Protocol for the preparation of primary amine-containing catalysts on the resin.

In light of escalating sustainability concerns, addressing catalyst usage and waste production challenges becomes crucial. Here, we introduce a robust protocol for crafting recyclable polystyrene-supported primary amines, providing a promising solution via heterogeneous catalysis. The protocol details immobilization onto insoluble resins through ester, ether, or amide bonds, facilitating the synthesis of heterogeneous catalysts with diverse organic components. For complete details on the use and execution of this protocol, please refer to Kanger et al.1.

Primary amines as heterogeneous catalysts in an enantioselective [2,3]-Wittig rearrangement reaction.

A series of heterogeneous catalysts anchored to different polystyrene-based supports has been prepared and applied in an asymmetric [2,3]-Wittig rearrangement reaction of cyclohexanone derivatives. Among them, primary amino acid-derived (aminomethylated)polystyrene-supported catalysts showed excellent reactivity leading to the formation of rearranged products in good enantioselectivities of both diastereomers. Reusability issues connected to the deactivation of the catalyst were proved to be dependent on the end-capping strategy chosen for the blocking of the unreacted active sites of the resin. This issue of end-capping has not previously been in focus. Using bulkier pivaloyl end-capping moiety, we were able to recycle the catalyst in six consecutive cycles with only marginal deceleration of the reaction. Moreover, the epimerization of the product that occurred while conducting a rearrangement reaction in the presence of a homogeneous catalyst was almost fully eliminated by switching the catalytic system to heterogeneous.

Aminocatalysts are More Environmentally Friendly than Hydrogen-Bonding Catalysts.

The importance of asymmetric organocatalysis in contemporary organic synthesis is widely acknowledged. However, there are practically no data on the environmental safety of organocatalysts, although this aspect is crucial for the sustainability of all new materials, chemicals, and technologies. To start to fill this data-gap, a library of 26 organocatalysts containing hydrogen-bonding catalysts [(thio)ureas and squaramides] and aminocatalysts (primary or secondary amines) was evaluated for their toxicity using the naturally luminescent Vibrio fischeri bacteria (ISO assay; one of the most widely used ecotoxicity tests). Thioureas and squaramides were shown to be relatively toxic: none of them was ranked as "not harmful" (i. e., half maximal effective concentration EC50 >100 mg L-1 ), whereas the presence of the trifluoromethyl moiety increased their toxic effect. Importantly, the aminocatalysts, whose EC50 values ranged from 25 to >300 mg L-1 , could be considered remarkably more environmentally safe or green alternatives.

Synthesis of 6'-galactosyllactose, a deviant human milk oligosaccharide, with the aid of Candida antarctica lipase-B.

Research on human milk oligosaccharides (HMOs) has increased over the past decade showing great interest in their beneficial effects. Here we describe a method for the selective deacetylation using immobilised Candida antarctica lipase-B, Novozyme N435 (N435), of pyranose saccharides in organic media with the aim of simplifying and improving the pathways for the synthesis of HMOs. By first studying in depth the deacetylation reaction of peracetylated D-glucose two reaction conditions were found, which were used on different HMO building blocks, peracetylated saccharides and thioglycosides. D-Glucose based saccharides showed selectivity towards the fourth and the sixth position deacetylation. While α-anomer of peracetylated D-galactose remained unreactive and ß-anomer favoured the first position deacetylation. Peracetylated L-fucose, on the other hand, had no selectivity as the main product was fully unprotected L-fucose. Taking the peracetylated D-glucose deacetylation reaction product and selectively protecting the primary hydroxyl group in the sixth position left only the fourth position open for the glycosylation. Meanwhile, the deacetylation product of D-galactose thioglycoside, with the sixth position deacetylated, had both acceptor and donor capabilities. Using the two aforementioned products derived from the N435 deacetylation reactions a deviant HMO, 6'-galactosyllactose (6'-GL) was synthesised.

Multifunctional Catalysts in the Asymmetric Mannich Reaction of Malononitrile with N-Phosphinoylimines: Coactivation by Halogen Bonding versus Hydrogen Bonding.

A multifunctional (noncovalent) catalyst containing halogen-bond donor, hydrogen-bond donor, and Lewis basic sites was developed and applied in an enantioselective Mannich reaction between malononitrile and diphenylphosphinoyl-protected aldimine affording products in high yields (up to 98%) and moderate to high enantiomeric purities (ee up to 89%). Typically, noncovalent catalysts rely on several weak interactions to activate the substrate, with one or two of these giving the most notable contribution to activation. In this instance, instead of the initially proposed coactivation by halogen bonding, it was revealed that hydrogen bonding plays a key role in determining the enantioselectivity.

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole.

An asymmetric Michael reaction between cyclopentane-1,2-dione and alkylidene oxindole was studied in the presence of a multifunctional squaramide catalyst. Michael adducts were obtained in high enantioselectivities and in moderate diastereoselectivities.

Asymmetric Chemoenzymatic One-Pot Synthesis of α-Hydroxy Half-Esters.

A new chemoenzymatic one-pot strategy has been developed for the synthesis of α-hydroxy half-esters containing consecutive quaternary and tertiary stereocenters using asymmetric cascade catalysis. In this study, an asymmetric Ca2+-catalyzed [2,3]-Wittig rearrangement reaction was proven to be suitable for a combination with porcine liver esterase-mediated hydrolysis resulting in the enhanced enantiomeric purity of the obtained products in a one-pot synthesis compared to the stepwise method.

Enantioselective Michael addition to vinyl phosphonates via hydrogen bond-enhanced halogen bond catalysis.

An asymmetric Michael addition of malononitrile to vinyl phosphonates was accomplished by hydrogen bond-enhanced bifunctional halogen bond (XB) catalysis. NMR titration experiments were used to demonstrate that halogen bonding, with the support of hydrogen-bonding, played a key role in the activation of the Michael acceptors through the phosphonate group. This is the first example of the use of XBs for the activation of organophosphorus compounds in synthesis. In addition, the iodo-perfluorophenyl group proved to be a better directing unit than different iodo- and nitro-substituted phenyl groups. The developed approach afforded products with up to excellent yields and diastereoselectivities and up to good enantioselectivities.

Designed whole-cell-catalysis-assisted synthesis of 9,11-secosterols.

A method for the synthesis of 9,11-secosteroids starting from the natural corticosteroid cortisol is described. There are two key steps in this approach, combining chemistry and synthetic biology. Stereo- and regioselective hydroxylation at C9 (steroid numbering) is carried out using whole-cell biocatalysis, followed by the chemical cleavage of the C-C bond of the vicinal diol. The two-step method features mild reaction conditions and completely excludes the use of toxic oxidants.

Enantioselective Organocatalytic Michael Addition to Unsaturated Indolyl Ketones.

An efficient enantioselective organocatalytic method for the synthesis of N-alkylated indoles with α-branched alkyl substituents from the corresponding unsaturated indolyl ketones via a Michael addition has been developed. The resulting products were obtained in high enantioselectivities and in good yields. Various nucleophiles (nitroalkanes, malononitrile, malonic esters) can be used. The substitution pattern of the indole ring had no significant impact on the reaction outcome. Both electron-withdrawing and electron-donating substituents in any position of the heteroaromatic ring were well-tolerated.

Supramolecular Halogen Bonds in Asymmetric Catalysis.

Halogen bonding has received a significant increase in attention in the past 20 years. An important part of this interest has centered on catalytic applications of halogen bonding. Halogen bond (XB) catalysis is still a developing field in organocatalysis, although XB catalysis has outgrown its proof of concept phase. The start of this year witnessed the publication of the first example of a purely XB-based enantioselective catalytic reaction. While the selectivity can be improved upon, there are already plenty of examples in which halogen bonds, among other interactions, play a crucial role in the outcome of highly enantioselective reactions. This paper will give an overview of the current state of the use of XBs in catalytic stereoselective processes.

[2,3]-Wittig Rearrangement as a Formal Asymmetric Alkylation of α-Branched Ketones.

The enantioselective [2,3]-Wittig rearrangement of cinnamyloxycyclopentanone derivatives was performed in the presence of a Cinchona-based primary amine. The described method provides synthetically valuable α-hydroxy ketones with quaternary stereogenic centers in excellent enantiomeric purities. Relying on the X-ray crystal structure of the product and the DFT calculations, we propose that the rearrangement is promoted by an intramolecular hydrogen bond between the substrate and the catalyst.

Halo-1,2,3-triazolium Salts as Halogen Bond Donors for the Activation of Imines in Dihydropyridinone Synthesis.

In the past decade halogen bond (XB) catalysis has gained considerable attention. Halo-triazoles are known XB donors, yet few examples detail their use as catalysts. As a continuation of our previous work the catalytic properties of substituted enantiomerically pure halo-triazolium salts were explored in the reaction between an imine and Danishefsky's diene leading to the formation of dihydropyridinone. The catalytic activity of the XB donors was highly dependent on the choice of the halogen atom and on the counterion. Also, it was found that impurities in the diene affected the rate of the reaction.

Tunable chiral triazole-based halogen bond donors: assessment of donor strength in solution with nitrogen-containing acceptors.

Strong halogen bond (XB) donors are needed for the activation of neutral substrates. We demonstrate that XB donor properties of iodo-triazoles can be significantly enhanced by quaternization in combination with varying the counterion and aromatic substituent, exemplified by association constants with quinuclidine as high as 1.1 × 104 M-1.

Synthesis and Characterisation of Chiral Triazole-Based Halogen-Bond Donors: Halogen Bonds in the Solid State and in Solution.

A general platform for the synthesis of various chiral halogen-bond (XB) donors based on the triazole core and the characterisation of factors that influence the strength of the halogen bond in the solid state and in solution are reported. The characterisation of XB donors in the solid state by X-ray crystallography and in solution by 1 H NMR titration can be used to aid the design of new XB donors. We describe the first example of a XB between iodotriazoles and thioureas in solution. In addition, the enantiodiscrimination of acceptors in solution through halogen-bond participation is described.

Two Catalytic Methods of an Asymmetric Wittig [2,3]-Rearrangement.

Two different approaches for asymmetric catalytic Wittig [2,3]-rearrangement were developed. Allyloxymalonate derivatives were converted into homoallyl alcohols via organocatalytic or Ca2+-catalyzed pathways in moderate to high enantioselectivities.

Asymmetric Organocatalytic Wittig [2,3]-Rearrangement of Oxindoles.

A highly enantioselective organocatalytic [2,3]-rearrangement of oxindole derivatives is presented. The reaction was catalyzed by squaramide, and this provides access to 3-hydroxy 3-substituted oxindoles in high enantiomeric purities.

CaCl2, Bisoxazoline, and Malonate: A Protocol for an Asymmetric Michael Reaction.

A mild protocol for the asymmetric Michael addition of dimethyl malonate to various α,ß-unsaturated carbonyl compounds was developed. The salient feature of this methodology is that a cheap and environmentally friendly Lewis acid, CaCl2, was used as a catalyst. An aminoindanol- and pyridine-derived ligand provided in the presence of CaCl2 Michael adducts in moderate to high enantioselectivities. The scope of the reaction was demonstrated.

Remote activation of the nucleophilicity of isatin.

The concept of the remote activation of reactivity was first applied in asymmetric organocatalysis. An isatin 3-phenylimine derivative acts as a donor in the thiourea catalyzed asymmetric addition to unsaturated 1,4-ketoesters, affording aza-Michael adducts in high enantiomeric purity and yield.

Asymmetric synthesis of congested spiro-cyclopentaneoxindoles via an organocatalytic cascade reaction.

Starting from simple alkylidene oxindoles and nitroketones, a highly stereoselective methodology was developed for the synthesis of spiro-cyclopentaneoxindoles with four consecutive stereogenic centers. Using an organocatalytic cascade of Michael and aldol reactions in the presence of a chiral thiourea catalyst products were obtained in moderate to high yields and excellent enantioselectivities. Nitro, ester, and hydroxyl groups were introduced to the spiro ring, which could be used to facilitate further functionalization of the products.