Synthesis of biotinylated keratan sulfate repeating disaccharides

Figures & data

Scheme 1. Retrosynthetic analysis for disaccharides 1–4.

Scheme 2. Synthesis of disaccharide 11.

Note: Reagents and conditions: (a) NaOMe, MeOH; (b) PhCH(OMe)₂, p-TsOH, 78% (2 steps); (c) BnBr, NaH, DMF, 0 °C-rt, 86%; (d) camphorsulfonic acid, CH₂Cl₂-MeOH; (e) TBDPSCl, imidazole, DMF, 69% (2 steps); (f) TMSOTf, CH₂Cl₂, −20 or −78 °C; (g) NaOMe, MeOH, 60% (2 steps).

Scheme 3. Synthesis of common disaccharide 18.

Note: Reagents and conditions: (a) 2-naphthaldehyde, p-TsOH·H₂O, CH₃CN, 89%; (b) MBzCl, DMAP, pyridine-CH₂Cl₂, quant.; (c) BH₃·Me₃ N, AlCl₃, cat. H₂O, THF, 92%; (d) MBzCl, DMAP, pyridine-CH₂Cl₂, 98%; (e) NIS, TfOH, MSAW300, Et₂O-(CH₂Cl)₂, quant.; (f) 1 M tetra-n-butyl ammonium fluoride, AcOH, THF, 79%.

Scheme 4. Synthesis of target compounds 1–4.

Note: Reagents and conditions: (a) Ac₂O, pyridine, quant.; (b) DDQ, cat. H₂O, CH₂Cl₂-MeOH, 84% for 19 (2 steps), 78% for 20; (c) SO₃· NMe₃, DMF, 60 °C, 88% for 21, quant. for 22, 90% for 23; (d) 1,3-diaminopropane, EtOH, reflux; (e) Ac₂O, Et₃N, MeOH; (f) NaOH, MeOH (for 21, 22), 50% MeOH (for 23), reflux; (g) H₂, Pd-black, aq. EtOH + dil. AcOH (for 18), aq. 2-PrOH + dil. AcOH (for 21, 22), dil. AcOH (for 23); (h) NHS-PEG₄-biotin, 1 M Na₃PO₄, 0.15 M NaCl.

Table 1. Selected chemical shifts (ppm) for 1–4 by 600 MHz ¹H-NMR.

	1	2	3	4
H-1	4.48	4.45	4.51	4.49
H-2	3.67	3.75	3.7	3.69
H-6ab	3.75–3.60	3.74, 3.59	4.35, 4.27	4.35, 4.24
H-1′	4.38	4.37	4.51	4.47
H-2′	3.45	3.57	3.46	3.48
H-6′ab	3.90, 3.75	4.13, 3.96	3.85–3.58	4.10, 3.93
NAc	1.96	1.90	1.96	1.94
H-b	4.33	4.27	4.38	4.35
H-c	4.51	4.45	4.54	4.54
H-d	2.90, 2.69	2.85, 2.63	2.91, 2.71	2.93, 2.72
H-e	3.24	3.36	3.28	3.27