Scientific Background on the Nobel Prize in Chemistry 2021
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Scheme 1. Synthesis of the Wieland-Miescher ketone (6) by Hajos and Wiechert.
In the 1990s, the group of Lerner and Barbas III successfully generated antibodies that catalyse the intramolecular aldol reaction. 32 The catalytic antibodies were generated so as to mimic class I aldolase enzymes. These enzymes and catalytic antibodies use the amine moiety of a lysine residue in the active site of the protein to form an enamine with the substrate, which then adds to an aldehyde to complete the aldol reaction. In particular, the catalytic antibody 38C2 showed a broad substrate scope and afforded products in high er (eq. 3). 33 This antibody was also elegantly applied in a key step in the synthesis of several brevicomins, which are pheromones of several bark beetles (Scheme 2). 34
6 (19)
Scheme 2. Synthesis of brevicomins 7 and 8 using the catalytic antibody Ab38C2 in the aldol reaction. Iminium ion catalysis: In 2000, Ahrendt, Borths and MacMillan showed that the chiral imidazolidinone 9 can catalyse the Diels-Alder reaction between α ,β-unsaturated aldehydes and dienes (eq. 4). 25 The organocatalyst 9, which is prepared in three steps from the methyl ester of the naturally occurring amino acid L -phenylalanine, condenses with the unsaturated aldehyde to form the corresponding iminium ion, in which the energy of the Lowest Unoccupied Molecular Orbital (LUMO) is lowered compared to that of the aldehyde. This lowering of the energy of the LUMO results in an increased reactivity towards the diene, and a higher reaction rate of the ensuing Diels-Alder reaction compared to the uncatalysed reaction. Similar LUMO lowering activation can be attained by using metal-based Lewis acids, a technique that has been much studied.
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7 (19)
In the case presented by MacMillan and colleagues, the catalyst is covalently attached to the substrate, which provides good possibilities for transferring the chiral information from the organocatalyst to the product, and the researchers discussed a model rationalizing the observed stereoinduction. In order to allow for efficient catalysis, the iminium ion of the initially formed cycloadduct (not shown in eq. 4) must be sufficiently kinetically labile to allow for its hydrolysis under the reaction conditions and regeneration of catalyst 9. The key insight in the work by MacMillan and co-workers is the concept that the LUMO lowering through catalytically generated iminium ion intermediates provides a general platform on which other asymmetric reactions can be designed and developed. This case also was preceded by important findings in the literature. Baum and Viehe (1976) showed that the unsaturated iminium ion 11, derived from the corresponding acetylenic amide, reacts with cyclopentadiene in a Diels-Alder reaction to furnish compound 12 (eq. 5). 36 In this study, the researchers concluded that the iminium ion moiety in 11 provides a substantial activation of the triple bond, i.e. LUMO lowering, compared to the situation in amide 10, which is the reason for the smooth conversion into adduct 12. This notion was further elaborated by Jung and co-workers (1989), who showed that the chiral iminium ion 13 underwent a smooth Diels-Alder reaction with cyclopentadiene to give adduct 14, which was hydrolysed to furnish amide 15 with high yields and excellent diastereomeric excess (eq. 6). 37 In both these cases, the iminium ions moieties in compounds 12 and 15 are not sufficiently kinetically labile to allow for a facile hydrolysis of these functionalities under the reaction condition, which precludes an organocatalytic reaction manifold.
Another important impetus was provided by Yamaguchi and co-workers in 1993. These researchers showed that the rubidium salt of L -proline (17) is an efficient catalyst in the Michael addition of diisopropyl malonate to a series of α,β-unsaturated aldehydes and ketones 16, to yield the corresponding addition products 19 (eq. 7). 38 It was noted that the secondary amine moiety and carboxylate functionality in catalyst 17 are essential for the catalyst activity, and it was proposed that the reaction proceeds through the reversible formation of iminium ion 18.
8 (19)
Thus, once the Michael addition to intermediate 18 has proceeded, hydrolysis of the iminium ion moiety will ensue to generate 19 and the catalyst. The following year, Kawara and Taguchi (1994) described a similar Michael reaction using catalyst 20 to promote the reaction (eq. 8). 39
Significance: The most significant advances in organic synthesis are those that clarify new principles for inducing reactivity and controlling reaction pathways; the development of the concept of organocatalysis and the fundamental design principles for developing such catalysis is clearly a significant advancement of the field. New opportunities to perform chemical reactions, such as organocatalysis, expand the toolbox that is available to chemists and allow for designing new reaction pathways for organic molecules. Such improvements and discoveries result in more efficient reaction pathways, which, as a consequence, will have a reduced environmental impact. The use of small organic molecules as catalysts for organic reactions is not unprecedented in organic chemistry. However, the work by List and MacMillan resulted in a turning point; there is a clear before and after. Their work conceptualized the area of organocatalysis, focusing on asymmetric catalysis, and indicated principles for designing new organocatalytic reactions based on modern concepts such as LUMO lowering and HOMO raising. In the years that followed these Laureates’ first publications in 2000, this research area has flourished: an impressive number of new reactions, catalysts and applications were described in the literature—this period has been referred to as the ‘organocatalysis gold rush’. 44 Today, the area is well established in organic chemistry and has branched into several new and exciting applications. Also, organocatalysis is now recognized as the third pillar of asymmetric catalysis, together with biocatalysis and transition metal catalysis.
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