Asymmetric Michael Addition of Acetone to  -Nitrostyrenes Catalyzed by Novel Organocatalysts Derived from D-Isomannide or L-Isoidide

Novel bifunctional organocatalysts were prepared from D-isomannide or L-isoidide in three steps. These catalysts were then evaluated in the asymmetric Michael addition of acetone to trans- -nitrostyrenes. Although moderate enantioselectivities were observed, this study has highlighted that a simple chiral primary diamine can catalyze this reaction. Furthermore, the reaction was also performed with an isomannide-derived diimine which was transformed in situ into the active catalyst under acidic conditions leading to the best enantioselectivity


Introduction
Asymmetric organocatalysis has been revived as an important field of asymmetric synthesis since the independent work of List, 1 MacMillan, 2 and Barbas. 35][6] In particular, bifunctional amine-thiourea-based catalysts have proved to be efficient in various asymmetric transformations owing to the ability of the thiourea moiety to highly activate carbonyl or nitro groups through double hydrogenbonding interactions. 7,8Therefore, this kind of organocatalyst has been widely studied in asymmetric nitro-Michael addition reactions. 9,10The first asymmetric Michael addition of ketones to trans--nitrostyrenes was performed independently by List 11 and Barbas 3 involving proline as catalyst.6][27][28][29][30][31][32] However, the chiral scaffold of these reported organocatalysts is limited and is mostly derived from 1,2-diaminocyclohexane and 1,2-phenylethylenediamine.
As part of an ongoing program, we were interested in the design of new bifunctional organocatalysts from original chiral building blocks, i.e. from D-isomannide and L-isoidide; two side-products of the starch industry.Although numerous examples of polymers containing this backbone have been reported, 33 only a few examples in the field of asymmetric catalysis have been investigated.In asymmetric organometallic catalysis, ligands derived from dianhydrohexitols have already been used to perform Diels-Alder reactions, 34 nucleophilic addition to aldehydes, 35 asymmetric allylic substitution, 36,37 hydrogen transfer reduction of prochiral ketones [38][39][40] and asymmetric hydrogenation of olefins. 41,42Recently, we described the first example of organocatalysts derived from dianhydrohexitols for the asymmetric Friedel-Craft alkylation of indoles. 43Herein, we report our preliminary results on asymmetric Michael addition of acetone to trans--nitrostyrenes catalyzed by chiral thioureas and imines organocatalysts derived from D-isomannide-or L-isoidide.

Results and Discussion
Herein, we report our preliminary results on asymmetric Michael addition of acetone to trans-nitrostyrenes catalyzed by D-isomannide-or L-isoidide-derived organocatalysts 1-8 (Figure 1).Catalysts 1-3 were obtained after reaction of one equivalent of the corresponding isothiocyanate and diamine 4, which was obtained in three steps from D-isomannide (Scheme 1).Around 10-15% of the corresponding dithioureas were also isolated.Monothiourea 6 was prepared from diamine 5 which was isolated in three steps from L-isoidide. 43Finally, using the same conditions as preparing thioureas 1-3, catalyst 6 was successfully obtained in 40% yield (Scheme 1).Diimines 7 and 8 were also prepared as precursor of amine-imine organocatalysts according to Cheng et al. 44 They were prepared from the corresponding diamine 4 under the usual conditions (Scheme 2).

Scheme 2. Synthesis of diimine derivatives.
With these organocatalysts in hand, the Michael addition of acetone to trans--nitrostyrene 9a, using 20 mol% of catalyst 1, was evaluated without any solvent (Table 1).In these conditions, the desired product was obtained with moderate yield and poor enantioselectivity (Table 1, entry 1).To improve the reaction rate and the enantioselectivity, we investigated the effect of acidic additives (1 equivalent related to the catalyst) on the reaction (Table 1, entries 1-9).Compared to the reaction performed without additive, in the presence of benzoic acid, the chemical yield and enantioselectivity were improved (Table 1, entries 1 and 2).With mandelic acids, both yields and ees decreased (Table 1, entries 3 and 4), no matched-mismatched double diastereoselectivity effects were observed.Moreover, the chirality of the acid had no influence on the enantioselectivity; the same major isomer being formed (entries 3 and 4).In the case of 2,2,2trichloroacetic acid (TCA), although better enantioselectivity was obtained, the product was isolated along with a side-product even after purification (Table 1, entry 5).The use of a strong acid such as trifluoroacetic acid led to deactivation of the catalyst (Table 1, entry 6).p-Toluenesulfonic acid was also not suitable for this asymmetric reaction (Table 1, entry 7).Finally, a weaker acid, such as acetic acid, gave the best results in terms of yield and ee (Table 1, entry 9).However, the use of larger amounts or less than 20 mol% of acetic acid had a dramatic effect on both yields and ees (Table 1, entries 10-12).Using the optimized conditions from Table 1 (entry 9), we then explored the different organocatalysts.Among all the primary amine-thiourea-based catalysts 1-3 and 6, catalyst 1 had the best performance, affording yields up to 87%.However, the ees were all in the same range (around 25%, Table 2, entries 1-3), except for catalyst 6 which led to a racemic product (Table 2, entry 6).
The formation of the racemic compound can be explained by the proximity of the two nitrogen group in the 'endo'-position which perhaps give rise to a strong intramolecular hydrogen bond either between the thiourea moiety and the oxygen of the bicycle or between the primary amine and the thiourea groups. 46he same stereochemical outcome was observed with the chiral primary diamine 5 (Table 2, entry 5).Surprisingly, the simple diamine catalyst 4 gave promising results in terms of both yield and ee (Table 2, entry 4).Although some examples using secondary or secondary-tertiary diamines as catalysts for this reaction have been reported, 47,48 to the best of our knowledge, a successful example with a chiral primary diamine has not yet been described.Finally, the asymmetric reaction was also performed in solvents such as toluene, CHCl3, DCM and MTBE, but the reaction rate dramatically decreased in all cases.With the diimine catalysts 7 and 8, some catalytic effect was observed.We think that, in the presence of acetic acid, the diimines are likely to be transformed in situ into primary amine-imines which might be potential catalysts, as demonstrated by Cheng et al. 44 With the quinolinederived diimine catalyst 8, we assumed that the pre-catalyst 8 led to the catalyst 11, able to both activate the nucleophile and electrophile.The activation of the nitro group is possible by a hydrogen-bonding interaction after in situ formation of the quinolinium cation (intermediate A, Scheme 3).In that case, the ee reached 59% (Table 2, entry 9).The difference in the ee observed between that obtained from pre-catalyst diimines 7 and 8 is probably attributed to the presence of the second aromatic ring in compound 8 which likely induced additional steric hindrance (Table 2, entries 7 and 8).Our attempts to perform the synthesis of the pure amino-imine 11 to test its reactivity on the catalytic reaction were unsuccessful as the organocatalyst could not be obtained pure even after chromatography on deactivated silica gel.
The asymmetric Michael addition was then performed with other substrates 9b-e to expand upon the scope of this reaction (Table 3).The reaction was carried out with catalyst 4 which afforded the best results in terms of both yields and enantioselectivities under the optimal conditions.

Scheme 3. Possible transition state A.
The reaction between different nitrostyrenes which had either electron-withdrawing groups or electron-donating groups were studied.The corresponding adducts were isolated in moderate to good yields and with ees in the similar range to those obtained previously (ca.40% ee) (Table 3, entries 1-4).However, when the naphthyl nitroolefin 9e was used, the ee of product 10e was only 24% (Table 3, entry 5).Furthermore, with our catalytic system, the Michael addition of aromatic ketones, such as acetophenone, was unsuccessful contrary to the Xu's catalysts. 31

Conclusions
In conclusion, we have developed a new series of organocatalysts derived from D-isomannide and L-isoidide, which have shown their ability to catalyze for the first time the asymmetric Michael addition of acetone to trans--nitroolefins.Although moderate enantioselectivities and yields were observed, this study has shown that the reaction can be catalyzed by a simple chiral primary diamine.On the other hand, the use of a chiral diimine in acidic conditions led to the best enantioselectivity, however, the reaction rate was low.Owing to their ease of preparation from D-isomannide even on large scale, these catalysts are ideal candidates for wider studies in this area.To determine the stereochemical outcome using the diimine catalyst and to improve the reaction rate, further investigations are in progress in our laboratory and the results will be reported in due course.

General procedure for the synthesis of catalysts 7-8
To a solution of diamine 4 (200 mg, 1.39 mmol) in dry DCM (8 mL) was added anhydrous MgSO4 (332.4 mg) and the aldehyde (2.77 mmol).The resulting mixture was stirred for 16 h at rt.The MgSO4 was filtered off.After evaporation of the solvent, the product was recrystallized in Et2O.Diimine 7. Prepared according to the general procedure to provide the product 7 as a solid in 85% yield, mp: 122. 3