Construction of Tetraalkylated Chiral Carbon Center utilizing Enantioselective Carroll rearrangement

Neovibsanins A和B是由Fukuyama等从日本荚莲（Viburnum awabuki）的叶中分离得到的荚烷型二萜类化合物，由于其具有挑战性的结构和有趣的神经营养活性，吸引了相当多的合成关注。已经发现它们显著促进NGF介导的PC 12细胞的神经突生长，因此已经显示出作为治疗神经退行性疾病如阿尔茨海默病的药物的潜力。最近，Nishizawa等实现了（±）-新维布沙宁B的全合成。然而，没有对映体选择性的合成研究neovibsanins已公布。本文首次报道了基于对称1，4-加成和改进的Negishi环状碳钯化-羰基酯化串联反应的（+）-新青藤碱B的对映体控制的形式合成。以4-戊炔-1-醇为原料，经3步反应制得三取代α，β-羧酸衍生物1，再与（H_2C=CH）_2Cu（CN）Li_2进行不对称1，4-加成反应，得到非对映异构体混合物2，产率为95（11 S）：5（11 R）。通过硅胶柱色谱分离后，光学纯的（11 S）-2立体选择性地转化为（Z）-碘代烯烃3。然后我们尝试构建环己烯核，发现在24当量的甲醇、4 MPa的CO和60 ℃的温度下，在约100 ℃下形成4。70%产率，为非对映异构体混合物（10 R：10 S =2.6：1）。通过硅胶柱色谱法容易地分离4的每种非对映异构体，得到（10 R）-4和（10 S）-4。此外，用MeOH中的MeOLi处理不希望的异构体（10 S）-4，得到平衡的非对映异构体。因此，重复该操作能够将不需要的异构体（10 S）-4转化为所需的异构体（10 R）-4。最后，（10 R，11 S）-4转化为Imagawa-Nishizawa的中间体5，为光学纯形式（[α]D^<22>+20.1（c 1.05，MeOH））。

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)).