Biocatalytic Synthesis of Allylic and Allenyl Sulfides through a Myoglobin‐Catalyzed Doyle–Kirmse Reaction

The first example of a biocatalytic [2,3]‐sigmatropic rearrangement reaction involving allylic sulfides and diazo reagents (Doyle–Kirmse reaction) is reported. Engineered variants of sperm whale myoglobin catalyze this synthetically valuable C?C bond‐forming transformation with high efficiency and product conversions across a variety of sulfide substrates (e.g., aryl‐, benzyl‐, and alkyl‐substituted allylic sulfides) and α‐diazo esters. Moreover, the scope of this myoglobin‐mediated transformation could be extended to the conversion of propargylic sulfides to give substituted allenes. Active‐site mutations proved effective in enhancing the catalytic efficiency of the hemoprotein in these reactions as well as modulating the enantioselectivity, resulting in the identification of the myoglobin variant Mb(L29S,H64V,V68F), which is capable of mediating asymmetric Doyle–Kirmse reactions with an enantiomeric excess up to 71 %. This work extends the toolbox of currently available biocatalytic strategies for the asymmetric formation of carbon–carbon bonds.     

Vinylation of Unprotected Phenols Using a Biocatalytic System

Readily available substituted phenols were coupled with pyruvate in buffer solution under atmospheric conditions to afford the corresponding para‐vinylphenol derivatives while releasing only one molecule of CO₂ and water as the by‐products. This transformation was achieved by designing a biocatalytic system that combines three biocatalytic steps, namely the C? C coupling of phenol and pyruvate in the presence of ammonia, which leads to the corresponding tyrosine derivative, followed by deamination and decarboxylation. The biocatalytic transformation proceeded with high regioselectivity and afforded exclusively the desired para products. This method thus represents an environmentally friendly approach for the direct vinylation of readily available 2‐, 3‐, or 2,3‐disubstituted phenols on preparative scale (0.5 mmol) that provides vinylphenols in high yields (65–83 %).     

Ruthenium Catalyzed C−H Acylmethylation of N‐Arylphthalazine‐1,4‐diones with α‐Carbonyl Sulfoxonium Ylides: Highway to Diversely Functionalized Phthalazino‐fused Cinnolines

A direct ortho‐Csp²‐H acylmethylation of 2‐aryl‐2,3‐dihydrophthalazine‐1,4‐diones with α‐carbonyl sulfoxonium ylides is achieved through a Ru^II‐catalyzed C?H bond activation process. The protocol featured high functional group tolerance on the two substrates, including aryl‐, heteroaryl‐, and alkyl‐substituted α‐carbonyl sulfoxonium ylides. Thereafter, 2‐(ortho‐acylmethylaryl)‐2,3‐dihydrophthalazine‐1,4‐diones were used as potential starting materials for the expeditious synthesis of 6‐arylphthalazino[2,3‐a]cinnoline‐8,13‐diones and 5‐acyl‐5,6‐dihydrophthalazino[2,3‐a]cinnoline‐8,13‐diones under Lawesson's reagent and BF₃?OEt₂ mediated conditions, respectively. Of these, the BF₃?OEt₂‐mediated cyclization proceeded in DMSO as a solvent and a methylene source via dual C?C and C?N bond formations.     

CYP505E3: A Novel Self‐Sufficient ω‐7 In‐Chain Hydroxylase

The self‐sufficient cytochrome P450 monooxygenase CYP505E3 from Aspergillus terreus catalyzes the regioselective in‐chain hydroxylation of alkanes, fatty alcohols, and fatty acids at the ω‐7 position. It is the first reported P450 to give regioselective in‐chain ω‐7 hydroxylation of C10–C16 n‐alkanes, thereby enabling the one step biocatalytic synthesis of rare alcohols such as 5‐dodecanol and 7‐tetradecanol. It shows more than 70 % regioselectivity for the eighth carbon from one methyl terminus, and displays remarkably high activity towards decane (TTN≈8000) and dodecane (TTN≈2000). CYP505E3 can be used to synthesize the high‐value flavour compound δ‐dodecalactone via two routes: 1) conversion of dodecanoic acid into 5‐hydroxydodecanoic acid (24 % regioselectivity), which at low pH lactonises to δ‐dodecalactone, and 2) conversion of 1‐dodecanol into 1,5‐dodecanediol (55 % regioselectivity), which can be converted into δ‐dodecalactone by horse liver alcohol dehydrogenase.     

Hydroarylation of 2‐Aryloxybut‐1‐en‐3‐ynes via Pd/Acid‐Catalyzed C−H Bond Activation: A Concise Synthesis of 2,3‐Bismethylene‐2,3‐dihydrobenzofurans

An intramolecular exo ‐hydroarylation of 2‐aryloxy‐1,4‐disilylbut‐1‐en‐3‐ynes via ortho ‐C−H bond activation under palladium(0) and acid catalysis was found to give 2,3‐bis(silylmethylidene)‐2,3‐dihydrobenzofurans. The two silyl groups present probably promoted the reaction and played a key role in stabilizing the diene moiety in the product. The products readily led to functionalized condensed cycles by a Diels–Alder reaction.     

Biocatalytic Reduction of 2‐Monosubstituted 3‐Thiazolines Using Imine Reductases

The application of a straightforward biocatalytic technology for the reduction of racemic 2‐monosubstituted 3‐thiazolines, which are easily prepared via Asinger‐multicomponent reaction, is reported. The biocatalytic reduction yields racemic 2‐monosubstituted 3‐thiazolidines, which are difficult to be prepared by means of classic chemical routes, in moderate to high yields. Moreover, our study clarifies the stereochemical reaction course of the biocatalytic reduction. Furthermore, the efficiency of this biocatalytic technology is demonstrated in an experiment at an elevated substrate concentration of 60 mM leading to 96% conversion.     

Molecular Iodine Promoted Synthesis of New Pyrido[2,3‐d]pyrimidin‐4‐ols

A highly ef?cient synthesis of novel pyrido[2,3‐d]pyrimidin‐4‐ols was developed via an iodine‐catalyzed tandem oxidative cyclization under focused microwave irradiation. Pyrido[2,3‐d]pyrimidin‐4‐ols were obtained from easily available 2‐amino‐4‐aryl‐6‐arylnicotinamides and benzylic amines with good to excellent yields.     

A Facile One‐Pot Synthesis of Functionalized 1,5‐Dihydro‐2H‐[1]benzopyrano[2,3‐b]pyridin‐5‐ones

The highly reactive 1 : 1 intermediate generated in the reaction between dialkyl acetylenedicarboxylate (=but‐2‐ynedioic acid dialkyl ester) 4 and triphenylphosphine was trapped by 2‐amino‐4‐oxo‐4H‐1‐benzopyran‐3‐carboxaldehydes 5 to yield highly functionalized dialkyl‐1,5‐dihydro‐5‐oxo‐1‐phenyl‐2H‐[1]benzopyrano[2,3‐b]pyridine‐2,3‐dicarboxylates in high yield.     

A Green Synthesis of 7‐amino‐5‐(4‐aroyl)‐1,3‐dimethyl‐2,4‐dioxo‐1,2,3,4,5,8‐hexahydropyrido[2,3‐d]pyrimidine‐6‐carbonitrile Derivatives by a One‐pot Three‐component Reaction

The synthesis of polyfunctionalized 7‐amino‐5‐(4‐aroyl)‐1,3‐dimethyl‐2,4‐dioxo‐1,2,3,4,5,8‐hexahydropyrido[2,3‐d ]pyrimidine‐6‐carbonitrile derivatives by a green approach was achieved via one‐pot three‐component reaction of arylglyoxals, malononitrile, and 1,3‐dimethyl‐6‐aminouracil in the presence of urea as organocatalyst in EtOH:H₂O (1:1) at 60°C. This protocol provides a mild and fast procedure to structurally diverse bicyclic pyridopyrimidines in good to excellent yields.     

Photoinitiated Thiol−Ene Reactions of Various 2,3‐Unsaturated O‐, C‐ S‐ and N‐Glycosides – Scope and Limitations Study

The photoinitiated thiol?ene addition reaction is a highly stereo‐ and regioselective, and environmentally friendly reaction proceeding under mild conditions, hence it is ideally suited for the synthesis of carbohydrate mimetics. A comprehensive study on UV‐light‐induced reactions of 2,3‐unsaturated O‐, C‐, S‐ and N‐glycosides with various thiols was performed. The effect of experimental parameters and structural variations of the alkenes and thiols on the efficacy and regio‐ and stereoselectivity of the reactions was systematically studied and optimized. The type of anomeric heteroatom was found to profoundly affect the reactivity of 2,3‐unsaturated sugars in the thiol?ene couplings. Hydrothiolation of 2,3‐dideoxy O‐glycosyl enosides efficiently produced the axially C2‐S‐substituted addition products with high to complete regioselectivity. Moderate efficacy and varying regio‐ and stereoselectivity were observed with 2,3‐unsaturated N‐glycosides and no addition occurred onto the endocyclic double bond of C‐glycosides. Upon hydrothiolation of 2,3‐unsaturated S‐glycosides, the addition of thiyl radicals was followed by elimination of the thiyl aglycone resulting in 3‐S‐substituted glycals.     

Cascade One‐Pot Synthesis of Orange‐Red‐Fluorescent Polycyclic Cinnolino[2,3‐f]phenanthridin‐9‐ium Salts by Palladium(II)‐Catalyzed C−H Bond Activation of 2‐Azobiaryl Compounds and Alkenes

Quaternary ammonium salts were synthesized in moderate to good yields through double oxidative C?H bond activation on azobenzenes. The mechanism of the highly regioselective reaction of 2‐azobiaryls with alkenes to give orange‐red‐fluorescent cinnolino[2,3‐f]phenanthridin‐9‐ium salts and 15H‐cinnolino[2,3‐f]phenanthridin‐9‐ium‐10‐ide is proposed to involve ortho C?H olefination of the 2‐azobiaryl compound with the alkene, intramolecular aza‐Michael addition, concerted metalation–deprotonation (CMD), reductive elimination, and oxidation.     

Asymmetric C‐Alkylation by the S‐Adenosylmethionine‐Dependent Methyltransferase SgvM

S ‐Adenosylmethionine‐dependent methyltransferases (MTs) play a decisive role in the biosynthesis of natural products and in epigenetic processes. MTs catalyze the methylation of heteroatoms and even of carbon atoms, which, in many cases, is a challenging reaction in conventional synthesis. However, C‐MTs are often highly substrate‐specific. Herein, we show that SgvM from Streptomyces griseoviridis features an extended substrate scope with respect to the nucleophile as well as the electrophile. Aside from its physiological substrate 4‐methyl‐2‐oxovalerate, SgvM catalyzes the (di)methylation of pyruvate, 2‐oxobutyrate, 2‐oxovalerate, and phenylpyruvate at the β‐carbon atom. Chiral‐phase HPLC analysis revealed that the methylation of 2‐oxovalerate occurs with R selectivity while the ethylation of 2‐oxobutyrate with S ‐adenosylethionine results in the S enantiomer of 3‐methyl‐2‐oxovalerate. Thus SgvM could be a valuable tool for asymmetric biocatalytic C‐alkylation reactions.     

The Fe‐N‐C Nanozyme with Both Accelerated and Inhibited Biocatalytic Activities Capable of Accessing Drug–Drug Interactions

Emerging as a cost‐effective and robust enzyme mimic, nanozymes have drawn increasing attention with broad applications ranging from cancer therapy to biosensing. Developing nanozymes with both accelerated and inhibited biocatalytic properties in a biological context is intriguing to peruse more advanced functions of natural enzymes, but remains challenging, because most nanozymes are lack of enzyme‐like molecular structures. By re‐visiting and engineering the well‐known Fe‐N‐C electrocatalyst that has a heme‐like Fe‐N_x active sites, herein, it is reported that Fe‐N‐C could not only catalyze drug metabolization but also had inhibition behaviors similar to cytochrome P450 (CYP), endowing it a potential replacement of CYP for preliminary evaluation of massive potential chemicals, drug dosing guide, and outcome prediction. In addition, in contrast to electrocatalysts, the highly graphitic framework of Fe‐N‐C may not be obligatory for a competitive CYP‐like activity.     

An Efficient Synthesis of 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐6‐methyl‐4‐(2‐oxo‐2‐phenylethoxy)‐3,4‐dihydro‐2H‐pyran‐2‐one Derivatives via Multi‐Component Approach

An easy, highly efficient and a new convenient one‐pot, two‐step approach to the synthesis of 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐6‐methyl‐4‐(2‐oxo‐2‐phenylethoxy)‐3,4‐dihydro‐2H‐pyran‐2‐one is described. These compounds were synthesized from 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐4‐hydroxy‐6‐methyl‐3,4‐dihydro‐2H‐pyran‐2‐one and α‐bromoketones in good yields. The compounds 4 were synthesized by a multi‐component reaction between 1 , 2 , and 3 and the prominent features of this protocol are mild reaction conditions, operation simplicity, and good to high yields of products.     

Enzyme‐Embedded Metal–Organic Framework Colloidosomes via an Emulsion‐Based Approach

Improving the activity and stability of enzymes is significant in enzyme immobilization. Here a facile approach to prepare ring‐like ZIF‐8 colloidosomes and spherical catalase‐embedded ZIF‐8 colloidosomes is developed via one‐step emulsion‐based technique at the water/butanol interface. The influence of the concentrations of ZIF‐8 nanocrystals and Pluronic F127 as well as the oil‐water ratio was investigated. Compared with in situ biomineralization, the colloidosomes prepared via the pickering emulsion method show successful encapsulation of positively charged enzymes. By using catalase as an immobilized model, the immobilized catalase exhibits high biocatalytic activity, stability and recyclability compared with free catalase.     

Synthesis of pyridazine derivatives through the unexpected intermediate 5‐amino‐ 4‐cyano ‐2,3‐dihydro‐furan‐2,3‐disulfonic acid disodium salt

An unexpected compound (5‐amino‐4‐cyano‐2,3‐dihydrofuran‐2,3‐disulfonic acid disodium salt, 4 ) was isolated from the reaction of glyoxale bis hydrogen sulfite disodium salt with malononitrile. Its structure was undoubtly identified through crystal structure analysis. Compound 4 was highly stable and it was isolated easily and in a very high yield. Its reactivity was studied in the reactions with some hydrazine derivatives in order to obtain different pyridazine analogs.     

Asymmetric Synthesis of 1,3‐Butadienyl‐2‐carbinols by the Homoallenylboration of Aldehydes with a Chiral Phosphoric Acid Catalyst

Asymmetric C(sp)? C(sp²) bond formation to give enantiomerically enriched 1,3‐butadienyl‐2‐carbinols occurred through a homoallenylboration reaction between a 2,3‐dienylboronic ester and aldehydes under the catalysis of a chiral phosphoric acid (CPA). A diverse range of enantiomerically enriched butadiene‐substituted secondary alcohols with aryl, heterocyclic, and aliphatic substituents were synthesized in very high yield with high enantioselectivity. Preliminary density functional theory (DFT) calculations suggest that the reaction proceeds via a cyclic six‐membered chairlike transition state with essential hydrogen‐bond activation in the allene reagent. The catalytic reaction was amenable to the gram‐scale synthesis of a chiral alkyl butadienyl adduct, which was converted into an interesting optically pure compound bearing a benzo‐fused spirocyclic cyclopentenone framework.     

Rhodium(III)‐Catalyzed [3+2] Annulation of 5‐Aryl‐2,3‐dihydro‐1H‐pyrroles with Internal Alkynes through C(sp2)H/Alkene Functionalization

This study describes a new rhodium(III)‐catalyzed [3+2] annulation of 5‐aryl‐2,3‐dihydro‐1H‐pyrroles with internal alkynes using a Cu(OAc)₂ oxidant for building a spirocyclic ring system, which includes the functionalization of an aryl C(sp²)? H bond and addition/protonolysis of an alkene C?C bond. This method is applicable to a wide range of 5‐aryl‐2,3‐dihydro‐1H‐pyrroles and internal alkynes, and results in the assembly of the spiro[indene‐1,2′‐pyrrolidine] architectures in good yields with excellent regioselectivities.     

Synthesis and Halogen Bonding in the Crystal Structures of the New 2,3‐Diiodo Indenone and 1‐Ethoxy‐2,3‐diiodo Indene

The CuI‐catalyzed addition of iodine to the C≡C triple bond of 3,3‐diethoxy‐1‐phenyl propyne ( 1 ) unexpectedly leads to the new cyclization products 2,3‐diiodo‐1H‐inden‐1‐one ( 2 ) and 1‐ethoxy‐2,3‐diiodo‐1H‐indene ( 3 ). Both compounds were isolated and characterized via ¹H, ¹³C NMR (Nuclear Magnetic Resonance) spectroscopy and HRMS (High Resolution Mass Spectrometry). The molecular and crystal structures of compounds 2 and 3 were determined by single crystal X‐ray diffraction. Their crystal structures are governed by extensive halogen bonding, involving I·I and I·O interactions.     

Sequential Ugi Four‐Component Reaction (4‐CR)/CH Activation Using (Diacetoxyiodo)benzene for the Synthesis of 3‐(Diphenylmethylidene)‐2,3‐dihydro‐1H‐indol‐2‐ones

A sequential Ugi four‐component reaction (4‐CR)/C? H activation using (diacetoxyiodo)benzene is reported. This process is a five‐component reaction of aromatic aldehydes, aniline derivatives, isocyanides, phenylpropiolic acid (3‐phenylprop‐2‐ynoic acid), and (diacetoxyiodo)benzene for the synthesis of 3‐(diphenylmethylidene)‐2,3‐dihydro‐1H‐indol‐2‐ones. This procedure offers several advantages such as good yields, high bond‐forming efficiency, selectivity, and short reaction times.