Thieme Cheminar: Rising Stars in Organic Chemistry, Session 5

The Science of Synthesis Early Career Board (ECAB), established in 2022, recognizes some of the most up-and-coming young organic chemists. We are very proud to present ECAB members of the 2025 board as speakers in this Rising Stars Cheminar. In this Thieme Cheminar, Science of Synthesis Early Career Advisory Board members Emma Davison (New Zealand), Chuan He (China), Tomohiro Hattori (Japan), Hyunwoo Kim (South Korea), Xiao-Hui Yang (China), and Durga Prasad Hari (India) will present their research. The session is chaired by Shu Kobayashi (Japan). Practical and Concise Synthesis of Nucleoside Analogues Nucleoside analogues possess a rich history spanning half a century as stand-alone treatments for cancer and viral infections. Nucleoside analogues are also indispensable commodities in the development of antisense oligonucleotides. However, the full exploitation of nucleoside analogues has been limited by their synthetic access. Despite decades of research, contemporary syntheses of nucleoside analogues are inefficient, reliant on chiral pool starting materials and are not readily amenable to diversification. In 2020 we disclosed a straightforward synthesis of nucleoside analogues from achiral starting materials in only 2-3 steps. The process employs proline catalysis to fluorinate simple heteroaryl-substituted aldehydes, which are then directly engaged in a one-pot enantioselective aldol reaction with a dioxanone [α-fluoroaldol reaction (αFAR)]. Reduction or organometallic addition followed by intramolecular annulative fluoride displacement (AFD) then forges the nucleoside. This novel methodology enables direct access to C3′/C5′ protected and C4′ functionalised nucleoside analogues such as locked nucleic acids (LNAs). Additionally, the process provides flexibility in nucleobase substitution and D- or L-configuration. More recently, we have recently described detailed protocols for the preparation of C3′/C5′-acetonide protected uridine on both research ( 3 g) and process ( 30 g) scales. Variations in the protocol for both scales were detailed alongside trouble shooting aspects of the protocols. New Adventures in Silicon-Stereogenic Silane Chemistry While carbon-centered chiral compounds have been extensively investigated, the chemistry of silicon-stereogenic silanes remains significantly underdeveloped. The stereoselective construction of enantioenriched organosilanes bearing silicon stereocenters presents a significant challenge, attributed to silicon's unique physicochemical characteristics. Over the past six years, our team has developed a series of Catalytic Asymmetric Dehydrogenative Coupling reactions towards Si-stereogenic silanes (Si-CADC) with high efficiency. This general Si-CADC strategy establishes a versatile platform for accessing diverse silicon-stereogenic architectures, addressing longstanding limitations in enantiocontrol, synthetic practicality, and scalability. The demonstrated efficacy of Si-CADC not only advances fundamental chiral organosilicon chemistry but also unlocks potential applications in asymmetric catalysis, functional materials, and pharmaceutical development. Convergent Peptide Elongation Using Unprotected Amino Acids In peptide synthesis, protection-deprotection process, which is repeated for each elongation reaction, has been cited as an issue due to the reduction of total yield and the production of huge amounts of waste. We have established a method for regioselective silyl protection of unprotected amino acids in situ that allows peptide bond formation to proceed smoothly at the desired position and yields the corresponding silacyclic dipeptide in high yield. Electrochemistry Unlocks New Possibilities in Unsaturated C-C Bond Functionalization In the first part of the talk, the strategic application of electricity in cobalt-MHAT catalysis will be discussed, which could provide a new way for the reactive intermediate to outcompete undesired side reactions. Moreover, this electrocatalytic platform has the potential to function as an efficient bypass for unfavorable intramolecular reactions which possess inherent kinetic challenges. In the second part, difluoromethylative functionalization of unsaturated C-C bonds under electrochemical conditions will be discussed. Despite the high prevalence and importance of vicinal hydrogen bond donors in pharmaceutical agents, a general synthetic method for doubly difluoromethylated compounds remains extremely rare. By leveraging electrochemistry to oxidize Zn(CF2H)2(DMPU)2 conventionally utilized anionic transmetalating sourcewe paved a way to utilize it as both CF2H radical and anion source to deliver CF2H groups in both terminal and internal position of alkenes, thereby granting access to doubly-difluoromethylated alkanes. Finally, a new redox strategy that obviates the need for redox-mediators, leveraged by direct photoactivation of substrate for chemical reactions followed by the electrochemical oxidation of photon-induced intermediates, will be discussed. Catalytic Alkene Hydrofunctionalization Catalytic hydrofunctionalization of readily available alkenes represents one of the most straightforward strategies for constructing diverse carbon-heteroatom (C–X) bonds. Nevertheless, achieving high levels of regio-, enantio- and chemo-selectivity remains a long-standing challenge. By employing metal-hydride catalysis via an inner-sphere pathway or ligand-to-ligand hydrogen transfer (LLHT), we have successfully achieved hydroamination, hydroalkoxylation, hydroselenation, hydrochlorination, hydrothiolation, and carbothiolation of a series of alkenes. Mechanistic studies combined with theoretical calculations have elucidated the origin of the excellent selectivities observed in these transformations. Carbene Mimics from Strained Rings Ring-strain in organic molecules is a powerful driving force that promotes reactivity through strain-release, allowing the facile construction of a myriad of useful scaffolds via ring-opening or ring-expansion reactions. Carbene chemistry has been extensively studied, leading to numerous applications in organic synthesis, including X–H insertions (where X can be C, Si, N, O, etc.), cyclopropanations, ylide formations, and 1,2-migrations. Due to their high reactivity, carbenes are particularly well-suited for initiating cascade sequences, which results in the rapid generation of structural complexity. The most common method for generating carbenes involves highly reactive diazoalkanes, typically using metal catalysts or photoirradiation. Alternative precursors for carbenes include substituted triazoles or alkynes combined with pyridine N-oxides, often utilizing transition metal catalysts. Generating carbenes through the activation of C−C bonds presents significant advantages, as it offers unique opportunities for constructing the backbones of organic molecules. However, this process is challenging due to the inertness of C−C bonds and the lack of metal-carbon bond interactions. In this context, the ring strain energy in small organic molecules has been effectively utilized to promote the activation of these difficult C−C bonds. In this lecture, I will first discuss how we generate carbene mimics from bicyclo[1.1.0]butane using Rh-catalysis for the synthesis of skipped dienes.[1] Next, I will present our approach to utilizing ring strain in [1.1.1]propellane to access carbenes for [2,3]-sigmatropic rearrangements[2] and skeletal editing of ketones.[3]

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