In-Depth Analysis of Catalyst Trends

Subjection of these catalysts to the Nutlin-3 aza-Henry addition yielded data points that could be considered for potential trends. These trends mainly center upon sterics, electronics, and amide acidity.

When examining the effects of sterics, a general trend that was observed was that an increase of amide size results in an enrichment of enantioselection. This trend was consistent among ring expansion of the amide functionality. As previous data indicates (Scheme 44), a change from a benzamide to a naphthamide does not result in an increase of enantioselection as ee is maintained at 91%. Yet when exchanging a naphthamide (78c or 78e) for an anthracenyl amide (78j), a substantial jump in selectivity is observed as this catalyst affords adduct 38 in 98% ee. This difference in enantioselectivity may revolve around the ability of the amide substituent to

Figure 14. Deactivation of the Catalyst via Introduction of a Salt

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rotate about the C-C sigma bond attached to the carbonyl of the amide. The rotation about this sigma bond, with asymmetric ring systems, can alter the size and shape of the chiral pocket, ultimately affecting enantioselection. When a 1- or 2-naphthyl ring is introduced as the amide substituent, two different chiral pockets can be acquired upon rotating 180° since they are non- symmetric substituents. It is plausible that the naphthamide moieties arrange themselves in such a way that they minimize their interaction in the chiral pocket as it is the lowest energy conformation (Figure 15). If the naphthamide substituents are arranged in this way, this may create a chiral environment similar to having a benzamide motif present. As a result, the degrees of enantioselection should be very similar. Yet when introducing a bulkier, symmetric anthracenyl functionality, this may change the chiral environment as the same conformation will be achieved upon rotating 180°. In other words, an anthracenyl amide does not have the ability to adapt a lower energy orientation. Part of the anthracenyl ring is forced inside creating a more shallow and narrow chiral pocket. This smaller pocket appears to be preferred for this aza-Henry system as the adduct was acquired in considerably higher ee (98% ee).

This same phenomenon was observed upon incorporation of substituents at the ortho, meta, and para positions of benzamide catalyst 78b. As previously mentioned, installation of methyl substituents at the ortho and para positions of the benzamide ring (catalyst 78g) resulted in higher selectivity as the desired adduct was afforded in 94% ee relative to standard benzamide 78b, which gave adduct 38 in 91% ee (Scheme 44). Installation of these methyl substituents at both meta positions did not seem to make much of a difference as the adduct was acquired in 95% ee. Altering

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the electronics of these methyl substituents to electron-withdrawing trifluoromethyl groups also had minimal enhancement in enantioselection as the adduct was obtained in 96% ee. What is consistent throughout these findings is that enantioselection is enhanced as steric bulk is increased via incorporation of neutral or electron-withdrawing substituents on the benzamide ring (Figure 16). The proposal made with the anthracenyl-amide catalyst (78j) also applies to the methylated benzamide catalysts. Each of the substituted benzamides are symmetric and larger compared to a standard benzamide. As the bulkier methylated benzamides rotate about the C-C sigma bond attached to the carbonyl of the amide, the same conformation will be achieved upon a 180° rotation. Like the anthracenyl amide, these methylated benzamides do not have the ability to choose a lower energy orientation. As a consequence, these methyl groups (i.e. more steric bulk) are once again forced inside creating a more shallow and narrow chiral pocket. This results in higher degrees of enantioselection relative to benzamide catalyst 78b, a very similar trend that was seen with ring expansion.

Electronic variations of the amide substituent also yielded an interesting trend. As shown in the steric trends, 3,5_(CF

3)2BenzAM (78a), furnishes adduct 38 in 96% ee relative to standard

benzamide counterpart 78b, which affords the adduct in 91% ee (Scheme 45). Although it is believed that this increase in enantioselectivity is largely due to increased steric bulk, some of it can be attributed to the electron-withdrawing character of the trifluoromethyl substituents as well. Not all electron-withdrawing motifs resulted in enhanced enantioselection, however. When introducing an electron-withdrawing nitro group at the ortho position, as shown in catalyst 78i, a drop in enantioselection was observed (84% ee). The nitro group is within proximity of the amide proton and depending on how this organocatalyst binds, it is feasible that one of the lone pairs of the nitro group is intramolecularly coordinated to the acidic proton of the amide (Figure 17). This unwanted interaction will disrupt the intended transition state in the sense that the proton of the

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amide will not bind as well to the imine or nitronate. This, in turn, may inhibit activation and reactivity as well as enantioselection. This hypothesis is also supported when two electron-

donating methoxy substituents are installed onto the benzamide ring. This particular catalyst (78h) gives the intended adduct in only 75% ee. Once again, lone pairs of electrons on these methoxy substituents may interact with the amide proton ultimately causing a diminished ee. When drawing conclusions based on these electronic alterations, it appears that electron-withdrawing groups can enrich enantioselection as long as there is no extra electronic activity (i.e. lone pairs) that can readily disrupt the ideal catalyst binding mode.

Acidity of the amide proton was another variable that lead to an interesting trend. The pKa

value of the Brønsted acidic proton can vary by changing the amide substituents to other functionalities. This can lead to different degrees of reactivity and selectivity. Benzamide catalyst 78b posseses an amide proton with a pKa value of approximately 23 in DMSO, and when subjected

to the benchmark aza-Henry addition, the desired adduct is furnished in 71% yield, 27:1 dr, and 91% ee (Scheme 46). When electron-withdrawing trifluoromethyl substituents are placed at the

Scheme 45. Electronic Trends Observed with Asymmetric Amidine-Amide Catalysts

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meta positions of the benzamide ring, the amide proton becomes more acidic with a pKa value of

17. Though this catalyst gives similar reactivity and diastereoselection compared to benzamide 78b, enantioselection is increased to 96% ee. Once again, this jump in enantioselectivity may be a direct result of increased steric bulk. Yet, it is also possible that the increased acidity plays a role in the acquisition of this higher ee as well. Acidity of this proton was lowered even further upon the installation of thioamide and sulfonamide moieties (78o and 78p). The approximate pKa values

for the thioamide and sulfonamide protons were 10.5 and 9.7 respectively (DMSO scale).44,45

When applying these catalysts to the aza-Henry addition however, considerably lower levels of enantioselection as well as diastereoselection and reactivity were observed, indicating that these more acidic thioamide and sulfonamide protons may be inhibiting the catalyst binding mode. In other words, lesser degrees of selection and reactivity may be due to unwanted intramolecular interactions, a phenomenon previously proposed in the electronics trend. In this case however, it is possible that the Brønsted basic quinoline ring can have a high binding affinity for the proton as it becomes more and more acidic (Figure 18). This intramolecular coordination will affect the abilities of the quinoline and amide to properly bind with the imine and nitronate resulting in diminished reactivity and selectivity. In essence, it is believed that increasing the proton acidity to a pKa of 17 may enhance enantioselection. Yet, if the proton is too acidic (pKa ~ 10), the ideal

catalyst transition state may be disrupted and optimal results will not be acquired.

44 _{Ripin, D. H.; Evans, D. A. pK}

a Table.1 <evans.rc.fas.harvard.edu/pdf/evans_pka_table.pdf> 45 _{Bordwell pKa Table (Acidity in DMSO). <www.chem.wisc.edu/areas/reich/pkatable/index.htm>}

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