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

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.

Multifaceted Behavior of 2‐Cyanobenzaldehyde and 2‐Acylbenzonitriles in the Synthesis of Isoindolinones, Phthalides and Related Heterocycles

“…This allowed the asymmetric synthesis of 3‐methylated analogue of ( S )‐PD172938 121 in very high enantiomeric purity (Scheme 47). [45] Also, in this case the key step of the route was the decarboxylation, performed simply heating in acetonitrile the dicarboxylic acid 116 , without decrease of the enantiopurity with respect to Krapcho decarboxylation that led to racemization. Then, LiBH 4 reduction of 115 , led to the alcohol 118 which was converted into 121 by two complementary pathways: displacement on 119 with piperazine or reductive amination of the aldehyde 120 without decreasing of the enantiomeric purity.…”

“…The synthesis of 124 and of 3-methylated pazinaclone 127 were carried out as racemate, respectively by CuI or palladiumxantphos catalyzed arylation of the NH lactam group of 123 and 126 (Scheme 48). [45] Scheme 45. Synthesis of the Isomer of entonalactam B from 2-cyanobenzophenones.…”

Asymmetric Organocatalytic Mannich Reaction in the Synthesis of Hybrid Isoindolinone-Pyrazole and Isoindolinone-Aminal from Functionalized α-Amidosulfone

“…It is worth noting that enantiopure isoindolinones have been reported to show enhanced biological properties, but often inefficient resolution of racemic mixtures or the use of chiral auxiliaries have been utilized to achieve this goal [ 13 ]. In this context, our group dedicated many efforts to the asymmetric synthesis of 3-substituted [ 14 , 15 , 16 ] and 3,3-disubstituted isoindolinones, [ 17 , 18 ] developing new cascade-type reactions often employing organocatalytic systems and producing several new enantioenriched products. Some of the obtained isoindolinones were also used in the total synthesis of biologically relevant compounds [ 5 , 15 , 18 ].…”

“…In this context, our group dedicated many efforts to the asymmetric synthesis of 3-substituted [ 14 , 15 , 16 ] and 3,3-disubstituted isoindolinones, [ 17 , 18 ] developing new cascade-type reactions often employing organocatalytic systems and producing several new enantioenriched products. Some of the obtained isoindolinones were also used in the total synthesis of biologically relevant compounds [ 5 , 15 , 18 ]. The reasons for the success of the developed methods also rely on the rational design and synthesis of suitable starting materials.…”

C(3)-Aryl isoindolinones: a PTSA-mediated access and improved synthesis of (±)-nuevamine

“…11 Pazinaclone 5 is a nonbenzodiazepine CNS active experimental drug belonging to the family of cyclopyrrolones. 12 It is an agonist to the human GABA-A receptor and displays excellent anxiolytic and sedative activities. 13 In addition to the two drugs listed here, many C(3)-substituted isoindolinones exhibit useful medicinal properties that include antiulcer, 14 antitussive, 15 antipsychotic, 16 antirheumatic, 17 and anorectic activities.…”