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. 2018 Jul 3;9(32):6685-6691.
doi: 10.1039/c8sc01743c. eCollection 2018 Aug 28.

Programmable one-pot synthesis of heparin pentasaccharides enabling access to regiodefined sulfate derivatives

Supriya Dey  1 , Chi-Huey Wong  1   2
Affiliations

Programmable one-pot synthesis of heparin pentasaccharides enabling access to regiodefined sulfate derivatives

Supriya Dey et al. Chem Sci. .

Abstract

Heparin (H) and heparan sulfate (HS) belong to the glycosaminoglycan (GAG) family of oligosaccharides, and their sequences and sulfation patterns are known to regulate the functions of various proteins in biological processes. Among these, the 6-O-sulfation of HS/H contributes most significantly to the structural diversity and binding interactions. However, the synthesis of HS with defined sulfation patterns remains a major challenge. Herein, we report a highly efficient and programmable one-pot method for the synthesis of protected heparin pentasaccharides using thioglycoside building blocks with optimized relative reactivities to allow the selective deprotection and preparation of regiodefined sulfate derivatives.

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Figures

Fig. 1
Fig. 1. Monosaccharide and disaccharide building blocks.
Scheme 1
Scheme 1. A retrosynthetic analysis of heparan pentasaccharide with regiodefined O-sulfation patterns. Fmoc = 9-fluorenylmethoxycarbonyl chloride, Ac = acetyl, Bn = benzyl, Bz = benzoyl, Lev = levulinyl, PMB = p-methoxybenzyl, TBDPS = tert-butyldiphenylsilyl, Me = methyl, Tol = 4-tolyl.
Scheme 2
Scheme 2. Reaction conditions: (a) NIS, TfOH, CH2Cl2, AW 300 MS, –45 °C to –30 °C, 2 h; 19: 76%, 20: 73%; (b) NH2NH2·H2O, AcOH : Py (2 : 3), rt, 2 h; 6: 90%, 21: 88% (c) HF-Py, Py, 0 °C to rt, 12 h, 81%; (d) (i) BAIB, TEMPO, CH2Cl2 : H2O (2 : 1), 0 °C to rt, 2 h; (ii) MeI, KHCO3, DMF, rt, 4 h, 0 °C to rt, 5a: 63%, 5b: 61% (two steps); (e) (i) NIS, TMSOTf, CH2Cl2, AW 300 MS, –20 °C to 0 °C, 15 min; 22b: 89%. (f) 80% AcOH, 70 °C, 3 h; 23: 79%.
Scheme 3
Scheme 3. Reaction conditions: (a) (i) NIS, TfOH, CH2Cl2, AW 300 MS, –60 °C to –30 °C, 1 h; (ii) Et3N, rt, 1 h.
Scheme 4
Scheme 4. Reaction conditions: (a) NIS, TfOH, CH2Cl2, AW 300 MS, –45 °C to –25 °C; (b) (i) DDQ, CH2Cl2 : H2O (10 : 1), rt, 1 h; (ii) BAIB, TEMPO, CH2Cl2 : H2O (2 : 1), rt, 2 h; (iii) MeI, KHCO3, DMF, 0 °C to rt, 4 h.
Scheme 5
Scheme 5. Synthesis of GlcNS-GlcA2S-GlcNS6S-IdoA2S-GlcNS6S-OMe (1a). Reaction conditions: (a) HF-Py, Py, 0 °C to rt, 12 h, 26a: 83%, 26b: 85%; (b) BnBr, Ag2O, n-Hex : CH2Cl2 (4 : 1), MS 4 Å, 70 °C, sealed tube, 12 h, 27a: 82%, 27b: 78%; (c) (i) 1 M LiOH, H2O2, THF, –5 °C to rt, 8 h; (ii) 4 M NaOH, MeOH, rt, 18 h; (iii) SO3–Et3N, DMF, 55 °C, 12 h, 75%; (d) (i) H2, 20% Pd(OH)2/C, MeOH, 36 h, rt; (ii) SO3–Py, 1 M NaOH, pH – 9.5, H2O, rt, 38 h, 40% (5 steps).
Scheme 6
Scheme 6. Synthesis of GlcNS-GlcA2S-GlcNS6S-IdoA2S-GlcNS-OMe (1b). Reaction conditions: (a) NH2NH2·AcOH, THF : MeOH (1 : 1), 0 °C to rt, 2 h, 85%; (b) BnBr, Ag2O, n-Hex : CH2Cl2 (4 : 1), MS 4 Å, 70 °C, sealed tube, 12 h, 81%; (c) (i) 1 M LiOH, H2O2, THF, –5 °C to rt, 8 h; (ii) 4 M NaOH, MeOH, rt, 18 h; (iii) SO3–Et3N, DMF, 55 °C, 12 h, 77%; (d) (i) H2, 20% Pd(OH)2/C, MeOH, 36 h, rt; (ii) SO3–Py, 1 M NaOH, pH – 9.5, H2O, rt, 38 h, 47% (5 steps).
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