Construction of Tetraalkylated Chiral Carbon Center utilizing Enantioselective Carroll rearrangement

点击翻译按钮获取中文摘要

Neovibsanins A and B, vibsane-type diterpenoids, which were isolated from the leaves of Viburnum awabuki by Fukuyama et al., have attracted considerable synthetic attention because of their challenging structures combined with interesting neurotrophic activity. They have been found to significantly promote the neurite outgrowth of NGF-mediated PC12 cells, and thus have shown potential as drugs for the treatment of neurodegenerative diseases such as Alzheimer's disease. Recently, Nishizawa et al. achieved the total synthesis of (±)-neovibsanin B. However, no enantioselective synthetic study on neovibsanins has been published. Herein, we report the first enantiocontrolled formal synthesis of (+)-neovibsanin B based on asynmmetric 1,4-addition and a modified Negishi cyclic carbopalladation-carbonylative esterification tandem reaction. The asymmetric 1,4-addition reaction of (H_2C=CH)_2Cu(CN)Li_2 to the trisubstituted α,β-carboxylic acid derivative 1, which was prepared from 4-pentyne-1-ol over 3 steps, gave rise to 2 as a diastereomeric mixture of 95 (11S):5 (11R) in good yield. After the separation by silica gel column chromatography, the optically pure (11S)-2 was stereoselectively transformed to (Z)-iodoalkene 3. Then we tried to construct the cyclohexene core and found that the following reaction conditions of 24 equiv of MeOH, 4 MPa CO and a temperature of 60 ℃, led to the formation of 4 in ca. 70% yield as a diastereomeric mixture (10R:10S=2.6:1). Each diastereomer of 4 was readily separated by silica gel column chromatography to give (10R)-4 and (10S)-4. Furthermore, treatment of the undesired isomer, (10S)-4 with MeOLi in MeOH gave the equilibrating diastereomers. Thus, repeating this operation enabled the conversion of the undesired isomer (10S)-4 to the desired isomer (10R)-4. Finally (10R, 11S)-4 was converted to the Imagawa-Nishizawa's intermediate 5 as an optically pure form ([α]D^<22> +20.1 (c 1.05, MeOH)).