Total Synthesis of Paliurine E by a Highly Convergent Block Approach

ABSTRACT Macrocycles occupy a privileged position in chemistry, biology and medicine, yet their broader exploitation is curtailed by the lack of general, efficient synthetic strategies. Current approaches to macrocycle construction rely largely on stepwise linear assembly, protecting‐group‐intensive fragment coupling, or symmetry‐restricted cyclization methods, all of which impose substantial limitations on efficiency, convergence, and structural diversity. Here we report a fundamentally new conceptual framework for macrocycle synthesis based on the direct, convergent assembly of two different bifunctional, unprotected building blocks. This “block” strategy constitutes the most straightforward entry to unsymmetrical macrocyclic architectures, minimizing step count and optimizing time economy while circumventing protecting‐group manipulations. Despite formidable challenges arising from competing oligomerization, stringent dilution requirements and the need for exceptional chemo‐ and regioselectivity, this approach is shown to be viable and its efficiency is demonstrated through an unusually concise total synthesis of the macrocyclic natural product paliurine E.