Iminium-Activated Cyclopropanations

A second-generation catalyst in which the carboxylic acid of (S)-(-)-indoline-2-carboxylic acid was replaced by tetrazolic acid was used to improve enantioselectiv-ity as a consequence of increased steric bulk while retaining important structural functionahty associated with the proposed directed electrostatic activation mode [101], Combination of the iminium catalysis with arsonium yhdes also provided access to cyclopropanes with high enantioselectivity [102]. 

Nitrocyclopropanation of enones [104] and enals [105] with 2-bromonitrometh-ane was also reported. 

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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. 

Enantioselective organocatalytic cyclopropanations have been performed using directed electrostatic activation conditions.164 Using a new class of iminium catalysts, cyclopropanation has been conducted with enals but not electron deficient alkenes, such as unsaturated nitrile, nitro, or alkylidene malonate systems. 

A novel method for enantioselective organocatalytic cyclopropanation has been developed, using a new class of iminium intermediates and based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide (153) and enal (152) substrates through the formation of the iminium intermediate (155) and electrostatic activation (156). The resulting (g) trisubstituted cyclopropanes (157) were obtained with high levels of enantio- and diastereo-control.180... 

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. 

Scheme 10.9 Synthesis of cyclopropanes through iminium-enamine activation mode.

Kunz, R. K., MacMillan, D. W. (2005). Enantioselective organocatalytic cyclopropanations. The identification of a new class of iminium catalyst based upon directed electrostatic activation. Journal of the American Chemical Society, 127, 3240-3241. 

In situ formed iminiums were also able to react with alkyltins in an intramolecular fashion, leading to the formation of cyclopropane [265] or cyclopentane rings (Scheme 6.30). Similarly, the intramolecular reaction of y-alkoxystarmane with hydrazones, activated by a Lewis acid, was used to prepare 5- or 6-membered /3-amino cyclic ethers, for which the trans preference for the cyclization was consistent with an acyclic transition state [266]. 

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