Iminium-Activated Epoxidations

SCHEME 1.63 Organocatalytic epoxidation of enals with hydrogen peroxide. 

In the reaction pathway, the imininm ion formed from corresponding a,P-unsaturated aldehyde with the chiral amine is subject to nucleophilic attack by the peroxide, leading to an enamine intermediate (Schane 1.64). Formation of the epoxide then takes place by attack of the nucleophilic enamine carbon atom on the electrophilic peroxygen atom. 

Despite the excellent results of epoxidation of simple a,p-unsaturated aldehydes, a general method for the epoxidation of a-branched ot,P-unsaturated aldehydes was challenging. After several years, the process was realized by the combination of a chiral primary Cinchona-based amine and a chiral phosphoric acid as cocatalysts, making it possible to achieve high efficiency (Schane 1.65) [107]. It is believed that chiral phosphoric acid provides additional enantiodisaimination in both steps as a chiral counterion in 160a and as a Brpnsted acid in 160b. This is supported by the match or mismatch observed when the phosphoric adds (7 )-TRIP and (S)-TRIP were used in parallel studies. 

SCHEME 1.66 a,a-Diphenyl-L-prolinol-catalyzed epoxidation of enones. 

SCHEME 1.67 Catalytic cycle proposed for epoxidation of enones. 

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Iminium-Activated Epoxidations Similar to ylide 153 and bromomalo-nates 157, it was proposed that hydrogen peroxide could also be used as an amphiphilic reactant for [2-1-1] reactions of a,P-unsaturated aldehydes to furnish epoxidation products. Inspired by this hypothesis, Jprgensen s group developed an organocatalytic asymmetric epoxidation system of a,P-unsaturated aldehydes with HjOj as the oxidant (Scheme 1.63) [ 106]. The reactions take place under mild conditions in good to high yields and enantio- and diastereoselectivities. 

Miscellaneous Iminium Catalyzed Transformations The enantioselective construction of three-membered hetero- or carbocyclic ring systems is an important objective for practitioners of chemical synthesis in academic and industrial settings. To date, important advances have been made in the iminium activation realm, which enable asymmetric entry to a-formyl cyclopropanes and epoxides. In terms of cyclopropane synthesis, a new class of iminium catalyst has been introduced, providing the enantioselective stepwise [2 + 1] union of sulfonium ylides and ot,p-unsaturated aldehydes.As shown in Scheme 11.6a, the zwitterionic hydro-indoline-derived catalyst (19) enables both iminium geometry control and directed electrostatic activation of sulfonium ylides in proximity to the incipient iminium reaction partner. This combination of geometric and stereoelectronic effects has been proposed as being essential for enantio- and diastereocontrol in forming two of the three cyclopropyl bonds. 

It is worth noting that use of unprotected diarylprolinol 33 provides an effective platform for the epoxidation of a,P-unsaturated ketones [148, 149]. Within these reports it was proposed that an alternative mode of activation of the substrate could be taking place. Hydrogen bonding catalysis, rather than iminium ion formation, could explain the results and would be consistent with the non-polar reaction medium adopted within these reactions. 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

More recently Bohe, a former co-worker with Lusinchi, has reported an improved achiral catalyst that prevents some of the common side reactions observed in iminium salt-mediated epoxidation [18]. Two factors are known to reduce the catalytic efficiency of the epoxidation process hydrolysis of the iminium salt directly by the reaction medium, which generally only affects the acyclic systems and loss of active oxygen from the intermediate oxaziridinium species, through a reaction that does not regenerate the iminium species, which... 

Epoxidations. Combination of Oxone and the iminium salt derived from pyrrolidine and o-trlfluoromethylbenzaldehyde is effective for epoxidation of alkenes. In the case of an active alkene (e.g., trisubstituted alkene), pyrrolidine is an adequate catalyst. Other types of mediators include a-functionalized ketones (e.g., ot-acetaminoacetone) and the A, A -dialkylalloxans 1. ... 

A diastereo- and enantioselective Michael addition combined with a Darzens condensation reaction can be used to form two products of interest in the field of medicinal and natural products chemistry [60]. Additionally, depending on the workup conditions, an optically active epoxycyclohexanone, 92, can be prepared through an Sf 2 reaction, or the ElcB reaction pathway to 91 can be accessed (Scheme 7.17). In the early stages of the proposed mechanism, a planar iminium ion is suggested between the 2-[bis(3,5-bistrifluoromethylphenyl) trimethylsilany-loxymethyljpyrrolidine 61 and the aldehyde moiety of compound 88, which is subsequently attacked by the P-ketoester 89. For the synthesis of the epoxide, a... 

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