Exploiting an Interrelationship between Axial and Planar Chirality in Natural Products Total Synthesis

近年来，《自然》杂志揭示了一些具有非凡立体化学特征的耐人寻味的分子目标。最突出的是万古霉素和相关的环肽，其中不同的立体元素(原子为中心的、轴向的、平面的和环状的立体异构体)共存于单个分子中。更令人困惑的是，各种刻板印象元素可能相互关联，也可能不相关，这使得在描述这些实体时很难采用标准的命名法。我们认为，在许多情况下，平面手性而不是轴向手性是区分给定天然产物的两个非对映异构体的重要决定因素。我们的计划是通过在动力学控制下利用自由基诱导的跨环收缩来证明这一点，以制备大环结构中的平面手性菲。这将在室温下以两个不同的非对映异构体的形式存在，每个异构体都有菲的不同面被环状大环包围。用于异构化的高能垒将确保菲转化为联芳基时保持平面手性。后者将自动产生正确的轴向手性，因为这两个立体元素是相互关联的。据我们所知，这一策略以前从未在完全综合的背景下被利用过。

In recent years Nature has revealed some intriguing molecular targets with extraordinary stereochemical features. Most prominent are the vancomycins and related cyclic peptides, where different stereoelements (atom centred, axial, planar and cyclo stereoisomerism) co-exist within a single molecule. To confuse matters further, the various stereoelements may or may not be interrelated, making it hard to apply standard nomenclature when describing such entities. We believe that in many cases planar chirality rather than axial chirality is the important determinant differentiating two diastereoisomers of a given natural product. Our plan is to demonstrate this by using a radical induced transannular ring contraction under kinetic control to prepare a planar chiral phenanthrene within a macrocyclic structure. This will exist as two distinct diastereoisomers at room temperature, each with different faces of the phenanthrene enumbered by the encircling macrocycle. A high energy barrier for isomerisation will ensure that planar chirality is preserved on conversion of the phenanthrene to a biaryl. The latter will automatically be create with the correct axial-chirality, as these two stereoelements are interrelated. To the best of our knowledge this tactic has never previously been exploited in the context of total synthesis.