Catalytic asymmetric synthesis of tubifolidine
Catalytic asymmetric synthesis of tubifolidine
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DOI：
10.1021/jo981069g
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发表时间：
1998-10-16
影响因子：
3.6
通讯作者：
Shibasaki, M
中科院分区：
文献类型：
--
作者：
Shimizu, S;Ohori, K;Shibasaki, M
马钱子生物碱是一类结构复杂、分布广泛的单萜类吲哚生物碱，包括管状联苯甲素(1)、管状联苯甲素和士的宁。2这些天然产物以外消旋或自然发生的形式已经由几个小组完成了全合成。3到目前为止，除了用酶法合成马钱子外，还没有完成马钱子生物碱的催化不对称合成。因此，我们启动了一项关于这些吲哚生物碱的催化不对称合成的研究计划。20-脱乙基二联苯甲醚(2)和二乙二联苯甲醚(1)被选为第一个目标化合物。在本文中，我们报道了1和2的催化不对称合成，其中关键步骤包括丙二酸二甲酯(4)到环己酮(3)的高度实用的催化不对称Michael加成反应，以及用DDQ一锅法构建ABDE环体系。外消旋Michael加合物5的相关化合物已经被Magnus和同事4用于这些生物碱的合成研究。因此，我们首先集中于以催化不对称方式有效地合成5。我们以前开发了多种异双金属不对称配合物，用于实现许多高效的催化不对称反应，包括Michael加成反应。5事实上，使用LaNa3tris(联萘氧化物)络合物、AlLibis(联萘氧化物)络合物(ALB)或GaNabis(联萘氧化物)络合物，可以在高达93%的ee中有效地合成5。在这些催化剂中，我们得出的结论是ALB对目前的Michael加成反应最有效。此外，我们还开发了一种激活ALB的策略：在ALB中加入近1当量的碱，如BuLi和KO-t-Bu，可以在不降低高对映体过剩的情况下加速催化不对称Michael加成。5，6但仍需3-5摩尔%的催化剂才能获得高产率和高对映体过量的产物。我们打算将催化不对称Michael加成反应改进到一个实用的水平。经过多次尝试，我们高兴地发现，在反应介质中加入MS 4A7大大提高了催化不对称Michael加成反应的效率。实际上，如表1所示，使用ALB(0.3mol%)，KO-t-Bu(0.27mol%)和MS 4A，即使在室温下也能得到58in 99%ee和94%的产率。此外，我们成功地在100g规模上进行了这一反应。添加MS 4A似乎可以去除微量的H2O，否则会逐渐分解ALB-KO-t-Bu催化剂。在大量获得近乎光学纯度的5之后，我们通过高区域选择性的Fischer方法4，9，然后进行脱碳氧基化，以92%的总收率有效地将5转化为吲哚衍生物6(方案1)。同样在这个阶段，对映体过量6被确认为99%。10吲哚衍生物6以三步反应序列进一步转化为胺7(总收率38%)。预计用DDQ处理7将通过脱氢中间体一锅反应生成四环化合物8。11事实上，我们可以发现，在脱气的四氢呋喃中，7与DDQ(1.1摩尔当量)和Na2HPO4(10摩尔当量)在0℃反应1小时，8的产率为77%。据我们所知，这是唯一一个一刀切的例子
The strychnos alkaloids, which include tubifolidine (1), tubifoline, and strychnine, constitute an important group of architecturally complex and widely distributed monoterpenoid indole alkaloids. 2 Total syntheses of these natural products in the racemic or naturally occurring form have already been achieved by several groups. 3 To date, however, no catalytic asymmetric syntheses of the strychnos alkaloids have been accomplished except for syntheses involving enzymatic methods. We therefore initiated a research program into the catalytic asymmetric synthesis of these indole alkaloids. 20-Deethyltubifolidine (2) and tubifolidine (1) were selected as the first target compounds. In this note we report the catalytic asymmetric synthesis of 1 and 2 in which a highly practical catalytic asymmetric Michael addition of dimethyl malonate (4) to cyclohexenone (3), as well as a one-pot construction of the ABDE ring systems using DDQ, were involved as key steps. The related compounds of the racemic Michael adduct 5 have already been utilized, by Magnus and co-workers, 4 for the synthetic studies of these alkaloids. We thus concentrated first on the efficient synthesis of 5 in a catalytic asymmetric manner. We previously developed a variety of heterobimetallic asymmetric complexes, which we used to realize many efficient catalytic asymmetric reactions, including a Michael addition. 5 In fact, 5 was efficiently synthesized in up to 93% ee using either LaNa3tris (binaphthoxide) complex, AlLibis (binaphthoxide) complex (ALB), or GaNabis (binaphthoxide) complex. Among these catalysts, we concluded that ALB was the most effective for the present Michael addition. Moreover, we have developed a strategy for the activation of ALB: the addition of nearly 1 equiv of bases, such as BuLi and KO-t-Bu, to ALB can accelerate a catalytic asymmetric Michael addition without lowering the high enantiomeric excess. 5, 6 However, 3-5 mol% of the catalyst is still required to obtain the product in excellent yield and high enantiomeric excess. We intended to improve the catalytic asymmetric Michael addition to a practically useful level. After many attempts, we were pleased to find that addition of MS 4A7 to the reaction medium greatly improved the catalytic asymmetric Michael addition. Actually, as shown in Table 1, the use of ALB (0.3 mol%), KO-t-Bu (0.27 mol%), and MS 4A gave 58 in 99% ee and 94% yield even at room temperature. Furthermore, we successfully carried out this reaction on a 100 g scale. Addition of MS 4A appears to remove a trace amount of H2O that would otherwise gradually decompose the ALB-KO-t-Bu catalyst. Having obtained nearly optically pure 5 in large quantities, we next efficiently converted 5 to the indole derivative 6 in 92% overall yield, through a highly regioselective Fischer method4, 9 followed by decarbalkoxylation (Scheme 1). Also at this stage, the enantiomeric excess of 6 was confirmed to be 99%. 10 The indole derivative 6 was further transformed into the amine 7 in a three-step reaction sequence (38% overall yield). It was expected that treatment of 7 with DDQ would produce the tetracyclic compound 8 in a one-pot reaction through the dehydrogenated intermediate. 11 Indeed, we could find that exposure of 7 to DDQ (1.1 molar equiv) and Na2HPO4 (10 molar equiv) in degassed THF at 0 C for 1 h gave 8 in 77% yield. To the best of our knowledge, this is the only example of a one-pot construction of the