Studies relevant to ellagitannin chemistry: Highly diastereoselective intramolecular biaryl coupling in bis(iodotrimethoxybenzoyl) hexopyranose derivatives

Article abstract of DOI:10.1021/jo971722k

Internal biaryl coupling reactions of carbohydrate derivatives carrying two 2-iodo-3,4,5-trimethoxybenzoyl groups under Ullmann conditions were investigated. With substituents at positions 2,3 or 4,6 of a D-glucopyranoside, 2,3 of a D-mannopyranoside, and 3,4 of a D-galactopyranoside, the coupling was found to proceed with a very high degree of stereoselectivity, leading exclusively to the (S)-epimer of the resulting hexamethoxydiphenoyl residue from the v-gluco and D-galacto substrates, and to the (R)-epimer from the D-manno substrate. With substituents at positions 2,4 of D-glucopyranose derivatives in the ¹C₄ conformation and at positions 5,6 of a D-glucofuranose derivative, the coupling proceeded efficiently but with modest stereoselectivity. Some deiodinated starting material was formed as a byproduct in all reactions. These results are relevant to ellagitannin chemistry in that they provide further understanding of the structural requirements for highly diastereoselective biaryl coupling within carbohydrate units. In addition, the efficient, complementary reactions of the D-manno and D-galacto substrates provide a method for the enantioselective synthesis of hexamethoxydiphenoic acid derivatives

Full text of DOI:10.1021/jo971722k

7628
J . Org. Chem. 1998, 63, 7628-7633
Stu d ies Releva n t to Ella gita n n in Ch em istr y: High ly
Dia ster eoselective In tr a m olecu la r Bia r yl Cou p lin g in
Bis(iod otr im eth oxyben zoyl) Hexop yr a n ose Der iva tives
Dongcheng Dai and Olivier R. Martin*,†
Department of Chemistry, State University of New York, P.O. Box 6016,
Binghamton, New York 13902-6016
Received September 16, 1997
Internal biaryl coupling reactions of carbohydrate derivatives carrying two 2-iodo-3,4,5-trimethoxy-
benzoyl groups under Ullmann conditions were investigated. With substituents at positions 2,3
or 4,6 of a D-glucopyranoside, 2,3 of a D-mannopyranoside, and 3,4 of a D-galactopyranoside, the
coupling was found to proceed with a very high degree of stereoselectivity, leading exclusively to
the (S)-epimer of the resulting hexamethoxydiphenoyl residue from the D-gluco and D-galacto
substrates, and to the (R)-epimer from the D-manno substrate. With substituents at positions 2,4
1
of D-glucopyranose derivatives in the C4 conformation and at positions 5,6 of a D-glucofuranose
derivative, the coupling proceeded efficiently but with modest stereoselectivity. Some deiodinated
starting material was formed as a byproduct in all reactions. These results are relevant to
ellagitannin chemistry in that they provide further understanding of the structural requirements
for highly diastereoselective biaryl coupling within carbohydrate units. In addition, the efficient,
complementary reactions of the D-manno and D-galacto substrates provide a method for the
enantioselective synthesis of hexamethoxydiphenoic acid derivatives
In tr od u ction
conformational constraints within the polysubstituted
glucopyranose substrate (“Schmidt-Haslam hypothesis,”
see ref 1d). While a biomimetic strategy would provide
a straightforward approach for the chemical synthesis
of ellagitannins, the implementation of such a strategy
has eluded the efforts of synthetic chemists until very
recently: Feldman and co-workers have now developed
an efficient methodology3 for internal oxidative couplings
of glucose galloates and have reported the first syn-
theses of a number of free, monomeric ellagitannins,
including tellimagrandin I and pedunculagin.4 Previous
syntheses of ellagitannin derivatives (per-O-methyl tel-
limagrandins) were achieved by esterification of glu-
cose diols with preformed (S)-hexamethoxydiphenoic
acid.5
Ellagitannins1 are gallic acid metabolites characterized
by the presence of one or more axially chiral hexahy-
droxydiphenoyl residues connected, in most cases, to a
glucopyranose scaffold by ester functions. Tellimagran-
din I (1) and pedunculagin (2) are two examples of
monomeric ellagitannins. According to Schmidt1a and
Haslam,1b,2 all ellagitannins arise from penta-O-galloyl-
â-D-glucopyranose, the ultimate biosynthetic precursor
of both gallotannins and ellagitannins; the
Intrigued by the dearth of precedent on the synthesis
of ellagitannins from carbohydrate substrates, we have
also carried out studies on hexopyranoses carrying
substituted benzoyl groups, with the goal of examining
both the feasibility and the stereochemistry of the
internal aryl-aryl bond formation process. Unsuccessful
attempts of linking adjacent 3,4,5-trimethoxybenzoyl
substituents in D-glucopyranosides under oxidative con-
6,7
ditions using reagents such as VOF3 prompted us to
(3) Feldman, K. S.; Ensel, S. M. J . Am. Chem. Soc. 1994, 116, 3357-
3366.
diphenoyl units are thought to be generated by oxidative
C-C couplings between adjacent galloyl esters, the
diastereoselectivity of the coupling being dictated by
(4) (a) Tellimagrandin I: Feldman, K. S.; Ensel, S. M.; Minard, R.
D. J . Am. Chem. Soc. 1994, 116, 1742-1745. (b) Sanguiin H-5:
Feldman, K. S.; Sambandam, A. J . Org. Chem. 1995, 60, 8171-8178.
(c) Pedunculagin: Feldman, K. S.; Smith, R. S. J . Org. Chem. 1996,
61, 2606-2612.
(5) (a) Nelson, T. D.; Meyers, A. I. J . Org. Chem. 1994, 59, 2577-
2580. (b) Lipshutz, B. H.; Liu, Z.-P.; Kayser, F. Tetrahedron Lett. 1994,
35, 5567-5570. Examples of synthesis of ellagitannins by way of the
diastereoselective esterification of glucose diols with racemic hexaal-
koxydiphenoic acid derivatives have been very recently reported: (c)
Itoh, T.; Chika, J .-I.; Shirakami, S.; Ito, H.; Yoshida, T.; Kubo, Y.;
Uenishi, J .-I. J . Org. Chem. 1996, 61, 3700-3705. (d) Khanbabaee,
K.; Schulz, C.; Lo¨tzerich, K. Tetrahedron Lett. 1997, 38, 1367-1368.
† New address: I.C.O.A., Universite´ d’Orle´ans, B. P. 6759, 45067
Orle´ans, France.
(1) (a) Schmidt, O. T. Fortschr. Chem. Org. Naturst. 1956, 13, 70-
136. (b) Haslam, E.; Cai, Y. Nat. Prod. Rep. 1994, 41-66. (c) Okuda,
T.; Yoshida, T.; Hatano, T. Prog Chem. Org. Nat. Prod. 1995, 66,
1-117. (d) Quideau, S.; Feldman, K. S. Chem. Rev. 1996, 96, 475-
503, and ref. cited.
(2) Gupta, R. K.; Al-Shafi, S. M. K.; Layden, K.; Haslam, E. J . Chem.
Soc., Perkin Trans. 1 1982, 2525-2534.
10.1021/jo971722k CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/08/1998

Studies Relevant to Ellagitannin Chemistry
J . Org. Chem., Vol. 63, No. 22, 1998 7629
consider performing the biaryl coupling reaction8 under
reductive, Ullmann-type conditions. We wish to report,
in this article, the results of our investigations on sugar
derivatives carrying 2-iodo-3,4,5-trimethoxybenzoyl sub-
stituents; the finding of substrates that lead to (R) or (S)-
atropisomers with a very high degree of stereoselectivity
is particularly noteworthy.
and reduction products was slightly improved when the
substituents were at position 4,6 of the D-glucopyranose
carrier (Table 1). The reaction of 6a with Cu(0) afforded
a mixture of three unseparable products in a ratio of ∼2:
1:1.19 The NMR spectral data of the major product were
found to match exactly those of per-O-methyl tellima-
grandin I,5a thus establishing its structure as 7a and the
configuration of the diphenoyl unit as S. The first minor
product was identified, by comparison with an authentic
sample, as deiodinated starting material 8a ; the struc-
ture of the second minor product remained uncertain.
With benzyl groups at positions 2 and 3 instead of tri-
methoxybenzoyl groups (substrate 6b), the reaction gave
a homogeneous mixture of only two products in a ∼1:1
ratio, namely the 4,6-diphenoyl derivative 7b and reduc-
tion product 8b. The configuration of the single atropi-
somer 7b was assigned to be S on the basis of its CD-
spectrum (Table 2). The most interesting and useful
results were obtained from substrates carrying the sub-
stituents in vicinal axial-equatorial position and having
the nonnatural D-manno and D-galacto configuration: the
reaction of 2,3-cis-disubstituted D-mannopyranoside 9
and of 3,4-cis-disubstituted D-galactopyranoside 12 gave
the desired diphenoyl derivatives 10 and 13 in very good
yields and readily separable from a minor amount of
deiodinated starting material (11 and 14). Both reactions
generated the biaryl unit as a single atropisomer. As
expected from the nearly enantiomeric relationship be-
tween the 2,3-positions in the D-manno series and the
4,3-positions in the D-galacto series, these substrates gave
products of opposite configuration: the CD-spectra of 10
and 13 established unambiguously1c,18 that the diphenoyl
groups in 10 and 13 have the (R)- and (S)-configuration,
respectively (Table 2).
Resu lts a n d Discu ssion
A series of methyl D-hexopyranosides carrying two
2-iodo-3,4,5-trimethoxybenzoyl substituents at positions
2,3 (3, 9), 3,4 (12), or 4,6 (6a , 6b) were prepared from
the corresponding diols by esterification with 2-iodo-3,4,5-
trimethoxybenzoic acid9 in the presence of DCC and
DMAP.10 Since the treatment of some of these substrates
with zerovalent nickel reagents [Ni(Ph3P)2Cl2-Ph3P-Zn
in DMF,11 NiI2-Zn-KI in HMPA,12 NiCl2-Ph3P-Zn in
DMF13] promoted exclusively the deiodination of the
starting material, subsequent studies were conducted
using classical Ullmann conditions.14,15 The reaction of
these substrates with pretreated copper powder15 under
the conditions described by Miyano16 (DMF, reflux tem-
perature or below17) led to the results that follow.
Considering that the diphenoyl residue can be readily
removed from the hexopyranoside under basic condi-
tions,5b,c the D-manno and D-galacto diols thus consti-
tute convenient templates for the asymmetric synthesis
of hexamethoxydiphenoic acid derivatives with a high
degree of enantiomeric purity. The method is comple-
mentary to that reported by Lipshutz (chiral template:
(S,S)-stilbene diol).5b
2,3-Disubstituted D-glucopyranoside 3 gave the corre-
sponding 2,3-diphenoyl derivative 5 as a single stereo-
isomer together with a relatively large amount of deio-
dinated starting material (4) (ratio of 4 and 5: ∼1.2:1).
A sample of 5 could be isolated by preparative TLC, and
its configuration was determined to be S on the basis of
its CD-spectrum1c,18 and by comparison with the data
reported by Itoh et al.5c for both epimers of the same
glucopyranose derivative. The ratio between coupling
To further probe the stereochemistry of the biaryl
coupling in carbohydrate substrates, we also investigated
the Ullmann reactions of the following systems; in all
cases, the reaction gave a nonseparable mixture of two
epimeric diphenoyl derivatives and some reduction prod-
uct (see results in Table 3).
(6) Damon, R. E.; Schlessinger, R. H.; Blount, J . F. J . Org. Chem.
1976, 41, 3772.
1,3-Diaxially disubstituted hexopyranoses: a number
of ellagitannins or their biosynthetic precursors contain
a diphenoyl group between positions 2 and 4 of a
(7) Feldman (ref 4a) reported the successful coupling of the tri-
methoxybenzoyl groups at O-4 and O-6 of methyl tetrakis-O-(3,4,5-
trimethoxybenzoyl)-R-D-glucopyranoside using VOF3.
(8) General review on biaryl coupling: Sainsbury, M. Tetrahedron
1980, 36, 3327-3359.
1
glucopyranose unit in the C4 conformation (chebulinic
acid, geraniin, etc.1c). The reactions of substrates 15 and
16 could therefore serve as models for the synthesis of
such natural products. The coupling between the groups
at O-2 and O-4 in 15 proceeded, however, with essentially
no stereoselectivity, a result that can be attributed to the
near symmetry of the substrate. With a 3,6-anhydro
(9) Beugelmans, R.; Chastanet, J .; Ginsburg, H.; Quintero-Corte`s,
L.; Roussi, G. J . Org. Chem. 1985, 50, 4933-4938.
(10) Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475-4478.
See also ref 5a.
(11) (a) Kende, A. S.; Liebeskind, L. S.; Braitsch, D. M. Tetrahedron
Lett. 1975, 3375-3378. (b) Zembayashi, M.; Tamao, K.; Yoshida, J .-I.;
Kumada, M. Tetrahedron Lett. 1977, 4089-4092.
(12) Takagi, K.; Hayama, N.; Inokawa, S. Chem. Lett. 1979, 917-
918.
(13) Colon, I.; Kelsey, D. R. J . Org. Chem. 1986, 51, 2627-2637.
(14) Fanta, P. E. Chem. Rev. 1946, 38, 139-196. Chem. Rev. 1964,
64, 613-632. Synthesis 1974, 9-21.
(18) Okuda, T.; Yoshida, T.; Hatano, T.; Koga, T.; Toh, N.; Kuriyama,
K. Tetrahedron Lett. 1982, 23, 3937-3940; 3941-3944. For com-
parative results, see Table 2. A negative Cotton effect at about 250
nm followed by a positive Cotton effect at about 225 nm was taken
as evidence for the (S)-configuation of the hexamethoxydiphenoyl
unit.
(15) Fuson, R. C.; Cleveland, E. A. Organic Syntheses; Wiley: New
York, 1955; Coll. Vol. III, pp 339-340.
(16) Miyano, S.; Handa, S.; Shimizu, K.; Tagami, K.; Hashimoto,
H. Bull. Chem. Soc. J pn. 1984, 57, 1942-1947.
(17) Despite the high temperature used, the reactions were clean,
and the conversion was essentially quantitative.
(19) The ratio of products was improved to 4:1:1 when the reaction
was performed at lower temperature (105 °C, 5 d).

7630 J . Org. Chem., Vol. 63, No. 22, 1998
Ta ble 1. In tr a m olecu la r Bia r yl Cou p lin gs
Dai and Martin
Ta ble 2. CD Sp ectr a l Da ta for 5, 7b, 10, a n d 13a
The results reported herein illustrate the strong de-
pendence of the stereochemistry of the internal coupling
process on the relative position of the two substituted
benzoyl groups within the carbohydrate framework. The
very high diastereoselectivity observed in the reactions
of substrates 3, 9, and 12 implies that a considerable
degree of preorganization already exists in the starting
hexopyranosides. The recently published X-ray crystal
structure of compound 5, prepared by Itoh and co-
workers5c by the esterification of the corresponding
glucose diol with racemic hexamethoxydiphenoic acid, is
particularly revealing in that respect: the diphenoyl ester
linkages adopt in 5 a near-(Z)-syn conformation, i.e., a
conformation strongly reminiscent of that of the starting
benzoates. It is indeed well-established, from numerous
crystal structure determinations,20 that benzoyl groups
at secondary positions in hexopyranosides adopt prefer-
entially a (Z)-syn conformation21 (see Figure 1) whether
the group is in equatorial or axial disposition. This
interpretation is consistent with the results of Feldman’s
molecular mechanics calculations1d on model 2,3-di-O-
galloyl glucopyranosides and coupling products: while a
compd
no.
molar ellipticities [θ] × 10-4 (λ, nm)
5
-1.3 (302)
-1.4 (301)
+1.9 (272)
+3.2 (266)
-2.1 (278)
+0.47 (278)
-4.2 (245)
-3.7 (246)
+1.2 (257)
-0.49 (254)
?
7b
10
13
+9.8 (222)
-3.2 (230)
∼0.8 (225)
-0.2 (308)
a
Spectra recorded in MeOH.
bridge and the configuration at C-1 inverted (compound
16), the coupling was more efficient and its stereoselec-
tivity was improved (3:1), but remained modest.
Vicinally disubstituted acyclic system: as shown by the
reaction of substrate 17 with Cu(0), the coupling was
efficient in this system, but the sugar carrier provided
very little control of its stereoselectivity.
Monosubstituted carbohydrate derivatives (intermo-
lecular reactions): the reactions of substrates 18 and 19
were each examined for comparison with the intramo-
lecular processes. The coupling was found to occur with
low efficiency and with no stereoselectivity. The carbo-
hydrate residues in this system appear, therefore, to be
too remote from the reaction site for controlling its
diastereoselectivity, in contrast with Myers’s tighter
molecular system which makes use of a chiral oxazoline
as a carboxyl surrogate.5a
(20) J effrey, G. A.; Sundaralingam, M. Adv. Carbohydr. Chem.
Biochem. 1985, 43, 203-421 and ref. cited.
(21) Fowler, P.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1996, 79,
269-287.

Studies Relevant to Ellagitannin Chemistry
J . Org. Chem., Vol. 63, No. 22, 1998 7631
Ta ble 3. Ullm a n n Rea ction s of 15-19: Resu ltsa
coupling products,
% yield (diast. ratio)
reduction
substrate
product,b % yield
15
16
17
18
19
42 (53:47)c
90 (73:27)
89 (59:41)
56 (50:50)
40 (50:50)
58
10
11
44
60
a
b
Product ratio determined by 1H NMR. I f H in starting
material. c 2,4-Coupling and deiodination of group at O-3.
F igu r e 1. Conformations of benzoates about the HsCsOsC
and CsOsCdO bonds.
small energy difference was found between starting
conformers leading to either atropisomers,22 this differ-
ence increases along the reaction path, and the final
epimers are more than 5 kcal/mol apart in energy in their
most favorable conformation, namely the more stable
S-epimer with the two ester linkages in a near (Z)-syn
conformation and the R-epimer with one of the linkages
in a near (E)-syn conformation. That the conformation
of the starting benzoates in hexopyranosides is conserved
in the final product is of considerable predictive useful-
ness: thus, the reactions of the D-manno and D-galacto
substrates having both participating benzoyloxy groups
in a (Z)-syn conformation were expected to lead to the
(R) and (S)-atropisomer, respectively, as has been ob-
served. Quite remarkably, the same degree of stereo-
control appears to be effective in internal couplings under
such different mechanistic conditions as reductive and
oxidative3,4 C-C bond formation.
A similar preorganization appears to be operative when
the groups are in position 4 and 6 of the glucopyranose
system. In the other systems (15-17), the control of the
stereoselectivity by the substrate is less efficient most
probably as a result of a greater conformational flexibility
around the C-O-C(O) bonds of the ester linkage.
Although the couplings are performed under conditions
far remote from those of the biosynthetic process, our
results provide further understanding of the structural
requirements for highly diastereoselective coupling within
carbohydrate units; they clearly illustrate the importance
of conformational effects in the substrate, thus lending
further experimental support for the “Schmidt-Haslam
hypothesis” for ellagitannin biosynthesis.
Exp er im en ta l Section
General procedures and methods of characterization have
been described previously.23 CD spectra were recorded on a
J asco J -20 ORD/UV-5 spectropolarimeter with a Sproul Sci-
entific SS 15-2 CD modification or on
spectropolarimeter (University of Rochester).
Ester ifica tion P r oced u r e. A mixture of diol (1 mmol),
2-iodo-3,4,5-trimethoxybenzoic acid9 (2.05 mmol), DCC (2.1
mmol), and DMAP (0.3 mmol) in CH2Cl2 (10 mL) was stirred
overnight at room temperature. The resulting solids were
removed by filtration, and the solvent was evaporated in vacuo.
Ether (20 mL) was added to the residue, the additional
precipitate of DCU was removed by filtration, and the filtrate
was concentrated. The product was purified by flash column
chromatography (FCC).
a J ASCO J -710
Met h yl 4,6-O-Ben zylid en e-2,3-b is-O-(2-iod o-3,4,5-t r i-
m eth oxyben zoyl)-r-D-glu cop yr a n osid e (3). Prepared from
methyl 4,6-O-benzylidene-R-D-glucopyranoside and purified by
FCC (hexane-ethyl acetate 1.6:1); yield: 93%. [R]20 - 18.4
D
(c 1.2, CHCl3); 1H NMR (CDCl3) δ 3.47, 3.71, 3.815, 3.82, 3.845,
3.86, 3.90 (7s, 7 × 3H, 7 OCH3), 3.8-3.92 (m occluded by 5s,
2H, H-4, 6A), 4.06 (td, 1H, J 4,5 ) J 5,6A ) 9.8, J 5,6B ) 4.8 Hz,
H-5), 4.37 (dd, 1H, J 6A,6B ) 10.3 Hz, H-6B), 5.19 (d, 1H, J 1,2
)
3.8 Hz, H-1), 5.33 (dd, 1H, J 2,3 ) 9.8 Hz, H-2), 5.56 (s, 1H,
PhCH), 6.00 (t, 1H, J 3,4 ) 9.8 Hz, H-3), 6.99 (s, 1H) and 7.37
(s, 1H) (2 ArH), 7.32-7.34 (m, 3H) and 7.47-7.50 (m, 2H) (Ph);
13C NMR (CDCl3) δ 55.6, 56.2, 56.4, 60.9, 61.0, 62.5, 68.9, 70.8,
72.6, 79.1, 83.4, 84.9, 97.8, 101.6, 110.6, 111.9, 126.3, 128.2,
128.4, 129.1, 131.2, 136.9, 144.9, 145.7, 153.4, 153.5, 153.9,
154.0, 165.0, 166.0. Anal. Calcd for C34H36I2O14: C, 44.27;
H, 3.93; I, 27.51. Found: C, 44.53; H, 4.37; I, 26.70.
Meth yl 4,6-Bis-O-(2-iod o-3,4,5-tr im eth oxyben zoyl)-2,3-
bis-O-(3,4,5-tr im eth oxyben zoyl)-r-D-glu copyr an oside (6a).
Prepared from methyl 2,3-bis-O-(3,4,5-trimethoxybenzoyl)-R-
D-glucopyranoside5a and purified by FCC (hexane-ethyl ac-
(22) The (R)-atropisomer is generated in this system if one of the
benzoyl groups is in the (E)-syn conformation.
(23) Saavedra, O. M.; Martin, O. R. J . Org. Chem. 1996, 61, 6987-
6993.

7632 J . Org. Chem., Vol. 63, No. 22, 1998
Dai and Martin
1
etate 3:2); yield: 96%. [R]20 +71.5 (c 1.9, CHCl3); H NMR
containing 2-iodo-3,4,5-trimethoxybenzoic acid (0.69 g, 2.05
mmol), DCC (0.452 g, 2.2 mmol), and DMAP (0.037 g) was
stirred at room temperature for 24 h. The solids were then
removed by filtration, and the solvent was evaporated. Ether
(10 mL) was added, the insoluble fraction was removed by
filtration, and the filtrate was concentrated. The residue was
submitted twice to flash chromatography (hexane-ethyl ac-
D
(CDCl3) δ 3.50 (s, 3H), 3.75 (s, 3H), 3.81-3.89 (several s, 27H),
3.93 (s, 3H), 3.96 (s, 3H) (13 OCH3), 4.41 (ddd, 1H, J 4,5 ) 9.9,
J 5,6A ) 4.5, J 5,6B ) 1.9 Hz, H-5), 4.53 (dd, 1H, J 6A,6B ) 12.3 Hz,
H-6A), 4.75 (dd, 1H, H-6B), 5.18 (dd, 1H, J 1,2 ) 3.5, J 2,3 ) 9.9
Hz, H-2), 5.30 (d, 1H, H-1), 5.78 (t, 1H, J 3,4 ) J 4,5 ) 9.9 Hz,
H-4), 6.10 (t, 1H, H-3), 6.92 (s, 1H) and 7.44 (s, 1H) (2 ArH),
7.19 (s, 2H) and 7.27 (s, 2H) (2 ArH2); 13C NMR (CDCl3) δ 56.0,
56.2, 56.5, 60.4, 60.9, 61.0, 61.1, 63.6, 67.3, 69.4, 71.0, 72.5,
83.5, 84.1, 97.2, 107.2, 107.4, 110.2, 111.1, 123.9, 124.0, 130.4,
130.5, 142.8, 142.9, 145.1, 145.2, 153.0, 153.5, 153.9, 154.0,
165.5, 165.6, 166.0; HR-FABMS calcd for C47H52I2O22 m/z
1222.1039, found 1222.1063.
etate 2:1) which afforded pure 15 (0.62 g, 97% based on the
1
benzoic acid): [R]20 -19.3 (c 1.5, CHCl3); H NMR (CDCl3) δ
D
3.71, 3.72, 3.86, 3.86, 3.87, 3.90, 3.91, 3.92, 3.93 (9s, 9 × 3H,
9 OCH3), ∼3.9 (occluded m, 1H, H-6A), 4.34 (d, 1H, J 6A,6B
)
7.9 Hz, H-6B), 4.89 (br d, 1H, J 5,6A ) 5.5 Hz, H-5), 5.10 (d,
1H), 5.17 (d, 1H) (H-2,4), 5.70 (t, 1H, J 2,3 = J 3,4 ) 3.6 Hz, H-3),
5.72 (s, 1H, H-1), 7.23, 7.24, 7.30 (3s, 3H, 3 ArH); 13C NMR
(CDCl3) δ 56.3, 56.4, 60.8, 60.9, 61.0, 61.1, 66.5, 70.7, 72.1,
72.9, 74.8, 84.1, 84.3, 84.7, 100.0, 111.0, 111.2, 111.5, 129.1,
129.7, 129.8, 145.5, 145.6, 153.4, 153.6, 154.0, 165.0, 165.3,
165.4. HR-FABMS calcd for C36H37I3O17 m/z 1121.9164, found
1121.9114.
Meth yl 2,3-Di-O-ben zyl-4,6-bis-O-(2-iod o-3,4,5-tr im eth -
oxyben zoyl)-r-D-glu cop yr a n osid e (6b ). Prepared from
methyl 2,3-di-O-benzyl-R-D-glucopyranoside24 and purified by
FCC (hexane-ethyl acetate 1:1); yield: 86.7%. [R]20 +3.6 (c
D
2.8, CHCl3); 1H NMR (CDCl3) δ 3.43, 3.65, 3.845, 3.855, 3.89,
3.90, 3.92 (7s, 7 × 3H, 7 OCH3), 3.66 (occluded dd, 1H, H-2),
4.10 (t, 1H, J 2,3 = J 3,4 ) 9.8 Hz, H-3), 4.18 (ddd, 1H, J 4,5
10.2, J 5,6A ) 4.8, J 5,6B ) 2.3 Hz, H-5), 4.39 (dd, 1H, J 6A,6B
)
)
Meth yl 3,6-An h yd r o-2,4-bis-O-(2-iod o-3,4,5-tr im eth oxy-
ben zoyl)-r-D-glu cop yr a n osid e (16). Prepared from methyl
3,6-anhydro-R-D-glucopyranoside27 and purified by FCC (hex-
ane-ethyl acetate 1:1); yield: 26%. [R]20D +34.2 (c 1.6, CHCl3);
1H NMR (CDCl3) δ 3.48, 3.51, 3.56, 3.80, 3.82, 3.83, 3.84 (7s,
7 × 3H, 7 OCH3), 4.11 (dd, 1H, J 5,6A ) 3.2, J 6A,6B ) 10.8 Hz,
H-6A), 4.31 (d, 1H, J 5,6B ) 0, H-6B), 4.69 (t, 1H, J 4,5 ) 2.9 Hz,
H-5), 4.89 (t, 1H, J 2,3 ) 4.0, J 3,4 ) 5.3 Hz, H-3), 5.02 (dd, 1H,
H-4), 5.19 (d, 1H, J 1,2 ) 3.8 Hz, H-1), 5.42 (t, 1H, H-2), 6.72 (s,
1H), 7.21 (s, 1H) (2 ArH); 13C NMR (CDCl3) δ 56.0, 56.1, 57.6,
60.7, 60.9, 68.7, 68.9, 70.5, 71.8, 73.3, 83.2, 84.1, 96.3, 110.3,
112.4, 128.9, 130.7, 144.6, 145.3, 152.8, 152.9, 153.7, 165.8,
166.1. HR-FABMS calcd for C27H30I2O13 m/z 815.9775, found
815.9772.
12.3 Hz, H-6A), 4.62 (dd, 1H, H-6B), ∼4.64 (d, 1H, J ) 12.1
Hz) and 4.79 (d, 1H) (OCHAHBPh), 4.65 (d, 1H, J 1,2 ) 3.7 Hz,
H-1), 4.71 (d, 1H, J ) 11.6 Hz) and 4.95 (d, 1H) (OCHAHBPh),
5.41 (t, 1H, H-4), 6.99 (s, 1H) and 7.38 (s, 1H) (2 ArH), 7.15-
7.35 (m, 10H, 2 Ph); 13C NMR (CDCl3) δ 55.8, 56.2, 56.6, 60.8,
61.0, 63.9, 67.3, 71.2, 73.5, 75.3, 79.1, 79.8, 83.9, 84.0, 98.3,
110.5, 111.2, 127.3, 127.4, 128.0, 128.1, 128.2, 128.5, 130.5,
130.5, 137.9, 138.3, 145.0, 145.1, 153.4, 153.5, 153.8, 153.9,
165.2, 166.1. Anal. Calcd for C41H44I2O14: C, 48.54; H, 4.37;
I, 25.02. Found: C, 48.65; H, 4.43; I, 25.12.
Meth yl 4,6-Di-O-ben zyl-2,3-bis-O-(2-iod o-3,4,5-tr im eth -
oxyben zoyl)-r-D-m a n n op yr a n osid e (9). Prepared from
methyl 4,6-di-O-benzyl-R-D-mannopyranoside25 and purified by
3-O-Ben zyl-5,6-bis-O-(2-iod o-3,4,5-tr im eth oxyben zoyl)-
1,2-O-isop r op ylid en e-r-D-glu cofu r a n ose (17). Prepared
from 3-O-benzyl-1,2-O-isopropylidene-R-D-glucofuranose and
FCC (hexane-ethyl acetate 2:1); yield: 93%. [R]20 -16.2 (c
D
1.7, CHCl3); 1H NMR (CDCl3) δ 3.45, 3.49, 3.67, 3.82, 3.84,
3.85, 3.91 (7s, 7 × 3H, 7 OCH3), 3.76-3.92 (m, 2H, H-6A, 6B),
3.99 (br d, 1H, J 4,5 ) 9.9 Hz, H-5), 4.37 (t, 1H, J 3,4 ) 9.8 Hz,
H-4), 4.52 and 4.67 (2d, AB, 2H, J ) 12.0 Hz, OCHAHBPh),
4.56 and 4.71 (2d, AB, 2H, J ) 11.3 Hz, OCHAHBPh), 4.95 (s,
1H, H-1), 5.67 (narrow m, 1H, H-2), 5.81 (dd, 1H, J 2,3 ) 3.2
Hz, H-3), 6.92 (s, 1H, 1 ArH), 7.16-7.19 (m, 5H, 4 PhH, 1 ArH),
7.26-7.33 (m, 6H, 6 PhH); 13C NMR (CDCl3) δ 54.9, 55.7, 60.5,
60.6, 60.7, 68.5, 71.1, 71.3, 72.8, 72.9, 73.4, 74.2, 83.3, 84.2,
98.1, 110.1, 111.3, 127.2, 127.3, 127.4, 127.6, 128.0, 128.1,
129.5, 130.9, 137.6, 137.7, 144.5, 145.2, 152.9, 153.0, 153.5,
153.7, 164.9, 165.2. Anal. Calcd for C41H44I2O14: C, 48.54;
H, 4.37; I, 25.02. Found: C, 48.80; H, 4.53; I, 25.23.
purified by FCC (hexane-ethyl acetate 3:1); yield: 93%. [R]20
D
1
-51.3 (c 1.4, CHCl3); H NMR (CDCl3) δ 1.32, 1.48 (2s, 2 ×
3H, CMe2), 3.74 (s, 3H), 3.81 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H),
3.89 (s, 6H) (6 OCH3), 4.14 (d, 1H, J 3,4 ) 3.2 Hz, H-3), 4.58-
4.66 (m, 4H, H-2,4, OCH2Ph), 4.68 (dd, 1H, J 5,6A ) 6.4, J 6A,6B
) 12.4 Hz, H-6A), 4.95 (dd, 1H, J 5,6B ) 2.1 Hz, H-6B), 5.86 (m,
1H, H-5), 5.96 (d, 1H, J 1,2 ) 3.6 Hz, H-1), 7.1 (s, 1H, ArH),
7.21-7.36 (m, 6H, Ph, ArH); 13C NMR (CDCl3) δ 26.3, 27.0,
56.4, 60.8, 61.0, 64.7, 70.1, 72.4, 78.6, 81.6, 81.9, 84.0, 84.1,
105.4, 111.2, 111.3, 112.1, 127.9, 128.0, 128.5, 130.5, 130.6,
137.1, 145.1, 145.2, 153.4, 153.4, 153.9, 153.9, 165.1, 165.9.
HR-FABMS calcd for C36H40I2O14 m/z950.0507,found: 950.0470.
Meth yl 2,6-Di-O-ben zyl-3,4-bis-O-(2-iod o-3,4,5-tr im eth -
oxyben zoyl)-r-D-ga la ctop yr a n osid e (12). Prepared from
methyl 2,6-di-O-benzyl-R-D-galactopyranoside26 and purified
3-O-(2-Iod o-3,4,5-t r im et h oxyben zoyl)-1,2:5,6-d i-O-iso-
p r op ylid en e-r-D-glu cofu r a n ose (18). Prepared from 1,2:
5,6-di-O-isopropylidene-R-D-glucofuranose (0.39 g, 1.5 mmol),
2-iodo-3,4,5-trimethoxybenzoic acid (0.53 g, 1.58 mmol), DCC
(0.37 g, 1.8 mmol), and DMAP (0.056 g) according to the
general procedure; crude 18 was purified twice by flash
by FCC (hexane-ethyl acetate 3:1); yield 70%. [R]20 +34.9
D
1
(c 1.6, CHCl3); H NMR (CDCl3) δ 3.47, 3.59, 3.65, 3.84, 3.85,
3.87, 3.91 (7s, 7 × 3H, 7 OCH3), ∼3.62 (m, 2H, H-6A, 6B), 4.18
(dd, 1H, J 1,2 ) 3.5, J 2,3 ) 10.5 Hz, H-2), 4.33 (t, 1H, J 4,5 = 0,
J 5,6A = J 5,6B = 6.1 Hz, H-5), 4.51 (AB, 2H, J ) 11.9
Hz, OCHAHBPh), 4.65 (d, 1H, J ) 12.5 Hz) and 4.75 (d, 1H)
(AB, OCHAHBPh), 4.84 (narrow d, 1H, H-1), 5.76 (dd, 1H, J 3,4
) 3.3 Hz, H-3), 5.94 (narrow m, 1H, H-4), 7.04 (s, 1H) and
7.08 (s, 1H) (2 ArH), 7.23-7.31 (m, 10H, 2 Ph); 13C NMR
(CDCl3) δ 55.6, 56.1, 56.2, 60.8, 61.0, 61.1, 67.8, 68.7, 71.0,
71.2, 73.0, 73.6, 74.1, 83.6, 83.9, 98.6, 110.8, 111.2, 127.6, 127.7,
127.8, 127.9, 128.4, 128.5, 130.6, 131.3, 137.8, 138.0, 144.8,
145.2, 153.3, 153.8, 154.0, 165.5, 165.6. Anal. Calcd for
chromatography (hexane-ethyl acetate 5:1). Yield: 0.848 g
1
(97%). [R]20 -36.5 (c 3.0, CHCl3); H NMR (CDCl3) δ 1.30,
D
1.35, 1.43, 1.56 (4s, 4 × 3H, 2 CMe2), 3.88 (s, 6H), 3.92 (s, 3H)
(3 OCH3), 4.05-4.15 and 4.30-4.37 (2m, 4H, H-4,5,6A,6B),
4.75 (d, 1H, J 1,2 ) 3.7 Hz, J 2,3 ) 0, H-2), 5.46 (d, 1H, J 3,4 ) 2.3
Hz, H-3), 5.97 (d, 1H, H-1), 7.17 (s, 1H, ArH); 13C NMR (CDCl3)
δ 25.4, 26.3, 26.8, 26.9, 56.3, 60.9, 61.1, 67.5, 72.8, 77.7, 80.0,
83.3, 83.8, 105.3, 109.4, 110.8, 112.5, 130.7, 145.3, 153.5, 154.0,
165.4. HR-FABMS calcd for C22H29IO10 m/z 580.0805, found
580.0780.
C
41H44I2O14: C, 48.54; H, 4.37; I, 25.02. Found: C, 48.63; H,
6-O-(2-Iod o-3,4,5-t r im et h oxyben zoyl)-1,2:3,4-d i-O-iso-
p r op ylid en e-r-D-ga la ctop yr a n ose (19). Prepared from 1,2:
3,4-di-O-isopropylidene-R-D-galactopyranose as described for
4.41; I, 25.51.
1,6-An h yd r o-2,3,4-tr is-O-(2-iod o-3,4,5-tr im eth oxyben -
zoyl)-r-D-glu cop yr a n ose (15). A suspension of 1,6-anhydro-
â-D-glucopyranose (0.162 g, 1.0 mmol) in CH2Cl2 (12 mL)
the preparation of 18 and purified by FCC (hexane-ethyl
1
acetate 5:1); yield: 97%. [R]20 -32 (c 1.7, CHCl3); H NMR
D
(CDCl3) δ 1.32, 1.35, 1.48, 1.51 (4s, 4 × 3H, 2CMe2), 3.87, 3.88,
(24) Giuliano, R. M.; Buzby, J . H. J . Carbohydr. Chem. 1987, 6, 541-
3.91 (3s, 3 × 3H, 3 OCH3), 4.20 (ddd, 1H, J 4,5 ) 1.8, J 5,6A
)
552.
(25) Kong, F.; Schuerch, C. Carbohydr. Res. 1983, 112, 141-147.
(26) Schneider, J .; Lee, Y. C.; Flowers, H. M. Carbohydr. Res. 1974,
36, 159-166.
(27) Haworth, W. N., Owen, L. N.; Smith, F. J . Chem. Soc. 1941,
88-102.

Studies Relevant to Ellagitannin Chemistry
J . Org. Chem., Vol. 63, No. 22, 1998 7633
7.9, J 5,6B ) 4.2 Hz, H-5), 4.34 (m, 2H, H-2,4), 4.43 (dd, 1H,
J 6A,6B ) 11.6 Hz, H-6A), 4.55 (dd, 1H, H-6B), 4.65 (dd, 1H, J 2,3
) 7.9, J 3,4 ) 2.4 Hz, H-3), 5.56 (d, 1H, J 1,2 ) 5.0 Hz, H-1),
7.24, (s, 1H, ArH); 13C NMR (CDCl3) δ 24.6, 25.0, 26.0, 26.2,
56.3, 60.8, 61.0, 64.7, 66.2, 70.6, 70.9, 71.2, 83.8, 96.4, 108.8,
109.8, 111.0, 131.2, 145.0, 153.4, 153.9, 166.4. Anal. Calcd
for C22H29IO10: C, 45.53; H, 5.04; I, 21.87. Found: C, 45.78;
H, 5.14; I, 21.63.
Ullm a n n Rea ction s. Gen er a l P r oced u r e. A solution of
acylated glycoside (0.5 mmol) in DMF (6 mL) was slowly added
(syringe-pump) to refluxing DMF (6 mL) containing pretreated
Cu15 (4 mmol) over a period of 4-5 h. The reaction mixture
was kept at reflux temperature for an additional period of 2
h. The solids were then removed by filtration through a pad
of Celite, the solvent was evaporated in vacuo, and the residue
was submitted to flash chromatography (hexane-ethyl ac-
etate).
Meth yl 4,6-O-Ben zylid en e-2,3-O-[(S)-4,4′,5,5′,6,6′-h exa -
m eth oxy-2,2′-d ip h en oyl]-r-D-glu cop yr a n osid e (5). Treat-
ment of 3 with Cu as described in the general procedure
(duration of addition: 1 h) gave compound 428 and 5 in a 1.2:1
ratio (NMR). Separation of the components of the mixture by
preparative TLC (ethyl acetate-hexane 1:2, multiple develop-
ments) afforded pure 5 in 40% yield. [R]20D +3.1 (c 1.6, CHCl3);
1H NMR (CDCl3) δ 3.49, 3.61, 3.67, 3.89, 3.925, 3.93, 3.94 (7s,
7 × 3H, 7 OCH3), 3.84, 3.87 (2t, 2H, J ∼ 10 Hz, H-4,6A), 3.99
(td, 1H, J 5,6A ) 4.6, J 4,5 = J 5,6B = 9.8 Hz, H-5), 4.33 (dd, 1H,
J 5,6A ) 4.6, J 6A,6B ) 10.2 Hz, H-6B), 4.97 (d, 1H, J 1,2 ) 3.6 Hz,
H-1), 5.20 (dd, 1H, J 2,3 ) 9.3 Hz, H-2), 5.58 (s, 1H, PhCH),
6.64 (t, 1H, H-3), 6.77 (s, 2H, 2 ArH), 7.38-7.41 (m, 3H) and
7.50-7.53 (m, 2H) (Ph). HR-FABMS calcd for C34H36O14 m/z
668.2103, found 668.2085.
152.3, 152.4, 153.0 (2C), 166.9, 168.0. HR-FABMS calcd for
C41H45O14 ([M + H]+) m/z 761.2809, found 761.2805.
Meth yl 4,6-Di-O-ben zyl-2,3-O-[(R)-4,4′,5,5′,6,6′-h exa -
m eth oxy-2,2′-diph en oyl]-r-D-m an n opyr an oside (10). Treat-
ment of 9 with Cu as described in the general procedure and
separation of the products by flash chromatography (ethyl
acetate-hexanes 2:9) gave compounds 10 and 11 in 77% and
21% yield, respectively. Compound 10: [R]20 -79.3 (c 1.2,
D
1
CHCl3); H NMR (CDCl3) δ 3.41, 3.51, 3.56, 3.83, 3.89, 3.95,
3.99 (7s, 7 × 3H, 7 OCH3), 3.65 (ABX, 2H, H-6A,6B), 3.7-3.8
(m, 2H, H-4,5), 4.00 (d, 1H, J AB ) 11.0 Hz) and 4.19 (d, 1H)
(OCHAHBPh), 4.47 (d, 1H, J AB ) 12.2 Hz) and 4.61 (d, 1H)
(OCHAHBPh), 4.97 (narrow d, 1H, J 1,2 ) 1.6 Hz, H-1), 5.12 (dd,
1H, J 2,3 ) 3.1 Hz, H-2), 5.32 (dd, 1H, J 3,4 ) 8.5 Hz, H-3), 7.06
(s, 1H) and 7.57 (s, 1H) (2 ArH), 6.93 (m, 2H), 7.19 (m, 3H)
and 7.28-7.35 (m, 5H) (2 Ph); 13C NMR (CDCl3) δ 55.0, 56.0,
56.2, 60.9, 61.0, 68.6, 69.3, 70.7, 72.7, 73.6, 74.6, 77.6, 77.9,
98.6, 105.4, 107.2, 111.0, 122.7, 123.9, 125.0, 127.6, 127.7,
127.8, 127.9, 128.3, 128.5, 129.4, 137.7, 138.1, 144.3, 146.6,
152.1, 152.4, 152.8, 165.6, 170.3. Anal. Calcd for C41H44O14
C, 64.73; H, 5.83. Found: C, 64.68; H, 5.90.
:
Meth yl
2,6-Di-O-ben zyl-3,4-O-[(S)-4,4′,5,5′,6,6′-h exa -
m eth oxy-2,2′-diph en oyl]-r-D-galactopyr an oside (13). Treat-
ment of 12 with Cu as described in the general procedure and
separation of the products by flash chromatography (ethyl
acetate-hexanes 1:4) gave compounds 13 and 14 in 69% and
29% yield, respectively. Compound 13: [R]20 +105.7 (c 0.8,
D
CHCl3); 1H NMR (CDCl3) δ 3.38, 3.56, 3.57, 3.92, 3.934, 3.95,
3.99 (7s, 7 × 3H, 7 OCH3), 3.67 (d, 2H, J 5,6 ) 6.3 Hz, H-6’s),
3.76 (dd, 1H, J 1,2 ) 3.5, J 2,3 ) 10.3 Hz, H-2), 3.98 (d, 1H, J AB
) 12.1 Hz, OCHAHBPh), 4.20 (br t, 1H, H-5), 4.47 (d, 1H, H-1),
4.52 (d, 1H, OCHAHBPh), 4.56 (AB, 2H, J AB ) 12.0 Hz, OCH2-
Ph), 5.31 (narrow dd, 1H, J 3,4 ) 3.0, J 4,5 ) 1.4 Hz, H-4), 5.41
(dd, 1H, H-3), 6.87 (s, 1H) and 7.55 (s, 1H) (2 ArH), 7.07 (m,
2H) and 7.24-7.32 (m, 8H) (2 Ph); 13C NMR (CDCl3) δ 55.6,
56.1, 56.3, 60.9, 61.1, 67.1, 68.6, 73.3, 73.6, 73.8, 75.5, 77.5,
99.2, 104.9, 110.8, 123.3, 123.7, 124.5, 127.7, 127.7, 128.0,
128.1, 128.4, 129.4, 137.8, 137.9, 144.2, 146.4, 152.3, 152.4,
Meth yl
2,3-Di-O-ben zyl-4,6-O-[(S)-4,4′,5,5′,6,6′-h exa -
m eth oxy-2,2′-diph en oyl]-r-D-glu copyr an oside (7b). Treat-
ment of 6b with Cu as described in the general procedure
afforded compound 7b and 8b in a 1:1 ratio (NMR). Separa-
tion of the components of the mixture by preparative TLC
(ethyl acetate-hexane 1:3, multiple developments) afforded
152.7, 152.8, 165.9, 170.7. Anal. Calcd for C41H44O14
64.73; H, 5.83. Found: C, 64.83; H, 6.37.
: C,
a sample of pure 7b: [R]20 -44 (c 1.5, CHCl3); 1H NMR
D
(CDCl3) δ 3.38, 3.69, 3.76, 3.85, 3.87, 3.947, 3.955 (7s, 7 × 3H,
7 OCH3), 3.62 (dd, 1H, J 1,2 ) 3.8, J 2,3 ) 9.2 Hz, H-2), 3.82 (br
d, 1H, J 5,6A < 1, J 6A,6B ) 12.9 Hz, H-6A), 3.97 (t, 1H, J ) 9.5
Hz, H-3), 4.13 (br dd, 1H, J 4,5 = 10, J 5,6B ) 6.1 Hz, H-5), 4.51
(d, 1H, H-1), 4.63 (d, 1H, J AB ) 12.1 Hz) and 4.81 (d, 1H), 4.76
(d, 1H, J AB ) 11.9 Hz) and 4.89 (d, 1H) (2 OCHAHBPh), 4.92
(t, 1H, J 3,4 = J 4,5 = 10 Hz, H-4), 5.04 (dd, 1H, H-6B), 6.54 (s,
1H) and 6.72 (s, 1H) (2 ArH), 7.21-7.35 (m, 5H, Ph); 13C NMR
(CDCl3) δ 55.6, 56.0, 56.1, 60.8, 61.0, 61.1, 63.8, 67.0, 72.3,
73.8, 74.8, 79.2, 80.0, 99.0, 105.6, 105.7, 122.5, 123.3, 127.5,
128.0, 128.1, 128.3, 128.5, 128.6, 137.9, 138.6, 144.2, 144.7,
Ack n ow led gm en t is made to the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for support of this research in its
initial stage.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
compounds 4, 8b, 11, and 14 (8 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.
(28) Data for the reduced products, 4, 8b, 11, and 14, are provided
in Supporting Information.
J O971722K