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Synlett 2007(16): 2492-2496  
DOI: 10.1055/s-2007-986645
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Efficient Synthetic Route to N-Glycosylamino Acids Using N α-Fmoc-Asp/Glu-5-oxazolidinone as Internal Protection

Rao Venkataramanarao, Vommina V. Sureshbabu*
Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India
e-Mail: hariccb@rediffmail.com;
Further Information

Publication History

Received 9 May 2007
Publication Date:
12 September 2007 (online)

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Abstract

A new facile synthetic route to prepare N-glycosylamino acids in fewer steps is reported. 5-Oxazolidinone served as an effective protecting moiety for N α-Fmoc-Asp/Glu and after glycosylation, the ring opening resulted in free α-carboxylic acid, which can be directly used to extend the chain to obtain N-glycopeptides. Both the minimum number of steps as well as circumvention of ortho­gonal protection strategy leads to a cost-effective route for their synthesis. This protocol can be easily scaled up to prepare N-glyco­sylated Asn/Gln acids in large quantities in fairly good yields.

Key words

5-oxazolidinone - glycosyl amine - protecting group - N-glycosylamino acid - coupling agent - building-block strategy

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Typical Procedure for the Synthesis of Glycosylated N α -Fmoc-Asp/Glu-5-oxazolidinones
To a solution of Fmoc-Asp/Glu-5-oxazolidinone (10 mmol) in 10 mL of THF was added 1-amino β-glucose (10 mmol) in THF (40 mL), HBTU (10 mmol), and DIPEA (11 mmol), and stirred at r.t. for about 30 min. The solvent was evaporated under reduced pressure and the residue was diluted with H2O (15 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with 10% citric acid (3 × 10 mL), 5% Na2CO3 solution (3 × 15 mL), brine, and dried over anhyd Na2SO4. The solution was concentrated and purified by column chromatography using EtOAc-hexane (2:8).
Selected Spectral Data Compound Fmoc-Asn(2,3,4,6-tetra-O-acetyl-β-d-gluco-pyranosyl)oxazolidinone (3a: n = 1): white solid. IR (KBr): νmax = 1700, 1735, 1801 cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.03-2.13 (4 s, 12 H), 2.81 (m, 2 H), 3.80 (m, 1 H), 4.03 (t, 1 H), 4.24 (m, 2 H), 4.42-4.52 (m, 2 H), 4.98 (t, 1 H), 5.05 (t, 1 H), 5.11 (s, 2 H), 5.21-5.35 (m, 2 H), 5.92 (br d, 1 H), 7. 33 (t, 2 H), 7.41 (t, 2 H), 7.52 (d, 2 H), 7.77 (d, 2 H). HRMS (ES): m/z calcd for C34H36N2NaO14 [M + Na]+: 719.2064; found: 719.2081.
Compound Fmoc-Gln(2,3,4,6-tetra-O-acetyl-β-d-gluco-pyranosyl)oxazolidinone (3b: n = 2): white solid. IR (KBr): νmax = 1698, 1730, 1800 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.86 (m, 2 H), 2.03-2.13 (4 s, 12 H), 2.22 (m, 2 H), 3.80 (m, 1 H), 4.03 (d, 1 H), 4.21-4.32 (m, 3 H), 4.48 (m, 2 H), 4.88 (t, 1 H), 5.06 (t, 1 H), 5.12 (s, 2 H), 5.27 (m, 2 H), 5.50 (br d, 1 H), 7. 33 (t, 2 H), 7.41 (t, 2 H), 7.52 (d, 2 H), 7.77 (d, 2 H). HRMS (ES): m/z calcd for C35H38N2NaO14 [M + Na]+: 733.2221; found: 733.2254.

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Typical Procedure for the Preparation of Glycosylated N α -Fmoc-Asn/Gln-OH To the glycosylated N α-Fmoc-Asn/Gln-5-oxazolidinone (10 mmol) dissolved in THF was added 1 N LiOH solution (1 equiv) and stirred at r.t. for 30 min. The reaction was monitored by TLC. After the completion of reaction, the reaction mixture was acidified with 10% citric acid solution and extracted with EtOAc. The organic layer was washed with brine and dried over anhyd Na2SO4. The solvent was removed in vacuo, and the resulted residue was purified by column chromatography using CHCl3, MeOH and AcOH (40:2:1).
Compound 4a: white solid. IR (KBr): νmax = 1705, 1733 cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.03-2.13 (4 s, 12 H), 2.81 (m, 2 H), 3.80 (m, 1 H), 4.03 (t, 1 H), 4.24 (m, 2 H), 4.42-4.52 (m, 2 H), 4.98 (t, 1 H), 5.05 (t, 1 H), 5.21-5.35 (m, 2 H), 5.92 (br d, 1 H), 7. 33 (t, 2 H), 7.41 (t, 2 H), 7.52 (d, 2 H), 7.77 (d, 2 H). HRMS (ES): m/z calcd for C33H36N2NaO14 [M + Na]+: 707.2064; found: 707.2080.
Compound 4e: white solid. IR (KBr): νmax = 1698, 1732 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.86 (m, 2 H), 2.03-2.13 (4 s, 12 H), 2.22 (m, 2 H), 3.80 (m, 1 H), 4.03 (d, 1 H), 4.21-4.32 (m, 3 H), 4.48 (m, 2 H), 4.88 (t, 1 H), 5.06 (t, 1 H), 5.27 (2 H, m), 5.50 (br d, 1 H), 7. 33 (t, 2 H), 7.41 (t, 2 H), 7.52 (d, 2 H), 7.77 (d, 2 H). HRMS (ES): m/z calcd for C34H38N2NaO14 [M + Na]+: 721.2221; found: 721.2413.