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Orthogonally Protected Sugar Diamino Acids as Building Blocks for Oligosaccharide Mimetics
Frank Sicherl and Valentin Wittmann
Institut für Organische Chemie und Chemische Biologie, Johann Wolfgang Goethe-Universität, Marie-Curie-Str. 11, 60439 Frankfurt am Main, Germany and
Fachbreich Chemie, Universität Konstanz, 78457 Konstanz, Germany Introduction
Sugar amino acids (SAAs) [1] have received considerable interest as building blocks for oligosaccharide and peptide mimetics and as pharmacophor-presenting scaffolds.
Used as monomers with a rigid pyran ring, functional pharmacophoric groups attached to the hydroxy, amino, and carboxyl groups can be presented in a distinct spatial arrangement following seminal studies by Hirschmann et al. [2]. Linear and cyclic oligomers of SAAs have been synthesized taking advantage of well-established peptide chemistry, and in certain cases adopting defined secondary structures [1, 3]. Branched structures employing sugar diamino acids, however, are not known.
Here we introduce the protected derivative 1 of 2,6-diamino-2,6-dideoxy-β-D- glucopyranosyl carboxylic acid, the first example of a sugar diamino acid (SDA) amenable to solid-phase synthesis (Figure 1). Compared to SAAs, the additional amino group can be used to increase diversity by selective functionalization and to form branched oligomers. Oligomeric SDAs with unprotected amino groups, on the other hand, are potential aminoglycoside mimetics.
O COOH MOMOMOMO
NHFmoc
NHBoc 1
Fig. 1. Orthogonally protected sugar diamino acid (SDA).
Results and Discussion
The synthesis of 1 started from glycosyl cyanide 2 which was prepared according to a published procedure [4]. After deacetylation the obtained triol was regioselectively tosylated at the 6 position followed by azide substitution to give 3 (Figure 2).
Hydrolysis of both the nitrile and acetamide under acidic conditions led to the free amino acid. To facilitate isolation, methyl ester 4 was formed by treatment with 2,2- dimethoxypropane and concentrated HCl. First attempts to obtain the free amino acid by basic hydrolysis of 3 (Ba(OH)2, H2O, reflux) were, however, not successful. Under these conditions the reaction stopped at the acetamido carboxylate stage.
AcO O AcO
OAc
HO O HO
N3
HO O HO
N3 1. HCl, reflux
2. 2,2-dimethoxy- propane, HCl
2 3 4
1. NaOMe, MeOH 2. TsCl, pyr 3. NaN3, DMF
86% 92%
NHAcCN NHAcCN OMe
O NH3Cl
Fig. 2. Formation of azido amino ester 3.
First publ. in: Peptide Revolution: Genomics, Proteomics & Therapeutics / Michael Chorev (ed.). - Boston: American Peptide Society, 2003, pp. 161-162
Konstanzer Online-Publikations-System (KOPS) URL: http://www.ub.uni-konstanz.de/kops/volltexte/2008/5570/
URN: http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-55709
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The amino group of 4 was protected by the Boc group with concomitant cleavage of the methyl ester. Methoxymethyl (MOM) groups were introduced by treatment with dimethoxymethane and P2O5 in order to circumvent toxic MOM-Cl to give 5 (Figure 3). The MOM ester contained in 5 was cleaved with NaOH. Finally, hydrogenation of the azide and subsequent Fmoc protection of the amine gave SDA building block 1.
O COOMOM MOMOMOMO
N3 1. Boc2O, NaOH (64%)
2. dimethoxymethane,
P2O5 (50%) 58%
5 4
NHBoc
1 1. NaOH
2. H2, Pd/C 3. FmocOSu
Fig. 3. Synthesis of SDA building block 1.
Building block 1 is suited for peptide coupling reactions in solution and on solid support using the Fmoc strategy as demonstrated in Figure 4. Diphenylmethyl protected β-alanine amide 6 served as a model for a solid-phase linked amino acid.
Stepwise coupling of 1 using HATU/HOAt as coupling reagents followed by complete deprotection led to β-alanine-linked pseudo disaccharide 8 within 5 steps (Figure 4).
MOMO O MOMO
NHFmoc O
MOMO O MOMO
NH
H2N N
H Ph O Ph
6 BocHN N
H Ph O Ph NH
BocHN O 1. 1, HATU, HOAt (84%)
2. piperidine
3. 1, HATU, HOAt (76%, 2 steps)
7
1. HCl 2. NEt3
HO O HO
NH2 O
HO O HO
NH
NH2 N
H Ph O Ph NH
NH2 O
8
Fig. 4. Application of SDA building block 1 in peptide coupling reactions.
Acknowledgments
This work was funded by the Deutsche Forschungsgemeinschaft (SFB 579).
References
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Commun. 2041-2042 (1998).
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