The solution-phase synthesis of a discovery library of 178 tricyclic pyrrole-2-carboxamides was accomplished in nine steps and seven purifications starting with three benzoyl-protected amino acid methyl esters. Further diversity was introduced by two glyoxaldehydes and 41 primary amines. The combination of Pauson-Khand, Stetter, and microwave-assisted Paal-Knorr reactions was applied as a key sequence. The discovery library was designed with the help of QikProp 2.1, and physicochemical data are presented for all pyrroles. Library members were synthesized and purified in parallel and analyzed by LC/MS. Selected compounds were fully characterized.
Evaporative light-scattering detection (ELSD) is widely applied in the HPLC analysis of organic compounds lacking a UV chromophore. However, this detection method is generally unsuitable for determination of enantiomeric ratios (er). The er calculated from a UV trace and an ELS trace of the same compound differs significantly. Because of the nonlinear concentration response of the ELS detector, a compound with an er of 95:5 appears to be enantiomerically pure by ELS detection. It is possible to obtain a calibration curve and to calculate a correction factor, but this procedure is time consuming and therefore not very practical for routine analyses. In contrast, a charged aerosol detector allows a very accurate determination of the enantiomeric ratios. Like the ELS detection, the CA detection is independent of the chromophore properties of the substrate. Therefore, we recommend the use of CA instead of ELS detection for determination of the enantiomeric ratios of non-UV active compounds.
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