Single-atom catalysts (SACs) and few-atom metal clusters have shown exceptional catalytic activity in various organic reactions, surpassing traditional organometallic complexes. However, their application in the total synthesis of complex molecules remains largely unexplored. This study aims to evaluate the efficacy of these ultrasmall catalysts in a multi-step synthesis. The chosen target, (±)-Licarin B, is a dehydrobenzofurane neolignan with diverse biological activities, but its synthesis has been limited by inefficient methodologies. Previous syntheses relied on non-catalytic procedures and protecting groups, resulting in low overall yields. This research proposes a new synthetic route for (±)-Licarin B, incorporating SACs and metal clusters at various stages, to enhance efficiency and potentially improve yield and sustainability. The study also seeks to identify and explain the role of any unexpected selectivities. The large family of lignans and neolignans represents an important area of research, offering a diversity of compounds with pharmaceutical properties. The dehydrobenzofurane subfamily, to which Licarin B belongs, is of particular interest. Despite this pharmaceutical interest, there is a notable lack of efficient synthetic routes for many of these compounds. This research addresses this gap by developing a modern catalytic approach.

The literature extensively documents the remarkable catalytic activity of SACs and few-atom metal clusters in various transformations, including hydrogenation, oxidation, hydroaddition, and cross-coupling reactions. These catalysts often exhibit higher metal efficiency than their organometallic counterparts, and several studies demonstrate successful applications in the synthesis of biologically relevant molecules. However, there is a limited body of work exploring their use in complex, multi-step syntheses, particularly in late-stage functionalizations. The existing syntheses of (±)-Licarin B are outdated and inefficient, highlighting the need for the development of a contemporary and streamlined approach.

The synthesis of (±)-Licarin B was achieved through an 11-step linear approach, employing different SACs and metal clusters as catalysts for several key steps. The synthesis started with commercially available and inexpensive starting materials. Detailed reaction conditions and characterization methods for each step are extensively provided. The characterization of the metal catalysts utilized spectroscopic techniques such as UV-vis, MALDI-TOF, and, in some cases, aberration-corrected HAADF-STEM and XANES/EXAFS. The authors detailed procedures for the synthesis of each of the individual and few-atom metal catalysts involved, including Pd₁, Cu_2-7, Pd_2-3, and Pt_3-5. Specific reaction conditions for each step (including temperature, time, solvent, equivalents of reagents, and catalyst loading) were meticulously described, enabling reproducibility. The characterization of intermediates and the final product involved techniques such as ¹H NMR, ¹³C NMR, DEPT, GC-MS, ESI-MS, IR, and HRMS. Metal content analysis was performed using ICP-OES. The study also details the experimental conditions for the unusual NaBH₄-mediated alkene hydrogenation and the acid-catalyzed intermolecular carbonyl-olefin metathesis. The trans selectivity of the final alkene product was verified through a comparison with a commercial sample of enantiomerically pure (±)-Licarin B and an independent synthesis using the Takai reaction. The characterization of the final product was done by FT-IR, GC, UV/vis spectrophotometry and ¹H and ¹³C NMR.

The research successfully synthesized (±)-Licarin B in 11 linear steps, with six steps catalyzed by individual metal atoms and few-atom metal clusters in solution. The overall yield achieved (13.1%) surpasses the yields reported in previous syntheses (as low as 2.5%). Specific catalytic highlights include: (1) Efficient aerobic oxidation of benzyl alcohol to benzoic acid using Pd₁; (2) Selective mono-hydroxylation of a di-iodo derivative using Cu_2-7 clusters; (3) Sonogashira coupling using Pd_2-3 clusters, achieving a higher turnover number (TON) than traditional organometallic catalysts; (4) Regioselective Markovnikov hydrosylilation of a terminal alkyne using Pt_3-5 clusters. The research also uncovers unexpected reactions: (1) Selective alkene hydrogenation over ketone reduction using NaBH₄, which seems to be metal free; (2) High trans selectivity achieved in an intermolecular carbonyl-olefin metathesis reaction in a late-stage synthetic step. The final product was carefully characterized and compared to commercial samples, confirming the structure and regioselectivity of the synthesized (±)-Licarin B.

The results demonstrate the significant advantages of using individual metal atoms and ultrasmall clusters in the total synthesis of complex molecules. The improved efficiency of the catalytic steps, combined with the use of mild reaction conditions, translates to a considerably higher overall yield compared to previously reported syntheses. The unexpected selectivity observed in the NaBH₄ reduction and the successful implementation of the carbonyl-olefin metathesis reaction showcase the potential of these catalysts in accessing non-traditional synthetic pathways. The synthetic route is adaptable for the preparation of other members of the neolignan family, and the methodology paves the way for the efficient synthesis of other dehydrobenzofurane neolignans with potential pharmacological properties. The study highlights the importance of exploring non-traditional catalytic systems in developing more efficient and sustainable synthetic strategies for the construction of complex natural products.

This research successfully demonstrates a more efficient and sustainable synthesis of (±)-Licarin B, employing soluble individual metal atoms and ultrasmall clusters as catalysts for key synthetic steps. The findings highlight the potential of these catalysts for the total synthesis of complex natural products. The methodology is versatile and could be adapted to prepare other neolignans, furthering research in this biologically active family of compounds. Future studies could explore the use of supported catalysts or heterogeneous conditions to further enhance sustainability and scalability.

The study primarily focuses on the synthesis of the racemic mixture of (±)-Licarin B. While the methodology provides access to both diastereomers, a future direction would be to investigate strategies to achieve enantioselective synthesis. Also, the yield for some intermediate steps, such as the Markovnikov hydrosylilation, could be potentially improved through further optimization of reaction conditions. Further investigations into the mechanism of the NaBH₄-mediated alkene hydrogenation are needed to fully understand the remarkable selectivity observed. While a commercial sample of enantiomerically pure Licarin B was used for comparison, the purity of the commercial sample may potentially impact the comparison.