Switchable supramolecular helices for asymmetric stereodivergent catalysis

The study addresses the unmet challenge of using a single switchable asymmetric catalyst to control multiple stereogenic centers within one molecular scaffold. Prior approaches combined molecular switches or non-covalent interactions with catalytic units to modulate enantioselectivity, yet primarily achieved enantiodivergency for single stereogenic elements. Achieving stereodivergency for multiple centers requires catalysts that can be rapidly reconfigured during the reaction, are compatible with substrates and stimuli, and deliver perfectly opposite selectivities in their pseudo-enantiomeric states. Supramolecular helical catalysts—specifically hydrogen-bonded benzene-1,3,5-tricarboxamide (BTA) assemblies bearing intrinsically achiral metal centers—offer dynamic, switchable handedness controlled by a small fraction of chiral BTA comonomer. The research aims to leverage these dynamic helices to direct a copper-hydride-catalyzed hydrosilylation/hydroamination cascade so that any of the four stereoisomers of an amino alcohol can be generated one-pot with similar selectivity, either without switching helix handedness (concomitant) or by switching handedness between steps (sequential).

Switchable asymmetric catalysis has been realized using molecular, macromolecular, or supramolecular chiroptical switches appended to intrinsically achiral catalytic sites to create pseudo-enantiomeric states under stimuli such as light, redox, or chemical triggers. These systems have largely focused on enantiodivergent outcomes for single stereogenic elements. Leigh and co-workers demonstrated stereodivergency by sequentially transforming a tethered substrate with two pre-existing complementary catalysts within a molecular machine. Other designs use pairs of enantioselective switchable catalysts with mutual inhibition to prevent simultaneous operation. Key challenges for in situ stereodivergency include compatibility between stimulus and reaction components, perfect selectivity inversion between states, and rapid switching relative to reaction timescales. Helical catalysts with achiral metal centers on covalent or supramolecular helices offer advantages: the reaction’s stereochemical outcome follows helix handedness; the sergeants-and-soldiers and diluted majority rule effects enable homochiral helices with minimal chiral monomer; and intrinsic dynamicity enables fast handedness interconversion. Prior BTA-based helical catalysts delivered good enantioselectivity in Cu-catalyzed hydrosilylation and hydroamination of separate substrates and showed rapid in situ selectivity inversion by adding the opposite BTA enantiomer. However, these were not applied to controlling two stereocenters within the same molecule.

Catalyst design and assembly: Supramolecular helical coassemblies are formed in toluene from an achiral BTA phosphine ligand (BTA P) coordinated to Cu, a chiral BTA comonomer (either (S)-BTA or (R)-BTA derived from leucine) to set handedness, and an achiral additive α-BTA to amplify homochirality via sergeants-and-soldiers and diluted majority rule effects. The helices are dynamic and can invert handedness upon addition of excess opposite enantiomer. ITC established the stability of the assemblies above 0.4 mM (293 K) and 1.3 mM (313 K) in toluene; BTA P concentration was set to 11 mM to maintain helices during catalysis at 313 K.

Catalytic system and substrate: Copper-hydride catalysis engages a hydrosilylation (HS) followed by hydroamination (HA) cascade on 3-vinylacetophenone (VPnone) to afford 1-[3-(1-dibenzylaminoethyl)]-acetophenol (APnol). The enantio-determining steps correlate with helix handedness controlled by the major BTA enantiomer in the assembly.

Concomitant process (no switch): Both HS and HA are initiated simultaneously. Typical composition: Cu(OAc)2 (5 mol%), BTA P (10 mol%) with [BTA P]=11 mM, α-BTA (10 mol%), chiral BTA (5 mol%) giving f=0.2 over all BTA monomers. Secondary ligand P(3,5-(CF3)2-C6H3)3 (5 mol%) improves yield. Solvent: toluene; temperature: 313 K; additives: dimethoxymethylsilane (DMMS, 5 equiv) and Amine-tBu (1.8 equiv). Reactions run without exclusion of air; optimization explored solvent and ligation effects.

Sequential process (with switch): HS and HA are temporally separated, with helix handedness inverted between steps by adding an excess of the opposite BTA enantiomer (chemical chiral trigger) to convert a terpolymer into a tetrapolymer containing a scalemic mixture of chiral monomers (e.g., f1=0.5 with 50% ee favoring the added enantiomer). Circular dichroism (CD) verifies rapid (≈minutes) and full inversion of handedness at 313 K. Initial sequential reactions under air used α-BTA at 10 mol%; improved selectivity was achieved by lowering α-BTA to 5 mol% to increase dynamicity. To address low yields attributed to catalyst deactivation, variants under nitrogen and anhydrous conditions were performed with extended HS (60 min) and HA (overnight) times while maintaining identical Cu loadings. Reaction workups included NH4F quench for excess DMMS and standard extraction; stereochemical outcomes were quantified by chiral HPLC (Chiralpak IG-3) and NMR with internal standard.

Analytical methods: CD spectroscopy monitored helix handedness pre- and post-trigger addition. ITC assessed assembly stability. Chiral HPLC provided ee, diastereomeric ratio (dr), and proportions of APnol stereoisomers; absolute/relative configurations were assigned via reactions using DTBM-SEGPHOS and MM/MD modeling.

• Concomitant process (single handedness throughout): Using (S)-BTA yields predominantly (R,S)-APnol; using (R)-BTA yields predominantly (S,R)-APnol.

  • With (S)-BTA: 76% NMR yield of APnol; main stereoisomer 78% (R,S); ee 96% for (R,S); dr 3.8:1; ee1(HS)=69%, ee2(HA)=84%.
  • With (R)-BTA: 78% NMR yield; main stereoisomer 75% (S,R); ee 96% (opposite sign); dr 3.3:1; ee1=-64%, ee2=-83%.
  • Minor by-products: EPnol (~10%) and VPnol (~14%), indicating incomplete HA under concomitant conditions; yield improved by adding P(3,5-(CF3)2-C6H3)3.

• Sequential process (handedness switched between HS and HA): Enables access to (R,R)- and (S,S)-APnol as major products by inverting helix handedness before HA.

  • Under air, initial conditions: main stereoisomer 57% for both (R,R) and (S,S); ees 83% and 77%, dr 1.6:1 and 1.8:1, respectively.
  • With reduced α-BTA (5 mol%): selectivity matched concomitant process—71% (R,R) at 95% ee, dr 2.7:1; 70% (S,S) at 93% ee, dr 2.7:1.
  • Under N2/anhydrous and scaled to 1.0 mmol: improved NMR yields (63–65%) and isolated yields (38–40%); main stereoisomer ~50–51% with ee ~79–81% and dr 1.3:1. Lower selectivity traced to non-optimal HS completion prior to switching, though HA showed ~70% ee with opposite sign to HS, confirming effective switch.

• CD spectroscopy confirms rapid (≈3 minutes mixing) and full stereochemical inversion of helix handedness upon addition of the opposite BTA enantiomer at 313 K, consistent with dynamic supramolecular behavior and diluted majority rule control.

• Overall, all four APnol stereoisomers ((R,S), (S,R), (R,R), (S,S)) are obtained one-pot with similar selectivities (major stereoisomer 70–79% under most selective conditions), using the same achiral phosphine-copper catalytic unit embedded in helical assemblies whose handedness is set by the majority chiral BTA.

The findings demonstrate that the handedness of dynamic supramolecular BTA helices dictates the stereochemical outcome of copper-hydride-catalyzed cascades, enabling predictable control over two newly formed stereogenic centers in a single molecule. By maintaining a fixed handedness (concomitant mode), enantiodivergent diastereomers (R,S) or (S,R) are selected, while inverting handedness between steps (sequential mode) favors the complementary diastereomers (R,R) or (S,S). This directly addresses the challenge of in situ stereodivergency using a single catalyst platform and shows that selectivity can be matched across all stereoisomers by tuning supramolecular composition and dynamicity (via α-BTA content) and operating conditions (air vs nitrogen). The results underscore the power of sergeants-and-soldiers and diluted majority rule effects to achieve homochiral, switchable catalysts from a largely achiral scaffold, providing an example of artificial chirogenesis where an achiral ligand achieves high asymmetric control through supramolecular organization. The approach simplifies asymmetric stereodivergent synthesis by avoiding multiple catalysts or multi-pot procedures and suggests generalizability to other catalytic manifolds and to controlling more than two stereocenters.

This work establishes a switchable supramolecular helical catalyst that enables asymmetric stereodivergency in a one-pot hydrosilylation/hydroamination cascade, accessing any of the four stereoisomers of an amino alcohol with comparable selectivities. The catalyst consists of an achiral BTA phosphine-copper complex embedded in dynamic BTA helices whose handedness—and thus stereochemical preference—is controlled and switched by the majority enantiomer of a chiral BTA comonomer. Optimization of supramolecular composition (including α-BTA) and operating conditions (secondary ligand, atmosphere) allowed major stereoisomer proportions of ~70–79% with high ees and useful yields. The strategy demonstrates artificial chirogenesis via supramolecular organization and offers a versatile platform to control multiple stereogenic centers. Future directions include designing monomers to further enhance catalytic performance and dynamicity, extending the concept to other catalytic reactions, and targeting control over more than two stereogenic centers in small molecules or polymers.

• In the initial sequential reactions under air, the HA step showed suboptimal selectivity due to incomplete or slow stereochemical switching, leading to a fraction of intermediate processed by helices of the undesired handedness.
• Under nitrogen and anhydrous conditions, overall selectivity decreased because the HS step was not fully complete before switching, reducing ee despite improved yields.
• Catalyst deactivation contributed to low yields under some conditions; minimizing O2 and water improved performance but required balancing catalyst activity (HS) and dynamicity (switching) that proved delicate.
• Formation of minor by-products (EPnol, VPnol) indicated incomplete HA or side reactions (e.g., protonation by residual water).
• The stereochemical switch for catalytically active species occurred on the timescale of minutes, slower than pre-catalyst assemblies, likely due to decreased dynamicity from Cu–H species and potential aggregation/crosslinking of helices.