Sequential Xanthalation and O-Trifluoromethylation of Phenols: A Procedure for the Synthesis of Aryl Trifluoromethyl Ethers.

Molecules containing trifluoromethoxyaryl groups are of interest in pharmaceutical, agrochemical, and materials science research, due to their unique physical and electronic properties. Many of the known methods to synthesize aryl trifluoromethyl ethers require harsh reagents and highly controlled reaction conditions and rarely occur when heteroaromatic units are present. The two-step O-trifluoromethylation of phenols via aryl xanthates is one such method that suffers from these drawbacks. Herein, we report a method for the synthesis of aryl trifluoromethyl ethers from phenols by the facile conversion of the phenol to the corresponding aryl and heteroaryl xanthates with newly synthesized imidazolium methylthiocarbonothioyl salts and conversion of these xanthates to the trifluoromethyl ethers under mild reaction conditions.

Reversal of the regiochemistry in the rhodium-catalyzed [4+3] cycloaddition between vinyldiazoacetates and dienes.

A regio-, diastereo-, and enantioselective [4+3] cycloaddition between vinylcarbenes and dienes has been achieved using the dirhodium tetracarboxylate catalyst [Rh2(S-BTPCP)4]. This methodology provides facile access to 1,4-cycloheptadienes that are regioisomers of those formed from the tandem cyclopropanation/Cope rearrangement reaction of vinylcarbenes with dienes.

Synthesis of Highly Substituted Aminotetrahydropyrans Enabled by Stereospecific Multivector C-H Functionalization.

Highly substituted aminotetrahydropyrans were synthesized via sequential C-H functionalizations. The process was initiated with a Pd(II)-catalyzed stereoselective γ-methylene C-H arylation of aminotetrahydropyran, followed by α-alkylation or arylation of the corresponding primary amine. The initial γ-C-H (hetero)arylation was compatible with a range of aryl iodides containing various substituents and provided the corresponding products in moderate to good yields. The subsequent α-alkylation or arylation of the isolated arylated products proceeded with high diastereoselectivity to afford value-added disubstituted aminotetrahydropyrans.

A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19.

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.

Rhodium(III)-catalyzed indazole synthesis by C-H bond functionalization and cyclative capture.

An efficient, one-step, and highly functional group-compatible synthesis of substituted N-aryl-2H-indazoles is reported via the rhodium(III)-catalyzed C-H bond addition of azobenzenes to aldehydes. The regioselective coupling of unsymmetrical azobenzenes was further demonstrated and led to the development of a new removable aryl group that allows for the preparation of indazoles without N-substitution. The 2-aryl-2H-indazole products also represent a new class of readily prepared fluorophores for which initial spectroscopic characterization has been performed.

Facile synthesis of unsymmetrical acridines and phenazines by a Rh(III)-catalyzed amination/cyclization/aromatization cascade.

We report formal [3 + 3] annulations of aromatic azides with aromatic imines and azobenzenes to give acridines and phenazines, respectively. These transformations proceed through a cascade process of Rh(III)-catalyzed amination followed by intramolecular electrophilic aromatic substitution and aromatization. Acridines can be directly prepared from aromatic aldehydes by in situ imine formation using catalytic benzylamine.

The combined C-H functionalization/Cope rearrangement: discovery and applications in organic synthesis.

The development of methods for the stereoselective functionalization of sp(3) C-H bonds is a challenging undertaking. This Account describes the scope of the combined C-H functionalization/Cope rearrangement (CHCR), a reaction that occurs between rhodium-stabilized vinylcarbenoids and substrates containing allylic C-H bonds. Computational studies have shown that the CHCR reaction is initiated by a hydride transfer to the carbenoid from an allyl site on the substrate, which is then rapidly followed by C-C bond formation between the developing rhodium-bound allyl anion and the allyl cation. In principle, the reaction can proceed through four distinct orientations of the vinylcarbenoid and the approaching substrate. The early examples of the CHCR reaction were all highly diastereoselective, consistent with a reaction proceeding via a chair transition state with the vinylcarbenoid adopting an s-cis conformation. Recent computational studies have revealed that other transition state orientations are energetically accessible, and these results have guided the development of highly stereoselective CHCR reactions that proceed through a boat transition state with the vinylcarbenoid in an s-cis configuration. The CHCR reaction has broad applications in organic synthesis. In some new protocols, the CHCR reaction acts as a surrogate to some of the classic synthetic strategies in organic chemistry. The CHCR reaction has served as a synthetic equivalent of the Michael reaction, the vinylogous Mukaiyama aldol reaction, the tandem Claisen rearrangement/Cope rearrangement, and the tandem aldol reaction/siloxy-Cope rearrangement. In all of these cases, the products are generated with very high diastereocontrol. With a chiral dirhodium tetracarboxylate catalyst such as Rh(2)(S-DOSP)(4) or Rh(2)(S-PTAD)(4), researchers can achieve very high levels of asymmetric induction. Applications of the CHCR reaction include the effective enantiodifferentiation of racemic dihydronaphthalenes and the total synthesis of several natural products: (-)-colombiasin A, (-)-elisapterosin B, and (+)-erogorgiaene. By combining the CHCR reaction into a further cascade sequence, we and other researchers have achieved the asymmetric synthesis of 4-substituted indoles, a new class of monoamine reuptake inhibitors.

Rhodium(III)-catalyzed alkenyl C-H bond functionalization: convergent synthesis of furans and pyrroles.

Ring in the new: a new annulation for the efficient synthesis of substituted furans and pyrroles is reported. The Rh(III) -catalyzed reaction of O-methyl α,ß-unsaturated oximes with aldehydes and N-tosyl imines affords secondary alcohol and amine intermediates, respectively. Cyclization and aromatization occurs under the reaction conditions to provide access to biologically relevant furans and pyrroles in good yields. Cp*=C(5)Me(5), DCE=1,2-dichloroethane, THF=tetrahydrofuran.

Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss.

The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.

Alkynoate synthesis through the vinylogous reactivity of rhodium(II) carbenoids.

Siloxy group migration: A rhodium(II) carbenoid approach has been developed for the synthesis of alkynoates. This transformation combines the addition of enol ethers at the vinylogous position of ß-siloxy-substituted vinyldiazo derivatives with a siloxy group migration to give the products as single diastereomers.

Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis.

Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.

Combined C-H functionalization/Cope rearrangement with vinyl ethers as a surrogate for the vinylogous Mukaiyama aldol reaction.

Vinyl ethers selectively undergo the combined C-H functionalization/Cope rearrangement reaction via an s-cis/boat transition state. With chiral dirhodium catalysts, products are generated in a highly diastereoselective and enantioselective fashion. This reaction can be considered as a surrogate to the traditional vinylogous Mukaiyama aldol reaction. Effective kinetic resolution has been achieved, leading to the recovery of a cyclic vinyl ether with axial chirality of high enantiomeric purity.

On the mechanism and selectivity of the combined C-H activation/Cope rearrangement.

The combined C-H activation/Cope rearrangement (CHCR) is an effective C-H functionalization process that has been used for the asymmetric synthesis of natural products and pharmaceutical building blocks. Up until now, a detailed understanding of this process was lacking. Herein, we describe a combination of theoretical and experimental studies that have resulted in a coherent description of the likely mechanism of the reaction. Density functional studies on the reactions of rhodium vinylcarbenoids at allylic C-H sites demonstrate that the CHCR proceeds through a concerted, but highly asynchronous, hydride-transfer/C-C bond-forming event. Even though most of the previously known examples of this process are highly diastereoselective, the calculations demonstrate that other transition-states and stereochemical outcomes might be possible by appropriate modifications of the reagents, and this was confirmed experimentally. The calculations also indicate that there is a potential energy surface bifurcation between CHCR and the competing direct C-H insertion.

Bi(OTf)3-, TfOH-, and TMSOTf-mediated, one-pot epoxide rearrangement, addition, and intramolecular silyl-modified Sakurai (ISMS) cascade toward dihydropyrans: comparison of catalysts and role of Bi(OTf)3.

Catalytic quantities of bismuth(III) triflate efficiently initiate the rearrangement of epoxides to aldehydes, which subsequently react with (Z)-δ-hydroxyalkenylsilanes to afford 2,6-disubstituted 3,6-dihydro-2H-pyrans. Isolated yields of desired products using Bi(OTf)(3) were compared with yields obtained when the reactions were run with TfOH and TMSOTf in the presence and absence of several additives. These studies, as well as NMR spectroscopic analyses, indicate an initial Lewis acid/base interaction between Bi(OTf)(3) and substrates providing TfOH in situ.

Mechanistic study of enantioselective Pd-catalyzed C(sp3)-H activation of thioethers involving two distinct stereomodels.

Enantioselective C(sp3)-H activation has gained considerable attention from the synthetic chemistry community. Despite the intense interest in these reactions, the mechanisms responsible for enantioselection are still vague. In the course of the development of aryl thioether-directed C(sp3)-H arylation, we noticed extreme variation in sensitivity of two substrate classes to substituent effects of ligands and directing groups: whereas 3-pentyl sulfides (prochiral α-center) responded positively to substitution on ligands and directing groups, isobutyl sulfides (prochiral ß-center) were entirely insensitive. Quantitative structure selectivity relationship (QSSR) analyses of directing group and ligand substitution and the development of a new class of mono-N-acetyl protected amino anilamide (MPAAn) ligands led to high enantiomeric ratios (up to 99:1) for thioether-directed C(sp3)-H arylation. Key to the realization of this method was the exploitation of transient chirality at sulfur, which relays stereochemical information from the ligand backbone to enantiotopic carbons of the substrate in a rate- and enantio-determining cyclometallation deprotonation. The absolute stereochemistry of the products for these two substrates were revealed to be opposite. DFT evaluation of all possible diastereomeric transition states confirmed initial premises that guided rational ligand and directing group design. The implications of this study will assist in the further development of enantioselective C(sp3)-H activation, namely by highlighting the non-innocence of directing groups, distal steric influences, and the delicate interplay between steric Pauli repulsion and London dispersion in enantioinduction.

Rhodium-catalyzed [3 + 2] annulation of indoles.

An effective Rh(2)(S-DOSP)(4)-catalyzed asymmetric cyclopentannulation of indolyl rings has been developed. Depending on the substitution pattern of the indole, two distinct regioisomeric products can be generated. These studies demonstrate that rhodium-catalyzed reactions of donor/acceptor carbenoids proceeding by means of zwitterionic intermediates can be carried out with very high asymmetric induction.

Catalyst-controlled formal [4 + 3] cycloaddition applied to the total synthesis of (+)-barekoxide and (-)-barekol.

The tandem cyclopropanation/Cope rearrangement between bicyclic dienes and siloxyvinyldiazoacetate, catalyzed by the dirhodium catalyst Rh(2)(R-PTAD)(4), effectively accomplishes enantiodivergent [4 + 3] cycloadditions. The reaction proceeds by a cyclopropanation followed by a Cope rearrangement of the resulting divinylcyclopropane. This methodology was applied to the synthesis of (+)-barekoxide (1) and (-)-barekol (2).

Asymmetric [4 + 3] cycloadditions between vinylcarbenoids and dienes: application to the total synthesis of the natural product (-)-5-epi-vibsanin E.

The total synthesis of (-)-5-epi-vibsanin E (2) has been achieved in 18 steps. The synthesis combines the rhodium-catalyzed [4 + 3] cycloaddition between a vinylcarbenoid and a diene to rapidly generate the tricyclic core with an effective end game strategy to introduce the remaining side-chains. The [4 + 3] cycloaddition occurs by a cyclopropanation to form a divinylcyclopropane followed by a Cope rearrangement to form a cycloheptadiene. The quaternary stereogenic center generated in the process can be obtained with high asymmetric induction when the reaction is catalyzed by the chiral dirhodium complex, Rh(2)(S-PTAD)(4).

Synthesis of 2,6-disubstituted dihydropyrans via an efficient BiBr(3)-initiated three component, one-pot cascade.

The rapid synthesis of cis-2,6-disubstituted dihydropyrans is achieved in a three-component, one-pot cascade reaction. BiBr(3)-ediated addition of ketene silyl acetals or silyl enol ethers to beta,gamma-unsaturated cis-4-trimethylsilyl-3-butenal provides a Mukaiyama aldol adduct containing a vinylsilane moiety tethered to a silyl ether. Addition of a second aldehyde initiates a domino sequence involving intermolecular addition followed by an intramolecular silyl-modified Sakurai (ISMS) reaction. Isolated yields of this one-pot reaction vary from 44 to 80% and all compounds were isolated as the cis-diastereomers (10 examples).

Metal-Free-Visible Light C-H Alkylation of Heteroaromatics via Hypervalent Iodine-Promoted Decarboxylation.

A metal-free photoredox C-H alkylation of heteroaromatics from readily available carboxylic acids using an organic photocatalyst and hypervalent iodine reagents under blue LED light is reported. The developed methodology tolerates a broad range of functional groups and can be applied to the late-stage functionalization of drugs and drug-like molecules. The reaction mechanism was investigated with control experiments and photophysical experiments as well as DFT calculations.