Unexpected loss of stereoselectivity in glycosylation reactions during the synthesis of chondroitin sulfate oligosaccharides

Abstract

Here, we present an exploratory study on the fluorous-assisted synthesis of chondroitin sulfate (CS) oligosaccharides. Following this approach, a CS tetrasaccharide was prepared. However, in contrast to our previous results, a significant loss of β-selectivity was observed in [2 + 2] glycosylations involving N-trifluoroacetyl-protected D-galactosamine donors and D-glucuronic acid (GlcA) acceptors. These results, together with those obtained from experiments employing model monosaccharide building blocks, highlight the impact of the glycosyl acceptor structure on the stereoselectivity of glycosylation reactions. Our study provides useful data about the substitution pattern of GlcA units for the efficient synthesis of CS oligomers.

Keywords: carbohydrate chemistry; chondroitin sulfate; glycosylation; oligosaccharide synthesis; stereoselectivity.

Scheme 1

Retrosynthetic analysis for the preparation of CS oligosaccharides. Lev = levulinyl; Piv = pivaloyl; PMP = 4-methoxyphenyl.

Scheme 2

Reagents and conditions: a) TMSOTf, CH₂Cl₂, 0 °C, 30 min, 97%; b) (HF)_n·Py, THF, 0 °C, 20 h, 90%; c) Ac₂O, Py, 24 h, 97%; d) CAN, CH₂Cl₂/CH₃CN/H₂O, 0 °C, 1 h, 99%; e) Cl₃CCN, DBU, CH₂Cl₂, 9 h, 98%. CAN = ceric(IV) ammonium nitrate.

Scheme 3

Reagents and conditions: a) C₈F₁₇CH₂CH₂COCl, Et₃N, DMAP, DMF/CH₂Cl₂, 0 °C to rt, 6 h, 70%; b) Ac₂O, Py, 24 h, 94%; c) CAN, CH₂Cl₂/CH₃CN/H₂O, 0 °C, 2 h, 54%; d) Cl₃CCN, DBU, CH₂Cl₂, 6 h, 76%; e) 2-propanol, TMSOTf, CH₂Cl₂, 0 °C, 30 min, 65%; f) NH₂NH₂·H₂O, Py/AcOH, CH₂Cl₂, 1 h, 94%.

Scheme 4

Reagents and conditions: a) TMSOTf, CH₂Cl₂, 0 °C, 30 min, 25% (14α) + 33% (14β).

Scheme 5

Reagents and conditions: a) LiOH, H₂O₂, THF, −5 °C to rt, 24 h, then NaOH, MeOH, 72 h, then Ac₂O, Et₃N, MeOH, 2 h, 38% (15); 30% (16α); 73% (16β).

Scheme 6

Reagents and conditions: a) 2-propanol, TMSOTf, CH₂Cl₂, 0 °C, 30 min, 73%; b) NH₂NH₂·H₂O, Py/AcOH, CH₂Cl₂, 1 h, 89%; c) 1, TMSOTf, CH₂Cl₂, 0 °C, 30 min, 18% (19α) + 53% (19β); d) 1, TMSOTf, CH₃CN, −20 °C, 30 min, 10% (19α) + 40% (19β).

Scheme 7

Reagents and conditions: a) NH₂NH₂·H₂O, Py/AcOH, CH₂Cl₂, 1 h, 55%; b) TMSOTf, CH₂Cl₂, 0 °C, 30 min, 18% (21α) + 20% (21β).

Scheme 8

Reagents and conditions: a) 4-Methoxyphenol, TMSOTf, CH₂Cl₂, 0 °C, 50 min, 92%; b) NH₂NH₂·H₂O, Py/AcOH, CH₂Cl₂, 1 h, 84%; c) 22, TMSOTf, CH₂Cl₂, 0 °C, 85% for 24β; 75% for 27α/β (1:2.6 α/β ratio); 70% for 29β.