No abstract

One of the most important aspects of protein function is the motion that occurs in response to substrate binding. [1] In the dynamics of enzyme catalysis, multiple weak hydrogenbonding interactions [2] in the polypeptide that are controlled by interrelated enthalpy and entropy changes play a significant role in governing the conformational changes that take place. [3] In contrast, the development of asymmetric organocatalysts has rarely focused on hydrogen-bond donors [4][5][6][7][8] that have conformationally flexible scaffolds [9][10][11] as a likely consequence of difficulties in controlling the conformation of acyclic skeletons. [12] However, recently our research group has successfully demonstrated the utility of conformationally flexible guanidine/bisthiourea organocatalysts 1 for organocatalytic carbon-carbon bond-forming reactions. [9] Herein, we describe studies that have led to the development of new acyclic C 3 -linked guanidine/bisthiourea organocatalysts 2. Analysis of these processes shows that the catalytic effect resides in a trade off between enthalpies and entropies of activation and reveals the existence of dramatic concentration effects. This investigation has uncovered a unique catalytic stereodiscrimination process controlled only by differences in the activation entropies.The primary aim of this study was to extend our newly developed organocatalytic system to asymmetric 1,4-additions reactions of nitroolefins. [13] A plausible interaction mode for the catalytic reactions of nitroolefins with nucleophilic anions is shown in Scheme 1. In the reactive complex involving an acyclic guanidine/bisthiourea organocatalyst, the thiourea moiety can interact with the nitro group in the acceptor and ionic interactions with the guanidinium cation can orient a nucleophilic anion. [14] We envisaged that a long chiral spacer between the two centers in the catalyst would be required for the promotion of the 1,4-addition reactions that take advantage of these synergistic proximity effects.In the current study, we initially selected catalytic asymmetric Friedel-Crafts (FC) reactions [15,16] of phenol derivatives. [17][18][19] Although a variety of electron-rich aromatic compounds such as indoles, pyrroles, and furans have been successfully utilized as nucleophiles in 1,4-addition processes, [15,16] asymmetric reactions of phenol derivatives have been rarely studied. The difficulty in employing phenol derivatives in these processes could be a result of two intrinsic factors that are related to the fact that phenoxide anions generated in situ 1) often promote ligand exchange with metal catalysts, [17] and 2) can participate in reactions that take place with low levels of chemo-and regioselectivity. In 2007, Chen and co-workers developed the first 1,4-type of FC reaction of naphthols with nitroolefins that utilize cinchona-based thiourea catalysts. These processes give ortho-selective FC products with 85-95 % ee. [18a] However, the undesired dimeric furans that are formed in these reactions cannot be easily se...

One of the most important aspects of protein function is the motion that occurs in response to substrate binding. [1] In the dynamics of enzyme catalysis, multiple weak hydrogenbonding interactions [2] in the polypeptide that are controlled by interrelated enthalpy and entropy changes play a significant role in governing the conformational changes that take place. [3] In contrast, the development of asymmetric organocatalysts has rarely focused on hydrogen-bond donors [4][5][6][7][8] that have conformationally flexible scaffolds [9][10][11] as a likely consequence of difficulties in controlling the conformation of acyclic skeletons.[12] However, recently our research group has successfully demonstrated the utility of conformationally flexible guanidine/bisthiourea organocatalysts 1 for organocatalytic carbon-carbon bond-forming reactions.[9] Herein, we describe studies that have led to the development of new acyclic C 3 -linked guanidine/bisthiourea organocatalysts 2. Analysis of these processes shows that the catalytic effect resides in a trade off between enthalpies and entropies of activation and reveals the existence of dramatic concentration effects. This investigation has uncovered a unique catalytic stereodiscrimination process controlled only by differences in the activation entropies.The primary aim of this study was to extend our newly developed organocatalytic system to asymmetric 1,4-additions reactions of nitroolefins.[13] A plausible interaction mode for the catalytic reactions of nitroolefins with nucleophilic anions is shown in Scheme 1. In the reactive complex involving an acyclic guanidine/bisthiourea organocatalyst, the thiourea moiety can interact with the nitro group in the acceptor and ionic interactions with the guanidinium cation can orient a nucleophilic anion. [14] We envisaged that a long chiral spacer between the two centers in the catalyst would be required for the promotion of the 1,4-addition reactions that take advantage of these synergistic proximity effects.In the current study, we initially selected catalytic asymmetric Friedel-Crafts (FC) reactions [15,16] of phenol derivatives. [17][18][19] Although a variety of electron-rich aromatic compounds such as indoles, pyrroles, and furans have been successfully utilized as nucleophiles in 1,4-addition processes, [15,16] asymmetric reactions of phenol derivatives have been rarely studied. The difficulty in employing phenol derivatives in these processes could be a result of two intrinsic factors that are related to the fact that phenoxide anions generated in situ 1) often promote ligand exchange with metal catalysts, [17] and 2) can participate in reactions that take place with low levels of chemo-and regioselectivity. In 2007, Chen and co-workers developed the first 1,4-type of FC reaction of naphthols with nitroolefins that utilize cinchona-based thiourea catalysts. These processes give ortho-selective FC products with 85-95 % ee.[18a] However, the undesired dimeric furans that are formed in these reactions cannot be easily separat...

A catalytic enantioselective phospha-Michael reaction of diphenyl phosphonate to nitroolefins was achieved by utilizing a 1,3-diamine-tethered guanidinium/bisthiourea organocatalyst. The procedure is applicable to nitroolefins having various aromatic and aliphatic substituents, and enables an efficient access to phospha-Michael products with 90-98% ee. Monomeric or oligomeric active species of the catalyst can be utilized, depending on the presence or absence of water.

Herein, we present details of our conformationally flexible, 1,3-diamine-tethered guanidine/bisthiourea organocatalysts for chemo-, regio-, and enantioselective 1,4-type Friedel-Crafts reactions of phenols. These organocatalysts show a unique stereo-discrimination governed by the differential activation entropy (ΔΔS(≠)), rather than by the differential activation enthalpy (ΔΔH(≠)). Extensive kinetic analyses using Eyring plots for a series of guanidine/bisthiourea organocatalysts revealed the key structural motif in the catalysts associated with a large magnitude of differential activation entropy (ΔΔS(≠)). A plausible guanidine-thiourea cooperative mechanism for the enantioselective Friedel-Crafts reaction is proposed.