Efficient generation of β-L-rhamnosidic linkages by the 2-ulosyl donor approach: Synthesis of a trisaccharide with a central β-L-rhamnose unit

Article abstract of DOI:10.1002/ejoc.200300149

Practical procedures for the production of variously blocked 6-deoxy-α-L-arabino-2-ketohexosyl bromides from L-rhamnose have been developed. These compounds are highly useful as indirect β-L-rhamnosyl donors: they undergo β-specific glycosidations under Koenigs-Knorr conditions, and the 2-keto group of the resulting 6-deoxy-β-L-hexosiduloses is reduced with high β-L-rhamno selectivity. The straightforward application of this 2-ulosyl donor approach for the synthesis of β-L-rhamnose-containing di- and trisaccharides is demonstrated. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200300149

FULL PAPER
Efficient Generation of β-
L
-Rhamnosidic Linkages by the 2-Ulosyl Donor
Approach: Synthesis of a Trisaccharide with a Central β- -Rhamnose Unit
L
Frieder W. Lichtenthaler*[a] and Thomas Metz[a]
Keywords: Carbohydrates / Glycosylation / Oligosaccharides / Reductions
Practical procedures for the production of variously blocked
6-deoxy-α- -arabino-2-ketohexosyl bromides from -rham- ward application of this 2-ulosyl donor approach for the syn-
nose have been developed. These compounds are highly thesis of β- -rhamnose-containing di- and trisaccharides is
useful as indirect β- -rhamnosyl donors: they undergo β-spe-
cific glycosidations under Koenigs-Knorr conditions, and the
reduced with high β-L-rhamno selectivity. The straightfor-
L
L
L
L
demonstrated.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
2-keto group of the resulting 6-deoxy-β-
L-hexosiduloses is
Introduction
group suppresses oxycarbenium ion formation at the anom-
eric center thereby resulting in direct SN2 displacement of
the bromine Ϫ and manno-selective reduction of the re-
sulting β--2-keto-glycosides III Ǟ IV (Scheme 1). When
selectrides are used rather than borohydride only, the car-
bonyl reduction is also essentially manno-specific.[8] Besides
its preparative simplicity, the procedure has the further ad-
vantage of providing the β--mannosides with free 2-OH
groups (i.e., mannosyl acceptors ready for further glycosid-
ation towards the oligosaccharides with β--Man-(1Ǟ2)--
Man linkages).
The 2-ulosyl donor approach, introduced in 1985,[1] has
proven to be highly expedient for the generation of β--
mannosidic linkages, as evidenced by the straightforward
synthesis of various β--mannose-containing oligosacchar-
ides up to the hexasaccharide level.[1Ϫ5] Central to this pro-
cedure is the ready preparation of variously blocked α--
arabino-2-ketohexosyl bromides of type II from -
glucose,[1,4Ϫ7] their essentially β-specific glycosidation
(Ǟ III) Ϫ the nonparticipating electron-withdrawing 2-keto
Scheme 1. The ulosyl donor approach to β--mannosides
Numerous bacterial antigens contain β--rhamnopyr-
anose units,[9] and the 6-deoxy- enantiomers of II, ulosyl
bromides of types 1؊5, should, if reasonably readily access-
ible, provide an expedient two-step procedure for their
[a]
Clemens-Schöpf-Institut für Organische Chemie und
Biochemie, Technische Universität Darmstadt,
Petersenstr. 22, 64287 Darmstadt, Germany
Fax: (internat.) ϩ 49-(0)6151/166674
Eur. J. Org. Chem. 2003, 3081Ϫ3093
DOI: 10.1002/ejoc.200300149
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3081

F. W. Lichtenthaler, T. Metz
FULL PAPER
straightforward synthesis. As a consequence, we opted to zene (ഠ 160 °C) in the presence of catalytic amounts of
evaluate this concept and here we present practical synth- pyridine for 5 h (81%). Final treatment of 2-acetoxy--
eses of a series of differently O-protected -ulosyl bromides rhamnal (12) with NBS/ethanol gave ulosyl bromide 2
1؊5, as well as illustrations of their utility as indirect β-- (87%), thus providing an overall yield of 35% for the seven
rhamnosyl donors:[10]
steps from -rhamnose.
For the synthesis of naturally occurring β--rhamnose
oligosaccharides both with (1Ǟ3)- and with (1Ǟ4)-inter-
saccharidic linkages, ulosyl donors with differentiated
blocking groups at O-3 and O-4 were required. These were
provided in the form of 3-O-benzyl ulosyl bromides 3 ؊5,
bearing either an acyl or a p-methoxybenzyl moiety at O-4,
by similar use of the respective orthoesters and 2-acetoxy-
rhamnals as the key intermediates, by starting with methyl
1-thio-α--rhamnoside (13) and its 2,3-O-isopropylidene
derivative 15, readily accessible in three steps Ϫ acety-
lation,[13] BF3-induced thiation with methyl sulfide, and de-
acetylation [14] (Ǟ 13) Ϫ and in four (isopropylidenation[14]
of 13) steps, respectively, a preparative advantage being that
Scheme 2
Results and Discussion
The practical preparation of the indirect β--rhamnosyl
donors 1Ϫ5 was based on -rhamnose as a suitable, readily
available starting material, and on the 2-acyloxy--rham-
nals of type 11 or 12 as key intermediates, these being ex-
pected to provide the desired ulosyl bromides smoothly
through brief treatment with NBS/methanol.[1,6]
The preparation of the 3,4-O-benzoyl-protected α--
rhamnosulosyl bromide 1 (Scheme 3) started with the mo-
lybdate-promoted C-2-epimerization of -rhamnose to pro-
vide 6-deoxy--glucose,[11] the resulting mixture of the two
epimers (ഠ 3:1 in favor of the gluco isomer) being readily
separable upon benzoylation, as the β--gluco-tetrabenzoate
6 crystallizes exceedingly well (65%). Subsequent conver-
sion into the known[12] glucosyl bromide by treatment with
HBr/HOAc (Ǟ8), followed by DBU-induced elimination of
HBr, smoothly gave the 2-benzoyloxy--rhamnal (11),
which provided the desired ulosyl bromide 1 in crystalline
form and in satisfactory overall yield (39% for the five steps
from -rhamnose) simply on treatment with NBS/methanol
in dichloromethane (30 min, 25 °C).
The 3,4-di-O-benzyl-blocked ulosyl bromide 2 similarly
required a seven-step sequence from -rhamnose (although
four of these steps were combinable into two one-pot oper-
ations). This approach involved conversion into the aceto-
bromo derivative 7[13] and then, by treatment with methanol/
Scheme 3. Conversion of -rhamnose into β--rhamnosyl donors 1
and 2
lutidine,[14] into orthoester 9, in which the exchange of ace- the sequences are easily adaptable to 100 g scale prep-
tyl for benzyl blocking groups 9 Ǟ 10 could be performed arations and allow overall yields in the 65% range.
in a one-pot operation by use of benzyl bromide/KOH in
For the preparation of the 4-O-acetyl- and 4-O-(p-meth-
THF. The subsequent thermal fragmentation[1,6] (10 Ǟ 12) oxybenzyl)-blocked ulosyl bromides (Scheme 4), the thio-
was satisfactorily effected by heating at reflux in bromoben- rhamnoside 13 was first converted by 2,3-O-stannylation-di-
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Eur. J. Org. Chem. 2003, 3081Ϫ3093

Efficient Generation of β-L-Rhamnosidic Linkages
FULL PAPER
As observed for orthoester 10, the analogues 17Ϫ19 also
underwent thermal fragmentation, simply on being heated
at reflux in bromobenzene (b.p. 165 °C) for 5 h, providing
the respective 2-acetoxy--rhamnals 22 Ϫ24 through elimin-
ation of methanol, yields being in the 85Ϫ90% range. Their
conversion into the ulosyl bromides 3 Ϫ5 proved to be simi-
larly efficient Ϫ yields were nearly quantitative Ϫ being
smoothly effected by treatment with N-bromosuccinimide/
methanol (or ethanol) in dichloromethane at ambient tem-
perature or 0 °C, the initial bromonium ion addition at
C-2 being followed by liberation of the carbonyl function
through loss of the acetyl group as methyl acetate.
Model Glycosidations of Ulosyl Donors 1 ؊5 and Uloside
Reductions
The utility of ulosyl bromides 1Ϫ5 as indirect β--rham-
nosyl donors was first examined with 2-propanol as model
acceptor. Under standard KoenigsϪKnorr conditions
(Ag2CO3 in dichloromethane at 25 °C), glycosidation was
consistently complete within 15Ϫ30 min, and no α-anom-
eric products were detectable in the reaction mixture by
1
TLC or H NMR spectroscopy. The glycosidation of the
ulosyl bromides 1Ϫ5 is therefore essentially β-specific Ϫ not
unexpected in view of the strongly electron-withdrawing ef-
fect of the carbonyl function, favoring direct SN2 displace-
ment of the bromide through suppression of carboxonium
ion formation at the anomeric center. The β--ulosides
25Ϫ29 were therefore isolable in yields of 80Ϫ90%
(Scheme 5).
Scheme 4. Reagents and conditions: a) Bu3SnO/toluene, reflux,
then BnBr/DMF, finally Ac2O/pyr.;[16] b) Me2(OMe)2, reflux;[15] c)
Br2/CH2Cl2, then MeOH/2,6-lutidine, 65 °C; d) BzCl/pyr.; e) 90%
TFA, room temp.; f) pMeOBnCl/KOH; g) reflux in PhBr with catal.
amounts of pyridine; h) NBS/MeOH or EtOH, 15 min, 0 °C
4rected selective benzylation and acetylation[16] into the eas-
ily crystallizing 2,4-di-O-acetyl-3-O-benzyl glycoside 14
(65%), and subsequently, by S-bromination and meth-
anolysis, into the orthoester 17, in which the 4-O-protecting
acetyl group could be directly exchanged for a p-meth-
oxybenzyl residue (17 Ǟ 18). An alternate route from S-
rhamnoside 13 to another orthoester differently blocked at
O-3 and O-4, the 3-O-benzyl-4-O-benzoyl derivative 19, in-
volved a straightforward six-step sequence performable in a
38% overall yield: benzoylation of its 2,3-O-isopropylidene
derivative 15 Ǟ 16, TFA-promoted removal of the isopro-
pylidene group (‘‘deacetonation’’ Ǟ 20), selective benzyl-
ation at O-3 via the 2,3-O-stannylidene derivative, followed
by acetylation (Ǟ 21) and methanolysis of the anomeric
SMe group upon S-bromination (Ǟ 19).
Scheme 5
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F. W. Lichtenthaler, T. Metz
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The rhamno/6-deoxy-gluco selectivities obtained in the reducing agent, for the acquisition of 6-deoxy-β--gluco-
carbonyl reductions of the glycosiduloses confirmed pre- sides as well.
vious findings[6Ϫ8] that the outcomes depend on the nature
of the 3-O-protection: uloside 25, on treatment with NaBH4
in dichloromethane/methanol (2 h, 0 °C Ǟ room tempera-
Di- and Trisaccharides with β-
L-Rhamnose Units
Given the viability of ulosyl bromides 1Ϫ5 as donors for
ture), gave a 3:1 mixture of the -rhamno (30) and 6-deoxy- the generation at least of simple β--rhamnosides Ϫ both
-gluco epimers, whereas use of the bulkier and more reac- steps required in the glycosidation/reduction procedure pro-
tive tri-sec-butylborohydride (-selectride) gave a sizably im- ceed in an essentially stereospecific manner Ϫ their utility
proved rhamno selectivity in the 25:1 range. Both re- for the synthesis of oligosaccharides had to be probed next.
ductions, though, were impeded by partial 3-OǞ2-O-ben- A series of glycosyl acceptors were evaluated for glycosyl-
zoyl migration during workup, resulting in product mix- ation with ulosyl bromide 4, with employment of, instead
tures best resolved either by de-O-benzoylation or by of silver carbonate, the more reactive[6] silver alumo-silicate
benzoylation.
catalyst [silver() immobilized on porous silica alumina],[17]
As the hydride reductions of the 3-O-benzylated ulosides as glycosidic OH groups were deemed to be less reactive
26Ϫ29 were already taking an essentially stereospecific co- than that of 2-propanol.
urse with sodium borohydride as the reductant Ϫ no 2-epi-
Primary OH groups in glycoside acceptors, such as in
1
mers were detectable in the reaction mixture either by H diacetone-galactose, were most readily glycosylated with
NMR or by TLC (Scheme 5) Ϫ recourse to more bulky ulosyl bromide 4, providing the galactosyl β--rhamnoside
hydrides for enhancement of selectivity was not necessary. 36 in 85% yield after in situ reduction (Scheme 6). Similarly,
When diborane was used as the reducing agent, however, the axially disposed 4-OH of a 1,6-anhydro--glucose read-
the reduction became gluco-selective, as also previously ob- ily underwent the two-step glycosidation/reduction pro-
served in the -hexosidulose series.[8] Uloside 25, for ex- cedure to provide the -rhamnosyl-β(1Ǟ4)--glucose de-
ample, on treatment with the borane/pyridine complex in rivative 37 in crystalline form (78%). In an analogous man-
THF at Ϫ78 °C for 30 min, underwent a high-yield conver- ner, rhamnobiosides with β(1Ǟ2)-, β(1Ǟ3)-, and β(1Ǟ4)-
sion (80%) to the 6-deoxy-β--glucoside 35. The ulosyl do- intersaccharidic linkages could be effectively prepared by
nor approach thus not only shows promise for the genera- starting from ulosyl bromide 4 and the corresponding -
tion of β--rhamnosidic linkages but, through changing the rhamnoside acceptors protected except for a free 2-OH
Scheme 6. Synthesis of a rhamnotrisaccharide with a central β--rhamnose unit
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Efficient Generation of β-L-Rhamnosidic Linkages
FULL PAPER
Preparation of the 6-Deoxy-β-
L
-arabino-2-ketohexosyl Bromides
(Ǟ 38, 79%), 3-OH (Ǟ 39, 77%), and 4-OH group (Ǟ 40,
80%) (Scheme 6).
Aside from the efficient generation of β--rhamnopyr-
3,4-Di-O-benzoyl-ulosyl Bromide (1)
anosidic linkages, the ulosyl donor approach has the advan- 1,2,3,4-Tetra-O-benzoyl-6-deoxy-β-L-glucopyranose (β-L-Quinovose-
tetrabenzoate) (6): A solution of -rhamnose monohydrate (50.0 g,
28 mmol) and molybdic acid (565 mg, 3.3 mmol) in water (250 mL)
was stirred at 95 °C for 3 h. The reaction mixture was filtered,
neutralized by addition of an anion-exchange resin (Amberlite
IRA 410; OHϪ form), and concentrated in vacuo to a syrup, which
was coevaporated twice with EtOH (50 mL). The resulting syrup
(49.0 g), an approximate 2:1 mixture of 6-deoxy--glucose and -
rhamnose (1H NMR), was dissolved in pyridine (125 mL), diluted
with CHCl3 (250 mL), cooled (0 °C), and benzoyl chloride
(175 mL, 1.5 mol) was added dropwise. The solution was stirred
tage of providing the di- or oligosaccharide with a free
rhamnosyl-2-OH, thus ready for further glycosylation.
Thanks to the differentiated group pattern at O-3 and O-4,
though, further glycosyl residues may also be introduced
at these positions. This option was demonstrated with the
synthesis of the 3-O-rhamnosylated rhamnosyl-β(1Ǟ4)-
rhamnoside 45, a trisaccharide sequence found in the re-
peating units of Klebsiella and Azotobacter vinelandii polys-
accharides[18] as well as various lipopolysaccharides:[19] the
readily accessible rhamnobioside 40 was converted by for 2 h, and was then warmed to room temperature, diluted with
CHCl3 (200 mL), and washed consecutively with water (200 mL),
HCl (2 , 3 ϫ 200 mL), and water (200 mL). The organic layer
was stirred with charcoal (6.5 g), filtered through Celite, and dried
(Na2SO4). Removal of the solvent in vacuo provided a crystalline
residue, which was triturated with diethyl ether (600 mL) and fil-
tered, to provide 6 (73.6 g) as colorless crystals. The mother liquor
was taken to dryness and the residue was crystallized from MeOH
(400 mL) to give additional 6 (29.6 g); overall yield: 103.1 g (65%,
based on -rhamnose). M.p. 177Ϫ179 °C; [α]2D0 ϭ ϩ16.0 (c ϭ 0.9,
CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.33 (d, 3 H, 6-H3),
4.09 (qd, 1 H, 5-H), 5.37 (dd, 1 H, 4-H), 5.74 (dd, 1 H, 2-H), 5.89
acetylation (Ǟ 41) and hydrogenolysis into an acceptor 42
with a free 3-OH (91% for the two steps). Silver triflate-
promoted glycosylation with acetobromo-rhamnose (7)
smoothly gave the protected rhamnotrisaccharide 43 (82%),
which afforded the target 45 on standard removal of the
blocking groups. Thus, by utilization of ulosyl bromide in
combination with two simple rhamnose derivatives a simple
synthesis of a rhamnotrisaccharide with a central β--rham-
nose unit could be carried out.
(dd, 1 H, 3-H), 6.14 (d, 1 H, 1-H) ppm; J1,2 ϭ 8.2, J2,3 ϭ J3,4
ϭ
J4,5 ϭ 9.6, J5,6 ϭ 6.2 Hz. MS (FD, 10 mA): m/z ϭ 580 [Mϩ].
Conclusion
C34H28O9 (580.6): calcd. C 70.34, H 4.86; found C 70.24, H 4.90.
The results described amply demonstrate the potential of
the ulosyl donor approach for the generation of β--rham-
nosidic linkages Ϫ an approach that compares favorably
2,3,4-Tri-O-benzoyl-6-deoxy-α-L-glucopyranosyl Bromide (8):
solution of 6 as obtained above (100.0 g, 0.17 mol) in CHCl3
A
(125 mL) was treated with a solution of HBr in AcOH (33%,
with existing methodologies,[20] in its β-specific glycosyl- 300 mL, 1.69 mol), and the mixture was stirred at room tempera-
ture for 5 h. Dilution with CHCl3 (350 mL), pouring onto crushed
ice (500 mL) containing Na2S2O3 (5 g), washing of the organic
layer with saturated aqueous NaHCO3 solution (4 ϫ 400 mL) and
water (2 ϫ 500 mL), followed by drying (Na2SO4) and concen-
tration in vacuo gave a crystalline residue, which was triturated
with Et2O (200 mL) and collected after standing for 6 h at Ϫ27 °C,
ation even meeting Ziegler’s strategy of intramolecular β--
rhamnosylation through pre-linked donor and acceptor
substrates.[20f]
Experimental Section
affording 8 (69.0 g, 71%) as colorless crystals. M.p. 160 °C. [α]D20
ϭ
Ϫ117.8 (c ϭ 1.0, CHCl3). ref.[12] M.p. 158Ϫ160 °C; [α]2D0 ϭ Ϫ108
General Remarks: All solvents were of reagent grade and were
further dried. All other reagents were used as received. Melting
points are uncorrected and were measured with a Büchi SMP-20
machine. Optical rotations were measured with a PerkinϪElmer
241 polarimeter at 20 °C in a cell of 1-dm path length. Mass spectra
were recorded with Varian MAT 311 and MAT 212 spectrometers.
Microanalyses were determined on a PerkinϪElmer 240 Elemental
Analyzer. Analytical thin-layer chromatography (TLC) was per-
1
(c ϭ 3.3, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 1.39 (d, 3 H,
6-H3), 4.48 (qd, 1 H, 5-H), 5.28 (dd, 1 H, 2-H), 5.45 (dd, 1 H, 4-
H), 6.19 (dd, 1 H, 3-H), 6.83 (d, 1 H, 1-H) ppm; J1,2 ϭ 4.0, J2,3
ϭ
J3,4 ϭ J4,5 ϭ 9.8, J5,6 ϭ 6.3 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ
17.1 (C-6), 70.5 (C-3), 71.1 (C-5), 71.9 (C-2), 72.7 (C-4), 87.4 (C-
1) ppm. MS (FI): m/z ϭ 459 [Mϩ Ϫ Br]. C27H23BrO7 (539.3): calcd.
C 60.13, H 4.28; found C 60.16, H 4.21.
formed on precoated Merck plastic sheets (0.2 mm silica gel 60 (1,5-Anhydro-2,3,4-tri-O-benzoyl-6-deoxy-L-arabino-hex-1-enitol
F254) with detection by UV (254 nm) and/or by spraying with (3,4-Di-O-benzoyl-2-benzoyloxy- -rhamnal) (11): DBU (3.2 g,
H2SO4 (50%) and heating. Column chromatography was carried 21.2 mmol) was added to a cooled solution (0 °C) of 8 (10.0 g,
L
out on Fluka silica gel 60 (70Ϫ230 mesh); eluents are given in
brackets. 1H and 13C NMR spectra were recorded with Bruker WM
300, AC 300, and AVANCE 500 spectrometers. Chemical shifts are
17.6 mmol) in 1,2-dichloroethane (30 mL). The mixture was stirred
in the dark for 0.5 h and warmed to room temperature The reaction
mixture was then diluted with CH2Cl2 (250 mL), and washed with
reported relative to sodium 2,2,3,3-tetradeuterio-3-trimethylsilyl HCl (2 , 2 ϫ 100 mL), water (2 ϫ 100 mL) and saturated aqueous
propionate (D2O) or Me4Si (all other solvents) as internal refer- NaHCO3 solution (100 mL). The organic layer was dried (Na2SO4)
ence. Coupling constants are listed separately if an assignment was and the solvents were evaporated to give a faintly red syrup that
possible. In the listings of 1H and 13C NMR spectroscopic data for
the individual compounds, signals originating from blocking
groups, such as those originating from benzyl and/or benzoyl moi-
eties, are omitted if well separated from the hexopyranoid hydrogen
and carbon signals.
crystallized from EtOH (40 mL), affording 11 (7.7 g, 96%) as color-
1
less crystals. M.p. 95Ϫ96 °C. [α]2D0 ϭ ϩ179.0 (c ϭ 1.0, CHCl3). H
NMR (500 MHz, CDCl3): δ ϭ 1.57 (d, 3 H, 6-H3), 4.56 (m, 1 H,
5-H), 5.56 (dd, 1 H, 4-H), 6.11 (dd, 1 H, 3-H), 6.89 (d, 1 H, 1-H)
ppm; J3,4 ϭ 4.3, J4,5 ϭ 5.7, J5,6 ϭ 6.8 Hz. 13C NMR (75 MHz,
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F. W. Lichtenthaler, T. Metz
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CDCl3): δ ϭ 16.1 (C-6), 67.6 (C-3), 72.1 (C-4), 72.8 (C-5),
reflux for 5 h. Evaporation in vacuo and purification of the residue
126.3Ϫ133.6 (3 C6H5, C-2), 139.9 (C-1) ppm. MS (FD, 0Ϫ10 mA): by elution from a silica gel column (toluene/EtOAc, 20:1) afforded
m/z ϭ 458 [Mϩ]. C27H22O7 (458.46): calcd. C 70.73, H 4.84; found
C 70.68, H 4.82.
12 (0.72 g, 78%) as a colorless syrup. [α]2D0 ϭ Ϫ8.7 (c ϭ 1.1, CHCl3).
1H NMR (300 MHz, CDCl3): δ ϭ 1.39 (d, 3 H, 6-H3), 2.06 (s, 3
H, AcCH3), 3.59 (dd, 1 H, 4-H), 4.12 (m, 1 H, 5-H), 4.47 (d, 1 H,
3-H), 4.55, 4.77 (2 d, each 1 H, BnCH2), 4.63 (m, 2 H, BnCH2),
The  enantiomer of 11, prepared from 2,3,4-tri-O-benzoyl-6-de-
oxy--glucosyl bromide (-8) had m.p. 93Ϫ95 °C and [α]D ϭ Ϫ182
(c ϭ 1.0, CHCl3).[21]
6.54 (d, 1 H, 1-H) ppm; J1,3 ϭ 0.6, J3,4 ϭ 5.5, J4,5 ϭ 7.7, J5,6
ϭ
2
6.6, JC,H ϭ 11.6 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 16.9 (C-
2
6), 20.6 (AcCH3), 72.1, 73.3 (2 BnCH2), 74.3 (C-5), 75.9 (C-3), 78.8
(C-4), 127.7Ϫ130.0 (2 BnCH2), 137.8 (C-2), 138.2 (C-1), 169.7
3,4-Di-O-benzoyl-6-deoxy-α-L-arabino-hexopyranos-2-ulosyl
Bro-
mide (1): solution of 2-benzoyloxy-rhamnal (11, 5.00 g,
A
(AcCO) ppm. MS (FD, 0Ϫ20 mA): m/z ϭ 368 [Mϩ], 369 [Mϩ
ϩ
10.9 mmol) and MeOH (0.53 mL, 0.42 g, 13.1 mmol) in CH2Cl2
(50 mL) was stirred over freshly desiccated molecular sieves (3 A).
H], 43 [Acϩ]. C22H24O5 (368.43): calcd. C 71.72, H 6.57; found C
71.77, H 6.61.
˚
After 15 min the mixture was cooled to 0 °C and treated with NBS
(2.33 g, 13.1 mmol), stirred at room temperature for 35 min, and
then diluted with CH2Cl2 (200 mL) and successively washed with
10% aqueous Na2S2O3 solution (3 ϫ 150 mL) and water (2 ϫ
150 mL). Drying (Na2SO4) and concentration gave a colorless
syrup that slowly crystallized in vacuo (finally at 10Ϫ2 mbar to
remove the methyl benzoate formed). The crude product was dis-
solved in diethyl ether, triturated with n-hexane to turbidity, and
kept for 16 h at Ϫ27 °C to give 1 (3.55 g, 75%) as colorless crystals.
M.p. 123Ϫ124 °C. [α]D20 ϭ Ϫ195.2 (c ϭ 1.1, CHCl3). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.44 (d, 3 H, 6-H3), 4.65 (qd, 1 H, 5-H),
5.64 (dd, 1 H, 4-H), 6.44 (d, 1 H, 3-H), 6.46 (s, 1 H, 1-H) ppm;
3,4-Di-O-benzyl-6-deoxy-α-L-arabino-hexopyranos-2-ulosyl Bromide
(2): A solution of 2-acetoxyrhamnal 12 (185 mg, 0.5 mmol) in
CH2Cl2 (5 mL) was treated with MeOH (25 µL, 1.9 mg, 0.6 mmol),
˚
stirred for 20 min over freshly desiccated molecular sieves (3 A),
and cooled to 0 °C. NBS (110 mg, 0.6 mmol) was then added and
stirring was continued for 15 min, followed by immediate workup
by dilution with cold CH2Cl2 (25 mL) and successive washings with
cold 10% aqueous Na2S2O3 solution (2 ϫ 10 mL) and ice-water (2
ϫ 10 mL). Drying (MgSO4) and concentration in vacuo provided
2 (177 mg, 87%) as a colorless syrup with [α]2D0 ϭ Ϫ229.2 (c ϭ 1.1,
CHCl3). The product is sufficiently pure for glycosidations. 1H
NMR (300 MHz, CDCl3): δ ϭ 1.35 (d, 3 H, 6-H3), 3.46 (dd, 1 H,
4-H), 4.21 (qd, 1 H, 5-H), 4.62, 4.63 (2 d, each 1 H, BnCH2), 4.87
(d, 1 H, 3-H), 4.90 and 5.00 (2 d, each 1 H, BnCH2), 6.27 (s, 1 H,
J
3,4 ϭ J4,5 ϭ 10.3, J5,6 ϭ 6.3 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ
17.0 (C-6), 71.5 (C-5), 72.8 (C-4), 73.1 (C-3), 83.8 (C-1), 189.1 (C-
2) ppm. MS (FD, 0Ϫ20 mA): m/z ϭ 435, 433 [Mϩ ϩ H], 434, 432
[Mϩ], 353 [Mϩ Ϫ Br]. C20H17BrO6 (433.3): calcd. C 56.36, H 3.96,
Br 2.22; found C 56.27, H 3.91, Br 2.30.
1-H) ppm; J3,4 ϭ J4,5 ϭ 9.6, J5,6 ϭ 6.2, 2JC,H2 ϭ 10.9, 11.2 Hz. 13
C
NMR (75 MHz, CDCl3): δ ϭ 17.3 (C-6), 72.7 (C-5), 74.2, 75.7 (2
BnCH2), 81.5 (C-3), 82.3 (C-4), 85.7 (C-1), 195.1 (C-2) ppm.
MS (FD, 0Ϫ20 mA): m/z ϭ 407, 405 [Mϩ ϩ H], 406, 404 [Mϩ],
325 [Mϩ Ϫ Br], 315, 313 [Mϩ Ϫ PhCH2], 91 [PhCH2ϩ].
The  enantiomer of 1, prepared in analogous fashion from 2,3,4-
tri-O-benzoyl-6-deoxy--glucosyl bromide (-8) [21] via 2-ben-
zoyloxy--glucal (-11), had m.p. 125Ϫ126 °C, [α]2D2 ϭ ϩ191.4 (c ϭ
1, CHCl3), and identical NMR spectroscopic data.[22]
4-O-Acetyl-3-O-benzyl-ulosyl Bromide (3)
3,4-Di-O-benzyl-ulosyl Bromide (2)
4-O-Acetyl-3-O-benzyl-1,2-O-[1-(exo-methoxy)ethylidene]-β-L-
rhamnopyranose (17): Bromine (0.6 mL, 1.85 g, 11.6 mmol) was ad-
ded to a cold (0 °C) solution of methyl 2,4-di-O-acetyl-3-O-benzyl-
1-thio-α--rhamnopyranoside (14,[16] 4.20 g, 11.4 mmol) in CH2Cl2
(50 mL), and after 15 min stirring, the mixture was concentrated in
vacuo. The resulting syrup was dissolved in a mixture of 2,6-luti-
dine (10 mL) and dry MeOH (2.3 mL, 1.82 g, 57.0 mmol) and the
solution was stirred at 60Ϫ65 °C for 21 h. Dilution with CH2Cl2
(300 mL), washings with saturated aqueous NaHCO3 solution (2
ϫ 200 mL) and water (2 ϫ 200 mL), drying (MgSO4), and removal
of the solvent in vacuo gave a syrup that crystallized from diethyl
ether/n-hexane to afford 17 (2.81 g, 71%) as colorless crystals.
M.p. 74Ϫ75 °C. [α]D20 ϭ ϩ36.0 (c ϭ 0.9, CHCl3). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.20 (d, 3 H, 6-H3), 1.73 (s, 3 H, 1Ј-CH3),
2.06 (s, 3 H, AcCH3), 3.28 (s, 3 H, OCH3), 3.38 (qd, 1 H, 5-H),
3.66 (dd, 1 H, 3-H), 4.45 (dd, 1 H, 2-H), 4.65, 4.73 (2 d, each 1 H,
BnCH2), 5.04 (dd, 1 H, 4-H), 5.33 (d, 1 H, 1-H) ppm; J1,2 ϭ 2.4,
3,4-Di-O-benzyl-1,2-O-[1-(exo-methoxy)ethylidene]-β-L-rhamno-
pyranose (10): Benzyl bromide (4.5 mL, 3.4 g, 39 mmol) and pow-
dered KOH (9.8 g, 177 mmol) were added to a solution of 3,4-
di-O-acetyl-1,2-O-[1-(exo-methoxy)ethylidene]-β--rhamno-
pyranose (9, 4.0 g, 13 mmol), prepared in 72% yield by treatment
of acetobromo--rhamnose (7) with MeOH/lutidine,[15] in dry THF
(150 mL), and the mixture was stirred under reflux for 2 h. Sub-
sequent dilution with CH2Cl2 (250 mL), extraction and washing
with water (4 ϫ 250 mL) and saturated aqueous NaHCO3 solution
(2 ϫ 250 mL), drying (Na2SO4), and evaporation to dryness gave
a crystalline residue, which was recrystallized from 2-propanol to
afford 10 (4.4 g, 81%) as colorless crystals. M.p. 109Ϫ111 °C.
[α]D20 ϭ ϩ0.9 (c ϭ 1.0, CHCl3). ref.[15] 68%; m.p. 109Ϫ111 °C;
1
[α]2D0 ϭ ϩ0.6 (c ϭ 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ
1.32 (d, 3 H, 6-H3), 1.73 (s, 3 H, CH3), 3.28 (s, 3 H, OCH3), 3.34
(qd, 1 H, 5-H), 3.49 (dd, 1 H, 4-H), 3.68 (dd, 1 H, 3-H), 4.38 (dd, 1
H, 2-H), 4.67 and 4.96 (2 d, 1 H, 3-BnCH2), 4.78 (s, 2 H, 4-
BnCH2), 5.27 (d, 1 H, 1-H) ppm; J1,2 ϭ 2.4, J2,3 ϭ 4.1, J3,4 ϭ J4,5 ϭ
9.1, J5,6 ϭ 6.1, 2JC,H2 ϭ 10.8 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ
17.9 (C-6), 24.5 (CH3), 49.8 (OCH3), 70.2 (C-5), 72.2 (3-CH2), 75.6
(4-CH2), 77.2 (C-2), 79.0 (C-3), 79.5 (C-4), 97.3 (C-1), 123.8 (C-1Ј)
ppm. MS (FD, 0Ϫ20 mA): m/z ϭ 401 [Mϩ ϩ H], 400 [Mϩ], 370
[Mϩ Ϫ MeOH], 309 [Mϩ Ϫ PhCH2], 91 [PhCH2ϩ]. C23H28O6
(400.47): calcd. C 68.98, H 7.05; found C 69.09, H 7.00.
J
2,3 ϭ 4.1, J3,4 ϭ J4,5 ϭ 9.6, J5,6 ϭ 6.2, 2JC,H2 ϭ 12.5 Hz. 13C NMR
(75 MHz, CDCl3): δ ϭ 17.5 (C-6), 21.0 (AcCH3), 24.4 (1Ј-CH3),
50.0 (OCH3), 69.1 (C-5), 71.8 (BnCH2), 71.8 (C-4), 76.0 (C-3), 76.8
(C-2), 97.4 (C-1), 124.2 (C-1Ј), 169.8 (AcCO) ppm. MS (FD,
0Ϫ5 mA): m/z ϭ 352 [Mϩ]. C18H24O7 (352.38): calcd. C 61.35, H
6.86; found C 61.06, H 6.61.
2,4-Di-O-acetyl-1,5-anhydro-3-O-benzyl-6-deoxy-
enitol (22): Pyridine (450 µL) was added to a solution of orthoester
L-arabino-hex-1- 17 (1.06 g, 3.0 mmol) in bromobenzene (30 mL), and the mixture
L-arabino-hex-1-
2-O-Acetyl-1,5-anhydro-3,4-di-O-benzyl-6-deoxy-
enitol (12): A solution of orthoester 10 (1.0 g, 2.5 mmol) in bromo-
benzene (20 mL) containing pyridine (0.3 mL) was stirred under
was heated at reflux for 2.5 h. Subsequent concentration in vacuo,
elution of the resulting syrup from a silica gel column (toluene/
3086
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3081Ϫ3093

Efficient Generation of β-L-Rhamnosidic Linkages
FULL PAPER
EtOAc, 30:1), and removal of the solvents from the respective elu-
ate gave 22 (0.86 g, 89%) as a colorless syrup. [α]2D0 ϭ Ϫ13.7 (c ϭ
1.1, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.38 (d, 3 H, 6-
(dd, 1 H, 2-H), 4.29 (qd, 1 H, 5-H), 5.14 (dd, 1 H, 4-H), 5.23 (d,
1 H, 1-H) ppm; J1,2 ϭ 1.0, J2,3 ϭ 3.5, J3,4 ϭ J4,5 ϭ 9.5, J5,6
ϭ
6.3 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 13.7 (SCH3), 17.5 (C-6),
H3), 2.03, 2.07 (2 s, each 3 H, AcCH3), 4.21Ϫ4.26 (m, 2 H, 3-H, 66.4 (C-5), 70.7 (C-3), 72.3 (C-2), 76.1 (C-4), 85.4 (C-1) ppm. MS
5-H), 4.62 (s, 2 H, BnCH2), 5.13 (d, 1 H, 4-H), 6.56 (s, 1 H, 1-H) (FD, 0Ϫ12 mA): m/z ϭ 298 [Mϩ], 251 [Mϩ Ϫ SMe], 105 [PhCOϩ].
ppm; J1,3 Ͻ 0.5, J3,4 ϭ 4.4, J4,5 ϭ 5.1, J5,6 ϭ 6.8 Hz. 13C NMR
(75 MHz, CDCl3): δ ϭ 16.0 (C-6), 20.6, 20.9 (2 AcCH3), 71.0
(BnCH2), 71.4 (C-4), 72.2 and 72.7 (C-3, C-5), 137.9 (C-1), 138.0
(C-2), 169.5, 170.0 (2 AcCO) ppm. MS (FD, 0Ϫ5 mA): m/z ϭ 320
[Mϩ]. C17H20O6 (320.34): calcd. C 63.74, H 6.29; found C 62.84,
H 6.25.
C14H18O5S (298.35): calcd. C 56.36, H 6.08; found C 55.87, H 6.06.
Methyl 2-O-Acetyl-4-O-benzoyl-3-O-benzyl-1-thio-α- -rhamno-
L
pyranoside (21): A suspension of 20 (1.70 g, 5.7 mmol) and n-dibu-
tyltin oxide (1.63 g, 6.5 mmol) in benzene (40 mL) was stirred at
reflux under a DeanϪStark trap for 5 h. Evaporation in vacuo gave
a colorless syrup, which was dissolved in benzene (20 mL). Benzyl
bromide (1.25 mL, 10.7 mmol) and n-tetrabutylammonium iodide
(2.11 g, 5.7 mmol) were then added, and the mixture was stirred at
50 °C for 6 h. The solution was then concentrated and the semicrys-
talline residue was stirred with EtOAc (20 mL). The solids were
removed by filtration and the filtrate was concentrated to a syrup,
which was dissolved in pyridine (6 mL) and cooled to 0 °C. Acetic
anhydride (6 mL, 63.5 mmol) was added dropwise to this solution,
which was then stirred at room temperature for 2 h, treated with
dry EtOH at 0 °C, and stirred for 20 min (room temperature).
Evaporation in vacuo and purification by elution from a silica gel
column with n-hexane/EtOAc (5:1) containing 1% triethylamine
gave 21 (1.68 g, 70%) as a colorless syrup. [α]2D0 ϭ Ϫ27.3 (c ϭ 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3). δ ϭ 1.27 (d, 3 H, 6-H3),
2.15 (s, 3 H, SCH3), 2.19 (s, 3 H, AcCH3), 3.89 (dd, 1 H, 3-H),
4.22 (qd, 1 H, 5-H), 4.40, 4.60 (2d, 2 H, 3-CH2), 5.16 (d, 1 H, 1-
H), 5.33 (dd, 1 H, 4-H), 5.50 (dd, 1 H, 2-H) ppm; J1,2 ϭ 1.4, J2,3 ϭ
4-O-Acetyl-3-O-benzyl-6-deoxy-α-L-arabino-hexopyranos-2-ulosyl
Bromide (3): Dry EtOH (70 µL, 55.3 mg, 1.2 mmol) and freshly
˚
desiccated molecular sieves (3 A) were added to a solution of 2-
acetoxyrhamnal 22 (320.3 mg, 1.0 mmol) in CH2Cl2 (5 mL), and
the mixture was stirred for 15 min and cooled to 0 °C. NBS
(213.6 mg, 1.2 mmol) was then added and stirring was continued
for 35 min, followed by immediate workup by dilution with cold
CH2Cl2 (30 mL) and successive washings with cold aqueous
Na2S2O3 solution (10%, 2 ϫ 15 mL) and ice-water (2 ϫ 15 mL).
Drying (MgSO4) and removal of the solvent in vacuo gave 3
(357 mg, 98%) as a colorless syrup with [α]2D0 ϭ Ϫ203.9 (c ϭ 1.0,
CHCl3). The product is sufficiently pure for glycosidations. 1H
NMR (300 MHz, CDCl3): δ ϭ 1.28 (d, 3 H, 6-H3), 2.03 (s, 3 H,
AcCH3), 4.27 (qd, 1 H, 5-H), 4.55, 4.97 (2 d, each 1 H, BnCH2),
4.72 (dd, 1 H, 3-H), 5.08 (dd, 1 H, 4-H), 6.32 (d, 1 H, 1-H) ppm;
2
J1,2 ϭ 0.4, J3,4 ϭ J4,5 ϭ 10.1, J5,6 ϭ 6.2, JC,H ϭ 12.0 Hz. 13C
2
2
3.4, J3,4 ϭ J4,5 ϭ 9.8, J5,6 ϭ 6.25, JC,H ϭ 12.3 Hz. 13C NMR
NMR (75 MHz, CDCl3): δ ϭ 16.8 (C-6), 20.7 (AcCH3), 71.4 (C-
5), 73.5 (BnCH2), 73.5 (C-4), 77.6 (C-3), 85.1 (C-1), 169.1 (AcCO),
194.0 (C-2) ppm. MS (FD): m/z ϭ 356, 358 [Mϩ], 277 [Mϩ Ϫ Br],
218 [Mϩ Ϫ AcO].
2
(75 MHz, CDCl3): δ ϭ 13.9 (SCH3), 17.6 (6-H3), 21.1 (AcCH3),
67.2 (C-5), 69.8 (C-2), 71.1 (BnCH2), 73.0 (C-4), 74.5 (C-3), 83.8
(C-1) ppm. MS (FD, 0Ϫ10 mA): m/z ϭ 430 [Mϩ], 383 [Mϩ
Ϫ
MeS]. C23H26O6S (430.52): calcd. C 64.17, H 6.09; found C63.65,
H 5.95.
4-O-Benzoyl-3-O-benzyl-ulosyl Bromide (4)
Methyl 4-O-Benzoyl-2,3-O-isopropylidene-1-thio-α-L-rhamno-
4-O-Benzoyl-3-O-benzyl-1,2-O-[1-(exo-methoxy)ethylidene]-β-L-
pyranoside (16): Benzoyl chloride (2.3 mL, 2.8 g, 24.8 mmol) was
added dropwise to a cooled solution (0 °C) of methyl 2,3-O-isopro-
pylidene-1-thio-α--rhamnopyranoside[15] (15, 3.33 g, 14.2 mmol)
in pyridine (10 mL), and the reaction mixture was stirred at room
temperature for 17 h. Dilution with CHCl3 (60 mL) and successive
washings with water (40 mL), saturated aqueous NaHCO3 solution
(2 ϫ 40 mL), and water (40 mL), gave, after drying (MgSO4) and
evaporation in vacuo, a syrup, which crystallized from diethyl ether
to afford 16 (4.71 g, 98%) as fine, colorless crystals. M.p. 155Ϫ156
°C. [α]2D0 ϭ Ϫ114.6 (c ϭ 1.1, CHCl3). 1H NMR (300 MHz, CDCl3):
δ ϭ 1.24 (d, 3 H, 6-H3), 1.35, 1.63 (2 s, each 3 H, C(CH3)2], 2.16
(s, 3 H, SCH3), 4.19 (qd, 1 H, 5-H), 4.25 (br. d, 1 H, 2-H), 4.33
(dd, 1 H, 3-H), 5.19 (dd, 1 H, 4-H), 5.47 (br. s, 1 H, 1-H) ppm;
J2,3 ϭ 5.3, J3,4 ϭ 7.9, J4,5 ϭ 10.0, J5,6 ϭ 6.3 Hz. 13C NMR
rhamnopyranose (19): A solution of thiorhamnoside 21 (4.0 g,
9.2 mmol) in dry CH2Cl2 (60 mL) was cooled to 0 °C, bromine (480
µL, 1.5 g, 9.3 mmol) was added, and the mixture was stirred for
0.5 h. Concentration in vacuo and coevaporation with CHCl3 gave
2-O-acetyl-4-O-benzoyl-3-O-benzyl-α--rhamnopyranosyl bromide
as a colorless syrup, which was directly subjected to methanolysis
by dissolution in CH2Cl2/2,6-lutidine (1:1, 20 mL), addition of dry
MeOH (1.9 mL, 1.5 g, 42.2 mmol), and stirring at 50 °C for 19 h.
Dilution with CH2Cl2 (80 mL), successive washings with saturated
aqueous NaHCO3 solution (2 ϫ 60 mL) and water (2 ϫ 60 mL),
drying (MgSO4), and evaporation to dryness left a syrup, which
crystallized on trituration with 2:1 n-hexane/diethyl ether to afford
19 (2.6 g, 68%) as fine, colorless crystals. M.p. 136.5Ϫ137 °C. [α]
20 ϭ ϩ50.5 (c ϭ 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ
D
(75 MHz, CDCl3):
δ ϭ 13.4 (SCH3), 17.2 (C-6), 26.5, 27.8
1.25 (d, 3 H, 6-H3), 1.78 (s, 3 H, 1Ј-CH3), 3.32 (s, 3 H, OCH3),
3.54 (qd, 1 H, 5-H), 3.82 (dd, 1 H, 5-H), 4.52 (dd, 1 H, 2-H), 4.64
and 4.72 (2 d, each 1 H, BnCH2), 5.32 (dd, 1 H, 4-H), 5.39 (d, 1
[C(CH3)2], 64.7 (C-5), 75.4 (C-4), 75.6 (C-3), 76.7 (C-2), 81.3 (C-
1), 110.0 [C(CH3)3] ppm. MS (FD, 0Ϫ20 mA): m/z ϭ 338 [Mϩ],
323 [Mϩ Ϫ Me], 292 [Mϩ Ϫ CH2S], 291 [Mϩ Ϫ SMe], 105
[PhCOϩ], 47 [SMeϩ]. C17H24O5S (338.42): calcd. C 60.34, H 6.55;
found C 60.18, H 6.53.
H, 1-H) ppm; J1,2 ϭ 2.3, J2,3 ϭ 4.0, J3,4 ϭ 9.6, J4,5 ϭ 9.5, J5,6
ϭ
6.2, 2JC,H1 ϭ 12.6, 12.7 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 17.6
(C-6), 24.4 (1Ј-CH3), 49.9 (OCH3), 69.3 (C-5), 71.5 (3-BnCH2), 72.4
(C-4), 75.6 (C-3), 76.7 (C-2), 97.5 (C-1), 124.2 (C-1Ј) ppm. MS
(FD, 0Ϫ12 mA): m/z ϭ 414 [Mϩ], 383 [Mϩ Ϫ OMe]. C23H26O7
(414.46): calcd. C 66.65, H 6.32; found C 66.62, H 6.39.
Methyl 4-O-Benzoyl-1-thio-α-L-rhamnopyranoside (20): A suspen-
sion of thiorhamnoside 16 (4.0 g, 11.8 mmol) in dry MeOH
(30 mL) and trifluoroacetic acid (5 mL) was heated at reflux for
4.5 h. Concentration in vacuo gave a syrup, which was purified by
elution from a silica gel column (n-hexane/EtOAc, 2:1) to yield 20
(2.98 g, 85%) as a colorless foam: [α]2D0 ϭ Ϫ206.5 (c ϭ 1.0, CHCl3).
2-O-Acetyl-1,5-anhydro-4-O-benzoyl-3-O-benzyl-6-deoxy-L-
arabino-hex-1-enitol (23): A solution of orthoester 19 (1.92 g,
4.6 mmol) in bromobenzene (40 mL) was treated with pyridine
1H NMR (300 MHz, CDCl3). δ ϭ 1.29 (d, 3 H, 6-H3), 2.15 (s, 3 (700 µL) and stirred under reflux for 3 h. The mixture was concen-
H, SCH3), 3.72 (br. s, 2 H, 2-OH, 3-OH), 4.01 (dd, 1 H, 3-H), 4.12 trated and purified by elution from a silica gel column (toluene/
Eur. J. Org. Chem. 2003, 3081Ϫ3093
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3087

F. W. Lichtenthaler, T. Metz
FULL PAPER
EtOAc, 30:1) to yield 23 (1.50 g, 85%) as a colorless syrup on evap-
oration of the respective eluate . [α]2D0 ϭ ϩ37.7 (c ϭ 1.1, CHCl3).
concentrated and purified by elution from a silica gel column (tolu-
ene/EtOAc, 40:1) to afford 23 (1.1 g, 85%) as a colorless syrup that
1H NMR (300 MHz, CDCl3). δ ϭ 1.44 (d, 3 H, 6-H3), 2.04 (s, 3 crystallized in vacuo. M.p. 75Ϫ77 °C; [α]2D0 ϭ Ϫ7.4 (c ϭ 1.0,
H, AcCH3), 4.38 (dd, 1 H, 3-H), 4.37Ϫ4.41 (m, 1 H, 5-H), CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.36 (d, 3 H, 6-H3),
4.64Ϫ4.72 (2 d, each 1 H, BnCH2), 5.41 (d, 1 H, 4-H), 6.63 (d, 1
2.04 (s, 3 H, AcCH3), 3.57 (d, 1 H, 4-H), 3.77 (s, 3 H, PhOCH3),
H, 1-H) ppm; J1,3 ϭ 0.4, J3,4 ϭ 4.3, J4,5 ϭ 5.3, J5,6 ϭ 6.9, 2JC,H2 ϭ 4.08 (qd, 1 H, 5-H), 4.45 (dd, 1 H, 3-H), 4.55, 4.58, 4.63, 4.70 (4
11.8 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 16.1 (C-6), 20.7 (2 d, 1 H each, BnCH2, MeOBnCH2), 6.53 (s, 1 H, 1-H) ppm; J3,4
ϭ
2
AcCH3), 71.2 (BnCH2), 71.9 (C-4), 72.4, 72.8 (C-3, C-5),
5.5, J4,5 ϭ 7.8, J5,6 ϭ 6.5, JC,H ϭ 11.2, 11.6 Hz. 13C NMR
127.8Ϫ133.4 (2 C6H5), 137.9 (C-2), 138.1 (C-1) ppm. MS (FD, (75 MHz, CDCl3): δ ϭ 17.0 (C-6), 220.7 (AcCH3), 55.3 (PhOCH3),
0Ϫ5 mA): m/z ϭ 382 [Mϩ], 383 [Mϩ ϩ H]. C22H22O6 (382.41):
72.2, 73.1 (BnCH2, MeOBnCH2), 74.5 (C-5), 76.1 (C-3), 78.6 (C-
4), 138.3 (C-1), 138.4 (C-2), 169.6 (AcCO) ppm. MS (FD,
0Ϫ5 mA): m/z ϭ 398 [Mϩ], 399 [Mϩ ϩ H]. C23H26O6 (398.46).
Calcd. C, 69.33, H 6.58; found C 69.10, H 6.65.
calcd. C 69.10, H 5.80; found C 68.96, H 5.74.
4-O-Benzoyl-3-O-benzyl-6-deoxy-α-L-arabino-hexopyranos-2-
ulosyl Bromide (4): A solution of 2-acetoxyrhamnal 23 (1.36 g,
3.6 mmol) in CH2Cl2 (25 mL) was treated with dry EtOH (250 µL,
3-O-Benzyl-4-O-(4-methoxybenzyl)-6-deoxy-α-L-arabino-hexo-
pyranos-2-ulosyl Bromide (5): Dry ethanol (88 µL, 70 mg,
197 mg, 4.3 mmol), stirred for 15 min over freshly desiccated mo-
˚
lecular sieves (3 A), and cooled to 0 °C. NBS (759 mg, 4.3 mmol) 1.5 mmol) was added to a solution of 2-acetoxy-rhamnal 24
was then added to the mixture and stirring was continued for
15 min. The solution was immediately worked up by dilution with
cold CH2Cl2 (50 mL) and successive washings with cold aqueous
Na2S2O3 solution (10%, 2 ϫ 30 mL) and ice-water (2 ϫ 30 mL).
Drying (MgSO4) and concentration in vacuo gave 4 (1.41 g, 95%)
as a colorless syrup. The product is sufficiently pure for glycosida-
(500 mg, 1.25 mmol) in CH2Cl2 (30 mL), and the mixture was
stirred for 15 min over freshly desiccated molecular sieves (3 A) and
cooled (0 °C), followed by the addition of NBS (269 mg, 1.5 mmol)
˚
and continued stirring for 15 min. Workup (as given for compound
4) provided 5 (535 mg, 98%) as a colorless syrup with [α]D20
ϭ
Ϫ196.4 (c ϭ 1.0, CHCl3), sufficiently pure for the ensuing glycosid-
tions: [α]2D0 ϭ Ϫ132.5 (c ϭ 1.1, CHCl3). 1H NMR (300 MHz, ations. 1H NMR (300 MHz, CDCl3): δ ϭ 1.33 (d, 3 H, 6-H3), 3.44
CDCl3): δ ϭ 1.34 (d, 3 H, 6-H3), 4.41 (qd, 1 H, 5-H), 4.59 and 4.94 (dd, 1 H, 4-H), 3.79 (s, 3 H, PhOCH3), 4.19 (qd, 1 H, 5-H), 4.57,
(2 d, each 1 H, BnCH2), 4.85 (d, 1 H, 3-H), 5.36 (dd, 1 H, 4-H),
4.65, 4.83, 5.01 (4 s, 1 H each, BnCH2, MeOBnCH2), 4.85 (d, 1 H,
6.37 (s, 1 H, 1-H) ppm; J3,4 ϭ 10.2, J4,5 ϭ 10.1, J5,6 ϭ 6.3, 2JC,H2 ϭ 3-H), 6.27 (s, 1 H, 1-H) ppm; J3,4 ϭ J4,5 ϭ 9.6, J5,6 ϭ 6.3, 2JC,H2 ϭ
12.1 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 16.8 (C-6), 71.5 (C-5), 10.6, 11.2 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 17.2 (C-6), 55.3
73.3 (BnCH2), 73.9 (C-4), 77.1 (C-3), 85.1 (C-1), 194.1 (C-2) ppm. (PhOCH3), 72.7 (C-5), 74.2, 75.2 (BnCH2, MeOBnCH2), 81.5 (C-
MS (FD, 0Ϫ12 mA): m/z ϭ 421, 419 [Mϩ ϩ H], 420, 418 [Mϩ].
3), 81.9 (C-4), 85.8 (C-1), 195.0 (C-2) ppm. MS (FD): m/z ϭ 434,
436 [Mϩ].
3-O-Benzyl-4-O-(4-methoxybenzyl)-ulosyl Bromide (5)
Model Glycosidations of Ulosyl Bromides with 2-Propanol
3-O-Benzyl-4-O-(4-methoxybenzyl)-1,2-O-[1-(exo-methoxy)-
ethylidene]-β-
L-rhamnopyranose (18): 4-Methoxybenzyl chloride
Isopropyl 3,4-Di-O-benzoyl-6-deoxy-β-L-arabino-hexopyranosid-2-
(1.7 mL, 2.0 g, 12.5 mmol), n-tetrabutylammonium iodide (20 mg),
ulose (25):
A
suspension of 2-propanol (0.88 mL, 0.69 g,
and powdered KOH (3.1 g, 55.4 mmol) were successively added to
a solution of 17 (1.5 g, 4.3 mmol) in dry THF (60 mL), and the molecular sieves (4 A) was stirred at room temperature for
11.5 mmol), Ag2CO3 (4.46 g, 16.2 mmol) in CH2Cl2 (80 mL), and
˚
mixture was heated at reflux for 3 h. Subsequent dilution with
CH2Cl2 (250 mL), extraction with water (4 ϫ 200 mL) and satu-
rated aqueous NaHCO3 solution (2 ϫ 200 mL), drying of the or-
ganic layer (MgSO4), and concentration in vacuo gave a syrup,
which was purified by flash chromatography on a short column of
silica gel. The nonpolar components were removed first, with n-
hexane/EtOAc (30:1) containing 1% triethylamine, and the product
was then eluted with n-hexane/EtOAc (2:1) containing 1% triethyl-
15Ϫ20 min with exclusion of moisture. A solution of ulosyl bro-
mide 1 (5.00 g, 11.5 mmol) in CH2Cl2 (20 mL) was then added,
stirring was continued for 30 min, and the mixture was filtered
through Celite, followed by removal of the solvent in vacuo to af-
ford 25 (4.55 g, 96%) as a colorless foam. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.20, 1.32 [2 d, each 3 H, C(CH3)2], 1.44 (d, 3 H, 6-
H3), 4.10 [qq, 1 H, CH(CHMe2], 4.21 (qd, 1 H, 5-H), 5.18 (s, 1 H,
1-H), 5.57 (dd, 1 H, 4-H), 5.88 (d, 1 H, 3-H) ppm; J3,4 ϭ 10.2,
amine. Evaporation of the eluate gave a colorless syrup, which was J4,5 ϭ 9.6, J5,6 ϭ 5.8, JC,H,CH3 ϭ 6.2, 1J1 ϭ 158.0 Hz. 13C NMR
crystallized from 2-propanol (8 mL) to afford 18 (1.7 g, 93%) as
(75 MHz, CDCl3): δ ϭ 17.9 (C-6), 22.0, 23.3 [C(CH3)2], 71.1 (C-
5), 72.7 [CH(CMe2)], 75 (C-4), 77.3 (C-3), 98.5 (C-1), 192.2 (C-
colorless needles. M.p. 98Ϫ99 °C. [α]2D0 ϭ Ϫ0.7 (c ϭ 0.9, CHCl3).
1H NMR (300 MHz, CDCl3): δ ϭ 1.30 (d, 3 H, 6-H3), 1.72 (s, 3 2) ppm.
H, 1Ј-CH3), 3.28 (s, 3 H, OCH3), 3.30 (qd, 1 H, 5-H), 3.46 (dd, 1
Isopropyl 3,4-Di-O-benzyl-6-deoxy-β-L-arabino-hexopyranosid-2-
ulose (26): A mixture of 2-propanol (0.70 mL, 0.55 g, 9.1 mmol),
H, 4-H), 3.66 (dd, 1 H, 3-H), 3.79 (s, 3 H, PhOCH3), 4.38 (dd, 1
H, 2-H), 4.60, 4.87 (2 d, 1 H each, BnCH2), 4.77 (s, 2 H,
MeOBnCH2), 5.26 (d, 1 H, 1-H) ppm; J1,2 ϭ 2.4, J2,3 ϭ 4.1, J3,4 ϭ
Ag2CO3 (2.51 g, 9.1 mmol) in CH2Cl2 (50 mL), and molecular si-
˚
eves (4 A) was stirred for 20 min at ambient temperature with ex-
2
J4,5 ϭ 9.1, J5,6 ϭ 6.1, JC,H ϭ 10.5 Hz. 13C NMR (75 MHz,
2
clusion of moisture. The ulosyl bromide 2 (1.49 g, 3.7 mmol), dis-
solved in CH2Cl2 (12 mL), was added and stirring was continued
for 20 min. The mixture was filtered through Celite and removal
of the solvent in vacuo provided an amorphous product, that was
crystallized from diisopropyl ether to afford 26 (1.28 g, 91%) as
colorless needles. M.p. 94Ϫ96 °C; [α]2D0 ϭ ϩ74.2 (c ϭ 1.0, CHCl3).
CDCl3): δ ϭ 18.0 (C-6), 24.4 (1Ј-CH3), 49.8 (1Ј-OCH3), 55.3
(PhOCH3), 70.3 (C-5), 72.3 (BnCH2), 75.2 (MeOBnCH2), 77.3 (C-
2), 79.2, 79.3 (C-3, C-4), 97.4 (C-1), 123.8 (C-1Ј) ppm. MS (FD,
0Ϫ5 mA): m/z ϭ 430 [Mϩ]. C24H30O7 (430.50): calcd. C 66.96, H
7.02; found C 67.37, H 7.08.
2-O-Acetyl-1,5-anhydro-3-O-benzyl-4-O-(4-methoxybenzyl)-6- 1H NMR (300 MHz, CDCl3): δ ϭ 1.23, 1.30 [2 d, each 3 H,
deoxy-
L
-arabino-hex-1-enitol (24): A solution of orthoester 18
CH(CH3)2], 1.36 (d, 3 H, 6-H3), 3.49 (dd, 1 H, 4-H), 3.73 (dq, 1
H, 5-H), 4.04 [qq, 1 H, CH(CH3)2], 4.18 (dd, 1 H, 3-H), 4.58, 4.64,
(1.4 g, 3.3 mmol) in bromobenzene (30 mL) was treated with pyri-
dine (500 µL) and stirred under reflux for 3 h. The mixture was 4.92, 4.99 (4 d, each 1 H, 2 BnCH2), 4.83 (d, 1 H, 1-H) ppm; J1,3 ϭ
3088 www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2003, 3081Ϫ3093

Efficient Generation of β-L-Rhamnosidic Linkages
FULL PAPER
0.6, J3,4 ϭ J4,5 ϭ 9.1, J5,6 ϭ 6.1, JC,H,CH ϭ 6.2, 2JC,H2 ϭ 11.0 and
55.3 (OCH3), 71.9 (C-5, CH(CH3)2], 73.4, 73.9 (BnCH2,
11.4, 1J1 ϭ 156.6 Hz. 13C NMR (75 MH3z, CDCl3): δ ϭ 18.1 (C-6), MeOBnCH2), 85.1 (C-3), 85.9 (C-4), 97.7 (C-1), 197.5 (C-2) ppm.
21.7, 23.2 [CH(CH3)2], 71.9, 72.0 [C-5, CH(CH3)2], 73.4, 75.3 (2 MS (FD, 0Ϫ12 mA): m/z ϭ 414 [Mϩ], 415 [Mϩ ϩ H]. C24H30O6
BnCH2), 85.5 (C-4), 85.8 (C-3), 97.7 (C-1), 197.4 (C-2) ppm. MS (414.50): calcd. C 69.55, H 7.30; found C 69.09, H 7.31.
(FD, 0Ϫ12 mA): m/z ϭ 384 [Mϩ].
Uloside Reductions
Isopropyl 4-O-Acetyl-3-O-benzyl-6-deoxy-β-L-arabino-hexo-
pyranosid-2-ulose (27): A mixture of 2-propanol (161 µL, 126 mg,
Isopropyl 2,3,4-Tri-O-benzoyl-β-L-rhamnopyranoside (30): A solu-
tion of K-Selectride in THF (1 , 0.97 mL, 0.97 mmol) was added
to a cold (Ϫ78 °C) solution of uloside 25 (400 mg, 0.97 mmol) in
THF (3 mL). After 1 min the reaction was stopped by addition of
acetic acid (0.2 mL) and CH2Cl2 (30 mL), followed by washing of
the mixture with HCl (2 , 30 mL) and satd. aqueous NaHCO3
(30 mL), drying (MgSO4), and evaporation of the solvent in vacuo.
The resulting residue was diluted in CH2Cl2 (5 mL) and benzoyl-
ated over 3 h with pyridine (1 mL), benzoyl chloride (0.5 mL), and
DMAP (50 mg). The mixture was diluted with CH2Cl2 (30 mL),
washed with HCl (2 , 30 mL) and NaHCO3 (30 mL), dried
(MgSO4), and concentrated to a syrup, which was subjected to col-
umn chromatography on silica gel (hexane/EtOAc, 3:1) to yield 30
(78%) as colorless needles. M.p. 133Ϫ134 °C. [α]2D0 ϭ ϩ218.6 (c ϭ
2.1 mmol), Ag2CO3 (580 mg, 2.1 mmol) in CH2Cl2 (4 mL), and
˚
molecular sieves (4 A) was stirred for 20 min at ambient tempera-
ture with exclusion of moisture. Ulosyl bromide 3 (357 mg,
1.0 mmol), dissolved in CH2Cl2 (3 mL), was then added, stirring
was continued for 20 min, the mixture was filtered through Celite,
and the solvent was removed in vacuo to give a syrup, which crys-
tallized from diisopropyl ether to afford 27 (302 mg, 90%) as color-
1
less crystals. M.p. 78Ϫ80 °C; [α]2D0 ϭ ϩ101.1 (c ϭ 0.9, CHCl3). H
NMR (300 MHz, CDCl3): δ ϭ 1.23, 1.31 [2 d, 6 H, CH(CH3)2],
1.30 (d, 3 H, 6-H3), 2.04 (s, 3 H, AcCH3), 3.81 (qd, 1 H, 5-H), 4.04
[qq, 1 H, CH(CH3)2], 4.08 (dd, 1 H, 3-H), 4.52, 4.93 (2 d, 2 H, 3-
CH2), 4.86 (d, 1 H, 1-H), 5.05 (dd, 1 H, 4-H) ppm; J1,3 ϭ 0.7,
2
J3,4 ϭ 9.6, J4,5 ϭ 9.4, J5,6 ϭ 6.3, JC,H ϭ 12.2, JC,H,CH3 ϭ 6.2,
2
1
0.9, CHCl3). H NMR (500 MHz, CDCl3): δ ϭ 1.19, 1.21 [2 d, 6
H, CH(CH3)2], 1.44 (d, 3 H, 6-H3), 3.84 (m, 1 H, H-5), 4.07 [m, 1
H, CH(CH3)2], 4.96 (d, 1 H, H-1), 5.57 (dd, 1 H, H-3), 5.60 (t, 1
1J1 ϭ 156.6 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 17.8 (C-6), 20.9
(AcCH3), 21.7, 23.2 [CH(CH3)2], 70.8 (C-5), 72.1 [CH(CH3)2], 72.5
(BnCH2), 76.4 (C-4), 81.9 (C-3), 97.9 (C-1), 197.0 (C-2) ppm. MS
H, H-4), 5.86 (dd, 1 H, 2-H) ppm; J1,2 ϭ 0.9, J2,3 ϭ 3.1, J3,4
ϭ
(FD): m/z ϭ 259 [Mϩ
Ϫ
Ph], 91 [PhCH2ϩ], 43 [Acϩ].
10.0, J4,5 ϭ 9.1, J5,6 ϭ 6.2, JC,H,CH3 ϭ 6.2 Hz. 13C NMR
(125 MHz, CDCl3): δ ϭ 18.1 (C-6), 21.9, 23.3 [CH(CH3)2], 70.8
(C-2), 71.1 (C-5), 71.6 [CH(CH3)2], 72.1 (C-4), 72.3 (C-3), 97.0 (C-
1) ppm. MS (FD, 0Ϫ20 mA): m/z ϭ 518 [Mϩ], 519 [Mϩ ϩ H], 122
[PhCO2Hϩ], 105 [PhCOϩ], 43 [C3H7ϩ]. C30H30O8 (518.56): calcd.
C 69.49, H 5.83; found C 69.45, H 5.81.
C18H24O6(336.4): calcd. C 64.27, H 7.19; found C 63.37, H 7.14.
Isopropyl 4-O-Benzoyl-3-O-benzyl-6-deoxy-β- -arabino-hexo-
L
pyranosid-2-ulose (28): A suspension of 2-propanol (0.55 mL,
0.43 g, 7.2 mmol), Ag2CO3 (1.99 g, 7.2 mmol) in CH2Cl2 (35 mL),
˚
and molecular sieves (4 A) was stirred for 20 min at room tempera-
ture with exclusion of moisture. A solution of ulosyl bromide 4
(1.38 g, 3.3 mmol) in CH2Cl2 (15 mL) was then added, stirring was
continued for 20 min, the mixture was filtered through Celite, and
the solvent was removed in vacuo to provide a syrup that crys-
tallized on trituration with diisopropyl ether to afford 28 (1.22 g,
93%) as colorless needles. M.p. 110 °C; [α]2D0 ϭ ϩ125.7 (c ϭ 0.6,
CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 1.25, 1.32 [2 d, each 3
H, CH(CH3)2], 1.36 (d, 3 H, 6-H3), 3.96 (qd, 1 H, 5-H), 4.07 [qq,
1 H, CH(CH3)2], 4.22 (dd, 1 H, 3-H), 4.57, 4.92, 4.92 (d, 1 H, 1-
When NaBH4 in CH2Cl2 was used for reduction of 25, a 3:1 mix-
ture of 30 and its -gluco epimer was obtained, allowing the iso-
lation of the major product in 60% yield only.
Isopropyl 3,4-Di-O-benzyl-β-L-rhamnopyranoside (31): -Selectride
(1  in THF, 1 mL, 1 mmol) was added to a cooled (Ϫ78 °C) stirred
solution of uloside 33 (385 mg, 1 mmol) in THF (3 mL), and after
1 min the reaction was stopped by the addition of AcOH (0.2 mL).
After dilution with CH2Cl2 (15 mL), the mixture was washed with
HCl (2 , 2 ϫ 20 mL) and satd. NaHCO3 (2 ϫ 20 mL) and dried
(MgSO4), and the solvents were evaporated in vacuo to give a
syrup, which was subjected to column chromatography on silica gel
(toluene/EtOAc, 4:1) to yield 31 (313 mg, 81%) as a colorless syrup
1
H), 5.32 (dd, 1 H, 4-H) ppm; J1,3 ϭ 0.5, J3,4 ϭ J4,5 ϭ 9.4, J5,6
ϭ
2
6.2, JC,H,CH3 ϭ 6.2, JC,H ϭ 12.4, 1J1 ϭ 157.1 Hz. 13C NMR
2
(75 MHz, CDCl3): δ ϭ 18.0 (C-6), 21.7, 23.2 [CH(CH3)2], 71.1 (C-
5), 72.1 [CH(CH3)2], 72.4 (BnCH2), 77.0 (C-4), 81.4 (C-3), 98.0 (C-
1), 197.1 (C-2) ppm. MS (FD, 0Ϫ12 mA): m/z ϭ 398 [Mϩ], 399
[Mϩ ϩ H]. C23H26O6 (398.5): calcd. C 69.33, H 6.58; found C
69.15, H 6.54.
1
on evaporation of the eluate. [α]2D0 ϭ ϩ29.8 (c ϭ 0.9, CHCl3). H
NMR (500 MHz, CDCl3): δ ϭ 1.16, 1.25 [2 d, each 3 H,
CH(CH3)2], 1.33 (d, 3 H, 6-H3), 2.80 (br. s, 1 H, 2-OH), 3.30 (m,
1 H, 5-H), 3.53 (m, 2 H, 3-H, 4-H), 4.03 [m, 1 H, CH(CH3)2], 4.05
(m, 1 H, 2-H), 4.46 (d, 1 H, 1-H), 4.63, 4.66, 4.77, 4.93 (4 d, each
H, 2 BnCH2), 7.25Ϫ7.40 (m, 10 H, 2 C6H5); J1,2 ϭ 0.8, J5,6 ϭ 6.2,
JC,H,CH3 ϭ 6.2 Hz. 13C NMR (125 MHz, CDCl3): δ ϭ 17.9 (C-6),
21.6, 23.4 [CH(CH3)2], 69.0 (C-2), 70.8 [CH(CH3)2], 71.3 (BnCH2),
71.4 (C-5), 75.3 (BnCH2), 79.6, 81.6 (C-3 and C-4), 97.4 (C-1),
127.7Ϫ138.4 (2 C6H5) ppm. MS (FD, 0Ϫ12 mA): m/z ϭ 387 [Mϩ
ϩ H], 386 [Mϩ]. C23H30O5 (386.49): calcd. C 71.48, H 7.82; found
C 70.51, H 7.78.
Isopropyl 3-O-Benzyl-4-O-(4-methoxybenzyl)-6-deoxy-β-L-
arabino-hexopyranosid-2-ulose (29): A suspension of 2-propanol
(230 µL, 180 mg, 3.0 mmol), Ag2CO3 (830 mg, 3.0 mmol) in
˚
CH2Cl2 (15 mL), and molecular sieves (4 A) was stirred at room
temperature for 20 min with exclusion of moisture. The ulosyl bro-
mide 5 (535 mg, 1.2 mmol), dissolved in CH2Cl2 (5 mL), was added
and stirring was continued for 25 min. The mixture was filtered
through Celite and removal of the solvent in vacuo gave a syrup
that crystallized from diisopropyl ether to afford 29 (435 mg, 95%)
as fine needles. M.p. 85Ϫ86 °C; [α]2D0 ϭ ϩ67.1 (c ϭ 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ ϭ 1.22, 1.30 (2 d, 6 H, CH(CH3)2],
1.33 (d, 3 H, 6-H3), 3.47 (dd, 1 H, 4-H), 3.70 (dq, 1 H, 5-H), 3.80
With NaBH4 as reducing agent, 31 was isolated in 76% yield.
Isopropyl 4-O-Acetyl-3-O-benzyl-β-L-rhamnopyranoside (32): Sub-
(s, 3 H, OCH3), 4.03 [qq, 1 H, CH(CH3)2], 4.17 (dd, 1 H, 3-H), jection of 27 to reduction with NaBH4 (100 mg) in CH2Cl2/MeOH
4.57, 4.59, 4.84, and 5.00 (4 d, each 1 H, BnCH2 and MeOBnCH2),
4.81 (d, 1 H, 1-H) ppm; J1,3 ϭ 0.5, J3,4 ϭ 9.1, J4,5 ϭ 9.1, J5,6
(1:1, 20 mL) at 0 °C, and stirring for 1 h, followed by dilution with
CH2Cl2 (120 mL) and workup (as described for compound 32) pro-
ϭ
2
6.2, JC,H,CH3 ϭ 6.2, JC,H ϭ 10.6 and 11.5, 1J1 ϭ 156.3 Hz. 13C vided a crude syrup, that was purified by elution from a silica gel
NMR (75 MHz, CDCl3):2 δ ϭ 18.1 (C-6), 21.7, 23.2 [CH(CH3)2],
column (n-hexane/EtOAc, 3:1) to give 32 (238 mg, 70%) as a color-
Eur. J. Org. Chem. 2003, 3081Ϫ3093
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3089

F. W. Lichtenthaler, T. Metz
FULL PAPER
less syrup. [α]2D0 ϭ ϩ77.0 (c ϭ 1.0, CHCl3). 1H NMR (300 MHz, and finally with aqueous NaCl (10%, 2 ϫ 10 mL). Drying (MgSO4)
CDCl3): δ ϭ 1.18, 1.27 [2 d, each 3 H, CH(CH3)2], 1.23 (d, 3 H, and concentration to dryness furnished a syrup, which was purified
6-H3), 2.03 (s, 3 H, 4-AcCH3), 2.52 (br. s, 1 H, 2-OH), 3.36 (qd, 1
by elution from silica gel (hexane/EtOAc, 3:1) to yield a 10:1 mix-
H, 5-H), 3.47 (dd, 1 H, 3-H), 4.04 [qq, 1 H, CH(CH3)2], 4.07 (d, 1 ture (1H NMR) of -glucoside 35 and the corresponding -rham-
H, 2-H), 4.51 (d, 1 H, 1-H), 4.54, 4.72 (2 d, each 1 H, BnCH2),
noside (326 mg, 81%). 1H NMR (500 MHz, CDCl3): δ ϭ 1.23, 1.29
[2 d, each 3 H, CH(CH3)2], 1.32 (d, 3 H, 6-H3), 2.70 (br. s, 1 H, 2-
5.09 (dd, 1 H, 4-H) ppm; J1,2 ϭ 0.5, J2,3 ϭ 3.3, J3,4 ϭ 9.5, J4,5
ϭ
2
1
9.6, J5,6 ϭ 6.2, JC,H2 ϭ 12.4, JC,H,CH ϭ 6.2, J1 ϭ 155.4 Hz. 13C OH), 3.73 (dd, 1 H, 2-H), 3.77 (m, 1 H, 5-H), 4.08 [m, 1 H,
3
NMR (75 MHz, CDCl3): δ ϭ 17.5 (C-6), 21.0 (4-AcCH3), 21.5, CH(CH3)2], 4.57 (d, 1 H, 1-H), 5.24 (t, 1 H, 4-H), 5.54 (t, 1 H, 3-
23.4 [CH(CH3)2], 68.7 (C-2), 70.1 (C-5), 71.0 [CH(CH3)2], 71.0 (3-
BnCH2), 72.3 (C-4), 78.5 (C-3), 97.5 (C-1), 169.9 (4-AcCO) ppm. NMR (125 MHz, CDCl3): δ ϭ 14.6 (C-6), 22.3, 23.8 [CH(CH3)2],
MS (FD): m/z
338 [Mϩ], 91 [PhCH2ϩ], 43 [MeCOϩ]. 70.7 (C-5), 72.6 [CH(CH3)2], 73.3 (C-2), 74.2 (C-4), 75.4 (C-3),
C18H26O6(338.40): calcd. C 63.89, H 7.74; found C 63.16, H 7.63.
H) ppm; J1,2 ϭ 7.8, J2,3 ϭ J3,4 ϭ J4,5 ϭ 9.6, J5,6 ϭ 6.2 Hz. 13C
ϭ
101.5 (C-1) ppm.
Isopropyl 4-O-Benzoyl-3-O-benzyl-β- -rhamnopyranoside (33):
L
Di- and Trisaccharides Containing β-L-Rhamnose Units
NaBH4 (0.75 g, 19.8 mmol) was added to a stirred, cooled (0 °C)
solution of uloside 28 (1.00 g, 2.5 mmol) in CH2Cl2/MeOH (1:1,
60 mL), and stirring was continued for 2 h. Dilution with CH2Cl2
(70 mL), successive washings with water (70 mL), aqueous citric
acid solution (1%, 2 ϫ 70 mL), and water (70 mL), and drying
(MgSO4), followed by concentration in vacuo, gave a syrupy prod-
uct that was purified by elution from a silica gel column (toluene/
General Glycosidation Procedure for Ulosyl Bromides with Glycoside
Acceptors: A suspension of acceptor (0.225 mmol), silver alumosil-
˚
icate catalyst (170 mg, 0.5 mmol), and molecular sieves (4 A) in dry
CH2Cl2 (1.5 mL) was stirred for 20Ϫ30 min at room temperature
with exclusion of moisture. The ulosyl bromide (0.45 mmol), dis-
solved in dry CH2Cl2 (1.0 mL), was added dropwise over
30Ϫ45 min and stirring was continued until no donor could be
observed in the reaction mixture by TLC. The mixture was filtered
through Celite and the solvent was removed in vacuo to obtain the
2-ulose. Subsequent treatment with NaBH4 (47 mg, 1.25 mmol) in
CH2Cl2/MeOH (1:1, 20 mL) at 0 °C, followed by stirring for
60 min, and evaporation in vacuo, provided a crude product that
was dissolved in CH2Cl2 (60 mL), washed successively with aque-
ous citric acid solution (1%, 25 mL) and water (2 ϫ 25 mL), and
dried (MgSO4). Concentration of the solution and chromato-
graphic purification by elution from a silica gel column yielded the
β-linked disaccharide.
EtOAc, 6:1) to afford 33 (0.72 g, 71%) as a colorless syrup. [α]D20
ϭ
1
ϩ87.7 (c ϭ 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 1.20
(d, 3 H, CHCH3), 1.28 (d, 6 H, 6-H3, CHCH3), 2.57 (br. s, 1 H, 2-
OH), 3.52 (qd, 1 H, 5-H), 3.63 (dd, 1 H, 3-H), 4.07 [qq, 1
H, CH(CH3)2], 4.13 (br. d, 1 H, 2-H), 4.53 (d, 1 H, CHaC6H5), 4.57
(d, 1 H, 1-H), 4.69 (d, 1 H, CHbC6H5), 5.38 (dd, 1 H, 4-H) ppm;
J1,2 ϭ 0.7, J2,3 ϭ 3.1, J3,4 ϭ J4,5 ϭ 9.5, J5,6 ϭ 6.2, JC,H,CH3 ϭ 6.1,
1
2JC,H ϭ 12.5, J1 ϭ 154.6 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ
17.6 2(C-6), 21.6, 23.4 [CH(CH3)2], 68.8 (C-2), 70.4 (C-5), 70.9
(BnCH2), 71.0 [CH(CH3)2], 73.0 (C-4), 78.1 (C-3), 97.6 (C-1) ppm.
MS (FD, 0Ϫ12 mA): m/z ϭ 400 [Mϩ], 401 [Mϩ ϩ H]. C23H28O6
(400.47): calcd. C 68.98, H 7.05; found C 68.08, H 6.99.
Silver Alumosilicate Catalyst:[17] A slurry of silica-alumina SHPV
catalyst (a porous aluminosilicate with a BET surface 473 m2/g;
AKZO Chemie, Amsterdam, 20 g) in NaOH ( , 250 mL) was
stirred at 100 °C for 1 h. The material was then filtered, washed
with water (5 ϫ 50 mL), and stirred with an aqueous solution of
AgNO3 (0.2 , 400 mL) in the dark for 16 h at ambient tempera-
ture. Filtration and washing of the residue with water (2 ϫ 30 mL)
and acetone (200 mL), followed by drying in vacuo for about 3 d
at 90 °C, gave the active material.
Isopropyl 3-O-Benzyl-4-O-(4-methoxybenzyl)-β-L-rhamnopyranoside
(34): NaBH4 (290 mg, 7.7 mmol) was added to a cooled (0 °C),
stirred solution of uloside 29 (400 mg, 0.97 mmol) in CH2Cl2/
MeOH (1:1, 20 mL), and stirring was continued for 1 h. Dilution
with CH2Cl2 (40 mL), successive washings with water (40 mL),
aqueous citric acid solution (1%, 2 ϫ 40 mL), and water (2 ϫ
40 mL), and drying (MgSO4), followed by evaporation in vacuo,
gave a syrup, that was purified by elution from a silica gel column
(toluene/EtOAc, 5:1) to yield 34 (292 mg, 73%) as a colorless syrup
6-O-(4-O-Benzoyl-3-O-benzyl-β-
L-rhamnopyranosyl)-1,2:3,4-di-O-
1
on evaporation of the eluate. [α]2D0 ϭ ϩ40.4 (c ϭ 1.1, CHCl3). H
isopropylidene-α- -galactopyranose (36): Glycosidation of 1,2:4,5-
D
NMR (300 MHz, CDCl3): δ ϭ 1.15, 1.25 [2 d, each 3 H,
CH(CH3)2], 1.32 (d, 3 H, 6-H3), 2.48 (br. s, 1 H, 2-OH), 3.28 (qd,
1 H, 5-H), 3.51Ϫ3.53 (m, 2 H, 3-H, 4-H), 3.78 (s, 3 H, C7H6OCH3),
3.98Ϫ4.07 [m, 2 H, 2-H, CH(CH3)2], 4.45 (d, 1 H, 1-H), 4.58, 4.67,
4.78, 4.86 (4d, 4 H, 2 CH2) ppm; J1,2 ϭ 0.7, J4,5 ϭ 9.2, J5,6 ϭ 6.1,
di-O-isopropylidene--galactose[23] with ulosyl bromide 4 (30 min)
and subsequent NaBH4 reduction according to the General Pro-
cedure, followed by chromatography (n-hexane/Et2O, 1:2) gave 36
(115 mg, 85%) as a colorless syrup; [α]2D0 ϭ ϩ8.2 (c ϭ 0.8, CHCl3).
1H NMR (300 MHz, CDCl3): β-rhamnosyl-H: δ ϭ 1.28 (d, 3 H, 6Ј-
H3), 2.70 (br. s, 1 H, 2Ј-OH), 3.54 (qd, 1 H, 5Ј-H), 3.60 (dd, 1 H,
3Ј-H), 4.23 (d, 1 H, 2Ј-H), 4.53, 4.69 (2 d, each 1 H, BnCH2), 4.54
(d, 1 H, 1Ј-H), 5.38 (dd, 1 H, 4Ј-H) ppm; J1Ј,2Ј Յ 0.5, J2Ј,3Ј ϭ 2.9,
2
JC,H,CH3 ϭ 6.2, JC,H ϭ 10.5, 12.0, 1J1 ϭ 155.3 Hz. 13C NMR
(75 MHz, CDCl3): δ2 ϭ 17.9 (C-6), 21.6, 23.4 [CH(CH3)2], 55.3
(C7H6OCH3), 69.1 (C-2), 70.7 [CH(CH3)2], 71.3 (CH2), 71.4 (C, 5),
75.1 (CH2), 79.3, 81.6 (C-3, C-4), 97.4 (C-1) ppm. MS (FD,
0Ϫ20 mA): m/z ϭ 416 [Mϩ]. C24H32O6 (416.51): calcd. C 69.21, H
7.74; found C 68.35, H 7.70.
2
1
J3Ј,4Ј ϭ J4Ј,5Ј ϭ 9.5, J5Ј,6Ј ϭ 6.2, JC,H ϭ 12.5, J1Ј ϭ 157.6 Hz. α-
2
galactosyl-H: δ ϭ 1.33, 1.37, 1.46, 1.53 (4s, 12 H, 4 CH3), 3.81 (dd,
1 H, 6-Ha), 3.97 (dd, 1 H, 6-Hb), 4.09 (ddd, 1 H, 5-H), 4.32 (dd, 1
H, 2-H), 4.38 (dd, 1 H, 4-H), 4.63 (dd, 1 H, 3-H), 5.52 (d, 1 H, 1-
H) ppm; J2,3 ϭ 5.0, J2,3 ϭ 2.4, J3,4 ϭ 8.0, J4,5 ϭ 1.8, J5,6a ϭ 8.7,
Isopropyl 3,4-Di-O-benzoyl-β-L-glucopyranoside (35): A solution of
BH3/pyridine (0.5 mL, 4 mmol) in THF (2.5 mL) was added drop-
wise to a cooled (Ϫ78 °C) solution of uloside 25 (400 mg,
0.97 mmol) in THF (10 mL). After stirring for 30 min the mixture
was allowed to warm up to room temp., stirred for another hour,
and quenched with water (2 mL). Removal of the solvents in vacuo
2
J5,6b ϭ 5.7, J6a,b ϭ 9.4, 1J1 ϭ 179.6 Hz. 13C NMR (75 MHz,
CDCl3): β-rhamnosyl-C: δ ϭ 17.5 (C-6Ј), 67.8 (C-2Ј), 70.6 (C-5Ј),
70.9 (BnCH2), 72.7 (C-4Ј), 77.7 (C-3Ј), 100.3 (C-1Ј). α-galactosyl-
C: δ ϭ 24.5, 24.9, 26.0, 26.1 (4 CH3), 65.7 (C-5), 67.6 (C-6), 70.5
afforded a residue, which was dissolved in CH2Cl2 (30 mL) and (C-3), 70.6 (C-2, C-4), 96.2 (C-1), 108.7, 109.2 (2 C(CH3)2] ppm.
vigorously stirred with HCl (2 , 10 mL) for 30 min, followed by MS (FD, 0Ϫ20 mA): m/z ϭ 600 [Mϩ]. C32H40O11 (600.66): calcd.
washing of the organic layer with satd. NaHCO3 solution (30 mL),
3090
C 63.99, H 6.71; found C 63.83, H 6.73.
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2003, 3081Ϫ3093

Efficient Generation of β-L-Rhamnosidic Linkages
FULL PAPER
1,6-Anhydro-2,3-di-O-benzyl-4-O-(4-O-benzoyl-3-O-benzyl-β-
L
-
Methyl 2,3-O-Isopropylidene-4-O-(4-O-benzoyl-3-O-benzyl-β-L-
rhamnopyranosyl)-β-
D
-glucopyranose (37): Treatment of 1,6-anhy-
rhamnopyranosyl)-α-L-rhamnopyranoside (40): Glycosylation of
dro-2,3-di-O-benzyl-β--glucopyranose[24] with ulosyl bromide 4
according to the General Procedure (vide supra, glycosylation time:
2.5 h), followed by purification on a silica gel column (toluene/
EtOAc, 2:1) and crystallization from 2-propanol gave 120 mg (78%)
of 37 as fine, colorless needles. M.p. 177 °C; [α]2D0 ϭ ϩ33.5 (c ϭ
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.25 (d, 3 H, 6Ј-
H3), 2.60 (br. s, 1 H, 2Ј-OH), 3.32Ϫ3.42 (m, 1 H, 5Ј-H), 3.39 (d, 1
methyl 2,3-O-isopropylidene-α--rhamnopyranoside[27] with ulosyl
bromide 4 according to the General Procedure (vide supra, glycos-
ylation time: 15 min), followed by elution from a silica gel column
(n-hexane/EtOAc, 3:2), gave 40 (100 mg, 80%) as a colorless syrup.
1
[α]2D0 ϭ ϩ29.8 (c ϭ 0.9, CHCl3). H NMR (300 MHz, CDCl3): β-
rhamnosyl-H: δ ϭ 1.29 (d, 3 H, 6Ј-H3), 2.60 (br. s, 1 H, 2Ј-OH),
3.52Ϫ3.57 (m, 1 H, 5Ј-H), 3.62 (dd, 1 H, 3Ј-H), 4.20 (d, 1 H, 2Ј-
H, 2-H), 3.47 (dd, 1 H, 3Ј-H), 3.61 (dd, 1 H, 3-H), 3.68 (dd, 1 H, 6- H), 4.54, 4.70 (2 d, each 1 H, BnCH2), 4.69 (d, 1 H, 1Ј-H), 5.38
Ha), 3.74 (d, 1 H, 4-H), 3.90 (d, 1 H, 6-Hb), 4.05 (d, 1 H, 2Ј-H), (dd, 1 H, 4Ј-H) ppm; J1Ј,2Ј Յ 0.5, J2Ј,3Ј ϭ 3.4, J3Ј,4Ј ϭ J4Ј,5Ј ϭ 9.4,
2
1
4.43 (s, 1 H, 1Ј-H), 4.48Ϫ4.72 (m, 7 H, 5-H, 3 BnCH2), 5.35 (dd,
1 H, 4Ј-H), 5.46 (s, 1 H, 1-H) ppm; J2,3 ϭ 3.7, J3,4 ϭ 4.1, J5,6a
J5Ј,6Ј ϭ 6.1, JC,H ϭ 12.4, J1Ј ϭ 156.8 Hz. α-rhamnosyl-H: δ ϭ
2
ϭ
1.31 (d, 3 H, 6-H3), 1.34, 1.53 (2s, 6 H, 2 CH3), 3.36 (s, 3 H, 1-
5.5, J6a,b ϭ 7.2, J2Ј,3Ј ϭ 3.0, J3Ј,4Ј ϭ J4Ј,5Ј ϭ 9.5, J5Ј,6Ј ϭ 6.2, J1 ϭ OCH3), 3.49 (dd, 1 H, 4-H), 3.74 (qd, 1 H, 5-H), 4.12 (d, 1 H, 2-
1
1
172.4, J1Ј ϭ 157.8 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 17.6 (C-
H), 4.34 (dd, 1 H, 3-H), 4.84 (d, 1 H, 1-H) ppm; J2,3 ϭ 6.0, J3,4 ϭ
6Ј), 66.8 (C-6), 68.0 (C-2Ј), 70.6 (C-5Ј), 70.9, 72.0 (2 BnCH2), 72.6 7.2, J4,5 ϭ 9.8, J5,6 ϭ 6.1, 1J1 ϭ 166.1 Hz. 13C NMR (75 MHz,
(C-4Ј), 73.1 (BnCH2), 76.6 (C-5), 77.3 (C-3), 77.6 (C-3Ј), 78.1 (C- CDCl3): β-rhamnosyl-C: δ ϭ 17.7 (C-6Ј), 68.0 (C-2Ј), 70.8 (C-5Ј),
4), 79.1 (C-2), 99.0 (C-1Ј), 100.8 (C-1) ppm. MS (FD): m/z ϭ 682
[Mϩ]. C40H42O10 (682.77): calcd. C 70.37, H 6.20; found C 69.97,
H 6.18.
70.9 (BnCH2), 72.8 (C-4Ј), 78.1 (C-3Ј), 97.7 (C-1Ј). α-rhamnosyl-C:
δ ϭ 17.5 (C-6), 26.1, 28.0 (2 CH3), 54.8 (1-OCH3), 64.3 (C-5), 75.9
(C-2), 76.6 (C-3), 81.7 (C-4), 98.2 (C-1), 109.1 [C(CH3)2] ppm. MS
(FD, 0Ϫ12 mA): m/z ϭ 558 [Mϩ]. C30H38O10 (558.63): calcd.
C 64.50, H 6.86; found C 64.04, H 6.83.
Methyl 3,4-Di-O-benzyl-2-O-(4-O-benzoyl-3-O-benzyl-β-
L-
rhamnopyranosyl)-α- -rhamnopyranoside (38): Ulosyl bromide 4,
L
Methyl 2,3-O-Isopropylidene-4-O-(2-O-acetyl-4-O-benzoyl-3-O-
dissolved in CH2Cl2, was injected into a suspension of methyl 3,4-
di-O-benzyl-α--rhamnopyranoside[25] and silver alumosilicate
catalyst as described in the General Procedure (vide supra, glycos-
ylation time: 80 min), followed by elution from a silica gel column
(toluene/EtOAc, 2:1) to give 38 (125 mg, 79%) as a colorless syrup.
[α]2D0 ϭ ϩ50.1 (c ϭ 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ
1.29 (d, 3 H, 6Ј-H3), 1.32 (d, 3 H, 6-H3), 2.60 (br. s, 1 H, 2Ј-OH),
3.34 (s, 3 H, 1-OCH3), 3.46Ϫ3.59 (m, 2 H, 4-H, 5Ј-H), 3.58 (dd, 1
H, 3Ј-H), 3.68 (qd, 1 H, 5-H), 3.87 (dd, 1 H, 3-H), 4.26 (d, 1 H,
2Ј-H), 4.39 (dd, 1 H, 2-H), 4.53, 4.54, 4.58, 4.72, 4.83, 4.89 (6 d,
each 1 H, 3 BnCH2), 4.66 (s, 1 H, 1Ј-H), 4.70 (s, 1 H, 1-H), 5.46
benzyl-β-L-rhamnopyranosyl)-α-L-rhamnopyranoside (41): Ac2O
(2 mL, 2.16 g, 21.2 mmol) was added dropwise to a cooled solution
(0 °C) of rhamnobioside 40 (930 mg, 1.7 mmol) in pyridine
(15 mL). The reaction mixture was stirred at room temperature for
12 h, cooled (0 °C), and treated with dry EtOH (0.64 mL). Stirring
was continued for 0.5 h, during which the mixture was allowed to
warm to room temperature. Concentration in vacuo and purifi-
cation by elution from a silica gel column (n-hexane/EtOAc, 4:1)
gave 41 (920 mg, 92%) as a colorless foam. [α]2D0 ϭ ϩ54.5 (c ϭ 1.1,
CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.27 (d, 3 H, 6-H3),
1.32 (d, 3 H, 6Ј-H3), 1.34, 1.55 (2 s, 6 H, 2 CH3), 2.22 (s, 3 H,
AcCH3), 3.35 (s, 3 H, 1-OCH3), 3.41 (dd, 1 H, 4-H), 3.59 (qd, 1
H, 5Ј-H), 3.64Ϫ3.75 (m, 1 H, 5-H), 3.67 (dd, 1 H, 3Ј-H), 4.11 (d,
1 H, 2-H), 4.32 (dd, 1 H, 3-H), 4.42, 4.66 (2 d, 2 H, BnCH2), 4.84
(s, 2 H, 1-H, 1Ј-H), 5.30 (dd, 1 H, 4Ј-H), 5.72 (d, 1 H, 2Ј-H) ppm;
(dd, 1 H, 4Ј-H) ppm; J1,2 ϭ 2.0, J2,3 ϭ 3.3, J3,4 ϭ 8.9, J4,5 ϭ 9.4,
2
J5,6 ϭ 6.2, J2Ј,3Ј ϭ 2.9, J3Ј,4Ј ϭ J4Ј,5Ј ϭ 9.4, J5Ј,6Ј ϭ 6.2, JC,H
ϭ
10.9, 11.4, 12.7, 1J1 ϭ 166.6, 1J1Ј ϭ 158.1 Hz. 13C NMR (75 M2Hz,
CDCl3): δ ϭ 17.7 (C-6Ј), 18.1 (C-6), 54.8 (1-OCH3), 67.7 (C-5),
68.2 (C-2Ј), 70.4 (BnCH2), 70.9 (C-5Ј), 71.1 (BnCH2), 71.6 (C-2),
72.8 (C-4Ј), 75.2 (BnCH2), 77.5 (C-3Ј), 78.2 (C-3), 79.8 (C-4), 97.4
(C-1Ј), 98.4 (C-1) ppm. MS (FD): m/z ϭ 698 [Mϩ]. C41H46O10
(698.81): calcd. C 70.47, H 6.64; found C 70.32, H 6.75.
J2,3 ϭ 5.8, J3,4 ϭ 7.2, J4,5 ϭ 9.8, J5,6 ϭ 6.2, J2Ј,3Ј ϭ 3.0, J3Ј,4Ј
ϭ
2
J4Ј,5Ј ϭ 9.7, J5Ј,6Ј ϭ 6.2, JC,H ϭ 12.7 Hz. 13C NMR (75 MHz,
2
CDCl3): δ ϭ 17.6 (C-6, C-6Ј), 21.2 (AcCH3), 26.2, 28.1 (2 CH3),
54.8 (1-OCH3), 64.0 (C-5), 67.0 (C-2Ј), 70.6 (BnCH2), 71.0 (C-5Ј),
72.8 (C-4Ј), 75.9 (C-2), 76.2 (C-3Ј), 76.8 (C-3), 82.0 (C-4), 98.1,
98.4 (C-1, C-1Ј), 109.2 [C(CH3)2] ppm. MS (FD): m/z ϭ 601 [Mϩ
ϩ H]. C32H40O11 (600.66): calcd. C 63.99, H 6.71; found C 63.89,
H 6.64.
Methyl 2,4-Di-O-benzyl-3-O-(4-O-benzoyl-3-O-benzyl-β-L-
rhamnopyranosyl)-α-L-rhamnopyranoside (39): Treatment of methyl
2,4-di-O-benzyl-α--rhamnopyranoside[25] with ulosyl bromide 4
according to the General Procedure (vide supra, glycosylation time:
100 min), followed by chromatography on silica gel (n-hexane/
Methyl 2,3-O-Isopropylidene-4-O-(2-O-acetyl-4-O-benzoyl-β-
L-
EtOAc, 2:1) gave 39 (120 mg, 77%) as a colorless syrup. [α]D20
ϩ19.5 (c ϭ 0.9, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 1.21 tion of 41 (738 mg, 1.2 mmol) in EtOAc (140 mL) was hydrogen-
ϭ
rhamnopyranosyl)-α- -rhamnopyranoside (42): A cooled (0 °C) solu-
L
1
(d, 3 H, 6Ј-H3), 1.36 (d, 3 H, 6-H3), 2.45 (br. s, 1 H, 2Ј OH), 3.33
ated over Pd(OH)2/C (20%, 350 mg) for 17 h, during which the mix-
(s, 3 H, 1-OCH3), 3.26Ϫ3.40 (m, 1 H, 5Ј-H), 3.45 (dd, 1 H, 3Ј-H), ture was warmed to room temperature. Filtration through Celite
3.55Ϫ3.73 (m, 3 H, 4-H, 5-H, 2-H), 3.98 (d, 1 H, 2Ј-H), 4.23 (dd, and concentration provided a residue, which was eluted from a sil-
1 H, 3-H), 4.33 (s, 1 H, 1Ј-H), 4.50, 4.59, 4.61, 4.67, 4.77, 5.01 (6 ica gel column (n-hexane/EtOAc, 1:1) to yield 42 (620 mg, 99%) as
20
d, each 1 H, 3 BnCH2), 4.73 (d, 1 H, 1-H), 5.35 (dd, 1 H, 4Ј-H) a colorless syrup. [α]2D0 ϭ ϩ3.0 (c ϭ 0.9, CHCl3). [α]
ϭ ϩ17.8
365
1
ppm; J1,2 ϭ 1.7, J2,3 ϭ 3.2, J3,4 ϭ 8.7, J5,6 ϭ 6.0, J2Ј,3Ј ϭ 3.0, (c ϭ 0.9, CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 1.26 (d, 3 H,
2
J3Ј,4Ј ϭ J4Ј,5Ј ϭ 9.6, J5Ј,6Ј ϭ 6.1, JC,H ϭ 10.6, 12.5, 12.6, 1J1
ϭ
6-H3), 1.35 (d, 3 H, 6Ј-H3), 1.34, 1.55 (2 s, 6 H, 2 CH3), 2.20 (s, 3
H, AcCH3), 2.75 (br. s, 1 H, 3Ј-OH), 3.35 (s, 3 H, 1-OCH3), 3.42
2
1
167.1, J1Ј ϭ 156.3 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 17.6 (C-
6Ј), 18.1 (C-6), 54.7 (1-OCH3), 67.7 (C-5), 68.4 (C-2Ј), 70.6 (C-5Ј), (dd, 1 H, 4-H), 3.67 (m, 2 H, 5-H, 5Ј-H), 3.95 (dd, 1 H, 3Ј-H), 4.11
70.8, 72.5 (2 BnCH2), 72.9 (C-4Ј), 74.6 (C-2), 74.9 (BnCH2), 76.9 (d, 1 H, 2-H), 4.30 (dd, 1 H, 3-H), 4.84 (s, 1 H, 1-H), 4.87 (d, 1 H,
(C-3), 77.9 (C-3Ј), 79.6 (C-4), 97.3 (C-1Ј), 98.6 (C-1) ppm. MS
(FD): m/z ϭ 698 [Mϩ]. C41H46O10 (698.81): calcd. C 70.47, H 6.64;
found C 70.46, H 6.70.
1Ј-H), 5.10 (dd, 1 H, 4Ј-H), 5.52 (d, 1 H, 2Ј-H) ppm; J2,3 ϭ 5.8,
J3,4 ϭ 7.2, J4,5 ϭ 9.8, J5,6 ϭ 6.2, J1Ј,2Ј ϭ 0.8, J2Ј,3Ј ϭ 3.0, J3Ј,4Ј
J4Ј,5Ј ϭ 9.6 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 17.5 (C-6, C-6Ј),
ϭ
Eur. J. Org. Chem. 2003, 3081Ϫ3093
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3091

F. W. Lichtenthaler, T. Metz
FULL PAPER
21.0 (AcCH3), 26.2, 28.0 (2 CH3), 54.8 (1-OCH3), 64.1 (C-5), 70.6 (1-OCH3), 67.6 (C-5), 69.8, 69.9, 70.1, 70.9 (C-2, C-3, C-3ЈЈ, C-5ЈЈ),
(C-5Ј), 71.0 (C-2Ј), 71.5 (C-3Ј), 75.1 (C-4Ј), 75.9 (C-2), 76.7 (C-3), 70.9 (C-2ЈЈ), 71.3 (C-2Ј), 71.9, 72.7, 72.8 (C-4Ј, C-4ЈЈ, C-5Ј), 81.2
82.3 (C-4), 98.0 (C-1), 98.6 (C-1Ј), 109.1 [C(CH3)2] ppm. MS (FD): (C-3Ј), 83.3 (C-4), 101.0 (C-1Ј), 101.4 (C-1), 103.2 (C-1ЈЈ) ppm. MS
m/z ϭ 495 [Mϩ Ϫ Me]. C25H34O11 (510.54): calcd. C 58.82, H 6.71;
(FD): m/z ϭ 471 [Mϩ ϩ H], 147 [Rhaϩ-OH].
found C 58.18, H 6.83.
Methyl 2,3-O-Isopropylidene-4-O-[2-O-acetyl-4-O-benzoyl-3-O-
(2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl)-β-L-rhamnopyranosyl]-α-
Acknowledgments
Support of these investigations by the Fonds der Chemischen
Industrie, Frankfurt and Südzucker AG, Mannheim/Ochsenfurt is
gratefully acknowledged.
L
-rhamnopyranoside (43): A solution of rhamnobioside 42 (150 mg,
0.3 mmol), acetobromo-rhamnose 7[13] (170 mg, 0.5 mmol), and
2,6-di-tert-butyl-4-methylpyridine (72 mg, 0.35 mmol) in dry
CH2Cl2 (3 mL) was stirred at room temperature for 10 min over
˚
molecular sieves (4 A) with exclusion of moisture. The solution was
cooled to Ϫ45 °C, treated with AgOTf (75 mg, 0.3 mmol), and
stirred for 100 min, during which the mixture was warmed to Ϫ5
°C. The mixture was filtered through Celite, diluted with CH2Cl2
(60 mL), and washed with saturated aqueous NaHCO3 solution (2
ϫ 25 mL) and water (2 ϫ 25 mL). Drying (MgSO4) and concen-
tration in vacuo provided a residue, which was purified by elution
from a silica gel column with CHCl3/n-hexane (15:1) to afford 43
(190 mg, 82%) as a colorless syrup. [α]2D0 ϩ ϭ 7.3 (c ϭ 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ ϭ 1.21 (d, 3 H, 6ЈЈ-H3), 1.26 (d, 3
H, 6-H3), 1.34 (d, 3 H, 6Ј-H3), 1.35, 1.56 (2 s, 6 H, 2 CH3), 1.82,
1.88, 2.03, 2.26 (4 s, 12 H, 4 AcCH3), 3.35 (s, 3 H, 1-OCH3), 3.42
(dd, 1 H, 4-H), 3.60Ϫ3.71 (m, 2 H, 5-H, 5Ј-H), 3.98 (qd, 1 H, 5ЈЈ-
H), 4.05 (dd, 1 H, 3Ј-H), 4.12 (d, 1 H, 2-H), 4.33 (dd, 1 H, 3-H),
4.84 (s, 2 H, 1-H, 1ЈЈ-H), 4.93 (d, 1 H, 2ЈЈ-H), 4.93 (s, 1 H, 1Ј-H),
4.95 (dd, 1 H, 4ЈЈ-H), 5.09 (dd, 1 H, 3ЈЈ-H), 5.36 (dd, 1 H, 4Ј-H),
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66, 8411Ϫ8423.
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5.56 (d, 1 H, 2Ј-H) ppm; J2,3 ϭ 5.7, J3,4 ϭ 7.2, J4,5 ϭ 9.8, J5,6
ϭ
[6]
[7]
[8]
F. W. Lichtenthaler, U. Kläres, M. Lergenmüller, S. Schwid-
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59, 6728Ϫ6734.
6.4, J2Ј,3Ј ϭ 3.0, J3Ј,4Ј ϭ J4Ј,5Ј ϭ 9.7, J5Ј,6Ј ϭ 6.2, J2ЈЈ,3ЈЈ ϭ 3.4,
1
1
J3ЈЈ,4ЈЈ ϭ 10.0, J4ЈЈ,5ЈЈ ϭ 9.8, J5ЈЈ,6ЈЈ ϭ 6.2, J1 ϭ 163.9, J1Ј ϭ 153.1,
1J1ЈЈ ϭ 171.8 Hz. 13C NMR (75 MHz, CDCl3): δ ϭ 17.4, 17.5 (C-
6, C-6Ј, C-6ЈЈ), 20.4, 20.5, 20.8, 21.0 (4 AcCH3), 26.2, 28.1
[C(CH3)2], 54.8 (1-OCH3), 63.9 (C-5), 67.3 (C-5ЈЈ), 68.3 (C-3ЈЈ),
69.5 (C-2ЈЈ), 69.8 (C-2Ј), 70.7 (C-5Ј) 70.8 (C-4ЈЈ), 73.6 (C-4Ј), 75.8,
75.9 (C-2, C-3Ј), 76.7 (C-3), 82.0 (C-4), 98.0 (C-1), 98.1 (C-1Ј), 99.0
(C-1ЈЈ), 109.1 [C(CH3)2] ppm. MS (FD): m/z ϭ 782 [Mϩ], 750 [Mϩ
Ϫ MeOH]. C37H50O18 (782.79): calcd. C 56.77, H 6.44; found
C 56.74, H 6.40.
F. W. Lichtenthaler, M. Lergenmüller, S. Peters, Z. Varga,
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Methyl 4-O-[3-O-(α-
L-Rhamnopyranosyl)-β-L-rhamnopyranosyl]-α-
L-rhamnopyranoside (45): Trisaccharide 43 (110 mg, 0.14 mmol)
was stirred in a solution of 2% trifluoroacetic acid in 96% AcOH
(2 mL) at 35 °C for 3.5 h. Removal of the solvent in vacuo and
coevaporation with toluene (3 ϫ 5 mL) delivered a colorless foam,
which was purified by elution from a silica gel column with n-hex-
ane/EtOAc (3:1). The intermediate product (44, 84 mg) was directly
subjected to saponification with NaOMe (cat. amount) in dry
MeOH (4 mL). The mixture was stirred for 3 days at room tem-
perature and neutralized by addition of ion-exchange resin (Am-
berlite IRC-86, Hϩ-form). Filtration and concentration in vacuo
provided a residue, which was purified by elution from a silica gel
column with CHCl3/MeOH (3:1) to afford 45 (51 mg, 75%) as an
amorphous powder. [α]2D0 ϭ Ϫ56.2 (c ϭ 1.4, MeOH). 1H NMR
(300 MHz, D2O): δ ϭ 1.30 (d, 3 H, 6ЈЈ-H3), 1.31Ϫ1.35 (m, 6 H, 6-
H3, 6Ј-H3), 3.40 (s, 3 H, 1-OCH3), 3.47 (dd, 2 H, 4Ј-H, 4ЈЈ-H), 3.49
(qd, 1 H, 5Ј-H), 3.58 (dd, 1 H, 4-H), 3.67 (dd, 1 H, 3Ј-H), 3.77 (qd,
1 H, 5-H), 3.82 (dd, 1 H, 3-H), 3.86 (dd, 1 H, 3ЈЈ-H), 3.80Ϫ3.90
(m, 1 H, 5ЈЈ-H), 4.00 (dd, 1 H, 2-H), 4.08 (dd, 1 H, 2ЈЈ-H), 4.12 (d,
1 H, 2Ј-H), 4.71 (d, 1 H, 1-H), 4.76 (s, 1 H, 1Ј-H), 5.04 (s, 1 H, 1ЈЈ-
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3.0, J3Ј,4Ј ϭ J4Ј,5Ј ϭ 9.8, J1ЈЈ,2ЈЈ ϭ 1.4, J2ЈЈ,3ЈЈ ϭ 3.4, J3ЈЈ,4ЈЈ ϭ J4ЈЈ,5ЈЈ
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3092
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