Cycloisomerization Reactions in Organic Synthesis

Cycloisomerization is described, the intramolecular reaction of a polyunsaturated substrate for the formation of 

FIGURE 7.6 Cycloisomerization reactions and their biosynthetic correlation with sesquiterpene synthases. 

Transition metal-catalyzed cycloisomerizations have been the subject of particular attention as atom-efficient methods for the construction of carbo- and heterocyclic molecules, which are fundamental constituents of natural products, pharmaceutical compounds, and functional materials. In view of their importance, several studies concerning their metal-catalyzed cyclization mechanisms have been undertaken in a,oo-bifunctional substrates such as dienes, enynes, and diynes. 

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The intramolecular Alder-ene reaction (enyne cydoisomerization reaction) with alkynes as the enophiles has found wide application compared with diene systems. The reason may be the ready chemo-differentiation between alkene and alkyne functionality and the more reactive alkyne moiety. Furthermore, the diene nature of the products will promote further applications such as Diels-Alder reactions in organic synthesis. Over the past two decades the transition metal-catalyzed Alder-ene cycloisomerization of l,n-enynes (typically n= 6, 7) has emerged as a very powerful method for constructing complicated carbo- or heterocydic frameworks. The transition metals for this transformation indude Pd, Pt, Co, Ru, Ni-Cr, and Rh. Lewis acid-promoted cydoisomerization of activated enynes has also been reported [11],... 

Transition-metal-catalyzed intramolecular cycloisomerization is one of the most useful carbocyclization reactions, and specifically, the Rh-catalyzed cycloisomerization of 1,6-enynes provides a powerful tool in organic synthesis. Cyclization of l,6-en5me 452 catalyzed by Wilkinson s catalyst gave 1-exo-methylene-2-cyclohexene 453 via a 6-exo-trig mode in 83% yield (Scheme 2-50). Terminal substitution on the alkene moiety dramatically suppressed the cyclization, and substitution of the terminal alkyne moiety was detrimental to the reaction as well. 

Cycloisomerization of Aiienenes and Alleneynes. Allenes are a special class of compounds that possess cumulated double-bond systems. For a long period of time, the development of the chemistry of allenes was impaired under the false notion that such cumulated double-bond systems are highly unstable (90-92). Unlike the chemistry of alkene and alkyne that have been comprehensively developed, allenes only started to emerge in recent decades as versatile precursors in organic synthesis. The Brummond Laboratory was the first to illustrate that cross-conjugated trienes 83 could be prepared by Rh-catalyzed allenic Alder-ene reaction of allenyne 82 (Scheme 42) (93). 

The catalytic activation of alkynes and alkenes by (CsR5)Ru complexes has been extensively explored during the past decade and can lead to the creation of carbon-carbon bonds, often via the formation of a ruthenacycle intermediate after an oxidative coupling process. [2+2+2] Cycloadditions, cycloisomerizations, or dienes formation are examples of the versatility of theses complexes. The diversity and the selectivity (regio- and often stereoselectivity) of these reactions, which can proceed under mild conditions [134—136], show the interest of (CsR5)Ru catalysts for new synthetic methodologies and the future potential in organic synthesis. 

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