Palladium-Catalyzed Cycloisomerizations

Intramolecular nucleophilic attack occurs at the carbon atom distal to the electronegative hydroxyl group 

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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). 

Another useful class of palladium-catalyzed cycloisomerizations is based on the general mechanistic pathway shown in Scheme 13. In this chemistry, a hydridopalladium acetate complex is regarded as the catalytically active species.27b-29 According to this pathway, coordination of a generic enyne such as 59 to the palladium metal center facilitates a hydropalladation reaction to give intermediate 60. With a pendant alkene, 60 can then participate in a ring-form-... 

Although the conversion of 63—>67 adequately expresses the utility of palladium-catalyzed cycloisomerizations for the construction of complex polycycles, the single-step, palladium-mediated conversion of compound 68 to the novel polyspirocycle 6930,31 (Scheme 15) can perhaps be regarded as the paragon of this chemistry. In this striking transformation, chemo- and regioselective... 

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... 

Incorporation of the carboxylic acid group into the substrate also had an effect on the stereochemistry of the Alder-ene products. Trost and Gelling60 observed diastereoselectivity in the palladium-catalyzed cycloisomerization of 1,7-enynes when the reactions were conducted in the presence of A,A-bis(benzylidene)ethylene diamine (BBEDA, Figure 2). They were able to synthesize substituted cyclohexanes possessing vicinal (Equation (53)) and... 

An intramolecular palladium-catalyzed cycloisomerization of enyne 170 was used to access the antifungal agent, chokol C (Scheme 43).102 The choice of ligand and catalyst was essential to the efficiency of the Alder-ene reaction. Enone 171 was obtained as a single olefinic isomer resulting from migration of only Ha during the cycloisomerization reaction. 

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... 

Scheme 15 Mechanisms of the palladium-catalyzed cycloisomerization of acyclic 1, -enynes ( = 6,7) [66-68]...

Yet another access to such [5.6.5]- and [6.6.5]-tricyclic skeletons is viable employing palladium-catalyzed cycloisomerizations of enediynes. Starting... 

Scheme 39 Tricyclizations by palladium-catalyzed cycloisomerizations followed by 6jt-electrocyclizations [126,127]...

Palladium-catalyzed cycloisomerization of lactone 276 produced the tricyclic lactone 277 (Scheme 31). The lactone was saponified and the generated acid was decarboxylated to the bicyclic sulfone 278. Oxidation of the primary alcohol to the acid with Jones reagent was followed by esterification yielding 279. Now, the... 

Trost BM (1990) Palladium-catalyzed Cycloisomerizations of Enynes and Related Reactions. Acc Chem Res 23 34... 

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 103104), hydropalladation of the alkyne is... 

Trost, B. M. Palladium-catalyzed cycloisomerizations of enynes and related reactions. Acc. Chem. Res. 1990, 23, 34-42. 

Trost, B.M., Ferreira, E.M. and Gutierrez, A.C. (2008) Ruthenium- and palladium-catalyzed enyne cycloisomerizations differentially stereoselective syntheses of bicyclic structures. Journal of the American Chemical Society, 130,16176-16177 Trost, B.M., Gutierrez, A.C. and Ferreira, E.M. (2010) Differential reactivities of enyne substrates in ruthenium- and palladium-catalyzed cycloisomerizations. Journal of the American Chemical Society, 132, 9206-9218. 

The comparison of intramolecular carbopalladation reactions of allenes and alkenes outlined in Schemes 9-5 and 9-6 illustrates that not every transition metal catalyzed ring closure necessarily involves a template effect. Others, however, clearly benefit from it. A prototype example is the palladium catalyzed cycloisomerization of alkenyl epoxides carrying distal pre-nucleophiles [38, 39], representing one variant of the famous Tsuji-Trost allylation [40]. 

Representative procedure for the gold- and palladium-catalyzed cycloisomerization of allyl allenoates. 4-Allyl-5-(4-bromophenyl)-3-methylfiiran-2(5H)-on ... 

Carboni and coworkers developed the appUcation of a one-pot palladium-catalyzed cycloisomerization reaction between enynes 6/Diels-Alder cycloaddition/allylboration sequence to efficiently generate tricyclic structures 7 with complete control of the four new stereogenic centers formed in this process (Scheme 4.5) [6]. 

Palladium-catalyzed cycloisomerization of methylenecyclopropyl ketone 101 was affected by added salts [119]. When the reaction was performed in the presence of 2 equiv. of Nal, furan 102 was obtained exclusively. However, when the reaction was performed in the absence of Nal, 4//-pyran 103 was obtained (Scheme 2.67). 

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. 

Ma et al. reported that the palladium-catalyzed cycloisomerization of methylenecy-clopropyl ketones 109 with Nal afforded 3-furyl ketones 110, while that without Nal produced 4/7-pyrans 111 (Scheme 27.37) [48]. The former reaction proceeds via nucleophilic attack of halogen anion to the carbon-carbon double bond, followed by ring opening to form an enolate type of intermediate 112. Sn2 type cyclization and... 

SCHEME 7.41 Examples of palladium-catalyzed cycloisomerization of dienes. 

Palladium-catalyzed cycloisomerization providing the thermodynamically less-favored exo-alkylidene compounds has been elusive. However, lately this unique selectivity has also been accessed by utilizing N-heterocyclic carbene and 1,5-cyclooctadiene-derived catalysts [65]. 

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