1,2,3-Trisubstituted cyclopropanes as conformationally restricted peptide isosteres: application to the design and synthesis of novel renin inhibitors

Abstract

The 1,2,3-trisubstituted cyclopropanes 6 and 7 are the first members of a novel class of isosteric replacements for peptide linkages that are more generally represented by the dipeptide mimics 2 and 3. These unique peptide surrogates are specifically designed to lock a section of a peptide backbone in an extended beta-strand conformation (phi-angle restriction) while simultaneously enforcing one of two specifically defined orientations for the amino acid side chain (chi 1-angle restriction). Methods were first developed for the stereoselective, asymmetric synthesis of the trisubstituted cyclopropanes 15a-d, 18a-d, 22a-d, and 23a-d (Scheme II), by an efficient approach featuring the Rh2(S-MEPY)4 (11) and Rh2(R-MEPY)4 (20) catalyzed cyclization of the allylic diazoacetates 10a-d to give the optically active lactones 12a-d and 21a-d, respectively, in up to greater than or equal to 94% enantiomeric excess. Nucleophilic opening of the lactone ring of 12a-d gave the corresponding morpholine amides 14a-d. By exploiting tactics that allowed for selective epimerization of one of the two functionalized side chains on the cyclopropane nucleus, 14a-d were transformed into the two series of diastereoisomeric morpholine amide carboxylic acids 15a-d and 18a-d. Epimerization of the morpholine amide group on 14a-d followed by Jones oxidation of the intermediate alcohols gave 15a-d. Alternatively, initial oxidation of the primary alcohol groups in 14a-d followed by selective, base-catalyzed inversion alpha to the aldehyde function and then Jones oxidation gave the diastereomeric dicarboxylic acid derivatives 18a-d. In a similar fashion, the enantiomeric lactones 21a-d were converted into the two corresponding enantiomeric series of dicarboxylic acid derivatives 22a-d and 23a-d. Inhibitors of aspartic proteinases, of which renin is a typical example, are known to bind to the enzyme active site cleft in an extended conformation. Thus, in order to evaluate the efficacy of 1,2,3-trisubstituted cyclopropanes as rigid replacements of beta-strand secondary structure in pseudopeptidic ligands, 15a-d, 18a-d, 22a-d, and 23a-d were incorporated at the P3 subsite of the potential renin inhibitors 24a-h and 25a-h by coupling with the tripeptide replacement 8. A significant number of substances inhibited renin at nanomolar concentrations. On the basis of this preliminary test, 1,2,3-trisubstituted cyclopropanes do appear to constitute a viable new class of peptide mimics. Since the stereochemistry at each carbon on the cyclopropane ring may be altered, these novel replacements may also function as stereochemical probes to establish the conformation of pseudopeptide ligands bound to their macromolecular targets.

Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp3)−H Bond Activation

“…[23,24] Additionally, they may be applied as conformationally restricted peptidei sosters. [25] However,i ns pite of their importance,s ynthesis of such scaffolds with cis configuration between the carboxylic acid and an aromatic ring and trans configuration relative to the alkyl moiety remains, to the best of our knowledge, unexplored not only in enantioselective but also in ar acemic manner. [26] Notably,b ecauseo ft he potentialb iological and agrochemical reactivity of such as caffold, straightforward access to both enantiomersi sh ighly desirable.…”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…We hypothesized that the cyclopropane-derived peptidomimetic 350 might mimic the bound conformation of 349 , a potent renin inhibitor discovered at Abbott Laboratories ( Figure 17). 189 Notably, 349 and 350 contain the same number and types of heavy atoms and the same number of hydrogen-bond donors and acceptors. We believe that meeting these criteria is critical because doing so increases the likelihood that desolvation parameters and binding interactions with solvent and the protein for the two compounds being compared will be closely similar.…”

Recent Advances in β‐Strand Mimetics

“…In the last 20 years small-molecule b-strand mimetics have been increasingly reported [6][7][8][9]. Small molecules that mimic b-strands could be useful enzyme inhibitors or protein antagonists with important applications in medicine.…”