Synthesis of verbascoside: A dihydroxyphenylethyl glycoside with diverse bioactivity

Article abstract of DOI:10.1002/(sici)1099-0690(199910)1999:10<2623::aid-ejoc2623>3.0.co;2-k

TMSOTf-mediated condensation of ethyl 4,6-O-benzylidene-1-thio-β-D- glucopyranoside (2) with peracetylated α-L-rhamnopyranosyl trichloroacetimidate donor 3a resulted in the formation of orthoester 4, which, after acetylation, rearranged into ethyl 3-O-(α-L-rhamnopyranosyl)-l- thio-β-D-glucopyranoside derivative 6a. The latter compound was converted into the corresponding trichloroacetimidate donors 8a-b. An alternative approach to trichloroacetimidate 8c commenced with the iodonium ion mediated glycosidation of ethyl 2,3,4-tri-O-benzoyl-1-thio-α-L-rhamnopyranside (15) with 1,2:5,6-diisopropylidene-D-glucofuranose (16) to afford disaccharide 17, which was transformed into 8c in five steps. Condensation of 8a-c with 2- [3,4-di-(tert-butyldimethylsilyloxy)phenyl]ethanol (12) gave, after deacylation, key intermediate 14. Protecting-group manipulation of 14 and subsequent esterification of resulting 22 with 3,4-di-O-tert- butyldimethylsilylcaffeic acid (27) gave, after deprotection, verbascoside (1).

Full text of DOI:10.1002/(sici)1099-0690(199910)1999:10<2623::aid-ejoc2623>3.0.co;2-k

FULL PAPER
Synthesis of Verbascoside: A Dihydroxyphenylethyl Glycoside with Diverse
Bioactivity
Howard I. Duynstee,[a] Martijn C. de Koning,[a] Huib Ovaa,[a] Gijs A. van der Marel,[a]
and Jacques H. van Boom*[a]
Keywords: Caffeic acid / Carbohydrates / Glycosidations / Orthoester
TMSOTf-mediated condensation of ethyl 4,6-O-benzylidene-
1-thio-β- -glucopyranoside (2) with peracetylated α-
of ethyl 2,3,4-tri-O-benzoyl-1-thio-α-
L-rhamnopyranside (15)
D
L-
with 1,2:5,6-diisopropylidene- -glucofuranose (16) to afford
D
rhamnopyranosyl trichloroacetimidate donor 3a resulted in
the formation of orthoester 4, which, after acetylation,
disaccharide 17, which was transformed into 8c in five steps.
Condensation of 8a–c with 2-[3,4-di-(tert-butyldimethyl-
silyloxy)phenyl]ethanol (12) gave, after deacylation, key
intermediate 14. Protecting-group manipulation of 14 and
rearranged into ethyl 3-O-(α-L-rhamnopyranosyl)-1-thio-β-D-
glucopyranoside derivative 6a. The latter compound was
converted into the corresponding trichloroacetimidate donors subsequent esterification of resulting 22 with 3,4-di-O-tert-
8a–b. An alternative approach to trichloroacetimidate 8c
commenced with the iodonium ion mediated glycosidation
butyldimethylsilylcaffeic acid (27) gave, after deprotection,
verbascoside (1).
gioselective introduction of an unsaturated caffeoyl func-
tion. The 1,2-trans-glycosidic linkages can in principle be
formed by neighboring-group participation of a 2-O-acyl
function in the -rhamnopyranoside and the -glucopyr-
anoside building blocks. It is evident, however, that the 2-
O-acyl functions are not compatible with the caffeoyl group
in the target molecule. In line with these considerations, di-
hydroxyphenylethyl α--Rhap-(1Ǟ3)-β--Glcp derivative 14
had to be prepared prior to the esterification of HO-4 of
the glucopyranosyl moiety with a suitably protected caffeic
acid derivative. An approach to key intermediate 14 is de-
picted in Scheme 1 and commences with the synthesis of the
ethyl 3-O-(α--rhamnopyranosyl)-1-thio--glucopyranoside
donor 6, which can be coupled with an appropriately pro-
tected 2-[3,4-dihydroxyphenyl]ethanol moiety.
Earlier studies from this laboratory showed[5] that re-
gioselective β-glucosylation of HO-3 in ethyl 4,6-O-benzyl-
idene-1-thio-β--glucopyranoside (2) with 2,3,4,6-tetra-O-
benzoyl--glucopyranosyl trichloroacetimidate could be ef-
fected in the presence of a catalytic amount of trimethylsilyl
triflate (TMSOTf) in dichloromethane at Ϫ20 °C. Unfortu-
nately, condensation of 2, under the same conditions, with
the relatively more reactive[6] perbenzoylated α--rhamno-
pyranosyl trichloroacetimidate 3b[7b] proceeded with a low
degree of regioselectivity. Similarly, glycosylation of 2 with
the peracetylated α--rhamnopyranosyl trichloroacetimid-
ate donor 3a[7a] gave an intractable mixture of products. On
the other hand, TMSOTf-catalyzed condensation of 2 with
3a in CH2Cl2/THF[8] at Ϫ40 °C led to the exclusive forma-
tion of orthoester 4 (see Scheme 1), which could be con-
verted by acetylation to 5, which subsequently underwent
acid-catalyzed (TfOH) rearrangement into the required di-
mer 6a, in an overall yield of 54% based on 2.
Introduction
Phenylethyl glycosides (PhGs) are an interesting group of
natural products which are widely distributed in the plant
kingdom.[1a,2] They have 2-phenylethyl β--glucopyrano-
side, which is functionalized with an aromatic acid (e.g.,
cinnamic acid, caffeic acid, ferulic acid), in common. There
may also be monosaccharides attached to the glucose moi-
ety.
Verbascoside, also known as[1] acteoside (1, see Figure
1), belongs to the largest class of PhGs, those with a rham-
nose sugar attached to the 3-position of the central glucose
unit. It has been established that verbascoside (1) is a potent
inhibitor[1] of protein kinase C and aldose reductase. Fur-
thermore, 1 possesses antibacterial,[1] antiviral,[1][3] and
antitumor[1] activity, as well as cytotoxic and immunomod-
ulatory properties.[1][4] We present here the first synthesis of
verbascoside (1).
Figure 1. Verbascoside (Acteoside)
Results and Discussion
The construction of the target molecule, 1, entails forma-
tion of two 1,2-trans-glycosidic bonds, as well as the re-
[a]
Leiden Institute of Chemistry, Gorlaeus Laboratories, Univer-
sity of Leiden,
At this stage, the glycosidation of 6a with 2-[3,4-di-(tert-
butyldimethylsilyloxy)phenyl]ethanol (12), prepared (see
Scheme 2) from 3,4-dihydroxyphenylacetic acid (9) by
P. O. Box 9502, NL-2300 RA Leiden, The Netherlands
Fax: (internat.) ϩ 31-71/527-4307
E-mail: j.boom@chem.leidenuniv.nl
Eur. J. Org. Chem. 1999, 2623Ϫ2632
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1010Ϫ2623 $ 17.50ϩ.50/0
2623

H. I. Duynstee, M. C. de Koning, H. Ovaa, G. A. van der Marel, J. H. van Boom
FULL PAPER
Rather rigorous basic conditions were used for the removal
of the 2-O-benzoyl in 13b, according to observations[18] that
the reaction would not proceed otherwise.
Scheme 2. Reagents and conditions: (i) HCl, MeOH; (ii)
TBDMSϪCl, imidazole, DMF, (85%, 2 steps); (iii) LiAlH4, Et2O,
91%
The synthetic route to key intermediate 14 (21% overall
yield in 7 steps) is not fully satisfactory due to the forma-
tion of orthoester 4 and the necessity to transform ethyl
1-thioglycoside 6a into trichloroacetimidate donor 8a. The
latter disadvantages could be circumvented, as outlined in
Scheme 3, by using 1,2:5,6-diisopropylidene--glucofur-
anose (16) as the glycosyl acceptor. Iodonium ion mediated
condensation of ethyl 2,3,4-tri-O-benzoyl-1-thio-α--rham-
nopyranoside[19] (15) with 16 gave disaccharide 17 in high
yield. Deacetonation of 17 with 20% trifluoroacetic acid[20]
at elevated temperature followed by acid-catalyzed (p-
TsOH) acetalization with benzaldehyde dimethyl acetal in
acetonitrile gave 18 in 69% yield. Acetylation of diol 18,
followed by selective anomeric deacetylation of 19 with hy-
drazinium acetate[21] in DMF furnished hemiacetal 7c,
which was transformed into imidate donor 8c by the ac-
tion[15] of cesium carbonate and trichloroacetonitrile.
BF3·Et2O-mediated condensation of 8c with phenylethanol
derivative 12 gave 13c, whose deesterification gave 14 in a
yield of 24% over the eight steps.
With key intermediate 14 available, we directed our atten-
tion to the introduction of the caffeoyl ester function at C-
4 of the glucose moiety. Towards this goal, the partially
protected derivative 14 was transformed into 22 which has
Scheme 1. Reagents and conditions: (i) 0.1 equiv. TMSOTf,
CH2Cl2/THF (3:1, v/v), Ϫ40 °C, 81%; (ii) Ac2O, pyridine, 87%; (iii)
cat. TfOH, CH2Cl2, 76%; (iv) NIS/cat. TfOH in CH2Cl2/H2O
(100:1, v/v), 7a: 81%, 7b: 81%; (v) CCl3CN, Cs2CO3, CH2Cl2, 8a:
86% 8b: 84%; (vi) (a) NaOMe, MeOH; (b) BzCl, pyridine, 85%;
(vii) cat. BF3·Et2O, CH2Cl2, (13a: 58%, 13b: 74%); (viii) cat.
NaOMe, MeOH (99%); (ix) excess of NaOMe, MeOH (42%)
sequential esterification (to form 10), silylation (to 11), and a free HO-4, by the following sequence of manipulations
reduction, was examined. Condensation of thioethyl donor (see Scheme 4). In the first step, the four hydroxy functions
6a with acceptor 12 (see Scheme 1) under the influence of in 14 were acylated with phenoxyacetyl chloride to give 20
N-iodosuccinimide (NIS) and catalytic triflic acid (cat. in high yield. Removal of the benzylidene group under mild
TfOH)[9]
or
dimethyl(methylthio)sulfonium
triflate acid conditions followed by regioselective tritylation[22] fur-
(DMTST)[10] was abortive.[11] Alternatively, transformation nished the dimethoxytrityl derivative 22 in an overall yield
of 6a into the corresponding trichloroacetimidate[12] donor of 69%. Esterification of 22 with 3,4-di-O-acetylcaffeoyl
8a seemed to be a viable option. To this end, the thioethyl chloride[23] in the presence of pyridine or 4-(dimethyl-
group in 6a[13] was hydrolyzed in good yield[14] with NIS/ amino)pyridine (DMAP) was not successful. Moreover, di-
cat TfOH in wet CH2Cl2. Treatment of the hemiacetal 7a cyclohexylcarbodiimide (DCC)/DMAP-mediated reaction
with cesium carbonate and excess trichloroacetonitrile fur- of 22 with 3,4-di-O-acetylcaffeic acid[23] led to the isolation
nished[15] trichloroacetimidate donor 8a. The subsequent of the acetylated product 23. The unexpected formation of
BF3·Et2O-assisted glycosylation of 12 with 8a gave the fully 23 may be explained by reaction of 22 with an acylϪDMAP
protected derivative 13a in 58% yield[16]; its deacetylation adduct, which is formed by the reaction of DMAP with the
proceeded in near quantitative yield to afford key inter- phenolic acetyl groups in the 3,4-di-O-acetylcaffeic acid. To
mediate 14 (see Scheme 1). Glycosylation of 12 with the overcome this problem, the silyl-protected caffeic acid de-
fully benzoylated 8b (see Scheme 1), readily available from rivative 27 was considered to be a good alternative.
6a, proceeded as expected[17] in higher yield (i.e., 74%).
The preparation of 27 could be realized by the sequence
However, complete debenzoylation of 13b was accompanied of reactions depicted in Scheme 5. Silylation of known
by the concomitant removal of the phenolic TBDMS methyl caffeate[23b] (25) with tert-butyldimethylsilyl chloride
groups, resulting in the isolation of 14 in only 42% yield. and subsequent reduction of 26 with LiAlH4 provided the
2624
Eur. J. Org. Chem. 1999, 2623Ϫ2632

Synthesis of Verbascoside
FULL PAPER
Scheme 3. Reagents and conditions: (i) NIS/cat. TfOH, CH2Cl2,
95%; (ii) 20% TFA in THF/H2O (4:1), 80 °C; (iii) PhCH(OCH3)2,
cat. TsOH, CH3CN, (69%, 2 steps); (iv) Ac2O, pyridine, 89%; (v)
H2NNH2·H2O, AcOH, DMF, 81%; (vi) CCl3CN, Cs2CO3, CH2Cl2,
86%; (vii) cat BF3·Et2O, CH2Cl2, 59%; (viii) cat NaOMe, MeOH,
98%
Scheme 4. Reagents and conditions: (i) PhOAcϪCl, pyridine,
CH2Cl2, 90%; (ii) HOCH2CH2OH, cat. TsOH, CH2Cl2, 88%; (iii)
DMTϪCl, pyridine, CH2Cl2, 87%; (iv) 3,4-di-O-acetylcaffeic acid,
DCC, DMAP, CH2Cl2, 77%; (v) DCC, DMAP, CH2Cl2, 67%; (vi)
0.001  K2CO3 in MeOH/CH2Cl2 (10:1, v/v), 86%; (vii) 3HF·Et3N,
Et3N, pyridine; (viii) AcOH, EtOH, CH2Cl2 (4:1:2, v/v/v), (76%,
2 steps)
corresponding allylic alcohol, which was transformed into
acid 27 by treatment with MnO2 followed by Pinnick oxi-
dation.[24]
Condensation of silyl-protected (E)-caffeic acid 27 with
22 in the presence of DCC/DMAP resulted in the isolation
of 28, the fully protected precursor of 1, as an E/Z (10/1)
mixture in 67% yield. Separation of the resulting isomers
was omitted since the E- and Z-isomers of verbascoside (1)
could be easily separated[25] by HPLC. Furthermore, it has
been reported[25] that storage of a single isomer of 1 in solu-
tion resulted in the formation of both isomers.
The fully protected verbascoside derivative 28 (see
Scheme 4) was completely deblocked as follows. Mild dees-
terification of the four phenoxyacetyl groups in 28 fur-
nished 29. In the next step, the four phenolic silyl ethers
were removed[26] effectively by the exposure of 29 to a slight
excess of HF·Et3N. Acid hydrolysis of the dimethoxytrityl
group gave, after purification by silica gel column chroma-
tography and subsequent gel filtration, the target molecule
1 in an overall yield of 7.1%. The physical and spectroscopic
data of compound 1 were in every aspect identical to those
reported[27] for naturally occurring verbascoside.
Scheme 5. Reagents and conditions: (i) HCl, MeOH; (ii)
TBDMSϪCl, imidazole, DMF, (81%, 2 steps); (iii) (a) LiAlH4 in
Et2O; (b) MnO2, Et2O; (c) NaClO2, NaH2PO4, tBuOH/H2O/2-me-
thyl-2-butene, (5:5:3, v/v/v), (82%, three steps)
transformed into verbascoside (1). It may be possible that
the same synthetic approach can be adopted to construct
other members of the phenylethyl glycoside family.
Experimental Section
General Methods and Materials: 1H- and 13C-NMR spectra were
recorded with a Bruker WM-200 (200/50.1 MHz), a Bruker WM-
300 (300/75.1 MHz), or a Bruker MDX-600 spectrometer (600/
150 MHz). Ϫ Electrospray mass spectra were recorded with a Per-
kinϪElmer SCIEX API 165 Single Quadruple LC/MS instrument.
Ϫ Optical rotations were measured with a Propol polarimeter. Ϫ
Conclusion
The results presented in this paper clearly show that key
intermediate 14, prepared in two different ways, can be were stored over molecular sieves (4 A) and used without further
1,2-Dichloroethane (Rathburn), N,N-dimethylformamide (Baker)
˚
Eur. J. Org. Chem. 1999, 2623Ϫ2632
2625

H. I. Duynstee, M. C. de Koning, H. Ovaa, G. A. van der Marel, J. H. van Boom
FULL PAPER
purification. Dichloromethane was dried by refluxing in the pres-
ence of CaH2 (5 g/L) for 5 h, then distilled and stored over molecu-
lar sieves (4 A). Pyridine and toluene were dried by refluxing in
thoacetate), 125.7Ϫ128.6 (CH, Ph), 136.9 (Cq, benzylidene), 169.4,
170.0 (CϭO, Ac).
˚
3,4-Di-O-acetyl-β-
L-rhamnopyranose 1,2-(Ethyl 2-O-acetyl-4,6-O-
the presence of P2O5 (5 g/L) for 5 h, then distilled and stored over
benzylidene-1-thio-β-
D-glucopyranose-3-yl) Orthoacetate (5): Com-
˚
molecular sieves (4 A). Tetrahydrofuran (Biosolve) and diethyl
pound 4 (2.81 g, 4.8 mmol) was dissolved in a mixture of pyridine
and acetic anhydride (25 mL, 2:1, v/v). TLC analysis indicated that
complete acetylation required 12 h and then the mixture was con-
centrated in vacuo. The residual oil was applied to a column of
silica gel and elution was effected with ethyl acetate/light petroleum
ether (1:1, v/v) to give 5 as a white solid. Ϫ Yield: 2.62 g, 87%. Ϫ
Rf ϭ 0.5 (toluene/ethyl acetate, 4:1, v/v). Ϫ 13C{1H} NMR
(CDCl3): δ ϭ 14.4 (CH3, SEt), 17.1 (C-6Ј), 20.3, 20.6 (CH3, Ac),
24.1 (CH2, SEt), 26.1 (CH3, orthoacetate), 68.1 (C-6), 65.5, 69.1,
69.9, 70.3, 70.5, 73.4, 75.4, 79.6 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-
4Ј, C-5Ј), 83.8 (C-1), 96.1 (C-1Ј), 101.4 (PhCH, benzylidene), 121.4
(Cq, orthoacetate), 125.9Ϫ128.9 (CH, Ph), 136.8 (Cq, benzylid-
ene), 164.8, 169.4, 169.9 (CϭO, Ac).
ether were freshly distilled from LiAlH4 and dried over molecular
˚
sieves (4 A) for 1 h. Methanol (Rathburn, HPLC-grade) was stored
˚
over molecular sieves (3 A). The following chemicals were obtained
from Acros Organics Co. and were used as received: triethylamine,
trimethylsilyl trifluoromethanesulfonate (TMSOTf), imidazole, tri-
fluoroacetic acid (TFA), trifluoromethanesulfonic acid (TfOH), N-
iodosuccinimide (NIS), trichloroacetonitrile, benzaldehyde di-
methyl acetal, benzoyl chloride, hydrazine monohydrate, phenoxy-
acetyl chloride, (3,4-dihydroxyphenyl)acetic acid, 2-methyl-2-but-
ene, p-toluenesulfonic acid (p-TsOH), tert-butyldimethylsilyl chlo-
ride (TBDMSCl), 4,4Ј-dimethoxytrityl chloride (DMTCl), manga-
nese(IV) oxide (MnO2), ethylene glycol, N,N-dicyclo-
hexylcarbodiimide (DCC), 4-(dimethylamino)pyridine (DMAP),
and caffeic acid (3,4-dihydroxycinnamic acid). Acetic anhydride
(Baker), acetic acid (Baker), acetyl chloride (Merck), boron trifluo-
rideϪdiethyl ether (Aldrich), and triethylamine trihydrofluoride
(3HF·Et3N; Aldrich) were used as received. Dowex 50 W X4 was
purchased from Fluka. Ϫ Reactions were monitored by TLC on
Schleicher and Schüll DC Fertigfolien (F 1500 LS 254). Com-
pounds were visualized by UV light and by spraying with 20% sulf-
uric acid in ethanol, followed by charring at 140 °C. Unsaturated
compounds were visualized by spraying with a solution of KMnO4
(2%) and (1%) K2CO3 in water. Eluents for column chromatogra-
phy were of technical grade and distilled before use. Ϫ All reactions
were performed under anhydrous conditions at room temperature
unless stated otherwise. Ϫ Gel-filtration was performed on Se-
phadex LH-20 (Pharmacia). Ϫ Column chromatography was per-
formed on silica gel 60 (0.063Ϫ0.200 mm) (Baker).
Ethyl
2-O-Acetyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-acetyl-␣-
L-
rhamnopyranosyl)-1-thio-β-
D
-glucopyranoside (6a): catalytic
A
amount of trifluoromethanesulfonic acid (30 µL) was added to a
solution of orthoester 5 (2.00 g, 3.19 mmol) in dichloroethane con-
˚
taining powdered molecular sieves (4 A) under a blanket of nitro-
gen. After stirring for 6 h, the reaction mixture was neutralized
with Et3N, filtered, washed with 10% aq. NaHCO3 and water. The
organic layer was dried (MgSO4), filtered and concentrated in va-
cuo. The crude product was crystallized from dichloromethane and
light petroleum ether to furnish 6a (1.52 g, 76%) as a white solid.
Ϫ Rf ϭ 0.5 (toluene/ethyl acetate, 4:1, v/v). Ϫ [α]D2 0 ϭ Ϫ38.2 (c ϭ
1.0, CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 0.64 (d, 3 H, J5Ј,6Ј ϭ 6.2 Hz,
6Ј-H), 1.26 (t, 3 H, CH3, SEt), 1.96, 1.99, 2.11, 2.14 (4 ϫ s, 12 H,
CH3, Ac), 2.76 (m, 2 H, CH2, SEt), 3.52 (m, 1 H, 5-H), 3.67 (t, 1
H, J4,5 ϭ 9.8 Hz, 4-H), 3.78 (t, 1 H, J6a,6b ϭ 9.2 Hz, 6-Ha), 4.09
(m, 1 H, 5Ј-H), 4.37 (dd, 1 H, J5,6b ϭ 4.8 Hz, 6-Hb), 4.45 (d, 1 H,
J1,2 ϭ 10.2 Hz, 1-H), 4.90 (m, 3 H, 1Ј-H, 2Ј-H, 4Ј-H), 5.28 (dd, 1
3,4-Di-O-acetyl-β-L-rhamnopyranose 1,2-(Ethyl 4,6-O-benzylidene-
1-thio-β- -glucopyranose-3-yl) Orthoacetate (4): To a mixture of
D
H, J3,4 ϭ 9.7 Hz, 2-H), 5.38 (dd, 1 H, J1Ј,2Ј ϭ 3.4 Hz, J2Ј,3Ј
ϭ
ethyl 4,6-O-benzylidene-1-thio-β--glucopyranoside (2) (2.03 g,
6.5 mmol) and 2,3,4-tri-O-acetyl-α--rhamnopyranosyl trichlo-
roacetimidate (3a) (3.53 g, 8.1 mmol) in dichloromethane/tetra-
hydrofuran (160 mL, 3:1, v/v) was added powdered molecular si-
10.0 Hz, 2Ј-H), 5.55 (s, 1 H, benzylidene), 7.26Ϫ7.49 (m, 5 H, CH,
Ph). Ϫ 13C{1H} NMR (CDCl3): δ ϭ 14.4 (CH3, SEt), 16.1 (C-6Ј),
20.3 (CH3, Ac), 23.5 (CH2, SEt), 68.0 (C-6), 65.9, 68.0, 71.1, 70.5,
70.8, 71.5, 77.8, 78.0 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј),
83.7 (C-1), 97.1 (C-1Ј), 101.4 (PhCH, benzylidene), 126.0Ϫ128.8
(CH, Ph), 136.7 (Cq, benzylidene), 169.2, 169.4, 169.5 (CϭO, Ac).
Ϫ MS: m/z ϭ 647.3 [M ϩ Na]ϩ. Ϫ C29H38O13S (582.19): calcd. C
55.58, H 6.11; found C 55.7, H 6.1.
˚
eves (4 A) and the solution was placed under nitrogen. After stir-
ring for 30 min, the solution was cooled to Ϫ40°C and a catalytic
amount of trimethylsilyl trifluoromethanesulfonate (117 µL,
0.65 mmol) was slowly added. TLC analysis showed complete dis-
appearance of 2 after a reaction time of 30 min. The reaction mix-
ture was neutralized with Et3N and filtered and subsequently 2-O-Acetyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-acetyl-α-L-
washed with 10% NaHCO3 and water. The organic layer was dried
(MgSO4), filtered and concentrated in vacuo. The crude product
was purified by silica gel column chromatography (Et2O/light
petroleum ether, 1:2, v/v) to afford the title compound 4 (3.08 g,
rhamnopyranosyl)-␣-D-glucopyranose (7a): Preparation of a 0.1 
stock solution of NIS/cat. TfOH: Trifluoromethanesulfonic acid
(60 µL) was added to a solution of N-iodosuccinimide (2.25 g,
10 mmol) in
a mixture of dichloromethane/tetrahydrofuran
81%) as a colorless foam. Ϫ Rf ϭ 0.4 (Et2O/light petroleum ether,
(100 mL, 40:1, v/v). To a mixture of thioglycoside 6a (2.11 g,
1
3:1, v/v). Ϫ H NMR (CDCl3): δ ϭ 0.86 (d, 3 H, J5Ј,6Ј ϭ 6.7 Hz, 3.37 mmol) in dichloromethane/water (25.25 mL, 100:1, v/v) was
6Ј-H), 1.31 (t, 3 H, CH3, SEt), 1.79 (s, 3 H, CH3, orthoacetate), added in approximately 45 min a 0.1  stock solution of NIS/cat.
2.02, 2.05 (2 ϫ s, 6 H, CH3, Ac), 2.74 (m, 2 H, CH2, SEt), 2.96 (d, TfOH (43 ± 4 mL) and the progress of the reaction was monitored
1 H, 2Ј-OH), 3.33Ϫ3.51 (m, 3 H, 2-H, 5-H, 4-H), 3.69 (t, 1 H, by TLC analysis (40% ethyl acetate in toluene). After complete dis-
J6a,6b ϭ 9.8 Hz, 6-Ha), 3.88 (t, 1 H, J3,4 ϭ 9.7 Hz, 3-H, J2,3
9.7 Hz), 4.35 (dd, 1 H, J5,6b ϭ 4.6 Hz, 6-Hb), 4.42 (d, 1 H, J2,3
ϭ
appearance of the starting material, the reaction was stopped by
adding a 10% aq. Na2S2O3 solution. The organic layer was sepa-
ϭ
9.7 Hz, 1-H), 4.75 (dd, 1 H, J2Ј,3Ј ϭ 3.6 Hz, 2Ј-H), 5.03 (m, 2 H, rated and washed with a 10% aq. NaHCO3 solution and water,
3Ј-H, 4Ј-H), 5.14 (d, 1 H, J1Ј,2Ј ϭ 2.4 Hz, 1Ј-H), 5.49 (s, 1 H, benzyl-
subsequently dried (MgSO4), filtered, and concentrated in vacuo.
idene), 7.35Ϫ7.49 (m, 5 H, CH, Ph). Ϫ 13C{1H} NMR (CDCl3): The crude product was purified by silica gel column chromatogra-
δ ϭ 14.9 (CH3, SEt), 17.1 (C-6Ј), 20.4 (CH3, Ac), 24.1 (CH2, SEt), phy (toluene/ethyl acetate, 85:15 Ǟ 70:30, v/v) to afford the title
24.2 (CH3, orthoacetate), 68.2 (C-6), 68.7, 69.5, 69.6, 70.3, 72.0,
compound 7a (1.59 g, 81%) as a foam. Ϫ Rf ϭ 0.3 (40% ethyl acet-
75.5, 76.0, 79.0 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 86.3 ate in toluene). Ϫ 1H NMR (CDCl3): δ ϭ 0.81 (d, 3 H, J5Ј,6Ј
ϭ
(C-1), 96.7 (C-1Ј), 101.1 (PhCH, benzylidene), 123.1 (Cq, or-
6.6 Hz, 6Ј-H), 1.97, 1.99, 2.12, 2.18 (4 ϫ s, 12 H, CH3, Ac), 4.98
Eur. J. Org. Chem. 1999, 2623Ϫ2632
2626

Synthesis of Verbascoside
FULL PAPER
(t, 1 H, J3Ј,4Ј ϭ 9.4 Hz, 4Ј-H), 5.15 (d, 1 H, J1Ј,2Ј ϭ 1.4 Hz, 1Ј-H), pressure. Silica gel column chromatography (light petroleum ether/
5.30 (m, 3 H, 2-H, 2Ј-H, 3Ј-H), 5.55 (s, 1 H, benzylidene), 6.17 (d, ethyl acetate, 1:0 Ǟ 1:2, v/v) of the residual oil afforded pure 12
1 H, J1,2 ϭ 3.7 Hz, 1-H), 7.26Ϫ7.41 (m, 5 H, CH, Ph). Ϫ 13C{1H} (3.50 g, 91%) as a colorless oil. Ϫ Rf ϭ 0.6 (light petroleum ether/
NMR (CDCl3): δ ϭ 16.0 (C-6Ј), 20.1 (CH3, Ac), 68.0 (C-6), 64.5,
ethyl acetate, 3:1, v/v). Ϫ 1H NMR (CDCl3): δ ϭ 0.18 (s, 12 H,
65.5, 68.0, 68.9, 68.9, 70.3, 71.2, 74.8, 78.1 (C-2, C-3, C-4, C-5, C- CH3, TBDMS), 0.98 [s, 18 H, C(CH3)3, TBDMS], 1.57 (s, 1 H,
2Ј, C-3Ј, C-4Ј, C-5Ј), 91.7 (C-1), 97.4 (C-1Ј), 101.1 (PhCH, benzyl- OH), 2.73 (t, 2 H, J ϭ 6.6 Hz, CH2CH2O), 3.78 (dd, 2 H, J ϭ
idene), 125.9Ϫ128.1 (CH, benzylidene), 136.7 (Cq, benzylidene),
169.4, 169.8, 170.0, 170.4 (CϭO, Ac).
12.4 Hz, CH2CH2O), 6.67 (m, 3 H, CH, Ph). Ϫ 13C{1H} NMR
(CDCl3): δ ϭ Ϫ4.9 (CH3, TBDMS), 17.4 (Cq, TBDMS), 25.1
[C(CH3)3, TBDMS], 37.7 (CH2CH2O), 62.6 (CH2CH2O), 120.0,
121.0 (CH, Ph), 130.9 (Cq, Ph), 144.2, 145.5 (CqϪO, Ph). Ϫ MS:
m/z ϭ 405.3 [M ϩ Na]ϩ.
2-O-Acetyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-acetyl-α-
L-
rhamnopyranosyl)-␣/β- -glucopyranosyl Trichloroacetimidate (8a):
D
Compound 7a (1.67 g, 2.87 mmol) was dried by co-evaporation of
toluene (3 ϫ 10 mL) and dissolved in CH2Cl2 (20 mL). Sub-
sequently, cesium carbonate (0.574 mmol, 187 mg) and trichlo-
roacetonitrile (8.61 mmol, 860 µL) were added. After stirring the
resulting mixture for 2 h, TLC analysis indicated that the starting
material was completely converted into a faster moving product.
The reaction mixture was filtered, concentrated in vacuo and the
resulting oil was purified by silica gel chromatography (toluene/
ethyl acetate/triethylamine, 100:0:0.5 Ǟ 80:20:0.5, v/v/v) to yield 8a
(1.79 g, 86%) as a white amorphous solid Ϫ Rf ϭ 0.7 (toluene/ethyl
acetate/triethylamine, 75:25:1, v/v/v). Ϫ 1H NMR (CDCl3): δ ϭ
5.90 (d, 1 H, J1,2 ϭ 7.3 Hz, 1-Hβ), 6.53 (d, 1 H, J1,2 ϭ 3.6 Hz, 1-
Hα). Ϫ 13C{1H} NMR (CDCl3): δ ϭ 16.1 (C-6Ј), 20.2 (CH3, Ac),
67.8 (C-6), 64.9, 65.9, 66.5, 68.0, 69.8, 70.0, 70.6, 71.6, 72.3, 76.0,
77.9, 78.1 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 89.9, 90.3
(CCl3), 93.1, 95.3 (C-1), 96.8, 97.2 (C-1Ј), 101.3 (PhCH, benzylid-
ene), 124.9Ϫ128.7 (CH, Ph), 137.2 (Cq, benzylidene), 160.2 (Cϭ
NH), 168.6, 169.3, 169.4, 169.5 (CϭO, Ac).
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl 2-O-Acetyl-4,6-O-
benzylidene-3-O-(2,3,4-tri-O-acetyl-␣-L-rhamnopyranosyl)-β-D-
glucopyranose (13a): A mixture of trichloroacetimidate donor 8a
(3.00 g, 4.12 mmol) and alcohol 12 (1.58 g, 4.12 mmol) was dried
by evaporation of toluene (3 ϫ 15 mL), dissolved in CH2Cl2
˚
(40 mL), and crushed molecular sieves (4 A, 2 g) were added. The
resulting mixture was stirred for 20 min under argon and then 250
µL of a 0.2  solution of BF3·OEt2 in CH2Cl2 was slowly added
(15 min). TLC analysis (toluene/ethyl acetate, 88:12, v/v) showed
the disappearance of the imidate 8a and the formation of two faster
moving products. The fastest moving product (Rf ϭ 0.43), presum-
ably an orthoester derivative, was converted into the slower moving
product (Rf ϭ 0.31) in the course of the reaction time. When this
transformation stopped, an additional amount (± 50 µL) of the 0.2
 BF3·OEt2 stock solution was added. After complete rearrange-
ment, the reaction mixture was neutralized with Et3N, filtered, and
the filtrate was washed with water. The organic phase was dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the
crude oil was accomplished using a silica gel column, eluted with
toluene and a gradient of 0Ǟ10% ethyl acetate to afford homo-
geneous 13a as a colorless oil. Yield: 2.27 g, 58%. Ϫ [α]D20 ϭ Ϫ31.5
Methyl [3,4-Bis(tert-butyldimethylsilyloxy)phenyl]acetate (11): At
0°C, acetyl chloride (6 mL) was added dropwise to a solution of
(3,4-dihydroxyphenyl)acetic acid (6.51 g, 38.7 mmol) in methanol
(240 mL). After 1 h, the mixture was allowed to warm to room
temperature. The progress of the reaction was monitored by TLC
analysis (light petroleum ether/ethyl acetate) which indicated com-
plete conversion after another 2 h. The solution was concentrated
to near dryness under reduced pressure, concentrated with dry tolu-
ene and redissolved in dry DMF (60 mL) upon which TBDMSCl
(14.0 g, 92.8 mmol) and imidazole (6.81 g, 100 mmol) were added.
The mixture was stirred for 2 h and diluted with Et2O. The mixture
was transferred to a separation funnel and water was added. The
layers were separated and the organic phase was washed with water
and dried (MgSO4), filtered and concentrated in vacuo. The re-
sidual oil was applied onto a column of silica gel and elution was
effected with ethyl acetate (0Ǟ10%) in light petroleum ether to
give, after concentration of the appropriated fractions, methyl [3,4-
bis(tert-butyldimethylsilyloxy)phenyl]acetate as an oil. Ϫ Yield:
13.51 g, 85%. Ϫ Rf ϭ 0.8 (light petroleum ether/ethyl acetate, 3:1,
1
(c ϭ 1.0, CHCl3). Ϫ H NMR (CDCl3/CD3OD): δ ϭ 0.18, 0.19 (2
ϫ s, 12 H, CH3, TBDMS), 0.96, 0.98 (s, 18 H, C(CH3)3, TBDMS),
0.64 (d, 3 H, J5Ј,6Ј ϭ 6.2 Hz, 6Ј-H), 1.97, 1.99, 2.05, 2.11 (4 ϫ s, 12
H, CH3, Ac), 2.74 (t, 2 H, CH2CH2O), 3.47 (m, 1 H, 5-H), 3.63
(m, 2 H, 4-H, CH2ϪHCHϪO), 3.80 (t, 1 H, J6a,6b ϭ 9.2 Hz, 6-
Ha), 3.91 (t, 1 H, J3,4 ϭ 9.7 Hz, 3-H), 4.05 (m, 2 H, 5Ј-H,
CH2ϪHCHϪO), 4.36 (dd, 1 H, J5,6a ϭ 4.8 Hz, 6-Hb), 4.47 (d, 1
H, J1,2 ϭ 8.0 Hz, 1-H), 4.87 (d, 1 H, J1Ј,2Ј ϭ 1.7 Hz, 1Ј-H), 4.92 (t,
1 H, J3Ј,4Ј ϭ J4Ј,5Ј ϭ 10.0 Hz, 4Ј-H), 4.97 (dd, 1 H, J2Ј,3Ј ϭ 3.6 Hz,
2Ј-H), 5.04 (dd, 1 H, J2,3 ϭ 9.7 Hz, 2-H), 5.27 (s, 1 H, benzylidene),
6.64 (m, 2 H, 2Ј-HЈ, 6ЈЈ-H), 6.73 (d, 1 H, J5ЈЈ,6ЈЈ, 5Ј-H), 7.26Ϫ7.49
(m, 5 H, CH, Ph). Ϫ 13C{1H} NMR (CDCl3/CD3OD): δ ϭ Ϫ5.4
(CH3, TBDMS), 15.1 (C-6Ј), 17.1 (Cq, TBDMS), 19.2 (CH3, Ac),
24.6 [C(CH3)3, TBDMS], 34.0 (CH2CH2O), 67.2 (C-6), 69.5
(CH2CH2O), 65.0, 65.3, 67.5, 69.2, 70.0, 72.4, 75.8, 77.7 (C-2, C-
3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 96.3 (C-1), 100.0 (C-1Ј), 100.7
(PhCH, benzylidene), 119.6, 120.6, 120.7 (C-2ЈЈ, C-5ЈЈ, C-6ЈЈ),
125.2Ϫ128.0 (CH, Ph), 130.4 (C-1ЈЈ), 135.7 (Cq, benzylidene),
144.0, 145.3 (C-3ЈЈ, C-4ЈЈ), 168.9, 169.1 (CϭO, Ac). Ϫ MS: m/z ϭ
969.5 [M ϩ Na]ϩ.
1
v/v). Ϫ H NMR (CDCl3): δ ϭ 0.24 (s, 12 H, CH3, TBDMS), 0.95
[s, 18 H, C(CH3)3, TBDMS], 2.95 (s, 2 H, CH2), 3.10 (s, 3 H, OMe),
5.65 (m, 3 H, CH, Ph). Ϫ 13C{1H} NMR (CDCl3): δ ϭ Ϫ4.3 (CH3,
TBDMS), 18.2 (Cq, TBDMS), 25.7 [C(CH3)3, TBDMS], 40.2
(CH2), 51.5 (OMe), 120.6, 121.9 (CH, Ph), 126.8 (Cq, Ph), 145.7,
146.5 (CqϪO, Ph), 171.7 (CϭO).
Ethyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-benzoyl-␣-
L-
rhamnopyranosyl)-1-thio-β- -glucopyranose (6b): To a solution of
D
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethanol (12): Methyl
compound 6a (947 mg, 2 mmol), in 10 mL of methanol, was added
NaOMe (54 mg, 1 mmol). After stirring for 4 h, the deacetylation
was complete, as judged by TLC analysis. The reaction was neu-
tralized with Dowex 50 W X4 (Hϩ form), filtered, and concen-
trated in vacuo. The obtained oil was three times concentrated with
a small amount of pyridine and subsequently dissolved in pyridine
(6 mL). To this solution was added benzoyl chloride and the reac-
tion mixture was stirred until TLC analysis revealed that the ben-
zoylation was complete. The excess of benzoyl chloride was de-
[3,4-bis(tert-butyldimethylsilyloxy)phenyl]acetate
(11,
4.13 g,
10.03 mmol) in diethyl ether (25 mL) was added dropwise to a co-
oled (0°C) suspension of LiAlH4 (400 mg, 10.5 mmol) in diethyl
ether (25 mL) and stirred for 15 min. TLC analysis revealed com-
plete disappearance of the starting material in this time period.
The reaction was quenched by dropwise addition of methanol and
diluted with diethyl ether and subsequent washed with water. The
organic layer was dried (MgSO4) and concentrated under reduced
Eur. J. Org. Chem. 1999, 2623Ϫ2632
2627

H. I. Duynstee, M. C. de Koning, H. Ovaa, G. A. van der Marel, J. H. van Boom
FULL PAPER
stroyed by addition of water and the mixture was concentrated in
vacuo. The oily residue was dissolved in ethyl acetate and washed
with water and aq. NaHCO3 (10%). The ethyl acetate layer was
dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified on a silica gel column (toluene/ethyl acetate,
1:3 Ǟ 0:1, v/v) to furnish the title compound 6b (1.48 g, 85%) as a
colorless foam. Ϫ Rf ϭ 0.6 (toluene/ethyl acetate, 4:1, v/v). Ϫ
Bz), 131.1 (C-1ЈЈ), 137.6 (Cq, benzylidene), 145.0, 146.3 (C-3ЈЈ, C-
4ЈЈ), 164.4, 164.7, 165.2, 165.4 (CϭO, Bz). Ϫ MS: m/z ϭ 1218.8
[M ϩ Na]ϩ.
1,2:5,6-Di-O-isopropylidene-3-O-(2,3,4-tri-O-benzoyl-␣-
rhamnopyranosyl)-␣- -glucofuranose (17): Ethyl 2,3,4-tri-O-ben-
zoyl-1-thio-α--rhamnopyranoside (15, 7.69 g, 14.3 mmol) and
1,2:5,6-di-O-isopropylidene-α--glucofuranose (16, 4.83 g,
L-
D
20
[α]D ϭ Ϫ42.0 (c ϭ 0.5, CHCl3). Ϫ 13C{1H} NMR (CDCl3): δ ϭ
18.6 mmol) were dissolved in 100 mL CH2Cl2. To the solution was
14.5 (CH3, SEt), 16.5 (C-6Ј), 23.6 (CH2, SEt), 68.2 (C-6), 66.3, 69.3,
70.1, 70.7, 71.3, 72.5, 76.8, 78.6 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-
4Ј, C-5Ј), 83.8 (C-1), 97.5 (C-1Ј), 101.5 (PhCH, benzylidene),
124.0Ϫ132.9 (CH, Ph, Bz), 127.8 (Cq, Bz), 136.7 (Cq, benzylidene),
164.1, 164.6, 164.9, 165.2 (CϭO, Bz). Ϫ MS: m/z ϭ 897.1 [M ϩ
Na]ϩ.
˚
added powdered molecular sieves (4 A) and the mixture was stirred
for 30 min under N2. N-Iodosuccinimide (4.18 g, 18.6 mmol) and
a catalytic amount of triflic acid were added. After stirring for 1 h,
TLC analysis showed complete consumption of the donor. The re-
action mixture was filtered, diluted with dichloromethane, washed
with aq. Na2S2O3 (10%, 50 mL), and aq. NaHCO3 (10%, 50 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. Purification by silica gel column chromatog-
raphy (eluent: toluene/ethyl acetate, 1:0 to 3:1) afforded disacchar-
ide 17 (9.76 g, 95%) as a colorless oil. Ϫ Rf ϭ 0.4 (toluene/ethyl
acetate, 4:1, v/v). Ϫ 13C{1H} NMR (CDCl3): δ ϭ 16.9 (C-6Ј), 25.0,
2-O-Benzoyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-benzoyl-␣-
L-
rhamnopyranosyl)-␣- -glucopyranose (7b): The method for the hy-
D
drolysis of the thioethyl group in 6b (1.31 g, 1.50 mmol) to afford
7b is identical to that described for the synthesis of hemiacetal 7a
from thioethyl derivative 6a. Purification by silica gel column chro-
matography (eluent: toluene/ethyl acetate, 100:0 Ǟ 85:15) gave 7b 25.7, 26.4 (CH3, iPr), 67.9 (C-6), 66.7, 69.8, 70.3, 71.2, 71.7, 76.8,
(1.01 g, 81%) as a foam. Ϫ Rf ϭ 0.3 (20% ethyl acetate in toluene). 80.7, 94.5 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 94.5 (C-1Ј),
13C{1H} NMR (CDCl3): δ ϭ 16.8 (C-6Ј), 68.6 (C-6), 65.1, 66.3, 105.1 (C-1), 108.9, 111.6 (Cq, iPr), 128.3 (Cq, Bz), 127.9Ϫ134.8
Ϫ
70.2, 70.5, 71.6, 72.2 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), (CH, Bz), 161.8, 165.1, 165.3 (CϭO, Bz). Ϫ MS: m/z ϭ 741.3 [M
92.9 (C-1), 97.8 (C-1Ј), 101.6 (PhCH, benzylidene), 125.1Ϫ133.5
(CH, Ph), 128.0 (Cq, Bz), 136.9 (Cq, benzylidene), 165.2, 165.5,
165.6, 165.8 (CϭO, Bz).
ϩ Naϩ], 757.3 [M ϩ Kϩ].
4 , 6 - O - B e n z y l i d e n e - 3 - O - ( 2 , 3 , 4 - t r i - O - b e n z o y l - ␣ - L -
rhamnopyranosyl)-␣/β-D-glucopyranose (18): Both acetonide func-
tions in compound 17 (2.10 g, 2.92 mmol) were removed by heating
17 in a mixture of tetrahydrofuran/water/trifluoroacetic acid (5:1:1,
2-O-Benzoyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-benzoyl-␣-
L-
rhamnopyranosyl)-␣/β- -glucopyranosyl Trichloroacetimidate (8b):
D
Trichloroacetimidate donor 8b was prepared from 7b (1.01 g, 60 mL) at 100°C. The progress of the reaction was monitored by
1.21 mmol) in the same way as compound 8a. Purification by silica
gel column chromatography (eluent: toluene/ethyl acetate, 100:0 Ǟ
85:15) gave 8b (997 mg, 84%) as a white amorphous solid. Ϫ Rf ϭ
TLC analysis (toluene/ethyl acetate, 1:3, v/v). After approximately
1 h, the starting material was converted into 1,2-O-isopropylidene-
3-O-(2,3,4-tri-O-benzoyl-α--rhamnopyranosyl)-α--glucofuranose
0.8 (toluene/ethyl acetate/triethylamine, 75:25:1, v/v/v). Ϫ 13C{1H} [Rf ϭ 0.85 (ethyl acetate)]. After maintaining the reaction mixture
NMR (CDCl3): δ ϭ 16.7 (C-6Ј), 68.4 (C-6), 65.3, 66.5, 66.7, 69.4,
70.3, 70.1, 70.3, 71.4, 72.7, 73.0, 73.2, 78.5 (C-2, C-3, C-4, C-5, C-
2Ј, C-3Ј, C-4Ј, C-5Ј), 90.1, 90.4 (CCl3), 93.5, 95.7, 97.0, 97.9 (C-1,
for approximately 12Ϫ18 h at elevated temperature, the mixture
was cooled, diluted with toluene and concentrated in vacuo. The
residue was repeatedly diluted with dry toluene and concentrated
C-1Ј), 101.2, 101.8 (PhCH, benzylidene), 124.9Ϫ133.0 (CH, Ph, under reduced pressure. The thus obtained oil was dissolved in
Bz), 128.0 (Cq, Bz), 136.6, 137.5 (Cq, benzylidene), 160.3, 160.7
(CϭNH), 164.4, 164.6, 165.1, 165.3 (CϭO, Bz).
acetonitrile (100 mL) and to the solution were added benzaldehyde
dimethyl acetal (1.8 mL) and a catalytic amount of p-toluenesul-
fonic acid. After 6 h, the reaction mixture was neutralized with
Et3N and concentrated in vacuo. Crude 18 was applied onto a col-
umn of silica gel. Elution with toluene/ethyl acetate (0:1 Ǟ 1:1, v/
v) and concentration of the appropriate fractions furnished the title
compound 18 (1.46, 69%) as a colorless foam. Ϫ 3-O-(2,3,4-Tri-O-
benzoyl-α--rhamnopyranosyl)--glucose: Rf ϭ 0.2 (ethyl acetate).
Ϫ 18: Rf ϭ 0.43 (toluene/ethyl acetate, 1:1, v/v). Ϫ 13C{1H} NMR
(CD3CN): δ ϭ 17.3 (C-6Ј), 69.7, 69.5 (C-6), 63.5, 66.9, 67.3, 71.2,
71.6, 74.2, 76.3, 77.3, 78.2, 80.0, 80.5 (C-2, C-3, C-4, C-5, C-2Ј, C-
3Ј, C-4Ј, C-5Ј), 94.3 (C-1Ј), 98.3, 98.6 (C-1), 102.5 (PhCH, benzylid-
ene), 128.3 (Cq, Bz), 127.3Ϫ134.6 (CH, Bz), 138.8 (Cq, benzylid-
ene), 166.3 (CϭO, Bz).
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl
4,6-O-benzylidene-3-O-(2,3,4-tri-O-benzoyl-␣-
β-
2-O-Benzoyl-
-rhamnopyranosyl)-
-glucopyranoside (13b): The glycosylation between 8b (450 mg,
L
D
0.46 mmol) and 12 (176 mg, 0.46 mmol) to obtain 13b was per-
formed as described above for the synthesis of 13a. Purification by
silica gel column chromatography (eluent: toluene/ethyl acetate,
10:0 Ǟ 9:1) gave 13b (407 mg, 74%) as a colorless oil. Ϫ Rf ϭ 0.8
(toluene/ethyl acetate, 9:1, v/v). Ϫ [α]D20 ϭ Ϫ36.3 (c ϭ 1.0, CHCl3).
1
Ϫ H NMR (CDCl3/CD3OD): δ ϭ 0.18, 0.19 (2 ϫ s, 12 H, CH3,
TBDMS), 0.89 (d, 3 H, J5Ј,6Ј ϭ 6.2 Hz, 6Ј-H), 0.94, 0.96 [2 ϫ s, 18
H, C(CH3)3, TBDMS], 2.71 (t, 2 H, CH2CH2O), 3.66 (m, 2 H,
6-Hb, CH2ϪHCHϪO), 3.89 (m, 2 H, 4-H, 5-H), 4.04 (m, 1 H,
CH2ϪHCHϪO), 4.25 (t, 1 H, J2,3 ഠ J3,4 ϭ 9.7 Hz, 2-H), 4.47 (m, 1,2-Di-O-acetyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-benzoyl-␣-
2 H, 5Ј-H, 6-Hb), 4.69 (d, 1 H, J1,2 ϭ 8.0 Hz, 1-H), 5.12 (s, 1 H, rhamnopyranosyl)-␣-
-glucopyranose (19): Diol 18 (2.61 g,
J1Ј,2Ј ϭ 1.1 Hz, 1Ј-H), 5.46 (m, 3 H, 2-H, 2Ј-H, 4Ј-H), 5.67 (s, 1 H, 3.6 mmol) was dissolved in a mixture of pyridine/acetic anhydride
benzylidene), 5.80 (dd, 1 H, J2Ј,3Ј ϭ 3.6 Hz, J3Ј,4Ј ϭ 10.0 Hz, 2Ј-H), (2:1, v/v, 50 mL). After stirring for 4 h, the mixture was concen-
L-
D
6.54 (s, 2 H, 2Ј-HЈ, 6ЈЈ-H), 6.61 (s, 1 H, 5ЈЈ-H), 7.26Ϫ8.04 (m, 25 trated in vacuo. Purification of the remaining oil on silica gel using
H, CH, Ph, Bz). Ϫ 13C{1H} NMR (CDCl3): δ ϭ Ϫ4.3 (CH3, toluene as eluent afforded the title compound 19 (2.60 g, 89%) as
TBDMS), 16.7 (C-6Ј), 17.1 (Cq, TBDMS), 25.8 [C(CH3)3,
an oil. Ϫ Rf ϭ 0.56 (toluene/ethyl acetate, 4:1, v/v). Ϫ 1H NMR
TBDMS], 35.2 (CH2CH2O), 67.6 (CH2CH2O), 70.8 (C-6), 66.4, (CDCl3): δ ϭ 0.90 (d, 3 H, J5Ј,6Ј ϭ 6.0 Hz, 6Ј-H), 2.16, 2.20 (2 ϫ
66.5, 68.6, 69.4, 71.6, 74.2, 78.7 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C- s, 6 H, CH3, Ac), 3.84 (m, 2 H, 4-H, 6-Ha), 4.05 (m, 1 H, 5-H),
4Ј, C-5Ј), 97.6 (C-1), 101.3, 101.7 (C-1, PhCH, benzylidene), 120.8,
121.5, 121.7 (C-2ЈЈ, C-5ЈЈ, C-6ЈЈ), 125.0Ϫ133.1 (CH, Ph), 129.2 (Cq, 9.7 Hz, 2-H), 5.31 (s, 1 H, 1Ј-H), 5.48 (br. s, 1 H, 2Ј-H), 5.61 (t, 1
4.36 (m, 2 H, 3-H, 6-Hb), 4.52 (m, 1 H, 5Ј-H), 5.15 (dd, 1 H, J2,3 ϭ
2628
Eur. J. Org. Chem. 1999, 2623Ϫ2632

Synthesis of Verbascoside
FULL PAPER
H, J3Ј,4Ј ϭ 9.3 Hz, 4Ј-H), 5.68 (s, 1 H, benzylidene), 5.47 (dd, 1 H, (CH2CH2O), 66.4, 66.5, 69.3, 71.3, 71.7, 73.3, 76.3, 79.0 (C-2, C-
J2Ј,3Ј ϭ 3.6 Hz), 6.36 (d, 1 H, J1,2 ϭ 3.6 Hz, 1-H), 7.20Ϫ8.04 (m, 3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 97.3 (C-1), 101.4, 101.8 (C-
20 H, CH, Ph, Bz). Ϫ 13C{1H} NMR (CDCl3): δ ϭ 16.9 (C-6Ј), 1Ј, PhCH, benzylidene), 120.7, 120.8, 121.8 (C-2ЈЈ, C-5ЈЈ, C-6ЈЈ),
20.4, 20.8 (CH3, Ac), 68.5 (C-6), 65.3, 66.4, 69.5, 71.0, 71.5, 72.3, 126.1Ϫ133.3 (CH, Ph), 131.2 (C-1ЈЈ), 136.8 (Cq, benzylidene),
72.9, 78.9 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 89.8 (C-1Ј),
145.1, 146.4 (C-3ЈЈ, C-4ЈЈ), 165.2, 165.3, 165.5 (CϭO, Bz), 169.4
97.4 (C-1), 102.0 (CH, Ph), 128.3 (Cq, Bz), 126.1Ϫ133.4 (CH, Bz), (CϭO, Ac). Ϫ MS: m/z ϭ 1155.8 [M ϩ Na]ϩ.
136.7 (Cq, benzylidene), 165.4, 165.5 (CϭO, Bz), 168.9, 170.1 (Cϭ
O, Ac).
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl
dene-3-O-(␣-L-rhamnopyranosyl)-β-D-glucopyranose (14): To a solu-
4,6-O-Benzyli-
tion of compound 13a (947 mg, 1 mmol) or 13c (1.13 g, 1 mmol)
in 10 mL of methanol was added NaOMe (26 mg, 0.5 mmol). After
stirring for 3.5 h, the deacylation was complete, as judged by TLC
analysis. The reaction mixture was neutralized with Dowex 50 W
X4 (Hϩ form), filtered, and concentrated in vacuo. The crude prod-
uct was purified on a silica gel column (toluene/ethyl acetate, 1:3
Ǟ 0:1, v/v) to furnish the title compound 14 (764 mg, 98%) as a
2-O-Acetyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-benzoyl-␣-
L-
rhamnopyranosyl)-␣/β- -glucopyranose (7c): Hydrazine monohydr-
D
ate (68 µL, 1.4 mmol) was added to a solution of 19 (1.10 g,
1.36 mmol) in 10 mL of DMF containing acetic acid (85 µL,
1.5 mmol). The mixture was stirred for 1 h and then concentrated
in vacuo. The residue was taken up in diethyl ether and washed
with water. The organic layer was dried (MgSO4), filtered, and con-
centrated in vacuo. Purification by silica gel column chromatogra-
phy (eluent: toluene/ethyl acetate, 10:0 Ǟ 9:1) gave 7c (847 mg,
81%) as a colorless oil. Ϫ Rf ϭ 0.3 (toluene/ethyl acetate, 4:1, v/v).
20
white amorphous solid. Ϫ [α]D ϭ Ϫ21.3 (c ϭ 0.4, CHCl3). Ϫ
Rf ϭ 0.3 (8% MeOH in CH2Cl2). Ϫ 1H NMR (CD3OD): δ ϭ 0.18,
0.19 (2 ϫ s, 12 H, CH3, TBDMS), 0.87 (d, 3 H, J5Ј,6Ј ϭ 6.2 Hz, 6Ј-
H), 0.99, 1.00 [s, 18 H, C(CH3)3, TBDMS], 2.81 (t, 2 H, CH2CH2O,
J ϭ 6.6 Hz), 3.25Ϫ4.01 (m, 11 H, 2-H, 3-H, 4-H, 5-H, 6-Ha, 6-Hb,
2Ј-H, 4Ј-H, 5Ј-H, CH2CH2O), 4.27 (dd, 1 H, J2Ј,3Ј ϭ 3.6 Hz, 3Ј-H,
J3Ј,4Ј ϭ 10.2 Hz), 4.42 (d, 1 H, J1,2 ϭ 7.4 Hz, 1-H), 5.14 (d, 1 H,
J1Ј,2Ј ϭ 1.5 Hz, 1Ј-H), 5.52 (s, 1 H, benzylidene), 6.75 (m, 3 H, 2ЈЈ-
H, 5ЈЈ-H, 6ЈЈ-H), 7.30Ϫ7.51 (m, 5 H, CH, Ph). Ϫ 13C{1H} NMR
(CD3OD): δ ϭ Ϫ3.8, Ϫ3.7 (CH3, TBDMS), 17.6 (C-6Ј), 19.2 (Cq,
TBDMS), 26.5 [C(CH3)3, TBDMS], 36.4 (CH2CH2O), 69.9 (C-6),
72.2 (CH2CH2O), 67.7, 69.5, 72.1, 73.8, 76.6, 79.5, 80.6, 84.3 (C-2,
C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 102.4, 102.7 (C-1, C-1Ј),
105.0 (PhCH, benzylidene), 122.0, 122.9, 123.0 (C-2ЈЈ, C-5ЈЈ, C-
6ЈЈ), 127.5Ϫ129.9 (CH, Ph), 133.3 (C-1ЈЈ), 138.9 (Cq, benzylidene),
146.3, 147.6 (C-3ЈЈ, C-4ЈЈ). Ϫ MS: m/z ϭ 801.3 [M ϩ Naϩ]. Ϫ
C39H62O12Si2 (778.37): calcd. C 60.13, H 8.02; found C 60.1, H 8.0.
Ϫ
13C{1H} NMR (CDCl3): δ ϭ 16.6 (C-6Ј), 20.6 (CH3, Ac), 68.8
(C-6), 62.6, 66.3, 68.8, 69.6, 71.0, 71.7, 72.8, 74.4, 79.5 (C-2, C-3,
C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 90.8 (C-1Ј), 96.2 (C-1β), 97.4 (C-
1α), 101.9 (PhCH, benzylidene), 125.9Ϫ128.1 (CH, Ph), 128.9 (Cq,
Bz), 136.9 (Cq, benzylidene), 165.4, 165.6 (CϭO, Bz), 170.8, 171.7
(CϭO α/β, Ac).
2-O-Acetyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-benzoyl-␣-
L-
rhamnopyranosyl)-␣- -glucopyranosyl Trichloroacetimidate (8c):
D
Trichloroacetimidate donor 8c was prepared from 7c (489 mg,
0.64 mmol) in a way identical to that described for the synthesis of
compound 8a. Purification by silica gel column chromatography
(eluent: toluene/ethyl acetate, 100:0 Ǟ 85:15) gave 8c (500 mg, 86%)
as a white amorphous solid. Ϫ Rf ϭ 0.6 (toluene/ethyl acetate, 4:1,
1
v/v). Ϫ H NMR (CDCl3): δ ϭ 0.92 (d, 3 H, J5Ј,6Ј ϭ 6.4 Hz, 6Ј-
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl 4,6-O-Benzylid-
H), 2.18 (s, 3 H, CH3, Ac), 3.86, 4.07, 4.44 (3 ϫ m, 5 H, 3-H, 4-
H, 5-H, 6-Ha, 6-Hb), 5.15 (dd, 1 H, J2,3 ϭ 9.6 Hz, 2-H), 5.28 (br.
s, 1 H, 1Ј-H), 5.43 (m, 1 H, 2Ј-H), 5.62 (t, 1 H, J3Ј,4Ј ϭ 9.3 Hz, 4Ј-
H), 5.70 (s, 1 H, benzylidene), 5.84 (dd, 1 H, J2Ј,3Ј ϭ 3.3 Hz), 6.60
(d, 1 H, J1,2 ϭ 3.5 Hz, 1-H), 7.10Ϫ8.14 (m, 20 H, CH, Ph, Bz),
8.67 (s, 1 H, NH). Ϫ 13C{1H} NMR (CDCl3): δ ϭ 16.7 (C-6Ј),
20.2 (CH3, Ac), 68.4 (C-6), 65.3, 66.0, 69.5, 70.9, 71.5, 72.2, 72.8,
73.1, 78.7 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 90.6 (CCl3),
93.5 (C-1), 97.5 (C-1Ј), 101.8 (CH, Ph), 125.1Ϫ133.3 (CH, Ph),
128.9 (Cq, Bz), 136.6 (Cq, benzylidene), 160.7 (CϭNH), 165.4 (Cϭ
O, Bz), 170.1 (CϭO, Ac).
ene-2-O-phenoxyacetyl-3-O-(2,3,4-tri-O-phenoxyacetyl-␣-
L-
rhamnopyranosyl)-β- -glucopyranose (20): Phenoxyacetyl chloride
D
(350 µL, 2.52 mmol) was added dropwise over a period of 15 min
to a mixture of 2-[3,4-bis(tert-butyldimethylsilyloxy)phenyl]ethyl
4,6-O-benzylidene-3-O-(α--rhamnopyranosyl)-β--glucopyranose
(411 mg, 0.526 mmol) in CH2Cl2 (7.8 mL) and pyridine (340 µL,
4.5 mmol). After stirring for 2 h, TLC analysis (toluene/ethyl acet-
ate, 7:1, v/v) showed the formation of one major spot. The reaction
was quenched by addition of methanol, diluted with dichlorometh-
ane, and washed with water. The organic layer was dried (MgSO4)
and concentrated under reduced pressure. The resulting syrup was
applied onto a column of silica gel. Elution was performed with
toluene/ethyl acetate (100:0 Ǟ 97:3, v/v), to furnish, after concen-
tration of the appropriate fractions, pure 20 as a light yellow oil.
Yield: 622 mg, 90%. Ϫ Rf ϭ 0.7 (toluene/ethyl acetate, 7:1, v/v). Ϫ
1H NMR (CDCl3): δ ϭ 0.19, 0.23 (2 ϫ s, 12 H, CH3, TBDMS),
0.69 (d, 3 H, J5Ј,6Ј ϭ 6.2 Hz, 6Ј-H), 1.00, 1.02 [s, 18 H, C(CH3)3,
TBDMS], 2.76 (t, 2 H, J ϭ 7.1 Hz, CH2CH2O), 3.48 (m, 1 H, 5-
H), 3.60 (m, 1 H, CH2ϪHCHϪO), 3.71 (t, 1 H, 4-H), 3.82 (t, 1 H,
J6a,6b ϭ 9.6 Hz, 6-Ha), 3.98 (m, 2 H, 3-H, CH2ϪHCHϪO), 4.14
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl 2-O-Acetyl-4,6-O-
benzylidene-3-O-(2,3,4-tri-O-benzoyl-␣-L-rhamnopyranosyl)-β-D-
glucopyranose (13c): The glycosylation between 8c (500 mg,
0.54 mmol) and 12 (210 mg, 0.54 mmol) to obtain 13c was per-
formed as described above for the synthesis of 13a. Purification by
silica gel column chromatography (eluent: toluene/ethyl acetate,
10:0 Ǟ 9:1) gave 13c (361 mg, 59%) as a colorless oil. Ϫ Rf ϭ 0.8
(toluene/ethyl acetate, 7:1, v/v). Ϫ [α]D20 ϭ Ϫ35.4 (c ϭ 1.1, CHCl3).
1
Ϫ H NMR (CDCl3/CD3OD): δ ϭ 0.14, 0.17 (2 ϫ s, 12 H, CH3,
TBDMS), 0.83 (d, 3 H, J5Ј,6Ј ϭ 5.8 Hz, 6Ј-H), 0.94, 0.95 [2 ϫ s, 18 (m, 1 H, 5Ј-H), 4.35 (m, 3 H, 6-Hb, CH2, PhOAc), 4.39 (AB, 2 H,
H, C(CH3)3, TBDMS], 2.05 (s, 3 H, CH3, Ac), 2.71 (t, 2 H, CH2, PhOAc), 4.47 (d, 1 H, J1,2 ϭ 7.8 Hz, 1-H), 4.49 (AB, 2 H,
CH2CH2O), 3.63 (m, 2 H, 6-Ha, CH2ϪHCHϪO), 3.78 (m, 3 H, 4-
CH2, PhOAc), 4.68 (AB, 2 H, CH2, PhOAc), 5.03 (t, 1 H, J3Ј,4Ј ഠ
H, 5-H, CH2ϪHCHϪO), 4.19 (t, 1 H, J3,4 ϭ 9.7 Hz, 3-H), 4.46 J4Ј,5Ј ϭ 9.8 Hz, 4Ј-H), 5.05 (d, 1 H, J1Ј,2Ј ϭ 1.8 Hz, 1Ј-H), 5.17
(m, 2 H, 5Ј-H, 6-Ha), 4.52 (d, 1 H, J1,2 ϭ 8.0 Hz, 1-H), 5.18 (m, 2 (m, 2 H, 2-H, 2Ј-H), 5.47 (dd, 1 H, J2Ј,3Ј ϭ 3.6 Hz), 5.27 (s, 1 H,
H, 1Ј-H, 2-H), 5.50 (m, 3 H, 4Ј-H, 2Ј-H, benzylidene), 5.79 (dd, 1
H, 3Ј-H), 6.54 (s, 2 H, 2ЈЈ-H, 6ЈЈ-H), 6.61 (s, 1 H, 5ЈЈ-H), 7.26Ϫ8.04
benzylidene), 6.75Ϫ7.36 (m, 28 H, 2ЈЈ-H, 6ЈЈ-H, 5ЈЈ-H, CH, arom.).
13C{1H} NMR (CDCl3): δ ϭ Ϫ4.2 (CH3, TBDMS), 16.3 (C-6Ј),
(m, 20 H, CH, Ph, Bz). Ϫ 13C{1H} NMR (CDCl3/CD3OD): δ ϭ 18.3 (Cq, TBDMS), 25.8 [C(CH3)3, TBDMS], 35.2 (CH2CH2O),
Ϫ4.2 (CH3, TBDMS), 16.5 (C-6Ј), 18.2 (Cq, TBDMS), 20.6 (CH3,
64.6, 65.1 (CH2, PhOAc), 68.5 (C-6), 70.8 (CH2CH2O), 65.9, 66.5,
Ac), 25.8 [C(CH3)3, TBDMS], 35.2 (CH2CH2O), 68.5 (C-6), 70.6 69.0, 70.7, 71.7, 74.1, 76.7, 78.7 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-
Eur. J. Org. Chem. 1999, 2623Ϫ2632
2629

H. I. Duynstee, M. C. de Koning, H. Ovaa, G. A. van der Marel, J. H. van Boom
FULL PAPER
4Ј, C-5Ј), 97.2 (C-1), 100.9 (C-1Ј), 101.9 (PhCH, benzylidene),
114.4, 114.5 (CH, PhOAc), 120.8, 121.7 (C-2ЈЈ, C-5ЈЈ, C-6ЈЈ), 3Ј, C-4Ј, C-5Ј), 86.5 (Cq, DMT), 97.7 (C-1), 100.3 (C-1Ј),
126.3Ϫ129.5 (CH, arom.), 131.0 (C-1ЈЈ), 136.8 (Cq, benzylidene), 113.1Ϫ114.6 (CH, PhOAc, DMT), 120.7, 121.3, 121.7 (C-2ЈЈ, C-
66.6, 69.3, 70.5, 71.5, 73.0, 73.9, 81.9 (C-2, C-3, C-4, C-5, C-2Ј, C-
145.2, 146.5 (C-3ЈЈ, C-4ЈЈ), 157.4 (Cq, PhOAc), 167.6, 167.8, 168.0, 5ЈЈ, C-6ЈЈ), 126.8Ϫ129.8 (CH, PhOAc, DMT), 131.2 (C-1ЈЈ), 135.4
168.2 (CϭO, PhOAc). Ϫ MS: m/z ϭ 1337.6 [M ϩ Na]ϩ.
(Cq, DMT), 144.3 (Cq, DMT), 145.2, 146.4 (C-3ЈЈ, C-4ЈЈ), 157.3,
157.6, 158.4 (Cq, PhOAc), 167.8, 167.9, 168.2 (CϭO, PhOAc).
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl 2-O-Phenoxyac-
etyl-3-O-(2,3,4-tri-O-phenoxyacetyl-␣-L-rhamnopyranosyl)-β-D-
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl 4-O-Acetyl-6-O-
(4,4Ј-dimethoxytrityl)-2-O-phenoxyacetyl-3-O-(2,3,4-tri-O-phenoxy-
acetyl-␣-L-rhamnopyranosyl)-β-D-glucopyranoside (23): N,N-Di-
glucopyranose (21): To a solution of 20 (2.303 g, 1.75 mmol) in di-
chloromethane was added ethylene glycol and a catalytic amount
(17 mg) of p-toluenesulfonic acid. After 48 h, the reaction mixture
was neutralized with triethylamine and concentrated in vacuo. The
resulting oil was purified on silica gel using light petroleum ether/
CH2Cl2/MeOH (10:90:0 Ǟ 0:100:0 Ǟ 0:96:4, v/v/v) as eluent to
afford the title compound 21 as a colorless foam and the starting
material (20). Ϫ Yield: 1.31 g, 61% (88% based on consumed 20).
Ϫ Rf ϭ 0.3 (4% MeOH in CH2Cl2). Ϫ 1H NMR (CDCl3): δ ϭ
0.15, 0.18 (2 ϫ s, 12 H, CH3, TBDMS), 0.96, 0.98 [2 ϫ s, 18 H,
C(CH3)3, TBDMS], 1.18 (d, 3 H, J5Ј,6Ј ϭ 5.8 Hz, 6Ј-H), 2.70 (t, 2
H, CH2CH2O, J ϭ 7.3 Hz), 3.32 (m, 1 H, 5-H), 3.50, 3.65, 3.88 (3
ϫ m, 6 H, CH2CH2O, 3-H, 4-H, 6-Ha, 5Ј-H), 4.19 (m, 1 H, 6-Hb),
4.31 (s, 2 H, CH2, PhOAc), 4.40 (d, 1 H, J1,2 ϭ 8.0 Hz, 1-H), 4.48
(s, 2 H, CH2, PhOAc), 4.57 (s, 2 H, CH2, PhOAc), 4.65 (AB, 2 H,
CH2, PhOAc), 5.02 (m, 2 H, 2Ј-H, 4Ј-H), 5.13 (t, 1 H, J2,3 ϭ 9.4 Hz,
cyclohexylcarbodiimide (74 mg, 0.35 mmol) and 4-(dimethyl-
amino)pyridine (8 mg) were added to a mixture of compound 22
(0.272 mg, 0.177 mmol) and 3,4-di-O-acetylcaffeic acid (96 mg,
0.35 mmol) in dichloromethane (1.6 mL). After stirring for 12 h,
the reaction mixture was diluted with diethyl ether (50 mL) and the
dicyclohexylurea salt was removed by filtration. The filtrate was
washed with water (10 mL), dried (MgSO4), and concentrated in
vacuo. Purification was performed by column chromatography
(toluene/ethyl acetate/triethylamine, 100:0:0.1 Ǟ 95:5:0.1, v/v/v) to
afford 23 (214 mg, 77%) as an oil. Ϫ Rf ϭ 0.8 (toluene/ethyl acetate/
triethylamine, 75:25:0.1, v/v/v). Ϫ 1H NMR (CDCl3): δ ϭ 0.14,
0.15 (2 ϫ s, 12 H, CH3, TBDMS), 0.96, 0.97 (2 ϫ s, 18 H, C(CH3)3,
TBDMS), 1.06 (d, 3 H, J5Ј,6Ј ϭ 5.9 Hz, 6Ј-H), 1.74 (s, 3 H, Ac),
2.82 (t, 2 H, J ϭ 7.1 Hz, CH2CH2O), 3.12 (m, 2 H, 6-Ha, 6-Hb),
3.40 (m, 1 H, 5-H), 3.64 (m, 1 H, CH2ϪHCHϪO), 3.76 (s, 6 H,
OMe, DMT), 3.80 (t, 1 H, 3-H), 3.87 (m, 1 H, 5Ј-H), 3.99 (1 H,
CH2ϪHCHϪO), 3.87 (m, 1 H, 5Ј-H), 4.24 (AB, 2 H, CH2,
PhOAc), 4.38 (m, 3 H, 1-H, CH2, PhOAc), 4.56 (s, 2 H, CH2,
PhOAc), 4.68 (s, 2 H, CH2, PhOAc), 4.88 (d, 1 H, J1Ј,2Ј ϭ 1.6 Hz,
1Ј-H), 5.03Ϫ5.29 (m, 5 H, 2Ј-H, 3Ј-H, 4Ј-H, 2-H, 4-H), 6.70Ϫ7.33
(m, 36 H, 2ЈЈ-H, 6ЈЈ-H, 5ЈЈ-H, CH, arom.). Ϫ 13C{1H} NMR
(CDCl3): δ ϭ Ϫ4.5 (CH3, TBDMS), 17.0 (C-6Ј), 18.4 (Cq,
TBDMS), 20.6 (CH3, Ac), 25.9 (C(CH3)3, TBDMS), 35.5
(CH2CH2O), 55.1 (OMe, DMT), 61.9 (C-6), 64.6, 65.3 (CH2,
PhOAc), 70.8 (CH2CH2O), 67.1, 69.6, 70.2, 71.0, 72.8, 73.5, 81.4,
86.9 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 86.0 (Cq, DMT),
98.9 (C-1), 100.5 (C-1Ј), 112.9Ϫ114.6 (CH, PhOAc, DMT), 120.8,
121.3, 121.8 (C-2ЈЈ, C-5ЈЈ, C-6ЈЈ), 126.7Ϫ129.5 (CH, PhOAc,
DMT), 131.2 (C-1ЈЈ), 135.7 (Cq, DMT), 144.3 (Cq, DMT), 145.3,
146.6 (C-3ЈЈ, C-4ЈЈ), 157.4, 157.8, 158.3 (Cq, PhOAc), 167.7, 168.0,
168.8 (CϭO, PhOAc, Ac). Ϫ MS: m/z ϭ 1593.8 [M ϩ Na]ϩ. Ϫ
C87H102O23Si2 (1570.63): calcd. C 66.48, H 6.54; found C 66.6, H
6.6.
2-H), 5.26 (d, 1 H, J1Ј,2Ј ϭ 1.4 Hz, 1Ј-H), 5.38 (dd, 1 H, J2Ј,3Ј
ϭ
3.6 Hz, 3Ј-H), 6.58Ϫ7.16 (m, 23 H, 2ЈЈ-H, 6ЈЈ-H, 5ЈЈ-H, CH,
arom.). Ϫ 13C{1H} NMR (CDCl3): δ ϭ Ϫ4.2 (CH3, TBDMS), 17.2
(C-6Ј), 18.4 (Cq, TBDMS), 25.9 [C(CH3)3, TBDMS], 35.3
(CH2CH2O), 62.0 (C-6), 64.6, 65.2 (CH2, PhOAc), 70.4
(CH2CH2O), 67.2, 69.2, 69.7, 70.4, 71.2, 72.6, 75.1, 83.1 (C-2, C-
3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 97.2 (C-1), 100.3 (C-1Ј), 114.4,
114.6 (CH, PhOAc), 121.5, 121.7, 121.8 (C-2ЈЈ, C-5ЈЈ, C-6ЈЈ), 129.4,
129.6 (CH, PhOAc), 131.1 (C-1ЈЈ), 145.4, 146.5 (C-3ЈЈ, C-4ЈЈ),
157.4, 157.7 (Cq, PhOAc), 167.8, 168.0, 168.3 (CϭO, PhOAc).
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl
oxytrityl)-2-O-phenoxyacetyl-3-O-(2,3,4-tri-O-phenoxyacetyl-
␣- -rhamnopyranosyl)-6-O-β- -glucopyranoside (22): Diol 21
(4,4Ј-Dimeth-
L
D
(1.17 g, 0.89 mmol) was dissolved in a mixture of CH2Cl2 (9 mL)
and pyridine (144 uL, 1.78 mmol) and 4,4Ј-dimethoxytrityl chloride
(392 mg, 1.15 mmol) was added. After stirring for 1 h, complete
conversion of the starting material had occurred, as was shown by
TLC analysis. Addition of a small amount of methanol destroyed
the excess of 4,4Ј-dimethoxytrityl chloride. The reaction mixture
was diluted with dichloromethane and transferred into a separation
funnel. The dichloromethane layer was washed with aq. NaHCO3
(10%) and water and dried (MgSO4). The mixture was filtered and
concentrated under reduced pressure. The residue was subjected
to silica gel purification (eluent: toluene/ethyl acetate/triethylamine,
100:0:1 Ǟ 85:15:1, v/v/v) to afford 22 (1.18 g, 87%) as a light yellow
oil. Ϫ Rf ϭ 0.5 (toluene/ethyl acetate/triethylamine, 85:15:0.1, v/v/
v). Ϫ 1H NMR (CDCl3): δ ϭ 0.20, 0.21 (2 ϫ s, 12 H, CH3,
Methyl 3,4-Bis(O-tert-butyldimethylsilyl)caffeate (26): Caffeic acid
(3,4-dihydroxycinnamic acid) (1.68 g, 10 mmol) was converted into
methyl 3,4-bis(O-tert-butyldimethylsilyl)caffeate (26) as described
for the synthesis of methyl [3,4-bis(tert-butyldimethylsilyloxy)phen-
yl]acetate (11) from (3,4-dihydroxyphenyl)acetic acid (9). The crude
methyl 3,4-bis(O-tert-butyldimethylsilyl)caffeate was purified on a
silica gel column, which was eluted with toluene/ethyl acetate (3:1,
v/v) to afford 26 (3.42 g, 81%) as a colorless oil. Ϫ Rf ϭ 0.8
(CH2Cl2/MeOH, 9:1, v/v). Ϫ 1H NMR (CDCl3): δ ϭ 0.20 (s, 12
H, CH3, TBDMS), 0.98 (s, 18 H, C(CH3)3, TBDMS), 3.78 (s, 3 H,
OMe), 6.24 (d, 1 H, JH,H ϭ 15.8 Hz, HCϭCHϪCϭO), 6.81 (d, 1
H, Ph), 7.00 (m, 2 H, CH, Ph), 7.57 (d, 1 H, HCϭCHϪCϭO).
13C{1H} NMR (CDCl3): δ ϭ Ϫ4.2 (CH3, TBDMS), 18.3 (Cq,
TBDMS), 25.7 [C(CH3)3, TBDMS], 51.3 (OMe), 115.3 (CHϭ
CHCϭO), 120.2, 121.0, 122.1 (CH, Ph), 127.9 (Cq, Ph), 144.5
(CHϭCHCϭO), 147.0, 149.2 (Cq, Ph), 167.4 (CϭO).
TBDMS), 1.01 [s, 18 H, C(CH3)3, TBDMS], 1.18 (d, 3 H, J5Ј,6Ј
ϭ
5.9 Hz, 6Ј-H), 2.80 (t, 2 H, CH2CH2O, J ϭ 7.3 Hz), 3.14 (d, 1 H,
4-OH), 3.45, 3.75, 4.30 (3 ϫ m, 5 H, 3-H, 4-H, 6-Ha, 6-Hb, 5Ј-H),
3.66 (m, 1 H, CH2ϪHCHϪO), 3.80 (s, 6 H, OMe, DMT), 4.01 (m,
1 H, CH2ϪHCHϪO), 4.36 (AB, 2 H, CH2, PhOAc), 4.36 (d, 1 H,
J1,2 ϭ 8.0 Hz, 1-H), 4.53 (AB, 2 H, CH2, PhOAc), 4.57 (AB, 2 H,
CH2, PhOAc), 4.67 (AB, 2 H, CH2, PhOAc), 5.08 (d, 1 H, J1Ј,2Ј
ϭ
1.5 Hz, 1Ј-H), 5.14 (t, 1 H, J3Ј,4Ј ഠ J4Ј,5Ј ϭ 9.8 Hz, 4Ј-H), 5.18 (t, 1
H, J2,3 ϭ 9.4 Hz, 2-H), 5.49 (dd, 1 H, J2Ј,3Ј ϭ 3.5 Hz, 3Ј-H),
6.75Ϫ7.40 (m, 36 H, 2ЈЈ-H, 6ЈЈ-H, 5ЈЈ-H, CH, arom.). Ϫ 13C{1H} 3,4-Bis(O-tert-butyldimethylsilyl)caffeic Acid (27): Methyl 3,4-
NMR (CDCl3): δ ϭ Ϫ4.2 (CH3, TBDMS), 16.9 (C-6Ј), 18.3 (Cq, bis(O-tert-butyldimethylsilyl)caffeate (26, 2.37 g, 6 mmol) in diethyl
TBDMS), 25.8 [C(CH3)3, TBDMS], 35.3 (CH2CH2O), 55.0 (OMe,
ether (25 mL) was added dropwise to a cooled (0°C) suspension of
DMT), 63.6 (C-6), 64.5, 65.1 (CH2, PhOAc), 70.5 (CH2CH2O), LiAlH4 (228 mg, 9 mmol) in diethyl ether (25 mL) and stirred for
2630
Eur. J. Org. Chem. 1999, 2623Ϫ2632

Synthesis of Verbascoside
15 min. After this time, TLC analysis revealed complete disappear- 3Ј-H, 2-H, 4-H), 5.52 [d, 0.09 H, JH,H ϭ 12.4 Hz, HCϭCHϪCϭ
FULL PAPER
ance of the starting material. The reaction was quenched by drop-
wise addition of methanol and washed with water. The organic
layer was dried (MgSO4) and concentrated under reduced pressure.
The crude allylic alcohol was dissolved in freshly distilled diethyl
ether and treated with 6 g of MnO2. After stirring for 2 h, the mix-
O (Z)], 5.96 [d, 0.91 H, JH,H ϭ 15.6 Hz, HCϭCHϪCϭO (E)],
6.71Ϫ7.30 (m, 40 H, 2ЈЈ-H, 6ЈЈ-H, 5ЈЈ-H, 2ЈЈЈ-H, 5ЈЈЈ-H, 6ЈЈЈ-H,
HCϭCHϪCϭO, CH, arom.). Ϫ 13C{1H} NMR (CDCl3): δ ϭ
Ϫ4.9 (CH3, TBDMS), 17.4 (C-6Ј), 18.4 (Cq, TBDMS), 26.4
[C(CH3)3, TBDMS], 35.6 (CH2CH2O), 54.9 (OMe, DMT), 61.9 (C-
ture was filtered, and the filtrate was concentrated in vacuo. The 6), 64.4, 64.6, 65.3 (CH2, PhOAc), 70.8 (CH2CH2O), 66.7, 69.1,
resulting crude aldehyde was taken up in a mixture of tert-butyl 69.3, 70.5, 71.3, 73.7, 73.9, 80.3 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-
alcohol/water/2-methyl-2-butene (200 mL, 15:15:9, v/v/v) and to
this mixture was added 5 g of NaH2PO4·H2O, followed by the ad-
dition of sodium chlorite (5 g). After stirring for 17 h, the reaction
mixture was diluted with diethyl ether. The organic solution was
washed with water, dried (MgSO4), filtered, and concentrated in
vacuo to afford a solid. Purification by silica gel column chroma-
tography (light petroleum ether/diethyl ether, 2:1, v/v) gave 27
4Ј, C-5Ј), 86.0 (Cq, DMT), 98.5 (C-1), 100.6 (C-1Ј), 113.0Ϫ129.8
(C-2ЈЈ, C-5ЈЈ, C-6ЈЈ, C-2ЈЈЈ, C-5ЈЈЈ, C-8ЈЈЈ, C-9ЈЈЈ, CH, DMT,
PhOAc), 127.5 (C-4ЈЈЈ), 131.3 (C-1ЈЈ), 135.6, 135.9 (Cq, DMT),
144.1 (Cq, DMT), 145.3, 146.5, 147.2, 149.9 (C-3ЈЈ, C-4ЈЈ, C-6ЈЈЈ,
C-7ЈЈЈ), 145.3 (C-3ЈЈЈ), 157.4, 157.8, 158.2 (Cq, PhOAc), 165.0 (C-
1ЈЈЈ), 167.6, 167.9, 168.0, 168.3 (CϭO, PhOAc). Ϫ MS: m/z ϭ
1941.7 [M ϩ Na]ϩ.
(2.01 g, 82%) as
a
colorless solid.
Ϫ
3,4-Bis(tert-
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl
Bis(O-tert-butyldimethylsilyl)caffeoyl]-6-O-(4,4Ј-dimethoxytrityl)-3-
O-(␣- -rhamnopyranosyl)-β- -glucopyranose (29): To a stirred solu-
4-O-[(E,Z)-3,4-
butyldimethylsilyloxy)cinnamyl alcohol: Rf ϭ 0.6 (light petroleum
ether/diethyl ether, 3:1, v/v). Ϫ 13C{1H} NMR (CDCl3): δ ϭ Ϫ4.2
(CH3, TBDMS), 18.4 (Cq, TBDMS), 25.9 [C(CH3)3, TBDMS],
63.5 (CH2), 118.9, 119.9, 121.0 (CH, Ph), 126.4 (PhCHϭCH),
130.4 (Cq, Ph), 130.8 (PhCHϭCH), 146.7 (Cq, Ph). Ϫ 3,4-Bis(tert-
butyldimethylsilyloxy)cinnamaldehyde: Rf ϭ 0.2 (light petroleum
ether/diethyl ether, 3:1, v/v). Ϫ 13C{1H} NMR (CDCl3): δ ϭ Ϫ4.2
(CH3, TBDMS), 18.3 (Cq, TBDMS), 25.7 [C(CH3)3, TBDMS],
120.3, 121.1, 123.0 (CH, Ph), 126.5 (CHϭCHCϭO), 127.5 (Cq,
Ph), 150.2, 148.7 (Cq, Ph), 152.7 (CHϭCHCϭO), 193.3 (CϭO). Ϫ
27: Rf ϭ 0.6 (light petroleum ether/diethyl ether, 3:1, v/v). Ϫ 1H
NMR (CDCl3): δ ϭ 0.22 (s, 12 H, CH3, TBDMS), 0.98 [s, 18 H,
C(CH3)3, TBDMS], 6.26 (d, 1 H, JH,H ϭ 16.1 Hz, HCϭCHϪCϭ
O), 6.83 (d, 1 H, Ph), 7.03 (m, 2 H, CH, Ph), 7.68 (d, 1 H, HCϭ
CHϪCϭO), 10.0 (br. s, 1 H, OH). Ϫ 13C{1H} NMR (CDCl3): δ ϭ
Ϫ4.2 (CH3, TBDMS), 18.4 (Cq, TBDMS), 25.8 [C(CH3)3,
TBDMS], 114.9 (CHϭCHCϭO), 120.5, 121.1, 122.6 (CH, Ph),
127.6 (Cq, Ph), 146.8 (CHϭCHCϭO), 147.1, 149.7 (Cq, Ph), 172.5
(CϭO). Ϫ MS: m/z ϭ 431.9 [M ϩ Na]ϩ.
L
D
tion of compound 29 (384 mg, 0.20 mmol) in CH2Cl2 (18 mL) was
added dropwise 2 mL of a 0.01  K2CO3 solution in MeOH. The
reaction mixture was stirred for 2 h, after which TLC analysis re-
vealed complete conversion of the starting material into a slower
moving product. Silica gel (1 g), first rinsed with CH2Cl2/Et3N
(99:1, v/v) and dried, was added and the mixture was concentrated
under reduced pressure. The resulting silica gel mixture was applied
to a column of silica gel (10 g) and eluted with CH2Cl2/MeOH/
Et3N (100:0:1 Ǟ 98:2:1, v/v/v), furnishing pure 29 as a white foam.
Ϫ Yield: 238 mg, 86%. Ϫ Rf ϭ 0.36 (CH2Cl2/MeOH/Et3N, 94:6:0.1,
1
v/v/v). Ϫ H NMR (CDCl3): δ ϭ 0.17 (m, 12 H, CH3, TBDMS),
0.96 [m, 8 H, C(CH3)3, TBDMS], 0.97 [d, 3 H, J5Ј,6Ј ϭ 5.9 Hz, 6Ј-
H (E)], 1.01 [d, 3 H, J5Ј,6Ј ϭ 5.9 Hz, 6Ј-H (Z)], 2.93 (t, 2 H,
CH2CH2O, J ϭ 7.1 Hz), 3.70 (s, 6 H, OMe, DMT), 4.32 [d, 1 H,
J1,2 ϭ 8.0 Hz, 1-H (Z)], 4.35 [d, 1 H, J1,2 ϭ 8.0 Hz, 1-H (E)], 4.96
[t, 1 H, J3Ј,4Ј ഠ J4Ј,5Ј ϭ 9.8 Hz, 4Ј-H (Z)], 5.09 [t, 1 H, J3Ј,4Ј
ഠ
J4Ј,5Ј ϭ 9.8 Hz, 4Ј-H (E)], 5.16 [d, 1 H, J1Ј,2Ј ϭ 1.5 Hz, 1Ј-H (E)],
5.18 [d, 1 H, J1Ј,2Ј ϭ 1.5 Hz, 1Ј-H (Z)], 5.53 [d, 0.09 H HCϭ
CHϪCϭO (Z), JH,H ϭ 12.4 Hz], 6.00 [d, 0.91 H, JH,H ϭ 15.3 Hz,
HCϭCHϪCϭO (E)], 6.71Ϫ7.30 (m, 20 H, 2ЈЈ-H, 6ЈЈ-H, 5ЈЈ-H,
2ЈЈЈ-H, 5ЈЈЈ-H, 6ЈЈЈ-H, HCϭCHϪCϭO, CH, arom.). Ϫ 13C{1H}
NMR (CDCl3): δ ϭ Ϫ4.4 (CH3, TBDMS), 17.4 (C-6Ј), 18.1 (Cq,
TBDMS), 25.6 [C(CH3)3, TBDMS], 35.5 (CH2CH2O), 54.7 (OMe,
DMT), 62.3 (C-6), 71.0 (CH2CH2O), 68.6, 69.0, 70.5, 70.7, 72.3,
73.6, 74.6, 80.2 (C-2, C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 85.7
(Cq, DMT), 101.3 (C-1), 102.9 (C-1Ј), 112.7 (CH, DMT), 114.5 (C-
2ЈЈЈ), 120.0Ϫ129.8 (C-2ЈЈ, C-5ЈЈ, C-6ЈЈ, C-5ЈЈЈ, C-8ЈЈЈ, C-9ЈЈЈ, CH,
DMT), 127.4 (C-4ЈЈЈ), 131.1 (C-1ЈЈ), 135.5, 137.7 (Cq, DMT), 144.4
(Cq, DMT), 145.1, 146.4, 146.9, 149.5 (C-3ЈЈ, C-4ЈЈ, C-6ЈЈЈ, C-7ЈЈЈ),
145.1 (C-3ЈЈЈ), 166.0 (CϭO). Ϫ MS: m/z ϭ 959.0 [M ϩ Na]ϩ.
2-[3,4-Bis(tert-butyldimethylsilyloxy)phenyl]ethyl
(O-tert-butyldimethylsilyl)caffeoyl]-6-O-(4,4Ј-dimethoxytrityl)-2-O-
phenoxyacetyl-3-O-(2,3,4-tri-O-phenoxyacetyl-␣- -rhamno-
pyranosyl)-4-O-β- -glucopyranose (28): To a solution of 3,4-bis(O-
[(E,Z)-3,4-Bis-
L
D
tert-butyldimethylsilyl)caffeic acid (27) (1.147 g, 2.25 mmol) and
compound 23 (918 mg, 0.75 mmol) in CH2Cl2 (4 mL) was added
N,N-dicyclohexylcarbodiimide (463 mg, 2.25 mmol) and a catalytic
amount of 4-(dimethylamino)pyridine (27 mg, 0.225 mmol). To the
stirring mixture were added additional amounts of 4-(dimethylami-
no)pyridine (15 mg) after 15 h, 24 h, and 40 h reaction time. The
progress of the esterification was monitored by TLC analysis (tolu-
ene/ethyl acetate/triethylamine, 92:8:0.1, v/v/v) and showed that the
reaction was complete after 48 h. The reaction mixture was diluted
with diethyl ether (50 mL) and the dicyclohexylurea salt was re-
moved by filtration. The filtrate was washed with water (10 mL),
dried (MgSO4), and concentrated in vacuo. Purification of the re-
sidual oil was accomplished by silica gel column chromatography
(eluent: toluene/ethyl acetate/triethylamine, 100:0:1 Ǟ 97:3:1, v/v/
v). Concentration of the appropriate fractions furnished 28 as an
oil. Ϫ Yield: 949 mg, 67%. Ϫ Rf ϭ 0.6 (toluene/ethyl acetate/tri-
2-(3,4-Dihydroxyphenyl)ethyl 4-O-(E,Z)-Caffeoyl-3-O-(␣-
nopyranosyl)-β- -glucopyranose (1, Verbascoside): Preparation of a
stock solution of 1.56 HF·Et3N in pyridine: 3HF·Et3N
L-rham-
D

(1.22 mmol, 200 µL) was added to a mixture of pyridine (1.80 mL)
and triethylamine (2.44 mmol, 339 µL). To a solution of compound
29 (246 mg, 188 µmol) in 4 mL of pyridine was added 800 µL of
1.56  HF·Et3N in pyridine. After stirring for 3 h, TLC analysis
ethylamine, 92:12:0.1, v/v/v). Ϫ 1H NMR (CDCl3): δ ϭ 0.17 (m, showed complete formation of a slower moving compound. The
12 H, CH3, TBDMS), 0.96 [m, 21 H, 6Ј-H, C(CH3)3, TBDMS], mixture was diluted with methanol and applied to a column of
2.85 (t, 2 H, J ϭ 7.1 Hz, CH2CH2O), 3.18 (m, 2 H, 6-Ha, 6-Hb),
3.51 (m, 1 H, 5-H), 3.61, 3.63 (2 ϫ s, 6 H, OMe, DMT), 3.64 (m,
Dowex 50 W X4 in Naϩ form, which was eluted with methanol.
The filtrate was concentrated in vacuo and the residue was redis-
1 H, CH2ϪHCHϪO), 3.84 (m, 1 H, 5Ј-H), 4.00 (m, 2 H, 3-H, solved in a mixture of CH2Cl2/EtOH/AcOH (12 mL, 3:1:8, v/v/v).
CH2ϪHCHϪO), 4.26 (m, 2 H, CH2, PhOAc), 4.32 (m, 2 H, CH2, The reaction mixture was stirred for 8 h, after which TLC analysis
PhOAc), 4.40 (m, 1 H, 1-H), 4.51 (m, 2 H, CH2, PhOAc), 4.64 (m, revealed complete removal of the dimethoxytrityl function. The
2 H, CH2, PhOAc), 5.01 (m, 2 H, 1Ј-H, 4Ј-H), 5.26 (m, 4 H, 2Ј-H, mixture was concentrated in vacuo and purification was performed
Eur. J. Org. Chem. 1999, 2623Ϫ2632
2631

H. I. Duynstee, M. C. de Koning, H. Ovaa, G. A. van der Marel, J. H. van Boom
FULL PAPER
[6b]
Ϫ
N. L. Douglas, S. V. Ley, U. Lücking, S. L. Warriner, J.
on a silica gel column. Elution was effected with dichloromethane/
methanol (9:1 Ǟ 8:2, v/v). Subsequent concentration of the appro-
priate fractions furnished verbascoside (89 mg, 76%) as a white
amorphous solid. Ϫ Rf ϭ 0.2 (CH2Cl2/MeOH/H2O, 80:20:1, v/v/
Chem. Soc., Perkin Trans. 1 1998, 51Ϫ66.
[7a] For synthesis of 3a see: M. K. Gurjar, A. S. Mainkar, Tetra-
[7]
[8]
[9]
[7b]
hedron 1992, 48, 6729Ϫ6738. Ϫ
Prepared in the same way
as 3a[7a] starting from 1,2,3,4-O-tetrabenzoyl-α/β--rhamnose.
Ethyl 4,6-O-benzylidene-1-thio-β--glucopyranoside (2) is not
soluble at Ϫ40 °C in CH2Cl2, therefore the reaction was per-
formed in a mixture of CH2Cl2/THF.
v). Ϫ [α]D20ϭ Ϫ86.1 (c ϭ 1, MeOH). Ϫ H NMR (CD3OD): δ ϭ
1
1.15 [d, 0.91 H, J5Ј,6Ј ϭ 7.2 Hz, 6Ј-H (E)], 1.22 [d, 0.09 H, J5Ј,6Ј
7.2 Hz, 6Ј-H (Z)], 2.82 (br. t, 2H CH2CH2O), 3.32 (dd, 1 H, J4Ј,3Ј
ϭ
ϭ
G. H. Veeneman, S. H. van Leeuwen, J. H. van Boom, Tetra-
hedron Lett. 1990, 31, 1331Ϫ1334.
9.2 Hz, 4Ј-H), 3.45 (t, 1 H, J2,3 ϭ 8.5 Hz, 2-H), 3.59 (m, 2 H, 5-H,
6-Ha), 3.62 (m, 1 H, 5Ј-H), 3.64 (dd, 1 H, J3Ј,4Ј ϭ 9.2 Hz, 3Ј-H),
3.66 (m, 1 H, 6-Hb), 3.76 (m, 1 H, CH2ϪHCHϪO, J ϭ 7.1 Hz),
3.83 (t, 1 H, J2,3 ϭ 8.9 Hz, 3-H), 3.93 (dd, 1 H, J2Ј,3Ј ϭ 3.0 Hz, 2Ј-
H), 4.09 (m, 1 H, CH2ϪHCHϪO, J ϭ 7.1 Hz), 4.32 [d, 0.09 H,
J1,2 ϭ 8.7 Hz, 1-H (Z)], 4.34 [d, 0.91 H, J1,2 ϭ 8.7 Hz, 1-H (E)],
[10] [10a]
P. Fügedi, P. J. Garegg, Carbohydrate Res. 1986, 149, C9-
[10b]
C12. Ϫ
F. Andersson, P. Fügedi, P. J. Garegg, M. Nashed,
Tetrahedron Lett. 1986, 27, 3919Ϫ3922.
[11]
[12]
The negative outcome of the glycosidation may be explained by
the occurrence of a competing electrophilic aromatic substi-
tution of the electron-rich phenyl ring in 12.
R. R. Schmidt, Angew. Chem. Int. Ed. Engl. 1986, 25, 212Ϫ235.
4.92 [t, 0.09 H, J3,4 ϭ 8.5 Hz, 4-H (Z)], 4.94 [t, 0.91 H, J3,4
8.5 Hz, 4-H (E)], 5.18 [d, 0.09 H, J1Ј,2Ј ϭ 1.6 Hz, 1Ј-H (Z)], 5.20
[d, 0.91 H, J1Ј,2Ј ϭ 1.6 Hz, 1Ј-H (E)], 5.76 [d, 0.09 H, JH,H
12.2 Hz, HCϭCHϪCϭO (Z)], 6.25 [d, 0.91 H, JH,H ϭ 18.1 Hz,
ϭ
[13] [13a]
Interestingly, no reaction of 6a with NIS in the presence of
acetic acid[9] in dichloromethane was observed, indicating that
ϭ
6a is more “disarmed”[13b] than a fully benzoylated ethyl 1-thio-
[13b]
pyranosyl donor. Ϫ
G. H. Veeneman, J. H. van Boom,
Tetrahedron Lett. 1990, 31, 275Ϫ278.
HCϭCHϪCϭO (E)], 6.58 (dd, 1 H, J6ЈЈ,2ЈЈ ϭ 1.9 Hz, J6ЈЈ,5ЈЈ
8.0 Hz, 6Ј-H), 6.74 (m, 2 H, 2ЈЈ-H, 5ЈЈ-H), 6.79 [d, 0.09 H, J6ЈЈЈ,5ЈЈЈ
ϭ
[14]
The conversion of 6a into 7a under standard conditions (HgCl2/
CH2Cl2; NBS/acetone; NIS/THF/CH2Cl2) was accompanied by
cleavage of the benzylidene acetal.
ϭ
7.8 Hz, 5ЈЈЈ-H (Z)], 6.81 [d, 0.91 H, J6ЈЈЈ,5ЈЈЈ ϭ 7.8 Hz, 5ЈЈЈ-H (E)],
6.91 [d, 0.09 H, JH,H ϭ 12.2 Hz, HCϭCHϪCϭO (Z)], 6.94 [dd,
0.91 H, 6ЈЈЈ-H (E)], 7.04 [dd, 0.09 H, 6ЈЈЈ-H (Z)], 7.06 [d, 0.91 H,
J6ЈЈ,2ЈЈ ϭ 2.1 Hz, 2ЈЈЈ-H (E)], 7.50 [d, 0.09 H, J6ЈЈ,2ЈЈ ϭ 2.1 Hz, 2ЈЈЈ-
H (Z)], 7.60 [d, 0.91 H, JH,H ϭ 18.1 Hz, HCϭCHϪCϭO (E)]. Ϫ
13C{1H} NMR (CD3OD): δ ϭ 19.3 (C-6Ј), 37.4 (CH2CH2O), 63.4
(C-6), 71.4 (C-5Ј), 71.7 (C-4), 73.1 (CH2CH2O), 73.2 (C-2Ј), 73.0
(C-3Ј), 74.6 (C-4Ј), 77.2 (C-2), 77.1 (C-5), 82.6 (C-3), 103.8 (C-1Ј),
105.1 (C-1), 115.8 (HCϭCHϪCϭO), 116.2 (C-2ЈЈЈ), 117.4 (C-2ЈЈ),
117.6 (C-5ЈЈЈ), 118.2 (C-5ЈЈ), 122.3 (C-6ЈЈ), 124.1 (C-6ЈЈЈ), 128.9 (C-
1ЈЈЈ), 132.4 (C-1ЈЈ), 145.5 (C-3ЈЈ), 147.0 (C-4ЈЈ), 147.7 (C-3ЈЈЈ),
148.8 (HCϭCHϪCϭO), 150.7 (C-4ЈЈЈ), 169.3 (CϭO). MS: m/z ϭ
647.3 [M ϩ Na]ϩ. Ϫ C29H36O15 (624.21): calcd. C 55.77, H 5.81;
found C 55.8, H 5.8.
[15] [15a] F. J. Urban, B. S. Moore, R. Breitenbach, Tetrahedron Lett.
[15b]
1990, 31, 4421Ϫ4424. Ϫ
N. M. Spijker, J. W. Slief, C. A.
A. van Boeckel, J. Carbohydr. Chem. 1993, 12, 1017Ϫ1042.
Monitoring the coupling reaction of 8a with 12 by TLC analysis
revealed the presence of an intermediate, which was tentatively
assigned as the corresponding orthoester.
[16]
[17]
[18]
[19]
[20]
[21]
[22]
P. J. Garegg, T. Norberg, Acta Chem. Scand. 1979, B33,
116Ϫ118.
´
´ ´
´
A. Liptak, Z. Szurmai, P. Nanasi, A. Neszmelyi, Carbohydr.
Res. 1982, 99, 13Ϫ21.
H. M. Zuurmond, G. H. Veeneman, G. A. van der Marel, J. H.
van Boom, Carbohydr. Res. 1993, 241, 153-164.
Y. Leblanc, J. Flitzsimmons, J. Adams, F. Perez, J. Rokack, J.
Org. Chem. 1986, 51, 789Ϫ793.
G. Excoffier, D. Gaqnaire, J-P. Utille, Carbohydr. Res. 1979,
39, 368Ϫ375.
To prevent migration of the caffeoyl ester function from HO-4
to HO-6 under mild basic conditions, the primary hydroxy
group was protected with an acid-labile dimethoxytrityl (DMT)
group see: S-Q. Zhang, Z-J. Li, A-B. Wang, M-S. Cai, R. Feng,
Carbohydr. Res. 1997, 299, 281Ϫ285.
[1a] For a review on the distribution of phenylethyl glycosides in
[1]
´
the plant kingdom and their biological activity see: C. Jimenez,
R. Riguera, Nat. Prod. Rep. 1994, 11, 591Ϫ606 and references
[23]
[24]
H. Freudenberg, Chem. Ber. 1953, 86, 190Ϫ207.
B. S. Bal, W. E. Childers, H. W. Pinnick, Tetrahedron 1981,
37, 2091Ϫ2096.
cited therein. For other interesting bioactivities of verbascoside,
see: [1b] M. Pennacchio, E. Alexander, Y. M. Syah, E. L. Ghisal-
[1c]
berti, Eur. J. Pharmacol. 1996, 305, 169Ϫ172. Ϫ
M. Inoue,
[25]
J. Rothenburger, E. Haslinger, Liebigs Ann. Chem. 1994,
1113Ϫ1115.
Z. Sakuma, Y. Ogihara, I. Saracoglu, Biol. Pharm. Bull. 1998,
[1d]
21, 81Ϫ83. Ϫ
J. Li, Y. Zheng, H. Zhou, B. Su, R. Zheng,
[26] [26a] Cleavage of the phenolic silyl protecting groups with TBAF
was reported to be troublesome; see: P. M. Kendall, J. V. John-
son, C. E. Cook, J. Org. Chem. 1979, 44, 1421Ϫ1424. See for
Planta Med. 1997, 63, 499Ϫ502.
[2]
[3]
P. Mølgaard, H. Ravn, Phytochemistry 1988, 27, 2411Ϫ2411.
M. R. Kernan, A. Amarquaye, J. L. Chen, J. Chan, D. F. Sesin,
N. Parkinson, Z. Ye, M. Barrett, C. Bales, C. A. Stoddart, B.
Sloan, P. Blanc, C. Limbach, S. Mrisho, E. J. Rozhon, J. Nat.
Prod. 1998, 61, 564Ϫ570.
alternative desilylation of phenolic tert-butyldimethylsilyl
[26b]
ethers:
G. Maiti, S. C. Roy, Tetrahedron Lett. 1997, 38,
[26c]
495Ϫ498. Ϫ
N. S. Wilson, B. A. Keay, Tetrahedron Lett.
[26d]
[4] [4a]
1997, 38, 187Ϫ190. Ϫ
N. S. Wilson, B. A. Keay, Tetra-
K. Hayashi, T. Nagamatsu, M. Ito, T. Hattori, Y. Suzuki,
[4b]
hedron Lett. 1996, 37, 153Ϫ156 and references cited therein. Ϫ
Jpn. J. Pharmacol. 1994, 65, 143Ϫ151. Ϫ
K. Hayashi, T.
K. Hayashi, T. Nagamatsu, M. Ito, H.
[26e]
C. Prakash, S. Saleh, A. I. Blair, Tetrahedron Lett. 1994,
Nagamatsu, M. Ito, T. Hattori, Y. Suzuki, Jpn. J. Pharmacol.
[26f]
[4c]
35, 7576Ϫ7568. Ϫ
For an excellent review on selective de-
1994, 66, 47Ϫ52. Ϫ
Yagita, Y. Suzuki, Jpn. J. Pharmacol. 1996, 70, 157Ϫ168.
protection of silyl ethers, see: T. D. Nelson, R. D. Crouch, Syn-
thesis 1996, 1031Ϫ1069.
[5] [5a]
R. Verduyn, M. Douwes, P. A. M. van der Klein, E. M.
Mösinger, G. A. van der Marel, J. H. van Boom, Tetrahedron
1993, 49, 7301Ϫ7316. Ϫ [5b] R. Verduyn, P. A. M. van der Klein,
M. Douwes, G. A. van der Marel, J. H. van Boom, Recl. Trav.
Chim. Pays-Bas 1993, 112, 464Ϫ466.
[27] [27a]
H. Kobayashi, H. Karasawa, T. Miyase, S. Fukushima,
Chem. Pharm. Bull. 1984, 32, 3009Ϫ3011. Ϫ [27b] C. Andary, R.
Wylde, C. Laffite, G. Privat, F. Winternitz, Phytochemistry 1982,
21, 1123Ϫ1127.
[6a] It has been reported[6b] that ethyl 1-thiorhamnopyranosides
are more reactive than the corresponding mannopyranosides.
Received March 4, 1999
[6]
[O99131]
2632
Eur. J. Org. Chem. 1999, 2623Ϫ2632