Fa-Guang Zhang

Aromatic polyketides have gained significant attention as prominent plant‐derived polyphenol molecules in recent years owing to their multi‐faceted therapeutic potentials against a variety of diseases. However, the introduction of unique fluorine atoms into the core structure of aromatic polyketides has received limited exploration thus far. In this study, a series of new‐to‐nature fluorinated aromatic polyketides, including resveratrol, naringenin chalcone, bisnoyangonin, and benzalactone, were obtained from readily available fluoro‐tyrosines in E. coli via a multi‐enzyme cascade pathway. A series of combinational optimization strategies, including metabolic regulations, double protein fusion (4CL::III‐PKS and MatB::III‐PKS), and directed evolution of the rate‐limiting enzymes, were conducted to improve the production of fluoro‐aromatic polyketides, thus enhancing the titers to >200 mg/L from an initial ∼10 mg/L. When both sides of the phenolic hydroxyl group of 4‐coumaroyl‐CoA contain fluorine atoms, a novel catalytic pathway of STS and CHS in synthesizing methyl ketone structures is unlocked, namely the “ proximal fluorine‐induced III‐PKS catalytic truncation ”. Further post‐functionalizations by enzymatic glycosylation reaction and chemocatalytic Friedel–Crafts‐type reaction provided the corresponding fluorinated derivatives of polyphenolic natural products (piceid and arahypin).

Aromatic polyketides have gained significant attention as prominent plant‐derived polyphenol molecules in recent years owing to their multi‐faceted therapeutic potentials against a variety of diseases. However, the introduction of unique fluorine atoms into the core structure of aromatic polyketides has received limited exploration thus far. In this study, a series of new‐to‐nature fluorinated aromatic polyketides, including resveratrol, naringenin chalcone, bisnoyangonin, and benzalactone, were obtained from readily available fluoro‐tyrosines in E. coli via a multi‐enzyme cascade pathway. A series of combinational optimization strategies, including metabolic regulations, double protein fusion (4CL::III‐PKS and MatB::III‐PKS), and directed evolution of the rate‐limiting enzymes, were conducted to improve the production of fluoro‐aromatic polyketides, thus enhancing the titers to >200 mg/L from an initial ∼10 mg/L. When both sides of the phenolic hydroxyl group of 4‐coumaroyl‐CoA contain fluorine atoms, a novel catalytic pathway of STS and CHS in synthesizing methyl ketone structures is unlocked, namely the “ proximal fluorine‐induced III‐PKS catalytic truncation ”. Further post‐functionalizations by enzymatic glycosylation reaction and chemocatalytic Friedel–Crafts‐type reaction provided the corresponding fluorinated derivatives of polyphenolic natural products (piceid and arahypin).

Catalytic decarboxylative allylic alkylation (DAA) reaction represents an efficient strategy for synthesizing molecules containing both carbonyl and alkenyl functionalities, yet is frequently challenged by multiple selectivity issues. Here we report the first intermolecular decarboxylative cross‐coupling of β‐ketoacids with internal allenes. Using a Rh ^(I) /( S , S )‐Ph‐BPE system, α‐ gem ‐difluoroallylic carbonyl compounds can be generated with excellent chemo‐, regio‐, and enantioselectivities. Mechanistic studies support “coordination‐assisted inner‐sphere addition–decarboxylation” pathway, where C─C bond formation occurs prior to the decarboxylation step. Fluorine‐induced anti → syn isomerization of π‐allyl‐rhodium species proves to be the key factor governing the stereoselectivity of this reaction. This cross‐coupling reaction tolerates a range of functional groups and advances the field of decarboxylative allylic alkylation.

Catalytic decarboxylative allylic alkylation (DAA) reaction represents an efficient strategy for synthesizing molecules containing both carbonyl and alkenyl functionalities, yet is frequently challenged by multiple selectivity issues. Here we report the first intermolecular decarboxylative cross‐coupling of β‐ketoacids with internal allenes. Using a Rh ^(I) /( S , S )‐Ph‐BPE system, α‐ gem ‐difluoroallylic carbonyl compounds can be generated with excellent chemo‐, regio‐, and enantioselectivities. Mechanistic studies support “coordination‐assisted inner‐sphere addition–decarboxylation” pathway, where C─C bond formation occurs prior to the decarboxylation step. Fluorine‐induced anti → syn isomerization of π‐allyl‐rhodium species proves to be the key factor governing the stereoselectivity of this reaction. This cross‐coupling reaction tolerates a range of functional groups and advances the field of decarboxylative allylic alkylation.

The direct conversion of trifluoromethyl ketones to valuable gem‐difluoroalkenes remains a synthetically useful but underexplored transformation. Herein, we report a base‐catalyzed, one‐pot domino reaction of trifluoromethyl ketones with dicyanoalkenes, enabling formal dual deoxygenation and defluorination. This protocol affords a diverse range of gem‐difluoroalkenyl unsaturated γ‐lactams in yields of 62–95% under mild and operationally simple conditions. A proposed mechanism involves a sequential vinylogous aldol reaction, cyclization, rearrangement, and defluorination.

Herein, we report a facile and versatile copper-catalyzed protocol for the chemo- and regioselective synthesis of highly substituted 2-(trifluoromethyl)pyrroles from readily available starting materials. This one-pot cascade reaction of CF₃CHN₂, nitrile, and nitroalkene proceeds efficiently under mild conditions, enabling access to a broad spectrum of 2-(trifluoromethyl)pyrroles. Furthermore, the utility of this method is demonstrated by the synthesis of a series of highly substituted pyrroles bearing both trifluoromethyl and cyano groups.

Here we report a photoinduced [3 + 2] radical cyclization reaction of α-diazodifluoroethane sulfonium reagent with hydrazones to give the corresponding N-amino-4-difluoromethyl-1,2,3-triazoles. This transformation proceeds under simple blue light irradiation conditions without the need of photocatalyst. Preliminary mechanistic studies indicate that the formation of an electron donor-acceptor (EDA) complex between electron-deficient α-diazo sulfonium triflate and electron-rich hydrazone operates as the key mediator.

In this study, we design and synthesize a reactive difluorodiazo hypervalent iodine^(III) reagent that facilitates the ring expansion of indene under mild basic conditions at room temperature. This protocol offers a practical and efficient route to a diverse array of 2-difluoromethyl naphthalene derivatives in good yields.

1,2,4-Triazines, also known as α-triazines, are a type of unsymmetrical six-membered heterocycle bearing three nitrogen atoms. A series of 1,2,4-triazine frameworks are emerging as core structures in an increasing number of bioactive small molecules such as remdesivir. The application of 1,2,4-triazines as cyclic aza-dienes in inverse electron-demand Diels–Alder (IEDDA) cycloaddition reactions has been established as a useful method in Nheterocycle synthesis, natural product preparation, and bioorthogonal chemistry. This update covers synthetic methods for the preparation 1,2,4-triazines published between 2013 to 2024.