C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

Abstract

To obtain key sugar derivatives of making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H-tX-OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H-cX-OH) from D-glucose is described here. The present synthetic route elaborated is i) appropriate for large-scale synthesis, ii) reagent costs reduced (e.g. by a factor of 400), iii) yields optimized are ~80% or higher for all six consecutive steps concluding -tX-or -cX-and iv) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for D-xylo and D-riboamino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous flow reactor). Multigram scale syntheses of these β-sugar amino acids, β-SAAs, now available on a larger scale made possible to test and optimize coupling reactions and conditions of making α/β-chimera peptides. Our study encompasses necessary building blocks (e.g. -X-OMe, -X-O i Pr, -X-NHMe, Fmoc-X-OH) and key coupling reactions making -Aaa-tX-Aaa-or -Aaa-tX-tXAaa-type "inserts". Completed for both stereoisomers of X, including the newly synthetized FmoccX-OH, producing longer oligomers for drug design and discovery is more of a reality than a wish. 2Graphical abstract: From D-glucose in 6 (7) steps both C-3 epimers of an azido-furanuronic acid (cAFU and tAFU) are obtained. Yield optimized, scalable and robust reactions made possible to get β-sugar amino acids in a more environment-friendly way. Useful derivatives were synthesized and probed as key intermediates of foldameric "Lego element" now ready to be built in into α/β-chimera peptides supporting drug design and discovery.3

Approaches to Pyranuronic β‐Sugar Amino Acid Building Blocks of Peptidosaccharide Foldamers

“…The combined EtOAc phases were washed with brine (100 mL), dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was treated with ether to give compound 20 ( 13 CCDC 1575872 (for 16) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.…”

“…[4,8] As regards the synthesis of peptidomimetics and glycomimetics derived from α-AAs, acyclic or cyclic -AAs [e.g., ACPC (2-aminocyclopentane-1-carboxylic acid) [9,10] and ACHC (2aminocyclohexane-1-carboxylic acid) [11,12] ], and -SAAs, we have completed the synthesis of selected 3-amino-3-deoxypentofuranuronic acids, [13] and studied their coupling potential to form peptidosaccharides. The corresponding pyranoid SAAs have seldom been used to make foldamers, as the building blocks are unavailable.…”

“…In the rare instances where pyranoid SAAs have been used for foldamer construction, the easily available Dglucosamine carboxylic acids have been used. [4,8] As regards the synthesis of peptidomimetics and glycomimetics derived from α-AAs, acyclic or cyclic -AAs [e.g., ACPC (2-aminocyclopentane-1-carboxylic acid) [9,10] and ACHC (2aminocyclohexane-1-carboxylic acid) [11,12] ], and -SAAs, we have completed the synthesis of selected 3-amino-3-deoxypentofuranuronic acids, [13] and studied their coupling potential to form peptidosaccharides. [14] In a comparative context, our interest turned towards hydrophilic versions of well-known foldamer building blocks (ACHC), as shown in Figure 1, namely methyl 4-amino-4-deoxy-α-D-glucopyranuronic acid [H-GlcAPU(Me)-OH; 1] and methyl 4-amino-4-deoxy-α-D-galactopyranuronic acid [H-GalAPU(Me)-OH; 2].…”

“…1 H NMR (CDCl 3 ): δ = 9.13 (s, 1 H, OH-oxime), 7.24-7.15 (m, BnO Ar-H), 4.96 (dd, 3 J H,H = 5.3, 1.8 Hz, 1 H, 5-H), 4.76 (d, 3 J H,H = 3.7 Hz, 1 H, 1-H), 4.53 (d, 3 J H,H = 11.6 Hz, 1 H, BnO-3: CH 2A ), 4.51 (d, 3 J H,H = 12.1 Hz, 1 H, BnO-2: CH 2A ), 4.45 (d, 3 J H,H = 12.1 Hz, 1 H, BnO-2: CH 2B ), 4.28 (d, 3 J H,H = 11.6 Hz, 1 H, BnO-3: CH 2B ), 4.06 (d, 3 J H,H = 3.4 Hz, 1 H, 3-H), 3.86 (dt, 3 J H,H = 11.5, 5.0 Hz, 1 H, 6-H A ), 3.78-3.74 (overlapped m, 1 H, 6-H B ), 3.77 (overlapped t, 3 J H,H = 3.6 Hz, 1 H, 2-H), 3.36 (s, 3 H, CH 3 ), 2.72 (very br. t, 1 H, 6-OH) ppm 13. C NMR (CDCl 3 ): δ = 153.0 (C-4), 137.6 (BnO-3: C-1′), 137.1 (BnO-2: C-1′), 128.6, 128.5, 128.4 (BnO-3: C-2′, C-3′, C-4′, C-5′, C-6′), 128.2, 128.1, 128.0 (BnO-2: C-2′, C-3′, C-4′, C-5′, C-6′), 97.2 (C-1), 79.0 (C-2), 76.6 (C-3), 72.1 (BnO-2: CH 2 ′), 70.6 (BnO-3: CH 2 ′), 68.5 (C-5), 62.1 (C-6), 56.6 (CH 3 ) ppm.…”

“…H NMR (CDCl 3 ): δ = 7.28-7.16 (m, BnO Ar-H), 4.65 (overlapped d, 3 J H,H = 11.5 Hz, 1 H, BnO-3: CH 2A ), 4.57 (overlapped d, 3 J H,H = 11.5 Hz, 1 H, BnO-3: CH 2B ), 4.57 (overlapped m, 1 H, BnO-2: CH 2A ), 4.55 (overlapped m, 1 H, BnO-2: CH 2B ), 4.52 (d, 3 J H,H = 3.6 Hz, 1 H, 1-H), 3.63 (overlapped dd, 3 J H,H = 6.3 Hz, 2 H, 6-H A and 6-H B ), 3.47 (t, 3 J H,H = 9.5 Hz, 1 H, 3-H), 3.41 (dd, 3 J H,H = 9.7, 3.3 Hz, 1 H, 2-H), 3.36 (overlapped dd, 3 J H,H = 5.1 Hz, 1 H, 5-H), 3.27 (s, 3 H, CH 3 ), 2.60 (t, 3 J H,H = 9.5 Hz, 1 H, 4-H), 2.29 (very br., 1 H, 6-OH) ppm. 13 C NMR (CDCl 3 ): δ = 138.1, 137.8 (BnO-2: C-1′ and BnO-3: C-1′), 128.03, 127.9, 127.BnO-3: C-2′, C-3′, C-4′, C-5′, C-6′), 127.45, 127.41, 126.4 (BnO-2: C-2′, C-3′, C-4′, C-5′, C-6′), 97.7 (C-1), 81.4 (C-3), 80.0 (C-2), 72.5 (BnO-2: CH 2 ′), 72.0 (BnO-3: CH 2 ′), 70.4 (C-5), 62.9 (C-6), 54.8 (CH 3 ), 54.6 (C-4) ppm.Data for compound 14: R f = 0.22 (EtOAc/methanol, 9:1).1 H NMR (CDCl 3 ): δ = 7.28-7.16 (m, BnO-2 Ar-H, BnO-3 Ar-H), 4.95 (d, 3 J H,H = 11.4 Hz, 1 H, BnO-3: CH 2A ), 4.71 (overlapped d, 3 J H,H = 12.1 Hz, 1 H, BnO-2: CH 2A ), 4.64 (overlapped m, 1 H, BnO-2: CH 2B ), 4.57 (overlapped d, 3 J H,H = 11.4 Hz, 1 H, BnO-3: CH 2B ), 4.57 (overlapped, 1 H, 1-H), 3.73 (overlapped t, 3 J H,H = 5.6 Hz, 1 H, 5-H), 3.72 (overlapped t, 3 J H,H = 5.2 Hz, 1 H, 6-H A ), 3.72 (overlapped t, 3 J H,H = 9.8 Hz, 1 H, 3-H), 3.69 (overlapped t, 3 J H,H = 5.2 Hz, 1 H, 6-H B ), 3.6 (dd, 3 J H,H = 6.4, 3.7 Hz, 1 H, 2-H), 3.27 (s, 3 H, CH 3 ), 3.21 (dd, 3 J H,H = 3.8 Hz, 1 H, 4-H), 2.29 (br., 1 H, 6-OH) ppm 13. C NMR (CDCl 3 ): δ = 137.9, 137.5 (BnO-2: C-1′ and BnO-3: C-1′), 128.1, 128.06, 127.2 (BnO-3: C-2′, C-3′, C-4′, C-5′, C-6′), 127.6, 127.5, 126.9 (BnO-2: C-2′, C-3′, C-4′, C-5′, C-6′), 98.11 (C-1), 77.4 (C-5), 75.1 (BnO-3: CH 2 ′), 75.0 (C-2), 72.8 (BnO-2: CH 2 ′), 68.1 (C-3), 62.4 (C-6), 54.7 (CH 3 ), 51.1 (C-4) ppm.…”