Solid-phase synthesis of diketopiperazines, useful scaffolds for combinatorial chemistry

Tetrahedron Letters

Volumn 39, Issue 17, 1998, Pages 2639-2642

  Del Fresno, Montserrat ^a   Alsina, Jordi ^a   Royo, Miriam ^a   Barany, George ^b   Albericio, Fernando ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

^b University of Minnesota ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIPEPTIDE; PIPERAZINEDIONE;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; PEPTIDE SYNTHESIS;

EID: 0032559999     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)00226-3     Document Type: Article

References (46)

1. 2O, acetic anhydride; Al, allyl; Alloc, allyloxycarbonyl; BAL, backbone amide linker; Bu, butyl; Bzl, benzyl; Ddz, 2-(3,5-dimethoxyphenyl)propyl[2]oxycarbonyl; DIEA, N,N-diisopropylethylamine; DKP, diketopiperazine, (2,5-piperazinedione); DMF, N,N-dimethylformamide; Fmoc, 9-fluorenylmethoxycarbonyl; HATU, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HPLC, high performance liquid chromatography; IRAA, internal reference amino acid; Mtt, 4-methyltrityl; MALDI-TOF, matrix assisted laser desorption ionization, time of flight; PALdehyde, 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid; PEG-PS, polyethylene glycol-polystyrene graft; PS, polystyrene; PyAOP, 7-azabenzotriazol-1-yl-oxytris(pyrrolidino)phosphonium hexafluorophosphate; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Trt, triphenylmethyl (trityl). Amino acid symbols denote L-configuration unless otherwise noted.
2. 2. Present address: Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
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18. 10. Solid-phase strategies for DKP synthesis have been described previously, but are not as versatile as the strategy shown in the present work. Thus, our strategy allows use of any combination of amino acids, unlike a scheme that starts by anchoring Asp or Glu to an appropriate resin: Krchnák, V.; Weichsel, A.S.; Cabel, D.; Lebl, M. in ref. 4c pp. 99-117, nor is the presence of an N-alkylamino acid mandatory to favor the cyclization as described by: Gordon, D.W.; Steele, J. Bioorg. Med. Chem. Lett. 1995, 5, 47-50; Szardenings, A.K.; Burkoth, T.S.; Lu, H.H.; Tien, D.W.; Campbell, D.A. Tetrahedron 1997, 53, 6573-6593.
19. 10. Solid-phase strategies for DKP synthesis have been described previously, but are not as versatile as the strategy shown in the present work. Thus, our strategy allows use of any combination of amino acids, unlike a scheme that starts by anchoring Asp or Glu to an appropriate resin: Krchnák, V.; Weichsel, A.S.; Cabel, D.; Lebl, M. in ref. 4c pp. 99-117, nor is the presence of an N-alkylamino acid mandatory to favor the cyclization as described by: Gordon, D.W.; Steele, J. Bioorg. Med. Chem. Lett. 1995, 5, 47-50; Szardenings, A.K.; Burkoth, T.S.; Lu, H.H.; Tien, D.W.; Campbell, D.A. Tetrahedron 1997, 53, 6573-6593.
20. 10. Solid-phase strategies for DKP synthesis have been described previously, but are not as versatile as the strategy shown in the present work. Thus, our strategy allows use of any combination of amino acids, unlike a scheme that starts by anchoring Asp or Glu to an appropriate resin: Krchnák, V.; Weichsel, A.S.; Cabel, D.; Lebl, M. in ref. 4c pp. 99-117, nor is the presence of an N-alkylamino acid mandatory to favor the cyclization as described by: Gordon, D.W.; Steele, J. Bioorg. Med. Chem. Lett. 1995, 5, 47-50; Szardenings, A.K.; Burkoth, T.S.; Lu, H.H.; Tien, D.W.; Campbell, D.A. Tetrahedron 1997, 53, 6573-6593.
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33. 13. Jensen, K.J.; Alsina, J.; Songster, M.F.; Vágner, J.; Albericio, F.; Barany, G. (a) In Peptides-Chemistry and Biology: Proceedings of the 14th American Peptide Symposium; Kaumaya, P.T.P.; Hodges, R.S. Eds.; Mayflower Worldwide Ltd., Kingswinford, England, 1996, pp 30-32;
34. (b) J. Am. Chem. Soc. submitted for publication.
35. 14. Built into the BAL approach (see text structure), the anchored first amino acid ester is N-alkylated and therefore more likely to form a DKP at the dipeptidyl ester stage.
36. α-Fmoc derivative under in situ neutralization/coupling conditions mediated by PyAOP in DMF in the presence of DIEA (see ref. 12c and 13).
37. 16. Albericio, F.; Kneib-Cordonier, N.; Biancalana, S.; Gera, L.; Masada, R.I.; Hudson, D.; Barany, G. J. Org Chem. 1990, 55, 3730-3743.
38. 17. PALdehyde (4 equiv) and HATU (4 equiv) (Carpino, L.A.; El-Faham, A.; Minor, C.A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1994, 201-203) were dissolved in DMF, then DIEA (8 equiv) was added, and after 1 min preactivation, this solution was added to amino-functionalized PS or PEG-PS-resin also containing an IRAA. Coupling was allowed to proceed at 25 °C for 2 h, at which time the resin was negative to the Kaiser ninhydrin test.
39. 18. Methyl ester of all amino acids are commercially available. The same chemistry was also successful for other esters; in particular the rates and yields of DKP formation (step i) were shown to be very similar for methyl, allyl, and benzyl esters.
40. 2 and MeOH, and finally dried. These conditions assure complete integrity of the amino acyl chiral center.
41. 2O-DMF (1:9, 20 min), and washed with DMF.
42. 21. Treatments with piperidine-DMF (1:4) were followed by washes with DMF. At this stage, the Kaiser ninhydrin test was in all cases negative.
43. 22. Yields were determined to be greater than 95%, as follows: Upon completion of the DKP-forming reaction, a third Fmoc-amino acid was coupled, and resin was subjected to acid hydrolysis followed by AAA. The ratio between this third amino acid and the initial two gave the amount of free amine, and could then be used to calculate the overall yield of DKP formation.
44. 2 (Bunin, B.A.; Ellman, J.A. J. Am. Chem. Soc. 1992, 114, 10997-10998).
45. 24. An orthogonal system is defined as a set of completely independent classes of protecting groups, such that each class of groups can be removed in any order and in the presence of all other class (Barany, G.; Merrifield, R.B. J. Am. Chem. Soc. 1977, 99, 7363-7365; and ref. 11f).
46. 3CN and 0.1% aqueous TFA, from 1:9 to 1:0, over 30 min, run at 1.0 mL/min. UV detection was at 220 nm. All DKPs studied showed purity similar to the example of DKP (5).