Synthesis of chiral 3-substituted phthalides by a sequential organocatalytic enantioselective aldol-lactonization reaction. Three-step synthesis of (S)-(-)-3-butylphthalide.
The development of efficient methods for the facile construction of important molecular frameworks is an important goal in organic synthesis. Chiral 3-substituted phthalides are widely distributed in a large collection of natural products with broad, potent, and potentially path-pointing biological activities. In this investigation, we have uncovered an unprecedented organocatalytic asymmetric aldol-lactonization reaction of 2-formylbenzoic esters with ketones/aldehydes for convenient construction of the enantioenriched "privileged" scaffold. As a result of the sensitive nature of substrate structures of an organocatalytic enantioselective aldol reaction, after extensive optimization of reaction conditions, catalyst L-prolinamide alcohol IV is identified as the best promoter. Interestingly, it is found that in this reaction, addition of an acid additive PhCO(2)H can significantly enhance reaction efficiency with use of only as low as 2.5 mol % IV for the process. Moreover, due to the sensitivity of reaction conditions toward a sequential aldol-lactonization process without affecting enantioselectivity and racemization, it is essential to remove the catalyst for the subsequent facile lactonization reaction in the presence of K(2)CO(3). The aldol-lactonization processes serve as a powerful approach to the preparation of synthetically and biologically important 3-substituted phthalides with a high level of enantioselectivities. A 3-step catalytic asymmetric synthesis of the natural product of 3-butylphthalide is reported.
Zhang
Haoyi
H
Department of Pharmaceutical Sciences, School of Pharmacy, East China University of Sciences & Technology, Shanghai 200237, China.
Zhang
Shilei
S
Liu
Lu
L
Luo
Guangshun
G
Duan
Wenhu
W
Wang
Wei
W
D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D003500:Cyclization; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000447:Aldehydes; D001572:Benzofurans; D007659:Ketones; C027125:3-n-butylphthalide; C082022:phthalide