Cascade Cycloadditions

Alkaloid syntheses by cascade cycloaddition/cyclization reactions of A-acyli-minium ion 98CC1417. 

Recently, Denmark and coworkers have developed a new strategy for the construction of complex molecules using tandem [4+2]/[3+2]cycloaddition of nitroalkenes.149 In the review by Denmark, the definition of tandem reaction is described and tandem cascade cycloadditions, tandem consecutive cycloadditions, and tandem sequential cycloadditions are also defined. The use of nitroalkenes as heterodienes leads to the development of a general, high-yielding, and stereoselective method for the synthesis of cyclic nitronates (see Section 5.2). These dipoles undergo 1,3-dipolar cycloadditions. However, synthetic applications of this process are rare in contrast to the functionally equivalent cycloadditions of nitrile oxides. This is due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8.29, the potential for a tandem process is formulated in the combination of [4+2] cycloaddition of a donor dienophile with [3+2]cycload-... 

Scheme 4.8 Boger s cascade cycloaddition chemistry to access indole alkaloids features dipolar cycloaddition to indole, and not Diels-Alder cycloaddition...

Alkynyl Fischer carbene complexes 64 (R = H) in the presence of a nitrone undergo a cascade cycloaddition/cyclopropanation process to afford 4-isoxazolines such as 65 in good yields. Under the same conditions, substituted complexes 64 (R = Me, Ph) gave naphthalenes 66 through a cycloaddition/metathesis process <07OL4143>. 

Evans, D. A., Starr, J. T. A cascade cycloaddition strategy leading to the total synthesis of (-)-FR182877. Angew. Chem., Int. Ed. Engl. 2002,41, 1787-1790. 

Jui NT, Lee ECY, MacMillan DWC (2010) Enantioselective Organo-SOMO Cascade Cycloadditions A Rapid Approach to Molecular Complexity from Simple Aldehydes and Olefins. J Am Chem Soc 132 10015... 

Faustino, H., Alonso, L, Mascarenas, J. L., Lopez, F. (2013). Gold(I)-catalyzed cascade cycloadditions between allenamides and carbonyl-tethered alkenes an enantioselective approach to oxa-bridged medium-sized carbocycles. Angewandte Chemie International Edition, 52, 6526-6530. 

Jui, N. T., Lee, E. C. Y., MacMillan, D. W. C. (2010). Enantioselective organo-SOMO cascade cycloadditions a rapid approach to molecular complexity from simple aldehydes and olefins. Journal of American Chemical Society, 132,10015-10017. 

Use in Isobenzofuran Synthesis. 1,2,4,5-Tetrazine has also been involved in multiple cascade cycloaddition reactions to generate complex substrates. The reactivity of isobenzofuran was delineated with Cgo (eq 5). Starting from a [4+2] cycloaddition between 19 and 1,2,4,5-tetrazine, intermediate 20 was generated. Next, a retro-[4+2] produced the desired isobenzofuran, which... 

The SOMO [44-2] cascade cycloaddition employs 3-arylpropionaldehydes having electron-rich aromatic rings, such as indoles, anisoles, catechols, benzofurans. 

Scheme 39.14 Mechanistic rationale of the SOMO [4+2] cascade cycloaddition and the reaction scope.

SCHEME 4.15 Formation of paesslerin s skeleton by [4+2]-[2+2] cascade cycloaddition reaction. 

The tandem double intramolecular [4 + 2]/[3 + 2] cycloadditions of 1,3,4-oxadiazoles developed by Boger and coworkers (Scheme 16.1) are also well represented. In this process, a 1,3,4-oxadiazole acts as an electron-poor heterodiene and engages in an inverse-electron-demand [4 + 2] cycloaddition. This step is followed by a retro-[3 + 2] cycloaddition that generates a dipole, reacting further via a [3 + 2] cycloaddition step. This cycloaddition has been used as the key step in the total syntheses of several Vinca alkaloids. Only tandem cascade cycloadditions of this type have been reported. 

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