A flexible enantioselective synthesis of (+)-centrolobine and 5-epi-diospongin-A using asymmetric transfer hydrogenation/tandem Grubbs cross-metathesis/oxy-Michael reaction as key steps

An efficient enantioselective synthesis of (+)-centrolobine and 5-epi-diospongin-A was achieved by the use of asymmetric transfer hydrogenation (ATH)/tandem Grubbs cross-metathesis/oxy-Michael reaction. Furthermore, this strategy allows for diastereodivergent access to every representative member of the family.

Graphical abstractAn efficient enantioselective synthesis of (+)-centrolobine and 5-epi-diospongin-A was developed. Essential to the development of this strategy was the successful execution of asymmetric transfer hydrogenation/tandem Grubbs cross-metathesis/oxy-Michael reaction.Figure optionsDownload full-size imageDownload as PowerPoint slide

(S)-Ethyl 3-hydroxy-3-phenylpropanoateC11H14O3[α]D23=-43 (c 1, CHCl3)96% eeSource of chirality: Asymmetric transfer hydrogenationAbsolute configuration: (S)

(R)-Ethyl 5-hydroxy-5-(4-methoxyphenyl)pentanoateC14H20O4[α]D23=+22.5 (c 1, CHCl3)Source of chirality: Asymmetric transfer hydrogenationAbsolute configuration: (R)

2-((2R,4R,6S)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-yl)-1-phenylethanoneC19H20O3[α]D23=-11.3 (c 0.6, CHCl3)Source of chirality: Asymmetric transfer hydrogenationAbsolute configuration: (2R)

1-(4-(tert-Butyldimethylsilyloxy)phenyl)-2-((2S,6R)-6-(4-methoxyphenyl)tetrahydro-2H-pyran-2-yl)ethanoneC26H37O4Si[α]D23=+9.5 (c 1.1, CHCl3)Source of chirality: Asymmetric transfer hydrogenationAbsolute configuration: (2S)