Frans J. J. de Kanter

Palladium-catalyzed synthesis of 4-aminophthalazin-1(2H)-ones by isocyanide insertion.

Palladium-catalyzed cross-coupling of a wide range of substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively by classical methods.

The Efficient One‐Pot Reaction of up to Eight Components by the Union of Multicomponent Reactions

The development of synthetic methods has advanced enormously in the past decades. At present, chemists can design and prepare almost any type of molecule. The typical approach for the synthesis of (complex) molecules with predefined properties is, however, still characterized by rather inefficient step-by-step reaction sequences. The greatest challenge for synthetic chemists is therefore the improvement of overall efficiency by using atom-, step-, and energyeconomic procedures that proceed with high yield and selectivity. 2] This goal can be achieved by focusing on bond construction and functional-group compatibility in the development of new reaction types. Multicomponent reactions (MCRs) are important tools for the accomplishment of this goal as they inherently involve the formation of several bonds in one operation. As such, MCRs are convergent stepefficient procedures that can take place with remarkably high atom economy and E factors, by reducing the number of functional-group manipulations and thus avoiding the use of protecting groups. Synthetic efficiency can be further improved by combining more than one MCR. Central to this concept of the union of MCRs is the orthogonal reactivity of functional groups, which can be combined in one molecule to allow the union of different reactions if their reactivity is fully independent (orthogonal). Such strategies avoid the use of protective groups and increase efficiency in organic synthesis. The most straightforward approach to such combinations is the incorporation of a functional group in one of the inputs of the primary MCR that does not participate in the reaction, but does react as one of the components in a secondary MCR (Figure 1). In an ideal case, both reactions are combined in one pot to create a higher-order MCR. Although there are several reports of combinations of MCRs in the literature, the true one-pot combination (union of MCRs first introduced by the research group of Ugi) is generally not possible because: 1) the experimental procedure limits the scope in substrate inputs, 2) additional (de)protection steps are required, and 3) solvent incompatibilities mean that the solvent must be changed between subsequent reaction steps. Consequently, one-pot sequences of MCRs have remained limited to isolated examples by Ugi and co-workers, Portlock and co-workers, and our research group. We report herein a novel approach that combines two or more MCRs in one pot to achieve higher-order MCRs with unprecedented possibilities for complexity generation and diversification. Our strategy is based on two recently reported MCRs that display extraordinary functional-group and solvent compatibilities and lead to 2H-2-imidazolines and N(cyanomethyl)amides, respectively. In an initial approach, we focused on the introduction of a carboxylic acid function in the 2H-2-imidazoline produced by the primary MCR using an amino acid as one of the starting materials. Thus, reaction of isocyanide 1, acetone, and sodium glycinate (2) led to a clean conversion to form intermediate A (Scheme 1). After protonation of the intermediate carboxylate A (methanolic HCl, one equivalent), a one-pot combination with iPrCHO, n-propylamine, and tBuNC in an Ugi 4CR led to the isolation of 3a in 38% yield. The yield could be improved to 62% by using benzylamine instead of npropylamine, which is excellent when considering the number Figure 1. Combination (or union) of MCRs.

Synthesis of 4-Aminoquinazolines by Palladium-Catalyzed Intramolecular Imidoylation of N-(2-Bromoaryl)amidines

Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.

Highly Stereoselective Synthesis of Substituted Prolyl Peptides Using a Combination of Biocatalytic Desymmetrization and Multicomponent Reactions

Time and pep-tide wait for no man: Optically pure 3,4disubstituted 1-pyrrolines, generated from the corresponding meso-pyrrolidines by biocatalytic desymmetrization (MAO-N=monoamine oxidase N), react with carboxylic acids and isocyanides in a highly diastereoselective Ugi-type multicomponent reaction to give substituted prolyl peptides of high pharmaceutical relevance. (Figure Presented)

Selective formation of 2-imidazolines and 2-substituted oxazoles by using a three-component reaction

Selective formation of 2H-2-imidazolines and 2-substituted oxazoles by using a multicomponent reaction of amines, either aldehydes or ketones, and alpha-acidic isocyano amides or esters is described. By selecting the appropriate solvent, Ag(I) or Cu(I) catalyst, or by employing a weak Brønsted acid, the product formation can be fully controlled and directed quantitatively to the desired heterocyclic scaffold. The described experimental procedures not only significantly increase the scope of compatible inputs for this complexity-generating three-component reaction, but also allow for considerable chemical diversity: At least four diversity points in two distinct scaffolds can be exploited in this way.

Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists.

Hit optimization of the class of quinazoline containing histamine H(4) receptor (H(4)R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H(4)R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H(4)R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H(4)R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H(4)R affinity and behave as inverse agonists at the human H(4)R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pK(i) = 8.31 +/- 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.

Asymmetric synthesis of synthetic alkaloids by a tandem biocatalysis/Ugi/Pictet-Spengler-type cyclization sequence

We have combined the biocatalytic desymmetrization of 3,4-cis-substituted meso-pyrrolidines with an Ugi-type multicomponent reaction followed in situ by a Pictet-Spengler-type cyclization reaction sequence for the rapid asymmetric synthesis of alkaloid-like polycyclic compounds.

Metabolic Regio- and Stereoselectivity of Cytochrome P450 2D6 towards 3,4-Methylenedioxy-N-alkylamphetamines: in Silico Predictions and Experimental Validation

A series of 3,4-methylenedioxy-N-alkylamphetamines (MDAAs) were automatically docked and subjected to molecular dynamics (MD) simulations in a cytochrome P450 2D6 (CYP2D6) protein model. The predicted substrate binding orientations, sites of oxidation, and relative reactivities were compared to the experimental data of wild-type and Phe120Ala mutant CYP2D6. Automated docking results were not sufficient to accurately rationalize experimental binding orientations of 3,4-methylenedioxy-N-methylamphetamine (MDMA) in the two enzymes as measured with spin lattice relaxation NMR. Nevertheless, the docking results could be used as starting structures for MD simulations. Predicted binding orientations of MDMA and sites of oxidation of the MDAAs derived from MD simulations matched well with the experimental data. It appeared the experimental results were best described in MD simulations considering the nitrogen atoms of the MDAAs in neutral form. Differences in regioselectivity and stereoselectivity in the oxidative metabolism of the MDAAs by the Phe120Ala mutant CYP2D6 were correctly predicted, and the effects of the Phe120Ala mutation could be rationalized as well.

Synthesis of Conformationally Constrained Peptidomimetics using Multicomponent Reactions

A novel modular synthetic approach toward constrained peptidomimetics is reported. The approach involves a highly efficient three-step sequence including two multicomponent reactions, thus allowing unprecedented diversification of both the peptide moieties and the turn-inducing scaffold. The turn-inducing properties of the dihydropyridone scaffold were evaluated by molecular modeling, X-ray crystallography, and NMR studies of a resulting peptidomimetic. Although modeling studies point toward a type IV beta-turn-like structure, the X-ray crystal structure and NMR studies indicate an open turn structure.

A novel four-component reaction for the synthesis of functionalised dihydropyrimidinesElectronic supplementary information (ESI) available: 1H and 13C NMR data for 9 and 10. See http://www.rsc.org/suppdata/cc/b3/b308243a

In a multi-component reaction (MCR) of a phosphonate, nitriles, aldehydes and isocyanates, N3-functionalised dihydropyrimidines can be synthesised efficiently via a Horner-Emmons/aza Diels-Alder pathway.