From Complex Targets to General Methods: Celebrating Jieping Zhu's 60th Birthday

Born in 1965 in Xiaoshan (Hangzhou, China), Jieping Zhu moved to France after completing his master's degree to pursue doctoral studies at Université Paris-XI, carried out at the Institut de Chimie des Substances Naturelles (ICSN) under the supervision of Profs. H.-P. Husson and J.-C. Quirion. After postdoctoral research with Sir D. H. R. Barton, he was appointed CNRS Researcher at the ICSN in 1992. From the outset of his career, Jieping Zhu's research has been guided by a clear philosophy: convergent synthesis inspired by structurally complex natural products of high biological and pharmaceutical relevance, with new synthetic methods emerging directly from target-oriented challenges (vancomycin, ecteinascidins, tiacumicin, among others) [1]. Vancomycin and related glycopeptide antibiotics were among the very first and particularly demanding targets addressed during the ICSN period. At that time, the construction of highly functionalized, stereochemically complex macrocycles represented a major synthetic challenge. A central contribution of this work is the development of intramolecular SNAr macrocyclizations to form biaryl ether motifs, enabling efficient access to vancomycin- and teicoplanin-inspired binding-pocket models under remarkably mild conditions [2, 3]. These studies demonstrated that macrocyclization could proceed efficiently without high-dilution conditions and that racemization-prone amino acids could be incorporated without erosion of stereochemical integrity, thereby establishing SNAr macrocyclization as a general and broadly applicable strategy for peptide-derived macrocycles [4]. In this context, atropisomerism evolved from an initially problematic feature into a controllable design element. The presence of strategically placed nitro substituents delivered atroposelective macrocyclizations and reliable configurational assignments, transforming stereochemical constraint into a synthetic advantage [5, 6]. This convergent strategy was subsequently extended to cyclopeptide alkaloids and strained aromatic macrocycles, where late-stage ring formation provided rapid access to paracyclophanes [7, 8] and other biologically relevant macrocycles [9]. Building on these advances, related design principles involving intramolecular cyclization later culminated in the total syntheses of complestatin (chloropeptin II) and arylomycins. In these cases, the development of intramolecular Suzuki–Miyaura reactions, sometimes combined with SNAr macrocyclizations, offered highly convergent construction of strained macrocyclic architectures and further demonstrated the generality of this strategy [10-12]. Zhu's program also delivered landmark syntheses of highly complex marine and indole alkaloids, notably the highly convergent total synthesis of ecteinascidin 743, addressing long-standing supply limitations of this clinically important antitumor agent, now marketed as an anticancer drug. This work was complemented by asymmetric total syntheses of ectein