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

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Abstract

To obtain key sugar derivatives for 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–t X–OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H–c X–OH) from d-glucose is described here. The present synthetic route elaborated is (1) appropriate for large-scale synthesis; (2) reagent costs reduced (e.g. by a factor of 400); (3) yields optimized are ~80% or higher for all six consecutive steps concluding –t X– or –c X– and (4) 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-ribo-amino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous-flow reactor). Our study encompasses necessary building blocks (e.g. –X–OMe, –X–OiPr, –X–NHMe, Fmoc–X–OH) and key coupling reactions making –Aaa–t X–Aaa– or –Aaa–t Xt X–Aaa– type “inserts”. Completed for both stereoisomers of X, including the newly synthesized Fmoc–c X–OH, producing longer oligomers for drug design and discovery is more of a reality than a wish.

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Abbreviations

H-RibAFU(ip)-OH or tX:

1,2-O-Isopropylidene-3-amino-3-deoxy-α-d-ribofuranuronic acid

H-XylAFU(ip)-OH or cX:

1,2-O-Isopropylidene-3-amino-3-deoxy-α-d-xylofuranuronic acid

N3-RibAFU(ip)-OH:

1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-ribofuranuronic acid

N3-XylAFU(ip)-OH:

1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-xylofuranuronic acid

H-XylAFU(ip)-NHMe:

N-Methyl-1,2-O-isopropylidene-3-amino-3-deoxy-α-d-xylofuranuronamide

H-RibAFU(ip)-NHMe:

N-Methyl-1,2-O-isopropylidene-3-amino-3-deoxy-α-d-ribofuranuronamide

Ac-RibAFU(ip)-NHMe:

N-Methyl-1,2-O-isopropylidene-3-acetamido-3-deoxy-α-d-ribofuranuronamide

Ac-XylAFU(ip)-NHMe:

N-Methyl-1,2-O-isopropylidene-3-acetamido-3-deoxy-α-d-xylofuranuronamide

References

  1. Altmayer-Henzien A, Declerck V, Farjon J, Merlet D, Guillot R, Aitken DJ (2015) Fine tuning of beta-peptide foldamers: a single atom replacement holds back the switch from an 8-helix to a 12-helix. Angew Chem Int Ed 54:10807–10810

  2. Austin GN, Baird PD, Fleet GWJ, Peach JM, Smith PW, Watkin DJ (1987) 3,6-Dideoxy-3,6-imino-1,2-O-isopropylidene-α-d-glucofuranose as a divergent intermediate for the synthesis of hydroxylated pyrrolidines: synthesis of 1,4-dideoxy-1,4-imino-l-gulitol, 1,4-dideoxy-1,4-imino-d-lyxitol, 2S,3S,4R-3,4-dihydroxyproline and (lS,2R,8S,RaR)-1,2,8-trihydroxyoctahydroindolizine [8-Episwainsonine]. X-ray crystal structure of (lS,2R,8S,8aR)-1,2,8-trihydroxy-5-oxooctahydroindolizine. Tetrahedron 43:3095–3108

  3. Cabrele C, Martinek TA, Reiser O, Berlicki L (2014) Peptides containing β-amino acid patterns: challenges and successes in medicinal chemistry. J Med Chem 57:9718–9739

  4. Chandrasekhar S, Reddy MS, Jagadeesh B, Prabhakar A, Rao MHVR, Jagannadh B (2004) Formation of a stable 14-helix in short oligomers of furanoid cis-β-sugar-amino acid. J Am Chem Soc 126:13586–13587

  5. Chandrasekhar S, Reddy MS, Babu BN, Jagadeesh B, Prabhakar A, Jagannadh B (2005) Expanding the conformational pool of cis-β-sugar amino acid: accommodation of β-hGly motif in robust 14-Helix. J Am Chem Soc 127:9664–9665

  6. Chandrasekhar S, Reddy GPK, Kiran MU, Nagesh C, Jagadeesh B (2008) Nucleoside derived amino acids (NDA) in foldamer chemistry: synthesis and conformational studies of homooligomers of modified AZT. Tetrahedron Lett 49:2969–2973

  7. Chandrasekhar S, Kiranmai N, Kiran MU, Devi AS, Reddy GPK, Idrisc M, Jagadeesh B (2010) Novel helical foldamers: organized heterogeneous backbone folding in 1:1 α/nucleoside-derived-β-amino acid sequences. Chem Commun 46:6962–6964

  8. Cheng RP, Gellman SH, DeGrado WF (2001) α-Peptides: from structure to function. Chem Rev 101:3219–3232

  9. Csordás B, Nagy A, Harmat V, Zsoldos-Mády V, Leveles I, Pintér I, Farkas V, Perczel A (2016) Origin of problems related to Staudinger reduction in carbopeptoide syntheses. Amino Acids. doi:10.100/s00726-016-2289-x

  10. Declerck V, Aitken DJ (2011) A refined synthesis of enantiomerically pure 2-aminocyclobutane carboxylic acids. Amino Acids 41:587–595

  11. Ferreira SB, Sodero ACR, Cardoso MFC, Lima ES, Kaiser CR, Silva FP FP Jr, Ferreira VF (2010) Synthesis, biological activity, and molecular modeling studies of 1H-1,2,3-triazole derivatives of carbohydrates as α-glucosidases inhibitors. J Med Chem 53:2364–2375

  12. Giri AG, Jogdand GF, Rajamohanan PR, Pandey SK, Ramana CV (2012) Synthesis and structural characterization of homochiral homo-oligomers of cis-γ-methoxy-substituted cis- and trans-Furanoid-β-Amino acids. Eur J Org Chem 13:2656–2663

  13. Giuliano MW, Maynard SJ, Almeida AM, Reidenbach AG, Guo L, Ulrich EC, Guzei IA, Gellman SH (2013) Evaluation of a cyclopentane-based γ-amino acid for the ability to promote α/γ-peptide secondary structure. J Org Chem 78:12351–12361

  14. Gomtsyan A, Savelyeva I, Belyakov S, Kalvinsh I (1992) Synthesis of methyl 3-amino-deoxy-d-alluronate. Carbohydr Res 232:341–348

  15. Gorrea E, Pohl G, Nolis P, Celis S, Burusco KK, Branchadell V, Perczel A, Ortuño RM (2012) Secondary structure of short beta-peptides as the chiral expression of monomeric building units: a rational and predictive model. J Org Chem 77(21):9795–9806

  16. Gruner SAW, Gy Kéri, Venetainer A, Kessler H (2001) Sugar amino acid containing somatostatin analogues that induce apoptosis in both drug-sensitive and multidrug-resistant tumor cells. Org Lett 3:3723–3725

  17. Gruner SAW, Locardi E, Lohof E, Kessler H (2002a) Carbohydrate-based mimetics in drug design: sugar amino acids and carbohydrate scaffolds. Chem Rev 102:491–514

  18. Gruner SAW, Truffault V, Voll G, Locardi E, Stöckle M, Kessler H (2002b) Design, synthesis, and NMR structure of linear and cyclic oligomers containing novel furanoid sugar amino acids. Chem Eur J 8:4365–4376

  19. Guichard G, Huc I (2011) Synthetic foldamers. Chem Commun 47:5933–5941

  20. Hale KJ, Hough L, Manaviazar S, Calabrese A (2015) Rules and stereoelectronic guidelines for the anionic nucleophilic displacement of furanoside and furanose O-sulfonates. Org Lett 17:1738–1741

  21. Hall LD, Miller DC (1976) Fluorinated sulphonic esters of sugars: their synthesis and reactions with pyridine. Carbohydr Res 47:299–305

  22. Helferich B, Dressler H, Griebel R (1939) Ester der Methansulfonsäure in der Zuckergruppe. J Prakt Chem 153:285–299

  23. Hetényi A, Tóth GK, Cs Somlai, Vass E, Martinek TA, Fülöp F (2009) Stabilisation of peptide foldamers in an aqueous medium by incorporation of azapeptide building blocks. Chem Eur J 15:10736–10741

  24. Horne WS, Gellman SH (2008) Foldamers with heterogeneous backbones. Acc Chem Res 41:1399–1408

  25. Jagannadh B, Reddy MS, Rao CL, Prabhakar A, Jagadeesh B, Chandrasekhar S (2006) Self-assembly of cyclic homo- and hetero-β-peptides with cis-furanoid sugar amino acid and β-hGly as building blocks. Chem Commun 46:4847–4849

  26. James WH III, Müller CW, Buchanan EG, Nix MGD, Guo L, Roskop L, Gordon MS, Slipchenko LV, Gellman SH, Zwier TS (2009) Intramolecular amide stacking and its competition with hydrogen bonding in a small foldamer. J Am Chem Soc 131:14243–14245

  27. Kiss L, Fülöp F (2014) Synthesis of carbocyclic and heterocyclic β-aminocarboxylic acids. Chem Rev 114:1116–1169

  28. Knapp K, Górecki M, Frelek J, Luboradzki R, Hollósi M, Zs Majer, Vass E (2014) Comprehensive chiroptical study of proline-containing diamide compounds. Chirality 26:228–242

  29. Kovář J, Jarý J (1969) Amino sugars. XXI. Synthesis of 3,6-diamino-3,6-dideoxy-d-glucose and its derivatives. Collect Czech Chem Commun 34:2619–2626

  30. Kulinkovich LN, Timoshchuk VA (1983) Synthesis of unsaturated nucleosides of uronic acids. Zh Obshch Khim 53:1652–1655

  31. Mándity IM, Fülöp F (2015) An overview of peptide and peptoid foldamers in medicinal chemistry. Expert Opin Drug Discov 10(11):1163–1177

  32. Martinek TA, Fülöp F (2012) Peptidic foldamers: ramping up diversity. Chem Soc Rev 41:687–702

  33. Nayak UG, Whistler RL (1969) Nucleophilic displacement in 1,2:5,6-di-O-isopropylidene-3-O-(p-tolylsulfonyl)-α-d-glucofuranose. J Org Chem 34:3819–3822

  34. Pandey SK, Jogdand GF, Oliveira JCA, Mata RA, Rajamohanan PR, Ramana CV (2011) Synthesis and structural characterization of homochiral homo-oligomers of parent cis- and trans-Furanoid-β-amino acids. Chem Eur J 17:12946–12954

  35. Perczel A, Hollósi M, Foxman BM, Fasman GD (1991) Conformational analysis of pseudocyclic hexapeptides based on quantitative circular dichroism (CD), NOE, and X-ray data. The pure CD spectra of type I and type II β-turns. J Am Chem Soc 113:9772–9784

  36. Pilsl LKA, Reiser O (2011) α/β-Peptide foldamers: state of the art. Amino Acids 41:709–718

  37. Pohl G, Gorrea E, Branchadell V, Ortuño RM, Perczel A, Gy Tarczay (2013) Foldamers of β-peptides: conformational preference of peptides formed by rigid building blocks The first MI-IR spectra of a triamide nanosystem. Amino Acids 45(4):957–973

  38. Reckendorf Z, Meyer W (1968) Diaminozucker, IX. Synthese der 3-Amino-3-desoxy- und 3.6-Diamino-3.6-didesoxy-d-glucose. Chem Ber 101:3802–3807

  39. Rjabovs V, Turks M (2013) Tetrahydrofuran amino acids of the past decade. Tetrahedron 69:10693–10710

  40. Schmidt OTH (1963) Reaction of carbohydrates. In: Whistler RL, Wolfrom ML, BeMiller JN (eds) Methods Carbohydr Chem, vol 2. Academic Press, New York, pp 318–325

  41. Theoneste M, Stephane G, Veronique C (2009) Synthesis and antibacterial activity of aminodeoxyglucose derivatives against Listeria innocua and Salmonella typhimurium. J Agric Food Chem 57:8770–8775

  42. Threlfall R, Davies A, Howarth NM, Fisher J, Cosstick R (2008) Peptides derived from nucleoside β-amino acids form an unusual 8-helix. Chem Commun 5:585–587

  43. Vatéle JM, Hanessian S (1996) Design and reactivity of organic functional groups—preparation and nucleophilic displacement reactions of imidazole-l-sulfonates (imidazylates). Tetrahedron 52:10557–10568

  44. Watterson PM, Pickering L, Smith MD, Hudson SJ, Marsh PR, Mordaunt JE, Watkin DJ, Newman CJ, Fleet GWJ (1999) 3-Azidotetrahydrofuran-2-Carboxylates: a family of five-ring templated β-aminoacid foldamers? Tetrahedron Asymmetry 10:1855–1859

  45. Whistler RL, Doner LW (1972) General carbohydrate methods. In: Whistler RL, BeMiller JN (eds) Methods Carbohydr Chem, vol 6. Academic Press, New York, pp 215–217

  46. Zsoldos-Mády V, Zbiral E (1986) A new approach to 6-Deoxy-d-allofuranose- and 6-Deoxy-l-talofuranose derivatives from 1,2:5,6-Di-O-isopropylidene-α-d-glucofuranose. Monatsh Chem 117:1325–1338

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Acknowledgements

The authors gratefully acknowledge Szebasztián Szaniszló for his contribution to the preparative work and Prof. Imre G Csizmadia for helpful discussion. The authors wish to thank László Kocsis and Gábor Szirbik from ThalesNano Inc. (Budapest, Hungary) for their help and advice in hydrogenation reaction and for their support with the equipment, and Anita Kapros for her help in MS measurements. This work was supported by Grants from the Hungarian Scientific Research Fund (OTKA NK101072).

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Correspondence to András Perczel.

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Nagy, A., Csordás, B., Zsoldos-Mády, V. et al. C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies. Amino Acids 49, 223–240 (2017). https://doi.org/10.1007/s00726-016-2346-5

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Keywords

  • Sugar amino acids
  • Azido sugars
  • Nucleophilic substitution
  • Foldamers