Natural product synthesis enyne cycloisomerization

Enyne metathesis reactions in the context of natural product synthesis have been reviewed recently by Mori <2007ASC121>. Using the same ruthenium catalyst, a novel tandem diyne cycloisomerization-CM process has been devised to furnish 3,4-divinyl-2,5-dihydrofurans (Equation 57) <1999CC237>. 

Cycloisomerization of enynes has been employed to construct an array of natural products.f " Although the precise mechanistic details of the reaction have not been elucidated, and may vary from case to case, one potential mechanism is shown in Scheme 28. Generation of an alkyl- or hydridopaUadium complex in the presence of enyne 183 may lead to carbo- or hydridopalladation to give an alkenyl palladium intermediate 184. Intramolecular cyclization (184 185) then follows to form five-, six-, or seven-membered rings followed by /3-hydride elimination to yield 1,4-diene 186 and/or 1,3-diene 187. There are also examples of yne-yne cyclizations in natural product synthesis. ... 

The Conia-ene reaction of P-ketoesters bearing a pendant triple bond involves the cycloisomerization of an enyne formed by enolization. This transformation is efficiently catalyzed by cationic gold(I) complexes and afforded cyclopentane derivatives with excellent yields and moderate to good diastereoselectivities (Scheme 4-40). Acetylenic silyl enol ethers or imines react in an analogous manner. By this method, iodoalkynes were converted into iodocyclopentenes, which are highly useful in natural product synthesis. 

Trost and co-workers have applied enyne cycloisomerizations to the synthesis of a variety of natural products. In an early example, 1,3-diene 106 was efficiently prepared by cyclization of enyne 105 (Scheme 6-18). Diels-Alder elaboration of a relative of 106 and... 

An illustration of the preparation of six-membered rings by enyne cycloisomerizations is found in Trost s total synthesis of (-t-)-cassiol (113) (Scheme 6-19) [44]. The key step of this synthesis involved conversion of enyne 111 to 1,4-diene 112. Although a mixture of diastereomers is produced, the offending stereocenter is not found in the natural product, allowing both diastereomers of 112 to be used. A reductive diyne cyclization (114 115) was recently described as the key step in a total synthesis of ( )-siccanin (116) [45]. Hydropalladation of the terminal alkyne, insertion of the internal alkyne, hydride transfer to palladium, and reductive elimination are proposed to account for the observed reaction. 

A number of interesting applications of cycloisomerization to natural product syntheses have been carried out by Trost. As an example, total synthesis of picro-toxinin has been achieved based on cycloisomerization (Alder-ene reaction) of the 1,6-enyne system 141 as a key reaction. No satisfactory cyclization of 141 occurred when phosphine ligands such as P(o-Tol)3, DPPB, and triisopropyl phosphite were used. However, smooth cyclization took place to give the Alder-ene product in a quantitative yield at 50 °C when A,A -bis(benzylidene)ethylenediamine (BBEDA) was used as a ligand, and the triol 142 was obtained in 75 % yield after... 

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],... 

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