| Research Abstract |
Syntheses of peptides containing very bulky alpha, alpha-disubstituted glycines, alpha, alpha-diisopropyl-glycine (Dip) and alpha, alpha-diphenylglycine (Dph), were investigated by using four-component condensation (Ugi reaction) at high pressure (9 kbar) and at atmospheric pressure. The results are as follows :
1. Dip which is the most bulky amino acid as far as we know, could be first synthesized by the Ugi reaction at 9 kbar using formic acid, Schiff base derived from diisopropyl ketone and benzyl-amine, and cyclohexyl isocyanide, followed by acidic hydrolysis and catalytic hydrogeno-lysis.
2. Various protections of N- and C-termini of Dip were tried but only esterification by HCI/MeOH at 9 kbar could afford Dip-OMe・HCI in a 10% yield.
3. Several tripeptides containing N-benzyl-Dip residue were first synthesied in good yields by the Ugi reaction at 9 kbar using Schiff base from diisopropylketone and benzylamine, several Z-amino acids, and methyl isocyanoacetate.
4. Catalytic hydrogenoly
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sis for removing N-benzyl group from Dip-containing tripeptides obtained above could afford no desired tripeptide esters, but the unexpected bicyclic acylamidines in medium yields.
5. By the Ugi reaction using formic acid, Schiff base from diisopropylketone and benzylamine, and methyl isocyanoacetate, N-benzyl-N-formyl-Dip-Gly-OMe was obtained. Catalytic hydrogenolysis of this compound could afford the first protected dipeptide containing Dip, HCO-Dip-Gly-OMe.
6. The Ugi reaction using diphenylmethanimine as a Schiff base, various Z-amino acids, and some isocyanides could first afford various tripeptides containing Dph, Z-AA_1-Dph-AA_3-OMe. Significantly, tripeptides in which both AA_1 and AA_3 are alpha, alpha-disubstituted glycines could be prepared easily by this method.
7. X-Ray crystal structural analysis of 6 tripeptides containing Dph clarified that Dph prefers not only C_5-conformation but also beta-turn.
8. The Ugi reaction using cyclohexanone oxime as a Schiff base could afford several N-hydroxytripeptides containing l-aminocyclohexanecarboxylic acid (Ac_6c). These peptides could be saponified quantitively and further converted to N-hydroxytetrapeptides in good yields. Less
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