Enynes Alder-ene reaction

The intermolecular ruthenium enyne Alder-ene reaction has been extended to the stereoselective preparation of enamines (Equation (26)).39 The yields obtained for this reaction were high with allylacetamides, -benzamides,... 

Trost and others have extensively studied the ruthenium-catalyzed intermolecular Alder-ene reaction (see Section 10.12.3) however, conditions developed for the intermolecular coupling of alkenes and alkynes failed to lead to intramolecular cycloisomerization due the sensitivity of the [CpRu(cod)Cl] catalyst system to substitution patterns on the alkene.51 Trost and Toste instead found success using cationic [CpRu(MeCN)3]PF6 41. In contrast to the analogous palladium conditions, this catalyst gives exclusively 1,4-diene cycloisomerization products. The absence of 1,3-dienes supports the suggestion that the ruthenium-catalyzed cycloisomerization of enynes proceeds through a ruthenacycle intermediate (Scheme 11). 

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. 

One of the major advantages of the rhodium(I)-catalyzed Alder-ene reaction is that mild conditions are used to effect the cycloisomerization process thus increasing the likelihood of being able to facilitate an asymmetric reaction. In fact, Zhang has demonstrated convincingly that the Alder-ene reaction of enynes can indeed be performed with excellent enantioselectivity and with similar efficiency. These examples are highlighted below in chronological order. 

The intramolecular iron-catalyzed Alder-ene reaction of enynes in the carbocy-clization reaction was recently reported by Furstner et al. (Scheme 9.8) [20], A low-valent cyclopentadienyliron catalyst, specifically the [CpFe(C2H4)2][Li(tmeda)] complex, is a reactive catalyst for enyne cydoisomerization reactions. Bicyclic products, also incorporating large ring systems, are thereby accessible, and the Thorpe-Ingold effect seems to be helpful for these types of reactions. 

Biological alkylation, organometallics stability, 12, 607 Biological effects, Ti(IV) complexes, 4, 662 Biologically active substances, via enyne metathesis, 11, 295 Biologically relevant compounds, via Alder-ene reactions,... 

Pd-catalyzed Intramolecular Alder-ene Reaction of 1,6- and 1,7-Diynes and Enynes... 

Some 1,6- and 1,7-enynes undergo interesting Pd, Pt and Ru-catalysed cyclizations, which are regarded as Alder-ene reaction and metathesis. These reactions offer a useful method for the construction of polycyclic compounds [132]. These cyclizations can be understood by the following two mechanisms as shown by Scheme 7.3. As the first possibility, the oxidative cyclization of 1,6-enyne 320 generates the palladacy-clopentene 321. Elimination of two different /1-hydrogens from 321 yields either 322 or 323, which undergoes reductive elimination to produce the 1,4-diene 324 as the Alder-ene product, and the 1,3-diene 325 [133]. Of course, the 1,4-diene is the expected product of the thermal ene reaction. 

The intramolecular Alder-ene reaction (enyne cydoisomerization reaction) with alkynes as the enophiles has found wide application compared with diene systems. The reason may be the ready chemo-differentiation between alkene and alkyne functionality and the more reactive alkyne moiety. Furthermore, the diene nature of the products will promote further applications such as Diels-Alder reactions in organic synthesis. Over the past two decades the transition metal-catalyzed Alder-ene cycloisomerization of l,n-enynes (typically n= 6, 7) has emerged as a very powerful method for constructing complicated carbo- or heterocydic frameworks. The transition metals for this transformation indude Pd, Pt, Co, Ru, Ni-Cr, and Rh. Lewis acid-promoted cydoisomerization of activated enynes has also been reported [11],... 

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... 

As variations of Rh-catalyzed cycloisomerization Widenhoefer and coworkers have developed asymmetric 1,6-enyne cyclization/hydrosilylation reactions by using the Rh(I)/biphemp system excellent de and ee were obtained [42]. Brum-mond et al. also discovered a rhodium(I)-catalyzed allenic Alder-ene reaction that... 

The ether-tethered allenyne 248 undergoes a rhodium(l)-catalyzed intramolecular allenic Alder ene reaction to afford the ( )-3,6-dihydropyran 249 as the major product (Equation 111) <2002JA15186>. Likewise, ether tethered enynes can undergo rhodium(i)-catalyzed cycloisomerizations to afford 3,6-dihydropyrans <2005JA10180>. 

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-... 

A cyclization similar to the Alder ene reaction is observed if 1,6-enynes are treated with palladium(II) salts at 25 70"C3o 33. Cyclopentane products with either 1,4- or 1,3-diene subunits (1-methylene-2-vinylcyclopentanes or 1,2-dimethylenecyclopentanes) are obtained. The reaction proceeds smoothly, even with substrates which under thermal Alder ene conditions give no products or only react at very high temperatures (flash vacuum pyrolysis at 500-600 =C). Similar reactions can be catalyzed by polymer-supported nickel-chromium catalysts34, iron carbonyls35, or other iron(0) precatalysts36 39. 

A number of interesting applications of cycloisomerization to natural product syntheses have been carried out by Trost. As an example, total synthesis of picro-toxinin has been achieved based on cycloisomerization (Alder-ene reaction) of the 1,6-enyne system 141 as a key reaction. No satisfactory cyclization of 141 occurred when phosphine ligands such as P(o-Tol)3, DPPB, and triisopropyl phosphite were used. However, smooth cyclization took place to give the Alder-ene product in a quantitative yield at 50 °C when A,A -bis(benzylidene)ethylenediamine (BBEDA) was used as a ligand, and the triol 142 was obtained in 75 % yield after... 

Scheme 2-58. Rh-catalyzed Alder-ene reaction of enynes with a tertiary amide tether. Typical procedure ...

In the 1980s, the group of Trost [10,11] discovered and developed intramolecular palladium-catalyzed Alder-ene reactions. Changing the mechanism from the classical pericyclic process to a reaction that proceeds via transition organometal-lic intermediates has enriched the understanding and realization of the concept of atom-economic processes [ 12]. Therefore, the cycloisomerization of 1,/i-enynes has remained an intensively pursued field of synthetic methodologies ever since [13]. In addition, major advances in enantioselective transition-metal-catalyzed cycloisomerizations of enynes have also been explored [14]. 

By the choice of the enyne substrates, the obtained cyclized products might contain functionalities other than dienes. The unusual catalyst combination of a Pd precatalyst and formic acid enables sequential catalysis initiated by cycloisomerization in a very peculiar way. Kressierer and Muller [16] demonstrated in several cases that the palladium(0)-catalyzed Alder-ene reaction of a-alkynyl M-allyl alcohols 7 furnishes cyclic y,5-enals 8 as a consequence of the in situ enol-aldehyde tautomerism (Scheme 12.2). 

Alder-ene reaction of l,n-enynes can be regarded as the archetypal of cycloisomerization reaction known for over 60 years in its uncatalyzed thermal form [28]. From mechanistic point of view, the reaction involves a six-electron pericyclic rearrangement between an aUylic hydrogen (the ene) and an... 

Intramolecular Alder-ene reactions of 1,6-enynes have been reported to proceed in the presence of the 18-electron iron(O) complexes [CpFe(C2H4)2][Li(tmeda)] for cyclic enynes or [CpFe(cod)][Li(dme)] for acyclic enynes (Scheme 4-317). 

Scheme 4-317. Example of a stereoselective Alder-ene reaction of an enyne catalyzed by an iron(O) complex.

Complex 38 also turned out to be an efficient catalyst for cycloisomerization reactions of enynes 41 (Scheme 8) [16, 17]. This seems reasonable if one considers the fact that Fe(0) is isoelectronic to Rh(+1), which is also a catalyst for Alder-ene cycloisomerizations [18, 19]. 

Equally to ferrate 38 ferrates 39 and 40 also catalyze Alder-ene cycloisomeriza-tions [17]. Compared to 38, they require somewhat longer reaction times, possibly due to the chelating cod-hgand, which is more difficult to substitute by the en)me. The presence of cod in the reaction turns out to be of advantage with more demanding substrates like acyclic enynes with a terminal aUcene moiety where ferrate 38 is not reactive. Cod is assumed to stabilize the catalyst in its resting state as ancillary hgand. 

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... 

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