Synthesis of a complex disaccharide precursor of phosphonate analogues of the antibiotic moenomycin A12

Article abstract of DOI:10.1016/S0040-4020(02)01049-9

An approach for the synthesis of moenomycin A₁₂ C-glycoside partial structures is reported.

Full text of DOI:10.1016/S0040-4020(02)01049-9

Tetrahedron 58 (2002) 8439–8451
Synthesis of a complex disaccharide precursor of phosphonate
analogues of the antibiotic moenomycin A12
Khalid Abu Ajaj,a Lothar Hennig,a Matthias Findeisen,a Sabine Giesa,a Dietrich Mu¨llerb
and Peter Welzela
,
*
a
¨ ¨
Fakultat fur Chemie und Mineralogie, Universitat Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
Institut fur Analytische Chemie, Ruhr-Universitat Bochum, D-44780 Bochum, Germany
¨
b
¨
¨
Received 4 July 2002; accepted 19 August 2002
Abstract—An approach for the synthesis of moenomycin A12 C-glycoside partial structures is reported. q 2002 Elsevier Science Ltd. All
rights reserved.
1. Introduction
molecular mass PBPs has been expressed as a truncated
protein lacking the membrane domain and purified to
homogeneity;6 (iii) one of the two substrates of the
transglycosylation step, the so-called lipid II, can now be
made in sufficient amounts;7 (iv) new and efficient in vitro
test systems have been developed which conveniently allow
to monitor the inhibition of the incorporation of lipid II
into uncross-linked peptidoglycan,7,8 and binding of
inhibitors to the enzyme, respectively.9
In view of the problem of antibiotic resistance1 anti-
infectives with novel modes of action are desperately
needed. The transglycosylation reaction,2 the penultimate
step in the biosynthesis of peptidoglycan (the main
structural polymer of the bacterial cell wall), occurs at
the outside of the cytoplasmic membrane and is catalyzed
by membrane proteins designated as bifunctional (class A)
high-molecular mass penicillin-binding proteins (PBPs).3
The reaction came recently into focus as a promising new
target for a number of reasons: (i) the methods for isolating
the enzyme(s) involved have improved considerably;4,5 (ii) a
monofunctional glycosyltransferase from Staphylococcus
aureus that shares considerable homology with the
transglycosylase domain of bifunctional (class A) high-
The assembly of the peptidoglycan polysaccharide strands
from lipid II is blocked by certain glycopeptides,10
ramoplanin,11 lantibiotics such as nisin,12 and the moeno-
mycin-type antibiotics.13 Of these, the moenomycins (see
Fig. 1) are the only compounds known to inhibit the enzyme
itself2 (i.e. the transglycosylase domain of the bifunctional
Figure 1. Moenomycin A12
.
Keywords: carbohydrates; antibiotics; ene reaction; Arbuzov reaction.
*
Corresponding author. Fax: þ49-341-9736599; e-mail: welzel@organik.chemie.uni-leipzig.de
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01049-9

8440
K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
Scheme 1.
high-molecular PBPs), whereas ramoplanin and nisin
interfere with lipid II. The mechanism of the glycopeptides
that inhibit the transglycosylation reaction is not clear.14
The moenomycins are, thus, unique tools for investigating
both the transglycosylation step and the corresponding
enzyme(s). In addition, they are highly promising lead
compounds for new anti-infectives. Based on structure–
activity relationships,15 a mechanism for their mode of
action has been proposed.4,16–18 It is assumed that they are
anchored to the cytoplasmic membrane via the lipid part19
and bind then highly selectively to the binding site of the
growing polysaccharide strand at the enzyme via the C-E-F
trisaccharide.
et al.23 but obviously the structures were too simple to elicit
antibiotic activity.22,23
2. Synthetic design
We decided to disconnect the target structure as indicated
in formula A to give a precursor of type B (Scheme 1).
A would be available from C-glycoside B (X¼Br) by an
Arbuzov reaction.23 We have recently reported on a new
approach for the synthesis of such C-glycosides which
started from a tartaric acid-derived aldehyde of general
structure D and a C-3 allyl stannane such as E to give an
open-chain olefin of type F. Subsequent mercuric ion-
induced cyclization and trapping the organomercurial
provided B (X¼I).24 In the present publication, we describe
a new synthetic approach which started from D-galactose
(C, Fig. 2). For the synthesis of C-glycosides from ordinary
sugars many methods exist. Carbocation, carbanion and
radical chemistry can be used to add carbon appendages to
C-1 of the starting sugar.25
The moenomycins do not induce resistance readily.
However, a weak point in this respect may be the phosphate
bond at unit F. Its cleavage by a yet poorly characterized
enzyme is the only enzymatic degradation reaction of the
moenomycins that is known to date.20 Furthermore, some
analogues which we expected to be antibiotically active
were devoid of antibiotic activity. It has been speculated
that these compounds are used as substrates by the
transglycosylase.17 With this in mind we started a program
aimed at synthesizing analogues of moenomycin A12 in
which the phosphate oxygen at C-1 of unit F is replaced by a
CH2 group.21 It seemed important to retain all other
functional groups in ring F as present in moenomycin A12
since they are known to be of major importance as far
as antibiotic activity is concerned. Some mono- and
disaccharide phosphonate models of moenomycin A have
already been prepared by Qiao and Vederas22 and by Brooks
3. Results and discussion
3.1. Synthesis of glycosyl acceptors 8c and 11d
Commercially available b-D-galactose-pentaacetate on
BF3-mediated reaction with allyltrimethylsilane was con-
verted into 2,6-anhydro-7,8,9-trideoxy-D-glycero-L-
galacto-non-8-enitol (1) as described by Giannis and
Figure 2. Synthetic design.

K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
8441
Scheme 2.
Sandhoff26 The C9 compound 1 had to be degraded to a C7
compound after shifting of the double bond. It is well known
that double bonds can be moved to thermodynamically more
stable positions in palladium-mediated reactions. This
approach that has been employed by Brooks et al.23 was
described to be not completely satisfactory since product
mixtures resulted.
In the present work, the same observation was made
(Scheme 1). When compound 1 was refluxed in toluene with
varying amounts of bis(benzonitrile)palladium(II) chloride,
TLC (using several solvent mixtures) showed a major spot
with exactly the same Rf value as 1 and a minor spot with a
slightly larger Rf. The major spot according to 13C NMR
corresponded to a 1:1 mixture of 1 and 2. The CH3 signal of

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K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
2 appeared at d¼18, while the CH2 vinylic signals of the
starting material appeared at d¼31. In the d¼115–135
range, the olefinic signals of the starting material 1 appeared
at d¼118 and 133, whereas the signals at d¼119 and 123
were assigned to the olefinic carbons of product 2. Changing
the amount of the catalyst and the reaction time did not
affect the result. The by-product, a white solid, was 3
according to the spectra. When a mixture of the two
compounds 1 and 2 was ozonolyzed, again compounds with
very close Rf values have been obtained (data not reported).
As a conclusion, we preferred to look for a more practical
route for the double bond rearrangement in compound 1.
Use of an ene reaction was an obvious option. An attempt in
this direction was made using singlet oxygen. The
photooxidation of 1 was tested using methylene blue and
Rose bengal as sensitizers and methanol and dichloro-
methane as solvents. In neither case, a reaction was
observed as indicated by TLC, using different eluents.
Guided by this result we looked for a more reactive reagent.
A good choice seemed to be 4-phenyl-3H-1,2,4-triazoline-
3,5-dione (PTAD).27–29 Compound 1 on reaction with
PTAD in dichloromethane at rt provided 4 in 83% yield.
Unreacted alkene (13%) were recovered (Scheme 2). The
typical red color of PTAD was quickly discharged when
PTAD was mixed with the alkene. Ozonolysis of 4 in dry
CH2Cl2–MeOH (10:1) at 2708C, and subsequent quench-
ing with dimethyl sulfide led to aldehyde 5a. No effort has
been made to obtain pure samples of the aldehyde.
Reduction of the crude ozonolysis products of 4 with
sodium acetoxyborohydride23 (prepared in situ from
NaBH4 and AcOH in THF) furnished primary alcohol 5b
in a non-satisfying yield of 42%. An identified problem
was the ready elimination of acetic acid to give the
a,b-unsaturated aldehyde 12 (Fig. 3). The formation of
this glycal was completely suppressed under dry conditions.
When the reaction was performed using freshly distilled
THF and acetic acid, the yield increased up to 85% with no
trace of the aldehyde 12 observable by TLC. The primary
hydroxyl group of 5b was mesylated,23 using methane-
sulfonyl chloride in pyridine, in the presence of catalytic
amount of p-dimethylaminopyridine (DMAP) at 48C to give
methanesulfonate 5c in 60% yield. The mesylate 5c was
converted in turn into 5d (80%) when heated in toluene at
808C with tetrabutylammonium bromide.23 Hydrolysis of
8b in 85% yield. The free hydroxyl groups at C-3 and C-4 in
compound 8b were protected by acid-catalyzed acetonide
formation with 2,2-dimethoxypropane in dry acetone to give
8c in 88% yield.31
As discussed above, the amide group at position 1 in unit F
(position 6 in normal moenomycin analogues) is essential
for the biological activity. Therefore, acceptor 8c was
converted into 11d, which we planned to use as an
alternative glycosyl acceptor. The hydroxyl group in 8c
was protected by acetylation to give 11a (88%), the silyl
ether of which was cleaved with a molar solution of TBAF
in THF at rt, affording 11b in 87% yield. The free hydroxyl
group was then subjected to an oxidation using the TEMPO
method (Flitsch conditions32) affording an aldehyde which
was in turn oxidized with sodium chlorite17 to the
corresponding acid. The acid was converted into amide
11c, making use of Staab’s method.33,34 The overall yield
was 95%. The required glycosyl acceptor 11d was obtained
in quantitative yield by cleavage of the ester bond at
´
position 5 under Zemplen conditions.
3.2. Disaccharide formation
Disaccharide formation was attempted employing the
Jacquinet and Blatter method,35 which involves the use of
glycosyl donor 3,4,6-tri-O-acetyl-2-deoxy-2-trichloro-
acetamido-a-D-glucopyranosyl trichloroacetamidate and
TMSOTf a promoter. No reaction was observed between
this donor and acceptor 11d, which may reflect the low
nucleophilicity of the acceptor. On the contrary, glycosyl-
ation with acceptor 8c gave 7a in 79% yield. The reaction
conditions had to be carefully optimized. A reaction time
not longer than 10 min and 08C are required to furnish 7a in
good yield. It was noticed by TLC that on longer reaction
times decomposition occurred to give many products, and
the desired disaccharide was obtained in low yield.
Deprotection of the silyl group in disaccharide 7a was
easily accomplished on treatment with a molar solution of
TBAF in THF at rt affording 7b (89%). It should be
recognized that the bromomethyl group survived the
reaction conditions. Synthesis of the uronamide 7c from
7b was achieved in an overall yield of 98% by: (i) oxidation
of the primary hydroxyl group in unit F to the corresponding
aldehyde with sodium hypochlorite and TEMPO; (ii) oxi-
dation of the crude aldehyde to the carboxylic acid with
sodium chlorite; (iii) amide formation according to Staab.
Removal of the isopropylidene group from 8c with
trifluoroacetic acid (TFA) at rt furnished diol 8d (89%).
No reaction was noticed when 8c was treated with 80%
AcOH at rt for 17 h.
the acetate groups without harming the primary bromide
30
was accomplished making use of the Zemplen method
´
(quantitative yield of 8a). The primary hydroxyl group of
8a was protected as t-butyldiphenylsilylether. Treatment of
8a with t-butyldiphenylsilyl chloride (TBDPSCl) in the
presence of bases such as pyridine and triethylamine and
catalytic amount of DMAP at 08C yielded 8b in 33% yield.
On the other hand, treatment of 8a with TBDPSCl in
N,N0-dimethylformamide (DMF) solution in the presence of
imidazole at 08C afforded the 6-(t-butyldiphenylsilyl) ether
3.3. Final reactions
For the introduction of the carbamoyl group into moeno-
mycin analogues a number of methods have successfully
been used, i.e. the reaction with trichloroacetylisocyanate
(TAI)36 to give the trichloroacetylurethane and subsequent
removal of the trichloroacetyl group.37,38 or the McLamore
et al.39 method which consists of the reaction with phenyl
chloroformate to give the phenyl carbonate and subsequent
treatment with ammonia.15 An alternative method to form
the urethane is the conversion of a 1,2-diol into the
Figure 3.

K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
8443
corresponding cyclic carbonate. The carbonate ring can then
4. Experimental
4.1. Methods and materials
be opened with ammonia from both sides in a non-selective
reaction, thus leading to two isomeric O-carbamoyl
compounds.40,41 We found (vide infra) the 4-O-carbamoyl
group in the C-glycosides of type 6a to be much more base-
labile than in the normal moenomycin unit F-type
compounds that we have studied before. The reason may
be that in the normal compounds the electron-withdrawing
anomeric oxygen stabilizes the urethane. Thus, in the C-
glycosides we were unable to prepare the urethane making
use of the trichloroacetyl isocyanate procedure.42 When we
tried to apply the method of McLamore et al., the cyclic
carbonate 7e was formed in 72% yield reflecting again the
instability of the urethane. The cyclic carbonate 7e was also
obtained on reaction of 7d with carbonyl diimidazole (CDI)
in CH2Cl2 solution (84%). Subsequent opening of the
carbonate ring by bubbling a stream of gaseous ammonia
into the CH2Cl2 solution at 08C gave 6a (62%) as well as
its isomer 6b (21%). Separation of the two isomers by
MPLC was difficult and time consuming. Flash chroma-
tography as well as reversed-phase chromatography were
unsuccessful. Both isomers were fully characterized by two-
dimensional NMR including H,H COSY, HMQC and
HMBC. The 3- and the 4-O-carbamoyl derivatives were
readily distinguishable. The 4-H signal of the 4-O-
carbamoyl derivative 6a was observed as a doublet of
doublets at d¼5.68 with coupling constants of 3.5 and
8.3 Hz, as expected for an axial proton. In contrast, the 3-H
signal of the 3-O-carbamoyl derivative 6b was observed at
d¼6.47 as a broad singlet.
See Ref. 52.
4.2. Pd-mediated rearrangement of 1
1 (1.00 g, 2.69 mmol) was added to a solution of bis(benzo-
nitrile)palladium(II) chloride (0.15 g, 0.15 equiv.;
0.40 mmol) in dry toluene (200 mL) under an argon
atmosphere. The reaction mixture was refluxed for 5 days.
The reaction progress was controlled by TLC (e.g. ethyl
acetate–petroleum ether 1:2) which showed the presence of
a major spot with the same Rf value as the reactant 1. The
reaction mixture was filtered, evaporated, and chromato-
graphed twice with ethyl acetate–petroleum ether 1:2.
Evaporation of the solvents gave 0.98 g of a yellow oil,
which appeared as a single spot, but was a 1:1 mixture of 1
and 2 as indicated by 13C NMR. Furthermore, 0.005 g of 3
were obtained. Characteristic signals of 2 at d¼18 (CH3),
119 and 123 (olefinic carbons). Characteristic signals of 1 at
d¼31 (vCH2), 118 and 133 (olefinic carbons).
4.2.1. 1,3,4,5-Tetra-O-acetyl-2,6-anhydro-7,8,9-trideoxy-
D-glycero-L-galacto-non-6-enitol (3). Rf: 0.26 (ethyl
acetate–petroleum ether 1:2). IR (KBr): n¼1754 cm21
.
˜
1H NMR (H,H COSY, 200 MHz, CDCl3): d¼0.95 (t, 3H,
CH3-9, J¼7.6 Hz), 2.00, 2.06, 2.12, 2.15 (4s, 12H,
4£CH3COO), 2.22–2.25 (m, 2H, CH2-8), 3.95 (ddd, 1H,
2-H, J¼1.7, 5.7, 7.2 Hz), 4.14 (dd, 1H, 1-H, J¼5.7,
11.4 Hz), 4.24 (dd, 1H, 1-H0, J¼7.2, 11.4 Hz), 4.89 (dt,
1H, 7-H, J¼1.8, 7.4 Hz), 5.02 (dd, 1H, 4-H, J¼3.4, 9.9 Hz),
5.50 (dd, 1H, 3-H, J¼1.7, 3.4 Hz), 5.62 (m, 1H, 5-H). 13C
NMR (50 MHz, CDCl3): d¼14.48 (C-9), 17.99 (C-8),
21.04, 21.21 (4£CH3COO), 62.13 (C-1), 67.68, 68.12,
71.97, 75.88, 114.71 (C-7), 145.56 (C-6), 170.08, 170.56,
170.71, 171.02 (4£CH3COO). C17H24O9 (372.37, 372.14),
ESI MS: m/z 373.1 [MþH]þ, 395.1 [MþNa]þ.
It was clear from the beginning that for the dehalogenation
of the N-trichloroacetyl group some of the usual reduc-
tive methods (radical dehalogenation with tributyltin
hydride,43–45 or (Me3Si)3SiH,46 activated zinc–acetic acid
in THF,47 or activated Zn–Cu couple in acetic acid15,48
)
were unsuitable because of the presence of CH2Br group.
Unfortunately, many other methods that we tried were not
compatible with the carbonate in 7e and the carbamoyl
group in urethane 6a, respectively. Hydrolysis of 7e with
0.5 M LiOH in MeOH–THF (1:1)49 followed by acetylation
gave 9c (73%), while reduction of 7e with NaBH4 in
ethanol50,51 followed by acetylation gave 9b (608C, 85%; rt,
83%). Similarly, attempted reduction of 6a with NaBH4 in
ethanol at 608C followed by acetylation gave 9b (78%),
whereas performing the reduction step at 58C (THF–
MeOH, 4:1) or at rt (ethanol or isopropanol) gave 9c in
an average yield of 65%. The reaction between the
N-trichloroacetyl group and NaBH3CN was fruitless. In
one experiment (NaBH4, EtOH, rt, then Ac2O, pyridine, rt),
the desired compound 9a was formed in 42% yield
accompanied by 9b (46%). This result shows that it is
possible to perform the conversion of 6a to 9a as
desired. However, until now the reaction is capricous.
The structure of 9a was fully confirmed by 1H and 13C NMR
as well as by high resolution ESI FT ICR mass
spectrometry. The phosphonate grouping was installed
making use of the Arbuzov reaction. 9d was obtained
from 9b in 70% yield.
4.2.2. (7E)-1,3,4,5-Tetra-O-acetyl-2,6-anhydro-7,8,9-tri-
deoxy-9-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl)-D-
glycero-L-galacto-non-7-enitol (4). To a solution of
compound 1 (0.518 g, 1.39 mmol) in dry dichloromethane
(20 mL),
a solution of PTAD (0.244 g, 1.0 equiv.;
1.39 mmol) in dichloromethane (20 mL) was added slowly
with stirring. The reaction mixture was stirred at rt, until the
red color had disappeared (overnight). The reaction progress
was controlled by TLC (ethyl acetate–petroleum ether 1:1).
Evaporation of the solvent left a slightly yellow semisolid,
which was purified by FC eluting with a gradient of ethyl
acetate–petroleum ether 2:1!ethyl acetate. Evaporation
left 4 (0.631 g, 83%) as a pale yellow solid. Compound 1 of
0.067 g, 13% were recovered. Mp: 75–768C (ethyl acetate–
petroleum ether). [a]D23¼þ46.15 (c 0.26, CH2Cl2). Rf: 0.36
(ethyl acetate). IR (KBr): n¼1229, 1709, 1749, 3440 cm21
.
˜
1H NMR (H,H COSY, 300 MHz, CDCl3): d¼2.06, 2.07,
2.09, 2.18 (4 s, 12H, 4£CH3COO), 3.99 (m, 1H, 1-H),
4.13 (m, 1H, 1-H0), 4.23 (m, 1H, 2-H), 4.28–4.32 (m, 2H,
CH2-9), 4.84 (m, 1H, 6-H), 5.13 (dd, 1H, 4-H, J¼3.3,
9.9 Hz), 5.32 (m, 1H), 5.36 (m, 1H), 5.96–6.02 (m, 2H, 7-H,
8-H), 7.50–7.54 (m, 5H, aromatic). 13C NMR (APT,
HETCOR, 75 MHz, CDCl3): d¼20.96, 21.00, 21.05, 21.09
In conclusion, we have shown that C-glycoside 1 can easily
be converted into structural analogues of unit F of the
moenomycins.

8444
K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
(2, 4£CH3COO), 49.04 (þ, C-9), 62.14 (þ, C-1), 68.07
(2), 68.19 (2), 68.62 (2, C-4), 68.88 (2, C-2), 71.99
(2, C-6), 125.85, 128.52, 128.68, 128.76, 129.49 (2,
5£CAr, C-7 and C-8), 131.35 (þ, NCAr), 153.00, 154.20 (þ,
2£NCON), 170.26, 170.34, 170.39 (þ, 4£CH3COO).
C25H29N3O11 (547.52, 547.18), FAB MS: m/z 548.1
[MþH]þ, 570.1 [MþNa]þ, ESI MS: m/z 548.2 [MþH]þ,
570.0 [MþNa]þ.
0.127 mmol) was dissolved in dry pyridine (4 mL) contain-
ing DMAP (0.002 g, cat. amount) and the mixture was
cooled to 48C. Methanesulfonyl chloride (12 mL, 1.2 equiv.;
0.152 mmol) was added, and the orange-red mixture was
stirred at 48C for 5 h (TLC, ethyl acetate). The mixture was
diluted with dichloromethane and 2 M sulfuric acid. The
organic layer was washed with aqueous sodium hydrogen-
carbonate and with brine. Drying, evaporation, and FC
(ethyl acetate–petroleum ether 1:1) gave 5c (0.034 g, 60%)
as a pale yellow oil. [a]2D3¼þ39.28 (c 0.56, CH2Cl2). Rf:
4.3. Preparation of alcohol 5b
0.56 (ethyl acetate). IR (film): n¼1055, 1175, 1227, 1367,
˜
(a) 4 (0.254 g, 0.464 mmol) was dissolved in dry dichloro-
methane (20 mL) and dry methanol (2 mL), then the
solution was cooled to 2708C. Ozone was bubbled through
the solution for ca. 1 h. Progress of the reaction was
controlled by TLC (ethyl acetate–petroleum ether 1:1).
Excess ozone was removed by purging with oxygen and
with argon. Dimethyl sulfide (1 mL) was added, and the
solution was left overnight at rt. The solvents were
evaporated, and the crude product 5a was redissolved in
THF (10 mL), and added to a mixture of sodium
borohydride (0.019 g, 1.1 equiv.; 0.510 mol) and acetic
acid (40 mL, 1.1 equiv.; 0.510 mmol) in THF (2 mL). The
mixture was left overnight, diluted with brine, and extracted
with ethyl acetate (3£20 mL). The extract was dried,
evaporated and left 0.192 g as a crude product mixture,
which on FC (ethyl acetate–petroleum ether 2:1) gave 5b
(0.071 g, 42%) and 12 (0.070 g, 50%) as pale yellow oils.
1749, 3446 cm21
.
1H NMR (H,H COSY, 200 MHz,
CDCl3): d¼2.05, 2.06, 2.11, 2.12 (4s, 12H, 4£CH3COO),
3.09 (s, 3H, SO2CH3), 4.11 (dd, 1H, 1-H, J¼2.6, 8.8 Hz),
4.20 (m, 1H, 2-H), 4.30 (m, 1H, 1-H00), 4.32 (m, 1H, 7-H),
4.48 (m, 1H, 6-H), 4.51 (m, 1H, 7-H ), 5.21 (dd, 1H, 4-H,
J¼3.1, 8.5 Hz), 5.31 (dd, 1H, 5-H, J¼4.0, 8.5 Hz), 5.43 (m,
1H, 3-H). 13C NMR (APT, HETCOR, 50 MHz, CDCl3):
d¼20.73, 20.79, 20.84 (2, 4£CH3COO), 38.05 (2,
SO2CH3), 60.95 (þ, C-1), 65.59 (þ, C-7), 67.02 (2, C-3),
67.11 (2, C-5), 67.81 (2, C-4), 69.81 (2, C-6), 70.36 (2,
C-2), 169.64, 169.69, 169.89, 170.64 (2, 4£CH3COO).
C16H24O12S (440.42, 440.10), FAB MS: m/z 345.1 [Mþ
H2MeSO3H]þ, 381.0 [MþH2AcOH]þ, 441.1 [MþH]þ,
463.0 [MþNa]þ, ESI MS: m/z 463.1 [MþNa]þ.
4.3.4. 1,3,4,5-Tetra-O-acetyl-2,6-anhydro-7-bromo-7-
deoxy-D-glycero-L-galacto-heptitol (5d). The methane-
sulfonate 5c (0.054 g, 0.122 mmol) was dissolved in dry
toluene (5 mL) containing tetrabutylammonium bromide
(0.098 g, 2.5 equiv.; 0.305 mmol), and the mixture was
heated at 808C for 20 h (TLC, ethyl acetate–petroleum ether
80:20). The mixture was partitioned between water (10 mL)
and ethyl acetate (20 mL), the organic layer was washed
with aqueous sodium hydrogencarbonate, and with brine.
Drying and evaporation left a crude mixture, which on FC
(ethyl acetate–petroleum ether 80:20) gave 5d (0.042 g,
80%) as a pale yellow oil. [a]2D3¼þ64.86 (c 0.3, CH2Cl2).
Rf: 0.60 (ethyl acetate–petroleum ether 80:20). IR (film):
(b) 4 (0.116 g, 0.212 mmol) was treated as above. However,
carefully dried solvents were used. 5b of 0.065 g (85%)
were obtained (pale yellow oil).
4.3.1. 4,5,7-Tri-O-acetyl-2,6-anhydro-3-deoxy-D-lyxo-
hept-2-enose (12). Rf: 0.60 (ethyl acetate). 1H NMR
(200 MHz, CDCl3): d¼2.07, 2.09, 2.12 (3s, 9H, 3£
CH3COO), 4.28–4.34 (m, 2H), 4.45 (m, 1H), 5.51 (m,
1H), 5.70 (m, 1H), 5.77 (m, 1H), 9.23 (s, 1H, 1-H). 13C
NMR (50 MHz, CDCl3): d¼21.03, 21.09, 21.19 (3£
CH3COO), 61.76, 62.98, 65.16, 74.31, 116.23 (C-3),
152.54 (C-2), 170.39, 170.52, 170.89 (3£CH3COO),
185.69 (C-1).
n¼1049, 1227, 1371, 1749, 3435 cm21
.
1H NMR (H,H
˜
COSY, 200 MHz, CDCl3): d¼2.05, 2.08, 2.11, 2.13 (4s,
12H, 4£CH3COO), 3.44 (dd, 1H, 7-H, J¼5.1, 11.4 Hz),
3.55 (dd, 1H, 7-H0, J¼9.2, 11.4 Hz), 4.11 (m, 1H, 2-H), 4.16
(m, 1H, 1-H), 4.30 (m, 1H, 1-H0), 4.45 (m, 1H, 6-H), 5.19
(dd, 1H, 4-H, J¼3.3, 8.7 Hz), 5.35 (dd, 1H, 5-H, J¼4.9,
8.7 Hz), 5.43 (t, 1H, 3-H, J¼2.9 Hz). 13C NMR (APT,
HETCOR, 50 MHz, CDCl3): d¼20.77, 20.82 (2, 4£
CH3COO), 27.49 (þ, C-7), 61.06 (þ, C-1), 67.22 (2,
C-3), 67.71 (2, C-5), 68.13 (2, C-4), 69.39 (2, C-2), 71.74
(2, C-6), 169.62, 169.79, 170.02, 170.74 (þ, 4£CH3COO).
C15H21BrO9 (425.23, 424.04), FAB MS: m/z 345.1
[MþH2HBr]þ, 365.0 [MþH2AcOH]þ, 425.0 [MþH]þ,
447.0 [MþNa]þ, ESI MS: m/z 447.1 [MþNa]þ.
4.3.2. 1,3,4,5-Tetra-O-acetyl-2,6-anhydro-D-glycero-L-
galacto-heptitol (5b). [a]2D3¼þ44.44 (c 0.18, CH2Cl2). Rf:
0.45 (ethyl acetate). IR (film): n¼1080, 1142, 1296, 1724,
˜
2929, 3491 cm21
.
1H NMR (H,H COSY, 200 MHz,
CDCl3): d¼2.05, 2.06, 2.10, 2.11 (4 s, 12H, 4£CH3COO),
3.65 (dd, 1H, 7-H, J¼4.6, 12.0 Hz), 3.83 (dd, 1H, 7-H0,
J¼7.5, 12.0 Hz), 4.07 (dd, 1H, 1-H, J¼4.0, 11.0 Hz), 4.27
(m, 1H, 6-H), 4.31 (m, 1H, 2-H), 4.41 (dd, 1H, 1-H0, J¼7.8,
11.0 Hz), 5.27 (m, 1H, 5-H), 5.29 (m, 1H, 4-H), 5.44 (t, 1H,
3-H, J¼3.0 Hz). 13C NMR (APT, HETCOR, 50 MHz,
CDCl3): d¼21.15, 21.22 (2, 4£CH3COO), 60.37 (þ, C-7),
61.48 (þ, C-1), 67.50 (2, C-3), 68.37 (2, C-4), 68.58 (2,
C-5), 70.82 (2, C-2), 71.77 (2, C-6), 170.20, 170.40,
170.63, 171.30 (þ, 4£CH3COO). C15H22O10 (362.33,
462.12), FAB MS: m/z 303.1 [MþH2AcOH]þ, 345.1
[MþH2H2O]þ, 363.1 [MþH]þ, 385.1 [MþNa]þ, ESI MS:
m/z 385.1 [MþNa]þ.
4.3.5. 2,6-Anhydro-7-bromo-7-deoxy-D-glycero-L-galacto-
heptitol (8a). To a solution of compound 5d (0.050 g,
0.118 mmol) in dry methanol (10 mL) at 08C, a solution of
sodium methoxide (0.013 g, 2.0 equiv.; 0.236 mmol) in dry
methanol (5 mL) was added. The reaction mixture was
stirred at rt for about 3 h until the reactant was consumed, as
shown by TLC (CH3OH–CHCl3 15:85). The mixture was
diluted with methanol, neutralized with Dowex 50-W X2
(Hþ). The mixture was stirred for a few minutes, and then
4.3.3. 1,3,4,5-Tetra-O-acetyl-2,6-anhydro-7-O-methysul-
fonyl-D-glycero-L-galacto-heptitol (5c). 5b (0.046 g,

K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
8445
the resin was filtered off, washed with methanol (3£5 mL).
The combined filtrate was concentrated. The residue was
applied to FC eluting with CH3OH–CHCl3 15:85, and
provided after solvent evaporation 8a (0.030 g, quant.) as a
white solid. Mp: 115–1168C (EtOH–petroleum ether).
[a]2D3¼þ73.68 (c 0.38, EtOH). Rf: 0.16 (CHCl3–MeOH
(m, 4H, aromatic). 13C NMR (APT, HETCOR, 50 MHz,
CDCl3): d¼19.76 (þ, (CH3)3CSi), 24.91, 27.11 (2,
(CH3)2COO), 27.31 (2,(CH3)3CSi), 30.46 (þ, C-7), 63.63
(þ, C-1), 67.53 (2, C-5), 71.24 (2), 71.33 (2), 72.11 (2),
74.59 (2), 110.02 (þ, (CH3)2COO), 128.05, 128.12, 130.10
(2, CAr), 134.04, 134.07 (þ, SiCAr), 136.11, 136.15 (2,
CAr). C26H35BrO5Si (535.55, 534.14), FAB MS: m/z 535.1
[MþH]þ, 557.1 [MþNa]þ.
85:15). IR (KBr): n¼1055, 1080, 3365, 3419 cm21
.
1H
˜
NMR (H,H COSY, 200 MHz, pyridine-d5): d¼4.20–4.30
(m, 2H, CH2-7), 4.32–4.38 (m, 2H), 4.52–4.55 (m, 2H,
CH2-1), 4.75–4.85 (m, 3H). 13C NMR (APT, HETCOR,
50 MHz, pyridine-d5): d¼31.09 (þ, C-7), 61.40 (þ, C-1),
69.44 (2), 69.77 (2), 71.79 (2), 74.51 (2), 76.03 (2).
C7H13BrO5 (257.08, 255.99), FAB MS: m/z 257.0 [MþH]þ,
ESI MS: m/z 278.8 [MþNa]þ.
4.3.8. 5-O-Acetyl-2,6-anhydro-7-bromo-1-O-(t-butyldi-
phenylsilyl)-7-deoxy-3,4-O-isopropylidene-D-glycero-L-
galacto-heptitol (11a). 8c (1.00 g, 1.87 mmol) was dis-
solved in dry pyridine (10 mL) and acetic anhydride (5 mL)
and was stirred at rt for 3 h, during which the reaction
progress was monitored by TLC (petroleum ether–ethyl
acetate 2:1). Coevaporation with toluene, followed by FC
(petroleum ether–ethyl acetate 2:1) gave the acetylated
compound 11a (0.950 g, 88%) as a pale yellow oil.
[a]2D3¼216.67 (c 0.48, CH2Cl2). Rf: 0.51 (ethyl acetate–
4.3.6. 2,6-Anhydro-7-bromo-1-O-(t-butyldiphenylsilyl)-
7-deoxy-D-glycero-L-galacto-heptitol (8b). To a cold
(08C) stirred solution of 8a (0.200 g, 0.781 mmol) and
imidazole (0.105 g, 2.0 equiv.; 1.56 mmol) in dry DMF
(4 mL) TBDPSCl (0.16 mL, 1.2 equiv.; 0.937 mmol) was
added. The mixture was stirred at 08C for about 2 h until the
reaction was complete (TLC, CH3OH–CHCl3 10:90). The
mixture was poured into ice-water (10 mL) and extracted
with chloroform (5£20 mL). The organic layer was
extracted with saturated aqueous sodium hydrogencarbo-
nate, water, dried, and evaporated. The residue was applied
to FC. Elution with a gradient CHCl3!CH3OH–CHCl3
2:98 and solvent evaporation afforded 8b (0.328 g, 85%) as
a white solid. Mp: 77–788C (CHCl3–petroleum ether).
[a]2D3¼þ50 (c 0.24, CH2Cl2). Rf: 0.42 (CHCl3–MeOH
petroleum ether 2:1). IR (film): n¼1068, 1105, 1153, 1221,
˜
1
1751, 2854, 3498 cm21. H NMR (H,H COSY, 600 MHz,
CDCl3): d¼1.08 (s, 9H, (CH3)3CSi), 1.35, 1.49 (2s, 6H,
(CH3)2COO), 2.14 (s, 3H, CH3COO), 3.27–3.31 (m, 2H,
CH2-7), 3.83 (dd, 1H, 1-H, J¼6.2, 9.9 Hz), 3.86 (dd, 1H,
1-H0, J¼7.7, 9.9 Hz), 3.98 (m, 1H, 2-H), 4.29 (ddd, 1H, 6-H,
J¼2.6, 6.2, 8.7 Hz), 4.34 (dd, 1H, 4-H, J¼2.6, 7.5 Hz), 4.45
(dd, 1H, 3-H, J¼1.3, 7.5 Hz), 5.25 (t, 1H, 5-H, J¼2.6 Hz),
7.38–7.44 (m, 6H, aromatic), 7.68–7.76 (m, 4H, aromatic).
13C NMR (APT, HMQC, HMBC, 100 MHz, CDCl3):
d¼19.42 (þ, (CH3)3CSi), 20.98 (2, CH3COO), 24.48,
26.68 (2, (CH3)2COO), 26.99 (2, (CH3)3CSi), 29.39 (þ,
C-7), 63.26 (þ, C-1), 68.63 (2, C-5), 70.08 (2, C-6), 71.19
(2, C-2), 71.56 (2, C-3), 71.76 (2, C-4), 110.02 (þ,
(CH3)2COO), 127.70, 127.75, 129.71, 129.78 (2, CAr),
133.62, 133.74 (þ, SiCAr), 135.72, 135.77 (2, CAr),
169.51 (þ, CH3COO). C28H37BrO6Si (577.59, 576.15),
ESI MS: m/z calculated [MþNa]þ 599.14350, found
599.14379.
90:10). IR (KBr): n¼703, 1079, 1110, 2930, 3405–
˜
3456 cm21
.
1H NMR (H,H COSY, 200 MHz, CDCl3):
d¼1.07 (s, 9H, (CH3)3CSi), 3.38 (m, 1H, 7-H), 3.50–3.55
(m, 2H), 3.65 (dd, 1H, 7-H0, J¼3.4, 11.6 Hz), 3.80–3.91 (m,
2H, CH2-1), 4.08–4.10 (m, 2H), 4.25 (m, 1H), 7.26–7.43
(m, 6H, aromatic), 7.66–7.73 (m, 4H, aromatic). 13C NMR
(APT, HETCOR, 50 MHz, CDCl3): d¼19.54 (þ,
(CH3)3CSi), 27.25 (2, (CH3)3CSi), 28.24 (þ, C-7), 64.04
(þ, C-1), 69.45 (2), 70.29 (2), 71.15 (2), 71.59 (2), 76.24
(2), 128.39, 128.44, 130.51 (2, CAr), 133.18, 133.40 (þ,
SiCAr), 136.10, 136.22 (2, CAr). C23H31BrO5Si (495.49,
494.11), FAB MS: m/z 413.2 [MþH2HBr]þ, 437.1 [Mþ
Na2HBr]þ, 495.0 [MþH]þ, 517.0 [MþNa]þ.
4.3.9. 5-O-Acetyl-2,6-anhydro-7-bromo-7-deoxy-3,4-O-
isopropylidene-D-glycero-L-galacto-heptitol (11b). To a
solution of compound 11a (0.550 g, 0.955 mmol) in THF
(20 mL) at rt, TBAF solution (1.0 M in THF, 1.15 mL,
1.2 equiv.; 1.146 mmol) was added. The reaction was stirred
at rt for 3 h (TLC, petroleum ether–ethyl acetate 1:1).
Water was added and the mixture was extracted with
chloroform (5£20 mL). The combined organic layers were
dried, and the solvent was removed by evaporation. The
residue was submitted to FC (petroleum ether–ethyl acetate
1:1) to give 11b (0.281 g, 87%) as a pale yellow oil.
[a]2D3¼þ8 (c 0.25, CH2Cl2). Rf: 0.28 (ethyl acetate–
4.3.7. 2,6-Anhydro-7-bromo-1-O-(t-butyldiphenylsilyl)-
3,4-O-isopropylidene-7-deoxy-D-glycero-L-galacto-hepti-
tol (8c). To a solution of 8b (0.045 g, 0.091 mmol) in
dry acetone (5 mL) 2,2-dimethoxypropane (2 mL) and
p-toluenesulfonic acid monohydrate (0.009 g) were added.
The reaction mixture was stirred at rt for 2 h until the
starting material was consumed (TLC, ethyl acetate–
petroleum ether 1:1). The reaction mixture was neutralized
by adding triethylamine and concentrated. The residue was
applied to FC (ethyl acetate–petroleum ether 1:1) to give 8c
(0.043 g, 88%) as a pale yellow oil. [a]2D3¼þ12.5 (c 0.32,
CH2Cl2). Rf: 0.50 (ethyl acetate–petroleum ether 1:1). IR
petroleum ether 1:1). IR (film): n¼1061, 1221, 1745 cm21
.
˜
1H NMR (H,H COSY, 400 MHz, CDCl3): d¼1.26, 1.43 (2s,
6H, (CH3)2COO), 2.06 (s, 3H, CH3COO), 2.50 (bs, 1H,
OH), 3.25–3.35 (m, 2H, CH2-7), 3.67 (dd, 1H, 1-H, J¼4.7,
11.6 Hz), 3.78 (dd, 1H, 1-H0, J¼6.7, 11.6 Hz), 3.93 (ddd,
1H, 2-H, J¼1.6, 4.7, 6.7 Hz), 4.23 (dd, 1H, 3-H, J¼1.6,
7.5 Hz), 4.27 (m, 1H, 4-H), 4.30 (m, 1H, 6-H), 5.21 (m, 1H,
5-H). 13C NMR (APT, HMQC, HMBC, 100 MHz, CDCl3):
d¼20.91(2, CH3COO), 24.36, 26.46 (2, (CH3)2COO),
29.31 (þ, C-7), 63.10 (þ, C-1), 67.98 (2, C-5), 70.13 (2,
C-4), 70.99 (2, C-2), 71.70 (2, C-6), 72.35 (2, C-3),
110.47 (þ, (CH3)2COO), 169.54 (þ, CH3COO).
(film): n¼1225, 1745 cm21
.
1H NMR (H,H COSY,
˜
200 MHz, CDCl3): d¼1.06 (s, 9H, (CH3)3CSi), 1.36, 1.46
(2s, 6H, (CH3)2COO), 3.37 (dd, 1H, 7-H, J¼5.4, 9.9 Hz),
3.51 (dd, 1H, 7-H0, J¼8.8, 9.9 Hz), 3.78–3.84 (m, 2H,
CH2-1), 4.12 (m, 1H, 2-H), 4.17 (m, 1H, 6-H), 4.18 (m, 1H,
5-H), 4.36 (dd, 1H, 4-H, J¼2.6, 7.6 Hz), 4.47 (dd, 1H, 3-H,
J¼1.6, 7.6 Hz), 7.33–7.43 (m, 6H, aromatic), 7.66–7.73

8446
K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
C12H19BrO6 (339.18, 338.04), ESI MS: m/z calculated
[MþNa]þ 361.02572, found 361.02609.
4.3.11. 2,6-Anhydro-7-bromo-7-deoxy-3,4-O-isopropyl-
idene-D-glycero-L-galacto-heptonamide (11d). A solution
of compound 11c (0.300 g, 0.855 mmol) in dry methanol
(10 mL) was treated at rt with sodium methoxide (0.092 g,
2.0 equiv.; 1.71 mmol). The reaction mixture was stirred
for 1 h (TLC, petroleum ether–CHCl3–EtOH, 5:2:2). The
mixture was diluted with methanol and neutralized with
Dowex 50-W X2 (Hþ). The mixture was stirred for a few
minutes, and then the resin was filtered off, washed with
methanol (5£10 mL), and the filtrate was concentrated. The
residue was chromatographed (FC) eluting with petroleum
ether–CHCl3–EtOH (8:2:2) to furnish compound 11d
(0.264 g, quant.) as a pale yellow oil. [a]2D3¼231.58 (c
0.19, CH2Cl2). Rf: 0.47 (petroleum ether–CHCl3–EtOH
4.3.10. 5-O-Acetyl-2,6-anhydro-7-bromo-7-deoxy-3,4-O-
isopropylidene-D-glycero-L-galacto-heptonamide (11c).
TEMPO oxidation. To a mixture of 11b (0.330 g,
0.940 mmol) TEMPO (0.161 g, 1.06 equiv.; 0.996 mmol),
tetrabutylammonium chloride (0.261 g, 1.0 equiv.;
0.940 mmol), potassium bromide (0.113 g, 1.0 equiv.;
0.95 mmol) and dichloromethane (20 mL) at 08C, a mixture
of saturated aqueous sodium chloride (10 mL), saturated
aqueous sodium hydrogencarbonate (11 mL), and saturated
aqueous sodium hypochlorite (1 mL, 12–14% active
chlorine) was added slowly. The reaction mixture was
vigorously stirred at rt for 3 h (TLC, petroleum ether–
CHCl3–EtOH 5:2:2). The pH was adjusted to 2–3 with
concentrated HCl. The organic layer was separated and the
aqueous layer was extracted five times with dichloro-
methane (10 mL portions). The combined organic extracts
were dried, and the solvent was removed.
5:2:2). IR (film): n¼1687, 3432 cm21
.
1H NMR (H,H
˜
COSY, 400 MHz, CDCl3): d¼1.27, 1.41 (2s, 6H,
(CH3)2COO), 3.41 (dd, 1H, 7-H, J¼6.6, 10.2 Hz), 3.48
(dd, 1H, 7-H0, J¼7.8, 10.2 Hz), 4.07 (bs, 1H, 5-H), 4.20 (m,
1H, 6-H), 4.35 (dd, 1H, 4-H, J¼2.5, 7.8 Hz), 4.50 (bs, 1H,
2-H), 4.66 (d, 1H, 3-H, J¼7.8 Hz), 5.74, 6.64 (2bs, 2H,
H2NCO). 13C NMR (APT, HMQC, HMBC, 100 MHz,
CDCl3): d¼24.28, 26.52 (2, (CH3)2COO), 30.98 (þ, C-7),
66.39 (2, C-5), 71.33 (2, C-2), 71.65 (2, C-6), 72.69 (2,
C-3), 73.83 (2, C-4), 110.11 (þ, (CH3)2COO), 172.69 (þ,
H2NCO). C10H16BrNO5 (310.14, 309.02), ESI MS: m/z
[MþH]þ (calculated 310.02846, found 310.02861),
[2MþH]þ (calculated 619.05019, found 619.05060).
Sodium chlorite oxidation. The crude product of the
TEMPO oxidation (max. 0.940 mmol), sodium chlorite
(0.846 g, 10.0 equiv.; 9.4 mmol), and sodium dihydrogen-
phosphate monohydrate (0.97 g, 7.5 equiv.; 7.0 mmol) were
placed in a reaction flask, and with stirring successively
2-methyl-2-butene (4.0 mL), t-butanol (18 mL) and water
(7.0 mL) were added. The reaction mixture was stirred at rt
for 4 h (TLC, petroleum ether–CHCl3–EtOH 5:2:2), and
then it was diluted with water (20 mL) and dichloromethane
(50 mL). The organic layer was separated and the aqueous
layer was extracted with dichloromethane (2£20 mL). The
aqueous layer was adjusted to pH 2 with concentrated HCl
and extracted with dichloromethane (3£10 mL). The
combined organic extracts were dried, and the solvent was
removed. The residue was dried at 0.1 mbar for ca. 2 h.
4.3.12. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroaceta-
mido)-b-D-glucopyranosyl-(1!5)-2,6-anhydro-7-bromo-
7-deoxy-3,4-O-isopropylidene-1-O-(t-butyldiphenyl-
silyl)-D-glycero-L-galacto-heptitol (7a). A mixture of 8c
(0.034 g, 0.064 mmol), 3,4,6-tri-O-acetyl-3-deoxy-2-tri-
chloroacetamido-a-D-glucopyranosyl trichloroacetamidate35
˚
(0.045 g, 1.2 equiv.; 0.077 mmol) and activated 3 A
molecular sieves in anhydrous 1,2-dichloroethane (5 mL)
was stirred for 1 h at rt under an argon atmosphere, then
cooled to 08C. Trimethylsilyl triflate (1.5 mL, 0.1 equiv.,
0.006 mmol) was added, and the mixture was stirred at 08C
for ca. 5 min (TLC, ethyl acetate–petroleum ether 1:1).
Triethylamine (0.1 mL) was added to stop the reaction, and
the mixture was diluted with CH2Cl2 (10 mL) and filtered.
The molecular sieves were washed with CH2Cl2 (3£5 mL)
and the combined filtrate was concentrated. The residue was
subjected to FC (petroleum ether–ethyl acetate 2:1) to
furnish 7a (0.048 g, 79%) as a white solid. Mp: 227–2288C
(CHCl3–petroleum ether), decomposition. [a]2D3¼216 (c
0.25, CH2Cl2). Rf: 0.36 (ethyl acetate–petroleum ether 1:1).
Amide formation according to Staab. The crude acid (max.
0.94 mmol) and CDI (0.386 g, 2.5 equiv.; 2.4 mmol) were
dissolved in dry dichloromethane (30 mL), and the mixture
was stirred at rt for 5 h. Through this solution at 08C,
gaseous ammonia was bubbled for 40 min (TLC, petroleum
ether–CHC13–EtOH 5:2:2), then the mixture was stirred at
rt for 1 h. The solvent was evaporated, and the residue was
purified by FC (petroleum ether–CHC13–EtOH 8:2:2) to
give amide 11c (0.286 g, 95%, based on 11b) as a pale
yellow oil. [a]D23¼218.18 (c 0.22, CH2Cl2). Rf: 0.50
(petroleum ether–CHCl –EtOH 5:2:2). IR (film): n¼
˜
3
1752, 1697, 1367, 1215, 1151, 1060 cm21. H NMR (H,H
IR (KBr): n¼1047, 1108, 1237, 1526, 1750, 3437 cm21. 1H
1
˜
COSY, 400 MHz, CDCl3): d¼1.26, 1.43 (2s, 6H,
(CH3)2COO), 2.06 (s, 3H, CH3COO), 3.26–3.36 (m, 2H,
CH2-7), 4.31 (dd, 1H, 4-H, J¼2.7, 7.5 Hz), 4.35 (d, 1H, 2-H,
J¼1.6 Hz), 4.37 (dd, 1H, 6-H, J¼2.2, 7.0 Hz), 4.65 (dd, 1H,
3-H, J¼1.6, 7.5 Hz), 5.15 (t, 1H, 5-H, J¼2.2 Hz), 6.15, 6.65
(2bs, 2H, H2NCO). 13C NMR (APT, HMQC, HMBC,
100 MHz, CDCl3): d¼20.82 (2, CH3COO), 24.19, 26.50
(2, (CH3)2COO), 30.06 (þ, C-7), 68.38 (2, C-5), 70.47 (2,
C-6), 71.56 (2, C-4), 71.67 (2, C-2), 72.50 (2, C-3),
110.60 (þ, (CH3)2COO), 169.33 (þ, CH3COO), 171.50 (þ,
H2NCO). C12H18BrNO6 (352.18, 351.04), ESI MS: m/z
[MþH]þ (calculated 352.03903, found 352.03928),
[MþNa]þ (calculated 374.02097, found 374.02106),
[MþK]þ (calculated 389.99491, found 389.99513).
NMR (H,H COSY, 300 MHz, CDCl3): d¼1.03 (s, 9H,
SiC(CH3)3), 1.31, 1.46 (2s, 6H, (CH3)2COO), 2.05 (s, 6H,
2£CH3COO), 2.09 (s, 3H, CH3COO), 3.30 (dd, 1H, 7F-H,
J¼5.9, 10.0 Hz), 3.55 (dd, 1H, 7F-H0, J¼8.1, 10.0 Hz), 3.75
(m, 1H, 5E-H), 3.77–3.80 (m, 2H, CH2-1F), 3.94 (m, 1H,
2E-H), 4.02 (m, 1H, 2F-H), 4.10 (m, 1H, 5F-H), 4.15 (m, 1H,
6F-H), 4.21 (m, 1H, 4F-H), 4.24–4.27 (m, 2H, CH2-6E), 4.47
(dd, 1H, 3F-H, J¼1.4, 7.1 Hz), 4.89 (d, 1H, 1E-H, J¼
8.5 Hz), 5.14 (dd, 1H, 4E-H, J¼9.6, 9.9 Hz), 5.39 (dd, 1H,
3E-H, J¼9.6, 10.7 Hz), 7.02 (d, 1H, NHCOCCl3, J¼
8.8 Hz), 7.35–7.41 (m, 6H, aromatic), 7.65–7.70 (m, 4H,
aromatic). 13C NMR (APT, HETCOR, 75 MHz, CDCl3):
d¼19.51 (þ, SiC(CH3)3), 20.85, 20.91, 21.09 (2, 3£
CH3COO), 24.62, 27.15 (2, (CH3)2COO), 27.06 (2,

K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
8447
SiC(CH3)3), 30.33 (þ, C-7F), 56.42 (2, C-2E), 62.29 (þ,
C-6E), 63.05 (þ, C-1F), 68.55 (2, C-4E), 70.19 (2), 71.09
(2, C-6F), 71.69 (2, C-3E), 71.96 (2, C-3F), 72.37 (2, C-4F),
72.49 (2, C-5E), 75.29 (2), 93.00 (þ, NHCOCCl3), 99.92
(2, C-1E), 109.86 (þ, (CH3)2COO), 127.87, 127.93, 129.87,
129.91 (2, C-Ar), 133.60, 133.67 (þ, SiCAr), 135.86, 135.97
(2, C-Ar), 162.19 (þ, NHCOCCl3), 169.60, 171.05, 171.34
(þ, 3£CH3COO). C40H51BrCl3NO13Si (968.19, 965.14),
FAB MS: m/z 966.1 [MþH]þ, 988.1 [MþNa]þ, ESI MS:
m/z calculated [MþNH4]þ 983.17169, found 983.17325.
adjusted to 2–3 with concentrated HCl. The organic layer
was separated and the aqueous layer was extracted with
dichloromethane (5£10 mL). The combined organic
extracts were dried, and the solvent was removed.
Sodium chlorite oxidation. The crude product of the
TEMPO oxidation (max. 0.094 mmol), sodium chlorite
(0.085 g, 10 equiv.; 0.94 mmol), and sodium dihydrogen-
phosphate monohydrate (0.097 g, 7.5 equiv.; 0.70 mmol)
were placed in a reaction flask, and with stirring
successively 2-methyl-2-butene (0.4 mL), t-butanol
(1.8 mL) and water (0.7 mL) were added. The reaction
mixture was stirred at rt for 4 h (TLC, petroleum ether–
CHCl3–EtOH 5:2:2), then it was diluted with water (2 mL)
and dichloromethane (5 mL). The organic layer was
separated, and the aqueous layer was extracted with
dichloromethane (4£10 mL). The aqueous layer was
adjusted to pH 2 with concentrated HCl, and extracted
with dichloromethane (3£10 mL). The combined organic
extracts were dried, and the solvent was removed. The
residue was dried at 0.1 mbar for ca. 2 h.
4.3.13. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroaceta-
mido)-b-D-glucopyranosyl-(1!5)-2,6-anhydro-7-bromo-
7-deoxy-3,4-O-isopropylidene-D-glycero-L-galacto-hepti-
tol (7b). To a solution of 7a (0.300 g, 0.311 mmol) in THF
(30 mL) a TBAF solution (1.0 M in THF, 0.37 mL,
1.2 equiv.; 0.373 mmol) was added. The mixture was stirred
at rt for 21 h (TLC, ethyl acetate–petroleum ether 1:1).
Water (15 mL) was added and the mixture was extracted
with chloroform (5£10 mL). The combined organic layers
were dried, and the solvent was evaporated. The residue was
chromatographed (FC) eluting with petroleum ether–ethyl
acetate 1:1 to give 7b (0.201 g, 89%) as a white solid.
Mp: 230–2318C (CHCl3–petroleum ether), decomposition.
[a]2D3¼230 (c 0.20, CH2Cl2). Rf: 0.13 (ethyl acetate–
Amide formation according to Staab. The crude acid (max.
0.094 mmol) and CDI (0.039 g, 2.5 equiv.; 0.24 mmol)
were dissolved in dry dichloromethane (10 mL), and the
mixture was stirred at rt for 5 h. Through this solution at 08C
gaseous ammonia was bubbled for 40 min (TLC, petroleum
ether–CHCl3–EtOH 5:2:2), then the mixture was stirred at
rt for 1 h. The solvent was evaporated, and the residue was
subjected to FC (petroleum ether–CHCl3–EtOH 8:2:2) to
furnish amide 7c (0.068 g, 98%, based on 7b) as a white
solid. Mp: 152–1538C (CHCl3 –petroleum ether),
decomposition. [a]2D3¼280 (c 0.15, CH2Cl2). Rf: 0.49
(petroleum ether–CHCl3 –EtOH 5:2:2). IR (KBr):
petroleum ether 1:1). IR (KBr): n¼1044, 1109, 1162, 1236,
˜
1
1374, 1529, 1750, 2923, 3393, 3492 cm21. H NMR (H,H
COSY, 200 MHz, pyridine-d5): d¼1.32, 1.54 (2s, 6H,
(CH3)2COO), 2.01, 2.02. 2.10 (3s, 9H, 3£CH3CO0O), 3.79
(dd, 1H, 7F-H, J¼7.0, 10.3 Hz), 3.92 (dd, 1H, 7F-H , J¼6.6,
10.3 Hz), 4.05 (ddd, 1H, 5E-H, J¼2.2, 4.8, 9.9 Hz), 4.21 (m,
1H, 1F-H), 4.24 (m, 1H, 1F-H0), 4.35 (m, 1H, 2E-H), 4.41 (m,
1H, 6E-H), 4.51 (m, 1H, 3F-H), 4.53 (m, 1H, 6E-H0), 4.58 (m,
1H, 2F-H), 4.58 (m, 1H, 6F-H), 4.74 (dd, 1H, 4F-H, J¼3.1,
7.2 Hz), 4.88 (dd, 1H, 5F-H, J¼1.3, 7.2 Hz), 5.51 (m, 1H,
4E-H), 5.67 (d, 1H, 1E-H, J¼8.4 Hz), 6.14 (dd, 1H, 3E-H,
n¼1046, 1108, 1148, 1233, 1374, 1531, 1685, 1750, 3378,
˜
3475 cm21
.
1H NMR (H,H COSY, 600 MHz, CDCl3):
J¼9.2, 10.6 Hz), 10.67 (d, 1H, NHCOCCl3, J¼8.1 Hz). 13
C
d¼1.33, 1.48 (2s, 6H, (CH3)2COO), 2.03, 2.05, 2.11 (3s, 9H,
3£CH3COO), 3.45, (dd, 1H, 7F-H, J¼6.5, 10.2 Hz), 3.57
(dd, 1H, 7F-H0, J¼7.1, 10.2 Hz), 3.77 (ddd, 1H, 5E-H,
J¼2.5, 4.7, 9.9 Hz), 3.95 (m, 1H, 2E-H), 4.07 (m, 1H, 5F-H),
4.21 (dd, 1H, 6E-H, J¼2.5, 12.2 Hz), 4.25 (dd, 1H, 6E-H0,
J¼4.7, 12.2 Hz), 4.29 (m, 1H, 6F-H), 4.37 (d, 1H, 2F-H,
J¼2.1 Hz), 4.41 (dd, 1H, 4F-H, J¼2.4, 7.6 Hz), 4.70 (dd,
1H, 3F-H, J¼1.6, 7.3 Hz), 4.95 (d, 1H, 1E-H, J¼8.4 Hz),
5.12 (dd, 1H, 4E-H, J¼9.4, 9.9 Hz), 5.39 (dd, 1H, 3E-H,
J¼9.4, 10.5 Hz), 6.07, 6.72 (2d, 2H, H2NCO, J¼3.7 Hz),
7.66 (d, 1H, NHCOCCl3, J¼8.4 Hz). 13C NMR (APT,
HETCOR, HMQC, HMBC, 150 MHz, CDCl3): d¼20.99,
21.05, 21.21 (2, 3£CH3COO), 24.65, 26.97 (2,
(CH3)2COO), 31.30 (þ, C-7F), 56.60 (2, C-2E), 62.36 (þ,
C-6E), 68.75 (2, C-4E), 71.41 (2, C-6F), 71.49 (2, C-2F),
71.55 (2, C-4F), 71.84 (2, C-3E), 72.75 (2, C-5E), 73.04
(2, C-3F), 74.08 (2, C-5F), 92.65 (þ, NHCOCCl3), 99.48
(2, C-1E), 110.85 (þ, (CH3)2COO), 162.97 (þ,
NHCOCCl3), 169.92, 171.26, 171.49 (þ, 3£CH3COO),
172.28 (þ, H2NCO). C24H32BrCl3N2O13 (742.78, 740.02),
FAB MS: m/z 741.0 [MþH]þ, 763.0 [MþNa]þ, ESI MS:
m/z [MþH]þ (calculated 741.022261, found 741.02190),
[MþNa]þ (calculated 763.00456, found 763.00636).
NMR (APT, HETCOR, 50 MHz, pyridine-d5): d¼20.49,
20.65 (2, 3£CH3COO), 24.55, 27.09 (2, (CH3)2COO),
31.86 (þ, C-7F), 57.18 (2, C-2E), 62.08 (þ, C-1F), 62.43
(þ, C-6E), 69.61 (2, C-4E), 71.73 (2, C-3E, C-2F), 71.96
(2, C-6F), 72.39 (2, C-5E), 72.82 (2, C-4F), 72.92 (2,
C-5F), 75.51 (2, C-3F), 93.73 (þ, NHCOCCl3), 99.37 (2,
C-1E), 109.78 (þ, (CH3)2COO), 163.28 (þ, NHCOCCl3),
169.81, 170.36, 170.43 (þ, 3£CH3COO). C24H33BrCl3NO13
(729.79, 727.02), FAB MS: m/z 728.0 [MþH]þ, 750.0
[MþNa]þ, ESI MS: m/z calculated [MþNa]þ 750.00931,
found 750.00868.
4.3.14. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroaceta-
mido)-b-D-glucopyranosyl-(1!5)-2,6-anhydro-7-bromo-
7-deoxy-3,4-O-isopropylidene-1-O-D-glycero-L-galacto-
heptonamide (7c). TEMPO oxidation. To a mixture of 7b
(0.068 g, 0.094 mmol), TEMPO (0.016 g, 1.06 equiv.;
0.099 mmol), tetrabutylammonium chloride (0.026 g,
1.0 equiv.; 0.094 mmol), potassium bromide (0.011 g,
1.0 equiv.; 0.095 mmol) and dichloromethane (2 mL) at
08C, a mixture of saturated aqueous sodium chloride
(1 mL), saturated aqueous sodium hydrogencarbonate
(1.1 mL), and saturated aqueous sodium hypochlorite
(1 mL, 12–14% active chlorine) was added slowly. The
reaction mixture was vigorously stirred at rt for 3 h (TLC,
petroleum ether–CHCl3–EtOH 5:2:2). The pH was
4.3.15. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroaceta-
mido)-b-D-glucopyranosyl-(1!5)-2,6-anhydro-7-bromo-
7-deoxy-D-glycero-L-galacto-heptonamide(7d). 7c (0.040 g,

8448
K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
0.054 mmol) was dissolved in CH2Cl2 (10 mL) and TFA
(21 mL, 5 equiv.; 0.270 mmol) was added. The reaction
mixture was stirred at rt for 2 h (TLC, petroleum ether–
CHCl3–EtOH 5:2:2). The solution was coevaporated three
times with toluene (3 mL). The residue was submitted to FC
(petroleum ether–CHCl3–EtOH 8:2:2) to give 7d (0.034 g,
89%) as a white solid. Mp: 241–2428C (EtOH–petroleum
ether), decomposition. [a]2D3¼250 (c 0.12, CH2Cl2). Rf:
[MþH]þ, 749.1 [MþNa]þ, ESI MS: m/z [MþNa]þ
(calculated 748.95252, found 748.95186), [MþK]þ (calcu-
lated 764.92646, found 764.92556).
4.4. Treatment of 7d with phenyl chloroformate
A solution of 7d (0.020 g, 0.028 mmol) and DMAP (0.004 g,
1.0 equiv.; 0.028 mmol) in dry CH2Cl2 (5 mL) was cooled to
08C, then dry triethylamine (4 mL, 1.0 equiv.; 0.028 mmol)
was added. Phenyl chloroformate (3.8 mL, 1.1 equiv.,
0.031 mmol) was added dropwise at 08C, and the reaction
mixture was stirred at rt for 1 h (TLC, petroleum ether–
CHCl3–EtOH 5:2:2). The solvent was evaporated, and the
residue was separated by FC, eluted with petroleum ether–
CHCl3–EtOH (8:2:2) to give compound 7e (0.015 g, 72%).
0.23 (petroleum ether–CHCl3–EtOH 5:2:2). IR (KBr):
1
n¼1635, 1678, 1746, 3443 cm21. H NMR (H,H COSY,
˜
400 MHz, pyridine-d5): d¼1.96, 1.99, 2.07 (3s, 9H, 3£
CH3COO), 3.82 (ddd, 1H, 5E-H, J¼2.5, 4.6, 9.8 Hz), 4.12
(dd, 1H, 7F-H, J¼3.7, ca. 11.7 Hz), 4.25 (dd, 1H, 7F-H0,
J¼3.0, ca. 11.7 Hz), 4.42–4.50 (m, 2H, CH2-6E), 4.51 (m,
1H, 5F-H), 4.65 (dd, 1H, 2E-H, J¼8.6, 10.6 Hz), 4.79 (d, 1H,
3F-H, J¼2.4 Hz), 4.83 (m, 1H, 2F-H), 4.91 (m, 1H, 6F-H),
5.01 (m, 1H, 4F-H), 5.49 (m, 1H, 4E-H), 5.58 (d, 1H, 1E-H,
J¼8.4 Hz), 5.95 (dd, 1H, 3E-H, J¼9.3, 10.6 Hz), 8.00, 8.78
(2bs, 2H, H2NCO), 10.63 (d, 1H, NHCOCCl3, J¼8.6 Hz).
13C NMR (APT, HMQC, HMBC, 100 MHz, pyridine-d5):
d¼20.28, 20.37, 20.48 (2, 3£CH3COO), 30.83 (þ, C-7F),
56.64 (2, C-2E), 62.15 (þ, C-6E), 69.40 (2, C-4E), 69.86
(2, C-4F), 70.07 (2, C-5F), 72.00 (2, C-5E), 72.55 (2,
C-3E), 73.39 (2, C-3F), 75.11 (2, C-6F), 78.19 (2, C-2F),
93.76 (þ, NHCOCCl3), 101.46 (2, C-1E), 163.18 (þ,
NHCOCCl3), 169.63, 170.30, 170.38 (þ, 3£CH3COO),
173.59 (þ, H2NCO). C21H28BrCl3N2O13 (702.72, 699.98),
FAB MS: m/z 700.9 [MþH]þ, 722.9 [MþNa]þ, ESI MS:
m/z calculated [MþNa]þ 722.97326, found 722.97544.
4.5. Reaction of 7e with ammonia
Dry ammonia gas was bubbled through a solution of 7e
(0.150 g, 0.207 mmol) in CH2Cl2 (10 mL) at 08C for 6 h
(TLC, petroleum ether–CHCl3–EtOH 5:2:2). The solvent
was evaporated, and the residue was separated using
repeated MPLC eluting with petroleum ether–ethyl acetate–
EtOH 5:2:1 to give 6a (0.095 g, 62%) and 6b (0.032 g, 21%)
as white solids.
4.5.1. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroaceta-
mido)-b-D-glucopyranosyl-(1!5)-2,6-anhydro-7-bromo-
4-carbamoyl-7-deoxy-D-glycero-L-galacto-heptonamide
(6a). Mp: 261–2628C (EtOH–petroleum ether), decompo-
4.3.16. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloro-
acetamido)-b-D-glucopyranosyl-(1!5)-2,6-anhydro-7-
bromo-3,4-O-carbonyl-7-deoxy-D-glycero-L-galacto-hep-
tonamide (7e). To a solution of 7d (0.313 g, 0.45 mmol) in
dry CH2Cl2 (20 mL) CDI (0.146 g, 2.0 equiv.; 0.90 mmol)
and DMAP (0.055 g, 1.0 equiv.; 0.45 mmol) were added.
The reaction mixture was stirred at rt for 2 h (TLC,
petroleum ether–CHCl3–EtOH 5:2:2). Evaporation, FC
(petroleum ether–CHCl3–EtOH 8:2:2) afforded 7e
sition. Rf: 0.14 (petroleum ether–CHCl3–EtOH 5:2:2). IR
˜
1
(KBr): n¼1690, 1706, 1743, 3310–3521 cm21. H NMR
(H,H COSY, 400 MHz, pyridine-d5): d¼2.00, 2.03, 2.10,
(3s, 9H, 3£CH3COO), 3.84 (m, 1H, 5E-H), 4.10 (dd, 1H,
7F-H, J¼3.3, 11.4 Hz), 4.30 (dd, 1H, 7F-H0, J,1, 11.4 Hz),
4.31 (m, 1H, 6E-H,), 4.42 (m, 1H, 6E-H0), 4.43 (m, 1H, 2E-
H), 4.84 (d, 1H, 2F-H, J¼1.8 Hz), 4.96 (m, 1H, 6F-H), 5.03
(m, 1H, 5F-H), 5.40 (dd, 1H, 3F-H, J¼1.8, 3.5 Hz), 5.50 (dd,
1H, 4E-H, J¼9.5, 9.9 Hz), 5.57 (d, 1H, 1E-H, J¼8.4 Hz),
5.68 (dd, 1H, 4F-H, J¼3.5, 8.3 Hz), 6.08 (dd, 1H, 3E-H,
J¼9.5, 10.6 Hz), 7.50 (bs, 2H, H2NCOO), 7.80, 8.49 (2s,
2H, H2NCO), 10.57 (d, 1H, NHCOCCl3, J¼8.1 Hz). 13C
NMR (APT, HMQC, HMBC, 100 MHz, pyridine-d5): d¼
20.12, 20.21, 20.31 (2, 3£CH3COO), 30.32 (þ, C-7F),
56.76 (2, C-2E), 61.83 (þ, C-6E), 67.63 (2, C-3F), 69.27
(2, C-4E), 71.58 (2, C-3E), 71.73 (2, C-5E), 72.71 (2,
C-4F), 73.17 (2, C-2F), 75.11 (2, C-5F), 75.66 (2, C-6F),
93.46 (þ, NHCOCCl3), 100.57 (2, C-1E), 156.83 (þ,
H2NCOO), 162.89 (þ, NHCOCCl3), 169.43, 170.06, 170.14
(þ, 3£CH3COO), 171.98 (þ, H2NCO). C22H29BrCl3N3O14
(745.74, 742.99), FAB MS: m/z 744.2 [MþH]þ, 766.2
[MþNa]þ, ESI MS: m/z calculated [MþH]þ 743.99712,
found 743.99616.
(0.272 g, 84%) as
a white solid. Mp: 153–1548C
(CHCl3–petroleum ether). [a]2D3¼213.33 (c 0.15,
CH2Cl2). Rf: 0.41 (petroleum ether–CHCl3–EtOH 5:2:2).
IR (KBr): n¼1047, 1069, 1236, 1696, 1749, 1816, 3420,
˜
3439 cm21. 1H NMR (H,H COSY, 400 MHz, pyridine-d5):
d¼2.02, 2.03, 2.12 (3s, 9H, 3£CH3COO), 3.760 (dd, 1H,
7F-H, J¼7.9, 10.9 Hz), 3.92 (dd, 1H, 7F-H , J¼5.9,
10.9 Hz), 4.12 (ddd, 1H, 5E-H, J¼2.6, 4.8, 9.9 Hz), 4.38
(dd, 1H, 2E-H, J¼8.1, 10.6 Hz), 4.47 (dd, 1H, 6E-H, J¼2.6
12.0 Hz), 4.51 (dd, 1H, 6E-H0, J¼4.8, 12.0 Hz), 4.63 (ddd,
1H, 6F-H, J¼3.7, 5.9, 7.9 Hz), 4.93 (t, 1H, 5F-H, J¼3.7 Hz),
5.01 (d, 1H, 2F-H, J¼1.7 Hz), 5.53 (m, 1H, 4E-H), 5.59 (m,
1H, 4F-H), 5.82 (d, 1H, 1E-H, J¼8.4 Hz), 5.95 (dd, 1H,
3F-H, J¼1.7, 8.4 Hz), 6.17 (dd, 1H, 3E-H, J¼9.2, 10.6 Hz),
7.92, 8.90 (2s, 2H, H2NCO), 10.78 (d, 1H, NHCOCCl3,
J¼8.6 Hz). 13C NMR (APT, HMQC, HMBC, 100 MHz,
pyridine-d5): d¼21.60, 21.77 (2, 3£CH3COO), 31.79
(þ, C-7F), 58.11 (2, C-2E), 63.42 (þ, C-6E), 70.64 (2,
C-4E), 72.02 (2, C-2F), 72.72 (2, C-3E), 73.28 (2, C-5F),
73.43 (2, C-4F), 73.76 (2, C-5E), 74.66 (2, C-6F), 76.52
(2, C-3F), 94.70 (þ, NHCOCCl3), 100.08 (2, C-1E),
155.16 (þ, OCOO), 164.80 (þ, NHCOCCl3), 170.71
(þ, H2NCO), 171.00, 171.57, 171.60 (þ, 3£CH3COO).
C22H26BrCl3N2O14 (728.72, 725.96), FAB MS: m/z 727.1
4.5.2. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroaceta-
mido)-b-D-glucopyranosyl-(1!5)-2,6-anhydro-7-bromo-
3-carbamoyl-7-deoxy-D-glycero-L-galacto-heptonamide
(6b). Mp: 257–2588C (EtOH–petroleum ether), decompo-
sition. Rf: 0.12 (petroleum ether–CHCl3–EtOH 5:2:2). IR
˜
1
(KBr): n¼1721, 3306–3445 cm21. H NMR (H,H COSY,
400 MHz, pyridine-d5): d¼2.01, 2.06, 2.10, (3s, 9H,
3£CH3COOO), 3.84 (m, 1H, 5E-H), 4.17 (dd, 1H, 7F-H,
J¼3.2, 11.5 Hz), 4.29 (dd, 1H, 7F-H0, J,1, 11.5 Hz), 4.34

K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
8449
(m, 1H, 6E-H), 4.47 (dd, 1H, 6E-H, J¼4.7, 12.2 Hz), 4.64
(m, 1H, 4F-H), 4.65 (m, 1H, 5F-H), 4.71 (ddd, 1H, 2E-H,
J¼8.5, 8.8, 10.4 Hz), 4.95 (m, 1H, 6F-H), 5.47 (d, 1H, 1E-H,
J¼8.5 Hz), 5.01 (d, 1H, 2F-H, J¼1.7 Hz), 5.52 (dd, 1H,
4E-H, J¼9.6, 9.9 Hz), 5.93 (dd, 1H, 3E-H, J¼9.6, 10.4 Hz),
6.47 (bs, 1H, 3F-H), 7.60 (bs, 2H, H2NCOO), 7.88, 8.54 (2s,
2H, H2NCO), 10.73 (d, 1H, NHCOCCl3, J¼8.8 Hz). 13C
NMR (APT, HMQC, HMBC, 100 MHz, pyridine-d5):
d¼20.28, 20.40, 20.53 (2, 3£CH3COO), 29.83 (þ, C-7F),
56.48 (2, C-2E), 62.24 (þ, C-6E), 68.71 (2, C-4F), 69.40
(2, C-4E), 71.93 (2, C-2F), 72.14 (2, C-5E), 72.54
(2, C-3F), 72.71 (2, C-3E), 76.52 (2, C-6F), 78.58 (2,
C-5F), 93.79 (þ, NHCOCCl3), 102.20 (2, C-1E), 157.78
(þ, H2NCOO), 163.22 (þ, NHCOCCl3), 169.60,
170.32, 170.45 (þ, 3£CH3COO), 170.84 (þ, H2NCO).
C22H29BrCl3N3O14 (745.74, 742.99), FAB MS: m/z744.2
[MþH]þ, 766.2 [MþNa]þ, ESI MS: m/z calculated
[MþH]þ 743.99712, found 743.99605.
(0.001 g, 1.0 equiv.; 0.034 mmol) in dry ethanol (10 mL)
was stirred at 08C for 15 h. The reaction progress was
controlled by TLC (petroleum ether–CHCl3–EtOH 5:2:2),
which showed no reaction. The temperature was then raised
to rt, and the reaction mixture was stirred for further 10 h.
The solution was diluted with dry EtOH (10 mL), cooled to
08C and neutralized with dry acetic acid. The solution was
coevaporated twice with MeOH (5 mL portions), and
taken up in dry pyridine (5 mL), and stirred overnight
with Ac2O (3 mL). The solution was coevaporated with
toluene, and the residue was purified by FC (petroleum
ether–CHCl3–EtOH 8:2:2) to furnish 9b (0.023 g, 83%) as
a white solid.
4.7.1. 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-gluco-
pyranosyl-(1!5)-3,4-di-O-acetyl-2,6-anhydro-7-bromo-
7-deoxy-D-glycero-L-galacto-heptonamide (9b). Mp:
179–1808C (CHCl3–petroleum ether), decomposition.
[a]2D3 þ142.8 (c 0.07, CH2Cl2). Rf: 0.28 (petroleum
4.6. Attempted conversion of 7e into 10 by LiOH
hydrolysis and acetylation
ether–CHCl –EtOH 5:2:2). IR (KBr): n¼1236, 1745,
˜
3
3423 cm21
.
1H NMR (H,H COSY, 400 MHz, pyridine-
d5): d¼2.00, 2.01, 2.04, 2.05, 2.09, 2.16 (6s, 18H,
5£CH3COO, NHCOCH3), 4.03 (m, 1H, 5E-H), 4.08 (m,
1H, 2E-H), 4.15 (m0, 1H, 7F-H), 4.43–4.44 (m, 2H, CH2-6E),
4.55 (m, 1H, 7F-H ), 4.80 (dd, 1H, 5F-H, J¼3.3, 10.5 Hz),
5.02 (m, 1H, 6F-H), 5.08 (d, 1H, 2F-H, J¼1.5 Hz), 5.45 (dd,
1H, 4E-H, J¼9.5, 10.3 Hz), 5.64 (d, 1H, 1E-H, J¼8.4 Hz),
5.85 (dd, 1H, 4F-H, J¼3.4, 10.5 Hz), 6.08 (dd, 1H, 3E-H,
J¼9.5, 10.6 Hz), 6.48 (dd, 1H, 3F-H, J¼1.5, 3.4 Hz), 7.90,
8.80 (2bs, 2H, H2NCO), 9.27 (d, 1H, NHCOCH3,
J¼8.1 Hz). 13C NMR (APT, HMQC, HMBC, 100 MHz,
pyridine-d5): d¼20.45, 20.49, 20.49, 20.67, 20.83 (2,
5£CH3COO), 23.13 (2, NHCOCH3), 29.52 (þ, C-7F),
56.15 (2, C-2E), 62.50 (þ, C-6E), 69.68 (2, C-4E), 69.87
(2, C-3F, C-4F), 71.04 (2, C-2F), 72.09 (2, C-5E), 72.55
(2, C-3E), 75.72 (2, C-5F), 76.83 (2, C-6F), 101.89
(2, C-1E), 169.84, 169.87, 170.14, 170.47 (þ, 5£CH3COO,
NHCOCH3, H2NCO). C25H35BrN2O15 (683.46, 682.12),
FAB MS: m/z 683.1 [MþH]þ, 705.11 [MþNa]þ, ESI
MS: m/z [MþH]þ (calculated 683.12936, found
683.12523), [MþNa]þ (calculated 705.11185, found
705.11001).
7e (0.015 g, 0.021 mmol) was treated with 0.5 M LiOH
in THF–MeOH (1:1) (10 mL) for 2 h (TLC, petroleum
ether–CHCl3–EtOH 5:2:2). The solution was diluted with
EtOH (10 mL), cooled to 08C and neutralized with dry
acetic acid. The solution was coevaporated with MeOH
(3£2 mL). The crude product was dissolved in dry pyridine
(5 mL) and stirred overnight with Ac2O (5 mL). The
solution was coevaporated with toluene, and the residue
was purified by FC (petroleum ether–CHCl3–EtOH 8:2:2)
to give 9c (0.012 g, 73%) as a white solid.
4.6.1. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2,2,2-trichloroaceta-
mido)-b-D-glucopyranosyl-(1!5)-3,4-di-O-acetyl-2,6-
anhydro-7-bromo-7-deoxy-D-glycero-L-galacto-heptona-
mide (9c). [a]D23¼þ61.54 (c 0.13, CH2Cl2). Rf: 0.44
(petroleum ether–CHCl –EtOH 5:2:2). IR (KBr): n¼
˜
3
1043, 1234, 1749, 3558 cm21
.
1H NMR (H,H COSY,
400 MHz, pyridine-d5): d¼2.01, 2.02, 2.05, 2.13, 2.21 (5s,
15H, 5£CH3COO), 4.05 (m, 1H, 5E-H), 4.15 (dd, 1H, 7F-H,
J¼3.3, 11.7 Hz), 4.27 (m, 1H, 2E-H), 4.43–4.47 (m, 2H,
CH2-6E), 4.54 (dd, 1H, 7F-H0, J,1, 11.7 Hz), 4.90 (m, 1H,
5F-H), 5.07 (m, 1H, 6F-H), 5.09 (d, 1H, 2F-H, J¼1.5 Hz),
5.52 (dd, 1H, 4E-H, J¼9.2, 9.9 Hz), 5.77 (d, 1H, 1E-H,
J¼8.1 Hz), 5.87 (dd, 1H, 4F-H, J¼3.6, 10.6 Hz), 6.20 (dd,
1H, 3E-H, J¼9.2, 10.6 Hz), 6.57 (dd, 1H, 3F-H, J¼1.5,
3.6 Hz), 8.02, 8.84 (2s, 2H, H2NCO), 10.67 (d, 1H,
NHCOCCl3, J¼7.7 Hz). 13C NMR (APT, HMQC, HMBC,
100 MHz, pyridine-d5): d¼20.04, 20.08, 20.12, 20.26, 20.94
(2, 5£CH3COO), 29.45 (þ, C-7F), 57.24 (2, C-2E), 62.20
(þ, C-6E), 69.52 (2, C-4E), 69.77 (2, C-3F), 70.22 (2,
C-4F), 70.94 (2, C-2F), 71.38 (2, C-3E), 72.24 (2, C-5E),
75.04 (2, C-5F), 76.79 (2, C-6F), 93.00 (þ, NHCOCCl3),
100.85 (2, C-1E), 162.67, 169.44, 169.84, 169.90,
169.98, 170.08 (þ, 5£CH3COO, NHCOCCl3, H2NCO).
C25H32BrCl3N2O15 (786.80, 784.00), ESI MS: m/z
calculated [MþNa]þ 806.99439, found 806.99427.
4.7.2. 2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-b-D-gluco-
pyranosyl-(1!5)-3-O-acetyl-2,6-anhydro-7-bromo-4-O-
carbamoyl-7-deoxy-D-glycero-L-galacto-heptonamide
(9a). A solution of 6a (0.040 g, 0.054 mmol) and NaBH4
(0.002 g, 1.0 equiv.; 0.054 mmol) in dry ethanol (10 mL)
was stirred at 08C for 48 h, after which TLC (petroleum
ether–CHCl3–EtOH 5:2:2) showed no reaction. The
temperature was then raised to rt, and the solution was
stirred for further 17 h. The solution was diluted with dry
EtOH (6 mL), cooled to 08C and neutralized with dry acetic
acid. The solution was coevaporated with MeOH (2£2 mL).
The crude product was dissolved in dry pyridine (10 mL),
and stirred overnight with Ac2O (3 mL). The solution was
coevaporated with toluene, and the residue was purified by
FC eluting with petroleum ether–CHCl3–EtOH (8:2:2)
furnishing 9a (0.015 g, 42%) and 9b (0.017 g, 46%) as
white solids. Rf: 0.12 (petroleum ether–CHCl3–EtOH
5:2:2). 1H NMR (H,H COSY, 400 MHz, pyridine-d5):
d¼1.99, 2.00, 2.06, 2.07, 2.16 (5s, 15H, 4£CH3COO,
NHCOCH3), 4.00 (m, 1H, 5E-H), 4.08 (m, 1H, 2E-H),
4.7. Attempted conversion of 7e into 10 by NaBH4
reduction and acetylation
A solution of 7e (0.025 g, 0.034 mmol) and NaBH4

8450
K. Abu Ajaj et al. / Tetrahedron 58 (2002) 8439–8451
4.14–4.18 (m, 2H, CH2-7F), 4.40–4.45 (m, 2H, CH2-6E),
4.76 (dd, 1H, 5F-H, J¼6.4, 10.8 Hz), 4.97 (m, 1H, 6F-H),
5.07 (d, 1H, 2F-H, J¼1.5 Hz), 5.43 (dd, 1H, 4E-H, J¼9.1,
10.2 Hz), 5.70 (d, 1H, 1E-H, J¼8.2 Hz), 5.93 (dd, 1H, 4F-H,
J¼3.2, 11.0 Hz), 6.20 (dd, 1H, 3E-H, J¼9.1, 10.8 Hz), 6.65
(dd, 1H, 3F-H, J¼1.5, 3.2 Hz), 7.70 (bs, 2H, H2NCOO),
7.90, 8.60 (2s, 2H, H2NCO), 9.31 (d, 1H, NHCOCH3,
J¼7.8 Hz). 13C NMR (APT, HMQC, 100 MHz, pyridine-
d5): d¼20.60, 20.71, 20.95 (2, 4£CH3COO), 23.29 (þ,
NHCOCH3), 29.92 (þ, C-7F), 56.34 (2, C-2E), 62.53 (þ,
C-6E), 69.73, 69.87 (2, C-4F, C-4E), 70.32 (2, C-3F), 71.32
(2, C-5F), 71.96 (2, C-2F), 72.46 (2, C-5E), 76.66 (2,
C-3E), 77.01 (2, C-6F), 102.09 (2, C-1E), 157.08 (þ,
H2NCOO), 169.51, 169.89, 170.11, 170.40, 170.50, 171.01
(2, 4£CH3COO, NHCOCH3, H2NCO). C24H34BrN3O15
(684.45, 683.12), ESI MS: m/z calculated [MþNa]þ
706.106551, found 706.10766.
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pyranosyl-(1!5)-3,4-di-O-acetyl-2,6-anhydro-7-deoxy-
7-(diethoxyphosphoryl)-D-glycero-L-galacto-heptona-
mide (9d). Compound 9c (0.010 g, 0.015 mmol) was
dissolved in degassed triethyl phosphite (5 mL) and heated
overnight in an oil bath to 1808C, while purging the solution
with an argon stream. The solution was cooled, and triethyl
phosphite was coevaporated with toluene under reduced
pressure. FC eluting with petroleum ether–CHCl3–EtOH
(8:2:2) gave 9d (0.007 g, 70%) as a white solid. Rf: 0.19
9. Stembera, K.; Vogel, S.; Buchynskyy, A.; Ayala, J. A.;
Welzel, P. ChemBioChem 2002, 3, 559–565.
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11. Lo, M.-C.; Helm, J. S.; Sarngadharan, G.; Pelczer, I.; Walker,
S. J. Am. Chem. Soc. 2001, 123, 8640–8641, and references
therein.
(petroleum ether–CHCl –EtOH 5:2:2). IR (KBr): n¼1236,
˜
3
1747, 3437 cm21
.
1H NMR (H,H COSY, 600 MHz,
pyridine-d5): d¼1.22 (t, 3H, POCH2CH3, J¼7.0 Hz), 1.26
(t, 3H, POCH2CH3, J¼7.0 Hz), 2.00, 2.03, 2.04, 2.08, 2.11,
2.19 (6s, 18H, 5£CH3COO; NHCOCH3), 2.69 (m, 1H,
7F-H), 3.06 (m, 1H, 7F-H0), 4.03 (m, 1H, 5E-H), 4.06 (m, 1H,
2E-H), 4.17–4.22 (m, 4H, PO(OCH2CH3)2), 4.39 (dd, 1H,
6E-H, J¼2.4, 12.2 Hz), 4.53 (dd, 1H, 6E-H0, J¼4.4,
12.2 Hz), 4.75 (m, 1H, 5F-H), 5.16 (m, 1H, 2F-H, partially
hidden by the water signal), 5.34 (m, 1H, 6F-H), 5.45 (t, 1H,
4E-H, J¼9.7 Hz), 5.68 (d, 1H, 1E-H, J¼8.4 Hz), 5.89 (dd,
1H, 4F-H, J¼3.3, 9.9 Hz), 6.11 (t, 1H, 3E-H, J¼9.8 Hz),
6.48 (m, 1H, 3F-H), 8.22, 8.62 (2s, 2H, H2NCO), 9.36 (d,
1H, NHCOCH3, J¼8.1 Hz). 13C NMR (50 MHz, pyridine-
12. Breukink, E.; Wiedemann, I.; van Kraaij, C.; Kuipers, O. P.;
Sahl, H.-G.; de Kruijff, B. Science 1999, 286, 2361–2364.
13. Vogel, S.; Bychynskyy, A.; Stembera, K.; Richter, K.; Hennig,
L.; Mu¨ller, D.; Welzel, P.; Maquin, F.; Bonhomme, C.;
Lampilas, M. Bioorg. Med. Chem. Lett. 2000, 10, 1963–1965,
and references therein.
14. Sun, B.; Chen, Z.; Eggert, U. S.; Shaw, S. J.; LaTour, J. V.;
Kahne, D. J. Am. Chem. Soc. 2001, 123, 12722–12723, and
references therein.
15. El-Abadla, N.; Lampilas, M.; Hennig, L.; Findeisen, M.;
Welzel, P.; Mu¨ller, D.; Markus, A.; van Heijenoort, J.
Tetrahedron 1999, 55, 699–722, and references therein.
16. Ritzeler, O.; Hennig, L.; Findeisen, M.; Welzel, P.; Mu¨ller, D.;
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Tetrahedron 1997, 53, 1675–1694.
3
d5): d¼16.44 (d, CH3CH2OP, JC,P¼6.1 Hz), 16.51 (d,
3
CH3CH2OP, JC,P¼6.1 Hz), 20.45, 20.52, 20.61, 20.61,
20.94 (5£CH3COO), 23.16 (NHCOCH3), 26.98 (C-7F),
2
56.20 (C-2E), 61.59 (d, CH3CH2OP, JC,P¼6.5 Hz), 61.91
17. Kosmol, R.; Hennig, L.; Welzel, P.; Findeisen, M.; Mu¨ller, D.;
Markus, A.; van Heijenoort, J. J. Prakt. Chem. 1997, 339,
340–358, and references therein.
(d, CH3CH2OP, 2JC,P¼6.5 Hz), 62.57 (C-6E), 69.54, 70.58,
71.80, 72.03, 72.54 (probably more than one signal), 75.67,
75.96, 101.85 (C-1E), 169.84, 170.21, 170.27, 170.44,
170.47, 170.60 (5£CH3COO, NHCOCH3, H2NCO). 31P
NMR (121 MHz, pyridine-d5): d¼27.94. C29H45N2O18P
(740.65, 740.24), FAB MS: m/z 741.2 [MþH]þ, 763.2
[MþNa]þ, ESI MS: m/z [MþH]þ (calculated 741.24778,
found 741.24687), [MþNa]þ (calculated 763.22972, found
763.22925).
18. For a recent review on transgylcosylase inhibition, see Ref. 10.
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