Solid-Phase Synthesis of Acyclic and Cyclic Amino Acid Derived Urea Peptidomimetics Using Phoxime Resin

Abstract

The use of Phoxime resin 2 (phosgenated p-nitrophenyl(polystyrene)ketoxime) in the synthesis of acyclic and heterocyclic amino acid derived ureas is described. Resin 2 was previously shown to be a useful precursor in the solid-phase preparation of nonsymmetric ureas from thermolysis of corresponding primary amine oxime carbamates and subsequent trapping with an amine in solution. Generation of functionalized polymersupported primary amine oxime carbamates (3 and 9) for further diversification was accomplished by addition of amino acids or substituted hydrazines to resin 2. The use of these functionalized oxime carbamate resins for the generation of acyclic R-ureidoacetamides 5, 3-aminohydantoins 7, and 1,2,4-triazine-3,6-diones 8 is suitable for combinatorial library generation.

Resin-to-Resin Acyl- and Aminoacyl-Transfer Reactions Using Oxime Supports

“…In previous work, we described the use of phosgenated oxime resin, which reacts with amines to form oxime-derived carbamates 9 . Thermolysis of these carbamates 9 in the presence of amines in solution leads to the formation of ureas 11 via freely diffusible isocyanate intermediates ( 10 ; see Scheme ). , However, secondary amine-derived carbamates of phosgenated oxime resin did not generate ureas, supporting in situ formation of the isocyanate by the mechanism proposed by Levine and Frech. , Furthermore, TGA-MS and IR studies of carbamates derived from oxime resin also indicated thermolytic isocyanate generation . These results led us to attempt the thermolysis of oxime carbamate resins 9 in the presence of polymer-supported amines ( 5 ; see Scheme ).…”

Three cheers for nitrogen: aza-DKPs, the aza analogues of 2,5-diketopiperazines

“…This strategy was also used on solid phase by the team of Scialdone in 1999. 37 Aer xing the desired hydrazine on a Phoxime® resin, the peptide coupling was performed with DIC and HOBt to add phenylalanine and to obtain the 2-aminoacetohydrazide precursors 35. Aer N-Boc deprotection with TFA, treatment with Hünig's base allowed isolation of the desired aza-DKPs 36 with low yields between 10 and 37% (Scheme 12).…”

“…§ 2.2.1., Scheme 15). 36,37,40 Thereby, several groups (alkyl, benzyl, aryl) have been introduced during the synthesis of the corresponding aza-DKPs 85 on nitrogen N1 (Scheme 30). Table 1 below summarizes the variations at the four positions of an aza-DKP, according to the precursor involved and the strategy employed, with the corresponding references from the literature.…”

1,5-DiphenylcarbonohydrazideN,N-dimethylformamide

“…For the structure of diphenylcarbonohydrazide, see: De Ranter et al (1979). For related structures, see: Hamuro et al (1999); Jian et al (2003); Wei et al(2006); Wang et al (2001).…”

“…1, 5-diphenylcarbonohydrazide, an artificial electron-donor material, has a variety of applications (Verma & Singh, 1995;Melis et al, 1992;Prasad et al, 1991;Sundari & Raghavendra, 1990;Mishra et al, 1993). The structure of diphenylcarbonohydrazide (C 13 H 14 N 4 O), (De Ranter et al, 1979) and a number of diphenylcarbonohydrazide derivatives have been prepared (Jian et al, 2003;Wang et al, 2001;Hamuro et al, 1999;Wei et al, 2006).…”