From Hydrogenation to Transfer Hydrogenation to Hydrogen Auto-Transfer in Enantioselective Metal-Catalyzed Carbonyl Reductive Coupling: Past, Present, and Future

Abstract

Atom-efficient processes that occur via addition, redistribution or removal of hydrogen underlie many large volume industrial processes and pervade all segments of chemical industry. Although carbonyl addition is one of the oldest and most broadly utilized methods for C-C bond formation, the delivery of non-stabilized carbanions to carbonyl compounds has relied on premetalated reagents or metallic/organometallic reductants, which pose issues of safety and challenges vis-à-vis large volume implementation. Catalytic carbonyl reductive couplings promoted via hydrogenation, transfer hydrogenation and hydrogen auto-transfer allow abundant unsaturated hydrocarbons to serve as substitutes to organometallic reagents, enabling C-C bond formation in the absence of stoichiometric metals. This perspective (a) highlights past milestones in catalytic hydrogenation, hydrogen transfer and hydrogen auto-transfer, (b) summarizes current methods for catalytic enantioselective carbonyl reductive couplings, and (c) describes future opportunities based on the patterns of reactivity that animate transformations of this type.

Graphical Abstract

I. Introduction and Historical Perspective

Beginning with Dobereiner’s lighter (1823),¹ catalytic hydrogenation is both the Proteus and Prometheus of metal-catalysis (Figure 1). The hydrogenation of unsaturated organic compounds was first reported by Sabatier (1897).^2,3 Sustaining half of all human life, the Haber-Bosch process (1905), the hydrogenation of atmospheric nitrogen to form ammonia, was developed shortly thereafter.⁴ The first homogenous hydrogenations were developed by Melvin Calvin (1938),⁵ who reduced 1,4-benzoquinone to 1,4-hydroquinone under an atmosphere of hydrogen using substoichiometric quantities of cuprous acetate in quinoline solvent. Mechanistic studies of homogenous hydrogenation were initiated by Halpern (1956),⁶ leading to the first homogenous hydrogenations of activated olefins (1961).⁷ This work, along with the observation of Vaska (1962) that IrCl(CO)(PPh₃)₂ and elemental hydrogen combine to form isolable dihydrides via “oxidative addition,”⁸ galvanized the conceptual foundations of catalytic hydrogenation. Finally, nearly 70 years after the discovery of heterogeneous hydrogenation by Sabatier, Wilkinson (1965) described the homogenous hydrogenations of unactivated alkenes using his eponymous rhodium catalyst, RhCl(PPh₃)₃.⁹ Empowered by advances in the synthesis and design of chiral phosphines,¹⁰ enantioselective rhodium-catalyzed hydrogenations were introduced by Knowles (1968).¹¹ Taken together with parallel progress in transfer hydrogenation, especially ruthenium-catalyzed processes,^12–14 a vast field of research was born. Catalytic hydrogenation is now applied across all segments of the chemical industry, with asymmetric hydrogenation superseding all other catalytic enantioselective methods for the manufacture of chiral compounds.¹⁴ For pharmaceutical ingredients, catalytic hydrogenation is estimated to encompass 14% of all GMP reactions,^14e and patent analyses indicate hydrogenation catalysis has yet to reach its apex and will continue to grow.¹⁵

Figure 1.

Selected milestones in catalytic hydrogenation, hydrogen transfer and hydrogen auto-transfer.

As organic molecules are composed of carbon and hydrogen, atom-efficient C-C bond forming processes that occur via addition, redistribution or removal of hydrogen underlie many large volume industrial processes. The Fischer-Tropsch process (1922)¹⁶ and alkene hydroformylation (Co, 1938; Rh, 1968)¹⁷ represent two iconic hydrogen-mediated reductive C-C couplings. The principal source of hydrogen used in these reactions is derived from methane-steam reforming (1912),¹⁸ that is, hydrocarbon dehydrogenation. The Guerbet reaction (1899),¹⁹ the prototypical “borrowing hydrogen” process,²⁰ converts lower alcohols to higher alcohols through rebounding hydrogen transfers that first generate carbonyl partners for aldol dehydration and then reduce the resulting enones (Figure 2, I). The ability to exploit alcohols as both carbonyl proelectrophiles and reducing agents is also exemplified by the Meerwein-Ponndorf-Verley reaction (1925),²¹ and the work of Adkins (1932)²² on heterogeneous nickel-catalyzed alcohol aminations, which occur through alcohol dehydrogenation-reductive amination (Figure 2, II). Homogenous metal catalysts for alcohol amination were subsequently reported by Grigg and Watanabe (1981).²³ Borrowing hydrogen processes²⁰ are finding ever-increasing use in commercial chemical synthesis,^24,25 as formal substitution of hydroxyl groups through dehydrogenation-condensation-reduction enhances step-economy and minimizes waste generation by avoiding discrete oxidation-state changes.

Figure 2.

Carbonyl condensation via hydrogen-borrowing and carbonyl addition via hydrogenation, transfer hydrogenation and H₂-auto-transfer.

Whereas borrowing hydrogen processes like the Guerbet reaction and alcohol amination operate through pathways involving carbonyl condensation,²⁰ related carbonyl additions that occur via hydrogenation, transfer hydrogenation and hydrogen auto-transfer have been developed in the present authors laboratory (Figure 2).²⁶ These carbonyl addition processes can occur by way of three general catalytic pathways (Figure 2, A-C).

• Mechanism A: C=O/C=C Oxidative coupling followed by (transfer)hydrogenolysis of the resulting oxametalacycles.

• Mechanism B: C-X Bond reductive cleavage promoted via (transfer) hydrogenation or hydrogen auto-transfer.

• Mechanism C: C=C Hydrometalation promoted via (transfer) hydrogenation or hydrogen auto-transfer.

Such metal-catalyzed carbonyl reductive couplings complement classical methods for carbonyl addition as they exploit neutral π-unsaturated feedstocks as equivalents to premetalated C-nucleophiles and enable carbonyl addition from the alcohol oxidation level. In this perspective, carbonyl and imine additions that occur via metal-catalyzed hydrogenation, transfer hydrogenation and hydrogen auto-transfer are surveyed. Coverage is limited to enantioselective reactions involving formal addition of H₂ across the π-unsaturated pronucleophile and the π-bond of the carbonyl (or imine) electrophile using low molecular weight feedstock reductants (hydrogen, 2-propanol or formic acid and its salts) or through hydrogen auto-transfer (processes in which alcohols serve dually as carbonyl proelectrophiles and hydrogen carriers). Transformations involving substrate/catalyst-directed asymmetric induction also are covered. Applications in natural product synthesis are not exhaustively described. As established by analysis of >9 million pharmaceutical industry patents, carbonyl addition (alongside cross-coupling) remains one of the most widely utilized methods for C-C bond formation.²⁷ By combining the characteristics of catalytic hydrogenation and carbonyl addition, it is the authors’ hope to advance a broad, new class of environmentally benign catalytic enantioselective carbonyl addition for use in chemical synthesis.

II. Hydrogenation

The aldol reaction was discovered in late 18^th century and is among the earliest examples of carbonyl additions.²⁸ The development of catalytic enantioselective aldol additions²⁹ remains a vibrant area of research as such methods are of great utility in type I polyketide total synthesis.³⁰ Stereoselective aldol additions are typically conducted using preformed (metallo)enolates based on lithium,³¹ boron^30a,32 and silicon.^30f We have found that hydrogenation of vinyl ketones in the presence of aldehyde using cationic rhodium catalysts results in carbonyl addition, representing a novel, atom-efficient reductive variant of the aldol reaction (Scheme 1).³³ Upon use of tri-2-furylphosphine³⁴ as ligand, high levels of syn-diastereoselectivity are achieved,^33e enabling asymmetric reductive aldol additions to N-Boc-α-aminoaldehydes.^33g Notably, the enantiomeric purity of the α-aminoaldehyde is preserved under the neutral condition of hydrogen-mediated reductive coupling. True catalytic enantioselective variants were subsequently developed using a benzothiophene-substituted TADDOL-like phosphonite ligand.^33h Remarkably, as illustrated in the total synthesis of the marine macrolide swinholide A, hydrogen-mediated reductive aldol addition occurs in a chemoselective manner in the presence of mono-olefins and conjugated dienes.³⁵ The collective data suggest these reactions occur through pathways involving enone-carbonyl oxidative coupling (Figure 2, Mechanism A). For stereochemical models and a detailed discussion of the reaction mechanism, the reader is directed to the review literature.³⁶ Cationic rhodium catalysts are required to suppress hydrogen oxidative addition³⁷ and vacate a coordination site to permit simultaneous binding of enone and aldehyde at the square planar metal center.

Scheme 1.

Catalytic asymmetric reductive aldol reactions of methyl vinyl ketone via rhodium-catalyzed hydrogenation.

The C=O/C=C oxidative coupling-hydrogenolysis pathway for hydrogen-mediated reductive aldol addition was transferable to carbonyl additions of alkyne pronucleophiles (Scheme 2). Using cationic rhodium catalysts under an atmosphere of hydrogen gas, reductive cyclizations of acetylenic aldehydes occur efficiently with high levels of enantioselectivity (Scheme 2, eq. B).³⁸ Intermolecular reductive coupling requires careful matching between the π-donicity of the metal catalyst and the π-acidity of the unsaturated reactant to achieve efficient C=X (X = O, NR)/C≡C oxidative coupling. For cationic rhodium catalysts, which are less strongly reducing, conjugated alkynes (1,3-enynes or 1,3-diynes) and vicinal dicarbonyl partners³⁹ (or related imines⁴⁰) are required (Scheme 2, eq. A, C, D). Isostructural iridium catalysts are more electron rich and are capable of promoting oxidative coupling between nonconjugated alkynes and unactivated carbonyl or imine partners (Scheme 2, eq. E).⁴¹ In hydrogen-mediated reductive couplings of acetylene, products of carbonyl or imine (Z)-dienylation are formed (Scheme 2, eq. F).⁴² Oxidative dimerization of acetylene is faster than C=O/C≡C oxidative coupling. As corroborated by detailed mechanistic studies,^42d the resulting rhodacyclopentadiene inserts the carbonyl or imine partner to deliver oxa- or azarhodacycloheptadienes, which upon hydrogenolysis provide the products (Z)-dienylation. Remarkably, in all cases, conventional hydrogenation of the reaction products is not observed as the alkyne pronucleophiles are more π-acidic and, hence, better ligands for the metal than the olefin containing adducts. Total syntheses of several natural products were accomplished using C-C bond forming hydrogenations of this type. For example, the anti-tumor promoting marine macrolide bryostatin and several of its analogues were prepared via asymmetric hydrogen-mediated enyne-α-ketoaldehyde reductive coupling (Scheme 2, Bottom).⁴³

Scheme 2.

Catalytic asymmetric alkyne-carbonyl reductive coupling via rhodium-catalyzed hydrogenation.

III.A. Transfer Hydrogenation and Hydrogen Auto-Transfer (Pathways Involving C-X Bond Cleavage)

Following Hoffmann’s seminal report of asymmetric carbonyl allylation using chiral diol-modified allylboron reagents (1978),^44a the first catalytic enantioselective carbonyl allylations were reported by Yamamoto (1991).^44b As documented in the review literature, the field of catalytic enantioselective carbonyl allylation has since experienced enormous growth.^45,46 However, notwithstanding protocols developed in the present authors laboratory,^26h all reported catalytic enantioselective carbonyl allylations rely on preformed allylmetal reagents⁴⁵ or, as exemplified by the Nozaki-Hiyama-Kishi allylations,^46,47 metallic reductants. Mechanistic pathways in which alcohol dehydrogenation is balanced by reductive C-X bond cleavage enable generation of transient allylmetal nucleophiles (Figure 2, Mechanism B). Based on this concept, diverse catalytic enantioselective carbonyl allylations were developed (Scheme 3, Top).⁴⁸ These processes are catalyzed by π-allyliridium-C,O-benzoate complexes discovered in our laboratory and are unique in that asymmetric allylation is achieved from the alcohol or aldehyde oxidation level in the absence of stoichiometric metals. The indicated catalytic cycle and stereochemical model are based on DFT calculations (Scheme 3, Bottom).⁴⁹ The iridium center of the π-allyliridium-C,O-benzoate is itself stereogenic, which provides an especially well-defined chiral environment for carbonyl addition (Scheme 3).

Scheme 3.

Enantioselective π-allyliridium-C,O-benzoate-catalyzed carbonyl allylations that occur via alcohol-mediated C-X reductive cleavage, reaction mechanism and stereochemical model. Levels of asymmetric induction typically exceed 90% ee.

Among the unique capabilities associated with π-allyliridium-C,O-benzoate-catalyzed enantioselective allylations, the capacity to engage diols and higher polyols in site-selective asymmetric allylation is especially powerful, as it precludes the use of hydroxyl protecting groups (Scheme 4, Left).^48f,g,v,w Such transformations are made possible by a pronounced kinetic (and contra-thermodynamic) preference for primary alcohol dehydrogenation. Additionally, chiral β-stereogenic alcohols are subject to asymmetric allylation with good levels of catalyst-directed diastereoselectivity, which avoids the handling of

Scheme 4.

Catalyst-directed diastereoselectivity in asymmetric allylations of 1,3-diols and two-directional allylation and crotylation of 1,3-diols and use of structurally complex nitrogen-rich allyl pronucleophiles.

configurationally labile chiral α-stereogenic aldehydes (Scheme 4, Middle).^48e,f Finally, whereas malondialdehydes are highly intractable, 1,3-diols are abundant chemical feedstocks and are subject to asymmetric double allylation^48c or double crotylation (Scheme 4, Top Right).⁴⁸ⁿ The products of such two-directional chain syntheses are formed as single enantiomers due to the Horeau effect,⁵⁰ and have been exploited as triketide building blocks in numerous total syntheses of polyketide natural products where they have been shown to significantly enhance step-economy.^35,43b,51,52

The functional group compatibility of the π-allyliridium-C,O-benzoate-catalysts is illustrated in reactions of nitrogen-rich allylic acetates incorporating the top 10 N-heterocycles found in FDA-approved drugs (eq. 1).^48b′ Allyl pronucleophiles of hitherto unattainable structural complexity are used as limiting reagents in C-C couplings of ethanol, the largest volume renewable small molecule feedstock (>85 million tons/year worldwide). The use of ethanol as a C2-feedstock in enantioselective C-C coupling was previously unknown.

(eq. 1)

Hydrogen auto-transfer mechanisms also can occur via internal redox processes wherein C-X bond reductive cleavage is balanced by oxidative esterification, as demonstrated in enantioselective allylations of o-phthalaldehydes (eq. 2).⁵³ As the iridium catalyst is highly sensitive to rather modest steric and electronic perturbations, the indicated nonsymmetric o-phthalaldehyde can be engaged in site-selective internal redox allylation. Using this method, formal syntheses of ent-spirolaxine methyl ether and CJ-12,954 were achieved.

(eq. 2)

Enantioselective carbonyl propargylations comprise another major class of carbonyl additions that traditionally have relied on the use of premetalated reagents or metallic reductants.⁵⁴ In a departure from prior art, it was found that iridium catalysts modified by SEGPHOS enable alcohol-mediated reductive C-Cl bond cleavage of trialkylsilyl substituted propargyl chlorides to furnish transient allenyliridium nucleophiles that participate in enantioselective carbonyl propargylation from alcohol or aldehyde oxidation level (Scheme 5).^55a 3-Hexyne was added to suppress competing transfer hydrogenation of the alkyne moiety of the homopropargyl alcohol products. Using rhodium catalysts modified by (R)-BINAP, the parent propargyl chloride could be deployed in asymmetric carbonyl additions to chiral α-stereogenic amino alcohol proelectrophiles to furnish products of propargylation with good to complete levels of diastereocontrol (Scheme 5).^55b

Scheme 5.

Catalytic enantioselective carbonyl propargylation via alcohol-mediated C-X reductive cleavage.

III.B. Transfer Hydrogenation and Hydrogen Auto-Transfer (Hydrometalative Pathways)

The activation of π-unsaturated pronucleophiles via alcohol-mediated hydrometalation represents another pathway for catalytic enantioselective carbonyl reductive coupling (Figure 2, Mechanism C). Neutral cyclometallated iridium(III) complexes have proven especially effective in reactions of this type. For example, as illustrated in reactions of allene gas (Scheme 6, eq. A),⁴⁹ (N-phthalimido)allene (Scheme 6, eq. B)⁵⁶ and dimethylallene (Scheme 6, eq. C),⁵⁷ metal hydrides that arise in the course of π-allyliridium-C,O-benzoate-mediated alcohol dehydrogenation can be intercepted via allene hydrometalation to generate transient allyliridium nucleophiles, directly converting primary alcohol reactants to (branched) secondary homoallylic alcohols in the absence of stoichiometric byproducts. Remarkably, the cyclometallated iridium complex derived from PhanePhos catalyzes highly regio-, diastereo- and enantioselective carbonyl reductive couplings of methanol with dienes (Scheme 6, eq. D)^58a and CF₃-allenes (Scheme 6, eq. E)^58b to form primary neopentyl alcohols bearing acyclic quaternary carbon stereocenters.⁵⁹ The cyclometallated iridium-PhanePhos complex is also competent in 2-propanol-mediated reductive couplings of 1,1-disubstituted allene with fluoral,^58c which are conducted in aqueous organic media (Scheme 6, eq. F).

Scheme 6.

Enantioselective carbonyl allylations via allene or diene hydrometalation catalyzed by cyclometallated iridium complexes. Levels of asymmetric induction typically exceed 90% ee.

Non-cyclometallated iridium and ruthenium complexes modified by (DM)-SEGPHOS or BINAP, respectively, are also competent catalysts for enantioselective carbonyl reductive coupling, as illustrated in enyne-mediated carbonyl propargylations (Scheme 7).⁶⁰ In these processes, alcohol-mediated enyne hydrometalation delivers allenylmetal nucleophiles, which engage in carbonyl addition through six-centered transition structures. For the indicated iridium-catalyzed propargylation, axial chirality of the chiral ligand is relayed to the allenyliridium intermediate and the central chirality of the product. This method was recently used in the total synthesis and structural assignment of formosalides A and B.⁶¹

Scheme 7.

Enantioselective carbonyl propargylations that occur via enyne hydrometalation catalyzed by non-cyclometallated iridium and ruthenium complexes.

Hydrometalative activation of diene pronucleophiles via alcohol-mediated hydrogen (auto)transfer underlies novel ruthenium-catalyzed carbonyl crotylation protocols (Scheme 8).⁶² Trialkylsilyl substituents at the C2-position of the butadiene define the geometry of the transient crotylruthenium nucleophile, which, in turn, directs syn-diastereoselectivity.^62a As initially observed in our laboratory in 2006,^39c chiral phosphate counterions are effective stereocontrol elements metal-catalyzed C-C coupling. Using a ruthenium complex modified by the indicated BINOL-derived phosphate counterion, anti-diastereo- and enantioselective carbonyl crotylation could be achieved from the alcohol or aldehyde oxidation level using butadiene, a chemical feedstock (12 × 10⁶ tons/year), as pronucleophile.^62b Less Lewis basic BINOL-phosphate counterions form non-contact ion pairs with the ruthenium catalyst. In contrast, as borne out by DFT calculations^62d and x-ray diffraction data, more Lewis basic TADDOL-phosphate counterions form contact ion pairs, permitting preservation of kinetic selectivity in the hydrometalation of the s-cis-diene conformer. The resulting (Z)-crotylruthenium intermediate engages in carbonyl addition faster than relaxation to the (E)-crotylruthenium isomer, enabling syn-diastereo- and enantioselective carbonyl crotylation to occur.^62c,d

Scheme 8.

Enantioselective ruthenium- catalyzed carbonyl crotylations that occur via diene hydrometalation.

Alkyne pronucleophiles are subject to a dual catalytic process in which metal-catalyzed alkyne-to-allene isomerization is followed by a second catalytic cycle involving allene-carbonyl reductive coupling (Scheme 9, Top).^63a,b A series of deuterium labelling experiments corroborate a mechanism involving allene hydrometalation to deliver a nucleophilic allylruthenium intermediate. Remarkably, propargyl ethers react through an entirely different and, to our knowledge, previously undescribed mechanism involving hydride shift enabled π-allyl formation (Scheme 9, Middle).^63c Here, alkyne coordination triggers the generation of a vinylruthenium carbene species, which upon protonation forms an allylruthenium nucleophile. This mechanism also could be enacted using an iridium catalyst modified by H8-BINAP to deliver products of (siloxy)allylation with complete levels of alkene (Z)-stereoselectivity and high levels of enantioselectivity (Scheme 9, Bottom).^63d Hydride shift enabled π-allyl formation does not involve hydrometalation and, mechanistically, represents a fourth distinct class of dehydrogenative carbonyl additions. These transformations demonstrate that tractable, commercially available alkynes can serve as synthetic equivalents to allylmetal nucleophiles.⁶⁴

Scheme 9.

Enantioselective carbonyl allylations and crotylations via alkyne pronucleophiles catalyzed by (non-cyclometallated) iridium and ruthenium complexes.

IV. Future Opportunities and Objectives

This emerging class of catalytic C-C couplings presents numerous unmet challenges (Scheme 10). The development of dehydrogenative imine additions of π-unsaturated pronucleophiles via hydrogen auto-transfer of amine proelectrophiles (so-called “hydroaminoalkylations”) has largely focused on early transition metal catalysts.⁶⁵ With only three exceptions,^66,67 corresponding late transition metal-catalyzed variants have required non-native directing groups.^68,69 Metal-catalyzed intermolecular reductive couplings of unactivated olefins with unactivated aldehydes using feedstock reductants have proven elusive, although promising strategies have emerged.^26g,70 While intra- and intermolecular hydrogenative and transfer hydrogenative carbonyl reductive couplings of aryl halides have been accomplished,⁷¹ enantioselective variants, the use of alkyl halide pronucleophiles and hydrogen auto-transfer processes have not been described. Additionally, despite truly impressive progress on the reductive carboxylation of π-unsaturated reactants with CO₂ mediated by silane,^72,73 the use of inexpensive feedstock reductants in such processes has not been described (although photochemical promotion may unlock this challenge).^73b

Scheme 10.

Unmet challenges in dehydrogenative carbonyl and imine addition of alcohol and amine proelectrophiles.

Beyond the transformations discussed in this perspective, there exist numerous other classical carbanionic and metal-mediated processes that could potentially be accomplished via hydrogenation, transfer hydrogenation or hydrogen auto-transfer, potentially availing more scalable, sustainable and cost-effective methods for chemical manufacture.⁷⁴ Indeed, progress toward transfer hydrogenative pinacol reactions⁷⁵ and cross-electrophile reductive couplings⁷⁶ has been described. Recent advances in catalytic asymmetric photoreduction might offer new approaches to the development of more benign reductive C-C coupling protocols.⁷⁷ Finally, the new patterns of reactivity described in this perspective can inform processes that have no counterpart in the lexicon of classical carbanion chemistry. For example, a broad, new family of ruthenium(0)-catalyzed cycloadditions of vicinal diols, ketols or diones with π-unsaturated partners has been developed based on transfer hydrogenative carbonyl addition (Scheme 11).⁷⁸ It is the authors’ hope that this perspective will encourage further research into catalytic C-C bond formations that occur through the addition or redistribution of hydrogen.

Scheme 11.

Catalytic transformations beyond the classical lexicon of carbonyl addition chemistry.