Enantioselective organocatalytic synthesis of non natural nucleosides by cross aldol addition

LETICIA LAFUENTE; LAUTARO MAIDANA; MARIANO NIGRO; ADOLFO IRIBARREN; ELIZABETH LEWKOWICZ

Baltimore

Congreso; IS3NA Virtual Workshop; 2021

Universidad de Maryland

In recent years, our research group has explored the synthesis and characterization of potential new antiviral agents such as acyclic nucleoside analogs using organocatalyzed aldol additions [2, 3]. While organocatalysis has emerged as a promising area for sustainable asymmetric synthesis [4] and aldol reactions have been widely used for the creation of the β-hydroxylcarbonyl structural motif, which is found in numerous biologically active natural products and biocative molecules, these combined approaches had not been applied to acyclic nucleoside synthesis.Since not only modifications of the sugar moiety but also the nature of the heterocycle is crucial for the biological activities of nucleosides analogs (1), benzimidazole was tested as a structural mimic of the purine base. The presence of this heterocycle conferes on its derivatives a broad spectrum of biological activities when interacting with DNA, RNA or protein [5]. To synthesize novel benzimidazole-based acyclic nucleosides, we screened a series of commercially available amines such as pyrrolidine, L-proline, L-prolinamide, among others, as chiral organocatalysts in the aldol reaction of oxo-benzimidazole derivative generated by N-alkylation of the bicyclic fused ring. Cyclohexanone was chosen as the aldol donor to study both enantioselectivity and diastereoselectivity of the reaction. The desired product was obtained with high stereo-and diastereoselectivity using L-prolinamide as catalyst.Encouraged by these results, the same synthetic route was carried out using the N-alkylated derivatives of cytosine, adenine, uracil, and acetone as donor substrate, obtaining the corresponding acyclic nucleoside analogs with high stereoselectivity