Department of Chemistry, Merkert Chemistry Center , Boston College , Chestnut Hill , Massachusetts 02467 , United States.
Supramolecular Science and Engineering Institute , University of Strasbourg , CNRS, 67000 Strasbourg , France.
J Am Chem Soc. 2019 Jul 31;141(30):12087-12099. doi: 10.1021/jacs.9b05465. Epub 2019 Jul 17.
Synthesis of complex bioactive molecules is substantially facilitated by transformations that efficiently and stereoselectively generate polyfunctional compounds. Designing such processes is hardly straightforward, however, especially when the desired route runs counter to the inherently favored reactivity profiles. Furthermore, in addition to being efficient and stereoselective, it is crucial that the products generated can be easily and stereodivergently modified. Here, we introduce a catalytic process that delivers versatile and otherwise difficult-to-access organoboron entities by combining an allenylboronate, a hydride, and an allylic phosphate. Two unique selectivity problems had to be solved: avoiding rapid side reaction of a Cu-H complex with an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly utilized boron-copper exchange. The utility of the approach is demonstrated by applications to concise preparation of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and enantioselective synthesis and structure confirmation of netamine C, a member of a family of anti-tumor and anti-malarial natural products. Completion of the latter routes required the following noteworthy developments: (1) a two-step all-catalytic sequence for conversion of a terminal alkene to a monosubstituted alkyne; (2) a catalytic S2'- and enantioselective allylic substitution method involving a mild alkylzinc halide reagent; and (3) a diastereoselective [3+2]-cycloaddition to assemble the polycyclic structure of a guanidyl polycyclic natural product.
复杂生物活性分子的合成可以通过高效和立体选择性地生成多功能化合物的转化来极大地促进。然而，设计这样的过程并非易事，特别是当所需的路线与固有反应性模式相悖时。此外，除了高效和立体选择性之外，生成的产物可以容易地和立体选择性地修饰也是至关重要的。在这里，我们介绍了一种催化过程，该过程通过结合烯丙基硼酸酯、氢化物和烯丙基磷酸盐来提供多功能且难以获得的有机硼实体。必须解决两个独特的选择性问题：避免铜-氢配合物与烯丙基磷酸盐的快速副反应，同时促进其与烯丙基硼酸酯的加成，而不是通常使用的硼-铜交换。该方法的实用性通过应用于 pumiliotoxin B（肌痛，心脏毒性）的线性片段的简洁制备和 netamine C 的对映选择性合成和结构确证得到证明，netamine C 是一组具有抗肿瘤和抗疟疾活性的天然产物的成员。完成后两个路线需要以下值得注意的发展：（1）将末端烯烃转化为单取代炔烃的两步全催化序列；（2）涉及温和的烷基卤化锌试剂的催化 S2'-和对映选择性烯丙基取代方法；和（3）用于组装胍基多环天然产物的多环结构的非对映选择性[3+2]-环加成。
