Conia-ene-type reactions

Malacria and coworkers [274] used an intermolecular trimerization of alkynes to gain efficient access to the skeleton of the phyllocladane family. Thus, the Co-cata-lyzed reaction of the polyunsaturated precursor 6/4-4 gave 6/4-5 in 42% yield. Here, six new carbon-carbon bonds and four stereogenic centers are formed. The first step is formation of the cyclopentane derivative 6/4-6 by a Co-catalyzed Conia-ene-type reaction [275] which, on addition o f his( Iri me ill y I si ly 1) e thy ne (btmse), led to the benzocyclobutenes 6/4-7 (Scheme 6/4.2). The reaction is terminated by the addition of dppe and heating to reflux in decane to give the desired products 6/4-5 by an electrocyclic ring opening, followed by [4+2] cycloaddition. 

It is noteworthy that the methylenecyclopentane 54 was generated in situ via a cobalt-catalyzed Conia-ene type reaction. By a subtle change in the position of the /J-kclocslcr substituent relative to the tether, the sequence could be reversed and allow the formation of the basic skeleton of the kaurane family [50]. 

The phyllocladane skeleton 131 was constructed efficiently by stereoselective formations of six carbon-carbon bonds and four rings via a one-pot sequence of cyclizations the ene type, [2+2+2], and [4+2] cycloadditions. In this synthesis, the Conia ene reaction of 127 takes place under mild conditions to generate 128, and the cyclotrimerization of its diyne with 118 gives 129. These two reactions are catalysed by CpCo(CO)2. Finally, ring-opening to give 130 and intramolecular Diels-Alder reaction in the presence of DPPE produced the phyllocladane skeleton 131 in a total yield of 42% [55]. 

Conia-type reactions have recently been reported using gold catalysis. Deuterium labelling experiments showed that the deutero-enol reacts with an Au-alkyne complex, illustrated by 53, to provide the Alder-Ene product 54 with 90% of the D-incorporated syn to the keto-ester. 

As with other intramolecular ene reactions, this reaction is best suited to the preparation of cyclopentanes, but can also be used for the preparation of cyclohexanes. The reaction cannot be used for the formation of cyclopropanes or cyclobutanes since the unsaturated carbonyl compound is more stable than the ene adduct. 8,e-Unsaturated ketones (167) do not give cyclobutanes (171) by enolization to give (170) followed by a type I reaction but instead give cyclohexanones (169) by enolization to give (168) followed by a type II reaction. Alkynes can replace alkenes as the enophile. Enols can be prepared from pyrolysis of enol esters, enol ethers and acetals and from -keto esters and 1,3-dicaibonyl compounds. Tlie reaction is well suited to the preparation of fused or bridged bicyclic and spirocyclic compounds. Tandem ene reactions in which two rings are formed in one pot from dienones have also been described. The examples discussed below 2-i63 restricted to those published since Conia and Le Perchec s 1975... 

Some Alder-Ene products remain quite reactive therefore, trapping of the initial product may be required. Alder-Ene reactions of SO2 have been reported with subsequent trapping of the sulfinate ester with an amine to provide sulfonamides. In this case, the TMS group serves as the transferring group, but 83 was not suitable for isolation, and the amide 84 was prepared in good yield for this Conia-type Alder-Ene reaction. ... 

For the Conia-type Alder-Ene reaction, placing groups a- to the carbonyl apparently promoted enolization and served to allow the reaction to occur at lower temperatures and without vapor-phase equipment. At lower temperatures, for shorter time periods, better yields were realized as shown for the conversion of 121 into 122 with various alpha substituents. 

An asymmetric and catalytic Conia-type Alder-Ene reaction has been reported using a combination of asymmetric Pd ligand [(DTBM-SEGPHOS)Pd(OTf)2, 171] and Yb(OT 3 with AcOH. The reactions are quite dilute, yet both conversion and optical purity were good for the p-keto ester or differentiated p-diketone substrates 172. 

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