Systematically Probing the Effect of Catalyst Acidity in a Hydrogen‐Bond‐Catalyzed Enantioselective Reaction

Abstract

Hydrogen bonding is ubiquitous in nature and is a prevalent mode of substrate activation in enzymes. Recently, chemists have begun to exploit this mode of activation in asymmetric catalysis by designing synthetic catalysts that use hydrogen bonds. [1][2][3] These catalysts feature a variety of structural motifs and hydrogen-bond-donating functional groups. In light of the rapid development of new hydrogen-bond-catalyzed reactions, we felt that a greater understanding of the connection between catalyst activity and structure would aid the advancement of the field. While detailed mechanistic studies have been performed to clarify the role of hydrogen bonding in many enzymatic systems and on general acid catalysis, [4,5] few have been performed on synthetic asymmetric catalysts. [6] Herein, we present a systematic study on the effect of catalyst acidity in a hydrogen-bond-catalyzed reaction, wherein linear free energy relationships are observed between the catalyst acidity and both the reaction rate and enantioselectivity.We have developed a hydrogen-bond catalyst which has a unique design featuring an oxazoline core with a pendant amine and alcohol group. This design provides two sites with hydrogen-bond donating groups which can be independently tuned (Scheme 1).[7] Catalysts of this type have been shown to be effective in the asymmetric hetero-Diels-Alder reaction between Rawals diene (D) and benzaldehyde (A). [7][8][9][10][11] The modular nature of the catalyst makes it well suited for a mechanistic study, as catalyst derivatives can be rapidly synthesized and evaluated to probe the relationship between the catalyst structure and activity.We hypothesized that a more acidic catalyst would be a better hydrogen-bond donor and thus would lead to enhanced substrate activation, as has been previously demonstrated. [12][13][14] To investigate this connection, systematic changes to the acidity of the N-H proton were made by synthesizing halogenated acetamide derivatives of the catalyst (Scheme 1). These variations were selected because of the substantial pK a range that may be studied while avoiding significant structural changes [15,16] and because the catalyst derivatives can be synthesized from a common precursor.[17]Compounds 1-5 were then evaluated as catalysts in the hetero-Diels-Alder reaction. [8][9][10][11] The yields of the isolated products after a 48 h reaction time suggest a relationship between acidity and catalyst activity (Scheme 1).[18] To our surprise, a trend in enantioselectivity was also observed, with the highest enantiomeric excess measured for the most acidic catalyst.To better understand the observed trends corresponding to the electronic nature of the catalyst, kinetic measurements were performed to probe the general mechanistic features of the reaction. Using the optimal catalyst 1, the following rate dependencies were observed: first-order dependence on [1], saturation in [aldehyde] (Figure 1), and first-order dependence on [diene] at high [aldehyde].[17] Based on these findings, a mechanism ...

Double Hydrogen Bonding in Asymmetric Organocatalysis: A Mechanistic Perspective

“…For both reactions, it was found that single-point activation of the dienophile resulted in a more efficient lowering of the reaction barrier, thereby confirming Rawal's hypothesis. This feature was exploited to carry out an experimental mechanistic study on the impact that catalyst acidity has on rate and selectivity in the previously described hDA reaction (Scheme 6.2) [19]. This result slightly revised the models for enantioselection originally proposed by Rawal et al [12] and, subsequently, by other authors based on computational studies at lower levels of theory, all of them featuring a π/π interaction between the phenyl ring of benzaldehyde and one naphthyl ring of TADDOL [16,17].…”

A Systematic Investigation of Quaternary Ammonium Ions as Asymmetric Phase-Transfer Catalysts. Application of Quantitative Structure Activity/Selectivity Relationships

“…12 Another recent example in the field of homogeneous catalysis is a systematic study of catalyst activity as a function of the hydrogen bond donating ability of a catalyst (p K a ). 13 Finally, attempts to utilize QSAR methods to study catalysts for polymerization, 14 homogeneous, 15 and heterogeneous catalysis are on record. 16 …”

Asymmetric Michael Addition of Oxindoles to Allenoate Catalyzed by N‐Acyl Aminophosphine: Construction of Functionalized Oxindoles with Quaternary Stereogenic Center

“…Recently, our group has focused on the development of novel and easily accessible bifunctional N-acyl aminophosphine catalysts from amino acids, which has unambiguously proved valuable in all sorts of asymmetric cycloaddition reactions with allenoates. Subsequently, an examination of catalysts 4f-4l with different groups on the nitrogen was carried out (Table 1, entries [6][7][8][9][10][11][12]. Initially, 3-phenyloxindole 1a was chosen as pronucleophile in the g-addition with ethyl buta-2,3-dienoate 2 for evaluation by the catalysts 4a-4l (Table 1).…”

“…Initially, 3-phenyloxindole 1a was chosen as pronucleophile in the g-addition with ethyl buta-2,3-dienoate 2 for evaluation by the catalysts 4a-4l (Table 1). [10] Introduction of a trifluoromethyl group into the catalyst 4f, which means a strong acidity on the NH functionality, turned out to be detrimental to the enantioselectivity, although an excellent yield was obtained (Table 1, entry 6). It was shown that the chiral backbones of these catalysts have a great effect on the enantioselectivity.…”