Chiral Phase Transfer Catalysis in the Asymmetric Synthesis of a 3,3-Disubstituted Isoindolinone and Determination of Its Absolute Configuration by VCD Spectroscopy

Abstract

In this work we report our endeavors toward the development of an asymmetric synthesis of a 3,3-disubstituted isoindolinone, dimethyl 2-(1-methyl-3-oxoisoindolin-1-yl)malonate, via asymmetric cascade reaction of 2-acetylbenzonitrile with dimethylmalonate and the determination of its absolute configuration (AC) by vibrational circular dichroism (VCD). Bifunctional ammonium salts, derived from trans-1,2-cyclohexanediamine in combination with inorganic bases under phase transfer conditions, were the most effective catalytic systems, leading to the target in high yields and moderate enantioselectivity. An efficient process of heterochiral crystallization allowed the increase of the enantiopurity up to 96% ee and in an acceptable overall yield. An important aim of the present work is the comparison of different VCD methodologies for AC determination of the target compound.

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

“…For direct applications in medicinal chemistry programs, the ability to selectively construct a new stereocenter with enantiocontrol is of great importance. Since convenient methods for the asymmetric synthesis of the key intermediate 8 and related compounds bearing a tetrasubstituted stereocenter are not available, we considered the previously investigated asymmetric cascade reaction of readily available 2-acetylbenzonitrile and dimethylmalonate for the direct access to enantioenriched 7 ( Scheme 5 and Scheme 6 ) [ 33 ]. The development of an effective asymmetric version of this cascade reaction proved to be particularly challenging.…”

“…The development of an effective asymmetric version of this cascade reaction proved to be particularly challenging. A large number of chiral neutral bifunctional organocatalysts and chiral ammonium salts were tested under a range of conditions [ 33 ]. The best results were obtained in the presence of the chiral bifunctional ammonium salt 21 -derived form ( S,S )-1,2-cyclohexanediamine and K 2 CO 3 as the inorganic base in CH 2 Cl 2 under phase transfer conditions ( Scheme 5 and Scheme 6 ), leading to moderate enantioselectivity [ 33 ].…”

“…However, the construction of the isoindolinone ring with a tetrasubstituted carbon stereocenter is a major challenge, especially when this has to be asymmetrically performed [ 14 , 23 , 24 ]. To our knowledge there are no examples in literature of 3-methylated analogs of the compounds described in Figure 2 and very few protocols on the synthesis of 3,3-disubstituted isoindolinones introducing a methyl group on the C-3 position have been reported [ 14 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. For instance, as described by Heibel in 2005, an asymmetric synthesis of 3,3-disubstituted isoindolinones involved the use of readily available (+) or (−)-trans-2-(α-cumyl) cyclohexanol (TCC) as the chiral auxiliary after the treatment with NaHMDS at temperatures ranging between −100 °C and −115 °C leading to good diastereoselectivity [ 25 ].…”

“…In this context, we report a convenient approach to 3,3-disubstituted isoindolinones via cascade reactions of readily available 2-acylbenzonitriles with several nucleophiles promoted by cheap and environmentally friendly K 2 CO 3 [ 30 , 31 , 32 ]. Asymmetric versions of these reactions have also been developed [ 33 ].…”

“…Based on our continuing research interest in the synthesis of isoindolinones [ 31 , 32 , 33 , 34 , 35 ], we report the application of our efficient and practical K 2 CO 3 promoted a cascade reaction to the first synthesis of 3-methylated analogs of Pazinaclone, PD172938 and related structures ( Scheme 1 ). An efficient asymmetric synthesis of 3-methylated analog of ( S )-PD172938 was also developed based on the combination of the asymmetric-phase transfer catalysis process and a recrystallization step.…”