Chemical synthesis of a heparan sulfate glycopeptide: syndecan-1

Abstract

The highly complex structure of syndecan-1 heparan sulfate glycopeptide was successfully assembled. The protective groups utilized and sequences for glycosyl linkage formation and protective group removal are critical for the success of synthesis. This is the first time this type of sulfated glycopeptides has been prepared, which lays the foundation to access other members of this important class of molecules.

Figure 1

Retrosynthetic analysis of octasaccharide amino ester 6.

Scheme 1

Reagents and conditions: a) AgOTf, p-TolSCl, MS 4Å, −78°C, then 11, TTBP, −78°C–0°C; b) (1) Mg(OMe)₂, DCM, −20°C–0°C; (2) LevOH, EDC-HCl, DMAP, DCM; (3) DDQ, DCM/H₂O; (4) HF/Pyridine; (5) TBDPSCl, imidazole, DCM; c) AgOTf, p-TolSCl, MS 4Å, −78°C, then 13, TTBP, −78°C–0°C; d) AgOTf, p-TolSCl, MS 4Å, −78°C, then 16, TTBP, −78°C–0°C; e) (1) DDQ, DCM/H₂O; (2) HF/Pyridine; (3) TBDPSCl, imidazole, DCM.

Scheme 2

Reagents and conditions: a) (1) AgOTf, p-TolSCl, MS 4Å, −78°C, then 19, TTBP, −78°C–0°C; (2) Tf₂O, THF, H₂O; b) AgOTf, p-TolSCl, MS 4Å, −78°C, then 5, TTBP, −78°C–0°C; c) (1) AcOH, NH₂NH₂, DCM/MeOH; (2) 22, AgOTf, p-TolSCl, MS 4Å, TTBP, −78°C–0°C; d) AgOTf, p-TolSCl, MS 4Å, −78°C, then 23, TTBP, −78°C–0°C; e) AgOTf, p-TolSCl, MS 4Å, −78°C, then 5, TTBP, −78°C–0°C; f) AcOH, NH₂NH₂, DCM/MeOH.

Scheme 3

Reagents and conditions: a) AgOTf, p-TolSCl, MS 4Å, −78°C, then 8, TTBP, −78°C–0°C; b) AgOTf, p-TolSCl, MS 4Å, −78°C, then 9, TTBP, −78°C–0°C; c) (1) HF/pyridine; (2) TEMPO, BAIB, DCM/H₂O/t-BuOH; (3) MeI, K₂CO₃, DMF.

Scheme 4

Reagents and conditions: a) (1) Ac₂O, pyridine, 50 °C; (2) piperidine, DCM; b) HATU, DIPEA, DMF; c) Pd/C, H₂, NH₄OAc, DCM/MeOH; d) multiple rounds of automated solid phase peptide synthesis; e) TFA/H₂O/Phenol/TIPS; f) (1) BnBr, DIPEA, DMF; (2) piperidine, DMF; g) HATU, DMF; h) (1) Zn, CuSO₄ (sat.), Ac₂O/THF/HOAc; (2) NH₂NH₂-H₂O, HOAc, DCM/MeOH; (3) SO₃-Et₃N, DMF, 55 °C; (4) H₂, Pd/C, DCM/MeOH; i) base catalyzed hydrolysis