Coupling of N-Boc-O-benzyl-L-tyrosine (I) with tert-butylamine by means of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) afforded amide (II). Subsequent acid cleavage of the Boc group of (II) gave O-benzyltyrosine tert-butyl amide (III).
N-Methyl-L-leucine (IV) was converted to tert-butyl ester (V) by treatment with isobutylene and H2SO4. Formation of the N,N-dialkyl derivative (VIII) was achieved by either alkylation of (V) with p-tert-butylbenzyl bromide (VI) or by reductive condensation of (V) with p-tert-butylbenzaldehyde (VII) and NaBH(OAc)3. Deprotection of the tert-butyl ester of (VIII) with trifluoroacetic acid gave amino acid (IX), which was activated as the mixed anhydride (X) upon treatment with isobutyl chloroformate and a polymer-supported morpholine base. Coupling of (X) with tyrosine amide (III) then afforded the title dipeptide amide. Unreacted starting materials were captured by the addition of polymer-supported polyamine and isocyanate resins.
The precursor amino acid derivatives were obtained as follows: The condensation of N-Boc-O-benzyltyrosine (I) with tert-butylamine using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) gave amide (II). Subsequent deprotection of the Boc group of (II) by means of trifluoroacetic acid provided O-benzyltyrosine tert-butyl amide (III). N-Methyl leucine benzyl ester (IV) was alkylated with 3-bromocyclohexene (V), yielding the cyclohexenyl amine (VI). Hydrogenation of the olefinic double bond of (VI) with concomitant benzyl ester hydrogenolysis in the presence of Pd/C furnished N-cyclohexyl-N-methylleucine (VII). The title dipeptide was finally obtained by HBTU-promoted coupling of amino acids (III) and (VII).
Alternatively, the compound was prepared using polymer-supported resins. Dialkyl leucine (VII) was first treated with isobutyl chloroformate and morpholine resin, tyrosine derivative (III) was added, and was then treated with isocyanate resin and tris(2-aminomethyl)amine resin. Filtration of the insoluble resins provided a solution of pure dipeptide derivative.
In a related procedure, N-Boc-N-methylleucine (XI) was coupled with O-benzyltyrosine amide (III) in the presence of HBTU to give the protected dipeptide (XII). Trifluoroacetic acid-promoted cleavage of the Boc group of (XII) provided amine (XIII). Finally, reductive alkylation of (XIII) with 4-tert-butylbenzaldehyde (VII) gave rise to the title compound.