Access to Unnatural Glycosyl Amino Acid Building Blocks via a One-Pot Ritter Reaction

Abstract

α-d-Galacto-2-deoxy-oct-3-ulopyranosonic acids, α-d-gluco-2-deoxy-oct-3-ulopyranosonic acids and α-l-galacto-2,8-dideoxy-oct-3-ulopyranosonic acids can be converted into unnatural glycosyl amino acids via a one-pot intramolecular Ritter reaction. Initially, a ketopyranoside-based acid condenses under Lewis acid-promoted conditions with a nitrile (benzonitrile or acetonitrile) and a partially protected diamino ester (Boc-DAB-Ot-Bu, Boc-Orn-Ot-Bu) to form unnatural glycosyl amino esters. The resulting glycosyl amino esters are useful building blocks for solid-phase glycopeptide synthesis. For example, the glycosyl amino acid derived by condensation of α-d-galacto-2-deoxy-oct-3-ulopyranosonic acid with benzonitrile and DAB was used to replace serine in the potent opioid peptide sequence H₂N-Tyr-d-Thr-Gly-Phe-Leu-Ser-CONH₂.

Key words

carbohydrates - glycopeptides - combinatorial chemistry - glycosyl amino acids - peptides

References

• 1 Dwek RA. Chem. Rev.  1996,  96:  683 
• 2 Varki A. Glycobiology  1993,  3:  97 
• 3 Grochee FC. Gramer MJ. Andersen DC. Bahr JB. Rasmusen JR. In Frontier in Bioprocessing II   Todd CP. Sikdar SK. Bier M. American Chemical Society; Washington: 1992.  p.199 
• 4 Fisher JF. Harrison AW. Bundy GL. Wilkinson KF. Rush BD. Ruwart MJ. J. Med. Chem.  1991,  34:  3140 
• 5 Mehta S. Meldal M. Duus JO. Bock K. J. Chem. Soc., Perkin Trans. 1  1999,  1445 ; and references cited therein
• 6 Lohof E. Planker E. Mang C. Burkhart F. Dechantsreiter MA. Haubner R. Wester H.-J. Schwaiger M. Hölzemann G. Goodman SL. Kessler H. Angew. Chem. Int. Ed.  2000,  39:  2761 
• 7 Weiss JB. Lote CJ. Bobinski H. Nature (London) New Biol.  1971,  234:  25 
• 8 Hofsteenge J. Müller DR. Beer T. Löffler A. Richter WJ. Vliegenhart JFG. Biochemistry  1994,  33:  13524 
• For recent reviews on artificial glycosylamino acids, sugar amino acids and combinatorial carbohydrate conjugates see:
• 9a Dondoni A. Marra A. Chem. Rev.  2000,  100:  4395 
• 9b Peri F. Cipolla L. Forni E. La Feria B. Nicotra F. Chemtracts  2001,  14:  481 
• 9c Barkley A. Arya P. Chem.-Eur. J.  2001,  7:  555 
• 9d Gruner SAW. Locardi E. Lohof E. Kessler H. Chem. Rev.  2002,  102:  491 
• 9e Schweizer F. Angew. Chem. Int. Ed.  2002,  41:  230 ; and references cited therein
• 10a Saha UK. Roy R. Tetrahedron Lett.  1995,  36:  3635 
• 10b Saha U. Roy R. Tetrahedron Lett.  1997,  38:  7697 
• 10c Kim JM. Roy R. Tetrahedron Lett.  1997,  38:  3487 
• 10d Kim JM. Roy R. Carbohydr. Res.  1997,  298:  173 
• 11a Hoffmann M. Burkhart F. Hessler G. Kessler H. Helv. Chim. Acta  1996,  79:  1519 
• 11b Frey O. Hoffmann M. Kessler H. Angew. Chem., Int. Ed. Engl.  1995,  34:  2026 
• 12a Marcaurelle LA. Rodriguez EC. Bertozzi CR. Tetrahedron Lett.  1998,  39:  8417 
• 12b Peri F. Cipolla L. Rescigno M. La Ferla B. Nicotra F. Bioconjugate Chem.  2001,  12:  325 
• 12c Cipolla L. Rescigno M. Leone A. Peri F. La Ferla B. Nicotra F. Bioorg. Med. Chem. Lett.  2002,  10:  1639 
• 14 Schweizer F. Lohse A. Otter A. Hindsgaul O. Synlett  2001,  1434 
• 15 Lohse A. Schweizer F. Hindsgaul O. Comb. Chem. High Throughput Screening  2002,  5:  389 
• 16 Orsini F. Di Teodoro E. Tetrahedron: Asymmetry  2003,  14:  2521 
• 19 Bilsky EJ. Egleton RD. Mitchell SA. Palian MM. Daid P. Huber JD. Jones H. Yamamura HI. Janders H. Davis TP. Porreca F. Hruby VJ. Polt R. J. Med. Chem.  2000,  43:  2586 
• 21 Stott K. Stonehouse J. Keeler J. Hwang TL. Shaka AJ. J. Am. Chem. Soc.  1995,  117:  4199 
• 22 Elmore DT. Guthrie DJS. Kay G. Williams CH. J. Chem. Soc., Perkin Trans. 1  1988,  1051 
• 23 Prepared according to the procedure by: Maetz P. Rodriguez M. Tetrahedron Lett.  1997,  38:  4221 
• 24 It has been suggested that incorporation of hydrophilic carbohydrate moieties into opioid peptides renders them amphipathic, promoting exchange between lipid and aqueous phases, which may lead to enhanced blood brain barrier penetration see: Palian MM. Boguslavky VI. O’Brien DF. Polt R. J. Am. Chem. Soc.  2003,  125:  5823 
• 27 Arya P. Barkley A. Randell K. J. Comb. Chem.  2002,  4:  193 
• 29 Handlon AL. Fraser-Reid B. J. Am. Chem. Soc.  1993,  115:  3796 

13

It is noteworthy that these β-galactosyl amides are not accessible via acylation of the corresponding galactosyl-amine. [14]

17

Yield calculation is based on the addition of the partially protected diamino ester.

18

Products were identified by MS.

20

Yields are based on isolated amount after reverse phase HPLC purification. Characteristic data for 22: ¹H NMR (600 MHz, CD₃OD, r.t.): δ = 3.93 (dd, J = 3.03 Hz, J < 1 Hz, H-6_Gal), 4.02 (d, J = 9.8 Hz, H-4_Gal), 6.80 (d, J = 8.4 Hz, 2 H), 7.15 (d, J = 8.4 Hz, 2 H), 7.20-7.35 (m, 4 H), 7.45-7.53 (m, 2 H), 7.55-7.62 (m, 2 H), 7.82 (d, J = 7.10 Hz, 2 H). MS (ES): m/z calcd [M + H]⁺: 1022.48; found: 1022.65.

25

The stereochemistry at the anomeric center in 28 has not yet been determined.

26

We speculate that the axial substituent at the C-4 position in mannose-configurated ulosonic acid 8 and rhamnose-configurated ulosonic acid 16 destabilizes the cyclic form and favors the open ketone form resulting in low yields of the corresponding unnatural glycosyl amino acids (Scheme [6] ).

28

A 40 ms gaussian pulse with a 560 ms mixing time was used.

30

Cyanoalanine and nitriles with branching at the β-position have previously been used without success in an intermolecular Ritter reaction (see ref. 29).