Synthesis of N-protected galactosamine building blocks from D-tagatose via the heyns rearrangement

Article abstract of DOI:10.1080/07328300500495795

N-Acetyl-D-galactosamine (11), a very important naturally occurring building block of oligosaccharides, is easily accessible via the Heyns rearrangement of D-tagatose (3) with benzylamine. The short and efficient synthesis of various differently N-protected D-galactosamine derivatives is reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/07328300500495795

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Synthesis of N‐Protected Galactosamine
Building Blocks from d‐Tagatose via the Heyns
Rearrangement
Tanja M. Wrodnigg a , Inge Lundt b & Arnold E. Stütz a
a Glycogroup, Institut für Organische Chemie , Technische Universität Graz ,
Graz, Austria
b Department of Chemistry , Technical University of Denmark (DTU) ,
Lyngby, Denmark
Published online: 21 Aug 2006.
To cite this article: Tanja M. Wrodnigg , Inge Lundt & Arnold E. Stütz (2006) Synthesis of N‐Protected
Galactosamine Building Blocks from d‐Tagatose via the Heyns Rearrangement, Journal of Carbohydrate
Chemistry, 25:1, 33-41, DOI: 10.1080/07328300500495795
To link to this article: http://dx.doi.org/10.1080/07328300500495795
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Journal of Carbohydrate Chemistry, 25:33–41, 2006
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300500495795
Synthesis of N-Protected
Galactosamine Building
Blocks from D-Tagatose via
the Heyns Rearrangement
Tanja M. Wrodnigg
¨
Glycogroup, Institut fu¨r Organische Chemie, Technische Universitat Graz,
Graz, Austria
Inge Lundt
Department of Chemistry, Technical University of Denmark (DTU), Lyngby, Denmark
Arnold E. Stu¨tz
¨
Glycogroup, Institut fu¨r Organische Chemie, Technische Universitat Graz,
Graz, Austria
N-Acetyl-D-galactosamine (11), a very important naturally occurring building block of
oligosaccharides, is easily accessible via the Heyns rearrangement of D-tagatose (3)
with benzylamine. The short and efficient synthesis of various differently N-protected
D-galactosamine derivatives is reported.
Keywords Heyns rearrangement, D-Galactosamine, N-Protected D-galactosamine
building blocks
INTRODUCTION
N-Acetyl-D-galactosamine (11) is a naturally occurring sugar present in glyco-
proteins, glycolipids, and glycosaminoglycans, which play important roles in
cell recognition events.[1] Furthermore, 11 is biosynthetically incorporated
into glycosphingolipids.[2]
Received August 22, 2005; accepted October 20, 2005.
Address correspondence to Tanja M. Wrodnigg, Glycogroup, Institut fu¨r Organische
¨
Chemie, Technische Universitat Graz, Stremayrgasse 16, A-8010, Graz, Austria.
E-mail: t.wrodnigg@tugraz.at
33

T. M. Wrodnigg et al.
34
Consequently, different synthetic approaches for this important sugar have
been investigated over the years. Paulsen and coworkers first synthesized
2-azido deoxy-D-galacto sugars starting from 1,6;2,3-dianhydro-b-D-talopyra-
nose by nucleophilic opening of the epoxide employing sodium azide.[3] Perry
showed the transformation of D-lyxose to 11 by base-catalyzed addition of nitro-
methane followed by introduction of the amino function at position C-2.[4]
D-Galactal was found by several groups to be a suitable starting material for
the synthesis of 11. By addition reactions, 2-azido-2-deoxy- and 2-deoxy-2-
nitro-D-galactose compounds were obtained that could easily be converted to
derivatives of 11.[5] Several synthetic approaches were based on the inversion
of the configuration at position C-4 of D-glucose derivatives, leading to the
corresponding galacto-configurated amino sugars but requiring time- and
cost-intensive protecting group manipulations with only moderate yields.[6]
The Heyns rearrangement,[7] wherein ketoses react with suitable amines
to form the corresponding ketosylamines, which subsequently isomerize to
the 2-amino-2-deoxyaldoses (Sch. 1), was first discovered by Fischer[8] during
his studies on the osazone formation of sugars and further investigated by
Heyns and Koch in the 1950s when they found that D-glucosamine 2 was
formed in the reaction of D-fructose 1 with ammonia.[9]
Subsequently, this reaction was extended to a wide range of different amines
yielding the corresponding N-substituted glucosamine derivatives. Other keto-
sugars such as D-tagatose, L-sorbose, and D-psicose were found to react accord-
ingly. In general, yields were found unsatisfactory and too low for preparative
purpose. For example, Heyns and his group[10] showed that the reaction of D-
tagatose with ammonia is straightforward and gave the best result in the keto-
sugar series, leading to D-galactosamine hydrochloride in an overall yield of
3.5%. Later, Weicker and coworkers[11] reinvestigated this reaction employing
silica gel for the condensation of D-tagatose with ammonia and ion exchange
resin for the rearrangement. This way, the crude yield of D-galactosamine
hydrochloride was increased to 22 to 26%, as determined by the colorimetric
Elson-Morgan method, but only 8% could be isolated after crystallization.
Recently, we showed that the Heyns rearrangement is a convenient
entry to valuable 2-deoxy-2-amino sugars such as lactosamine[12] by varying
the reaction conditions and choosing a suitable nitrogen protecting group.
Scheme 1: Heyns rearrangement of D-fructose.

N-Protected Galactosamine Building Blocks
35
Now we want to report the synthesis of various differently N-protected deriva-
tives (7–11) of D-galactosamine starting from D-tagatose 3. This ketose gained
interest due to its approval as an alternative, nonnutritious sweetener[13] used
in soft drinks and ready-to-eat cereals. Therefore, a change from a rare to a
common status could be recognised for D-tagatose during the last few years,
now easily prepared, for example, from galactose[14] or in a one-step de novo
synthesis.[15] The N-protected galactosamine building blocks were synthesized
in overall yields of up to 25%.
RESULTS AND DISCUSSION
D-Tagatose 3 was reacted with commercial-grade benzylamine to give the corre-
sponding N-benzyl-tagatosylamine 4, which was obtained as yellowish syrup
together with unreacted starting material and side products. This mixture under-
went the rearrangement in methanol in the presence of glacial acetic acid (v:v
10:1) at room temperature within 2 h to give mainly N-benzyl-D-galactosamine
5. No epimerization at C-2 could be observed in the course of the rearrangement
under the conditions employed, although formation of small amounts of the talo-
configurated product has been found by other workers.[10] Hydrogenolysis of the
N-benzyl group was performed in MeOH or water/dioxane at pH 1-2 employing
Pearlman’s catalyst (20%) to yield a mixture of galactosamine hydrochloride 6
and unreacted 3. N-Protection was achieved in methanol employing trietylamine
and 1,3-dimethyl-5-[(dimethylamino)methylene] 2,4,6 (1H, 3H, 5H)-trioxopyri-
midine (DTPM-reagent).[16] Per-O-acetylation in pyridine with acetic anhydride
allowed, after recrystallization from diisopropyl ether, access to the fully pro-
tected derivative 7 in an overall yield of 25% starting form D-tagatose, ready
for further transformations. Likewise, the amino function of 6 can be reacted
with other protecting groups. Reaction with tetrachlorophthaloyl anhydride
(TCPA) in MeOH using Et3N as base gave, after per-O-acetylation, the N-TCP-
per-O-acetylated galactosamine 8.[17] Employing trichloroethoxycarbonylchlor-
ide (TrocCl) in aqueous dioxane in the presence of NaHCO3 followed by per-
O-acetylation yielded 9. Accordingly, 9-fluorenylmethoxycarbonylchloride[18]
(FmocCl) furnished 10. In all cases the per-O-acetylated differently N-protected
galactosamine derivatives were isolated in overall yields of 15 to 25% calculated
from 3. Additionally, regioselective N-acetylation performed in MeOH or
simple per-O-acetylation led to known N-acetyl-D-galactosamine and
per-O-acetylated D-galactosamine, respectively (Sch. 2).[19]
CONCLUSION
In summary, we have synthesized different N-protected galactosamine deriva-
tives (7–11) via the Heyns rearrangement starting from commercially available
D-tagatose 3 in overall yields of up to 25%. The reaction sequence is short and

T. M. Wrodnigg et al.
36
Scheme 2: Synthesis of N-protected D-galactosamine derivatives 7–11 in overall yields of
up to 25%.
easy to handle, requiring only cheap materials. With suitable protecting groups,
a range of D-galactosamine building blocks are now readily available.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian INOVA 500 operating at
499.925 MHz. 13C NMR spectra were recorded at 75.47 or 50.29 MHz.
Residual nondeuterated solvent was used as internal standard for determi-
nation of chemical shifts. Signals of protecting groups were found in the
expected regions and are not listed explicitly. Mass spectra were measured
on an HP 1100 series MSD, Hewlett Packard. Samples were dissolved in
acetonitrile or acetonitrile/water mixtures. The scan mode for positive ions
(mass range 100–1,000 D) was employed varying the fragmentation voltage
from 50 to 250 V, with best molecular peaks observed at 150 V. Analytical
TLC was performed on precoated aluminum plates silica gel 60 F254
(Merck 5554), detected with UV light (254 nm), as well as staining with
5% vanillin/sulfuric acid or cercic ammonium molybdate (100 g ammonium-
molybdate/4 g cerium sulfate in 1 L 10 % H2SO4) and heated on a hotplate.
For column chromatography silica gel 60 (230–400 mesh, Merck 9385)
was used.
1,3,4,6,-Tetra-O-Acetyl-N-(1,3-Dimethyl-2,4,6 (1H, 3H, 5H)-
Trioxopyrimidine-5-ylidene)Methyl-a-D-Galactosamine (7)
N-Benzyl-D-Galactosamine 5: To D-tagatose 3 (3.0 g, 16.7 mmol) ben-
zylamine (7.5 mL, 68.7 mmol) was added at 08C and the reaction mixture

N-Protected Galactosamine Building Blocks
37
stirred at 408C over night until TLC (CH3Cl/MeOH/NH4OH5/1/1%) showed
the condensation product as the main component in the mixture. Methanol
(3 mL) was added and this solution was stirred into 400 mL petrol ether
and stirred at rt for 2 h. The petrol ether layer was separated and this pro-
cedure was repeated. Obtained were 4.3 g of a mixture containing N-benzyl-
tagatosylamine (4), starting material 3, and side products. The residue was
dissolved in a mixture of methanol (25 mL) and glacial acetic acid (2.5 mL)
and kept at rt for 1 h. The solution was stirred into petrol ether (400 mL)
and stirring was continued for 3 h. After separation of the layers, an oily
brown residue, containing N-benzylgalactosamine 5, D-tagatose 3, and side
products was obtained.
D-Galactosamine Hydrochloride (6): The residue obtained from the
rearrangement (5.6 g) was dissolved in deionized water (15 mL) containing
8 mL of dioxane and dropwise acidified with concd HCl to pH 1. Pd(OH)2/C
(0.6 g) was added and this mixture was stirred under a hydrogen atmosphere
at ambient pressure and ambient temperature until TLC (MeOH/CHCl3/
NH4OH2/2/1) showed completed removal of the N-benzyl group. The
catalyst was filtered off and the solution was concentrated under reduced
pressure. The obtained yellowish residue (4.6 g) contained the D-galactosamine
hydrochloride 6 and unreacted starting material.
DTPM Protection: The residue obtained from hydrogenolysis (4.6 g) was dis-
solved in 20 mL methanol, and triethylamine (7 mL, 50.5 mmol), and DTPM
reagent (8 g, 38.0 mmol in methanol) were added and the reaction was kept
at rt for 2 h. The solid precipitate was filtered off, and the filtrate was concen-
trated to 11.3 g of N-DTPM-protected D-galactosamine in a mixture with D-
tagatose 3. To a 10% solution of this crude material in pyridine, acetic anhy-
dride (15 mL) was added dropwise at 08C, a catalytic amount of dimethylami-
nopyridine was added, and the reaction was kept at rt for 16 h. The solvent
was removed under reduced pressure, the residue was dissolved in CHCl3,
and the solution was consecutively washed with 6% HCl and sat aqueous
NaHCO3, then dried over Na2SO4. Column chromatography with ethyl
acetate/petrol ether 1/2 gave exclusively the a-anomer 7 in an overall yield
1
from 3 of 25%. [a]20; ¼ þ47.9 (c ¼ 2.0, CH2Cl2). H NMR (CDCl3): d ¼ 10.09
D
(m, 1H, NHDPTM), 8.10 (d, 1H, HC55CDPTM), 6.25 (d, 1H, H-1, J1,2 3.9 Hz),
5.43 (m, 1H, H-4, J4,5 2.9 Hz), 5.19 (dd, 1H, H-3, J2,3 11.0 Hz, J3,4 3.4 Hz),
4.25 (m, 1H, H-6, J5,63.8 Hz), 4.05–4.03 (m, 2H, H-5, H-60), 3.94 (ddd, 1H,
H-2). 13C NMR (CDCl3): d ¼ 170.55, 170.09, 170.04, 168.98 (acetyl), 165.07,
162.82, 159.53, 152.10 (DPTM), 92.78 (DPTM), 90.84 (C-1), 69.0, 68.45, 66.36
(3C, C-3, C-4, C-5) 61.17 (C-6), 57.52 (C-2), 28.14, 27.44 (DPTM), 21.03,
20.86, 20.84, 20.79 (acetyl). m/z: 514.4 [Mþ-H]. Anal. calcd for C21H27O12N3
(513.5): C, 49.12; H, 5.31. Found: C 49.01, H 5.36.

T. M. Wrodnigg et al.
38
1,3,4,6-Tetra-O-Acetyl-2-Deoxy-2-(Tetrachlorophthalimido)-
a/b-D-Galactosamine (8)
To a 10% solution of crude galactosamine hydrochloride 6 (6.1 g,
28.3 mmol) in methanol, tetrachlorophthaloyl anhydride (TCPA, 10.0 g,
45.5 mmol) and triethylamine (8.0 mL, 57.7 mmol) were added at 08C; 1 mL
THF and 1 mL dioxane were added for better solubility; and the reaction
was stirred at ambient temperature for 20 h until TLC (CHCl3/MeOH/
NH4OH4/4/1) showed completed conversion of the starting material. The
reaction mixture was concentrated to a residue that was per-O-acetylated in
150 mL pyridine, 50 mL acetic anhydride, and a catalytic amount of dimethy-
lamino pyridine. The solvent was removed under reduced pressure, the
residue was dissolved in CH2Cl2, and the solution was consecutively washed
with 6% HCl and sat aqueous NaHCO3, then dried over Na2SO4. Column
chromatography with ethyl acetate/petrol ether 1/4 gave an a/b mixture
1
with a ratio of 3:1 of 8 in an overall yield from D-tagatose of 15%. H NMR
(CDCl3): d ¼ 6.41 (d, 1H, H-3a,J2,3 12.2 Hz, J3,4 2.9 Hz), 6.38 (d, 1H,
H-1b,J1,2 8.8 Hz), 6.28 (d, 1H, H-1a, J1,2 3.4 Hz), 5.83 (dd, 1H, H-3b, J3,4
3.4 Hz, J2,3 11.2 Hz), 5.65 (bd, 1H, H-4a, J4,5 2 Hz), 5.50 (bd, 1H, H-4b, J4,5
3 Hz), 4.87 (dd, 1H, H-2a), 4.63 (dd, 1H, H-2b), 4.49 (m, 1H, H-5a, J5,6
6.8 Hz, J5,6 4.4 Hz), 4.21–4.10 (m, 5H, H-6a, H-60a, H-5b, H-6b, H-60b).
0
13C NMR (CDCl3): d ¼ 91.3 (C-1a), 90.2 (C-1b), 72.0 (C-5b), 69.6 (C-5a),
67.8 (C-4b), 67.0 (C-4a), 66.5 (C-3b), 64.7 (C-3a), 61.5 (C-6a), 61.3 (C-6b),
51.2 (C-2a), 50.3 (C-2b). m/z: 616.3 [Mþ-H]; Anal. calcd for C22H19O11NCl4
(615.24): C, 42.95; H 3.12. Found: C, 42.85; H, 3.15.
1,3,4,6-Tetra-O-Acetyl-2-Deoxy-2-(Trichloroethoxycarbonyl)-
a/b-D-Galactosamine (9)
To a 10% solution of crude galactosamine hydrochloride 6 (1.3 g,
6.12 mmol) in deionized water, NaHCO3 (1.8 g, 21.4 mmol) and trichloroethox-
ycarbonyl chloride (TrocCl, 1.3 mL, 9.4 mmol) were added and the reaction
stirred at ambient temperature for 20 h until TLC (CHCl3/MeOH/
NH4OH4/4/1) showed complete conversion of the starting material. The
reaction mixture was concentrated to a residue, which was treated with
10 mL pyridine, 5 mL acetic anhydride, and a catalytic amount of dimethyla-
minopyridine. The solvent was removed under reduced pressure, the residue
was dissolved in CH2Cl2, and the solution was consecutively washed with 6%
HCl and sat aqueous NaHCO3, then dried over Na2SO4. Column chromato-
graphy with ethyl acetate/petrol ether 1/5 gave an a/b mixture with a
ratio of 2:1 of 9 in an overall yield from D-tagatose of 20%. 1H NMR
(CDCl3): d ¼ 6.25 (d, 1H, H-1a, J1,2 3.4 Hz), 5.74 (d, 1H, H-1b, J1,2 8.8 Hz),
5.42 (bd, 1H, H-4a, J4,5 2.0 Hz), 5.37 (bd, 1H, H-4b, J4,5 2.0 Hz), 5.20 (dd,
1H, H-3a, J2,3 11.5 Hz, J3,4 3.4 Hz,), 5.12 (dd, 1H, H-3b, J2,3 11.2 Hz, J3,4

N-Protected Galactosamine Building Blocks
39
3.4 Hz), 4.82 (d, 1H, CH2 Troc, a, J 12.2 Hz), 4.73 (d, 1H, CH2 Troc, b, J
12.2 Hz), 4.69 (d, 1H, CH2 Troc, b, J 12.2 Hz), 4.60 (d, 1H, CH2 Troc, a, J
12.2 Hz), 4.42 (m, 1H, H-2a), 4.24 (bdd, 1H, H-60a), 4.16–4.03 (m, 6H,
H-2b, H-5a, H-5b, H-6a, H-6b, H-60b). 13C NMR (CDCl3): d ¼ 171.0, 170.7,
170.6, 170.4, 169.5, 169.1 (acetyl), 154.6 (C55O Troc, b), 154.4 (C55O Troc,
a), 95.5 (C-1a), 92.8 (C-1b), 91.3 (CCl3), 74.6 (CH2 Troc, a), 74.6 (CH2 Troc,
b), 71.9 (C-5b), 70.3 (C-3b), 68.8 (C-5a), 68.1 (C-3a), 66.9 (C-4a), 66.6 (C-
4b), 61.4 (2C, C-6a, C6b), 51.8 (C-2b), 49.3 (C-2a). m/z: 616.3 [Mþ-H];
Anal. calcd for C17H22O11NCl3 (522.75): C, 39.06; H, 4.25. Found: C, 39.01;
H, 4.29.
1,3,4,6-Tetra-O-Acetyl-2-deoxy-2-(9-
Fluorenylmethoxycarbonylamino)-a-D-Galactose (10)
To a 10% solution of crude galactosamine hydrochloride 6 (1.8 g,
8.4 mmol) in dioxane, NaHCO3 (2.5 g, 30 mmol) and 9-fluorenylmethoxycar-
bonylchloride (3.5 g, 13.5 mmol) were added and the reaction stirred at
ambient temperature until TLC (CHCl3/MeOH/NH4OH4/4/1) showed
complete conversion of the starting material. The reaction mixture was con-
centrated to a residue, which was treated with 20 mL pyridine, 10 mL acetic
anhydride, and a catalytic amount of dimethylaminopyridine. The solvent
was removed under reduced pressure, the residue was dissolved in
CH2Cl2, and the solution was consecutively washed with 6% HCl and sat
aqueous NaHCO3, then dried over Na2SO4. Column chromatography with
ethyl acetate/petrol ether 1/5 gave exclusively the a-anomer of 10 in an
overall yield from D-tagatose of 26%. [a]20 ¼ þ24.5 (c ¼ 1.7, CH2Cl2).
;D
1H NMR (CDCl3): d ¼ 10.09 (m, 1H, NHDPTM), 7.70 (d, 2H, Fmoc), 7.53
(d, 1H, Fmoc), 7.50 (d, 1H, Fmoc), 7.38 (t, 2H, Fmoc), 7.28 (t, 2H, Fmoc),
6.25 (d, 1H, H-1, J1,2 3.9 Hz), 5.44 (m, 1H, H-4, J4,5 1.9 Hz), 5.21 (dd, 1H,
H-3, J2,3 11.4 Hz, J3,4 3.0 Hz), 4.45 (dd, 1H, H-60, J5,6 7.2 Hz, J5,6 6.8 Hz,
0
J6,6 11.2 Hz), 4.36 (dd, 1H, H-6), 4.26 (t, 1H, CH2Fmoc), 4.19 (t, 1H,
CH2Fmoc), 4.15–4.05 (m, 3H, H-2, H-5, CHFmoc). 13C NMR (CDCl3):
d ¼ 171.2, 170.7, 170.5, 169.2, 156.1 (acetyl), 143.9, 141.4, 128.0, 127.3,
125.1, 120.3 (Fmoc), 91.7 (C-1), 68.8 (CH2Fmoc), 68.2, 67.2, 67.0 (C-3, C-4,
C-5), 61.6 (C-6), 49.0 (C-2), 47.3 (CHFmoc), 21.1, 20.9 (Acetyl). m/z: 570.8
[Mþ-H]; Anal. calcd for C29H31O11N (569.62): C, 61.15; H, 5.50. Found: C,
60.95; H, 5.57.
ACKNOWLEDGMENT
Glycogroup appreciates financial support by the Austrian Fonds zur Fo¨rderung
der Wissenschaftlichen Forschung (FWF), Vienna, Project P-13593 CHE.

T. M. Wrodnigg et al.
40
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