Effective Synthesis of α‐d‐GlcN‐(1→4)‐d‐GlcA/l‐IdoA Glycosidic Linkage under Gold(I) Catalysis

Abstract

An effective glycosylation procedure for the stereoselective construction of the a-d-GlcN-(1!4)-d-GlcA/l-IdoA glycosidicl inkagefound in heparina nd heparan sulfate is reported. The condensation occurs between 2-deoxy-2azido-d-glucopyranosyl (d-GlcN) ortho-hexynylbenzoate donors and uronate acceptors (d-GlcA/l-IdoA) under mild gold(I)-catalyzed conditions. Optimalr esults are obtained when performingt he reaction in CH 2 Cl 2 ,f rom À72 8Ct o room temperature in the presence of 4 molecular sieves and under the promotion of [Ph 3 PAuCl]/AgOTf or [(1,1-bis-(diphenylphosphino)methane)(AuCl) 2 ]/AgOTf as as ource of the gold(I) catalyst. Ad onor/acceptor ratio of 3:1a sw ell as al oading of 0.6 equivalents of the gold(I) catalysta re essential to attain high yields and a selectivity,p articularly for the [1+ +1] and [1+ +2] glycosylations.

Stereoselectivity of Conformationally Restricted Glucosazide Donors

“…Spectroscopic data were in accord with those reported previously. 21 IR (neat): 696, 735, 914, 989, 1028, 1045, 1090, 1267, 1369, 1454, 1749, 2108, 2870, 2916. Data reported for a 1:1 mixture of anomers: 1 H NMR (CDCl 3 , 400 MHz, H–H COSY, HSQC, HMBC): δ 7.48–7.41 (m, 4H, CH arom ), 7.41–7.24 (m, 36H, CH arom ), 5.53 (s, 1H, C H Ph α ), 5.51 (d, 1H, J = 3.9 Hz, H-1′ α ), 5.47 (s, 1H, C H Ph β ), 5.04 (d, 1H, J = 10.5 Hz, C H H Bn), 4.94 (d, 1H, J = 11.0 Hz, C H H Bn), 4.91–4.82 (m, 4H, 2 × CH H Bn, 2 × C H H Bn), 4.81–4.72 (m, 4H, 2 × CH H Bn, 2 × C H H Bn), 4.64–4.58 (m, 2H, 2 × CH H Bn), 4.57 (d, 2H, J = 3.5 Hz, H-1 α,β ), 4.43 (d, 1H, J = 8.1 Hz, H-1′ β ), 4.26 (dd, 1H, J = 10.3, 4.8 Hz, H-6′ α ), 4.24–4.19 (m, 2H, H-5 α , H-5 β ), 4.09–3.99 (m, 4H, H-3 β , H-4 α , H-4 β , H-6′ β ), 3.97 (t, 1H, J = 9.5 Hz, H-3′ α ), 3.89 (t, 1H, J = 9.2 Hz, H-3 α ), 3.82 (s, 3H, CH 3 CO 2 Me), 3.81 (s, 3H, CH 3 CO 2 Me), 3.72–3.56 (m, 4H, H-2 β , H-4′ α , H-4′ β , H-6′ α ), 3.56–3.46 (m, 3H, H-2 α , H-3′ β , H-5′ α ), 3.46–3.38 (m, 7H, 2 × CH 3 OMe, H-6′ β ), 3.36–3.29 (m, 2H, H-2′ α , H-2′ β ), 3.26 (td, 1H, J = 9.7, 5.0 Hz, H-5′ β ).…”

“…R f 0.54 (4:1 pentane/EtOAc). Spectroscopic data were in accord with those reported previously . IR (neat): 696, 735, 914, 989, 1028, 1045, 1090, 1267, 1369, 1454, 1749, 2108, 2870, 2916.…”

“…The extrapolation of the stereoselectivity of benzylidene glucose donors to their glucosazide counterparts suggests that benzylidene or analogously protected glucosazides might represent an attractive class of 1,2- cis -selective glucosamine donor synthons. 20 , 21 …”

“…The in-depth research conducted on conformationally restricted benzylidene mannose and glucose donors has provided important insight into the glycosylation mechanisms of this type of 1,2- cis -selective donor. − To construct 1,2- cis linkages of glucosamine donors, the C-2-amino group is most commonly masked as the nonparticpating azide. , Notably, benzylidene glucosazides have not been systematically investigated with respect to the stereoselectivity of glycosylations in which they are employed. The extrapolation of the stereoselectivity of benzylidene glucose donors to their glucosazide counterparts suggests that benzylidene or analogously protected glucosazides might represent an attractive class of 1,2- cis -selective glucosamine donor synthons. , …”

Developments in the Chemical Synthesis of Heparin and Heparan Sulfate

“…In 2015 Yu and co‐workers’ reported using ortho ‐hexynylbenzoate donors of type 41 for the successful synthesis of d ‐GlcN‐α‐1,4‐ d ‐GlcA/ l ‐IdoA linkages under Au(I) catalysis (Scheme 9). [24] The optimised reaction conditions used Ph 3 PAuCl/AgOTf and a donor/acceptor ratio of 3 : 1. Given the known low reactivity of uronate d ‐GlcA/ l ‐IdoA acceptors, high levels (3.0 equiv.)…”