Diastereoselective auxiliary- and catalyst-controlled intramolecular aza-Michael reaction for the elaboration of enantioenriched 3-substituted isoindolinones. Application to the synthesis of a new pazinaclone analogue

A new asymmetric organocatalyzed intramolecular aza-Michael reaction by means of both a chiral auxiliary and a catalyst for stereocontrol is reported for the synthesis of optically active isoindolinones. A selected cinchoninium salt was used as phase-transfer catalyst in combination with a chiral nucleophile, a Michael acceptor and a base to provide 3-substituted isoindolinones in good yields and diastereomeric excesses. This methodology was applied to the asymmetric synthesis of a new pazinaclone analogue which is of interest in the field of benzodiazepine-receptor agonists.

Two strategies can be applied for the asymmetric synthesis of 3-substituted isoindolinones. First, diastereoselective reactions implying the use of a chiral auxiliary resulted effectively in various optically pure compounds [10,[18][19][20]. Second, enantioselective syntheses of these bicylic lactams were performed by using chiral transition metal-or organocatalysts which control the configuration of the trisubstituted carbon stereocenter alpha to the nitrogen [10,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Though various metal or organic catalysts were used to promote the aza-Michael reaction in different syntheses for the creation of nitrogen-carbon bonds, phase-transfer catalysts were less studied (see reviews [35][36][37][38]) in intermolecular [39][40][41][42][43] and intramolecular [44][45][46] sequences. Among the latter, a short regio-and stereoselective organocatalyzed intramolecular aza-Michael reaction was reported by us for the asymmetric synthesis of several isoindolinones [20,34]. Indeed, we noticed along our studies some intramolecular aza-Michael reactions were effectively catalysed by cinchoninium phase-transfer catalysts (PCT) affording the targeted 3-substituted isoindolinones with promising enantioselectivities (up to 91%) [20]. However, high enantioselectivities were reached only for specific substitution patterns on the amide nitrogen atom and to a lesser extent on the Michael acceptor. In order to overcome these limitations, we decided to incorporate a chiral auxiliary in our substrates combined with a proper chiral phasetransfer organocatalyst to operate an efficient stereocontrol. To the best of our knowledge such approach involving a double auxiliary and catalyst stereocontrol was never applied before to asymmetric synthesis of enantioenriched isoindolinones.

Synthesis of parent chiral benzamides 6-8
The use of a stereoselective chiral auxiliary which could be incorporated and removed easily without racemization was crucial for the success of our strategy. These requirements prompted us to incorporate α-methylbenzylamine-type chiral auxiliaries, which have been extensively used by Davies et al. to gain access to a wide range of chiral N-heterocycles via intermolecular aza-Michael reactions [34,[47][48][49][50][51]. The starting unsaturated benzoic acids 14a-e and 15 were readily prepared via a two steps sequence involving first a palladium-catalyzed Heck cross coupling between 2-bromobenzoic tert-butyl esters 9 and 10 with acrylamides 11a-e (69-72% isolated yields, Scheme 2, Figure 2). The subsequent removal of the t-butyl group in esters 12a-e and 13 ( Figure 2) was then achieved by treatment with trifluoroacetic acid to provide in-situ the corresponding benzoic acids 14a-e and 15. The direct coupling of these functionalized carboxylic acids with chiral benzylic primary amines, (R) or

Diastereoselective intramolecular aza-Michael reaction
First, the study of the diastereoselective intramolecular aza-Michael reaction of benzamide substrate (S)-6a allowed us to optimize the reaction conditions (Table 1) and latter to screen various privileged phase-transfer catalysts ( Figure 4, Table 2). As some aza-Michael reactions were shown to be performed without the use of any catalyst or additional reagent [52][53][54][55][56][57][58][59][60], we performed control experiments ( Table 1). The reaction of reagent (S)-6a led to product (S)-3a solely by using a base like Cs 2 CO 3 in toluene with a good yield (74%) and a modest diastereomeric excess (37% de, Table 1, entry 1). Increasing the reaction time from 16 h to 36 h led to higher diastereomeric excess but no further improvement was noticed with longer reaction times (Table 1, entries 2 and 3). Such chiral amplification versus time was already found to operate through a retroaza-Michael reaction [61,62]. Indeed, through an equilibration of aza-Michael and retro-aza-Michael reactions, the minor diastereoisomer of 3a may lead back to a racemic starting material and subsequently favour the major diastereoisomer (Table 1, entries 1-3). The use of a catalytic amount of base led to product 3a in a good yield (Table 1, entry 4) but with a loss of diastereoselectivity. Because the optically pure auxiliary and the conjugated ketone were not interacting well, a significant diastereoselectivity could not be obtained and we looked for improvements through the use of an appropriate chiral organocatalyst [63][64][65]. Indeed, within the same reaction conditions, the use of cinchoninium catalyst 18a afforded isoindolinone  In order to identify the most active catalyst for the aza-Michael reaction of (S)-and (R)-6a, an array of phase-transfer catalysts was screened ( Figure 4, Table 2). By comparing catalysts 18a and 18b, a bromide anion was shown to be preferred to a chlo-  ride one ( Table 2, entries 1 and 2). Catalyst 18c para-substituted with a tert-butyl increased significantly the diastereoselectivity of the reaction with 62% de ( Table 2, entry 3).
No de improvements resulted from the use of catalysts 18d,e which were modified by methylation or allylation of the cinchoninium alcohol fragment ( Table 2, entries 4 and 5). While using cinchoninium catalyst 18a and the same reaction conditions, we noticed amide reagent (R)-6a led to a higher diastereomeric excess (de) of 66% for product (R)-3a as compared to reagent (S)-6a for product (S)-3a, one configuration being preferred from the other ( Table 2, entry 6). A quite similar effect was previously observed in other Michael-additions involving chiral auxiliaries on the nucleophile and on the Michael acceptor [62]. As for (S)-6a, catalyst 18c bearing a bulky tertbutyl group at the benzyl para-position gave the best results in term of stereoselectivity (80% de, Table 2, entry 7). However, the use of bulkier benzyl, naphthyl and anthracenyl fragments, e.g., catalysts 18i-l, did not enhance the reaction diastereoselectivity ( With the optimized reaction conditions in hand, catalyst 18c was employed in the asymmetric intramolecular aza-Michael reaction of benzamides (R)-6a-d bearing an array of acrylamide groups (Scheme 3). Substrate 6a bearing a (R)-α-methylbenzyl chiral auxiliary led to isoindolinone 3a in 80% de and a pure diastereoisomer was recovered after chromatography on silica gel (EtOAc/hexanes 3:7) and crystallization from hexanes/toluene. Reactions of substrates 6b-d highlighted the diastereoselection of the reaction was highly dependent of the starting benzamide substitution, 44 to 60% de being obtained for 3b-d. Finally, whereas diastereoisomers issued from 6b could be separated by flash chromatography, this was not possible for products 3c and d. Cyclisation of chiral benzamides (R)-7a-e and (R)-8 led to isoindolinones (2R)-4a-e, Scheme 4: Removal of the chiral auxiliary. Synthesis of isoindolinones 1a-c, 1e, 2; isolated yield, ee by HPLC.
(2R)-5 in good yields and average to good diastereoselectivities (Scheme 3). In some cases, purification by flash chromatography afforded products 4b, 4c and 5 in higher diastereomeric purity.
In order to access to the targeted NH-free isoindolinones, the cleavage of the (R)-α-methylbenzyl chiral auxiliary was performed in acidic conditions but the reactions proved to be ineffective. However, a change in our models for the more electron rich (R)-α-methyl-para-methoxybenzyl group resulted in a straightforward and selective cleavage in mild acidic conditions without racemization (Scheme 4). Indeed, further cleavage of the α-methyl-para-methoxyphenyl chiral auxiliary in protected isoindolinones 4a-c, 4e and 5 resulted in the corresponding NH-free lactams 1a-c, 1e and 2 without any racemization (Scheme 4).
A subsequent X-ray analysis of a single crystal allowed us to assert the (2R,3S) configuration of 3a ( Figure 5). This result allowed for the determination of the absolute configurations of all isolated isoindolinones.

Asymmetric synthesis of a new pazinaclone analogue
With this handful methodology in hands, we then turned our attention to the asymmetric synthesis of a new pazinaclone analogue, which could be of particular interest in the field of benzodiazepine-receptor agonists [8][9][10][11][12][13][14][15][16][17]. Indeed, pazinaclone produces its sedative and anxiolytic effects by acting as a partial agonist at GABA A (γ-aminobutyric acid type A) benzodiazepine receptors [17]. In order to circumvent any hydrolysis of the ketal group during the preparation of the starting benzamide (see Supporting Information File 1), the synthesis of intermediate 24 was performed according another pathway depicted in Scheme 5. Aldehyde 23 was first readily prepared via a Heck cross coupling reaction between 2-bromobenzaldehyde (22) and acrylamide 11f. Next, a Pinnick oxidation of the aldehyde 23 followed with a coupling reaction with chiral benzylamine 17 delivered the targeted benzamide 24 in good yield (65%).

Conclusion
Herein, a new synthetic route towards optically active 3-substituted isoindolinones was developed. These organic compounds are useful for the development of agonists of GABA A (γ-aminobutyric acid type A) benzodiazepine-receptors. Various functionalized isoindolinones were prepared in good yields and diastereomeric excesses by intramolecular aza-Michael reactions using a double stereo-induction approach. The combined use of selected cinchoninium salts as phase-transfer catalysts and of nucleophiles bearing a chiral auxiliary enabled an effective match effect between the diastereomeric ion pair formed by the nucleophile, the Michael acceptor and the cinchoninium salt. Further investigations on this synthetic methodology will be reported in due course.

Supporting Information
Supporting Information File 1 File Name S1.pdf. Experimental procedures, characterization data, copies of the 1 H, 13 C NMR spectra, HPLC chromatograms, ORTEP drawing of 3a and the summary of 3a crystallographic information.

Supporting Information File 2
File Name S1.cif. Crystallographic information file of compound 3a. [