Phosphonylacylation of Alkenes Enabled by Visible-Light-Induced N-Heterocyclic Carbene Catalysis.

Herein, we report the phosphonylacylation of alkenes via visible-light-induced N-heterocyclic carbene (NHC) catalysis to afford a series of γ-ketophosphonates in moderate to good yields. This protocol features mild conditions, free of photocatalyst, and good compatibility of functional groups. The excited Breslow enolate intermediate was proposed to undergo single-electron transfer with oxime phosphonate to generate the corresponding ketyl radical and phosphonyl radical.

Distal p-benzylic deuteration via N-heterocyclic carbene catalyzed ring opening of p-cyclopropylbenzaldehydes.

Deuterium incorporation at selective sites of organic compounds has long attracted the interest of the pharmaceutical industry. Here, we present a distal p-benzylic deuteration via N-heterocyclic carbene catalyzed ring-opening of cyclopropylbenzaldehydes with MeOD as the deuterium source. The corresponding 4-alkylbenzoates with high deuterium incorporation at the benzylic position were obtained in good yields. The stable benzylic deuterium remained intact for further chemical transformations.

Bifunctional NHC-Catalyzed Remote Enantioselective Mannich-type Reaction of 5-(Chloromethyl)furfural via Trienolate Intermediates.

N-heterocyclic carbene (NHC)-catalyzed enantioselective Mannich-type reactions of the biomass-derived platform compound 5-(chloromethyl)furfural (CMF) with imines were developed. A series of high-value-added chiral amines were afforded in good to high yields with excellent regio- and enantioselectivities. The bifunctional NHC derived from ʟ-pyroglutamic acid efficiently steered the remote addition of the trienolate intermediate to the imine in a highly stereocontrolled manner. This represents the first enantioselective reaction proceeding via an NHC-bound trienolate intermediate.

Enantioselective N-Heterocyclic Carbene Catalyzed α-Oxidative Coupling of Enals with Carboxylic Acids Using an Iodine(III) Reagent.

The enantioselective α-oxidative coupling of enals with carboxylic acids was developed via the umpolung of an NHC-bound enolate with an iodine(III) reagent. The corresponding α-acyloxyl-ß,γ-unsaturated esters were afforded in good yields, with high regio- and enantioselectivities. The key step of the reaction involves the formation of enol iodine(III) intermediate from the enolate with iodosobenzene, which changes the polarity of α-carbon of the enal from nucleophilic to electrophilic, and thus facilitates the subsequent addition of carboxylate.

Iminoacylation of Alkenes via Photoredox N-Heterocyclic Carbene Catalysis.

The iminoacylation of alkenes via photoredox N-heterocyclic carbene catalysis is developed with the employment of alkene-tethered α-imino-oxy acids and acyl imidazoles. The corresponding substituted 3,4-dihydro-2H-pyrroles were afforded in moderate to good yields with good to high diastereoselectivities in most cases. The reaction involves the 5-exo-trig radical cyclization of an alkene-tethered iminyl radical and the following coupling with a ketyl radical from acyl imidazole under NHC catalysis.

ε-Benzylation via Cooperative Photoredox and N-Heterocyclic Carbene Catalysis.

The ε-benzylation of γ-alkenyl-γ-oxidized enals via dual photoredox and N-heterocyclic carbene catalysis has been developed, affording the corresponding ε-benzyl-α,ß-γ,δ-bisunsaturated esters in moderate to good yields with exclusive regioselectivities. The reaction is proposed via the generation of benzyl radical under photocatalysis, followed by its addition to an NHC-bound trienolate intermediate.

Photoredox cooperative N-heterocyclic carbene/palladium-catalysed alkylacylation of alkenes.

Three-component carboacylation of simple alkenes with readily available reagents is challenging. Transition metal-catalysed intermolecular carboacylation works for alkenes with strained ring or directing groups. Herein, we develop a photoredox cooperative N-heterocyclic carbene/Pd-catalysed alkylacylation of simple alkenes with aldehydes and unactivated alkyl halides to provide ketones in good yields. This multicomponent coupling reaction features a wide scope of alkenes, broad functional group compatibility and free of exogenous photosensitizer or external reductant. In addition, a series of chlorinated cyclopropanes with one or two vicinal quaternary carbons is obtained when chloroform or carbon tetrachloride is used as the alkyl halide. The reaction involves the alkyl radicals from halides and the ketyl radicals from aldehydes under photoredox cooperative N-heterocyclic carbene/Pd catalysis.

NHC/Copper-Cocatalyzed [4 + 3] Annulations of Salicylaldehydes with Aziridines for the Synthesis of 1,4-Benzoxazepinones.

N-heterocyclic carbene/copper-cocatalyzed [4 + 3] annulation of salicylaldehydes with aziridines was developed, giving the corresponding 1,4-benzoxazepinones in good yields with exclusive regioselectivity. Copper serves as a Lewis acid to activate the small strained aziridines, and the formation of NHC-salicylaldehyde adduct plays an important role in improving the regioselectivity.

Bifunctional N-Heterocyclic Carbenes Derived from l-Pyroglutamic Acid and Their Applications in Enantioselective Organocatalysis.

In nature, enzymes are a powerful medium for the construction of enantiomerically pure chemicals, which always inspires synthetic chemists to explore new catalysts to imitate the enzyme machinery for asymmetric transformations. Vitamin B1, a bifunctional thiazolium N-heterocyclic carbene (NHC) precursor, is the coenzyme for transketolase. In the past two decades, a series of chiral NHCs, including monocyclic, bicyclic, tetracyclic, and even bridged ones, have been synthesized and successfully utilized as efficient organocatalysts for a wide variety of asymmetric organic reactions. The utility of bifunctional catalysts can enhance catalytic activity and improve stereochemical control through their synchronous activation of both reaction partners. However, the NHCs possessing multiple activation sites are far less developed.This Account gives an overview of our research on the design, development, and applications of bifunctional NHCs in organocatalysis. We synthesized a series of l-pyroglutamic acid-derived bifunctional NHCs bearing a free hydroxyl group which can interact with carbonyl or imino groups via hydrogen-bonding. Further studies revealed that these bifunctional catalysts worked well for a variety of reactions. We have developed bifunctional NHC-catalyzed aza-benzoin reactions, [2 + 2], [2 + 3], and [2 + 4] cycloadditions of ketenes, [3 + 2] and [3 + 4] annulations of enals, and aza-MBH and Rauhut-Currier reactions of Michael acceptors. In addition to these reactions via nucleophilic Breslow intermediates, enolates, homoenolates, and zwitterionic azolium intermediates, the bifunctional NHC-catalyzed [3 + 3] annulation via 1,3-biselectrophilic α,ß-unsaturated acyl azolium intermediates was also developed.In these reactions, bifunctional NHCs showed amazing effects compared to normal nonbifunctional NHCs. In some cases, the bifunctional NHCs facilitated reactions which did not work under normal NHC catalysis, possibly due to additional activation via H-bonding. More interestingly, the bifunctional NHCs could not only improve but also switch the enantioselectivity to get products with opposite stereochemistry through H-bond controlled stereochemical directing. Furthermore, the reaction mode could be totally changed from [3 + 2] to [3 + 4] annulation to give kinetically favored products when bifunctional NHCs were employed. In future, the applications of bifunctional NHCs in other challenging reactions, such as asymmetric reactions with carbon-carbon unsaturated bonds, and the reactions involving alkyl or heteroatom radicals will be the major focus in our group.

N-Heterocyclic carbene/photo-cocatalyzed oxidative Smiles rearrangement: synthesis of aryl salicylates from O-aryl salicylaldehydes.

The N-heterocyclic carbene/photo-cocatalyzed oxidative Smiles rearrangement of O-aryl salicylaldehydes was developed. Both electron-deficient and electron-rich aryls worked well as migrating groups, giving the corresponding aryl salicylates in good yields. This reaction features formation of two new C-O bonds and one C-O bond cleavage via metal-free oxidation of the Breslow intermediate using oxygen as the terminal oxidant and following the Smiles rearrangement under photocatalysis.

Visible-Light-Driven N-Heterocyclic Carbene Catalyzed γ- and ϵ-Alkylation with Alkyl Radicals.

The merging of photoredox catalysis and N-heterocyclic carbene (NHC) catalysis for γ- and ϵ-alkylation of enals with alkyl radicals was developed. The alkylation reaction of γ-oxidized enals with alkyl halides worked well for the synthesis γ-multisubstituted-α,ß-unsaturated esters, including those with challenging vicinal all-carbon quaternary centers. The synthesis of ϵ-multisubstituted-α,ß-γ,δ-diunsaturated esters by an unprecedented NHC-catalyzed ϵ-functionalization was also established.

Visible-Light-Promoted Oxo-difluoroalkylation of Alkenes with DMSO as the Oxidant.

Visible-light-promoted oxo-difluoroalkylation (acetylation and acetamidation) of alkenes with dimethyl sulfoxide as both the solvent and the oxidant was developed, affording the corresponding α,α-difluoro-γ-ketoacetates and acetamides in modest yields. Both terminal and internal alkenes worked well for the reaction. This reaction features simple starting materials, a green oxidant, mild reaction conditions, and highly functional products.

Visible light mediated oxidative lactonization of 2-methyl-1,1'-biaryls for the synthesis of benzocoumarins.

A visible light mediated oxidative lactonization of 2-methyl-1,1'-biaryls was developed, giving benzocoumarins in good yields. The reaction features multiple C-H functionalization processes with oxygen as the final oxidant. The corresponding 2-aldehdyes, alcohols and carboxylic acids of the 1,1'-biaryls also worked well for the reaction.

Impact of depth filtration on disulfide bond reduction during downstream processing of monoclonal antibodies from CHO cell cultures.

Monoclonal antibody interchain disulfide bond reduction was observed in a Chinese Hamster Ovary manufacturing process that used single-use technologies. A similar reduction has been reported for processes that involved high mechanical shear recovery unit operations, such as continuous flow centrifugation and when the clarified harvest was stored under low dissolved oxygen (DO) conditions (Trexler-Schmidt et al., 2010. Biotechnology and Bioengineering, 106(3), 452-461). The work described here identifies disposable depth filtration used during cell culture harvest operations as a shear-inducing unit operation causing cell lysis. As a result, reduction of antibody interchain disulfide bonds was observed through the same mechanisms described for continuous flow centrifugation. Small-scale depth-filtration models were developed, and the differential pressure (Δ P) of the primary depth filter was identified as the key factor contributing to cell lysis. Strong correlations of Δ P and cell lysis were generated by measuring the levels of lactate dehydrogenase and thiol in the filtered harvest material. A simple risk mitigation strategy was implemented during manufacturing by providing an air overlay to the headspace of a single-use storage bag to maintain sufficient DO in the clarified harvest. In addition, enzymatic characterization studies determined that thioredoxin reductase and glucose-6-phosphate dehydrogenase are critical enzymes involved in antibody reduction in a nicotinamide adenine dinucleotide phosphate (NADP + )/NADPH-dependent manner.

N-Heterocyclic Carbene Catalyzed Synthesis of Dihydroxybenzophenones from ß-Methylenals and Aurones.

N-heterocyclic carbene catalyzed synthesis of 2,2'-dihydroxybenzophenones from ß-methylenals and aurones was developed. The cleavage of the C-O bond by a retro-Michael addition is the key step from the spirocyclic intermediate to final product.

(Dynamic) Kinetic Resolution of Enamines/Imines: Enantioselective N-Heterocyclic Carbene Catalyzed [3+3] Annulation of Bromoenals and Enamines/Imines.

The enantioselective N-heterocyclic carbene catalyzed [3+3] annulation of α-bromoenals by dynamic kinetic resolution (DKR) of enamines and normal resolution of α,α-disubstituted imines were developed. The corresponding substituted dihydropyridones were isolated in good yields with excellent diastereo- and enantioselectivities, and a high selective factor (up to 83) was realized for the resolution of α,α-disubstituted imines.

Enantioselective N-Heterocyclic Carbene-Catalyzed Synthesis of Spirocyclic Oxindole-benzofuroazepinones.

Herein, we report an enantioselective synthesis of azepinones via the N-heterocyclic carbene (NHC) catalyzed [3+4] annulation reaction of isatin-derived enals and aurone-derived azadienes. The corresponding spirocyclic oxindole-benzofuroazepinones were obtained in good yields, with excellent diastereo- and enantioselectivities. The resulted azepinones were evaluated for their in vitro cytotoxic activities against six human tumor cell lines, with two compounds showing significant inhibitory activity comparable with that of cisplatin.

Switchable Decarboxylative Heck-Type Reaction and Oxo-alkylation of Styrenes with N-Hydroxyphthalimide Esters under Photocatalysis.

The switchable visible-light-mediated decarboxylative Heck-type reaction and oxo-alkylation reaction of N-hydroxyphthalimide esters under photocatalysis were developed. Disubstituted or trisubstituted alkenes were obtained in good yield with high E-selectivity in the presence of Brønsted acid as the additive, while ketones resulted in the absence of the acidic additive.

N-Heterocyclic Carbene-Catalyzed Annulation of α-Chloroaldehydes with γ-/δ-Amino-α,ß-Unsaturated Ketones: Enantioselective Synthesis of Pyrrolidones and Piperidones.

The N-heterocyclic carbene-catalyzed [2+3] and [2+4] annulations of α-chloroaldehydes with γ-/δ-amino-α,ß-unsaturated ketones were developed, giving the corresponding pyrrolidones and piperidones in good yields with exclusive trans-selectivities and excellent enantioselectivities.

Formylation or methylation: what determines the chemoselectivity of the reaction of amine, CO2, and hydrosilane catalyzed by 1,3,2-diazaphospholene?

DFT computations have been performed to gain insight into the mechanisms of formylation/methylation of amines (e.g. methylaniline (1a)/2,2,4,4-tetramethylpiperidine (2a)) with CO2 and hydrosilane ([Si]H2, [Si] = Ph2Si), catalyzed by 1,3,2-diazaphospholene ([NHP]H). Different from the generally proposed sequential mechanism for the methylation of amine with CO2, i.e. methylation proceeds via formylation, followed by further reduction of formamide to give an N-methylated amine, the study characterized a competition mechanism between formylation and methylation. The chemoselectivity originates from the competition between the amine and [NHP]H hydride to attack the formyloxy carbon of [Si](OCHO)2 (the insertion product of CO2 into [Si]H2). When the attack of an amine (e.g.1a) wins, the transformation affords formamide (1b) but would otherwise (e.g.2a) result in an N-methylated amine (2c). The reduction of formamide by [Si]H2 or [NHP]H is highly unfavorable kinetically, thus we call attention to the sequential mechanism for understanding the methylation of amine with CO2. In addition, the study has the following key mechanistic findings. The activation of CO2 by [NHP]H establishes an equilibrium: [NHP]H + CO2 ⇄ [NHP]OCHO ⇄ [NHP]+ + HCO2-. The ions play catalytic roles to promote formylation via HCO2- or methylation via[NHP]+ . In 1a formylation, HCO2- initiates the reaction, giving 1b and silanol byproducts. However, after the initiation, the silanol byproducts acting as hydrogen transfer shuttles are more effective than HCO2- to promote formylation. In 2a methylation, [NHP]+ promotes the generation of the key species, formaldehyde and a carbocation species (IM17+ ). Our experimental study corroborates our computed mechanisms.