Alkyl Donor Research Articles

Catalytic Intramolecular Ketone Haloacylation Enabled Stereoselective Heterolytic Cleavage of Cyclopropyl Ketones with Enhanced Reactivity and Regioselectivity beyond Electronics.

By integration of oxocarbenium activation and Lewis acid coordination activation via conformational proximity-driven, Pd(II)- or Cu(I)-catalyzed intramolecular ketone haloacylation, regio- and stereoselective heterolytic ring-opening 1,5-haloacylation of cyclopropyl ketones, including those with weak single alkyl donors, has been developed for the synthesis of valuable α-quaternary halo-γ-butenolides. The vicinal carboxylic acid and ketone acceptors are no longer just spectator activators. Further, this reaction delivers a constant regioselectivity regardless of the electronic nature of substituents, even the malonate.

Multicomponent Synthesis of α-Branched Amines via a Zinc-Mediated Carbonyl Alkylative Amination Reaction.

Methods for the synthesis of α-branched alkylamines are important due to their ubiquity in biologically active molecules. Despite the development of many methods for amine preparation, C(sp3)-rich nitrogen-containing compounds continue to pose challenges for synthesis. While carbonyl reductive amination (CRA) between ketones and alkylamines is the cornerstone method for α-branched alkylamine synthesis, it is sometimes limited by the sterically demanding condensation step between dialkyl ketones and amines and the more restricted availability of ketones compared to aldehydes. We recently reported a "higher-order" variant of this transformation, carbonyl alkylative amination (CAA), which utilized a halogen atom transfer (XAT)-mediated radical mechanism, enabling the streamlined synthesis of complex α-branched alkylamines. Despite the efficacy of this visible-light-driven approach, it displayed scalability issues, and competitive reductive amination was a problem for certain substrate classes, limiting applicability. Here, we report a change in the reaction regime that expands the CAA platform through the realization of an extremely broad zinc-mediated CAA reaction. This new strategy enabled elimination of competitive CRA, simplified purification, and improved reaction scope. Furthermore, this new reaction harnessed carboxylic acid derivatives as alkyl donors and facilitated the synthesis of α-trialkyl tertiary amines, which cannot be accessed via CRA. This Zn-mediated CAA reaction can be carried out at a variety of scales, from a 10 μmol setup in microtiter plates enabling high-throughput experimentation, to the gram-scale synthesis of medicinally-relevant compounds. We believe that this transformation enables robust, efficient, and economical access to α-branched alkylamines and provides a viable alternative to the current benchmark methods.

Accessing Highly Substituted Indoles via B(C6F5)3-Catalyzed Secondary Alkyl Group Transfer.

Herein, we report a synthetic method to access a range of highly substituted indoles via the B(C6F5)3-catalyzed transfer of 2° alkyl groups from amines. The transition-metal-free catalytic approach has been demonstrated across a broad range of indoles and amine 2° alkyl donors, including various substituents on both reacting components, to access useful C(3)-alkylated indole products. The alkyl transfer process can be performed using Schlenk line techniques in combination with commercially available B(C6F5)3·nH2O and solvents, which obviates the requirement for specialized equipment (e.g., glovebox).

Engineering of halide methyltransferases for synthesis of SAE and its application in biosynthesis of ethyl vanillin

Halide methyltransferase (HMT)-catalyzed synthesis of alkyl donors from S-adenosyl-L-homocysteine (SAH) and haloalkanes is a promising method for biocatalytic alkylation. However, the reported halide methyltransferases show limited catalytic capacity towards unnatural substrates such as ethyl iodide, which limits their application in biocatalytic ethylation. In this work, we performed structure-based directed evolution starting from the wild-type Aspergillus clavatus halide methyltransferase (AcHMT). The best variant, AcHMTM3, was identified with an activity of up to 421.5 mU mg–1 towards ethyl iodide, 38.7-fold higher than that of the wild type AcHMT. Subsequently, molecular dynamics simulations provide structural insights into how mutations improve the catalytic activity towards iodoethane. Finally, AcHMTM3 was utilized in one-pot cascade with the reported O-methyltransferase RnCOMT+Y200L to synthesize ethyl vanillin from 3,4-dihydroxybenzaldehyde (79% conversion). Our work demonstrated the potential of the engineered HMT in further biocatalytic alkylation.

Investigating Metal-Metal Bond Polarization in a Heteroleptic Tris-Ylide Diiron System.

This article describes the synthesis, characterization, and S-atom transfer reactivity of a series of C3v-symmetric diiron complexes. The iron centers in each complex are coordinated in distinct ligand environments, with one (FeN) bound in a pseudo-trigonal bipyramidal geometry by three phosphinimine nitrogens in the equatorial plane, a tertiary amine, and the second metal center (FeC). FeC is coordinated, in turn, by FeN, three ylidic carbons in a trigonal plane, and, in certain cases, by an axial oxygen donor. The three alkyl donors at FeC form through the reduction of the appended N═PMe3 arms of the monometallic parent complex. The complexes were studied crystallographically, spectroscopically (NMR, UV-vis, and Mössbauer), and computationally (DFT, CASSCF) and found to be high-spin throughout, with short Fe-Fe distances that belie weak orbital overlap between the two metals. Further, the redox nature of this series allowed for the determination that oxidation is localized to the FeC. S-atom transfer chemistry resulted in the formal insertion of a S atom into the Fe-Fe bond of the reduced diiron complex to form a mixture of Fe4S and Fe4S2 products.

Continuous synthesis of cinnamate ester using membrane reactor in a solvent-free system

Cinnamic acid is a phenolic compound with the potential to act as a natural antioxidant. Cinnamic acid esterification can be performed by adding a long-chain alcohol to one of its hydroxyl groups to improve its antioxidant activity. In this study, cinnamic esters were synthesized in an enzymatic membrane reactor (EMR) and were carried out continuously. This study aimed to determine the optimum conditions for the synthesis of cinnamic esters using various types of alcohols (e.g., butanol, hexanol, and octanol) as alkyl group donors and the impact of the esterification on the antioxidant activity. The continuous synthesis of cinnamic esters with TL IM lipozyme as the biocatalyst had the highest conversion (20.91%) with 1-butanol as the alkyl donor, in a synthesis strategy of a 12-h batch followed by continuous operation with a residence time of 9 h. The resulting ester increased the antioxidant activities by 2.18 and 3.85-fold, respectively based on the DPPH and FRAP assays.

Four-Coordinate Fe N2 and Imido Complexes Supported by a Hemilabile NNC Heteroscorpionate Ligand.

Inspired by mechanistic proposals for N2 reduction at the nitrogenase FeMo cofactor, we report herein a new, strongly σ-donating heteroscorpionate ligand featuring two weak-field pyrazoles and an alkyl donor. This ligand supports four-coordinate Fe(I)-N2, Fe(II)-Cl, and Fe(III)-imido complexes, which we have characterized using a variety of spectroscopic and computational methods. Structural and quantum mechanical analysis reveal the nature of the Fe–C bonds to be essentially invariant between the complexes, with conversion between the (formally) low-valent Fe-N2 and high-valent Fe-imido complexes mediated by pyrazole hemilability. This presents a useful strategy for substrate reduction at such low-coordinate centers and suggests a mechanism by which FeMoco might accommodate the binding of both π-acidic and π-basic nitrogenous substrates.

Photoredox-Catalyzed Oxidative Radical–Polar Crossover Enables the Alkylfluorination of Olefins

The three-component alkylfluorination of olefins via an oxidative radical-polar crossover under visible light-induced photocatalysis is disclosed. A key feature of this reaction is the incorporation of two synthetically meaningful components involving a three-dimensional alkyl group and a fluorine atom using easily preparable N-hydroxyphthalimide esters as the alkyl donors and a low-cost hydrogen fluoride as the fluorine source. Furthermore, a one-step procedure using commercially available carboxylic acids demonstrated the versatility of this new method.

The Cloke-Wilson rearrangement of aroyl-substituted donor-acceptor cylopropanes containing arylethyl donors.

The chemistry of donor-acceptor (D-A) cyclopropanes containing alkyl donors has been scantily investigated. In the present work, we have synthesized new D-A cyclopropanes containing arylethyl donors and explored their reactivity in the presence of Lewis acids. Upon treatment with SnCl4, these cyclopropanes underwent the Cloke-Wilson rearrangement to yield 3,4,5-trisubstituted γ-butyrolactones in good yields with high diastereoselectivity.

Practical and Regioselective Synthesis of C-4-Alkylated Pyridines.

The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.

Recent Advances in the Pd-Catalyzed Coupling of Arylhydrazines and Ammonium Salts via C-N Bond Cleavage.

Both arylhydrazines and quaternary ammonium salts are readily accessible or commercially available chemicals that show versatile reactivity in Pd-catalyzed coupling reactions via C-N bond cleavage. A tremendous array of coupling reactions involving reaction partners such as organoborons, aryl silanes, alkenes, alkynes, arylation or alkylation reagents in C-H functionalization and carbonylation reactions are summarized, in which arylhydrazines or quaternary ammonium salts function as aryl or alkyl donors. This account mainly focuses on recent advances in Pd-catalyzed coupling reactions with arylhydrazines or quaternary ammonium salts via C-N bond cleavage, including mechanistic elucidations.

Synthesis of Acridinium Photocatalysts via Site-Selective C–H Alkylation

Acridinium dyes have been broadly used as photocatalysts, but it remains synthetically challenging to fine-tune their catalytic performance by functionalization of their structural cores. Acridiniu...

Nickel-catalyzed site- and stereoselective reductive alkylalkynylation of alkynes

Nickel-catalyzed site- and stereoselective reductive alkylalkynylation of alkynes

Alkyl halides as both hydride and alkyl sources in catalytic regioselective reductive olefin hydroalkylation

Among the plethora of catalytic methods developed for hydrocarbofunctionalization of olefins to date, reactions that regioselectively install a functionalized alkyl unit at the 2-position of a terminal unactivated C=C bond to afford branched products are scarce. Here, we show that a Ni-based catalyst in conjunction with a stoichiometric reducing agent promote Markovnikov-selective hydroalkylation of unactivated alkenes tethered to a recyclable 8-aminoquinaldine directing auxiliary. These mild reductive processes employ readily available primary and secondary haloalkanes as both the hydride and alkyl donor. Reactions of alkenyl amides with ≥ five-carbon chain length regioselectively afforded β-alkylated products through remote hydroalkylation, underscoring the fidelity of the catalytic process and the directing group’s capability in stabilizing five-membered nickelacycle intermediates. The operationally simple protocol exhibits exceptional functional group tolerance and is amenable to the synthesis of bioactive molecules as well as regioconvergent transformations.

Non‐catalytic and heterogeneous acid/base‐catalyzed biodiesel production: Recent and future developments

AbstractBiodiesel production technologies, which are non‐catalytic and those involving the use of heterogeneous catalyst(s), have gained much interest owing to its high biodiesel and pure glycerol throughput. During the past 15 years, many studies were devoted to explore new catalysts as well as improve non‐catalytic technologies with aims to ultimately industrialize such biodiesel production processes. This review elucidates the main process parameters that influences non‐catalytic and heterogeneous‐catalyzed biodiesel production processes. The common parameters among these technologies include the process temperature, alcohol/oil molar ratio, pressure, catalyst loading, and feedstock quality. Optimization of these process parameters is discussed according to the use of conventional method (one factor at a time [OFAAT]) or the use of statistical methods such as response surface methodology (RSM), artificial neural network (ANN), and Taguchi method. In addition, recent development on non‐catalytic process and those involving the use of heterogeneous catalyst(s), such as glycerol‐free processes under supercritical conditions of alkyl donors and strategies to improve properties of heterogeneous catalyst, are also reviewed. Finally, insight based on the published techno‐economical evaluations is also tackled, and future prospects and research directions on these technologies are also discussed.

Easy reuse of magnetic cross-linked enzyme aggregates of lipase B from Candida antarctica to obtain biodiesel from Chlorella vulgaris lipids

In this work, magnetic cross-linked enzyme aggregates (mCLEAs) of CALB (lipase B from Candida antarctica) were prepared and characterized. Moreover, a method for an easy, sustainable and economic extraction of lipids from nitrogen-starved cells of Chlorella vulgaris var L3 was developed. Then, the extracted lipids (oils and free fatty acids, FFAs) were converted to biodiesel using mCLEAs and chemical acid catalysis. Among several lipid extraction methods, saponification was selected given the amount of wet microalgal biomass it can process per unit of time, its low market value, and because it allows for the use of less toxic solvents. A biodiesel conversion of 80.2±4.4% was obtained by chemical catalysis (1h at 100°C) using FFAs and methanol as the alkyl donor. However, a biodiesel conversion of more than 90% (3h at 30°C) was obtained using mCLEAs and methanol. Both chemical and enzymatic catalysts gave biodiesel with similar fatty acid alkyl ester (FAAE) composition. Methanol, at 15% (v/v) or higher concentration, caused a decrease of lipase activity and a concomitant increase in the size of mCLEA aggregates (up to 2μm), as measured by dynamic light scattering (DLS). The magnetic character of the novel biocatalyst permits its easy recovery and reuse, for at least ten consecutive catalytic cycles (retaining 90% of the initial biodiesel conversion), using mild reaction conditions and environmentally-friendly solvents.

Determination of Alkyl-Donor Promiscuity of Tyrosine-O-Prenyltransferase SirD from Leptosphaeria maculans.

Natural product prenyltransferases are known to display relaxed acceptor substrate specificity. Although recent studies with a small set of unnatural alkyl donors have revealed that prenyltransferases are flexible with regard to their alkyl donors, the scope of their alkyl donor specificity remains poorly understood. Towards this goal, we report the synthesis of 20 unnatural alkyl pyrophosphate donors and an assessment of the reactions of these synthetic unnatural alkyl pyrophosphate analogues catalyzed by tyrosine O-prenyltransferase SirD. This study demonstrates that SirD can utilize 16 out of 21 alkyl pyrophosphate analogues (including the natural donor) in catalyzing mostly O-alkylation of l-tyrosine. This study reveals the broad alkyl donor specificity of SirD and opens the door for the interrogation of the alkyl donor specificity of other prenyltransferases for potential utility as biocatalysts for differential alkylation applications.

Cobalt-Catalyzed Monoselective ortho-C–H Ethylation of Carboxamides with Triethylaluminum

A 1,10-phenanthroline ligated cobalt catalyst is reported for the ortho-C–H ethylation of aromatic, heteroaromatic, and alkenyl carboxamides with inexpensive triethylaluminum. This reaction represented the first example of cobalt-catalyzed monoselective direct ortho-C–H ethylation reaction with aluminum reagent as an alkyl donor.

Practical Approach for Quantitative Green Esterifications

Subquantitative synthetic esterification reactions have been transformed into quantitative aqueous reactions. The esterification reactions involve carboxylic acids, alkyl halides or mesylate with granular polytetrafluoroethylene (PTFE), lithium carbonate, tetrabutyl ammonium bromide and were mediated solely by water. Various alkyl donors were employed including α-halo ketones, α-halo esters, α-halo amide, allyl bromide, benzyl chloride, alkyl iodides and alkyl mesylate. The scope of the carboxylic acids ranged from aromatic to aliphatic and from water-soluble to water-insoluble. Among the 58 reaction examples, 54 esterifications were quantitative and the other four had yields above 94%. Six of the reactions were scaled up to more than 10 g. In 30 examples and all the enlarged scale examples, no organic solvents were used at all and the products were collected simply by filtration. The yields for esterification reactions with secondary halides were quantitative compared to previous reported yields of only ...

Capturing Unknown Substrates via in Situ Formation of Tightly Bound Bisubstrate Adducts: S-Adenosyl-vinthionine as a Functional Probe for AdoMet-Dependent Methyltransferases.

Identifying an enzyme's substrates is essential to understand its function, yet it remains challenging. A fundamental impediment is the transient interactions between an enzyme and its substrates. In contrast, tight binding is often observed for multisubstrate-adduct inhibitors due to synergistic interactions. Extending this venerable concept to enzyme-catalyzed in situ adduct formation, unknown substrates were affinity-captured by an S-adenosyl-methionine (AdoMet, SAM)-dependent methyltransferase (MTase). Specifically, the electrophilic methyl sulfonium (alkyl donor) in AdoMet is replaced with a vinyl sulfonium (Michael acceptor) in S-adenosyl-vinthionine (AdoVin). Via an addition reaction, AdoVin and the nucleophilic substrate form a covalent bisubstrate-adduct tightly complexed with thiopurine MTase (2.1.1.67). As such, an unknown substrate was readily identified from crude cell lysates. Moreover, this approach is applicable to other systems, even if the enzyme is unknown.