Synthesis and conformational analysis of bicyclic extended dipeptide surrogates

Abstract

Regio- and diastereoselective reactions of a homoproline enolate enable the synthesis of novel extended dipeptide surrogates. Bicyclic carbamate 9 and fused beta-lactam scaffold 11 were prepared from L-pyroglutamic acid via substrate-controlled electrophilic azidation. Synthesis of orthogonally protected hexahydropyrrolizine, hexahydropyrrolizinone, and hexahydropyrroloazepinone dipeptide surrogates relied on allylation of proline derivative 5, followed by Curtius rearrangement to introduce the N-terminal carbamate group. A total of six azabicycloalkane derivatives were evaluated for conformational mimicry of extended dipeptides by a combination of X-ray diffraction and molecular modeling. Analysis of putative backbone dihedral angles and N- to C-terminal dipeptide distances indicate that compounds (alpha'S)-14b and 21 approximate the conformation of dipeptides found in beta-sheets, while tripeptide mimic 28 is also highly extended in the solid state. Structural data suggest that ring size and relative stereochemistry have a profound effect on the ability of these scaffolds to act as beta-strand mimetics and should inform the design of related conformational probes.

Figure 1

Selected examples of β-strand peptidomimetics.

Figure 2

Design of azabicycloalkane-based dipeptide surrogates.

Figure 3

Backbone torsions and N-to-C dipeptide distance for β-strands and synthetic dipeptide surrogates.

Figure 4

X-ray structures and calculated torsions, in degrees, for compounds (α′S)-14b, 23, and 28 (most hydrogens omitted for clarity).

Scheme 1

Diastereoselective azidation of homoproline derivative 3.

Scheme 2

Synthesis of scaffolds 9 and 11.

Scheme 3

Epimerization en route to bicyclic lactams 14 and 17.

Scheme 4

Diastereoselective synthesis of 21 and 23.

Scheme 5

Unexpected formation of hexahydropyrrolizine 26.

Scheme 6

C-terminal coupling of scaffolds 9, 21, and 23.

Scheme 7

Introduction of lactam constraint after incorporation.