MCRs isocyanide-based

For this reason, we have included an extra chapter in this book which deals with this topic. Quite recently, an excellent book on multicomponent transformations, as well as many highly informative reviews on the subject [la,b,2] have been published. Therefore, only general aspects and the latest developments will be presented here, especially of isocyanide-based MCRs. 

Banfi L, Basso A, Guanti G, Riva R (2005) Asymmetric isocyanide-based MCRs. In Zhu J, Bienayme H (eds) Multicomponent reactions. Wiley-VCH, Weinheim, pp 1-32... 

A recent literature survey revealed >3,000 piperazine substructure containing compounds accessed by isocyanide-based MCRs. Many of these piperazines are of commercial interest and therefore are described in patents as a primary literature source. Moreover, 430,000 piperazine derivatives are commercially available (according to a substructure search in eMolecules) [1]. Inspecting the general scaffold types in the database of the commercially available piperazine derivatives, it can be speculated that a considerable fraction of them were made by MCR technology. Some examples of piperazine derivatives via isocyanide-based MCRs from patent literature are listed in Table 1. 

Isocyanide-based MCR was also applied for the total synthesis studies of natural products containing piperazine substructure. For example, trabectedin (also known as ecteinascidin 743 or ET-743) is undergoing clinical trials for the treatment of breast, prostate, and pediatric sarcomas. Ecteinascidin 743 (2) is an extremely potent antitumor agent isolated from a marine tunicate, Ecteinascidia turbinate [12]. Eukuyama et al. developed the total synthesis of ecteinascidin 743 from a Ugi reaction [13]. The reaction of p-methoxyphenyl isocyanide 3 gave Ugi product 7, which was cyclized to DKP intermediate 8 (Scheme 1). 

Table 1 Patent examples of isocyanide-based MCRs for the assembly of piperazine scaffolds in medicinal chemistry and their use...

Scheme 3 Synthetic aspects of two conceptually different strategies for the introduction of piperazines via isocyanide based MCRs and two representative 3D conformations of 18A (blue) and 18B (cyan). An intramolecular hydrogen bond in compound 18B was shown in red dots...

DKP as opposed to 2,5-DKPs are rather rarely described by isocyanide-based MCRs. Ugi et al. describes the only 2,6-DKP synthesized by isocyanide MCR [48]. This reaction (Scheme 25) uses the well known five-center-four-component reaction (U-5C-4CR) of an a-amino acid, an aldehyde or ketone, an isocyanide,... 

Scheme 25 The only known synthesis of 2,6-DKPs using isocyanide-based MCR chemistry with two representative 3D conformations of 153A (blue) and 153B (cyan). Yield shown represents yield over all steps...

Piperazines and derivatives are archaetypical scaffolds and can be considered as efficient, however, structurally simple peptidomimics. The scaffolds combine conformational rigidity with peptide-like spacial placement of amino acid side chains or isosteres thereof. Moreover, piperazines can be used to confine compounds with beneficial properties such as water solubihty. Piperazines are therefore in the center of synthetic interest and many different synthetic pathways have been designed [16-19]. A preferred way to synthesize different piperazine scaffolds with plenty of variabihty provides MCR chemistry. Several piperazine scaffolds are currently only accessible by isocyanide-based MCR. Likely they could be assembled by sequential synthesis as well however, the synthetic efficiency, the diversity, and the size of the alternative chemical space will be inferior. The application of... 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

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