A compound’s overall contour impacts its ability to elicit biological response, rendering access to distinctly shaped molecules desirable. A natural product’s framework can be modified, but only if it is abundant and contains suitably modifiable functional groups. Here we introduce a programmable strategy for concise synthesis of precisely altered scaffolds of scarce bridged polycyclic alkaloids. Central to our approach is a scalable catalytic multi-component process that delivers diastereo- and enantiomerically enriched tertiary homoallylic alcohols bearing differentiable alkenyl moieties. We used one product to launch progressively divergent syntheses of a naturally occurring alkaloid and its precisely expanded, contracted and/or distorted framework analogues (average number of steps/scaffold of seven). In vitro testing showed that a skeleton expanded by one methylene in two regions is cytotoxic against four types of cancer cell line. Mechanistic and computational studies offer an account for several unanticipated selectivity trends.

化合物的整体轮廓会影响其引发生物反应的能力，从而需要获得形状独特的分子。天然产物的框架可以被修改，但前提是它丰富并且包含适当可修改的官能团。在这里，我们介绍了一种可编程策略，用于简洁合成精确改变的稀有桥连多环生物碱的支架。我们方法的核心是可扩展的催化多组分工艺，可提供带有可区分的烯基部分的非对映体和对映体富集的叔高烯丙醇。我们使用一种产品对天然存在的生物碱及其精确扩展、收缩和/或扭曲的框架类似物进行逐步发散的合成（平均步骤数/支架数为七个）。体外测试表明，在两个区域由一个亚甲基扩展的骨架对四种类型的癌细胞系具有细胞毒性。机理和计算研究提供了几种意想不到的选择性趋势的解释。