Alternative and Complementary Approaches to the Asymmetric Synthesis of 3-Aryl or Alkyl Substituted NH Free Isoindolinones

Alternative and complementary synthetic approaches to the asymmetric synthesis of poly and diversely substituted isoindolinones alkylated or arylated at C-3 have been developed. They mainly differ from the creation of the stereogenic center embedded in the benzolactam nucleus which can be inserted in the models at early or later stage as well in the synthetic process. Introduction The 3-substituted isoindolinone ring system has recently emerged as a valuable pharmacophore exhibiting a wide range of therapeutic activities [1]. In particular, enantiopure compounds substituted at C-3 (Figure 1), such as thiazoloisoindolinone 1 (non-nucleosidic HIV-reverse transcriptase inhibitor [2]), pazinaclone (2) (anxiolytic [3]), 3piperazinylethyl isoindolinone derivative 3 (dopamine D4 receptor antagonist [4]) as well as the architecturally more sophisticated staurosporine analogue 4 (protein kinase inhibitor [5]), have been extensively studied. Consequently the chemistry of 3-aryl and alkylisoindolinone has attracted much attention but despite the great progress made in asymmetric synthesis within recent decades few flexible methods are available for the asymmetric synthesis of simple 3-aryl and alkylisoindolinones in high enantiomeric excess.

Consequently the chemistry of 3-aryl and alkylisoindolinone has attracted much attention but despite the great progress made in asymmetric synthesis within recent decades few flexible methods are available for the asymmetric synthesis of simple 3-aryl and alkylisoindolinones in high enantiomeric excess.We disclose here alternative and complementary synthetic approaches to these synthetically challenging compounds, which differ mainly by the incorporation of the stereogenic center at the early or at the later stage of the synthetic process.The scope and limitations of theses methods are also presented.

Incorporation of the Stereogenic Center at the Early Stage of the Synthesis
The key step of this synthetic route is based upon the highly diastereoselective addition of aliphatic organometallic reagents 5 on prochiral aldimines 6 derived from (S)-valinol (Scheme 1) [6].Removal of the chiral auxiliary followed by installation of a pivaloyl group liable to favor and facilitate a planned bis-metallation process delivered the pivaloyl amides 7.As anticipated, capture of the dilithiated species 8 with dimethyl carbonate afforded the annulated compounds 9 and removal of the pivaloyl functionality spared the stereochemistry at C-3 and delivered high yield of the virtually enantiopure NH free isoindolinones 10 (Scheme 1, Table 1).This technique allowed access to the poly and diversely substituted models 10a,c,e but in the case of 7b and 7d only opened models 11b and 11d were obtained.Owing to the rather limited scope of the first approach we set out to achieve an alternative strategy which is based upon the construction of the C-3 substituted isoindolinone template through an aromatic carbanionic cyclization sequence.
For this purpose the bromobenzyl carbamates 12f-h were readily assembled from the benzylamime derivatives 13f-h prepared as described in Scheme 1 (Scheme 2, Table 2) and subsequently exposed to n-BuLi to ensure the mandatory bromine-lithium exchange.This technique led to the complete consumption of the starting materials and to the isolation solely of the targeted isoindolinones 10f-h.The NH free model 10i was obtained as described in Scheme 3 ( This technique gave access to a range of C-3 aryl and alkyl substituted N-substituted and NH free models 10f-i but was invariably confined to models incorporating substitution patterns on the aromatic nucleus prone to force and facilitate the regioselective bromination of the opened carbamates and the exclusive formation of 12f-h and 14.
To obviate this problem an alternative approach was developed.

Creation of the Stereogenic Center at the Last Step of the Synthesis
This tactically new synthetic route is based upon the high facial selectivity observed in the nucleophilic addition onto the prochiral C=N group of N-acylhydrazonium ions bearing a SMP chiral auxiliary [7].
For the generation of such species two different synthetic routes were developed.They differ from the assembling of hemiaminals of general structure 15.

Synthetic Route via the Intermediacy of Models Structurally Related to 15 Derived from the Corresponding Phthalhydrazides
This new synthetic route is depicted in Scheme 4. The high level of enantioselectivity observed (Table 3) can be attributable to the pyramidal stability of the adjacent trivalent nitrogen atom in 16 which thus constitutes a stereogenic center.The antiperiplanar approach of the hydride to the azomethine group therefore occurs preferentially from the sterically less hindered face of the energetically favored conformer 15, providing the isoindolinone 17a-f with excellent ees (Table 3) after removal of the chiral auxiliary from the preliminary formed compounds 18a-f.This technique hallowed the installation of pendant aryl and alkyl units but since the nucleophilic attack of organometallic species onto the phthalhydrazides 19 is regioselectively compromised this synthetic approach was confined to models unsubstituted on the benzene nucleus.This problem was circumvented by the development of an alternative synthetic route to 15.

Synthetic Approach to Hemiaminals 15 via a Parham Type
Cyclization Process [8] This new route hinges upon the intramolecular anionic cyclization of opened acylated hydrazones 20 (Scheme 5).The hemiaminals 21 were treated as described in the earlier procedure to afford high yields and high level of enantioselectivity of C-3 aryl and alkyl substituted isoindolinones that can be also poly, diversely and unsymmetrically substituted on the aromatic nucleus (Figure 2).

Table 2
, entry 4) upon preliminary elaboration of a model 14 tailed with a dicarbamate function.Such function was expected to be sensitive to a nucleophilic attack by lithium methylate released upon the annulation process.