Palladium-catalyzed 1,6-enyne cycloisomerizations

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

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... 

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. 

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. 

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 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). 

Hashmi et al. investigated a number of different transition metals for their ability to catalyze reactions of terminal allenyl ketones of type 96. Whereas with Cu(I) [57, 58] the cycloisomerization known from Rh(I) and Ag(I) was observed (in fact the first observation that copper is also active for cycloisomerizations of allenes), with different sources of Pd(II) the dimer 97 was observed (Scheme 15.25). Under optimized conditions, 97 was the major product. Numerous substituents are tolerated, among them even groups that are known to react also in palladium-catalyzed reactions. Examples of these groups are aryl halides (including iodides ), terminal alkynes, 1,6-diynes, 1,6-enynes and other allenes such as allenylcarbinols. This che-moselectivity might be explained by the mild reaction conditions. 

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-... 

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

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. 

Recently, the transition-metal-catalyzed enanti-oselective enyne cycloisomerization has been reported.99 Cao and Zhang reported that, in the presence of catalytic amounts of [Rh(bicpo)Cl]2 and AgSbFe, the enantioselective cycloisomerization of the 1,6-enynes 50 gave the functionalized lactams 51 in good yields with high ee values (Scheme 17).99a Hatano et al. reported that, in the presence of catalytic amounts of palladium(II) and (i )-SEG-PHOS, the asymmetric cycloisomerization of the 1,6-enyne 52 gave the tetrahydrofuran derivative 53 in 99% yield with >99% ee (Scheme 18).99b It should be noted that the quaternary chiral center is constructed with extremely high ee in almost quantitative yield. 

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