Palladium-catalyzed 1,6-enyne

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. 

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. 

Krische MJ, Trost BM (1998) Total Synthesis of Methyl Picrotoxate via the Palladium Catalyzed Enyne Cycloisomerization Reaction. Tetrahedron 54 3693... 

Trost BM, Haffner CD, Jebaratnam DJ, Krische MJ, Thomas AP (1999) The Palladium-Catalyzed Enyne Cycloisomerization Reaction in a General Approach to the Asymmetric Syntheses of the Picrotoxane Sesquiterpenes. Part. I. First-Generation Total Synthesis of Corianin and Formal Syntheses of Picrotoxinin and Picrotin. J Am Chem Soc 121 6183... 

Scheme 6-17 Possible mechanisms for palladium-catalyzed enyne cyclizations.

Scheme 3-45 Mechanistic aspects of the palladium-catalyzed enyne cycloisomerizations [168, 199].

Trost, B. M., Trost, M. K. Mechanistic dichotomies in palladium catalyzed enyne metathesis of cyclic olefins. Tetrahedron Lett. 1991, 32, 3647-3650. 

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. 

An interesting possibility for the construction of bicyclic systems containing one six-membered ring arises when an intramolecular Heck reaction or palladium-catalyzed enyne cycloisomerization [311] to give a vicinal exodimethylenecy-cloalkane is immediately followed by a Diels-Alder reaction (Scheme 8.15 and Scheme 8.19). This sequence is normally conducted in two steps, but may also... 

Palladium Catalyzed Enyne-yne [4 + 2] Benzannulation as a New and General Approach to Polysubstituted Benzenes. 

The palladium-catalyzed enyne synthesis is achievable via the decarboxylative coupling of propiolic acids with alkenyl bromides (Scheme 4.62) [63]. Propiolic acids also couple with benzyl halides through decarboxylation and subsequent sp C-sp C bond formation (Scheme 4.63) [64]. 

Gevorgyan, V., Quan, LG. and Yamamoto, Y. (1998) Regiospecific synthesis of polysubstituted phenols via the palladium-catalyzed enyne-diyne [4-1-2] cross-benzannulation pathway. Journal of Organic Chemistry, 63(4), 1244-1247. 

Krische, M.J. and Trost, B.M. (1998) Total synthesis of methyl picrotoxate via the palladium catalyzed enyne cydoisomerization reaction. Tetrahedron, 54, 3693-3704. 

Trost, B. and Krische, M.J. (1999) Palladium-catalyzed enyne cydoisomerization reaction in an asymmetric approach to the picrotoxane sesquiterpemes. 2. Second-generation total synthesis of corianin, picrotoxinin, picrotin, and methylpicrotoxate. J. Am. Chem. Soc., 121,6131-6141. 

A cascade Michael/annulation process combining amino and palladium catalysis is shown in Fig. 8.27. In the first step, optically active chiral aldehydes are generated with a secondary amine catalyst, which followed by palladium-catalyzed enyne cycloisomerization. 

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-... 

The palladium-catalyzed stannylboration (90) [124] or silylboration (87) [109, 114] succeeds in the intramolecular carbocyclization of diynes and enynes (Scheme 1-27). It is interesting that a very strained four-membered cycUzation of hexa-l,5-diyne proceeds without any difficulties, similarly to five- or six-membered cycUzation. The boryl group is selectively introduced into the more reactive C=CH rather than C=C for enynes and into the terminal C=CH rather than the internal C=CR for diynes, again suggesting a mechanism proceeding through the first insertion into the Pd-B bond in preference to the Pd-Sn or Pd-Si bond. 

Few other examples of such reaction sequences have been described to date. Oh has reported the palladium-catalyzed reductive cyclizations of 1,6-enynes in the presence of formic acid or triethylsilane via an alkylpalladium intermediate and its application to organic synthesis. Palladium complexes also catalyze the conversion of a range of enynes to cyclic 6,7-unsaturated carboxylic acids in the presence of CO.260... 

The palladium-catalyzed hydrostannylative cyclization of enynes is dealt with first, since mechanistically it is closely related to hydrometallation. Lautens262 reported the formation of homoallyl stannanes through the reaction of 1,6-enynes with tributyltin hydride in the presence of a catalytic amount of Pd(OAc)2.263 The active catalytic species is... 

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... 

The first rhodium-catalyzed reductive cyclization of enynes was reported in I992.61,61a As demonstrated by the cyclization of 1,6-enyne 37a to vinylsilane 37b, the rhodium-catalyzed reaction is a hydrosilylative transformation and, hence, complements its palladium-catalyzed counterpart, which is a formal hydrogenative process mediated by silane. Following this seminal report, improved catalyst systems were developed enabling cyclization at progressively lower temperatures and shorter reaction times. For example, it was found that A-heterocyclic carbene complexes of rhodium catalyze the reaction at 40°C,62 and through the use of immobilized cobalt-rhodium bimetallic nanoparticle catalysts, the hydrosilylative cyclization proceeds at ambient temperature.6... 

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). 

For the synthesis of heterocycles, an efficient strategy has been introduced utilizing the dual transition metal sequences (Scheme 6).11,lla The key issue is the compatibility of the two catalyst systems. Jeong et al. studied the one-pot preparation of bicyclopentenone 35 from propargylsulfonamide 33 and allylic acetate.11 This transformation includes two reactions the first palladium-catalyzed allylation of 33 generates an enyne 34 and the following Pauson-Khand type reaction (PKR) of 34 yields a bicyclopentenone 35. The success of this transformation reflects the right combination of catalysts which are compatible with each other because the allylic amination can be facilitated by the electron-rich palladium(O) catalyst and the PKR needs a Lewis-acidic catalyst. Trost et al. reported the one-pot enantioselective... 

Stannaboration of diynes and enyne provide cycloalkanes incorporating both stannyl and boryl groups, which are otherwise difficult to synthesize. Palladium-catalyzed reactions of 1,4-, 1,5-, and 1,6-diynes with 9 give the corresponding cyclization products in good yields (Equation (99)).247 The reaction is so efficient that even a strained four-membered ring is readily formed. 

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