Ugi multicomponent reactions

R = alkyl, aryl R = H, alkyl R = alkyl, aryl R = alkyl, aryl R = alkyl, aryl solvent MeOH, EtOH, CF3CH2OH, DMF, CHCI3, 

The potential application of the Ugi four-component reaction for amino acid and polypeptide natural product synthesis was recognized and utilized early on by M.M. Joullie. A representative example is the total synthesis of (+)-furanomycin, a naturally occurring antibiotic. As the exact stereochemistry of the compound was not confirmed, total synthesis of the natural product and its stereoisomers was used to elucidate the stereochemistry. 

Ecteinascidin 743 is an extremely potent antitumor agent isolated from a marine tunicate. The total synthesis of this natural product was realized in the laboratory of T. Fukuyama. To achieve the synthesis of the key dipeptide fragment, they utilized the Ugi four-component reaction. The transformation was carried out under mild conditions providing the product with excellent yield. 

ULLMANN BIARYL ETHER AND BIARYL AMINE SYNTHESIS / CONDENSATION 

Biaryl ether and amine synthesis (Ullmann 1903 Goldberg 1906)  

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Ugi, I. (1998) MCR. XXIII. The Highly Variable Multidisciplinary Preparative and Theoretical PossibUities of the Ugi Multicomponent Reactions in the Past, Now, and in the Future. Proceedings of the Estonian Academy of Science Chemistry, 47, 107-127. 

In this context it must be mentioned that the procedure by Kennedy and coworkers, in which a novel resin-bound isonitrile is applied in an Ugi multicomponent reaction for the synthesis of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones, was discussed earlier, in Chapter 9. 

B. Westermann and S. Domer, Synthesis of multivalent aminoglycoside mimics via the Ugi multicomponent reaction, Chem. Commun. (2005) 2116-2118. 

The four component Ugi reaction is a condensation between a carboxylic acid, a ketone or an aldehyde, an amine and an isonitrile. Basically each of the reaction components can be attached to the resin. The Ugi reaction is employed for the synthesis of small molecule combinatorial libraries on solid supports. Recently a novel resin bound isonitrile has been used in the Ugi multicomponent reaction for synthesizing diversity libraries of diketopiperazines and benzodiazepindiones (Scheme 3.25) [285]. 

Scheme 3.25 Ugi multicomponent reaction to form intermediates (179) for the synthesis of benzodiazepinediones [285].

Banfi L, Basso A, Guanti G, Kielland N, Repetto C, Riva R (2007) Ugi multicomponent reaction followed by an intramolecular nucleophilic substitution convergent multicomponent synthesis of 1 -sulfonyl 1,4-diazepan-5-ones and of their benzo-fused derivatives. J Org Chem 72 2151-2160... 

Pyranoisoxazoles 425 have been prepared by intramolecular 1,3-dipolar cycloaddition of nitrile oxides obtained by treatment of nitrooxaheptynes with -BuLi and AC2O (Scheme 102) <2003H(59)685>. The coupling of the Ugi multicomponent reaction with the intramolecular T-oxide cyclization (Ugi/INOC) provided access to novel fused isoxazoles 426 in two steps from easily available starting materials in moderate to good overall yields... 

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. K. MCR.XXIII. The highly variable multidisciplinary preparative and theoretical possibilities of the Ugi multicomponent reactions in the past, now, and in the future. Proc. Est. Acad. ofSci. Chem. 1998, 47, 107-127. 

Different novel resin-bound isonitriles have been prepared in order to perform Ugi multicomponent reactions on the solid phase. Thus, Kennedy et al. [346] prepared a novel resin-bound carbonate convertible isonitrile (CCI) that was applied in the preparation of constrained 2,5-diketopiperazine and l,4-benzodiazepine-2,5-dione libraries in parallel 80-well format The first step of the synthetic strategy was a Ugi reaction with a wide variety of amines, aldehydes, and carboxylic acids. Further manipulations of the Ugi MCR products were achieved after basic cleavage from the resin. 

More recently, a novel resin-bound isonitrile has been reported to be suitable for synthesizing libraries of l,4-benzodiazepine-2,5-diones through Ugi multicomponent reactions [25]. The method produces solid-supported Ugi products, which are cleaved by base activation to form N-acyloxazolidone intermediates that can be further elaborated. The flexibility of the approach was demonstrated by an analogous preparation of 2,5-diketopiperazines by simply replacing the 2-aminobenzoyl building blocks with a-amino acids. 

Scheme 7.12 Chemical modification of alginate through Ugi multicomponents reaction...

Garcia, A., Hernandez, K., Chico, B., Garcia, D., Villalonga, M.L., Villalonga, R. Preparation of thermostable trypsin-polysaccharide neoglycoenzymes trough Ugi multicomponent reaction. J. Mol. Catal. B Enzym. 59,126-130 (2009)... 

Scheme 14.22 Kobayashi s formal synthesis of omuralide (147) using a Ugi multicomponent reaction (TFE, trifluoroethanol).

SCHEME 6.5 Synthesis of key fragment 60 in the total synthesis of ecteinascidin 743 48, using the Ugi multicomponent reaction. 

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