Prof. Zhi-Xiang Yu and his students at the College of Chemistry and Molecular Engineering, Peking University are interested in inventing ring formation reactions that could become tools for synthetic chemists. They are also endeavoring to apply these reactions in the synthesis of natural products and pharmaceuticals. So far, a dozen of ring formation reactions (such as four-types of [3 + 2], [3 + 2 + 1], [5 + 1], [4 + 2], [5 + 2], [4 + 2 + 1], [5 + 2 + 1], [7 + 1], benzo-[7 + 1] reaction, ene-diene cycloisomerization, diene-diyne cycloisomerization etc.) have been developed in the Yu group, and several of these reactions have been used in synthesizing natural products by the Yu and other groups in the world, as briefly summarized in Fig. 1.
Fig. 1 Selected ring formation reactions developed in the Yu group and application of some of these reactions in the synthesis of natural products.
Recently, Prof. Yu and his students developed Rh and Zn cocatalyzed [4 + 2] cycloaddition of newly designed yne-vinylcyclobutanones, which can generate 5/6 or 6/6 bicyclic products with all-carbon quaternary bridgehead center (Fig. 2). The reaction has broad scope and can realize chirality transfer from enantio-enriched substrates to the cycloadducts. The key to the success of this [4 + 2] reaction is the introduction of a vinyl group to cyclobutanones, which helps the C−C cleavage of vinylcyclobutanones via oxidative addition. This C−C cleavage step is synergistically aided by Zn coordination to the carbonyl group of vinylcyclobutanones. Of the same importance, visual kinetic analysis and computational studies have been carried out to support the dual activation in the rate-determining C−C cleavage, to derive the rate law of the [4 + 2] reaction, to understand another role of Zn in helping the in situ generation of cationic Rh catalyst and preventing catalyst deactivation, and to analyze the key transition states and intermediates involved (Fig. 3).
Fig. 2 [4 + 2] reaction of yne-vinylcyclobutanones catalyzed by Rh and Zn.
Fig. 3 The proposed reaction mechanism of [4 + 2] reaction supported by kinetics and quantum chemistry calculations.
This [4 + 2] reaction can be regarded as an equivalent of the previous [3 + 2 + 1] reaction, developed also in the Yu group. Several natural products with bridgehead quaternary carbon substitution have been synthesized by using [3 + 2 + 1] reaction. It can be envisioned that the [4 + 2] reaction of yne-vinylcyclobutanones will also become a powerful tool for synthetic chemists to synthesize multi-cyclic compounds with bridgehead carbon substitution.
Guan-Yu Zhang, Pan Zhang and Bing-Wen Li, Ph.D. students from Yu Group, are the co-first authors. Dr. Kang Li and Dr. Jun Li carried out initial studies of this reaction. Prof. Zhi-Xiang Yu is the corresponding author. This research was funded by the National Natural Science Foundation of China, Beijing National Laboratory for Molecular Sciences, and High-Performance Computing Platform of Peking University.
Dual Activation Strategy to Achieve C−C Cleavage of Cyclobutanes: Development and Mechanism of Rh and Zn Co-catalyzed [4 + 2] Cycloaddition of Yne-Vinylcyclobutanones.
Guan-Yu Zhang, Pan Zhang, Bing-Wen Li, Kang Liu, Jun Li, and Zhi-Xiang Yu, J. Am. Chem. Soc. 2022, 144, 21457–21469.
