatograhy prevented their separation for
complete characterization. Their identification by 1H NMR
analysis (benzene-d6) is based on the observation of three sets
of two aromatic doublets (J ) 2.0 Hz) resonating at 7.87/7.37
Deh yd r od iga lla te 33. The orthoquinone 11 (200 mg, 0.57
mmol) was dissolved in CDCl3 (4 mL) and converted to a 2:1
regioisomeric mixture of the benzylated analogs of 31a /31b

Galloyl-Derived Orthoquinones
J . Org. Chem., Vol. 61, No. 19, 1996 6665
(156 mg, 78%) as described in procedure E. Diagnostic 1H
NMR (CDCl3) signals of the benzylated analogs of the 1,4-
dioxene intermediates 29a /b included two sets of two singlets
resonating at 5.58/6.27 ppm and 5.67/6.18 ppm. The benzyl-
ated analogs of 31a /31b each exhibited a diagnostic 1H NMR
(CDCl3) singlet at 5.90 ppm and 5.76 ppm. Reduction of the
benzylated analogs of 31a /31b (54 mg) with Na2S2O4 as
described in procedure E, followed by benzylation with benzyl
chloride (4 equiv), K2CO3 (5 equiv), and KI (0.6 equiv) in
refluxing acetone for 10 h furnished, after standard workup,
crude 33 as the sole diaryl ether regioisomer. Purification by
preparative TLC, eluting with light petroleum-Et2O (3:2),
afforded 43 mg of pure 33 as an oil (57%). IR (CHCl3) 1714
cm-1; 1H NMR (CDCl3) δ 4.92 (s, 2 H), 4.95 (s, 2 H), 5.07 (s, 2
H), 5.09 (s, 2 H), 5.12 (s, 2H), 5.16 (s, 2 H), 5.25 (s, 2 H), 6.94
(d, J ) 1.9 Hz, 1 H), 7.06-7.46 (m, 37 H); 13C NMR (CDCl3) δ
165.7, 164.8, 152.7, 152.6, 150.0, 147.0, 146.5, 142.5, 141.9,
137.9, 136.8, 136.7, 136.3, 136.1, 135.4, 128.6, 128.5, 128.4,
128.3, 128.17, 128.15, 128.11, 128.08, 128.05, 127.97, 127.94,
127.87, 127.7, 127.6, 127.5, 124.8, 120.0, 111.0, 109.5, 109.2,
75.61, 75.56, 74.9, 71.4, 71.3, 67.1, 66.5; FABMS m/ z (relative
intensity) 969 (MH+, 100), 878 (40); HRMS (FAB) calcd for
C63H52O10 968.3560, found 968.3564. Anal. Calcd for
C63H52O10: C, 78.08; H, 5.41. Found: C, 77.46; H, 5.70.
Diels-Ald er Ad d u ct 35. Cu(OAc)2.H2O (86 mg, 0.43
mmol) was added to a solution of the orthoquinone 8 (84 mg,
0.43 mmol) in CDCl3 (4 mL). The reaction mixture was stirred
at rt for 24 h, after which time it was filtered. The filtrate
was evaporated, and the residue was submitted to column
chromatography at -78 °C, eluting with hexane-EtOAc (1:
1), to afford 35 (32 mg, 36%) as a white solid, mp 174 °C (from
CH2Cl2). IR (CHCl3) 3508, 3453, 3356, 3156, 1794, 1763, 1725,
J ) 4.7, 2.2 Hz, 1 H), 6.07 (s, 1 H), 6.51 (s, 1 H), 6.93 (s, 1 H),
7.57 (d, J ) 2.2 Hz, 1 H); 13C NMR (CD3COCD3) δ 197.4, 185.9,
170.6, 164.1, 149.2, 137.1, 132.2, 112.8, 97.8, 96.9, 90.5, 56.1,
55.8, 54.3, 53.6, 52.6, 51.3, 45.2; EIMS m/ z (relative intensity)
410 (M+, 3.9), 392 (M+ - H2O, 2.6); HRMS calcd for C18H16O10
392.0743, found 392.0747.
Dim eth yl 2,2′,3,3′-Tetr a h yd r oxy-4,4′-d im eth oxybip h e-
n yl-6,6′-d ica r boxyla te (36). Anhydrous ZnBr2 (118 mg, 0.52
mmol) was added to a solution of the orthoquinone 8 (103 mg,
0.52 mmol) in CDCl3 (4 mL). The reaction mixture was stirred
at rt. Monitoring of the reaction by 1H NMR analysis indicated
complete disappearance of the starting quinone 8 after ca. 20
h. The resulting mixture was filtered, and the filtrate was
submitted to preparative TLC, eluting with CH2Cl2-MeOH
(20:1), to afford 36 (16 mg, 15%) as a beige solid, mp 280 °C
dec (from CH2Cl2). IR (KBr) 3539, 3386, 1778, 1695 cm-1; 1H
NMR [CD3COCD3-CD3SOCD3, (9:1)] δ 3.48 (s, 6 H), 3.88 (s,
6 H), 7.15 (s, 2 H); 13C NMR [CD3COCD3-CD3SOCD3, (9:1)] δ
167.5, 146.9, 144.4, 138.4, 121.8, 121.6, 106.0, 56.3, 51.3; EIMS
m/ z (relative intensity) 394 (M+, 18.2), 363 (4.9), 332 (4.8),
288 (2.1); HRMS calcd for C18H18O10 394.0900, found 394.0913.
Ack n ow led gm en t. This work was supported by
NSF IBN-9407308.
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C NMR
spectra for 14b, 16, 18, 20-22, 26c, 27c, 27d , 30a /b, 31a /b,
35, and 36 (14 pages). This material is contained in libraries
on microfiche, immediately 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
1701 cm-1; H NMR (CD3COCD3) δ 3.29 (d, J ) 4.7 Hz, 1 H),
3.63 (s, 3 H), 3.67 (s, 3 H), 3.71 (s, 3 H), 3.80 (s, 3 H), 4.43 (dd,
J O961043U