Synthesis of ganglioside mimics for binding studies with myelin-associated glycoprotein (MAG)

Article abstract of DOI:10.1080/07328300500176312

Glycosylation of 3-O-unprotected 2-azido-2-deoxy-galactopyranoside (compound 5) with O-(2,3-di-O-acyl-4,6-O-benzylidene-D-galactopyranosyl) trichloroacetimidates (compounds 4A, B) as glycosyl donors afforded β(1-3)-linked disaccharides (9A, B) in high yie

Full text of DOI:10.1080/07328300500176312

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Synthesis of Ganglioside Mimics for
Binding Studies with Myelin‐Associated
Glycoprotein (MAG)
Sascha Janssen a & Richard R. Schmidt a
a Fachbereich Chemie, Universität Konstanz , Konstanz, Germany
Published online: 16 Aug 2006.
To cite this article: Sascha Janssen & Richard R. Schmidt (2005) Synthesis of Ganglioside Mimics for
Binding Studies with Myelin‐Associated Glycoprotein (MAG) , Journal of Carbohydrate Chemistry,
24:4-6, 611-647
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Journal of Carbohydrate Chemistry, 24:611–647, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300500176312
Synthesis of Ganglioside
Mimics for Binding Studies
with Myelin-Associated
Glycoprotein (MAG)
Sascha Janssen and Richard R. Schmidt
¨
Fachbereich Chemie, Universitat Konstanz, Konstanz, Germany
Glycosylation of 3-O-unprotected 2-azido-2-deoxy-galactopyranoside (compound 5) with
O-(2,3-di-O-acyl-4,6-O-benzylidene-D-galactopyranosyl) trichloroacetimidates (com-
pounds 4A, B) as glycosyl donors afforded b (1–3)-linked disaccharides (9A, B) in
high yield. Removal of the 2,3-O-acyl groups and selective 3-O-alkylation with a-benzyl-
oxycarbonyl-alkyl triflates furnished the protected target molecules, which could be
readily transformed into the desired ganglioside mimics.
Keywords Carbohydrate mimics, Glycosidation, O-Alkylation, Trifluoromethane-
sulfonates, MAG, Inhibition
INTRODUCTION
Damage of the central nervous system of higher vertebrates generally leads to
persistent functional deficits. The first myelin protein that was characterized
as an inhibitor of the required axonal neurite outgrowth after such events
was myelin-associated glycoprotein (MAG).[1–3] MAG is a member of the
“sialic acid-binding immunoglobulin-like lectin” (Siglec) family and binds to
neurons in a sialic acid-dependent manner.[4] As neurite outgrowth inhibition
is abolished either by desialylation of the neurons by sialidase or by including
small sialic acid-bearing sugars to the cell cultures,[4] it has been assumed that
MAG mediates neurite outgrowth inhibition by the interaction with ganglio-
sides (sialic acid-containing glycosphingolipids),[5] which are the major
Received January 31, 2005; accepted May 24, 2005.
Dedicated to the memory of late Professor Jacques H. van Boom.
¨
Address correspondence to Richard R. Schmidt, Fachbereich Chemie, Universitat
Konstanz, Fach M 725, D–78457, Konstanz, Germany. E-mail: Richard.Schmidt@uni-
konstanz.de
611

S. Janssen and R. R. Schmidt
612
glycans on the surface of nerve cells and the major sialic acid-containing glyco-
conjugates in the brain.[6,7] Studies with these structurally diverse compounds
led in binding studies to the conclusion that GQ1ba (Fig. 1, A) and the structu-
rally derived GD1a (lacking Neu5Ac residues d and h) and GT1b (lacking
Neu5Ac residue h) bind with high specificity and affinity to MAG.[8]
As concluded from these studies, the Neu5Aca(2–3)Galb(1–3)GalNAc
(Sch. 1, B) or the Neu5Aca(2–3)Galb(1–3)[Neu5Aca(2–6)]GalNAc terminus
(Sch. 1, C) is important to mediate neurite outgrowth inhibition.[8,9] Further
investigations on the contribution of substructures of B and C led to further
important features for MAG binding: the neuraminic acid moiety g, and par-
ticularly its carboxylate group, and the carboxylate group of neuraminic acid
residue h are decisive for binding, and modifications at the functional groups
of the Neu5Ac residues can also strongly influence the binding event.[5–12]
Because of the generally low binding affinity of carbohydrate epitopes to
protein receptors and the observed poor bioavailability of carbohydrates,[13,14]
carbohydrate mimics have been successfully employed to replace the natural
structures.[13,15] For instance, the Neu5Ac residue has been substituted by
mimics in the selectin research,[16] in the search for anti-influenza agents,[17]
and in sialyltransferase inhibition studies.[18] In some studies, the a-anomeri-
cally linked Neu5Ac residue has been replaced by a-hydroxycarbonyl-alkyl
residues.[16,19–21] Hence we have designed target compounds 1 and 2 (Sch. 1)
Figure 1: Structure of GQ1ba (A) and constituents B and C.

Synthesis of Ganglioside Mimics
613
Scheme 1: Target molecules (R)-1aa, -1ab, -1b and (S)-1ab, -1b, -1c and disconnection
into building blocks 3–5.
in which the Neu5Ac residues are replaced by hexahydromandelic acid (1aa,
1ab), phenyllactic acid (1b), and cyclohexyllactic acid (1c, 2c).[22]
RESULTS AND DISCUSSION
The disconnection of the target molecules 1 and 2 leads to building blocks 4 and
5, which are typical precursors for the construction of the Galb(1–3)GalNAc

S. Janssen and R. R. Schmidt
614
moiety, and to triflates 3a–c. Triflates of this type were successfully employed
by us for the construction of structurally related muramic acids[23] and later by
others also in the synthesis of sLeX mimetics.[16] The SN2 mechanism of the
reaction with sugar hydroxy groups could be ascertained.[23]
The synthesis of glycosyl donors 4A, B (Sch. 2) followed essentially pub-
lished procedures. Readily available 4,6-O-benzylidene-D-galactose (6)[24,25]
was benzoylated or acetylated under standard conditions ( ! 7A,[26] 7B[27]);
regioselective 1-O-deacylation with hydrazinium acetate in DMF ( ! 8A,[28]
8B[28–30]), and then treatment with trichloroacetonitrile and 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) as base afforded trichloroacetimidates 4A and
4B,[29,30] respectively, in high overall yields.
Glycosylation of known 3-O-unprotected acceptor 5[31] (Sch. 3) with 4A or
4B in dichloromethane and trimethylsilyl trifluoro methanesulfonate
(TMSOTf) as catalyst furnished disaccharides 9A and 9B, respectively, in
very high yields. From the NMR coupling constants (10-H: J1 ,2 ꢀ8 Hz) the
b(1–3)-linkage could be assigned. Treatment of 9A, B with NaOMe in
methanol[32] led to 20,30-O-unprotected derivative 10. For the regioselective
30-O-alkylation of 10 with trifluoromethanesulfonate (S)-3a, which was
readily obtained from benzyl (S)-hexahydromandelate,[33] dibutyltin oxide
treatment in refluxing toluene was peRformed[34] and then (S)-3a was added,
thus leading to (R)-11a in 47% yield. In addition, under loss of benzylalcohol,
concomitant lactone formation with the 20-hydroxy group occurred, thus
0
0
Scheme 2: Synthesis of glycosyl donors 4A and 4B. Reagents and conditions: (a) BzCl, pyr,
.
DMAP (96%); (b) Ac2O, Pyr (82%); (c) N2H4 HOAc, DMF (70%); (d) CCl3-CN, DBU, CH2Cl2 (4A:
97%; 4B: 94%).

Synthesis of Ganglioside Mimics
615
Scheme 3: Synthesis of target molecule (R)-1aa. Reagents and conditions: (a) TMSOTf, CH2Cl2
(9A: 83%; 9B: 89%); (b) NaOMe, MeOH/CH2Cl2 (70% from 9A; 88% from 9B); (c) Bu2SnO,
toluene; (S)-3a, CsF, DME (47% þ lactone 24%); (d) propane-1,3-dithiol, pyr/H2O, NEt3; Ac2O
(90%); (e) Pd/C, H2, MeOH/HCO2H (43%).
leading also to isolation of the lactone in 24% yield; the lactone could be trans-
formed with alcoholate into the desired product. Azide group reduction in (R)-
11a with propane-1,3-dithiol in pyridine/water in the presence of triethyl-
amine[35] led to the amino compound from which, on acetylation with acetic
anhydride, the acetylamino derivative (R)-12a was obtained. Hydrogenolytic

S. Janssen and R. R. Schmidt
616
O-debenzylation and O-debenzylidenation with palladium on carbon (Pd/C)as
catalyst gave target molecule (R)-1aa, which could be characterized by NMR
and MS data (13C NMR, d 78.5, C-3; 81.8, C-30).
For the synthesis of target molecules (R)- and (S)-1ab, (R)- and (S)-1b, and
(S)-1c, disaccharide 9B was selectively desilylated by treatment with HF†pyr-
idine complex in pyridine ( ! 13, Sch. 4).
Reaction with trichloroacetonitrile in dichloromethane in the presence of
DBU as base afforded known trichloroacetimidate 14 in high yield;[36] 14 is a
useful glycosyl donor in ganglioside synthesis. Here, reaction with methanol
and tin(II) trifluoromethanesulfonate as catalyst in acetonitrile as solvent
(use of the nitrile effect)[37] was carried out affording the desired b-glycoside
15 in good yield; no a-glycoside was found. Treatment of 15 with NaOMe in
methanol[32] afforded the desired 20,30-O-unprotected disaccharide 16 in high
overall yield.
Reaction of 16 with dibutyltin oxide in refluxing toluene[34] and then with
the (R)-configurated trifluoromethanesulfonates 3a–c or the (S)-configurated
trifluoromethanesufonates 3a, b afforded exclusively the 30-O-alkylated deriva-
tives (S)-17a–c and (R)-17a, b, respectively, in mainly very good yields (Sch. 5).
.
Scheme 4: Synthesis of acceptor 16. Reagents and conditions: (a) HF pyr, pyr (71%); (b) CCl3–
CN, DBU, CH2Cl2 (95%); (c) MeOH, Sn(OTf)2, MeCN (59%); (d) NaOMe, MeOH/CH2Cl2 (88%).

Synthesis of Ganglioside Mimics
617
Scheme 5: Synthesis of target molecules 1ab, 1b, and 1c. R55C6H11, a; R55PhCH2, b;
R55C6H11–CH2, c. Reagents and conditions: (a) Bu2SnO, toluene; (R)-3a-c/(S)-3a, b, CsF, DME
[(S)-17a: 59%; (S)17b: 73%; (S)-17c: 49% þ lactone: 28%; (R)-17a: 80%; (R)-17b: 62%];
(b) propane-1,3-dithiol, NEt3, pyr H2O; Ac2O, pyr [(S)-18a: 83%; (S)-18b: 54%; (S)-18c: 75%;
(R)-18a: 84%; (R)-18b: 43%]; (c) EtSH, p-TsOH, CH2Cl2/MeOH; Ac2O, pyr [(S)-19a: 50%; (S)-19b:
53%; (S)-19c: 72%; (R)-19a: 28%; (R)-19b: 69%]; (d) Pd/C, H2, MeOH; NaOMe [(S)-1ab: 69%;
(S)-1b: 86%; (S)-1c: 87%; (R)-1ab: 55%; (R)-1b: 90%].
Only the transformation of 16 with (R)-3c led also to lactone formation with the
20-hydroxy group (yield: 28%). The connections in compounds (S)-17a–c and
(R)-17a, b are again supported by the NMR and MS data (13C NMR: d ꢀ77.5,
C-3; ꢀ80.5, C-30). Azide group reduction with propane-1,3-dithiol in the
presence of triethylamine in pyridine/water[35] and then N-acetylation with
acetic anhydride in pyridine afforded acetylamino derivatives (S)-18a–c and
(R)-18a, b. Next the O-benzylidene groups were removed with ethylmercaptan
in dichloromethane/methanol in the presence of p toluenesulfonic acid as
catalyst;[38] ensuing per-O-acetylation furnished (S)-19a–c and (R)-19a, b.
Hydrogenolytic O-debenzylation with Pd/C as catalyst and then treatment
with NaOMe in methanol afforded the desired target compounds (S)-1ab,
(S)-1b, (S)-1c, (R)-1ab, and (R)-1b.
For the synthesis of (S)-2c as mimetic of substructure C of GQ1ba (Fig. 1
and Sch. 1), a strategy was chosen that enables attachment of different
Neu5Ac mimetics at the GalNAc residue and at the Gal residue. To this end,
azidogalactoside 20 (Sch. 6), readily available from galactosamine via the
same procedure as described for 5,[31] was treated with 4-methoxybenzylidene

S. Janssen and R. R. Schmidt
618
Scheme 6: Synthesis of target molecule (S)-3a. Reagents and conditions: (a) MeO–C6H4–
.
CH(OMe)2, p-TsOH, DMF (36%); (b) TMSOTf, CH2Cl2 (66%); (c) HF pyr, pyr (59%); (d) CCl3–CN,
DBU, CH2Cl2; Sn(OTf)2, MeOH CH3CN (64%); (e) TFA/H2O, CH2Cl2 (90%); (f) Bu2SnO, toluene; (S)-
3c, CsF, DME (85%); (g) NaOMe, MeOH (78%); (h) propane-1,3-dithiol, NEt3, pyr, H2O; Ac2O, pyr
(77%); (i) Et-SH, p-TsOH, CH2Cl2; Ac2O, pyr (79%); (j) NaOMe, MeOH; LiOH, H2O, MeOH (51%).

Synthesis of Ganglioside Mimics
619
dimethylacetal in the presence of p-TsOH to afford the 4,6-O-(4-methoxybeny-
lidene)-protected compound 21. Glycosylation with galactosyl donor 4B in the
presence of TMSOTf as catalyst afforded the desired b-linked disaccharide 22
(1H NMR: J1 ,2 ¼ 7.9 Hz). 1-O-Desilylation ( ! 23), transformation into the tri-
chloroacetimidate, and reaction with methanol, as described for 15, afforded
methyl glycoside 24. Treatment with aqueous trifluoroacetic acid (TFA) led to
selective removal of the 4-methoxybenzylidene group, thus furnishing 4,6-O-
unprotected disaccharide 25 in high yield. Treatment of 25 with dibutyltin
oxide in refluxing toluene and then with (R)-3c as alkylating agent in DME
0
0
in the presence of CsF furnished selectively 6-O-alkylated compound 26.
[32]
0
0
´
Removal of the 2 ,3 -O-acetyl group under Zemplen conditions
led also to
transformation of the benzyl to the methyl ester 27; following alkylation
with (R)-3c under the above described conditions afforded protected target
molecule 28. Azide group reduction and acetylation with acetic anhydride in
pyridine led to acetylamino derivative 29. The 40,60-O-benzylidene group was
removed with ethylmercaptan in the presence of p-TsOH as catalyst; ensuing
[32]
´
acetylation gave compound 30. De-O-acetylation under Zemplen conditions
and then methyl ester hydrolysis with LiOH in aqueous methanol led to liber-
ation of target molecule (S)-2c.
All compounds could be characterized by NMR and MS data. The biologic
evaluation of these compounds is under investigation.
In conclusion, mimics of the important ganglioside constituent
Neu5Aca(2–3)Galb(1–3)GalNAcb(1-OR) could be readily obtained. The 3b-
O-linked Neu5Ac residue was replaced by a-hydroxycarbonyl-alkyl groups,
which could be attached via the corresponding trifluoromethanesulfonates as
alkylating agents.
EXPERIMENTAL
General Procedures
Solvents were dried according to the standard procedures. NMR spectro-
scopic measurements were performed at 228C with Bruker DRX600 and
BrukerAC250 Cryospec instruments. TMS or the resonances of the deuterated
solvents were used as internal standard. CDCl3 (d ¼ 7.24 ppm) was used as
external standard; 85% of phosphoric acid was used as external standard for
31P spectra. MALDI mass spectra were recorded with a Kratos Kompact
Maldi II spectrometer; 2,5-dihydroxybenzoic acid (DHB) or p-nitroaniline
and NaI were used as matrices for positive mode measurements, and trihydrox-
yacetophenone (THAP) was used as a matrix for negative mode measurements.
Optical rotations were measured with a Perkin Elmer polarimeter 241/MS in a
1-dm cell at 228C. Thin layer chromatography (TLC) was performed on Merck

S. Janssen and R. R. Schmidt
620
silica gel 60 F254 plastic plates. Compounds were visualized by treatment with
.
a solution of (NH4)6Mo7O24 4H2O (20 g) and Ce(SO4)2 (0.4 g) in 10% sulphuric
acid (400 mL). Flash chromatography was peRformed on J. T Baker silica gel
60 (0.040–0.063 mm) at a pressure of 0.3 bar.
Benzyl (R)-2-Trifluormethane sulfonyloxy-cyclohexylacetate ((R)-3a).
Benzyl (R)-2-Hydroxy-cycloheylacetate. A solution of (R)-hexahydroman-
delic acid (10.0 g, 63.2 mmol) in MeOH/H2O (9 : 1, 125 mL) was neutralized
with Cs2CO3 (20%). Then the solvent was removed in vacuo and the residue
was coevaporated with DMF (130 mL). The white salt was dissolved in dry
DMF (65 mL) under argon and cooled to 08C. Within 10 min benzyl bromide
(6.76 mL, 9.73 g, 56.9 mmol) was added dropwise, then stirred for 2 hr at 08C
and for 14 hr at rt. After removal of the solvent the residue was dissolved in
Et2O (950 mL) and washed with H2O (950 mL). The organic phase was
washed with 1 M NaHCO3 (3 ꢁ 320 mL) and with saturated NaCl
(3 ꢁ 320 mL), and then dried over MgSO4. Removal of the solvent furnished
3 (13.6 g, 54.9 mmol, 97%) as yellow oil; further purification was not
required. TLC (toluene/ethyl acetate 12 : 1): Rf ¼ 0.48. [a]D ¼ þ 5.5 (c ¼ 1,
CHCl3). 1H NMR (250 MHz, CDCl3): d 1.14–1.74 (m, 11H, C6H11), 2.67
(d, JH,OH ¼ 6.3 Hz, 1H, OH), 4.06 (dd, JH,OH ¼ 6.3, Jvic ¼ 3.5 Hz, 1H,
CHC6H11), 5.22 (s, 2H, CH2Ph), 7.35–7.38 (m, 5H, Ph). C15H20O3 (248.3)
Calcd.: C: 72.55, H: 8.12. Found: C: 72.27, H: 8.33.
(R)-3a. To a solution of 3 (13.2 g, 53.0 mmol) in dry CH2Cl2 (105 mL) under
argon was added 2,6-lutidine (8.00 mL, 7.38 g, 68.9 mmol) and then cooled to
2788C. After 5 min Tf2O (10.1 mL, 17.3 g, 61.2 mmol) was added. After 30 min
at 2788C the reaction mixture was warmed to rt over a period of 1.5 hr and
after further 45 min diluted with CH2Cl2 (1000 mL)and washed with H2O
(750 mL). The aqueous phase was then reextracted with CH2Cl2 (2 ꢁ 250 mL),
the combined organic phases dried over MgSO4, and the solvents removed in
vacuo. The residue was dissolved in CH2Cl2/petroleum ether (1 : 1) and
filtered over silica gel. Removal of the solvent furnished (R)-3a (19.4 g,
50.9 mmol, 96%) as orange oil, which could be used without further purification.
TLC (petroleum ether/CH2Cl2 20 : 1): Rf ¼ 0.67. [a]D ¼ þ34 (c ¼ 1, CHCl3). 1H
NMR (250 MHz, CDCl3): d 1.16–2.13 (m, 11H, C6H11), 4.96 (d, Jvic ¼ 4.3 Hz,
1H, CHC6H11), 5.26 (s, 2H, CH2Ph), 7.34–7.37 (m, 5H, Ph). C16H19F3O5S
(380.4) Calcd.: C: 50.52, H: 5.03. Found: C: 50.27, H: 5.04.
Benzyl (S)-2-Trifluormethansulfonyloxy-cyclohexylacetate ((S)-3a).
Benzyl (S)-2-Hydroxy-cyclohexylacetate. A solution of (S)-hexahydroman-
delic acid (10.0 g, 63.2 mmol) in MeOH/H2O (9 : 1, 125 mL) was neutralized
with Cs2CO3 (20%). The solvent was removed in vacuo and the residue was coe-
vaporated with DMF (130 mL).

Synthesis of Ganglioside Mimics
621
The white salt was dissolved in dry DMF (65 mL) under argon and cooled to
08C. Within 10 min benzyl bromide (6.76 mL, 9.73 g, 56.9 mmol) was added
dropwise, then stirred for 2 hr at 08C and then for 14 hr at rt. After removal of
the solvent the residue was dissolved in Et2O (950 mL) and washed with H2O
(950 mL). The organic phase was washed additionally with 1 M NaHCO3
(3 ꢁ 320 mL) and with saturated NaCl (3 ꢁ 320 mL), and then dried over
MgSO4. Removal of the solvent furnished 4 (13.6 g, 54.9 mmol, 97%) as yellow
oil, without need of further purification. TLC (toluene/ethyl acetate 12 : 1):
Rf ¼ 0.48. [a]D ¼ –5.5 (c ¼ 1, CHCl3). 1H NMR (250 MHz, CDCl3): d 1.14–1.74
(m, 11H, C6H11), 2.67 (d, JH,OH ¼ 6.3 Hz, 1H, OH), 4.06 (dd, JH,OH ¼ 6.3,
Jvic ¼ 3.5 Hz, 1H, CHC6H11), 5.22 (s, 2H, CH2Ph), 7.35–7.38 (m, 5H, Ph).
C15H20O3 (248.3). Calcd.: C: 72.55, H: 8.12. Found: C: 72.37, H: 7.30.
(S)-3a. To a solution of 4 (13.2 g, 53.0 mmol) and dry CH2Cl2 (105 mL) under
argon was added 2,6-lutidine (8.00 mL, 7.38 g, 68.9 mmol) and then cooled to
2788C. After 5 min Tf2O (10.1 mL, 17.3 g, 61.2 mmol) was added. After
30 min at 2788C the reaction mixture was warmed to rt over a period of
1.5 hr and after further 45 min diluted with CH2Cl2 (1000 mL) and washed
with H2O (750 mL). The aqueous phase was reextracted with CH2Cl2
(2 ꢁ 250 mL), the combined organic phases dried over MgSO4, and the
solvents removed in vacuo. The residue was dissolved in CH2Cl2/petroleum
ether (1 : 1) and filtered over silica gel. Removal of the solvent furnished
(S)-3a (19.4 g, 50.9 mmol, 96%) as orange oil, which could be used
without further purification. TLC (petroleum ether/CH2Cl2 20 : 1): Rf ¼ 0.67.
1
[a]D ¼ 234 (c ¼ 1,CHCl3). H NMR (250 MHz, CDCl3): d 1.16–2.13 (m, 11H,
C6H11), 4.96 (d, Jvic ¼ 4.3 Hz, 1H, CHC6H11), 5.26 (s, 2H, CH2Ph), 7.34–7.37
(m, 5H, Ph). C16H19F3O5S (380.4) Calcd.: C: 50.52, H: 5.03. Found: C: 50.57,
H: 4.92.
1,2,3-Tri-O-benzoyl-4,6-O-benzylidene-a/ß-D-galactopyranose (7A). A
solution of 6 (2.76 g, 10.3 mmol) and pyridine (75 mL) was cooled to 48C in
ice/water. Then benzoyl chloride (4.21 mL, 5.10 g, 36.3 mmol) was added
dropwise and also a pinch of DMAP. After 3 d at rt the solvent was removed
in vacuo and the residue coevaporated twice with toluene.
Purification by flash chromatography (petroleum ether/ethyl acetate 2 : 1
to 1 : 1) furnished 7A (5.08 g, 8.75 mmol, 85%) as colorless foam. The physical
data are identical with the literature.[26]
2,3-Di-O-benzoyl-4,6-O-benzylidene-a/ß-D-galactopyranose (8A).
A
.
solution of 7A (5.60 g, 9.65 mmol) and N2H4 HOAc (1.33 g, 14.4 mmol) in dry
DMF (30 mL) under argon was stirred for 3 hr at 458C and then diluted with
H2O (3 ꢁ 50 mL) and extracted with ethyl acetate (100 mL). The aqueous
phase was reextracted with ethyl acetate (2 ꢁ 50 mL), the combined organic

S. Janssen and R. R. Schmidt
622
phases dried over MgSO4, and the solvent removed in vacuo. Purification by
flash chromatography (toluene/ethyl acetate 9 : 1) furnished 8A (1.31 g,
2.75 mmol, 29%) as colorless foam. The physical data are identical with the
literature.[28]
O-(2,3-Di-O-benzoyl-4,6-O-benzylidene-a-D-galactopyranosyl) trichlor-
acetimidate (4A). To a solution of 8A (1.84 g, 3.86 mmol) and dry CH2Cl2
(30 mL) under argon was added CCl3CN (4.25 mL, 6.12 g, 43.3 mmol). After
addition of DBU (5 drops) the reaction mixture was stirred for 45 min at rt,
and then concentrated to approximately 5 mL. Purification by flash chromato-
graphy (petroleum ether/ethyl acetate 1 : 1 þ 1% Et3N) furnished 4A (2.13 g,
3.43 mmol, 89%) as colorless foam. TLC (toluene/ethyl acetate 3 : 1):
Rf ¼ 0.74. [a]D ¼ þ 159(c ¼ 1, CHCl3). 1H NMR (250 MHz, CDCl3): d 4.14
(d, J6,6 ¼ 11.6 Hz, 1H, 60-H), 4.17 (s,1H, 5-H), 4.41 (d, J6,6 ¼ 11.6 Hz, 1H,
6-H), 4.77 (d, J3,4 ¼ 3.3 Hz, 1H, 4-H), 5.60 (s, 1H, CHPh), 5.85–6.09 (2dd, 2H,
2-H, 3-H), 6.88 (d, J1,2 ¼ 3.4 Hz, 1H, 1-H), 7.32–8.03 (m, 15H, 3Ph), 8.59
(s, 1H, NH). MALDI-MS (positive mode, DHB): [M þ Na]þ, m/z ¼ 642.1;
found: m/z ¼ 642.8, [M þ K]þ, m/z ¼ 658.2; found: m/z ¼ 658.8.
Thexyldimethylsilyl 2-Azido-4,6-O-benzylidene-2-deoxy-ß-D-galacto-
pyranoside (5).[31] To a solution of thexyldimethylsilyl 2-azido-2-deoxy-b-D-
galactopyranoside6 (10.0 g, 28.8 mmol) in dry DMF (250 mL) under argon
was added benzaldehyde dimethylacetal (11.9 mL, 12.1 g, 79.5 mmol). Then
p-TsOH (120 mg, 0.62 mmol) was added and stirred for 5 hr at 508C. After
cooling to rt the reaction mixture was neutralized with Et3N (1.00 mL) and
the solvent removed in high vacuo at 408C. Purification by flash chromato-
graphy (petroleum ether/ethyl acetate 1 : 1) furnished 20 (7.86 g, 18.0 mmol,
63%) as colorless oil. The physical data are identical with the literature.[31]
Thexyldimethylsilyl O-(2,3-Di-O-benzoyl-4,6-O-benzylidene -ß-D-galac-
topyranosyl)-(1!3)-2-azido-4,6-O-benzylidene-2-deoxy-ß-D-galactopyr-
anoside (9A). A solution of 4A (1.10 g, 1.77 mmol) and 5 (670 mg, 1.54 mmol) in
dry CH2Cl2 (75 mL) under argon was cooled to 08C. After addition of TMSOTf
(0.1 N, 0.77 mL, 0.05 eq.) the reaction mixture was stirred for 1 hr at rt, then
neutralized with Et3 N (0.30 mL) and the solvent removed in vacuo. Purifi-
cation by flash chromatography (toluene/ethyl acetate 9 : 1) furnished 9A
(1.14 g, 1.27 mmol, 83%) as colorless foam. TLC (toluene/ethyl acetate 3 : 1):
Rf ¼ 0.37. [a]D ¼ þ 45 (c ¼ 1,CHCl3). 1H NMR (250 MHz, CDCl3): d 0.17
(2 ꢁ s, 6H, Si(CH3)2), 0.85 (m, 12H, C(CH3)),1.64 (m, 1H, C(CH3)2H), 3.34
(s, 1H, 5-H), 3.63 (m, 2H, 2-H, 3-H), 3.71 (s, 1H, 50-H), 4.01(dd, J5,6 ¼ 1.5,
J6,6 ¼ 12.3 Hz, 1H, 6-H), 4.18 (m, 2H, 60-H, 6-H), 4.33 (d, J3,4 ¼ 2.1 Hz, 1H,
4-H), 4.38 (dd, J5,6 ¼ 1.2, J6,6 ¼ 12.5 Hz, 1H, 60-H), 4.53 (d, J1,2 ¼ 7.3 Hz, 1H,
1-H), 4.61 (d, J3,4 ¼ 3.6 Hz, 1H, 40-H), 5.17 (d, J1,2 ¼ 8.0 Hz, 1H, 10-H), 5.36

Synthesis of Ganglioside Mimics
623
(dd, J3,4 ¼ 3.6, J2,3 ¼ 10.4 Hz, 1H, 30-H), 5.55 (s, 2H, 2CHPh), 5.88 (dd,
J1,2 ¼ 8.0, J2,3 ¼ 10.4 Hz, 1H, 20-H), 7.18–8.02 (m, 20H, 4Ph). MALDI-MS
(positive mode, DHB): [M þ Na]þ, m/z ¼ 916.4; found: m/z ¼ 917.0,[M þ K]þ,
m/z ¼ 932.5; found: m/z ¼ 932.7. C48H55N3O12Si (894.1) Calcd.: C: 64.48, H:
6.20, N: 4.70. Found: C: 63.92, H: 6.28, N: 4.62.
Thexyldimethylsilyl O-(2,3-Di-O-acetyl-4,6-O-benzylidene-ß-D-galacto-
pyranosyl)-(1!3)-2-azido-4,6-O-benzylidene-2-deoxy-ß-D-galactopyra-
noside (9B). A solution of 4B (4.72 g, 9.50 mmol) and 5 (3.77 g, 8.65 mmol) in
dry CH2Cl2 (100 mL) under argon was cooled to 08C. After addition of
TMSOTf (0.1 N, 4.00 mL, 0.05 eq) the reaction mixture was stirred for 1 hr at
08C, then neutralized with Et3 N (3.50 mL) and the solvent removed in vacuo.
Purification by flash chromatography (toluene/ethyl acetate 5 : 1) furnished
9B (5.93 g, 7.70 mmol, 89%) as colorless foam. TLC (toluene/ethyl acetate
1 : 1): Rf ¼ 0.59. [a]D ¼ þ 45 (c ¼ 1,CHCl3). 1H NMR (250 MHz, CDCl3):
d 0.20 þ 0.21 (2 ꢁ s, 6H, Si(CH3)2), 0.89–0.91 (m,12H, C(CH3)), 1.64–1.74
(m, 1H, C(CH3)2H), 2.06 þ 2.07 (2 ꢁ s, 6H, 2 ꢁ COCH3), 3.34 (s,1H, 5-H),
3.51–3.57 (m, 2H, 3-H, 50-H), 3.71 (dd, J1,2 ¼ 7.5, J2,3 ¼ 9.6 Hz, 1H, 2-H),
3.99–4.33(m, 5H, 4-H, 6-H, 6-H, 60-H, 60-H), 4.38 (d, J3,4 ¼ 3.6 Hz, 1H, 40-H),
4.52 (d, J1,2 ¼ 7.5 Hz, 1H,1-H), 4.88 (d, J1,2 ¼ 7.9 Hz, 1H, 10-H), 4.97 (dd,
J2,3 ¼ 10.4, J3,4 ¼ 3.6 Hz, 1H, 30-H), 5.42 (dd, J1,2 ¼ 7.9, J2,3 ¼ 10.4 Hz, 1H,
20-H), 5.51 þ 5.56 (2 ꢁ s, 2H, 2 ꢁ CHPh), 7.32–7.57 (m, 10H, Ar). MALDI-MS
(positive mode, CHCA): [M þ Na]þ, m/z ¼ 792.3; found: m/z ¼ 792.2,
[M þ K]þ, m/z ¼ 792.3; found: m/z ¼ 792.2. C38H51N3O12Si (769.9) Calcd.: C:
59.28, H: 6.68, N: 5.46. Found: C: 59.17, H: 6.84, N: 5.69.
Thexyldimethylsilyl O-(4,6-O-Benzylidene-b-D-galactopyranosyl)-(1!
3)-2-azido-4,6-Obenzylidene-2-deoxy-b-D-galactopyranoside (10). To a
solution of 9A (1.16 g, 1.30 mmol) in dry MeOH/CH2Cl2 (1 : 1, 30 mL) under
argon was added NaOMe (0.2 N, 0.50 mL). After 20 hr at rt the reaction
mixture was neutralized with ion exchange resin IR 120 (Hþ-Form) and the
solvent removed in vacuo. Purification by flash chromatography (toluene/
ethyl acetate 2 : 1 to 1 : 1) furnished 10 (315 mg, 0.46 mmol, 35%) as colorless
foam. TLC (toluene/ethyl acetate 1 : 1): Rf ¼ 0.16. [a]D ¼ þ 5.8 (c ¼ 0.57,
CHCl3). 1H NMR (600 MHz, CDCl3): d 0.22 (2 ꢁ s, 6H, Si(CH3)2), 0.91
(m, 12H, C(CH3)), 1.69 (m, 1H, C(CH3)2H), 2.50 þ 2.71 (m, 2H, 2 ꢁ OH), 3.36
(s, 1H, 5-H), 3.47 (s, 1H, 50-H), 3.57 (dd, J2,3 ¼ 10.6, J3.4 ¼ 3.5 Hz, 1H, 3-H),
3.71 (s, 1H, 30-H), 3.79–3.81 (m, 2H, 20-H, 2-H), 4.02 (dd, J6,6 ¼ 12.3,
J5,6 ¼ 1.6 Hz, 1H, 6-H), 4.09 (dd, J6,6 ¼ 12.3, J5,6 ¼ 1.7 Hz, 1H, 60-H), 4.20
(d, J3,4 ¼ 3.9 Hz, 1H, 40-H), 4.25 (dd, J6,6 ¼ 12.3, J5,6 ¼ 1.6 Hz, 1H, 6-H), 4.29
(dd, J6,6 ¼ 12.3, J5,6 ¼ 1.7 Hz, 1H, 60-H), 4.33 (d, J3,4 ¼ 3.5 Hz,1H, 4-H), 4.57
(d, J1,2 ¼ 7.6 Hz, 1H, 1-H), 4.59 (d, J1,2 ¼ 7.7 Hz, 1H, 10-H), 5.55 (s, 1H,
CHPh), 5.56 (s, 1H, CHPh), 7.34–7.55 (m, 10H, 2Ph). 13C NMR (150.9 MHz,

S. Janssen and R. R. Schmidt
624
CDCl3): d 64.7 (2-C), 66.6 (5-C), 66.8 (50-C), 69.1 (6-C), 69.2 (60-C), 71.6 (20-C),
72.3 (30-C), 75.2 (40-C), 75.4 (4-C), 77.5 (3-C), 97.3 (1-C), 101.2 (2 ꢁ CHPh),
104.0 (10-C). MALDI-MS (positive mode, DHB): [M þ Na]þ, m/z ¼ 708.3;
found:
m/z ¼ 708.0,
[M þ K]þ,
m/z ¼ 724.4;
found:
m/z ¼ 724.0.
C34H47N3O10Si (685.8) Calcd.: C: 59.54, H: 6.91, N: 6.13. Found: C: 59.24, H:
6.80, N: 5.98.
Thexyldimethylsilyl O-(4,6-O-Benzylidene -3-O-[(R)-1-benzyloxycarbo-
nyl-1-cyclohexylmethyl]-ß-D-galactopyranosyl)-(1!3)-2-azido-4,6-O-
benzylidene-2-deoxy-ß-D-galactopyranoside((R)-11a) and Thexyldi-
methylsilyl O-(4,6-O-Benzylidene-3-O-[(R)-1-carboxy-1-cyclohexylmet-
hyl]-ß-D-galactopyranosyl-2b-lactone)-(1!3)-2-azido-4,6-Obenzyli-
dene-2-deoxy-ß-D-galactopyranoside (Lactone). To a mixture of 10
(261 mg, 0.38 mmol) and Bu2SnO (113 mg, 0.45 mmol) under argon was added
dry toluene (10 mL); the mixture was heated for 2 hr under reflux over molecu-
lar sieves (0.4 nm). After cooling to rt CsF (704 mg, 1.90 mmol), (S)-3a (723 mg,
1.90 mmol), and 1,2-dimethoxyethane (10 mL) were added to the pale yellow
reaction mixture and stirred for 3 hr at rt, then diluted with CHCl3 (40 mL)
and washed with H2O (2 ꢁ 30 mL). The aqueous phase was reextracted
withCHCl3 (2 ꢁ 30 ml), the combined organic phases dried over MgSO4, and
the solvent removed under vacuo. Purification by flash chromatography
(toluene/ethyl acetate 7 : 1) furnished (R)-11a (164 mg, 0.18 mmol, 47%) as col-
orless, amorphous solid and Lactone (74 mg, 0.09 mmol, 24%) as colorless,
amorphous solid.
(R)-11a. TLC (toluene/ethyl acetate 3 : 1): Rf ¼ 0.39. [a]D ¼ þ 45 (c ¼ 0.67,
1
CHCl3). H NMR (600 MHz, CDCl3): d 0.20 þ 0.23 (2 ꢁ s, 6H, Si(CH3)2), 0.90
(m, 12H, C(CH3)), 1.02–1.75(m, 12H, CHC6H11, C(CH3)2H), 3.33–3.34
(m, 3H, 30-H, 5-H, 50-H), 3.57 (dd, J2,3 ¼ 10.6, J3,4 ¼ 3.3 Hz, 1H, 3-H), 3.82
(dd, J1,2 ¼ 7.7, J2,3 ¼ 10.6 Hz, 1H, 2-H), 3.88 (d, Jvic ¼ 5.4 Hz, 1H, CHC6H11),
3.94 (dd, J1,2 ¼ 7.7, J2,3 ¼ 8.5 Hz, 1H, 20-H), 4.00–4.30 (m, 6H, 4-H, 40-H,
6-H, 6-H,60-H, 60-H), 4.55 (d, J1,2 ¼ 7.7 Hz, 1H, 1-H), 4.61 (d, J1,2 ¼ 7.7 Hz,
1H, 10-H), 5.12 þ 5.20 (2 ꢁ d, Jgem ¼ 12.1 Hz, 2H, CO2CH2Ph), 5.50 (s, 1H,
CH’Ph), 5.94 (s, 1H, CHPh), 7.31–7.53 (m, 15H, 3Ph). 13C NMR (150.9 MHz,
CDCl3): d 64.7 (2-C), 66.6 (5-C, 50-C), 68.9 (20-C), 69.1(6-C), 69.4 (60-C), 72.3
(40-C), 75.3 (4-C), 76.7 (3-C), 80.3 (30-C), 81.8 (CHC6H11), 97.3 (1-C), 100.7
(C’HPh), 101.0 (CHPh), 103.8 (10-C). MALDI-MS (positive mode, CHCA):
[M þ Na]þ, m/z ¼ 938.4; found: m/z ¼ 938.2, [M þ K]þ, m/z ¼ 954.5; found:
m/z ¼ 954.1. C49H65N3O12Si (916.1) Calcd: C: 64.24, H: 7.15, N: 4.59. Found:
C: 63.92, H: 7.45, N: 4.46.
Lactone. TLC (toluene/ethyl acetate 1 : 1): Rf ¼ 0.39. [a]D ¼ þ 25 (c ¼ 0.36,
1
CHCl3). H NMR(600 MHz, CDCl3): d 0.21 (2 ꢁ s, 6H, Si(CH3)2), 0.91 (m, 12H,

Synthesis of Ganglioside Mimics
625
C(CH3)), 1.08–1.75 (2 ꢁ m, 11H, C6H10H, C(CH3)2H), 1.98 (m, 1H, C6H10H), 3.34
(s, 1H, 5-H), 3.49 (s, 1H, 50-H), 3.56(dd, J2,3 ¼ 10.7, J3,4 ¼ 3.3 Hz, 1H, 3-H), 3.66
(dd, J2,3 ¼ 9.7, J3,4 ¼ 3.3 Hz, 1H, 30-H), 3.82 (dd, J1,2 ¼ 7.6, J2,3 ¼ 10.7 Hz, 1H,
2-H), 4.00 (dd, J6,6 ¼ 12.2, J5,6 ¼ 1.1 Hz, 1H, 6-H), 4.13 (dd, J6,6 ¼ 12.4,
J5,6 ¼ 1.0 Hz, 1H, 60-H), 4.22 (d, J6,6 ¼ 12.2 Hz, 1H, 6-H), 4.28–4.33 (m, 4H, 60-
H, 40-H, CHC6H11, 4-H), 4.54 (d, J1,2 ¼ 7.6 Hz, 1H, 1-H), 4.60 (dd, J1,2 ¼ 7.9,
J2,3 ¼ 9.7 Hz, 1H, 20-H), 4.91 (d, J1,2 ¼ 7.9 Hz, 1H, 10-H), 5.53 þ 5.59 (2 ꢁ s, 2H,
2 ꢁ CHPh), 7.31–7.53 (m, 10H, 2Ph). 13C NMR (150.9 MHz, CDCl3): d 64.8 (2-
C), 66.7 (5-C), 66.8 (50-C), 69.1 (6-C, 60-C), 73.0 (30-C), 73.3 (40-C), 74.3 (20-C),
75.3 (4-C), 77.1 (3-C), 81.0 (CHC6H11), 97.5 (1-C), 100.8 (10-C), 100.5 þ 101.8
(2 ꢁ CHPh). MALDI-MS (positive mode, DHB): [M þ Na]þ, m/z ¼ 846.4;
found: m/z ¼ 846.0.
Thexyldimethylsilyl O-(4,6-O-Benzylidene-3-O-[(R)-1-benzyloxycarbo-
nyl-1-cyclohexylmethyl]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-
O-benzylidene -2-deoxy-ß-D-galactopyranoside((R)-12a). To a solution
of (R)-11a (150 mg, 0.16 mmol) and pyridine/H2O (5 : 1, 9.25 mL) was added
1,3-propanedithiol (0.29 mL, 0.32 g, 2.93 mmol) and the pH value adjusted to
9–10 with Et3 N (0.3 mL). After 20 h at rt the solvent was removed in vacuo
and the residue coevaporated with toluene/EtOH (5 : 1, 4 ꢁ 25 ml). The
residue was dissolved in dry CH2Cl2 (8.00 mL) and Ac2O (1.90 mL, 2.10 g,
20.5 mmol) added. After 6 h at rt the solvent was removed in vacuo and the
crude product coevaporated with toluene (3 ꢁ 25 mL). Purification by flash
chromatography (toluene/ethyl acetate 1 : 2) furnished (R)-12a (138 mg,
0.15 mmol, 90%) as colourless, amorphous solid. TLC (toluene/ethyl acetate
1 : 2): Rf ¼ 0.31. MALDI-MS (positive mode, DHB): [M þ Na]þ, m/z ¼ 954.5;
found: m/z ¼ 954.7, [M þ K]þ, m/z ¼ 970.6; found: m/z ¼ 970.8.
Thexyldimethylsilyl O-(3-O-[(R)-1-Hydroxycarbonyl-1-cyclohexyl-
methyl]-ß-D-galactopy ranosyl)-(1!3)-2-acetamido-2-deoxy-ß-D-galac-
topyranoside ((R)-1aa). To a solution of (R)-12a (50 mg, 54mmol) and dry
MeOH (2.5 mL) was added Pd/C (10%, 15 mg) and stirred for 24 hr under H2-
atmosphere. If the starting material was not totally consumed, HCO2H
(0.10 mL) was added and the reaction mixture stirred for further 24 hr under
H2-atmosphere. The catalyst was filtered off over Celite; the reaction mixture
was neutralized with NH3 solution (1 : 100) and then concentrated under
reduced pressure. Purification by flash chromatography (CHCl3/MeOH/H2O
30 : 20 : 1) furnished (R)-1aa (15 mg, 23mmol, 43%) as colorless, amorphous
solid. TLC (CHCl3/MeOH/H2O 6 : 4 : 1): Rf ¼ 0.52. 1H NMR (600 MHz, d6-
DMSO): d 0.07 (2 ꢁ s, 6H, Si(CH3)2), 0.76–0.81 (m, 12H, C(CH3)), 1.07–1.73
(m, 15H, NHCOCH3, CHC6H11, C(CH3)2H), 3.02 (d, J2,3 ¼ 9.7 Hz, 1H, 30-H),
3.22 þ 3.28 (2 ꢁ m, 2H, 5-H, 50-H), 3.41–3.52 (m, 5H, 20-H, 6-H, 6-H, 60-H, 60-
H), 3.67 (d, J2,3 ¼ 10.8 Hz, 1H, 3-H), 3.73 (s, 1H, 40-H), 3.77 (m, 1H, 2-H),

S. Janssen and R. R. Schmidt
626
3.83–3.85 (m, 2H, 4-H, CHC6H11), 4.23 (d, J1,2 ¼ 7.6 Hz, 1H, 10-H), 4.52
(d, J1,2 ¼ 7.8 Hz, 1H, 1-H), 7.55 (d, JN,NH ¼ 9.0 Hz, 1H, NH). 13C NMR
(150.9 MHz, d6-DMSO): d 52.0 (2-C), 59.9 (6-C, 60-C), 64.5 (40-C), 66.8 (4-C),
68.5 (20-C),69.1 (CHC6H11), 74.9 þ 75.0 (5-C, 50-C), 78.5 (3-C), 81.8 (30-C), 96.1
(1-C), 103.9 (10-C). FAB-MS (positive mode, NBA): [M þ Na]þ, m/z ¼ 688.3;
found: m/z ¼ 688, [M þ 2Na-H]þ, m/z ¼ 710.3; found: m/z ¼ 710,
[M þ Na þ K-H]þ, m/z ¼ 726.4; found: m/z ¼ 726. FAB-MS (positive mode,
NBA þ NaI): [M þ 2Na-H]þ, m/z ¼ 710.3; found: m/z ¼ 710. MALDI-MS
(positive mode, DHB): [M þ Na]þ, m/z ¼ 688.3; found: m/z ¼ 688.6,
[M þ K]þ, m/z ¼ 704.4; found: m/z ¼ 704.7.
Methyl
O-(2,3-Di-O-acetyl-4,6-O-benzylidene-b-D-galactopyranosyl)-
(1 ! 3)-2-azido-4,6-O-benzylidene-2-deoxy-b-D-galactopyranoside (15).
A solution of 14[38] (1.44 g, 186 mmol) and dry MeOH (0.18 mL, 0.14 g,
4.4 mmol) in dry CH3CN (17.0 mL) was cooled under argon to –188C and
stirred for 2 hr at this temperature after adding Sn(OTf)2-solution (0.1 N,
0.19 mL, 0.01 eq.). The reaction mixture was diluted with Et2O (150 mL) and
washed with saturated NaHCO3 solution (90 mL) and H2O (90 mL), and the
organic phase was dried over MgSO4. The solvent was evaporated under
reduced pressure. Purification by flash chromatography (toluene/ethyl
acetate 2 : 1 ! 1 : 1) furnished 15 (710 mg, 1.11 mmol, 59%) as colorless foam.
1
TLC (toluene/ethyl acetate 1 : 1): Rf ¼ 0.20. [a]D ¼ þ 44 (c ¼ 0.92, CHCl2). H
NMR (250 MHz, CDCl3): d 2.05 þ 2.07 (2 ꢁ s, 6H, 2 ꢁ COCH3), 3.37 (s, 1H,
5-H), 3.54–3.64 (m, 5H, 3-H, 50-H, OCH3), 3.80 (dd, J1,2 ¼ 7.9, J2,3 ¼ 10.5 Hz,
1H, 2-H), 4.01–4.11 (m, 2H, 6-H, 60-H), 4.18 (d, J1,2 ¼ 7.9 Hz, 1H, 1-H), 4.27–
4.38 (m, 4H, 4-H, 40-H, 6-H, 60-H), 4.90 (d, J1,2 ¼ 7.9 Hz, 1H, 10-H), 4.98 (dd,
J2,3 ¼ 10.4, J3,4 ¼ 3.6 Hz, 1H, 30-H), 5.43 (dd, J1,2 ¼ 7.9, J2,3 ¼ 10.4 Hz, 1H,
20-H), 5.51 þ 5.57 (2 ꢁ s, 2H, 2 ꢁ CHPh), 7.29–7.56 (m, 10H, Ar). MALDI-MS
(positive mode, CHCA): [M þ Na]þ, m/z ¼ 664.2; found: m/z ¼ 664.2,
[M þ K]þ, m/z ¼ 680.3; gef.: m/z ¼ 680.1. C31H35N3O12 (641.6) Calcd.: C:
58.03, H: 5.50, N: 6.55. Found: C: 58.09, H: 5.32, N: 7.13.
Methyl O-(4,6-O-Benzylidene-b-D-galactopyranosyl)-(1 ! 3)-2-azido-
4,6-O-benzylidene -2-deoxy-b-D-galactopyranoside (16). To a solution of
15 (710 mg, 1.11 mmol) and dry MeOH/CH2Cl2 (1 : 1, 40 mL) was added
NaOMe solution (1.2 M, 1.50 mL) under argon. After18 hr at rt the solution
was neutralized with ion exchange resin IR 120 (Hþ-Form) and the solvent
removed under reduced pressure. Purification by flash chromatography
(toluene/acetone 1 : 1) furnished 16 as colorless amorphous solid. TLC
(toluene/acetone 1 : 1):Rf ¼ 0.42. [a]D ¼ –98 (c ¼ 0.11, CHCl3). 1H NMR
(600 MHz, d6-DMSO): d 3.36 (m, 1H, 20-H), 3.47–3.51 (m, 5H, 3-b, 5-H,
OCH3), 3.57–3.61 (m, 2H, 2-H, 50-H), 3.70 (dd, J2,3 ¼ 10.5, J3,4 ¼ 3.0 Hz, 1H,
3-H), 4.06–4.08 (m, 5H, 40-H, 6-H, 6-H, 60-H, 60-H), 4.30 (d, J3,4 ¼ 3.0 Hz,

Synthesis of Ganglioside Mimics
627
1H,4-H), 4.36 (d, J1,2 ¼ 8.0 Hz, 1H, 1-H), 4.47 (d, J1,2 ¼ 7.7 Hz, 1H, 10-H), 4.90
(d, JH,OH ¼ 6.0 Hz,1H, 30-OH), 5.04 (d, JH,OH ¼ 4.5 Hz, 1H, 20-OH), 5.56 þ 5.63
(2 ꢁ s, 2H, 2 ꢁ CHPh), 7.31–7.47(m, 10H, 2Ph). 13C NMR (150.9 MHz, d6-
DMSO): d 56.3 (OCH3), 62.8 (2-C), 65.8 þ 66.2 (5-C, 50-C), 68.1 þ 68.6 (6-C, 60-
C), 69.8 (20-C), 71.7 (30-C), 74.8 (4-C), 75.9 (40-C), 76.9 (3-C), 99.5 þ 99.8
(2 ꢁ CHPh), 102.0 (1-C), 104.7 (10-C). MALDI-MS (positive mode, CHCA):
[M þ Na]þ, m/z ¼ 580.2; found: m/z ¼ 580.2, [M þ K]þ, m/z ¼ 596.3; found:
m/z ¼ 596.1. C27H31N3O10 (557.6) Calcd.: C: 58.16, H: 5.60, N: 7.54. Found:
C: 57.48, H: 5.94, N: 7.53.
Methyl O-(4,6-Benzylidene -3-O-[(R)-1-benzyloxycarbonyl-1-cyclohex-
ylmethyl]-b-D-galactosylpyranosyl)-(1 ! 3)-2-azido-4,6-O-benzylidene-
2-deoxy-b-D-galactopyranoside ((R)-17a). To a solution of 16 (116 mg,
0.21 mmol) and Bu2SnO (66 mg, 0.26 mmol) was added dry toluene under
argon and then heated for 1.5 hr under reflux over molecular sieves (0.4 nm).
After cooling to rt CsF (402 mg, 1.04 mmol), (S)-3a (306 mg, 1.04 mmol) and
1,2-dimethoxyethane (4.00 mL) were added to the pale yellow reaction
mixture and stirred for 2 hr at rt. Then it was diluted with CHCl3 (30 mL)
and washed with H2O (2 ꢁ 20 mL). The aqueous phase was reextracted with
CHCl3 (2 ꢁ 20 mL), the combined organic phases dried over MgSO4, and the
solvent removed in vacuo. Purification by flash chromatography (toluene/
acetone 2 : 1) furnished (R)-17a (131 mg, 0.17 mmol, 80%) as colorless amor-
phous solid. TLC (toluene/acetone 1 : 1): Rf ¼ 0.30. [a]D ¼ þ 39 (c ¼ 0.31,
CHCl3). 1H NMR (600 MHz, CDCl3): d 0.80–1.65 (m, 11H, C6H11), 3.33
(m, 2H, 3-b, 5-H), 3.37 (s, 1H, 50-H), 3.58(s, 3H, OCH3), 3.64 (dd, J2,3 ¼ 10.5,
J3,4 ¼ 3.3 Hz, 1H, 3-H), 3.88–4.05 (m, 5H, 2-H, 20-H, 6-H,60-H, CHC6H11),
4.12 (d, J3,4 ¼ 3.1 Hz, 1H, 40-H), 4.20 (d, J1,2 ¼ 8.0 Hz, 1H, 1-H), 4.29–
4.34(m, 3H, 4-H, 6-H, 60-H), 4.62 (d, J1,2 ¼ 7.7 Hz, 1H, 10-H), 5.13 þ 5.20
(2 ꢁ d, Jgem ¼ 12.1 Hz, 2H, CO2CH2Ph), 5.49 þ 5.55 (2 ꢁ s, 2H, 2 ꢁ CHPh),
7.26–7.48 (m, 15H, 3Ph). 13C NMR (150.9 MHz, CDCl3): d 56.9 (OCH3), 61.9
(2-C), 66.5 þ 66.7 (5-C, 50-C), 68.8 (20-C), 68.9 þ 69.2 (6-C, 60-C), 72.2 (40-C),
75.3 (4-C), 76.9 (3-C), 80.5 (30-C), 81.6 (CHC6H11), 100.7 þ 101.0 (2 ꢁ CHPh),
103.3 (1-C), 104.0 (10-C). MALDI-MS (positive mode, CHCA): [M þ Na]þ, m/
z ¼ 810.3; found: m/z ¼ 810.4, [M þ K]þ, m/z ¼ 826.4; found: m/z ¼ 826.4.
C42H49N3O12 (787.9) Calcd.: C: 64.03, H: 6.27, N: 5.33. Found: C: 64.03, H:
6.60, N: 5.44.
Methyl O-(4,6-O-Benzylidene-3-O-[(S)-1-benzyloxycarbonyl-1-cyclohex-
ylmethyl]-b-D-galactopyranosyl)-(1 ! 3)-2-azido-4,6-O-benzylidene-2-
deoxy-b-D-galactopyranoside ((S)-17a). As described for (R)-17a from 16
(125 mg, 0.22 mmol), Bu2SnO (60 mg, 0.25 mmol), CsF (440 mg, 1.14 mmol),
and (R)-3a (434 mg, 1.14 mmol), after flash chromatography (toluene/acetone
5 : 1) 102 mg (0.13 mmol, 59%) of (S)-17a were obtained as colorless oil. TLC

S. Janssen and R. R. Schmidt
628
(toluene/acetone 1 : 1): Rf ¼ 0.42. [a]D ¼ –15 (c ¼ 0.40, CHCl3). 1H NMR
(600 MHz, CDCl3): d 0.80–1.81 (m, 11H, C6H11), 2.54 (d, JH,OH ¼ 1.9 Hz, 1H,
OH), 3.29 (s, 1H, 5-H), 3.37–3.38 (m, 2H, 30-H, 50-H), 3.58–3.60 (m, 4H, 3-H,
OCH3), 3.85 (dd, J1,2 ¼ 8.2, J2,3 ¼ 10.4 Hz, 1H, 2-H), 4.00 (m, 3H, 20-H, 6-H,
60-H), 4.18–4.23 (m, 4H, 1-H, 40-H, 6-H, CHC6H11),4.30–4.34 (m, 2H, 4-H, 60-
H), 4.52 (d, J1,2 ¼ 7.6 Hz, 1H, 10-H), 5.07 (2 ꢁ s, 2H, CO2CH2Ph), 5.42 þ 5.54
(2 ꢁ s, 2H, 2 ꢁ CHPh), 7.31–7.52 (m, 15H, 3Ph). 13C NMR (150.9 MHz,
CDCl3): d 57.1 (OCH3), 62.0 (2-C), 66.8 þ 66.9 (5-C, 50-C), 68.9 þ 69.0 (6-C, 60-
C), 71.2 (20-C), 74.9 (40-C), 75.4 (4-C), 77.5 (3-C), 79.3 (30-C), 84.2 (CHC6H11),
100.6 þ 101.1 (2 ꢁ CHPh), 103.3 (1-C), 104.3 (10-C). MALDI-MS (positive
mode, CHCA): [M þ Na]þ, m/z ¼ 810.3; found: m/z ¼ 810.4, [M þ K]þ, m/
z ¼ 826.4; found: m/z ¼ 826.4. C42H49N3O12 (787.9) Calcd.: C: 64.03, H:6.27,
N: 5.33. Found: C: 64.25, H: 6.17, N: 5.50.
Methyl O-(4,6-O-Benzylidene-3-O-[(S)-1-benzyloxycarbonyl-2-pheny-
lethyl]-ß-D-galactopyranosyl)-(1!3)-2-azido-4,6-O-benzylidene-2-deoxy-
ß-D-galactopyranoside ((S)-17b). As described for (R)-17a from 16 (125 mg,
0.22 mmol), Bu2SnO (60 mg, 0.25 mmol), CsF (440 mg, 1.14 mmol), (R)-3b[33]
(434 mg, 1.14 mmol), and 1,2-dimethoxyethane (1.50 mL), after flash chromato-
graphy (toluene/acetone 5 : 1) 127 mg (0.16 mmol, 73%) of (S)-17b were
obtained as colorless oil. TLC (toluene/acetone 1 : 1): Rf ¼ 0.40. [a]D ¼ –4.0
(c ¼ 1, CHCl3). 1H NMR (600 MHz, CDCl3):
d
3.06 (dd, Jvic ¼ 8.0,
Jgem ¼ 13.9 Hz, 1H, CHCHHPh), 3.11 (dd, Jvic ¼ Hz, Jgem ¼ 13.9 Hz, 1H,
CHCHHPh), 3.30 þ 3.36 (2 ꢁ s, 2H, 5-H, 50-H), 3.46 (dd, J2,3 ¼ 9.7,
J3,4 ¼ 3.3 Hz, 1H, 30-H), 3.55–3.58 (m, 4H, 3-H, OCH3), 3.82–3.90 (m, 2H,
2-H, 20-H), 3.95–4.01 (m, 2H, 6-H, 60-H), 4.18–4.21 (m, 3H, 1-H, 40-H, 60-H),
4.29–4.31 (m, 2H, 4-H, 6-H), 4.47 (d, J1,2 ¼ 7.7 Hz, 10-H), 4.75 (m, 1H,
CHCHHPh), 5.05–5.09 (2 ꢁ d, 2H, Jgem ¼ 12.1 Hz, CO2CH2Ph), 5.43 þ 5.53
(2 ꢁ s, 2H, 2 ꢁ CHPh), 7.19–7.52 (m, 20H, 4Ph). 13C NMR (150.9 MHz,
CDCl3): d 39.1 (CHCH2Ph), 56.9 (OCH3), 61.9 (2-C), 66.6 (5-C), 66.8 (50-
C),68.9 (60-C), 69.0 (6-C), 71.1 (20-C), 74.9 (40-C), 75.3 (4-C), 77.7 (3-C), 79.1
(30-C), 80.2 (CHCH2Ph), 100.5 þ 101.1 (2 ꢁ CHPh), 103.1 (1-C), 104.1 (10-C).
MALDI-MS (positive mode, CHCA): [M þ Na]þ, m/z ¼ 818.3; found: m/
z ¼ 818.1, [M þ K]þ, m/z ¼ 834.4; found: m/z ¼ 834.3. C43H45N3O12 (795.8)
Calcd.: C: 64.90, H: 5.70, N: 5.28. Found: C: 64.27, H: 5.88, N: 5.23.
Methyl
O-(4,6-O-Benzylidene-3-O-[(R)-1-benzyloxycarbonyl-2-pheny-
lethyl]-ß-D-galactopyranosyl)-(1!3)-2-azido-4,6-O-benzylidene-2-deoxy-
ß-D-galactopyranoside ((R)-17b). As described for (R)-17a from 16 (90 mg,
0.16 mmol), Bu2SnO (43 mg, 0.18 mmol), CsF (317 mg, 0.82 mmol), (S)-3b[33]
(318 mg, 0.82 mmol), and 1,2-dimethoxyethane (1.50 mL), after flash chromato-
graphy (toluene/acetone 3 : 1) 79 mg (0.10 mmol, 62%) of (R)-17b were obtained
as colorless amorphous solid. TLC (toluene/acetone 1 : 1): Rf ¼ 0.28. [a]D ¼ þ20

Synthesis of Ganglioside Mimics
629
(c ¼ 0.64, CHCl3). 1H NMR (600 MHz, CDCl3): d 2.97 (dd, Jvic ¼ 9.5,
Jgem ¼ 14.0 Hz, 1H, CHCHHPh), 3.09 (dd, Jvic ¼ 3.2, Jgem ¼ 14.0 Hz, 1H,
CHCHHPh), 3.19 (s, 1H, 5-H), 3.26 (dd, J2,3 ¼ 9.6, J3,4 ¼ 3.2 Hz, 1H, 30-H),
3.35 (s, 1H, 50-H), 3.57–3.60 (m, 5H, 3-H, 40-H, OCH3), 3.89–4.32 (m, 9H, 1-H,
2-H, 20-H, 4-H, 6-H, 60-H, CHCHHPh), 4.56 (d, J1,2 ¼ 7.6 Hz, 1H, 10-H), 5.09
(d, Jgem ¼ 12.1 Hz, 1H, CO2CHHPh), 5.20 (d, Jgem ¼ 12.1 Hz, 1H,
CO2CHHPh), 5.19 þ 5.54 (2 ꢁ s, 2H, 2 ꢁ CHPh), 7.09–7.43 (m, 20H, 4Ph). 13
C
NMR (150.9 MHz, CDCl3): d 39.4 (CHCH2Ph), 56.9 (OCH3), 62.0 (2-C),
66.4 þ 66.7 (5-C, 50-C), 68.9–69.0 (20-C, 6-C, 60-C), 72.9 (40-C), 75.3 (4-C), 77.2
(3-C), 80.3 (CHCH2Ph), 81.8 (30-C), 100.6 þ 100.9 (2 ꢁ CHPh), 103.2 (1-C),
103.9 (10-C). MALDI-MS (positive mode, CHCA): [M þ Na]þ, m/z ¼ 818.3;
found: m/z ¼ 818.1, [M þ K]þ, m/z ¼ 834.4; found: m/z ¼ 834.3. C43H45N3O12
(795.8) Calcd.: C: 64.90, H: 5.70, N: 5.28. Found: C: 64.41, H: 5.28, N: 5.38.
Methyl
O-(4,6-O-Benzylidene-3-O-[(S)-1-benzyloxycarbonyl-2-cyclo-
hexylethyl]-ß-D-galactopyranosyl)-(1!3)-2-azido-4,6-O-benzylidene-2-
deoxy-ß-D-galactopyranoside ((S)-17c) and Methyl O-(4,6-O-benzyli-
dene-3-O-[(S)-1-carboxy-2-cyclohexylethyl]-ß-D-galactopyranosyl-2b-
lactone)-(1!3)-2-azido-4,6-O-benzylidene-2-deoxy-ß-D-galactopyran-
oside (Lactone). To a solution of 16 (240 mg, 0.44 mmol) and Bu2SnO
(115 mg, 0.48 mmol) was added dry toluene (6.00 mL) under argon and the
reaction mixture heated for 1.5 hr under reflux over molecular sieves
(0.4 nm). After cooling CsF (850 mg, 2.19 mmol), (R)-3c[39] (850 mg,
2.19 mmol), and 1,2-dimethoxyethane (3.00 mL) were added to the pale
yellow solution and stirred for 1.25 hr at rt. The reaction mixture was then
diluted with CHCl3 (40 mL) and washed with H2O (2 ꢁ 25 mL). The aqueous
phase was then reextracted with CHCl3 (2 ꢁ 20 mL), the combined organic
phases dried over MgSO4, and the solvent removed in vacuo. Purification by
flash chromatography (toluene/acetone 4 : 1) furnished (S)-17c (173 mg,
0.22 mmol, 49%) as colorless oil and Lactone (93 mg, 0.13 mmol, 28%). TLC
(toluene/acetone 1 : 1): Rf ¼ 0.51 ((S)-17c); Rf ¼ 0.26 (Lactone). (S)-17c):
1
[a]D ¼ –3.2 (c ¼ 1, CHCl3). H NMR (600 MHz, CDCl3): d 0.81–1.69 (m, 13H,
CH2C6H11), 3.30 (s, 1H, 50-H),3,38 (s, 1H, 5-H), 3.45 (dd, J2,3 ¼ 9.8,
J3,4 ¼ 3.0 Hz, 1H, 30-H), 3.58–3.61 (m, 4H, 3-H, OCH3), 3.87 (dd, J1,2 ¼ 8.1,
J2,3 ¼ 10.5 Hz, 1H, 2-H), 3.97–4.02 (m, 3H, 20-H, 6-H, 60-H), 4.20–4.24
(m,3H, 1-H, 40-H, 60-H), 4.30 (d, J6,6 ¼ 12.6 Hz, 1H, 6-H), 4.34
(d, J3,4 ¼ 3.1 Hz, 1H, 4-H), 4.51(d, J1,2 ¼ 7.6 Hz, 1H, 10-H), 4.62 (dd,
Jvic ¼ 3.9, Jvic ¼ 9.1 Hz, 1H, CHCH2), 5.06 þ 5.16 (2 ꢁ d, Jgem ¼ 12.2 Hz, 2H,
CO2CH2Ph), 5.47 þ 5.55 (2 ꢁ s, 2H, 2 ꢁ CHPh), 7.30–7.52 (m, 15H, 3Ph).
13C NMR (150.9 MHz, CDCl3): d 57.0 (OCH3), 62.1 (2-C), 66.7 (5-C), 67.0
(50-C), 68.9 (6-C), 69.0 (60-C), 71.3 (20-C), 75.2 (40-C), 75.4 (4-C), 77.6
(3-C), 77.9 (CHCH2), 78.7 (30-C), 100.6 þ 101.2 (2 ꢁ CHPh), 103.2 (1-C),
104.5 (10-C). MALDI-MS (positive mode, CHCA): [M þ Na]þ, m/z ¼ 824.4;

S. Janssen and R. R. Schmidt
630
found: m/z ¼ 824.5, [M þ K]þ, m/z ¼ 840.5; found: m/z ¼ 840.4. C43H51N3O12
(801.9) Calcd.: C: 64.41, H: 6.41, N: 5.24. Found: C: 63.67, H: 6.35, N: 5.20.
Methyl
O-(2-O-acetyl-4,6-O-Benzylidene-3-O-[(S)-1-benzyloxycarbo-
nyl-1-cyclohexylmethyl]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-
O-benzylidene-2-deoxy-ß-D-galactopyranoside ((S)-18a). To a solution of
(S)-17a (38 mg, 48mmol) in pyridine/H2O (5 : 1, 2.80 mL) was added 1,3-propa-
nedithiol (0.10 mL, 0.11 g, 1.00 mmol) and the pH value adjusted with Et3N
(0.10 mL) to 9–10. After 3.75 hr at rt the solvent was removed in vacuo and
the residue coevaporated with toluene (4 ꢁ 15 mL). The residue was then dis-
solved in pyridine (3.00 mL) and Ac2O (0.90 mL, 1.00 g, 9.7 mmol) was added.
After 48 hr at rt the solvent was evaporated in vacuo and the crude product coe-
vaporated with toluene (3 ꢁ 10 mL). Purification by flash chromatography
(toluene/acetone 2 : 1 to 1 : 2) furnished (S)-18a (34 mg, 40mmol, 83%) as color-
less amorphous solid. TLC (toluene/acetone 2 : 1): Rf ¼ 0.14. [a]D ¼ –8.0
1
(c ¼ 0.30, CHCl3). H NMR (600 MHz, CDCl3): d 1.02–1.74 (m, 11H, C6H11),
1.97 (s, 3H, NHCOCH3), 2.03 (s, 3H, OAc), 3.26 (s, 1H, 50-H), 3.40–3.44
(m, 2H, 30-H, 5-H), 3.49 (s, 3H, OCH3), 3.62 (m, 1H, 2-H), 3.77 (d, Jvic ¼ 6.2 Hz,
1H, CHC6H11), 3.88 (d, J6,6 ¼ 11.5 Hz, 1H, 60-H), 4.03 (d, J6,6 ¼ 12.3 Hz, 1H,
6-H), 4.14–4.16 (m, 2H, 40-H, 60-H), 4.29 (d, J6,6 ¼ 12.3 Hz, 1H, 6-H), 4.37
(d, J3,4 ¼ 3.0 Hz, 1H, 4-H), 4.51 (dd, J2,3 ¼ 11.2, J3,4 ¼ 3.0 Hz, 1H, 3-H), 4.70
(d, J1,2 ¼ 7.9 Hz, 1H, 10-H), 4.79 (d, J1,2 ¼ 8.2 Hz, 1H, 1-H), 5.07 (s, 2H,
CO2CH2Ph), 5.27 (dd, J1,2 ¼ 7.9, J2,3 ¼ 9.3 Hz, 1H, 20-H), 5.32 þ 5.53 (2 ꢁ s, 2H,
2 ꢁ CHPh), 5.83 (d, JH,NH ¼ 6.3 Hz, 1H, NH), 7.27–7.54 (m, 15H, 3Ph). 13C
NMR (150.9 MHz, CDCl3): d 53.4 (2-C),56.6 (OCH3), 66.5 (CO2CH2Ph), 66.7 (5-
C, 50-C), 69.1 (60-C), 69.3 (6-C) 71.5 (20-C), 74.2 (3-C), 74.6 (40-C), 75.8 (4-C), 79.1
(30-C), 85.6 (CHC6H11) 100.6 (10-C), 100.8 (2 ꢁ CHPh),100.9 (1-C). MALDI-MS
(positive mode, CHCA): [M þ Na]þ, m/z ¼ 868.4; found: m/z ¼ 867.7,[M þ K]þ,
.
m/z ¼ 884.4; found: m/z ¼ 883.6. C46H55NO14 0.5H2O (854.9) Calcd.: C: 64.63,
H:6.60, N: 1.64. Found: C: 64.36, H: 6.83, N: 1.81.
Methyl
O-(2-O-Acetyl-4,6-O-benzylidene-3-O-[(R)-1-benzyloxycarbo-
nyl-1-cyclohexylmethyl]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-
O-benzylidene-2-deoxy-ß-D-alactopyranoside((R)-18a). To a solution of
(R)-17a (32 mg, 41 mmol) in pyridine/H2O (5:1, 2.35 mL) was added 1,3-propa-
nedithiol (0.07 mL, 0.08 g, 0.71 mmol) and the pH value adjusted with Et3 N
(0.10 mL) to 9–10. After 3.5 hr at rt the solvent was removed in vacuo
andthe residue coevaporated with toluene (4 ꢁ 15 mL), dissolved in pyridine
(2.50 mL) and Ac2O(0.75 mL, 0.82 g, 8.1 mmol) was added. After 48 hr at rt
the solvent was removed in vacuo and the crude product was coevaporated
with toluene (3 ꢁ 15 mL). Purification by flash chromatography (toluene/
acetone 3:2) furnished (R)-18a (29 mg, 34 mmol, 84%) as colorless amorphous
solid. TLC (toluene/acetone 1:1): Rf ¼ 0.36. [a]D ¼ þ62 (c ¼ 0.45, CHCl3). 1H

Synthesis of Ganglioside Mimics
631
NMR (600 MHz, CDCl3): d ¼ 1.02–1.71 (m, 11H, C6H11), 1.95 (s, 3H,
NHCOCH3), 2.00 (s, 3H, OAc),3.34 (s, 1H, 50-H), 3.40 (s, 1H, 5-H), 3.50–3.52
(m, 4H, 30-H, OCH3), 3.60 (m, 1H, 2-H), 3.85(d, Jvic ¼ 5.3 Hz, 1H, CHC6H11),
4.00–4.02 (m, 2H, 6-H, 60-H), 4.15 (dd, J3,4 ¼ 3.0, J4,5,1 Hz,1H, 40-H), 4.22–
4.27 (m, 2H, 6-H, 60-H), 4.35 (dd, J3,4 ¼ 3.0, J4,5 ,1 Hz, 1H, 4-H), 4.49 (dd,
J2,3 ¼ 11.0, J3,4 ¼ 3.0 Hz, 1H, 3-H), 4.71 (d, J1,2 ¼ 8.0 Hz, 1H, 10-H), 4.82
(d, J1,2 ¼ 8.2 Hz, 1H, 1-H), 5.06–5.13 (2 ꢁ d, Jgem ¼ 12.2 Hz, 2H, CO2CH2Ph),
5.21 (dd, J1,2 ¼ 8.0, J2,3 ¼ 8.8 Hz, 1H, 20-H), 5.46 þ 5.51 (2 ꢁ s, 2H, 2 x
CHPh), 5.92 (d, JH,NH ¼ 6.2 Hz, 1H, NH), 7.25–7.51 (m, 15H, 3Ph). 13C NMR
(150.9 MHz, CDCl3): d 53.4 (2-C), 56.7 (OCH3), 66.2 (50-C), 66.4(CO2CH2Ph),
66.6 (5-C), 69.2 (6-C, 60-C), 69.7 (20-C), 71.5 (40-C), 74.4 (3-C), 75.9 (4-C),77.0
(30-C), 79.8 (CHC6H11) 100.5 (10-C), 100.6 þ 100.7 (CHPh), 100.8 (1-C).
MALDI-MS(positive mode, CHCA): [M þ Na]þ, m/z ¼ 868.4; found: m/
z ¼ 867.7, [M þ K]þ, m/z ¼ 884.4; found: m/z ¼ 883.6. C46H55NO14 (845.9)
Calcd.: C: 65.31, H: 6.55, N: 1.66. Found: C: 64.92,H: 6.78, N: 1.68.
Methyl
O-(2-O-Acetyl-4,6-O-benzylidene-3-O-[(S)-1-benzyloxycarbo-
nyl-2-phenylethyl]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-O-
benzylidene-2-deoxy-ß-D-galactopyranoside((S)-18b). To a solution of
(S)-17b (127 mg, 0.16 mmol) in pyridine/H2O(5:1, 9.25 mL) was added 1,3-pro-
panedithiol (0.30 mL, 0.33 g, 3.00 mmol) and the pH valueadjusted with Et3 N
(0.30 mL) to 9–10. After 3.75 hr at rt the solvent was removed in vacuo and
the residue coevaporated with toluene (3 ꢁ 15 mL). The residue was dissolved
in pyridine (10.0 mL) and Ac2O (2.70 mL, 3.00 g, 29 mmol) was added. After
20 hr at rt the solvent wasremoved in vacuo and the residue coevaporated
with toluene (3 ꢁ 10 mL). Purification by flash chromatography (toluene/
acetone 3:1) furnished (S)-18b (74 mg, 0.09 mmol, 54%) as colorless amorphous
solid. TLC (toluene/acetone 1:1): Rf ¼ 0.49. [a]D ¼ þ 18 (c ¼ 1, CHCl3).1H NMR
(250 MHz, CDCl3): d 1.76 (s, 3H, NHCOCH3), 1.93 (s, 3H, COCH3), 2.99–
3.01(m, 2H, CHCH2), 3.15–3.59 (m, 8H, 2-H, 3-H, 30-H, 5-H, 50-H, OCH3),
3.86–4.53 (m, 7H, 4-H, 40-H, 6-H, 6-H, 60-H, 60-H, CHCH2), 4.63
(d, J1,2 ¼ 7.8 Hz, 1H, 1-H), 4.84 (d, J1,2 ¼ 8.3 Hz,1H, 10-H), 5.03 (s, 2H,
OCH2Ph), 5.21 (dd, J1,2 ¼ 8.3, J2,3 ¼ 9.2 Hz, 1H, 20-H), 5.34 þ 5.52 (2 ꢁ s, 2H,
2 ꢁ CHPh), 5.82 þ 5.94 (2 ꢁ d, JH,NH ¼ 6.8 Hz, 1H, NH), 7.16–7.51 (m, 20H,
Ar). MALDI-MS (positive mode, CHCA): [M þ Na]þ, m/z ¼ 876.3; found: m/
z ¼ 876.5, [M þ K]þ,m/z ¼ 892.4; found: m/z ¼ 892.5. C47H51NO14 (879.9).
Calcd.: C: 64.16, H: 5.84, N: 1.59.Found: C: 64.65, H: 6.34, N: 1.70.
Methyl O-(2-O-Acetyl-4,6-O-benzylidene-3-O-[(R)-1-benzyloxycarbonyl-
2-phenylethyl]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-O-benzyli-
dene-2-deoxy-ß-D-galactopyranoside((R)-18b). To a solution of (R)-17b
(79 mg, 0.10 mmol) in pyridine/H2O (5:1, 5.60 mL) was added 1,3-propandithiol
(0.20 mL, 0.22 g, 2.00 mmol) and the pH value adjusted with Et3 N (0.20 mL) to

S. Janssen and R. R. Schmidt
632
9–10. After 4 hr at rt the solvent was removed in vacuo and the residue was coe-
vaporated with toluene (3 ꢁ 10mL). The residue was dissolved in pyridine
(6.00 mL) and Ac2O (1.80 mL, 2.00 g, 19.5 mmol) was added. After 19 hr at rt
the solvent removed in vacuo and the residue was coevaporated with toluene
(3 ꢁ 10mL). Purification by flash chromatography (toluene/acetone 3:1 to 2:1)
furnished (R)-18b (36 mg, 0.04 mmol, 43%) as colorless amorphous solid. TLC
(toluene/acetone 1:1): Rf ¼ 0.44. [a]D ¼ þ 66 (c ¼ 0.46, CHCl3). 1H NMR
(600 MHz, d6-DMSO): d 1.78 (s, 3H, NHCOCH3), 1.88 (s, 3H,COCH3), 2.92
(m, 2H, CHCH2), 3.34 (s, 3H, OCH3), 3.49 (s, 1H, 50-H), 3.53 (s, 1H, 5-H), 3.71
(dd, J2,3 ¼ 10.1, J3,4 ¼ 3.2 Hz, 1H, 30-H), 3.82 (bs, 2H, 2-H, 3-H), 4.00–4.14
(m, 4H, 6-H,6-H, 60-H, 60-H), 4.24 (d, J3,4 ¼ 2.7 Hz, 1H, 40-H), 4.31 (s, 1H, 4-H),
4.35 (bs, 1H, 1-H), 4.49 (m, 1H, CHCH2), 4.59 (d, J1,2 ¼ 8.1 Hz, 1H, 10-H), 4.89
(dd, J1,2 ¼ 8.1, J2,3 ¼ 10.1 Hz, 1H, 20-H), 5.04 (s, 2H, OCH2Ph), 5.49 þ 5.59
(2 ꢁ s, 2H, 2 ꢁ CHPh), 7.13–7.46 (m, 20H, Ar), 7.66(d, JH,NH ¼ 6.8 Hz, 1H,
13
NH). C NMR (150.9 MHz, d6-DMSO): d 38.5 (CHCH2), 49.8 (2-C), 65.5 (50-C),
65.7 (5-C, OCH2Ph), 68.3 (6-C, 60-C), 68.9 (20-C), 71.8 (40-C), 74.6 (4-C),76.8
(CHCH2), 77.2 (3-C), 77.3 (30-C), 99.4 (CHPh), 99.5 (CHPh), 101.0 (10-C), 101.3
(1-C). MALDI-MS (positive mode, CHCA): [M þ Na]þ, m/z ¼ 876.3; found: m/
z ¼ 876.5, [M þ K]þ, m/z ¼ 892.4; found: m/z ¼ 892.5. C47H51NO14 (879.9)
Calcd.: C: 64.16, H: 5.84, N: 1.59. Found: C: 64.78, H: 6.28, N: 1.43.
Methyl O-(2-O-Acetyl-4,6-O-benzylidene-3-O-[(S)-1-benzyloxycarbonyl-
2-cyclohexylethyl]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-O-ben-
zylidene-2-deoxy-ß-D-galactopyranoside((S)-18c). To a solution of (S)-17c
(130 mg, 0.16 mmol) in pyridine/H2O (5:1, 8.75 mL) was added 1,3-propane-
dithiol (0.29 mL, 0.32 g, 2.94 mmol) and the pH value adjusted with Et3 N
(0.25 mL) to 9–10. After 4.5 hr at rt the solvent was removed in vacuo and the
residue was coevaporated with toluene (3 ꢁ 25 mL). The residue was dissolved
in pyridine (10.0 mL) and Ac2O (3.00 mL, 3.28 g, 32.4 mmol) was added. After
16 hr at rt the solvent was removed in vacuo and the residue was coevaporated
with toluene (3 ꢁ 20 mL). Purification by flash chromatography (toluene/
acetone 4:1 to 2:1) furnished (S)-18c (105 mg, 0.12 mmol, 75%) as colorless
amorphous solid. TLC (toluene/acetone 1:1): Rf ¼ 0.50. [a]D ¼ þ 4.6
1
(c ¼ 1,CHCl3). H NMR (600 MHz, CDCl3): d 0.84–1.67 (m, 13H, CH2C6H11),
1.97 (s, 3H,NHCOCH3), 2.04 (s, 3H, OAc), 3.29 (s, 1H, 50-H), 3.40–3.53
(m, 5H, 30-H, 5-H, OCH3), 3.64 (m, 1H, 2-H), 3.89 (d, J6,6 ¼ 11.5 Hz, 1H, 60-H),
4.01 (d, J6,6 ¼ 11.8 Hz, 1H, 6-H), 4.11 (dd, Jvic ¼ 4.9, Jvic ¼ 8.0 Hz, 1H,
CHCH2), 4.16–4.18 (m, 2H, 40-H, 60-H), 4.27 (d, J6,6 ¼ 11.8 Hz, 1H, 6-H), 4.35
(d, J3,4 ¼ 3.0 Hz, 1H, 4-H), 4.50 (dd, J2,3 ¼ 11.2, J3,4 ¼ 3.0 Hz, 1H, 3-H), 4.71
(d, J1,2 ¼ 7.9 Hz, 1H, 10-H), 4.77 (d, J1,2 ¼ 8.4 Hz, 1H, 1-H), 5.08 (s, 2H,
CO2CH2Ph), 5.25 (dd, J1,2 ¼ 7.9, J2,3 ¼ 9.4 Hz, 1H, 20-H), 5.34 þ 5.53 (2 ꢁ s,
2H, 2 ꢁ CHPh), 6.02 (bs, 1H, NH), 7.27-7.53(m, 15H, 3Ph). 13C NMR
(150.9 MHz, CDCl3): d 53.2 (2-C), 56.6 (OCH3), 66.6 (5-C, 50-C,CO2CH2Ph),

Synthesis of Ganglioside Mimics
633
69.0 (60-C), 69.2 (6-C), 71.3 (20-C), 74.2 (3-C), 74.4 (40-C), 75.8 (4-C), 78.6 (CHCH2),
78.7 (30-C), 100.6 (CHPh, 10-C), 100.7 (CHPh), 100.8 (1-C). C47H57NO14 2.5
.
H2O(905.0) Calcd.: C: 62.38, H: 6.91, N: 1.55. Found: C: 62.41, H: 7.03, N: 1.30.
Methyl O-(2,4,6-Tri-O-acetyl-3-O-[(S)-1-benzyloxycarbonyl-1-cyclohex-
ylmethyl]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-di-O-acetyl-2-
deoxy-ß-D-galactopyranoside((S)-19a). To a solution of (S)-18a (83 mg,
98 mmol) in dry CH2Cl2/MeOH (1:1, 4.60 mL)under argon was added EtSH
(75 mL, 64 mg, 0.97 mmol). After adding p-TsOH (2.0 mg, 9mmol) the reaction
mixture was stirred at rt for 15 hr, then neutralized with Et3 N (0.10 mL) and
the solvent removed in vacuo. The residue was dissolved in pyridine
(5.00 mL) and Ac2O(2.50 mL, 2.75 g, 27.5 mmol) was added. After 24 hr at rt
the solvents were removed in vacuo andthe residue coevaporated with
toluene (3 ꢁ 20 mL). Purification by flash chromatography(toluene/acetone
4:1) furnished (S)-18a (41 mg, 49 mmol, 50%) as colorless amorphoussolid.
1
TLC (toluene/acetone 1:1): Rf ¼ 0.48. [a]D ¼ þ 15 (c ¼ 0.55, CHCl3). H NMR
(600 MHz, CDCl3): d 1.01–1.68 (m, 11H, C6H11), 1.99 (s, 3H, NHCOCH3),
2.06–2.09 (5 ꢁ s,15H, 5 ꢁ OAc), 3.27 (m, 1H, 2-H), 3.45 (dd, J2,3 ¼ 9.9,
J3,4 ¼ 3.1 Hz, 1H, 30-H), 3.50 (s, 3H,OCH3), 3.62 (m, 1H, 50-H), 3.82–3.86
(m, 2H, 5-H, CHC6H11), 3.94 (dd, J5,6 ¼ 6.6, J6,6 ¼ 11.4Hz, 1H, 60-H), 4.04
(dd, J5,6 ¼ 7.2, J6,6 ¼ 11.6 Hz, 1H, 6-H), 4.10 (dd, J5,6 ¼ 5.8, J6,6 ¼ 11.4 Hz,
1H, 60-H), 4.17 (dd, J5,6 ¼ 5.3, J6,6 ¼ 11.6 Hz, 1H, 6-H), 4.45 (d, J1,2 ¼ 7.9 Hz,
1H, 10-H), 4.63 (dd, J2,3 ¼ 10.7, J3,4 ¼ 2.9 Hz, 1H, 3-H), 4.98 (d, J1,2 ¼ 8.2 Hz,
1H, 1-H), 5.11-5.15 (m, 2H, 20-H, CO2CHHPh), 5.20 (d, Jgem ¼ 12.1 Hz, 1H,
CO2CHHPh), 5.40 (d, J3,4 ¼ 2.9 Hz, 1H, 4-H), 5.46 (d, J3,4 ¼ 3.1 Hz, 1H, 40-H),
5.65 (d, JH,NH ¼ 6.7 Hz, 1H, NH), 7.35–7.38 (m, 5H, C6H5).13C NMR
(150.9 MHz, CDCl3): d 55.3 (2-C), 57.0 (OCH3), 61.9 (60-C), 62.6 (6-C),
67.0(CO2CHHPh), 68.0 (40-C), 68.1 (4-C), 71.3 (5-C), 71.6 (50-C), 71.8 (20-C),
74.5 (3-C), 77.4 (30-C), 84.1 (CHC6H11), 99.8 (1-C), 100.0 (10-C). MALDI-MS
(positive mode, CHCA): [M þ Na]þ, m/z ¼ 860.3; found: m/z ¼ 859.9.
C40H55NO18 (837.9) Calcd.: C: 57.34, H: 6.62, N:1.67. Found: C: 57.12, H:
7.09, N: 1.43.
Methyl O-(2,4,6-Tri-O-acetyl-3-O-[(R)-1-benzyloxycarbonyl-1-cyclohex-
ylmethyl]-ß-Dgalactopyranosyl)-(1!3)-2-acetamido-4,6-di-O-acetyl-2-
deoxy-ß-D-galactopyranoside((R)-19a). To a solution of (R)-18a (27 mg,
32 mmol) in dry CH2Cl2/MeOH (1:1, 1.50 mL) was added EtSH (24 mL, 21 mg,
0.32 mmol). After adding p-TsOH (1.0 mg, 5 mmol) the reaction mixture was
stirred at rt for 20 hr, then neutralized with Et3 N (0.20 mL) and the solvent
removed in vacuo. The residue was dissolved in pyridine (3.00 mL) and Ac2O
(1.50 mL, 1.65 g, 16.5 mmol) was added. After 48 hr at rt the solvents were
removed in vacuo and the residue was coevaporated with toluene
(3 ꢁ 20 mL). Purification by flash chromatography (toluene/acetone 4:1 to 3:1)

S. Janssen and R. R. Schmidt
634
furnished (R)-19a (7 mg, 8.4 mmol, 26%) as colorless amorphous solid. TLC
(toluene/acetone 1:1): Rf ¼ 0.50. [a]D ¼ þ 17 (c ¼ 0.24, CHCl3). 1 HNMR
(600 MHz, CDCl3): d0.98–1.66 (m, 11H, C6H11), 1.97 (s, 3H, NHCOCH3),
2.05–2.10 (5 ꢁ s, 15H, 5 ꢁ OAc), 3.23 (m, 1H, 2-H), 3.44 (dd, J2,3 ¼ 9.9,
J3,4 ¼ 3.1 Hz, 1H, 30-H), 3.52 (s,3H, OCH3), 3.66 (m, 1H, 50-H), 3.87 (m, 1H,
5-H), 3.94–3.98 (m, 2H, 60-H, CHC6H11), 4.05–4.09 (m, 1H, 6-H), 4.11–4.20
(m, 2H, 6-H, 60-H), 4.53 (d, J1,2 ¼ 8.0 Hz, 10-H), 4.70 (dd, J2,3 ¼ 10.8,
J3,4 ¼ 3.2 Hz, 1H, 3-H), 5.08 (m, 2H, 1-H, 20-H), 5.14 þ 5.19 (2 ꢁ d,
Jgem ¼ 12.2 Hz, 2H,CO2CHHPh), 5.37 (d, J3,4 ¼ 3.1 Hz, 1H, 40-H), 5.45
(d, J3,4 ¼ 2.8 Hz, 1H, 4-H), 5.67 (d, JH,NH ¼ 5.9 Hz, 1H, NH), 7.36–7.41
(m, 5H, C6H5). 13C NMR (150.9 MHz, CDCl3): d 55.70 (2-C),57.5 (OCH3),
61.7 (60-C), 62.8 (6-C), 64.7 (40-C), 66.7 (CO2CHHPh), 67.5 (4-C), 70.5 (20-
C),71.3 (5-C), 71.4 (50-C), 74.7 (3-C), 76.3 (30-C), 79.6 (CHC6H11), 99.5 (10-C),
100.0 (1-C). MALDI-MS (positive mode, CHCA): [M þ Na]þ, m/z ¼ 860.3;
found: m/z ¼ 859.9. C40H55NO18 (837.9) Calcd.: C: 57.34, H: 6.62, N: 1.67.
Found: C: 56.81, H: 7.11, N: 1.68.
Methyl
O-(2,4,6-Tri-O-acetyl-3-O-[(S)-1-benzyloxycarbonyl-2-pheny-
lethyl]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-di-O-acetyl-2-
deoxy-ß-D-galactopyranoside ((S)-19b). To a solution of (S)-18b (61 mg,
71 mmol) in dry CH2Cl2/MeOH (1:1, 3.35 mL) was added EtSH (55 ml, 47 mg,
0.73 mmol) under argon. After adding p-TsOH (1.5 mg, 7 mmol) the reaction
mixture was stirred for 15 hr at rt, then neutralized with Et3 N (0.05 mL) and
the solvent removed in vacuo. The residue was dissolved in pyridine
(4.00 mL) and Ac2O (2.00 mL, 2.20 g, 22 mmol) was added. After 18 hr at rt
the solvents were removed in vacuo and the residue was coevaporated with
toluene (3 ꢁ 20 mL). Purification by flash chromatography (toluene/acetone
4:1 to 3:1) furnished (S)-19b (32 mg, 37 mmol, 53%) as colorless amorphous
solid. TLC (toluene/acetone 1:1): Rf ¼ 0.46. [a]D ¼ þ 21 (c ¼ 0.48, CHCl3).
1HNMR (600 MHz, CDCl3): d 1.80 (s, 3H, NHCOCH3), 1.95 (s, 3H, OAc),
2.06–2.10 (4 ꢁ s, 12H, 4 ꢁ OAc), 2.94 (dd, Jvic ¼ 7.0, Jgem ¼ 11.0 Hz, 1H,
CHCHHPh), 2.97 (dd, Jvic ¼ 5.2, Jgem ¼ 11.0 Hz, 1H, CHCHHPh), 3.22
(m, 1H, 2-H), 3.49–3.53 (m, 4H, 30-H, OCH3), 3.61 (m, 1H, 50-H), 3.83 (m, 1H,
5-H), 3.94 (dd, J5,6 ¼ 6.6, J6,6 ¼ 11.4 Hz, 1H, 60-H), 4.01–4.08 (m, 2H, 6-H,60-
H), 4.16 (dd, J5,6 ¼ 5.2, J6,6 ¼ 11.7 Hz, 1H, 6-H), 4.24 (dd, Jvic ¼ 5.2,
Jvic ¼ 7.0 Hz, 1H, CHCHHPh), 4.40 (d, J1,2 ¼ 8.0 Hz, 1H, 10-H), 4.61 (dd,
J2,3 ¼ 10.7, J3,4 ¼ 3.0 Hz, 1H, 3-H), 4.96 (d, J1,2 ¼ 8.2 Hz, 1H, 1-H), 5.04 (dd,
J1,2 ¼ 8.0, J2,3 ¼ 9.6 Hz, 1H, 20-H), 5.07 þ 5.11 (2 ꢁ d, Jgem ¼ 12.0 Hz, 2H,
CO2CHHPh), 5.37 (d, J3,4 ¼ 3.0 Hz, 1H, 4-H), 5.46 (d, J3,4 ¼ 2.6 Hz, 1H, 40-H),
5.62 (d, JH,NH ¼ 6.8 Hz, 1H, NH), 7.08–7.36 (m, 10H, Ar). 13C NMR
(150.9 MHz,CDCl3): d 39.0 (CHCHHPh), 55.4 (2-C), 57.2 (OCH3), 61.8 (60-C),
62.8 (6-C), 68.0 (40-C), 68.3 (4-C), 71.2 (5-C), 71.4 (50-C), 71.6 (20-C), 74.7 (3-
C), 77.4 (30-C), 80.8 (CHCHHPh), 100.0 (1-C), 100.4 (10-C). MALDI-MS

Synthesis of Ganglioside Mimics
635
(positive mode, CHCA): [M þ Na]þ, m/z ¼ 868.3;found: m/z ¼ 867.8, [M þ K]þ,
m/z ¼ 884.4; found: m/z ¼ 883.8. C40H55NO18 (837.9) Calcd.: C: 58.22, H: 6.08,
N: 1.66. Found: C: 58.09, H: 6.64, N: 1.59.
Methyl O-(2,4,6-Tri-O-acetyl-3-O-[(R)-1-methoxycarbonyl-2-phenylethyl]-
ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-di-O-acetyl-2-deoxy-ß-D-
galactopyranoside ((R)-19b). To a solution of (R)-18b (27 mg, 32 mmol) in
dry CH2Cl2/MeOH (1:1, 1.50 mL) under argon was added EtSH (24 mL,
21 mg, 0.32 mmol). After adding p-TsOH (1.0 mg, 5 mmol) the reaction
mixture was stirred for 4 hr at rt, then neutralized with Et3 N (0.05 mL) and
the solvent evaporated in vacuo. The residue was dissolved in pyridine
(3.00 mL) and Ac2O (1.50 mL,1.65 g, 16.5 mmol) was added. After 72 h at rt
the solvents were removed in vacuo and the residue coevaporated with
toluene (3 ꢁ 20 mL). Purification by flash chromatography (toluene/acetone
4:1 to 2:1) furnished (R)-19b (17 mg, 22 mmol, 69%) as colorless amorphous
1
solid. TLC (toluene/acetone 1:1): Rf ¼ 0.33. [a]D ¼ þ40 (c ¼ 0.33, CHCl3). H
NMR (600 MHz, CDCl3): d 1.97 (s, 3H, NHCOCH3), 2.04–2.12 (5 ꢁ s, 15H,
5 ꢁ OAc), 2.85–2.91 (m, 2H, CHCHHPh), 3.22–3.25 (m, 1H, 2-H), 3.49–3.51
(m, 4H, 30-H, 1-OCH3), 3.63 (s, 3H, CO2CH3), 3.73 (m, 1H, 50-H), 3.86 (m, 1H,
5-H), 4.00–4.17 (m, 4H, 6-H, 6-H, 60-H, 60-H), 4.36 (m, 1H, CHCHHPh), 4.55
(d, J1,2 ¼ 8.0 Hz, 1H, 10-H), 4.70 (dd, J2,3 ¼ 10.7, J3,4 ¼ 3.1 Hz, 1H, 3-H), 5.05
(d, J1,2 ¼ 8.3 Hz, 1H, 1-H), 5.09 (dd, J1,2 ¼ 8.0, J2,3 ¼ 9.5 Hz, 1H, 20-H), 5.33
(d, J3,4 ¼ 2.5 Hz, 1H, 40-H), 5.43 (d, J3,4 ¼ 3.1 Hz, 1H, 4-H), 5.67
(d, JH,NH ¼ 6.8 Hz,1H, NH), 7.12–7.27 (m, 5H, Ar). 13C NMR (150.9 MHz,
CDCl3): d 39.3 (CHCHHPh), 51.7(CO2CH3), 55.5 (2-C), 57.2 (1-OCH3), 61.4
(60-C), 62.4 (6-C), 64.6 (40-C), 67.5 (4-C), 70.2 (20-C), 70.9 (50-C), 71.1 (5-C),
74.6 (3-C), 76.3 (30-C), 76.5 (CHCHHPh), 99.5 (10-C), 99.9 (1-C). C35H47NO18
(769.7) Calcd.: C: 54.61, H: 6.15, N: 1.82. Found: C: 54.51, H: 6.62, N: 1.90.
Methyl O-(2,4,6-Tri-O-acetyl-3-O-[(S)-1-benzyloxycarbonyl-2-cyclohex-
ylethyl]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-4,6-di-O-acetyl-2-deoxy-
ß-D-galactopyranoside((S)-19c). To a solution of (S)-18c (70 mg, 81 mmol) in
dry CH2Cl2/MeOH (1:1, 3.80 mL)under argon was added EtSH (62 mL, 53 mg,
0.80 mmol). After adding p-TsOH (2.0 mg, 9 mmol) the reaction mixture was
stirred for 24 hr at rt, then neutralized with Et3 N (0.15 mL) and the solvent
removed in vacuo. The residue was dissolved in pyridine (5.00 mL) and Ac2O
(2.50 mL, 2.75 g, 27.5 mmol) was added. After 72 hr at rt the solvents were
removed in vacuo and the residue coevaporated with toluene (3 ꢁ 20 mL). Puri-
fication by flash chromatography (toluene/acetone 4:1 to 3:1) furnished (S)-19c
(50 mg, 59 mmol, 72%) as colorless amorphous solid. TLC (toluene/acetone 1:1):
1
Rf ¼ 0.55. [a]D ¼ þ8.7 (c ¼ 0.38, CHCl3). H NMR (600 MHz, CDCl3): d 0.82–
1.65 (m, 13H, CH2C6H11), 1.99 (s, 3H, NHCOCH3), 2.05–2.11 (5 ꢁ s, 15H,
5 ꢁ OAc), 3.28 (m, 1H, 2-H), 3.48–3.50 (m, 4H, 30-H, OCH3), 3.63 (m, 1H,

S. Janssen and R. R. Schmidt
636
50-H), 3.85 (m, 1H, 5-H), 3.95 (dd, J5,6 ¼ 6.6, J6,6 ¼ 11.4 Hz, 1H, 60-H), 4.03–4.11
(m, 3H, 6-H, 60-H, CHCH2), 4.16 (dd, J5,6 ¼ 5.3, J6,6 ¼ 11.6 Hz, 1H, 6-H), 4.45
(d, J1,2 ¼ 7.9 Hz, 1H, 10-H), 4.64 (dd, J2,3 ¼ 10.7, J3,4 ¼ 2.9 Hz, 1H, 3-H), 4.97
(d, J1,2 ¼ 8.2 Hz, 1H, 1-H), 5.07–5.13 (m, 2H, 20-H, CO2CHHPh), 5.19
(d, Jgem ¼ 12.1 Hz, 1H, CO2CHHPh), 5.39 (d, J3,4 ¼ 2.9 Hz, 1H, 4-H), 5.45
(d, J3,4 ¼ 2.7 Hz, 1H, 40-H), 5.66 (d, JH,NH ¼ 6.8 Hz, 1H, NH), 7.32–7.38
(m, 5H, C6H5). 13C NMR (150.9 MHz, CDCl3): d 55.4 (2-C), 57.1 (OCH3), 61.9
(60-C), 62.6 (6-C), 68.0 (40-C), 68.1 (4-C), 71.2 (5-C), 71.5 (50-C), 71.8 (20-C), 74.6
(3-C), 77.3 (30-C), 78.0 (CHCH2), 100.0 (1-C), 100.2 (10-C). MALDI-MS
(positive mode, CHCA): [M þ Na]þ, m/z ¼ 874.4; found: m/z ¼ 874.3,
[M þ K]þ, m/z ¼ 890.5; found: m/z ¼ 890.2.
Methyl O-(3-O-[Triethylammonium-(S)-1-cyclohexylmethyl-1-carboxy-
late]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-2-deoxy-ß-D-galactopy-
ranoside ((S)-1ab). To a solution of (S)-19a (22 mg, 26 mmol) in MeOH
(3.00 mL) was added Pd/C (10 mg) and the reaction mixture was stirred for
10 h under H2 atmosphere. The catalyst was filtered off, the solvent removed
in vacuo, and the residue diluted in dry MeOH (3.00 mL). Then NaOMe-
solution (0.1 N, 0.20 mL) was added and the reaction mixture stirred for
48 hr at rt. After neutralization with ion exchange resin IR 120 (Hþ-Form)
the solvent was removed in vacuo. Purification by flash chromatography
(CHCl3/MeOH/Et3 N 60:40:1) furnished (S)-1ab (9.7 mg, 18 mmol, 69%) as
colorless amorphous solid. TLC (CHCl3/MeOH/H2O 60:40:1): Rf ¼ 0.32.
1H NMR (600 MHz, D2O): d 0.99–1.18 þ 1.47–1.62 (2 ꢁ m, 20H, C6H11,
N(CH2CH3)3), 1.89 (s, 3H, NHCOCH3), 3.08 (q, 6H, N(CH2CH3)3), 3.26 (dd,
J2,3 ¼ 9.6, J3,4 ¼ 3.0 Hz, 1H, 30-H), 3.39 (s, 3H, OCH3), 3.49–3.53 (m, 2H,
20-H, 50-H), 3.57–3.74 (m, 7H, 3-H, 5-H, 6-H, 6-H, 60-H, 60-H, CHC6H11), 3.83
(d, J3,4 ¼ 3.0 Hz, 1H, 40-H), 3.89 (dd, J1,2 ¼ 8.8, J2,3 ¼ 10.6 Hz, 1H, 2-H), 4.07
(d, J3,4 ¼ 2.7 Hz, 1H, 4-H), 4.31 (m, 2H, 1-H, 10-H). 13C NMR (150.9 MHz,
D2O): d 50.6 (2-C), 56.5 (OCH3). 60.7 (6-C, 60-C), 66.0 (40-C), 67.6 (4-C), 69.7
(20-C), 74.2 (50-C), 74.4 (5-C), 80.3 (3-C), 82.3 (30-C), 84.7 (CHC6H11), 101.8
(1-C), 104.5 (10-C). MALDI-MS (positive mode, CHCA): [M þ Na]þ, m/z
¼ 560.2; found: m/z ¼ 560.1, [M þ K]þ, m/z ¼ 576.3; found: m/z ¼ 576.1,
[M 2 H þ Na þ K]þ, m/z ¼ 598.3; found: m/z ¼ 598.1.
Methyl O-(3-O-[Triethylammonium-(R)-1-cyclohexylmethyl-1-carbox-
ylate]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-2-deoxy-ß-D-galacto-
pyranoside ((R)-1ab). To a solution of (R)-19a (4.5 mg, 5.4 mmol) in MeOH
(1.00 mL) was added Pd/C (5 mg) and the reaction mixture was stirred for
2 hr under H2 atmosphere. The catalyst was filtered off, the solvent removed
in vacuo, and the residue diluted in dry MeOH (1.00 mL). Then NaOMe-
solution (0.1 N, 0.10 mL) was added and the reaction mixture stirred for 4 hr
at rt. After neutralization with ion exchange resin IR 120 (Hþ-Form) the

Synthesis of Ganglioside Mimics
637
solvent was removed in vacuo. Purification by flash chromatography (CHCl3/
MeOH/Et3 N 60:40:1) furnished (R)-1ab (1.9 mg, 3.0 mmol, 55%) as colorless
amorphous solid. TLC (CHCl3/MeOH/H2O 60:40:1): Rf ¼ 0.37. 1H NMR
(600 MHz, D2O): d 0.99–1.61 (m, 20H, C6H11, N(CH2CH3)3), 1.90 (s, 3H,
NHCOCH3), 3.08(q, 6H, N(CH2CH3)3), 3.21 (dd, J2,3 ¼ 10.0, J3,4 ¼ 3.1 Hz, 1H,
30-H), 3.39 (s, 3H, OCH3), 3.48 (m, 2H, 20-H, 50-H), 3.58–3.70 (m, 6H, 5-H, 6-H,
6-H, 60-H, 60-H, CHC6H11), 3.76 (dd, J2,3 ¼ 10.8, J3,4 ¼ 2.8 Hz, 1H, 3-H), 3.87–
3.92 (m, 2H, 2-H, 40-H), 4.06 (d, J3,4 ¼ 2.8 Hz, 1H, 4-H), 4.32–4.35 (m, 2H, 1-H,
13
10-H). C NMR (150.9 MHz, D2O): d 51.1 (2-C), 57.2 (OCH3), 61.1 (6-C, 60-C),
65.7 (40-C), 68.0 (4-C), 69.5 (20-C), 74.9 (5-C), 75.6 (50-C), 80.3 (3-C), 81.1(30-C),
85.4 (CHC6H11), 102.5 (1-C), 105.2 (10-C). MALDI-MS (positive mode,
CHCA):[M þ Na]þ, m/z ¼ 560.2; found: m/z ¼ 560.1, [M þ K]þ, m/z ¼ 576.3;
found: m/z ¼ 576.1, [M 2 H þ Na þ K]þ, m/z ¼ 598.3; found: m/z ¼ 598.1.
Methyl O-(3-O-[Triethylammonium-(S)-2-phenylethyl-1-carboxylate]-
ß-D-galactopyranosyl)-(1!3)-2-acetamido-2-deoxy-ß-D-galactopyrano-
side ((S)-1b). To a solution of (S)-19b (15 mg, 18 mmol) in MeOH (3.00 mL)
was added Pd/C (10 mg) and the reaction mixture was stirred for 20 hr
under H2 atmosphere. The catalyst was filtered off, the solvent removed in
vacuo and the residue diluted in dry MeOH (3.00 mL). Then NaOMe-solution
(0.1 N, 0.20 mL) was added and the reaction mixture stirred for 10 hr at rt.
After neutralization with ion exchange resin IR 120 (Hþ-Form) the solvent
was removed in vacuo. Purification by flash chromatography (CHCl3/MeOH/
Et3 N 60:40:1) furnished (S)-1b (8.3 mg, 15 mmol, 86%) as colorless amorphous
1
solid. TLC (CHCl3/MeOH/H2O 6:4:1): Rf ¼ 0.31. H NMR (600 MHz, D2O): d
1.15 (t, 9H, N(CH2CH3)3), 1.86 (s, 3H, NHCOCH3), 2.87 (dd, Jvic ¼ 8.3,
Jgem ¼ 14.0 Hz, 1H, CHCHH), 3.02 (dd, Jvic ¼ 4.7, Jgem ¼ 14.0 Hz, 1H,
CHCHH), 3.02 (q, 6H,N(CH2CH3)3), 3.17 (dd, J2,3 ¼ 9.6, J3,4 ¼ 2.8 Hz, 1H, 30-
H), 3.38–3.47 (m, 5H, 20-H, 50-H, –OCH3), 3.55–3.70 (m, 6H, 3-H, 5-H, 6-H,
6-H, 60-H, 60-H), 3.81 (d, J3,4 ¼ 2.8 Hz, 1H, 40-H), 3.86 (dd, J1,2 ¼ 8.6,
J2,3 ¼ 10.7 Hz, 1H, 2-H), 4.03 (d, J3,4 ¼ 2.6 Hz, 1H, 4-H), 4.09 (dd, Jvic ¼ 4.7,
Jvic ¼ 8.3 Hz, 1H, CHCHH), 4.23 (d, J1,2 ¼ 7.9 Hz, 1H, 10-H), 4.30
(d, J1,2 ¼ 8.6 Hz, 1H, 1-H), 7.18–7.26 (m, 5H, Ar). 13C NMR (150.9 MHz,
D2O): d 38.6 (CHCHH), 50.4 (2-C), 56.5 (OCH3), 60.5 (6-C, 60-C), 65.7 (40-C),
67.4 (4-C), 69.3 (20-C), 73.9 (50-C), 74.3 (5-C), 80.0 (3-C), 81.2 (CHCHH), 81þ.9
(30-C), 101.7 (1-C), 104.1 (10-C). MALDI-MS (positive mode, CHCA): [M þ Na] ,
m/z ¼ 568.2; found: m/z ¼ 568.3, [M þ K]þ, m/z ¼ 584.3; found: m/z ¼ 584.2,
[M 2 H þ 2Na]þ, m/z ¼ 590.2; found: m/z ¼ 590.3, [M 2 H þ Na þ K]þ, m/
z ¼ 606.3; found: m/z ¼ 606.3.
Methyl O-(3-O-[Triethylammonium-(R)-2-phenylethyl-1-carboxylate]-
ß-D-galactopyranosyl)-(1!3)-2-acetamido-2-deoxy-ß-D-galactopyrano-
side ((R)-1b). To a solution of (R)-19b (8 mg, 10 mmol) in dry MeOH (1.00 mL)

S. Janssen and R. R. Schmidt
638
was added NaOMe-solution (0.1 N, 0.20 mL) and the reaction mixture was
stirred for 12 hr at rt. Then LiOH-solution (1 N, 0.10 mL) was added and the
reaction mixture stirred for further 7 hr at rt. After neutralization with ion
exchange resin IR 120 (Hþ-Form) the solvent was removed in vacuo. Purifi-
cation by flash chromatography (CHCl3/MeOH/Et3 N 60:40:1) furnished (R)-
1b (5.8 mg, 9 mmol, 90%) as colorless amorphous solid. TLC (CHCl3/MeOH/
H2O 60:40:1): Rf ¼ 0.37. 1H NMR (600 MHz, D2O):
d 1.16 (t, 9H,
N(CH2CH3)3), 1.89 (s, 3H, NHCOCH3), 2.77 (dd, Jvic ¼ 9.2, Jgem ¼ 14.0 Hz,
1H, CHCHH), 3.02–3.30 (m, 7H, CHCHH, N(CH2CH3)3), 3.21 (dd, J2,3 ¼ 9.7,
J3,4 ¼ 2.9 Hz, 1H, 30-H), 3.36–3.46 (m, 7H, 20-H, 40-H, 50-H, 60-H, OCH3),
3.50–3.69 (m, 2H, 5-H, 60-H), 3.62–3.69 (m, 2H, 6-H, 6-H), 3.72 (dd,
J2,3 ¼ 10.9, J3,4 ¼ 2.6 Hz, 1H, 3-H), 3.86 (dd, J1,2 ¼ 8.6, J2,3 ¼ 10.9 Hz, 1H,
2-H), 4.02 (d, J3,4 ¼ 2.6 Hz, 1H, 4-H), 4.08 (dd, Jvic ¼ 4.2, Jvic ¼ 9.2Hz, 1H,
CHCHH), 4.28 (d, J1,2 ¼ 7.8 Hz, 1H, 10-H), 4.31 (d, J1,2 ¼ 8.6 Hz, 1H, 1-H). 13
C
NMR (150.9 MHz, D2O): d 38.8 (CHCHH), 50.7 (2-C), 56.7 (OCH3), 60.6 (6-C,
60-C), 65.4 (40-C), 67.3 (4-C), 68.9 (20-C), 74.4 (5-C, 50-C), 79.8 (3-C), 80.5 (30-C),
81.2 (CHCHH), 101.8 (1-C), 104.2 (10-C). MALDI-MS (positive mode, CHCA):
[M þ Na]þ, m/z ¼ 568.2; found: m/z ¼ 568.3, [M þ K]þ, m/z ¼ 584.3;
found: m/z ¼ 584.2, [M 2 H þ 2Na]þ, m/z ¼ 590.2; found: m/z ¼ 590.3,
[M 2 H þ Na þ K]þ, m/z ¼ 606.3; found: m/z ¼ 606.3.
Methyl O-(3-O-[Triethylammonium-(S)-2-cyclohexylethyl-1-carboxy-
late]-ß-D-galactopyranosyl)-(1!3)-2-acetamido-2-deoxy-ß-D-galacto-
pyranoside ((S)-1c). To a solution of (S)-19c (18 mg, 21 mmol) in MeOH
(3.00 mL) was added Pd/C (10 mg) and the reaction mixture was stirred for
16 hr under H2 atmosphere. The catalyst was filtered off, the solvent
removed in vacuo and the residue diluted in dry MeOH (3.00 mL). Then
NaOMe-solution (0.1, 0.20 mL) was added and the reaction mixture stirred
for 24 hr at rt. After neutralization with ion exchange resin IR 120 (Hþ-
Form) the solvent was removed in vacuo. Purification by flash chromatography
(CHCl3/MeOH/Et3 N 60:40:1) furnished (S)-1c (10.1 mg, 18.3 mmol, 87%) as
colorless amorphous solid. TLC (CHCl3/MeOH/H2O 60:40:1): Rf ¼ 0.39.
1H NMR (600 MHz, D2O): d 0.77–0.85, 1.02–1.70, 1.42–1.55, 1.66–1.68
(4 ꢁ m, 22H, CH2C6H11, N(CH2CH3)3), 1.89 (s, 3H, NHCOCH3), 3.08 (q, 6H,
N(CH2CH3)3), 3.27 (dd, J2,3 ¼ 9.6, J3,4 ¼ 2.7 Hz, 1H, 30-H), 3.39 (s, 3H,
OCH3), 3.47–3.51 (m, 2H, 20-H, 50-H), 3.57–3.72 (m, 6H, 3-H, 5-H, 6-H, 6-H,
60-H, 60-H), 3.83 (d, J3,4 ¼ 2.7 Hz, 1H, 40-H), 3.89 (dd, J1,2 ¼ 8.7,
J2,3 ¼ 10.6 Hz, 1H, 2-H), 3.98 (dd, J ¼ 3.2, J ¼ 8.9 Hz, 1H, CHCH2), 4.08
(d, J3,4 ¼ 2.7 Hz, 1H, 4-H), 4.30–4.32 (m, 2H, 1-H, 10-H). 13C NMR
(150.9 MHz, D2O): d 50.5 (2-C), 56.3 (OCH3), 60.5 (6-C, 60-C), 66.1 (40-C), 67.6
(4-C), 69.4 (20-C), 73.9 (50-C), 74.3 (5-C), 78.3 (CHCH2), 80.1 (3-C), 82.1 (30-C),
101.5 (1-C), 104.5 (10-C). MALDI-MS (positive mode, CHCA): [M þ Na]þ,
m/z ¼ 574.3; found: m/z ¼ 574.2, [M þ K]þ, m/z ¼ 590.4; found: m/z ¼ 590.2.

Synthesis of Ganglioside Mimics
639
Thexyldimethylsilyl 2-Azido-2-deoxy-4,6-O-(4-methoxybenzylidene)-ß-
D-galactopyranoside(21). To a solution of 2031 (1.00 g, 2.88 mmol) in dry
DMF (25 mL) under argon was added anisaldehyde dimethylacetal (1.35 mL,
1.45 g, 7.95 mmol) and p-TsOH (50 mg) and then stirred for 90min at 558C. The
reaction mixture was neutralized with Et3 N (1.00 mL) and evaporated to
dryness. Purification by flash chromatography (PE/EA 5:1 to 1:1) furnished 21
(479 mg, 1.03 mmol, 36%) as colorless oil. TLC (PE/EE 1:1): Rf ¼ 0.46.
[a]D ¼ 24.4 (c ¼ 0.50, CHCl3). 1H NMR (250MHz, CDCl3): d 0.21 þ 0.23 (2 ꢁ s,
6H, Si(CH3)2), 0.91–0.93 (m, 12H, C(CH3)), 1.65–1.73 (m, 1H, C(CH3)2H),
2.56 (d, JH,OH ¼ 9.3 Hz, 1H, 3-OH), 3.38 (m, 1H, 5-H), 3.47–3.51 (m, 2H, 2-H,
3-H), 3.81 (s, 3H, OCH3), 4.03 (dd, J5,6 ¼ 1.9, J6,6 ¼ 12.4 Hz, 1H, 6-H), 4.12
(m, 1H, 4-H), 4.25 (dd, J5,6 ¼ 1.5, J6,6 ¼ 12.4 Hz, 1H, 60-H), 4.53 (d, J1,2
¼
7.4 Hz, 1H, 1-H), 5.50 (s, 1H, CHAr), 6.88–6.94 þ 7.10–7.45 (2 ꢁ m, 4H,
Ar).C22H35N3O6Si (465.6) Calcd.: C: 56.75, H: 7.58, N: 9.02. Found: C: 57.11, H:
7.18, N: 8.68.
Thexyldimethylsilyl O-(2,3-Di-O-acetyl-4,6-O-benzylidene-ß-D-galacto-
pyranosyl)-(1!3)-2-azido-2-deoxy-4,6-O-(4-methoxybenzylidene)-ß-D-
galactopyranoside (22). A solution of 4B (2.53 g, 5.10 mmol) and 21 (1.90 g,
4.08 mmol) in dry CH2Cl2 (40.0 mL) under argon was cooled to 08C. After
adding TMSOTf-solution (0.1 N, 0.83 mL, 0.02 eq.) the reaction mixture was
stirred for 1 hr at 08C, then neutralized with Et3 N (1.00 mL) and the
solvent removed in vacuo. Purification by flash chromatography (toluene/
ethyl acetate 5:1 to 3:1) furnished 22 (2.14 g, 2.68 mmol, 66%) as colorless
foam. TLC (toluene/acetone 3:1): Rf ¼ 0.59. [a]D ¼ þ27 (c ¼ 1, CHCl3). 1H
NMR (250 MHz, CDCl3): d 0.20 þ 0.21 (2 ꢁ s, 6H, Si(CH3)2), 0.89–0.93
(m, 12H, C(CH3)), 1.65–1.71 (m, 1H, C(CH3)2H), 2.06 þ 2.07 (2 ꢁ s, 6H,
COCH3), 3.32(s, 1H, 5-H), 3.49–3.55 (m, 2H, 3-H, 50-H), 3.71 (dd, J1,2 ¼ 7.6,
J2,3 ¼ 10.5 Hz, 1H, 2-H), 3.79(s, 3H, ArOCH3), 3.97–4.11 (m, 2H, 6-H, 60-H),
4.19–4.33 (m, 3H, 4-H, 6-H, 60-H), 4.38 (d, J3,4 ¼ 3.6 Hz, 1H, 40-H), 4.51
(d, J1,2 ¼ 7.6 Hz, 1H, 1-H), 4.87 (d, J1,2 ¼ 7.9 Hz, 1H, 10-H), 4.97 (dd,
J2,3 ¼ 10.4, J3,4 ¼ 3.6 Hz, 1H, 30-H), 5.41 (dd, J1,2 ¼ 7.9, J2,3 ¼ 10.4 Hz, 1H,
20-H), 5.51 (s, 2H, 2 ꢁ CHAr), 6.83–7.54 (m, 9H, Ar). MALDI-MS (positive
mode, CHCA): [M þ Na]þ, m/z ¼ 822.3; found: m/z ¼ 822.3, [M þ K]þ,
m/z ¼ 838.4; found: m/z ¼ 838.3.
O-(2,3-Di-O-acetyl-4,6-O-benzyliden-ß-D-galactopyranosyl)-(1!3)-2-
azido-2-deoxy-4,6-O-(4-methoxybenzylidene)-a/ß-D-galactopyranose
(23). To a solution of 22 (2.10 g, 2.63 mmol) in pyridine (20.0 mL) was added HF
pyridine (4.00 mL). After 21 hr at rt the reaction mixture was neutralized with
saturated NaHCO3-solution and the solvent removed in vacuo. The residue
was suspended in CH2Cl2 and adsorbed on silica gel. Purification by flash
chromatography (toluene/acetone 3:1) furnished 23 (1.01 g, 1.54 mmol, 59%)