Absolute Configuration Sensing of Chiral Aryl- and Aryloxy-Propionic Acids by Biphenyl Chiroptical Probes

Abstract

The absolute configuration of chiral 2-aryl and 2-aryloxy propionic acids, which are among the most common chiral environmental pollutants, has been readily and reliably established by either electronic circular dichroism spectroscopy or optical rotation measurements employing suitably designed 4,4′-disubstituted biphenyl probes. In fact, the 4,4′-biphenyl substitution gives rise to a red shift of the diagnostic electronic circular dichroism signal of the biphenyl A band employed for the configuration assignment, removing its overlap with other interfering dichroic bands and allowing its clear sign identification. The largest A band red shift, and thus the most reliable results, are obtained by employing as a probe the 4,4′-dinitro substituted biphenylazepine 3c. The method was applied to the absolute configuration assignment of 2-arylpropionic acids ibuprofen (1a), naproxen (1b), ketoprofen (1c) and flurbiprofen (1d), as well as to the 2-aryloxypropionic acids 2-phenoxypropionic acid (2a) and 2-naphthoxypropionic acid (2b). This approach, allowing us to reveal the sample’s absolute configuration by simple optical rotation measurements, is potentially applicable to online analyses of both the enantiomeric composition and absolute configuration of these chiral pollutants.

5,5,7,7-Tetrametyl-6,7-dihydro-5H-dibenzo[c,e]azepine

“…Dibenz[c,e]azepines constitute an important class of compounds widely employed as chiral or pro-chiral scaffolds for the construction of chiral catalysts for asymmetric synthesis or probes for chiral molecular recognition. In particular, 1,1 -binaphthylazepines have been widely employed as chiral ligands in organometallic catalysis [1][2][3][4][5] and organocatalysis [6][7][8][9][10], while not-atropisomerically stable (i.e., tropos) 1,1 -biphenylazepines have been reported both as structural motifs for the construction of the chiral ligands [9][10][11][12][13][14][15] and as the chiroptical probes for the absolute configuration assignment to the chiral acids [16][17][18][19] and amines [14,20]. In fact, in 1,1 -biphenylazepines the low phenyl-phenyl rotational barrier allows, at room temperature, a free interconversion of the two possible M and P atropisomeric forms.…”

“…This makes this molecular system a unique probe for detection of molecular chirality because, when this moiety is linked to a chiral compound, a centralto-axial chirality induction occurs and the stereogenic center(s) of the substrate induces a preferred biphenyl twist in the azepine, making this chiral itself. As reported above, this effect has been exploited to assemble chiral catalysts and reagents, joining the flexible biphenyl moiety to an atropisomerically stable binaphthyl moiety [10][11][12][13][14] or introducing one or two stereogenic centers on the benzylic positions [21,22], and to build chiroptical probes for the absolute configuration assignment to chiral acids [16][17][18][19] and amines [14,20]. In this latter application, the biphenylazepine moiety acts as a chirality sensor, assuming a preferred twist in dependence of the chiral substrate absolute configuration.…”

Synthesis and Stereochemical Characterization of a Novel Chiral α-Tetrazole Binaphthylazepine Organocatalyst

“…A particular family of binaphthyls is constituted by 1,1 -binaphthylazepines which, since the first example reported by Cram and Mazaleyrat in 1981 [6], have been widely employed both as chiral ligands in organometallic catalysis [7][8][9][10] and catalysts in organocatalysis [11]. Moreover, structurally similar tropos biphenylazepine analogues have been described both as structural motifs for the construction of chiral ligands [12] and as chiroptical probes for the absolute configuration assignment to chiral acids [13][14][15][16] and amines [12,17]. One of the most successful applications of 1,1 -binaphthylazepines in asymmetric catalysis have been reported by Maruoka and coworkers, who described the use of differently functionalized chiral binaphthylazepiniun ions in phase transfer catalysis for asymmetric alkylations, Michael additions, and aldol reactions [18][19][20][21][22].…”

Computational Approaches and Use of Chiroptical Probes in the Absolute Configuration Assignment to Natural Products by ECD Spectroscopy: A 1,2,3-Trihydroxy-p-menthane as a Case Study

“…Although many chiroptical probes have been described so far, very few examples report their application to natural products of unknown AC [23,24]. Only very recently we have shown that 2,2 -bridged biphenyls, introduced by us some years ago for the AC assignment of chiral threo [25] and erythro [26] diols, carboxylic acids [27][28][29], and primary amines [30,31], also provide a versatile probe for the AC assignment of complex natural products [32,33]. In particular, we applied the biphenyl approach to assign AC to natural phytotoxins bearing a threo diol moiety [32] or a chiral acid group [33].…”