Synthesis, Separation and Absolute Configuration Determination by ECD Spectroscopy and TDDFT Calculations of 3‐Amino‐β‐lactams and Derived Guanidines

Abstract

Four isomeric chiral 3-amino-β-lactams 4 with p-fluorophenyl and p-methoxyphenyl substituents at N and C-4 positions, similar to the cholesterol absorption inhibitor ezetimibe, have been prepared as diastereomerically and enantiomerically pure compounds by ester enolate/imine cyclocondensation. The same route afforded analogues with a 1,3-benzodioxole instead of the p-methoxyphenyl group. Moreover, β-lactams 4a,b were converted into benzoylguanidine derivatives. The series of chiral β-lactams and β-lactam guanidines was characterized by electronic circular dichroism (ECD) spectroscopy, and their absolute configurations were assigned based on ECD TDDFT calculations. The calculations also demonstrated that the β-lactam sector and helicity rules cannot be applied to β-lactams appended with aromatic chromophores such as the present ezetimibe analogues

Absolute Configuration Determination by Quantum Mechanical Calculation of Chiroptical Spectra: Basics and Applications to Fungal Metabolites

“…What all the aforementioned semi-empirical rules have in common is: a) they focus on only one or a few transitions of a specific chromophore, therefore their scope is intrinsically limited; b) they are semi-empirical, in the sense they depend on a collection of previous experimental data, therefore exceptions are always possible. [71] Despite these known limitations, some semi-empirical rules have been very popular in the field of natural products until the advent of modern computational techniques to be discussed below. SCHEME 2: Application of the isochroman helicity rule to pseudoanguillosporin A and B.…”

Enantioseparation of (±)-trans-β-lactam Ureas by Supercritical Fluid Chromatography

“…[10] Recently, we reported on the synthesis, separation and absolute configuration determination of 3-amino-βlactams and corresponding guanidines. [12,13] β-Lactams are an important group of heterocyclic compounds and can be found as a structural motif in biologically active natural products, and active pharmaceutical compounds. [14,15,16,17] β-Lactams are therefore extremely useful synthetic scaffolds and versatile precursors in medicinal chemistry due to their diverse biological activity.…”

Chirality sensing of bioactive compounds with amino alcohol unit via circular dichroism

“…Many of their applications consist of their use as ligands in asymmetric synthesis to afford small heterocyclic derivatives as, for example, pyrrolidine, morpholinones, 2 or transoxazolines. [10][11][12][13][14][15][16][17][18][19][20][21][22][23] Far from it, in the recent literature, there are many trusted examples of assignments using only one chiroptical method, mainly electronic [24][25][26][27][28] or vibrational 29-34 circular dichroism (ECD, VCD, respectively). 5 As a consequence of significant biological activity and broad applicability in organic synthesis, vic-amino alcohols are an important class of organic compounds, whose absolute configuration (AC) determination is vital.…”

“…methods increases the confidence level of stereochemical elucidation substantially. [10][11][12][13][14][15][16][17][18][19][20][21][22][23] Far from it, in the recent literature, there are many trusted examples of assignments using only one chiroptical method, mainly electronic [24][25][26][27][28] or vibrational [29][30][31][32][33][34] circular dichroism (ECD, VCD, respectively). However, in the present work we utilize the first-mentioned approach to assign the AC of selected bioactive compounds with the amino alcohol unit.…”