Enynes, cyclization

In 2009, Chirik reported a hydrogen-mediated reductive enyne cyclization catalyzed by the bis(imino)pyridine iron complex 5 (Scheme 37) [119]. In the... 

Scheme 38 Catalytic cycle for the hydrogen-mediated enyne cyclization...

Cationic palladium complex 121 reductively coupled enynes (Eq. 20) using trichlorosilane as the stoichiometric reductant [71]. This combination of catalyst and silane afforded silylated methylenecyclopentanes such as 122 in good yield from enynes such as 123. Attempts to develop an enantioselective version of this reaction were not successful [71]. When enediyne 124 was cyclized in the presence of trichlorosilane, the reaction favored enyne cycli-zation 126 by a 3 1 ratio over diyne cyclization to 125 (Eq. 21). In contrast, when the more electron-rich dichloromethylsilane was used as the reductant, diyne cyclization product 125 was preferred in a ratio of 4 1 [71]. Selectivities of up to 10 1 for enyne cyclization were observed, depending on the substrate employed [72],... 

Scheme 26 Dependence of Pd(II)-catalyzed enyne cyclization upon solvent and added silane...

Scheme 27 Mechanism of the Pd(II)-catalyzed enyne cyclization with formate or silane as reductant...

An enantioselective variant of the enyne cyclization has been reported. For example, cationic palladium oxalzoline catalyst 111 and Et3SilI reductively cyclized 129a to 130a (shown in racemic form in Eq. 24) in 88% yield of the cyclized products with 24% ee [76]. 

Scheme 31 Scope and selectivity of reductive enyne cyclization by Rh4(CO)i2...

Scheme 32 Dependence of enyne cyclizations on alkene substitution...

Scheme 33 Enantioselective enyne cyclizations with rhodium in the presence of 163...

The stereocontrol and functional group tolerance exhibited by the palladium-catalyzed silane-mediated reductive enyne cyclization has led to its use as a key bond formation en route to structurally complex natural products. These include /3-necrodol,59 (—)-4a,5-dihydrostreptazolin,S9b ( )-laurene,S9c and, as illustrated by the conversion of 1,6-enyne 35a to furan 35b, ( )-phyllanthocin (Scheme 25).S9a... 

A single report appears in the literature regarding the use of chirally modified palladium catalysts in reductive enyne cyclization.60 Upon exposure of 1,6-enyne 36a to the indicated palladium pyridine-oxazoline complex in the presence of EtjSiH, cyclization product 36b is formed in good yield, but with only modest levels of asymmetric induction (Scheme 26). 

In analogy to the mechanism of the palladium-catalyzed enyne cyclization, it is postulated that exposure of palladium(O) to acetic acid promotes in situ generation of hydridopalladium acetate LnPd"(H)(OAc). Alkyne hydrometallation affords the vinylpalladium complex A-10, which upon r-carbopalladation of the appendant alkyne provides intermediate B-7. Silane-mediated cleavage of carbon-palladium bond liberates the cyclized product along palladium(O), which reacts with acetic acid to regenerate hydridopalladium acetate to close the cycle (Scheme 33). 

Trost [10] discovered a palladium-catalyzed enyne metathesis during the course of his study on palladium-catalyzed enyne cyclization. Treatment of the 1,6-enyne 25 with palladacyclopentadiene (TCPT, 26a) in the presence of tri-o-tolyl-phophite and dimethyl acetylene dicarboxylate (DMAD) in dichloroethane at 60°C led to cycloadduct 27 and vinylcyclopentene 28 in 97% yield in a ratio of 1 to 1 (Eq. 10). The latter compound 28 is clearly the metathesis product. 

In their total synthesis of isolaurallene (66), Crimmins and co-workers [85] relied on the anti-selective S -substitution of a propargylic sulfonate with LiCuBr2 (cf. Schemes 18.21 and 18.22) instead of the enyne cyclization sequence, which had turned out to be unsatisfactory in terms of stereocontrol (Scheme 18.26). 

Particularly interesting is the reaction of enynes with catalytic amounts of carbene complexes (Figure 3.50). If the chain-length between olefin and alkyne enables the formation of a five-membered or larger ring, then RCM can lead to the formation of vinyl-substituted cycloalkenes [866] or heterocycles. Examples of such reactions are given in Tables 3.18-3.20. It should, though, be taken into account that this reaction can also proceed by non-carbene-mediated pathways. Also Fischer-type carbene complexes and other complexes [867] can catalyze enyne cyclizations [267]. Trost [868] proposed that palladium-catalyzed enyne cyclizations proceed via metallacyclopentenes, which upon reductive elimination yield an intermediate cyclobutene. Also a Lewis acid-catalyzed, intramolecular [2 + 2] cycloaddition of, e.g., acceptor-substituted alkynes to an alkene to yield a cyclobutene can be considered as a possible mechanism of enyne cyclization. 

Gyclization/hydrosilylation of enynes catalyzed by rhodium carbonyl complexes tolerated a number of functional groups, including acetate esters, benzyl ethers, acetals, tosylamides, and allyl- and benzylamines (Table 3, entries 6-14). The reaction of diallyl-2-propynylamine is noteworthy as this transformation displayed high selectivity for cyclization of the enyne moiety rather than the diene moiety (Table 3, entry 9). Rhodium-catalyzed enyne cyclization/hydrosilylation tolerated substitution at the alkyne carbon (Table 3, entry 5) and, in some cases, at both the allylic and terminal alkenyl carbon atoms (Equation (7)). 

Table 3 Rhodium-catalyzed enyne cyclization/hydrosilylation...

Yttrium-catalyzed enyne cyclization/hydrosilylation was proposed to occur via cr-bond metathesis of the Y-G bond of pre-catalyst Cp 2YMe(THF) with the Si-H bond of the silane to form the yttrium hydride complex Ig (Scheme 8). Hydrometallation of the C=G bond of the enyne coupled with complexation of the pendant G=G bond could form the alkenylyttrium alkyl complex Ilg. Subsequent / -migratory insertion of the alkene moiety into the Y-C bond of Ilg could form cyclopentylmethyl complex Illg. Silylation of the resulting Y-C bond via cr-bond metathesis could release the silylated cycloalkane and regenerate the active yttrium hydride catalyst. Predominant formation of the /ra //j--cyclopentane presumably results from preferential orientation of the allylic substituent in a pseudo-equatorial position in a chairlike transition state for intramolecular carbometallation (Ilg —IHg). 

Lanthanide-catalyzed enyne cyclization/hydrosilylation was also applied to the synthesis of silylated alkylidene cyclohexane derivatives. For example, reaction of the 3-silyloxy-l,7-enyne 17 with methylphenylsilane catalyzed by Gp 2YMe(THF) at 50°G for 8h gave 18 in quantitative yield as a 4 1 mixture of trans cis isomers (Equation (11)). Employment of methylphenylsilane in place of phenylsilane was required to inhibit silylation of the initially formed yttrium alkenyl complex, prior to intramolecular carbometallation (see Scheme 8). 

The key step in this synthesis is the palladium-catalyzed domino- 1.6-enyne cyclization. which creates the bicyclic skeleton of the natural product in a single diastereoselective step. 

One conceivable pathway for the 1,6-enyne cyclization is a cyclo-pal ladation via complex 42 to cyclic palladium compound 43, which contains Pdlv, followed by cleavage of the latter to intermediate 44 that subsequently releases hydridopalIndium acetate and product 14-/. An alternative route proceeds by way of hydropalla-dation of the C-C triple bond to intermediate 45, which after addition to the C-C double bond gives bicyclic system 46. This leads to product L4-Z following a p-hydride elimination. The appearance of double-bond isomeric compound 15-Z is explained by another addition of the palladium species to the cyclic C-C double bond in 14-Z and subsequent p-hydride elimination. 

Enyne cyclization. Cyclization of an enyne such as 2 to the diene 3 with Pd(OAc)2 in combination with Ar3P provides mixtures and in low yield. In contrast, cyclization with Pd(OAc)2 and N,N -bis(benzylidene)ethylenediamine (1) provides the desired diene 3 in 81% yield. The product was used for a synthesis of ( —)-sterepolide (4) in 11 steps and 34% overall yield. 

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