Initiation Allylic Alkylation

In order to achieve a true comparison between both catalytic systems, colloidal and molecular, which display very different reaction rates, a series of experiments were carried out with the homogeneous molecular system, decreasing the catalyst concentration in the studied allylic alkylation reaction. The reaction evolution is monitored taking samples at different reaction times and analysing each of them by NMR spectroscopy (to determine the conversion) and HPLC chromatography with chiral column (to determine the enantioselectivity of I and II). For molecular catalyst systems, the Pd/substrate ratio was varied between 1/100 and 1/10,000. For the latter ratio, the initial reaction rate was found comparable to that of the colloidal system (Figure 2a), but interestingly the conversion of the substrate is quasi complete after ca. 100 h in... 

The first iridium catalysts for allylic substitution were published in 1997. Takeuchi showed that the combination of [fr(COD)Cl]2 and triphenylphosphite catalyzes the addition of malonate nucleophiles to the substituted terminus of t -allyliridium intermediates that are generated from allylic acetates. This selectivity for attack at the more substituted terminus gives rise to the branched allylic alkylation products (Fig. 4), rather than the linear products that had been formed by palladium-catalyzed allylic substitution reactions at that time [7]. The initial scope of iridium-catalyzed allylic substitution was also restricted to stabilized enolate nucleophiles, but it was quickly expanded to a wide range of other nucleophiles. 

The effect of the nature of ion pairs as nucleophiles in a metal-catalysed substitution reaction has been investigated by determining product ratios for the Pd-catalysed allylic alkylations of substrates (9)-(ll) under various conditions, particularly with respect to catalyst ligands, nucleophiles, and counterions. Each dienyl acetate ionizes to form initially the vinyl (7r-allyl)-Pd intermediate corresponding most closely to the leaving group, i.e. (12) from (9), (13) from (11), but (12) and (13) from (10). The initial intermediate can then either be trapped by the nucleophile or it can begin to equilibrate to some mixture of vinyl 7r-allyl intermediates. If nucleophilic addition occurs before full equilibration, the product ratio is different for each substrate if... 

Evans and Nelson examined the stereospecificity of the rhodium-catalyzed allylic alkylation, with the expectation that it would provide additional insight into the mechanism for this particular reaction [16]. They reasoned that the enantiomerically enriched allylic alcohol derivative i would furnish the enantioenriched product iv, provided the initial enyl intermediate ii does not isomerize to the achiral rr-organorhodium intermediate iii prior to alkylation (k2>ki Scheme 10.3). Alternatively, the product of re-... 

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... 

The radical-initiated allylation of alkyl halides with allyltris(trimethylsilyl)silanes proceeds via an SH2 process mediated by a tris(trimethylsilyl)silyl radical.225 The radical-allylating agents react with alkenes, alkynes, and aldehydes via a radical chain process to give the corresponding allylsilylation products.226... 

Trost and coworkers [116] found that palladium-catalyzed intramolecular allylic alkylation to a-sulfonyl ketones is a good means of performing macrocyclization. This reaction involves the intermediacy of a tt-allylpalladium complex as an enolonium equivalent to initiate cyclization. For instance, this method was used in the synthesis of the cytochalasin ( — )-aspochalasin B (201) [117]. As shown in Scheme 66, cyclization of the linear precursor 199 using 10 mol% (Ph3P)4Pd in the presence of 10 mol% DPPP in THF created the 11-membered carbocycle 200 as a single diastereoisomer in 49% yield. 

The stereochemistry of Pd -catalyzed allylic alkylation is net retention (equation 62). This arises from sequential inversion steps. Initially, the Pd approaches from the face of the C3 unit opposite the leaving group, to form the jt-allyl complex. Subsequently, the nucleophile adds to the face of the TT-allyl opposite palladium. If a bulky or umeactive nucleophile is used with allylic acetates, the acetoxy group can add again to the complex. Ultimately, this results in the production of a mixture of stereoisomers upon nucleophihc addition. As an example of the range of allylic substrates that react, nitrogen nucleophiles, in particular primary and secondary amines, undergo palladium-catalyzed substimtion with aUyhc alcohols, acetates, and ethers (equation 63). 

Similarly, a Pd[(S,S)-N0RPH0S]( 7 -C3H5) Cl04 precursor prepared from 2-acetoxy-4,4-diphenylbut-3-ene has been shown to react with sodium dimethylmalonate, a soft nucleophile. The corresponding [Pd (chiral phosphine)] species is thereby generated in situ, which serves to initiate the catalytic cycle that results in allylic alkylation of the nucleophile. The resulting allylation product is formed in 76% ee (eq 8). ... 

High yields of seven-membered rings can be achieved by treating ally] acetates with Lewis acids. The dimethylsilyl enol ether exclusively attacks the least alkylated terminus of the initial allyl cation3. 

Nemoto and Hamada [50] has described the development of a new class of chiral phosphorus ligand - aspartic acid-derived P-chirogenic diaminophosphine oxides, DIAPHOXs - and their application to several Pd-catalyzed asymmetric allylic substitution reactions. Pd-catalyzed asymmetric allylic alkylation was initially examined in detail using diaminophosphine oxides 77, resulting in the highly enantioselective construction of quaternary stereocenters. With the use of the Pd-DIAPHOX catalyst system, asymmetric allylic alkylation, asymmetric allylic amination, and enantioselective construction of quaternary carbons were achieved with high ee (up to 97-99% in many cases) (Scheme 24). 

Abstract This account describes the circumstances leading to our group s innovations in the area of decarboxylative asymmetric allylic alkylation reactions and the initial discovery of palladium phosphinooxazoline complexes as efficient enantioselective catalysts. This chapter also chronicles the growth of the methodology to include several substrate classes, the expansion of the project into several other reaction manifolds, and the use of these reactions in natural product synthesis. Finally, important contributions from other research groups involving related methods or products similar to the ot-quatemary products that are the focus of our studies, as well as future directions for asymmetric alkylation reactions, are discussed. 

Table 1 Initial screening of chiral ligands in the Tsuji allylic alkylation...

A comprehensive review of asymmetric allylic alkylation since our initial publication would be beyond the scope of this accotmt. Instead, we will highlight the use of prochiral nucleophiles in asymmetric allylic alkylation reactions. Unlike the majority of asymmetric allylic alkylation reactions, reactions involving prochiral nucleophiles generate a stereocenter on the nucleophile. Major advances have occurred with regard to the classes of prochiral nucleophiles that can be used in these reactions. 

Moving away from ketones to other prochiral nucleophiles has also been an important goal in our group. We choose to explore lactam-derived substrates in part because we envisioned that the products formed would be useful intermediates in the synthesis of various alkaloids and because we would be able to modulate the electronics and sterics of the lactam enolate by attaching different groups at nitrogen with the aim of optimizing the enantioselectivity of the allylic alkylation. In the event, we chose to initially test tosyl-protected lactam allyl ester 29 and Boc-protected lactam aUyl ester 30 with two Pd PHOX catalysts in several solvents (Scheme 18). 

Scheme 18 Initial studies of N-protected lactams in asymmetric allylic alkylation...

Reaction of [2- " C]acetone with vinylmagnesium bromide (Figure 6.75, Procedure A) provided 2-methyl-3-[2- " C]buten-2-ol (257), which upon treatment with PBra rearranged to give 3,3-dimethyl[3- " C]allyl bromide (258). The latter was used for the alkylation of ethyl acetoacetate, thereby extending the carbon skeleton of the /3-keto ester by a labeled five-carbon (isoprenyl) unit. The initially formed alkylated intermediate 259 was not isolated but immediately saponified and decarboxylated to give ketone 260. Subsequent Homer-Wadsworth-Emmons olefination and reduction of the separated trans-ester 261 converted 260 into [T- Clgeraniol 12621. 

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