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.

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 

13

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

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 

17

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

18

Products were identified by MS.

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 

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.

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 

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] ).

27 Arya P. Barkley A. Randell K. J. Comb. Chem.  2002,  4:  193 

28

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

29 Handlon AL. Fraser-Reid B. J. Am. Chem. Soc.  1993,  115:  3796 

30

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