MCRs, cyclization

Cyclic Peptides and Their Mimetics from MCR/Cyclization Strategies. 202... 

Dipolar cycloadditions are among the most efficient and amenable transformations to produce macrocycles via MCR/cyclization strategies. The functionalities... 

Generally, MCRs based on aminoazoles and synthetic precursors of a,p-unsaturated carbonyl compounds proceed via a sequence of Knoevenagel-type condensation, which was already mentioned (see Scheme 3), Michael-like addition, cyclization, and water elimination. For example, the authors of [47] considered the following mechanism (Scheme 9). 

However, in MCRs based on pyruvic acids no formation of a,(3-unsaturated carbonyl compounds was observed. Instead of Knoeveganel condensation, the first step of the process was the formation of the corresponding azolmethine 34, which when treated with enole form of pyruvic acid gave adduct 35. The final stage was cyclization into compounds 29 or 32 [51, 53] (Scheme 14). 

The mechanism of these MCRs, according to [70], should include formation of unsaturated nitrile, its treatment with aminopyrazole and cyclization following with water elimination and, sometimes, oxidation (Scheme 17). 

The key step of this MCR according to the opinion of the authors is an interaction of bromacetic ester with aminoazole via ring nitrogen atom to the 3-carboxymethyl-2-iminothiazoline 105, also isolated as a product in the steps-sequence reaction (Scheme 49). Further cyclization of 105 leads to the formation of thiazolo[3,2-a] imidazol-6-one 106, which then reacts with aldehyde affording the desired ylidene in moderate-to-good yields. 

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). 

This procedure can be used to synthesize the key intermediate 34 of Merck s HIV protease inhibitor Crixivan 35 (Fig. 5) [25]. This reaction is done using dichloroacetaldehyde 26 instead of chloroacetaldehyde, forming the classical Ugi product 30. This intermediate is then treated with triethylamine to obtain the corresponding vinylchloride 31. Cyclization with KO Bu followed by stereoselective hydrogenation using the chiral catalyst Rh-BINAP afforded the Crixivan intermediate 34. (Scheme 5) The classical way to make this intermediate requires five steps, and thus makes the MCR route more attractive [25]. 

Combination of MCR with the Pictet-Spengler cyclization also leads to different types of scaffolds with ketopiperazine fused ring systems. Tetrahydro-jS-carboline scaffold 221 was prepared in a convergent, two-step procedure [67]. An array of indole derivatives was prepared by the reaction of tryptophan derivative 222, aldehyde 223, carboxylic acid 224, and bifunctional amine 214 (Scheme 40). 

The combination of pept(o)id-introducing MCRs with subsequent and efficient post-condensation transformations, especially ring-closing protocols, is an efficient concept to produce (cyclic) pseudopeptides. The most important versions make use of protected or convertible functional building blocks to allow later condensation, specially cycfization. Most relevant are Ugi-deprotection-cyclization (UDC), Ugi-activation-cyclization (UAC), and the Ugi-deprotection-activation-cycfization (UDAC), which take advantage of the diverse functionalities incorporated into the previously synthesized MCR-adduct as bi- or polyfunctional building block (Fig. 3) [15, 16]. 

Fig. 3 The three most common modes to activate linear Ugi-products for cyclization, especially if the cyclization involves Ugi-reactive groups (e.g., acid, oxo-compound, or amine). Activation is mostly achieved with convertible isonitriles, i.e., activated amides (see text). Other MCRs follow similar concepts. With orthogonal second functionalities for cyclizations such deprotection and/or activation is not required (see below, e.g., RCM or cycloadditions)...

One of the pioneer works in the synthesis of DKPs through MCRs was reported by Hulme and coworkers in a three-step solution phase protocol based on UDC [33, 34]. They have obtained a series of different DKPs by reacting Armstrong s convertible isocyanide with aldehydes, M-Boc-protected amino acids as bifunctional acid component containing a protected internal amino nucleophile, and amines in methanol at room temperature. After Ugi-reaction, the isonitrile-derived amide is activated with acid (UAC) and allows cyclization to the DKP with the... 

Andreana and Santra have investigated the influence of the solvent on the generation of molecular diversity arising from a set of MCR substrates under microwave irradiation [36]. They have found that by using water as solvent, both 2,5-DKPs and 2-azaspiro[4.5]deca-6,9-diene-3,8-diones were obtained through aza-Michael reaction and 5-exo Michael cyclization, respectively. Nevertheless,... 

There are only a few records of macrocycle synthesis where the linear precursor was cyclized by a MCR. The first one to observe an MCR-macrocyclization by coincidence were Failli et al. who tried to couple oligoglycines [92]. 

Cyclization of imidoyl azides 150 into 1,5-disubstituted tetrazoles 5 (Equation 10) is widely used both in the laboratory and on an industrial scale. Imidoyl azides form in situ in the course of various multistage processes, and sometimes in the multicomponent reactions (MCRs). The problems related to generation of imidoyl azides and also to electrocyclization of these intermediates into 1-mono- and 1,5-disubstituted tetrazoles are of crucial importance for the tetrazole chemistry. These problems are traditionally treated at length in basic reviews <1984CHEC(4)791, 1996CHEC-II(5)621>. The traditional methods for the synthesis and cyclization of imidoyl azides into tetrazoles were broadly employed and further refined in more recent works <1997MI1375>. Several new methods based on this approach have also been developed. 

An example of another MCR affording tetrazoles has been described <2005TL7393>. In an extension of the method developed in 1961 by Ugi, Mayer et al. introduced into the reaction four components simultaneously aldehyde (ketone), amine, trimethylsilyl azide, and ethyl 3-isocyano-3-phenylpropionate. 1,5-Disubstituted tetrazoles 515 formed in 37-89% yields via cyclization of the imidoyl azides 514 (Scheme 69 Table 28) <2005TL7393>. 

Polysubstituted 1,3-oxazolidines were prepared in a one-pot diversity oriented four-component reaction (4-MCR), comprising two linked domino processes. Thus, domino synthesis of enol ethers 9 was followed by a sequential amine addition-cyclization sequence [74]. While strong microwave irradiation (900 W) of silica-gel absorbed conjugated alkynoates 9 and amines afforded tetrasubstituted pyrroles (via the skeletal rearrangement of 1,3-oxazolidines, see Sect. 2.1 and Scheme 5) [24], the use of milder microwave conditions (160 W power, 90 min) furnished 1,3-oxazolidines. Under these mild conditions the 1,3-oxazolidines did not rearrange to pyrroles and with respect to diastereoselectivity, the 1,3-oxazolidines were obtained as mixtures of syn/anti isomers. Overall, the formation of one C-C bond, one C-0 bond, two C - N bonds and a ring in this MCR required less than 3 hours and utilized simple and commercially available reagents (Scheme 26). 

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