Asymmetric synthesis of amino sugars. Part 2. A novel versatile approach to the chiral non-racemic synthesis of 2-amino-2-deoxy sugars. Preparation of L-glucosamine, L-mannosamine and L-talosamine derivatives

Article abstract of DOI:10.1039/b001721n

The asymmetric synthesis of 2-amino-2-deoxy sugars, starting from chiral building block and 2,3-O-isopropylideneglyceraldehyde via Julia olefination and subsequent dihydroxylation was discussed. The essential feature of the process is the transformation of the readily available building blocks into a fully protected derivative of 2-amino polyol followed by cyclization to 2-amino-2-deoxy sugar. The versatility of the approach was exemplified by the preparation of L-glucosamine, L-mannosamine and L-talosamine derivatives in highly diastereometrically pure forms.

Full text of DOI:10.1039/b001721n

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Asymmetric synthesis of amino sugars. Part 2.† A novel versatile
approach to the chiral non-racemic synthesis of 2-amino-2-deoxy
sugars. Preparation of L-glucosamine, L-mannosamine and
L-talosamine derivatives
1
Ludmila Ermolenko, N. André Sasaki* and Pierre Potier
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse,
91198 Gif-sur-Yvette, France. Fax: ϩ330169077247; E-mail: andre.sasaki@icsn.cnrs-gif.fr
Received (in Cambridge, UK) 2nd March 2000, Accepted 4th April 2000
Published on the Web 5th May 2000
A novel methodology for asymmetric synthesis of 2-amino-2-deoxy sugars is developed, starting from readily
available chiral building block 1 and 2,3-O-isopropylideneglyceraldehyde 2, via Julia olefination and subsequent
dihydroxylation as key steps. The versatility of this approach is exemplified by the preparation of -glucosamine,
-mannosamine and -talosamine derivatives in highly diastereometrically pure forms.
protected derivative of 2-amino polyol 3 followed by cyclization
to 2-amino-2-deoxy sugar 4 as shown in Chart 1.
Introduction
2-Amino-2-deoxy sugars are widely distributed in nature and
play many important biological roles. They are constituents of
nucleoside and aminoglycoside antibiotics,1 skeletal material
(Crustacea chitin), connective tissue and body-movement
lubricants (glycolipids), serum mucoproteins, and biopolymers
responsible for cell recognition, differentiation and protection.2
Furthermore, the neoconjugates derived from oligosaccharides
of natural and synthetic origin containing 2-amino-2-deoxy
sugars are of great importance as extremely sensitive selective
research and diagnostic tools and synthetic vaccines devoid of
side effects. In spite of such omnipresence, only a few 2-amino-
2-deoxy sugars are available from natural sources in quantities
sufficient to satisfy the growing demands for research, medical
and diagnostic uses. Moreover, several 6-deoxyaminohexoses,
important carbohydrate units of many antibiotics, also belong
to the 2-amino-2-deoxy sugar family normally of the L-form.3
These 2-amino dideoxyhexoses are rather difficult to obtain by
the traditional methods of chemical transformation of mono-
saccharides.
Chart 1
The E-selective Julia olefination of (R)- or (S)-2,3-isopropyl-
ideneglyceraldehyde 2 with either (R)- or (S)-1 sets two chiral
centres within the six-carbon chain of the 2-amino-2-deoxy
sugar precursors. The remaining hydroxy functional groups
can be introduced by stereoselective dihydroxylation of the
double bond. Molecular mechanics calculation of the E-olefins
reveals significant inherent face differentiation of the double
bond (at least for R,R and S,S pairs obtained from 2 and 1) so
that the 2-aminohexanepentols with - and -gluco and - and
-manno configurations can be preferentially obtained by cis-
dihydroxylation. Other configurations of the 2-aminohexane-
pentols are potentially available either by regioselective
modification of the newly formed hydroxy groups or by
trans-dihydroxylation of the double bond. After appropriate
protection of the two newly created hydroxy groups and
transformation of the C-1 functionality of a 2-amino polyol 3
into aldehyde, cleavage of the cyclic acetal, and concomitant
intramolecular cyclization would provide the corresponding
2-amino-2-deoxy sugars in their pyranose form.
The well recognised biological importance of 2-amino-2-
deoxy sugars has stimulated significant efforts towards the syn-
theses of this class of compounds. Traditionally they have
been synthesized through multistep transformation of other
relatively inexpensive and ready available carbohydrates.4 But
recent interest increasingly has focused on non-carbohydrate
precursors.5 Some examples of this non-carbohydrate method-
ology are direct amination of carbocycles,6a–c transformation of
isoxazolines6d–g and 2-thiazolyl-N-alkylhydroxylamines,6h,i the
use of hetero-Diels–Alder addition,6j,k [3 ϩ 2] cycloaddition of
nitrones with vinylene carbonate6l and the utilization of readily
available natural products such as amino acids6m–q and lactic
acid6r–t as chiral pool materials for the construction of amino
sugar frameworks. However, some of these approaches still
suffer from low stereoselectivity, their need of lengthy reaction
sequences, and limited versatility.
In our previous preliminary communication,7 we have
reported a novel methodology for asymmetric synthesis of
2-amino sugars either in - or -configuration. The essential
feature of our strategy is the transformation of the readily
available chiral building blocks 18 and 29,10 into a fully
As part of our continuing efforts in developing a novel
efficient methodology for the synthesis of amino sugars,
herein we describe the syntheses of fully protected forms of
-mannosamine, -glucosamine and -talosamine, which are
difficult to obtain by other methods.11
† For Part 1 see ref. 7.
DOI: 10.1039/b001721n
J. Chem. Soc., Perkin Trans. 1, 2000, 2465–2473
This journal is © The Royal Society of Chemistry 2000
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Scheme 1 Reagents and conditions (yields): (a) n-BuLi, THF, Ϫ78 ЊC, 3 h; then RT, 1 h (85%); (b) 6% Na–Hg, Na2HPO4, MeOH, 0 ЊC, 3 h (80%); (c)
OsO4, NMO, THF–H2O (9:1), RT, 3 h (95%); (d) TBDMSCl, imidazole, DMF, RT, 24 h (95%); (e) Ac2O, Et3N, DMAP, CH2Cl2, RT, 24 h (80%);
(f) H2, 10% Pd/C, EtOAc, RT, 18 h (98%); (g) PyؒSO3, Et3N, DMSO, 0 ЊC, 2 h (90%); (h) HCl, MeOH, RT, 8 h; then Ac2O, Et3N, DMAP, CH2Cl2, RT,
3 h (80%).
the primary isopropylidene group has been reported,19 signifi-
cant loss of both isopropylidene groups took place in our case.
Results and discussion
Synthesis of 1,4,6-tri-O-acetyl-2-(tert-butoxycarbonylamino)-
3-O-tert-butyldimethylsilyl-2-deoxy--mannopyranose is shown
in Scheme 1.
Eventually, the silylation20 of diol 8 was found to proceed with
very high selectivity, providing C-3-O-mono-TBDMS ether 10
in 95% yield with only trace amounts of the undesired regio-
isomer that is easily separable by column chromatography.
Subsequent acetylation of the hydroxy group at the C-4
position in 10 was achieved after 24 h in 80% yield. The fully
protected 2-aminohexanepentol 11 was subjected to hydro-
genolysis to give α-amino alcohol 12 in excellent yield. The
corresponding aldehyde 13 was obtained by oxidation of 12
using either the Dess–Martin periodinane21 or the complex
PyؒSO3 in DMSO.22 Both methods gave good yields, but we
routinely used the latter for reasons of practicality. Swern oxid-
ation and chromium reagents (PCC and PDC) gave poor
results. Removal of the acetonide from 13 in MeOH in the
presence of a catalytic amount of HCl followed by acetylation
afforded, in 80% yield, the fully protected -mannosamine 14 as
a mixture of α- and β-anomers in approximately 2:1 ratio. No
trace of the corresponding methyl glycosides was found under
these mild conditions.
Coupling of the dilithiate (S)-5, prepared from chiral
synthon (S)-1,12 with (2S)-2,3-O-isopropylideneglyceraldehyde
2 afforded a diastereomeric mixture of hydroxy sulfones 6 in
good yield.13 Treatment of the β-hydroxy sulfone 6 with 6%
sodium amalgam furnished the olefin 7 in 80% yield as an easily
separable mixture of E- and Z-isomer (≈4:1). The reductive
elimination from the corresponding acetate was attempted with
anticipation to improve the selectivity,14 but provided exactly
the same ratio of E- and Z-isomer in only moderate overall
yield. We first investigated the dihydroxylation of E-olefin 7
using the Sharpless chiral reagent AD-mix-β.15 The reaction
was sluggish and only 40% conversion of the olefin was attained
after 48 h to give a mixture of the diols 8 and 9 with 9:1 ratio,16
in good agreement with earlier results on similar substrates.17
On the other hand, osmium-catalysed dihydroxylation with-
out chiral auxiliary18 proceeded rapidly and afforded a
mixture of these diols in high yield (95%) and with acceptable
selectivity (8:9 = 77:23). Since the diols were easily separable
by preparative column chromatography, we opted for the
use of the latter method. With the enantiomerically pure
2-aminohexanepentol 8 in hand, the route to desired 2-
amino-2-deoxy-L-mannose derivatives seemed straightforward.
However, protection of the hydroxy groups of the diol 8 was
found to be more difficult than expected. Attempts to prepare
the MEM derivative failed to provide the desired 3,4-
bis-protected product and only a mixture of C-3- and C-4-
mono-protected diols was obtained in ≈3:2 ratio even under
forced conditions.
Synthesis
of
1,4,6-tri-O-acetyl-2-(tert-butoxycarbonyl-
amino)-3-O-tert-butyldimethylsilyl-2-deoxy--glucopyranose
23 was then carried out from synthon (R)-5 and (S)-2,3-
isopropylideneglyceraldehyde 2 in the same synthetic sequence
described above for its -mannopyranose analogue (Scheme 2).
β-Hydroxy sulfone 15 was obtained in the same good yield as
6, and treatment of 15 with 6% Na–Hg furnished the olefin 16
with the same selectivity (E:Z ≈ 4:1). Dihydroxylation of the
olefin 16 afforded a mixture of the diols 17 and 18 in excellent
yield but with rather poor selectivity (2:1), presumably as a
result of change in the steric environment around the double
bond (R,S pair obtained from 1 and 2). Fortunately, the regio-
selectivity of silylation of the diol 17 was not changed, and the
desired TBDMS ether 19 was obtained in the good yield though
sluggishly. On the other hand, acetylation of the hydroxy func-
tion in 19 proceeded rapidly (after 1 h, compared with 24 h
required for 10) and afforded totally protected 2-aminohex-
anepentol 20 in excellent yield. Catalytic hydrogenation of the
latter provided the alcohol 21, which was then oxidized to the
α-amino aldehyde 22. Deprotection of the acetonide in 22 in
MeOH in the presence of a catalytic amount of HCl followed
Successful bis-protection was achieved only in the case of
acetyl and isopropylidene protecting groups, both of which
were of no synthetic use for our goal. The presence of an
acetoxy group at the C-3 position of the diol 8 led to undesired
α,β-elimination during the oxidation of the C-1 primary alco-
hol to an aldehyde (step g), whereas 3,4;5,6-di-O-isopropylidene
protection of the 2-aminohexanepentol 8 caused difficulty in
the selective cyclization of the aldehyde 13 to the pyranose form
of amino sugar (step h). Although a selective deprotection of
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Scheme 2 Reagents and conditions (yields): (a) n-BuLi, THF, Ϫ78 ЊC, 3 h; then RT, 1 h (84%); (b) 6% Na–Hg, Na2HPO4, MeOH, 0 ЊC, 3 h (80%);
(c) OsO4, NMO, THF–H2O (9:1), RT, 3 h (87%); (d) TBDMSCl, imidazole, DMF, RT, 24 h (90%); (e) Ac2O, Et3N, DMAP, CH2Cl2, RT, 1 h (95%);
(f ) H2, 10% Pd/C, EtOAc, RT, 18 h (98%); (g) PyؒSO3, Et3N, DMSO, 0 ЊC, 6 h (70%); (h) HCl, MeOH, RT, 48 h; then Ac2O, Et3N, DMAP, CH2Cl2,
RT, 1 h (60%).
by acetylation afforded the fully protected -glucosamine 23 as
almost pure α-anomer.
The stereochemistry of diols 8, 9, 17 and 18 was assigned by
NMR studies of the corresponding N,O-diacetyloxazolidin-
ones 24, 25, 26 and 27 obtained from 8, 9, 17 and 18, respec-
tively, by treatment with NaH followed by acetylation. The
coupling constants J2,3 are 7.0 and 9.3 Hz for the 2,3-threo-
isomers 24 and 27, and 3.1 and 2.5 Hz for the 2,3-erythro-
isomers 25 and 26, respectively. These values are in agreement
with corresponding data for related compounds23 and are also
consistent with the dihedral angles from molecular mechanics
calculations. Furthermore, an intense nuclear Overhauser effect
(NOE) observed between H-2 and H-3, and between H-1 and
H-4 in 2D NOESY experiments for oxazolidinone 24 is in
accordance with the stereochemistry depicted in Scheme 3.
By choosing the appropriate set of starting synthons 1 and 2,
the sequence described above allows the synthesis of suitably
protected 2-amino-2-deoxyhexopyranoses of gluco and manno
configurations in both - and, more interestingly, -series.
Further extension of the scope of our approach is possible by
selective modification of the stereochemistry on the inter-
mediates, as was demonstrated (vide infra) in the synthesis of a
2-amino-2-deoxy-L-talopyranose derivative. The free hydroxy
group at C-4 in the ether 10 provides the possibility for modifi-
cation of the configuration at this centre. Our first idea was to
utilize the chloroacetate modification of the Mitsunobu reac-
tion24 which was found to be very efficient for the inversion of
sterically hindered alcohols. However, upon treatment of 10
with chloroacetic acid in the presence of triphenylphosphine
and diethyl azodicarboxylate, merely the starting material was
recovered. We therefore directed our attention toward the
oxidation of the hydroxy function at C-4 into a keto group,
Scheme 3 Reagents and conditions (yields): (a) NaH, THF, 60 ЊC, 4 h,
(60–80%); (b) Ac2O, Et3N, DMAP, 1 h (95%).
followed by selective reduction to obtain the inverted product
(Scheme 4). However, we anticipated that no reasonable model
to predict the desired selectivity could be formulated a piori for
this densely functionalized substrate.
The hydroxy group of TBDMS ether 10 was oxidized
uneventfully by the tetrapropylammonium perruthenate
(TPAP) method25 and the resultant ketone 28 was reduced with
a number of hydride reagents. As can been seen from Table 1,
L-Selectride in THF26 provided the best result among the
reagents examined (sodium borohydride in methanol; DIBAL;
zinc borohydride; and sodium borohydride in the presence of
CeCl3).
The mixture of two alcohols 29 and 10 (85:15) was easily
separated by column chromatography and the main isomer 29
was acetylated to give the fully protected 2-amino polyol 30 of
the desired -talo stereochemistry. The latter was subjected to
hydrogenolysis to afford α-amino alcohol 31. Oxidation of 31
J. Chem. Soc., Perkin Trans. 1, 2000, 2465–2473
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Scheme 4 Reagents and conditions (yields): (a) TPAP, NMO, CH3CN, RT, 2 h (93%); (b) L-Selectride, THF, Ϫ78 ЊC, 30 min (88%); (c) Ac2O, Et3N,
DMAP, CH2Cl2, RT, 30 min (98%); (d) H2, 10% Pd/C, EtOAc, RT, 18 h (93%); (e) PyؒSO3, Et3N, DMSO, 0 ЊC, 2 h (80%); (f) HCl, MeOH, RT, 48 h;
then Ac2O, Et3N, DMAP, CH2Cl2, RT, 3 h (65%).
δC 77.14 for 13C, unless otherwise specified. Chemical ionization
Table 1 Reduction of ketone 28
mass spectra were recorded on an AEI MS-9 spectrometer
Entry
Reduction conditions
Yield (%)
Ratio (29:10)
(isobutane), and high-resolution mass spectra were obtained
on a Kratos MS-80 spectrometer by CI (methane). Elemental
analyses were performed by the microanalytical laboratory at
the ICSN, CNRS, Gif-sur-Yvette.
1
2
3
4
5
NaBH4–CeCl3–MeOH
NaBH4–MeOH
DIBAL–CH2Cl2
Zn(BH4)2–Et2O
L-Selectride
85
90
95
60
88
Only 10
70:30
60:40
50:50
85:15
(2S,5S)-6-Benzyloxy-5-[(tert-butoxycarbonyl)amino]-1,2-iso-
propylidenedioxy-4-(phenylsulfonyl)hexan-3-ol 6
using the complex PyؒSO3 afforded the expected α-amino alde-
hyde 32, which was subjected to acidic methanolysis followed
by acetylation. The product obtained in this manner was a
mixture of the α- and β-anomers of 1,4,6-tri-O-acetyl-2-(tert-
butoxycarbonylamino)-3-O-tert-butyldimethylsilyl-2-deoxy--
talopyranose 33a and 33b (2:1) which were separated by
column chromatography.
It is noteworthy that the strategy described here can also
be highly suitable for the acquisition of chiral, non-racemic
furanose forms of 2-amino-2-deoxy sugars as well as poly-
hydroxylated pyrrolidine and piperidine derivatives.
To a solution of (S)-5 (4.05 g, 10 mmol) in THF (100 ml),
obtained from (S)-1,11 was added n-BuLi (1.6 M in hexane; 12.5
mol, 20 mmol) dropwise at Ϫ78 ЊC under dry argon. The mix-
ture was stirred for 20 min and then a solution of (2S)-2,3-O-
isopropylideneglyceraldehyde 2 (1.69 g, 13 mmol) in THF (10
ml) was added. After stirring for 3 h at Ϫ78 ЊC, the reaction
mixture was allowed to warm to room temperature while being
stirred for 1 h, quenched with saturated aq. NH4Cl (30 ml) and
concentrated. The residue was dissolved in EtOAc (500 ml), the
solution washed successively with water (2 × 100 ml) and brine
(200 ml), dried over Na2SO4, and the solvent was removed
under reduced pressure. Flash chromatography of the resi-
due (CH2Cl2–EtOAc 25:1) afforded an isomeric mixture of
β-hydroxy sulfones 6 (4.55 g, 85%) (Found: C, 60.2; H, 6.9; N,
2.6; S, 6.0. C27H37NO8S requires C, 60.5; H, 7.0; N, 2.6; S,
6.0%); νmax (neat)/cmϪ1 3483, 3428, 2984, 2934, 2880, 1714,
1692, 1498, 1454, 1449, 1370, 1308, 1251; δH (CDCl3) 7.97–7.92
(2H, m), 7.68–7.50 (3H, m), 7.32–7.15 (5H, m), 5.93–5.98 (1H,
m), 4.65–4.52 (1H, m), 4.50–4.31 (2H, m), 4.30–4.20 (1H, m),
4.18–4.08 (1H, m), 4.08–3.95 (2H, m), 3.85–3.75 (1H, m), 3.70–
3.45 (3H, m), 1.44, 1.42 (9H, 2s), 1.40, 1.35, 1.31, 1.24 (6H, 4s);
δC (CDCl3) 155.3, 155.2, 137.5, 137.3, 134.1, 134.0, 129.6, 129.3,
129.2, 128.6, 128.4, 128.0, 127.8, 127.6, 110.0, 109.9, 80.0, 79.6,
75.7, 73.1, 72.2, 71.6, 70.6, 69.3, 68.8, 67.9, 66.1, 65.0, 63.5,
60.5, 49.8, 48.6, 28.4, 26.9, 26.3, 25.2, 25.1, 21.1; m/z (CI) 536
[M ϩ H]ϩ, 480, 436.
Conclusions
We have developed a novel, efficient methodology for the stereo-
selective synthesis of chiral, non-racemic 2-amino-2-deoxy
sugars. According to the present approach, the desired stereo-
chemistry of the pyranose ring at the C-2 and C-5-positions is
predetermined by appropriate selection of (R)- or (S)-1 and
(R)- or (S)-2 as chiral starting materials. This in turn dictates
the stereooutcome at the remaining C-3 and C-4 positions via
E-selective Julia olefination and subsequent dihydroxylation.
Experimental
Reagents, obtained from commercial sources, were used with-
out further purification. THF was distilled from sodium
benzophenone ketyl. All other organic solvents were dried and
distilled before use. Column chromatography was performed on
Merck 60 silica gel (230–400 mesh) at medium pressure (300
mbar).‡ Analytical TLC was carried out on plates precoated
with 0.25 mm of silica gel containing 60F-254 indicator.
Optical rotations were measured with a Perkin-Elmer 241
polarimeter for samples in CHCl3 solution; [α]D-values are
reported in units of 10Ϫ1 deg cm2 gϪ1. IR spectra were obtained
on Perkin-Elmer Spectrum BX spectrometer. 1H NMR spectra
were recorded at 300, 250, and 200 MHz, and 13C NMR spectra
were recorded at 75.5, 62.5, and 50 MHz with chemical shifts
reported in ppm (δ) downfield from TMS (internal reference)
(2R,5R)-1-Benzyloxy-2-[(tert-butoxycarbonyl)amino]-5,6-iso-
propylidenedioxyhex-3-ene
To a solution of hydroxy sulfone 6 (4.55 g, 8.5 mmol) in HPLC-
grade methanol (70 ml) containing Na2HPO4 (12.1 g, 85 mmol)
was added 6% Na-Hg (25 g, 65 mmol) at 0 ЊC. The mixture was
stirred at this temperature for 3 h. Mercury was removed by
decanting the reaction mixture, and methanol was evaporated.
The residue was diluted in water (200 ml) and extracted with
EtOAc (3 × 100 ml). The organic extracts were washed succes-
sively with water (2 × 100 ml) and brine (100 ml), dried over
Na2SO4 and evaporated. Flash chromatography of the residue,
eluting with heptane–EtOAc 3:1, provided two olefins (2.54 g,
80%): 1.95 g (77%) of the E-isomer 7 and 0.59 g (23%) of the
Z-isomer.
1
for H and relative to the centre line of the triplet of CDCl3 at
‡ 1 bar = 105 Pa.
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E-Isomer 7. [α]D20 Ϫ7.3 (c 2.0) (Found: C, 66.5; H, 8.7; N, 3.6.
C21H31NO5 requires C, 66.8; H, 8.3; N, 3.7%); νmax (neat)/cmϪ1
3348, 3030, 2982, 2934, 2869, 1715, 1511, 1498, 1455, 1391,
1368, 1247; δH (CDCl3) 7.33–7.30 (5H, m), 5.83 (1H, dd, J 5.1,
15.6 Hz), 5.64 (1H, ddd, J 1.2, 7.1, 15.6 Hz), 4.92 (1H, br s),
4.58–4.44 (3H, m), 4.35 (1H, br), 4.07 (1H, dd, J 6.1, 8.0 Hz),
3.56 (1H, t, J 8.0 Hz), 3.54–3.45 (2H, m), 1.44 (9H, s), 1.41, 1.38
(6H, 2s); δC (CDCl3) 155.4, 137.9, 132.4, 128.9, 128.5, 127.8,
127.7, 109.4, 79.6, 76.6, 73.2, 72.0, 69.5, 51.4, 28.4, 26.7, 26.0;
m/z (CI) 378 [M ϩ H]ϩ, 278, 264.
was purified by column chromatography, eluting with heptane–
EtOAc 5:1, to afford 10 (1.48 g, 95%) as colourless oil; [α]D20
ϩ11.0 (c 1.5) (Found: C, 61.2; H, 8.9; N, 2.8. C27H47NO7Si
requires C, 61.7; H, 9.03; N, 2.7%); νmax (neat)/cmϪ1 3428br,
2980, 2954, 2931, 2886, 2858, 1715, 1693, 1501, 1473, 1455,
1367, 1253; δH (CDCl3) 7.18–7.05 (5H, m), 5.30 (1H, d, J 7.1
Hz), 4.57, 4.45 (2H, 2d, J 11.9 Hz), 4.10–4.03 (2H, m), 4.02–
3.78 (3H, m), 3.75–3.40 (3H, m), 2.85 (1H, d, J 7.1 Hz), 1.42
(9H, s), 1.36, 1.32 (6H, 2s), 0.91 (9H, s), 0.15, 0.14 (6H, 2s);
δC (CDCl3) 156.0, 138.0, 128.5, 127.7, 109.4, 79.4, 75.0, 73.3,
72.4, 69.5, 69.4, 68.1, 53.6, 28.5, 27.0, 26.1, 25.4, 18.3, Ϫ4.4,
Ϫ4.5; m/z (CI) 582 [M ϩ 57]ϩ, 526 [M ϩ H]ϩ, 470, 436.
Z-Isomer. [α]D20 ϩ3.7 (c 2.0) (Found: MHϩ, 378.2282. C21H32-
NO5 requires m/z, 378.2280); νmax (neat)/cmϪ1 3347, 3030, 2982,
2933, 2969, 1715, 1511, 1498, 1455, 1391, 1368, 1247;
δH (CDCl3) 7.35–7.30 (5H, m), 5.68 (1H, dd, J 10.4, 11.0 Hz),
5.33 (1H, dd, J 8.7, 11.0 Hz), 5.10–4.90 (2H, m), 4.65–4.55 (1H,
m), 4.57, 4.49 (2H, 2d, J 11.9 Hz), 4.18 (1H, dd, J 6.2, 8.1 Hz),
3.61–3.45 (2H, m), 1.44 (9H, s), 1.41, 1.36 (6H, 2s); δC (CDCl3)
155.1, 137.9, 131.9, 130.3, 129.8, 128.5, 127.9, 127.8, 109.4,
79.6, 73.4, 72.3, 72.2, 69.8, 48.0, 28.5, 26.9, 25.9; m/z (CI) 378
[M ϩ H]ϩ, 278, 264.
4-O-Acetyl-1-O-benzyl-2-[(tert-butoxycarbonyl)amino]-3-O-
(tert-butyldimethylsilyl)-2-deoxy-5,6-O-isopropylidene-L-
mannitol 11
A solution of 10 (1.05 g, 2 mmol), triethylamine (0.93 ml, 6.6
mmol), Ac2O (0.58 ml, 6 mmol) and DMAP (100 mg) in 5 ml of
CH2Cl2 was stirred at room temperature for 24 h. Methanol
(3 ml) was added, and stirring was continued for 30 min. The
solvent was diluted with EtOAc (150 ml), and the mixture was
washed successively with water (50 ml), 1 M HCl (50 ml), satur-
ated aq. NaHCO3 (50 ml) and brine (50 ml), dried over Na2SO4
and evaporated. After removal of the solvent, the residue was
purified by column chromatography, eluting with heptane–
EtOAc 5:1, to afford 11 (910 mg, 80%); [α]D20 Ϫ7.3 (c 0.6)
(Found: MHϩ, 568.3309. C29H50NO8Si requires m/z, 568.3306);
νmax (neat)/cmϪ1 3455, 3362, 2980, 2957, 2931, 2887, 2858, 1751,
1716, 1496, 1474, 1455, 1368, 1228; δH (CDCl3) 7.35–7.39 (5H,
m), 5.16 (1H, dd, J 2.5, 6.8 Hz), 4.84 (1H, d, J 6.6 Hz), 4.50 (2H,
s), 4.23–4.12 (2H, m), 4.02 (1H, t, J 4.8 Hz), 3.92–3.80 (2H, m),
3.70–3.62 (1H, m), 3.50 (1H, dd, J 3.5, 9.4 Hz), 2.06 (3H, s),
1.43 (9H, s), 1.36, 1.34 (6H, 2s), 0.88 (9H, s), 0.10, 0.09 (6H,
2s); δC (CDCl3) 170.3, 155.6, 138.1, 128.5, 127.8, 109.4, 79.4,
74.0, 73.5, 73.2, 70.8, 68.5, 66.4, 52.7, 28.5, 26.6, 26.0, 25.7,
21.3, 18.4, Ϫ4.4, Ϫ4.5; m/z (CI) 568 [M ϩ H]ϩ, 512, 468.
1-O-Benzyl-2-[(tert-butoxycarbonyl)amino]-2-deoxy-5,6-O-iso-
propylidene-L-mannitol 8 and 1-O-benzyl-2-[(tert-butoxycarb-
onyl)amino]-2-deoxy-5,6-O-isopropylidene-L-iditol 9
To a solution of E-isomer 7 (1.885 g, 5 mmol) in 15 ml of THF–
H2O (9:1) were successively added a solution of osmium
tetraoxide (0.2 M in tBuOH; 2.5 ml, 0.5 mmol) and N-
methylmorpholine N-oxide (NMO) (60% weight in H2O; 2.58
ml, 15 mmol). The mixture was stirred at room temperature for
3 h, quenched by addition of saturated aq. Na2SO3 (50 ml), and
stirred for an additional 30 min. THF was evaporated, and the
residue was diluted with water (50 ml) and extracted with
EtOAc (3 × 100 ml). The combined organic extracts were
washed successively with water (100 ml) and brine (100 ml),
dried over Na2SO4 and evaporated. Flash chromatography of
the residue, eluting with heptane–EtOAc 1:1, provided the two
diols (2.055 g, 95%): 1.58 g and 0.47 g (77:23).
4-O-Acetyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-mannitol 12
Major isomer 8. [α]D20 ϩ5.6 (c 1.2) (Found: C, 61.3; H, 8.8; N,
3.3. C21H33NO7 requires C, 61.3; H, 8.9; N, 3.4%); νmax (neat)/
cmϪ1 3439br, 2981, 2933, 1709, 1504, 1454, 1367, 1248;
δH (CDCl3) 7.35–7.25 (5H, m), 5.29 (1H, d, J 7.9 Hz), 4.57, 4.50
(2H, 2d, J 11.8 Hz), 4.22–4.08 (3H, m), 3.97–3.87 (2H, m),
3.80–3.72 (1H, m), 3.68–3.58 (2H, m), 3.49 (1H, dd, J 3.4, 7.2
Hz), 2.73 (1H, d, J 8.9 Hz), 1.44 (9H, s), 1.38, 1.34 (6H, 2s);
δC (CDCl3) 157.3, 137.8, 128.5, 127.8, 109.2, 80.5, 74.8, 73.5,
71.4, 69.9, 68.9, 67.8, 52.1, 28.3, 26.9, 25.3; m/z (CI) 468
[M ϩ 57]ϩ, 412 [M ϩ H]ϩ, 356, 312.
A stirred solution of 11 (850 mg, 1.5 mmol) in EtOAc (5 ml)
was treated with hydrogen in the presence of 10% Pd/C (80 mg)
at atmospheric pressure for 18 h. After removal of the catalyst
by filtration through Celite, the solvent was evaporated. Purifi-
cation of the residue by column chromatography, eluting with
heptane–EtOAc 1:1, afforded 12 (680 mg, 98%); [α]D20 Ϫ26.7
(c 1.5) (Found: C, 55.2; H, 9.1; N, 2.8. C22H43NO8Si requires
C, 55.3; H, 9.1; N, 2.9%); νmax (neat)/cmϪ1 3455br, 2958, 2932,
2890, 2859, 1749, 1712, 1500, 1474, 1370, 1252; δH (CDCl3) 5.28
(1H, br d, J 6.2 Hz), 5.12 (1H, dd, J 6.2, 8.0 Hz), 4.22–4.05 (3H,
m), 3.92–3.80 (3H, m), 3.60–3.70 (1H, m), 2.10 (3H, s), 1.44
(9H, s), 1.38, 1.35 (6H, 2s), 0.90 (9H, s), 0.13, 0.12 (6H, 2s);
δC (CDCl3) 170.1, 156.1, 109.6, 79.7, 73.9, 73.4, 72.0, 66.2, 62.4,
54.5, 28.4, 26.5, 25.9, 25.5, 21.2, 18.2, Ϫ4.6, Ϫ4.7; m/z (CI) 534
[M ϩ 57]ϩ, 478 [M ϩ H]ϩ, 434, 426, 378, 360.
Minor isomer 9. [α]D20 ϩ7.7 (c 1.5) (Found: MHϩ, 412.2327.
C21H34NO7 requires m/z, 412.2325); νmax (neat)/cmϪ1 3440br,
3031, 2980, 2933, 1709br, 1504, 1455, 1367, 1248; δH (CDCl3)
7.22–7.15 (5H, m), 5.21 (1H, d, J 9.1 Hz), 4.55, 4.48 (2H, 2d,
J 11.8 Hz), 4.35–4.25 (1H, m), 4.18–3.92 (3H, m), 3.90–3.68
(2H, m), 3.65–3.63 (2H, m), 3.50–3.15 (2H, m), 1.43 (s), 1.36 (s)
(15H); δC (CDCl3) 156.2, 137.7, 128.5, 127.9, 127.8, 109.6, 79.7,
76.1, 73.3, 71.7, 71.1, 70.2, 66.0, 51.3, 28.3, 26.4, 25.3 ; m/z (CI)
468 [M ϩ 57]ϩ, 412 [M ϩ H]ϩ, 356, 312.
4-O-Acetyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-mannose 13
To a solution of 12 (600 mg, 1.25 mmol) in DMSO (3 ml) were
added successively triethylamine (1.2 ml, 8.25 mmol) and
PyؒSO3 (954 mg, 6 mmol) at 0 ЊC. After 2 h, the mixture was
dissolved in EtOAc (100 ml) and washed successively with
water (3 × 20 ml), 1 M HCl (30 ml), saturated aq. NaHCO3 (30
ml) and brine (30 ml), dried over Na2SO4 and evaporated. After
removal of the solvent, the residue was purified by column
chromatography, eluting with heptane–EtOAc 3:1, to afford 13
(477 mg, 90%); [α]D20 Ϫ26.7 (c 1.5) (Found: C, 55.6; H, 8.6; N,
2.8. C22H41NO8Si requires C, 55.6; H, 8.7; N, 3.0%); νmax (neat)/
cmϪ1 3437br, 2958, 2932, 2896, 2859, 1752br, 1713br, 1490,
1-O-Benzyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-mannitol 10
A solution of diol 8 (1.223 g, 3 mmol), imidazole (1.02 g, 15
mmol), and tert-butyldimethylsilyl chloride (TBDMSCl) (1.13
g, 7.5 mmol) in DMF (10 ml) was stirred at room temperature
for 24 h. The mixture was dissolved in EtOAc (300 ml), and the
solution was washed successively with water (50 ml), 1 M HCl
(50 ml), saturated aq. NaHCO3 (50 ml) and brine (50 ml) and
dried over Na2SO4. After removal of the solvent, the residue
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1474, 1370, 1253; δH (CDCl3) 9.67 (1H, s), 5.55 (1H, d, J 6.0
Hz), 5.25 (1H, t, J 7.0 Hz), 4.50 (1H, dd, J 3.0, 7.0 Hz), 4.34
(1H, dd, J 2.6, 8.5 Hz), 4.23 (1H, 2d, J 7.0, 14.0 Hz), 4.05 (1H,
dd, J 6.0, 8.3 Hz), 3.79 (1H, t, J 8.0 Hz), 2.11 (3H, s), 1.45
(9H, s), 1.42, 1.35 (6H, 2s), 0.85 (9H, s), 0.08, 0.07 (6H, 2s);
δC (CDCl3) 198.2, 169.9, 155.4, 110.2, 80.1, 74.5, 73.7, 73.2,
66.8, 63.0, 28.3, 26.5, 26.0, 25.7, 21.1, 18.1, Ϫ4.7 ; m/z (CI) 476
[M ϩ H]ϩ, 418, 362, 318.
E-Isomer 16. [α]D20 Ϫ11.3 (c 1.5) (Found: MHϩ, 378.2308.
C21H32NO5 requires m/z, 378.2280); νmax (neat)/cmϪ1 3348br,
3064, 3030, 2982, 2934, 2869, 1715, 1511, 1498, 1455, 1391,
1368, 1247; δH (CDCl3) 7.20–7.10 (5H, m), 5.82 (1H, dd, J 5.8,
15.6 Hz), 5.66 (1H, ddd, J 0.9, 6.8, 15.6 Hz), 4.87 (1H, br s),
4.58–4.45 (3H, m), 4.33 (1H, br s), 4.08 (1H, dd, J 6.3, 8.3 Hz),
3.62–3.47 (3H, m), 1.44 (9H, s), 1.42, 1.39 (6H, 2s); δC (CDCl3)
155.3, 138.0, 132.4, 129.3, 128.5, 127.9, 127.8, 109.4, 79.7, 76.7,
73.3, 72.1, 69.5, 51.7, 28.5, 26.8, 26.0; m/z (CI) 378 [M ϩ H]ϩ,
266, 210.
1,4,6-Tri-O-acetyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-
butyldimethylsilyl)-2-deoxy-L-mannopyranose 14
Z-Isomer. [α]D20 Ϫ8.7 (c 1.0) (Found: MHϩ, 378.2272); νmax
(neat)/cmϪ1 3348br, 2982, 2934, 2869, 1715, 1511, 1498, 1455,
1368, 1247; δH (CDCl3) 7.30–7.20 (5H, m), 5.60–5.50 (2H, m),
5.00–4.75 (2H, m), 4.60–4.45 (3H, m), 3.94 (1H, dd, J 6.3, 8.1
Hz), 3.50–3.42 (3H, m), 1.44 (9H, s), 1.41, 1.36 (6H, 2s);
δC (CDCl3) 155.2, 137.9, 131.7, 129.3, 128.6, 128.0, 127.8, 109.5,
73.4, 72.7, 72.4, 69.6, 48.6, 28.5, 26.8, 26.0; m/z (CI) 378
[M ϩ H]ϩ, 322, 278.
A solution of 13 (143 mg, 0.3 mmol) in methanol (3 ml) was
treated with conc. HCl (2.5 µl) and the mixture was stirred for
8 h at room temperature. After addition of triethylamine (0.1
ml), the solvent was evaporated. To a solution of the residue
in CH2Cl2 (2 ml) were added triethylamine (0.93 ml, 6.6 mmol),
Ac2O (0.58 ml, 6 mmol) and DMAP (100 mg) successively. The
mixture was stirred at room temperature for 3 h. Methanol
(3 ml) was added, and stirring was continued for 30 min. The
solvent was evaporated, and the residue was dissolved in EtOAc
(30 ml), washed successively with water (15 ml), 1 M HCl (15
ml), saturated aq. NaHCO3 (15 ml) and brine (15 ml), dried
over Na2SO4 and evaporated. After removal of the solvent, the
residue was purified by column chromatography, eluting with
heptane–EtOAc 3:1, to afford 14 as a mixture of the α- and
β-anomer in the ratio 2:1 (118 mg, 80%); [α]D20 ϩ2.8 (c 1) (Found:
C, 51.7; H, 7.6; N, 2.4. C23H41NO10SiؒH2O requires C, 51.40; H,
8.0; N, 2.6%); νmax (neat)/cmϪ1 3449, 3031, 2959, 1748, 1714,
1504, 1392, 1369, 1233; δH (CDCl3) 6.15 (br s, α-anomer H-1)
and 5.85 (d, J1,2 2.4 Hz, β-anomer H-1) (1H), 5.05–4.80 (m,
α-H-4 and β-H-4, α-NH and β-NH) (2H), 4.45–4.30 (m), 4.28
(m), 4.04 (dd, J 2.5 and 12.3 Hz), 3.95–3.85 (m), 3.82–3.75 (m)
(5H), 2.14 (s), 2.10 (s), 2.09 (s), 2.08 (s) (9H), 1.44 (s, 9H), 0.89
(s), 0.86 (s) (9H), 0.12 (s), 0.10 (s), 0.09 (s) (6H); δC (CDCl3)
170.8, 170.6, 169.8, 169.6, 169.2, 168.4 (CH3CO), 155.7
(Me3COCO), 92.3 (C-1, α-anomer), 91.6 (C-1, β-anomer), 80.2
(Me3COCO, α), 80.0 (Me3COCO β), 72.9 (C-3-β or C-5-β
interchangeable attribution), 70.1 (C-3-α or C-5-α), 69.3 (C-5-β
or C-3-β), 68.8 (C-5-α or C-3-α), 68.4 (C-4-β), 68.1 (C-4-α), 62.9
(C-6-β), 62.3 (C-6-α), 53.9 (C-2-β), 51.1 (C-2-α), 28.3 (Me3CO-
CO), 25.0 (Me3CSiMe2), 21.0 and 20.8 (CH3CO), 17.9 (Me3-
CSiMe2), Ϫ4.8 (Me3CSiMe2 β), Ϫ5.0 (Me3CSiMe2 α); m/z (CI)
537 [M ϩ NH4]ϩ, 436.
1-O-Benzyl-2-[(tert-butoxycarbonyl)amino]-2-deoxy-5,6-O-iso-
propylidene-L-glucitol 17 and 1-O-benzyl-2-[(tert-butoxycarb-
onyl)amino]-2-deoxy-5,6-O-isopropylidene-L-gulitol 18
Starting from 16 (1.4 g, 3.7 mmol), exactly the same procedure
as described for the preparation of compounds 8 and 9
furnished a mixture of two isomers (1.323 g, 87%). The diols
17 (major, 882 mg) and 18 (minor, 441 mg) were separated by
column chromatography, eluting with CH2Cl2–acetone 5:1.
Isomer 17. [α]D20 Ϫ10.3 (c 1.5) (Found: C, 61.1; H, 7.9; N, 3.2.
C21H33NO7 requires C, 61.3; H, 8.1, N, 3.4%); νmax (neat)/cmϪ1
3442br, 3333br, 2982, 2933, 1710, 1505, 1455, 1369, 1249;
δH (CDCl3) 7.30–7.22 (5H, m), 5.26 (1H, d, J 8.1 Hz), 4.52 (2H,
s), 4.17–4.00 (2H, m), 4.00–3.85 (3H, m), 3.70 (1H, d, J 10 Hz),
3.65–3.56 (2H, m), 3.50 (1H, br s), 3.34 (1H, br s), 1.43 (9H, s),
1.38, 1.34 (6H, 2s); δC (CDCl3) 156.6, 137.4, 129.7, 128.5, 127.9,
127.8, 109.2, 80.0, 76.6, 75.7, 73.5, 72.2, 70.2, 66.9, 52.7, 28.4,
26.8, 25.3; m/z (ESI) 434 [M ϩ Na]ϩ, 412 [M ϩ H]ϩ, 356, 312.
Isomer 18. [α]D20 Ϫ10.6 (c 2.4) (Found: C, 61.4; H, 7.6; N, 3.1%).
νmax (neat)/cmϪ1 3443br, 2981, 2933, 1710, 1499, 1454, 1368,
1249; δH (CDCl3) 7.35–7.30 (5H, m), 5.24 (1H, d, J 8.5 Hz),
4.57, 4.50 (2H, 2d, J 11.7 Hz), 4.30 (1H, m), 4.05 (1H, dd, J 6.4,
8.2 Hz), 4.38–4.00 (2H, m), 3.80–3.66 (1H, m), 3.62–3.52 (3H,
m), 3.00 (1H, d, J 8.3 Hz), 1.43 (s), 1.39 (s) (15H); δC (CDCl3)
156.9, 137.8, 128.6, 128.0, 127.8, 109.9, 80.5, 77.8, 73.6, 71.7,
69.8, 68.7, 66.1, 52.2, 28.4, 26.6, 25.7; m/z (ESI) 434 [M ϩ Na]ϩ,
412 [M ϩ H]ϩ, 356, 312.
(2S,5R)-6-Benzyloxy-5-[(tert-butoxycarbonyl)amino]-1,2-iso-
propylidenedioxy-4-(phenylsulfonyl)hexan-3-ol 15
Starting with (R)-5 (4.05 g, 10 mmol), obtained from (R)-1,11
exactly the same procedure as described for the preparation of
compound 6 furnished 15 (4.5 g, 84%) (Found: MHϩ, 536.2285.
C27H38NO8S requires m/z, 536.2379); νmax (CHCl3)/cmϪ1 3543,
3439, 3031, 3012, 2985, 2932, 1709, 1498, 1448, 1393, 1368,
1308, 1250; δH (CDCl3) 8.05–7.90 (2H, m), 7.70–7.40 (3H, m),
7.30–7.15 (5H, m), 6.15 (d, J 8.5 Hz), 5.98 (d, J 8.8 Hz), 5.15 (d,
J 8.5 Hz) (1H), 4.60–4.30 (3H, m), 4.10–4.00 (2H, m), 4.00–3.80
(2H, m), 3.80–3.60 (2H, m), 3.60–3.36 (2H, m), 1.45 (9H, s),
1.42, 1.40 (6H, 2s); δC (CDCl3) 155.2, 139.6, 139.2, 138.1, 137.6,
137.3, 134.1, 134.0, 129.6, 129.4, 129.1, 128.5, 128.3, 127.9,
127.8, 127.7, 127.5, 110.1, 109.9, 109.7, 79.7, 79.5, 69.7, 67.8,
67.3, 66.9, 66.3, 65.9, 60.3, 56.6, 48.6, 47.9, 46.7, 28.3, 28.2,
26.7, 26.3, 26.0, 25.5, 20.9; m/z (ESI) 558 [M ϩ Na]ϩ, 536
[M ϩ H]ϩ, 406, 349.
1-O-Benzyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-glucitol 19
Starting from 17 (700 mg, 1.7 mmol), exactly the same pro-
cedure as described for the preparation of compound 10 gave
19 (805 mg, 90%); [α]D20 Ϫ3.0 (c 1.2) (Found: C, 61.2; H, 8.8; N,
2.6. C27H47NO7Si requires C, 61.7; H, 9.0; N, 2.7%); νmax (neat)/
cmϪ1 3450br, 2981, 2954, 2931, 2885, 2858, 1715, 1497, 1473,
1455, 1381, 1368, 1254; δH (CDCl3) 7.35–7.30 (5H, m), 4.92
(1H, d, J 8.3 Hz), 4.53 (2H, s), 4.18–4.05 (2H, m), 4.00–3.85
(2H, m), 3.82–3.65 (1H, m), 3.57–3.43 (2H, m), 3.02 (1H, d,
J 6.3 Hz), 1.43 (9H, s), 1.36, 1.32 (6H, 2s), 0.89 (9H, s), 0.15
(6H, s); δC (CDCl3) 155.4, 137.5, 129.8, 128.6, 128.5, 127.9,
109.2, 79.5, 75.2, 73.4, 71.3, 69.9, 68.0, 67.7, 53.0, 28.5, 27.0,
26.0, 25.4, 18.2, Ϫ4.3, Ϫ4.6; m/z (CI) 526 [M ϩ H]ϩ, 426, 368.
(2S,5R)-1-Benzyloxy-2-[(tert-butoxycarbonyl)amino]-5,6-iso-
propylidenedioxyhex-3-ene
4-O-Acetyl-1-O-benzyl-2-[(tert-butoxycarbonyl)amino]-3-O-
(tert-butyldimethylsilyl)-2-deoxy-5,6-O-isopropylidene-L-
glucitol 20
Starting from 15 (4.15 g, 7.8 mmol), exactly the same procedure
as described for the preparation of compound 7 provided a
mixture of two olefins (2.34 g, 80%): E-isomer 16 1.80 g (77%)
and Z-isomer 0.54 g (23%).
Starting from 19 (650 mg, 1.24 mmol), exactly the same
2470
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procedure as described for the preparation of compound 11
furnished 20 (667 mg, 95%) after 1 h of stirring; [α]D20 Ϫ40.7
(c 1.2) (Found: C, 61.3; H, 8.9; N, 2.5. C29H49NO8Si requires C,
61.3; H, 8.7; N, 2.5%); νmax (neat)/cmϪ1 3450, 3354, 2995, 2958,
2932, 1745, 1717, 1498, 1455, 1368, 1230; δH (CDCl3) 7.37–7.22
(5H, m), 5.12 (1H, t, J 5.3 Hz), 4.94 (1H, d, J 8.6 Hz), 4.52, 4.48
(2H, 2d, J 11.5 Hz), 4.28 (1H, dt, J 5.7, 6.3 Hz), 4.12 (1H, dd,
J 2.0, 5.2 Hz), 3.98–3.82 (2H, m), 3.79 (1H, dd, J 6.7, 8.2 Hz),
3.50–3.38 (2H, m), 2.07 (3H, s), 1.45 (9H, s), 1.36, 1.33 (6H, 2s),
0.90 (9H, s), 0.14, 0.10 (6H, 2s); δC (CDCl3) 170.3, 155.4, 138.2,
128.5, 127.7, 127.6, 109.3, 79.7, 73.9, 73.8, 72.9, 68.9, 68.6, 65.8,
51.0, 28.5, 26.5, 26.0, 25.3, 21.3, 18.3, Ϫ4.3, Ϫ4.7; m/z (CI) 568
[M ϩ H]ϩ, 468.
washed successively with water (2 × 50 ml) and brine (50 ml),
dried over Na2SO4, and the solvent was evaporated. To a solu-
tion of the residue in CH2Cl2 (2 ml) were added triethylamine
(0.46 ml, 3.3 mmol), Ac2O (0.29 ml, 3 mmol) and DMAP (50
mg) successively. The mixture was stirred at room temperature
for 1 h. Methanol (1 ml) was added, and stirring was continued
for 30 min. The solvent was evaporated, and the residue was
dissolved in EtOAc (150 ml). The organic extracts were washed
successively with water (30 ml), 1 M HCl (30 ml), saturated aq.
NaHCO3 (50 ml) and brine (50 ml), dried over Na2SO4 and
evaporated. After removal of the solvent, the residue was puri-
fied by column chromatography, eluting with heptane–EtOAc
1:2, to afford 24 (110 mg, 73%); [α]D20 ϩ57.0 (c 2.3) (Found: C,
59.4; H, 6.5; N, 3.1. C21H27NO8 requires C, 59.8; H, 6.5; N,
3.3%); νmax (neat)/cmϪ1 2982, 2937, 2884, 1790, 1749, 1705,
1496, 1480, 1455, 1374, 1294; δH (CDCl3) 7.35–7.25 (5H, m),
5.50 (1H, t, J 7.0 Hz), 4.69 (1H, t, J 7.0 Hz), 4.59 (1H, ddd,
J 2.0, 4.8, 7.0 Hz), 4.55, 4.40 (2H, 2d, J 12.0 Hz), 4.10–3.98 (2H,
m), 3.85 (1H, dd, J 2.0, 10.4 Hz), 3.75–3.65 (2H, m), 2.47 (3H,
s), 2.07 (3H, s), 1.28, 1.20 (6H, 2s); δC (CDCl3) 170.0, 169.4,
152.9, 137.2, 128.5, 128.1, 128.0, 110.1, 76.0, 74.9, 73.6, 69.7,
67.3, 65.3, 56.1, 26.0, 25.3, 23.6, 20.8 m/z (CI) 422 [M ϩ H]ϩ.
4-O-Acetyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-glucitol 21
Starting from 20 (650 mg, 1.15 mmol), exactly the same pro-
cedure as described for the preparation of compound 12,
afforded 21 (535 mg, 98%): [α]D20 Ϫ11.4 (c 2.2) (Found: C,
55.6; H, 8.7; N, 2.8. C22H43NO8Si requires C, 55.3; H, 9.1; N,
2.9%); νmax (neat)/cmϪ1 3446br, 2982, 2956, 2932, 2887, 2859,
1747, 1716, 1497, 1474, 1370, 1232; δH (CDCl3) 5.13–5.03 (2H,
m), 4.28–4.20 (1H, m), 4.18–4.05 (2H, m), 3.99 (1H, t, J 7.5 Hz),
3.78 (1H, t, J 7.5 Hz), 3.70–3.60 (1H, m), 3.60–3.50 (1H, m),
2.50 (1H, br s), 2.10 (3H, s), 1.45 (9H, s), 1.38, 1.35 (6H, 2s),
0.92 (9H, s), 0.16, 0.15 (6H, 2s); δC 170.4, 156.3, 109.5, 80.1,
73.9, 69.3, 66.2, 63.2, 53.9, 28.5, 26.6, 26.0, 25.3, 21.3, 18.3,
Ϫ4.3, Ϫ4.6; m/z (CI) 478 [M ϩ H]ϩ.
2-Acetamido-4-O-acetyl-1-O-benzyl-2-N,3-O-carbonyl-2-deoxy-
5,6-O-isopropylidene-L-iditol 25
Starting from 9 (80 mg, 0.24 mmol), exactly the same procedure
as described for the preparation of compound 24 gave 25 (80
mg, 80%); [α]D20 ϩ17.3 (c 2.3) (Found: C, 59.7; H, 6.7; N, 3.1%);
νmax (neat)/cmϪ1 2988, 2937, 2866, 1790, 1749, 1706, 1497, 1455,
1375, 1292, 1217; δH (CDCl3) 7.35–7.20 (5H, m), 5.06 (1H, t,
J 4.7 Hz), 4.66 (1H, dd, J 3.1, 4.7 Hz), 4.52 (2H, s), 4.55–4.45
(1H, m), 4.35 (1H, ddd, J 1.5, 6.2, 10.9 Hz), 4.05 (1H, dd, J 8.7,
9.6 Hz), 3.79 (1H, dd, J 5.9, 8.7 Hz), 3.69 (1H, dd, J 5.0, 9.8
Hz), 3.57 (1H, dd, J 2.9, 9.8 Hz), 2.47 (3H, s), 2.04 (3H, s), 1.39,
1.29 (6H, 2s); δC 170.1, 169.8, 153.1, 137.4, 128.6, 128.1, 127.8,
110.3, 74.3, 73.4, 73.1, 67.7, 65.4, 55.4, 26.1, 25.3, 23.6, 20.6;
m/z (CI) 422 [M ϩ H]ϩ.
4-O-Acetyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-glucose 22
Starting from 21 (160 mg, 0.34 mmol), exactly the same pro-
cedure as described for the preparation of compound 13 gave
22 (111 mg, 70%); [α]D20 ϩ89.7 (c 2.0) (Found: C, 55,6; H, 8.6; N,
2.8. C22H41NO8Si requires C, 55.6; H, 8.7; N, 3.0%); νmax (neat)/
cmϪ1 3434, 2981, 2957, 2933, 2889, 2859, 1747, 1715, 1497,
1473, 1370, 1227; δH (CDCl3) 9.85 (1H, s), 5.35 (1H, d, J 6.5
Hz), 5.04 (1H, dd, J 1.5, 7.8 Hz), 4.59 (1H, dd, J 1.7, 5.9 Hz),
4.36 (1H, t, J 6.3 Hz), 4.21–4.12 (1H, m), 3.83–3.78 (1H, m),
1.98 (3H, s), 1.44 (9H, s), 1.37, 1.33 (6H, 2s), 0.96 (9H, s), 0.28,
0.21 (6H, s); δC (CDCl3) 199.1, 170.4, 155.3, 109.6, 80.3, 73.5,
71.8, 71.1, 66.7, 61.9, 28.3, 26.7, 25.9, 20.8, 18.2, Ϫ4.4, Ϫ4.9;
m/z (ESI) 498 [M ϩ Na]ϩ, 398.
2-Acetamido-4-O-acetyl-1-O-benzyl-2-N,3-O-carbonyl-2-deoxy-
5,6-O-isopropylidene-L-glucitol 26
Starting from 17 (300 mg, 0.73 mmol), exactly the same pro-
cedure as described for the preparation of compound 24 gave
26. After removal of the solvent, the residue was purified by
column chromatography, eluting with CH2Cl2–acetone 4:1, to
afford 26 (180 mg, 60%); [α]D20 Ϫ6.1 (c 2.0) (Found: MHϩ,
422.1773. C21H28NO8 requires m/z, 422.1815); νmax (neat)/cmϪ1
3065, 2988, 2938, 2884, 1789, 1750, 1705, 1497, 1480, 1455,
1372, 1294, 1225; δH (CDCl3) 7.30–7.20 (5H, m), 5.03 (1H, dd,
J 2.5, 7.9 Hz), 4.80 (1H, t, J 2.5 Hz), 4.55, 4.50 (2H, 2d, J 12.0
Hz), 4.38–4.22 (2H, m), 4.04 (1H, dd, J 6.1, 8.7 Hz), 3.79 (1H,
dd, J 5.5, 8.7 Hz), 3.70 (1H, dd, J 4.9, 9.8 Hz), 3.62 (1H, dd,
J 3.0, 9.8 Hz), 2.48 (3H, s), 2.03 (3H, s), 1.39, 1.35 (6H, 2s);
δC (CDCl3) 170.1, 169.9, 153.3, 137.4, 128.6, 128.1, 127.7, 110.1,
75.1, 73.4, 73.3, 73.2, 67.6, 66.7, 55.5, 26.6, 25.3, 23.6, 20.5; m/z
(ESI) 444 [M ϩ Na]ϩ, 422 [M ϩ H]ϩ.
1,4,6-Tri-O-acetyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-
butyldimethylsilyl)-2-deoxy-L-glucopyranose 23
Starting from 22 (90 mg, 0.19 mmol), exactly the same pro-
cedure as described for the preparation of compound 14
afforded 23 (65 mg, 60%) as the α-anomer; [α]D20 Ϫ57.5 (c 1.6)
(Found: C, 53.5; H, 8.3; N, 2.6. C23H41NO10Si requires C, 53.2;
H, 8.0; N, 2.7%); νmax (neat)/cmϪ1 3447, 3029, 2958, 1747, 1715,
1503, 1390, 1368, 1228; δH (CDCl3) 6.10 (1H, d, J 3.4 Hz, H-1),
5.04 (1H, dd, J 8.9, 10.0 Hz, H-4), 4.33 (1H, d, J 9.6 Hz, NH),
4.25–4.10 (1H, m), 4.10–3.95 (2H, m), 3.90–3.70 (2H, m), 2.18
(s), 2.10 (s) (9H), 1.44 (9H, s), 0.85 (9H, s), 0.10, 0.05 (6H, 2s);
δC (CDCl3) 170.9, 169.4, 169.1 (CH3CO), 154.7 (Me3COCO),
91.9 (C-1), 80.1 (Me3COCO), 71.2 (C-3 or C-5 interchangeable
attribution), 70.9 (C-5 or C-3), 70.2 (C-4), 62.2 (C-6), 54.1
(C-2), 28.3 (Me3COCO), 25.0 (Me3CSiMe2), 21.3, 21.2 and 20.8
(CH3CO), 18.0 (Me3CSiMe2), Ϫ4.8 (Me3CSiMe2); m/z (CI) 537
[M ϩ NH4]ϩ, 436.
2-Acetamido-4-O-acetyl-1-O-benzyl-2-N,3-O-carbonyl-2-deoxy-
5,6-O-isopropylidene-L-gulitol 27
Starting from diol 18 (80 mg, 0.20 mmol), exactly the same
procedure as described for the preparation of compound 26
gave 27 (49 mg, 60%); [α]D20 Ϫ63.6 (c 3.2) (Found: MHϩ,
422.1780); νmax (neat)/cmϪ1 3056, 2988, 2937, 2884, 1790, 1749,
1705, 1497, 1480, 1455, 1373, 1294, 1226; δH (CDCl3) 7.40–7.30
(5H, m), 5.57 (1H, dd, J 2.2, 9.3 Hz), 4.79 (1H, dd, J 6.7, 9.3
Hz), 4.70–4.62 (1H, m), 4.52, 4.47 (2H, 2d, J 8.1 Hz), 4.21 (1H,
m), 3.80–3.60 (4H, m), 2.47 (3H, s), 2.14 (3H, s), 1.41, 1.26 (6H,
2s); δC (CDCl3) 170.3, 169.9, 152.8, 136.9, 128.7, 128.3, 110.3,
75.7, 73.7, 73.5, 68.9, 65.4, 65.1, 55.5, 26.0, 25.2, 23.7, 21.0; m/z
(ESI) 444 [M ϩ Na]ϩ, 422 [M ϩ H]ϩ.
2-Acetamido-4-O-acetyl-1-O-benzyl-2-N,3-O-carbonyl-2-deoxy-
5,6-O-isopropylidene-L-mannitol 24
A solution of diol 8 (300 mg, 0.73 mmol) in THF (3 ml) con-
taining 60% NaH (59 mg, 1.46 mmol) was stirred at 60 ЊC for
4 h. The reaction mixture was quenched with water (20 ml) and
concentrated. The residue was dissolved in EtOAc (300 ml),
J. Chem. Soc., Perkin Trans. 1, 2000, 2465–2473
2471

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1-O-Benzyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-lyxo-hex-4-
ulose 28
furnished 31 (348 mg, 93%); [α]D20 Ϫ13.8 (c 2.5) (Found: C, 55.2;
H, 8.9; N, 2.8. C22H43NO8Si requires C, 55.3; H, 9.1; N, 2.9%);
νmax (neat)/cmϪ1 3452br, 2957, 2933, 2889, 2859, 1744, 1713,
1504, 1473, 1369, 1252; δH (CDCl3) 5.17 (1H, d, J 7.5 Hz), 5.10–
5.07 (1H, m), 4.35–4.31 (1H, m), 4.16–4.05 (4H, m), 3.77–3.64
(3H, m), 2.14 (3H, s), 1.46 (9H, s), 1.40, 1.33 (6H, 2s), 0.90 (9H,
s), 1.14 (6H, s); δC (CDCl3) 170.6, 155.2, 109.8, 79.7, 74.3, 73.9,
73.5, 66.0, 63.2, 52.4, 28.5, 26.1, 25.9, 25.6, 21.1, 18.1, Ϫ4.8; m/z
(ESI) 500 [M ϩ Na]ϩ, 478 [M ϩ H]ϩ, 378.
To a solution of 10 (900 mg, 1.71 mmol) in CH3CN (15 ml)
were added successively NMO (382 mg, 2.57 mmol), TPAP
(50 mg, 10% mol) and molecular sieves (1.5 g). After 2 h, the
solvent was evaporated, 100 ml of heptane–EtOAc 1:1 was
added, and the mixture was filtered through silica gel. After
evaporation of solvents, the residue was purified by column
chromatography, eluting with heptane–EtOAc 5:1, to afford 28
(835 mg, 93%); [α]D20 ϩ10.9 (c 2.3) (Found: C, 62.2; H, 9.2; N, 2.5.
C27H45NO7Si requires C, 61.9; H, 8.7; N, 2.7%); νmax (neat)/cmϪ1
3454, 2980, 2954, 2932, 2897, 2832, 1716, 1498, 1368, 1254;
δH (CDCl3) 7.38–7.32 (5H, m), 4.87 (1H, d, J 9.3 Hz), 4.83 (1H,
t, J 7.0 Hz), 4.49–4.44 (1H, m), 4.42 (2H, s), 4.19–4.11 (2H, m),
4.05–3.99 (1H, m), 3.60–3.50 (1H, m), 1.44 (9H, s), 1.41, 1.37
(6H, 2s), 0.93 (9H, s), 0.10, 0.07 (6H, 2s); δC 206.8, 155.2,
137.4, 128.5, 127.9, 110.8, 79.8, 76.8, 76.5, 73.2, 67.9, 66.2, 52.6,
28.4, 25.9, 25.6, 18.3, Ϫ4.7, Ϫ5.1; m/z (CI) 524 [M ϩ H]ϩ, 468,
438, 424.
4-O-Acetyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-talose 32
Starting from 31 (200 mg, 0.42 mmol), exactly the same
procedure as described for the preparation of compound 13
gave 32 (160 mg, 80%); [α]D20 Ϫ74.3 (c 2.8) (Found: C, 55.6; H,
8.6; N, 2.8. C22H41NO8Si requires C, 55.6; H, 8.7; N, 3.0%); νmax
(neat)/cmϪ1 3434, 2981, 2954, 2932, 2889, 2859, 1746, 1715,
1498, 1474, 1370, 1227; δH (CDCl3) 9.74 (1H, s), 5.46 (1H, br d,
J 8.8 Hz), 5.12 (1H, dd, J 3.1, 9.4 Hz), 4.72 (1H, dd, J 3.1, 8.6
Hz), 4.46–4.37 (2H, m), 4.10 (1H, dd, J 8.7, 10.4 Hz), 3.71 (1H,
dd, J 7.5, 10.4 Hz), 2.09 (3H, s), 1.45 (9H, s), 1.43, 1.35 (6H,
2s), 0.85 (9H, s), 0.11, 0.10 (6H, 2s); δC (CDCl3) 197.9, 170.6,
110.0, 79.9, 73.6, 72.6, 72.3, 66.1, 63.1, 28.4, 26.1, 25.7, 25.4,
21.0, Ϫ4.9; m/z (CI) 476 [M ϩ H]ϩ, 376, 318.
1-O-Benzyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-talitol 29
L-Selectride (1.9 ml, 1.9 mmol) was added dropwise to a
solution of 28 (490 mg, 0.94 mmol) in THF at Ϫ78 ЊC. After 30
min, the reaction mixture was allowed to warm to 0 ЊC, then
water (2 ml), H2O2 (30%; 5.7 mmol), and NaHCO3 (5.7 mmol)
were added successively and stirring was continued for 30 min
at 50 ЊC. The mixture was dissolved in water (100 ml) and
extracted with EtOAc (3 × 70 ml). The organic extracts were
washed successively with water (2 × 50 ml) and brine (50 ml),
dried over Na2SO4 and evaporated. After removal of the
solvent, the residue was purified by column chromatography,
eluting with heptane–EtOAc 3:1, to afford two alcohols 29 (365
mg) and 10 (65 mg) in 88% total yield, in the ratio 85:15. Com-
pound 29: [α]D20 ϩ6.5 (c 2.8) (Found: C, 61.2; H, 8.8; N, 2.6.
C27H47NO7Si requires C, 61.7; H, 9.0; N, 2.7%); νmax (neat)/
cmϪ1 3450br, 2981, 2954, 2931, 2858, 1716, 1473, 1497, 1455,
1369, 1254; δH (CDCl3) 7.38–7.22 (5H, m), 4.86 (1H, d, J 7.3
Hz), 4.51 (2H, s), 4.30 (1H, dt, J 2, 7.6 Hz), 4.20–4.10 (1H, m),
4.03 (1H, t, J 7.0 Hz), 3.93 (1H, dd, J 3.7, 7.2 Hz), 3.85 (1H, t,
J 7.8 Hz), 3.70–3.55 (2H, m), 3.48–3.38 (1H, m), 2.67 (1H, br d,
J 8.6 Hz), 1.44 (9H, s), 1.42, 1.37 (6H, 2s), 0.9 (9H, s), 0.1 (6H,
s); δC (CDCl3) 155.7, 138.0, 128.5, 127.9, 109.0, 79.5, 74.4, 73.8,
73.0, 71.2, 68.5, 66.4, 52.1, 28.5, 26.5, 26.1, 25.5, 18.3, Ϫ4.3,
Ϫ4.5; m/z (ESI) 548 [M ϩ Na]ϩ, 526 [M ϩ H] ϩ, 426.
1,4,6-Tri-O-acetyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-
butyldimethylsilyl)-2-deoxy-L-talopyranose 33
A solution of 32 (95 mg, 0.2 mmol) in methanol (3 ml) was
treated with conc. HCl (2.5 µl) and the mixture was stirred for
48 h at room temperature. After addition of triethylamine (0.1
ml), the solvent was evaporated. To a solution of the residue in
CH2Cl2 (2 ml) were added successively triethylamine (0.93 ml,
6.6 mmol), Ac2O (0.58 ml, 6 mmol) and DMAP (100 mg). The
mixture was stirred at room temperature for 3 h. Methanol
(3 ml) was added, and stirring was continued for 30 min. The
solvent was evaporated, and the residue was dissolved in EtOAc
(50 ml), and the solution was washed successively with water
(15 ml), 1 M HCl (15 ml), saturated aq. NaHCO3 (20 ml) and
brine (20 ml), dried over Na2SO4 and evaporated. After removal
of the solvent, the residue was purified by column chrom-
atography, eluting with heptane–EtOAc 3:1, to afford 33 (70
mg, 65%): 47 mg of α-anomer 33a and 23 mg of β-anomer 33b.
ꢀ-Anomer 33a. [α]D20 Ϫ29.1 (c 1.6) (Found: C, 53.5; H, 8.1; N,
2.8. C23H41NO10Si requires C, 53.2; H, 8.0; N, 2.7%); νmax (neat)/
cmϪ1 3447, 3032, 2957, 1749, 1715, 1503, 1392, 1368, 1233;
δH (CDCl3) 6.10 (1H, br s), 5.40 (1H, br d, J 9.1 Hz), 5.27 (1H,
d, J 3.1 Hz), 4.25–4.40 (4H, m), 3.90–3.80 (1H, m), 2.15, 2.12,
2.05 (9H, 3s), 1.43 (9H, s), 0.86 (9H, s), 0.10 (6H, s); δC (CDCl3)
170.7, 169.0, 168.4, 155.6, 93.7, 79.7, 69.5, 68.6, 63.9, 62.1,
51.8, 28.5, 25.6, 21.0, 20.8, 18.0, Ϫ5.0, Ϫ5.1; m/z (CI) 537
[M ϩ NH4]ϩ, 436.
4-O-Acetyl-1-O-benzyl-2-[(tert-butoxycarbonyl)amino]-3-O-
(tert-butyldimethylsilyl)-2-deoxy-5,6-O-isopropylidene-L-talitol
30
Starting from 29 (430 mg, 0.82 mmol), exactly the same pro-
cedure as described for the preparation of compound 11
furnished 30 (455 mg, 98%) after 30 min of stirring; [α]D20 Ϫ1.3
(c 2.1) (Found: C, 61.1; H, 8.6; N, 2.4. C29H49NO8Si requires C,
61.3; H, 8.7; N, 2.5%); νmax (neat)/cmϪ1 3451, 3354, 2932, 2895,
2859, 1747, 1718, 1499, 1368, 1230; δH (CDCl3) 7.39–7.22 (5H,
m), 4.98 (1H, t, J 5.0 Hz), 4.89 (1H, d, J 10.3 Hz), 4.47 (2H, s),
4.34 (1H, dt, J 5.1, 8.4 Hz), 4.10–4.00 (2H, m), 3.97–3.84 (1H,
m), 3.78 (1H, t, J 9.9 Hz), 3.60 (2H, d, J 5.8 Hz), 2.10 (3H, s),
1.45 (9H, s), 1.38, 1.34 (6H, 2s), 0.87 (9H, s), 0.12, 0.07 (6H,
2s); δC (CDCl3) 170.6, 155.6, 138.1, 128.5, 127.9, 127.8, 109.4,
79.5, 74.1, 73.0, 72.6, 68.0, 66.0, 52.0, 28.5, 26.2, 26.0, 25.8,
21.2, 18.3, Ϫ4.4, Ϫ4.8; m/z (CI) 568 [M ϩ H]ϩ, 468.
ꢁ-Anomer 33b. [α]D20 ϩ8.2 (c 0.9) (Found: C, 53.4, H, 8.2, N,
2.9%); νmax (neat)/cmϪ1 3448, 3031, 2958, 1747, 1715, 1504,
1396, 1369, 1231; δH (CDCl3) 5.69 (1H, d, J 1.8 Hz), 5.33 (1H,
br d, J 9.9 Hz), 5.22–5.18 (1H, m), 4.22–4.08 (3H, m), 4.00–3.90
(2H, m), 2.14, 2.11, 2.06 (9H, 3s), 1.44 (9H, s), 0.86 (9H, s),
0.10, 0.09 (6H, 2s); δC (CDCl3) 170.7, 169.2, 169.0, 156.1, 92.7,
79.4, 72.5, 68.9, 67.3, 65.8, 62.2, 52.3, 28.4, 25.6, 21.0, 20.8,
20.7, 18.0, Ϫ4.9, Ϫ5.0; m/z (CI) 537 [M ϩ NH4]ϩ, 436.
References
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4-O-Acetyl-2-[(tert-butoxycarbonyl)amino]-3-O-(tert-butyldi-
methylsilyl)-2-deoxy-5,6-O-isopropylidene-L-talitol 31
Starting from 30 (444 mg, 0.78 mmol), exactly the same
procedure as described for the preparation of compound 12
2472
J. Chem. Soc., Perkin Trans. 1, 2000, 2465–2473

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