CHEMICAL SCIENCE

Iridium catalyzes new developments in Z-type retention asymmetric allyl substitution reactions


On December 8, 2022, the team of You Shuli, a researcher at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, published a new paper in the journal Nature Catalysis, titled “Structurally defined anti-π-allyliridium complexes catalyse Z-retentive asymmetric allylic alkylation of.” oxindoles”。

This work reports on the synthesis, separation and characterization of key anti-π-allyliridium complex intermediates in Z-retained asymmetric allyl substitution reactions, and in-depth study of their formation, isomerization and reaction with nucleophiles.

Z-olefin fragments are widely found in natural products and drug molecules. However, due to the high steric hindrance substituent located on the ipsilateral side of the double bond, Z-olefins are thermodynamically unstable relative to E-olefins, so their highly selective synthesis is extremely challenging. Transition metal-catalyzed asymmetric allyl substitution reactions efficiently construct chiral compounds containing olefin fragments by capturing π-allyl metal complex intermediates using nucleophiles. However , this type of reaction generally undergoes thermodynamically stable syn-π-allyl metal complexes to obtain terminal olefin or E-olefin products.

In 2021, You Shuli’s research team from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, used the strategy of “active prechiral nucleophiles to capture metastable anti-π-allyl metal complexes” to achieve iridium-catalyzed Z-retained asymmetric allyl substitution reactions, and efficiently constructed a series of complex chiral molecules containing Z-olefin fragments (Fig. 1, Science 2021, 371, 380; J. Am. Chem. Soc. 2022, 144, 4770.)。 In such reactions, anti-π-allyliridium complexes are generally presumed to be key catalytically active intermediates, which are of great significance for their separation, characterization and property study. However, the intermediates are thermodynamically unstable and are easily converted into thermodynamically stable syn-π-allyliridium complexes through the isomerization process of π-σ-π, resulting in challenging separation and characterization.

Figure 1: Iridium catalyzes Z-style retention asymmetric allyl substitution reactions

In previous work, the researchers characterized the generation and isomerization of a class of chiral phosphorus/olefin ligand-derived anti-π-allyliridium complexes (trifluoromethanesulfonate as antiions) and isomerization by nuclear magnetic resonance phosphorus spectroscopy (31P NMR) and high-resolution mass spectrometry (HRMS), but failed to achieve the separation and identification of the complex. Recently, researchers have successfully synthesized a series of anti-π-allyliridium complexes by introducing strongly coordinated halogen ions into the system to improve the stability of anti-π-allyliridium complexes, and confirmed their structure by single crystal X-ray diffraction (Figure 2). At the same time, the isomerization process of anti-π-allyl-iridium complexes to thermodynamically stable syn-π-allyliridium complexes was characterized by nuclear magnetic resonance phosphorus spectroscopy, and it was confirmed that the time required for isomerization was longer than that of nucleophilic attack. This is a key factor in achieving asymmetric allyl substitution reactions with Z-style retention.

Figure 2: Synthesis and characterization of anti-π-allyliridium complexes

These anti-π-allyliridium complexes efficiently catalyze asymmetric allyl substitution reactions with Z-retained asymmetric allyl of a series of indole-2-one-derived chiral nucleophiles with Z-allyl carbonate (Figure 3). It was found that the use of pre-prepared iridium complexes could achieve yield (81~98%) and selectivity (L/B > 19/1, Z/E >19/1, 90-94% ee) comparable to that of iridium catalysts generated in situ, and shortened the reaction time from 2 hours to 1 day to 5 minutes to 1 hour.

Figure 3: Iridium-catalyzed Z-style retention asymmetric allyl substitution with indole-2-one derivatives

The researchers did this by analyzing anti-π-allyliridium complexes ([Ir]The geometry and electronic structure of /L = 1:1) reveal the cause of the selectivity of the reaction region (Figure 4). Since the phosphorus ligand is not in the opposite position of either end of the allyl group (C1 and C3), the bond length and Mayer bond level of the C1–Ir bond and C3–Ir bond are basically the same, so the nucleophile preferentially attacks the C1 position with a smaller steric block. This is consistent with the reported literature of iridium complexes derived from homogeneous chiral ligands ([Ir]/L = 1:2) is significantly different. The researchers further used DFT calculations to investigate the transition state of indole-2-one anion attacking anti-π-allyliridium complexes, and proposed a chiral control model of the reaction.

Figure 4: Iridium-catalyzed region/enantioselectivity model of Z-style retention asymmetric allyl substitution reactions

In summary, this work reports the synthesis, isolation and characterization of key anti-π-allyliridium complex intermediates in Z-type asymmetric allyl substitution reactions, and deeply studies the mechanisms of their formation, isomerization and reaction with nucleophiles. On this basis, a new class of Z-type asymmetric allyl substitution reactions was developed, and a selective genesis and chiral induction model of reaction region were proposed. This achievement laid a solid foundation for the further development of Z-type retention asymmetric allyl substitution reaction and the synthesis of chiral Z-olefins.

The above research work was supported by the Ministry of Science and Technology, the National Natural Science Foundation of China, the Chinese Academy of Sciences, the Shanghai Municipal Science and Technology Commission, and the Tencent Foundation. (Source: Science Network)

Related paper information:https://doi.org/10.1038/s41929-022-00879-z



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