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. 2006 May-Jun;8(3):368-80.
doi: 10.1021/cc050160c.

Solution-phase synthesis of a tricyclic pyrrole-2-carboxamide discovery library applying a stetter-Paal-Knorr reaction sequence

Stefan Werner  1 , Pravin S Iyer, Matthew D Fodor, Claire M Coleman, Leslie A Twining, Branko Mitasev, Kay M Brummond
Affiliations

Solution-phase synthesis of a tricyclic pyrrole-2-carboxamide discovery library applying a stetter-Paal-Knorr reaction sequence

Stefan Werner et al. J Comb Chem. 2006 May-Jun.

Abstract

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.

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Figures

Figure 1
Figure 1
Examples of bioactive pyrrole-carboxamides.
Figure 2
Figure 2
Forward synthetic analysis of the title compounds C.
Figure 3
Figure 3
Diversity elements 8{1-3} for R1, 9{1-2} for R2 and 10{1-41} for R3; a 33% in ethanol. b 50% in iso-propanol.
Figure 4
Figure 4
Purity of the 178 library members before purification by HPLC (light grey) and after purification by HPLC (dark grey); if the purity was lower than 50% or no molecular mass was detected by LC-MS analysis the reaction was classified as “failed”.
Figure 5
Figure 5
Distribution for the Rule of Five parameters molecular weight (A), log of the octanol/water partition coefficient (logP) (B), number of hydrogen donor bonds (HBD) (C), sum of nitrogen and oxygen atoms (D) and for the number of rotatable bonds (E) and the hydrophilic component of the solvent accessible surface area (FISA) (F); calculated for the 178 pyrroles 17{1-3,1-2,1-41} using QikProp 2.1.
Scheme 1
Scheme 1
Synthesis route to the tricyclic pyrrole-carboxamides 17.
See this image and copyright information in PMC

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