Versatile Copper-Catalyzed γ-C(sp3)-H Lactonization of Aliphatic Acids.

Site-selective C(sp3)-H oxidation is of great importance in organic synthesis and drug discovery. γ-C(sp3)-H lactonization of free carboxylic acids provides the most straightforward means to prepare biologically important lactone scaffolds from abundant and inexpensive carboxylic acids; however, a versatile catalyst for this transformation with a broad substrate scope remains elusive. Herein, we report a simple yet broadly applicable and scalable γ-lactonization reaction of free aliphatic acids enabled by a copper catalyst in combination with inexpensive Selectfluor as the oxidant. This lactonization reaction exhibits compatibility with tertiary, benzylic, allylic, methylene, and primary γ-C-H bonds, affording access to a wide range of structurally diverse lactones such as spiro, fused, and bridged lactones. Notably, exclusive γ-methylene C-H lactonization of cycloalkane carboxylic acids and cycloalkane acetic acids was observed, giving either fused or bridged γ-lactones that are difficult to access by other methods. δ-C-H lactonization was only favored in the presence of tertiary δ-C-H bonds. The synthetic utility of this methodology was demonstrated by the late-stage functionalization of amino acids, drug molecules, and natural products, as well as a two-step total synthesis of (iso)mintlactones (the shortest synthesis reported to date).

Ligand-accelerated non-directed C-H functionalization of arenes.

The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.

Remote C-H Olefination of Heterocyclic Biaryls Enabled by Reversibly Bound Templates.

Remote C-H functionalization of heterocyclic biaryls will be of great importance in synthesis and medicinal chemistry. Through adjusting the geometric relationship of the directing atom and target C-H bonds, two new catalytic templates have been developed to enable the functionalization of the more hindered ortho-C-H bonds of heterobiaryls bearing directing heteroatom at the meta- or para-positions, affording unprecedented site-selectivity. The use of template chaperone also overcomes product inhibition and renders the directing templates catalytic. The utility of this protocol was demonstrated by olefination of heterocyclic biaryls with various substituents, overriding conventional steric and electronic effects. These ortho-C-H olefinated heterobiaryls are sterically hindered and can often be challenging to prepare through aryl-aryl coupling reactions.

Ligand-Enabled C-H Hydroxylation with Aqueous H2O2 at Room Temperature.

With the large number of Pd(II)-catalyzed C-H activation reactions of native substrates developed in the past decade, the development of catalysts to enable the use of green oxidants under safe and practical conditions has become an increasingly important challenge. Notably, the compatibility of Pd(II) catalysts with sustainable aqueous H2O2 has been a long-standing challenge in catalysis including Wacker-type oxidations. We report herein a bifunctional bidentate carboxyl-pyridone (CarboxPyridone) ligand that enables room-temperature Pd-catalyzed C-H hydroxylation of a broad range of benzoic and phenylacetic acids with an industry-compatible oxidant, aqueous hydrogen peroxide (35% H2O2). The scalability of this methodology is demonstrated by a 1000 mmol scale reaction of ibuprofen (206 g) using only a 1 mol % Pd catalyst loading. The utility of this protocol is further illustrated through derivatization of the products and synthesis of polyfluorinated natural product coumestan and pterocarpene from phenol intermediates prepared using this methodology.

Ligand-Enabled ß-C(sp3 )-H Lactamization of Tosyl-Protected Aliphatic Amides Using a Practical Oxidant.

The development of C(sp3 )-H functionalization reactions that use common protecting groups and practical oxidants remains a significant challenge. Herein we report a monoprotected aminoethyl thioether (MPAThio) ligand-enabled ß-C(sp3 )-H lactamization of tosyl-protected aliphatic amides using tert-butyl hydrogen peroxide (TBHP) as the sole oxidant. This protocol features exceedingly mild reaction conditions, reliable scalability, and the use of practical oxidants and protecting groups. Further derivatization of the ß-lactam products enables the synthesis of a range of biologically important motifs including ß-amino acids, γ-amino alcohols, and azetidines.

Ligand Enabled Pd(II)-Catalyzed γ-C(sp3)-H Lactamization of Native Amides.

γ-Lactams form important structural cores of a range of medicinally relevant natural products and clinical drugs, principal examples being the new generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family. Compared to conventional multistep synthesis, an intramolecular γ-C-H amination of aliphatic amides would allow for the direct construction of valuable γ-lactam motifs from abundant amino acid precursors. Herein we report a novel 2-pyridone ligand enabled Pd(II)-catalyzed γ-C(sp3)-H lactamization of amino acid derived native amides, providing the convenient synthesis of γ-lactams, isoindolinones, and 2-imidazolidinones. C6-Substitution of the 2-pyridone ligand is crucial for the lactam formation. This protocol features the use of N-acyl amino acids, which serve as both the directing group and cyclization partner, practical and environmentally benign tert-butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and a broad substrate scope. The utility of this protocol was demonstrated through the two-step syntheses of a lenalidomide analog and brivaracetam from readily available carboxylic acids and amino acids.

meta-Selective C-H Arylation of Fluoroarenes and Simple Arenes.

Fluorine is known to promote ortho-C-H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho-palladation intermediate and is then relayed to the meta position, leading to meta-selective C-H arylation of fluoroarenes. Deuterium experiment suggests that this meta-arylation is initiated by ortho C-H activation and the catalytic cycle is terminated by C-2 protonation. A dual-ligand system is crucial for the observed high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity.

Rational Development of Remote C-H Functionalization of Biphenyl: Experimental and Computational Studies.

A simple and efficient nitrile-directed meta-C-H olefination, acetoxylation, and iodination of biaryl compounds is reported. Compared to the previous approach of installing a complex U-shaped template to achieve a molecular U-turn and assemble the large-sized cyclophane transition state for the remote C-H activation, a synthetically useful phenyl nitrile functional group could also direct remote meta-C-H activation. This reaction provides a useful method for the modification of biaryl compounds because the nitrile group can be readily converted to amines, acids, amides, or other heterocycles. Notably, the remote meta-selectivity of biphenylnitriles could not be expected from previous results with a macrocyclophane nitrile template. DFT computational studies show that a ligand-containing Pd-Ag heterodimeric transition state (TS) favors the desired remote meta-selectivity. Control experiments demonstrate the directing effect of the nitrile group and exclude the possibility of non-directed meta-C-H activation. Substituted 2-pyridone ligands were found to be key in assisting the cleavage of the meta-C-H bond in the concerted metalation-deprotonation (CMD) process.

PdII -Catalyzed Enantioselective C(sp3 )-H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group.

The use of chiral transient directing groups (TDGs) is a promising approach for developing PdII -catalyzed enantioselective C(sp3 )-H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C-H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to PdII centers, which can result in a mixture of reactive complexes. We report a PdII -catalyzed enantioselective ß-C(sp3 )-H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono-substituted cyclobutane through sequential C-H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron-deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.

meta C-H Arylation of Electron-Rich Arenes: Reversing the Conventional Site Selectivity.

Controlling site selectivity of C-H activation without using a directing group remains a significant challenge. While Pd(II) catalysts modulated by a mutually repulsive pyridine-type ligand have been shown to favor the relatively electron-rich carbon centers of arenes, reversing the selectivity to favor palladation at the relatively electron-deficient positions has not been possible. Herein we report the first catalytic system that effectively performs meta C-H arylation of a variety of alkoxy aromatics including 2,3-dihydrobenzofuran and chromane with exclusive meta site selectivity, thus reversing the conventional site selectivity governed by native electronic effects. The identification of an effective ligand and modified norbornene (NBE-CO2Me), as well as taking advantage of the statistics, are essential for achieving the exclusive meta selectivity.

Ligand-Promoted Non-Directed C-H Cyanation of Arenes.

This article reports the first example of a 2-pyridone accelerated non-directed C-H cyanation with an arene as the limiting reagent. This protocol is compatible with a broad scope of arenes, including advanced intermediates, drug molecules, and natural products. A kinetic isotope experiment (kH /kD =4.40) indicates that the C-H bond cleavage is the rate-limiting step. Also, the reaction is readily scalable, further showcasing the synthetic utility of this method.

Bioactivation of cyclopropyl rings by P450: an observation encountered during the optimisation of a series of hepatitis C virus NS5B inhibitors.

1. Due to its unique C-C and C-H bonding properties, conformational preferences and relative hydrophilicity, the cyclopropyl ring has been used as a synthetic building block in drug discovery to modulate potency and drug-like properties. During an effort to discover inhibitors of the hepatitis C virus non-structural protein 5B with improved potency and genotype-coverage profiles, the use of a pyrimidinylcyclopropylbenzamide moiety linked to a C6-substituted benzofuran or azabenzofuran core scaffold was explored in an effort to balance antiviral potency and metabolic stability. 2. In vitro metabolism studies of two compounds from this C6-substituted series revealed an NADPH-dependent bioactivation pathway leading to the formation of multiple glutathione (GSH) conjugates. Analysis of these conjugates by LC-MS and NMR demonstrated that the cyclopropyl group was the site of bioactivation. Based on the putative structures and molecular weights of the cyclopropyl-GSH conjugates, a multi-step mechanism was proposed to explain the formation of these metabolites by P450. This mechanism involves hydrogen atom abstraction to form a cyclopropyl radical, followed by a ring opening rearrangement and reaction with GSH. 3. These findings provided important information to the medicinal chemistry team which responded by replacing the cyclopropyl ring with a gem-dimethyl group. Subsequent compounds bearing this feature were shown to avert the bioactivation pathways in question.

A General Amino Acid Synthesis Enabled by Innate Radical Cross-Coupling.

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.

Diverse ortho-C(sp2)-H Functionalization of Benzaldehydes Using Transient Directing Groups.

Pd-catalyzed C-H functionalizations promoted by transient directing groups remain largely limited to C-H arylation only. Herein, we report a diverse set of ortho-C(sp2)-H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd(II)-catalyzed C-H arylation, chlorination, bromination, and Ir(III)-catalyzed amidation, could be achieved on benzaldehyde substrates. The transient directing groups formed in situ via imine linkage can override other coordinating functional groups capable of directing C-H activation or catalyst poisoning, significantly expanding the scope for metal-catalyzed C-H functionalization of benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-stage diversification of a drug analogue.

Phosphocholine conjugation: an unexpected in vivo conjugation pathway associated with hepatitis c ns5b inhibitors featuring a bicyclo[1.1.1]pentane.

During a medicinal chemistry campaign to identify inhibitors of the hepatitis C virus nonstructural protein 5B (RNA-dependent RNA polymerase), a bicyclo[1.1.1]pentane was introduced into the chemical scaffold to improve metabolic stability. The inhibitors bearing this feature, 5-(3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-4-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (1) and 5-(3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (2), exhibited low turnover in incubations with liver S9 or hepatocytes (rat, human), with hydroxylation of the bicyclic moiety being the only metabolic pathway observed. In subsequent disposition studies using bile-duct-cannulated rats, the metabolite profiles of bile samples revealed, in addition to multiple products of bicyclopentane-oxidation, unexpected metabolites characterized by molecular masses that were 181 Da greater than those of 1 or 2. Further LC/MSn and NMR analysis of the isolated metabolite of 1 demonstrated the presence of a phosphocholine (POPC) moiety bound to the methine carbon of the bicyclic moiety through an ester bond. The POPC conjugate of the NS5B inhibitors was assumed to result from two sequential reactions: hydroxylation of the bicyclic methine to a tertiary alcohol and addition of POPC by CDP-choline: 1,2-diacylglycerol cholinephosphotransferase, an enzyme responsible for the final step in the biosynthesis of phosphatidylcholine. However, this pathway could not be recapitulated using CDP-choline-supplemented liver S9 or hepatocytes due to inadequate formation of the hydroxylation product in vitro. The observation of this unexpected pathway prompted concerns about the possibility that 1 and 2 might interfere with routine phospholipid synthesis. These results demonstrate the participation in xenobiotic metabolism of a process whose function is ordinarily limited to the synthesis of endogenous compounds.

Ligand-enabled ß-C-H arylation of α-amino acids using a simple and practical auxiliary.

Pd-catalyzed ß-C-H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C-H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct ß-C-H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N-methoxyamide auxiliary, leading to a significant improvement of ß-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis(oxazoline) ligands.

Inhibitors of HIV-1 attachment. Part 9: an assessment of oral prodrug approaches to improve the plasma exposure of a tetrazole-containing derivative.

7-(2H-Tetrazol-5-yl)-1H-indole 3 was found to be a potent inhibitor of HIV-1 attachment but the compound lacked oral bioavailability in rats. The cause of the low exposure was believed to be poor absorption attributed to the acidic nature of the tetrazole moiety and, in an effort to address this liability, three more lipohilic tetrazole analogs, N-acetoxymethyl 4, N-pivaloyloxymethyl 5, and N-methyl 6, were evaluated as potential oral prodrugs in rats. Prodrug 5 was ineffective in improving the plasma concentration of 3 in vivo but compound 4 provided a 15-fold enhancement of the plasma concentration of 3. Most interestingly, oral dosing of analog 6 afforded a substantial increase in the plasma concentration of the parent in rats when compared to dosing of parent. This represents a novel example of a methyl tetrazole that acts as a prodrug for a free NH tetrazole-containing compound.

Inhibitors of HIV-1 attachment. Part 7: indole-7-carboxamides as potent and orally bioavailable antiviral agents.

A series of substituted carboxamides at the indole C7 position of the previously described 4-fluoro-substituted indole HIV-1 attachment inhibitor 1 was synthesized and the SAR delineated. Heteroaryl carboxamide inhibitors that exhibited pM potency in the primary cell-based assay against a pseudotype virus expressing a JRFL envelope were identified. The simple methyl amide analog 4 displayed a promising in vitro profile, with its favorable HLM stability and membrane permeability translating into favorable pharmacokinetic properties in preclinical species.

Inhibitors of HIV-1 attachment. Part 8: the effect of C7-heteroaryl substitution on the potency, and in vitro and in vivo profiles of indole-based inhibitors.

As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M- and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure.

Degradation of Protein Kinases: Ternary Complex, Cooperativity, and Selectivity.

In targeted protein degradation of kinases, key discoveries have been made specifically involving selective kinase degradation. Structural and biophysical studies on the ternary complex formation have provided a clear understanding of the basis for achieving degradation selectivity which is important in guiding the design of efficient and selective protein degraders.