Using Soluble Polymers to Enforce Catalyst‐Phase‐Selective Solubility and as Antileaching Agents to Facilitate Homogeneous Catalysis

The enforced phase‐selective solubility of polyisobutylene (PIB)‐bound Rh^II catalysts in biphasic heptane/acetonitrile mixtures can be used not only to recycle these catalysts but also to minimize bimolecular reactions with ethyl diazoacetate. When cyclopropanation and O? H insertion reactions are carried out with PIB‐bound Rh^II catalysts either with or without addition of an unfunctionalized hydrocarbon polymer cosolvent, dimer by‐product formation is suppressed even without slow syringe pump addition of the ethyl diazoacetate. This suppression of by‐product formation is shown to be due to increased phase segregation of the soluble polymer‐bound catalyst and the ethyl diazoacetate reactant. These studies also reveal that added hydrocarbon polymer cosolvents can function as antileaching agents, decreasing the already small amount of a soluble polymer‐bound species that leaches into a polar phase in a biphasic mixture during a liquid/liquid separation step.     

Stereoconvergent,Redox‐Neutral Access to Tetrahydroquinoxalines through Relay Epoxide Opening/Amination of Alcohols

We present an economical catalytic procedure to convert readily available 1,2‐diaminobenzenes and terminal epoxides into valuable 1,2,3,4‐tetrahydroquinoxalines in a highly enantioselective fashion. This procedure operates through relay zinc and iridium catalysis, and achieves redox‐neutral and stereoconvergent production of valuable chiral heterocycles from racemic starting materials with water as the only side product. The use of commercially available reagents and catalysts and a convenient procedure also make this catalytic method attractive for practical application.     

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates SNAr Reactions of Heterocycles with Arylamines

Small‐molecule drug discovery requires reliable synthetic methods for attaching amino compounds to heterocyclic scaffolds. Trifluoroacetic acid‐2,2,2‐trifluoroethanol (TFA‐TFE) is as an effective combination for achieving S_NAr reactions between anilines and heterocycles (e.g., purines and pyrimidines) substituted with a leaving group (fluoro‐, chloro‐, bromo‐ or alkylsulfonyl). This method provides a variety of compounds containing a “kinase‐privileged fragment” associated with potent inhibition of kinases. TFE is an advantageous solvent because of its low nucleophilicity, ease of removal and ability to solubilise polar substrates. Furthermore, TFE may assist the breakdown of the Meisenheimer–Jackson intermediate by solvating the leaving group. TFA is a necessary and effective acidic catalyst, which activates the heterocycle by N‐protonation without deactivating the aniline by conversion into an anilinium species. The TFA‐TFE methodology is compatible with a variety of functional groups and complements organometallic alternatives, which are often disadvantageous because of the expense of reagents, the frequent need to explore diverse sets of reaction conditions, and problems with product purification. In contrast, product isolation from TFA‐TFE reactions is straightforward: evaporation of the reaction mixture, basification and chromatography affords analytically pure material. A total of 45 examples are described with seven discrete heterocyclic scaffolds and 2‐, 3‐ and 4‐substituted anilines giving product yields that are normally in the range 50–90 %. Reactions can be performed with either conventional heating or microwave irradiation, with the latter often giving improved yields.     

Recombinant Cyanobacteria for the Asymmetric Reduction of C=C Bonds Fueled by the Biocatalytic Oxidation of Water

A recombinant enoate reductase was expressed in cyanobacteria and used for the light‐catalyzed, enantioselective reduction of C=C bonds. The coupling of oxidoreductases to natural photosynthesis allows asymmetric syntheses fueled by the oxidation of water. Bypassing the addition of sacrificial cosubstrates as electron donors significantly improves the atom efficiency and avoids the formation of undesired side products. Crucial factors for product formation are the availability of NADPH and the amount of active enzyme in the cells. The efficiency of the reaction is comparable to typical whole‐cell biotransformations in E. coli. Under optimized conditions, a solution of 100 mg prochiral 2‐methylmaleimide was reduced to optically pure 2‐methylsuccinimide (99 % ee, 80 % yield of isolated product). High product yields and excellent optical purities demonstrate the synthetic usefulness of light‐catalyzed whole‐cell biotransformations using recombinant cyanobacteria.     

Asymmetric γ‐Allylation of α,β‐Unsaturated Aldehydes by Combined Organocatalysis and Transition‐Metal Catalysis

The first asymmetric regio‐ and diastereodivergent γ‐allylation of cyclic α,β‐unsaturated aldehydes based on combined organocatalysis and transition‐metal catalysis is disclosed. By combining an aminocatalyst with an iridium catalyst, both diastereomers of branched allylated products can be achieved in moderate to good yields and excellent regio‐ and stereoselectivities. Furthermore, by replacing the iridium catalyst with a palladium catalyst, the linear allylated products are formed in good yields and excellent regio‐ and enantioselectivities. The developed method thus provides selective access to all six isomers of the γ‐allylated product in a divergent fashion by choosing the appropriate combination of organocatalyst, transition‐metal catalyst, and ligand.     

Facile Synthesis,Characterization, and Catalytic Behavior of a Large‐Pore Zeolite with the IWV Framework

Large‐pore microporous materials are of great interest to process bulky hydrocarbon and biomass‐derived molecules. ITQ‐27 (IWV) has a two‐dimensional pore system bounded by 12‐membered rings (MRs) that lead to internal cross‐sections containing 14 MRs. Investigations into the catalytic behavior of aluminosilicate (zeolite) materials with this framework structure have been limited until now due to barriers in synthesis. The facile synthesis of aluminosilicate IWV in both hydroxide and fluoride media is reported herein using simple, diquaternary organic structure‐directing agents (OSDAs) that are based on tetramethylimidazole. In hydroxide media, a zeolite product with Si/Al=14.8–23.2 is obtained, while in fluoride media an aluminosilicate product with Si/Al up to 82 is synthesized. The material produced in hydroxide media is tested for the hydroisomerization of n‐hexane, and results from this test reaction suggest that the effective pore size of zeolites with the IWV framework structure is similar to but slightly larger than that of ZSM‐12 (MTW), in fairly good agreement with crystallographic data.     

Protection Group Effects During α,γ‐Diol Lignin Stabilization Promote High‐Selectivity Monomer Production

Protection groups were introduced during biomass pretreatment to stabilize lignin's α,γ‐diol group during its extraction and prevent its condensation. Acetaldehyde and propionaldehyde stabilized the α,γ‐diol without any aromatic ring alkylation, which significantly increased final product selectivity. The subsequent hydrogenolysis catalyzed by Pd/C generated lignin monomers at near‐theoretical yields based on Klason lignin (48 % from birch, 20 % from spruce, 70 % from high‐syringyl transgenic poplar), and with high selectivity to a single 4‐n‐propanolsyringol product (80 %) in the case of the poplar. Unlike direct hydrogenation of native wood, hydrogenolysis of protected lignin with Ni/C also led to high selectivity to this single product (78 %), paving the way to high‐selectivity lignin upgrading with base metal catalysts. The use of extracted lignin facilitated valorization of polysaccharides, leading to high yields of all three major biomass polymers to a single major product.     

Catalytic Selective Synthesis

Complete control of the product of a catalytic reaction can be achieved on the basis of catalyst structure, even when the reaction conditions are nearly identical. Catalyst‐controlled selectivity is well established for enantioselective catalysis but less formulated for catalytic regio‐, chemo‐, or product‐selective reactions. This Review describes selective transformations of the same starting materials into two or more different products simply by the choice of catalyst. By collecting and highlighting examples of selective catalysis, we hope that the field will be encouraged by the progress that has been made while bringing attention to unmet needs in the design and mechanistic understanding of selective catalysts.     

Diastereo‐ and Enantioselective 1,4‐Difunctionalization of Borylenynes by Catalytic Conjunctive Cross‐Coupling

Enantioselective conjunctive cross‐coupling of enyne‐derived boronate complexes occurs with 1,4 addition of the electrophile and migrating group across the π system. This reaction pathway furnishes α‐boryl allenes as the reaction product. In the presence of a chiral catalyst, both the central and axial chirality of the product can be controlled during product formation.     

Ruthenium‐Catalyzed Synthesis of 2,3‐Cyclo[3]dendralenes and Complex Polycycles from Propargyl Alcohols

Ruthenium‐catalyzed cascade transformations for the synthesis of 2,3‐cyclo[3]dendralenes and multicomponent processes based thereon to generate complex polycycles are presented. The combination of allylation–cyclization sequences with diene‐transmissive Diels–Alder reactions allows the rapid and selective construction of natural‐product‐like motifs from easily accessible starting materials in a one‐pot process and provides a new method to access potential drug candidates.     

Synthesis of Cyclic Polyamines by Enzymatic Generation of an Amino Aldehyde In Situ

Multifunctional polycationic polyamines, for example, used in drug and gene delivery, have product range limitations in their synthesis methods. Here, we synthesize a polyamine by forming a self‐assembling amino aldehyde from the corresponding amino alcohol with horse liver alcohol dehydrogenase (HLADH), followed by reduction. Circular polyamines were synthesized from 3‐amino‐propan‐1‐ol as starting material, analogous to cyclic polyamines formed from azetidin. The product had an isolated yield of 89.7% or 15.3 g L⁻¹. The predicted range of possible polyamine products by this method is broad since many amino alcohols are putative substrates for HLADH. The enzyme also had activity for 2‐amino‐propan‐1‐ol and 2‐amino‐2‐phenyl‐ethanol, for which the enantioselectivity was 330 (S) and 32 (R), respectively.     

Continuous Consecutive Reactions with Inter‐Reaction Solvent Exchange by Membrane Separation

Pharmaceutical production typically involves multiple reaction steps with separations between successive reactions. Two processes which complicate the transition from batch to continuous operation in multistep synthesis are solvent exchange (especially high‐boiling‐ to low‐boiling‐point solvent), and catalyst separation. Demonstrated here is membrane separation as an enabling platform for undertaking these processes during continuous operation. Two consecutive reactions are performed in different solvents, with catalyst separation and inter‐reaction solvent exchange achieved by continuous flow membrane units. A Heck coupling reaction is performed in N,N‐dimethylformamide (DMF) in a continuous membrane reactor which retains the catalyst. The Heck reaction product undergoes solvent exchange in a counter‐current membrane system where DMF is continuously replaced by ethanol. After exchange the product dissolved in ethanol passes through a column packed with an iron catalyst, and undergoes reduction (>99 % yield).     

Transition‐Metal‐Catalyzed Hydrogen‐Transfer Annulations: Access to Heterocyclic Scaffolds

The ability of hydrogen‐transfer transition‐metal catalysts, which enable increasingly rapid access to important structural scaffolds from simple starting materials, has led to a plethora of research efforts on the construction of heterocyclic scaffolds. Transition‐metal‐catalyzed hydrogen‐transfer annulations are environmentally benign and highly atom‐economical as they release of water and hydrogen as by‐product and utilize renewable feedstock alcohols as starting materials. Recent advances in this field with respect to the annulations of alcohols with various nucleophilic partners, thus leading to the formation of heterocyclic scaffolds, are highlighted herein.     

A Switchable Gold Catalyst by Encapsulation in a Self‐Assembled Cage

Dinuclear gold complexes have the ability to interact with one or more substrates in a dual‐activation mode, leading to different reactivity and selectivity than their mononuclear relatives. In this contribution, this difference was used to control the catalytic properties of a gold‐based catalytic system by site‐isolation of mononuclear gold complexes by selective encapsulation. The typical dual‐activation mode is prohibited by this catalyst encapsulation, leading to typical behavior as a result of mononuclear activation. This strategy can be used as a switch (on/off) for a catalytic reaction and also permits reversible control over the product distribution during the course of a reaction.     

Mechanochemical Rhodium(III)‐ and Gold(I)‐Catalyzed C−H Bond Alkynylations of Indoles under Solventless Conditions in Mixer Mills

Mechanochemical activations in Rh^III‐ and Au^I‐catalyzed C?H alkynylations lead selectively to C₂‐ and C₃‐alkynylated indoles. The processes show excellent functional group tolerance, do not require additional heating and proceed under solventless conditions. Compared to solvent‐based standard protocols, the reaction times are shorter and the catalyst quantities lower resulting in high product yields under ambient atmosphere in mixer mills.     

Readily Accessible Bulky Iron Catalysts exhibiting Site Selectivity in the Oxidation of Steroidal Substrates

Bulky iron complexes are described that catalyze the site‐selective oxidation of alkyl C?H bonds with hydrogen peroxide under mild conditions. Steric bulk at the iron center is introduced by appending trialkylsilyl groups at the meta‐position of the pyridines in tetradentate aminopyridine ligands, and this effect translates into high product yields, an enhanced preferential oxidation of secondary over tertiary C?H bonds, and the ability to perform site‐selective oxidation of methylenic sites in terpenoid and steroidal substrates. Unprecedented site selective oxidation at C6 and C12 methylenic sites in steroidal substrates is shown to be governed by the chirality of the catalysts.     

Minor Enantiomer Recycling: Metal Catalyst,Organocatalyst and Biocatalyst Working in Concert

A minor enantiomer recycling one‐pot procedure employing two reinforcing chiral catalysts has been developed. Continuous regeneration of the achiral starting material is effected via selective enzyme‐catalyzed hydrolysis of the minor product enantiomer from Lewis acid–Lewis base catalyzed addition of acyl cyanides to prochiral aldehydes in a two‐phase solvent system. The process provides O‐acylated cyanohydrins in close to perfect enantioselectivities, higher than those obtained in the direct process, and in high yields. A combination of a (S,S)‐salen Ti Lewis acid and Candida antarctica lipase B provides the products with R absolute configuration, whereas the opposite enantiomer is obtained from the (R,R)‐salen Ti complex and Candida rugosa lipase.     

Ruthenium‐Catalyzed Cascade Annulation of Indole with Propargyl Alcohols

Cascade transformations forming multiple bonds and one‐pot procedures provide rapid access to natural‐product‐like scaffolds from simple precursors. These atom‐economic processes are valuable tools in organic synthesis and drug discovery. Herein, we report on ruthenium‐catalyzed cascade annulations of indole with readily available propargyl alcohols. These provide rapid access to diverse carbazoles, cyclohepta[b]indoles, and further fused polycycles with high selectivity. A bifunctional ruthenium complex featuring a redox‐coupled cyclopentadienone ligand acts as a common catalyst for the different cascade processes.     

Impact of Hydrogenolysis on the Selectivity of the Fischer–Tropsch Synthesis: Diesel Fuel Production over Mesoporous Zeolite‐Y‐Supported Cobalt Nanoparticles

Selectivity control is a challenging goal in Fischer–Tropsch (FT) synthesis. Hydrogenolysis is known to occur during FT synthesis, but its impact on product selectivity has been overlooked. Demonstrated herein is that effective control of hydrogenolysis by using mesoporous zeolite Y‐supported cobalt nanoparticles can enhance the diesel fuel selectivity while keeping methane selectivity low. The sizes of the cobalt particles and mesopores are key factors which determine the selectivity both in FT synthesis and in hydrogenolysis of n‐hexadecane, a model compound of heavier hydrocarbons. The diesel fuel selectivity in FT synthesis can reach 60 % with a CH₄ selectivity of 5 % over a Na‐type mesoporous Y‐supported cobalt catalyst with medium mean sizes of 8.4 nm (Co particles) and 15 nm (mesopores). These findings offer a new strategy to tune the product selectivity and possible interpretations of the effect of cobalt particle size and the effect of support pore size in FT synthesis.     

Synthesis of Linear (Z)‐α,β‐Unsaturated Esters by Catalytic Cross‐Metathesis. The Influence of Acetonitrile

Kinetically controlled catalytic cross‐metathesis reactions that generate (Z)‐α,β‐unsaturated esters selectively are disclosed. A key finding is that the presence of acetonitrile obviates the need for using excess amounts of a more valuable terminal alkene substrates. On the basis of X‐ray structure and spectroscopic investigations a rationale for the positive impact of acetonitrile is provided. Transformations leading to various E,Z‐dienoates are highly Z‐selective as well. Utility is highlighted by application to stereoselective synthesis of the C1–C12 fragment of biologically active natural product (?)‐laulimalide.