Total synthesis of flavocommelin, a component of the blue supramolecular pigment from Commelina communis, on the basis of direct 6-C-glycosylation of flavan

Article abstract of DOI:10.1021/jo0494681

We succeeded in a first total synthesis of flavocommelin (1), a component of the blue supramolecular pigment, commelinin (2), from Commelina communis, by direct 6-C-glycosylation of the flavan 4 using perbenzylglucosyl fluoride 8 in the presence of MS 5 A in CH₂Cl₂ and a catalytic amount of BF₃·Et₂O. After 6-C-glycosylation of 4, oxidation with CAN to flavanone 18 and subsequent 4′-O-glycosylation, promoted with a combination of BF₃·Et₂O and DTBMP, afforded diglucosylflavanone 20. DDQ oxidation of 20 and deprotection successively gave 1.

Full text of DOI:10.1021/jo0494681

Tota l Syn th esis of F la vocom m elin , a Com p on en t of th e Blu e
Su p r a m olecu la r P igm en t fr om Com m elin a com m u n is, on th e Ba sis
of Dir ect 6-C-Glycosyla tion of F la va n
Kin-ichi Oyama† and Tadao Kondo*,‡
Chemical Instrument Center and Graduate School of Bioagricultural Sciences, Nagoya University,
Chikusa, Nagoya 464-8601, J apan
kondot@agr.nagoya-u.ac.jp
Received March 31, 2004
We succeeded in a first total synthesis of flavocommelin (1), a component of the blue supramolecular
pigment, commelinin (2), from Commelina communis, by direct 6-C-glycosylation of the flavan 4
using perbenzylglucosyl fluoride 8 in the presence of MS 5 Å in CH2Cl2 and a catalytic amount of
BF3‚Et2O. After 6-C-glycosylation of 4, oxidation with CAN to flavanone 18 and subsequent 4′-O-
glycosylation, promoted with a combination of BF3‚Et2O and DTBMP, afforded diglucosylflavanone
20. DDQ oxidation of 20 and deprotection successively gave 1.
In tr od u ction
We have focused our attention on flavocommelin (1),
a 7-O-methylapigenin 6-C-,4′-O-di-â-D-glucoside, and one
of the components of commelinin (2), a blue supramo-
lecular pigment that is a metalloanthocyanin (a metal-
complex anthocyanin) in Commelina communis.3b Com-
melinin (2), to our knowledge, is the most stable of the
metalloanthocyanins due to the presence of C-glucosyl-
flavone. Its structure has been established by X-ray
crystallographic analysis3b and the pigment is a stoichio-
metric self-assembled supramolecule composed of six
molecules of malonylawobanin (3), six molecules of 1, and
two atoms of magnesium ion (Figure 1). The components
of 2 spatially self-assemble on the basis of very strict
chiral molecular recognition. Recognition by self-associa-
tion (itself) of 1 and 3, and copigmentation between 1
and 3 might be caused by chiral hydrophobic π-π
interactions and some hydrogen bonding among the
sugar residues.3b,11 To elucidate the basis for molecular
chiral recognition in the formation of commelinin (2), 1
and its analogues bearing various D- and/or L-glucose are
necessary. We herein report the first successful synthesis
of flavocommelin (1) using a newly developed approach
for efficient C-glycosylation of flavan as a key reaction.
A variety of C-glycosylflavonoids are found widely
distributed in the plant kingdom.1 The C-glycosides are
generally linked at C-6 and/or C-8 on the A-ring of the
flavonoid nucleus. Their biological activities as antioxi-
dants,2 flower-color-development,3 DNA binding,4 hy-
potension,5 and ovipositional6 and feeding7 stimulation
for insects are well-known. Carthamin, a C-glucosylchal-
cone, is practically used as a red pigment.8 Despite the
attractive biological characteristics and commercial util-
ity, only a few synthetic methods for C-glycosylflavonoids
have been reported.1,9,10 In fact, the synthesis of a flavone
bearing both O- and C-glucosides has hitherto never been
reported.
* Address correspondence to this author. Phone: (+81)52-789-4138.
Fax: (+81)52-789-4138.
† Chemical Instrument Center.
‡ Graduate School of Bioagricultural Sciences.
(1) (a) Harborne, J . B., Ed. The Flavonoids: Advances in Research
since 1986; Chapman and Hall: London, UK, 1994. (b) Harborne, J .
B., Ed. The Flavonoids: Advances in Research since 1980; Chapman
and Hall: London, UK, 1988. (c) Takeda, Y.; Okada, Y.; Masuda, T.;
Hirata, E.; Shinzato, T.; Otsuka, H. Phytochemistry 2004, 65, 463.
(2) (a) Hertog, M. G. L.; Feskens, E. J . M.; Hollman, P. C. H.; Katan,
M. B.; Kromhout, D. Lancet 1993, 342, 1007. (b) Cren-Olive´, C.; Hapiot,
P.; Pinson, J .; Rolando, C. J . Am. Chem. Soc. 2002, 124, 14027.
(3) (a) Goto, T.; Kondo, T. Angew. Chem. 1991, 103 17. (b) Kondo,
T.; Yoshida, K.; Nakagawa A.; Kawai, T.; Tamura, H.; Goto, T. Nature
1992, 358, 515.
(4) Carte´, B. K.; Carr, S.; DeBrosse, C.; Hemling, M. E.; MacKenzie,
L.; Offen, P.; Berry, D. E. Tetrahedron 1991, 47, 1815.
(5) Kumamoto, H.; Matsubara, Y.; Iizuka, Y.; Okamoto, K.; Yokoi,
K. Agric. Biol. Chem. 1986, 50, 781.
(6) Ohsugi, T.; Nishida, R.; Fukami, H. Agric. Biol. Chem. 1985, 49,
1897.
(7) Besson, E.; Dellamoica, G.; Chopin, J .; Markham, K. R.; Kim,
M.; Koh, H.-S.; Fukami, H. Phytochemistry 1985, 24, 1061.
(8) (a) Obara, H.; Onodera, J .-I. Chem. Lett. 1979, 201. (b) Taka-
hashi, Y.; Miyasaka, N.; Tasaka, S.; Miura, I.; Urano, S.; Ikura, M.;
Hikichi, K.; Matsumoto, T.; Wada, M. Tetrahedron Lett. 1982, 23, 5163.
(c) Kumazawa, T.; Sato, S.; Kanenari, D.; Kunimatsu, A.; Hirose, R.;
Matsuba, S.; Obara, H.; Suzuki, M.; Sato, M.; Onodera, J .-I. Chem.
Lett. 1994, 2343.
Resu lts a n d Discu ssion
Syntheses of C-glycosylflavonoids have been realized
on the basis of both C-glycosylations, Fries-type rear-
(9) For synthesis of C-glucosyl flavone via C-glucosyl phloroaceto-
phenone: (a) Mahling, J .-A.; J ung, K.-H.; Schmidt, R. R. Liebigs Ann.
1995, 461. (b) Kumazawa, T.; Minatogawa, T.; Matsuba, S.; Sato, S.;
Onodera, J .-I. Carbohydr. Res. 2000, 329, 507. (c) Kumazawa, T.;
Kimura, T.; Matsuba, S.; Sato, S.; Onodera, J .-I. Carbohydr. Res. 2001,
334, 183.
(10) For synthesis of 6-C-glucosyl flavone with a lithiated aromtic
compound: (a) Frick, W.; Schmidt, R. R. Liebigs Ann. Chem. 1989,
565. (b) Lee, D. Y. W.; Zhang, W.-Y.; Karnati, V. V. R. Tetrahedron
Lett. 2003, 44, 6857.
(11) Kondo, T.; Oyama, K.-I.; Yoshida, K. Angew. Chem., Int. Ed.
2001, 40, 894.
10.1021/jo0494681 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/02/2004
5240
J . Org. Chem. 2004, 69, 5240-5246

Total Synthesis of Flavocommelin
F IGURE 1. Commelinin (2) and the structure of its components.
SCHEME 1. Retr osyn th esis of F la vocom m elin (1)
We have already achieved efficient O-glycosylation of 4′-
OH of a flavone12 using peracetylglucosyl fluoride 5
promoted with BF3‚Et2O as a Lewis acid and 2,6-di-tert-
butyl-4-methylpyridine (DTBMP) as a Lewis base.11,13
Aryl C-glycosylation depends on the electron density
of the aromatic ring14 and protecting groups of glycosyl
donors.15 Because 1,3,5-trimethoxybenzene has a high
electron density on the ring, a variety of glycosyl donors
such as glycosyl imidate,16a pyridyl thioglycoside,16b gly-
cosyl fluoride,16c glycosyl dinitrobenzoate,16d glycosyl tri-
fluoroacetate,16e and glycosyl dimethylphosphinothioate16f
in the presence of Lewis acid are applicable for C-
glycosylation. Recently, Kumazawa reported 2,4-O-ben-
zyloxy-6-hydroxyacetophenone to be C-glycosylated, in-
volving Fries rearrangement.9b,c,17
At first we focused on (() naringenin (6) having a
flavanone skeleton like trihydroxyacetophenone for direct
C-glycosylation. Attempts at glycosylation of 7,4′-O-
dimethylnaringenin (7b ) with 2,3,4,6-tetra-O-benzyl-
â-D-glucopyranosyl fluoride (8), using BF3‚Et2O17 or Cp2-
(12) The reactivity of 4′-OH of flavone is low: (a) Harborne, J . B.;
Mabry, T. J .; Mabry, H., Eds. The Flavonoids, Part 1; Academic
Press: New York, 1975; p 166. (b) Lewis, P.; Kaltia, S.; Wa¨ha¨la¨, K. J .
Chem. Soc., Perkin Trans. 1 1998, 2481. (c) Du, Y.; Wei, G.; Linhardt,
R. J . Tetrahedron Lett. 2003, 44, 6887.
(13) (a) Oyama, K.-I.; Kondo, T. Synlett 1999, 1627. (b) Oyama, K.-
I.; Kondo, T. Tetrahedron 2004, 60, 2025.
rangement of O- to C-glycoside,9 and coupling reaction
between lithiated aromatic compounds and sugar deriva-
tives.10 Usually, with 2,4,6-trihydroxybenzene derivatives
the following difficulties are encountered:9,10 multistep
selective protection of 2,4,6-trihydroxybenzene deriva-
tives, nonregioselective cyclization to a flavone skeleton,
and insufficient C-glycosylation.
We have developed an efficient synthetic strategy to
derive 1 from a flavan derivative as a presumed impor-
tant intermediate based on the stepwise glycosylation of
O- and C-glycosides capable of replacing D-glucose with
L-glucose for preparation of chiral analogues (Scheme 1).
As use of flavan 4 as a starting material avoids the above-
mentioned difficulties, direct C-glycosylation to a fla-
vonoid nucleus would allow the concise synthesis of 1.
(14) In general the C-glycosylation of electron-rich aromatic com-
pounds proceeds smoothly, while it is remarkably suppressed by
substitution of electron withdrawing and/or steric hindrance groups
on the aromatic ring: (a) J aramillo, C.; Knapp, S. Synthesis 1994,
1. (b) Plante, O. J .; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H.
J . Am. Chem. Soc. 2001, 123, 9545. (c) Kumazawa, T.; Ishida,
M.; Matsuba, S.; Sato, S.; Onodera, J .-I. Carbohydr. Res. 1997, 297,
379.
(15) Kanai, A.; Kamino, T.; Kuramochi, K.; Kobayashi, S. Org. Lett.
2003, 5, 2837.
(16) (a) Schmidt, R. R.; Hoffmann, M.; Chemie, F. Tetrahedron Lett.
1982, 23, 409. (b) Williams, R. M.; Stewart, A. O. Tetrahedron Lett.
1983, 24, 2715. (c) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron
Lett. 1989, 30, 833. (d) Cai, M.-S.; Qiu, D.-X. Synth. Commun. 1989,
19, 851. (e) Cai, M.-S.; Qiu, D.-X. Carbohydr. Res. 1989, 191, 125. (f)
Yamanoi, T.; Fujioka, A.; Inazu, T. Bull. Chem. Soc. J pn. 1994, 67,
1488.
(17) Kumazawa, T.; Ohki, K.; Ishida, M.; Sato, S.; Onodera, J .-I.;
Matsuba, S. Bull. Chem. Soc. J pn. 1995, 68, 1379.
J . Org. Chem, Vol. 69, No. 16, 2004 5241

Oyama and Kondo
SCHEME 2. Attem p ted C-Glycosyla tion of
SCHEME 3. Syn th esis of F la va n 4a
F la va n on e 7b
a
Reagents and conditions: (a) CH3I (1.5 equiv of 6), K2CO3,
DMF, rt (7a : R ) H (76%); 7b: R ) CH3 (3%)); (b) AcCl, Et3N,
DMAP, CH2Cl2, rt (90%) (from 7a ); (c) NaBH4, THF/H2O, 0 °C
(85%).
HfCl2/AgClO4,18 however, provided no naringenin C-
glucoside (Scheme 2). This might have been due to an
electron deficiency on the A-ring of 7b arising from the
carbonyl group19 and strong hydrogen bonding between
6-OH and the carbonyl group, suggesting that transfor-
mation of a flavanone to a flavan is necessary for
C-glycosylation.
TABLE 1. Glycosyla tion of F la va n 4 w ith
P er ben zylglu cosyl F lu or id e 8a
We assumed that flavan 4 is most suitable as an
intermediate for synthesis of 1. Regioselective methyla-
tion of commercially available (() naringenin (6) with 1.5
equiv of CH3I/K2CO3 in DMF at room temperature
afforded the 7-O-methylnaringenin (7a ) and 7,4′-O-dim-
ethylnaringenin (7b) in 76% and 3% yields, respectively.
Acetylation of 7a with AcCl/Et3N/DMAP in CH2Cl2 af-
forded diacetate 9 in 90% yield. Removal of the carbonyl
group was carried out by reduction of 9 with 2 equiv of
NaBH4 in THF and H2O at 0 °C for 30 min to give an
85% yield of the monoacetate 4 as a racemate (Scheme
3).20 C-Glycosylation of the flavan 4 with glucosyl fluo-
rides, using BF3‚Et2O as a promoter, was investigated.
Glycosylation with perbenzylglucosyl fluoride 8 and BF3‚
Et2O (100 mol %) in CH2Cl2 in the presence of MS 5 Å
provided an inseparable diastereomeric mixture of the
6-C-â-glucoside 10, the 8-C-â-glucoside 11, and the 5-O-
R- and â-glucosides 12a and 12b in 53%, 2%, and 16%
yields, respectively,21 but no C-R-glucoside (Table 1, entry
1). Determination of the anomeric configuration of the
products was very difficult by NMR analysis because of
overlapping signals for the anomeric and benzylic protons
(vide infra).
yield (%)b
promotor
(mol %)
entry
additive solvent 10c 11c 12a d 12be
1
BF3‚Et2O (100) MS 5 Å CH2Cl2 53
Cp2HfCl2 (200)/ MS 4 Å CH2Cl2 39
AgClO4 (100)
2
6
11
8
5
6
2f
3
4
5
6
7
BF3‚Et2O (20)
BF3‚Et2O (20)
BF3‚Et2O (20)
BF3‚Et2O (20)
BF3‚Et2O (10)
none
CH2Cl2 21
1
9
7
5
9
13
8
11
2
4
6
2
5
MS 4 Å CH2Cl2 39
MS 5 Å CH2Cl2 56
MS 5 Å CH3CN 19 23
MS 5 Å CH2Cl2 49
9
a
All reactions were carried out with 2 equiv of 4 to 8 for 1.5 h.
The yield was determined by 1H NMR on the basis of an isolated
b
mixture of 10, 11, 12a , and 12b. c C-Glucosides 10 and 11 were
d
obtained as â-isomers exclusively. 12a was a R-glucoside. e 12b
was a â-glucoside. f The reaction mixture was allowed to stand
from -10 °C to rt for 1.5 h.
With Cp2HfCl2/AgClO4,18 a similar trend was observed,
but yields were low (Table 1, entry 2), while using
peracetylglucosyl fluoride 522 promoted with BF3‚Et2O in
CH2Cl2 gave only a trace amount of the desired 6-C-â-
glucoside 1323 (Table 2, entries 1 and 2). However,
glycosylation of 4 with 5 promoted with a Lewis acid and
a base combination of BF3‚Et2O and DTBMP11,13 gave
predominantly the 5-O-â-glucoside (14b/13 ) 92/8, Table
2). These results showed that the phenolate, deproto-
nated with DTBMP, gives the O-glycoside. As a result of
the screening of the reaction condition, this C-glycosy-
lation could proceed smoothly with catalytic amounts
(>20 mol %) of BF3‚Et2O and the yield of the desired 10
(18) Matsumoto, T.; Katsuki, M.; J ona, H.; Suzuki, K. J . Am. Chem.
Soc. 1991, 113, 6982.
(19) In the case of aryl C-glycosylation of juglone,
a similar
phenomenon was observed: Matsuo, G.; Miki, Y.; Nakata, M.; Mat-
sumura, S.; Toshima, K. J . Org. Chem. 1999, 64, 7101.
(20) (a) Sweeny, J . G.; Iacobucci, G. A. Tetrahedron 1977, 33, 2927.
(b) Mitchell, D.; Doecke, C. W.; Hay, L. A.; Koenig, T. M.; Wirth, D. D.
Tetrahedron Lett. 1995, 36, 5335.
(21) All compounds 10-20 feature a diastereomeric mixture, arising
from the stereochemistry of the C-2 position. As these were an
inseparable mixture by silica gel column chromatography, 1H NMR
assignment in a diastereomeric mixture was carried out.
(22) For an example of the aryl C-glycosylation with peracetylated
glycosyl donor: Kuribayashi, T.; Ohkawa, N.; Satoh, S. Tetrahedron
Lett. 1998, 39, 4537.
(23) The regiochemistry and anomeric configuration of 13 were
determined by peracetylation (see Supporting Information).
5242 J . Org. Chem., Vol. 69, No. 16, 2004

Total Synthesis of Flavocommelin
TABLE 2. Glycosyla tion of F la va n 4 w ith
P er a cetylglu cosyl F lu or id e 5
TABLE 3. Attem p t a t O-to-C Rea r r a n gem en t of th e
O-Glu cosid es 12a a n d 12ba
BF3‚Et2O
(mol %)
yield
(%)b,c
ratio
entry
((12a + 12b)/10)d
1
2
20
100
72
61
98/2
81/19
a
Ratio of 12a and 12b as starting materials was ca. 70/30.
Isolated yield. c 8-C-Glucosides were not obtained. Ratios were
b
d
determined by 1H NMR.
to 1 equiv gave the same result (Table 3, entry 2). Thus,
this major reaction involves a different mechanism from
Fries-type O-to-C rearrangement. The glucosyl cation,
generated from 8 with BF3‚Et2O, might form a π-com-
plex25 by interacting with an aromatic ring and 5-OH of
4 directly for 6-C-glycosylation.
time yield
(h)
ratio
entry
condition
(%)a (13/14b)b,c
1
2
3
BF3‚Et2O (1 equiv), MS 5 Å
BF3‚Et2O (4 equiv)
BF3‚Et2O (4 equiv), DTBMP
1.5
1
<1
6
ndd
94/6
8/92
1
82
Treatment of a mixture of the 6-C-glucoside 10 and the
O-glucosides 12a and 12b with AcCl/Et3N/DMAP acety-
lated only 10 to give diacetate 16 (a diastereomeric
mixture), which could be readily isolated from 12a and
12b (Scheme 5). The J anomeric of 16 was 10.8 Hz (δ 4.70
Hz), indicating the glucoside to be in the C-â-configura-
tion. The remaining 12a and 12b were hydrogenated
with H2/Pd(OH)2 and acetylated to provide the pentaac-
etates 14a (J anomeric ) 2.7 Hz (δ 5.72, 5.73 Hz), R-gluco-
side) and 14b (J anomeric ) 8.1 Hz (δ 5.46 Hz), â-glucoside)
(Scheme 6).
a
b
Isolated yield. Both O- and C-glucosides were obtained only
as â-isomers. c Ratios of 13 and 14b, inseparable by column
chromatography, were determined by 1H NMR. nd ) not deter-
mined.
d
SCHEME 4. Acetyla tion of 11
To oxidize 16 with CAN26 (ceric ammonium nitrate),
the benzyl ester 16 was transformed to the benzoate 17,
for which the rotamer was observed by NMR, quantita-
tively by hydrogenolysis,27 and then benzoylation was
accomplished with BzCl/pyridine/DMAP. 17 was oxidized
with CAN26 in AcOH/H2O/CH3CN at 60 °C for 30 min to
the corresponding flavanone 18 in 43% yield, but DDQ28
(2,3-dichloro-5,6-dicyano-1,4-benzoquinoe) oxidation and
the other oxidations29 failed to give the desired product.
Regioselective deacetylation at 4′-OH of 18 with AcCl/
CH3OH30 afforded the monoacetate 19 in 80% yield. 19
was glycosylated with peracetylglucosyl fluoride 5 by a
combination of BF3‚Et2O and DTBMP11,13 in CH2Cl2 to
give the desired di-â-glucoside 20 in 84% yield. Further-
was improved to 56% (total conversion yield based on 8
was 82%) (Table 1, entry 5). In this reaction, molecular
sieves (MS 5 Å) played an important role. Without MS 5
Å the yield was decreased to 29% and on changing MS 5
Å to MS 4 Å reduction to 39% was apparent (Table 1,
entries 4 and 5). Therefore, MS 5 Å may be a HF-
scavenger in the catalytic cycle. Change of CH2Cl2 to CH3-
CN as the solvent altered the mole ratio of the products,
the 8-C-â-glucoside 11 predominating (10/11 ) 19/23)
(Table 1, entry 6).
To determine the anomeric configuration of 11 the
corresponding acetate 15 was derived by hydrogenolysis
and acetylation (83% yield, Scheme 4). As the J anomeric was
10.2 Hz (δ 5.13 Hz), 15 was a C-â-glucoside.
It is hypothesized that C-glycosylation of phenol in-
volves Fries-type O-to-C rearrangement24 via O-gluco-
sides. To clarify this reaction, a mixture of the isolated
O-glucosides (12a and 12b) was treated with 20 mol %
of BF3‚Et2O in the presence of MS 5 Å in CH2Cl2 for 15
h at room temperature. Most of starting materials were
recovered with only a trace amount of 6-C-glucoside 10
(Table 3, entry 1) and further addition of the catalyst up
(25) (a) Olah, G. A.; Schlosberg, R. H.; Porter, R. D.; Mo, Y. K.;
Kelly, D. P.; Mateescu, G. D. J . Am. Chem. Soc. 1972, 94, 2034. (b)
Olah, G. A.; Kobayashi, S.; Nishimura, J . J . Am. Chem. Soc. 1973, 95,
564.
(26) For CAN oxidation of the C-4 position of chroman: (a) Kan-
vinde, M. N.; Kulkarni, S. A.; Paradkar, M. V. Synth. Commun. 1990,
20, 3259. (b) Bissada, S.; Lau, C. K.; Bernstein, M. A.; Dufresne, C.
Can. J . Chem. 1994, 72, 1866.
(27) For hydrogenolysis with H2/Pd(OH)2/C: Tu¨ckmantel, W.;
Kozikowski, A. P.; Romanczyk, L. J ., J r. J . Am. Chem. Soc. 1999, 121,
12073. Debenzylation of 16 with H2 and Pd/C could not proceed and
also with H2, HCl aq, and Pd/C the yield was low (62%, 2 steps).
(28) For DDQ oxidation of the C-4 position of catechin: (a) Steen-
kamp, J . A.; Ferreira, D.; Roux, D. G. Tetrahedron Lett. 1985, 26, 3045.
(b) Steenkamp, J . A.; Mouton, C. H. L.; Ferreira, D. Tetrahedron Lett.
1991, 47, 6705. (c) Ohmori, K.; Ohrui, H.; Suzuki, K. Tetrahedron Lett.
2000, 41, 5537.
(29) Oxidations with RuO2/NaIO4/EtOAc/H2O,29a KMnO4/CuSO4‚
5H2O,29b and MCPBA (m-chloroperbenzoic acid)/Air/NaHCO3 gave
29c
no desired compound 18: (a) Zhang, X.; Schmitt, A. C.; J iang, W.
Tetrahedron Lett. 2001, 42, 5335. (b) Noureldin, N. A.; Zhao, D.; Lee,
D. G. J . Org. Chem. 1997, 62, 8767. (c) Ma, D.; Xia, C.; Tian, H.
Tetrahedron Lett. 1999, 40, 8915.
(30) Byramova, N.; Ovchinnikov, M. V.; Backinowsky, L. V.; Kochet-
kov, N. K. Carbohydr. Res. 1983, 124, C8.
(24) (a) Kometani, T.; Kondo, H.; Fujimori, Y. Synthesis 1988, 1005.
(b) Herzner, H.; Palmacci, E. R.; Seeberger, P. H. Org. Lett. 2002, 4,
2965.
J . Org. Chem, Vol. 69, No. 16, 2004 5243

Oyama and Kondo
SCHEME 5. Syn th esis of F la vocom m elin (1)a
Con clu sion
We have succeeded in the first total synthesis of
flavocommelin (1) by C-glycosylation of flavan. This first
direct C-glycosylation of a flavonoid nucleus provides a
promising methodology for synthesis of other natural
occurring potential O- and C-glycosyl flavonoids. Prepa-
ration of chiral analogues of flavocommelin (1) having a
variety of sugars is now in progress to facilitate studies
of the flower-color-development of commelinin (2).
Exp er im en ta l Section
7-O-Meth yln a r in gen in (7a ) a n d 7,4′-O-Dim eth yln a r in -
gen in (7b). To a solution of naringenin (6) (1.634 g, 6 mmol)
and K2CO3 (0.829 g, 6 mmol) in DMF (20 mL) was added CH3I
(0.56 mL, 9 mmol) at room temperature. The solution was
stirred for 12 h and then quenched by addition of saturated
aqueous NH4Cl and extracted with AcOEt. The combined
extracts were dried over anhydrous MgSO4 and evaporated
in vacuo. The crude product was purified by flash column
chromatography (hexane-AcOEt 2:1) to afford 7a (1.300 g,
76%) and 7b (56 mg, 3%) as white solids.
Data for 7a : mp 144-143 °C; IR (KBr) 3241, 1642, 1520,
1459, 1159 cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.77 (1H, dd, J
) 17.2, 3.0 Hz), 3.07 (1H, dd, J ) 17.2, 13.1 Hz), 3.79 (3H, s,
OCH3), 5.06 (1H, s, OH), 5.34 (1H, dd, J ) 13.1, 3.0 Hz), 6.03
(1H, d, J ) 2.2 Hz), 6.05 (1H, d, J ) 2.2 Hz), 6.86 (2H, d, J )
8.5 Hz), 7.31 (2H, d, J ) 8.5 Hz), 11.99 (1H, s, OH); 13C NMR
(CDCl3, 67.5 MHz) δ 43.3, 55.7, 79.0, 94.2, 95.1, 103.1, 115.6,
127.9, 130.5, 156.0, 162.7, 164.0, 167.8, 195.8; HRMS (EI) calcd
for C16H14O5 [M]+ 286.0841, found 286.0854.
Data for 7b: mp 114-115 °C; IR (KBr) 2950, 1630, 1307,
1212, 1159 cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.77 (1H, dd, J
) 17.2, 3.0 Hz), 3.08 (1H, dd, J ) 17.2, 13.2 Hz), 3.78 (3H, s,
OCH3), 3.82 (3H, s, OCH3), 5.34 (1H, dd, J ) 13.2, 3.0 Hz),
6.02 (1H, d, J ) 2.1 Hz), 6.05 (1H, d, J ) 2.1 Hz), 6.93 (2H, d,
J ) 8.5 Hz), 7.36 (2H, d, J ) 8.5 Hz), 12.01 (1H, s, OH); 13C
NMR (CDCl3, 125 MHz) δ 43.2, 55.3, 55.6, 79.0, 94.2, 95.1,
103.1, 114.2, 127.7, 130.4, 160.0, 162.9, 164.1, 167.9, 196.0;
HRMS (EI) calcd for C17H16O5 [M]+ 300.0998, found 300.1009.
5,4′-Dia cetoxy-7-m eth oxyfla va n on e (9). To a solution of
7a (3.722 g, 13 mmol), Et3N (14.5 mL, 104 mmol), and DMAP
(1.588 g, 13 mmol) in CH2Cl2 (80 mL) was added AcCl (7.4
mL, 104 mmol) at room temperature. The solution was stirred
for 15 h at room temperature, diluted with AcOEt, and washed
with 1 N HCl. After neutralization with saturated aqueous
NaHCO3, the organic layer was dried over anhydrous MgSO4
and evaporated in vacuo. The resulting crude product was
purified by flash column chromatography (hexane-AcOEt 3:2)
to afford 9 (4.315 g, 90%) as a white solid: mp 103-104 °C;
IR (KBr) 2954, 1768, 1621, 1444, 1189 cm-1; 1H NMR (CDCl3,
270 MHz) δ 2.30 (3H, s, OAc), 2.37 (3H, s, OAc), 2.71 (1H, dd,
J ) 16.6, 3.0 Hz), 2.98 (1H, dd, J ) 16.6, 13.5 Hz), 3.81 (3H,
s, OCH3), 5.44 (1H, dd, J ) 13.5, 3.0 Hz), 6.27 (1H, d, J ) 2.6
Hz), 6.41 (1H, d, J ) 2.6 Hz), 7.14 (2H, d, J ) 8.5 Hz), 7.45
(2H, d, J ) 8.5 Hz); 13C NMR (CDCl3, 67.5 MHz) δ 21.1, 45.0,
55.8, 78.9, 99.4, 104.7, 107.8, 121.9, 127.2, 135.8, 150.7, 151.6,
163.8, 165.2, 169.0, 169.2, 188.2; HRMS (FAB) calcd for
a
Reagents and conditions: (a) AcCl, Et3N, DMAP, CH2Cl2, rt
(16: 69%; recovered 12a and 12b: 24%); (b) H2, Pd(OH)2/C, AcOEt/
CH3OH, rt and then BzCl, pyridine, DMAP, rt (95%, 2 steps); (c)
CAN, AcOH/CH3CN/H2O, 60 °C (43%); (d) AcCl/CH3OH, CHCl3,
rt (80%); (e) BF3‚Et2O, DTBMP, CH2Cl2, rt (84%); (f) DDQ, PhCl,
140 °C (84%); (g) KOH, MeOH/THF, rt (90%).
SCHEME 6. Acetyla tion of th e O-Glu cosid es 12a
a n d 12b
more, DDQ dehydrogenation of 20 with DDQ in PhCl at
140 °C afforded a single compound, flavone 21, in 83%
yield, but under previously described conditions11,13b,31
(110 °C in 1,4-dioxane) production of 21 was only minor.
Finally deprotection of flavone 21 with KOH/CH3OH gave
flavocommelin (1) in 90% yield (12 steps, 6.2% overall
yield). Synthetic 1 proved identical with an authentic
C
20H19O7 [M + H]+ 371.1131, found 371.1132.
1
sample of the natural occurring component with H NMR
4′-Acetoxy-5-h yd r oxy-7-m eth oxyfla va n (4). To a solution
and optical rotation.32
of 9 (2.103 g, 5.1 mmol) in THF (18 mL) and H2O (9 mL) was
added NaBH4 (386 mg, 10.2 mmol) at 0 °C. The solution was
stirred for 30 min at 0 °C then quenched by addition of
saturated aqueous NH4Cl and extracted with AcOEt. The
combined extracts were dried over anhydrous MgSO4 and
evaporated in vacuo. The crude product was purified by flash
column chromatography (hexane-AcOEt 2:1) to afford 4 (1.356
g, 85%) as a white solid: mp 169-170 °C; IR (KBr) 3374, 2960,
1747, 1629, 1198 cm-1; 1H NMR (CDCl3, 270 MHz) δ 1.9-2.1
(1H, m), 2.2-2.3 (1H, m), 2.29 (3H, s, OAc), 2.6-2.7 (2H, m),
(31) For DDQ dehydration of flavanone with 1,4-dioxane as
solvent: Shanker, C. G.; Mallaiah, B. V.; Srimannarayana, G. Synthesis
1983, 310.
(32) Natural flavocommelin (1) was obtained according to Takeda’s
method.32a (a) Takeda, K.; Mitsui, S.; Hayashi, K. Bot. Mag. Tokyo
1966, 79, 578. (b) Goto, T.; Yoshida, K.; Yoshikane, M.; Kondo, T.
Tetrahedron Lett. 1990, 31, 713. (c) Ohsawa, Y.; Ohba, S.; Kosemura,
S.; Yamamura, S.; Nakagawa, A.; Yoshida, K.; Kondo, T. Acta Crys-
tallogr. 1994, C50, 645.
a
5244 J . Org. Chem., Vol. 69, No. 16, 2004

Total Synthesis of Flavocommelin
3.71 (3H, s, OCH3), 4.78 (1H, s, OH), 4.98 (1H, dd, J ) 10.3,
2.4 Hz), 6.00 (1H, d, J ) 2.3 Hz), 6.10 (1H, d, J ) 2.3 Hz),
7.09 (2H, d, J ) 8.6 Hz), 7.41 (2H, d, J ) 8.6 Hz); 13C NMR
(CDCl3, 67.5 MHz) δ 19.0, 21.2, 29.5, 55.3, 77.1, 94.2, 94.8,
101.8, 121.5, 127.1, 139.0, 150.1, 154.4, 156.4, 159.1, 169.4;
HRMS (FAB) calcd for C18H18O5 [M + H]+ 314.1154, found
314.1145.
dd, J ) 10.3, 2.0 Hz), 5.05 (0.5H, dd, J ) 10.3, 2.0 Hz), 5.07
(0.5H, dd, J ) 9.8, 8.1 Hz), 5.08 (0.5H, dd, J ) 9.8, 8.1 Hz),
5.40 (0.5H, t, J ) 9.8 Hz), 5.41 (0.5H, t, J ) 9.8 Hz), 5.46 (1H,
d, J ) 8.1 Hz, H-1′′), 6.19 (1H, d, J ) 2.2 Hz), 6.25 (0.5H, d, J
) 2.2 Hz), 6.26 (0.5H, d, J ) 2.2 Hz), 7.13 (2H, d, J ) 8.8 Hz),
7.44 (1H, d, J ) 8.8 Hz), 7.45 (1H, d, J ) 8.8 Hz); HRMS (FAB)
calcd for C32H37O14 [M + H]+ 645.2183, found 645.2180.
4′-Acetoxy-6-C-(2,3,4,6-tetr a -O-ben zyl-â-D-glu cop yr a n o-
syl)-5-h yd r oxy-7-m et h oxyfla va n (10), 4′-Acet oxy-8-C-
(2,3,4,6-tetr a -O-ben zyl-â-D-glu cop yr a n osyl)-5-h yd r oxy-7-
m eth oxyflavan (11), 4′-Acetoxy-5-O-(2,3,4,6-tetr a-O-ben zyl-
r-D-glu cop yr a n osyl)-5-h yd r oxy-7-m eth oxyfla va n (12a ),
a n d 4′-Acetoxy-5-O-(2,3,4,6-tetr a -O-ben zyl-â-D-glu cop y-
r a n osyl)-5-h yd r oxy-7-m eth oxyfla va n (12b). To a solution
of 4 (189 mg, 0.6 mmol), 8 (163 mg, 0.3 mmol), and MS 5 Å
(0.9 g) in CH2Cl2 (5 mL) was added BF3‚Et2O (7.6 µL, 0.06
mmol) at room temperature. The solution was stirred for 90
min at room temperature then quenched by addition of
saturated aqueous NaHCO3 and extracted with AcOEt. The
combined extracts were dried over anhydrous MgSO4 and
evaporated in vacuo. The crude product was purified by flash
column chromatography (hexane-AcOEt 5:2 and then 3:2) to
afford a mixture of 10, 12a , and 12b (187 mg, 74%, 10:12a :
12b ) 75:17:8) and 11 (17 mg, 7%) as white foams. All 10-12
products were inseparable diastereomeric mixtures (1:1), with
5,4′-Dia cetoxy-8-C-(2,3,4,6-tetr a -O-a cetyl-â-D-glu cop y-
r a n osyl)-7-m eth oxyfla va n (15). To a solution of a mixture
of 11 (50 mg, 0.06 mmol) in CH3OH (1 mL) and AcOEt (1 mL)
was added 20 wt % of Pd(OH)2/C (8 mg). The solution was
stirred under 1 atm of H2 for 4 h at room temperature. The
catalyst was then removed by filtration through Celite followed
by washing with CH3OH. The filtrate was concentrated in
vacuo to afford the debenzylated product. To a solution of this
crude product and DMAP (7.3 mg, 0.06 mmol) in pyridine (1
mL) was added Ac2O (1 mL) at room temperature. After being
stirred for 14 h, the reaction mixture was diluted with AcOEt
and washed with 1 N HCl. After neutralization with saturated
aqueous NaHCO3, the organic layer was dried over anhydrous
MgSO4. After evaporation, the resulting crude product was
purified by thin-layer chromatography (hexane-AcOEt 1:1)
affording 15 (34 mg, 83%) as an amorphous material. The
product was an inseparable diastereomeric mixture (1:1), with
rotamers observed by 1H NMR: IR (KBr) 2941, 1755, 1619,
1
1
rotamers observed by H NMR.
1371, 1222 cm-1; H NMR (DMSO-d6, 600 MHz) δ 1.65-2.00
Data for 11: IR (KBr) 3424, 1759, 1609, 1200, 1066 cm-1
;
(12H, m, OAc), 2.15-2.50 (3H, m), 2.24-2.29 (6H, m, OAc),
2.56-2.64 (1H, m), 3.70, 3.72, 3.73, and 3.74 (3H, s, OCH3),
3.92-4.14 (3H, m), 4.89-4.95 (1H, m), 5.08 and 5.10 (1H, br
s), 5.13 (1H, d, J ) 10.2 Hz, H-1′′), 5.22-5.33 (1H, m), 6.34
and 6.45 (1H, s), 7.13-7.19 (2H, m), 7.45, 7.48, 7.64, and 7.68
(2H, d, J ) 8.4 Hz); HRMS (FAB) calcd for C34H39O15 [M +
H]+ 687.2289, found 687.2277.
1H NMR (CDCl3, 500 MHz) δ 1.75-2.00 (1H, m), 2.10-2.17
(1H, m), 2.28 (3H, s, OAc), 2.52-2.69 (2H, m), 3.45-3.90 and
4.10-5.12 (16H, m), 3.62 and 3.71 (3H, s, OCH3), 5.96 (0.4H,
s, H-6), 6.02 (0.6H, s, H-6), 6.80-7.55 (24H, m); HRMS (FAB)
calcd for C52H53O10 [M + H]+ 837.3639, found 837.3633.
4′-Acetoxy-5-O-(2,3,4,6-tetr a -O-a cetyl-r-D-glu cop yr a n o-
syl)-7-m et h oxyfla va n (14a ) a n d 4′-Acet oxy-5-O-(2,3,4,6-
tetr a-O-acetyl-â-D-glu copyr an osyl)-7-m eth oxyflavan (14b)
(fr om 12a a n d 12b). To a solution of a mixture of 12a and
12b (84 mg, 0.1 mmol) in CH3OH (2 mL) and AcOEt (2 mL)
was added 20 wt % of Pd(OH)2/C (7 mg). The solution was
stirred under 1 atm of H2 for 3.5 h at room temperature. The
catalyst was then removed by filtration through Celite followed
by washing with CH3OH. The filtrate was concentrated in
vacuo to afford the debenzylated product. To a solution of this
crude product in pyridine (0.5 mL) was added Ac2O (0.5 mL)
at room temperature. After being stirred for 24 h, the reaction
mixture was diluted with AcOEt and washed with 1 N HCl.
After neutralization with saturated aqueous NaHCO3, the
organic layer was dried over anhydrous MgSO4. After evapora-
tion, the resulting crude product was purified by thin-layer
chromatography (hexane-AcOEt 1:1) affording 14a (31 mg,
47%) and 14b (17 mg, 26%) as amorphous material. The
products 14a and 14b were an inseparable mixture of dia-
stereomers (1:1), respectively.
5,4′-Dia cetoxy-6-C-(2,3,4,6-tetr a -O-ben zyl-â-D-glu cop y-
r a n osyl)-7-m eth oxyfla va n (16). To a solution of a mixture
of 10, 12a , and 12b (1.623 g, 1.94 mmol), Et3N (1.62 mL, 11.64
mmol), and DMAP (0.237 g, 1.94 mmol) in CH2Cl2 (40 mL)
was added AcCl (0.83 mL, 11.64 mmol) at 0 °C. The solution
was stirred for 1.5 h at room temperature, diluted with AcOEt,
and washed with 1 N HCl. After neutralization with saturated
aqueous NaHCO3, the organic layer was dried over anhydrous
MgSO4. After evaporation, the resulting crude product was
purified by flash column chromatography (hexane-AcOEt 5:2)
to afford 16 (1.170 g, 69%) as a white foam and recovered 12a
and 12b (0.410 g, 24%). The product 16 was an inseparable
1
mixture of diastereomers (1:1), with rotamers observed by H
NMR.
Data for 16: IR (KBr) 2924, 1770, 1625, 1196, 1870 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 1.92-2.04 (1H, m), 2.07 and 2.08
(3H, s, OAc), 2.14-2.16 (1H, m), 2.29 (3H, s, OAc), 2.42-2.62
(2H, m), 3.44-3.46 (1H, br), 3.73 and 3.74 (3H, s, OCH3), 3.66-
3.83 and 4.04-4.14 (6H, m), 4.45-4.55 (3H, m), 4.70 (1H, d, J
) 10.8 Hz, H-1′′), 4.85-5.04 (5H, m), 6.41 and 6.40 (1H, s),
6.96-7.43 (24H, m); HRMS (FAB) calcd for C54H54O11 [M +
Na]+ 878.3666, found 878.3676.
Data for 14a : IR (KBr) 2958, 1755, 1223, 1147, 1042 cm-1
;
1H NMR (DMSO-d6, 500 MHz) δ 1.90-2.00 (1H, br), 1.96
(1.5H, s, OAc), 1.97 (1.5H, s, OAc), 1.99 (6H, s, OAc), 2.00
(1.5H, s, OAc), 2.04 (1.5H, s, OAc), 2.19-2.25 (1H, br), 2.26
(3H, s, OAc), 2.67-2.73 (2H, m), 3.67 (3H, s, OCH3), 3.99-
4.22 (3H, m), 5.03-5.10 (3H, m), 5.50 (1H, t, J ) 9.8 Hz), 5.72
(0.5H, d, J ) 2.7 Hz, H-1′′), 5.73 (0.5H, d, J ) 2.7 Hz, H-1′′),
6.20 (0.5H, d, J ) 2.6 Hz), 6.21 (0.5H, d, J ) 2.6 Hz), 6.31
(0.5H, d, J ) 2.6 Hz), 6.32 (0.5H, d, J ) 2.6 Hz), 7.14 (2H, d,
J ) 8.5 Hz), 7.47 (2H, d, J ) 8.5 Hz); HRMS (FAB) calcd for
Data for the mixture of 12a and 12b: IR (KBr) 2921, 1758,
1
1620, 1497, 1023 cm-1; H NMR (CDCl3, 500 MHz) δ 1.89-
2.01 (2H, m), 2.07-2.17 (2H, m), 2.29 (6H, s, OAc), 2.58-2.97
(4H, m), 3.58-3.90 and 4.41-5.03 (36.6H, m), 4.12 (0.35H, t,
J ) 9.3 Hz, for 12a ), 4.13 (0.35H, t, J ) 9.3 Hz, for 12a ), 5.47
(0.35H, d, J ) 3.3 Hz, for 12a , H-1′′), 5.51 (0.35H, d, J ) 3.3
Hz, for 12a , H-1′′), 6.18 (1.4H, d, J ) 2.5 Hz, for 12a ), 6.20
(0.6H, d, J ) 2.5 Hz, for 12b), 6.31 (0.3H, d, J ) 2.5 Hz, for
12b), 6.32 (0.3 H, d, J ) 2.5 Hz, for 12b), 6.36 (0.7H, d, J )
2.5 Hz, for 12a ), 6.37 (0.7H, d, J ) 2.5 Hz, for 12a ), 7.07-7.43
(48H, m); HRMS (FAB) calcd for C52H53O10 [M + H]+ 837.3639,
found 837.3633.
C
32H37O14 [M + H]+ 645.2183, found 645.2194.
Data for 14b: IR (KBr) 2939, 1754, 1219, 1141, 1048 cm-1
;
1H NMR (DMSO-d6, 500 MHz) δ 1.84-1.95 (1H, m), 1.96 (1.5H,
s, OAc), 1.97 (1.5H, s, OAc), 1.98 (1.5H, s, OAc), 2.00 (3H, s,
OAc), 2.01 (1.5H, s, OAc), 2.02 (1.5H, s, OAc), 2.04 (1.5H, s,
OAc), 2.11-2.18 (1H, m), 2.26 (3H, s, OAc), 2.37-2.55 (2H,
m), 3.68 (3H, s, OCH3), 4.06 (0.5H, dd, J ) 12.3, 2.8 Hz), 4.07
(0.5H, dd, J ) 12.3, 2.8 Hz), 4.18 (0.5H, dd, J ) 12.3, 5.9 Hz),
4.19 (0.5 H, dd, J ) 12.3, 5.9 Hz), 4.25-4.29 (1H, m), 4.96
(0.5H, t, J ) 9.8 Hz), 4.97 (0.5H, t, J ) 9.8 Hz), 5.03 (0.5H,
5,4′-Dia cetoxy-6-C-(2,3,4,6-tetr a -O-ben zoyl-â-D-glu cop y-
r a n osyl)-7-m eth oxyfla va n (17). To a solution of a mixture
of 16 (770 mg, 0.876 mmol) in CH3OH (4 mL) and AcOEt
(4 mL) was added 20 wt % of Pd(OH)2/C (62 mg). The solution
was stirred under 1 atm of H2 for 1.5 h at room temperature,
J . Org. Chem, Vol. 69, No. 16, 2004 5245

Oyama and Kondo
then the catalyst was removed by filtration through Celite
followed by washing with CH3OH. The filtrate was concen-
trated in vacuo to afford the debenzylated product. To a
solution of this crude product and DMAP (107 mg, 0.876 mmol)
in pyridine (3 mL) was added BzCl (2.0 mL, 17.520 mmol) at
60 °C. After being stirred for 1 h, the reaction mixture was
diluted with AcOEt and washed with 1 N HCl. After neutral-
ization with saturated aqueous NaHCO3, the organic layer was
dried over anhydrous MgSO4. After evaporation, the resulting
crude product was purified by flash column chromatography
(hexane-AcOEt 5:3) affording 17 (778 mg, 95%) as a white
foam. The products 17 were an inseparable mixture of dia-
stereomers (1:1), with rotamers observed by 1H NMR: IR (KBr)
2942, 1771, 1732, 1268, 1170 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 1.88-1.96 (1H, br), 2.05-2.15 (1H, br), 2.27 and 2.30 (6H,
s, OAc), 2.40-2.70 (2H, br), 3.67 (3H, br s, OCH3), 4.20 (1H,
br s), 4.44 (1H, dd, J ) 12.3, 4.5 Hz), 4.60 (1H, br d, J ) 12.3
Hz), 4.93 and 4.90 (1H, d, J ) 10.6, H-1′′; signals of rotamer
were overlapped), 5.40 (0.7H, br s), 5.76 (1H, t, J ) 9.8 Hz),
5.95 (1H, br t, J ) 9.3 Hz), 6.02 (0.3H, br s), 6.18 (1H, br s),
7.04-7.50 and 7.75-7.97 (25H, m); HRMS (FAB) calcd for
DTBMP in CH2Cl2 (1 mL) was added BF3‚Et2O (20 µL, 0.16
mmol) at room temperature. The solution was stirred for 1 h
at room temperature then quenched by addition of saturated
aqueous NaHCO3 and extracted with AcOEt. The combined
extracts were dried over anhydrous MgSO4 and evaporated
in vacuo. The crude product was purified by flash column
chromatography (hexane-AcOEt 1:1) to afford 20 (20.7 mg,
84%) as white foam. The product 20 was an inseparable
1
mixture of diastereomers (1:1), with rotamers observed by H
1
NMR: IR (KBr) 2966, 1736, 1615, 1264, 1070 cm-1; H NMR
(CDCl3, 500 MHz) δ 2.01 (3H, s, OAc), 2.02 (3H, s, OAc), 2.03
(3H, s, OAc), 2.05 (3H, s, OAc), 2.34 and 2.44 (3H, br s, OAc),
2.61 (1H, br d, J ) 16.9 Hz), 2.77-2.99 (1H, br), 3.70 and 3.88
(3H, br s, OCH3), 3.83 (1H, dd, J ) 9.8, 5.4, 2.2 Hz), 4.15 (1H,
dd, J ) 12.2, 2.2 Hz), 4.26 (1H, dd, J ) 12.2, 5.4 Hz), 4.41
(1H, br s), 4.62 (1H, br s), 5.06 (1H, d, J ) 7.4 Hz, H-1′′′), 5.14
(1H, t, J ) 9.8 Hz), 5.25 (1H, dd, J ) 9.8, 7.4 Hz), 5.28 (1H, t,
J ) 9.8 Hz), 5.35 (2H, br, H-2, 1′′), 5.76 (1H, t, J ) 9.8 Hz),
5.94 (1H, br s), 6.05 and 6.38 (1H, br s), 6.20 (1H, br s), 6.99
(2H, d, J ) 8.5 Hz), 7.31 (2H, d, J ) 8.5 Hz), 7.20-7.55 and
7.70-8.05 (20H, m); HRMS (FAB) calcd for C66H60O24Na [M
+ Na]+ 1259.3372, found 1259.3346.
C
54H47O15 [M + H]+ 935.2915, found 935.2929.
5,4′-Dia cetoxy-6-C-(2,3,4,6-tetr a -O-ben zoyl-â-D-glu cop y-
5-Acetoxy-6-C-(2,3,4,6-tetr a -O-ben zoyl-â-D-glu cop yr a -
n osyl)-4′-O-(2,3,4,6-tetr a -O-a cetyl-â-D-glu cop yr a n osyl)-7-
m eth oxyfla von e (21). A solution of 20 (136 mg, 0.11 mmol)
and DDQ (122 mg, 0.44 mmol) in PhCl (5 mL) was refluxed
for 13 h at 140 °C. After concentration in vacuo, the reaction
mixture was purified by thin-layer chromatography (hexane-
r a n osyl)-7-m eth oxyfla va n on e (18). To a solution of 17 (232
mg, 0.248 mmol) in CH3CN (2 mL), AcOH (2 mL), and H2O (1
mL) was added CAN (816 mg, 1.488 mmol) at room temper-
ature. The solution was stirred for 30 min at 50 °C then
quenched by addition of saturated aqueous NaHCO3 and
extracted with AcOEt. The combined extracts were dried over
anhydrous MgSO4 and evaporated in vacuo, and purified by
flash column chromatography (hexane-AcOEt 5:4) to afford
18 (100 mg, 43%) as a white foam. The product 18 was an
inseparable mixture of diastereomers (1:1), with rotamers
AcOEt 1:2) to afford 21 (109 mg, 83%) as a foam. [R]24 -48.9
D
(c 0.3, CHCl3); IR (KBr) 2938, 1735, 1605, 1233, 1094 cm-1
;
1H NMR (DMSO-d6, 500 MHz) δ 1.97, 2.00, and 2.01 (3H, s,
OAc), 3.90 and 3.91 (3H, s, OCH3), 4.07 (1H, dd, J ) 12.3, 2.2
Hz), 4.19 (1H, dd, J ) 12.3, 5.3 Hz), 4.30 (1H, ddd, J ) 9.5,
5.3, 2.2 Hz), 4.41-4.59 (3H, m), 5.02 (1H, t, J ) 9.5 Hz), 5.09
(1H, dd, J ) 9.5, 8.1 Hz), 5.41 (1H, dd, J ) 9.5 Hz), 5.58 (1H,
br d, J ) 9.5, H-1′′), 5.69 (1H, t, J ) 9.5 Hz), 5.75 (1H, d, J )
8.1 Hz, H-1′′′), 6.02 and 6.05 (1H, t, J ) 9.5 Hz), 6.20 and 6.31
(1H, t, J ) 9.5 Hz), 6.82 and 6.87 (1H, s), 6.95 and 7.00 (1H,
s), 7.14 (2H, d, J ) 8.4 Hz), 7.33-8.02 (20H, m), 8.05 (2H, d,
J ) 8.4 Hz), 13.60 and 13.67 (1H, s, OH); HRMS (FAB) calcd
for C64H57O23 [M + H]+ 1193.3291, found 1193.3274.
1
observed by H NMR: IR (KBr) 2950, 1734, 1615, 1266, 1067
cm-1; 1H NMR (CDCl3, 500 MHz) δ 2.28 (3H, s, OAc), 2.34 and
2.44 (3H, br s, OAc), 2.56 (1H, br), 2.96 (1H, br), 3.71 and 3.89
(3H, br s, OCH3), 4.18 (1H, br s), 4.41 (1H, br s), 4.61 (1H, br
s), 5.05 and 5.38 (2H, br, H-2, 1′′), 5.76 (1H, t, J ) 9.8 Hz),
5.94 (1H, br s), 6.22 (1H, br s), 6.06 and 6.39 (1H, br s), 7.10
(1H, d, J ) 8.5 Hz), 7.11 (1H, d, J ) 8.5 Hz), 7.39 (2H, d, J )
8.5 Hz), 7.10-7.55 and 7.74-8.01 (20H, m); HRMS (FAB) calcd
for C54H44O16Na [M + Na]+ 971.2527, found 971.2531.
F la vocom m elin (1). To a solution of 21 (31.0 mg, 26 µmol)
in a mixture of THF (1 mL) and CH3OH (1 mL) was added
KOH (0.2 mL, 0.5 mol/L of CH3OH solution) at room temper-
ature. After being stirred for 16 h, the reaction mixture was
neutralized with Dowex 50W-8X (H+), filtered, and evaporated
in vacuo. The residue was recrystallized from H2O and CH3-
5-Acetoxy-6-C-(2,3,4,6-tetr a -O-ben zoyl-â-D-glu cop yr a -
n osyl)-4′-h yd r oxy-7-m eth oxyfla va n on e (19). To a solution
of 18 (256 mg, 0.27 mmol) in CHCl3 was added a mixed
solution33 of AcCl (0.2 mL) and CH3OH (4 mL) at room
temperature. The solution was stirred for 2 h at room tem-
perature, then quenched by addition of saturated aqueous
NaHCO3 and extracted with AcOEt. The combined extracts
were dried over anhydrous MgSO4 and evaporated in vacuo,
and purified by flash column chromatography (hexane-AcOEt
1:1) to afford 19 (197 mg, 80%) as a white foam. The product
19 was an inseparable mixture of diastereomers (1:1), with
rotamers observed by 1H NMR: IR (KBr) 2950, 1735, 1616,
1
CN to afford 1 (14.2 mg, 90%), with rotamers observed by H
NMR: mp 209-210 °C [natural: mp 209-210 °C]; [R]25D -57.6
(c 0.3, H2O) [natural: [R]24D -57.7 (c 0.3, H2O)]; IR (KBr) 3418,
2926, 1654, 1244, 1204 cm-1; 1H NMR (DMSO-d6, 600 MHz) δ
3.03-3.47 (10H, m), 3.68-3.70 (2H, m), 3.86 and 3.89 (3H, s,
OCH3), 3.96-4.00 (0.5H, m), 4.15-4.19 (0.5H, m), 4.57 (0.5H,
d, J ) 9.6 Hz, H-1′′), 4.59 (0.5H, d, J ) 9.6 Hz, H-1′′), 5.04
(1H, d, J ) 7.2 Hz, H-1′′′), 6.88 (0.5H, s), 6.89 (0.5H, s), 6.98
(0.5H, s), 7.00 (0.5H, s), 7.19 (2H, d, J ) 8.4 Hz), 8.09 (2H, d,
J ) 8.4 Hz), 13.41 (0.5H, s), 13.43 (0.5H, s); HRMS (FAB) calcd
for C28H33O15 [M + H]+ 609.1819, found 609.1814.
1
1267, 1070 cm-1; H NMR (CDCl3, 500 MHz) δ 2.45 and 2.35
(3H, br s, OAc), 2.56 (1H, br d, J ) 16.4 Hz), 2.91 (1H, br t, J
) 15.3 Hz), 3.68 and 3.84 (3H, br s, OCH3), 4.18 (1H, br s),
4.41 (1H, br s), 4.64 (1H, br s), 5.05 and 5.37 (1H, br d, J )
8.6 Hz, H-1′′), 5.25 (1H, br t, J ) 12.0 Hz), 5.71 and 5.68 (1H,
br s, OH), 5.77 (1H, t, J ) 9.8 Hz), 5.96 (1H, br s), 6.06 and
6.34 (1H, br s), 6.18 (1H, br s), 6.76 (2H, dd, J ) 8.6, 2.0 Hz),
7.19 (2H, dd, J ) 8.6, 2.2 Hz), 7.20-7.50 amd 7.70-8.02 (20H,
m); HRMS (FAB) calcd for C52H42O15Na [M + Na]+ 929.2421,
found 929.2419.
Ack n ow led gm en t. This work was supported by
Grant-in-Aids for Scientific Research (COE) No.
07CE2004 and Scientific Research on Priority Area No.
10169224 from the Ministry of Education, Culture,
Sports, Sciences, and Technology of J apan.
5-Acetoxy-6-C-(2,3,4,6-tetr a -O-ben zoyl-â-D-glu cop yr a -
n osyl)-4′-O-(2,3,4,6-tetr a -O-a cetyl-â-D-glu cop yr a n osyl)-7-
m eth oxyfla va n on e (20). To a solution of acetylglucosyl
fluoride 5 (14.0 mg, 0.04 mmol), 19 (18.0 mg, 0.02 mmol), and
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of all new compounds and natural 1 and experimental
details of acetylation of 13. This material is available free of
charge via the Internet at http://pubs.acs.org.
(33) This mixed solution was prepared according to the following
procedure. To CH3OH (4 mL) was added AcCl (0.2 mL) dropwise at 0
°C and this solution was stirred for 15 min at 0 °C.
J O0494681
5246 J . Org. Chem., Vol. 69, No. 16, 2004