Synthesis of C-glycosyl compounds of N-acetylneuraminic acid from D-gluconolactone

Article abstract of DOI:10.1016/S0008-6215(02)00176-3

A general strategy towards the synthesis of C-glycosyl compounds of N-acetylneuraminic acid (Neu5Ac) has been developed and successfully applied to the synthesis of C-methyl and C-phenyl derivatives. The key strategic elements are (i) chain extension of a D-gluconolactone derivative as C₆-precursor with an allyl Grignard reagent as C₃-precursor having in 2 position the C-linked aglycon moiety, (ii) stereoselective C-4/C-5 erythro-diol formation, (iii) 6-exo-trig selective heterocyclization, and (iv) instalment of the 5-acetylamino and C-1 carboxylate functionalities. The efficiency and potential versatility of this approach was exemplified in the synthesis of C-methyl derivative 1 as target molecule.

Full text of DOI:10.1016/S0008-6215(02)00176-3

Carbohydrate Research 337 (2002) 1967–1978
www.elsevier.com/locate/carres
Synthesis of C-glycosyl compounds of N-acetylneuraminic acid
from -gluconolactone
D
Ahmed I. Khodair,† Richard R. Schmidt*
Fachbereich Chemie, Uni6ersita¨t Konstanz, Fach M 725, D-78457 Konstanz, Germany
Received 15 May 2002; accepted 24 June 2002
Dedicated to Professor Derek Horton on the occasion of his 70th birthday
Abstract
A general strategy towards the synthesis of C-glycosyl compounds of N-acetylneuraminic acid (Neu5Ac) has been developed
and successfully applied to the synthesis of C-methyl and C-phenyl derivatives. The key strategic elements are (i) chain extension
of a D-gluconolactone derivative as C6-precursor with an allyl Grignard reagent as C3-precursor having in 2 position the C-linked
aglycon moiety, (ii) stereoselective C-4/C-5 erythro-diol formation, (iii) 6-exo-trig selective heterocyclization, and (iv) instalment
of the 5-acetylamino and C-1 carboxylate functionalities. The efficiency and potential versatility of this approach was exemplified
in the synthesis of C-methyl derivative 1 as target molecule. © 2002 Elsevier Science Ltd. All rights reserved.
Keywords: C-Glycosides; Synthesis; Neuraminic acid; Cyclization; Chain extension
1. Introduction
the glycoconjugate by neuraminidases, specific hy-
drolytic enzymes. Following cleavage, antigenic
oligosaccharides are unmasked, thereby permitting the
catabolism of the entire glycoconjugate. The replace-
ment of the glycosidic oxygen by a corresponding car-
bon substituent provides an interesting approach to
rationally control many of these important processes in
glycobiology, since this structural transformation ren-
ders the natural O-glycoside a nonhydrolyzable C-gly-
cosyl analogue which is inert to catabolism.
Despite numerous methodologies available for the
synthesis of C-glycosyl derivatives of aldoses,¶ only a
few syntheses of C-glycosyl derivatives of sialic acids
have been reported.12 The work of Linhardt and
coworkers,13 using samarium iodide for sialyl interme-
diate generation, provided more complex C-glycosyl
derivatives of various sialic acids. Herein, we extend
our previously reported strategy to the synthesis of the
highly valuable Neu5Ac-a(2-3)-Gal C-disaccharide,14 to
a general synthesis of Neu5Ac C-glycosyl derivatives
(Scheme 1, 1, R Me, Ph). This versatile approach is
based on the electrophilic cyclization of open-chain
As terminating constituents of many glycoconjugates,
sialic acids are often found at the nonreducing end of
the oligosaccharide moiety, and, due to this peripheral
position they are involved in a significant number of
biological events.‡ Thus, they mediate numerous molec-
ular recognition events.2–10 The most ubiquitous mem-
ber of this class of structurally unique carbohydrates is
N-acetylneuraminic acid (Neu5Ac) (Scheme 1, 1, R
OH).1 Typically, Neu5Ac is attached via an a-O-glyco-
sidic linkage to the carbohydrate chain of these glyco-
conjugates.§ In vivo, terminal Neu5Ac is removed from
* Corresponding author. Tel.: +49-7531-882538; fax: +
49-7531-883135
E-mail address: richard.schmidt@uni-konstanz.de (R.R.
Schmidt).
† On leave from Chemistry Department, Faculty of Educa-
tion, Tanta University, Kafr El-Sheikh Branch, Kafr El-
Sheikh, Egypt.
‡ For reviews, see Ref. 1.
§ Important motifs are Neu5Aca(2-3)Gal-, Neu5Aca(2-
6)Gal- and the Neu5Aca(2-8)-Neu5Ac-disaccharide moieties.
¶ For reviews, see Ref. 11.
0008-6215/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00176-3

1968
A.I. Khodair, R.R. Schmidt / Carbohydrate Research 337 (2002) 1967–1978
precursor A using phenylselenyl triflate**,†† as cycliza-
tion reagent followed by the generation of the carboxy-
late moiety and introduction of the nitrogen.
Intermediate A can be readily obtained from C6- and
C3-precursors B and C, respectively. For B, D-glucono-
lactone seemed to be an ideal starting material because
it can be efficiently transformed into tri-O-isopropyli-
dene derivative 2, which fulfils all demands for the
required C6-building block.
2. Results and discussion
Reaction of tri-O-isopropylidene-
-gluconate 217
D
with 2-methyl- and 2-phenyl-allylmagnesium bromide
(3a and 3b) Grignard reagents at −95 °C led, after
work-up, to addition products 4a and 4b, respectively,
in very high yields (Scheme 2). Due to the low reaction
temperature, no isomerization of 4a,b to the thermody-
namically more stable a,b-unsaturated enone system
was observed; also further addition of the C-nucle-
ophiles to the ketone carbonyl group of 4 were only
minor byproducts (B5%). Next, the a-hydroxyketone
moiety of 4a,b was stereoselectively reduced with zinc
Scheme 2. Transformation of gluconate 2 into nonenitol
derivatives 7a,b. Reagents and conditions: (a) 2:1, Et2O–
THF, −95 °C, 4a (87%), 4b (82%); (b) Zn(BH4)2, Et2O,
−10 °C, (a: 95%, 5a:6a 30:1; b: 86%, 5b:6b 13:1); (c) diphos-
gene, DMAP, pyr/CH2Cl2, 0 °C (7a: 88%; 7b: 92%).
boronhydride18 in Et2O at −10 °C to afford diols 5a,
6a and 5b, 6b, respectively, in very high yields. Obvi-
ously, prior to carbonyl group reduction some double
bond migration had occurred. As expected from previ-
ous experiments,14,19 a 30:1 mixture of isomers 5a/6a
and a 13:1 mixture of isomers 5b/6b in favour of 5a and
5b, respectively, with the desired C-4/C-5 erythro-
configuration was obtained. The structural assignment
of 5a, 5b was confirmed by the subsequent reactions.
Transformation of 5a and 5b with diphosgene in the
presence of Steglich’s reagent (4-dimethylaminopyridine
DMAP) in dichloromethane/pyridine furnished cyclic
carbonate derivatives 7a,b in high yields.
For the ring closure, the O-isopropylidene groups of
7a,b were removed with trifluoroacetic acid (TFA) in
THF/water, thus affording 8a and 8b (Scheme 3). We
reasoned that out of four hydroxyl groups present in 8,
only the 6-hydroxy group leading to a six-membered
cyclization product would participate in the cyclization
step in an exo-trig selective manner,20 thus rendering a
selective protection of the other hydroxy groups unnec-
essary. In addition, we decided to postpone the intro-
duction of the nitrogen to a later stage of the synthesis,
i.e., after the cyclization step, in order to avoid a
competitive participation of the nitrogen during the
cyclization reaction. We furthermore anticipated that
embedding of the erythro-diol unit of 5 into a cyclic
Scheme 1. Retrosynthetic analysis for the generation of target
molecule 1.
** For the use of phenylselenyl triflate for electrophilic
cyclization see Ref. 15.
†† For early work on electrophilic cyclization for the syn-
thesis of C-glycosyl derivatives with other electrophiles see
Ref. 16.

A.I. Khodair, R.R. Schmidt / Carbohydrate Research 337 (2002) 1967–1978
1969
carbonate framework would decrease the combinatorial
flexibility of the acyclic scaffold and facilitate the elec-
trophilic cyclization.‡‡ Thus, open-chain precursors 8a
and 8b were pivotal intermediates. On the basis of the
potential and versatility of selenium based reagents22 as
well as our own results,14,23 the capability of cationic
selenium species to induce an electrophilic heterocy-
clization between the olefin moiety and the 6-hydroxy
group was investigated. Addition of 8a to phenylselenyl
triflate at −80 °C in propionitrile resulted in almost
quantitative formation of a 2:1 ratio of cyclization
products 9a and 10a; application of the same reaction
to 8b led to a 1:2 ratio of cyclization products 9b and
10b. For further transformation and characterization,
these compounds were O-acetylated to provide 11a,
11b, 12a, and 12b, which could be fully assigned by the
NMR data. The assignment of the stereochemistry of
the quaternary carbon centre formed in 11a,b on one
side and 12a,b on the other side could be readily based
on NOE cross-peaks between the protons of the corre-
sponding axial methylene group in 11a,b and 4-H and
6-H, respectively.
Following our strategy, the next task was the intro-
duction of the nitrogen functionality§§ (Scheme 4). To
this end, in 11a all ester groups were cleaved by treat-
ment with NaOMe in methanol affording O-unpro-
tected derivative 13. Regioselective O-benzoylation
with benzoyl cyanide in the presence of triethylamine as
Scheme 4. Synthesis of target molecule 1. Reagents and
conditions: (a) NaOMe, MeOH (98%); (b) BzCN, NEt3,
THF, 0 °C (67%; 14/15 1:1); (c) NAOMe, MeOH (qu); (d)
Tf2O, pyr, 0 °C (qu); (e) TBAA, toluene (96%); (f) NaOMe,
MeOH; Ac2O, pyr (94%); (g) MCPBA, THF, −80 °C; Ac2O,
NaOAc, −80 °C“refl.; NaOMe, MeOH; Ac2O, pyr (80%);
(h) NaClO2, KH2PO4, Me2CCHMe, MeCN/tBuOH; CH2N2,
Et2O (79%); (i) Pd/CaCO3, H2, MeOH (77%); (j) Ac2O, pyr
(91%).
base at 0 °C afforded, as expected,¶¶ 5-O-unprotected
15 together with fully O-benzoylated 14, which could
be readily converted into the starting material.25 The
regiochemical assignment can be derived from the
chemical shift of 5-H (14: l 5.86–5.95; 15: l 4.34).
Next, the axial hydroxyl group of tetrabenzoate 15 was
converted into a leaving group by triflate activation
(“16), which was then displaced by treatment with
tetra-n-butylammonium azide to afford azido com-
pound 17 in practically quantitative yield. The inver-
sion of the configuration could be unambiguously
confirmed by the value of the vicinal coupling constants
J4,5 J5,6:10 Hz.
Scheme 3. Ring closure of 8a,b. Reagents and conditions: (a)
TFA, THF/H2O: 8a (91%), 8b (98%); (b) PhSeCl, AgOTf,
EtCN, rt; a: 92% (9a:10a:2:1); b: 66% (9b:10b 1:2); (c)
Ac2O, DMAP, pyr; 11a (95%), 11b (86%), 12a (96%), 12b
(84%).
‡‡ For an illustrative example, see Ref. 21.
§§ Successful transformation of 3-deoxy-2-glyculosonates
into the corresponding 5-azido-3,5-dideoxy derivatives has
been already described. See Ref. 24.
¶¶ Such regioselective benzoylations are not without prece-
dent. See Ref. 25.

1970
A.I. Khodair, R.R. Schmidt / Carbohydrate Research 337 (2002) 1967–1978
The next task was the installation of the carboxylate
tical rotations were determined using a Perkin–Elmer
Polarimeter 241MC (1 dm cell, temperature 21 °C, u
589 nm). 1H NMR and 13C NMR spectra were
recorded at room temperature either on Bruker AC 250
Cryospec or Bruker DRX 600. Chemical shifts are
given in l relative to Me4Si, the coupling constants J
are given in Hz. For 1H NMR, Me4Si served as internal
standard (l 0 ppm), and CDCl3 was used as internal
standard (l 77.0 ppm), for 13C NMR. Assignment of
peaks and stereochemistry was based upon DQF-
COSY, HMQC, HMBY and ROESY experiments.
functionality. After transformation of 17 into O-acetyl
protected 18, this functional group transformation
could be achieved in a straightforward manner by
subjecting phenylselenide 18 to a selena-Pummerer
rearrangement14 to afford aldehyde 19 in four steps in
80% overall yield. Oxidation of the aldehyde and subse-
quent esterification of the carboxylic acid with dia-
zomethane then provided methyl ester 20 in 79% yield.
Liberation of the amino group from the azido function-
ality was performed by hydrogenation with Pd/CaCO3
as catalyst affording amino derivative 21 which on
immediate N-acetylation furnished target molecule 1.
The structural assignment could be based on the NMR
data (NOE cross-peaks between H-4 and H-6, H-4 and
Heq-3, H-5 and Hax-3).
a
Geminal diastereotopic protons were distinguished by
b
and . EIMS were recorded on a Finnigan MAT 312.
MALDI-TOF mass spectra were recorded on a Kratos
Kompact MALDI instrument, using a 2,5-dihydroxy
benzoic acid matrix.
1,2,3-Trideoxy-6,7:8,9-di-O-isopropylidene-2-methyl-
D
-gluco-non-1-eno-4-ulose (4a).—1,2:3,4:5,6-Tri-O-iso-
3. Conclusion
propylidene-
D
-gluconate17 (2) (4.00 g, 12.64 mmol) was
dissolved in anhyd Et2O (200 mL) and cooled to
−95 °C. Then a −95 °C cold soln of freshly prepared
b-methallyl magnesium chloride (3a) in anhyd THF (40
mmol in 100 mL) was quickly pumped to this soln via
a transfer cannula and the mixture was stirred for 20
min at this temperature. The cold mixture was poured
onto a 10% HCl soln (100 mL) and stirred for 5 min.
The layers were separated, the aq layer was washed
with Et2O (2×20 mL), the combined organic layers
were washed with brine (5×40 mL) and dried
(MgSO4). Filtration, concentration under diminished
pressure and purification of the residue by flash chro-
matography (SiO2, 9:1 petroleum ether–EtOAc) af-
forded hydroxy ketone 4a (3.44 g, 87%) as a colourless
syrup. TLC (2:1 petroleum ether–EtOAc): Rf 0.43; [h]D
We have developed a novel approach to the synthesis
of C-glycosyl derivatives of Neu5Ac. Important fea-
tures of this strategy are the following: (a) The ap-
proach is assumed to be general and should allow for
variability within the C-glycosyl part as well as the
sialic acid moiety; (b) the key steps of the strategy
consist of a C3-chain extension of a readily available
gluconate derivative, diastereoselective generation of an
erythro-diol moiety, and a 6-exo-trig selective elec-
trophilic cyclization; (c) the strategy is not based on
expensive Neu5Ac precursors but uses inexpensive and
readily available precursors as starting materials; and
(d) due to the masked amino functionality as an azide
group, upon reduction a large variety of substituents
other than N-acetyl can be attached.
1
−43.80° (c 2; CHCl3); H NMR (600 MHz, CDCl3): l
4.99 (1 H, s, 1-Hb), 4.86 (1 H, s, 1-Ha), 4.39 (1 H, br d,
J 7.0 Hz, 5-H), 4.32 (1 H, br d, J 5.7 Hz, 6-H),
4.17–4.11 (3 H, m, 9-Hb, 7-H, 8-H), 4.00 (1 H, m,
9-Ha), 3.53 (1 H, d, J 7.0 Hz, 5-OH), 3.34 (1 H, d, J
17.0 Hz, 3-Hb), 3.30 (1 H, d, J 17.0 Hz, 3-Ha), 1.78 (3
H, s, CH3), 1.44, 1.35, 1.34 (12 H, 3 s, 2×CMe2); 13C
NMR (150.8 MHz, CDCl3): l 206.7 (C-4). 138.1 (C-2),
115.7 (C-1), 110.1, 109.8 (2×CMe2), 79.9 (C-6), 77.5
(C-7), 76.7 (C-8), 75.0 (C-5), 67.9 (C-9), 47.4 (C-3), 27.1
(CH3), 26.7, 26.4, 25.3, 22.6 (4 CH3); EIMS: m/z 314
(M+). Anal. Calcd for C16H26O6 (314.4): C, 61.13; H,
8.34. Found: C, 60.72; H, 8.36.
4. Experimental
General methods.—All organometallic reactions were
performed under an inert atmosphere of nitrogen and
for reactions at low temperatures, cryostats were used
in combination with threefold coated cryogenic flasks.
Chemicals and solvents were either purchased puriss.
p.A. from commercial suppliers or purified by standard
techniques. THF was distilled from sodium-benzophe-
none. For analytical thin layer chromatography (TLC),
silica gel plastic plates E. Merck 60 F254 were used and
compounds were visualized by irradiation with UV
light and/or by immersion into a soln of ammonium
molybdate (20 g), Ce(SO4)2 (400 mg), 10% H2SO4 (400
mL) followed by heating or by treatment with 15%
H2SO4 soln followed by heating. Preparative flash chro-
matography was performed at a pressure of 1.2–1.4 bar
using J. T. Baker silica gel 60 (0.040–0.063 mm, 230–
400 mesh ASTM). Melting points are uncorrected. Op-
1,2,3-Trideoxy-6,7:8,9-di-O-isopropylidene-2-phenyl-
D-gluco-non-1-eno-4-ulose (4b).—Triacetonide 2 (4.00
g, 12.64 mmol) was dissolved in anhyd Et2O (200 mL)
and cooled to −95 °C. Then a −95 °C cold soln of
freshly prepared a-bromomagnesium methylstyrene (3b)
in anhyd THF (40 mmol in 100 mL) was quickly
pumped to this soln via transfer cannula and the mix-
ture was stirred for 20 min at this temperature. The
cold mixture was poured onto a 10% HCl soln (100

A.I. Khodair, R.R. Schmidt / Carbohydrate Research 337 (2002) 1967–1978
1971
mL) and stirred for 5 min. The layers were separated,
the aq layer was washed with Et2O (2×20 mL), the
combined organic layers were washed with brine (5×
40 mL) and dried (MgSO4). Filtration, concentration
under diminished pressure and purification of the
residue by flash chromatography (SiO2, 9:1 petroleum
ether–EtOAc) afforded the hydroxy ketone 4b (3.90 g,
82%) as a colourless syrup. TLC (95:5 CH2Cl2–
2×CMe2). Anal. Calcd for C16H28O6·0.25 H2O (320.9):
C, 59.89; H, 8.95. Found: C, 59.93; H, 9.05.
1,2,3-Trideoxy-6,7:8,9-di-O-isopropylidene-2-phenyl-
D-glycero-
D-gulo-non-1-enitol (5b) and 1,2,3-trideoxy-
6,7:8,9-di-O-isopropylidene-2-phenyl-
D
-glycero- -gulo/id
D
o-non-1-enitol (6b).—A soln of hydroxy ketone 4b
(1.88, 5.00 mmol) in anhyd Et2O (25 mL) was cooled to
−10 °C and a soln of Zn(BH4)2 in anhyd Et2O18 (12
mL) was added. The mixture was stirred for about 1 h
at this temperature until the reaction was complete
(TLC). Then 1N HCl soln (12 mL) was carefully added,
the mixture was stirred for 5 min and the layers were
separated. The aq layer was extracted with Et2O (2×50
mL), the combined organic layers were washed with
brine until the aq layer showed pH 6–7, and dried
(MgSO4). Filtration, concentration under diminished
pressure and purification of the residue by flash chro-
matography (SiO2, 2:1 petroleum ether–EtOAc) af-
forded diol 5b (1.52 g, 80%) as a white foams and diol
6b (120 mg, 6%) as a colourless syrup.
1
MeOH): Rf 0.40; [h]D −1.71° (c 0.7; CHCl3); H NMR
(250 MHz, CDCl3): l 7.36–7.21 (5 H, m, Ar-H), 5.58 (1
H, s, 1-Hb), 5.19 (H, s, 1-Ha), 4.33 (1 H, d, J 6.5 Hz,
5-H), 4.10–4.01 (4 H, m, 9-Hb, 7-H, 8-H, 6-H), 3.93 (1
H, m, 9-Ha), 3.82 (1 H, d, J 17.0 Hz, 3-Hb), 3.70 (1 H,
d, J 17.0 Hz, 3-Ha), 3.48 (1 H, d, J 7.3 Hz, 5-OH), 1.37,
1.35, 1.28 (12 H, 3 s, 2×CMe2); 13C NMR (62.9 MHz,
CDCl3): l 207.2 (C-4), 141.0 (C-2), 129.1, 128.6, 126.6,
118.0 (C-Ar), 110.8, 110.5 (2×CMe2), 80.7 (C-6), 78.2
(C-7), 78.1 (C-8), 75.7 (C-5), 68.5 (C-9), 46.1 (C-3),
27.8, 27.3, 27.1, 26.0 (4 CH3); EIMS: m/z 376 (M+).
Anal. Calcd for C21H28O6 (376.4): C, 67.00; H, 7.50.
Found: C, 66.87; H, 8.00.
5b: TLC (2:1 petroleum ether/EtOAc): Rf 0.35; [h]D
1
1,2,3-Trideoxy-6,7:8,9-di-O-isopropylidene-2-methyl-
+11.00° (c 0.7; CHCl3); H NMR (600 MHz, CDCl3):
D
-glycero-
D
-gulo-non-1-enitol (5a) and 1,2,3-trideoxy-
l 7.42 (2 H, d, J 7.4 Hz, Ar-H), 7.28 (3 H, m, Ar-H),
5.41 (H, s, 1-Hb), 5.22 (1 H, s, 1-Ha), 4.25 (1 H, d, J 7.2
Hz, 6-H), 4.12 (1 H, dd, J 5.8, 8.4, 9-Hb), 4.05 (1 H, m,
8-H), 4.02 (1 H, m, 7-H), 3.95 (1 H, dd, J 4.6, 8.5 Hz,
9-Ha), 3.70 (1 H, m, 4-H), 3.61 (1 H, m, 5-H), 3.13 (1
H, dd, J 3.16, 14.5 Hz, 3-Hb), 2.62 (1 H, dd, J 9.3, 14.5
Hz, 3-Ha), 2.50 (1 H, br d, J 7.0 Hz, C(5)-OH), 2.15 (1
H, br.s, C(4)-OH), 1.40, 1.37, 1.33 (12 H, 3 s, 2×
CMe2); 13C NMR (150.8 MHz, CDCl3): l 144.9, 140.4,
140.4, 128.4, 127.7, 126.2 (C-Ar), 115.4 (C-1), 109.7,
109.6 (2×CMe2), 79.5 (C-6), 77.1 (C-8), 71.5 (C-4),
71.2 (C-5), 67.7 (C-9), 40.3 (C-3), 27.1, 26.8, 26.6, 25.2
(4 CH3); EIMS: m/z 378 (M+). Anal. Calcd for
C21H30O6·0.25 H2O (383.0): C, 65.86; H, 8.03. Found:
C, 65.60; H, 8.16.
6,7:8,9-di-O-isopropylidene-2-methyl-
D
-glycero- -gulo/
D
ido-non-2-enitol (6a).—A soln of hydroxy ketone 4a
(3.40, 10.86 mmol) in anhyd Et2O (50 mL) was cooled
to −10 °C and a soln of Zn(BH4)2 in anhyd Et2O3 (25
mL) was added. The mixture was stirred for about 1 h
at this temperature until the reaction was complete
(monitored by TLC). Then a 1N HCl soln (25 mL) was
carefully added, the mixture was stirred for 5 min and
the layers were separated. The aq layer was extracted
with Et2O (2×50 mL), the combined organic layers
were washed with brine until the aq layer showed pH
6–7 and dried (MgSO4). Filtration, concentration un-
der diminished pressure and purification of the residue
by flash chromatography (SiO2, 2:1 petroleum ether–
EtOAc) afforded diol 5a (3.16 g, 92%) and diol 6a (10
mg, 3%) as colourless syrups.
6b: TLC (2:1 petroleum ether–EtOAc): Rf 0.30; [h]D
1
−3.57° (c 0.7; CHCl3); H NMR (250 MHz, CDCl3): l
5a: TLC (2:1 petroleum ether–EtOAc): Rf 0.25; [h]D
+8.86° (c 0.7; CHCl3); H NMR (250 MHz, CDCl3): l
7.38–7.16 (5 H, m, Ar-H), 5.78 (1 H, dd, J 1.3, 8.3 Hz,
3-H), 4.58 (1 H, dd, J 5.6, 8.1 Hz, 4-H), 4.16–3.81 (5 H,
7-H, 8-H, 9-Ha, 9-Hb, 6-H), 3.69 (1 H, m, 5-H), 2.70 (1
H, br d, J 9.2 Hz, C(5)-OH), 2.55 (1 H, br d, J 9.0 Hz,
C(4)-OH), 2.05 (3 H, d, J 1.3 Hz, CH3), 1.36, (12 H, 3
s, 2×CMe2), 1.33, 1.23; EIMS: m/z 378 (M+). Anal.
Calcd for C21H30O6·0.25 H2O (383.0): C, 65.86; H, 8.03.
Found: C, 65.65; H, 8.03.
1
4.87 (1 H, br s, 1-Hb), 4.82 (1 H, br s, 1-Ha), 4.24 (1 H,
dd, J 1.5, 7.2 Hz, 6-H), 4.17–3.91 (4 H, m, 9-Ha, 7-H,
8-H, 9-Hb), 3.76 (1 H, m, 4-H), 3.56 (1 H, m, 5-H), 2.46
(1 H, dd, J 3.1, 14.1 Hz, 3-Hb), 2.40–2.30 (2 H, m,
C(4)-OH, C(5)-OH), 2.17 (1 H, dd, J 9.8, 14.1 Hz,
3-Ha), 1.77 (1 H, s, CH3), 1.42, 1.40, 1.33 (12 H, 3 s,
2×CMe2); EIMS: m/z 316 (M+). Anal. Calcd for
C16H28O6 (316.39): C, 60.74; H, 8.92. Found: C, 60.65;
H, 9.14.
4,5-O-Carbonylidene-1,2,3-trideoxy-6,7:8,9-di-O-iso-
propylidene-2-methyl-D -glycero-D -gulo-non-1-enitol
(7a).—A soln of diol 5a (3.13, 9.90 mmol) and DMAP
(cat.) in anhyd 4:1 CH2Cl2–pyridine (75 mL) was
cooled to 0 °C, then diphosgene (0.69 mL, 5.46 mmol)
was added via a syringe and the mixture was allowed to
warm to rt. After stirring for 30 min, MeOH was added
and the mixture was stirred further for 5 min. Then the
solvents were removed under diminished pressure and
1
6a: H NMR (250 MHz, CDCl3): l 5.26 (1 H, dd, J
1.3, 7.4 Hz, 3-H), 4.43 (1 H, m, 4-H), 4.18–3.90 (5H,
7-H, 8-H, 9-Ha, 9-Hb, 6-H), 3.57 (1 H, dd, J 6.6, 6.9 Hz,
5-H), 2.60 (1 H, d, J 9.2, C(5)-OH), 2.34 (1 H, d, J 9.0
Hz, C(4)-OH), 1.75 (3 H, d, J 1.1 Hz, CH3), 1.69 (3 H,
d, J 1.1 Hz, CH3), 1.39, 1.37, 1.36, 1.31 (12 H, 4s,

1972
A.I. Khodair, R.R. Schmidt / Carbohydrate Research 337 (2002) 1967–1978
the residue was dissolved in Et2O followed by addition
of water with vigorous stirring. The layers were sepa-
rated and the aq layer was extracted with Et2O (6×20
mL). The combined organic layers were dried (MgSO4),
filtration, concentrated under diminished pressure and
purified by flash chromatography (SiO2, 9:1 petroleum
ether–EtOAc) to afford diol 7a (3.00 g, 88%) as a white
foams. TLC (2:1 petroleum ether–EtOAc): Rf 0.70; [h]D
CHCl3–MeOH) to afford diol 8a (1.79 g, 91%) as a
white solid, mp 134–136 °C. TLC (4:1 CHCl3–MeOH):
Rf 0.50; [h]D +46.75° (c 0.8; CHCl3); H NMR (250
MHz, Me2SO-d6+D2O): l 5.01 (1 H, m, 4-H), 4.92 (1
H, m, 5-H), 4.82 (1 H, s, 1-Hb), 4.81 (1 H, m, 6-H), 4.75
(1 H, s, 1-Ha), 3.57 (1 H, dd, J 2.5, 10.3 Hz, 9-Hb),
3.50–3.32 (3 H, m, 7-H, 8-H, 9-Ha), 2.58 (1 H, dd, J
9.4, 15.5 Hz, 3-Hb), 2.40 (1 H, dd, J 3.8, 15.6 Hz, 3-Ha),
1.71 (1 H, s, CH3). Anal. Calcd for C11H18O7 (262.3):
C, 50.38; H, 6.92. Found: C, 50.10; H, 7.36.
1
1
+25.86° (c 0.7; CHCl3); H NMR (600 MHz, CDCl3):
l 4.95 (2 H, m, 1-Hb, 4-H), 4.83 (2 H, m, 5-H, 1-Ha),
4.16 (1 H, dd, J 6.1, 8.4 Hz, 9-Hb), 4.06–3.96 (4 H, m,
9-Ha, 7-H, 8-H, 6-H), 2.77 (1 H, dd, J 8.8, 15.6 Hz,
3-Hb), 2.55 (1 H, dd, J 4.7, 15.6 Hz, 3-Ha), 1.82 (3 H,
s, CH3), 1.42, 1.41, 1.40, 1.33 (12 H, 4s, 2×CMe2); 13C
NMR (150.8 MHz, CDCl3): l 154.5 (CO); 140.2 (C-2),
113.2 (C-1), 111.0, 109.9 (2×CMe2), 78.0 (C-6), 77.8
(C-4), 77.0 (C-8), 76.5 (C-5, C-7), 68.0 (C-9), 36.7 (C-3),
27.1, 26.9, 26.0, 25.2 (2×CMe2), 22.9 (CH3); EIMS:
m/z 342 (M+). Anal. Calcd for C17H26O7 (343.0): C,
59.64; H, 7.65. Found: C, 59.72; H, 7.77.
4,5-O-Carbonylidene-1,2,3-trideoxy-2-phenyl-
D-glyc-
ero- -gulo-non-1-enitol (8b).—Cyclic carbonate 7b
D
(1.18 g, 2.92 mmol) was dissolved in 1:1 THF/water (50
mL) and TFA (25 mL) was added. After stirring at rt
for 10 min cleavage of the primary isopropylidene ketal
moiety was complete (monitored by TLC). Then the
mixture was stirred at 70 °C until cleavage of the
second O-isopropylidene ketal moiety was complete
(60–70 min, monitored by TLC). The solvents were
removed under diminished pressure and the residue was
purified by flash chromatography (SiO2, 1:0 to 19:1
CHCl3–MeOH) to afford diol 8b (0.93 g, 98%) as a
white solid, mp 152–155 °C. TLC (4:1 CHCl3–MeOH):
4,5-O-Carbonylidene-1,2,3-trideoxy-6,7:8,9-di-O-iso-
propylidene-2-phenyl-D -glycero-D -gulo-non-1-enitol
(7b).—A soln of diol 5b (1.36, 3.60 mmol) and DMAP
(cat.) in anhyd 4:1 CH2Cl2–pyridine (25 mL) was
cooled 0 °C, then diphosgene (0.25 mL, 2.00 mmol) was
added via a syringe and the mixture was allowed to
warm to rt. After stirring for 30 min, MeOH was added
and the mixture was stirred further for 5 min. Then the
solvents were removed under diminished pressure and
the residue was dissolved in Et2O followed by addition
of water with vigorous stirring. The layers were sepa-
rated and the aq layer was extracted with Et2O (6×20
mL). The combined organic layers were dried (MgSO4),
filtration, concentrated under diminished pressure and
purified by flash chromatography (SiO2, 9:1 petroleum
ether–EtOAc) to afford diol 7b (1.34 g, 92%) as a white
foam. TLC (2:1 petroleum ether–EtOAc): Rf 0.50; [h]D
1
Rf 0.40; [h]D +43.50° (c 0.6; CHCl3); H NMR (250
MHz, CD3COCD3): l 7.47–7.28 (5 H, m, Ar-H), 5.42(1
H, s, 1-Hb), 5.25 (1 H, s, 1-Ha), 4.92 (1 H, m, 4-H), 4.14
(1 H, dd, J 1.9, 3.5 Hz, 5-H), 3.77–3.58 (5 H, m, 9-Ha,
9-Hb, 7-H, 8-H, 6-H), 3.30 (2 H, m, 3-Ha 3-Hb). Anal.
Calcd for C16H20O7·0.5 H2O (333.3): C, 57.65; H, 6.35.
Found: C, 57.88; H, 6.49.
2,6 - Anhydro - 4,5 - O - carbonylidene - 1,3 - dideoxy - 2-
methyl-1-phenylseleno-
2,6-anhydro-4,5-O-carbonylidene-1,3-dideoxy-2-methyl-
1-phenylseleno- -erythro- -galacto-nonitol (10a).—
D-erythro-L-talo-nonitol (9a) and
D
L
Compound 8a was coevaporated several times with
anhyd toluene prior to use and dried under diminished
pressure. All operations were carried out under an inert
atmosphere of argon. To a soln of phenylselenyl chlo-
ride (1.00 g, 5.20 mmol) in anhyd propionitrile (25 mL)
silver trifluoromethanesulfonate (1.33 g, 5.20 mmol)
was added at rt. A white solid precipitated and the
yellow mixture was quickly cooled to −80 °C and
stirred for 60 min. Then a soln of 8a (1.05 g, 4 mmol)
in anhyd propionitrile (50 mL) was added within 2 min
via a syringe and the mixture was stirred for another 60
min. The reaction was worked up by pouring the cold
reaction mixture on a cold (0 °C) mixture of CH2Cl2
and brine with vigorous stirring (5 min). The layers
were separated, the aq layer was extracted with CH2Cl2
(3×50 mL), the combined organic layers were dried
(MgSO4). Filtration, concentration under diminished
pressure and purification of the residue by flash chro-
matography (SiO2, 19:1 CH2Cl2–MeOH) afforded 9a
(1.02 g, 61%) as a white foam and 10a (0.52 g, 31%) as
a white foam.
1
+24.62° (c 0.8; CHCl3); H NMR (250 MHz, CDCl3):
l 5.52 (1 H, s, 1-Hb), 5.24 (1 H, s, 1-Ha), 4.88 (1 H,
ddd, J 5.6, 8.1, 13.0 Hz, 4-H), 4.76 (1 H, d, J 7.6 Hz,
5-H), 4.18–3.93 (5 H, m, 9-Ha, 9-Hb, 7-H, 8-H, 6-H),
3.28 (1 H, dd, J 8.1, 15.5, 3-Hb), 3.10 (1 H, dd, J 5.6,
15.5 Hz, 3-Ha), 1.42, 1.41, 1.39, 1.34 (12 H, 4 s,
2×CMe2). Anal. Calcd for C22H28O7·0.25 H2O (409.0):
C, 64.62; H, 7.02. Found: C, 64.47; H, 7.25.
4,5-O-Carbonylidene-1,2,3-trideoxy-2-methyl-
D-glyc-
ero- -gulo-non-1-enitol (8a).—Cyclic carbonate 7a
D
(2.57 g, 7.50 mmol) was dissolved in 1:1 THF/water
(100 mL) and TFA (50 mL) was added. After stirring at
rt for 10 min cleavage of the primary isopropylidene
ketal moiety was complete (monitored by TLC). Then
the mixture was stirred at 70 °C until cleavage of the
second O-isopropylidene ketal moiety was complete
(60–70 min, monitored by TLC). The solvents were
removed under diminished pressure and the residue was
purified by flash chromatography (SiO2, 1:0 to 19:1

A.I. Khodair, R.R. Schmidt / Carbohydrate Research 337 (2002) 1967–1978
1973
9a: TLC (4:1 CHCl3–MeOH): Rf 0.50; [h]D +5.66°
(c 0.3; CHCl3); H NMR (250 MHz, CDCl3): l 7.48 (2
2.60 (1 H, d, J 14.6 Hz, 3-Hb), 2.30 (1 H, d, J 14.6 Hz,
3-Ha). Anal. Calcd for C22H24O7Se·0.5 H2O (488.4): C,
54.11; H, 5.16. Found: C, 53.65; H, 5.60.
1
H, m, Ar-H), 7.25 (3 H, m, Ar-H), 5.06 (2 H, d, J 11.1
Hz, 4-H, 5-H), 3.90–3.60 (4 H, 7-H, 8-H, C(7)-OH,
C(8)-OH), 3.40–3.02 (6 H, m, 1-Ha, 1-Hb, 9-Ha, 9-Hb,
6-H, C(9)-OH), 2.35 (1 H, d, J 15.7 Hz, 3-Hb), 1.80 (1
10b: TLC (9:1 CHCl3–MeOH): Rf 0.35; [h]D −30.0°
1
(c 0.3; CHCl3); H NMR (250 MHz, CDCl3): l 7.37–
7.06 (10 H, m, Ar-H), 4.95 (1 H, dd, J 7.8, 15.6 Hz,
5-H), 4.76 (1 H, d, J 7.7 Hz, 4-H), 4.00–3.60 (8 H, m,
6-H, 7-H, 8-H, 9-Ha, 9-Hb, C(9)-OH, C(8)-OH, C(7)-
OH), 3.40 (1 H, d, J 13.2 Hz, 1-Hb), 3.27 (1 H, d, J 12.7
Hz, 1-Ha), 2.55 (2 H, m, 3-Ha, 3-Hb). Anal. Calcd for
C22H24O7Se·0.5 H2O (488.4): C, 54.11; H, 5.16. Found:
C, 53.75; H, 5.58.
1
H, d, J 15.7 Hz, 3-Ha), 1.31 (3 H, s, CH3); H NMR
(250 MHz, CD3OD): l 7.55–7.60 (2 H, m, Ar-H),
7.31–7.24 (3 H, m Ar-H), 5.09–4.98 (2 H, m, 5-H,
4-H), 3.90–3.62 (5 H, m, 6-H, 7-H, 8-H, 9-Ha, 9-Hb),
3.26 (2 H, s, 1-Ha, 1-Hb), 2.30 (1 H, dd, J 3.2, 16.0 Hz,
3-Hb), 1.90 (1 H, dd, J 3.0, 16.1 Hz, 3-Ha), 1.43 (3 H,
s
CH3); MS: m/z 418 (M+). Anal. Calcd for
7,8,9-Tri-O-acetyl-2,6-anhydro-4,5-O-carbonylidene-
C17H22O7Se·0.25 H2O (421.8): C, 48.41; H, 5.37.
Found: C, 48.36; H, 5.72.
1,3-dideoxy-2-methyl-1-phenyl-seleno-D-erythro-L-talo-
nonitol (11a).—Compound 9a (0.26 g, 0.62 mmol) was
dissolved in pyridine (6 mL), Ac2O (4 mL) and DMAP
(cat.) were added and the soln was stirred at rt for 12 h.
The solvents were removed under diminished pressure
and purification of the residue by flash chromatography
(SiO2, 1:1 petroleum ether–EtOAc) afforded 11a (320
mg, 95%) as a white foam. TLC (1:1 petroleum ether–
10a: TLC (4:1 CHCl3–MeOH): Rf 0.45; [h]D −8.60°
1
(c 0.5; CHCl3); H NMR (250 MHz, CDCl3): l 7.49 (2
H, m, Ar-H), 7.21 (3 H, m, Ar-H), 4.86 (2 H, d, J 12.0
Hz, 4-H, 5-H), 4.30–3.36 (8 H, m, 6-H, 7-H, 8-H, 9-Ha,
9-Hb, C(9)-OH, C(8)-OH, C(7)-OH), 3.33 (1 H, d, J
12.4 Hz, 1-Hb), 3.05 (1 H, d, J 12.5 Hz, 1-Ha), 2.30 (1
H, d, J 15.5 Hz, 3-Hb), 1.80 (1 H, d, J 15.3 Hz, 3-Ha),
1.31 (3 H, s, CH3); EIMS: m/z 418 (M+). Anal. Calcd
for C17H22O7Se·0.25 H2O (421.8): C, 48.41; H, 5.37.
Found: C, 48.83; H, 6.04.
1
EtOAc): Rf 0.40; [h]D +8.60° (c 0.6; CHCl3); H NMR
(600 MHz, CDCl3): l 7.50 (2 H, m, Ar-H), 7.27 (3 H,
m, Ar-H), 5.47 (1 H, dd, J 3.6, 6.2 Hz, 7-H), 5.30 (1 H,
m, 8-H), 4.99 (1 H, m, 4-H), 4.76 (1 H, d, J 8.8 Hz,
5-H), 4.46 (1 H, dd, J 2.1, 12.3 Hz, 9-Hb), 4.15 (1 H,
dd, J 5.9, 12.3 Hz, 9-Ha), 3.84 (1 H, d, J 3.6 Hz, 6-H),
3.07 (1 H, d, J 12.0, 1-Hb), 2.95 (1 H, d, J 12.0, 1-Ha),
2.27 (1 H, dd, J 3.2, 16.0 Hz, 3-Hb), 2.15, 2.04, 2.03 (9
H, 3 s, 3×Ac), 1.81 (1 H, dd, J 3.0, 16.0 Hz, 3-Ha),
1.45 (3 H, s, CH3); 13C NMR (150.8 MHz, CDCl3): l
170.7, 170.1, 169.8 (3×Ac), 153.4 (CO), 133.0, 130.2,
129.4, 127.5 (C-Ar), 75.7 (C-2), 73.7 (C-5), 73.2 (C-4),
69.9 (C-8), 69.3 (C-7), 67.7 (C-6), 61.7 (C-9), 39.1 (C-1),
32.5 (C-3), 28.2 (CH3), 21.0, 20.9, 20.7 (3×Ac); EIMS:
m/z 544 (M+). Anal. Calcd for C23H28O10Se (543.4): C,
50.83; H, 5.19. Found: C, 50.66; H, 5.60.
2,6 - Anhydro - 4,5 - O - carbonylidene - 1,3 - dideoxy - 2-
phenyl-1-phenylseleno-
2,6-anhydro-4,5-O-carbonylidene-1,3-dideoxy-2-phenyl-
1-phenylseleno- -erythro- -galacto-nonitol (10b).—
D-erythro-L-talo-nonitol (9b) and
D
L
Compound 8b was coevaporated several times with
anhyd toluene prior to use and dried under diminished
pressure. All operations were carried out under an inert
atmosphere of argon. To a soln of phenylselenyl chlo-
ride (385 mg, 2.00 mmol) in anhyd propionitrile (25
mL), silver trifluoromethanesulfonate (520 mg, 2.03
mmol) was added at rt. A white solid precipitated and
the yellow mixture was quickly cooled to −80 °C and
stirred for 60 min. Then a soln of 8b (500 mg, 1.54
mmol) in anhyd propionitrile (50 mL) was added within
2 min via a syringe and the mixture was stirred for
another 60 min. The reaction was worked up by pour-
ing the cold reaction mixture on a cold (0 °C) mixture
of CH2Cl2 and brine with vigorous stirring (5 min). The
layers were separated, the aq layer was extracted with
CH2Cl2 (3×50 mL), the combined organic layers were
dried (MgSO4). Filtration, concentration under dimin-
ished pressure and purification of the residue by flash
chromatography (SiO2, 19:1 CH2Cl2–MeOH) afforded
9b (147 mg, 20%) and 10b (340 mg, 46%) as white
foams.
7,8,9-Tri-O-acetyl-2,6-anhydro-4,5-O-carbonylidene-
1,3-dideoxy-2-methyl-1-phenyl-seleno-D-erythro-L-talo-
nonitol (12a).—Compound 10a (0.31 g, 0.62 mmol) was
dissolved in pyridine (3 mL), Ac2O (2 mL) and DMAP
(cat.) were added with stirring at rt for 12 h. The
solvents were removed under diminished pressure and
purification of the residue by flash chromatography
(SiO2, 1:1 petroleum ether–EtOAc) afforded 12a (162
mg, 96%) as a white foam. TLC (1:1 petroleum ether–
1
EtOAc): Rf 0.20; [h]D −7.60° (c 0.5; CHCl3); H NMR
(600 MHz, CDCl3): l 7.53 (2 H, m, Ar-H), 7.26 (3 H,
m, Ar-H), 5.50 (1 H, dd, J 3.5, 6.4 Hz, 7-H), 5.22 (1 H,
ddd, J 2.4, 5.6, 8.4, 8-H), 4.93 (1 H, m, 4-H), 4.73 (1 H,
dd, J 1.5, 8.4 Hz, 5-H), 4.46 (1 H, dd, J 1.9, 12.6 Hz,
9-Hb), 4.12 (1 H, dd, J 5.6, 12.6 Hz, 9-Ha), 3.78 (1 H,
dd, J 1.5, 3.5 Hz, 6-H), 3.28 (1 H, d, J 12.7, 1-Hb), 3.14
(1 H, d, J 12.7, 1-Ha), 2.42 (1 H, dd, J 3.9, 15.9 Hz,
3-Hb), 2.12, 2.07, 2.03 (9H, 3 s, 3×Ac), 1.72 (1 H, dd,
J 3.2, 15.9 Hz, 3-Ha), 1.26 (3 H, s, CH3); 13C NMR
9b: TLC (9:1 CHCl3–MeOH): Rf 0.30; [h]D −13.3°
1
(c 0.3; CHCl3); H NMR (250 MHz, CDCl3): l 7.36–
7.13 (10 H, m, Ar-H), 5.04 (1 H, d, J 9.1 Hz, 5-H), 4.86
(H, d, J 8.0 Hz, 4-H), 4.10–3.80 (8 H, m, 6-H, 7-H,
8-H, 9-Ha, 9-Hb, C(9)-OH, C(8)-OH, C(7)-OH), 3.48 (1
H, d, J 12.8 Hz, 1-Hb), 3.35 (1 H, d, J 12.0 Hz, 1-Ha),

1974
A.I. Khodair, R.R. Schmidt / Carbohydrate Research 337 (2002) 1967–1978
(150.8 MHz, CDCl3): l 170.2, 169.7, 169.2 (3×Ac),
152.4 (CO), 132.2, 130.0, 128.7, 126.6 (C-Ar), 75.5
(C-2), 73.6 (C-5), 72.9 (C-4), 69.4 (C-8), 68.5 (C-7), 67.0
(C-6), 61.1 (C-9), 39.8 (C-1), 31.7 (C-3), 24.1 (CH3),
20.4, 20.4, 20.2 (3×Ac); EIMS: m/z 544 (M+). Anal.
Calcd for C23H28O10Se (543.4): C, 50.83; H, 5.19.
Found: C, 51.08; H, 5.60.
CH2Cl2–MeOH): Rf 0.27; [h]D −22.86° (c 0.7; CHCl3);
1H NMR (250 MHz, CDCl3): l 7.49 (2 H, m, Ar-H),
7.26 (3 H, m, Ar-H), 4.10–3.70 (7 H, m, 6-H, 7-H, 8-H,
9-Ha, 9-Hb, 4-H, 5-H), 3.52 (1 H, d, J 11. 7 Hz, 1-Hb),
3.00 (1 H, d, J 11.7 Hz, 1-Ha), 2.75 (5 H, br s, 5×OH),
1.86 (2 H, m, 3-Ha, 3-Hb), 1.44 (3 H, s, CH3). Anal.
Calcd for C16H24O6Se (391.3): C, 49.11; H, 6.18.
Found: C, 49.68; H, 6.04.
7,8,9-Tri-O-acetyl-2,6-anhydro-4,5-O-carbonylidene-
1,3-dideoxy-2-phenyl-1-phenyl-seleno-D-erythro-L-talo-
2,6-Anhydro-4,5,7,8,9-penta-O-benzoyl-1,3-dideoxy-
nonitol (11b).—Compound 9b (80 mg, 0.167 mmol) was
dissolved in pyridine (4 mL), Ac2O (2 mL) and DMAP
(cat.) were added and the soln was stirred at rt for 12 h.
The solvents were removed under diminished pressure
and purification of the residue by flash chromatography
(SiO2, 1:1 petroleum ether–EtOAc) afforded 11b (87
mg, 86%) as a white foam. TLC (2:1 petroleum ether–
2-methyl-1-phenylseleno-
and 2,6-anhydro-4,7,8,9-tetra-O-benzoyl-1,3-dideoxy-2-
methyl-1-phenylseleno- -erythro- -talo-nonitol (15).—
D-erythro-L-talo-nonitol (14)
D
L
Deprotected 13 (2.08 g, 5.30 mmol) was dissolved in
anhyd 1:1 THF–NEt3 (200 mL) and cooled to 0 °C.
Then, 2.65 mL of a freshly prepared soln of benzoyl
cyanide (3.07 g, 23.32 mmol) in anhyd THF (10.60 mL)
were added every 60 min while stirring at 0 °C. After
complete addition, the reaction mixture was stirred at
0 °C (22 h). Then further benzoyl cyanide (0.76 g) was
added and stirring was continued for 6 h. Then further
benzoyl cyanide (1.74 g, 13.22 mmol) was added, the
mixture was warmed up to +5 °C and stirring was
continued for 36 h. For work-up, MeOH was added,
the mixture was allowed to warm up to rt and stirred
for 2 h. Removal of the solvents under diminished
pressure and purification by flash chromatography
(SiO2, 99.5:0.5 CH2Cl2–MeOH) afforded 14 (1.65 g,
34%) as a white foam and 15 (1.40 g, 33%) as a white
foam.
1
EtOAc): Rf 0.50; [h]D −2.00° (c 0.5; CHCl3); H NMR
(600 MHz, CDCl3): l 7.44–7.23 (10 H, m, Ar-H), 5.62
(1 H, m, 7-H), 5.45 (1 H, m, 8-H), 4.99 (1 H, d, J 9.1
Hz, 4-H), 4.80 (1 H, d, J 9.1 Hz, 5-H), 4.60 (1 H, dd,
J 1.1, 12.4 Hz, 9-Hb), 4.33 (1 H, d, J 3.6 Hz, 6-H), 4.28
(1 H, dd, J 5.8, 12.4 Hz, 9-Ha), 3.36 (1 H, d, J 12.9,
1-Hb), 3.26 (1 H, d, J 12.9, 1-Ha), 2.66 (1 H, dd, J 2.0,
15.9 Hz, 3-Hb), 2.60 (1 H, dd, J 3.3, 15.9 Hz, 3-Ha),
2.19, 2.14, 2.07 (9H, 3 s, 3×Ac). Anal. Calcd for
C28H30O10Se (605.5): C, 55.54; H, 4.99. Found: C,
55.09; H, 5.18.
7,8,9-Tri-O-acetyl-2,6-anhydro-4,5-O-carbonylidene-
1,3-dideoxy-2-phenyl-1-phenyl-seleno-D-erythro-L-talo-
nonitol (12b).—Compound 10b (210 mg, 0.44 mmol)
was dissolved in pyridine (6 mL), Ac2O (4 mL) and
DMAP (cat.) were added and the soln was stirred at rt
for 12 h. The solvents were removed under diminished
pressure and purification of the residue by flash chro-
matography (SiO2, 1:1 petroleum ether–EtOAc) af-
forded 12b (223 mg, 84%) as a white foam. TLC (2:1
petroleum ether–EtOAc): Rf 0.60; [h]D −12.00° (c 0.5;
14: TLC (99:1 CH2Cl2–MeOH): Rf 0.20; [h]D
1
−3.33° (c 0.3; CHCl3); H NMR (250 MHz, CDCl3): l
7.95–7.07 (30 H, m, Ar-H), 5.95–5.86 (3 H, m, 5-H,
8-H, 7-H), 5.24 (1 H, m, 4-H), 4.92 (1 H, dd, J 2.7, 12.4
Hz, 9-Hb), 4.43 (1 H, dd, J 5.2, 12.4 Hz, 9-Ha), 4.30 (1
H, d, J 3.4 Hz, 6-H), 3.28 (1 H, d, J 11.9, 1-Hb), 3.00
(1 H, d, J 11.9, 1-Ha), 2.07 (2 H, m, 3-Ha, 3-Hb), 1.44
(3 H, s, CH3); 13C NMR (150.8 MHz, CDCl3): l 166.0
165.4, 165.3, 165.0 (5×Bz), 133.1, 132.9, 132.9, 132.8,
132.7, 130.2, 130.0, 129.7, 129.7, 129.6, 129.5, 129.4,
129.2, 129.1, 128.8, 128.3, 128.1, 128.0, 127.9, 127.0,
126.5 (C-Ar), 76.0 (C-2), 71.3 (C-4), 70.7 (C-6), 69.4
(C-8), 68.6 (C-7), 67.7 (C-5), 62.5 (C-9), 34.2 (C-3), 34.0
(C-1), 29.0 (CH3). Anal. Calcd for C51H44O11Se (911.8):
C, 67.18; H, 4.86. Found: C, 67.04; H, 5.14.
1
CHCl3); H NMR (600 MHz, CDCl3): l 7.34–7.12 (10
H, m, Ar-H), 5.50 (1 H, dd, J 4.6, 6.0 Hz, 7-H), 5.24 (1
H, m, 8-H), 4.98 (1 H, dd, J 7.2, 12.4 Hz, 4-H), 4.57 (1
H, dd, J 1.3, 7.2 Hz, 5-H), 4.40 (1 H, dd, J 2.3, 12.5 Hz,
9-Hb), 4.08 (1 H, dd, J 5.6, 12.5 Hz, 9-Ha), 3.65 (1 H,
m, 6-H), 3.38 (1 H, d, J 12.5, 1-Hb), 3.31 (1 H, d, J 12.5
Hz, 1-Ha), 2.75 (1 H, dd, J 5.0, 14.9 Hz, 3-Hb), 2.54 (1
H, dd, J 7.5, 14.9 Hz, 3-Ha), 2.19, 2.17, 1.93 (9 H, 3 s,
3×Ac). Anal. Calcd for C28H30O10Se (605.5): C, 55.54;
H, 4.99. Found: C, 55.35; H, 5.40.
15: TLC (99:1 CH2Cl2–MeOH): Rf 0.10; [h]D
1
+6.40° (c 0.5; CHCl3); H NMR (250 MHz, CDCl3): l
2,6-Anhydro-1,3-dideoxy-2-methyl-1-phenylseleno-
D-
8.14–7.13 (25 H, m, Ar-H), 6.03–5.95 (2 H, m, 8-H,
7-H), 5.18 (1 H, m, 4-H), 5.02 (1 H, dd, J 3.2, 12.3 Hz,
9-Hb), 4.60 (1 H, dd, J 6.2, 12.3 Hz, 9-Ha), 4.34 (1 H,
d, J 2.4 Hz, 5-H), 4.12 (1 H, d, J 5.1 Hz, 6-H), 3.32 (1
H, d, J 11.9, 1-Hb), 3.00 (1 H, d, J 11.9, 1-Ha), 2.10 (2
H, m, 3-Ha, 3-Hb), 1.40 (3 H, s, CH3). Anal. Calcd for
C44H40O10Se (807.7): C, 65.43; H, 4.99. Found: C,
65.47; H, 4.95.
erythro- -talo-nonitol (13).—A soln of 11a (1.60 g, 3
L
mmol) in anhyd MeOH (50 mL) was treated with a 1
M NaOMe in MeOH (1 mL) and the mixture was
stirred at rt until the reaction was complete (TLC).
Then the mixture was neutralized with Amberlite 120
(H+), filtered, concentrated under diminished pressure
and coevaporated with anhyd toluene several times to
afford 13 (1.15 g, 98%) as a white foam. TLC (4:1

A.I. Khodair, R.R. Schmidt / Carbohydrate Research 337 (2002) 1967–1978
1975
2,6-Anhydro-4,7,8,9-tetra -O-benzoyl-1,3-dideoxy-2-
methyl-5-O-trifluoromethansulfonyl-1-phenylseleno-
erythro- -talo-nonitol (16).—A soln of 15 (0.7 g, 0.86
ene several times afforded 2,6-anhydro-5-azido-1,3-
dideoxy-2-methyl-1-phenylseleno- -erythro- -manno-no
nitol, which was directly subjected to acetylation with-
D-
D
L
L
mmol) in anhyd CH2Cl2 (50 mL) was cooled to 0 °C,
pyridine (2.50 mL) was added followed by trifl-
uoromethane sulfonic anhydride (2 mL) and the mix-
ture was stirred for 12 h while warming up to rt. Then,
the mixture was diluted with CH2Cl2 (100 mL), a satd
aq NaHCO3 soln (150 mL) was added, the layers were
separated and the organic layer was extracted with
CH2Cl2. The combined organic layers were concen-
trated under diminished pressure at rt and purified by
rapid flash chromatography to afford triflate 16 (0.80 g,
99%) as a white foam which was immediately used in
the next step. TLC (99:1 CH2Cl2–MeOH): Rf 0.60; [h]D
out further purification. 2,6-Anhydro-5-azido-1,3-
dideoxy-2-methyl-1-phenylseleno-D-erythro-L-manno-no
nitol was dissolved in pyridine (6 mL), Ac2O (4 mL)
and DMAP (cat.) were added and the mixture stirred at
rt for 12 h. Evaporation of the solvents under reduced
pressure gave the product which was purified by flash
chromatography (SiO2, 9:1 petroleum ether–EtOAc) to
afford 18 (0.44 g, 94%) as a colourless syrup. TLC (95:5
CH2Cl2–MeOH): Rf 0.40; [h]D −23.50° (c 0.8; CHCl3);
1H NMR (600 MHz, CDCl3): l 7.45 (2 H, m, Ar-H),
7.26 (3 H, m, Ar-H), 5.51 (1 H, dd, J 1.4, 7.0 Hz, 7-H),
5.30 (1 H, m, 8-H), 5.08 (1 H, m, 4-H), 4.53 (1 H, dd,
J 2.1, 12.6 Hz, 9-Hb), 4.23 (1 H, dd, J 5.1, 12.6 Hz,
9-Ha), 3.56 (1 H, dd, J 1.4, 10.5, 6-H), 3.37 (1 H, d, J
12.4 Hz, 1-Hb), 3.14 (1 H, dd, J 10.0, 10.1 Hz, 5-H),
2.96 (1 H, d, J 12.4 Hz, 1-Ha), 2.33 (1 H, dd, J 5.0, 13.2
Hz, 3-Hb), 2.17, 2.09, 2.05, 2.03 (12 H, 4 s, 4×Ac),
1.57 (1 H, m, 3-Ha), 1.36 (3 H, s, CH3); 13C NMR
(150.8 MHz, CDCl3): l 170.78, 170.06, 169.93 (4×Ac),
132.89, 129.77, 129.30, 129.30, 127.30 (C-Ar), 75.60
(C-2), 71.84 (C-4), 70.36 (C-8), 70.32 (C-6), 68.93 (C-7),
61.94 (C-9), 60.85 (C-5), 39.22 (C-3), 33.94 (C-1), 28.51
(CH3), 21.21, 20.98, 20.81, 20.74 (4×Ac). Anal. Calcd
for C24H31N3O9Se (584.5): C, 49.32; H, 5.35; N, 7.19.
Found: C, 49.36; H, 5.76; N, 6.86.
1
+5.33° (c 0.6; CHCl3); H NMR (250 MHz, CDCl3): l
8.11–7.10 (25 H, m, Ar-H), 5.92–5.80 (2 H, m, 8-H,
7-H), 5.45 (1 H, d, J 2.5 Hz, 5-H), 5.20 (1 H, m, 4-H),
4.90 (1 H, dd, J 4.2, 12.1 Hz, 9-Hb), 4.45 (1 H, dd, J
5.4, 12.1 Hz, 9-Ha), 4.34 (1 H, d, J 7.6 Hz, 6-H), 3.26 (1
H, d, J 12.2, 1-Hb), 2.90 (1 H, d, J 12.2, 1-Ha), 2.10 (2
H, m, 3-Ha, 3-Hb), 1.26 (3 H, s, CH3).
2,6 - Anhydro - 5 - azido - 4,7,8,9 - tetra - O - benzoyl-1,3-
dideoxy-2-methyl-1-phenylseleno-D-erythro-L-manno-
nonitol (17).—The triflate 16 (0.80 g, 0.85 mmol) was
dissolved in anhyd toluene (50 mL) and treated with
tetra-n-butylammonium azide (2.60 g). After stirring
for 15 min the mixture was concentrated under dimin-
ished pressure and purified by flash chromatography
(SiO2, 99.07:0.03 CH2Cl2–MeOH) to afford azide 17
(0.68 g, 96%) as a white foam. TLC (99:1 CH2Cl2–
MeOH): Rf 0.60; [h]D +60.00° (c 0.3; CHCl3); 1H
NMR (600 MHz, CDCl3): l 8.19–7.16 (25 H, m,
Ar-H), 6.12 (1 H, d, J 6.8 Hz, 7-H), 5.94 (1 H, m, 8-H),
5.28 (1 H, m, 4-H), 5.09 (1 H, dd, J 1.8, 12.4 Hz, 9-Hb),
4.56 (1 H, dd, J 5.7, 12.5 Hz, 9-Ha), 3.90 (1 H, d, J 10.2
Hz, 6-H), 3.45 (1 H, dd, J 10.2 Hz, 5-H), 3.27 (1 H, d,
J 11.8, 1-Hb), 3.05 (1 H, d, J 11.8, 1-Ha), 2.55 (1 H, dd,
J 4.8, 12.6 Hz, 3-Hb), 1.65 (1 H, dd, J 12.5, 12.6 Hz,
3-Ha), 1.44 (3 H, s, CH3); 13C NMR (150.8 MHz,
CDCl3): l 166.2, 165.5, 165.3 (4×Bz), 133.7, 133.4,
133.2, 132.9, 130.1, 129.8, 129.7, 129.7, 129.3, 129.1,
128.7, 128.5, 128.3, 127.1 (C-Ar), 76.0 (C-2), 72.7 (C-4),
71.0 (C-8), 70.9 (C-6), 70.0 (C-7), 63.1 (C-9), 61.3 (C-5),
39.1 (C-3), 33.9 (C-1), 28.7 (CH3). Anal. Calcd for
C44H39N3O9Se (832.8): C, 63.46; H, 4.72; N, 5.05.
Found: C, 63.33; H, 5.21; N, 4.71.
4,7,8,9-Tetra-O-acetyl-1-aldehydo-2,6-anhydro-5-
azido-3-deoxy-2-methyl-D -erythro-L -manno-nonitol
(19).—A soln of 18 (0.42 g, 0.72 mmol) in THF (30
mL) was cooled to −80 °C and then 70% m-chloroper-
benzoic acid (177 mg, 0.73 mmol) in THF (12 mL) was
added dropwise via a syringe within 2 min. After
stirring for 30 min, Ac2O (324 mL) was added followed
by anhyd sodium acetate (209 mg). Then the mixture
was allowed to warm up to rt and was finally heated to
reflux for 90 min. The solvents were removed under
diminished pressure, the residue was dissolved in
EtOAc and water was added with vigorous stirring. The
layers were separated, the aq layer was extracted with
EtOAc (3×30 mL) and the combined organic layers
were dried (MgSO4). Filtration, concentration under
diminished pressure and purification of the residue (Rf
0.50–0.60, 2:1 petroleum ether–EtOAc) by flash chro-
matography (SiO2, 9:1 petroleum ether–EtOAc) af-
forded a mixture of acetoxy selenides (0.42 g, 91%) that
was immediately subjected to further conversion by
dissolution in anhyd 3:1 MeOH–THF (40 mL) and
treatment with a 1 M NaOMe in MeOH (1 mL). After
stirring for 24 h, the mixture was neutralized by addi-
tion of Amberlite IR 120 (H+), filtered and concen-
trated, and the residue was peracetylated in a mixture
of pyridine and Ac2O. Coevaporation with toluene and
flash chromatography (SiO2, 99:1 CH2Cl2–MeOH) af-
forded 19 (0.25 g, 80%) as a colourless syrup which was
4,7,8,9 - Tetra - O - acetyl - 2,6 - anhydro - 5 - azido - 1,3-
dideoxy-2-methyl-1-phenylseleno-D-erythro-L-manno-
nonitol (18).—To a stirred suspension of the protected
compound 17 (0.66 g, 0.80 mmol) in anhyd MeOH (25
mL) was added portionwise MeONa (172 mg, 3.2
mmol) in anhyd MeOH (25 mL) at rt and the soln was
stirred for 12 h. Then the mixture was neutralized with
Amberlite IR 120 (H+) and filtered. Concentration
under diminished pressure and coevaporation with tolu-

1976
A.I. Khodair, R.R. Schmidt / Carbohydrate Research 337 (2002) 1967–1978
immediately used in the next step. TLC (95:5 CH2Cl2–
MeOH): Rf 0.55; H NMR (250 MHz, CDCl3): l 9.39
6-H), 2.62 (1 H, dd, J 4.6, 12.8 Hz, 3-Hb), 2.47 (1 H,
dd, J 9.9, 10.0 Hz, 5-H), 2.12, 2.11, 2.05, 2.02 (12 H, 4
s, 4×Ac), 1.40 (1 H, m, 3-Ha), 1.37 (3 H, s, CH3);
EIMS: m/z 447 (M+).
Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhy-
dro-3-deoxy-2-methyl-D -erythro-L -manno-nononate
1
(1 H, s, CHO), 5.46 (2 H, m, 8-H, 7-H), 4.82 (1 H, ddd,
J 5.1, 9.7, 13.9 Hz, 4-H), 4.38 (1 H, dd, J 2.0, 12.7,
9-Hb), 4.17 (1 H, dd, J 4.2, 12.7, 9-Ha), 3.55 (1 H, dd,
J 1.2, 10.5 Hz, 6-H), 3.18 (1 H, dd, J 10.1, 10.2 Hz,
5-H), 2.64 (1 H, dd, J 5.1, 13.9 Hz, 3-Hb), 2.20, 2.16,
2.12, 2.07 (12 H, 4 s, 4×Ac), 1.54 (1 H, dd, J 12.4, 12.6
Hz, 3-Ha), 1.29 (3H, s, CH3).
(1).—Compound 21 (20 mg, 0.045 mmol) was dissolved
in pyridine (3 mL), Ac2O (2 mL) and DMAP (cat.)
were added under stirring at rt for 24 h. The solvents
were removed under diminished pressure and purifica-
tion of the residue by flash chromatography (SiO2, 49:1
CH2Cl2–MeOH) afforded 1 (20 mg, 91%) as a white
solid, mp 60–62 °C. TLC (19:1 CH2Cl2–MeOH): Rf
0.37; [h]D −33.66° (c 0.3; CHCl3); 1H NMR (600
MHz, CDCl3): l 5.36 (1 H, ddd, J 2.4, 6.4, 9.3 Hz,
8-H), 5.31 (2 H, dd, J 1.8, 6.9 Hz, 7-H), 5.13 (1 H, d,
J 10.1 Hz, NH), 4.83 (H, ddd, J 4.3, 12.0, 12.0 Hz,
4-H), 4.43 (1 H, dd, J 2.3, 12.3 Hz, 9-Hb), 4.11 (1 H,
dd, J 6.1, 12.3 Hz, 9-Ha), 4.02 (1 H, dd, J 10.3, 10.5 Hz,
5-H), 3.92 (1 H, dd, J 1.8, 10.5 Hz, 6-H), 3.75 (3 H, s,
OCH3), 2.55 (1 H, dd, J 4.5, 12.5 Hz, 3-Hb), 2.10, 2.09,
2.05, 2.01 (12 H, 3 s, 4×Ac), 1.98 (3 H, s, NHAc), 1.74
(1 H, dd, J 12.3, 12.5 Hz, 3-Ha), 1.44 (3 H, s, CH3), 13C
NMR (150.8 MHz, CDCl3): l 172.7, 171.0, 170.6,
170.3, 170.2, 170.1 (6×CO), 77.7 (C-2), 73.5 (C-6),
70.2 (C-4), 70.0 (C-8), 67.9 (C-7), 62.4 (C-9), 52.5
(OCH3), 49.6 (C-5), 39.0 (C-3), 26.7 (CH3), 23.2
(NHAc), 21.1, 20.9, 20.8 (4×Ac); EIMS: m/z 489
(M+). Anal. Calcd for C21H31NO12 (489.5): C, 51.53;
H, 6.40; N, 2.86. Found: C, 51.30; H, 6.89; N, 2.77.
Methyl 4,7,8,9-tetra-O-acetyl-2,6-anhydro-5-azido-3-
deoxy-2-methyl-D-erythro-L-manno-nononate (20).—A
soln of NaClO2 (0.50 g, 5.50 mmol) and KH2PO4 (0.69
g, 5.07 mmol) in water (3.63 mL) was added to a soln
of aldehyde 19 (0.25 g, 0.56 mmol) in 4:4:1 CH3CN–t-
BuOH–2-methyl-2-butene (24.20 mL, 4:4:1). The mix-
ture was stirred for 10 min at rt, then a 10% aq
hydrogen chloride soln (60.5 mL) was added and the
mixture was extracted with EtOAc (3×20 mL). The
combined organic layers were concentrated, and the
residue, TLC (SiO2): Rf 0.25 (19:1 CH2Cl2–MeOH),
was dissolved in Et2O (30 mL) and treated with an
excess of diazomethane in anhyd Et2O, the excess being
consumed by addition of AcOH. Concentration under
diminished pressure, coevaporation with toluene and
purification of the residue by flash chromatography
(SiO2, 99:1 CH2Cl2–MeOH) afforded the methyl ester
20 (0.21 g, 79%) as a colourless syrup which was
immediately used in the next step. TLC (19:1 CH2Cl2–
1
MeOH): Rf 0.50; [h]D −30.00° (c 1; CHCl3); H NMR
(250 MHz, CDCl3): l 5.46 (1 H, dd, J 1.5, 8.6 Hz, 7-H),
5.32 (1 H, ddd, J 2.3, 4.5, 6.8 Hz, 8-H), 4.80 (1 H, ddd,
J 4.7, 9.8, 11.8 Hz, 4-H), 4.32 (1 H, dd, J 2.3, 12.6 Hz,
9-Hb), 4.20 (1 H, dd, J 4.6, 12.6 Hz, 9-Ha), 3.71 (3 H,
s, OCH3), 3.65 (1 H, dd, J 1.5, 10.6 Hz, 6-H), 3.12 (1 H,
dd, J 10.3, 9.9 Hz, 5-H), 2.66 (1 H, dd, J 4.8, 13.0 Hz,
3-Hb), 2.14, 2.10, 2.06, 2.02 (12H, 4 s, 4×Ac), 1.50 (1
H, dd, J 12.7, 12.1 Hz, 3-Ha), 1.38 (3 H, s, CH3); 13C
NMR (62.9 MHz, CDCl3): l 172.2, 170.7, 169.9, 169.7,
169.6 (5×CO), 77.3 (C-2), 72.0 (C-6), 71.9 (C-4), 68.8
(C-8), 68.3 (C-7), 61.9 (C-9), 60.4 (C-5), 52.5 (OCH3),
38.5 (C-3), 26.6 (CH3), 21.0, 20.8, 20.7 (4×Ac);
MALDI-MS: m/z 496 [MNa+].
Acknowledgements
This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemis-
chen Industrie. A.I.K. is grateful for an Alexander von
Humboldt-Fellowship. We are grateful to Ms. Anke
Friemel and Mr. Klaus Ha¨gele, Fachbereich Chemie,
Universita¨t Konstanz, for recording NMR and MS
spectra.
Methyl 5-amino-4,7,8,9-tetra-O-acetyl-2,6-anhydro-
3-deoxy-2-methyl-D-erythro-L-manno-nononate (21).—
References
To a soln of azide 20 (44 mg, 0.09 mmol) in MeOH (5
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filtered through a Celite pad and washed with MeOH.
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