Heterocyclic scaffolds

The use of microwave-assisted multicomponent cycloaddition reactions allows unique heterocyclic scaffolds to be assembled rapidly from readily accessible starting materials. The three-component reaction of M-alkyl-l,4-DHP... 

Bicyclic 2-pyridones fused over the nitrogen is another important heterocyclic scaffold. In the quest towards the total synthesis of Camptothecin, Danishefsky and co-workers developed a method where a vinylogous urethane was reacted with 1,3-dicarboxymethoxyallene generated in situ from dimethyl 3-chloroglutaconate to a bicyclic 2-pyridone intermediate [31-34]. This method has later been successfully applied in the synthesis of other... 

The heterocyclic scaffolds are prepared from pyroglutamic acid [154, 155]. 1-aminoalkyl boronic acid pinanediol esters are readily available through a diastereoselective homologation with dichloromethyllithium, providing (5)-a-chloroboronic esters. Aminolysis of the chloride yielded... 

Zhu and coworkers have also discovered an interesting switch in the synthesis of different heterocyclic scaffolds from the same starting material, simply by changing the metal [161]. 

Recent literature examples involve the use of the Suzuki protocol for the highspeed decoration of various heterocyclic scaffolds of pharmacological or biological interest, including pyrimidines [45], pyridazines [46], pyrazines [47], chromanes [48], and pyrazoles [49] (Scheme 6.19). 

A variety of related microwave-promoted N-alkylations involving more elaborate heterocyclic scaffolds are summarized in Scheme 6.116 [230-234]. Additional examples concerning the synthesis of ionic liquids can be found in Section 4.3.3.2. 

In more recent work by other researchers, sealed-vessel microwave technology has been utilized to access valuable medicinally relevant heterocyclic scaffolds or intermediates (Scheme 6.120) [240-245]. Additional examples not shown in Scheme 6.120 can be found in the most recent literature (see also Scheme 6.20) [246-249]. Examples of nucleophilic aromatic substitutions in the preparation of chiral ligands for transition metal-catalyzed transformations are displayed in Scheme 6.121 [106,108]. 

Heterocyclic scaffolds form the cores of many pharmaceutically relevant substances. Not surprisingly, therefore, many publications in the area of microwave-assisted organic synthesis, both from academia and industry, deal with the preparation of heterocycles [5], In this final section of this chapter, the description of heterocycle synthesis is structured according to ring-size and the number of heteroatoms in the ring. 

The best results in the imidazole synthesis were obtained by microwave-assisted reaction of an eightfold excess of the polymer-supported isonitrile suspended in 1,2-dimethoxyethane (DME) with the appropriate amines. Cleavage with 50% trifluoroacetic acid in dichloromethane afforded the desired heterocyclic scaffolds in moderate yields. 

Some important vitamins, 16—20, are constructed on an aromatic heterocyclic scaffold (Scheme 7). 

Xing XL, Wu JL, Peng GP, Dai WM (2006) Microwave-assisted one-pot U-4CR and intramolecular O-aUcylation toward heterocyclic scaffolds. Tetrahedron 62 6774—6781... 

Gracias V, Moore JD, Djuric SW (2004) Sequential Ugi/Heck cyclization strategies for the facile construction of highly functionalized N-heterocyclic scaffolds. Tetrahedron Lett 45 417 20... 

The structural diversity (and complexity) of the products obtained by the MCR between tertiary isocyano amides, aldehydes, and amines could be increased to various heterocyclic scaffolds by combining the initial 2,4,5-tiisubstituted oxazole MCR with in situ intramolecular tandem processes (Fig. 17). Most tandem processes reported are based on the reactivity of the oxazole ring toward C=C or C=C bonds in hetero Diels-Alder reactions followed by ring opening reactions generating the rather complex heterocyclic products with high degrees of variation. 

A vast array of piperidine containing cores, both natural and synthetic, are of biological and medicinal interest. These heterocyclic scaffolds have been the subjects of considerable synthetic efforts, especially for the construction of optically active compounds. In this context, Khan et al. reported a catalytic bromodi-methylsulfonium bromide (BDMS) three-component reaction of 1,3-dicarbonyls with aromatic aldehydes and aromatic amines for a facile access to highly functionalized piperidines (Scheme 24) [104]. This strategy is an interesting illustration of... 

Sulfahydantoins 87 and 88 are analogues of hydantoins and provide heterocyclic scaffolds with a great potential for the construction of bioactive compounds. A total of 28 derivatives, with crude purity generally higher than 85%, were prepared by parallel synthesis using an oxime resin as a solid support (Scheme 46) . The results constitute the first report of successful Mitsunobu reactions and reductive alkylations on the oxime resin. 

Various N-alkylated derivatives of amino acids are natural products [e.g., H-D-(Me)Tyr-OH (D-surinamine) and H-(Me)Trp-OH (abrin) were found in cabbage tree bark1691] and many of them are used as enzyme inhibitors, receptor agonists and antagonists, building blocks for heterocyclic scaffolds in combinatorial chemistry, etc. In this section the preparation of N-alkyl amino acids in solution for their use in peptide synthesis is described. This implies that the synthetic procedures described in this section will ultimately result in V-alkyl amino acids appropriately protected for peptide synthesis. 

Derivatization Reactions of Heterocyclic Scaffolds on Solid Phase Tools for the Synthesis of Drug-Like Molecule Libraries... 

Here we illustrate selected examples of common derivatization reactions on heterocycles grafted on the solid phase. The aim is to provide a sense of the relevant factors and experimental conditions that allow application of known chemical reactions on solid supported heterocyclic substrates for the preparation of novel compounds. In industry, it is not uncommon to seek and secure novelty in a whole chemical class rather than in single derivatives. A direct route to broad coverage aims at the development of a novel heterocyclic scaffold, which in turn is derivatized with standard reactions in order to create a thematic library. The novel scaffold material may be prepared in bulk, typically in solution. Subsequently it is loaded onto a solid support, which is then appropriately portioned for multiple derivatizations in parallel. The latter may involve common reactions, but the resulting products are novel. 

Examples of such reactions, ordinary in nature, but powerful when applied to innovative heterocyclic scaffolds, will be discussed. Attention is focused on specific steps of interest, which stand out as representatives... 

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