Teaching Aldehydes New Tricks Using Rhodium- and Cobalt-Hydride Catalysis

Abstract

By using transition metal catalysts, chemists have altered the "logic of chemical synthesis" by enabling the functionalization of carbon-hydrogen bonds, which have traditionally been considered inert. Within this framework, our laboratory has been fascinated by the potential for aldehyde C-H bond activation. Our approach focused on generating acyl-metal-hydrides by oxidative addition of the formyl C-H bond, which is an elementary step first validated by Tsuji in 1965. In this Account, we review our efforts to overcome limitations in hydroacylation. Initial studies resulted in new variants of hydroacylation and ultimately spurred the development of related transformations (e.g., carboacylation, cycloisomerization, and transfer hydroformylation).Sakai and co-workers demonstrated the first hydroacylation of olefins when they reported that 4-pentenals cyclized to cyclopentanones, using stoichiometric amounts of Wilkinson's catalyst. This discovery sparked significant interest in hydroacylation, especially for the enantioselective and catalytic construction of cyclopentanones. Our research focused on expanding the asymmetric variants to access medium-sized rings (e.g., seven- and eight-membered rings). In addition, we achieved selective intermolecular couplings by incorporating directing groups onto the olefin partner. Along the way, we identified Rh and Co catalysts that transform dienyl aldehydes into a variety of unique carbocycles, such as cyclopentanones, bicyclic ketones, cyclohexenyl aldehydes, and cyclobutanones. Building on the insights gained from olefin hydroacylation, we demonstrated the first highly enantioselective hydroacylation of carbonyls. For example, we demonstrated that ketoaldehydes can cyclize to form lactones with high regio- and enantioselectivity. Following these reports, we reported the first intermolecular example that occurs with high stereocontrol. Ketoamides undergo intermolecular carbonyl hydroacylation to furnish α-acyloxyamides that contain a depsipeptide linkage.Finally, we describe how the key acyl-metal-hydride species can be diverted to achieve a C-C bond-cleaving process. Transfer hydroformylation enables the preparation of olefins from aldehydes by a dehomologation mechanism. Release of ring strain in the olefin acceptor offers a driving force for the isodesmic transfer of CO and H₂. Mechanistic studies suggest that the counterion serves as a proton-shuttle to enable transfer hydroformylation. Collectively, our studies showcase how transition metal catalysis can transform a common functional group, in this case aldehydes, into structurally distinct motifs. Fine-tuning the coordination sphere of an acyl-metal-hydride species can promote C-C and C-O bond-forming reactions, as well as C-C bond-cleaving processes.

Figure 1.

Overview of divergent transformations triggered by formyl C–H bond activation and ligands featured in this Account as they appear in chronological order (black: commercially available, blue: ligands our lab designed and synthesized).

Figure 2.

(A) Olefin hydroacylation mechanism and (B) strategy for suppressing decarbonylation.

Figure 3.

Overview of the developed olefin hydroacylations with chelating substrates.

Figure 4.

Enantioselective intramolecular hydroacylation for the synthesis of seven- and eight-membered heterocycles.

Figure 5.

Enantioselective desymmetrization of cyclopropenes by intermolecular hydroacylation.

Figure 6.

(A) Regio- and enantioselective coupling of salicylaldehydes and homoallylic sulfides. (B) Analogous regioselective hydroacylations of allylic and homoallylic alcohols.

Figure 7.

Rh-catalyzed hydroacylation of unactivated olefins and octaketide natural product synthesis.

Figure 8.

Olefin-directed hydroacylation with non-chelating aldehydes.

Figure 9.

Design and strategy for the intramolecular DKR hydroacylation of racemic 4-pentenals.

Figure 10.

Optimal ligands for the enantioselective DKR hydroacylation.

Figure 11.

Co-catalyzed hydroacylation of 1,3-dienes.

Figure 12.

(A) Enzyme directed cyclizations of geranyl pyrophosphate. (B) Transition metal-catalyzed hydroacylation to afford various carbocyclic frameworks.

Figure 13.

Divergent cyclizations of a dienyl aldehyde 22a based on ligand choice.

Figure 14.

Rh-catalyzed desymmetrization of quaternary centers by hydroacylation.

Figure 15.

Asymmetric cycloisomerization to access cyclohexenes.

Figure 16.

Mechanistic pathways for the Rh-catalyzed cyclizations of dienyl aldehydes.

Figure 17.

Co-catalyzed hydroacylation affords enantioenriched cyclobutanones.

Figure 18.

(A) Inspiration for carbonyl hydroacylation and (B) challenges to overcome.

Figure 19.

Rh-catalyzed carbonyl hydroacylations furnishes medium-sized heterocyclic lactones.

Figure 20.

Design of a strategy uses coordinating counterions to expand the scope to non-chelating aldehydes.

Figure 21.

Enantioselective preparation of phthalides by Rh-catalyzed carbonyl hydroacylation.

Figure 22.

Diastereodivergent construction of bicyclic lactones by enantioselective carbonyl hydroacylation.

Figure 23.

Enantioselective coupling of aldehydes and ketoamides.

Figure 24.

(A) Nature’s approach to dehydroformylation. (B) Rh-catalyzed transfer hydroformylation.

Figure 25.

Rh-catalyzed C–C bond cleavage by transfer hydroformylation.