Allylic alkylation transition-metal catalyzed

In addition to the applications reported in detail above, a number of other transition metal-catalyzed reactions in ionic liquids have been carried out with some success in recent years, illustrating the broad versatility of the methodology. Butadiene telomerization [34], olefin metathesis [110], carbonylation [111], allylic alkylation [112] and substitution [113], and Trost-Tsuji-coupling [114] are other examples of high value for synthetic chemists. 

Trost and co-workers have explored asymmetric transition metal-catalyzed allylic alkylations. Details on this subject have been well reviewed by Trost and others.90 With the use of asymmetric palladium-catalyzed desymmetrization of meso-2-ene-l,4-diols, cw-l,4-dibenzoy-loxy-2-cyclopentene can be converted to the enantiometrically pure cA-4-tert-butoxycar-bamoyl-l-methoxycarbonyl-2-cyclopentene.91 The product is a useful and general building block for synthesis of carbocyclic analogs of nucleosides as presented in Scheme 5.12. 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

Although transition metal-catalyzed allylic alkylation has become one of the most powerful methods in chemical synthesis, the formation of ether bonds using this process has been slow to evolve.119-121 The main reasons for this disparity are the lower nucleophilicity and higher basicity of oxygen nucleophiles, particularly those derived from aliphatic alcohols, compared to their carbon or nitrogen analogs. However, this notion has rapidly been revised, as recent advances in the O-allylation area have largely addressed the issue of the reactivity mismatch between the hard alkoxide and the soft 7r-allylmetal species to provide a considerable body of literature. 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

Pd-catalyzed allylic alkylation with soft nucleophiles1151 is probably the most important categoiy within the more general area of transition metal-catalyzed allylic substitution (Scheme 6).116,171... 

Ketone and ester enolates have historically proven problematic as nucleophiles for the transition metal-catalyzed allylic alkylation reaction, which can be attributed, at least in part, to their less stabilized and more basic nature. In Hght of these limitations, Tsuji demonstrated the first rhodium-catalyzed allylic alkylation reaction using the trimethly-silyl enol ether derived from cyclohexanone, albeit in modest yield (Eq. 4) [9]. Matsuda and co-workers also examined rhodium-catalyzed allylic alkylation, using trimethylsilyl enol ethers with a wide range of aUyhc carbonates [22]. However, this study was problematic as exemplified by the poor regio- and diastereocontrol, which clearly delineates the limitations in terms of the synthetic utihty of this particular reaction. 

Transition metal-catalyzed allylic alkylation is generally considered to involve mechanistically four fundamental steps as shown in Scheme 1 coordination, oxidative addition, ligand exchange, and reductive elimination. A key step of the catalytic cycle is an initial formation of a (7r-allyl)metal complex and its reactivity. The soft carbon-centered nucleophiles, defined as those derived from conjugate acids whose pAj, < 25, usually attack the allyl ligand from the opposite side... 

In sharp contrast to the transition metal-catalyzed allylic alkylation of allylic alcohols and their derivatives (see Chapter 11.03) where 77 -allyl-transition metal complexes are key intermediates, the benzyiic alkylation of benzyiic alcohols and their derivatives catalyzed by transition metal complexes has been quite unexplored, although 7] -benzyl-transition metal complexes have often been considered to explain the regioselectivity of transition metal-catalyzed addition to vinylarenes (Scheme 21). A3,63a... 

Vranken, D.L. (1996) Asymmetric transition metal-catalyzed allylic alkylations. Chem. Rev., 96, 395—422. 

Transition Metal-Catalyzed Asymmetric Allylic Alkylations... 

Scheme 8E.1. Catalytic cycle of transition metal catalyzed allylic alkylation.

A unique feature of the transition-metal-catalyzed allylic alkylation is its ability to convert starting materials of various symmetry types, such as racemic, meso- and achiral compounds, into optically pure material, Strategies to effect such transformations derive from recognition of the stereochemical courses in each step of the catalytic cycle and analysis of symmetry elements in the substrate or intermediate. Figure 8E.1 summarizes potential sources of enantio-discrimination in transition-metal-catalyzed allylic alkylation. 

E. Ketone Enolates as Nucleophiles in Transition-metal Catalyzed Allylic Alkylations... 

The two established pathways for transition metal-catalyzed alkene isomerization are the jr-allyl metal hydride and the metal hydride addition-elimination mechanisms. The metal hydride addition-elimination mechanism is the more common pathway for transition metal-catalyzed isomerization. In this mechanism, free alkene coordinates to a metal hydride species. Subsequent insertion into the metal-hydride bond yields a metal alkyl. Formation of a secondary metal alkyl followed by y3-elimination yields isomerized alkene and regenerates the metal hydride. The jr-allylhydride mechanism is the less commonly found pathway for alkene isomerization. Oxidative addition of an activated allylic C-H bond to the metal yields a jr-allyl metal hydride. Transfer of the coordinated hydride to the opposite end of the allyl group yields isomerized alkene. 

The transition metal-catalyzed allylation of carbon nucleophiles was a widely used method until Grieco and Pearson discovered LPDE-mediated allylic substitutions in 1992. Grieco investigated substitution reactions of cyclic allyl alcohols with silyl ketene acetals such as Si-1 by use of LPDE solution [95]. The concentration of LPDE seems to be important. For example, the use of 2.0 M LPDE resulted in formation of silyl ether 88 with 86 and 87 in the ratio 2 6.4 1. In contrast, 3.0 m LPDE afforded an excellent yield (90 %) of 86 and 87 (5.8 1), and the less hindered side of the allylic unit is alkylated regioselectively. It is of interest to note that this chemistry is also applicable to cyclopropyl carbinol 89 (Sch. 44). 

Applications of asymmetric transition metal-catalyzed allylic alkylations in total synthesis 03CRV2921. 

In general, the catalytic cycle for the transition-metal catalyzed allylic substitution reactions involves initial attack of the metal at the double bond followed by oxidative insertion into the antiperiplanar C-0 bond to afford the Ti-allyl system. At this point, depending on whether soft or hard nucleophiles are used, however, the alkylation reaction proceeds through distinctly different pathways (Scheme 10). With soft nucleophiles, where Pd is often the metal center of choice. 

Transition metal-catalyzed allylic substitutions or, as these reactions are also called, allylic alkylations or allylations , Eq. (1), are highly versatile reactions that have become part of the standard repertoire of modern organic synthesis [ 1,... 

Asymmetric Transition Metal Catalyzed Allylic Alkylations Applications in Total Synthesis ... 

Metal Enolates. In parallel with additives, transition metals may be added to enolates to give transmetallated species which can undergo cross-coupling chemistry. Perhaps the earliest example of metal-catalyzed enolate reactions is the Reformatsky reaction. Transition metal-catalyzed enolate chemistry has been recently revived in the literature, particularly in the field of asymmetric catalysis. The transition metal-catalyzed coupling reactions of aryl halides, allyl epoxides, and allylic esters with alkyl enolates have been recently investigated. Generally the choice of base employed depends on the substrate and on the reaction performed. For enolate arylation, KHMDS seems to be the most... 

Transition Metal-catalyzed Allylic Alkylation. Simple ketone enolates were found to be suitable nucleophiles for palladium-catalyzed allylic alkylations. The palladium-catalyzed asymmetric allylic alkylation of a-aryl ketones will take place in the presence of NaHMDS and allyl acetate to produce the desired a,a-disubstituted ketone derivative in high yields andee (eq 16). ... 

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