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. Author manuscript; available in PMC: 2025 Mar 27.
Published in final edited form as: J Am Chem Soc. 2024 Mar 13;146(12):7905–7914. doi: 10.1021/jacs.4c01857

Leveraging the Stereochemical Complexity of Octahedral Diastereomeric-at-Metal Catalysts to Unlock Regio-, Diastereo- and Enantioselectivity in Alcohol-Mediated C-C Couplings via Hydrogen Transfer

Jonathan Z Shezaf †,§, Catherine G Santana †,§, Eliezer Ortiz †, Cole C Meyer †, Peng Liu ‡, Ken Sakata §, Kuo-Wei Huang ⊥, Michael J Krische †,*
PMCID: PMC11446212  NIHMSID: NIHMS2025814  PMID: 38478891

Abstract

Experimental and computational studies illuminating the factors that guide metal-centered stereogenicity and, therefrom, selectivity in transfer hydrogenative carbonyl additions of alcohol proelectrophiles catalyzed by chiral-at-metal-and-ligand octahedral d6-metal ions, iridium(III) and ruthenium(II), are described. To augment or invert regio-, diastereo- and enantioselectivity, predominantly one from among as many as 15 diastereomeric-at-metal complexes is required. For iridium(III) catalysts, cyclometallation assists in defining the metal stereocenter, and for ruthenium(II) catalysts, iodide counterions play a key role. Whereas classical strategies to promote selectivity in metal catalysis aim for high-symmetry transition states, well-defined low-symmetry transition states can unlock selectivities that are otherwise difficult to achieve or inaccessible.

Keywords: Chirality, Octahedral Stereogenic Center, Iridium, Ruthenium, Enantioselective

Graphical Abstract

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I. Introduction:

The development of atom-efficient catalytic methods for the conversion of abundant, renewable feedstocks to value-added products is an important objective of modern chemical research.1 As demonstrated by hydrogenation (e.g. the Haber-Bosch reaction),2–4 methane-steam reforming,5 hydroformylation6 and related Fischer-Tropsch process,7 and the cracking of ethane to ethylene,8 the atom-efficiency of transformations that occur through the addition, redistribution or removal of hydrogen is a key, enabling characteristic for implementation of any catalytic process at large volume. Guided and inspired by this characteristic, our laboratory has developed diverse catalytic carbonyl additions that operate through the reductive activation of π-unsaturated pronucleophiles under the conditions of hydrogenation or hydrogen auto-transfer from alcohol proelectrophiles (Figure 1).9 These processes represent an alternative to carbonyl additions mediated by stoichiometric organometallic reagents, which are often hazardous, functional group intolerant, and generate metal-containing waste. Hydrogen auto-transfer for carbonyl addition is mechanistically distinct from related “borrowing hydrogen” reactions that promote hydroxyl substitution of alcohol reactants.10

Figure 1.

Figure 1.

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Carbonyl addition beyond stoichiometric organometallic nucleophiles.

To date, nearly all asymmetric reactions of this type are catalyzed by iridium(III) and ruthenium(II) complexes.9 Such octahedral d6-metal ions possess unoccupied dz2 and dx2−y2 orbitals. This electronic configuration is especially conducive to alkoxide β-hydride elimination (alcohol dehydrogenation), an event that is likely preceded by an agostic interaction with the carbinol C-H bond. As shown, occupancy of the dx2−y2 orbital would place a relatively high-energy pair of electrons in the spatial domain of the migrating hydride (Figure 2). Alternatively, if the vacant coordination site of the pentacoordinate metal alkoxide is in the northern apical position, the unoccupied dz2 orbital would similarly facilitate alkoxide β-hydride elimination (not shown). We have found that the development of highly regio-, diastereo- and enantioselective carbonyl additions of alcohol proelectrophiles using iridium(III) and ruthenium(II) catalysts requires control of metal-centered stereogenicity,11 which is a daunting challenge given the multiplicity of stereoisomers associated with octahedral metal ions, as described in the tertiary literature.12 For an octahedral metal ion bearing six different monodentate ligands, there exist 15 enantiomeric pairs, meaning 30 stereoisomers are possible. Chiral nonracemic bidentate ligands can reduce the number of possible stereoisomers, but do not necessarily enforce formation of a single diastereomeric-at-metal complex. For example, when bound to a C1-symmetric ligand such as JOSIPHOS,13 12 diastereomeric-at-metal complexes remain possible. Similarly, when bound to a C2-symmetric ligand such as SEGPHOS,14 6 diastereomeric-at-metal complexes can exist. Naturally, to enforce optimal levels of regio-, diastereo- and enantioselectivity, intervention of predominantly one diastereomeric-at-metal complex is required. However, while chiral-at-metal-and-ligand catalysts are ubiquitous, metal-centered stereogenicity in such systems is often poorly understood or entirely ignored. Here, factors that guide metal-centered stereogenicity and, therefrom, regio-, diastereo- and enantioselectivity in C-C couplings of alcohols catalyzed by octahedral chiral-at-metal-and-ligand complexes are surveyed.

Figure 2:

Figure 2:

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The unique reactivity and stereochemical complexity of octahedral d6-metal ions (an idealized octahedral splitting diagram is shown).

II.A. Cyclometallated π-Allyliridium-C,O-Benzoates:

π-Allyliridium-C,O-benzoate complexes bound by various chelating axially chiral C2-symmetric phosphine ligands (BINAP, SEGPHOS, etc) catalyze an exceptionally diverse array of highly enantioselective carbonyl allylations from alcohol proelectrophiles (Figure 3).15,16 The π-allyliridium-C,O-benzoate complex, which is stable to conventional silica gel chromatography, can exist as four possible diastereomeric-at-metal complexes. The relative energies of these complexes have been estimated by DFT calculations.17 The three most stable diastereomers are observed when the complex is formed and can be separated by HPLC, but they slowly equilibrate upon standing. The most stable diastereomer has been characterized by single crystal X-ray diffraction.17 A catalytic cycle corroborated by DFT calculations17 reveals that the initially formed diastereomeric mixture of π-allyliridium complexes is inconsequential, as the stereocenter at iridium is ablated upon deprotonation of the iridium hydride18 to form a transient square planar iridium(I) complex. Thus, the enantiodetermining step of the catalytic cycle is not carbonyl addition, but oxidative addition of the allylic acetate, which defines the stereochemistry at iridium. The carbonyl addition, which occurs in a stereospecific manner through a closed Zimmerman-Traxler-type transition structure,19 simply transfers stereochemical information from the stereogenic center at iridium to carbon. Due to full occupancy of coordination sites in the XY-plane, the vacant dz2 orbital facilitates β-hydride elimination in a manner akin to that shown for the vacant dx2−y2 orbital in Figure 2.

Figure 3.

Figure 3.

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Metal-centered stereogenicity in enantioselective π-allyliridium-C,O-benzoate-catalyzed carbonyl allylations of alcohol proelectrophiles.

This interpretation of the reaction mechanism suggests that stereochemistry at iridium might be more important in directing the enantiofacial selectivity of carbonyl addition than the chiral phosphine ligand. Indeed, using the same antipode of chiral ligand, (S)-tol-BINAP, roughly equal yet opposite enantioselectivities are observed in carbonyl allylations mediated by allyl acetate versus allene, H2C=C=CH2 (Figure 4).17 Our collective experimental and computational studies demonstrate that the observed inversion in enantioselectivity stems from an inversion in stereochemistry at iridium. Specifically, while the square planar iridium(I) complex oxidatively adds allyl acetate to form the most stable diastereomer of the π-allyliridium complex, allene hydrometallation from the octahedral iridium(III) hydride delivers the less stable π-allyliridium complex in which the stereocenter at iridium is inverted. Thus, the inversion of enantioselectivity observed upon aldehyde addition for diastereomeric π-allyliridium complexes, each bearing (S)-BINAP, demonstrates that the stereocenter at iridium overrides the influence of the chiral ligand in defining the enantioselectivity of carbonyl addition.

Figure 4:

Figure 4:

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Inversion of enantioselectivity in carbonyl allylations catalyzed by diastereomeric-at-iridium complexes.

II.B. Cyclometallated π-Allyliridium-PhanePhos Complexes:

Another distinct class of diastereomeric-at-metal catalysts for alcohol-mediated C-C coupling are ortho-cyclometallated iridium-PhanePhos complexes.20 These catalysts are generated in situ from [Ir(cod)Cl]2 and (R)-PhanePhos and were initially identified in connection with their ability to catalyze enantioselective C-C couplings of methanol with dienes or CF3-bearing allenes to form primary neopentyl alcohols via formaldehyde allylation (Figure 5, eq. 1 and 2).9k,20a,b Notably, the latter process enables enantioselective formation of CF3-bearing quaternary carbon stereocenters (Figure 5, eq. 2).20b At first, it was not recognized that the active catalysts were ortho-cyclometallated. However, in subsequent work, a chromatographically stable ortho-cyclometalated iridium-(R)-PhanePhos complex was isolated, characterized by single crystal X-ray diffraction and demonstrated to be catalytically competent in the redox-neutral C-C couplings of methanol and related 2-propanol mediated allene-fluoral reductive couplings (Figure 5, eq. 3).20c This ortho-cyclometallated iridium-PhanePhos complex is chiral-at-metal-and-ligand and, given the tridentate nature of ortho-cyclometallated ligand, 6 diastereomeric-at-metal complexes are potentially active. Only one diastereomeric-at-metal complex is observed in the solid state in which the chloride and C-aryl ligands are trans, and DFT calculations of the possible stereoisomeric transition states for carbonyl addition suggest the analogous diastereomeric-at-metal transition structure is most stable. Mechanistic studies involving a combination of deuterium labelling, reaction progress kinetic analysis (RPKA), and DFT calculations were applied to the allene-fluoral reductive couplings. The collective data corroborate a catalytic mechanism in which rapid, reversible allene hydrometalation precedes turnover-limiting carbonyl addition.20c As shown in the indicated stereochemical model, interactions involving the ortho-CH2 group of the ethano-bridge that lies proximal to iridium play a key role in directing relative and absolute stereochemistry. More recently, the ortho-cyclometallated iridium-PhanePhos complexes were found to catalyze enantioselective 2-propanol-mediated reductive couplings of 2-substituted dienes with oxetanones and N-acyl-azetidinones (Figure 5, eq. 4).20d Here, in contrast to reactions of methanol/formaldehyde, which result in coupling of the diene at the 2-position to form quaternary carbon stereocenters, C-C bond formation occurs at the diene 3-position to form tertiary carbon stereocenters. These data suggest a Curtin-Hammet scenario in which the steric demand of the carbonyl electrophile influences the relative energies of competing transition states for rate-determining carbonyl addition from a rapidly equilibrating pool of isomeric allyliridium haptomers (not shown).

Figure 5.

Figure 5.

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Metal-centered stereogenicity in enantioselective ortho-cyclometallated π-allyliridium-PhanePhos-catalyzed carbonyl allylations.

III.A. Iodide-Bound π-Allylruthenium(JOSIPHOS) Complexes:

The formation of racemic homoallylic alcohols via ruthenium-catalyzed reductive or redox neutral couplings of dienes or allenes with aldehydes or alcohol proelectrophiles was first described in 2008.21 The development of related enantioselective processes proved to be quite challenging due to the inability to control stereochemistry at ruthenium in the requisite chiral-at-ligand-and-metal catalysts. Catalysts modified by chiral phosphate counterions displayed good levels of diastereo- and enantioselectivity in certain cases,22 but the chiral phosphate counterions are not commercially available, which impelled efforts toward a more practical solution. Eventually, it was found that ruthenium-JOSIPHOS catalysts modified by iodide counterions are highly efficient catalysts for the enantioselective carbonyl allylation of alcohol proelectrophiles (Figure 6).23,24 These processes exploit alkynes as precursors to nucleophilic allylruthenium species.25 At first, Bu4NI was exploited as an exogenous iodide source (Figure 6, eq. 5, 6),23a-c however, the iodide-containing precatalyst RuI(CO)(JOSIPHOS)(η3-C3H5) is also effective (Figure 6, eq. 7).23d As the corresponding chloride- or bromide-modified catalysts displayed lower enantioselectivities and diminished turnover, experimental and computational studies were undertaken to understand the origins of iodide’s uniquely beneficial effects. Analysis of X-ray crystallographic data for the halide-bound π-allylruthenium complexes, RuX(CO)(JOSIPHOS)(η3-C3H5), where X = Cl, Br, I, revealed a trans-relationship between the π-acidic carbonyl ligand and π-donating halide in each case. However, occupancy of the diastereotopic northern and southern apical coordination sites varied. For the chloride and bromide complexes, mixtures of diastereomeric-at-metal complexes were evident, but for the iodide complex a single diastereomer was observed (Figure 7). Additionally, for the iodide complex, QTAIM analysis26 implicated the presence of a formyl CH···I hydrogen bond that stabilizes the preferred transition state for carbonyl addition.27 The collective data are consistent with the indicated catalytic cycle where, from a plurality of stereoisomeric structures, predominantly one diastereomeric-at-metal complex intervenes in the enantiodetermining transition state for carbonyl addition due to the enhanced size and polarizability of iodide versus chloride or bromide.

Figure 6.

Figure 6.

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Metal-centered stereogenicity in enantioselective π-allylruthenium-JOSIPHOS-catalyzed carbonyl allylations.

Figure 7.

Figure 7.

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Structures of RuX(CO)(JOSIPHOS)(?3-C3H5), where X = Cl, Br, I, determined by X-ray diffraction.

The development of iodide-bound ruthenium-JOSIPHOS catalysts unlocked numerous enantioselective alcohol-mediated C-C couplings that occur with complete atom-efficiency (Figure 8).28 This includes the redox-neutral C−C couplings of primary alcohols with methylallene (not shown) or 1,3-butadiene to form products of anti-crotylation (Figure 8, eq. 8).28a Similarly, related C-C couplings of primary alcohols with gaseous allene (propadiene) deliver highly enantiomerically enriched secondary homoallylic alcohols (Figure 8, eq. 9).28b Ruthenium hydrides obtained via primary alcohol dehydrogenation catalyze the isomerization of skipped dienes to form conjugated dienes, which, in turn, participate in transfer hydrogenative carbonyl addition. Thus, 1,4-pentadiene and 1,5-hexadiene provide entry to products of (α-ethyl)allylation and (α-propyl)allylation, respectively (Figure 8, eq. 10).28c Finally, primary alcohols react with 2-butyne to form chiral allylic alcohols (Figure 8, eq. 11).28d Distinct from other methods for asymmetric aldehyde allylations16 and vinylations,29 a kinetic preference for primary alcohol dehydrogenation enables primary-secondary diols to participate in highly chemoselective C-C coupling at the primary alcohol, meaning unprotected secondary alcohols are tolerated (not shown). For each process, use of the corresponding chloride- and bromide-bound ruthenium catalysts led to lower yields and enantioselectivities, corroborating iodide’s uniquely capacity to define stereochemistry at ruthenium and stabilize the preferred transition state for carbonyl addition via formyl CH···I hydrogen bonding.

Figure 8.

Figure 8.

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The control of metal-centered stereogenicity unlocks diverse enantioselective ruthenium-JOSIPHOS-catalyzed carbonyl additions.

III.B. Iodide-Bound π-Allylruthenium(SEGPHOS) Complexes:

An especially compelling illustration of the effect of metal-centered stereogenicity on selectivity is found in the C-C coupling of primary alcohols with isoprene (Figure 9).30 Here, pseudo-diastereomeric chiral-at-ruthenium complexes RuX(CO)[η3-prenyl][(S)-SEGPHOS], where X = Cl and I, deliver products of sec-prenylation and tert-prenylation, respectively. To determine the origins of regiodivergence,31 the parent chloride- and iodide-bound π-allylruthenium complexes modified by SEGPHOS were analyzed via single crystal X-ray diffraction. For the chloride-bound complex, the normal trans-diapical relationship between the π-acidic carbonyl ligand and π-donating chloride ligand was retained. This is a preference that persists across diverse phosphine-modified ruthenium carbonyl complexes bearing π-allyl,33a π-propargyl,33b hydride,33c,d,e vinyl,33f,g and acetylide ligands.33h In contrast, for the iodide complex, a highly uncommon cis-relationship between an apical carbonyl ligand and equatorial iodide was observed. This anomalous preference is due to nonbonded interactions that would be incurred between the equatorial diphenylphosphino moiety of SEGPHOS with an apical iodide. Solid and solution phase 31P NMR analysis revealed that the observed diastereomeric preferences persist in solution and are not an artifact of crystal packing forces. Furthermore, DFT calculations suggest the trans-halide/carbonyl diastereomers of both the π-allyl and π- prenyl complexes are more stable in the case of the chloride complex and, conversely, the cis-halide/carbonyl diastereomers are more stable in the case of the iodide complex. DFT calculations of the iodide-bound catalyst point to a Curtin-Hammett scenario in which the relative energies of competing transition states for aldehyde coordination from an equilibrating mixture of sec- and n-prenylruthenium complexes is rate- and product-determining. Whereas the influence of metal-centered stereogenicity on enantioselectivity is well-established, to our knowledge, these data represent the first correlation between metal-centered stereogenicity and regioselectivity in metal catalysis.

Figure 9.

Figure 9.

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Divergent regioselectivity guided by metal-centered stereogenicity in enantioselective π-allylruthenium-SEGPHOS-catalyzed C-C couplings of primary alcohols with isoprene.

IV. Conclusion and Outlook:

Classical strategies for optimizing enantioselectivity in metal catalysis have emphasized minimization of the number of competing transition structures, for example, through use of square planar d8-metal ions bound by chelating C2-symmetric ligands.32 However, with reliable strategies for the stereocontrolled formation of octahedral chiral-at-metal-and-ligand complexes, one may craft low-symmetry environments for catalysis that are topologically distinct and may unlock selectivities that are otherwise difficult to achieve or inaccessible. In this monograph, strategies for the generation of diastereomeric-at-metal catalysts based on the octahedral d6-metal ions, iridium(III) and ruthenium(II), were described and correlations of metal-centered stereochemistry to regio, diastereo- and enantioselectivity were made using experimental and computational methods. Surprising outcomes include the fact that metal-stereochemistry can override ligand-stereochemistry to invert enantioselectivity (Figure 4) or invert regioselectivity (Figure 9). It is our hope that the present approaches to generating stereochemically-defined chiral-at-metal-and-ligand octahedral complexes will inform and accelerate advances in the broader field of regio- and stereoselective metal catalysis.

ACKNOWLEDGMENTS

The Robert A. Welch Foundation (F-0038), the NIH-NIGMS (RO1-GM069445, R35 GM128779), JSPS (KAKENHI 20H05671) and KAUST are acknowledged for partial support of this research.

Footnotes

The authors declare no competing financial interest.

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