Asymmetric Direct Aldol Reaction in Confined Space: Molecular Conformations of Organocatalyst Affect Chiral Induction

Abstract

We have demonstrated that chiral induction in the aldol product is possible by generating an enzyme‐like cavity in molecular framework of the amphiphlic catalyst. The esters of trans‐4‐hydroxy‐L‐proline and long chain fatty acids have been synthesized by O‐acylation. Synthesized molecules were used as organocatalysts for asymmetric direct aldol reaction between 4‐nitrobenzaldehyde and cyclohexanone. The molecular framework of the catalyst not only induces the amphiphilicity but also acquires specific conformation leads to formation of catalytic cavity facilitating stereo‐induction in the aldol product. Systematic addition of olefinic bonds in the long hydrocarbon chain makes this cavity more robust stabilizing transition state of the aldol product. By proper tuning of the water content and % loading of the catalyst in aldol reaction, o/w or w/o type emulsion is formed due to aggregation of catalyst molecules. Performance based evaluation of catalytic activity suggests that aldol reaction proceeds with ∼ 99% yield, 84% dr and 97.94% ee in presence of 10% catalyst (having three π bonds), in an o/w emulsion (85 equiv. of water) within 12 h. The stereoselectivity of the catalyst is almost maintained up to 2.5% loading. The high stereoselectivity of the aldol reaction is maintained even on increasing the amount of water to 300 equiv. A plausible reason has been proposed for retaining the high stereoselectivity and corroborated by computational analysis.

Synthesis of Extended Bipyridine‐proline Chiral Catalysts and Resulting Effects on the Asymmetric Aldol Reactions of Bulkier Aldehyde Derivatives with Cyclohexanone

“…Hence, how to realize and improve the stereoselectivity of the proline‐catalyzed asymmetric aldol reactions by using relatively low catalyst amounts has undoubtedly become one of the new challenges . To overcome the above issues, the strategy for the structural modification of proline has been explored by other researchers.…”

Proline‐derived Long‐aliphatic‐chain Amphiphilic Organocatalysts (PDLACAOs) for Asymmetric Reactions in Aqueous Media

“…The last article regarding compounds of this type was published by Soni and Patel in 2019. [45] In this interesting report, the authors demonstrated that in addition to hydrophobicity, the structure and conformation of the catalytic framework enabled high stereo-induction. Four new catalysts 34 a-d were synthesized, which were all based on trans-4-hydroxi-L-proline, which was esterified with various fatty acids that contained 18carbon alkyl chains and from zero to three cys-alkenes, respectively (Scheme 16).…”

“…The last article regarding compounds of this type was published by Soni and Patel in 2019 [45] . In this interesting report, the authors demonstrated that in addition to hydrophobicity, the structure and conformation of the catalytic framework enabled high stereo‐induction.…”