Cinchona primary amines

Asymmetric Cydoaddition Reactions Catalyzed by Cinchona-Based Primary Amines... 

The power of column-like reactors for continuous flow processes lies in the possibility to sequentially link them up in order to carry out multistep syntheses in solution in one run (see also Schemes 1 and 2). Lectka and coworkers utilized conventional fritted and jacketed columns for this purpose. These columns were filled with conventional functionalized polymeric beads [47]. The continuous flow was forced by gravity. En route to / -lactams polymer beads functionalized with the Schwesinger base 17, a cinchona alkaloid derivative 18 as a chiral catalyst, and a primary amine 19 were sequentially employed. They first guaranteed the generation of phenyl ketene from phenyl... 

Scheme 2.10 Enantioselective Michael addition of ketones to nitroalkenes catalyzed by primary amine-sulfonamide catalysts 27a-b and by 9-epi amino cinchona alkaloid 28a.

Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds 12AG(E)9748. 

The conceptually different activation of carbonyl substrates through the formation of a nucleophilic enamine or an electrophilic iminium ion is achieved by use of 9-deo>q -ep/-9-amino Cinchona catalysts. In contrast to typical secondary amine-based catalysts i.e. derived from proline), the primary amine of these modified Cinchona alkaloids can combine also with sterically biased substrates, such as ketones and hindered aldehydes. This class of catalyst has thus allowed the scope of aminocatalysis to be extended beyond unhindered aldehydes/enals, and has proved to be remarkably powerful and general. 

Moving to the use of 9-deo3gr-9-amino-epi Cinchona-, in 2007, shortly after the disclosure of their usefulness in conjugate additions, summarised in Section 14.2, Liu and coworkers demonstrated that these primaiy amines are also efficient in catalytic asymmetric 1,2-additions proceeding through enamine intermediates. The authors reported a highly enantioselective aldol addition of cyclic ketones to aromatic aldehydes catalysed by a primary amine derived from cinchonine (CNA) and proceeding in the absence of... 

An important contribution elucidating the potential of primary amines derived from Cinchona alkaloids has been the aldol cyclodehydration of achiral 4-substituted-2,6-heptanediones to enantiomerically enriched 5-substituted-3-methyl-2-cyclohexene-l-ones, presented by List and coworkers in 2008 (Scheme 14.26). Both 9-deo>y-9-amino-epr-quinine (QNA) and its pseudoenantiomeric, quinidine-derived amine QDA, in combination with acetic acid as cocatalyst, proved to be efficient and highly enantio-selective catalysts for this transformation, giving both enantiomers of 5-substituted-3-methyl-2-cyclohexene-l-ones with very good results. The authors observed that proline and the catalytic antibody 38C2 delivered poor enantioselectivity in this reaction. Furthermore, the synthetic utility of the reaction was exemplified by the first asymmetric synthesis of both... 

List s group investigated a-benzoylo g lation of cyclic ketones and observed an improvement in selectivity when the Cinchona-derived primary amine, 9-amino-9-deo3q -epz-quinine 9-epi-QA) was used as a carboxylic acid salt. ° Thus, with 1.5 equivalents of benzoyl peroxide, various cyclic ketones were benzylojq lated in 45-81% yield (Scheme 15.24). The benzyloxylation of more challenging aldehydes and enals provided inferior results this time tri-chloroacetate was found to be more efficient than other acid salts tested. 

Very recently, the same group successfully extended this methodology also to a-branched aldehydes [128], Cinchona based primary amine LX (Scheme 8.27) for activation of aldehydes and (-)-CSA as chiral acid for carbocation formation efficiently catalyzed alkylation reaction, giving best results in solvent system CH3CN/H2O. 

Tu and co-workers [11] reported an intriguing methodology for the synthesis of spirocyclic compounds. Hydroxy enones 13 undergo semipinacol-type 1,2-carbon migration in the presence of cinchona-derived primary amines to afford spirocyclic diketones via iminium catalysis. 

In the second case, Melchiorre and co-workers [59] used a Michael—Michael cascade reaction between an unsaturated spirocycle and an enone. This reaction is efficiently catalyzed by a primary amine derived (XIII) in a single step from the cinchona alkaloid hydroquinine. The reaction afforded the final spirooxindoles in... 

A similar approach was reported by Wang et al. [60] a year later, consisting of a double Michael reaction of simple oxindoles with dienones. The reaction was simply catalyzed by a cinchona-based primary amine catalyst (XIII). The reaction afforded the final spirocyclic oxindoles in good yields and excellent enantioselectivities when diaryldienones were used. The only limitation of the reaction was the need to use carbamate-protected oxindoles thus, the use of unprotected or benzylated oxindoles is ineffective for this transformation. In 2010, the same research group proposed a similar approach [61]. They performed a reaction with an oxindole derivative decorated with a ketone in position 3 of the oxindole and acyclic enones. This reaction was catalyzed by chiral primary amines, affording the final spirooxindoles in good yields and enantioselectivities. 

The efficiency of secondary amine catalysts is often eroded when moving from aldehydes to ketones as the donor carbonyl substrates, a trend that can be explained in terms of either the greater difficulty in the generation of the intermediate enamine species or their attenuated reactivity. To alleviate this situation, primary amines have emerged as a complementary family of amine catalysts. For instance, proline and related chiral secondary amines are not useful catalysts for the a-amination of aromatic enolizable ketones. As in other similar situations involving ketones as substrates, primary amines proved to be superior catalysts, although in these cases the presence of an acid co-catalyst seems to be crucial for reactivity. For instance (Scheme 11.4), primary amines derived from cinchona alkaloids can efficiently... 

An enamine-catalyzed asymmetric a-fluorination of ketones, which are notoriously challenging substrates for this reaction, was reported by MacMillan and coworkers in 2011 [27]. After exhaustive automated screening of over 250 organo-catalysts, a Cinchona alkaloid-derived primary amine organocatalyst was identified as the optimal catalyst for this transformation (Scheme 13.11). Only cyclic ketones provided fluorinated products in high yields and enantiomeric excesses. 

---