Polycyclic multicomponent reactions

Scheme 2.97. Multicomponent reaction leading to polycyclic N,N-, N.O- and A/.S-aminals 2-409.

The domino [4 + 2]/[3 - - 2] cycloaddition of an enol ether, a nitroalkene and a third alkene is a representative example of a multicomponent reaction in which a polycyclic N-containing system is formed in a single transformation [10, 11]. In this domino reaction, a nitroalkene reacts as a heterodiene with an electron-rich alkene such as an enol ether, in an inverse electron-demand Diels-Alder reaction, to form a cyclic nitronate, which then reacts with another alkene in a 1,3-dipolar cycloaddition to produce a nitroso acetal (Scheme 9.4). 

Another approach is the use of multicomponent reactions (MCRs) to rapidly and efficiently construct structurally complex and varied polycyclic natural product-like compounds (Figure 1.5). A number of synthetic transformations played a key role in the rapid assembly of such molecules including isocyanide-based reactions, aza- and non-aza [4+2] cycloadditions, [3+2] cycloadditions, and dansition-metal-catalyzed reactions. Using isocyanide-based MCRs, pyrrolopyridines exemplified by mappicine represent an atttactive library target for their biological activity. Furthermore, the furoquinoline alkaloid tecleabine represents a common quinoline alkaloid core similar to strnctnres fonnd in a polycyclic library. ... 

Ulaczyk-Lesanko, A. and Hall, D.G., Wanted new multicomponent reactions for generating libraries of polycyclic natural products, Curr. Opin. Chem. Biol, 9, 266, 2005. 

SCHEME 6.38 Isocyanide-based multicomponent reaction to build polycyclic spiroindobnes 253 and natural products tabersonine and akuammicine. 

Wanted new multicomponent reactions for generating libraries of polycyclic natural products. 

X. Wang, S.-Y. Wang, S.-J. Ji, Org. Lett. 2013,15,1954-1957. Isocyanide-hased multicomponent reactions catalyst-free stereoselective construction of polycyclic spiroindolines. 

Keywords Indoles, aromatic amines, oxetanyl aldehydes, asymmetric catalyst A, diethyl ether, room temperature, asymmetric multicomponent reaction, aza-Diels-Alder reaction, indole-alkaloid-type polycycles, diastereoseltivity... 

Guchhait and Madaan (2010) reported a novel microwave-assisted one-pot novel tandem de-tert-butylation of tert-butyl amine in an Ugi-type multicomponent reaction product. Tert-butyl isocyanide has been explored as a useful convertible isonitrile for the first time affording access to molecular diversity of pharmaceutically important polycyclic N-fused imidazo-heterocycles. 

El Kaim and coworkers introduced a new variation for the formation of polycyclic DKPs via Ugi/Pictet-Spengler multicomponent combination [35]. The reaction of homoveratryl isocyanide with different aldehydes, amines, and a-keto acids leads to the expected Ugi-adducts, which are not isolated. Addition of trifluoroacetic acid promotes a cyclodehydratation affording the tricyclic DKPs (Scheme 2). 

Simon C, Peyronel JF, Rodriguez J (2001) A new multicomponent domino reaction of 1,3-dicarbonyl compounds One-pot access to polycyclic N/0-, N/S-, andN/N-aminals. Org Lett 3 2145-2148... 

Lieby-Muller E, Simon C, Imhof K, Constantieux T, Rodriguez J (2006) A multicomponent domino reaction and in situ aerobic oxidation sequence for the first one-pot synthesis of polycyclic benzimidazoles from 1,3-dicarbonyl derivatives. Synlett 1671-1674... 

As seen in the preceding sections, many multicomponent procedures are based on the production of conjugated dienes that are in situ involved in Diels-Alder reactions to obtain polycyclic compounds. In recent years, intramolecular enyne metathesis has become a very popular method by which to access cyclic conjugated dienes [172]. In line with this, Lee [173] has developed a new three-component re-... 

Bartlett proposed some early guidelines for library synthesis (a) The sequence should involve a small number of steps, (b) no more than one variable should be introduced in any step, (c) starting materials should be readily obtained with a diverse selection of substituents, and (d) cyclic, nonoligomeric structures represent the most interesting targets [18]. Furthermore, Armstrong did some early work toward libraries composed of multiple scaffolds, derived from common synthetic intermediates [19, 20]. In one case, Ugi multicomponent coupling reaction products were converted to various linear and cyclic derivatives (Fig. 9.1-4(a)). In another, squaric acid was proposed as a precursor that could be converted to multiple cyclic and polycyclic products (Fig. 9.1-4(b)) and several such transformations were demonstrated. 

In this chapter, the intermolecular multicomponent aromatic ring construction reactions and intramolecular single-component aromatic ring construction reactions are described. Among them, the [2+2+2] cycloaddition and intramolecular hydroarylation reactions are the most widely employed and reliable method. Various polycyclic and sterically hindered aromatic compounds have been synthesized by this method. In the past 10 years, the asymmetric [2+2+2] cycloaddition and intramolecular hydroarylation reactions have been developed, which enabled the enantioselec-tive synthesis of sterically hindered chiral aromatic compounds, such as axially chiral biaryls, planar chiral cyclophanes, and helically chiral heUcenes. Details of the transition metal-mediated aromatic ring construction reactions are comprehensively covered in the recently published book... 

Z. Chen, B. Wang, Z. Wang, G. Zhu, J. Sun, Angew. Chem. Int. Ed. 2013, 52, 2027-2031. Complex bioactive alkaloid-type polycycles through efficient catalytic asymmetric multicomponent aza-Diels-Alder reaction of indoles with oxetane as directing group. 

A novel three-component coupling reaction for the synthesis of 2-(aminomethyl) indoles and polycyclic indole derivatives from readily available N-protected ethynylanilines, amines, and aldehydes was reported by Ohno, Fujii, and coworkers. This is the first copper catalytic multicomponent construction of an indole ring that produces water as the only by-product. Two C-N bonds and one C-C bond are formed, whereas C(sp)-H bonds of alkynes and C(sp )-H bonds of aldehydes were activated in this reaction [45-48] (Scheme 8.19). 

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