Amination reactions enantioselective Baylis-Hillman

A highly enantioselective Baylis-Hillman reaction based on the combined use of an activated alkene (23) and a chiral amine catalyst (QDA) derived from cincho-nane has been developed. The reaction permits the conversion of a wide variety of aldehydes to the corresponding a-methylene-jS-hydroxy esters (28) with high ee in reasonable yields. 

Conditions for a highly enantioselective Baylis-Hillman reaction (142) + (143) (144) have been developed (Scheme 20). The new protocol relies on the use of 1,1,1,3,3,3-hexafluoroisopropyl acrylate (144) as an activated alkene and (3R,8R,9S)-10,ll-dihydro-3,9-epoxy-6 -hydroxycinchonane (145) as a chiral amine catalyst. The highest enantioselectivity (99% ee) was obtained for R = cyclohexyl. A mechanism has been proposed that highlights an important synergism of the tertiary nitrogen and the phenolic OH of the alkaloid (143) + (145) —> (146) + (147). 9 However, the reviewer feels that the proposed mechanism would be disfavoured by the entropy factor. 

A remarkable increase in enantioselectivity achieved by applying high pressure was observed by Hirama et al. [81] for an asymmetric Baylis-Hillman reaction, in addition an enhancement of the reaction rate was also found. The Baylis-Hillman reaction refers to the condensation of acrylates and aldehydes catalyzed by tertiary amines. Using various enantiopure 2,3-disubstituted l,4-diazabicyclo[2.2.2]octanes (DABCOs) as chiral amine bases the influence of high pressure on the reaction... 

The Wang group also realized enantioselective oxidative cross-coupling reactions between tertiary amines and the activated olefins by merging Cu(OTf)2 with quinine as the best cooperative catalysts/ A Morita-Baylis-Hillman-type mechanism is in operation. It was notable that molecular oxygen was employed as the sole oxidant. As shown in Scheme 2.12, the reactions between Ai-aryl THIQs and the a,p-unsaturated aldehydes or ketones 30 proceeded smoothly to afford the a-functionalized products 31 in up to 81% yield and 99% ee. 

Cinchona alkaloid derivatives can also serve as useful Lewis basic catalysts, as very well exemplified by their successful employment in the Morita-Baylis-Hillman (MBH) reaction and its aza variant (aza-MBH), which provide a convenient access to functionalised allylie aleohols and amines. As early as 1999 Hatakeyama and coworkers reported the use of p-isocupreidine (P-ICPD) as a catalyst for the reaction of aliphatic and aromatic aldehydes with 1,1,1,3,3,3-hexafluoroisopropyl acrylate, affording the desired adducts with very high enantioselectivities (Scheme 14.19). The concomitant formation of the dioxanone derivatives lowered the yield in the MBH adducts and caused difficulties in the experimental proeedure. Interestingly, the dioxanone derivatives had the opposite eonfiguration at the alcoholic stereocentre compared to the MBH produet, highlighting an intriguing mechanistic feature of this Lewis-base catalysed reaction. ... 

A phosphine sulfonamide derived from L-threonine promotes aza-Morita-Baylis-Hillman (aza-MBH) reactions of sulfinylimines in up to 96% yield and 97% ee. A review describes the synthesis of chiral amines under mild conditions via catalytic asymmetric aza-MBH reactions. Proline/DABCO (l,4-diazabicyclo[2.2.2]octane) co-catalysis of enantioselective aza-MBH reactions gives good to high yields and up to 99%... 

As an extension of this work, the same authors have used polystyrene-supported proline as a recyclable catalyst in the Morita-Baylis-Hillman reaction of a range of aryl aldehydes with methyl or ethyl vinyl ketone. These reactions were performed in the presence of imidazole and provided a series of Morita-Baylis-Hillman adducts in moderate to high yields (17 88%) combined with high enantioselectivities of up to 95% ee (Scheme 2.55). This study represented the first example of supported proline as heterogeneous catalyst for the Morita-Baylis-Hillman reaction. In addition, Zhou et al. reported that these reactions could be eatalysed by combinations of L-proline with chiral tertiary amines derived from various readily available chiral sources, such as L-proline or (5)-a-phenylethylamine. In these conditions, the Morita-Baylis-Hillman adducts were obtained in reasonable chemical yields (34-97%) and low to good enantioselectivities (12 83% ee). In this study, it was demonstrated that the proline stereochemistry was the sole factor to determine the eonfiguration of the newly formed chiral centre. 

In the 1990s, examples of high-pressure Baylis-Hillman reactions catalyzed by chiral tertiary amines appeared in the literature [15-17]. In 1991 Isaacs group [15] reported a few results of the reaction between acrylonitrile and acetaldehyde with different chiral amines under 5-9kbar quinine (0%), (lR,2S)-N-methylephedrine (18%, 10%ee), (S)-(-)-nicotine (15%, ll%ee), (S)-(-)- -methylpyrrolidenylmethanol (28%, 17% ee), and ( )-3-hydroxyquinuclidine in ethyl L-(-l-)-lactate (81%, 3% ee). In general, for this reaction the combination of chiral amines and pressure resulted in low yields and enantioselectivities up to 17%. 

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