An efficient and versatile synthesis of GlcNAcstatins-potent and selective O-GlcNAcase inhibitors built on the tetrahydroimidazo[1,2-a]pyridine scaffold

Abstract

We report a novel approach to the synthesis of GlcNAcstatins-members of an emerging family of potent and selective inhibitors of peptidyl O-GlcNAc hydrolase build upon tetrahydroimidazo[1,2-a]pyridine scaffold. Making use of a streamlined synthetic sequence featuring de novo synthesis of imidazoles from glyoxal, ammonia and aldehydes, a properly functionalised linear GlcNAcstatin precursor has been efficiently prepared starting from methyl 3,4-O-(2',3'-dimethoxybutane-2',3'-diyl)-α-d-mannopyranoside. Subsequent ring closure of the linear precursor in an intramolecular S(N)2 process furnished the key fused d-mannose-imidazole GlcNAcstatin precursor in excellent yield. Finally, a sequence of transformations of this key intermediate granted expeditious access to a variety of the target compounds bearing a C(2)-phenethyl group and a range of N(8) acyl substituents. The versatility of the new approach stems from an appropriate choice of a set of acid labile permanent protecting groups on the monosaccharide starting material. Application was demonstrated by the synthesis of GlcNAcstatins containing polyunsaturated and thiol-containing amido substituents.

Graphical abstract

Figure 1

Figure 2

Scheme 1

Scheme 2

Reagents and conditions: (i) PMBCl, NaH, n-Bu₄NI, DMF, rt, 16 h, 50%; (ii) I₂, ImH, PPh₃, toluene, 70 °C, 3 h, 75%; (iii) H₂, Pd/C, MeOH/EtOAc, 3 h, 50%; (iv) (a) Zn, THF/H₂O (10:1), 65 °C, 1 h, (b) 40% aqueous glyoxal, 7 M NH₃/MeOH, 0–70 °C, 2 h, 70%.

Scheme 3

Reagents and conditions: (i) (a) K₂(OsO₄)/K₃[Fe(CN)₆], K₂CO₃, CH₃SO₂NH₂, t-BuOH/THF/water, rt, 24 h, (b) TIPSCl, Py, 50 °C, 16 h, 78%; (ii) Tf₂O, pyridine, −15 °C tort, 1 h, 92%; (iii) (a) (COCl)₂, DMSO, DCM, −60 °C then Et₃N, (b) NaBH₄, EtOH, rt, 16 h, 80%; (iv) Tf₂O, Py, C₂H₄Cl₂, −15 °C then 50 °C, 3 h, 90%.

Scheme 4

Reagents and conditions: (i) NIS 2.5 equiv, MeCN, 6 h, rt, 95%; (ii) Tf₂O, Py, C₂H₄Cl₂, −15 °C then 50 °C; (iii) NIS 10 equiv, DMF, 85 °C, 36 h, 80% or NIS 3 equiv, MeCN, PPTS, 80 °C, 3 h, 65%; (iv) EtMgBr, THF, 0 °C, 10 min, 88%.

Scheme 5

Reagents and conditions: (i) NIS 3 equiv, MeCN, 6 h, rt, 78%.

Scheme 6

Reagents and conditions: (i) PhCCH, CuI, Et₃N, Pd(PPh₃)₄, DMF, 80 °C, 16 h, 93%; (ii) DDQ, DCM/H₂O, 4 h, 83%; (iii) DPPA, DBU, toluene, rt then 80 °C, 2 h, 93%; (iv) (a) H₂, Pd/C, MeOH or EtOAc, 1 h (b) (RCO)₂O, Et₃N, DCM for 29–31 or PyBOP, DIPEA, RCO₂H, DCM, rt, 16 h, for 32–34; (v) TFA/H₂O (95:5), rt, 36 h, 60–80%; (vi) DMF, MeONa/MeOH, DTT, 2 h, 56%.