Identificador: TDX:1321
Autores: Liu, Chunhui
Resumen:
For a long time, homogeneous catalysis was almost synonymous with transition metal catalysis, with a small niche reserved to biocatalysis. Things have changed very much in recent years. Since about the year 2000, organocatalysis, where the catalyst is a small organic molecule, often with chiral properties, has grown rapidly to become one of the most important fields in organic chemistry. As the research field is expanding its role, mechanistic knowledge becomes more critical to understand the reaction modes and as¬sist in the development of more efficient processes. Theoretical chemistry, with its abil¬ity to locate intermediates and transition states, can be very helpful in this concern. This thesis is devoted to the computational study of the mechanism of three representative organocatalytic reactions. 1. Asymmetric Friedel-Crafts hydroxyalkylation of indoles catalyzed by chiral Brønsted-acids Chiral Brønsted¬acid catalysis is a rapidly growing area of organocatalysis. Water is one of the simplest molecules with Brønsted–acid capabilities. The coordination of water molecules to the carbonyl function in Diels–Alder reactions and Claisen rearrangements results in the enhancement of the reaction rate. Carmona and co¬workers used a water molecule attached to a chiral iridium fragment as a Brønsted–acid catalyst to yield the Friedel–Crafts (FC) reaction between ethyl 3,3,3 trifluoromethylpyruvate and indole at the low temperature. Based on their experimental results, we have carried out a computational study on the mechanism of this reaction and evaluated the catalytic role of the metal complex and water in this reaction. The mechanism of this reaction is stepwise, the first step is the formation of a C¬C bond together with the transfer of a proton from water molecule to the substrate; the second step is the rate determining one, which is the transfer of a proton from indole to the ¬OH moiety of the water molecule. The catalytic role of the metal complex is the modulation of the acid/base properties of the coordinated water, and the water molecule acts as a proton donor and acceptor. We have been also able to explain the origin of the the stereoselectivity of the process, which is a result of a subtle combination of the non¬covalent interactions, both attractive and repulsive, between catalyst and substrate. 2. Mechanism for the enantioselective synthesis of a Wieland-Miescher ketone The Wieland¬Miescher (W¬M) ketone is a key intermediate for many reactions. The efficient preparation of Wieland¬Miescher ketone¬type compounds with high enantioselectivity is thus a challenging problem in organic chemistry. In an attempt to address this issue, the Bonjoch group reported a highly efficient and enantioselective synthesis of a W¬M ketone using N¬Ts-(Sa)¬Binam¬L¬prolinamide as the organocatalyst, under solvent¬free conditions and the assistance of benzoic acid. The key step is a Robinson annulation reaction; it requires 1 mol% triethylamine as the base in the initial Michael process and 1 mol% of N¬Ts¬(Sa)¬binam¬L-prolinamide and 2.5 mol% of benzoic acid in the intramolecular aldol process. We studied the mechanism of the intramolecular aldol process in collaboration with the experimental group. We were able to clarify the mechanism of the reaction with prolinamide. It follows the general trends of the mechanism with proline, with the important caveat that the presence of a carboxylic acid as co¬catalyst is mandatory in the initial steps of the reaction, in particular for the formation of the iminium intermediate. In contrast, the carboxylic has no effect on the enantioselectivity, as it departs the system after enamine formation, and is absent in the transition state leading to C¬C bond formation, where the enantioselectivity of the reaction is decided. The origin of the enantioselectivity of the reaction has been also clarified. It is based on the rigidity of the catalyst, which has two anchoring points for the substrate, the C=N double bond in the enamine intermediate, and the N¬H...O hydrogen bonds between catalyst and substrate. The substrate has to distort to bind properly to this anchoring points, and this distortion is smaller for the transition state leading to the favored enantiomer. 3. Mechanism of [4+2] cycloaddition reaction catalyzed by chiral phosphoric acid derivatives N¬ and O¬containing heterocyclic compounds are prominent in nature and exhibit a wide range of interesting biological properties, including antihypertensive and anti¬ischemic behavior. Pyranobenzopyran and furanobenzopyran frameworks, containing three fused rings are particularly interesting. An appealing approach to the synthesis of these compounds is a [4+2] cycloaddition between a hydroxybenzaldimine and a furan. This reaction is catalyzed by phosphoric acid derivatives. We have analyzed in detail the recent puzzling results by the groups of Fochi and Rueping. Fochi and co¬workers reported in 2010 the synthesis of cis¬fused furanobenzopyrans obtained through inverse¬electron¬demand (IED) [4+2] cycloaddition of ο-hydroxybenzaldimines with 2,3¬dihydro¬2H¬furan (DHF) catalyzed by (S)¬BINOL¬derived phosphoric acid. In the same year, Rueping and Lin reported the synthesis of the trans¬fused furanobenzopyrans from the same reactants but with a (S)¬BINOL¬derived N-triflylphosphoramide catalyst. The same reactants and slightly different catalysts produced different diastereomers of the product. The transition state for the attack of DHF on the adduct between hydroxybenzldimine and catalyst controls the selectivity of the process. Hydrogen bonds play a critical role on the structure of the transition state, but their strength does not rule the selectivity. The lowest energy transition states have one hydrogen bond, while some higher energy transition states have two hydrogen bonds of similar strength. The selectivity is instead controlled by attractive ring¬ring interactions between catalysts and substrates. The lower energy transition states have more interactions, or shorter (thus likely stronger) ones. The difference between the (S)¬BINOL¬derived phosphoric acid (Fochi system), leading to a cis¬fused furanobenzopyran, and the (S)¬BINOL¬derived N¬triflylphosphoramide system (Rueping system), leading to a trans¬fused furanobenzopyran, could be reproduced and explained. The presence of the triflyl substituent on the nitrogen atom of the Rueping system constrains the possible orientations of the hydrogen atom on this same atom, and as a result precludes the optimal orientation of the furan ring that led to the stabilization of the key transition state in the Fochi system leading to the cis¬fused product. The cis¬fused product being disfavored because of this constraint, the trans¬fused product is formed with the Rueping catalyst. 4. General observations We have studied three different organocatalytic processes leading to chiral products with density functional theory (DFT) and density functional theory / molecular mechan¬ics (DFT/MM) methods and we have been able to obtain a reasonable agreement with experimental results, and to provide qualitative explanations for the origin of enantiose-lectivity in each of the cases. The computational study of enantioselective organocatalysis closely resembles that of enantioselective transition metal catalysis, but there are some significant nuances. In first place, the electronic description of the organocatalytic system is in principle easier, although the introduction of dispersion corrections is mandatory, as in any process where steric interactions may play an important role. In second place, the problems re¬lated to isomeric and conformational complexity are much more critical in organocatal¬ysis. The density of available isomers, conformational or not, available at low energy is much higher, and this poses a severe strain in the effort that has to be made to obtain quantitatively accurate energy barriers. The whole body of work in this thesis confirms the power of computational chemistry for the study of chiral organocatalysis. It also gives insight into the different mechanisms by which enantioselectivity can be transmitted in organocatalysis, from the usual steric interactions between catalyst and substrate to the less frequent key role of catalyst rigidity observed in the prolinamide system. The field of computational enantioselective organocatalysis is just starting, and we can expect new exciting results in the foreseeable future.
Repositori URV