Intramolecular palladium-catalyzed allylic alkylations

By 1984, the palladium-catalyzed aUyhc alkylation reaction had been extensively studied as a method for carbon-carbon bond formation, whereas the synthetic utility of other metal catalysts was largely unexplored [1, 2]. Hence, prior to this period rhodium s abihty to catalyze this transformation was cited in only a single reference, which described it as being poor by comparison with the analogous palladium-catalyzed version [6]. Nonetheless, Yamamoto and Tsuji independently described the first rhodium-catalyzed decarboxylation of allylic phenyl carbonates and the intramolecular decarboxylative aUylation of aUyl y9-keto carboxylates respectively [7, 8]. These findings undoubtedly laid the groundwork for Tsuji s seminal work on the regiospecific rho-... 

Only a few reports on the simple diastereoselectivity within palladium(0)-catalyzed allylic alkylation exist. Either the diastereomeric ratio is not reported7-8 or determined because stereoisomeric products have been simplified by further manipulation, or the reaction gives only moderate to no selectivity. This section is divided into two subsections discussing inter-and intramolecular palladium(0)-catalyzed substitutions, respectively. The different classes of substrates are treated separately. 

A palladium-catalyzed allylation of indoles with allyl carbonates furnished 3-alkylated indoles <04OL3199>. An intramolecular variation with indolyl carbonates provided a novel synthesis of tetrahydro-p-carbolines and pyrazinoll,2-a indoles. 

Our first approach to 1 is based on a retrosynthetic analysis depicted in Fig (8). The crucial step to construct the cw-fused bicyclic ring skeleton of 1 is the intramolecular allylic amination of a cw-allylic carbonate 25. The palladium-catalyzed allylation takes place with retention of the configuration [76] and requires the cis-isomer 25 for the ring closure. Compound 25 may be derived from keto acid 24 through a sequence of reactions including esterification, O-methoxycarbonylation, removal of the Boc and benzylidene groups, dehydrative cyclization, reductive alkylation and ureido formation. The last five transformations are to be conducted in a successive manner, i.e., without isolation of the intermediates. The 4-carboxybutyl chain of 1 may be installed by the reaction of 0-trimethylsilyl (TMS) cyanohydrin 23 with a di-Grignard... 

In 2010, Dorta and coworkers [83] reported a new synthetic strategy to access functionalizable 3-allyl oxindoles bearing a chiral quaternary carbon stereocenter via a direct palladium-catalyzed a-arylation protocol. This elegant methodology, previously accessible only via a two-step procedure involving a Pd-catalyzed intramolecular a-arylation followed by an asymmetric Pd-catalyzed allylic alkylation [84], afforded impressive reactivities, and high chemoselectivities and enantioselectivities were also achieved in the synthesis of oxindoles using a new chiral Pd-NHC catalyst (Scheme 8.45). 

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... 

The final modes of enantioselective allyl alkylations catalyzed by palladium involve the use of chiral nucleophiles447 and chiral leaving groups.448-449 Chiral enamines were found to undergo allylation in 100% optical yield in an intramolecular case and in up to 50% optical yield in intermolecular reactions (equation 358). 

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. 

Continuing with palladium chemistiy, Trost proposed a new asymmetric synthesis of anatoxin-a (Trost and Oslob, 1999) and the crucial step was the introduction of chirality by a catalytic process involving an intramolecular asymmetric allylic alkylation (Trost 2004) of the intermediate ( )-29 affording (+)-31 (Scheme 7.7). This step was catalyzed by palladium in presence of a chiral phosphine ligand. 

On the other hand, unsaturated aldehydes and ketones were obtained using allylic alcohols as alkene components [68]. Similarly, allyl f-butyldimethylsilyl ether and N-allylamides gave silyl enol ethers [69] and enamides [70], respectively. The ruthenium-catalyzed alkene-alkyne coupling was successfully combined with the palladium-catalyzed intramolecular asymmetric allylic alkylation [71] to provide a novel one-pot heterocyclization method [72]. 

In 2002, Trost and Tang reported the chiral total synthesis of (-)-codeine in short reaction steps using a palladium-catalyzed asymmetric allylic alkylation (AAA) [53] as the key transformation [54], In 2005, a detailed full account of their synthesis was published [55]. The key features of their synthesis are (1) a preparation of an aryl ether with high optical purity by the Pd-catalyzed AAA reaction, (2) the intramolecular Heck reaction to generate the A-C-E benzofuran skeleton, (3) the second intramolecular Heck reaction of Z-vinyl bromide providing the phenan-throfuran core, and (4) the intramolecular hydroamination for the construction of D-ring by the action of LDA and visible light. 

Scheme 28 Palladium(II)-catalyzed inter- and intramolecular oxidative allylic alkylation...

In another example, a palladium-catalyzed intramolecular allylic alkylation protocol has been developed by Toyota et al. to construct the 8-lactone intermediate... 

Toyota, M., Hirota, M., Nishikawa, Y., Fukumoto, K., and Ihara, M. (1998) Palladium-catalyzed intramolecular allylic alkylation reaction in marine natural product synthesis enantioselective synthesis of (-l)-methyl pederate, a key intermediate in syntheses of mycalamides. J. Org. Chem., 63, 5895-5902. 

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