Isocyanides combinatorial libraries

Peptide mimetics containing the a-ketoamide moiety are very important because they act as cysteine protease inhibitors. In fact, the a-ketoamide residue forms hemithioacetals with the -SH group of the cysteine residue of the enzyme [32], Nakamura et al. [26b] reported the preparation of a 100-member combinatorial library of a-ketoamides by means of a two-step one-pot synthesis. The first step consisted of the Ugi-4CR between (+/— )lactic acid, amines, isocyanides, and aldehydes leading to the formation of the lactamides 40 which were oxidized to the corresponding pyruvamides 41. This one-pot procedure was performed in THF since the PDC oxidation was incompatible with the presence of methanol. Five a-ketoamides showed an 80% average purity (Scheme 2.17). 

A four-component (aldehyde, amine, isocyanide, and a carboxyl group) condensation resnlting in an a-aminoacyl amide. See Lin, X.C., Clark, D.S., and Dordick, J.S., Chemoenzymatic constrnction of a four-component Ugi combinatorial library, Biotechnol. Bioeng. 69, 457 60, 2000 Bayer, T.,... 

This reaction was first reported by Hofmann in 1868. It is the synthesis of isonitriles (also known as isocyanides) from primary amines and chloroform in the presence of alkali and is known as the Hofmann isonitrile synthesis, Hofmann carbylamine reaction, or Hofmann carbylamine synthesis. This reaction has been used to test the presence of primary amines from the order of isocyanides. Alternatively, the isonitriles can be prepared by means of the treatment of formamide of primary amines with toluenesulfonyl chloride" or phosphorus oxychloride (POCls)." Currently, the isonitriles have gained much attention in organic synthesis because of their application as versatile building blocks for heterocycles and in multicomponent reactions to generate combinatorial libraries, such as that in the Passerini reaction and Ugi reaction ... 

The isopropyl isocyanide (II) was conserved for the entire combinatorial library (reproduced from (17) with permission from Elsevier)... 

Also in this case, Curran and coworkers produced a library of 64 mappicine analogues by automated solution-phase combinatorial synthesis, as well as a 48-mem-ber library of mappicine ketone derivatives [88]. Furthermore, these authors were successful in building up a 115-member library of rac-homosilatecans 3-216 using different iodopyridones 3-214 and aryl isocyanides as substrates 3-215 (Scheme 3.56) [89]. 

In combinatorial chemistry, the development of multicomponent reactions leading to product formation is an attractive strategy because relatively complex molecules can be assembled with fewer steps and in shorter periods. For example, the Ugi multicomponent reaction involving the combination of an isocyanide, an aldehyde, an amine, and a carboxylic acid results in the synthesis of a-acyl amino amide derivatives [32]. The scope of this reaction has been explored in solid-phase synthesis and it allows the generation of a large number of compounds with relative ease. This reaction has been employed in the synthesis of a library of C-glycoside conjugated amino amides [33]. Scheme 14.14 shows that, on reaction with carboxylic acids 38, isocyanides 39, and Rink amide resin derivatized with different amino acids 40, the C-fucose aldehyde 37 results in the library synthesis of C-linked fucosyl amino acids 41 as potential mimics of sialyl Lewis. ... 

Ugi, I., Domiing, A. Multi-component reactions (MCRs) of isocyanides and their chemical libraries. Combinatorial Chemistry 2000, 287-302. 

The two early types of MCRs remained separate entities for a whole century [7,8], but in January 1959 [11] they were combined [12] and became the U-4CR (U = Ugi) [2-4,8]. This soon also included the libraries of combinatorial chemistry [8,13a]. The educts and products of the U-4CR and its unions with other chemical reactions are by many orders of magnitude more variable than those of any other chemical reactions, and even of the entire spectrum of other MCRs. Under suitable reaction conditions, the U-4CR may produce almost quantitative yields of pure product, and with minimal preparative work [4,8,10]. Nevertheless, this profound preparative progress was of no general chemical interest until early 1995 [2-5,14], when almost overnight the one-pot MCR chemistry of the isocyanides and their libraries became one of the most intensely used areas of industrial chemical research. The technique is used not only to find new chemical products, but also to produce them far more conveniently and in higher yields than might other multistep syntheses. 

The industrial quest for new, desirable chemical products is now accomplished by the combinatorial chemistry of the MCRs and their libraries, including those of the isocyanides [20-22]. The reactions of the isocyanides proceed especially well, as all correspond to irreversible transitions of divalent carbon atoms, C", into their CIV atoms. If no byproducts are formed by some competing reactions, then quantitative yields of MCR products are formed. 

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