On August 30th, the research team from Wanbin Zhang from Shanghai Jiao Tong University, in collaboration with the team of Academician Shengming Ma from the Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, published a groundbreaking study in Science. The article is titled "Stereodivergent access to non-natural α-amino acids via enantio- and Z/E-selective catalysis". In this study, a Pd/Cu synergistic catalytic system that enables the stereodivergent synthesis of enantiopure non-natural α-quaternary amino acids bearing Z- and E-trisubstituted alkene moieties via a ligand controlled three-component assembly with readily available aryl iodides, simple allenes, and α-amino acid-derived aldimine esters was reported. The complete stereocontrol over the configurations of the C=C bond and chiral center was achieved for the first time using π-allyl metal chemistry [(E,R), (Z,R), (E,S), (Z,S)]。

Twenty proteinogenic amino acids pave the foundation of the origin and evolution of life. The incorporation of latent (bio)orthogonal reactive alkene functional groups into α-amino acids not only enriches their biological properties, but also opens up more possibilities for drug design as well as protein and peptide modifications. In addition, due to multiple transformations of alkenes, it will establish a versatile platform that enables generating structurally diverse non-natural α-amino acids. It is known that molecules with different stereochemistry (Z and E, R and S) exhibit distinctly different biological activities. Therefore, the development of an efficient and general catalytic strategy for the stereodivergent synthesis of chiral non-natural α-amino acids bearing stereodefined alkene moieties [(Z,R), (Z,S), (E,R), (E,S)] is of significant research importance.

The precise control of Z and E configurations of the C=C bond in alkene synthesis has long been a fundamental yet elusive topic in synthetic chemistry. This challenge becomes even more pronounced when striving for the simultaneous control over both C=C bond E/Z selectivity and enantioselectivity. Among the limited methods that exist, chemistry involving π-allyl metal intermediates may, in principle, offer a direct and elegant strategy for the selective preparation of Z- or E-olefinic compounds bearing chiral centers. However, in such reactions, the difficulty in precisely controlling the thermodynamic and kinetic properties of the generated π-allyl-metal intermediates often leads to the production of only a single configuration or a Z/E mixture of olefinic products. To date, the divergent synthesis of both Z- and E-alkenes through the selective formation and capture of anti- or syn-π-allyl metal intermediates remains an elusive goal. Furthermore, this task becomes more challenging for the full stereodivergent synthesis of all four stereoisomers of enantiopure Z- and E-trisubstituted alkenes [(Z,R), (Z,S), (E,R), (E,S)] from just a single set of starting materials (Figure 1).

Figure 1. The stereodivergent synthesis of non-natural α-quaternary amino acids bearing trisubstituted alkene moieties via π-allyl metal chemistry.

The research team employed iodobenzene 1a, 4-methylphenylpropadiene 2a, and aldimine ester 3a as model substrates, Cs₂CO₃ as the base, 1,2-dichloroethane as the solvent under a Pd/Cu dual catalytic system for this three-component assembly process. After a comprehensive evaluation of two chiral catalysts, two sets of Pd/Cu synergistic catalytic systems were established. The substrate compatibility was then investigated under two optimal reaction conditions in a stereodivergent manner. Firstly, the substrate scope of iodobenzene 1 was evaluated. It was apparent that iodobenzenes with various substituents, (hetero)aryl iodides, and iodobenzene tethered to bioactive molecules all reacted smoothly in this dual-catalytic system. Next, the scope of the allenes 2 was also explored for this stereodivergent process. A series of aromatic allenes, (hetero)aryl-substituted allenes, and a cyclohexenyl substituted allene all worked well, yielding the desired products in moderate to high yields with excellent Z- and E-selectivities and enantioselectivities. Additionally, alkyl-substituted allenes were also effective substrates for this transformation, with no observation of β-H elimination by-products. Subsequently, an array of α-substituted aldimine esters 3 derived from natural and non-natural amino acids were evaluated, and a series of α-quaternary amino acids containing Z- and E-trisubstituted alkenes have been prepared.

To gain a deeper understanding of the origin of the observed Z- and E-selectivity in the current Pd/Cu catalytic system, detailed mechanistic experiments and density functional theory (DFT) calculations were conducted by the research team (Figure 2). Ultimately, the authors concluded that: 1) In the Pd/L3 catalytic system, migratory insertion is the stereo-determining step; the generated anti-π-allylpalladium intermediate serves as both a thermodynamic and kinetic product, which is directly attacked by the nucleophile to yield E-selective products. 2) In the Pd/L2 catalytic system, nucleophilic attack is the stereo-determining step; both syn- and anti-π-allylpalladium intermediates can be formed and readily interconverted, with the nucleophile selectively attacking the syn-π-allylpalladium intermediate to produce Z-selective products. Control experiments indicate that the thermodynamic stabilities of the syn- and anti-π-allyl-palladium intermediates and their reactivities towards prochiral nucleophiles could be comprehensively regulated by employing two chiral catalysts to achieve high stereoselectivities. The computational results were well aligned with the experimental findings

Figure 2. Mechanistic studies.

In conclusion, the success of the comprehensive control of alkene configuration and point chirality has been realized via synergistic dual chiral metal catalysis. This study not only addresses a longstanding challenge in π-allyl metal chemistry for the stereocontrol over both Z- and E-configurations of C=C bonds but also provides a potentially general strategy for the stereodivergent synthesis of enantiopure molecules bearing Z- and E-alkene moieties. Furthermore, the exploration of all stereoisomers [(Z,R), (Z,S), (E,R), (E,S)] of enantioenriched non-natural α-quaternary amino acids, featuring trisubstituted alkene moieties, opens up more possibilities for drug design as well as protein and peptide modifications.

Professor Wanbin Zhang from the School of Chemistry and Chemical Engineering in Shanghai Jiao Tong University and Academician Shengming Ma from the Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences/Fudan University are co-corresponding authors of this paper. Panpan Li, a doctoral student from Zhang's group at Shanghai Jiao Tong University, is the first author of the paper. En Zheng, a doctoral student from Ma's group, as well as doctoral students Guanlin Li, Yicong Luo (for DFT calculations) from Shanghai Jiao Tong University, and Professor Xiaohong Huo also made significant contributions to the completion of this research. This study was supported by two National Natural Science Foundation of China (Grant No.: 21831005; 21991112) and two National Key R&D Program of China (Grant No.: 2023YFA1506700; 2022YFA1503200).

Paper link:

https://www.science.org/doi/10.1126/science.ado4936