Anomeric reactivity-based one-pot synthesis of heparin-like oligosaccharides

Abstract

A highly efficient one-pot methodology is described for the synthesis of heparin and heparan sulfate oligosaccharides utilizing thioglycosides with well-defined reactivity as building blocks. L-Idopyranosyl and D-glucopyranosyl thioglycosides 5 and 10 were used as donors due to low reactivity of uronic acids as the glycosyl donors in the one-pot synthesis. The formation of uronic acids by a selective oxidation at C-6 was performed after assembly of the oligosaccharides. The efficiency of this programmable strategy with the flexibility for sulfate incorporation was demonstrated in the representative synthesis of disaccharides 17, 18, tetrasaccharide 23, and pentasaccharide 26.

Figure 1

Schematic view of heparin

Scheme 1

Preparation of the 1-thio uronic acid building blocks 5 and 10^{a a}Reagents and conditions: (a) TolSH, BF₃·Et₂O, 2: 93% (9:1 α/β), 7: 87%; (b) i. NaOMe, MeOH; ii. PhCH(OMe)₂, p-TsOH, CH₃CN/DMF; iii. BzCl, Pyridine; iv. 60% TFA in H₂O, CH₂Cl₂, 3: 78%, 8: 81%; (c) TBDPSCl, Pyridine, 4: 91%, 9: 95%; d) Lev₂O, Pyridine, 5: 89%, 10: 91%.

Scheme 2

Preparation of azidoglucosyl acceptors 15 and 16^{a a}Reagents and conditions: (a) i. Bu₂SnO, Toluene ii. Bu₄NBr, BnBr, 65% in two steps; (b) PhCH(OMe)₂, CSA, 89%; (c) i. Tf₂O, Pyr-CH₂Cl₂, ii. NaN₃, DMF, 83% in two steps; (d) i. 80% AcOH, ii. AcCl, Pyridine, 15: 89%; (e) PhBCl₂, Et₃SiH, CH₂Cl₂, 92%; (f) Ac₂O, Pyridine, 16: 95%;

Scheme 3

One-pot synthesis of disaccharide derivatives 17 – 20 ^aReagents and conditions: (a) NIS, TfOH, CH₂Cl₂, -45°C to room temperature, 17: 92%, 18: 89%, 19: 96%; (b) BSP, Tf₂O, CH₂Cl₂, -45°C to room temperature, 17: 72%, 18: 75%; (c) N-(phenylythio)-ε-caprolactam, Tf₂O, CH₂Cl₂, -45°C to room temperature, 17: 85%, 18: 88%; (d) NH₂NH₂/AcOH/Pyridine, 20: 95%.

Scheme 4

One-pot synthesis of tetrasaccharide derivative 23^{a a}Reagents and conditions: (a) NIS, TfOH, CH₂Cl₂, -45°C to room temperature, 35%; (b) HF·Pyr, THF, 87%; (c) i. TEMPO, KBr, NaOCl, CH₂Cl₂, H₂O, ii. MeI, KHCO₃, DMF, 68% in two steps.

Scheme 5

One-pot synthesis of pentasaccharide derivative 27^{a a}Reagents and conditions: (a) i. HF·Pyr, THF; ii. TEMPO, KBr, NaOCl, CH₂Cl₂, H₂O, then MeI, KHCO₃, DMF; iii. NH₂NH₂/AcOH/Pyridine, 24: 45%, 25: 77%; (b) i. NIS, TfOH, CH₂Cl₂, -45°C to room temperature; ii. NIS, TfOH, CH₂Cl₂, -45°C to room temperature, 20%; c) i. LiOOH, THF; ii. Et₃N·SO₃, DMF; ii. H₂, Pd/C; iv- Pyr·SO₃, H₂O, 33%.