Manno- versus gluco-Selectivity in reductions of 2-keto-β-D-arabino-hexopyranosides

Article abstract of DOI:10.1016/S0957-4166(03)00028-4

Tri-sec-butylborohydrides (L- or K-Selectride) reduce the carbonyl group in acylated 2-keto-β-D-arabino-hexopyranosides to β-D-mannosides in an essentially stereospecific fashion, whereas borane reduction gives the 2-epimeric β-D-glucosides with high preference. As preparative yields are in the 70-85% range, the ulosyl donor approach can thus be utilized for the straightforward construction of oligosaccharides containing either β-D-Man or β-D-Glc units.

Full text of DOI:10.1016/S0957-4166(03)00028-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 727–736
manno- versus gluco-Selectivity in reductions of
2-keto-b- -arabino-hexopyranosides
D
Frieder W. Lichtenthaler,* Matthias Lergenmu¨ller, Siegfried Peters and Zsolt Varga
Institut fu¨r Organische Chemie, Technische Universita¨t Darmstadt, Petersenstraße 22, D-64287 Darmstadt, Germany
Received 4 December 2002; accepted 3 January 2003
Abstract—Tri-sec-butylborohydrides (L- or K-Selectride) reduce the carbonyl group in acylated 2-keto-b-
osides to b- -mannosides in an essentially stereospecific fashion, whereas borane reduction gives the 2-epimeric b-
with high preference. As preparative yields are in the 70–85% range, the ulosyl donor approach can thus be utilized for the
D
-arabino-hexopyran-
D
D
-glucosides
straightforward construction of oligosaccharides containing either b-
D
-Man or b-D-Glc units. © 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
advantage of providing the b-D-mannosides with a free
2-OH group, i.e. mannosyl acceptors ready for further
glycosidation towards the various oligosaccharides with
The 2-ulosyl donor approach for the expedient synthe-
sis of b-
fully been employed for the construction of various
b- -mannose-containing oligosaccharides up to the
hexasaccharide level.1–5 Central to this procedure are
the ready preparation of variously blocked a- -ara-
bino-2-ketohexosyl bromides II from
-glucose,1,4–7
D
-mannosides, introduced in 1985,1 has success-
b-D
-Man-(1“2)-D-Man linkages.
D
As the glycos-ulosyl bromides are accessible from D-glu-
cose in four simple, high yielding steps—the first three
to the hydroxyglucal ester I can be combined into one
successive operation and its conversion to the ulosyl
bromide II is straightforward4–7—not only is their
access amenable to large-scale preparation, but to stereo-
chemically uniform glycosidation as well. Only the
reduction with sodium borohydride III“IV is some-
what capricious, as preparatively useful 20:1 to 50:1
manno/gluco-selectivities are only obtained in cases
with benzyl protection or at least an O-benzyl group
D
D
their essentially b-specific glycosidation (“III) — the
electron-withdrawing 2-keto group suppresses oxocar-
benium ion formation at the anomeric center
implementing direct SN2 displacement of the
bromine — and manno-selective reduction of the
-2-keto-glycosides (II“III). Aside of its
preparative simplicity, the procedure has the additional
resulting b-
D
* Corresponding author. Fax +49-6151-166674; e-mail: fwlicht@sugar.oc.chemie.tu-darmstadt.de
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00028-4

728
F. W. Lichtenthaler et al. / Tetrahedron: Asymmetry 14 (2003) 727–736
next to the carbonyl function. b-
D
-Ulosides carrying an
pivaloyl protecting groups, and each accessible from
the respective ulosyl bromide in high yield (85–90%),
were employed as model compounds. The results
obtained with a series of different borohydride reagents
are shown in Table 1.
acyl group at O-3 give manno-preferences in the range
of 2:1 to 5:1 only, apparently due to complexation of
the borohydride with the ester and pyranoid carbonyl
groups, thereby making hydride delivery less uniform.
Since ulosyl bromides with acyl blocking groups such as
As observed previously,7 a standard NaBH4 reduction
acetyl, benzoyl or pivaloyl, and, hence, the b-D-ulosides
derived therefrom, are more readily accessible than
their benzylated analogs, a study of various hydride
reducing agents towards a substantial improvement of
the manno-selectivities appeared opportune, as well as
of isopropyl b-
D
-arabino-hexosidulose 1 carrying only
O-benzyl blocking groups provides the respective b-
D
-
mannoside 4 in a stereochemically uniform course and
excellent yield, a result which is not further improved
by using lithium tri-sec-butylborohydride in THF at
−78°C (entries 1–4 in Table 1). With ulosides 2 and 3,
however, carrying O-benzoyl and O-pivaloyl protection
instead, the steric outcome of the respective NaBH4
reductions and those with LiB(iBu)3H or its K-analog
are distinctly different: 2:1 to 3:1 selectivities in favor of
the mannosides with NaBH4 (entries 5/6 and 12/13),
versus high, essentially full, manno-stereoselectivities
with the sterically bulky, sec-butyl-substituted borohy-
drides (entries 10/11 and 16/17).
an evaluation of conceivable possibilities to turn b-D-
arabino-hexosuloside reductions gluco-selective. In this
paper we report on both of these objectives, near
manno-specificity being attained by the use of sterically
demanding borohydrides such as L- or K-Selectride,
whilst reduction with borane, notably, reverses the
selectivity towards the gluco-epimers.
2. Results and discussion
2.1. manno-Selective hydride reductions of b- -arabino-
D
A number of other hydride reagents have also been
evaluated, with clearly less favourable results. Neither
Zn(BH4)2, useful for the reduction of a variety of
functionalised ketones,8 nor its tetrabutylammonium
analog showed any substantial improvement in the
2-oxoglycosides
To evaluate comparatively the manno-selectivities
-arabino-2-ketohexosides, the iso-
attainable with b-
D
propyl hexosiduloses 1–3, featuring benzyl, benzoyl and
Table 1. Stereoselectivities of hydride reductions of isopropyl b-
D
-arabino-hexosid-2-uloses
Entry
Uloside
Reagentb
Solvent
Temp. (°C)
Time (min)
Ratioa
manno/gluco
b-D-Mannoside
(isol. yield,%)
1
2
3
4
5
6
7
8
1 (R=Bn)
1 (R=Bn)
1 (R=Bn)
1 (R=Bn)
2 (R=Bz)
2 (R=Bz)
2 (R=Bz)
2 (R=Bz)
2 (R=Bz)
2 (R=Bz)
2 (R=Bz)
3 (R=Piv)
3 (R=Piv)
3 (R=Piv)
3 (R=Piv)
3 (R=Piv)
3 (R=Piv)
NaBH4
NaBH4
LiB(iBu)3H
KB(iBu)3H
NaBH4
MeOH/CH2Cl2 (1:1)7
MeOH/CH2Cl2 (1:1)
THF
rt
rt
−78
−78
rt
rt
0
rt
0
−78
−78
rt
rt
rt
120
20
1
50:1
50:1
50:1
50:1
3:1
5:2
1:1
2:1
10:1
50:1
50:1
3:1
5:1
6:1
10:1
50:1
50:1
91 (4)
90 (4)
86 (4)
THF
1
89 (4)
d
MeOH/CH2Cl2 (1:1)
20
22 h
45
1
1
1
7
d
d
d
d
NaBH4
CH2Cl2
Zn(BH4)2
Bu4NBH4
Bu4NBH4
LiB(iBu)3H
KB(iBu)3H
NaBH4
DME
THF
9
THF/Ac2O/DMSOc
THF
10
11
12
13
14
15
16
17
85 (5)
THF
1
79 (5)
Dioxane/water (9:1)7
MeOH/CH2Cl2 (1:1)
THF
30
20
1
1
1
d
d
d
d
NaBH4
Bu4NBH4
Bu4NBH4
LiB(iBu)3H
KB(iBu)3H
THF/Ac2O/DMSOc
THF
0
−78
−78
87 (6)
89 (6)
THF
1
a A 50:1 ratio signifies that no gluco isomer was detectable by 1H NMR or TLC. All other ratios were determined by 1H NMR.
b LiB(iBu)3H and KB(iBu)3H refers to lithium and potassium triisobutyl borohydride (i.e. L- and K-Selectride), respectively.
c Conditions recommended in Ref. 9: stirring a 2:1 DMSO/Ac2O mixture for 16 h, then coevaporation with toluene, followed by addition to a
THF solution of the uloside and addition of Bu4NBH4.
d Mixture of manno and gluco isomers not separated.

F. W. Lichtenthaler et al. / Tetrahedron: Asymmetry 14 (2003) 727–736
729
manno-selectivities (Table 1, entries 7, 8 and 14). Con-
ditions propagated recently for reaching high manno-
selectivities in a number of disaccharide-ulosides,9 i.e.
exposure of the uloside to DMSO/acetic anhydride
(‘activated’ DMSO), followed by reduction with tetra-
butylammonium borohydride in THF (entries 9 and
15), indeed showed some improvement (ꢀ10:1 in
donors as well as their S-aglycones can subsequently be
activated under appropriate conditions.10
favour of the b-D-mannosides), yet not comparable to
the results obtained with the sterically bulky selectrides,
which have the additional advantage of combining low
reaction temperature (−78°C) with exceedingly short
reaction times (1 min).
The essentially manno-specific course in the selectride
reductions of acylated isopropyl ulosides 2 and 3
prompted experiments towards the general applicability
in systems with larger anomeric residues. As clearly
borne out by examples 8–12, featuring octyl 8,
cholestanyl 9, and a number of unwieldy glycoside
residues 10–12, the 2:1 to 3:1 manno-selectivities of their
NaBH4 reductions are transformed into essentially
stereospecific formation of the desired b-D-mannosides
13–17 when employing K- or L-Selectride in THF
(Table 2).
Table 2. Stereoselectivities (1H NMR) obtained on reduc-
tion of ulosides 8–12 with NaBH4 and K- or L-Selectride
Thus, at last, the most readily accessible acylated 2-
oxoglycosides of b-
either via the ulosyl bromide approach or via oxidation
of 2-OH-free b-
-glucosides11—can be turned to
preparative use for the expedient generation of
oligosaccharides with b- -mannose units.
D-arabino-configuration—generated
Educt
Ratio manno/gluco
b-D-Mannosides
(isol. yield,%)
D
D
NaBH4
Selectride
8
9
3:1
5:2
3:1
3:2
3:2
50:1
50:1
50:1
50:1
50:1
13a
2.2. gluco-Selective borane reductions of 2-oxo-b-
arabino-hexopyranosides
D-
14 (82)
15 (79)
16 (80)
17 (76)
7 (via 10)
7 (via 11)
7 (via 12)
In the course of these studies, the reduction of the
2-keto group in b- -arabino-hexosiduloses with dibo-
D
a Not isolated.
rane or various borane complexes was also evaluated,
in as much as this type of reductants has been used for
the straightforward conversion of 2-ketoximes into 2-
aminosugars,1,12,13 yet not for simple carbonyl reduc-
tions in sugars. To our surprise, when employing a five
molar excess of the borane–pyridine complex for reduc-
The same steric outcome is observed for anomerically
thiated glycosiduloses of type 18–20, providing the
respective 1-thio-b- -mannosides 21–23 in excellent
D
yield. These are not only useful mannosyl acceptors but

730
F. W. Lichtenthaler et al. / Tetrahedron: Asymmetry 14 (2003) 727–736
tion of b-
D
-arabino-uloside in THF solution at ambient
units.1,13 Thus, the initial coordination of the borane
with the benzoyloximino derivatives of b- -arabino-
temperature, a reversal in the carbonyl reduction selec-
tivities as compared to those with ionic borohydrides is
D
hexulosides obviously occurs from the a-face, conceiv-
ably by complexation with the oxygen of the N-OBz
group as outlined in 30, which not only preforms the
benzoylborane (BzOBH2) as a good leaving group, but
provides the predisposition for delivering the hydride
from the bottom face. This sort of complexation may
be facilitated by the fact, that the pyranoid ring in the
oximino derivatives is substantially distorted, the
unusually small J3,4 coupling constants of 3.5–4.5
Hz1,13 indicating a twist type conformation as depicted
in 30. By contrast, the 2-oxo-hexosides 29 invariably
show J3,4 values around 8–9 Hz, hence adopt the usual
4C1 chair geometry.
observed: b-D-Glucosides are obtained with preferences
that make the procedure preparatively useful. This
steric course is exemplified by the borane reductions of
ulosides 2, 8–10 and 12 which give gluco/manno ratios
from 7:1 to better than 20:1 and allow the isolation of
the major product in yields of 70–80%.
As these b-D-glucosides are obtained with free 2-OH
groups, they are ideal glucosyl acceptors for the genera-
tion of oligosaccharides carrying 2-O-linked glucosyl
residues.
In trying to rationalize this sterically reverse borane
reduction course of 2-keto-b-D-arabino-hexopyran-
3. Experimental
osides, a preferential complexation of the neutral
borane with the upper side (b-face) of the molecule
appears most likely, such that not only the carbonyl
oxygen is involved but due to the Lewis acid nature of
borane the pyranoid ring oxygen and the anomeric
oxygen as well. This pre-orientation of the reducing
agent to the uloside, as depicted in formula 29, obvi-
ously results in the preferential delivery of the hydride
to the carbonyl carbon from the b-face to yield the
3.1. General remarks
Reactions were carried out under Ar. All solvents were
of reagent grade and were further dried. All other
reagents were used as received. Melting points are
uncorrected and were measured on a Bu¨chi SMP-20.
Optical rotations were measured on a Perkin–Elmer
241 polarimeter at 20°C using a cell of 1 dm path
length. Mass spectra were recorded on Varian MAT
311 and MAT 212 spectrometers. Microanalyses were
determined on a Perkin–Elmer 240 elemental analyzer.
Analytical thin layer chromatography (TLC) was per-
formed on precoated Merck plastic sheets (0.2 mm
silica gel 60 F254) with detection by UV (254 nm) and/or
spraying with H2SO4 (50%) and heating. Column chro-
matography was carried out on Fluka silica gel 60
b-D-glucosides.
1
(70–230 mesh); eluents are given in brackets. H and
13C NMR spectra were recorded on Bruker WM-300,
AC-300 and AVANCE 500 spectrometers. The struc-
tures of all new compounds were confirmed by COSY,
TOCSY, selective TOCSY, and/or decoupling experi-
ments. Chemical shifts are reported relative to sodium
2,2,3,3-tetradeutero-3-trimethylsilyl propionate (D2O)
or Me4Si (all other solvents) as internal reference. Cou-
pling constants are listed separately if an assignment
It has to be noted though that the borane–tetra-
hydrofuran reduction of the O-benzoyloximino deriva-
tives of b-
D-arabino-ulosides, i.e. compounds of type
30, reliably proceed with high manno-selectivity,1,13 to
provide (after subsequent N-acetylation) N-acetyl-b-D-
mannosaminides in excellent yields—a procedure that
1
was possible. In the listings of H and 13C NMR data
has successfully been used for the straightforward gen-
eration of oligosaccharides with b-D-ManNAc
for the individual compounds, signals originating from
blocking groups are omitted if well separated from the

F. W. Lichtenthaler et al. / Tetrahedron: Asymmetry 14 (2003) 727–736
731
hexopyranoside hydrogen and carbon signals, e.g. those
originating from benzyl and/or benzoyl moieties.
min, followed by the addition of ulosyl bromide 76
(5.53 g, 10.0 mmol). After stirring for 6 h (TLC moni-
toring), the mixture was diluted with CH2Cl2 (100 mL),
filtered through Celite, and the filtrate was concentrated
to dryness to afford 8.36 g (97%) of 9 as a colorless
3.2. Preparation of 2-keto-b-
D
-arabino-hexopyranosides
-arabino-hexopy-
1
3.2.1. Isopropyl 3,4,6-tri-O-pivaloyl-b-
D
solid; [h]2D0=−23.2 (c 1.0, CHCl3). H NMR (300 MHz,
ranosid-2-ulose, 3. To a solution of i-PrOH (185 mL, 2.4
CDCl3): l 0.50–2.00 (m, 46H, Hcholestanyl), 3.73 (m, 1H,
3-Hcholestanyl), 4.50 (ddd, 1H, 5-H), 4.59 (dd, 1H, 6-Ha),
4.68 (dd, 1H, 6-Hb), 5.24 (s, 1H, 1-H), 5.89 (dd, 1H,
4-H), 5.95 (d, 1H, 3-H); J3,4=10.1, J4,5=8.4, J5,6a=6.0,
mmol) in CH2Cl2 (15 mL) was added Ag2CO3 (330 mg,
,
1.2 mmol) and molecular sieve (3 A, 500 mg) and the
mixture was stirred for 30 min at rt. 3,4,6-Tri-O-pival-
oyl-b-
D
-arabino-hexopyranos-2-ulosyl bromide6 (600
J5,6b=3.5, J6a,b=11.8 Hz. The presence of the monohy-
mg, 1.2 mmol) was then added and stirring was contin-
ued for 1 h. After filtration through Celite the solvent
was evaporated in vacuo and the residue was crystal-
lized by trituration with Et2O: 540 mg (95%) of uloside
3 as a microcrystalline solid; mp 121–128°C; [h]2D0=
−22.2 (c 1, CHCl3); Rf=0.3 (CCl4/EtOAc, 4:1). 1H
NMR (300 MHz, CDCl3): l 1.19, 1.22, 1.24 (3s, 27 H,
3 (C(CH3)3), 1.23, 1.31 (2d, each 3H, two CH3), 4.04
(m, 1H, CH(CH3)2), 4.16 (m, 2H, 5-H, 6-H), 4.31 (m,
1H, 6-H%), 5.05 (s, 1H, 1-H), 5.36 (dd, 1H, 4-H), 5.49
(d, 1 H, 3-H); J3,4=10.1, J4,5=9.1, JCH3,CH=6.2 Hz.
Partial presence of the monohydrate of 3 was indicated
by substantially highfield-shifted minor signals for 1-H
(5.05“4.52) and 3-H (5.49“5.10). 13C NMR (75.5
drate form (ꢀ15%) in the product was indicated by
substantial highfield shift for 1-H (l=4.76 ppm), 3-H
(5.50), and 5-H (4.10). 13C NMR (75.5 MHz, CDCl3): l
12.2–56.6 (26Ccholestanyl), 63.7 (C-6), 71.3 (C-4), 72.9
(C-5), 77.0 (C-3), 79.8 (C-3%), 98.2 (C-1), 191.8 (C-2).
Anal. calcd for C54H68O9 (861.13): C, 75.30; H, 7.96.
Found: C, 75.24; H, 8.06.
3.2.4.
pyranos - 2 - ulosyl) - 1,2:3,4 - di - O - isopropylidene - a -
galactopyranose, 10. A mixture of 1,2:3,4-di-O-iso-
propylidene-a-
-galactopyranose15 (210 mg, 0.8 mmol),
6-O-(3,4,6-Tri-O-benzoyl-b- -arabino-hexo-
D
D
-
D
,
molecular sieve (3 A), silver carbonate (1.1 g, 4 mmol),
and CH2Cl2 (20 mL) was stirred at rt under exclusion
of light for 15 min. Ulosyl bromide 76 (390 mg, 0.7
mmol) was added and stirring continued for 3 h. After
addition of CH2Cl2 (20 mL) and filtration through
Celite, the solution was washed with 10% aqueous
Na2S2O3 (20 mL) and water (2×20 mL). Drying
(Na2SO4) and concentration of the solution afforded
MHz, CDCl3):
l 21.8, 23.2 (2CH3), 27.0, 27.1
(3C(CH3)3), 38.8, 38.9, 39.1 (3C(CH3)3), 62.4 (C-6),
69.6 (C-4), 72.7 (C-5), 72.9 (CH(CH3)2), 76.4 (C-3),
98.4 (C-1), 176.2, 177.4, 178.1 (3PivCO), 191.9 (C-2).
MS (FD, 15 mA): m/z 472 [M+], 473 [M++1]. Anal.
calcd for C24H40O9 (472.57): C, 61.00; H, 8.53. Found:
C, 61.05; H, 8.61.
1
425 mg (83%) 10 as a colorless foam. H NMR (300
MHz, CDCl3): l 1.30–1.53 (4s, 3H, each, 4CH3), 3.70–
4.74 (m, 9H, 2-H, 3-H, 4-H, 5-H, 6-H2, 5%-H, 6%-H2),
5.40 (s, 1H, 1%-H), 5.57 (d, 1H, 1-H), 5.93 (dd, 1H,
3.2.2. Octyl 3,4,6-tri-O-benzoyl-b- -arabino-hexopyran-
D
osid-2-ulose, 8. A suspension of n-octanol (1.25 mL, 8
mmol), silver alumosilicate14 (8.00 g, 24.6 mmol) and
4%-H), 5.99 (d, 1H, 3%-H); J1,2=4.7, J3%,4%=10.0, J4%,5%=
,
molecular sieve (3 A, 1 g) in CH2Cl2 (100 mL) was
10.1 Hz. Partial presence of the monohydrate of 10 was
indicated by substantially highfield-shifted minor sig-
nals for 1%-H (5.40“4.81) and 3%-H (5.99“5.61). 13C
NMR (75.5 MHz, CDCl3): l 24.3–27.4 (2C(CH3)2),
62.2 (C-6%), 68.4 (C-6), 67.8–68.2, 69.2–73.0 (C-2, C-3,
C-4, C-5, C-4%, C-5%), 76.7 (C-3%), 96.2 (C-1), 99.3 (C-1%),
108.6–109.6 (2C(CH3)2), 191.6 (C-2%). MS (FD, 20 mA):
m/z 733 [M++H], 717 [M+−CH3]. Anal. calcd for
C39H40O14 (732.75): C, 63.93; H, 5.50. Found: C, 63.59;
H, 5.40.
stirred at 0°C and under exclusion of light for 10 min,
followed by the addition of ulosyl bromide 76 (4.42 g, 8
mmol). After stirring for another 2 min (TLC monitor-
ing) the mixture was filtered through Celite. The filtrate
was washed with 10% aqueous Na2S2O3 (20 mL), water
(20 mL) and dried (Na2SO4). Removal of the solvent in
vacuo and trituration with di-isopropyl ether yielded
4.05 g (84%) of 8 as colorless crystals; mp 82–84°C;
[h]2D0=−34.5 (c 1.2, CHCl3). 1H NMR (300 MHz,
CDCl3): l 0.86 (t, 3H, CH3), 1.12–1.46, 1.66 (m, 12H,
6CH2), 3.68 (dt, 1H, CH2O), 3.92 (dt, 1H, CH2O), 4.52
(ddd, 1H, 5-H), 4.58 (dd, 1H, 6-H), 4.71 (dd, 1H, 6-H%),
5.15 (s, 1H, 1-H), 5.94 (dd, 1H, 4-H), 5.98 (d, 1H, 3-H);
When starting from the ulosyl iodide6 and employing
silver alumosilicate14 instead of silver carbonate, the
reaction time is reduced to 30 s.
J
3,4=9.5, J4,5=9.6, J5,6=5.6, J5,6%=3.3, J6,6%=11.8. 13C
NMR (75.5 MHz, CDCl3): l 14.2 (CH3), 22.8, 25.9,
29.3, 29.4, 29.5, 31.9 (6CH2), 63.6 (C-6), 70.6 (CH2O),
70.9 (C-4), 73.1 (C-5), 76.9 (C-3), 99.8 (C-1), 191.8
(C-2). MS (FD, 20 mA): m/z 603 (M++H). Anal. calcd
for C35H38O9 (602.68): C, 69.75; H, 6.36. Found: C,
69.74; H, 6.18.
3.2.5. Methyl 4-O-(3,4,6-tri-O-benzoyl-b-
D
-arabino-
hexopyranos-2-ulosyl)-2,3,6-tri-O-benzyl-a-
D
-glucopy-
ranoside, 12. To
2,3,6-tri-O-benzyl-a-
a
stirred solution of methyl
D
-glucopyranoside16 (145 mg, 0.31
mmol) in CH2Cl2 (1.5 mL) was added molecular sieve
,
(4 A, 200 mg) and silver alumosilicate (500 mg, 1.6
mmol). A solution of ulosyl bromide 76 (258 mg, 0.47
mmol) in CH2Cl2 (1 mL) was then injected and stirring
continued at rt for 16 h. The suspension was diluted
with CH2Cl2 (10 mL), filtered through Celite and freed
from the solvent in vacuo. The crude product was
purified by flash chromatography on silica gel (2.5×20
3.2.3. 5a-Cholestan-3b-yl 3,4,6-tri-O-benzoyl-b- -ara-
D
bino-hexopyranosid-2-ulose, 9. A suspension of 5a-
cholestan-3b-ol (3.89 g, 10.0 mmol), silver
alumosilicate14 (10.0 g, 30.8 mmol) and molecular sieve
,
(4 A, 5 g) in CH2Cl2 (30 mL) was stirred at rt for 20

732
F. W. Lichtenthaler et al. / Tetrahedron: Asymmetry 14 (2003) 727–736
cm) with CH2Cl2/EtOAc (5:1) to afford 225 mg (77%)
12 as a colorless foam. H NMR (300 MHz, CDCl3): l
3.3. manno-Selective hydride reduction of 2-keto-b-
arabino-hexopyranosides
D-
1
3.37 (s, 3H, CH3O), 3.52 (m, 2H, 2-H, 5-H), 3.72 (dd,
1H, 6-Ha), 3.80–4.10 (m, 4H, 3-H, 4-H, 5%-H, 6-Hb),
4.29 (dd, 1H, 6%-Ha), 4.37 (dd, 1H, 6%-Hb), 4.60 (d, 1H,
1-H), 4.42–4.98 (m, 6H, 3C6H5CH2), 5.13 (s, 1H, 1%-H),
5.57 (d, 1H, 3%-H), 5.82 (dd, 1H, 4%-H); J5,6a=1.3,
3.3.1. General procedures
3.3.1.1. K- or L-Selectride reduction (procedure A). A
1 M THF solution of K- or L-Selectride (1 mL, 1
mmol) was added under Ar to a cold (−78°C) solution
of the 2-uloside (1 mmol) in THF (3 mL). After 1 min
the reaction was stopped by addition of acetic acid (0.2
mL), CH2Cl2 (30 mL) was added for dilution, followed
by washing of the mixture with 2 M HCl (30 mL) and
satd aq. NaHCO3 (30 mL), drying (MgSO4) and
removal of the solvent under diminished pressure.
J3%,4%=10.1, J4%,5%=9.9, J5%,6%a=4.2, J5%,6%b=3.2, J6%a,b
=
12.2 Hz. Partial presence of the monohydrate of 12 was
indicated by a set of lower intensity signals (ca. 10%),
of which singlet for 1%-H (4.68 ppm) and the doublet for
3%-H (5.23) were substantially shifted. 13C NMR (75.5
MHz, CDCl3): l 55.3 (CH3O), 62.6 (C-6%), 68.2 (C-6),
70.6 (C-4%), 72.3 (C-5%), 73.4-75.3 (3C6H5CH2), 77.1
(C-3%), 77.5–80.6 (C-2, C-3, C-4, C-5), 98.2 (C-1), 100.8
(C-1%), 191.8 (C-2%). MS (FD, 20 mA): m/z 936 [M+],
845 [M+−C6H5CH2].
3.3.1.2. NaBH4 reduction (procedure B). NaBH4 (150
mg, 4 mmol) was added at rt to a solution of the
2-uloside (1 mmol) in a mixture of CH2Cl2/MeOH 1:1
(10 mL) and stirred for 20 min. After quenching with
water (5 mL) and acetic acid (0.2 mL), the mixture was
diluted with CH2Cl2 (30 mL) followed by washing with
2 M HCl (30 mL) and satd aq. NaHCO3 (30 mL),
drying (MgSO4) and evaporation of the solvent in
vacuo.
On using the respective ulosyl iodide6 instead of bro-
mide 7, the glycosidation is complete within 3 min.
3.2.6. Ethyl 4,6-di-O-benzoyl-3-O-benzyl-1-thio-b-
bino-hexopyranosid-2-ulose, 19. A solution of 4,6-di-O-
benzoyl-3-O-benzyl-1-thio-a- -arabino-hexopyranos-2-u
D
-ara-
D
losyl bromide4 (2.20 g, 4 mmol), tetramethylurea (1
mL) and ethanethiol (0.5 mL, 8 mmol) in CH2Cl2 (35
mL) was stirred for 6 h, followed by dilution with
CH2Cl2 (300 mL) washing with 2N HCl and 5%
NaHCO3 solution (3×) to yield after drying (MgSO4)
and removal of the solvent in vacuo, a residue which
crystallized on trituration with ethanol: 1.54 g (74%) of
19; mp 132–134°C. 1H NMR (300 MHz, CDCl3): l 1.27
(t, 3H, SCH2CH3), 2.63–2.82 (m, 2H, SCH2CH3), 4.28
(m, 1H, 5-H), 4.29 (d, 1H, 3-H), 4.47 (dd, 1H, 6-H),
4.63 (dd, 1H, 6-H%), 4.60, 4.76 (2d, 2H, PhCH2), 5.25 (s,
3.3.2. Isopropyl 3,4,6-tri-O-benzoyl-b-
oside, 5. A solution of isopropyl 3,4,6-tri-O-benzoyl-b-
-arabino-2-ketohexoside6 2 (535 mg, 1 mmol) in THF
D-mannopyran-
D
(3 mL) was exposed to L-Selectride in THF (1 min)
according to procedure A. The residue obtained on
work-up was purified by flash elution from a silica gel
column with CH2Cl2/EtOAc (50:1), to give, after
removal of the solvents from the appropriate fraction
(Rf=0.18 in eluent), a syrupy residue which crystallized
on trituration with ether: 455 mg (85%) of 5 as colorless
crystals; mp 136–137°C; [h]2D0=−66.9 (c 0.8, CHCl3). 1H
NMR (300 MHz, CDCl3): l 1.21, 1.27 (2d, each 3H,
CH(CH3)2), 2.56 (d, 1H, 2-OH), 4.03 (ddd, 1H, 5-H),
4.10 (qq, 1H, OCH(CH3)2), 4.33 (m, 1H, 2-H), 4.51
(dd, 1H, 6-H), 4.63 (dd, 1H, 6-H%), 4.87 (d, 1H, 1-H),
1H, 1-H), 5.68 (dd, 1H, 4-H); J3,4=9.0, J4,5=9.3, J5,6
=
3.3, J5,6%=5.9, J6,6%=12.2 Hz. 13C NMR (75.5 MHz,
CDCl3): l 14.9 (SCH2CH3), 24.2 (SCH2CH3), 63.5
(C-6), 72.4 (C-4), 73.0 (PhCH2), 76.3 (C-5), 81.7 (C-3),
86.5 (C-1), 197.0 (C-2). Anal. calcd for C29H28O7S
(520.60): C, 66.91; H, 5.42. Found: C, 66.87; H, 5.36.
5.40 (dd, 1H, 3-H), 5.95 (dd, 1H, 4-H); J1,2=0.9, J2,3
=
3.2, J3,4=9.8, J4,5=9.6, J5,6=5.9, J5,6%=3.5 J6,6%=11.9
Hz. 13C NMR (75.5 MHz, CDCl3): l 21.7, 23.3
(CH(CH3)2), 63.8 (C-6), 67.3 (C-4), 69.7 (C-2), 71.9
(CH(CH3)2), 72.2 (C-5), 73.9 (C-3), 97.6 (C-1). MS
(FD, 20 mA): m/z 535 [M++H], 534 [M+], 491 [M+−
C3H7]. Anal. calcd for C30H30O9 (534.56): C, 67.41; H,
5.66. Found: C, 67.19; H, 5.56.
3.2.7. Phenyl 4,6-di-O-benzoyl-3-O-benzyl-1-thio-b-
arabino-hexopyranosid-2-ulose, 20. A solution of 4,6-di-
-arabino-hexopyranos-
D-
O-benzoyl-3-O-benzyl-1-thio-a-
D
2-ulosyl bromide4 (2.37 g, 4.3 mmol), thiophenol (0.88
mL, 8.6 mmol), and 1,1,3,3-tetramethylurea (1.1 mL, 9
mmol) in CH2Cl2 (35 mL) was stirred for 30 min at
ambient temperature. After dilution with CH2Cl2 (300
mL), the solution was washed with 2N HCl, 5%
NaHCO3 solution, and three times with water. After
drying (MgSO4) the solvent was evaporated giving an
amorphous residue, which crystallized to yield 2.01 g
(82%) of 18 as a colorless, uniform (TLC in CH2Cl2/
Longer exposure of 2 to the Selectride resulted in
partial 3-O“2-O-benzoyl migration to the 2,4,6-tri-O-
benzoyl isomer (1H NMR); on exceedingly long contact
with silica gel, e.g. slow elution from a column, causes
partial elimination of benzoic acid from the 3,4-posi-
tions, i.e. formation of the respective 2,6-dihydropyran-
1
1
EtOAc, 20:1) syrup. H NMR (300 MHz, CDCl3): l
3-one, clearly detectable in the H NMR.
4.30 (m, 2H, 3-H, 5-H), 4.47 (dd, 1H, 6-H), 4.59, 4.94
(2d, 2H, PhCH2), 4.66 (dd, 1H, 6H%), 5.40 (s, 1H, 1-H),
3.3.3. Isopropyl 3,4,6-tri-O-pivaloyl-b-D-mannopyran-
5.64 (dd, 1H, 4-H); J3,4=9.3, J4,5=9.4, J5,6=7.1, J5,6%
=
oside, 6. Uloside 3 (472 mg, 1 mmol) was reacted with
L-Selectride according procedure A. Column chro-
matography of the resulting residue on silica gel (tolu-
2.7, J6,6%=12.1, JPhCH2=12.3 Hz. 13C NMR (75.5 MHz,
CDCl3): l 63.70 (C-6), 72.63 (C-4), 73.02 (PhCH2),
76.62 (C-5), 81.73 (C-3), 89.51 (C-1), 196.25 (C-2).
Anal. calcd for C33H28O7S (568.64): C, 69.70; H, 4.96.
Found: C, 69.60; H, 4.89.
ene/EtOAc, 8:1) yielded the b- -mannoside 6 (420 mg,
D
89%); Rf=0.54 (toluene/EtOAc, 4:1). 1H NMR (300
MHz, CDCl3): l 1.16–1.22 (m, 33H, 2CH3, 3C(CH3)3),

F. W. Lichtenthaler et al. / Tetrahedron: Asymmetry 14 (2003) 727–736
733
,
2.39 (brs, 1H, 2-OH), 3.67 (m, 1H, 5-H), 3.96–4.10 (m,
2H, 6-H, OCH(CH3)2), 4.04 (d, 1H, 2-H), 4.25 (dd, 1H,
6-H%), 4.68 (d, 1H, 1-H), 4.95 (dd, 1H, 3-H), 5.36 (t, 1H,
4-H); J1,2=1.1, J2,3=3.1, J3,4=9.7, J4,5=9.6, J5,6%=2.3,
J6,6%=12.0 Hz. 13C NMR (125 MHz, CDCl3): l 21.6, 23.3
(2CH3), 27.1 (3C(CH3)3), 38.1–38.9 (3C(CH3)3), 62.7
(C-6), 65.7 (C-4), 69.3 (C-2), 71.5 (CH(CH3)2), 72.7
(C-5), 73.1 (C-3), 97.3 (C-1), 176.7–178.3 (3PivCO). MS
(FD/15 mA): m/z 474 [M+], 475 [M++1]. Anal. calcd for
C24H42O9 (474.59): C, 60.74; H, 8.92. Found: C, 60.71;
H, 8.92.
Ag2CO3 (138 mg, 0.5 mmol) and molecular sieve (3 A,
500 mg) in CH2Cl2 (5 mL) was stirred for 30 min followed
by
addition
of
2,3:4,5-di-O-isopropylidene-b-D-
fructopyranose (130 mg, 0.5 mmol) and stirring was
continued for 4 h. After filtration through Celite the
filtrate was evaporated in vacuo to give crude uloside 11
(470 mg, 85%) as a colorless foam, which as such was
subjected to reduction with L-Selectride by procedure A.
The resulting syrup was purified by elution from a silica
gel column with toluene/EtOAc (4:1): 295 mg (80%) of
16; Rf=0.39 (toluene/EtOAc, 2:1); [h]2D0=−42.3 (c 1.0,
CHCl3). 1H NMR (500 MHz, CDCl3): l 1.31, 1.41, 1.42,
1.55 (4s, each 3H, 4CH3), 2.60 (brs, 1H, 2b-OH), 3.75 (d,
1H, 6a-H), 3.88 (d, 1H, 1a-H), 3.92 (dd, 1H, 6a-H%), 3.99
(d, 1H, 1a-H%), 4.03 (ddd, 1H, 5b-H), 4.21 (dd, 1H, 5a-H),
4.40 (d, 1H, 3a-H), 4.45 (d, 1H, 2b-H), 4.50 (dd, 1H,
6b-H), 4.58 (dd, 1H, 4a-H), 4.62 (dd, 1H, 6b-H%), 4.97
(d, 1H, 1b-H), 5.57 (dd, 1H, 3b-H), 5.98 (t, 1H, 4b-H);
3.3.4.
5a-Cholestan-3b-yl
3,4,6-tri-O-benzoyl-b-D-
mannopyranoside, 14. Reduction of uloside 9 (200 mg,
0.23 mmol) with K-Selectride was conducted according
to procedure A and the product obtained was purified
by column chromatography on silica gel (toluene/EtOAc,
15:1) to yield 163 mg (82%) of 14. Rf=0.84 (toluene/
EtOAc, 8:1); mp 160–162°C; [h]2D0=−31.2 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): l 0.57–2.00 (m, 46H,
Hcholestanyl), 2.49 (brs, 1H, 2-OH), 3.72 (m, 1H, 3-
J1a,1a%=11.7, J3a,4a=2.7, J4a,5a=7.9, J5a,6a%=1.8, J6a,6a%
12.9, J1b,2b=0.5, J2b,3b=3.0, J3b,4b=9.9, J4b,5b=9.8,
5b,6b=5.4, J5b,6b%=3.2, J6b,6b%=12.0 Hz. 13C NMR (125
=
J
H
cholestanyl), 4.03 (ddd, 1H, 5-H), 4.31 (brs, 1H, 2-H), 4.54
MHz, CDCl3): l 24.4, 25.9, 26.2, 27.0 (4CH3), 61.7
(C-6a), 63.9 (C-6b), 67.3 (C-4b), 69.4 (C-2b), 70.2 (C-1a),
70.4, 70.5 (C-3a, C-4a), 71.3 (C-5a), 72.9 (C-5b), 74.3
(C-3b), 100.5 (C-1b), 102.6 (C-2a), 109.2, 109.5
(2C(CH3)2). MS (ESI): m/z 757.3 [(M+Na)+], 773.2
[(M+K)+]. Anal. calcd for C39H42O14 (734.76): C, 63.75;
H, 5.76. Found: C, 63.60; H, 5.87.
(dd, 1H, 6-H), 4.60 (dd, 1H, 6-H%), 4.90 (d, 1H, 1-H), 5.38
(dd, 1H, 3-H), 5.89 (t, 1H, 4-H); J1,2=0.6, J2,3=3.0,
J
3,4=J4,5=9.8, J5,6=6.4, J5,6%=3.6, J6,6%=11.9 Hz. 13C
NMR (125 MHz, CDCl3): l 12.5–56.9, 79.0 (Ccholestanyl),
64.3 (C-6), 67.9 (C-4), 71.1 (C-2), 72.6 (C-5), 74.3 (C-3),
97.7 (C-1). MS (ESI): m/z 885.5 [(M+Na)+]. Anal. calcd
for C54H70O9 (863.14): C, 75.14; H, 8.17. Found: C,
75.24; H, 7.82.
3.3.7. Methyl 4-O-(3,4,6-tri-O-benzoyl-b-
D-mannopyran-
osyl)-2,3,6-tri-O-benzyl-a- -glucopyranoside, 17. A sus-
D
3.3.5. 6-O-(3,4,6-Tri-O-benzoyl-b-
D
-mannopyranosyl)-
pension of methyl 2,3,6-tri-O-benzyl-a-D-gluco-
1,2:3,4-di-O-isopropylidene-a- -galactopyranose, 15. A
D
pyranoside16 (474 mg, 1.0 mmol), powdered molecular
14
,
suspension
of
1,2:3,4-di-O-isopropylidene-a-
D
-
sieve (4 A, 600 mg) and silver alumosilicate (1.6 g, 5.1
galactopyranose15 (262 mg, 1.0 mmol), silver
mmol) in CH2Cl2 (5 mL) was stirred at rt for 30 min. A
solution of ulosyl bromide 76 (837 mg, 1.5 mmol) in
CH2Cl2 (4 mL) was added and the mixture was stirred
at rt for 16 h. Dilution with CH2Cl2 (15 mL), filtration
through Celite and evaporation of the solvent afforded
a hard foam (1.16 g), which was dissolved in THF (5 mL)
and reacted with K-Selectride according procedure A.
Column chromatography on silica gel (toluene/EtOAc,
5:1), evaporation of the appropriate fractions (Rf=0.11
in eluent), and crystallization from ether/hexane afforded
710 mg (76%) of 17; mp 127°C; [h]2D0=−10.2; [h]365
nm20=−57.5 (c 0.7, CHCl3). 1H NMR (300 MHz,
CDCl3): l 2.67 (d, 1H, 2%-OH), 3.37 (s, 3H, CH3O), 3.52
(dd, 1H, 2-H), 3.56 (ddd, 1H, 5%-H), 3.65–3.78, 3.99 (m,
5H, 3-H, 4-H, 5-H, 6-H2), 4.14 (m, 1H, 2%-H), 4.25 (dd,
1H, 6%-Ha), 4.40 (dd, 1H, 6%-Hb), 4.45 (d, 1H, C6H5CH2),
4.60 (d, 1H, 1-H), 4.62, 4.66, 4.76 (3d, 1H, each,
3C6H5CH2), 4.83 (brs, 1H, 1%-H), 4.91 (2d, 1H, each,
2C6H5CH2), 5.08 (dd, 1H, 3%-H), 5.84 (dd, 1H, 4%-H);
alumosilicate14 (1.0 g, 3.1 mmol) and powdered molecu-
,
lar sieve (4 A, 400 mg) in CH2Cl2 (5 mL) was stirred at
rt and under exclusion of light for 30 min. A solution of
bromide 76 (615 mg, 1.1 mmol) in CH2Cl2 (2 mL) was
added and the solution was stirred for another 20 min.
Dilution with CH2Cl2 (5 mL), filtration and evaporation
of the solvent afforded 740 mg of crude uloside 10 as a
colorless foam. This was dissolved in THF (3 mL) and
reduced with K-Selectride according procedure A. The
residue obtained was subjected to column chromatogra-
phy on silica gel (toluene/EtOAc, 5:1) to furnish 15 (580
1
mg, 79%). H NMR (300 MHz, CDCl3): l 1.31 (s, 6H,
2CH3), 1.43, 1.51 (2s, each 3H, 2CH3), 2.35 (brs, 1H,
2%-OH), 3.85 (m, 1H, 6-H), 4.07 (m, 4H, 5-H, 6-H%, 2%-H,
5%-H), 4.16 (dd, 1H, 4-H), 4.31 (dd, 1H, 2-H), 4.51 (dd,
1H, 6%-H), 4.58 (dd, 1H, 3-H), 4.63 (dd, 1H, 6%-H%), 4.91
(d, 1H, 1%-H), 5.41 (dd, 1H, 3%-H), 5.54 (d, 1H, 1-H), 5.97
(dd, 1H, 4%-H); J1,2=5.0, J2,3=2.5, J3,4=7.8, J4,5=1.8,
J
5,6b=3.0, J6a,b=11.2, J1%,2%=0.7, J2%,3%=3.1, J3%,4%=9.8,
J
1,2=3.6, J2,3=9.2, J1%,2%=<0.5, J2%,3%=2.9, J2%,OH=2.7,
J3%,4%=10.0, J4%,5%=9.9, J5%,6%a=4.8, J5%,6%b=3.3, J6%a,b=12.2,
CH2=11.5, 11.7, 12.1 Hz. Anal. calcd for C55H54O16
(939.03): C, 70.35; H, 5.80. Found: C, 70.26; H, 5.77.
J4%,5%=9.7, J5%,6a=5.1, J5%,6%b=3.4, J6%a,b=11.8 Hz. 13C
NMR (75 MHz, CDCl3): l 23.3, 24.9, 26.0 (4CH3), 63.6
(C-6%), 67.1 (C-4%), 68.0, 72.1 (C-5, C-5%), 68.9 (C-2%), 69.2
(C-6), 70.4 (C-2), 70.7 (C-3), 71.3 (C-4), 73.6 (C-3%), 96.2
(C-1), 100.1 (C-1%), 108.7, 109.5 (2(CH3)2C).
J
3.3.8. Phenyl 3,4,6-tri-O-benzoyl-1-thio-b-D-mannopyran-
oside, 21. Uloside 186 (250 mg, 0.43 mmol) was subjected
to K-Selectride reduction according to procedure A. The
resulting residue was then purified by elution from a silica
gel column with hexane/EtOAc (2:1). Removal of the
3.3.6. 2,3:4,5-Di-O-isopropylidene-1-O-(3,4,6-tri-O-ben-
zoyl-b-D-mannopyranosyl)-a-D-fructopyranose, 16. A sus-
pension of ulosyl bromide 76 (277 mg, 0.5 mmol),

734
F. W. Lichtenthaler et al. / Tetrahedron: Asymmetry 14 (2003) 727–736
solvent from the appropriate eluents in vacuo gave a
residue which crystallized from an EtOAc solution on
addition of n-hexane: 215 mg (85%) of 21 as colorless
crystals of mp 170–172°C; Rf=0.45 (hexane/EtOAc,
column with CH2Cl2/EtOAc (95:5), removal of the
solvents from the appropriate fractions and crystalliza-
tion of the residue by trituration with ethanol gave 470
mg (82%) of 23; mp 119–121°C; [h]2D0=−85.8 (c 1.0,
1
1
CHCl3). H NMR (300 MHz, CDCl3): l 2.88 (s, 1H,
2:1). H NMR (500 MHz, CDCl3): l 2.80 (brs, 1H,
2-OH), 3.74 (dd, 1H, 3-H), 3.93 (ddd, 1H, 5-H), 4.40
(broad s, 1H, 2-H), 4.43 (dd, 1H, 6-H), 4.55, 4.70 (2d,
2H, PhCH2), 4.59 (dd, 1H, 6-H%), 4.88 (s, 1H, 1-H), 5.63
(dd, 1H, 4-H); J1,2=undetectable, J2,3=3.3, J3,4=9.4,
2-OH), 4.12 (ddd, 1H, 5-H), 4.52 (dd, 1H, 6-H), 4.63
(m, 2H, 2-H, 6-H%), 5.09 (d, 1H, 1-H), 5.40 (dd, 1H,
3-H), 5.91 (t, 1H, 4-H); J1,2=0.9, J2,3=3.2, J3,4=J4,5
=
10.0, J5,6=7.2, J5,6%=2.8, J6,6%=12.2 Hz. 13C NMR (125
MHz, CDCl3): l 63.9 (C-6), 66.9 (C-4), 70.9 (C-2), 75.0
(C-3), 76.8 (C-5), 87.5 (C-1). MS (ESI): m/z 607.2
[M+Na]+. Anal. calcd for C33H28O8S (584.64): C, 67.80;
H, 4.83. Found: C, 67.59; H, 5.19.
J
4,5=9.7, J5,6=7.7, J5,6%=2.8, J6,6%=12.0, JPhCH2=12.2
Hz. 13C NMR (75.5 MHz, CDCl3): l 64.2 (C-6), 68.5
(C-4), 69.8 (C-2), 71.6 (PhCH2), 76.4 (C-5), 78.8 (C-3),
87.0 (C-1). Anal. calcd for C33H30O7S (570.65): C,
69.45; H, 5.30; S, 5.62. Found: C, 69.40; H, 5.20; S,
5.49.
3.3.9. Ethyl 4,6-di-O-benzoyl-3-O-benzyl-1-thio-b-D-
mannopyranoside, 22. A solution of 520 mg (1.0 mmol)
of thio-uloside 19 in THF (3 mL) was treated with
K-Selectride according to procedure A. After work-up,
the resulting residue was subjected to column chro-
matography on silica gel (CH2Cl2/EtOAc, 95:5) to yield
after removal of the solvent from the appropriate frac-
tions (Rf 0.42 in the eluent) and crystallization of the
residue from EtOH 405 mg (78%) of 22; mp 142–143°C;
[h]2D0=−52.4 (c 1.1, CHCl3). 1H NMR (300 MHz,
CDCl3): l 1.29 (t, 3H, SCH2CH3), 2.72 (m, 2H,
SCH2CH3), 2.76 (s, 1H, 2-OH), 3.73 (dd, 1H, 3-H), 3.88
(ddd, 1H, 5-H), 4.23 (broad s, 1H, 2-H), 4.42 (dd, 1H,
6-H), 4.54 (dd, 1H, 6-H%), 4.53, 4.69 (2d, 2H, PhCH2),
4.71 (s, 1H, 1-H), 5.63 (dd, 1H, 4-H); J1,2=unde-
Reduction of thio-uloside 20 (1.88 g, 3.3 mmol) with
NaBH4 according procedure B gave an approximate
12:1 mixture (1H NMR) of the manno-isomer 23 and
the corresponding glucoside. Separation was effected by
elution from a silica gel column with CH2Cl2/EtOAc
(95:5). The product eluted first (Rf 0.30 in eluent) was
the mannoside which crystallized on trituration with
ethanol: 1.57 g (83%), identical with 23 described
above. The product eluted next (Rf=0.53), on similar
work-up and crystallization from ethanol afforded 104
mg (5.5%) of phenyl 4,6-di-O-benzoyl-3-O-benzyl-1-
thio-b-
D
-glucopyranoside; mp 146–148°C; [h]2D0=−24.1
1
(c 1.2, CHCl3). H NMR (300 MHz, CDCl3): l 2.56
(broad s, 1H, OH), 3.54 (dd, 1H, 2-H), 3.67 (dd, 1H,
3-H), 3.85 (ddd, 1H, 5-H), 4.25 (dd, 1H, 6-H), 4.52 (d,
1H, 1-H), 4.54 (dd, 1H, 6-H%), 4.62, 4.70 (2d, 2H,
tectable, J2,3=3.3, J3,4=9.4, J4,5=9.7, J5,6=6.5, J5,6%
=
3.3, J6,6%=12.0, JPhCH2=12.3 Hz. 13C NMR (75.5 MHz,
CDCl3): l 15.1 (SCH2CH3), 24.7 (SCH2CH3), 64.1
(C-6), 68.6 (C-4), 69.3 (C-2), 71.3 (PhCH2), 76.2 (C-5),
78.7 (C-3), 83.8 (C-1). Anal. calcd for C29H30O7S
(522.61): C, 66.65; H, 5.78; S, 6.13. Found: C, 66.60; H,
5.80; S, 6.01.
PhCH2), 5.29 (dd, 1H, 4-H); J1,2=9.6, J2,3=8.9, J3,4
9.6, J4,5=9.7, J5,6=5.7, J5,6%=2.7, J6,6%=12.1, JPhCH2
=
=
11.5 Hz. Anal. calcd for C33H30O7S (570.65): C, 69.45;
H, 5.30; S, 5.62. Found: C, 69.39; H, 5.27; S, 5.55.
3.4. gluco-Selective borane reduction of 2-keto-b-
D-
arabino-hexopyranosides
When conducting the reduction of thio-uloside 19 (1.40
g, 2.69 mmol) with NaBH4 following procedure B, a
15:1 mixture (1H NMR) of b-
D
-mannoside 22 and the
3.4.1. Isopropyl 3,4,6-tri-O-benzoyl-b-D-glucopyranoside,
24. Isopropyl uloside 26 (2.00 g, 3.7 mmol), dissolved in
THF (15 mL), was added dropwise to a cooled (−78°C)
solution of BH3–pyridine (1.80 mL, 18 mmol) in THF
(50 mL). The mixture was stirred for 1 h, warmed up to
rt, and quenched with water (5 mL). After removal of
the solvents the syrupy residue was diluted with CH2Cl2
(50 mL), followed by vigorous stirring with 2N HCl (20
mL) for 30 min, separation of the layers and washing of
the organic phase with satd NaHCO3 solution (10 mL)
and water (10 mL). Drying (Na2SO4) and evaporation
of the solvent led to a crude product, comprising (1H
NMR) an 11:1 mixture of glucoside 24 and mannoside.
Purification by elution from a silica gel column (3×15
cm) with CH2Cl2/acetone (30:1) gave a hard foam,
which crystallized on trituration with ether: 1.50 g
(75%) of 24; mp 129–131°C; [h]2D0=−52.1 (c 0.8,
respective b-
D-glucoside was obtained, which was sub-
jected to column chromatography on silica gel (eluent:
CH2Cl2/EtOAc, 95:5). The mannoside 22 eluted first (Rf
0.42 in the eluent) to yield after removal of the solvent
and crystallization of the residue from EtOH 1.18 g
(84%) identical with 22 described above. The minor
fraction eluted next (Rf=0.57), upon analogous work-
up gave 70 mg (5%) of ethyl 4,6-di-O-benzoyl-3-O-ben-
zyl-1-thio-b-D-glucopyranoside of mp 108–109°C;
[h]2D0=−24.4 (c 1.2, CHCl3). 1H NMR (300 MHz,
CDCl3): l 1.29 (t, 3H, SCH2CH3), 2.73 (m, 2H,
SCH2CH3), 3.74 (m, 2H, 2-H, 3-H), 3.91 (ddd, 1H,
5-H), 4.35 (dd, 1H, 6-H), 4.45 (d, 1H, 1-H), 4.53 (dd,
1H, 6-H%), 4.72, 4.80 (2d, 2H, PhCH2), 5.41 (dd, 1H,
4-H); J1,2=9.3, J3,4=9.2, J4,5=9.7, J5,6=5.8, J5,6%=3.0,
J6,6%=12.1, JPhCH2=12.1 Hz.
1
CHCl3). H NMR (300 MHz, CDCl3): l 1.24, 1.28 (2d,
3H, each, CH(CH3)2), 2.58 (d, 1H, 2-OH), 3.78 (ddd,
1H, 2-H), 4.05 (m, 2H, 5-H, CH(CH3)2), 4.47 (dd, 1H,
6-H), 4.58 (dd, 1H, 6-H%), 4.63 (d, 1H, 1-H), 5.55 (dd,
1H, 4-H), 5.63 (dd, 1H, 3-H); J1,2=7.7; J2,3=9.4;
3.3.10. Phenyl 4,6-di-O-benzoyl-3-O-benzyl-1-thio-b-D-
mannopyranoside, 23. Thio-uloside 20 (570 mg, 1.0
mmol) was dissolved in THF (3 mL) and exposed to
K-Selectride as described in procedure A. Subsequent
purification of the product by elution from a silica gel
J
2,OH=2.5; J3,4=9.5; J4,5=9.5; J5,6=5.8; J5,6%=3.5;
J6,6%=12.1 Hz. 13C NMR (75.5 MHz, CDCl3): l 22.0,

F. W. Lichtenthaler et al. / Tetrahedron: Asymmetry 14 (2003) 727–736
735
23.4 (2CH3), 63.5 (C-6), 69.7 (C-4), 72.6 (C-2), 72.0,
72.8 (C-5, CH(CH3)2), 74.9 (C-3), 101.5 (C-1). Anal.
calcd for C30H30O9 (534.56): C, 67.41; H, 5.66. Found:
C, 67.49; H, 5.65.
(26Ccholestanyl), 63.2 (C-6), 69.6 (C-4), 71.7 (C-5), 72.3
(C-2), 74.6 (C-3), 79.2 (C-3%), 101.0 (C-1). Anal. calcd
for C54H70O9 (863.15): C, 75.14; H, 7.17. Found: C,
74.93; H, 7.36.
The second fraction (Rf=0.25) contained mannoside
14, which crystallized from MeOH: 180 mg (5%) as
colorless needles, identical in physical data with the
product described earlier (vide supra).
The presence of the C-2 epimeric mannoside in the
reaction mixture was indicated by a low intensity 0.9
Hz d at l=4.87 for the anomeric proton.
3.4.2. Octyl 3,4,6-tri-O-benzoyl-b-D-glucopyranoside, 25.
3.4.4.
1,2:3,4-di-O-isopropylidene-a-
suspension of 1,2:3,4-di-O-isopropylidene-a-
galactopyranose15
(1.57 g, mmol), silver
6-O-(3,4,6-Tri-O-benzoyl-b-
D-glucopyranosyl)-
A solution of BH3–pyridine (1.3 mL, 13 mmol) in THF
(5 mL) was added dropwise to a cooled (−78°C) solu-
tion of octyl uloside 8 (1.60 g, 2.65 mmol) in THF (50
mL). After stirring for 30 min the mixture was allowed
to warm up to rt, stirred for another h and quenched
with water (5 mL). Removal of the solvents in vacuo
afforded a residue, which was dissolved in CH2Cl2 (60
mL) vigorously stirred with 2N HCl (20 mL) for 30
min, followed by washing of the organic layer with satd
NaHCO3 solution (20 mL), and finally with 10% aq.
NaCl (2×10 mL). Drying (Na2SO4) and concentration
to dryness furnished a syrup, consisting (1H NMR) of
an approximate 8:1 mixture of 25 and its manno-epimer
13. Separation was achieved by elution from silica gel
(5×18 cm) with cyclohexane/EtOAc (4:1). Processing of
the fractions with Rf=0.27 afforded 1.10 g (69%) of a
D
-galactopyranose, 27. A
D
-
6
alumosilicate14 (6.20 g, 19 mmol) and powdered molec-
,
ular sieve (4 A, 2.5 g) in CH2Cl2 (30 mL) was stirred at
rt and under exclusion of light for 30 min. A solution of
bromide 76 (3.69 g, 6.67 mmol) in CH2Cl2 (15 mL) was
added and the solution was stirred for another 20 min.
Dilution with CH2Cl2 (25 mL), filtration and evapora-
tion of the solvent afforded 4.68 g of crude product as
a colorless foam, which was dissolved in THF (20 mL).
This solution was added dropwise during 15 min to a
cooled (−78°C) solution of BH3/pyridine (2.4 mL, 24
mmol) in THF (20 mL). The mixture was allowed to
warm up to rt, quenched with water (10 mL) and
evaporated to dryness. The residue, comprising an
approximat 8:1 mixture of 27 and its manno-isomer 15
(1H NMR) was subjected to column chromatography
on silica gel (eluent: CH2Cl2/acetone, 15:1). Processing
of the fractions containing 27 (Rf=0.36 in eluent) in the
usual manner gave 3.25 g (74%, based on ulosyl bro-
mide 7) as a colorless foam. 1H NMR (300 MHz,
CDCl3): l 1.31 (s, 6H, 2CH3), 1.44, 1.52 (2s, 3H, each,
2CH3), 3.42 (brs, 1H, 2%-OH), 3.80–3.90 (m, 2H, 2%-H,
6-Ha), 4.00–4.13 (m, 3H, 5-H, 6-Hb, 5%-H), 4.19 (dd, 1H,
4-H), 4.31 (dd, 1H, 2-H), 4.45 (dd, 1H, 6%-Ha), 4.58 (m,
2H, 3-H, 6%-Hb), 4.70 (d, 1H, 1%-H), 5.54 (d, 1H, 1-H),
5.56 (dd, 1H, 4%-H), 5.67 (dd, 1H, 3%-H); J1,2=5.0,
1
syrupy 25. H NMR (300 MHz, CDCl3): l 0.88 (t, 3H,
CH3), 1.26 (m, 10H, 5CH2), 1.65 (m, 2H, CH2CH2O),
2.68 (brd, 1H, 2-OH), 3.61 (dt, 1H, CH2O), 3.82 (ddd,
1H, 2-H), 3.93 (dt, 1H, CH2O), 4.06 (ddd, 1H, 5-H),
4.47 (dd, 1H, 6-H), 4.57 (d, 1H, 1-H), 4.59 (dd, 1H,
6-H%), 5.57 (dd, 1H, 4-H), 5.63 (dd, 1H, 3-H); J1,2=7.6,
J2,3=9.4, J2,OH=2.3, J3,4=9.4, J4,5=9.3, J5,6=3.6 and
5.5, J6,6%=12.0 Hz. Anal. calcd for C35H40O9 (604.73):
C, 69.52; H, 6.67. Found: C, 68.97; H, 6.59.
3.4.3.
5a-Cholestan-3b-yl
3,4,6-tri-O-benzoyl-b-D-
glucopyranoside, 26. To a cooled (−78°C) solution of
cholestanyl uloside 9 (3.90 g, 4.5 mmol) in THF (50
mL) was added dropwise a solution of BH3–pyridine
(2.30 mL, 23 mmol) in THF (15 mL). The mixture was
stirred for 1 h, allowed to warm up to rt, and was
quenched with water (5 mL). After removal of the
solvents the syrupy residue was diluted with CH2Cl2 (60
mL). The organic layer was stirred vigorously for 30
min in a two-phase system with 2N HCl (20 mL).
Washing with 2N HCl (20 mL), satd NaHCO3/NaCl
solution (1:1, 40 mL), drying (Na2SO4) and evaporation
of the solvent led to a syrup, containing the gluco- and
manno-isomers in an approximate 10:1 ratio (1H
NMR). Silica gel chromatography (4.5×22 cm column)
with toluene/EtOAc (50:1) as eluted the glucoside first
(Rf=0.35 in eluent) to give on processing the appropri-
ate fractions and crystallisation of the residue from
MeOH, 2.70 g (69%) of 26 as colorless needles; mp
J
2,3=2.3, J3,4=7.8, J4,5=1.8, J1%,2%=7.8, J2%,3%=9.5,
J3%,4%=9.6, J4%,5%=9.7, J5%,6%a=5.4, J6%a,b=11.9 Hz. 13C
NMR (75.5 MHz, CDCl3): l 23.3, 24.9, 26.0 (4CH3),
63.4 (C-6%), 69.6 (C-4%), 69.9 (C-6), 70.4 (C-2), 70.7
(C-3), 71.1 (C-4), 68.0, 72.3, 72.4 (C-2%, C-5%, C-5), 74.7
(C-3%), 96.2 (C-1), 104.3 (C-1%). Anal. calcd for
C39H42O14 (734.75): C, 63.75; H, 5.76. Found: C, 64.71;
H, 5.85.
3.4.5. Methyl 4-O-(3,4,6-tri-O-benzoyl-b-
D
-glucopyran-
(methyl
osyl)-2,3,6-tri-O-benzyl-a- -glucopyranoside
D
2,3,6-tri-O-benzyl-3%,4%,6%-tri-O-benzoyl-a-cellobioside),
28. A suspension of methyl 2,3,6-tri-O-benzyl-a-D-
glucopyranoside16 (2.05 g, 4.3 mmol), powdered molec-
14
,
ular sieve (4 A, 2.50 g) and silver alumosilicate (6.90
g, 22 mmol) in CH2Cl2 (15 mL) was stirred at rt for 30
min. A solution of ulosyl bromide 7 (3.60 g, 6.46 mmol)
in CH2Cl2 (15 mL) was added and the mixture was
stirred at rt for 16 h. Dilution with CH2Cl2 (50 mL),
filtration through Celite and evaporation of the solvent
afforded a hard foam (4.97 g), which was dissolved in
THF (50 mL) and cooled (−78°C). BH3–pyridine (1.80
mL, 18 mmol) in THF (15 mL) was added dropwise
and after stirring for 30 min the mixture was allowed to
warm up to rt and quenched with water (4.5 mL).
1
99–101°C; [h]2D0=−20.8 (c 1.3, CHCl3). H NMR (300
MHz, CDCl3): l 0.50–2.00 (m, 46H, Hcholestanyl), 2.57
(d, 1H, 2-OH), 3.67 (m, 1H, 3-Hcholestanyl), 3.79 (ddd,
1H, 2-H), 4.06 (ddd, 1H, 5-H), 4.49 (dd, 1H, 6-Ha),
4.55 (dd, 1H, 6-Hb), 4.66 (d, 1H, 1-H), 5.52 (dd, 1H,
4-H), 5.62 (dd, 1H, 3-H); J1,2=7.8, J2,3=9.4, J2,OH
=
2.5, J3,4=9.5, J4,5=9.6, J5,6a=6.0, J5,6b=3.7, J6a,b=12.0
Hz. 13C NMR (75.5 MHz, CDCl3): l 11.7–56.2

736
F. W. Lichtenthaler et al. / Tetrahedron: Asymmetry 14 (2003) 727–736
Evaporation of the solvents in vacuo yielded a syrup,
which was dissolved in CH2Cl2 (100 mL) and stirred
vigorously with 2N HCl (25 mL) for 30 min. The
organic layer was washed with satd NaHCO3 solution
(100 mL) and water (2×50 mL), dried (Na2SO4), and
freed from the solvent. The residue, consisting of an
approximate 10:1 mixture of gluco- (28) and manno-iso-
mers (17) was subjected to chromatography on silica gel
(5×30 cm, eluent: toluene/EtOAc, 5:1).
Glycosci. Glycotechnol. 1993, 5, 121–142; (b) Gridley, J.
J.; Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1 2000,
1471–1491; (c) Pozsgay, V. In Carbohydrates in Chemistry
and Biology; Ernst, B.; Hart, G. W.; Sinay¨, P., Eds.;
Wiley-VCH: Weinheim, 2000; Part I, pp. 332–336.
3. Lichtenthaler, F. W.; Schneider-Adams, T.; Immel, S. J.
Org. Chem. 1994, 59, 6735–6738.
4. Lichtenthaler, F. W.; Kla¨res, U.; Szurmai, Z.; Werner, B.
Carbohydr. Res. 1998, 305, 293–303.
5. (a) Nitz, M.; Byron, W. P.; Bundle, D. R. Org. Lett.
2000, 2, 2939–2942; (b) Nitz, M.; Bundle, D. R. J. Org.
Chem. 2001, 66, 8411–8423.
6. Lichtenthaler, F. W.; Kla¨res, U.; Lergenmu¨ller, M.;
Schwidetzky, S. Synthesis 1992, 179–184.
The major product with Rf=0.15 (in eluent) was eluted
first to afford after removal of the solvents from the
appropriate fractions 2.91 of 28 (72%, based on bro-
20
365 nm
mide 7) as a colorless foam; [h]2D0=−2.7; [h]
=
1
−32.5 (c 1, CHCl3). H NMR (300 MHz, CDCl3): l
3.35 (s, 3H, CH3O), 3.47–3.53 (m, 1H, 5%-H), 3.51 (dd,
1H, 2-H), 3.58 (d, 1H, 2%-OH), 3.63–3.69 (m, 2H, 2%-H,
6-Ha), 3.79 (m, 1H, 5-H), 3.97 (dd, 1H, 3-H), 4.04 (dd,
1H, 6-Hb), 4.05 (dd, 1H, 4-H), 4.16 (dd, 1H, 6%-Ha),
4.31 (dd, 1H, 6%-Hb), 4.49 (d, 1H, C6H5CH2), 4.57 (d,
1H, 1-H), 4.58 (d, 1H, C6H5CH2), 4.67 (d, 1H, 1%-H),
4.73, 4.74, 4.90, 5.00 (4d, 1H, each, 4C6H5CH2), 5.33
(dd, 1H, 3%-H), 5.47 (dd, 1H, 4%-H); J1,2=4.0, J2,3=9.1,
7. Lichtenthaler, F. W.; Schneider-Adams, T. J. Org. Chem.
1994, 59, 6728–6734.
8. Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338–344.
´
9. Kere´kgya´rto´, J.; Ra´ko´, J.; Agoston, K.; Gye´mo´nt, G.;
Szurmai, Z. Eur. J. Org. Chem. 2000, 3931–3935.
10. Garegg, P. Adv. Carbohydr. Chem. Biochem. 1997, 52,
179–205.
11. (a) Ekborg, G.; Lindberg, B.; Lo¨nngren, J. Acta Chem.
Scan. 1972, 26, 3287–3292; (b) Shaban, M. A. E.; Jean-
loz, R. W. Carbohydr. Res. 1976, 52, 103–114, Carbohydr.
Res. 1976, 52, 115–127; (c) Waren, C. D.; Auge´, C.;
Laver, M. L.; Suzuki, S.; Power, D.; Jeanloz, R. W.
Carbohydr. Res. 1980, 82, 71–83; (d) Kere´kgya´rto´, J.;
Kamerling, J. P.; Bouwstra, J. B.; Vliegenthart, J. F. G.;
Lipta´k, A. Carbohydr. Res. 1989, 186, 51–62; (e) Kere´kg-
ya´rto´, J.; van der Ven, J. G. M.; Kamerling, J. P.; Lipta´k,
A.; Vliegenthart, J. F. G. Carbohydr. Res. 1993, 238,
135–145; (f) Kere´kgya´rto´, J.; Agoston, K.; Batta, G.;
Kamerling, J. P.; Vliegenthart, J. F. G. Tetrahedron Lett.
1998, 39, 7189–7192.
J3,4=9.2, J4,5=9.4, J5,6b=3.7, J6a,b=11.3, JCH2=11.4,
12.1, 12.2, J1%,2%=7.8; J2%,3%=9.5, J2%,OH=3.2, J3%,4%=9.6,
J4%,5%=9.7, J5%,6%a=4.7, J5%,6%b=3.3, J6%a,b=12.2 Hz. 13C
NMR (75.5 MHz, CDCl3): l 55.5 (CH3O), 63.5 (C-6%),
68.7 (C-6), 69.7 (C-4%, C-5), 72.2 (C-5%), 73.6 (C-2%),
73.7, 73.9, 75.3 (3C6H5CH2), 75.6 (C-3%), 77.5 (C-4),
79.4 (C-2), 80.8 (C-3), 98.6 (C-1), 103.3 (C-1%). MS (FD,
20 mA): m/z 938 [M+], 937 [M+−H], 936 [M+−2H], 847
[M+−C7H7], 846 [M+−C7H7−H]. Anal. calcd for
C55H54O16 (939.03): C, 70.35; H, 5.80. Found: C, 70.37;
H, 5.68.
12. (a) Lemieux, R. U.; James, K.; Nagabhushan, T. L.; Ito,
Y. Can. J. Chem. 1973, 51, 33–41; (b) Lemieux, R. U.;
James, K.; Nagabhushan, T. L. Can. J. Chem. 1973, 51,
48–52.
Acknowledgements
13. (a) Kaji, E.; Lichtenthaler, F. W.; Nishino, T.; Yamane,
A.; Zen, S. Bull. Chem. Soc. Jpn. 1988, 61, 1291–1297; (b)
Kaji, E.; Lichtenthaler, F. W.; Osa, Y.; Takahashi, K.;
Zen, S. Bull. Chem. Soc. Jpn. 1995, 68, 2401–2408.
14. The term ‘silver alumosilicate’ refers to silver(I) immobi-
lized on porous silica-alumina, prepared according to:
Van Boeckel, C. A. A.; Beetz, T.; Klock-van Dalen, A.
C.; van Bekkum, H. Recl. Trav. Chim. Pays-Bas 1987,
106, 596–599.
Support of these investigations by the Fonds der
Chemischen Industrie, Frankfurt, the Su¨dzucker AG,
Mannheim/Ochsenfurt, and the Volkswagen-Stiftung,
Hannover (fellowship to Z. S.) is gratefully
acknowledged.
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1. (a) Lichtenthaler, F. W.; Kaji, E.; Weprek, S. J. Org.
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