Synthesis of Enantiopure Pyrrolidine-Derived Peptidomimetics and Oligo-β-peptides via Nucleophilic Ring-Opening of β-Lactams

Abstract

The synthesis of the two enantiomers of pyrrolidine-derived spiro beta-lactams by resolution with D- and L-Boc phenylalanine is described. The potential of these optically active spiro beta-lactams on the synthesis of peptidomimetics as analogues of melanostatin is evaluated. Theoretical studies of several models, at the Becke3LYP/6-31+G* level of theory, together with previous experimental evidences from our group, gathered by NMR, allow us to design structures that can efficiently mimic some biologically active peptide-type molecules. On the other hand, the spiro beta-lactams have shown their utility in the preparation of beta-peptides. As an example, a homo-tetra-beta-peptide was synthesized. This research will continue in the future in order to obtain higher peptides with potential biological activity.

Inhibition of prolyl oligopeptidase with a synthetic unnatural dipeptide

“…The reaction was first attempted on amine 7 using equimolar amounts of cbz-proline and slight excess of both DCC and DMAP 20,21 in DCM under an argon atmosphere. This approach was partially successful, producing desired product 8, albeit in only 15% yield.…”

Stereoselective Synthesis of Quaternary Proline Analogues

“…The β-lactams 62 and 63 were prepared by [2+2] cycloadditions between a cyclic ketene generated in situ and optically active imines (Scheme 16). [53] The [2+2] cycloaddition reactions took Scheme 16.…”

Synthesis and reactivity of spiro-fused β-lactams

“…26,27 The reaction of this acid chloride has also been performed using methyleneimines to produce spiroazetidinones. 28 …”

“…69 A -amino ester and a -amino acid have also been formed by cleavage of a pyrrolidine spiro-fused 2-azetidinone ring by potassium cyanide in methanol and by sodium hydroxide in tetrahydrofuran, respectively. 28 In contrast, 4-oxoazetidine-2-carbaldehyde 143 undergoes a C4-N1 bond fission using 2-(trimethylsilyl)thiazole (TMST) yielding amide 144 (Scheme 49). 70 The azetidinones 37, spiro- Hydrogenolysis of spiro β-lactams 146 bearing a formyl group has led to the rearranged bicyclic systems 147 via a C3-C4 β-lactam ring cleavage (Scheme 51).…”

“…23 Similar reactions have been performed on 2-azetidinones spiro-fused to pyrrolidine. 28 Another example of 2-azetidinone (160) nitrogen deprotection followed by reaction of the corresponding product 161 with phenylacetaldehyde 162 affording the spiroazetidinone 163 is shown in Scheme 58. Table 4).…”