Synthesis and Transformation of (-)-Isopulegol-Based Chiral β-Aminolactones and β-Aminoamides

Abstract

A library of isopulegol-based β-amino acid derivatives has been developed from commercially-available (-)-isopulegol. Michael addition of primary and secondary amines towards α,β-unsaturated γ-lactones was accomplished resulting in β-aminolactones in highly-stereoselective reactions. Ring-opening of β-aminolactones with different amines furnished excellent yields of β-aminoamides. Moreover, the applicability of aminolactones in peptide synthesis was examined by opening the lactone ring with α- and β-aminoesters, providing dipeptides as promising chiral substrates for the synthesis of foldamers. The antiproliferative activities of β-aminolactones and β-aminoamides were explored, and the structure-activity relationships were studied from the aspects of the stereochemistry of the monoterpene ring and the substituent effects on the β-aminoamide ring system. The N-unsubstituted (-)-isopulegol-based β-aminoamides exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and MDA-MB-231).

Stereoselective synthesis and application of isopulegol-based bi- and trifunctional chiral compounds

“…[69][70][71][72][73][74] Nucleophilic addition of primary amines to a-methylene-gbutyrolactone 4 has proved to be an efficient method for the preparation of a highly diversied library of b-aminolactones 5-8. 58,75 Treatment of b-aminolactones with LiAlH 4 resulted in secondary aminodiols 9-12. Debenzylation via hydrogenolysis of aminodiols 9-11 over Pd/C in MeOH gave primary aminodiol 13 in moderate yields.…”

“…41,42 Apart from their biological interest, monoterpenebased aminodiols have been demonstrated to be excellent chiral auxiliaries in a wide range of stereoselective transformations including intramolecular radical cyclisation, 43 intramolecular [2 + 2] photocycloaddition 44 and Grignard addition. 45,46 In order to combine the properties of monoterpenes and aminodiols as well as to develop new, efficient and commercially available chiral ligands, naturally occurring chiral monoterpenes such as (+)-and (À)-a-pinene, [47][48][49] (+)-carene, 50,51 (+)-camphor, 52,53 (À)-fenchone, 54 (À)-menthone, 55 (À)-myrtenol, 56,57 (+)-neoisopulegol, 58,59 (S)-perillyl alcohol, 60 (À)-pulegone, 61 or (+)-sabinol 62 have been widely used as key intermediates for the synthesis of aminodiols.…”

Stereoselective Synthesis and Investigation of Isopulegol-Based Chiral Ligands

“…Nucleophilic addition of primary amines to α-methylene-γ-butyrolactone 4 has proved to be an efficient method for the preparation of a highly diversified library of β-aminolactones 5 – 8 [38,39,40]. Treatment of β-aminolactones with LiAlH 4 resulted in secondary aminodiols 9 – 12 [16].…”

“…(+)-Neoisopulegol 2 , diol 3 and ( − )- α -methylene- γ -butyrolactone 4 were prepared according to literature procedures, and all spectroscopic data were similar to those described therein [35]. The nucleophilic addition of α -methylene- γ -butyrolactone to amines were carried out according to our literature procedures with all spectroscopic data of compounds 5 – 7 being consistent with literature values [38].…”

Enantiomeric Isopulegol as the Chiral Pool in the Total Synthesis of Bioactive Agents

“…[82] Hence, a library of monoterpenebased β-aminolactones and β-aminoamides applying (À )isopulegol 2 was developed in the laboratories of Ferenc Fülöp in 2019. [83] Key intermediate (+)-α-methylene-γ-butyrolactone 35 was prepared from (À )-2 by regioselective hydroxylation, followed by two-step oxidation and ring closure of the obtained γhydroxy-substituted α,β-unsaturated carboxylic acid. [39] Nucleophilic addition of primary and secondary amines to (+)-35 produced β-aminolactones 36-44.…”