Huw M L Davies

Emory University | EU · Department of Chemistry

(−)-Cylindrocyclophane A is a 22-membered C 2 -symmetric [7.7]paracyclophane that bears bis-resorcinol functionality and six stereocenters. We report a synthetic strategy for (−)-cylindrocyclophane A that uses 10 C−H functionalization reactions, resulting in a streamlined route with high enantioselectivity and efficiency (17 steps). The use of chir...

A catalyst-in-bag system facilitates the recovery and recycling of chiral dirhodium carboxylate catalysts used for enantioselective, intermolecular cyclopropanation. The catalyst-in-bag system incorporates a soluble enantioselective dirhodium complex catalyst within a reusable, commercial dialysis membrane. Dirhodium catalysts of different sizes ar...

Cereblon (CRBN) has been successfully co-opted to affect the targeted degradation of “undruggable” proteins with immunomodulatory imide drugs (IMiDs). IMiDs act as molecule glues that facilitate ternary complex formation between CRBN and a target protein, leading to ubiquitination and proteasomal degradation. Subtle structural modifications often c...

Dirhodium tetrakis(2,2′-binaphthylphosphate) catalysts were successfully developed for asymmetric C–H functionalization with trichloroethyl aryldiazoacetates as the carbene precursors. The 2,2′-binaphthylphosphate (BNP) ligands were modified by introduction of aryl and/or chloro functionality at the 4,4′,6,6′ positions. As the BNP ligands are C2-sy...

Chiral [2.2]paracyclophane derivatives are of considerable interest because of their potential in asymmetric catalysis and the development of chiral materials. This study describes the scope of rhodium-catalyzed reactions of aryldiazoacetates with [2.2]paracyclophanes. The reaction with the parent [2.2]paracyclophane resulted in cyclopropanation at...

A novel donor/acceptor carbene intermediate has been developed using diaryldiazoketones as carbene precursors. In the presence of the chiral dirhodium catalyst, Rh2(S-TPPTTL)4, diaryldiazoketones undergo highly regio-, stereo-, and diastereoselective C–H functionalization of activated and unactivated secondary and tertiary C–H bonds. Computational...

Immunomodulatory imide drugs form the core of many pharmaceutically relevant structures, but Csp²–Csp² bond formation via metal-catalyzed cross coupling is difficult due to the sensitivity of the glutarimide ring ubiquitous in these structures. We report that replacement of the traditional alkali base with a fluoride source enhances a previously ch...

Although cyclopropanation with donor/acceptor carbenes can be conducted under low catalyst loadings (<0.001 mol %), such low loading has not been generally effective for other classes of carbenes such as acceptor carbenes. In this current study, we demonstrate that ethyl diazoacetate can be effectively used in the cyclopropanation of N-Boc-2,5-dihy...

Catalyst-controlled C–H functionalization using donor/acceptor carbenes has been shown to be an efficient process capable of high levels of site control and stereocontrol. This study demonstrated that the scope of the donor/acceptor carbene C–H functionalization can be extended to systems where the acceptor group is a phosphonate. When using the op...

Cystic fibrosis (CF) is an autosomal genetic disorder caused by disrupted anion transport in epithelial cells lining tissues in the human airways and digestive system. While cystic fibrosis transmembrane conductance regulator (CFTR) modulator compounds have provided transformative improvement in CF respiratory function, certain patients exhibit mar...

Rapid access to 2,2-difluorobicylco[1.1.1]pentanes is enabled from an α-allyldiazoacetate precursor in a one-pot process through cyclopropanation to afford a 3-aryl bicyclo[1.1.0]butane, followed by reaction with difluorocarbene in the same reaction flask. The modular synthesis of these diazo compounds affords novel 2,2-difluorobicyclo[1.1.1]pentan...

A series of chiral bowl-shaped diruthenium(II,III) tetracarboxylate catalysts were prepared and evaluated in asymmetric cyclopropanations with donor/acceptor carbenes derived from aryldiazoacetates. The diruthenium catalysts self-assembled to generate C4-symmetric bowl-shaped structures in an analogous manner to their dirhodium counterparts. The op...

The rhodium-catalyzed enantioselective C-H functionalization of unactivated C-H bonds by means of donor/acceptor carbene-induced C-H insertion was extended to substrates containing nitrogen functionality. The rhodium-stabilized donor/acceptor carbenes were generated by rhodium-catalyzed decomposition of aryldiazoacetates. The phthalimido group was...

Rhodium-catalyzed C-H functionalization of cyclohexadiene derivatives with diaryldiazomethanes followed by oxidation with DDQ provides ready access to triarylmethanes. Two chiral dirhodium tetracarboxylates, Rh2(S-PTAD)4 and Rh2(S-TPPTTL)4, were found to be the optimum chiral catalysts for these transformations. This method showcases the ability of...

A stereoselective, solvent- and metal-free endocyclic C-C bond cleavage of monocyclopropanated cyclopentadienes mediated by strong acids was developed, leading to highly functionalized six-membered carbocycles with high stereocontrol. The critical step for this ring-expansion is the formation of a cyclopropyl carbocation that undergoes endocyclic r...

Hole-transport materials (HTMs) based on triarylamine derivatives play important roles in organic electronics applications including organic light-emitting diodes and perovskite solar cells. For some applications, triarylamine derivatives bearing appropriate binding groups have been used to functionalize surfaces, while others have been incorporate...

Rhodium(II) catalyst-controlled site- and stereoselective carbene insertion into the distal allylic C(sp3)-H bond of allyl boronates is reported. The optimum chiral catalyst for this reaction is Rh2(S-TPPTTL)4. The fidelity and asymmetric induction of this catalytic transformation allows for a highly diastereoselective and enantioselective C-C bond...

Rhodium-catalyzed enantioselective synthesis of 1-phenoxycyclopropane-1-carbaldehydes by intermolecular cyclopropanation of terminal alkenes followed by imine hydrolysis is described. This methodology utilizes 4-aryloxy-1-sulfonyl-1,2,3-triazoles as the carbene precursors and the chiral dirhodium(II) tetracarboxylates Rh2(S-NTTL)4 or Rh2(S-DPCP)4 a...

Detailed kinetic studies on the functionalization of unactivated hydrocarbon sp3 C-H bonds by dirhodium-catalyzed reaction of aryldiazoacetates revealed that the C-H functionalization step is rate-determining. The efficiency of this step was increased by using the hydrocarbon as solvent and using donor/acceptor carbenes with an electron-withdrawing...

The synthesis and evaluation of six C4-symmetric bowl-shaped dirhodium tetracarboxylate catalysts are described. These elaborate high-symmetry catalysts are readily generated by means of the self-assembly of four C1-symmetric ligands around the dirhodium core. These catalysts are capable of highly site-selective, diastereoselective, and enantiosele...

The C-H functionalization of silyl ethers via carbene-induced C-H insertion represents an efficient synthetic disconnection strategy. In this work, site- and stereoselective C(sp3)-H functionalization at α, γ, δ, and even more distal positions to the siloxy group has been achieved using donor/acceptor carbene intermediates. By exploiting the predil...

An enantioselective formal synthesis of (−)-aflatoxin B2 from 4-methoxyphenylacetic acid has been achieved by an approach that produces a key carbon–carbon bond, a benzylic stereocenter, and two arene carbon–oxygen bonds in the course of three site-selective C–H functionalizations. The carbonyl-directed acetoxylation of two arene C–H bonds describe...

This study describes general methods for the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates through dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation of vinyl heterocycles with aryl- or heteroaryldiazoacetates. The reactions are highly diastereoselective an...

Computational studies revealed that dirhodium tetrakis(1,2,2‐triarylcyclopropanecarboxylate) (Rh2(TPCP)4) catalysts adopt distinctive high symmetry orientations, which are dependent on the nature of the aryl substitution pattern. The parent catalyst, Rh2(TPCP)4, and those with a p‐substituent at the C1 aryl, such as Rh2(p‐BrTPCP)4 and Rh2(p‐PhTPCP)...

Dirhodium triarylcyclopropanecarboxylate catalysts (Rh2TPCP4) are sterically demanding and capable of con-trolling the site selectivity of C—H functionalization by means of C—H insertion with donor/acceptor carbenes. This study compares the structures and the reactivity pro-files of dirhodium triarylcyclopropanecarboxylates with dirhodium diarylcyc...

Herein we demonstrate a packed bed flow reactor capable of achieving highly regio‐ and stereoselective C−H functionalization reactions using a newly developed Rh2(S‐2‐Cl‐5‐CF3TPCP)4 catalyst. To optimize the immobilized dirhodium catalyst employed in the flow reactor, we systematically study both (i) the effects of ligand immobilization position, d...

Supported rhodium catalysts anchored to mesoporous silica in three different locations demonstrate optimal tethering location, allowing for deployment in a fixed bed flow reactor for enantio‐ and regioselective C−H functionalization. Tuning silica particle size/shape enhances reactivity and the catalyst immobilization methodology is widely applicab...

Rhodium-stabilized diaryl carbenes typically generated from diaryldiazomethanes have been generally classified as donor/donor carbenes. This combined computational and experimental study demonstrates that diarylcarbenes display reactivity characteristics that are more reminiscent of donor/acceptor carbenes. When the reactions are carried out with c...

A visible light mediated ring expansion of readily available carbo- and heterocyclic anellated cyclopropanes by molecular oxygen at ambient pressure has been developed. Tolerating a variety of functional groups, the...

Bicyclo[1.1.1]pentanes (BCPs) are highly strained carbocycles that have fascinated the chemical community for decades because of their unique structure. Despite the immense interest in this scaffold and extensive synthetic efforts, the construction of BCP derivatives still relies substantially on the manipulation of dimethyl bicyclo[1.1.1]pentane-1...

Metal carbenes, derived from the decomposition of diazo compounds, are valued for their capacity to perform a variety of transformations. A unique class of acyclic, bis-diazo compounds, the donor-acceptor-acceptor 1,3-bisdiazo compounds, are described herein. These compounds are available from acyclic β-keto esters and especially reactive at the do...

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Recent developments in controlled C–H functionalization transformations continue to inspire new retrosynthetic disconnections. One tactic in C–H functionalization is the intermolecular C–H insertion reaction of rhodium-bound carbenes. These intermediates can undergo highly selective transformations through the modulation of the ligand framework of...

Chiral cyclooctadiene (COD) derivatives are readily prepared by rhodium-catalyzed allylic C-H functionalization of COD. Either mono- or difunctionalization of COD is possible generating the products in high yield, diastereoselectivity and enantioselectivity. The double C-H functionalization generates C2-symmetric COD derivatives with four new stere...

Here we report Rh(II)-catalyzed monocyclopropanation reactions on pyrroles in the presence of aryldiazoacetates, providing the corresponding dearomatized products with high levels of enantioselectivity (up to >99% ee). Under the catalysis of Rh2(R-p-PhTPCP)4, a broad range of pyrrole substrates and aryldiazoacetates are shown to be compatible. Util...

The regioselective and enantioselective intermolecular sp3 C-H functionalization of silicon-substituted alkanes with aryl diazoacetates was accomplished using the recently developed dirhodium catalyst Rh2( S-TPPTTL)4. These reactions generate a diverse array of stereodefined substituted silacycloalkanes with high enantioselectivity and diastereosel...

C–H functionalization has become widely recognized as an exciting new strategy for the synthesis of complex molecular targets. Instead of relying on functional groups as the controlling elements of how molecules are assembled, this strategy offers an altogether different logic for organic synthesis. For this type of strategy to be successful, reage...

Carbon‐hydrogen (C‐H) bonds are ubiquitous in organic compounds, and their selective functionalization is of considerable current interest. This chapter focuses on the development of dirhodium(II)‐catalyzed enantioselective C‐H functionalization reactions that address the challenges of site selectivity and enantioselectivity associated with this ch...

Carbon–hydrogen (C–H) bonds have long been considered unreactive and are inert to traditional chemical reagents, yet new methods for the transformation of these bonds are continually being developed1–9. However, it is challenging to achieve such transformations in a highly selective manner, especially if the C–H bonds are unactivated¹⁰ or not adjac...

Research in the total synthesis of natural products has changed considerably in recent years. Much of the research effort has moved away from only focusing on the synthesis of a specific natural product, and instead toward the development of general synthetic strategies that enable the synthesis of a broad family of natural products. The new approa...

C-H functionalization represents a promising approach for the synthesis of complex molecules. Instead of relying on modifying the functional groups present in a molecule, the synthetic sequence is achieved by carrying out selective reactions on the C-H bonds, which traditionally would have been considered to be the unreactive components of a molecu...

A new chiral dirhodium tetracarboxylate catalyst, Rh2(S-2-Cl-5-BrTPCP)4, has been developed for C–H functionalization reactions by means of donor/acceptor carbene intermediates. The dirhodium catalyst contains four (S)-1-(2-chloro-5-bromophenyl)-2,2-diphenylcyclopropane-1-carboxylate ligands, in which all four 2-chloro-5-bromophenyl groups are on t...

This paper describes the influence of replacement of one of the rhodium atoms by bismuth in a chiral dirhodium tetracarboxylate catalyst on asymmetric induction in the cyclopropanation and C-H functionalization chemistry of trichloroethyl aryldiazoacetates. The chiral ligand used in this study is S-tert-butylsulphonylprolinate (S-TBSP), which was u...

We demonstrate a scalable flow reactor for enantiomeric and regioselective rhodium carbene reactions (cyclopropanation and C‐H functionalization) by developing cascade reaction protocols employing a microfluidic flow reactor system containing immobilized dirhodium catalysts in conjunction with the flow synthesis of diazo compounds. This allows for...

The synthesis of β-arylpyrrolidines via a catalytic enantioselective intermolecular allylic C(sp)³–H functionalization of trans-alkenes followed by immediate reduction, ozonolysis, and then in situ diversification of the resulting cyclic hemiaminal to furnish highly substituted, stereoenriched β-arylpyrrolidines is reported. This methodology utiliz...

Donor/acceptor carbenes provide a powerful platform for building molecular complexity, but the majority of their reactions have been limited to aryl and vinyl donor groups. We found that a N-containing donor/acceptor carbene precursor, 4-phthalimido-N-methanesulfonyl-1,2,3-triazole, reacts with unactivated arenes resulting in a mixture of [3+2]-cyc...

We demonstrate a scalable flow reactor for enantiomeric and regioselective rhodium carbene reactions (cyclopropanation and C‐H functionalization) by developing cascade reaction protocols employing a microfluidic flow reactor system containing immobilized dirhodium catalysts in conjunction with the flow synthesis of diazo compounds. This allows for...

Aryldiazoacetates can undergo photolysis under blue light irradiation (460-490 nm) to generate free carbenes at room temperature and under air. These free carbenes can react selectively with numerous trapping agents,...

The regioselective and enantioselective intermolecular sp³ C–H functionalization of silicon-substituted alkanes was accomplished using Rh2(S-NTTL)4 with readily available 1-sulfonyl-1,2,3-triazoles as carbene precursors. These reactions generate a diverse array of stereodefined substituted silaalkanes.

Rhodium(II)-catalyzed reactions between isopropyl acetate and trichloroethyl aryldiazoacetates result in the formation of oxirane intermediates that ring open under the reaction conditions to form tertiary alcohols. When the reaction is catalyzed by the dirhodium tetrakis(triarylcyclopropanecarboxylate) complex, Rh2(S-2-Cl,4-BrTPCP)4, the tertiary...

The synthesis of complex organic compounds usually relies on controlling the reactions of the functional groups. In recent years, it has become possible to carry out reactions directly on the C-H bonds, previously considered to be unreactive. One of the major challenges is to control the site-selectivity because most organic compounds have many sim...

Two approaches were developed for the conversion of isoxazol-5-ones to 2,3-dihydro-6H-1,3-oxazin-6-ones. The first involves dirhodium-catalyzed reaction of aryl diazoacetates, leading to rhodium carbene intermediates that undergo insertion into the N–O bond of isoxazol-5-ones. The second approach involves conversion of the aryldiazoacetates to the...

This manuscript describes the collaborative efforts within the NSF CCI Center for Selective C−H Functionalization (CCHF) to bring C−H functionalization into the mainstream of organic chemistry.

Rh(II)-catalyzed enantioselective cyclopropanations of furans, providing access to synthetically useful building blocks, are reported. After screening of 10 Rh(II) catalysts, Rh2(S-TCPTTL)4 was identified as a highly efficient and selective catalyst (up to 98% ee, TON 88000, and TOF 24/s) for the cyclopropanation of furans. These cyclopropanes were...

A tandem reaction system has been developed for the preparation of donor/acceptor-substituted diazo compounds in continuous flow coupled to dirhodium-catalyzed C–H functionalization or cyclopropanation. Hydrazones were oxidized in flow by solid-supported N-iodo-p-toluenesulfonamide potassium salt (PS-SO2NIK) to generate the diazo compounds, which w...

An efficient synthesis of tetrahydrocarboline-type products and polycyclic spiroindolines has been achieved. The transformation proceeds via rhodium(II)-catalyzed intramolecular annulations of indolyl- and pyrrolyl-tethered N-sulfonyl-1,2,3-triazoles. The reaction could be tuned toward either the formal [3 + 2] cycloaddition or the C-H functionaliz...

Thermally induced reactions of donor/acceptor diazo compounds generate carbene intermediates capable of C-H functionalization reactions of alkanes. A variety of C-H insertion products were obtained in moderate to good yields and in certain cases with good site selectivity, favoring the functionalization of the more highly substituted C-H bond.

An efficient and convenient synthesis of 2,2,2-trichloroethyl (TCE) aryl- and vinyldiazoacetates was achieved by palladium-catalyzed cross-coupling reactions between TCE diazoacetates and aryl or vinyl iodides. The broad substrate scope allows for rapid and facile formation of TCE aryl- and vinyl-diazoacetates, which recently have emerged as versat...

The products are often formed with high enantiomeric excess.

The enantioselective intermolecular sp(3) C-H functionalization at the allylic and benzylic positions was achieved using rhodium-catalyzed reactions with 4-phenyl-N-(methanesulfonyl)-1,2,3-triazole. The optimum dirhodium tetracarboxylate catalyst for these reactions was Rh2(S-NTTL)4. The rhodium-bound α-imino carbene intermediates preferentially re...

The laboratory synthesis of complex organic molecules relies heavily on the introduction and manipulation of functional groups, such as carbon-oxygen or carbon-halogen bonds; carbon-hydrogen bonds are far less reactive and harder to functionalize selectively. The idea of C-H functionalization, in which C-H bonds are modified at will instead of the...

A novel access to fused 5/7 ring systems through rhodium-catalyzed [4 + 3] cycloaddition of mono- and disubstituted furans to cyclic donor-acceptor diazocarboxylate (II) is described.

Methods for functionalizing carbon-hydrogen bonds are featured in a new synthesis of the tricyclic core architecture that characterizes the indoxamycin family of secondary metabolites. A unique collaboration between three laboratories has engendered a design for synthesis featuring two sequential C-H functionalization reactions, namely a diastereos...

Methods for functionalizing carbon–hydrogen bonds are featured in a new synthesis of the tricyclic core architecture that characterizes the indoxamycin family of secondary metabolites. A unique collaboration between three laboratories has engendered a design for synthesis featuring two sequential C−H functionalization reactions, namely a diastereos...

Enantioselective C-H functionalization of relatively electron-deficient methyl sites was achieved with the combination of 2,2,2-trichloroethyl (TCE) aryldiazoacetates and tetrakis(triarylcyclopropanecarboxylate) dirhodium catalysts. The substrate scope of the transformation was relatively broad, and C-H functionalization products were furnished wit...

An efficient method to directly access the bicyclo[5.3.0]decane core was achieved by rhodium-catalyzed reaction of a novel donor-acceptor cyclopentenyl diazocarboxylate with a variety of furans. As this motif is commonly found within bioactive antitumor natural products, selected systems were further manipulated and evaluated against cancer cell li...

The field of organic synthesis has undergone a startling shift of emphasis during the past 20 years. The pinnacle of research was once the total synthesis of natural products. Many research groups fiercely competed to be the first to make a particular molecular target. Consequently, the field developed a highly competitive atmosphere, and it was ra...

Highly functionalized cyclopropanecarboxylates were readily prepared by rhodium-catalyzed cyclopropanation of alkenes with aryldiazoacetates and styryldiazoaceates, in which the ester functionality is either trimethylsilylethyl (TMSE) or trichlorethyl (TCE). By having labile protecting groups on the ester, chiral triarylcyclopropane carboxylate lig...

Flexible composite polymer/oxide hollow fibers are used as flow reactors for heterogeneously catalyzed reactions in organic synthesis. The fiber synthesis allows for a variety of supported catalysts to be embedded in the walls of the fibers, thus leading to a diverse set of reactions that can be catalyzed in flow. Additionally, the fiber synthesis...

Flexible composite polymer/oxide hollow fibers are used as flow reactors for heterogeneously catalyzed reactions in organic synthesis. The fiber synthesis allows for a variety of supported catalysts to be embedded in the walls of the fibers, thus leading to a diverse set of reactions that can be catalyzed in flow. Additionally, the fiber synthesis...