Cycloisomerization reactions formation

Brummond [28] was the first to illustrate that cross-conjugated trienes could be obtained via an allenic Alder-ene reaction catalyzed by [Rh(CO)2Cl]2 (Eq. 14). Selective formation of the cross-conjugated triene was enabled by a selective cycloisomerization reaction occurring with the distal double bond of the aUene. Typically directing groups on the allene, differential substitution of the aUene termini, or intramolecularization are required for constitutional group selectivity. However, rhodium(f), unlike other transition metals examined, facihtated selective cyclization with the distal double bond of the allene in nearly aU the cases examined. 

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). 

Metal-catalyzed cycloisomerization reactions of w-alkynols (4-pentyn-l-ol derivatives) provide a rapid and efficient access to tetrahydrofurans. In general, these reactions may proceed through two different reaction pathways, formally leading to endo- or r-vo-cycloisomerization products. The formation of the rwn-tetrahydrofuran product can be achieved with catalytic amounts of tungsten pentacarbonyl (Equation 85) <2005CEJ5735>. 

The success of cycloisomerization reactions of this type is critically dependent on factors that influence the conformational mobility of the side chain bearing the alkene moiety. Additionally, functional groups which are able to serve as ligands at palladium may also be of importance. As an example, neither the (E)- nor the (Z)-crotonate derivative ( -IS or (Z)-13 gives rise to the formation of bicyclic products on treatment with bis(dibenzylideneacetone)palladium/tri-isopropyl phosphite. Instead, the corresponding isomeric substituted butadienes, methyl (2E or 2Z,6 )-7,8-dimethylnona-2,6,8-trienoate (14) and methyl (2E or 2Z)-8-methyl-7-methyl-enenona-2,8-dienoate (15), are formed. 

A variety of allenynamides undergo cycloisomerization reactions in the presence of silver triflate leading to the formation of A-containing heterocycles incorporating cross-conjugated trienes (Scheme 160). ... 

The same researchers also reported a very facile cycloisomerization reaction of allenyl ketones 15 into furans 16 in the presence of gold(III) catalyst (Scheme 8.7) [46, 103-112]. Furthermore, the authors extended this reaction to the cydoisomeriza-tion-addition cascade process of allenyl ketones 15 with enones 17 to produce 2,5-disubstituted furans 18 (Scheme 8.8) [111]. Formation of the latter products was rationalized via two proposed pathways. According to path A, fiiran intermediate 16 undergoes an auration with Au(III)-catalyst to produce the furyl-gold species, which, upon subsequent 1,4-addition to the Michael acceptor 17, generates intermediate 19... 

Kirsch et al. reported that vinyl propargyl ethers 36 could be converted into the densely substituted furans 38 via the Au(I)-catalyzed cycloisomerization reaction (Scheme 8.17) [125] A variety of substituted furans 38 (Table 8.1) could be obtained under very mild reaction conditions at only 2 mol% catalyst loading. It is believed that this cascade process begins vith the Au(I)-catalyzed Claisen-type rearrangement of 36 leading to the formation of skipped allenyl ketone 37, vhich, upon the Au(I)-catalyzed 5-exo-dig-cyclization, provides furan 38. 

In a more demanding 1,7-enyne cycloisomerization reaction (36 to give 37), six-membered ring formation using standard conditions proved unfeasible due to the presence of a carbonyl group in the tether and steric hindrance in the alkene moiety. The employment of Pd2 (dba)3 and formic acid, a mandatory acid, allowed smooth cycloisomerization to occur cortpound 37 is an intermediate in the synthesis of (+)-cassiol. Cyclopentenone synthesis is also possible from related 1,6-enynes under similar conditions (eq 23).35... 

All these results seemed to indicate that this reaction was ideal for the con-stmction of the (—)-berkelic acid skeleton. However, a serious problem was still unresolved at this point how to constmct the additional pyran ring contained in the natural product. Nevertheless, our experience on cycloisomerization reactions led us to speculate on the possibility that a unique metal complex could promote the cycloisomerization of alkynol 15 to give the exo-cyclic enol ether 19 and also that the cycloisomerization of an alkynyl-substituted salicylaldehyde 23 would give 25. Thus, activation of the alkyne of 15 should promote a hydroalkoxylation reaction to give the exocyclic enol ether 19. On the other hand, activation of the alkyne in 23 should promote a cascade cyclization process to finally give the 8//-isochromen-8-one derivative 25. The formal [4-F 2]-cycloaddition reaction between intermediates 19 and 25 would result in the formation of the core structure of (—)-berkehc acid 24 in a very simple way (Scheme 7). 

Scheme 1.23 Formation of dendralene via Alder-ene or metal catalyzed cycloisomerization reaction.

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... 

The reaction mechanism leading to advanced intermediate 85 starts with rhodium insertion into the aldehyde moiety. Rhodacycle formation follows to promote hydroacylation into the 4,6-diene providing cycloheptene compound 86. Then, rhodium catalyze a highly regioselective cycloisomerization reaction on the resulting triene to produce the final product 87 (Scheme 7.54 please refer also to Scheme 7.51). 

The cycloisomerization reaction was also catalyzed by copper(I) complexes. The examples were well reviewed by Fehr [267]. Cycloisomerization of 1,5-enyne compounds 411 was explored using transition metal-catalyzed conditions (Scheme 1.191) [268]. Among the metal complexes examined, Cu(CH3CN)4BF4 provided the best results for the formation of tricyclic cyclopropanes 412. 1,6-Enyne 413 also underwent a similar cycloisomerization reaction to give polycyclic cyclopropanes 414 (Scheme 1.192) [269]. 

The authors confirmed the formation of vinyl Ru-complex 21 by the reaction of [Cp Ru(SBu-t)]2 with methyl propiolate (Eq. 7.15). To my knowledge, this is the first observation of the insertion of an alkyne into the M-S bond within a catalytically active metal complex. In 2000, Gabriele et al. reported the Pd-catalyzed cycloisomerization of (Z)-2-en-4-yne-l-thiol affording a thiophene derivative 22 (Eq. 7.16) [26]. 

This reaction is now well understood, including its stereochemical features.209 242 It should be noted that six-membered rings can be formed besides five-membered rings through this pathway, and their formation is facile with the catalytic system Pd(ll)-Pd(rv). All of these set the stage for numerous synthetic applications, such as cycloisomerization [4 + 2] tandem processes,243 and the enantioselective approach to the total synthesis of potent antiulcerogenic cassiol 247 (Scheme 62).244... 

Scheme 27. Domino Heck-Diels-Alder reaction and formation of dendralenes by cycloisomerization of enediynes...

Tab. 8.1 summarizes the various substrates that were subjected to the rhodium-catalyzed reaction using a Rh-dppb catalyst system. Only ds-alkenes were cycloisomerized under these conditions, because the trans-alkenes simply did not react. Moreover, the formation of the y-butyrolactone (Tab. 8.1, entry 8) is significant, because the corresponding palladium-, ruthenium-, and titanium-catalyzed Alder-ene versions of this reaction have not been reported. In each of the precursors shown in Tab. 8.1 (excluding entry 7), a methyl group is attached to the alkene. This leads to cycloisomerization products possessing a terminal alkene, thus avoiding any stereochemical issues. Also,... 

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