Aldol reactions 5 - methylamines

Houk and Bahmanyar began a series of computational studies of organocat-alyzed aldol reactions with an examination of simple intermolecular aldol reactions catalyzed by small amines. They first looked at the methylamine-catalyzed aldol... 

Aldol reaction. Triflyl and nonaflyl derivatives of (5)-(2-pyirolidinyl)methylamine mediate asymmetric aldol reactions in aqueous media/ The latter is a typically recyclable fluorous catalyst ... 

The intramolecular organocatalytic asymmetric a-alkylation of aldehydes was developed by Vignola and List in 2004 [34]. Experimentally, it was found that 2-methylproline was a much better catalyst than proline itself, and Methylamine accelerated the reaction. A subsequent theoretical study by Fu, List, and Thiel [35] concluded that the reaction proceeds via an enamine displacement of the halogen. Triethylamine was found to provide a salt bridge between the carboxylic acid and the departing halide, and the stereoselectivity of the reaction was shown to arise from preferred cyclization (by 1 kcal/mol) of an a ri-enamine relative to that of the syn-enamine (Figure 2.12). The calculations also indicated that the enhanced enantio-selectivity of the 2-methylproline catalyzed aldol reaction compared with the proline-catalyzed process is due to the inherently larger steric interactions between the methyl and the aldehyde substituent in the syn transition state. 

Fukuyama also presented an alternative route to the advanced intermediate 114 as shown in Scheme 18 with an early introduction of the protected amino functionality. Reaction of y-butyrolactone with the Grignard reagent derived from 1,4-dibromobutane (120) afforded diol 121. Mesylation of the primary hydroxyl functionality with concomitant elimination of the tertiary one was followed by reaction with methylamine and protection of the resulting secondary amine to give alkene 122. Ozonolysis of the double bond in 122 and subsequent intramolecular aldol condensation of the resulting ketoaldehyde afforded cycohexenone 123. Rubottom oxidation and acetylation gave 124, which served as substrate in the lipase-... 

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