Alder-ene cycloisomerization

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]. 

However, in contrast to Fe(0)-ate complexes 38-40 (cf. Sect. 4.2), complex 67 failed to catalyze Alder-ene cycloisomerizations, which may be attributed to the thermal lability of this complex [17]. 

Trost and Toste51 isolated unexpected cycloheptene 69 upon exposing enyne 68 to their optimized ruthenium-based Alder-ene conditions (Equation (42)). Further exploration into the effects of quaternary substitution at the propargylic carbon revealed the ability of ruthenium to catalyze a non-Alder-ene cycloisomerization to form seven-membered rings, presumably via allylic C-H activation (Scheme 15). 

Zhang54 published the first and only account of a non-asymmetric rhodium-catalyzed Alder-ene cycloisomerization of 1,6-enynes.55 The conditions developed by Zhang and co-workers are advantageous in that, similar to the ruthenium conditions developed by Trost, selectivity for 1,4-diene products is exhibited. The rhodium conditions are dissimilar from many other transition metal conditions in that only (Z)-olefins give cycloisomerization products. 

Figure 2 Ligands for effecting asymmetric transition metal-catalyzed Alder-ene cycloisomerization.

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],... 

Scheme 12.3 Pd(0)-catalyzed Alder-ene cycloisomerization-reductive amination sequence to p-amino ethyl alkylidene tetrahydrofurans and pyrrolidines 9.

Scheme 12.4 Pd(0)-catalyzed Alder-ene cycloisomerization-Knoevenagel to five-membered carbo- and heterocycles 10 with super-Michael acceptor side chains.

The Rh-BINAP-catalyzed intramolecular Alder-ene cycloisomerization is very rapid and, therefore, sequentially Rh-catalyzed sequences for the efficient enantioselective generation of five-membered carbo- and heterocycles were envisioned. Korber et al. [21] reported the enantioselective rhodium-catalyzed cycloisomerization of alkyl and (hetero)aryl alkynyl allyl alcohols for the generation of aldehyde-bearing chiral 4-alkyl 3-alkylidene THFs and tetrahydro-furanones, which were converted into a,P-unsaturated carbonyl side chains in a one-pot manner via a concluding Wittig olefination in good yields. 

Based on the initial Alder-ene cycloisomerization of alkyl and (hetero)aryl-substituted alkynyl allyl alcohols 13, the rhodium(I)-BINAP complex subsequently can be employed in the reduction of the primary products with hydrogen, furnishing 2,7-dioxabicyclo[3.2.1]octanes 14 in the sense of a sequentially Rh-catalyzed one-pot process (Scheme 12.7) [22]. 

Brummond s group [23] and independentlythe group of Shibata [24] discovered that rhodium(I) complexes are excellent catalysts in the formal Alder-ene cycloisomerization of allenynes to give cross-conjugated trienes under mild conditions... 

Kummeter et al. [34] successfully employed this type of Alder-ene cycloisomerization as an entry to a sequentially Ir-catalyzed cycloisomerization-Murahashi reaction sequence in a one-pot manner, where the intermediate aldehyde arising from the Alder-ene tautomerization step was condensed with cyano acetic esters without addition of acids or bases, furnishing five-membered heterocycles 19 with super-Michael acceptors in the side chain (Scheme 12.10). 

Fig. 10.17 Rh-BINAP promoted Alder-ene cycloisomerization of a sulfonamide tethered enyne [30]...

Zhang s group has reported highly enantioselective cycloisomerization processes catalyzed by rhodium(i) chiral complexes (Scheme 53). For instance, (A)-BINAP gives excellent asymmetric induction in the reaction of enediyne 212 to furnish the quasi-enantiopure Alder-ene product 213.219... 

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). 

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... 

Buchwald and co-workers56 found that ( )-olefins cycloisomerized upon exposure to [Cp2Ti(GO)2] giving exclusively the 1,4-diene Alder-ene products (Equation (46)). In contrast to the palladium conditions developed by Trost (see Section 10.12.4.1), the 1,4-diene is formed exclusively, even from substrates containing a tertiary carbon at the allylic position 75. It was noted, however, that heating the reaction mixture for an extended period of time in some instances led to olefin isomerization, forming 1,3-dienes. The mechanism of this titanium-catalyzed... 

A novel use of Buchwald s titanium-based Alder-ene protocol is the cycloisomerization of dienynes to allenes (Equation (47)). Somewhat surprisingly, the Diels-Alder product was observed in trace amounts only in the cycloisomerization of amine 76. 

The [4+ 4]-homolog of the [4 + 2]-Alder-ene reaction (Equation (48)) is thermally forbidden. However, in the presence of iron(m) 2,4-pentanedioate (Fe(acac)3) and 2,2 -bipyridine (bipy) ligand, Takacs57 found that triene 77 cyclizes to form cyclopentane 78 (Equation (49)), constituting an unprecedented formal [4 + 4]-ene cycloisomerization. The proposed mechanism for this transformation involves oxidative cyclization followed by /3-hydride elimination and reductive elimination to yield the cyclized product (Scheme 18). 

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... 

Allenes, while arguably underused in synthesis as a whole, have become popular functionalities in cycloisomerization chemistry and provide access to a wide variety of products. Ruthenium, cobalt, platinum, palladium, rhodium, and iridium catalysts are efficient in the transition metal-catalyzed Alder-ene reactions of allenes. 

Malacria and co-workers76 were the first to report the transition metal-catalyzed intramolecular cycloisomerization of allenynes in 1996. The cobalt-mediated process was presumed to proceed via a 7r-allyl intermediate (111, Scheme 22) following C-H activation. Alkyne insertion and reductive elimination give cross-conjugated triene 112 cobalt-catalyzed olefin isomerization of the Alder-ene product is presumed to be the mechanism by which 113 is formed. While exploring the cobalt(i)-catalyzed synthesis of steroidal skeletons, Malacria and co-workers77 observed the formation of Alder-ene product 115 from cis-114 (Equation (74)) in contrast, trans-114 underwent [2 + 2 + 2]-cyclization under identical conditions to form 116 (Equation (75)). 

PtCl2 was shown to catalyze a similar Alder-ene transformation, as in the cycloisomerization of allenyne 117 to triene 118 (Equation (76)).78 In the same study, it was noticed that tetrasubstituted allenes cyclized to bicyclic compounds, such as 120 (Scheme 23), under identical PtCl2 conditions, presumably due to A(1,3) strain in intermediate 119. 

Brummond and Shibata independently reported the Rh(i)-catalyzed cycloisomerization of allenynes to cross-conjugated trienes. The rhodium conditions were shown to have broad functional group tolerance. Brummond et al 9 observed rate and selectivity enhancements when they switched to an iridium catalyst (Equation (77)). The rate acceleration observed in the Alder-ene cyclization of aminoester containing allenyne 121 (Equation (78)) was attributed to the Thorpe-Ingold effect.80... 

Using a protocol for tandem carbonylation and cycloisomerization, Mandai et al.83 were able to synthesize cyclopentene and cyclohexene derivatives in high yield, including fused and 5/>/>0-bicycles (Scheme 25). The cyclohexene Alder-ene products were not isolable methanol addition across the exocyclic double bond (in MeOH/ toluene solvent) and olefin migration (in BuOH/toluene solvent) were observed. The mechanism of methanol addition under the mild reaction conditions is unknown. In contrast to many of the other Pd conditions developed for the Alder-ene reaction, Mandai found phosphine ligands essential additionally, bidentate ligands were more effective than triphenylphosphine. 

Weinreb86 has reported the Alder-ene cyclization of enallenes under thermal conditions (Equation (85)). Varying the substitution pattern of alkene and allene groups had little effect on the yield of cyclized product. One exception was a,/ -unsaturated ester 130(Equation (86)) cycloisomerization under thermal conditions led to the formation of the Alder-ene product 131 and the unexpected hetero-Diels-Alder product 132 in a 3 1 ratio. 

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. 

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,... 

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. 

Ester-tethered enyne systems cycloisomerized to give lactone products (Eq. 11) [24]. Eor example, enyne 6 reacted under the Alder-ene conditions of [Rh(COD)Cl]2/BlNAP/ AgSbEg to give the corresponding lactone (Eq. 11). Once again free hydroxyl groups on the allylic terminus were incorporated into the cyclization precursors and subjected to the Alder-ene conditions, which led to the exclusive formation of the tautomerized products in good yields and enantioselectivities (Eq. 12). 

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. 

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