New glycosyl α-hydroxyesters as key intermediates in a convenient route to glycosyl α-aminoester chirons

Article abstract of DOI:10.1016/S0040-4020(02)00193-X

This article examines the stereoselective preparation of glycosyl α-hydroxyesters via the asymmetric reduction of glycosyl α-ketoesters, using various chiral or achiral reagents and Bakers' yeast. The diastereomeric excess could exceed 98% for the galacto-series. These glycosyl α-hydroxyesters are used as chiral precursors for the diastereoselective synthesis of glycosyl α-aminoesters synthons.

Full text of DOI:10.1016/S0040-4020(02)00193-X

TETRAHEDRON
Pergamon
Tetrahedron 58 22002) 2735±2741
New glycosyl a-hydroxyesters as key intermediates in a
convenient route to glycosyl a-aminoester chirons
p
Claude Grison, Frederic Coutrot and Philippe Coutrot
 Â
   Â
Institut Nanceien de Chimie Moleculaire, FR CNRS 1742, UMR 7565, Universite Henri Poincare, Nancy 1, BP 539,
54506 Vandoeuvre-les-Nancy, France
Received 7 September 2001; revised 26 December 2001; accepted 20 February 2002
AbstractÐThis article examines the stereoselective preparation of glycosyl a-hydroxyesters via the asymmetric reduction of glycosyl
a-ketoesters, using various chiral or achiral reagents and Bakers' yeast. The diastereomeric excess could exceed 98% for the galacto-series.
These glycosyl a-hydroxyesters are used as chiral precursors for the diastereoselective synthesis of glycosyl a-aminoesters synthons.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
completes a recent approach described by us based on a
stereoselective aminoreduction of glycosyl a-ketoesters
114 and another direct route to glycosyl a-hydroxyesters
based on the reaction between sodium cyanoborohydride
and glucidic a-chloroglycidic esters.15 The aim is to obtain
increased stereoselectivity to novel C-linked glycosyl
a-aminoacid derivatives, which can be used as convenient
building blocks for the synthesis of glycopeptide libraries
2Scheme 1).
The synthesis of a-hydroxyesters and hydroxyacids has
received much interest during past years as these
compounds are good chiral building blocks for the synthesis
of biologically active natural or analogous products,1 and
also since they are used as analogues or precursors of
a-aminoesters.2 As a result, numerous enantioselective
preparations of these compounds from a-ketoesters have
already been described, especially those concerning the
reduction of aliphatic a-ketoesters using different reagents
2such as hydrogen with catalyst in heterogen3 or homogen4
phase, hindered metallic aluminohydrides or borohydrides,5
homochiral hydroborating reagents,6 sodium borohydride/
tartric acid,7 hydrosilane/diop,8 mimics of nicotinamide
adenine dinucleotide 2NADH),9 Bakers' yeast10 or other
biotransformations11 or recently with SmI212). However,
no stereoselective reduction has been achieved on glycosyl
pyruvic esters since, until recently, these compounds were
practically unknown. We were recently the ®rst to describe
an ef®cient synthesis of such glycosyl pyruvic esters from
dialdoses.13 Here, we report the asymmetric reduction of
these glycosyl a-ketoesters 1a±c, into the corresponding
glycosyl a-hydroxyesters 2a±c in the a-d-galactose 2a),
b-d-ribose 2b) and a-d-lyxose 2c) series. Subsequently, we
describe the substitution with a complete inversion of the
tri¯ates derived from these glycosyl a-hydroxyesters 2a±c
using sodium azide, followed by the hydrogenation of the
resulting azido compounds 3a±c leading to the glycosyl
a-aminoesters 5a±c. The route to these last compounds
2. Results and discussion
Based on the assumption that the carbohydrate moiety could
induce an asymmetric reduction of the a-carbonyl function-
ality, the ®rst procedure used to reduce the a-ketoesters 1
into the corresponding a-hydroxyesters 2 was via catalytic
hydrogenation in isopropyl alcohol at ambient temperature
and under different pressure of hydrogen using palladium
over charcoal 210%) as catalyst 2procedure A). The results
reported in Table 1 showed that the three a-ketoesters 1a±c
studied were cleanly converted to the corresponding
expected carbinols 2a±c in .73% yield, but with a
moderate diastereomeric excess 216,de,60%). Even
though the hydrogenation was slower under 1bar 2entry 1)
than under 50bar 2entry 2), this resulted in the best dia-
stereomeric excess 2de:60%) to give the diastereomer 2a.
The absolute con®gurations-2R) and 2S) of the new asym-
metric carbon C7 in 2a/20a 2as a viscous oil) were deter-
mined by the chemical correlation leading to the glycosyl
a-aminoester 4a/40a described later in the text. An attempt
using sodium borohydride as the reducing reagent with
galactosyl a-ketoester 1a 2entry 5) neither improved the
diastereomeric excess nor the yield for 2a. The reason for
this poor yield was due to a side reaction that occurred
between sodium borohydride and the isopropyl ester of
Keywords: glycosyl a-ketoester; glycosyl a-hydroxyester; glycosyl a-
aminoester; Bakers' yeast; sodium cyanoborohydride; catecholborane±
oxazaborolidine; sodium azide.
Corresponding author. Fax: 133-03-83-91-2033;
e-mail: claude.grison@lco2.uhp-nancy.fr
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020202)00193-X

2736
C. Grison et al. / Tetrahedron 58 02002) 2735±2741
Scheme 1.
1a, leading the corresponding diol.5b The C7 con®guration
of the major diastereomeric product 2a was again 2S), result-
ing from an attack on the Re side of the a-keto moiety.
catecholborane assisted by 2R) or 2S)-5,5-diphenyl-2-
methyl-3,4-propano-1,3,2-oxazaborolidine as chiral
a
catalyst auxiliary 2procedure C).17 By this method, only
known to apply to ketones, it was possible to obtain
compounds 2a±c with a high diastereomeric excess. It is
noteworthy that the change of the catalyst con®guration
induced the change of the diastereoselectivity in favour of
the other diastereomer 20a±c in approximately the same
ratio that characterised a stereospeci®c catalysis 2entries
7±12). The best results 2yield and diastereomeric excess)
were obtained in galactose series as the result of the attack
of the less hindered Re face of the ketyl group when
catecholborane-2R) oxazaborolidine was used 2C7 2S))
2entry 8), whereas Si face appeared favoured with catechol-
borane-2S) oxazaborolidine 2C7 2R)) 2entry 7). These results
provided additional evidence for the transition state
assembly postulated by Itsuno et al.18 and veri®ed on the
basis of NMR18a and X-ray crystallography studies.19 They
illustrated a novel interesting case of enzyme-like behaviour
of such oxazaborolidine that brought together the reductant
and the carbonyl substrate.20
With the use of the mild reducing reagent sodium cyano-
borohydride 2entry 6), the reaction was found to be much
more selective for the a-keto moiety, but with very low
diastereomeric excess 2procedure B). Although the reduc-
tion of ketone with NaBH3CN was known to require acidic
pH as activator,16 it is noteworthy that in this case the reac-
tion could be carried out in high yield without any activating
additive, since the a-keto moiety was highly reactive as a
result of the presence of the ester at the a site.
The preliminary results showed that the carbohydrate
moiety induced a relatively moderate asymmetric effect
on the a-keto moiety of 1a±c, in contrast to the well
known powerful asymmetric induction of a chiral ester
moiety on the reduction of aliphatic alkyl pyruvates in the
corresponding a-hydroxyesters.5a
As a consequence, we studied the asymmetric reduction of
these a-ketoesters 1a±c with a chiral borohydride reagent,
The reduction of a-ketoesters 1a±c using a large amount of
Table 1. Diastereoselective reduction of C-glycosyl a-ketoesters 1 using different reducing agents
Yielda 2%)
Diastereomeric
ratiob
deb 2%)
c
C7
Entry
Starting
substrate
1
Product 2
Reducing agent and catalyst
Conditions
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1a
1c
1a
1a
1b
1b
1c
1c
1a
1a
1b
1c
2a/20a
2a/20a
2b/20b
2c/20c
2a/20a
2c/2`0c
2a/20a
2a/20a
2b/20b
2b/20b
2c/20c
2c/20c
20a
Hydrogen, Pd/C 10%
Hydrogen, Pd/C 10%
Hydrogen, Pd/C 10%
Hydrogen, Pd/C 10%
NaBH4
Pˆ1 bar, 48 h, iPrOH
Pˆ50 bar, 24 h, iPrOH
Pˆ50 bar, 24 h, iPrOH
Pˆ50 bar, 24 h, iPrOH
iPrOH, 1 h
iPrOH, 24 h
CH2Cl2, 18 h
CH2Cl2, 18 h
CH2Cl2, 18 h
CH2Cl2, 18 h
CH2Cl2, 18 h
CH2Cl2, 18 h
H2O, 17 h
H2O, 69 h
H2O, 17 h
H2O, 17 h
73
85
81
86
47
82
94
81
61
39
76
73
44
61
48
70
80/20
60/40
58/42
73/27
67/33
55/45
11/89
95/05
85/15
16/84
23/77
92/08
60
20
16
46
34
10
78
90
70
68
54
84
.98
.98
10
S
S
±
±
S
±
R
S
±
±
±
±
R
R
±
±
NaBH3CN
Catecholborane-2S)oxazaborolidine
Catecholborane-2R)oxazaborolidine
Catecholborane-2S)oxazaborolidine
Catecholborane-2R)oxazaborolidine
Catecholborane-2S)oxazaborolidine
Catecholborane-2R)oxazaborolidine
Bakers' yeast
Bakers' yeast
Bakers' yeast
Bakers' yeast
9
10
11
12
13
14
15
16
d
±
±
d
20a
2b/20b
2c/20c
45/55
83/17
66
a
Yield of isolated products after chromatography on a silica gel column.
Determined on the crude product by H NMR analysis.
Con®guration of the C7 of the major diastereomer 2.
Only one diastereomer could be seen by 1H NMR spectroscopy.
b
c
d
1

C. Grison et al. / Tetrahedron 58 02002) 2735±2741
2737
Table 2. Preparation of the a-azidoesters 3/30 from the a-hydroxyesters 2/
relatively hindered secondary tri¯ate functionality and with
a pure inversion of con®guration at the C7 2Table 2,
Scheme 2).
20
Entry
2/20
C7a
3/30
C7a deb 2%) Yieldc 2%)
1
2
3
4
5
6
2a/20a 295/05)
20ad
2b/20b 285/15)
2b/20b 212/88)
2c/20c 292/08)
2c/20c 223/77)
S
R
±
±
±
±
3a/30a 205/95)
3ad
3b/30b 215/85)
3b/30b 288/12)
3c/30c 208/92)
3c/30c 277/23)
R
S
±
±
±
±
90
.98
70
76
84
60
42
61
52
61
62
Moreover, the reaction between the tri¯ate issued from
2a/20a 235/65) and 2S)-a-methylbenzylamine afforded the
corresponding product 4a/40a 239/61). This stereospeci®c
substitution allowed the unambiguous assignment of the
2S) C7 con®guration to 2a 2and 2R) C7 to 20a) since the
absolute con®guration of 4a was known to be 2S).14 This
54
a
1
Con®guration of the C7 of the major diastereomer 3.
Determined on the crude product by 1H NMR analysis.
Yield of isolated products after chromatography on a silica gel column.
Only one diastereomer could be seen by 1H NMR spectroscopy.
assignment was obtained by comparison of the H NMR
data of 4a obtained by this route with the H NMR data of
b
c
d
1
an authentic crystallised sample of 4a previously obtained
by reductive amination of the a-ketoester 1a and for which
the X-ray crystallographic analysis was realised.23 Unfortu-
nately, such a correlation did not permit determination of
the con®guration of the new stereogenic centre of 2b/20b
and 2c/20c because the pure crystallised derivative 4b or 4c
could never be obtained; as a result, X-ray crystallographic
analysis could not be carried out 2Scheme 3).24
Scheme 2.
Bakers' yeast 2Saccharomyces cerevisiea) 2procedure D)
was also studied 2entry 13±16). The best diastereomeric
excess 2.98%) was observed for the reduction of the
most hindered starting substrate 1a, but the reaction was
not complete, even after 69 h. With the aim to increase
the stereoselectivity in the lyxose series 2entry 16), a reduc-
tion with Bakers' yeast in the presence of b-cyclodextrin as
described by Nakamura et al.21 was tried but without any
amelioration.
Scheme 3.
In summary, stereoselective reduction of a-ketoesters 1a±c
to the chiral a-hydroxy esters 2a±c was achieved with two
ef®cient reagents: the catecholborane-2S)- or 2R)-5,5-
diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine that
gave C-glycosyl a-hydroxyester diastereomers with good
diastereomeric excess 254±90%), in rather good yields
281±94% for 2a/20a; 73±76% for 2c/20c), and the micro-
organism Bakers' yeast that reduced the C-glycosyl
a-ketoesters in a relatively modest yield 244±62%) but
with a good diastereomeric excess, especially in the
galactose series 2.98%). However, it should be noted that
the diastereomeric mixtures obtained were not separable.
The C-glycosyl a-azidoesters 3/30 were then hydrogenated
in isopropyl alcohol under a pressure of 5 bar, for 14 h,
leading to the expected C-glycosyl a-aminoesters 5/50 in
excellent yields with complete retention of con®guration
at the C7 2Table 3, Scheme 4).
Table 3. Reduction of the C-glycosyl a-azidoesters 3/30 into C-glycosyl a-
aminoesters 5/50
Entry
3/30
C7a
5/50
C7a deb 2%) Yieldc 2%)
1
2
3
4
5
6
3a/30a 205/95)
3ad
3b/30b 215/85)
3b/30b 288/12)
3c/30c 208/92)
3c/30c 277/23)
R
S
±
±
±
±
5a/50a 205/95)
5a
5b/50b 215/85)
5b/50b 288/12)
5c/50c 208/92)
5c/50c 277/23)
R
S
±
±
±
±
90
.98d
72
76
84
93
98
94
95
91
87
The azido compounds 3 derived from a-hydroxyesters 2
were then investigated with the aim to further obtain the
C-glycosyl a-aminoesters 5 with a better diastereo-
selectivity than that previously described by us in the
preparation of 5 by reductive amination of the a-ketoesters
1.14 This method used the 2S)-a-methylbenzyl amine
followed by a hydrogenation step, which was disappointing
concerning the selectivity of the asymmetric reduction of
imines. Consequently, the C-glycosyl a-hydroxyesters 2
were transformed into the corresponding tri¯ates22 using
tri¯uoromethanesulfonic anhydride, in the presence of
pyridine, in dichloromethane, at 08C. The non-isolated
tri¯ates were directly submitted to a very mild substitution
by addition of sodium azide in dimethylformamide, at
ambient temperature for 18 h. A stereospeci®c nucleophilic
substitution resulted in a rather good overall yield using a
54
a
Con®guration of the C7 of the major diastereomer 5.
Determined on the crude product by H NMR analysis.
b
c
d
1
Yield of crude products.
Only one diastereomer could be seen by H NMR spectroscopy.
1
Scheme 4.

2738
C. Grison et al. / Tetrahedron 58 02002) 2735±2741
3. Conclusion
ester 1a 20.35 g, 0.98 mmol) in 6 ml of dichloromethane
was added 0.1 equiv. of 2S)-5,5-diphenyl-2-methyl-3,4-
propano-1,3,2-oxazaborolidine 20.027 g, 0.098 mmol) and
1 equiv. of catecholborane 20.118 g, 0.98 mmol). The
mixture was stirred during 18 h, then hydrolysed and
extracted with dichloromethane. The organic layer was
washed three times with water, dried with magnesium
sulfate, evaporated, and puri®ed on a silica gel chromato-
graphic column to give 0.33 g of diastereomers 2a/20a
211/89).
In conclusion, the asymmetric reduction of C-glycosyl
a-ketoesters allows access to new C-glycosyl a-hydroxy-
esters with a high stereoselectivity. These compounds can
be easily transformed into the corresponding C-glycosyl
a-aminoesters containing a stable C±C bond between the
carbohydrate and the aminoester moiety. The conventional
methods which are applied to transform the C-glycosyl
a-hydroxyesters were revealed to be entirely stereospeci®c
and gave access to C-glycosyl a-aminoesters with good to
excellent diastereomeric excess, allowing the asymmetric
synthesis of each diastereomer. This strategy can be advan-
tageous compared to our precedent route based on the
stereoselective aminoreduction of C-glycosyl a-ketoesters
to prepare C-glycosyl a-aminoesters.
Typical procedure D. To a solution of a-ketoester 1a
20.119 g, 0.33 mmol) in 15 ml of water was added Bakers'
yeast 23 g). The mixture was stirred at room temperature for
69 h. Acetone 220 ml) was then added; and the mixture was
®ltered. The ®ltrate was concentrated and extracted with
chloroform 23£20 ml). The organic phase was dried over
magnesium sulfate, ®ltered and evaporated under reduced
pressure to yield a colourless oil. The crude product 20a was
puri®ed on a silica gel chromatographic column to afford
0.072 g of pure 20a 261%).
4. Experimental
4.1. General
Thin layer chromatographies were carried out on silica gel-
coated plates 2Kieselgel 60-F254, Merck); spots were
developed using sulphuric acid. Column chromatographies
were performed on silica gel 60 or 70±230 mesh using the
indicated eluent, dried and distilled shortly before use. IR
spectra of liquids were recorded as thin ®lms on KBr plates
with a Nicolet 210 FT-IR spectrophotometer. NMR spectra
were recorded on Bruker spectrometers [250 or 400 MHz
21H) and 62.896 MHz 213C)] and reference used was CDCl3.
Chemical shifts were given as d ppm values and J values
were given in Hertz 2Hz). Mass spectra 2FAB) were
measured on an Autospec Fited Cesium Gun 2Micromass,
Manchester). All reactions 2except the reactions using
Bakers' yeast in water and the reactions under high
pressure) were performed under a nitrogen atmosphere.
Solvents were puri®ed by standard procedures just before
use.
4.2.1. Isopropyl 6-deoxy-1,2:3,4-di-O-isopropylidene-l-
glycero-a-d-galacto-octopyranuronate 2a. TLC 2hexane/
1
AcOEt 22/1)) Rf 0.4; IR n 2cm21): 3469, 1731; H NMR
2250 MHz, CDCl3): dˆ5.43 21H, d, Jˆ5.1 Hz, H1), 5.17±
5.02 21H, m, COOCH2Me)2), 4.61 21H, dd, Jˆ2.6, 7.7 Hz,
H3), 4.29 21H, dd, Jˆ5.1, 2.6 Hz, H2), 4.31±4.26 21H, m,
CHCOO), 4.16±4.09 22H, m, H4, H5), 3.25 21H, d,
Jˆ4.3 Hz, OH), 2.28±2.16 21H, m, CH2), 2.05±1.96 21H,
m, CH2), 1.55 23H, s, CH3), 1.45 23H, s, CH3), 1.35 23H, s,
CH3), 1.32 23H, s, CH3), 1.27 23H, d, Jˆ6.0 Hz,
COOCH2CH3)2), 1.26 23H, d, Jˆ6.4 Hz, COOCH2CH3)2).
13C NMR d: 174.1, 109.2, 108.7, 96.2, 72.9, 71.0, 70.3,
69.2, 67.5, 63.7, 33.6, 25.9, 25.8, 24.9, 24.6, 21.7, 21.5;
MS FAB1: m/z 361 2MH1, 100%); 345 230).
4.2.2. Isopropyl 6-deoxy-1,2:3,4-di-O-isopropylidene-d-
glycero-a-d-galacto-octopyranuronate 20a. TLC 2hexane/
20
AcOEt 21/2)) Rf 0.67; [a]D ˆ241 2c 1.3 in CHCl3); IR n
1
2cm21): 3441, 1731. H NMR 2250 MHz, CDCl3): dˆ5.54
4.2. Synthesis of C-glycosyl a-hydroxyesters 2/20 by
asymmetric reduction of C-glycosyl a-ketoesters 1
21H, d, Jˆ4.7 Hz, H1), 5.09 21H, h, Jˆ6.4 Hz,
COOCH2Me)2), 4.63 21H, dd, Jˆ2.6, 8.1 Hz, H3), 4.32
21H, dd, Jˆ4.7, 2.6 Hz, H2), 4.38±4.28 21H, m, CHCOO),
4.17±4.12 22H, m, H4, H5), 2.89 21H, d, Jˆ6.0 Hz, OH),
2.26±2.15 21H, m, CH2), 1.72±1.57 21H, m, CH2), 1.57 23H,
s, CH3), 1.49 23H, s, CH3), 1.36 23H, s, CH3), 1.34 23H, s,
CH3), 1.27 26H, d, Jˆ6.4 Hz, COOCH2CH3)2). 13C NMR d:
174.7, 109.2, 108.8, 96.1, 73.0, 70.6, 70.4, 69.6, 67.3, 63.7,
34.7, 25.7, 25.6, 24.8, 24.0, 21.6, 21.4; MS FAB1: m/z 361
2MH1, 100%), 345 230).
Typical procedure A. A solution of 0.34 g 20.95 mmol) of
a-ketoester 1a in 25 ml of isopropyl alcohol with 0.18 g of
Pd/C 10% was stirred under a 50 bar pressure of hydrogen
for 24 h. The crude product was then ®ltered on celite to
remove the catalyst, the ®ltrate was evaporated under
reduced pressure, and eluted on a silica gel chromatographic
column to give 0.29 g 285%) of diastereomers 2a/20a
260/40).
4.2.3. Isopropyl 5-deoxy-1-O-methyl-2,3-O-isopropyl-
idene-d,l-glycero-b-d-ribo-heptofuranuronate 2b/20b.
Compound 2b. TLC 2hexane/AcOEt 22/1)) Rf 0.4; IR n
2cm21): 3473, 1736. 1H NMR 2250 MHz, CDCl3):
dˆ5.17±5.05 21H, m, COOCH2Me)2), 5.0 21H, s, H1),
4.68±4.61 22H, m, H2, H3), 4.56±4.51 21H, m, H4), 4.37±
4.28 21H, m, CHCOO), 3.38 23H, s, OCH3), 2.84 21H, d,
Jˆ6.0 Hz, OH), 2.23±2.04 21H, m, CH2), 1.76±1.57 21H,
m, CH2), 1.49 23H, s, CH3), 1.33 23H, s, CH3), 1.29 23H, d,
Jˆ6.4 Hz, COOCH2CH3)2), 1.28 23H, d, Jˆ6.2 Hz,
COOCH2CH3)2). 13C NMR d: 174.4, 112.1, 109.5, 85.3,
Typical procedure B. To a solution of 1 equiv. of a-keto-
ester 1c 20.19 g, 0.63 mmol) in 10 ml of isopropyl alcohol
was added 1 equiv. 20.040 g, 0.63 mmol) of sodium cyano-
borohydride. The mixture was stirred at ambient tempera-
ture for 24 h. The crude product was quenched with 2 ml of
water, concentrated, extracted with chloroform, dried with
magnesium sulfate, evaporated, and eluted on a silica gel
chromatographic column to give 0.157 g 282%) of dia-
stereomers 2c/20c 255/45).
Typical procedure C. To a solution of 1 equiv. of a-keto-

C. Grison et al. / Tetrahedron 58 02002) 2735±2741
2739
84.1, 83.6, 69.2, 68.0, 54.8, 39.7, 26.3, 24.9, 21.5; MS
FAB1: m/z 305 2MH1, 15%), 273 2100), 231 238).
TLC 2hexane/AcOEt 22/1)) Rf 0.66; IR n 2cm21): 2108,
1738. 1H NMR 2250 MHz, CDCl3): dˆ5.48 21H, d,
Jˆ5.1 Hz, H1), 5.16±5.02 21H, m, COOCH2Me)2), 4.61
21H, dd, Jˆ2.6, 8.1 Hz, H3), 4.30 21H, dd, Jˆ5.1, 2.6 Hz,
H2), 4.14 21H, dd, Jˆ8.1, 1.7 Hz, H4), 4.06 21H, dd, Jˆ6.0,
8.1 Hz, CHCOO), 3.93 21H, ddd, Jˆ1.7, 9.0, 4.7 Hz, H5),
2.26±1.97 22H, m, CH2), 1.52 23H, s, CH3), 1.46 23H, s,
CH3), 1.35 23H, s, CH3), 1.32 2s, 3H, CH3), 1.30 23H, d,
Jˆ6.4 Hz, COOCH2CH3)2), 1.29 23H, d, Jˆ6.4 Hz,
COOCH2CH3)2). 13C NMR d: 169.4, 109.4, 108.7, 96.3,
72.4, 70.9, 70.4, 69.7, 64.3, 58.9, 31.8, 26.0, 25.8, 24.9,
24.5, 21.7, 21.6.
Compound 20b. TLC 2hexane/AcOEt 22/1)) Rf 0.4; IR n
2cm21): 3473, 1736. 1H NMR 2250 MHz, CDCl3):
dˆ5.16±5.06 21H, m, COOCH2Me)2), 4.97 21H, s, H1),
4.69±4.61 22H, m, H2, H3), 4.40 21H, t, Jˆ7.3 Hz, H4),
4.27 21H, dd, Jˆ5.1, 7.3 Hz, CHCOO), 3.36 23H, s,
OCH3), 3.07 21H, br s, OH), 2.11±1.90 22H, m, CH2),
1.48 23H, s, CH3), 1.32 23H, s, CH3), 1.29 26H, d,
Jˆ6.0 Hz, COOCH2CH3)2). 13C NMR d: 173.8, 112.2,
109.5, 85.2, 84.1, 83.7, 69.4, 68.3, 54.8, 39.1, 26.3, 24.8,
21.4; MS FAB1: m/z 305 2MH1, 15%), 289 215), 273 2100),
231 238).
4.3.2. Isopropyl 7-azido-6,7-dideoxy-1,2:3,4-di-O-isopro-
pylidene-d-glycero-a-d-galacto-octopyranuronate 30a.
TLC 2hexane/AcOEt 22/1)) Rf 0.71; IR n 2cm21): 2115,
1738. 1H NMR 2250 MHz, CDCl3): dˆ5.52 21H, d,
Jˆ5.1 Hz, H1), 5.17±5.02 21H, m, COOCH2Me)2), 4.63
21H, dd, Jˆ2.6, 8.1 Hz, H3), 4.33 21H, dd, Jˆ5.1, 2.6 Hz,
H2), 4.17 21H, dd, Jˆ3.0, 11.5 Hz, CHCOO), 4.12 21H, dd,
Jˆ8.1, 1.7 Hz, H4), 4.03±3.97 21H, m, H5), 2.27±2.15 21H,
m, CH2), 1.75±1.63 21H, m, CH2), 1.58 23H, s, CH3), 1.47
23H, s, CH3), 1.35 26H, s, CH3), 1.30 23H, d, Jˆ6.4 Hz,
COOCH2CH3)2), 1.29 23H, d, Jˆ6.4 Hz, COOCH2CH3)2).
13C NMR d: 170.0, 109.3, 108.7, 96.3, 72.9, 70.9,
70.6, 69.6, 63.8, 59.2, 32.0, 25.9, 25.6, 25.0, 24.2, 21.7,
21.6.
4.2.4. Isopropyl 5-deoxy-1-O-methyl-2,3-O-isopropyl-
idene-d,l-glycero-a-d-lyxo-heptofuranuronate 2c/20c.
Compound 2c. TLC 2hexane/AcOEt 22/1)) Rf 0.35; IR n
2cm21): 3451, 1731. 1H NMR 2250 MHz, CDCl3):
dˆ5.15±5.05 21H, m, COOCH2Me)2), 4.79 21H, s, H1),
4.65 21H, dd, Jˆ3.9, 6.0 Hz, H3), 4.54 21H, d, Jˆ6.0 Hz,
H2), 4.36±4.30 21H, m, CHCOO), 4.20±4.11 21H, m, H4),
3.27 23H, s, OCH3), 3.16 21H, d, Jˆ3.8 Hz, OH), 2.22±2.17
22H, m, CH2), 1.45 23H, s, CH3), 1.32 23H, s, CH3), 1.29
23H, d, Jˆ6.4 Hz, COOCH2CH3)2), 1.28 23H, d, Jˆ6.4 Hz,
COOCH2CH3)2). 13C NMR d: 174.2, 112.3, 106.6, 85.0,
80.6, 75.3, 69.3, 67.9, 54.2, 32.6, 26.0, 25.0, 21.6, 21.4;
MS FAB1: m/z 305 2MH1, 35%), 289 231), 273 2100),
231 285).
4.3.3. Isopropyl 6-azido-5,6-dideoxy-1-O-methyl-2,3-O-
isopropylidene-d,l-glycero-b-d-ribo-heptofuranuronate
3b/30b. Compound 3b. TLC 2hexane/AcOEt 22/1)) Rf 0.74;
Compound 20c. TLC 2hexane/AcOEt 22/1)) Rf 0.35; IR n
2cm21): 3451, 1731. 1H NMR 2250 MHz, CDCl3): dˆ5.16±
5.06 21H, m, COOCH2Me)2), 4.89 21H, s, H1), 4.65 21H, dd,
Jˆ3.4, 6.0 Hz, H3), 4.54 21H, d, Jˆ6.0 Hz, H2), 4.39±4.31
21H, m, CHCOO), 4.21±4.15 21H, m, H4), 3.34 23H, s,
OCH3), 3.04 21H, d, Jˆ7.2 Hz, OH), 2.32±2.19 21H, m,
CH2), 2.01±1.90 21H, m, CH2), 1.48 23H, s, CH3), 1.33
23H, s, CH3), 1.29 23H, d, Jˆ6.4 Hz, COOCH2CH3)2),
1.28 23H, d, Jˆ6.4 Hz, COOCH2CH3)2). 13C NMR d:
174.2, 112.3, 106.6, 85.0, 80.6, 76.2, 69.2, 68.4, 54.2,
33.2, 25.9, 24.8, 21.6, 21.4; MS FAB1: m/z 305 2MH1,
35%), 289 231), 273 2100), 231 285).
1
IR n 2cm21): 2109, 1738. H NMR 2250 MHz, CDCl3):
dˆ5.17±5.05 21H, m, COOCH2Me)2), 4.97 21H, s, H1),
4.63 21H, d, Jˆ6.0 Hz, H2), 4.59 21H, d, Jˆ6.0 Hz, H3),
4.30 21H, dd, Jˆ6.4, 8.5 Hz, H4), 3.97 21H, t, Jˆ7.3 Hz,
CHCOO), 3.36 23H, s, OCH3), 2.18±1.93 22H, m, CH2),
1.49 23H, s, CH3), 1.33 23H, s, CH3), 1.32 23H, d,
Jˆ6.0 Hz, COOCH2CH3)2), 1.31 23H, d, Jˆ6.0 Hz,
COOCH2CH3)2). 13C NMR d: 169.3, 112.5, 109.8, 85.2,
83.8, 83.6, 70.0, 59.3, 55.1, 36.4, 26.3, 24.9, 21.6.
Compound 30b. TLC 2hexane/AcOEt 22/1)) Rf 0.70; IR n
2cm21): 2112, 1739. 1H NMR 2250 MHz, CDCl3): dˆ5.16±
5.01 21H, m, COOCH2Me)2), 4.98 21H, s, H1), 4.63 21H, d,
Jˆ5.6 Hz, H2), 4.57 21H, d, Jˆ5.6 Hz, H3), 4.36 21H, dd,
Jˆ3.4, 11.5 Hz, H4), 4.08 21H, dd, Jˆ3.0, 11.5 Hz,
CHCOO), 3.37 23H, s, OCH3), 2.14±2.03 21H, m, CH2),
1.84±1.72 21H, m, CH2), 1.49 23H, s, CH3), 1.32 23H, s,
CH3), 1.29 23H, d, Jˆ6.4 Hz, COOCH2CH3)2), 1.28 23H,
d, Jˆ6.4 Hz, COOCH2CH3)2). 13C NMR d: 169.9, 112.4,
109.8, 85.3, 83.9, 83.2, 69.7, 59.5, 55.2, 36.6, 26.3, 24.9,
21.6.
4.3. Preparation of the azido compounds 3/30
Typical procedure. A mixture of 1 equiv. of a-hydroxyester
2a/20a 295/5) 20.21 g, 0.58 mmol) and 4 equiv. of pyridine
20.18 g, 2.3 mmol) in 15 ml of dichloromethane was added
dropwise at 08C to a solution of 1.4 equiv. of tri¯uoro-
methane sulfonic anhydride 20.23 g, 0.82 mmol) diluted in
2 ml of dichloromethane. The mixture was stirred for 5 min,
then 50 equiv. of sodium azide 21.9 g, 29 mmol) and 20 ml
of dimethylformamide were added. The mixture was stirred
for 16 h, and then concentrated under reduced pressure
before 10 ml of water was added. The aqueous layer was
extracted with dichloromethane, the organic phase was dried
on magnesium sulfate, ®ltered, and evaporated. Toluene was
added, and evaporated again. The crude product was then
puri®ed on a silica gel chromatographic column to give
0.135 g 260%) of a colourless oil of 3a/30a 25/95).
4.3.4. Isopropyl 6-azido-5,6-dideoxy-1-O-methyl-2,3-O-
isopropylidene-d,l-glycero-a-d-lyxo-heptofuranuronate
3c/30c. Compound 3c. TLC 2hexane/AcOEt 22/1)) Rf 0.74;
1
IR n 2cm21): 2112, 1739. H NMR 2250 MHz, CDCl3):
dˆ5.18±5.03 21H, m, COOCH2Me)2), 4.88 21H, s, H1),
4.65 21H, dd, Jˆ3.4, 6.0 Hz, H3), 4.58 21H, d, Jˆ6.0 Hz,
H2), 4.13±4.05 22H, m, CHCOO, H4), 3.33 23H, s, OCH3),
2.34±2.22 21H, m, CH2), 2.05±1.92 21H, m, CH2), 1.47 23H,
s, CH3), 1.32 23H, s, CH3), 1.31 23H, d, Jˆ6.4 Hz,
COOCH2CH3)2), 1.30 23H, d, Jˆ6.4 Hz, COOCH2CH3)2).
4.3.1. Isopropyl 7-azido-6,7-dideoxy-1,2:3,4-di-O-isopro-
pylidene-l-glycero-a-d-galacto-octopyranuronate
3a.

2740
C. Grison et al. / Tetrahedron 58 02002) 2735±2741
13C NMR d: 169.7, 112.5, 106.7, 85.2, 80.2, 75.7, 69.7,
59.9, 54.4, 30.4, 26.0, 24.8, 21.6, 21.5.
Asymmetry 1993, 4, 2219±2228. 2g) Inoguchi, K.; Sakuraba,
S.; Achiwa, K. Synlett 1992, 169±178. 2h) Splindler, F.;
Pittelkow, U.; Blaser, H. U. Chirality 1991, 370.
2i) Takahashi, H.; Morimoto, T.; Achiwa, K. Chem. Lett.
1987, 855.
Compound 30c. TLC 2hexane/AcOEt 22/1)) Rf 0.7; IR n
2cm21): 2111, 1739. 1H NMR 2250 MHz, CDCl3):
dˆ5.19±5.04 21H, m, COOCH2Me)2), 4.85 21H, s, H1),
4.65 21H, dd, Jˆ3.4, 6.0 Hz, H3), 4.56 21H, d, Jˆ6.0 Hz,
H2), 4.15±4.01 22H, m, CHCOO, H4), 3.31 23H, s, OCH3),
2.28±2.19 22H, m, CH2), 1.47 23H, s, CH3), 1.33 23H, s,
CH3), 1.31 23H, d, Jˆ6.4 Hz, COOCH2CH3)2), 1.30 23H,
d, Jˆ6.0 Hz, COOCH2CH3)2). 13C NMR d: 169.6, 112.6,
106.7, 85.0, 80.1, 75.9, 69.8, 59.5, 54.4, 30.4, 26.0, 24.9,
21.7, 21.6.
5. 2a) Chu, Y.-Y.; Yu, C.-S.; Chen, C.-J.; Yang, K.-S.; Lain,
J.-C.; Lin, C.-H.; Chen, K. J. Org. Chem. 1999, 64, 6993±
6998 and references cited therein. 2b) Dalla, V.; Catteau, J. P.;
Pale, P. Tetrahedron Lett. 1999, 40, 5193±5196. 2c) Ghosh,
A. K.; Chen, Y. Tetrahedron Lett. 1995, 36, 6811±6814.
2d) Uday, M.; Packiarajan, M. Tetrahedron: Asymmetry
1994, 5, 1171±1174. 2e) Takahiko, A.; Hiroyuki, N.; Takaaki,
K.; Shoichiro, O. Bull. Chem. Soc. Jpn 1994, 67, 180±188.
Â
2f) Solladie-Cavallo, A.; Bencheqroun, M. Tetrahedron:
Asymmetry 1991, 2, 1165±1171. 2g) Seyden-Penne, J.
4.4. Reduction of the azido compounds 3/30 into the
aminoesters 5/50
Â
Á
Reductions par les Alumino- et Borohydrures en Synthese
Organique; Technique et Documentation 2Lavoisier), Paris
1988; pp 1±175. 2h) Whitesell, J. K.; Dey, D.; Bhattacharya,
A. J. Chem. Soc., Chem. Commun. 1983, 802.
In a typical procedure, 60 mg of Pd/C 10% was added to a
solution of a-azidoester 3a/30a 25/95) 2120 mg, 0.34 mmol)
in 10 ml of isopropanol. The mixture was hydrogenated
under a pressure of 5 bar for 14 h. The crude product was
®ltered on celite to remove the catalyst, and the ®ltrate was
reduced in vacuo to yield 5a/50a 25/95) 2114 mg, 93%).
Spectral data of 5a±c/50a±c were recently given in Ref. 14.
6. Midland, M. M. Chem. Rev. 1989, 89, 1553±1561. 2b) Brown,
H. C.; Pai, G. G.; Jadhav, P. K. J. Am. Chem. Soc. 1984, 106,
1531±1533. 2c) Brown, H. C.; Pai, G. G. J. Org. Chem. 1982,
47, 1608±1610.
7. Yatagai, M.; Ohnuki, T. J. Chem. Soc., Perkin Trans. 1 1990,
1826±1828.
8. 2a) Nishizawa, M.; Noyori, R. Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 8, p 159. 2b) Ojima, I.; Clos, N.; Bastos, C.
Tetrahedron 1989, 45, 6901±6939. 2c) Ojima, I.; Hirai, K.
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New
York, 1985; Vol. 5, p 103.
Acknowledgements
We are very grateful to Dr Van Dorsselaer 2Strasbourg
University) for the mass spectra.
9. 2a) Eguchi, T.; Fukuda, M.; Toyooka, Y.; Kakinuma, K.
Tetrahedron 1998, 54, 705±714. 2b) Leroy, C.; Levacher,
V.; Dupas, G.; Queguiner, G.; Bourguignon, J. Tetrahedron:
Asymmetry 1997, 8, 3309 and references cited therein.
2c) Levacher, V.; Dupas, G.; Queguiner, G.; Bourguignon, J.
Trends Heterocycl. Chem. 1995, 4, 293. 2d) Stryer, L.
Biochemistry; W. H. Freeman & Co.: New York, 1995.
2e) Burgess, V. A.; Davies, S. G.; Skerlj, R. T.; Whittaker,
M. Tetrahedron: Asymmetry 1992, 3, 871±901. 2f) Kellog,
R. M. Comprehensive Organic Synthesis; Trost, B., Fleming,
M. I., Eds.; Pergamon: Oxford, 1991; Vol. 8, p 79.
2g) Belokon, Y. N.; Bulychev, A. G.; Pavlov, V. A.; Fedorova,
E. B.; Tsyryapkin, V. A.; Bakhmutov, V. A.; Belikov, V. M.
J. Chem. Soc., Perkin Trans. 1 1988, 2075±2083. 2h) Inouye,
O. Y.; Baba, N. Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic: New York, 1983; Vol. 2. p 92.
References
1. Coppola, G. M.; Schuster, H. F. a-Hydroxy Acids in
Enantioselective Syntheses; VCH: Weinheim, 1997; pp 1±
511. 2b) Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron:
Asymmetry 1997, 8, 1877±1894 and references cited therein.
2c) Ghosh, A. K.; Chen, Y. Tetrahedron Lett. 1995, 36, 6811±
6814 and references cited therein.
2. Williams, R. M. Organic Chemistry Series: Synthesis of
Optically Active a-Aminoacids, Vol. 7; Pergamon: Oxford,
1989; pp 186±207.
3. ter Halle, R.; Schulz, E.; Spagnol, M.; Lemaire, M. C. R. Acad.
Â
Sci. Paris, Serie IIc 2000, 3, 553±556. 2b) BuÈrgi, T.; Baiker,
A. J. Catal. 2000, 194, 445±451. 2c) Zuo, X.; Liu, H.; Guo, D.;
Yang, X. Tetrahedron 1999, 55, 7787±7804 and references
cited therein. 2d) Augustine, R. L.; Tanielyan, S. K.; Doyle,
L. K. Tetrahedron: Asymmetry 1993, 4, 1803±1827.
2e) Blaser, H. U. Tetrahedron: Asymmetry 1991, 2, 843±
866. 2f) Garland, M.; Blaser, H. U. J. Am. Chem. Soc. 1990,
112, 7048±7050.
10. 2a) Kayser, M. M.; Mihovilovic, M. D.; Kearns, J.; Feicht, A.;
Stewart, J. D. J. Org. Chem. 1999, 64, 6603±6608.
2b) Hayakawa, R.; Nozawa, K.; Kimura, K.; Shimizu, M.
Tetrahedron 1999, 55, 7519±7528. 2c) Kawai, Y.; Hida, K.;
Tsujimoto, M.; Kondo, S.-I.; Kitano, K.; Nakamura, K.; Ohno,
A. Bull. Chem. Soc. Jpn 1999, 72, 99±101. 2d) North, M.
J. Chem. Ed. 1998, 75, 630±631. 2e) Rotthaus, O.; Krueger,
D.; Demuth, M.; Schaffner, K. Tetrahedron 1997, 53, 935±
938. 2f) Jian-Xin, G.; Yu-Yi, L.; Guo-Qiang, L. Tetrahedron
4. 2a) Benicori, T.; Piccolo, O.; Rizzo, S.; Sannicolo, F. J. Org.
Chem. 2000, 65, 8340±8347. 2b) Raluca, A.; Howard, A.
J. Org. Chem. 1998, 63, 9425±9426. 2c) Roucoux, A.;
Devocelle, M.; Carpentier, J.-F.; Agbossou, F.; Mortreux, A.
Ã
Synlett 1995, 358±360. 2d) Genet, J. P.; Pinel, C.;
È
1993, 49, 5805±5816. 2g) Csuk, R.; Glanzer, B. I. Chem. Rev.
Ratovelomanana-Vidal, S.; Mallart, S.; P®ster, X.; Bischoff,
L.; Cano De Andrade, M. C.; Darses, S.; Galopin, C.; Laf®tte,
J. A. Tetrahedron: Asymmetry 1994, 5, 675±690.
2e) Roucoux, A.; Agbossou, F.; Mortreux, A.; Petit, F.
1991, 91, 49±97. 2h) Servi, S. Synthesis 1990, 1±25.
2i) Ridley, D. D.; Stralow, M. J. Chem. Soc., Chem. Commun.
1975, 400. 2j) Buisson, D.; Henrot, S.; Larcheveque, M.;
Azerad, R. Tetrahedron Lett. 1987, 28, 5033. 2k) Brooks,
D. W.; Wilson, M.; Webb, M. J. Org. Chem. 1987, 52,
2244±2248.
È
Tetrahedron: Asymmetry 1993, 4, 2279±2282. 2f) Borner,
A.; Ward, J.; Kortus, K.; Kagan, H. B. Tetrahedron:

C. Grison et al. / Tetrahedron 58 02002) 2735±2741
2741
11. 2a) Ishihara, K.; Yamaguchi, H.; Hamada, H.; Nakajima, N.;
Nakamura, K. J. Mol. Catal. B: Enzym. 2000, 10, 419±428 pp
21. Nakamura, K.; Kondo, S.-I.; Kawai, Y.; Ohno, A.
Tetrahedron: Asymmetry 1993, 4, 1253±1254.
È
429±434. 2b) Adam, A.; Lazarus, M.; Saha-Moller, C. R.;
22. 2a) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem. 1990, 55,
3853±3857. 2b) Binkley, E. R.; Binkley, R. W. In Preparative
Carbohydrate Chemistry; Hanessian, S., Ed.; 1997; pp 87±
104. 2c) Kinzy, W.; Schmidt, R. R. Liebigs Ann. Chem.1987,
407±415. 2d) Burkard, U.; Effenberger, F. Chem. Ber. 1986,
119, 1594±1612. 2e) Effenberger, F.; Burkard, U.; Willfahrt, J.
Liebigs Ann. Chem. 1986, 314±333.
Schreier, P. Tetrahedron: Asymmetry 1998, 9, 351±355.
12. Fukuzawa, S.-I.; Miura, M.; Matsuzawa, H. Tetrahedron Lett.
2001, 42, 4167±4169.
13. 2a) Coutrot, P.; Grison, C.; Tabyaoui, M. Tetrahedron Lett.
1993, 34, 5089±5092. 2b) Coutrot, P.; Grison, C.; Tabyaoui,
Â
M.; Czernecki, S.; Valery, J. M. J. Chem. Soc., Chem.
Commun. 1988, 1515±1516. 2c) Coutrot, P.; Legris, C.
Synthesis 1975, 118±120.
23. Coutrot, F.; Grison, C.; Coutrot, P.; Toupet, L. Acta
Crystallogr. 2001, E57, 519±520.
24. An attempt to determine the con®guration of the new stereo-
genic centre in the case of the inseparable diastereomeric
mixture 2c/20c with the Mosher's method25 using 2-methoxy-
2-phenyl-2-2tri¯uoromethyl)acetic acid 2MTPA) esters did not
14. Grison, C.; Coutrot, F.; Coutrot, P. Tetrahedron 2001, 57,
6215±6227.
15. Grison, C.; Coutrot, F.; Comoy, C.; Lemilbeau, C.; Coutrot, P.
Tetrahedron Lett. 2000, 41, 6571±6574.
1
succeed. The Dd variations observed on H NMR spectra of
16. Hutchins, R. O.; Natale, N. R. Org. Prep. Proced. Int. 1979,
11, 201±246.
Mosher esters derived from 2c/20c shown a conformational
deviation of the MPTA moiety from the ideal position. As a
consequence, the Mosher rule could not be applied to deter-
mine the con®guration in the case of this type of compound.
25. 2a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512±519. 2b) Sullivan, G. R.; Dale, J. A.; Mosher, H. S.
J. Org. Chem. 1973, 38, 2143±2147. 2c) Ohtani, I.; Kusumi,
T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092±4096.
17. Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611±
614.
18. 2a) Itsuno, Y.; Sakurai, Y.; Ito, K.; Hirao, A.; Nakahama, S.
Bull. Chem. Soc. Jpn 1987, 60, 395±396. 2b) Corey, E. J.;
Bakshi, R. K.; Shibata, S. J. Am. Chem.Soc. 1987, 109,
5551±5553.
19. Corey, E. J.; Azimiora, M.; Sarshar, S. Tetrahedron Lett.
1992, 33, 3429±3430.
20. Corey, E. J. Pure Appl. Chem. 1990, 62, 1209±1216.