Increased molecular complexity correlates with improved chances of success in the drug development process. Here, a strategy for the creation of sp3-rich, non-planar heterocyclic scaffolds suitable for drug discovery is described that obviates the need to generate multiple stereogenic centers with independent control. Asymmetric transfer hydrogenation using a tethered Ru-catalyst is used to efficiently produce a range of enantiopure cyclic hydrazine building blocks (up to 99% ee). Iterative C-N functionalization at the two nitrogen atoms of these compounds produces novel hydrazine and hydrazide based chemical libraries. Wide chemical diversification is possible through variation in the hydrazine structure, use of different functionalization chemistries and coupling partners, and controlled engagement of each nitrogen of the hydrazine in turn. Principal Moment of Inertia (PMI) analysis of this small hydrazine library reveals excellent shape diversity and three-dimensionality. NMR and crystallographic studies confirm these frameworks prefer to orient their substituents in three-dimensional space under the control of a single stereogenic center through exploitation of the fluxional behavior of the two nitrogen atoms.

中文翻译：

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利用氮通量易于获得的富含sp3的环状肼骨架。

分子复杂性的提高与药物开发过程中成功机会的提高相关。在此，描述了用于创建适合药物发现的富含sp3的非平面杂环支架的策略，该策略消除了产生具有独立控制的多个立体异构中心的需要。使用束缚的Ru催化剂进行不对称转移氢化可有效生产一系列对映纯的环状肼结构单元（ee最高可达99％）。在这些化合物的两个氮原子上进行的CN迭代官能化可生成基于肼和酰肼的新型化学文库。通过改变肼的结构，使用不同的官能化化学物质和偶联伙伴以及依次控制肼的每个氮，可以实现广泛的化学多样化。这个小型肼库的惯性矩（PMI）分析显示出极好的形状多样性和三维性。NMR和晶体学研究证实，这些框架更倾向于通过利用两个氮原子的通量行为，在单个立体中心的控制下，将其取代基定向在三维空间中。