Obtaining enantiomerically pure organic molecules is currently one of the main objectives of organic synthesis. One of the reasons is the potential application of these molecules as drugs whose desired biological activity is associated with a specific isomer [1]. Among the methodologies available for asymmetric synthesis, organocatalysis can be singled out for being considered non-toxic, low-cost, stable in an open atmosphere, and environmentally friendly [2,3]. There are even some examples in the literature, where bifunctional organocatalysts were successfully applied for key steps of asymmetric synthesis of drugs such as pregabalin [4], (R)-Baclofen, and (R)-phenibut [5].

Asymmetric bifunctional organocatalysts, like thioureas [6] and squaramides [7], have a wide application in different organic reactions [8] and are distinguished by the capability of activating both the nucleophile and electrophile synchronously [6]. With increasingly elaborate structures, each group has a specific and essential role in the catalyst performance. These organocatalysts are constituted by a hydrogen bond donor group such as thiourea [9]. which the use of the 3,5-bis(trifluoromethyl)phenyl group as one of its substituents increases the acidity of nitrogen-hydrogen bonds, favoring the enantioselectivity [10]. The other substituent group is generally a tertiary amine that acts as a base [10,11] or a primary amine that works via covalent catalysis (enamine [12] or iminium catalysis [13]). Fig. 1 presents some activation modes.

An early combination of these two functional groups was done by Takemoto in 2003 in the highly enantioselective Michael addition reaction of malonates to nitroolefins, where the amine group of the amino-thiourea organocatalyst was a tertiary amine (Fig. 1) [10]. Takemoto's catalyst was also successfully applied in enantioselective and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins, where a reaction mechanism was proposed in which nitroolefin interacts with thiourea group and the 1,3-dicarbonyl compound with the protonated amine [11]. A theoretical study conducted by Pápai e coworkers [14] pointed out that the interaction between protonated amine with nitroolefin and thiourea with malonate was an energetically more favorable pathway. Recent reliable theoretical calculations have pointed out that these two pathways contribute to the enantioselective formation of the product, although the mechanism proposed by Papai is the most important [15].

Despite their success in Michael addition reactions of 1,3-dicarbonyl compounds to nitroolefins, Takemoto's catalyst when used in the addition reaction of nitromethane to benzylideneacetophenone in toluene solution, in an amount of 0.5 mol%, leads to obtaining only trace amounts of the product at room temperature and atmospheric pressure [16]. Already when used as a catalyst in an amount of 15 mol% in the addition reaction of nitromethane to 4-phenylbut-3-en-2-one in a reaction time of 5 days, no reaction is observed [17]. Pedrosa and co-workers have also investigated tertiary amine-thiourea for the catalysis of nitromethane addition to enone, resulting in a very long reaction time [18]. On the other hand, when primary amines are combined with thioureas in bifunctional organocatalysts, the reaction between enones and nitromethane occurs with good to high yields and high enantiomeric excess [5,17]. Aliphatic primary and tertiary amines are bases with close pKa values of the protonated species [19,20]. The inactivity of Takemoto's catalyst in these reactions can be attributed to its tertiary amino group, which is not a base able to efficiently deprotonate nitromethane. In the case of primary amino-thioureas, the reaction proceeds via the formation of an imine intermediate between catalyst and enone (Fig. 1), and this intermediate acts as a base able to deprotonate nitromethane [13]. Therefore, one key point to be explored for improving the reactivity of this reaction kind is increasing the basicity of the tertiary amine group of the catalyst.

In the past decade, Dixon's group has reported a new class of bifunctional organocatalysts, constituted by a strongly basic group (iminophosphorane) and a hydrogen bond donor group (Fig. 1) [21,22]. The authors determined the basicity in acetonitrile of two model structures: triphenylphosphine-derived iminophosphorane (IPP1) and tris(4-methoxyphenyl)phosphine-derived iminophosphorane (IPP2) (Fig. 2) [21]. The basicity values are higher than aniline, pyridine, and triethylamine, and specifically in the case of tris(4-methoxyphenyl)phosphine-derived iminophosphorane, its basicity is higher than DBU (Fig. 2) [19]. Indeed, different structures of bifunctional iminophosphorane superbase organocatalysts have been successfully applied with high reactivity in nitro-Mannich reactions [21], sulfa-Michael additions [[23], [24], [25]], Michael additions [26], and phosphate-Mannich reactions [27], which makes the iminophosphorane superbases prominent catalysts with the potential to be explored in different reactions.

Although the iminophosphorane-thiourea organocatalyst is effective for many reactions, only very recently was reported a new iminophosphorane derivative able to catalyze more efficiently the Michael addition of nitromethane to α,β-unsaturated esters, requiring 15 mol% of the catalyst and 24 h of reaction time [28]. Therefore, more advance is needed to have a structure with lower catalyst loading. Thus, the present work aims to design a new iminophosphorane-thiourea catalyst effective for Michael addition of nitromethane to α,β-unsaturated ketones. The idea was to provide more stabilization of the transition state via an additional hydrogen bonding, as presented in Fig. 3. A similar idea has been explored in ionic reactions [29]. Thus, three new structures based on the TD catalyst (Fig. 3) were designed and tested for their ability to decrease the overall ΔG‡ barrier and to maintain the high enantioselectivity, using reliable theoretical methods. Following the computation of the complete free energy profile of the most promising catalyst, a detailed microkinetic analysis was also done to predict the reaction time and enantiomeric excesses. The rational design of catalysts by theoretical methods has increased in importance in the past years [[30], [31], [32], [33], [34]].