The dehydroformylation of aldehydes to generate olefins occurs during the biosynthesis of various sterols, including cholesterol in humans. A mild and chemoselective synthetic version has been developed that features the transfer of a formyl group and hydride from an aldehyde substrate to a strained olefin acceptor. A Rh(Xantphos)(benzoate) catalyst activates aldehyde C–H bonds with high chemoselectivity to trigger C–C bond cleavage and generate olefins at low loadings (0.3 to 2 mol%) and temperatures (22 to 80 °C). This mild protocol is tolerant of several functional groups and can be applied to various natural products, including a deoxycholic acid derivative.

Previous efforts to directly transform alcohols to olefins via dehomologation have been limited to isolated examples and/or occur at harsh conditions (>380 ºC). This same Rh(Xantphos)(benzoate) catalyst enables access to olefins from primary alcohols by a C–C bond cleavage that results in dehomologation. This functional group interconversion proceeds by an oxidation-dehydroformylation enabled by N,N-dimethylacrylamide as a sacrificial acceptor of hydrogen gas. Alcohols with diverse functionality and structure undergo oxidative dehydroxymethylation to access the corresponding olefins. This catalyst protocol enables a two-step semi-synthesis of (+)-yohimbenone and dehomologation of feedstock olefins. Under mild conditions, the olefin remains intact without further reduction or isomerization.

Hydrofunctionalization is an attractive method for transforming alkynes that addresses the need for atom-economic, green, and sustainable processes. Alkyne hydrofunctionalizations typically generate achiral poly-substituted olefins. We envisioned that using metal-hydride catalysis would enable novel alkyne activation and functionalization. We have developed metal-hydride catalysts that isomerize alkynes to generate metal-allyl species which are then coupled with a variety of partners to generate new alkyne hydrofunctionalization motifs bearing a chiral center and terminal olefin. By careful choice of metal-hydride catalyst, we can control the polarity of the generated metal-allyl species (nucleophilic vs. electrophilic) and engage with an appropriate coupling partner to achieve (1) alkyne hydroacylation with unprecedented regiocontrol via Ru–H catalysis, (2) decarboxylative alkyne hydroalkylation with β-keto acids via Rh–H catalysis, (3) stereodivergent alkyne hydroalkylation with aldehydes via synergistic Rh–H/enamine catalysis, and (4) enantioselective alkyne hydroheteroarylation via Rh–H catalysis. Ultimately, we hope that this new mode of alkyne functionalization would enable chemists to use alkynes as an alternative synthetic disconnection.

Hydrofunctionalization, which is defined as the addition of a hydrogen atom and another fragment to a degree of unsaturation, is an attractive method for transforming unsaturated hydrocarbons to value-added molecules. We developed Rh-, Pd-, and Cu-H catalysts that are capable of coupling both heteroatom and carbon nucleophiles to unsaturated hydrocarbons. The judicious choice of transition metal source (e.g., transition metal and counterion), bisphosphine ligand, and reaction conditions all play a role in selectively accessing one stereoisomeric product when many other outcomes exist.In Chapter 1, we develop an enantioselective Rh-catalyzed addition of thiols to 1,3-dienes. The use of Rh(cod)2SbF6 and a bisphosphine ligand allows for the synthesis of allylic sulfides with high regio- and enantiocontrol. The catalyst loading can be lowered to 0.1 mol% and an array of functional groups are compatible. By matching the bisphosphine ligand to the 1,3-diene’s substitution pattern, we can transform a wide-range of 1,3-dienes (e.g., cyclic, disubstituted, and butadiene) into chiral sulfide building blocks. In Chapter 2, we investigate the mechanism of the enantioselective 1,3-diene hydrothiolation (Chapter 1) and determine the fundamental steps that govern regioselectivity. Guided by these insights, we then develop a complementary hydrothiolation to provide access to homoallylic sulfides. It is now possible for allylic and homoallylic sulfides to be synthesized in a regiodivergent manner by simply switching the Rh source. Mechanistic investigations shed light on the origin of the high regioselectivity observed for both hydrothiolations. In Chapter 3, we showcase an enantioselective Pd-catalyzed 1,3-diene hydro- phosphinylation. This method allows for complementary access to chiral tertiary phosphine oxides. Secondary phosphine oxides and 1,3-dienes can be coupled in high yields, regioselectivities, and enantioselectivities. Mechanistic studies suggest that the reaction proceeds through a reversible 1,3-diene hydrometallation followed by an irreversible C–P reductive elimination. In Chapter 4, we found that Rh-H catalysis offers an approach to novel α-amino acids (α- AAs). Alkynes and α-nitroesters couple to form allylic α-AA precursors under mild conditions. We apply this method to the synthesis of an α,α-disubstituted α-amino ester. Moreover, initial mechanistic studies suggest that the isomerization of the alkyne starting material to an allene intermediate is reversible and occurs before C–C bond formation. In Chapter 5, we report preliminary results for an enantioselective Cu-catalyzed olefin hydroacylation. This hydroacylation couples activated acyl electrophiles with a,b-unsaturated carbonyls to afford enantioenriched 1,3-dicarbonyls. The identity of the acyl electrophile has a pronounced effect on enantioselectivity. Future efforts are needed to (1) expand the scope of this transformation and (2) understand the step(s) that control enantioselectivity.

The efficient and stereoselective conversion of simple chemical building blocks, including olefins, alkynes, and aldehydes, into value-added products represents a modern challenge in synthetic organic chemistry. Significant research efforts have led to the discovery that rhodium-based catalysts can promote a variety of novel transformations. To this end, my co-workers and I have developed new synthetic methods, where we leveraged catalytically generated rhodium-hydride intermediates to achieve stereo- and regiocontrolled hydrofunctionalizations (Chapter 1) and cycloisomerizations (Chapter 2). Both processes are attractive methods that address the need for atom-economical and sustainable chemistry.

Typically, the hydrofunctionalization of alkynes yields achiral olefin products. We showed that rhodium-hydride catalysis can switch the regioselectivity of these processes to generate chiral products by (1) isomerization of an alkyne to an allene, (2) Rh–H reinsertion to generate an electrophilic Rh–allyl intermediate, and (3) allylic substitution with various (pro)nucleophiles. By careful choice of the catalyst, we developed an asymmetric alkyne hydroamination with amines (Chapter 1.1) and a regioselective decarboxylative hydroalkylation with β-keto acids (Chapter 1.2).

Despite the numerous catalysts available for asymmetric reduction, allenes are challenging substrates for stereo- and regiocontrolled reduction. In light of this challenge, we envisioned that our aforementioned strategy of alkyne hydrofunctionalization could be applied to achieve an asymmetric semireduction of allenes. We described a method that generates a Rh–allyl intermediate from a 1,1-disubstituted allene, which reacts with a Hantzsch ester (a hydride donor) to produce a chiral olefin product (Chapter 1.3). A designer Josiphos ligand was key to generate the products with high regio- and enanatioselectivity.

Desymmetrizations are powerful strategies to form multiple chiral centers in a single step. When coupled with cycloisomerizations, various carbocyclic motifs can be stereoselectively formed. We describe a desymmetrization of prochiral diketoaldehydes by ketone hydroacylation to generate chiral bicylic ketolactones (Chapter 2.1). In this process, a Rh–H intermediate generated from aldehyde C–H activation inserts into one of the carbonyl groups, and subsequent reductive elimination yields the product. By tuning the reaction conditions, we can selectively form each diastereomer of the product. Using aldehyde C–H activation, we showed that prochiral dienyl aldehydes can be transformed into chiral cyclohexenes (Chapter 2.2). This method complements the Diels-Alder cycloaddition and is a rare example of a cycloisomerization to generate six-membered rings.

Dynamic kinetic resolutons have emerged as an attractive to transform racemic building blocks into enantioenriched products. We described a dynamic kinetic resolution (DKR) of racemic α-allyl aldehydes by olefin hydroacylation to generate α,γ-disubstituted cyclopentanones with high enantio- and diastereoselectivity (Chapter 2.3). A bulky primary amine co-catalyst is important for selective racemization of the aldehyde substrate, and a bulky bisphosphine ligand is needed for cycloisomerization. Three different classes of aldehydes can be efficiently resolved with different amine and ligand combinations.

Fused cyclic ketones (e.g. tetralones) are commonly found in natural products and used as building blocks in chemical synthesis. Several tetralone derivatives were needed by Genentech scientists for the synthesis of drug candidates. However, no satisfactory general method existed for the preparation of these motifs. Toward a solution to this challenge, I collaborated with two process chemists to develop a strategy towards the synthesis of tetralones from aryl iodides and cyclopropane diesters (Chapter 3.1). This strategy proceeds via a homoconjugate addition between the corresponding aryl organocopper intermediate and the cyclopropyl electrophile followed by a decarboxylative Dieckmann annulation.

Hydrofunctionalizations are an attractive method for functionalizing olefins, forging new bonds in an atom-economic and sustainable fashion. We developed a variety of Rh–H catalysts that can couple heteroatom nucleophiles with olefin coupling partners. Choice of bisphosphine ligands for the Rh catalysts is important for achieving selectivity when the hydrofunctionalization has many potential outcomes. In the first example, we developed an intermolecular anti-Markovnikov hydroamination of 1,3-dienes to form homoallylic amines. In this case, the regioselectivity of the hydroamination is under both catalyst and substrate control, since the choice of ligand and diene substitution pattern are both critical for anti-Markovnikov regioselectivity. Mechanistic studies highlight the importance of the carboxylic acid additive for achieving reactivity between the Rh catalyst and the amine nucleophile.In the second example, we developed a divergent hydrothiolation of cyclopropenes. Depending on the choice of bisphosphine ligand on the Rh–H catalyst, either direct hydrothiolation occurs to from cyclopropyl sulfide products, or ring-opening of the cyclopropenes occurs to form allylic sulfide products. Mechanistic studies suggest that the two reaction pathways share a common cyclopropyl-Rh(III) intermediate. Another way to form Rh–H intermediates is through the activation of aldehyde C–H bonds by a Rh catalyst. One pathway from this Rh–H intermediate is to cleave the aldehyde C–C bond through dehydroformylation and form an olefin. Given Rh’s ability to catalyze transfer hydrogenation reactions, we expand this dehomologation to primary alcohols. This oxidative-dehydroformylation cascade to dehomologate primary alcohols to olefins is enabled by the addition of N,N-dimethylacrylamide as a hydrogen acceptor. The use of different acceptors for dehydroformylation inspired a collaboration with Chevron Phillips, where we tried to find new conditions for dehydroformylation to make it amenable towards industrial scale chemical synthesis. Another reaction that takes advantage of Rh activation of aldehyde C–H bonds is hydroacylation, where aldehydes and olefins are coupled to form ketones in a direct and atom-economical manner. Our lab previously developed a dynamic kinetic resolution of aldehydes through intramolecular hydroacylation. A bulky primary amine co-catalyst was used to selectively racemize the aldehyde starting material over epimerizing the cyclopentanone product. By further activating the Rh catalyst through hydrogenation and employing acrylamides as the coupling partner, we extend this dynamic kinetic resolution of aldehydes through intermolecular hydroacylation. Future studies include exploring the substrate scope and determining the rate of racemization.

Chapter 1 focuses on the use of C–H activation in total synthesis and the strategies that these methods enable. Following a review of recent total syntheses using C–H activation to form a variety of rings, we discuss our efforts towards two total syntheses using C–H activation methodology. In this instance, desymmetrizing olefin hydroacylation offers a method to generate quaternary stereocenters on cyclic ketones in a rapid manner with high atom economy. The resulting cyclic scaffolds were used to develop a formal synthesis of the natural product (+)- tanikolide, a cyanotoxin from lyngbya majuscula, and in efforts towards the total synthesis of (– )-adalinine, an alkaloid natural product isolated from adalia bipunctata and adalia decempunctata.

Chapter 2 describes recent efforts to use aldehyde C–H activation in a tandem oxidation- dehydroformylation reaction that we have worked to develop. This new methodology offers the ability to directly transform primary alcohols directly to olefins while cleaving a carbon-carbon bond, a previously undocumented transformation.