Brasholz Malte, Reissig Hans-Ulrich, Zimmer Reinhold
Freie Universität Berlin, Institut für Chemie and Biochemie, Takustrasse 3, D-14195 Berlin, Germany.
Acc Chem Res. 2009 Jan 20;42(1):45-56. doi: 10.1021/ar800011h.
As master craftsmen, modern synthetic chemists are challenged to achieve remarkable feats of efficiency and elegance toward molecular targets. The nature of this pursuit necessitates the collection of synthetic repertoires that are tried and true. With methodologies and pathways increasingly scrutinized, the adept chemist must seek out propitious tools to incorporate into the arsenal. With this in mind, this Account highlights the versatility of alkoxyallenes as precursors to valuable heterocyclic building blocks for such efforts as natural product synthesis. Accessed by the etherification of either propargyl alcohols or propargylic halides, alkoxyallenes are obtained after base-catalyzed isomerizations of the propargylic ethers. A host of umpolung synthons are available through this scheme after metalation, generating C(3) nucleophiles synthetically equivalent to vital anionic and zwitterionic synthons. Reactions with a diverse set of heteroatomic electrophiles yield carbohydrates, spiroketals, alkaloids, and heteroaromatics via [3 + 2] or [3 + 3] cyclizations. By employing lithiated alkoxyallenes into transformation routes, the natural product chemist can utilize this methodology as a viable resource in stereoselective synthesis. A survey of our own utilization of alkoxyallenes along synthetic pathways toward natural product targets reveals their suitability for generating advantageous precursors. A set of four stereoisomeric 2,6-dideoxyhexoses were stereoselectively obtained after an initial lithiated alkoxyallene and lactaldehyde cyclization, followed by the oxidative ring opening of the dihydrofurans. Through the addition of a lithiated alkoxyallene to a functionalized benzaldehyde, an essential spiroketal diastereomer was rapidly achieved in a few steps. We greatly benefitted from alkoxyallenes in the construction of complex nitrogen-containing synthetic targets, whether pyrrolidine alkaloids, substituted imidazole derivatives, or functionalized pyridines. A pinnacle example of their utility came from the coupling of alkoxyallenes to nitrones affording 1,2-oxazines, which served as a gateway to an array of novel polyfunctionalized compounds such as aminopolyols, hydroxylated pyrrolidines, or carbohydrate mimetics. Alkoxyallenes have proven themselves to be powerful C(3) building blocks toward complex molecular targets, revealing novel pathways to a variety of desirable highly functionalized heterocycles. In our view, the full extent of their synthetic utility has yet to be truly realized.
作为技艺精湛的大师，现代合成化学家面临着挑战，要在朝着分子目标进发的过程中实现效率和精妙性方面的非凡成就。这种追求的本质需要收集经过实践检验且可靠的合成方法库。随着方法和途径受到越来越严格的审查，熟练的化学家必须寻找合适的工具纳入其武器库。考虑到这一点，本综述突出了烯丙基醚作为有价值的杂环结构单元前体的多功能性，可用于诸如天然产物合成等工作。通过丙炔醇或丙炔卤的醚化反应可得到烯丙基醚，再经过碱催化的异构化反应得到烯丙基醚。通过该方案，在金属化后可得到一系列极性反转合成子，生成在合成上等同于重要阴离子和两性离子合成子的C(3)亲核试剂。与各种杂原子亲电试剂的反应通过[3 + 2]或[3 + 3]环化反应生成碳水化合物、螺缩酮、生物碱和杂芳烃。通过将锂化的烯丙基醚应用于转化路线，天然产物化学家可以将这种方法作为立体选择性合成中的一种可行资源。对我们自己在沿着合成途径制备天然产物目标时对烯丙基醚的利用情况进行的调查表明，它们适合生成有利的前体。在最初的锂化烯丙基醚与乳醛环化反应之后，接着进行二氢呋喃的氧化开环反应，立体选择性地得到了一组四个立体异构的2,6 - 二脱氧己糖。通过将锂化的烯丙基醚加成到官能化的苯甲醛上，几步之内就迅速得到了一种重要的螺缩酮非对映异构体。无论是在构建吡咯烷生物碱、取代咪唑衍生物还是官能化吡啶等复杂含氮合成目标时，我们都从烯丙基醚中受益匪浅。它们效用的一个巅峰例子来自烯丙基醚与硝酮的偶联反应，生成1,2 - 恶嗪，这为一系列新型多官能化化合物，如氨基多元醇、羟基化吡咯烷或碳水化合物模拟物，提供了一条途径。烯丙基醚已证明自身是构建复杂分子目标的强大C(3)结构单元，揭示了通往各种所需的高度官能化杂环的新途径。在我们看来，它们合成效用的全部范围尚未真正实现。
