Adaptive Dynamic Kinetic Resolution Enables Alteration of Chiral Induction with Ring Sizes​

Article in Press

In drug discovery, constructing libraries of analogous compounds based on bioactive molecular scaffolds with similar skeletons but structural variations is an effective strategy for discovering innovative drugs. Modifying the ring size and stereochemistry of the chiral heterocyclic core in lead compounds significantly impacts their pharmacological activity and pharmacokinetics. While asymmetric catalytic cyclization strategies have advanced the construction of polycyclic compounds, a unified strategy that adaptively changes product configuration with varying ring sizes remains elusive. To address this, the team of Prof. Hanmin Huang at the University of Science and Technology of China envisioned modifying the dynamic kinetic resolution (DKR) process to allow adaptive configuration changes based on the ring size of the cyclization product. In classical DKR, efficient utilization of racemic substrates is achieved through rapid interconversion between enantiomers, with the stereochemical outcome intrinsically linked to the substrate-catalyst binding step. By decoupling chiral induction from this binding step and incorporating it into subsequent transformations, the configuration of the substrate-catalyst adduct becomes tunable, enabling stereocontrol that adapts to subtle structural perturbations, including changes in ring size. Building on their expertise in aminoalkylpalladacycle complexes, the Huang team proposed an adaptive DKR strategy. Using aldehydes and aminodienes as substrates and leveraging distinct conformational transition states, they efficiently constructed contiguous stereocenters to synthesize various aza-polycyclic skeletons. This strategy was successfully applied to the concise total synthesis of (-)-martinellic acid (Figure 1).

The authors tested the feasibility of the strategy using salicylaldehyde and aminodienes of varying chain lengths. Employing the same [Pd/(R)-MeOBIPHEP(OAc)₂] catalyst, the asymmetric cyclization proceeded smoothly to afford nitrogen-oxygen heteropolycyclic products (Figure 2). Experiments demonstrated that the catalyst exhibits an adaptive response to ring size, generating unique stereochemical diversity: for six- and seven-membered ring products 3a​ and 7p, the absolute configuration of the stereocenter adjacent to the nitrogen atom is S; for the five-membered ring product 5a, it is R. Consistent results were obtained using N-(2-formylphenyl)-4-methylbenzenesulfonamide as the substrate, yielding 4a​ and 6a. Under identical chiral catalyst and reaction conditions, this strategy enabled the stereospecific construction of polycyclic compounds with diverse ring sizes, varied heteroatom-containing skeletons, and multiple configurations.

The authors investigated the substrate scope of the adaptive DKR cyclization reaction (Figure 3). The chiral bisphosphine ligand L4​ afforded product 3a​ in 77% yield, 97:3 e.r., and as a single diastereomer. Salicylaldehyde derivatives bearing phenyl or naphthyl substituents reacted efficiently with 1a​ to yield [6-6-6] nitrogen-oxygen tricyclic compounds (3a–3q), tolerating various functional groups. The strategy was also compatible with tyrosine and estrone derivatives (3r–3s). Replacing salicylaldehyde with ortho-amino aromatic aldehydes, and using Pd(acac)₂ with ligand L3​ in CPME at 80 °C, exclusively afforded the [6,6,6] diaza-polycyclic compound 4a​ (86% yield, 94:6 e.r.). Substrates with aryl sulfonyl groups or substituted aromatic rings (4a–4p) reacted well. The product 4m​ derived from 3-aminothiophene-2-carboxaldehyde achieved an e.r. of 99:1. Reaction with 3-toluenesulfonamide alkyl aldehyde yielded 4q, albeit with slightly reduced yield and selectivity. For aminodienes, various heptadienamines reacted smoothly with 2a. The method efficiently constructed [6-6-7] tricyclic systems, with the structure of 7p​ confirmed by X-ray crystallography. Electron-deficient N-alkyl or dienyl-substituted aminodienes coupled with aldehydes to give products in moderate yields.

To demonstrate synthetic utility, the authors performed gram-scale preparation and derivatization of the [6,6,6]-fused polycyclic product 4a​ (Figure 4). 4a​ was obtained on a 1.2 g scale in 82% yield (94:6 e.r.), and enantiopurity reached 99:1 after recrystallization. Detosylation of 4a​ afforded compound 8​ (90% yield, unchanged e.r.), which underwent N-allylation and ring-closing metathesis to yield azatetracyclic compound 10​ (62% overall yield). The double bond in 4a​ could be converted via hydroboration-oxidation to alcohol 11​ (72% yield) or via palladium-catalyzed hydroaminocarbonylation to amide 12​ (73% yield). Furthermore, leveraging the adaptive DKR strategy as the key chiral construction and skeleton-forming step, the authors completed a concise total synthesis of martinellic acid from commercially available materials in 9 steps with an 11% overall yield.

A series of mechanistic experiments were conducted to elucidate the reaction pathway (Figure 5). High-resolution mass spectrometry indicated the potential presence of palladium complexes A′​ or C′​ in the reaction mixture. Nonlinear effect studies showed a linear correlation between product enantiopurity and catalyst enantiopurity, suggesting the involvement of a monomeric palladium intermediate. Two control experiments ruled out a carbocation mechanism: adding p-toluenesulfonic acid yielded no target product, and replacing the conjugated diene with styrene prevented cyclization. Subsequent experiments confirmed the critical role of hydrogen bonding for reactivity and diastereoselectivity. For instance, using potassium 2-formylphenolate as the substrate lowered both yield and d.r.; removal or masking of the hydrogen bond acceptor in electron-deficient 2-hydroxy aromatic aldehydes led to failed migratory insertion. Based on previous reports, a plausible mechanism was proposed: Addition of aminodiene 1​ to salicylaldehyde 2​ generates racemic N,O-hemiacetal H, whose enantiomers can interconvert via dissociation-recombination. For constructing the [6-6-6] nitrogen-oxygen heterocycle, H​ undergoes oxidative addition with Pd(0) to form palladacycle A. (S, RCat)-A​ proceeds through diene insertion, etc., to yield product 3. For the [6-6-5] system, due to differences in transition state conformation, the pathway via (R, RCat)-A′​ forming C′​ is favored.

This study developed an adaptive DKR strategy that efficiently constructs various aza-polycyclic compounds with high stereoselectivity by leveraging the dynamic interconversion of diastereomeric aminoalkylpalladacycle complexes. Notably, this innovative adaptive DKR model employs the same chiral bisphosphine-palladium catalyst to regulate the absolute configuration of contiguous stereocenters by simply varying the ring size of the cyclization product. Furthermore, using this adaptive DKR process as the key step for chiral construction and skeleton establishment, the concise and efficient total synthesis of martinellic acid was successfully accomplished, further validating the strategy's effectiveness.

Authors:​ Bangkui Yu, Yao Huang, Haocheng Zhang, and Hanmin Huang*

Title:​ Adaptive dynamic kinetic resolution enables alteration of chiral induction with ring sizes

Journal:​ Nature Chemistry

DOI:​ 10.1038/s41557-025-01850-8