Construction of Tetraalkylated Chiral Carbon Center utilizing Enantioselective Carroll rearrangement

Neovibsanins A和B是vibsane-type二萜类化合物，由Fukuyama等人从Viburnum awabuki的叶子中分离得到，由于其具有挑战性的结构和有趣的神经营养活性而引起了广泛的合成关注。研究发现，它们能显著促进ngf介导的PC12细胞的神经突生长，因此有可能成为治疗阿尔茨海默病等神经退行性疾病的药物。最近，Nishizawa等人实现了（±）-neovibsanin b的全合成，但尚未有对映体选择性合成neovibsanins的研究发表。在此，我们报道了基于不对称1,4加成和改性根岸环碳化-羰基化酯化串联反应的(+)-neovibsanin B的首次对映控制形式合成。以4-戊烷-1-醇为原料，经3步反应得到（H_2C=CH）_2Cu(CN)Li_2与三取代α，β-羧酸衍生物1的不对称1,4加成反应，得到95 (11S):5 （11R）的非对映体混合物2，收率高。经硅胶柱层析分离后，光学纯的(11S)-2立体选择性转化为(Z)-碘烯烃3。然后我们尝试构建环己烯核，发现在24当量的MeOH， 4 MPa的CO， 60℃的反应条件下，可以生成4，产率约为70%的非对映体混合物（10R:10S=2.6:1）。4的每个非对映体都很容易通过硅胶柱层析分离得到(10R)-4和(10S)-4。此外，用MeOLi在MeOH中处理不需要的异构体(10S)-4得到平衡的非对映体。因此，重复该操作可以将不需要的异构体(10S)-4转化为需要的异构体(10R)-4。最后(10R, 11S)-4转化为Imagawa-Nishizawa的中间体5，得到光纯形式（[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)).