A Novel and Efficient Route towards α-GalNAc-Ser and α-GalNAc-Thr Building Blocks for Glycopeptide Synthesis

✍ Scribed by Gottfried A. Winterfeld; Yukishige Ito; Tomoya Ogawa; Richard R. Schmidt

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 269 KB
• Volume: 1999
• Category: Article
• ISSN: 1434-193X
• DOI: 10.1002/(sici)1099-0690(199905)1999:5<1167::aid-ejoc1167>3.0.co;2-2

✦ Synopsis

Michael addition of serine and threonine derivatives 4a-4c compounds by platinized Raney nickel T4. Manipulation of the protecting groups afforded known N-Fmoc-O-(2-to 3,4,6-tri-O-benzyl-2-nitro-D-galactal (1) afforded the corresponding 2-deoxy-2-nitro-α-D-galactopyranosides 5a-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-galactopyranosyl)-L-serine (8a) and -threonine (8b), valuable building 5c in good yield and stereoselectivity. 2-deoxy-2nitroglycosides 5a and 5b were reduced to the 2-acetamido blocks for O-glycopeptide synthesis.

The α-glycosidic linkage between 2-acetamido-2-deoxy--galactopyranose and the side-chain hydroxy groups of serine or -threonine is a common motif in numerous glycoproteins. [1] It is found in mucins, cell-membrane glycoproteins, blood-group determinants, immunoglobulins, anti-freeze glycoproteins and glycoprotein hormones. [1Ϫ3] Chemical synthesis of this 1,2-cis-glycosidic bond of 2-acetamido-2-deoxy--galactopyranosides proved to be difficult, since it necessitates a non-participating latent amino function at the C-2 atom of the glycosyl donor. [4] Lemieux et al. [5] addressed this problem using addition reactions to 2-Scheme 1 nitrosoglycals and observed good α stereoselectivity. The reduction of the resulting 2-acetoximino-α--lyxo-hexopyrequired N-Boc/OtBu amino acids 4a and 4b were obtained ranosides, however, afforded mixtures of epimeric galacto from commercial Boc-serine/threonine-(O-benzyl)-OH (3a and talo products. [6] After the introduction of 2-azido-2and 3b) in two steps using tert-butyltrichloroacetimidate [20] deoxyaldoses to glycoside synthesis by Paulsen et al. [7Ϫ9] and subsequent debenzylation (Scheme 2). and the azidonitration protocol by Lemieux, [10] derivatives of 2-azido-2-deoxygalactose remained the only possible glycosyl donors for the construction of the α-glycosidic bond of N-acetylgalactosamine to serine and threonine. [11Ϫ17] Recently, Michael-type addition to 3,4,6-tri-O-benzyl-2-nitro--galactal (1) [18] was shown to be a convenient glycosylation method for the synthesis of α-glycosides of galactosamine, [18] avoiding the often lengthy preparation of 2-azido-2-deoxygalactosyl donors. We present a new and efficient procedure based on this concept for the preparation of α-Scheme 2. Reagents: i) tert-butyltrichloroacetimidate,

GalNAc-Ser and α-GalNAc-Thr building blocks of type A for glycopeptide synthesis (Scheme 1).

First, the glycosylation of Fmoc--Ser-tBu (4c) [19,21] with As glycosyl donor known 3,4,6-tri-O-benzyl-2-nitro--1 was established (Scheme 3). Since strong bases were regalactal (1) was used, which was prepared according to a ported to favour addition of the aglycon from the α side, [18] slight modification of the reported procedure from 1-Osterically hindered potassium tert-butoxide was chosen as acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-nitro-α--galactopyrabase and found to be most efficient in catalytic quantities nose (2). [18] Glycosylation was performed with serine (0.1 equiv.) in combination with dry toluene as solvent. The and threonine acceptors carrying the protecting-group reaction proceeds reasonably fast at room temperature and patterns N-fluoren-9-ylmethoxycarbonyl (Fmoc)/O-tert-buall of 1 is consumed after 3 h. As products the α-glycoside tyl (tBu) [19] and N-tert-butyloxycarbonyl (Boc)/OtBu. The 5c (83%) and the corresponding β-glycoside 5cβ (14%) were isolated, showing a very good overall yield of glycosides [a]