Enol-ethers, cycloisomerizations

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... 

Another rhodium vinylidene-mediated reaction for the preparation of substituted naphthalenes was discovered by Dankwardt in the course of studies on 6-endo-dig cyclizations ofenynes [6]. The majority ofhis substrates (not shown), including those bearing internal alkynes, reacted via a typical cationic cycloisomerization mechanism in the presence of alkynophilic metal complexes. In the case of silylalkynes, however, the use of [Rh(CO)2Cl]2 as a catalyst unexpectedly led to the formation of predominantly 4-silyl-l-silyloxy naphthalenes (12, Scheme 9.3). Clearly, a distinct mechanism is operative. The author s proposed catalytic cycle involves the formation of Rh(I) vinylidene intermediate 14 via 1,2-silyl-migration. A nucleophilic addition reaction is thought to occur between the enol-ether and the electrophilic vinylidene a-position of 14. Subsequent H-migration would be expected to provide the observed product. Formally a 67t-electrocyclization process, this type of reaction is promoted by W(0)-and Ru(II)-catalysts (Chapters 5 and 6). 

PREPARATION OF ENDOCYCLIC ENOL ETHERS VIA ALKYNOL CYCLOISOMERIZATION... 

Few examples of ene-yne cycloisomerization reactions are seen in the literature. The first results for ene-yne cycloisomerizations were with systems bearing an heteroatom (amine or oxygen) next to the alkene counterpart (forming an enamine or an enol ether). Indeed, Dake s group reported the cyclization of enesulfonamides on alkynes (69-70, Scheme 5.30) under catalysis by platinum and silver salts.85 Catalysis using AgOTf (1 1 mol%) was particularly efficient with systems such as 69 (Scheme 5.30)... 

Belmont s group87 reported a cycloisomerization reaction on quinolines 77 (Scheme 5.34) bearing a silyl enol ether group on position 3 and an alkynyl group on position 2, leading to acridine derivatives 78. 

Catalytic Cycloisomerizations to Enol-Ethers or Enol-Lactones... 

The Conia-ene reaction of P-ketoesters bearing a pendant triple bond involves the cycloisomerization of an enyne formed by enolization. This transformation is efficiently catalyzed by cationic gold(I) complexes and afforded cyclopentane derivatives with excellent yields and moderate to good diastereoselectivities (Scheme 4-40). Acetylenic silyl enol ethers or imines react in an analogous manner. By this method, iodoalkynes were converted into iodocyclopentenes, which are highly useful in natural product synthesis. 

An intermolecular diene cycloisomerization was the key step in a synthesis of the putative structure of fistulosin 11.248, an anti-fungal compound from Welsh onion roots (Scheme 11.82)." The substrate 11.246 could be prepared by Mitsunobu alkylation of a sulfonamide 11.243, followed by migration of the double bond with a ruthenium catalyst. The cycloisomerization was achieved using a species generated from the Grubbs second-generation catalyst and the silyl enol ether of acetaldehyde. When the target structure 11.248 was finally reached, the spectroscopic data showed that the reported structure of the natural product was incorrect. 

Functionalized benzo[b]furans 27 are formed by Pd-catalyzed cycloisomerization of (o-hydroxyphenyl)-substituted propargyl alcohols 25 leading to enol ethers 26 followed by acid-catalyzed allyhc rearrangement with solvent incorporation (26 — 27) [50] ... 

With the electTOTi-poor allenic esters, palladium(0) is able to catalyze the reaction without gold. The reactiOTi then is initiated at the other end, after oxidative addition of the aryl halide to the electrophilic palladium(II) species cycloisomerizes the allenic ester and then forms the product by reductive elimination. With o-alkynylbenzoates, the intermediate vinylgold species contains an enol ether substructure and is able to directly intercept the activated allyl donors, even in the absence of palladium. In both cases, by careful trace analysis (ICP), the presence of the other metal was excluded [78]. 

Mainly because of the strong relativistic effect, exaltation of the % and a Lewis acidities of gold cations has been largely used over the past decade [31,32]. To begin with, a diastereoselective Au(in)-catalyzed 5-pjt -cycloisomerization of alkenynols 61 to enol ether 62 followed by an intermolecular Diels-Alder reaction was reported by Barluenga et al. for the preparation of the desired spiro adduct 63 (Scheme 9.17) [33]. The total diastereoselectivity observed could be explained by an endo-approach... 

Arisawa and Nishida showed that treating the Grubbs II catalyst with silyl enol ethers produced a catalyst capable of cycloisomerizing A-allyl-o-vinylaniline... 

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). 

The ruthenium complex [Ru(N3P)(OAc)][BPh4], in which N3P is the N,P mixed tetradentate ligand A,A-bis[(pyridin-2-yl)methyl]-[2-(diphenylphosphino)phenyl] methanamine, was found to be catalytically active for the endo cycloisomerization of aliphatic aUcynols to five-, six-, and seven-membered endo-cyc c enol ethers in good to excellent yield (Scheme 13) [102, 103]. 

Scheme 13 Endo cycloisomerization of aliphatic alkynols to five-, six- and seven-membered cyclic enol ethers...

Treatment of spicifemin-inspired alkynol 307 and pulvilloric acid-inspired fragment 306 with AgSbFs resulted in cycloisomerization of 307 to enol ether 309 formation of o-QM 308 from 306 and subsequent HDA of 308 and 309 to give an inseparable mixture of spiroacetal 311 as the major component, along with a mixture of four other diastereomers in an approximate ratio of 6 4. Careful regioselective demethylation to the free acid allowed separation of the diastereomers, and berkelic acid 96 was therefore obtained in 46 % after one recycle. 

The cycloisomerization/cycloaddition cascade approach has been extended to bis (benzannulated) 5,6-spiroacetals recently by Xue et al. [166] (Scheme 80). Thus, Cu (I)-catalyzed cycloisomerization of aUcynol 327 gives the enol ether 329, which then undergoes HDA with the o-QM 330, generated in situ from 328 under flie thermal reaction conditions. The bis(benzannulated) spiroacetals 331 were obtained in good yield and selectivity (dr >20 1), favoring the doubly anomeric configuration. 

The silver(I)-catalysed 5(Q-exo-dig cycloisomerization of alkynyl silyl enol ethers, such as (267), has been reported to produce the spiro-cyclic derivatives (268). Trapping the vinyl silver intermediate with NIS afforded the alkenyl iodides (269). ... 

In previous work using Pd catalysts, cycloisomerizations involving substrates bearing siloxy groups at the allylic position generated 1,3-dienes preferentially (Equation 1.49, path a), in contrast to their normal behavior [47]. In the Ru-catalyzed version, the normal 1,4-diene is obtained (Equation 1.49, path b), which generates a very useful enol silyl ether with excellent chemo-, regio-, and diastereoselectivity [48]. 

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