Enantioselective transition-metal catalysis via an anion-binding approach

Asymmetric transition-metal catalysis represents a powerful strategy for accessing enantiomerically enriched molecules1–3. The classical strategy for inducing enantioselectivity with transition-metal catalysts relies on direct complexation of chiral ligands to produce a sterically constrained reactive metal site that allows formation of the major product enantiomer while effectively inhibiting the pathway to the minor enantiomer through steric repulsion4. The chiral-ligand strategy has proven applicable to a wide variety of highly enantioselective transition-metal-catalysed reactions, but important scenarios exist that impose limits to its successful adaptation. Here, we report a new approach for inducing enantioselectivity in transition-metal-catalysed reactions that relies on neutral hydrogen-bond donors (HBDs)5,6 that bind anions of cationic transition-metal complexes to achieve enantiocontrol and rate enhancement through ion pairing together with other non-covalent interactions7–9. A cooperative anion-binding effect of a chiral bis-thiourea HBD is demonstrated to lead to high enantioselectivity (up to 99% enantiomeric excess) in intramolecular ruthenium-catalysed propargylic substitution reactions10. Experimental and computational mechanistic studies show the attractive interactions between electron-deficient arene components of the HBD and the metal complex that underlie enantioinduction and the acceleration effect. Chiral hydrogen-bond donors bind anions of organometallic catalysts to achieve enantiocontrol and reaction-rate enhancement through ion pairing together with other non-covalent interactions.

of the metal catalyst 32,33 . In addition, chiral organic compounds bearing HBD components have been used as cocatalysts in asymmetric transition-metal-catalysed transformations [34][35][36][37][38][39] . The proposed mechanisms of stereoinduction in the reported examples primarily involve the organocatalyst acting as a ligand on the metal or associating with other organic components in the reaction. However, in one intriguing report, Mattson and coworkers postulated an anion-binding interaction between a chiral binaphthyl-derived silanediol organocatalyst and a copper(II) triflate Lewis acid in moderately enantioselective conjugate additions of indoles to alkylidene malonates 39 . Inspired by the well-documented effectiveness of dual HBDs in promoting asymmetric reactions through ion-pairing mechanisms, we envisioned that anion binding with chiral HBDs could serve as a broadly applicable principle for achieving highly enantioselective cocatalysis with achiral organometallic complexes (Fig. 1b).
We explored the concept of cooperative catalysis between chiral HBDs and transition-metal complexes in the context of an intramolecular ruthenium-catalysed substitution of racemic propargylic alcohols (1) to access chiral chromane derivatives (2) (Fig. 2). In pioneering work, Nishibayashi and coworkers demonstrated that thiolate-bridged diruthenium complexes (3) activate propargylic alcohols to form ionic ruthenium-allenylidene intermediates that can react with a variety of nucleophiles 10,[40][41][42][43] . Although an asymmetric variant of the intramolecular propargylic substitution was developed using chiral thiolates 44 , incorporation of sterically hindered ligands was observed to impart diminished reactivity of the diruthenium catalyst 10 . We proposed that chiral HBDs (4) could bind the anion of the diruthenium complex to increase the reactivity of the metal centre and induce enantioselectivity through attractive non-covalent interactions within the ion pair.
We found that the combination of HBD 4a 45,46 and the commercially available diruthenium dichloride complex 3a catalysed the substitution of propargylic alcohol 1a to form chromane 2a in low yield and enantioselectivity (Fig. 2a, entry 1). The ionic diruthenium tosylate complex 3b together with 4a promoted the cyclization more effectively, albeit still with low enantioselectivity (entry 2). Marked improvements in both yield and enantioselectivity were obtained using bis-thiourea HBD 4b as a cocatalyst (entries 3 and 4). This observation reveals a new application of this class of specifically linked HBDs, which were originally designed to facilitate cooperative anion abstraction from chloroacetals 47 and subsequently demonstrated as effective catalysts in glycosylation reactions with phosphate electrophiles [48][49][50][51] . The aryl-pyrrolidine components of the HBD catalysts have been previously shown to exert profound effects on the outcomes of various reactions involving organic electrophiles by engaging in specific attractive π interactions 52,53 . Variation of the aryl substituents in the present system also proved fruitful, leading to the identification of catalyst 4c, which promoted the model reaction in 90% enantiomeric excess (e.e.) and 22:1 diastereomeric ratio (d.r.) (entry 5). A further notable improvement in the reaction outcome was achieved using the desmethyl analogue 4d (entry 6). Lowering the reaction temperature and using a solvent blend to improve solubility of the catalysts enabled a decrease of the loading of 3b and 4d, and resulted in formation of 2a in 98% e.e. and 63:1 d.r. (entry 7). Control experiments demonstrated that the cooperative effect between 3b and 4d is essential for the observed reactivity, as little or no product formation was observed in the absence of either the HBD (entries 8 and 9) or the diruthenium complex (entry 10).
The substrate scope of the developed cocatalytic cyclization reaction was examined (Fig. 2b, further examples in Supplementary Figs. 2 and 3). Aryl alkynyl carbinols bearing a variety of substituents at positions 4-6 underwent cyclization to the corresponding chromane products in generally high yields, greater than or equal to 20:1 d.r. and enantioselectivities in the range of 94-99% e.e. A substrate containing a phenyl-substituted (Z )-alkene moiety demonstrated a lower reactivity in the propargylic substitution reaction but provided 2j with high selectivity. Other classes of linked alkenyl propargylic alcohols proved to be effective substrates, allowing the generation of tetralin 2k and indane 2l with high enantioselectivity.
We sought to unravel the mechanistic basis of the highly enantioselective cooperative effect between the bis-thiourea HBD and the diruthenium complex, with the goal of identifying principles that might guide the discovery of other transition-metal-catalysed reactions amenable to this cocatalytic approach. As noted above, the development of the stereoselective propargylic substitution was inspired by the possibility of applying the anion-binding effect of the chiral HBD to form a chiral ion-pair complex with the diruthenium catalyst. However, an alternative scenario wherein 4d acts as a chiral ligand coordinated to the reactive diruthenium cation through any of its Lewis-basic functional groups could also potentially occur. Therefore, we directed the first line of our inquiry towards distinguishing between these two fundamentally different mechanistic possibilities.
Diruthenium complexes containing a variety of different anions promoted the reaction in combination with 4d with moderate-to-high e.e., indicating the potential extension of this cocatalytic strategy to other transition-metal complexes containing various common anions. By contrast, racemic product was obtained in the reaction cocatalysed by the diruthenium complex possessing the tetrakis(3, 5-bis(trifluoromethyl)phenyl)borate (BAr F 4 ) anion (3c). In an effort to explain this notable anion effect on enantioselectivity, we performed a 1 H nuclear magnetic resonance (NMR) study of the interaction of 4d with tosylate (5a) and BAr F 4 (5b) salts of an analogue of the catalytically relevant ruthenium-allenylidene intermediate lacking the nucleophilic moiety. Addition of 4d to a solution of 5a in a 19:1 mixture of benzene-d 6 :dichloromethane-d 2 (DCM-d 2 ) led to shifts in the resonances corresponding to both the ruthenium-allenylidene cation (labelled [Ru] + ) and the tosylate anion (labelled OTs -) (part II in Fig. 3a). By contrast, addition of 4d to a solution of 5b resulted in no detectable shifting of signals, consistent with the absence of any interaction between the BAr F 4 salt 5b and 4d (part I in Fig. 3a). Association of the

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HBD to the diruthenium complexes thus depends directly on the identity of the anion, and this interaction is tied to effective stereocontrol in the propargylic substitution reaction.
The nature of the interactions between the sulfonate anion of the metal complex and the HBD was probed by NMR analysis of a representative 1:1 ruthenium-allenylidene-HBD complex (stoichiometry determined by Job plot analysis: Supplementary Fig. 34 and accompanying discussion). The mesylate salt 5c and the conformationally constrained monomethylated bis-thiourea 4e were selected as the closest analogues to the optimal system that afforded clearly interpretable rotating-frame Overhauser effect spectroscopy (ROESY) NMR data (Supplementary Information). The solution structure deduced from the spectral data shows that the mesylate anion of 5c is positioned in similar proximity to both thiourea groups of 4e, consistent with a cooperative hydrogen-bonding interaction between the HBD and the anion of 5c (Fig. 3b).
In addition to the counterion effect on e.e., profound solvent effects were observed in the propargylic substitution reaction (Fig. 3a, right). The inverse correlation between enantioselectivity and the dielectric constant of the reaction medium indicates that tight ion pairing between the HBD-bound tosylate anion and the cationic diruthenium complex is necessary for efficient enantioinduction 16,[54][55][56] . In support of this mechanistic interpretation, 1 H NMR titration experiments between 5a and 4d performed using DCM-d 2 as the solvent showed little effect on the chemical shifts of signals corresponding to [Ru] + after addition of 4d, as would be expected in the case of a solvent-separated ion pair (part III in Fig. 3a). The chemical shifts of signals corresponding to OTswere still affected by addition of the HBD, consistent with the preservation of the hydrogen-bonding interaction between OTsand 4d in the polar solvent. We conclude from these results that the association between diruthenium complexes and the bis-thiourea HBDs relies on anion binding and does not involve any dative bonding interactions.
In addition to promoting high enantioselectivity, bis-thiourea 4d was found to induce a 20-fold rate enhancement in the enantioselective propargylic substitution reaction catalysed by the diruthenium complex 3b (part I in Fig. 4a). By contrast, the presence of 4d had no effect on the rate of the propargylic substitution catalysed by the diruthenium BAr F 4 complex 3c (part II in Fig. 4a)    combination with 3b is correlated to anion binding. The rate of the reaction catalysed by 3b in the presence of 4d was higher than the rate of the reaction catalysed by 3c containing the non-coordinating BAr F 4 anion. This observation suggests that the acceleration effect of 4d in the 3b-catalysed reaction cannot be ascribed simply to attenuated coordinating ability of the tosylate anion when binding to the HBD, and points to the existence of stabilizing non-covalent interactions between 4d and the diruthenium-substrate complex in the rate-determining event.
The nature of these putative non-covalent interactions and their role in enantioinduction was probed in a kinetic analysis of the propargylic substitution using structurally modified HBD cocatalysts. As noted above in the discussion of catalyst optimization studies, the aryl-pyrrolidine components of the bis-thioureas were found to have a significant effect on the enantioselectivity of the reaction. In particular, bis-thiourea catalysts with sterically unencumbered aryl-pyrrolidine groups containing electron-deficient arenes afforded the highest levels of enantioselectivity (Fig. 4b and Supplementary Figs. 4-7). Further analysis of the effect induced by the aryl groups of the HBD catalysts showed that enantioselectivity correlates positively with the rate of the propargylic substitution reactions cocatalysed by HBDs bearing aryl   Article groups with different substituents. Decomposition of the observed rate into contributions from the two enantiomeric pathways revealed that the increased enantioselectivity stems from an acceleration of the pathway leading to the major enantiomer and a simultaneous but lower deceleration of the pathway to the minor enantiomer (Fig. 4b).
These results indicate that the aryl groups of the bis-thiourea cocatalysts effect selective stabilization of the rate-determining transition state leading to the major product enantiomer in the ruthenium-catalysed propargylation reaction. Enantioselectivity and reaction rate catalysed by the desmethyl HBD 4d follow the same correlation, suggesting that the less sterically encumbered aryl-pyrrolidines allow more effective transition-state stabilization by the aryl groups. Closer analysis of the ROESY NMR data corresponding to the 1:1 complex of 5c-4e revealed that both p-nitrophenyl groups of 4e reside in proximity to the electron-rich Cp* ligands of 5c. A density functional theory analysis of the 5c-4e complex informed by the ROESY NMR data led to the identification of several low-energy conformations that all included at least one face-to-face stacking interaction between the electron-deficient arenes of 4e and the Cp* ligands of 5c ( Fig. 4c and Supplementary  Information).   This study provides compelling evidence that chiral HBDs can associate with ruthenium complexes by binding their anions and induce enantioselectivity and rate enhancement through ion pairing in combination with other non-covalent interactions. Given the wide variety of anions recognized by HBDs and the number of synthetically valuable transformations catalysed by organometallic complexes containing ligands such as Cp* groups capable of engaging in non-covalent interactions, we anticipate that the cooperative anion-binding strategy explored in this study may find broad application in asymmetric transition-metal catalysis.

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