Divalent nickel catalyzes chiral convergence synthesis of dialenephosphine chiral compounds

Recently, Zhang Qingwei’s team at the University of Science and Technology of China achieved the high enant-selectivity synthesis of a series of phosphine chiral phosphine compounds under the catalytic action of divalent nickel by using the method of in situ synthesis of secondary phosphine hydrogen compounds, and also realized the synthesis of phosphine-centered chiral and axial chiral phosphine compounds.

On July 28, 2022, the study was published online in the journal Nature Synthesis under the title “Enantioselective synthesis of P-stereogenic allenylphosphines through Ni-catalysed propargylic substitution.” The work was also invited to write a research briefing “Enantioconvergent synthesis of P-stereogenic allenylphosphines”.

The first author of the paper is Wang Weihan of the University of Science and Technology of China, and the co-first author is Wu Yue, a 2018 undergraduate student of the University of Science and Technology of China.

Phosphine-center chiral compounds have very important applications in the fields of drug synthesis and asymmetric catalysis. However, due to synthetic challenges, further research has been greatly limited. Dienylphosphorus compounds contribute to the diversification of products due to their multiple reaction sites and reaction patterns. However, the synthesis of chiral phenylphosphine compounds due to the lack of a common synthesis strategy and there are high challenges, the traditional method mainly uses pre-prepared phosphine-center chiral secondary phosphine oxygen compounds by propyl alkyne to achieve the synthesis of phosphine chiral phosphine compounds, and this method usually requires more stringent reaction conditions, pre-prepared chiral raw materials and longer reaction routes. How to achieve catalytic methods to efficiently synthesize asymmetrical synthetic chiral compounds is an important research topic.

Recently, Zhang Qingwei’s team at the University of Science and Technology of China built on the previous work (J. Am. Chem. Soc. 2019, 141, 16584.; J. Am. Chem. Soc. 2021, 143, 11309.; Org. Lett. 2021, 23, 8683−8687.;Org. Lett. 2022, 24, 1258−1262.;Chem. Sci. 2022, 13, 4095–4102), by using the method of in situ synthesis of secondary phosphine hydrogen compounds, a series of phosphine chiral compounds were synthesized with high enantectivity under the catalytic action of divalent nickel, and the synthesis of phenyl compounds with both phosphine-center chiral center and axial chirality was also realized. A rare chiral convergence phenomenon was found: chiral raw materials did not undergo racemic or symmetry, and the products of chiral convergence were obtained through different reaction paths. The above mechanism was confirmed by catalyst structure identification, control experiments and DFT calculations.

The reaction is adapted to various substituted secondary phosphine oxide compounds as well as propyl alkyne compounds, with a high functional tolerance, which greatly enriches the structural diversity of the phosphine-center chiral lyenyl compounds. Wherein the secondary propyl alkyne compound can also be reacted smoothly to obtain a dienylphosphine compound having both phosphine-center chiral and axal chirality. Moreover, the results show that under the catalysis of divalent nickel, the racemic propyl alkyne compound can achieve chiral convergence reaction, and the corresponding products are obtained with high enantioselectivity and non-enantioselectivity.

In order to further verify the applicability of the reaction in asymmetric catalysis, the authors of this paper can obtain a high enantioselectivity by adding transition metal precursor compounds (ruthenium, rhodium, iridium) in situ, the metal complex has both phospholary and metal chiral centers, and the phosphalanx can be well maintained. Directly coordinated platinum metal complexes can be obtained by coordinating with platinum. By adding diphenylphosphine and divalent nickel in situ in the system, in situ phosphine hydrogenation reaction can be realized, and the resulting product can be directly complexed with divalent nickel to obtain a chiral nickel complex. The polyenylphosphorus compound can also obtain a variety of chiral compounds through Michael’s addition reaction.

In order to study the mechanism of the reaction, the authors designed a series of experiments, first obtaining a divalent nickel complex (Ni-PH) structure by single crystal diffraction, such a nickel complex has a similar catalytic activity under the action of alkalis, indicating that the complex may be a real catalyst or its precursor. By comparing the reaction with the zero-valent nickel-catalyzed reaction, it can be seen that the reaction is different from the mechanism of the subsequent reaction of the traditional zero-valent nickel and the propyl-alkyne compound by the nickel-linked alkenyl. Chiral secondary propyl ester can obtain the same results as racemic propyl ester and the recovered raw material ee value is substantially unchanged indicating that the enantiomers of propyne ester in the reaction will not be converted to each other, and the same product can be obtained.

In order to further verify the reaction mechanism, the authors explored the mechanism of the reaction by DFT calculation, and the results showed that a pair of enantiomers of racemic propyl feedstocks were carried out in different reaction paths in the reaction. After migration insertion, propyl carbonate of the S configuration is obtained by cis-eliminating trans (β- oxygen elimination) of the lithium compound, while the R configuration obtains the corresponding product by trans-elimination. Reaction pathways for chiral convergence by double-bond isomerization can also be ruled out by calculation.

Based on the above results, a variety of structurally diverse dienylphosphine compounds were obtained by divalent nickel-catalyzed propyl substitution reaction, and a rare chiral convergence phenomenon of racemic raw materials that can occur without racemic or symmetrization was found. This new discovery will provide a new way of thinking to achieve a transition metal-catalyzed chiral convergence reaction. (Source: Science Network)

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