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. 2022 Sep 1;27(17):5647.
doi: 10.3390/molecules27175647.

Scalable (Enantioselective) Syntheses of Novel 3-Methylated Analogs of Pazinaclone, (S)-PD172938 and Related Biologically Relevant Isoindolinones

Antonia Di Mola  1 , Giorgia Nicastro  1 , Lorenzo Serusi  1 , Rosanna Filosa  2 , Mario Waser  3 , Antonio Massa  1
Affiliations

Scalable (Enantioselective) Syntheses of Novel 3-Methylated Analogs of Pazinaclone, (S)-PD172938 and Related Biologically Relevant Isoindolinones

Antonia Di Mola et al. Molecules. .

Abstract

Herein, we report the application of an efficient and practical K2CO3 promoted cascade reaction of 2-acetylbenzonitrile in the synthesis of novel 3-methylated analogs of Pazinaclone and PD172938, belonging to isoindolinones heterocyclic class bearing a tetrasubstituted stereocenter. Organocatalytic asymmetric synthesis of the key intermediate and its transformation into highly enantioenriched 3-methylated analog of (S)-PD172938 was also developed. These achievements can be of particular interest also for medicinal chemistry, since the methyl group is a very useful structural modification in the rational design of new and more effective bioactive compounds.

Keywords: asymmetric synthesis; heterocycles; isoindolinones.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Example of CH methylation where a magic methyl effect was observed.
Figure 2
Figure 2
Some bioactive isoindolinones.
Scheme 1
Scheme 1
This work: new isoindolinones bearing a methyl group installed in 3-position.
Scheme 2
Scheme 2
Synthesis of key intermediate 10.
Scheme 3
Scheme 3
Synthesis of racemic amidic compounds 13 and 16.
Scheme 4
Scheme 4
Synthesis of 3-methyl-PD172938 in racemic form.
Scheme 5
Scheme 5
Proposed mechanism for the base-catalyzed cascade reaction of 2-acetylbenzonitrile and dimethylmalonate.
Scheme 6
Scheme 6
Enantioselective synthesis of (S)-20, the 3-methylated analog of (S)-PD172938.
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