Cycloisomerization enynes

Scheme 9 Enyne cycloisomerization catalyzed by different Fe(0)-ate complexes 38-40 E = COOEt [17]...

Trost has shown some mechanistic dichotomy in the ruthenium(ll)-catalyzed enyne cycloisomerization.233 Thus, as mentioned above, the cyloisomerization of enynes proceeds well for the formation of five- or six-membered ring for a variety of precursors. In sharp contrast, in the case of 1,6-enynoates with a quaternary propargylic position, a seven-membered ring is produced in good yield (Scheme 58). 

For rhodium-catalyzed enantioselective enyne cycloisomerization and hydrosily-lation-cyclization, see (a) C. Ping,... 

The Lee group originated rhodium alkenylidene-mediated catalysis by combining acetylide/alkenylidene interconversion with known metal vinylidene functionalization reactions [31], Thus, the first all-intramolecular three-component coupling between alkyl iodides, alkynes, and olefins was realized (Scheme 9.17). Prior to their work, such tandem reaction sequences required several distinct chemical operations. The optimized reaction conditions are identical to those of their original two-component cycloisomerization of enynes (see Section 9.2.2, Equation 9.1) except for the addition of an external base (Et3N). Various substituted [4.3.0]-bicyclononene derivatives were synthesized under mild conditions. Oxacycles and azacycles were also formed. The use of DMF as a solvent proved essential reactions in THF afforded only enyne cycloisomerization products, leaving the alkyl iodide moiety intact. 

Scheme 9.20 Substitution-dependent modes of Pt-catalyzed enyne cycloisomerization.

A ruthenium based catalytic system was developed by Trost and coworkers and used for the intermolecular Alder-ene reaction of unactivated alkynes and alkenes [30]. In initial attempts to develop an intramolecular version it was found that CpRu(COD)Cl catalyzed 1,6-enyne cycloisomerizations only if the olefins were monosubstituted. They recently discovered that if the cationic ruthenium catalyst CpRu(CH3CN)3+PF6 is used the reaction can tolerate 1,2-di- or tri-substituted alkenes and enables the cycloisomerization of 1,6- and 1,7-enynes [31]. The formation of metallacyclopentene and a /3-hydride elimination mechanism was proposed and the cycloisomerization product was formed in favor of the 1,4-diene. A... 

Scheme 5. The first rhodium-catalyzed enantioselective enyne cycloisomerization.

A highly stereoselective kinetic resolution process for Rh-catalyzed enyne cycloisomerization has also been developed by Zhang et al. [41]. This transformation has enabled the highly enantioselective synthesis of polyfunctionalized tetrahydrofurans and lactones with two or three adjacent stereocenters and it is regarded as a major breakthrough in enynes cycloisomerization and in kinetic resolution (Scheme 7). 

Considering the mechanistic rationales of the transition metal-catalyzed enyne cycloisomerization, different catalytic pathways have been proposed, depending on the reaction conditions and the choice of metal catalyst [3-5, 45], Complexation of the transition metal to alkene or alkyne moieties can activate one or both of them. Depending on the manner of formation of the intermediates, three major mechanisms have been proposed. The simultaneous coordination of both unsaturated bonds to the transition metal led to the formation of metallacydes, which is the most common pathway in transition metal-catalyzed cycloisomerization reactions. Hydrometalation of the alkyne led to the corresponding vinylmetal species, which reacts in turn with olefins via carbometalation. The last possible pathway involves the formation of a Jt-allyl complex which could further react with the alkyne moiety. The Jt-allyl complex could be formed either with a functional group at the allylic position or via direct C-H activation. Here the three major pathways will be discussed in a generalized form to illustrate the mechanisms (Scheme 8). 

The last plausible pathway is a jt-allylmetal pathway. n-Allylmetal species are well known in organometallic chemistry for alkylations and cyclizations [53]. This pathway is not common for enyne cycloisomerization and most examples available in the literature are associated with the cyclization of polyenes [54, 55]. The... 

Besides enyne metathesis [66] (see also the chapter Recent Advances in Alkenes Metathesis in this volume), which generally produces 1-vinylcyclo-alkenes, ruthenium-catalyzed enyne cycloisomerization can proceed by two major pathways via hydrometallation or a ruthenacycle intermediate. The RuClH(CO)(PPh3)3 complex catalyzed the cyclization of 1,5- and 1,6-enynes with an electron-withdrawing group on the alkene to give cyclized 1,3-dienes, dialkylidenecyclopentanes (for n=2), or alkylidenecyclopentenes (for n= 1) [69,70] (Eq. 51). Hydroruthenation of the alkyne can give two vinylruthenium complexes which can undergo intramolecular alkene insertion into the Ru-C bond. 

When enyne cycloisomerization takes place in the presence of an unsaturated molecule an insertion reaction can occur. Thus, Ru3(CO)12 catalyzes the cycloisomerization of 1,6-enynes under a CO atmosphere to give an insertion of carbon monoxide and the formation of bicyclic cyclopentenones as a catalytic Pauson-Khand reaction [78] (Eq. 57). 

Most of the 1,6-enyne cycloisomerizations reported here lead to five-mem-bered rings. However, when the enyne was substituted with a quaternary... 

Furthermore, the choice of enyne substrates can lead to cyclized products that contain other functionalities than dienes. Very recently, Muller and Kressierer [148] have shown that yne allyl alcohols 200 can be rapidly cyclo-isomerized by a Pd2dba3-W-acetyl phenyl alanine catalyst system to furnish heterocyclic enals 202 in excellent yields (Scheme 82). The intermediate product of the enyne cycloisomerization in this case is the enol 201, which rapidly tautomerizes to the aldehyde 202. 

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... 

Trost and co-workers have applied enyne cycloisomerizations to the synthesis of a variety of natural products. In an early example, 1,3-diene 106 was efficiently prepared by cyclization of enyne 105 (Scheme 6-18). Diels-Alder elaboration of a relative of 106 and... 

An enyne cycloisomerization was employed in Wender and McDonald s second-generation formal total synthesis of ( )-phorbol (128) (Scheme 6-21) [49]. In this impressive example, enyne 126 was cyclized in 58% yield to provide tricycle 127. Apparently, a tricyclic alkylpalladium intermediate is reduced in situ with (Mc2SiH)20 prior to / -hydride elimination, preventing diene formation. 

Scheme 6-21 An enyne cycloisomerization from a formal total synthesis of ( )-phorbol.

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

Scheme 6-18 Enyne cycloisomerizations forming five-membered rings.

An illustration of the preparation of six-membered rings by enyne cycloisomerizations is found in Trost s total synthesis of (-t-)-cassiol (113) (Scheme 6-19) [44]. The key step of this synthesis involved conversion of enyne 111 to 1,4-diene 112. Although a mixture of diastereomers is produced, the offending stereocenter is not found in the natural product, allowing both diastereomers of 112 to be used. A reductive diyne cyclization (114 115) was recently described as the key step in a total synthesis of ( )-siccanin (116) [45]. Hydropalladation of the terminal alkyne, insertion of the internal alkyne, hydride transfer to palladium, and reductive elimination are proposed to account for the observed reaction. 

Enyne cycloisomerizations can also be exploited to annulate a cyclopentane onto an existing ring system. An example drawn from Trost and co-workers asymmetric total synthesis of picrotoxinin (119) is the conversion of bridged bicyclic intermediate 117 into tricycle 118 (Scheme 6-20) [46]. The optimal cyclization conditions in this case were unusual, requiring an internal proton delivery and a bidentate phosphine. A related example is the conversion of 120 to 121, which was the pivotal step in Trost s synthesis of (—)-dendrobine (122) [47]. An all-carbon tether is not required, as is exemplified by the conversion of 123 to 124 in the total synthesis of ( )-phyllanthocin (125) [48]. Note that in-situ reduction of the o-palladium species prior to /5-hydride elimination has occuined in this latter-example. The enyne disconnection in the synthesis of ( )-phyllanthocin was... 

Trost, B.M., Jean-Philippe Surivet, J.-P. and Toste, F.D. (2004) Ruthenium-catalyzed enyne cycloisomerizations. Effect of allylic silyl ether on regioselectivity. Journal of the American Chemical Society, 126, 15592-15602. 

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. 

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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