Abstract
A series of poly(2-oxazoline) (POX) derivatives bearing prolinamide pendants were designed as organocatalysts and evaluated in the direct asymmetric aldol reaction between aromatic aldehydes and cyclic ketones. The structural variation of the alkyl spacer connecting the polymer backbone with the catalytic unit was applied so as to deduce structure–performance relationships combined with comparable experiments from model catalysts. Results showed that the POX-bound prolinamides can promote the aldol reaction more effectively as compared to their small-molecular and non-POX-bound analogs. The catalyst P3 containing the pyrrolidine moiety closer to the tertiary amide backbone exhibited the overall best catalytic efficiency, affording anti-products in 84% yield with 89% ee in the representative aldol addition of cyclohexanone to 4-nitrobenzaldehyde at a 10 mol.% catalyst loading. Furthermore, the influence of trifluoroacetic acid as an additive on the asymmetric transformation was investigated. Theoretical calculations revealed that the protonation of the aldehyde carbonyl group switched the activation mode of the aldol acceptor through hydrogen bond interactions, thereby changing the relative energy barrier of the enamine/aldehyde reaction transition states, which accounted well for the significant improvement in the enantioselectivity of the acidic additives observed experimentally.
Highlights
Since List and co-workers reported asymmetric direct aldol reactions catalyzed by proline [1], immobilization of chiral organocatalysts on polymer matrices has attracted increasing interest in recent decades, owing to the advantages of easy product separation and catalyst recycling, as well as the possibility of mimicking the enzymatic systems [2,3,4,5]
These findings indicated that the benzyl group in the side chain may provide P1 with a rigid environment that preferred the stereocontrol in enamine/aldehyde reaction transition by steric hindrance, which could be one of the factors responsible for the observed lower conversion because the bulky substituent prevents the access of substrates
N-Boc-glycine, N-Boc-L-alanine, N-Boc-L-proline, O-(1H-benzotriazol-1-yl)-N,N,N’,N’tetramethyluroniumtetrafluoroborate (TBTU), trifluoroacetic acid (TFA), and Boc anhydride were purchased from Qiude Chemical Co. (Shanghai, China). 4-Nitrobenzaldehyde (PNBA) was purchased from Acros (Shanghai, China)
Summary
Since List and co-workers reported asymmetric direct aldol reactions catalyzed by proline [1], immobilization of chiral organocatalysts on polymer matrices has attracted increasing interest in recent decades, owing to the advantages of easy product separation and catalyst recycling, as well as the possibility of mimicking the enzymatic systems [2,3,4,5]. Poly(2-oxazoline)s (POXs), obtained using cationic ring-opening polymerization of 2-substituted 2-oxazoline monomers, have attracted considerable attention for their potential applications in biomedical areas [15,16,17,18]. These polymers are regarded as pseudopeptides, bioinspired polymers, due to their structural relation to polypeptides. Based on this unique polymer backbone, as well as a great deal of flexibility in molecular design and synthetic accessibility, we recently
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