Synthetic Approaches to A Challenging and Unusual Structure-An Amino-Pyrrolidine Guanine Core

Abstract

The synthesis of an unreported 2-aminopyrrolidine-1-carboxamidine unit is here described for the first time. This unusual and promising structure was attained through the oxidative decarboxylation of amino acids using the pair of reagents, silver(I)/peroxydisulfate (Ag(I)/S₂O₈^2-) followed by intermolecular (in the case of l-proline derivative) and intramolecular trapping (in the case of acyl l-arginine) by N-nucleophiles. The l-proline approach has a broader scope for the synthesis of 2-aminopyrrolidine-1-carboxamidine derivatives, whereas the intramolecular cyclization afforded by the l-acylarginines, when applied, results in higher yields. The former allowed the first synthesis of cernumidine, a natural alkaloid isolated in 2011 from Solanum cernuum Vell, as its racemic form.

Keywords: Cernumidine; amino acid decarboxylation; cyclic-guanidine; radical decarboxylation.

Figure 1

Structure of cernumidine (1); in marked blue is the 2-aminopyrrolidine-1-carboxamidine unit presenting the cyclic-guanidine core.

Figure 2

Reported efforts on the synthesis of a cyclic-guanidine core. Works from: (a) Ascenzi, P., et al. [24], (b) Boto, A., et al. [25,27], and (c) Silva et al [29].

Scheme 1

Retrosynthetic approach to the synthesis of 2-aminopyrrolidine-1-carboxamidine derivatives.

Scheme 2

Proposed mechanism for the oxidative decarboxylation of N^α-acyl-l-arginine derivatives (3) to 2-aminopyrrolidine-1-carboxamidine derivatives (4).

Scheme 3

Proposed mechanism for the oxidative decarboxylation of carbamimidoyl-l-proline (2) to 2-aminopyrrolidine-1-carboxamidine (4a).