Ugi Four-Component Reactions

It is clear from the Hst of reactants presented above that the bottleneck for potential combinatorial expansions of this reaction arises from the limited commercial availabihty of isonitriles, along with the intrinsic difficulty in handling these chemicals because of their toxicity and malodor. These are the reasons why the great majority of Ugi MCRs on the soHd phase were performed by anchoring the isonitrile component on the resin. 

Compound 75 ((R)-l-ferrocenyl-2-methyl-propanamine) is a powerful chiral auxiliary R -NH2. 

3 Ruthenium-mediated Coupiing of Aryi Ethers Ibr the Synthesis of Cyciic Peptides 

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In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

The application of the one-pot Ugi four-component reaction by stirring a mixture of the aldehyde 486, benzyl amine 487, isocyanide 479, and acrylic acid 385 in methanol at room temperature for 36 h afforded the triene 488 as a 74 26 mixture of amine rotational isomers in 80% combined yield. The triene 488 on heating in DMSO at 120 °C for 12 h underwent cycloaddition to give the tricyclic compound 489 as a single diastereomer in 98% yield (Scheme 111). 

An elegant two-step solution-phase methodology was developed for the synthesis of the benzodiazepine-2,5-diones (93 e.g. R1 = PhCH R2 = Me, R3 = Me, R4 = H, R5 = Me, 32%). The first step was a Ugi four-component reaction followed in the second step by a palladium-mediated intramolecular IV-arylation reaction. This methodology has considerable scope for further application in heterocyclic synthesis <06TL3423>. 

Y. Li, X. Zhang, S. Chu, K. Yu, and H. Guan, Synthesis of cluster mannosides via a Ugi four-component reaction and their inhibition against the binding of yeast mannan to concanavalin A, Carbohydr. Res., 339 (2004) 873-879. 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

Perhaps the most useful and most widely employed multicomponent reaction in this context is the Ugi four-component reaction (U4CR and variations, Fig. 11), where an isonitrile, an aldehyde, an amine, and a carboxylic acid react to form a single product [65, 66]. The principal product is a dipeptide or dipeptide derivative and a high degree of diversity can be introduced by substituents (each of the four components can be varied), subsequent reactions, or by other reaction paths, which can lead to a vast varia-... 

Lindhorst T, Bock H, Ugi I (1999) A new class of convertible isocyanides in the Ugi four-component reaction. Tetrahedron 55 7411-7420... 

Bonnaterre F, Bois-Choussy M, Zhu JP (2006) Rapid access to oxindoles by the combined use of an Ugi four-component reaction and a microwave-assisted intramolecular Buchwald-Hartwig amidation reaction. Org Lett 8 4351-4354... 

Wu JL, Jiang Y, Dai WM (2009) Assembly of l,3-dihydro-2H-3-henzazepin-2-one conjugates via Ugi four-component reaction and palladium-catalyzed hydroamidation. Synlett 1162-1166... 

Dai WM, Shi JY, Wu JL (2008) Synthesis of 3-arylideneindolin-2-ones from 2-aminophe-nols by Ugi four-component reaction and Heck carbocyclization. Synlett 2716-2720... 

Faggi et al. describes the synthesis of a 1,6-dihydro-6-oxopyrazine-2-carboxylic acid derivative via the Ugi four-component reaction (Scheme 8) [28]. Arylglyoxals 44, an amine 45, benzoylformic acid 46, and an isocyanide 47 afforded the Ugi intermediate 48, which was cyclized in a [5+1] fashion with ammonium acetate to give the final product 49 in good yields. 

Scheme 8 Synthesis of a l,6-dihydro-6-oxopyrazine-2-carboxylic acid derivatives via the Ugi four-component reaction and two representative 3D conformation of 49A (cyan) and 49B (blue). Yield shown represents yield over all steps...

A library of fused tetrazole-ketopiperazines 187 was obtained by Nixey et al. via Ugi four-component reaction in the solution phase [56]. The reaction of an oxo component 188, primary amine 189, methyl isocyanoacetate 190, and trimethylsi-lylazide 181 in methanol at reflux affords bicyclic tetrazole-ketopiperazines 187 in good yield (Scheme 33). The cyclization to afford the tetrazole-ketopiperazines is performed spontaneously under the reaction conditions. 

Benzopiperazinones 200 were prepared by Erb et al. via the Ugi four-component reaction followed by palladium-catalyzed intramolecular Al-arylation [61]. XPhos was used as a supporting ligand to afford the 3,4-dihydroquinoxalin-3-ones 200 (Scheme 36). Microwave irradiation was found to be determinant on the reaction efficiency. 

Lin Q, Blackwell HE (2006) Rapid synthesis of iketopiperazine macroarrays via Ugi four-component reactions on planar solid supports. Chem Commun (27) 2884-2886... 

Dyker et al. reported an effective combination of an Ugi four-component reaction and gold catalysis to build highly functionalized isoindoles and dihydroisoquinolines with relatively good stereoselectivity [116] (Scheme 8.21). 

In 1998, three different research groups discovered a novel multi-component reaction almost simultaneously40. They found (partly by serendipity ) that when using 2-aminopyridines as the amine component in the Ugi four-component reaction (4CR), the formation of imidazo-pyridines was observed. The imidazo-pyridine is the product... 

Fig. 10.1. Using the systematic variation of 10 starting materials, the Ugi four-component reaction product was re-discovered .

The earliest reports of constrained Ugi adducts derived from bi-functional precursors appeared in the 1960s with the preparation of penicillin derivatives such as 68, involving sequential Asinger and Ugi four-component reactions (Scheme 11.13). As such, the synthesis represents the shortest preparation of a known penicillin derivative [65], The /Mactam ring is formed after isocyanide addition to the cyclic Schiff base, followed by carboxylate nitrilium ion trapping and acyl transfer to give the final penicillin core. In this example, the amine and carboxylic acid inputs may be considered tethered. 

The Ugi four-component reaction (4CR) stands as a powerful method for the... 

The potent amino acid antibiotic furanomycin 236 (Scheme 12.34), isolated from Streptomyces threomyceticus [121], was synthesized by Joullie and co-workers using an Ugi four-component reaction as key step [122]. 

The Ugi four-component reaction can frequently offer an interesting alternative to the difficult coupling between secondary amines and carboxylic acids when using traditional methods for amide bond formation. Guided by this premise, Armstrong and co-workers efficiently synthesized the N-methylated dipeptide 245 en route to motuporin 241 (Scheme 12.35) [124], an inhibitor of protein phosphatases [125]. 

A few other biologically interesting and naturally occurring peptides and amino acids of rather simple structure were synthesized using the Ugi four-component reaction (Figure 12.5) the phosphonic acid antibiotics plumbemycin A 249 and B 250 [126], both epimers of the polychlorinated antihypertensive peptide (+)-demethyldysidenin 251 [127], and the nucleoside antibiotic nikkomycin 252 [128]. 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

This multigeneration strategy for the synthesis of pyrimidines combines efficiently a novel cyclocondensation reaction using the highly reactive acetylenic ketones 153215,218 to build the pyrimidine skeleton, with a multicomponent reaction, and a multidirectional cleavage procedure. The Ugi four component reaction is especially useful in the context of building peptidomimetic-derived combinatorial libraries as it affords directly dipeptide analogues of type 159. 

Keating and Armstrong [17,18] have developed a solution-phase Ugi four-component reaction (Fig. 4) which utilises a universal isocyanide. The a-acylamino amides can be... 

P-unsaturated carbonyl compounds. In a recent example, the products of an Ugi four-component reaction, such as amide 10S, were converted photochemically into uniquely shaped 3-azabicyclo[4.2.0]octan-4-ones, such as cyclobutane 106 (Scheme 6.38) [101]. 

Figure 4. Construction of a library using an Ugi four component reaction...

The Ugi four-component reaction (4CR) produced a-acetamidoamide by simply stirring a methanol solution of an aldehyde, an amine, a carboxylic acid and an isocyanide [57, 58]. The Mumm rearrangement (step 5, Scheme 5), being irreversible, drives the reaction towards the formation of the Ugi adduct in good to excellent yield under extremely mild conditions. 

The Ugi four-component reaction is currently the most investigated MCRs in both target-oriented [95] as well as diversity-oriented S3mthesis of compound libraries (for reviews, see [33-52]). As one of the rare truly and highly versatile... 

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