A novel amino protecting group: DTPM

Article abstract of DOI:10.1016/S0040-4039(01)00366-5

A novel hydrazine and primary amine labile (1,3-dimethyl-2,4,6 (1H,3H,5H)-trioxopyrimidine-5-ylidene)methyl (DTPM) vinylogous amide type protecting group was developed to protect aminosugars and other primary amines in a facile and cost effective manner.

Full text of DOI:10.1016/S0040-4039(01)00366-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3129–3132
A novel amino protecting group: DTPM
Gyula Dekany, Laurent Bornaghi,* John Papageorgiou and Stephen Taylor
Alchemia Pty Ltd, PO Box 6242, Upper Mt Gravatt, Brisbane, Queensland 4122, Australia
Received 8 January 2001; revised 19 February 2001; accepted 28 February 2001
Abstract—A novel hydrazine and primary amine labile (1,3-dimethyl-2,4,6 (1H,3H,5H)-trioxopyrimidine-5-ylidene)methyl
(DTPM) vinylogous amide type protecting group was developed to protect aminosugars and other primary amines in a facile and
cost effective manner. © 2001 Elsevier Science Ltd. All rights reserved.
Aminosugars are important constituents of various
glycoconjugates1 including peptidoglycans, muco-
polysaccharides, glycopeptides and proteins and
oligosaccharides of human milk and blood group deter-
minants. Aminosugars are also often encountered in
bacterial and tumor-associated carbohydrate antigens.2
Oligosaccharide synthesis using 2-amino-2-deoxy sugars
requires the presence of suitable amino protecting
groups. For the preparation of 1,2-trans-glycosides,
protecting groups such as phthaloyl,3 tetra-
chlorophthaloyl,4 trichloroethoxycarbonyl,5 allyloxy-
carbonyl,6 2,5-dimethylpyrrole7 or N,N-diacetyl8 have
been used. Recently, Schmidt and co-workers also pro-
posed the use of thiodiglycoloyl9 and dimethylmaleoyl10
DTPM protection can be achieved in high yield by
reacting an amino sugar with the cheap 1,3-dimethyl-5-
[(dimethylamino)methylene]2,4,6 (1H,3H,5H)-trioxo-
pyrimidine13 (DTPM-reagent) 1 in H2O or in organic
solvents, such as methanol and CH2Cl2. The reaction
usually goes to completion at room temperature with
product precipitation in less than a minute when
MeOH is used as solvent. The synthesis of (1,3-
dimethyl-2,4,6
(1H,3H,5H)-trioxopyrimidine-5-yli-
dene)methyl (DTPM) protected aminosugars, the
deprotection conditions and the stability of the pro-
tected carbohydrates towards a wide range of reaction
conditions will be discussed.
derivatives of
D-glucosamine to synthesize 1,2-trans-
linked glycosides. The azido group has received much
attention in carbohydrate chemistry, since it serves as a
masked, non-participating amino functionality, thereby
allowing the synthesis of 1,2-cis-linked 2-amino-2-
deoxy-glycosides.11,12 Using the above mentioned pro-
tecting groups
a
large number of complex
oligosaccharides containing aminosugars have been
synthesized. However, these protecting groups always
present some limitations. Difficulties of introduction or
cleavage of a protecting group, stability or reactivity
problems of the protected compounds can reduce over-
all yields. Development of novel protecting groups is
important, providing new options in stability, orthogo-
nality and reactivity.
Herein, we report the use of a non-acidic reagent
suitable for vinylogous amide type protection of base
sensitive primary amines in carbohydrate chemistry.
Keywords: protecting groups; carbohydrates; vinylogous amides; pri-
mary amines.
* Corresponding author. E-mail: lbornaghi@alchemia.com.au
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00366-5

3130
G. Dekany et al. / Tetrahedron Letters 42 (2001) 3129–3132
Scheme 2.
DTPM protected
D
-glucosamine 2 and
D
-galactosamine
Benzylidene protection of DTPM protected thiogly-
coside 7 was carried out using a,a-dimethoxytoluene
(a,a-DMT) in the presence of p-toluene sulphonic acid
(TsOH) in MeCN affording the 4,6-O-acetal 9 in 92%
yield. Reductive ring opening of DTPM protected ace-
tal 9 using sodium cyanoborohydride in acidic condi-
tions gave 6-O-benzyl thioglycoside 10 in 87% yield.
Perbenzylation of thioglycoside 7 was achieved in DMF
using NaH/benzyl bromide. Compound 11 was
obtained in 61% yield (Scheme 2).
3 were prepared in 90 and 86% yields, respectively, by
reaction with 1 in MeOH (Scheme 1).14
DTPM protected
with acetic anhydride in pyridine to afford peracetyl-
ated a/b- -galactopyranose 4 in quantitative yield.
D
-galactosamine 3 was acetylated
D
Treatment of anomeric acetates 4 with HBr/AcOH
(30%) in CH2Cl2 gave the glycosyl bromide 5, which
was reacted with potassium thioacetate in ethyl acetate,
in the presence of a saturated solution of NaHCO3
containing
tetrabutylammonium
hydrogensulfate,
Treatment of methyl 2-deoxy-2-N-DTPM-amino-1-
affording thioacetate 6 in 53% yield. Approximately 5%
of the a-thioacetate was also formed in the reaction,
thus multiple crystallizations were necessary to get the
pure b-anomer 6. Zemplen deprotection of peracetate 6
and subsequent treatment of the product with MeI gave
thioglycoside 7 in 73% yield. Acetylation of b-thiogly-
coside 7 with acetic anhydride in pyridine gave perac-
etate 8.
thio-b-
-glucopyranoside 1215 with a,a-dimethoxy-
D
toluene and TsOH in MeCN furnished 4,6-O-acetal 13
(77%), which was subsequently alkylated in DMF using
p-methoxybenzyl chloride/NaH to give substituted ben-
zyl ether 14 in 82% yield. Cleavage of the benzylidene
moiety of 14 was carried out in MeOH/MeCN (1/10) in
the presence of TsOH to provide diol 15 in 70% yield.
Cleavage of the p-methoxybenzyl ether was realized in
Scheme 3.

G. Dekany et al. / Tetrahedron Letters 42 (2001) 3129–3132
3131
Scheme 4.
Table 1.
CH2Cl2/H2O (95/5) in the presence of 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) to afford compound
13 in 84% yield. Silylation of 12 using tert-butyl-
diphenylsilyl chloride (TBDPSCl)/dimethylaminopy-
ridine (DMAP) in 1,2-dichloroethane (1,2-DCE)
yielded 6-O-silyl 16 (95%). The tert-butyldiphenylsilyl
protecting group was cleaved in 84% yield using tetra-
butylammonium fluoride in THF (Scheme 3).
such as ethanolamine or hydroxylamine, at room tem-
perature, in a few minutes (Scheme 5).17
In order to examine the influence of the DTPM protect-
ing group on the stereochemical outcome of glycosyla-
tion reactions, experiments were performed using
glycosyl donors 5 and 8 on a limited number of accep-
tors (DTPM protected ethanolamine and biphenol-
methanol). The results (Scheme 6, Table 1) display
predominantly the b product although a reasonable
amount of the a glycoside was also formed (20–40%).
In addition to 2-deoxy-2-amino sugars, the DTPM
group was shown to protect glycosylamine 1716 and the
amino functions of 4-aminobenzyl alcohol 19 and
ethanolamine 21 in high yields (Scheme 4).
Stereochemical control of glycosylations using DTPM
protected donors is currently under more detailed
investigation.
Deprotection of the DTPM protecting group was easily
achieved with ammonia, hydrazine or primary amines
In conclusion, the DTPM protecting group has demon-
strated stability in most of the conditions commonly
employed in carbohydrate chemistry including acyla-
tion, deacylation, alkylation, hydrogenolysis, acetal for-
mation and cleavage, reductive ring opening of acetals,
silylation and glycosylation. The advantageous features
of this protecting group make it a viable alternative to
existing methodologies in the synthesis of aminosugar
containing carbohydrates.
Scheme 5.
References
1. Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 21–121.
Scheme 6.

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G. Dekany et al. / Tetrahedron Letters 42 (2001) 3129–3132
2. Toyokuni, T.; Singhal, A. K. Chem. Soc. Rev. 1995,
evaporated to dryness under vacuum. The residue was
re-suspended in diethyl ether (750 mL), filtered and
washed on the funnel with additional diethyl ether (500
mL) to yield 1,3-dimethyl-5-[(dimethylamino)methylene]-
2,4,6 (1H, 3H,5H)-trioxopyrimidine 1 as a yellow solid
(271.85 g, 67%).
231–241.
3. Lemieux, R. U.; Takeda, T.; Chung, B. Y. ACS. Symp.
Ser. 1976, 39, 90–115.
4. Castro-Palomino, J. G.; Schmidt, R. R. Tetrahedron Lett.
1995, 36, 5343–5346.
5. Imoto, M.; Yoshimura, H.; Shimamoto, T.; Skaguchi,
N.; Kusumoto, S.; Shiba, T. Bull. Chem. Soc. Jpn. 1987,
2205–2214.
14. Sodium (2.66 g, 116 mmol) was dissolved in dry methanol
(500 mL). The solution was left to return to room tem-
perature.
D-Galactosamine hydrochloride (25 g, 115.91
6. Boulanger, P.; Banoud, J.; Descotes, G. Can. J. Chem.
mmol) was added and the suspension was vigorously
agitated for 8 minutes and filtered. DTPM reagent 1
(25.71 g, 1.05 equiv.) was dissolved in dry methanol (75
mL) and added to the aminosugar containing filtrate. The
mixture was stirred at room temperature for 30 seconds.
The product was filtered out and washed with diethyl
ether (2×200 mL). Compound 3 was obtained in 85%
yield as a white solid.
1987, 65, 1343–1346.
7. Bowers, S. G.; Coe, D. M.; Boons, G.-J. J. Org. Chem.
1998, 63, 4570–4571.
8. Castro-Palomino, J. C.; Schmidt, R. R. Tetrahedron Lett.
1995, 36, 6871–6874.
9. Castro-Palomino, J. C.; Schmidt, R. R. Tetrahedron Lett.
2000, 41, 629–632.
10. Aly, M. R. E.; Castro-Palomino, J. C.; El-Sayed Ibrahim,
I.; El-Sayed El-Ashry, H.; Schmidt, R. R. Eur. J. Org.
Chem. 1998, 2305–2316.
11. Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 54,
1244–1251.
15. Toth, I.; Dekany, G.; Kellam, B. Aust. Pat. Application,
No P05367 (1997). The Dde protected glucosamine thio-
glycoside was deprotected using ammonia solution
(100°C for 1 hour). The free amine was re-protected using
the DTPM reagent in MeOH. Compound 12 was isolated
in 80% yield as a pure white solid (see Ref. 11).
12. Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M.
Helv. Chim. Acta 1991, 74, 2073–2077.
16. Lubineau, A.; Drouillat, B.; Auge, J.; Metech, J. Eur.
Pat. Application No 93402053.8 (1993).
13. Synthesis of 1,3-dimethyl-5-[(dimethylamino)methylene]-
2,4,6 (1H,3H,5H)-trioxopyrimidine 1: N,N-dimethylfor-
mamide dimethyl acetal (252 g, 2.11 mol) was stirred at
0°C in CHCl3 (750 mL). 1,3-Dimethylbarbituric acid (300
g, 1.92 mol) in CHCl3 (2 L) was added to the stirring
solution over 2 hours. The reaction mixture was washed
with water (3×1 L) and saturated brine solution (1 L).
The organic phase was dried over MgSO4, filtered and
17. DTPM protected
D-glucosamine 7 (1 g) was taken up in
ammonia solution (10 mL) and stirred at room tempera-
ture for 10 minutes. The resulting suspension was filtered
and the filtrate washed with CHCl3 (3×50 mL). The
aqueous phase was evaporated to dryness to give com-
pound 23 in 91% yield.
.
.