Enantioselective synthesis of diarylcyclopropanecarboaldehydes by organocatalysis

Unveiling the beauty of cyclopropane formation: a comprehensive survey of enantioselective Michael initiated ring closure (MIRC) reactions

“…The cyclopropane synthesis by MIRC reaction was the key step in the total synthesis of (+)-podophyllic aldehydes A, B, and C. The reaction involved treating aldehyde (190) with α-bromomalonate 44 in the presence of Jørgensen-Hayashi amine catalyst 181, 2,6-lutidine, and dichloromethane to yield cyclopropane intermediate (191) in high yield (91%) and excellent enantioselectivity (95% ee) (Scheme 41). 183 Yang and coworkers made a recent breakthrough by introducing a small modification to the aldehyde used by Nishii et al By using the aldehyde (E)-3-((S)-1-[(R)-1-phenylethyl)aziridin-2-yl]acrylaldehyde (195), they synthesized enantioenriched cyclopropylaziridine (196) using (181) as organocatalyst and diethyl bromomalonate 89 as nucleophile in good yield (68%) and excellent diastereoselectivity (>30 : 1) (Scheme 42). 184 This interesting design represents a significant advancement in the field of stereoselective synthesis.…”

“…Mechanistic investigations revealed that the reaction proceeded through an initial activation of the α,β-unsaturated aldehyde (197) In the same year, Li and Wang reported a similar transformation by substituting the organocatalyst with chiral diphenylprolinol TBDMS ether (234) and using triethylamine as a base under mild reaction conditions (Scheme 52). 195 Veselý and coworkers applied a similar approach for the enantioselective synthesis of 1,2,3-trisubstituted cyclopropanes using heteroaryl chloride ( 102) as an ambiphilic reagent. In this method, the MIRC reaction was performed between 5-(chloromethyl)-3-methyl-4-nitroisoxazole ( 102) and α,β-unsaturated aldehydes (235), using catalyst 239 resulting in the formation of the desired cyclopropanes (236,237,238) in high yields (up to 98%), moderate diastereoselectivity and excellent enantioselectivity (99% ee), and (Scheme 53).…”

“…In the same year, Li and Wang reported a similar transformation by substituting the organocatalyst with chiral diphenylprolinol TBDMS ether ( 234 ) and using triethylamine as a base under mild reaction conditions (Scheme 52). 195…”