Interhalogens (ICl/IBr) and AgOTf in thioglycoside activation; synthesis of bislactam analogues of ganglioside GD3

Article abstract of DOI:10.1021/jo049184g

The novel promoter system IX/AgOTf (X = Cl or Br) has been evaluated in the synthesis of two bislactam analogues of GD3. We have carried out two high-yielding galactosylations in 97% and 98% yield, respectively, using ICl/AgOTf, and four sialylations in 9

Full text of DOI:10.1021/jo049184g

In ter h a logen s (ICl/IBr ) a n d AgOTf in Th ioglycosid e Activa tion ;
Syn th esis of Bisla cta m An a logu es of Ga n gliosid e GD3
Andre´as Meijer and Ulf Ellervik*
Organic and Bioorganic Chemistry, Center for Chemistry and Chemical Engineering, Lund University,
P.O. Box 124, SE-221 00 Lund, Sweden
ulf.ellervik@bioorganic.lth.se
Received May 14, 2004
The novel promoter system IX/AgOTf (X ) Cl or Br) has been evaluated in the synthesis of two
bislactam analogues of GD3. We have carried out two high-yielding galactosylations in 97% and
98% yield, respectively, using ICl/AgOTf, and four sialylations in 93%, 59%, 40%, and 44% yield,
using IBr/AgOTf. The choice of interhalogen (IX) is determined by the donor type used in the
glycosylation. We also report some mechanistic investigations leading to further optimization of
the IX/AgOTf promoter system.
In tr od u ction
ganglioside has been used to immunize patients, and it
was concluded that the lactonized form is a stronger
immunogen than the open form.5 The need for hydrolyti-
cally stable analogues of ganglioside lactones has led to
the synthesis of lactam analogues.
The lactam functionality is more hydrolytically stable
and the structural similarities of lactones and lactams
have been shown using both computational methods and
NMR investigations.6,7 The monolactam analogues of
GM2, GM3, GM4, and GD3 have been synthesized
earlier,8,9 and we now present a synthesis of bislactam
analogues of GD3.
The naturally occurring GD3 can form several different
lactones. The carboxylic acid functionality of the terminal
sialic acid residue readily forms a 1-9 lactone,6 whereas
the carboxylic acid functionality of the nonterminal sialic
acid residue is capable of forming both a 1-2 as well as a
1-4 lactone.10 The two possible bislactam analogues cho-
sen as target compounds were the 1′′-2′,1′′′-9′′ bislactam
1 and 1′′-4′,1′′′-9′′ bislactam 2 (Figure 1). A retrosynthetic
analysis of the target compounds led us to a convergent
block synthesis approach, where three building blocks,
3, 4, and 5, are formed from monosaccharide fragments
6,11 7, 8,12 9, and 1012 (Figure 1). The stereoselective
construction of the R(2-8) bis-sialo bond is notoriously
difficult, and several strategies have emerged.9,13 The
most recent application exchanges the acetamido func-
tionality of the sialic acid donor and acceptor for a
O-Glycosides are biologically significant as, for ex-
ample, tumor-associated antigens and receptors for vari-
ous bacterial and viral pathogens. Consequently, numer-
ous methods of O-glycosylation have been developed,1 of
which thioglycoside methodology is one of the most
versatile and widespread. In short, such methodology
employs a thioglycoside donor that is activated in the
presence of a thiophilic agent, generated by a promoter
system. We have recently introduced interhalogens (i.e.,
ICl and IBr) in combination with silver trifluoromethane-
sulfonate as promoter systems for thioglycoside activa-
tion.2,3 We showed that ICl/AgOTf works well for glyco-
sylations with donors carrying a participating group next
to the anomeric center, whereas IBr/AgOTf is superior
for donors not carrying any participating group (e.g.,
sialic acid donors).
We now report the synthesis of two ganglioside bis-
lactam analogues assembled using a combination of the
two promoter systems, vide supra, and present IX/AgOTf
as a general promoter system in oligosaccharide synthe-
sis. We also report some mechanistic investigations
leading to further optimization of the IX/AgOTf promoter
system.
Gangliosides are considered to be potent tumor immu-
nogens, and several ganglioside derivatives have been
evaluated in various studies.4 Because gangliosides are
hydroxy-carboxylic acids, they form lactones on treatment
with acids. Lactonization changes the overall three-
dimensional shape of the ganglioside in a dramatic way.
However, immunizations using lactonized gangliosides
as antigen will result in antibodies of low specificity as
a result of the hydrolytical instability of the lactone.
Despite its instability, the corresponding lactone of a
(5) Ragupathi, G.; Meyers, M.; Adluri, S.; Howard, L.; Musselli, C.;
Livingston, P. O. Int. J . Cancer 2000, 85, 659.
(6) Ercegovic, T.; Magnusson, G. J . Org. Chem. 1996, 61, 179.
(7) Ray, A. K.; Nilsson, U.; Magnusson, G. J . Am. Chem. Soc. 1992,
114, 2256.
(8) Wilstermann, M.; Kononov, L. O.; Nilsson, U.; Ray, A. K.;
Magnusson, G. J . Am. Chem. Soc. 1995, 117, 4742.
(9) Hossain, N.; Zapata, A.; Wilstermann, M.; Nilsson, U. J .;
Magnusson, G. Carbohydr. Res. 2002, 337, 569.
(10) Ellervik, U.; Grundberg. H.; Magnusson, G. J . Org. Chem. 1998,
63, 9323.
(1) Davies, B. G. J . J . Chem. Soc., Perkin Trans. 1 2000, 14, 2137.
(2) Ercegovic, T.; Meijer, A.; Ellervik, U.; Magnusson, G. Org. Lett.
2001, 3, 913.
(11) Komba, S.; Yamaguchi, M.; Ishida, H.; Kiso, M. Biol. Chem.
2001, 382, 233.
(3) Meijer, A.; Ellervik, U. J . Org. Chem. 2002, 67, 7407.
(4) Bitton, R. J .; Guthmann, M. D.; Gabri, M. R.; Carnero, A. J . L.;
Alonso, D. F.; Fainboim, L.; Gomez, D. E. Oncol. Rep. 2002, 9, 267.
(12) Ellervik, U.; Magnusson, G. J . Org. Chem. 1998, 63, 9314.
(13) Castro-Palomino, J . C.; Simon, B.; Speer, O.; Leist, M.; Schmidt,
R. R. Chem. Eur. J . 2001, 7, 2178.
10.1021/jo049184g CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/18/2004
J . Org. Chem. 2004, 69, 6249-6256
6249

Meijer and Ellervik
F IGURE 1. Retrosynthetic analysis of the synthesis of GD3 bislactam analogues using the IX/AgOTf promoter system.
SCHEME 1 a
F IGURE 2. Formation of dehydroimidazole byproduct by
reaction with acetonitrile.
SCHEME 2 a
a
Reaction conditions: (i) BnBr, NaH, DMF; (ii) NaBH3CN, HCl,
THF.
trifluoroacetamido group, which will ensure a stereose-
lective formation of the R(2-8) bond in high yields.14 The
TFA groups are removed at the end of the synthesis using
mild conditions, and we therefore used this procedure.
Resu lts a n d Discu ssion
Glucose acceptor 9 was synthesized by benzylation,
using standard reaction conditions, followed by regiose-
lective opening of the benzylidene acetal of the known
compound 1115 (Scheme 1).
The first attempts to construct the 2′-deoxy-2′-amino-
lactose building block by glycosylation of acceptor 9 with
Troc donor 8 under standard reaction conditions1 gave
only low yields (approximate 50%). After careful purifica-
tion of the reaction products, a dehydroimidazole com-
pound 15 was isolated in various yields, approximately
40% (Figure 2). Apparently the activated donor reacted
with the solvent, thus trapping the intermediate â-nitri-
lium ion by an attack of the carbamate nitrogen, forming
the dehydroimidazole 15. When acetonitrile was left out,
and the reaction was performed in neat dichloromethane,
the yield rose to an excellent 97% (Scheme 2).16
a
Reaction conditions: (i) 1.5 equiv of donor, ICl/AgOTf, CH2Cl2,
-45 °C; (ii) 13: guanidinium nitrate/NaOMe/MeOH, 14: NaOMe/
MeOH.
yield. The 4′-deoxy-4′-amino-lactose building block was
constructed by glycosylation of acceptor 9 with the azide
donor 10 in an excellent 98% yield, using ICl/AgOTf in
neat dichloromethane. The disaccharide 14 was de-O-
acetylated using NaOMe in MeOH to give acceptor 5 in
90% yield.
Disaccharide 13 was then de-O-acetylated using a
guanidinium nitrate buffer17 to give acceptor 4 in 75%
(14) De Meo, C.; Demchenko, A.; Boons, G. J . J . Org. Chem. 2001,
66, 5490.
(15) Nitz, M.; Bundle, D. J . Org. Chem. 2000, 65, 3064.
6250 J . Org. Chem., Vol. 69, No. 19, 2004

Bislactam Analogs of Ganglioside GD3
F IGURE 3. Graph illustrating the substoichiometric need of
iodine monochloride in the glycosylation reaction between 8
and 9.
During the investigations leading to the interhalogen
promoter systems we have been able to isolate disulfides
of the corresponding donor aglycons in the reaction
mixtures.3 This indicates that an electrophilic sulfur
species is present in the reaction mixture.18 We postulate
that the species responsible are the sulfenyl iodides
formed from the reaction between the iodonium ion (from
IX/AgOTf) and the thio donor.19 Thus, the role of the
sulfur leaving group is not only to be reactive enough to
be activated by the thiophilic species but also to form a
“second” thiophilic species in the reaction mixture.
To investigate these thiophilic species, we performed
the high yielding glycosylation of acceptor 9 and donor 8
(Scheme 2) using substoichiometric amounts of ICl,
together with unimolecular amounts of acceptor, donor,
and AgOTf. Several small-scale reactions were run and
then quenched with diisopropylamine and cyclohexene
at various time intervals, after which the conversion of
donor into product was determined by NMR, using the
pMP group as an internal standard.
F IGURE 4. Proposed mechanistic scheme describing the
reaction pathway of an IX/AgOTf-promoted thioglycoside
activation.
SCHEME 3 a
A graph was constructed illustrating the substoicho-
metric need of ICl for complete conversion of donor 8 into
product 13 (Figure 3). Apparently only 0.5 equiv of ICl
are necessary for complete activation, and 0.25 equiv of
ICl result in almost 50% conversion. These results
indicate that 1 equiv of ICl together with 2 equiv of
AgOTf can activate 2 equiv of donor.
a
Reaction conditions: (i) Me3Si(CH2)2OH, IBr/AgOTf, CH3CN,
-40 °C, 1 h; (ii) NaOMe/MeOH; (iii) acetone, 2,2-dimethoxypro-
pane, pTSA, 30 min; (iv) (a) pyridine, BzCl, 0 °C, 30 min, (b) HOAc,
MeOH, reflux 2 h; (v) (a) TsCl, CH2Cl2, pyridine, 16 h, (b) NaN3,
DMF, 60 °C, 20 h.
We suggest that interhalogens and silver triflate
activate thioglycosides according to the mechanistic
scheme found in Figure 4. The interhalogen forms an
activated complex, depicted as an iodonium ion in Figure
4, with the silver ion, which then reacts with a thiogly-
coside A forming an activated complex B. This reactive
complex then collapses into an oxocarbenium ion C,
which can react with an acceptor to form product, and a
sulfenyl iodide compound. The latter can be activated by
a second silver ion, forming a reactive sulfonium ion
species, which can activate a second thioglycoside A,
forming the reactive intermediate D. This reactive com-
plex collapses into an oxocarbenium ion C and a disulfide.
Because of the lesser reactivity of the sulfonium species
compared to that of the iodonium species, there will be
an accumulation of sulfenyl iodide when equimolar
amounts of interhalogen is used. The lower reactivity of
the sulfonium ion has consequences for unreactive do-
nors. When performing sialylations using donor 6 (Scheme
3) a substoichiometric amount of IBr failed to activate
all donor.20 The more reactive galactosyl donors 8 and 9
were both activated by 0.5 equiv of ICl.21
The mechanistic scheme in Figure 4 explains the
presence of disulfides in the reaction mixture, as well as
the substoichiometric need of interhalogen for complete
activation. A similar reaction pathway has recently been
(16) Because AgOTf is poorly soluble in dichloromethane it was
anticipated that the reaction would form large amounts of galactosyl
chloride, which is formed when the reaction is run in the absence of
AgOTf; however, no chloride derivatives were found.
(17) Ellervik, U.; Magnusson, G. Tetrahedron Lett. 1997, 38, 1627.
(18) Martichonok, V.; Whitesides, G. M. J . Org. Chem. 1996, 61,
1702.
(20) The low reactivity of donor 6 is due to the electron-withdrawing
trifluoroacetyl group (TFA) on the C-5 nitrogen.
(21) For a compilation of the reactivity of thioglycosides, see: (a)
Zhang, Z.; Ollmann, I. R.; Ye, X.; Wischnat, R.; Baasov, T.; Wong, C.
H. J . Am. Chem. Soc. 1999, 121, 734. (b) Yu, C. S.; Niikura, K.; Lin,
C. C.: Wong, C. H. Angew. Chem., Int. Ed. 2001, 40, 2900.
(19) Veeneman, G. H.; Van Leuwen, S. H.; Van Boom, J . H.
Tetrahedron Lett. 1990, 31, 1331.
J . Org. Chem, Vol. 69, No. 19, 2004 6251

Meijer and Ellervik
SCHEME 4 a
reported by Wong, where a substoichometric amount of
promoter was used to activate thioglycosides using both
a BSP/Tf2O promoter protocol22 and a modified NIS-
TfOH-AgOTf 23 system, indicating the generality of the
reaction pathway in Figure 4.
In the synthesis of the bis-sialic acid fragment we used
the TFA methodology,14 where a TFA-protected amide
functionality will ensure high stereoselectivity and yield
in the formation of the notoriously difficult R(2-8) bis-
sialic acid bond. A temporary anomeric protecting group
was introduced, using an improved procedure with IBr
and AgOTf as promoter system, to give an inseparable
mixture (R: â 88:12) of compound 1614 (Scheme 3).24
Compound 16 was then de-O-acetylated using standard
procedures to give compound 17,14 which was used
without purification in the next step. The introduction
of the azide functionality at the 9-position was more
problematic than anticipated. Erce´govic5 has previously
been able to selectively tosylate the 9-hydroxyl of the
acetamide analogue of compound 17 in an excellent yield
of 91%. When the same reaction was performed on tetraol
17, the reaction was too slow to be of practical value. The
selectivity was also poor; the 4-hydroxyl and 9-hydroxyl
seemed to be equally reactive, resulting in a reaction
mixture consisting of unreacted 17 together with the
products of mono- and bistosylation of the 4- and 9-hy-
droxyl groups. Increasing the reaction temperature and
changing the solvent improved the reactivity and selec-
tivity somewhat, but not enough to make the procedure
a viable route to 7.
Because the 4- and 9-hydroxyl groups are almost
equally reactive, we decided to use an acetal to selectively
protect the 9-hydroxyl.14,25 Compound 17 was treated
with 2,2-dimethoxypropane in acetone under acidic con-
ditions to give the isopropylidene-protected sialoside. At
this point the diastereomeric mixture obtained when
introducing the anomeric protective group could be
separated to give 18 as a pure R-anomer in excellent 78%
yield. The 4-hydroxyl group was then selectively benzoyl-
ated using 1.2 equiv of benzoyl chloride in pyridine at 0
°C, and then the isopropylidene acetal was removed by
refluxing in methanol and acetic acid to give compound
19 in 87% yield. The 7-hydroxyl group was deliberately
left unprotected because it has been shown that acetate
groups at the C-7 position are prone to migrate to the
C-8 position under azide substitution conditions.6 It was
also shown that the 7-hydroxyl group is of such low
reactivity that the 7,8-diol will selectively be sialylated
at the 8-hydroxyl. With the reactive 4-hydroxyl group
protected as a benzoate, the selective tosylation proceeded
in high yield even with 5 equiv of tosyl chloride in
dichloromethane and pyridine at room temperature for
16 h. The crude tosylation mixture was subjected to
sodium azide in DMF to give acceptor 7 in 78% yield.
a
Reaction conditions: (i) 3 equiv of donor, IBr/AgOTf, CH2Cl2,
CH3CN, -72 °C; (ii) Ph3P, THF, H2O; (iii) (a) TFA, CH2Cl2, (b)
pyridine, Ac2O; (iv) PhSH, CH2Cl2, BF3‚OEt2.
Acceptor 7 was then sialylated with 3 equiv of donor
6, using IBr and AgOTf as promoter system, to form
disialoside 20 in an excellent yield of 59%, as a single
diastereomer (Scheme 4). The high yield and excellent
stereoselectivity are attributed to the TFA groups of both
the donor and the acceptor. Compound 20 was subjected
to triphenylphosphine in THF and water at 60 °C to form
lactam 21 in 86% yield.
The anomeric protective group of lactam 21 was then
converted to thioglycoside 326 (R:â 84:16) via the acetate
22.
Sialylation of Troc acceptor 4 with donor 3 gave
tetrasaccharide 23 in a yield of 40% as a single diaster-
eomer (Scheme 5). Sialylation of azide acceptor 5 with
donor 3 gave tetrasaccharide 24 in a slightly higher yield
of 44% as a single diastereomer. The benzyl groups of
tetrasaccharide 24 were removed by hydrogenolysis using
Pd/C. The azide group was at the same time reduced to
the free amine, which spontaneously formed the lactam
according to MALDI-TOF mass analysis. The N-TFA
groups were transformed into N-acetates, and the ester
groups were deprotected by treatment with NaOMe at
50 °C27 followed by acetylation to give bislactam 2 in 74%
yield. The Troc-protected tetrasaccharide 23 was soni-
cated with activated zinc to give the free amine,28 which
lactamized upon addition of triethylamine according to
NMR and MALDI-TOF analysis. The bislactam inter-
mediate was then deprotected by hydrogenolysis, basic
solvolysis, and acetylation using same procedures as
(22) Mong, T. K. K.; Lee, H. K.; Duron, S. G.; Wong, C. H. Proc.
Natl. Acad. Sci. U.S.A. 2003, 100, 797.
(23) Zhang, Z.; Niikura, K.; Huang, X. F.; Wong, C. H. Can. J . Chem.
2002, 80, 1051.
(24) The yield of compound 16 is lowered when the reaction is
performed at larger scale. The upscaling problems of this reaction are
related to the acid lability of sialoside 16. Apparently the molecular
sieves are crucial for the neutralization of formed acid. However, due
to the heterogeneous nature of the molecular sieves, the neutralization
is sensitive to the stirring efficiency.
(26) The anomeric mixture could be separated using flash cromatog-
raphy, but since the two diastereomers showed equal reactivity, the
anomeric mixture was used in the following sialylation reactions.
(27) Otsubo, N.; Ishida, H.; Kiso, M. Carbohydr. Res. 2001, 330, 1.
(28) Zhu, X.; Schmidt, R. R. Synthesis 2003, 1262.
(25) von Itzstein, M.; Thomson, R. J . Top. Curr. Chem. 1997, 186,
119.
6252 J . Org. Chem., Vol. 69, No. 19, 2004

Bislactam Analogs of Ganglioside GD3
SCHEME 5 a
first on a Sephadex (LH-20, MeOH/CH2Cl2 1:1) column and
after concentration on a C-18 plug (H2O/MeCN gradient) to
1
give bislactam 1 (3.5 mg, 33%). [R]22 -19° (c 0.3, MeOH). H
D
NMR (MeOD) δ 6.98-6.90 (m, 2H), 6.76-6.70 (m, 2H), 4.73
(d, 1H, J ) 7.8), 4.55 (d, 1H, J ) 8.0), 4.37-4.24 (m, 2H), 4.01-
3.88 (m, 3H), 3.83 (d, 1H, J ) 1.0), 3.77-3.30 (m, 20H), 3.65
(s, 3H), 2.47 (dd, 1H, J ) 5.4, 13.0), 2.37 (dd, 1H, J ) 5.3,
13.0), 1.92, 1.91 (s, 3H each), 1.56-1.39 (m, 2H). 13C NMR
(MeOD) δ 174.4, 167.8, 151.8, 118.2, 114.2, 102.0, 98.1, 97.4,
80.9, 78.4, 76.6, 74.2, 73.7, 73.2, 72.3, 71.5, 71.0, 70.6, 68.8,
68.1, 66.0, 64.1, 62.2, 61.2, 54.8, 53.2, 52.4, 50.3, 42.1, 40.5,
21.5, 21.4. HRMS calcd for C41H60N4O24Na (M + Na) 1015.3495,
found 1015.3493.
4-Meth oxyp h en yl (3,5-Did eoxy-5-a ceta m id o-D-glycer o-
r-D-ga la cto-n on -2-u lop yr a n osyl)-(2f8)-[(9-a m in o-3,5,9-
tr id eoxy-5-a ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop y-
r a n o s y l)o n a t e ]-(2f3)-(4-a m in o -4-d e o x y -â-D -g a la c t o -
p yr a n osyl)-(1f4)-â-D-glu cop yr a n osid e (1′′′ -9′′)-(1′′- 4′)-
bisla cta m (2). Compound 24 (10 mg, 0.0055 mmol) was
dissolved in MeOH (0.7 mL), and Pd/C (30 mg) was added.
The mixture was pressurized (1000 psi) with hydrogen gas for
4 h. The residue was filtered on Celite and concentrated to
give the bislactam intermediate according to MALDI-TOF. The
mixture was dissolved in MeOH (2 mL), and NaOMe (1 M,
0.1 mL) was added dropwise. The mixture was heated at 50
°C in a sealed vessel for 48 h and then neutralized with
Amberlite IR 120 H+. After filtration and concentration the
residue was dissolved in a mixture of MeOH/H2O/Ac2O (2.8:
0.8:0.6 mL), stirred for 2 h, and then concentrated with
toluene. The residue was purified first on a Sephadex column
(LH-20, MeOH/CH2Cl2 1:1) and after concentration on a C-18
column (H2O/MeCN gradient) to give bislactam 2 (4 mg, 74%).
[R]21 -28° (c 0.1, MeOH). 1H NMR (MeOD) δ 7.05-7.00 (m,
2H), 6.85-6.80 (m, 2H), 4.80 (d, 1H, J ) 7.8), 4.46 (d, 1H, J )
7.9), 4.24-4.13 (m, 2H), 4.31 (dd, 1H, J ) 1.0, 4.8), 3.86-3.77
(m, 2H), 3.69 (d, 2H, J ) 2.9), 3.65 (d, 2H, J ) 3.5), 3.62-3.20
(m, 17H), 3.54 (s, 3H), 2.32 (dd, 1H, J ) 5.5, 12.8), 2.26 (dd,
1H, J ) 5.3, 12.8), 1.81 (s, 6H), 1,46 (t, 1H, J ) 11.2), 1.29 (t,
1H, J ) 11.4). 13C NMR (MeOD) δ 173.8, 173.5, 154.8, 151.1,
117.3, 113.5, 101.3, 96.8, 96.7, 78.0, 74.6, 74.3, 72.8, 72.6, 71.5,
70.6, 70.5, 69.7, 69.4, 67.6, 66.9, 63.3, 61.6, 54.1, 52.3, 51.8,
50.2, 39.6, 39.5, 20.7, 20.6. HRMS calcd for C41H60N4O24Na (M
+ Na) 1015.3495, found 1015.3495.
a
Reaction conditions: (i) 1 equiv of donor, IBr/AgOTf, CH2Cl2,
CH3CN, -72 °C; (ii) Zn, HOAc; (iii) H2, Pd/C; (iv) NaOMe/MeOH,
50 °C; (v) Ac2O/MeOH/H2O.
above to give bislactam 1 in 33% yield. Surprisingly, the
acetylation leading to compound 1 took 4 days compared
to the acetylation leading to compound 2, which took less
than 2 h.29 One reason for this large difference in reaction
time might be that the tetrasaccharide is folding so that
the free amine is hidden within the molecule.
Con clu sion s
We have for the first time been able to synthesize two
GD3 bislactam analogues using a novel interhalogen
promoter system strategy where the choice of either ICl
or IBr is determined by the donor structure. We have
carried out two high-yielding galactosylations in 97% and
98% yield, respectively, using ICl/AgOTf and four sialy-
lations in 93%, 59%, 40%, and 44% yield using IBr/
AgOTf.
Meth yl [(4,7,8,9-Tetr a -O-a cetyl-3,5-d id eoxy-5-tr iflu o-
r oa ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop yr a n osyl)-
(2f8)-(ph en yl 7-O-acetyl-9-am in o-4-O-ben zoyl-3,5,9-tr ide-
oxy-2-t h io-5-t r iflu or oa cet a m id o-D-glycer o-r-D-ga la cto-
n on -2-u lop yr a n osid e)]on a te 1′-9 La cta m (3r) a n d Meth yl
[(4,7,8,9-Tetr a-O-acetyl-3,5-dideoxy-5-tr iflu or oacetam ido-
D-glycer o-r-D-ga la cto-n on -2-u lop yr a n osyl)-(2f8)-(p h en -
yl 7-O-a cetyl-9-a m in o-4-O-ben zoyl-3,5,9-tr id eoxy-2-th io-
5-t r i flu o r o a c e t a m i d o -D-g l yc er o-â-D-g a l a c t o-n o n -2-
u lop yr a n osid e)]on a te 1′-9 La cta m (3â). Compound 22 (420
mg, 0.396 mmol) was dissolved in CH2Cl2 (7 mL), and then
PhSH (0.12 mL, 1.2 mmol) and BF3‚OEt2 (0.160 mL, 1.2 mmol)
were added. After 18 h the reaction mixture was diluted with
CH2Cl2 and extracted twice with saturated aqueous NaHCO3
and once with water. The organic phase was dried (Na2SO4)
and concentrated. The residue was chromatographed (SiO2,
4:1 f 1:1 toluene/acetone gradient) to give compound 3 (307
mg, 70%) as an anomeric mixture (84:16). The anomers could
be separated (SiO2, 1:1 f 1:3 toluene/EtOAc gradient). Da ta
Exp er im en ta l Section
4-Meth oxyp h en yl (3,5-Did eoxy-5-a ceta m id o-D-glycer o-
r-D-ga la cto-n on -2-u lop yr a n osyl)-(2f8)-[(9-a m in o-3,5,9-
tr id eoxy-5-a ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop y-
r a n o s y l)o n a t e ]-(2f3)-(2-a m in o -2-d e o x y -â-D -g a la c t o -
p yr a n osyl)-(1f4)-â-D-glu cop yr a n osid e (1′′′ -9′′)-(1′′-2′)-
bisla cta m (1). Compound 23 (21 mg, 0.0106 mmol) was
dissolved in HOAc (1.0 mL), and freshly activated Zn10 (200
mg) was added. The mixture was sonicated for 1 h, filtered on
Celite, and concentrated. The residue was dissolved in dichlo-
romethane (2 mL) and triethylamine (0.5 mL) and concen-
trated. The residue was filtered on silica (heptane/EtOAc 1:1)
to give the bislactam according to MALDI-TOF and NMR
analysis. The bislactam was dissolved in MeOH (1.5 mL), and
Pd/C (60 mg) was added. The reaction mixture was pressurized
(1000 psi) with hydrogen gas for 1.5 h, filtered on Celite, and
concentrated. The residue was dissolved in MeOH (2 mL), and
NaOMe/MeOH (0.4 mL, 1 M) was added dropwise. The
reaction mixture was heated in a sealed vessel at 50 °C for 64
h and then neutralized with Amberlite IR 120 H+. After
filtration and concentration the residue was dissolved in a
mixture of MeOH/H2O/Ac2O (2.8:0.8:0.6 mL), stirred for 4 days,
and then concentrated with toluene. The residue was purified
for 3â: [R]21 -34° (c 1.0, CDCl3). 1H NMR (CDCl3) δ 7.96-
D
8.02 (m, 3H), 7.74-7.78 (m, 2H), 7.57-7.63 (m, 1H), 7.42-
7.50 (m, 3H), 7.33-7.41 (m, 3H), 6.72-6.78 (bs, 1H), 5.67 (dt,
1H, J ) 4.4, 11.2), 5.59-5.65 (m, 1H), 5.44 (dt, 1H, J ) 4.8,
11.4), 5.35 (dd, 1H, J ) 2.5, 9.0), 5.31 (dd, 1H, J ) 2.1, 7.8),
5.19 (dd, 1H, J ) 2.4, 10.6), 4.76 (dd, 1H, J ) 2.1, 10.6), 4.37-
4.47 (m, 2H), 4.33 (dd, 1H, J ) 2.6, 12.5), 4.10-4.25 (m, 2H),
3.53 (s, 3H), 3.47-3.52 (m, 1H), 3.37-3.46 (m, 1H), 3.13 (dd,
1H, J ) 4.6, 13.5), 2.49 (dd, 1H, J ) 4.9, 13.1), 2.32 (dd, 1H,
J ) 11.7, 13.4), 2.21, 2.15, 2.08, 2.03, 1.69 (s, 3H each), 2.10-
(29) A MALDI-TOF analysis of the acetylation leading to 1 showed
that one of the two amines was acetylated instantly while the second
required 4 days of reaction time.
J . Org. Chem, Vol. 69, No. 19, 2004 6253

Meijer and Ellervik
2.00 (m, 1H). 13C NMR (CDCl3) δ 172.2, 171.3, 171.1, 171.0,
170.2, 169.4, 167.8 (C-1, J C1-H-3ax ) 2.3),30 166.3, 136.9, 133.9,
130.3, 130.2, 129.4, 129.1, 128.9, 96.5, 90.7, 73.6, 71.2, 70.4,
70.24, 70.20, 69.3, 68.6, 67.7, 63.0, 52.9, 50.7, 49.9, 41.2, 40.0,
39.5, 21.3, 21.2, 21.1, 21.0, 20.3. HRMS calcd for C46H49F6N3O20-
toluene and filtered on a short plug of silica (4:1 toluene/
acetone) to give the crude tosylate intermediate, which was
dissolved in DMF (6 mL). To the stirred solution were added
NaN3 (350 mg, 5.385 mmol) and 18-crown-6 (150 mg, 0.567
mmol). The solution was heated to 60 °C for 20 h, filtered on
a short plug of silica (4:1 toluene/acetone), and concentrated.
The residue was chromatographed (SiO2, 6:1 f 4:1 toluene/
acetone gradient) to give 7 (472 mg, 78%). Lyophilization from
SNa (M + Na) 1132.2432, found 1132.2423. Da ta for 3R: [R]21
D
+3° (c 0.9, CDCl3). 1H NMR (CDCl3) δ 7.84-7.89 (m, 2H),
7.43-7.52 (m, 4H), 7.30-7.38 (m, 3H), 7.23-7.29 (m, 2H),
7.01-7.10 (m, 1H), 6.76-6.84 (bs, 1H), 5.30-5.40 (m, 2H),
5.13-5.25 (m, 2H), 5.01 (d, 1H, J ) 8.7), 4.40 (dd, 1H, J )
3.0, 10.2), 4.35 (dd, 1H, J ) 2.4, 12.5), 4.27 (dt, 1H, J ) 3.7,
8.9), 4.06-4.20 (m, 4H), 3.67 (s, 3H), 3.43-3.50 (m, 1H), 3.25-
3.35 (m, 1H), 3.03 (dd, 1H, J ) 4.7, 12.8), 2.24 (dd, 1H, J )
5.2, 13.3), 2.15, 2.04, 2.02, 1.96, 1.90 (s, 3H each), 2.05-2.00
(m, 1H), 1.75 (t, 1H, J ) 12.5). 13C NMR (CDCl3) δ 171.7, 171.5,
170.9, 170.6, 170.4, 168.3, 168.2, 166.4, 158.5, 158.1, 137.0,
134.0, 130.6, 130.2, 129.3, 129.2, 128.9, 97.5, 87.7, 73.7, 73.1,
71.2, 71.0, 70.5, 70.0, 69.6, 68.8, 62.9, 53.4, 50.4, 49.9, 41.8,
38.5, 38.2, 21.4, 21.2, 21.1, 21.03, 20.98. HRMS calcd for
benzene gave 7 as a white powder. [R]25 -36° (c 1.0, CDCl3).
D
1H NMR (CDCl3) δ 8.03-7.98 (m, 2H), 7.59-7.65 (m, 1H),
7.44-7.50 (m, 2H), 7.36 (d, 1H, J ) 7.9), 5.19-5.28 (m, 1H),
4.15-4.24 (m, 1H), 4.04-4.11 (m, 1H), 3.85-3.95 (m, 1H), 3.82
(d, 1H, J ) 4.0), 3.79 (s, 3H), 3.73-3.79 (m, 1H), 3.67 (d, 1H,
J ) 5.8), 3.64 (dd, 1H, J ) 2.2, 12.9), 3.36-3.55 (m, 3H), 2.87
(dd, 1H, J ) 4.9, 13.0), 2.18 (t, 1H, J ) 12.7), 0.88 (t, 2H, J )
7.8), 0.00 (s, 9H). 13C NMR (CDCl3) δ 169.8, 160.1, 159.8, 134.7,
130.4, 129.2, 98.9, 73.4, 71.0, 69.9, 69.8, 62.9, 54.0, 53.9, 52.6,
37.9, 18.3, -0.9. HRMS calcd for C24H33F3N4O9SiNa (M + Na)
629.1867, found 629.1876.
C
46H49F6N3O20SNa (M + Na) 1132.2432, found 1132.2437.
4-Meth oxyp h en yl (6-O-Ben zyl-2-d eoxy-2-(2,2,2-tr ich lo-
4-Meth oxyp h en yl 2,3,6-Tr i-O-ben zyl-â-D-glu cop yr a n o-
sid e (9). To a slurry of compound 12 (2.95 g, 5.3 mmol) in
THF (75 mL) at 0 °C were added molecular sieves (6 g, 3Å,
activated) and NaBH3CN (4.65 g). An ice-cold saturated
solution of HCl in Et2O was slowly added until the pH reached
2. After 2 h the reaction mixture was filtered (Celite) and
rinsed with CH2Cl2. The filtrate was washed with saturated
aqueous NaHCO3, water, and brine and then concentrated.
The residue was chromatographed (SiO2, 3:1 f 1:1 heptane/
EtOAc gradient) to give compound 9 (2.60 g, 88%). [R]23D -15°
r oet h oxyca r b on yla m in o)-â-D-ga la ct op yr a n osyl)-(1f4)-
2,3,6-tr i-O-ben zyl-â-D-glu cop yr a n osid e (4). Compound 13
(300 mg) was dissolved in 16 mL of guanidine solution31 at
room temperature. After 20 min the reaction was neutralized
with Amberlyst IR-120-H+ and concentrated. Column purifica-
tion (SiO2, 3:1 f 1:1 heptane/EtOAc gradient) gave 4 (207 mg,
1
75%). [R]21 -2° (c 1.0, CDCl3). H NMR (CDCl3) δ 7.22-7.45
D
(m, 20H), 6.99-7.04 (m, 2H), 6.84-6.90 (m, 2H), 5.32-5.41
(bs, 1H), 5.00, 4.83 (ABq, 1H each, J ) 11.2), 5.00, 4.82 (ABq,
1H each, J ) 10.9), 4.86-4.90 (m, 1H), 4.77 (s, 2H), 4.74, 4.59
(ABq, 1H each, J ) 12.0), 4.43, 4.36 (ABq, 1H each, J ) 12.0),
4.38 (d, 1H, J ) 8.0), 3.90-4.01 (m, 2H), 3.80-3.85 (m, 1H),
3.83 (s, 3H), 3.35-3.75 (m, 10H), 2.65 (d, 1H, J ) 3.5). 13C
NMR (CDCl3) δ 155.8, 151.8, 139.6, 138.7, 129.4, 129.2, 128.9,
128.8, 128.6, 128.2, 128.12, 128.07, 128.0, 127.7, 118.9, 115.0,
103.2, 101.0, 95.4, 83.0, 82.1, 75.7, 75.5, 75.2, 74.4, 74.3, 74.0,
73.5, 69.5, 69.1, 68.5, 56.6, 56.1. HRMS calcd for C50H54Cl3-
NO13Na (M + Na) 1004.2559, found 1004.2539.
1
(c 1.3, CHCl3). H NMR (CDCl3) δ 7.10-7.30 (m, 15H), 7.01-
7.07 (m, 2H), 6.80-6.86 (m, 2H), 5.07, 4.84 (ABq, 1H each, J
) 11.0), 4.98, 4.77 (ABq, 1H each, J ) 11.4), 4.93 (d, 1H, J )
7.8), 4.62, 4.58 (ABq, 2H, J ) 12.0, 14.9), 3.84 (dd, 1H, J )
3.7, 10.4), 3.80 (s, 3H), 3.65-3.77 (m, 3H), 3.51-3.61 (m, 2H),
2.54 (bs, 1H). 13C NMR (CDCl3) δ 155.8, 151.9, 139.0, 138.6,
138.4, 129.0, 128.9, 128.83, 128.77, 128.7, 128.4, 128.3, 128.2,
128.13, 128.09, 118.8, 115.0, 103.3, 84.5, 82.0, 75.8, 75.4, 74.8,
74.1, 71.8, 70.6, 56.1. HRMS calcd for C34H36O7Na (M + Na)
579.2359, found 579.2352.
4-Meth oxyp h en yl 2,3,6-Tr i-O-ben zyl-4-O-(6-O-ben zyl-
4-d eoxy-4-a zid o-â-D-ga la ctop yr a n osyl)-â-D-glu cop yr a n o-
sid e (5). Compound 14 (100 mg, 0.109 mmol) was dissolved
in methanol (8.5 mL), and NaOMe/MeOH (0.17 mL, 1 M) was
added to the stirred mixture. After 15 min the reaction was
neutralized with Amberlite IR-120-H+. The mixture was
filtered and concentrated, and the residue was chromato-
graphed (SiO2, 2:1 f 1:3 heptane/EtOAc gradient) to give
4-Meth oxyp h en yl 2,3-Di-O-ben zyl-4,6-O-ben zylid en e-
â-D-glu cop yr a n osid e (12). Compound 11 (1.96 g, 5.2 mmol)
was dissolved in DMF (50 mL). NaH (1.8 g, 75 mmol) was
added, followed by benzyl bromide (3.0 mL, 25 mmol). After
18 h the remaining NaH was quenched by addition of MeOH.
The mixture was diluted with CH2Cl2, washed with H2O, dried
(MgSO4), and concentrated. The residue was chromatographed
(SiO2, 4:1 f 2:1 heptane/EtOAc gradient) to give compound
1
compound 5 (82 mg, 90%). [R]21 -15° (c 0.9, CHCl3). H NMR
1
12 (2.72 g, 94%). [R]24 (0° (c 0.9, CHCl3). H NMR (CDCl3) δ
D
(CDCl3) δ 7.42-7.29 (m, 20H), 7.08-7.03 (m, 2H), 6.90-6.85
(m, 2H), 5.04, 4.84 (ABq, 1H each, J ) 10.9), 5.00-4.89 (m,
3H), 4.75, 4.63 (ABq, 1H each, J ) 12.0), 4.59 (d, 1H, J ) 7.42),
4.41 (s, 3H), 4.12-4.06 (m, 1H), 4.04-3.98 (m, 1H), 3.96 (d,
1H, J ) 2.8), 3.86-3.81 (m, 1H), 3.83 (s, 3H), 3.78-3.71 (m,
2H), 3.70-3.63 (m, 1H), 3.62-3.44 (m, 3H), 3.32 (dd, 1H, J )
4.7, 8.3), 2.78-2.71 (m, 1H), 1.76-1.66 (m, 1H). 13C NMR
(CDCl3) δ 155.9, 151.8, 139.3, 138.5, 138.1, 137.7, 128.9, 128.9,
128.9, 128.69, 128.67, 128.5, 128.4, 128.29, 128.26, 127.8,
127.5, 119.1, 115.0, 103.9, 103.5, 84.0, 82.4, 75.6, 75.5, 74.8,
74.3, 73.9, 73.7, 73.3, 72.6, 68.9, 68.4, 61.6, 56.1. HRMS calcd
for C47H51N3O11Na (M + Na) 856.3421, found 856.3422.
Meth yl [2-(Tr im eth ylsilyl)eth yl 9-Azid o-4-O-ben zoyl-
3,5,9-tr ideoxy-5-tr iflu or oacetam ido-D-glycer o-r-D-ga la cto-
2-n on u lop yr a n osid ]on a te (7). Compound 19 (580 mg, 0.992
mmol) was dissolved in CH2Cl2 (40 mL) and pyridine (2.5 mL).
pTsCl (927 mg, 4.862 mmol) was added to the stirred solution
at room temperature. After 16 h an excess of MeOH (2 mL)
was added. The reaction mixture was concentrated with
7.45-7.54 (m, 2H), 7.28-7.41 (m, 13H), 6.99-7.03 (m, 2H),
6.83-6.86 (m, 2H), 5.60 (s, 1H), 5.01 (d, 1H, J ) 7.5), 4.99,
4.86 (ABq, 1H each, J ) 10.8), 4.95, 4.83 (ABq, 1H each, J )
11.4), 4.38 (dd, 1H, J ) 5.0, 10.5), 3.69-3.86 (m, 4H), 3.79 (s,
3H), 3.45-3.55 (m, 1H).13C NMR (CDCl3) δ 156.0, 151.6, 138.9,
138.6, 137.7, 129.4, 128.81, 128.76, 128.7, 128.6, 128.5, 128.2,
128.1, 126.5, 119.0, 115.1, 103.7, 101.6, 82.3, 81.8, 81.3, 76.0,
75.6, 69.2, 66.6, 56.1. HRMS calcd for C34H34O7Na (M + Na)
577.2203, found 577.2200.
4-Meth oxyp h en yl (3,4-Di-O-a cetyl-6-O-ben zyl-2-d eoxy-
2-(2,2,2-tr ich lor oeth oxyca r bon yla m in o)-â-D-ga la ctop yr a -
n osyl)-(1f4)-2,3,6-tr i-O-ben zyl-â-D-glu cop yr a n osid e (13).
To compound 8 (80 mg, 0.135 mmol), compound 9 (50 mg, 0.090
mmol), AgOTf (35 mg, 0.137 mmol), and molecular sieves (60
mg, 3Å, activated) was added CH2Cl2 (2.5 mL). The reaction
mixture was cooled to -45 °C under Ar. ICl (0.068 mL, 1 M in
CH2Cl2) was added dropwise. After 60 min the reaction was
quenched by the addition of diisopropylamine (0.1 mL). The
cold reaction mixture was filtered (SiO2, 5:1 f 2:1 cyklohexane/
EtOAc gradient) and concentrated to give compound 13 (95
mg, 97%). [R]21D -29° (c 1.0, CHCl3). 1H NMR (CDCl3) δ 7.19-
7.55 (m, 20H), 6.90-6.96 (m, 2H), 6.73-6.79 (m, 2H), 5.30,
(d, 1H, J ) 3.0), 4.90, 4.76 (ABq, 1H each, J ) 10.9), 4.90,
4.68 (ABq, 1H each, J ) 10.8), 4.78 (d, 1H, J ) 7.4), 4.76, 4.30
(30) Hori, H.; Nakajima, T.; Nishida, Y.; Ohrui, H.; Meguro, H.
Tetrahedron Lett. 1988, 29, 6317.
(31) A clear stock solution of the guanidium solution was prepared
by dissolving guanidinium nitrate (622 mg, 5 mmol) in MeOH/CH2-
C12 (50 mL, 9:1) and adding methanolic MeONa (1 mL, 1 M).
6254 J . Org. Chem., Vol. 69, No. 19, 2004

Bislactam Analogs of Ganglioside GD3
(ABq, 1H each, J ) 12.0), 4.64, 4.59 (ABq, 2H, J ) 12.1, 16.0),
4.55 (dd, 1H, J ) 3.0, 11.2), 4.37, 4.11 (ABq, 1H each, J )
12.0), 4.24 (d, 1H, J ) 8.3), 3.84-3.96 (m, 2H), 3.72 (s, 3H),
3.65-3.72 (m, 2H), 3.47-3.62 (m, 4H), 3.34 (d, 1H, J ) 9.7),
3.09-3.23 (m, 2H), 1.92 (s, 3H), 1.90 (s, 3H). 13C NMR (CDCl3)
δ 169.70, 169.66, 154.9, 153.7, 151.1, 138.7, 138.0, 137.3, 137.0,
129.0, 128.7, 128.4, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4,
127.24, 127.20, 126.9, 118.1, 114.1, 102.5, 100.3, 82.2, 81.1,
75.0, 74.7, 74.1, 73.9, 73.4, 73.0, 71.2, 70.12 67.0, 66.3, 66.2,
55.3, 52.4, 20.2. HRMS calcd for C54H58Cl3NO15Na (M + Na)
1088.2770, found 1088.2771.
4-Meth oxyp h en yl (3,4-Di-O-a cetyl-4-a zid o-6-O-ben zyl-
4-d eoxy-â-D-ga la ct op yr a n osyl)-(1f4)-2,3,6-t r i-O-b en zyl-
â-D-glu cop yr a n osid e (14). To compound 10 (65 mg, 0.135
mmol), compound 9 (50 mg, 0.090 mmol), AgOTf (35 mg, 0.137
mmol), and molecular sieves (60 mg, 3Å, activated) was added
CH2Cl2 (2.5 mL). The reaction mixture was cooled to -45 °C
under Ar. ICl (0.068 mL, 1 M in CH2Cl2) was added dropwise.
After 60 min the reaction was quenched by the addition of
diisopropylamine (0.10 mL). The cold reaction mixture was
filtered on a short plug of silica (1:0 f 1:1 toluene/acetone
gradient) followed by purification on sephadex LH-20. Some
of the fractions of 14 were contaminated, but additional
purification of these fractions on a short silica plug (1:1
toluene/EtOAc) gave pure compound 14. Combination of all
fractions gave pure 14 (80 mg, 98%). [R]21D -23° (c 1.0, CHCl3).
1H NMR (CDCl3) δ 7.29-7.44 (m, 20H), 7.03-7.08 (m, 2H),
6.82-6.89 (m, 2H), 5.22 (dd, 1H, J ) 7.9, 10.2), 5.03, 4.86 (ABq,
1H each, J ) 10.9), 4.97 (dd, 1H, J ) 3.8, 10.2), 4.95, 4.84
(ABq, 1H each, J ) 10.7), 4.88 (d, 1H, J ) 7.6), 4.76, 4.53 (ABq,
1H each, J ) 12.0), 4.59 (d, 1H, J ) 7.9), 4.45, 4.38 (ABq, 1H
each, J ) 11.8), 4.10 (d, 1H, J ) 3.0), 3.99 (t, 1H, J ) 8.7),
3.83 (s, 3H), 3.73-3.80 (m, 2H), 3.60-3.72 (m, 2H), 3.35-3.55
(m, 4H), 2.16 (s, 3H), 2.03 (s, 3H). 13C NMR (CDCl3) δ 170.5,
169.6, 155.8, 151.9, 139.3, 138.8, 138.3, 138.1, 128.92, 128.91,
128.8, 128.6, 128.5, 128.34, 128.27, 128.26, 128.1, 127.8, 118.9,
115.0, 103.2, 100.8, 83.0, 82.0, 75.9, 75.6, 75.3, 74.0, 73.9, 73.3,
71.9, 70.5, 68.2, 67.8, 60.6, 56.1, 21.2, 21.0. HRMS calcd for
Meth yl [2-(Tr im eth ylsilyl)eth yl 3,5-Did eoxy-5-tr iflu o-
r oa cet a m id o-D-glycer o-D-ga la cto-2-n on u lop yr a n osid ]-
on a te (17). To compound 16 (3.70 g, 5.73 mmol) was added
MeOH (130 mL) and NaOMe/MeOH (29 mL, 1 M). After 1 h
the reaction mixture was neutralized by addition of Amberlyst
1R-120-H+, which was filtered off, and the reaction mixture
was concentrated. Lyophilization from water gave 17 (2.63 g,
98%), which was used without further purification.
Met h yl [2-(Tr im et h ylsilyl)et h yl 3,5-Did eoxy-8,9-iso-
p r op ylid en e-5-tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-
2-n on u lop yr a n osid ]on a te (18). Compound 17 (1.00 g, 2.09
mmol) was dissolved in acetone (30 mL) and stirred at room
temperature. 2,2-Dimethoxypropane (2.95 mL, 24 mmol) to-
gether with a catalytic amount of pTSA (20 mg) were added.
After 30 min the reaction was quenched by the addition of
pyridine (1 mL) and concentrated with toluene. The residue
was chromatographed (SiO2, 6:1 f 1:4 toluene/EtOAc gradient)
1
to give 18 (785 mg, 78%). [R]25 +7° (c 1.0, CHCl3). H NMR
D
(CD3OD) δ 4.20 (q, 1H, J ) 6.2, 12.3), 3.84-4.07 (m, 4H), 3.78
(s, 3H), 3.74 (dd, 1H, J ) 1.1, 10.6), 3.61-3.69 (m, 1H), 3.56
(d, 1H, J ) 5.8), 3.46 (q, 1H, J ) 8.5, 16.9), 2.62 (dd, 1H, J )
4.7, 12.7), 1.69 (t, 1H, J ) 12.6), 1.33 (d, 6H, J ) 6.4), 0.85 (t,
2H, J ) 8.2), -0.01 (s, 9H). 13C NMR (CD3OD) δ 170.0, 108.6,
99.3, 76.7, 73.2, 68.9, 67.0, 65.9, 61.7, 52.8, 51.6, 40.6, 25.8,
24.6, 17.7, -2.5. HRMS calcd for C20H34F3NO9SiNa (M + Na)
540.1853, found 540.1847
Meth yl [2-(Tr im eth ylsilyl)eth yl 4-O-Ben zoyl-3,5-dideoxy-
5-tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-2-n on u lop y-
r a n osid ]on a te (19). Compound 18 (468 mg, 0.904 mmol) was
dissolved in pyridine (7 mL) and cooled to 0 °C, after which
benzoyl chloride (0.126 mL 1.085 mmol) was added dropwise.
After 30 min an excess of MeOH was added, and the reaction
mixture was concentrated with toluene. The residue was
dissolved in AcOH/MeOH (14 mL, 4:1) and refluxed for 2 h,
after which the mixture was concentrated with toluene. The
residue was chromatographed (SiO2, 6:1 f 1:2 heptane/acetone
gradient) to give 19 (460 mg, 87%). [R]25 -14° (c 1.0, CHCl3).
D
1H NMR (CD3OD) δ 7.75-7.79 (m, 2H), 7.38-7.43 (m, 1H),
7.23-7.29 (m, 2H), 4.98-5.06 (m, 1H), 4.25 (t, 1H, J ) 10.5),
3.89 (dd, 1H, J ) 1.6, 10.6), 3.73-3.81 (m, 1H), 3.70 (s, 3H),
3.61-3.69 (m, 2H), 3.46 (dd, 1H, J ) 5.9, 11.7), 3.27-3.36 (m,
2H), 2.68, (dd, 1H, J ) 4.9, 12.5), 1.76 (t, 1H, J ) 12.2), 0.64-
0.72 (m, 2H), -0.19 (s, 9H). 13C NMR (CD3OD) δ 169.4, 165.9,
133.4, 129.5, 128.4, 98.9, 72.4, 71.5, 70.5, 68.7, 63.4, 61.9, 52.2,
49.7, 37.6, 17.7, -2.5. HRMS calcd for C24H34F3NO10SiNa (M
+ Na) 604.1802, found 604.1819.
C
51H55N3O13Na (M + Na) 940.3633, found 940.3636.
3,4-Di-O-a cetyl-6-O-ben zyl-1,2-d id eoxy-1,2-N-[-3-(2,2,2-
tr ich lor oeth oxyca r bon yl)-a ceta m id in e]-â-D-ga la ctop yr a -
n ose (15). Byproduct isolated in the glycosylation reaction of
1
thioglycoside 8 and acceptor 9. [R]24 -17° (c 0.9, CHCl3). H
D
NMR (CDCl3) δ 7.27-7.37 (m, 5H), 5.70 (dd, 1H, J ) 1.7, 7.2),
5.44 (d, 1H, J ) 3.3), 5.12 (dd, 1H, J ) 3.3, 8.2), 4.95, 4.68
(ABq, 1H each, J ) 12.0), 4.57, 4.46 (ABq, 1H each, J ) 12.0),
4.42 (dd, 1H, J ) 8.0, 7.4), 4.12 (t, 1H, J ) 6.6), 3.61 (dd, 1H,
J ) 5.4, 9.5), 3.39 (dd, 1H, J ) 7.3, 9.5), 2.45 (d, 3H, J ) 1.9),
2.10, 2.05 (s, 3H each). 13C NMR (CDCl3) δ 170.4, 170.1, 149.4,
137.5, 128.4, 127.9, 127.8, 94.4, 92.6, 75.5, 73.5, 71.4, 69.8, 67.6,
65.9, 58.2, 20.9, 20.7, 18.8. HRMS calcd for C22H26Cl3N2O8 (M
+ H) 551.0754, found 551.0763.
Meth yl [(Meth yl 4,7,8,9-Tetr a -O-a cetyl-3,5-d id eoxy-5-
tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop yr a -
n osylon a te)-(2f8)-(2-(tr im eth ylsilyl)eth yl 9-Azid o-4-O-
ben zoyl-3,5,9-tr id eoxy-5-tr iflu or oa ceta m id o-D-glycer o-r-
D-ga la cto-n on -2-u lop yr a n osid e)]on a te (20). To a mixture
of 6 (315 mg, 0.494 mmol), 7 (100 mg, 0.165 mmol), molecular
sieves (415 mg, 3Å, activated), and AgOTf (170 mg, 0.664
mmol) was added CH2Cl2 (3.3 mL). The reaction mixture was
stirred and cooled to -78 °C under Ar, and MeCN (3.3 mL)
was added. After 45 min IBr (0.500 mL, 1 M in CH2Cl2, 0.5
mmol) was added dropwise. After an additional 120 min the
reaction was quenched by addition of diisopropylamine (0.250
mL). The cold reaction mixture was filtered on silica (1:0 f
1:2 toluene/acetone gradient) and concentrated. The residue
was purified on sephadex LH-20 to give compund 20 (110 mg,
Meth yl [2-(Tr im eth ylsilyl)eth yl 4,7,9-Tr i-O-a cetyl-3,5-
d id eoxy-5-tr iflu or oa ceta m id o-D-glycer o-D-ga la cto-2-n on -
u lop yr a n osid ]on a te (16). To compound 6 (500 mg, 0.784
mmol), powdered molecular sieves (650 mg, 3Å, activated) and
AgOTf (300 mg, 1.176 mmol) was added MeCN (20 mL). The
mixture was cooled to -40 °C under Ar and vigorous stirring.
After 30 min trimethylsilylethanol (0.225 mL, 1.568 mmol) was
added, followed by dropwise addition of IBr (0.865 mL, 1 M in
CH2Cl2, 0.865 mmol). After 1 h the reaction was quenched by
the addition of an excess of diisopropylamine (0.5 mL). The
cold reaction mixture was filtered on a short plug of silica and
concentrated. The residue was chromatographed (SiO2, 4:1 f
1:1 heptane/EtOAc gradient) to give 16 (492 mg, 86%, R:â 88:
12). The reaction is sensitive to upscaling, probably as a result
of the acid sensitivity of the TMSEt group. When performed
on a 5 g scale the yield dropped to 72% and when scaled down
to 0.1 g the yield rose to 93%. Because no base is present the
neutralization of the formed triflic acid is conducted by the
molecular sieves, which action is dependent on the stirring
efficiency. Compound identical to the one reported by Boons.14
59%) as a white powder. [R]25 +5° (c 1.1, CHCl3). 1H NMR
D
(CDCl3) δ 7.95-8.01 (m, 2H), 7.57-7.63 (m, 2H), 7.43-7.54
(m, 3H), 6.44 (d, 1H, J ) 9.3), 5.45-5.51 (m, 1H), 5.22-5.33
(m, 2H), 5.09-5.17 (m, 1H), 5.62-5.67 (m, 1H), 4.24-4.35 (m,
2H), 4.16 (dd, 1H, J ) 1.7, 10.8), 4.06 (dd, 1H, J ) 1.1, 10.4),
3.95 (q, 1H, J ) 10.2), 3.88 (s, 3H), 3.82-3.88 (m, 1H), 3.78 (s,
3H), 3.74-3.79 (m, 1H), 3.65-3.70 (m, 1H), 3.58 (dd, 1H, J )
7.8, 13.4), 3.41-3.51 (m, 1H), 3.05 (d, 1H, J ) 7.0), 2.77-2.88
(m, 2H), 2.19 (s, 3H), 2.16 (s, 3H), 2.03-2.14 (m, 2H), 2.08 (s,
3H), 2.05 (s, 3H), 0.89-0.95 (m, 2H), 0.04 (s, 9H). 13C NMR
(CDCl3) δ 171.68, 171.66, 171.5, 171.3, 170.6, 169.2(C-1,
J . Org. Chem, Vol. 69, No. 19, 2004 6255

Meijer and Ellervik
1
J C1-H-3ax ) 6.0),30 168.8(C-1, J C1-H-3ax ) 6.0),30 167.0, 134.1,
130.2, 129.3, 129.0, 99.3, 97.9, 75.8, 73.9, 71.9, 69.7, 69.3, 69.0,
68.4, 67.2, 63.0, 62.7, 53.6, 51.9, 51.7, 50.9, 38.5, 38.1, 21.5,
+17° (c 0.4, CHCl3). H NMR (CDCl3) δ 8.32 (d, 1H, J ) 9.9),
8.03 (d, 2H, J ) 7.5), 7.52-7.65 (m, 2H), 7.41-7.45 (m, 8H),
7.25-7.37 (m, 13H), 7.17 (d, 1H, J ) 10.0), 7.00-7.06 (m, 2H),
6.82-6.88 (m, 2H), 6.50-6.58 (bs, 1H), 5.66 (dt, 1H, J ) 5.3,
10.7), 5.50-5.57 (m, 1H), 5.30-5.39 (m, 1H), 5.33 (dd, 1H, J
) 2.3, 9.1), 5.11 (dd, 1H, J ) 1.5, 9.5), 5.03, 4.84 (ABq, 1H
each, J ) 11.0), 5.02, 4.84 (ABq, 1H each, J ) 10.9), 4.97 (dd,
1H, J ) 1.5, 10.9), 4.87-4.91 (m, 1H), 4.80, 4.49 (ABq, 1H each,
J ) 12.1), 4.61-4.72 (m, 2H), 4.39-4.54 (m, 3H), 4.45, 4.34
(ABq, 1H each, J ) 11.8), 4.01-4.32 (m, 8H), 4.00 (s, 3H), 3.82
(s, 3H), 3.67-3.80 (m, 5H), 3.44-3.55 (m, 3H), 3.09-3.18 (m,
1H), 2.91-3.00 (m, 1H), 2.85-2.90 (bs, 1H), 2.82 (dd, 1H, J )
5.1, 13.0), 2.30 (dd, 1H, J ) 4.6, 13.2), 2.15, 2.13, 2.10, 2.07,
2.05 (s, 3H each), 1.89-1.99 (m, 2H). 13C NMR (CDCl3) δ 172.2,
171.4, 170.7, 169.8, 169.7, 167.8(C-1, J C1-H-3ax ) 5.4),30 166.0,
155.8, 154.5, 151.9, 139.6, 138.9, 138.7, 138.5, 134.0, 130.1,
129.4, 129.3, 129.1, 128.8, 128.7, 128.7, 128.6, 128.2, 128.11,
128.05, 127.8, 127.7, 118.9, 117.4, 115.0, 103.2, 100.3, 95.8,
95.6, 83.3, 82.1, 75.8, 75.6, 75.0, 73.9, 73.8, 73.7, 72.9, 72.2,
70.3, 69.2, 69.0, 68.8, 68.6, 68.5, 67.5, 62.8, 56.1, 54.3, 53.6,
21.1, 21.0, 20.9, 18.5, -1.0. HRMS calcd for C44H57F6N5O21
SiNa (M + Na) 1156.3118, found 1156.3124.
-
Meth yl [(4,7,8,9-Tetr a -O-a cetyl-3,5-d id eoxy-5-tr iflu o-
r oa ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop yr a n osyl)-
(2f8)-(2-(tr im eth ylsilyl)eth yl 9-Am in o-4-O-ben zoyl-3,5,9-
tr id eoxy-5-tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-n on -
2-u lop yr a n osid e)]on a te 1′-9 La cta m (21). Compound 20
(385 mg, 0.340 mmol) was dissolved in THF (26 mL) and water
(6 mL), followed by addition of Ph3P (280 mg, 1.07 mmol). The
stirred reaction mixture was then heated to 60 °C in a sealed
vessel for 48 h. The reaction mixture was then concentrated
and chromatographed (SiO2, 3:1 f 1:1 toluene/acetone gradi-
ent), followed by additional purification on sephadex LH-20
to give 21 (332 mg, 86%) as a white foam. [R]24 -21° (c 0.8,
D
1
CHCl3). H NMR (CDCl3) δ 7.98-8.03 (m, 2H), 7.95 (d, 1H, J
) 10.1), 7.57-7.63 (m, 1H), 7.50-7.61 (m, 1H), 7.42-7.48 (m,
2H), 7.16 (d, 1H, J ) 7.1), 5.41-5.52 (m, 3H), 5.04-5.10 (m,
1H), 4.60 (dd, 1H, J ) 1.6, 12.5), 4.42 (dd, 1H, J ) 2.8, 10.4),
4.20-4.33 (m, 2H), 4.10-4.18 (m, 2H), 4.06 (dd, 1H, J ) 8.5,
12.5), 3.40-3.86 (m, 1H), 3.84 (s, 3H), 3.62-3.71 (m, 1H),
3.50-3.59 (m, 3H), 3.47 (d, 1H, J ) 7.2), 2.86 (dd, 1H, J )
4.9, 12.8), 2.58 (dd, 1H, J ) 5.4, 12.9), 2.14 (s, 3H), 2.04-2.11
(m, 1H), 2.09 (s, 3H), 2.03 (s, 3H), 1.93 (s, 3H), 1.72-1.80 (m,
1H), 0.86-0.92 (m, 2H), 0.00 (s, 9H). 13C NMR (CDCl3) δ 172.4,
171.4, 170.7, 170.4, 168.7, 168.1, 167.5, 134.3, 130.3, 129.2,
129.0, 99.4, 98.2, 73.9, 73.4, 72.1, 71.8, 71.1, 70.9, 69.4, 69.3,
63.4, 62.8, 53.2, 52.6, 49.2, 42.1, 38.2, 37.7, 21.6, 21.1, 21.0,
20.9, 18.5, -0.9. HRMS calcd for C43H55F6N3O20SiNa (M + Na)
1098.2950, found 1098.2961.
50.4, 50.1, 40.6, 21.2, 21.00, 20.96, 14.6. HRMS calcd for C90H97
Cl3F6N4O33Na (M + Na) 2003.4903, found 2003.4877.
-
4-Meth oxyp h en yl (4,7,8,9-Tetr a -O-a cetyl-3,5-d id eoxy-
5-tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop y-
r a n osyl)-(2f8)-[m eth yl(7-O-a cetyl-9-a m in o-4-O-ben zoyl-
3,5,9-tr ideoxy-5-tr iflu or oacetam ido-D-glycer o-r-D-ga la cto-
n on -2-u lop yr a n osyl)on a te]-(2f3)-(4-a zid o-6-O-ben zyl-4-
d eoxy-â-D-ga la ct op yr a n osyl)-(1f4)-2,3,6-t r i-O-b en zyl-â-
D-glu cop yr a n osid e 1′′′ -9′′ La cta m (24). To a mixture of
compound 3 (80 mg, 0.072 mmol), 5 (65 mg, 0.072 mmol),
AgOTf (24 mg, 0.094 mmol), and molecular sieves (96 mg, 3Å,
activated) were added CH2Cl2 (0.72 mL) and MeCN (0.72 mL)
at -72 °C under Ar. The mixture was stirred for 30 min, and
then IBr (0.090 mL, 1 M solution in CH2Cl2, 0.090 mmol) was
added dropwise. After 2.5 h the reaction was quenched by
addition of an excess of diisopropylamine (0.1 mL) and Na2S2O3
(50 mg). The cold reaction mixture was filtered on silica (1:0
f 1:2 toluene/acetone gradient). The residue was purified on
sephadex LH-20 and then chromatographed (SiO2, 1:1 heptane/
Meth yl [(4,7,8,9-Tetr a -O-a cetyl-3,5-d id eoxy-5-tr iflu o-
r oa ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop yr a n osyl)-
(2f8)-(2,7-di-O-acetyl-9-am in o-4-O-ben zoyl-3,5,9-tr ideoxy-
5-t r iflu or oa cet a m id o-D-glycer o-r/â-D-ga la cto-n on -2-u lo-
p yr a n ose)]on a te 1′-9 La cta m (22). Compound 21 (332 mg,
0.309 mmol) was dissolved in CH2Cl2 (25 mL), and then TfOH
(5 mL) was added to the stirred mixture. After 2 h pyridine
(10 mL) was added slowly to the ice-cooled mixture, followed
by addition of Ac2O (10 mL). The reaction mixture was stirred
at room temperature for 15 h and then quenched by addition
of MeOH (10 mL). The reaction mixture was concentrated with
toluene. The crude reaction mixture was dissolved in CH2Cl2,
extracted twice with saturated aqueous NaHCO3 and once
with water, dried (Na2SO4), and concentrated. The residue was
purified on sephadex LH-20, concentrated, and chromato-
graphed (SiO2, 5:1 f 3:1 toluene/acetone gradient). The residue
was dissolved in ethyl acetate (50 mL) and stirred with
activated charcoal (3 g). The mixture was filtered (Celite) and
concentrated to give compound 22 (240 mg, 73%) as an
inseparable anomeric mixture (82:18), which was used in the
next step without separation.
EtOAc) to give 24 (58 mg, 44%). [R]22 +20° (c 1.0, CHCl3). 1H
D
NMR (CDCl3) δ 8.02-7.97 (m, 2H), 7.89 (d, 1H, J ) 9.9), 7.62-
7.56 (m, 1H), 7.49-7.42 (m, 2H), 7.40-7.22 (m, 20H), 7.19-
7.13 (m, 1H), 7.05-6.99 (m, 2H),6.85-6.80 (m, 2H), 6.64-6.57
(m, 1H), 5.53 (td, 1H, J ) 5.0, 10.8), 5.44 (td, 1H, J ) 2.5,
7.1), 5.40-5.32 (m, 2H), 5.04-4.99 (m, 1H), 5.01, 4.79 (ABq,
1H each, J ) 10.8), 4.93 (s, 2H), 4.90-4.85 (m, 1H), 4.77 (dd,
1H, J ) 2.8, 10.4), 4.68, 4.54 (ABq, 1H each, J ) 11.6), 4.60
(d, 1H, J ) 7.6), 4.47 (dd, 1H, J ) 1.6, 10.7), 4.38-4.26 (m,
5H), 4.24-4.14 (m, 2H), 4.11-3.94 (m, 5H), 3.95 (s, 3H), 3.89-
3.84 (m, 1H), 3.79 (s, 3H), 3.74-3.50 (m, 6H), 3.42-3.35 (m,
1H), 3.24 (dd, 1H, J ) 4.8, 8.6), 3.11-2.95 (m, 1H), 2.88 (dd,
1H, J ) 5.0, 13.5), 2.36 (dd, 1H, J ) 4.8, 13.3), 2.27-2.19 (m,
1H), 2.11 (s, 3H), 2.06 (s, 3H), 2.04 (s, 6H), 1.97 (s, 3H), 1.96-
1.85 (m, 1H). 13C NMR (CDCl3) δ 172.0, 171.5, 171.2, 170.5,
170.1, 169.2, 168.1 (C-1, J C1-H-3ax ) 6.1),30 166.3, 155.8, 151.8,
139.5, 138.5, 138.4, 138.0, 134.0, 130.2, 129.4, 129.0, 128.83,
128.75, 128.67, 128.61, 128.39, 128.35, 128.25, 128.1, 127.7,
127.6, 118.9, 115.0, 104.3, 103.4, 100.0, 96.3, 83.8, 82.3, 75.6,
75.5, 75.1, 74.2, 73.8, 73.6, 72.1, 71.8, 71.2, 70.3, 70.1, 70.0,
69.5, 68.4, 62.9, 62.6, 56.1, 53.5, 50.4, 50.0, 41.2, 39.6, 36.9,
30.1, 21.2, 21.01, 20.97. HRMS calcd for C87H94F6N6O31Na (M
+ Na) 1855.5765, found 1855.5756.
4-Meth oxyp h en yl (4,7,8,9-Tetr a -O-a cetyl-3,5-d id eoxy-
5-tr iflu or oa ceta m id o-D-glycer o-r-D-ga la cto-n on -2-u lop y-
r a n osyl)-(2f8)-[m eth yl(7-O-a cetyl-9-a m in o-4-O-ben zoyl-
3,5,9-tr ideoxy-5-tr iflu or oacetam ido-D-glycer o-r-D-ga la cto-
n on -2-u lop yr a n osyl)on a te]-(2f3)-[6-O-ben zyl-2-d eoxy-2-
(2,2,2-t r ic h lo r o e t h o x y c a r b o n y la m in o )-â-D-g a la c t o -
p yr a n osyl]-(1f4)-2,3,6-t r i-O-b e n zyl-â-D-glu co-p yr a n -
osid e 1′′′ -9′′ La cta m (23). To a mixture of compound 3 (100
mg, 0.090 mmol), 4 (90 mg, 0.090 mmol), AgOTf (30 mg, 0.117
mmol), and molecular sieves (120 mg, 3Å, activated) were
added CH2Cl2 (0.090 mL) and MeCN (0.090 mL) at -72 °C
under Ar. The mixture was stirred for 30 min, and then IBr
(0.090 mL, 1 M solution in CH2Cl2, 0.090 mmol) was added
dropwise. After 2.5 h the reaction was quenched by addition
of an excess of diisopropylamine (0.1 mL) and Na2S2O3 (50 mg).
The reaction mixture was concentrated and filtered on silica
(4:1 f 1:2 heptane/acetone gradient). The residue was purified
on sephadex LH-20 and then chromatographed (SiO2, 1:1 f
Ack n ow led gm en t. This work was supported by the
Swedish Research Council and the Crafoord Founda-
tion. We thank Anna Andersson for technical assistance.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal conditions and NMR spectra of compounds 1-5, 7, 9, 12-
15, 18-21, 23, and 24. This material is available free of charge
via the Internet at http://pubs.acs.org.
1:3 heptane/EtOAc gradient) to give 23 (72 mg, 40%). [R]22
J O049184G
D
6256 J . Org. Chem., Vol. 69, No. 19, 2004