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 ecteinascidin 597 and ecteinascidin 583, clearly demonstrating that stereochemical complexity could be efficiently controlled within a convergent synthetic framework 13, 14. These advances were later extended through an aziridine-based lynchpin strategy, which enabled concise asymmetric total syntheses of (–)-renieramycin M and G as well as (–)-jorumycin and jorunnamycin A, rapidly assembling complex pentacyclic frameworks 15. Innovative retrosynthetic planning, step minimization, one-pot, and domino sequences, together with key diastereoselective elements, were central to the success of this particularly demanding program. The importance of step economy is further illustrated by the protecting-group-free total synthesis of (E)- and (Z)-alstoscholarine, achieved by exploiting intrinsic reactivity rather than protecting-group control 16. This work naturally extends the target-oriented strategies developed at the ICSN and sets the stage for subsequent advances in complex molecule synthesis. In parallel with these target-oriented syntheses, Zhu developed a coherent and influential program in synthetic methodology, guided by the same principles of convergence, step economy, and complexity generation. These advances were not isolated reaction discoveries, but strategic solutions to real synthetic problems, allowing rapid access to complex, natural product–like molecules from simple starting materials. A central element of this work is Zhu's major contribution to isocyanide-based multicomponent reactions (MCRs). By moving beyond classical Ugi and Passerini reactions, his studies showed how carefully designed three- and four-component processes could become powerful tools for complexity generation 17-19. Particularly impactful were strategies combining Ugi reactions with post-condensation transformations, enabling one-pot access to heterocycles, macrocycles, and polycyclic frameworks with high bond-forming efficiency 20, 21. These MCR strategies were often integrated into domino and cascade sequences, where intermediates act as built-in activators for further cyclization or rearrangement. A key conceptual advance is traceless activation, in which transient motifs formed during an MCR—such as oxazole units—trigger macrocyclization or macrolactonization without external coupling reagents. This concept led to atom-economic and operationally simple routes to macrocycles and cyclodepsipeptides 21-23. In parallel, the scope of the Passerini and Ugi reactions was further expanded through oxidative variants, in which amines or alcohols are directly used via in situ redox activation, circumventing the need for aldehydes or preformed imines that can be unstable or difficult to access 24, 25. Zhu has also made broad contributions to metal-catalyzed synthesis, particularly using palladium and copper. Many of these transformations operate through domino or metal-switchable pathways, where small changes in catalyst or conditions lead to different molecular scaffolds 26, 27. Such strategies allowed efficient access to oxindoles, benzodiazepines, phenanthridines, and spirocycles, while offering valuable insight into catalytic reaction mechanisms 28, 29. In several transformations, transient organometallic intermediates embedded in domino sequences allowed unusual direct CH functionalization, including at C(sp3) centers, thereby enabling the rapid construction of complex architectures from simple precursors 30, 31. Zhu has made also significant contributions to asymmetric synthesis. His studies include chiral Lewis acid catalysis 32, 33, Lewis-base organocatalysis 34, and chiral Brønsted acid–catalyzed enantioselective reactions 35. These activities were pursued from the outset in an international context, including close and long-standing collaborations laying important foundations for the later development of asymmetric multicomponent reactions 32, 33. After moving to EPFL as a full professor in 2011, Zhu continued and broadened these research directions, further strengthening the interplay between total synthesis, multicomponent reactions, catalysis, and asymmetric synthesis. In the field of alkaloid total synthesis, the development of one-pot integrated oxidation/reduction/cyclization sequences led to the very efficient synthesis of complex targets such as Goniomitine 37, 36, 38, Mesicarpine 38, 39, Rhazinilam 40, Terengganensine A 41, Uleine 42, or Vocafricine A 43, among many others. The careful orchestration of these impressive reaction cascades allowed to diminish the average step counts required to access the natural products. A second key methodology exploited by the Zhu group was indoline synthesis via the TiCl3-mediated reduction of nitro compounds, which was exploited for example in the total synthesis of Aspidophylline A 44, Aspidospermidine 45, Strictamine 46, and Tubifoline 47. In addition, many other alkaloids were synthesized by developing target-specific strategies. Zhu's total synthesis work at EPFL also involved other target classes besides alkaloids, such as the peptide macrocycle Discobahamin A using a Passerini MCR as key step 48, lignan-based natural products accessed via photochemically generated radical cations 49, 50, and complex terpenes such as Crokonoid A 51 and Punctaporonin U 52. Zhu's work on catalysis continued to blossom at EPFL. Many of the new catalytic reactions developed were also used as key steps in total synthesis projects. Palladium catalysis remains a main focus of the group. Domino reactions gave access to complex (hetero)cyclic systems 53-56. The development of enantioselective Heck and aza-Heck reactions gave access to enantioenriched building blocks, which could be used in the total synthesis of natural products 57-60. Finally, starting in 2021, Jieping Zhu pioneered the use of dyotropic rearrangements in Pd(IV) catalysis 61. In this fascinating transformation, a PdC and a CC bond migrate simultaneously, enabling novel and unexpected skeletal reorganization of organic compounds. In a few years only, an impressive number of new reactions were discovered 62-72. An impressive example is the oxidative Wacker-type rearrangement of 1,1-disubstituted alkenes to give ring-expanded ketones 73. During his time at EPFL, Zhu also made major contributions to copper catalysis. A first area of research is the use of chiral copper complexes as Lewis acid in rearrangement reactions, such as the a-ketol 74 or the benzylic ester rearrangements 75. A second main area of applications is the combination of copper catalysis with radical chemistry. This enabled on one hand the development of new MCR reactions involving non-activated alkenes, resulting in multiple CC and CN bond formations 76-80,and on the other hand the activation of inert CH bonds 81-84. Finally, organocatalysis remained a main area of research for Jieping Zhu at EPFL. The use of binaphthol-based phosphoric acids and imides was at the core of this program, with especially a strong impact in enantioselective pinacol-related rearrangements (including vinylogous pinacol 85, Meinwald 86, acyloin 87 and aza-benzylic ester rearrangements 88, 89). This type of catalyst was also successfully applied to bislactones desymmetrization 90, hydrazone addition to imines 91, Diels–Alder reactions 92, and high order cycloadditions 93. Other organocatalysts investigated by Zhu at EPFL included bifunctional cinchona catalysts for atroposelective heteroannulation 94 and squaramide/urea catalysts for the Pictet–Spengler reaction 95-97. Throughout his career, Zhu has been actively engaged in academic exchanges and international cooperation. Notably, he has maintained a long-term collaboration with Wang and coworkers at the Institute of Chemistry, Chinese Academy of Sciences, and at Tsinghua University, in the field of catalytic asymmetric reactions, leading to significant advances. Although isocyanide-based multicomponent reactions have flourished in organic synthesis, their catalytic asymmetric variants remained highly challenging at the outset of this collaboration. He developed, under chiral (salen)Al(III)Cl catalysis, the first efficient enantioselective Passerini three-component reaction involving a broad range of non-chelating aldehydes, carboxylic acids, and isocyanides 98. He also reported the first example of enantioselective α-addition of α-isocyanides to imines, catalyzed by a chiral phosphoric acid, enabling the construction of chiral molecules 99. These studies established isocyanide-based multicomponent reactions as practical and powerful tools for asymmetric synthesis and laid the foundation for the subsequent development of enantioselective Ugi reactions 100. In addition, domino reactions involving tertiary enamides and isocyanides were explored, providing new methods for the construction of structurally diverse heterocyclic compounds 101, 102. In more recent years, Jieping Zhu has focused on inherently chiral macrocycles—chiral molecules devoid of conventional stereogenic elements—and has made significant contributions to the development of transition-metal-catalyzed and organocatalytic syntheses of a variety of such systems 103. These studies open new avenues for the creation of unique chiral compounds with promising applications across multiple disciplines. Together, these achievements highlight the coherence and breadth of Jieping Zhu's contributions to organic synthesis. This special collection brings together contributions from former PhD students, postdoctoral researchers, collaborators, and friends to celebrate his 60th birthday. We hope you will enjoy this collection. Yanxing Jia was born in Mancheng, Hebei, China. He studied chemistry at Lanzhou University, where he obtained his BS.c. (1997) and Ph.D. (2002) degrees with Prof. Yongqiang Tu. In 2002, he joined the group of Prof. Jieping Zhu at Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique (CNRS), France. He joined the School of Pharmaceutical Sciences of Peking University, China, as an associate professor in 2007 and was promoted to full professor in 2011. His research interests focus on the total synthesis of natural products, medicinal chemistry, and chemical biology. Mei-Xiang Wang received his B.S. from Fudan University and M.S. and Ph.D. from Institute of Chemistry, Chinese Academy of Sciences (ICCAS). After working 17 years at ICCAS, he moved to Tsinghua University in 2009. He is currently the Professor of Chemistry and the Member of Chinese Academy of Sciences. His research spans macrocyclic and supramolecular chemistry, anion-pi noncovalent bond interactions, high valent organocopper chemistry and catalysis, and (bio)catalytic enantioselective synthesis. Jérôme Waser was born in Sierre, Valais, Switzerland. He studied chemistry at ETH Zurich, where he obtained his PhD degree in 2006 with Prof. Erick M. Carreira. In 2006, he joined Prof. Barry M. Trost at Stanford University as a SNF postdoctoral fellow. Since October 2007 he has been professor of organic chemistry at the Ecole Polytechnique Fédérale de Lausanne (EPFL), where he was promoted full professor in 2019. Since 2020, he is also co-director of the National Centre of Competence in Research (NCCR) Catalysis of the Swiss National Science Foundation. Géraldine Masson obtained her Ph.D. in organic chemistry from Joseph Fourier University (Grenoble, France) in 2003, under the supervision of Dr. Sandrine Py and Prof. Yannick Vallée followed by a Marie Curie postdoctoral fellowship at the University of Amsterdam with Prof. Jan van Maarseveen and Prof. Henk Hiemstra. In 2005, she joined the CNRS at the Institut de Chimie des Substances Naturelles (ICSN) in the group of Prof. Jieping Zhu. She launched her independent research program in 2011. She was promoted to CNRS Research Director (DR2) in 2014 and to DR1 in 2020. Since 2021, she has been co-director of the CNRS–SEQENS LabCom HitCat, and since 2026 she has served as Deputy Director of the ICSN.