Asymmetric organocatalysts pyrrolidines

Pyrrolidin-2-yltetrazole 204 has been found to be a new, catalytic, and more soluble alternative to proline in a highly selective, organocatalytic route to chiral dihydro-1,2-oxazines <05OL4189> and as an asymmetric organocatalyst for Mannich, nitro-Michael and aldol... 

In parallel, Xu and coworkers discovered that in the presence of similar I L-tagged pyrrolidines 84c,d the reaction proceeded nearly as efficiently in the [bmimJIPFs] medium, so there is no need to dehver the acid co-catalyst (TFA) to the system because this role is obviously played by the IL fragment [96]. Catalysts 84a,b were recovered from the reactant medium by precipitation with ether, while the 84c,d/ IL systems were reused after product extraction without further purification. Four reaction cycles of catalysts 84 did not reduce reaction diastereo- and enantioselec-tivities however, the recovered catalysts gradually became less active with each cycle. Surfactant-type IL-supported asymmetric organocatalyst 84e synthesized by Luo and Cheng and coworkers in 2006 catalyzed Michael addition to nitroalkenes with high stereoselectivities in water without any additives [97]. 

The 1,3-dipolar cycloaddition of azomethine yUdes with olefins gives rise to pyrrolidines which represent structural elements of organocatalysts, natural products, and drug candidates. Asymmetric metal-catalyzed variants attracted considerable attention over the last few years [64], Recently, Vicario et al. reported an organo-catalytic [3 -i- 2] cycloaddition of azomethine ylides and a,p-unsaturated aldehydes mediated by a chiral secondary amine [65]. 

Nomicotine, an organocatalyst studied by Dickerson and co-workers (Entry 5 [52, 58d], Appendix 7.B), reinforces the important principle that even catalysts from Nature can present problems when it comes to toxicity. The family of nicotinic receptor agonists (Figure 7.9) contains several chiral pyrrolidines and piperidines with the potential to act as asymmetric aldol catalysts. Nomicotine, which can be isolated from plants such as tobacco, or readily synthesized by demethylation of the maj or tobacco alkaloid nicotine, was investigated in some depth as an aldol catalyst by Dickerson and Janda in 2002 [52]. 

Pyrrolidin-2-yltetrazole has been found to be a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones.45 Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via generation of an iminium species. 

Very recently, the first catalytic asymmetric intramolecular a-alkylation of an aldehyde has been achieved by the List group [70]. In the presence of a-methyl-substituted L-proline, (S)-61, as organocatalyst, ring-forming reactions leading to chiral cyclopentanes, cyclopropanes, and pyrrolidines proceed with high enantioselectivity - in the range 86-96% ee. Selected examples are shown in Scheme... 

The first asymmetric direct a-iodination of aldehydes has also been described to provide products in moderate to good enan-tioselectivities using an organocatalyst. 3-Methyl-1-butanal was reacted with NIS in the presence of a chiral pyrrolidine catalyst to provide the halogenated product in 78% yield with 89% ee (eq 27). 

Numerous 2-substituted pyrrolidine organocatalysts have been prepared from L-proline and its derivatives, and have been proven to be highly efficient for many asymmetric reactions. Representative organocatalysts have been selected and categorised on the basis of the 2-substituted group that includes di- and tri-amine (la-m), dithioacetal (2a-f), guanidine (2g-i), sulfonamide (3a-j), amide and thioamide (3k-n), urea (4a and 4e), thiourea (4b-d, f-j) and heterocycles such as tetrazole (5a,b), triazole (5c-g), imidazole (5h-j) and benzoimidazole (5k) (Figure 9.1). 

In 2006, Takabe and Barbas et al. developed a water-compatible pyrrolidine-based diamine organocatalyst (Id) for direct asymmetric aldol reactions. The long hydrocarbon chain containing diamine (Id TFA) catalysed the aldol reaction in the presence of water at ambient temperature. Various ketones and isobutyraldehyde were treated with aromatic aldehydes to provide aldol products in high chemical yields, with favourable diastereos-electivity and high enantioselectivity (Scheme 9.5). ... 

---