Entropy‐Controlled Catalytic Asymmetric 1,4‐Type Friedel–Crafts Reaction of Phenols Using Conformationally Flexible Guanidine/Bisthiourea Organocatalyst

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...

Kinetic Evidence of an Apparent Negative Activation Enthalpy in an Organocatalytic Process

“…methyl and ethyl groups)24. It is also noted that the calculated differences in activation free energies of these transition states were similar to those in activation enthalpies, suggesting that the observed selectivities are not due to the entropic control in Sohtome and Nagasawa's systems4247.…”

“…Moreover, for pTS-I , the α-C-H bonds (to the ammonium group and to the indole ring) are in proximity (2.1 to 2.4 Å) with the ester carbonyl oxygen (Figure 4), alluding to the possibility of the formation of a non-classical C-H δ+ …O δ− binding pocket. Such secondary interactions have been observed to play an important role in molecular recognition and stereoselective catalytic processes414243. To confirm that such short bond distances are result of hydrogen bonding interactions rather than simple steric arrangement, two-center Mayer bond order analysis44 was carried out.…”

Solvent‐Dependent Enantiodivergent Mannich‐Type Reaction: Utilizing a Conformationally Flexible Guanidine/Bisthiourea Organocatalyst

“…[23d] As seen by inspecting the data in Table 3, both enthalpy (DDH°) and entropy (DDS°) compensation govern the stereodetermining step of solvent-dependent organocatalytic reactions promoted by 1 a. In contrast, negative values of DDH°R -S and DDS°R -S control the stereodiscrimination processes in R-selective reactions in aprotic polar solvents (Table 3, entries [5][6][7][8], in which the DDH°R -S term has a major influence on lowering the DDG°R -S in the R-selective reactions. In these cases, differential activation entropies (DDS°S -R ) contribute to lowering the DDG°S -R of reactions having unfavorable enthalpic contributions.…”

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Hydrogen bonding promoted asymmetric catalysis has rapidly grown over the past decade. [8] A new perspective described herein concerns the possibility of bringing about dynamic control of the stereochemical outcomes in the organocatalytic system by tuning the enthalpy and entropy related external factors (e.g., reaction solvents, the substrate concentration, and pressure). [2] In contrast, recent findings from our group have shown that conformationally flexible guanidine/bisthiourea organocatalysts 1 [3][4][5][6][7] display unique stereodiscrimination processes that are governed by differential activation entropy (DDS°= 25.4 J mol À1 K À1 ) rather than differential activation enthalpy (DDH°=~0 kJ mol À1 ) in ortho-and enantioselective 1,4-type Friedel-Crafts alkylations of sesamol.

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“…[1] Most organocatalysts probed to date have conformationally rigid chiral backbones that participate in structurally rigid transition states. [8] A new perspective described herein concerns the possibility of bringing about dynamic control of the stereochemical outcomes in the organocatalytic system by tuning the enthalpy and entropy related external factors (e.g., reaction solvents, the substrate concentration, and pressure). [8] A new perspective described herein concerns the possibility of bringing about dynamic control of the stereochemical outcomes in the organocatalytic system by tuning the enthalpy and entropy related external factors (e.g., reaction solvents, the substrate concentration, and pressure).…”