MONITOREO AMBIENTAL

Although the mechanistic pathway for these catalysts has not been completely studied at this point, it is evident that the combination of amidine and amide motifs allows for a fully bifunctional organocatalyst for this aza-Henry addition en route to Nutlin-3 (35). Having both the amidine and amide functionalities in the same chiral pocket can lead to a number of proposed transition states. In model A, the hydrogen of the amide can act as hydrogen bond donor to activate the N-Boc-protected imine electrophile (Figure 10). Conversely, the nitrogen of the quinoline ring serves as a Brønsted base to deprotonate the nitroalkane to form the nucleophilic nitronate. The simultaneous activation of the electrophile and generation of the nucleophile can allow for the formation of the desired masked cis-stilbene diamine adduct in a diastereo- and enantioselective fashion.

In another possible model, model B, the quinoline can fully deprotonate the nitroalkane, generating a positively-charged amidinium and a negatively-charged nitronate. The protons of the amidinium species can readily coordinate with the carbonyl of the Boc group and the nitrogen of the imine causing activation of the electrophile. Simultaneously, an oxygen of the nitronate, bearing a negative charge, can coordinate with the proton of the amide (Figure 11). Here, the amide can be oriented in one of two ways relative to the cyclohexyl ring. If the amide is oriented in an s- trans fashion, the substituent α to the carbonyl of the amide may be sterically repulsed by the cyclohexyl ring. However, if the amide is arranged in an s-cis manner, then the amide substituent may sterically interact with the non-coordinating oxygen of the nitronate. The varying sizes of the amide substituents, as shown in the catalyst library, can have an effect on the degree of steric repulsion. The size of the substituent may dictate if the amide will orient itself cis or trans relative to the cyclohexane ring, which may ultimately affect selectivity. Furthermore, varying the electronics of the amide entity may inductively influence the amide’s hydrogen bond donor ability.

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This can affect the strength of coordination with the nitronate, which, in turn, may further influence the degrees of diastereo- and enantioselection of this addition.

Opposite to model B, it is also plausible that coordination between functionalities can be reversed. For a third model, model C, the quinoline once again deprotonates the nitroalkane generating an amidinium and a nitronate. Unlike the previous model however, model C proposes that the negatively-charged nitronate readily binds to both protons of the positively-charged amidinium, while the nitrogen of the imine binds to the hydrogen of the amide (Figure 12). Again, the amide functionality has the ability to orient itself in an s-cis or s-trans manner. Yet in this case, it is believed that the lowest-energy transition state will be achieved if the amide is arranged in an s-cis fashion as steric interactions should be minimized. An s-trans arrangement would be disfavored as there would be a considerable amount of steric repulsion between the amide substituent and the cyclohexyl ring as seen in model C. Once again, this model is susceptible to variations in the size and electronics of the amide motif as they can alter steric interaction and amide acidity. These variations can change the levels of selectivity of this reaction system as a consequence.

Lastly, model D proposes a binding pattern similar to model C, but with different charge coordination. Upon deprotonation of the nitroalkane by the quinoline, the resulting amidinium ion

Figure 11. Proposed Amidine-Amide Activation and Stereochemical Model B

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can be in equilibrium with the carbonyl of the Boc-imine and generate an acidic oxonium ion. Here, the proton of the oxonium can readily coordinate with the carbonyl of the amide while the nitrogen of the imine can bind to the hydrogen of the amide. Conversely, the negatively-charged nitronate can coordinate with the lone proton of the amidine (Figure 13). If the aryl Boc-imine were to bind to the amide moiety in this proposed fashion, then it is believed that the amide would have to be in an s-trans orientation for easier accessibility versus an s-cis conformation. Forcing the amide to be in an s-trans arrangement in this model may once again cause steric repulsion between the amide substituent and the cyclohexyl ring. If the degree of steric repulsion was the only change taking place with varying sizes of the amide, then the ability of the amide substituent to have an effect on selectivity may be significantly reduced as this interaction is occurring outside of the chiral pocket. Furthermore, model D also hypothesizes that the aromatic portion of the imine is within the chiral pocket. As a consequence, it is possible that the sterics of the imine can have a critical influence on the selectivity of this addition. This is a potential phenomenon that needs to be examined more closely. Finally, it is also plausible that the acidity of the amide proton can change the degree of activation of the electrophile and ultimately have an effect on reactivity. Data shows that when going from an amide to a thioamide/sulfonamide species, reactivity is significantly diminished. It is feasible through this model that having an amide proton of higher acidity can cause unwanted interactions in this chiral pocket and, consequently, result in less imine activation and reactivity.

Based on the proposed transition states, it is reaffirmed that both the amidine and the amide components allow for a completely bifunctional organocatalyst system for the aza-Henry addition en route to Nutlin-3. The binding of these asymmetric catalysts is unique in the sense that unlike the traditional bis(amidine) organocatalysts, introduction of a salt is unnecessary as both Brønsted sites are present in its free base form. If a salt is indeed introduced to these amidine-amide moieties,

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the lone Brønsted basic site of the quinoline will be protonated and reactivity will be lost as a result (Figure 14).