title: Simultaneous diastereo- and enantioseparation of farnesoid X receptor (FXR) agonists with a quinine carbamate-based chiral stationary phase.
abstract: In the frame of a project aimed at finding non-steroidal farnesoid X receptor (FXR) agonists, we identified 4-(2,4-dimethoxyphenyl)-3,6-dimethyl-1-(2-tolyl)-4,8-dihydro-1H-pyrazole[3,4-e][1,4]thiazepin-7-one (1) as a hit endowed with FXR activity. Most of the compounds synthesised during the hit-to-lead optimisation work were characterised by the presence of two chiral centres and were therefore obtained as mixtures of anti(±)- and syn(±)-diastereoisomers. A restricted sub-set of species harboured with a carboxylic acid group on the distal phenyl ring of the biphenyl (a(±)5 (A1) and s(±)5 (S1)) or the phenoxyphenyl (a(±)6 (A2) and s(±)6 (S2)) moiety at C-4 position of the pyrazole[3,4-e][1,4]thiazepin-7-one core, resulted in suitable diastereo- and enantioresolution with a quinine (QN) carbamate-derived chiral stationary phase (CSP). Differently from the compounds usually analysed with QN-based CSPs, the couples A1/S1 and A2/S2 were atypical selectands, in which the two chiral carbon atoms reside at a remote position with respect to the carboxylic function, the main "point of attack" to the CSP. We produced evidence that the scarcely employed normal-phase (NP) eluent systems represent the elective choice for achieving the simultaneous diastereo- and enantioseparation of this class of compounds over the usually preferred reversed-phase (RP) and polar-organic (PO) modes of elution. Indeed, after the optimisation of the eluent composition, NP conditions allowed to obtain profitable enantioselectivity profiles, along with excellent diastereoselectivity levels (α(A1) = 1.07, R (S)(A1) = 1.15; α(S1) = 1.09, R (S)(S1) = 1.47; α(A2) = 1.08, R (S)(A2) = 1.31; and α(S2) = 1.06, R (S)(S2) = 1.18). The optimised NP methods are suitable for simultaneously providing information on the diastereo- and enantiopurity of the investigated compounds.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Roccaldo
authors.initials: R
authors.lastname: Sardella
authors.forename: Maura
authors.initials: M
authors.lastname: Marinozzi
authors.forename: Federica
authors.initials: F
authors.lastname: Ianni
authors.forename: Antonella
authors.initials: A
authors.lastname: Lisanti
authors.forename: Benedetto
authors.initials: B
authors.lastname: Natalini
mesh_terms: D002219:Carbamates / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation / Q000379:methods*; D008024:Ligands; D015394:Molecular Structure; D011803:Quinine / Q000737:chemistry*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013237:Stereoisomerism
chemical_list: D002219:Carbamates; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011803:Quinine