The Interplay between Kinetics and Thermodynamics in Furan Diels-Alder Chemistry for Sustainable Chemicals Production.

Biomass-derived furanic platform molecules have emerged as promising building blocks for renewable chemicals and functional materials. To this aim, the Diels-Alder (DA) cycloaddition stands out as a versatile strategy to convert these renewable resources in highly atom-efficient ways. Despite nearly a century worth of examples of furan DA chemistry, clear structure-reactivity-stability relationships are still to be established. Detailed understanding of the intricate interplay between kinetics and thermodynamics in these very particular [4+2] cycloadditions is essential to push further development and truly expand the scope beyond the ubiquitous addend combinations of electron-rich furans and electron-deficient olefins. Herein, we provide pertinent examples of DA chemistry, taken from various fields, to highlight trends, establish correlations and answer open questions in the field with the aim to support future efforts in the sustainable chemicals and materials production.

Vanillic acid and methoxyhydroquinone production from guaiacyl units and related aromatic compounds using Aspergillus niger cell factories.

BACKGROUND: The aromatic compounds vanillin and vanillic acid are important fragrances used in the food, beverage, cosmetic and pharmaceutical industries. Currently, most aromatic compounds used in products are chemically synthesized, while only a small percentage is extracted from natural sources. The metabolism of vanillin and vanillic acid has been studied for decades in microorganisms and many studies have been conducted that showed that both can be produced from ferulic acid using bacteria. In contrast, the degradation of vanillin and vanillic acid by fungi is poorly studied and no genes involved in this metabolic pathway have been identified. In this study, we aimed to clarify this metabolic pathway in Aspergillus niger and identify the genes involved. RESULTS: Using whole-genome transcriptome data, four genes involved in vanillin and vanillic acid metabolism were identified. These include vanillin dehydrogenase (vdhA), vanillic acid hydroxylase (vhyA), and two genes encoding novel enzymes, which function as methoxyhydroquinone 1,2-dioxygenase (mhdA) and 4-oxo-monomethyl adipate esterase (omeA). Deletion of these genes in A. niger confirmed their role in aromatic metabolism and the enzymatic activities of these enzymes were verified. In addition, we demonstrated that mhdA and vhyA deletion mutants can be used as fungal cell factories for the accumulation of vanillic acid and methoxyhydroquinone from guaiacyl lignin units and related aromatic compounds. CONCLUSIONS: This study provides new insights into the fungal aromatic metabolic pathways involved in the degradation of guaiacyl units and related aromatic compounds. The identification of the involved genes unlocks new potential for engineering aromatic compound-producing fungal cell factories.

Dynamic Trapping as a Selective Route to Renewable Phthalide from Biomass-Derived Furfuryl Alcohol.

A novel route for the production of the versatile chemical building block phthalide from biorenewable furfuryl alcohol and acrylate esters is presented. Two challenges that limit sustainable aromatics production via Diels-Alder (DA) aromatisation-an unfavourable equilibrium position and undesired regioselectivity when using asymmetric addends-were addressed using a dynamic kinetic trapping strategy. Activated acrylates were used to speed up the forward and reverse DA reactions, allowing for one of the four DA adducts to undergo a selective intramolecular lactonisation reaction in the presence of a weak base. The adduct is removed from the equilibrium pool, pulling the system completely to the product with a fixed, desired regiochemistry. A single 1,2-regioisomeric lactone product was formed in up to 86 % yield and the acrylate activating agent liberated for reuse. The lactone was aromatised to give phthalide in almost quantitative yield in the presence of Ac2 O and a catalytic amount of strong acid, or in 79 % using only catalytic acid.

Stereoselective Synthesis of Functionalized Bicyclic Scaffolds by Passerini 3-Center-2-Component Reactions of Cyclic Ketoacids.

We report the use of bifunctional starting materials (ketoacids) in a diastereoselective Passerini three-center-two-component reaction. Study of the reaction scope revealed the required structural features for stereoselectivity in the isocyanide addition. In this system, an interesting isomerization of the primary Passerini product - the α-carboxamido lactone - into an atypical product, an α-hydroxy imide, was found to occur under acidic conditions. Furthermore, enantioenriched Passerini products can be generated from an enantioenriched ketoacid obtained by chemoenzymatic synthesis.

Trityl Isocyanide as a Mechanistic Probe in Multicomponent Chemistry: Walking the Line between Ugi- and Strecker-type Reactions.

Herein, we describe the versatile application of triphenylmethyl (trityl) isocyanide in multicomponent chemistry. This reagent can be employed as a cyanide source in the Strecker reaction and as convertible isocyanide in the preparation of N-acyl amino acids by Ugi 4CR/detritylation and free imidazo[1,2-a]pyridin-3-amines by a Groebke-Blackburn-Bienaymé 3CR condensation/deprotection protocol. The mechanisms of these three classical MCRs intersect at the common N-trityl nitrilium ion intermediate, whose predictable reactivity can be exploited towards chemoselective transformations.

One-Pot Synthesis of N-Substituted ß-Amino Alcohols from Aldehydes and Isocyanides.

A practical two-stage one-pot synthesis of N-substituted ß-amino alcohols using aldehydes and isocyanides as starting materials has been developed. This method features mild reaction conditions, broad scope, and general tolerance of functional groups. Based on a less common central carbon-carbon bond disconnection, this protocol complements traditional approaches that involve amines and various carbon electrophiles (epoxides, α-halo ketones, ß-halohydrins). Medicinally relevant products can be prepared in a concise and efficient way from simple building blocks, as demonstrated in the synthesis of the antiasthma drug salbutamol. Upgrading the synthesis to an enantioselective variant is also feasible.

Asymmetric Synthesis of Tetracyclic Pyrroloindolines and Constrained Tryptamines by a Switchable Cascade Reaction.

The interrupted Fischer indole synthesis of arylhydrazines and biocatalytically generated chiral bicyclic imines selectively affords either tetracyclic pyrroloindolines or tricyclic tryptamine analogues depending on the reaction conditions. We demonstrate that the reaction is compatible with a variety of functional groups. The products are obtained in high optical purity and in reasonable to good yield. We present a plausible reaction mechanism to explain the observed reaction outcome depending on the stoichiometry of the acid mediator. To demonstrate the synthetic utility of our method, pharmaceutically relevant examples of both product classes were synthesized in highly efficient reaction sequences, including a phenserine analogue as a potential cholinesterase inhibitor and constrained tryptamine derivatives as selective inhibitors of the 5-HT6 serotonin receptor and the TRPV1 ion channel.

Efficient synthesis of fully renewable, furfural-derived building blocks via formal Diels-Alder cycloaddition of atypical addends.

Diels-Alder (DA) cycloaddition of furanics is emerging as a key transformation in circular chemistry, providing access to highly versatile, biobased platform molecules. Further development of this technology into viable industrial applications faces major challenges, a notorious one being the lack of reactivity of the most readily available furans, i.e. the furfural derivatives. Herein we describe the remarkably-facile intramolecular DA reaction of allyl acetals of different furfurals to efficiently afford formal DA adducts with the atypical, unreactive dienophile allyl alcohol. Our methodology gives access to unprecedented oxanorbornene derivatives in high chemo-, regio- and stereoselectivity, which can be readily diversified into valuable products. This offers the potential of scalable production of renewable chemical building blocks from cheap, bioderived platform molecules.

Sustainable synthesis of diverse privileged heterocycles by palladium-catalyzed aerobic oxidative isocyanide insertion.

O(2) in, H(2)O out: Various diamines and related bisnucleophiles readily undergo oxidative isocyanide insertion with Pd(OAc)(2) (1 mol %) as the catalyst and O(2) as the terminal oxidant to give a diverse array of medicinally relevant N heterocycles. The utility of this highly sustainable method is demonstrated by a formal synthesis of the antihistamines astemizole and norastemizole.

Targeting Valuable Chemical Commodities: Hydrazine-mediated Diels-Alder Aromatization of Biobased Furfurals.

A hydrazine-mediated approach towards renewable aromatics production via Diels-Alder aromatization of readily available, biobased furfurals was explored as alterative to the more classical approaches that rely on reactive but uneconomical reduced dienes (e. g., 2,5-dimethylfuran). To enable cycloaddition chemistry with these otherwise unreactive formyl furans, substrate activation by N,N-dimethyl hydrazone formation was investigated. The choice of the reaction partner was key to the success of the transformation, and in this respect acrylic acid showed the most promising results in the synthesis of aromatics. This strategy allowed for selectivities up to 60 % for a complex transformation consisting of Diels-Alder cycloaddition, oxabridge opening, decarboxylation, and dehydration. Exploration of the furfural scope yielded generic structure-reactivity-stability relationships. The proposed methodology enabled the redox-efficient, operationally simple, and mild synthesis of renewable (p-disubstituted) aromatics of commercial importance under remarkably mild conditions.

Synthesis of Carbazoles by a Diverted Bischler-Napieralski Cascade Reaction.

An unforeseen twist in a seemingly trivial Bischler-Napieralski reaction led to the selective formation of an unexpected carbazole product. The reaction proved to be general, providing access to a range of diversely substituted carbazoles from readily available substrates. Judicious variation of substituents revealed a complex cascade mechanism comprising no less than 10 elementary steps, that could be diverted in multiple ways toward various other carbazole derivatives.

Furoic acid and derivatives as atypical dienes in Diels-Alder reactions.

The furan Diels-Alder (DA) cycloaddition reaction has become an important tool in green chemistry, being central to the sustainable synthesis of many chemical building blocks. The restriction to electron-rich furans is a significant limitation of the scope of suitable dienes, in particular hampering the use of the furans most readily obtained from biomass, furfurals and their oxidized variants, furoic acids. Herein, it is shown that despite their electron-withdrawing substituents, 2-furoic acids and derivatives (esters, amides) are in fact reactive dienes in Diels-Alder couplings with maleimide dienophiles. The reactions benefit from a substantial rate-enhancement when water is used as solvent, and from activation of the 2-furoic acids by conversion to the corresponding carboxylate salts. This approach enables Diels-Alder reactions to be performed under very mild conditions, even with highly unreactive dienes such as 2,5-furandicarboxylic acid. The obtained DA adducts of furoic acids are shown to be versatile synthons in the conversion to various saturated and aromatic carbocyclic products.

Brønsted Acid-Catalyzed Cyanotritylation of Aldehydes by Trityl Isocyanide.

Cyanohydrins are versatile intermediates toward valuable organic compounds like α-hydroxy carboxylic acids, α-amino acids, and ß-amino alcohols. Numerous protocols are available for synthesis of (O-protected) cyanohydrins, but all procedures invariably rely on the use of toxic cyanide sources. A novel cyanide-free synthesis of O-trityl protected cyanohydrins via a catalytic Passerini-type reaction involving aldehydes and trityl isocyanide is reported. The feasibility of a catalytic asymmetric reaction is demonstrated using chiral phosphoric acid catalysis.

Synthesis of polycyclic spiroindolines by highly diastereoselective interrupted Ugi cascade reactions of 3-(2-isocyanoethyl)indoles.

We report a highly diastereoselective interrupted Ugi reaction to construct a broad range of structurally congested and stereochemically complex spiroindolines from tryptamine-derived isocyanides. The reaction is facilitated by using fluorinated alcohols (TFE or HFIP) as solvents and tolerates a broad range of amines, aldehydes and 2-isocyanoethylindoles to give polycyclic products in moderate to excellent yields.