Diene cycloisomerization palladium-catalyzed

Palladium catalyzed cycloisomerizations of 6-cn-l-ynes lead most readily to five-membered rings. Palladium binds exclusively to terminal C = C triple bonds in the presence of internal ones and induces cyclizations with high chemoselectivity. Synthetically useful bis-exocyclic 1,3-dienes have been obtained in high yields, which can, for example, be applied in Diels-Alder reactions (B.M. Trost, 1989). 

Trost and others have extensively studied the ruthenium-catalyzed intermolecular Alder-ene reaction (see Section 10.12.3) however, conditions developed for the intermolecular coupling of alkenes and alkynes failed to lead to intramolecular cycloisomerization due the sensitivity of the [CpRu(cod)Cl] catalyst system to substitution patterns on the alkene.51 Trost and Toste instead found success using cationic [CpRu(MeCN)3]PF6 41. In contrast to the analogous palladium conditions, this catalyst gives exclusively 1,4-diene cycloisomerization products. The absence of 1,3-dienes supports the suggestion that the ruthenium-catalyzed cycloisomerization of enynes proceeds through a ruthenacycle intermediate (Scheme 11). 

The Alder-ene cyclization of allylic silyl ethers represents a clever use of cycloisomerization chemistry, as the enol ether products can be easily unmasked to yield aldehydes. Palladium-catalyzed cycloisomerization of 1,6- and 1,7-enynes containing an allylic oxygen most often gives rise to 1,3-dienes (see Section 10.12.4.1). However, enynes of type 63 underwent facile Alder-ene cyclization to the corresponding five- or six-membered rings (Equation (40)) using both [CpRu(MeCN)3]PF6 41 and the Cp analog ([Cp Ru(MeCN)3]PF6, 64).53... 

Kibayashi and co-workers103 implemented the palladium-catalyzed cycloisomerization reaction in a stereoselective total synthesis of enantiomerically pure (+)-streptazolin. The cycloisomerization of enyne 172 to provide diene 173 was remarkably selective when performed in the presence of A,Ar -bis(benzylidene)ethylenediamine (BBEDA) as a ligand and water as a proton source (Scheme 44). 

Enamines (cf. 63JCE194, 82T1975,88MI1,08H(75)1849) play an important role in the syntheses under review, both as target substances (see Schemes 16 and 17) and as precursors (see Scheme 9 and following Schemes 19-21). Thus, noble-metal-catalyzed enyne and diene cyclizations have been described (Scheme 19) palladium-catalyzed cycloisomerization of... 

Yet another palladium-catalyzed transformation leading to 1,2-dialkyl-idenecycloalkanes was established by Trost et al. when investigating a catalytic Alder-ene reaction (path D in Scheme 12). They showed that two different catalyst systems are capable of cycloisomerizing enynes 92 to either cyclic 1,4-dienes 96—the products of regular Alder-ene reactions— or the 1,3-dienes 95 (Scheme 15) [66-68]. Starting from palladium acetate, the reaction presumably occurs by coordination of both unsaturated moieties (intermediate 93) and subsequent cycloisomerization to the ring-... 

Trost and co-workers have made great strides in developing the palladium-catalyzed cycloisomerization of enynes into a powerful ring-forming method [39]. In most cases, the intimate details of these reactions are unknown. They are considered here, since a Heck cyclization is a potential step of one possible mechanistic sequence [40]. Two plausible mechanisms for palladium-catalyzed cycloisomerization of enynes are depicted in Scheme 6-17. In the Heck pathway (101 102 -> 103 - 104), hydropalladation of the alkyne is followed by alkene insertion and /3-hydride elimination to provide cyclic diene 104. 

A new synthesis of monocyclic cross-conjugated carbotrienes ([Sjdendralenes) was presented by de Meijere and coworkers (Scheme 2.19) [30], which included palladium-catalyzed cycloisomerization of 2-bromoalka-l, -dienes with tetra-substituted methylenecyclopropane end groups and the corresponding 1,6- and 1,7-enynes. Carbotriene 119 underwent DTHDA cycloaddition with Ph-TAD in a domino fashion to give a single diastereomer of the pentacyclic aza-heterocycle 121 in 81% yield. 

SCHEME 7.41 Examples of palladium-catalyzed cycloisomerization of dienes. 

Buchwald and co-workers56 found that ( )-olefins cycloisomerized upon exposure to [Cp2Ti(GO)2] giving exclusively the 1,4-diene Alder-ene products (Equation (46)). In contrast to the palladium conditions developed by Trost (see Section 10.12.4.1), the 1,4-diene is formed exclusively, even from substrates containing a tertiary carbon at the allylic position 75. It was noted, however, that heating the reaction mixture for an extended period of time in some instances led to olefin isomerization, forming 1,3-dienes. The mechanism of this titanium-catalyzed... 

Finally, the intramolecular cycloaddition methodology also provides access to heterocyclic systems when methylenecyclopropanes with heteroatom-containing side chains are employed. However, as shown above, very complex structural requirements are deary operable. For example, methyl 4-[(l-methyl-2-methylenecyclopropyl)methoxy]but-2-ynoate only yields a complex product mixture mainly containing conjugated dienes (arising from a ring cleavage/ -elimination sequence) upon attempted palladium(0)-catalyzed cycloisomerization. ... 

R. A. Widenhoefer, Synthetic and mechanistic studies of the cycloisomerization and cyclization/hydroxylation of functionalized dienes catalyzed by cationic palladium(II) complexes, Acc. Chem. Res., 35 (2002) 905-913. 

By the choice of the enyne substrates, the obtained cyclized products might contain functionalities other than dienes. The unusual catalyst combination of a Pd precatalyst and formic acid enables sequential catalysis initiated by cycloisomerization in a very peculiar way. Kressierer and Muller [16] demonstrated in several cases that the palladium(0)-catalyzed Alder-ene reaction of a-alkynyl M-allyl alcohols 7 furnishes cyclic y,5-enals 8 as a consequence of the in situ enol-aldehyde tautomerism (Scheme 12.2). 

Inducing Asymmetry in -Elimination Pathway Apart from its racemic variants, cycloisomerization of enynes has been successfully employed in asymmetric synthesis. In the first example of an asymmetric cycloisomerization reaction, Trost et al. used a combination of palladium(O) and a chiral acid to catalyze the cycloisomerization of 1,6-enynes resulting in a rather low enantioselectivity of 33% ee for the formation of 1,4-diene (35) (Scheme 7.17(a)) [35]. Modem development of chiral phosphoric acids has allowed the reexamination of this approach. Thus, when palladium(O) and chiral (5)-TRIP were used with enyne 36 a 71% yield of diene 37 was isolated in 88% ee [36]. Under the same eon-cept, Mikami and coworkers found that cationic palladium... 

In contrast to nickel- and rhodium-catalyzed reactions, palladium cycloisomerizations of 1,6-dienes produce different isomers as the major products [62,63]. Palladium catalysts show a preference on electron-deficient alkenes for the... 

The utility of the platinum-catalyzed enyne cycloisomerization for the formal synthesis of Rosephilin, which is a member of prodiginine family of alkaloids, was reported by Trost and Doherty (Scheme 7.44) [94]. The critical step in the synthesis was the conversion of enyne 221 to bicyclic diene 222 by platinum-catalyzed enyne cycloisomerization. While palladium catalysis was found to be ineffective, the desired cyclopentene 222 was obtained when 221 was treated with the platinum-based catalytic system developed by Murai. Diene 222 was converted to tricyclic pyrrole intermediate 223 in an 11-step sequence. Since 223 had been converted to roseophilin 224, the entire procedure represented a formal synthesis of the alkaloid. 

---