Decarboxylative allylic alkylation

The enantioselective palladium-catalysed decarboxylative allylic alkylation has been highlighted.50... 

Tanaka T, Okamura N et al (1986) Syntheses of (5E)-PGE2 and new 6-functionalized derivatives by the use of palladium-catalyzed decarboxylative allylic alkylation. Tetrahedron 42 6747-6758... 

The rate of the decarboxylative allylic alkylation appears to be limited by the rate of decarboxylation. For example, Ohta and co-workers described the decarboxylative allylic alkylation of a-phenyl substituted malonic ester derivatives which occurred at much lower temperature when compared to its a-alkyl counterpart. Hence the rate of decarboxylation is dependent on the stability of the enolate which is formed in situ. The benzylic enolate has a lower pK by around 6-7 units. 

Scheme 12.44 Substrate-controlled decarboxylative allylic alkylation of ketone...

Scheme 2.56 Ion pair 194 and palladium complex 195 as alternatives of enolates formed in the course of decarboxylative allylic alkylation.

Scheme 5.30 Mechanistic pathways in the palladium-catalyzed decarboxylative allylic alkylation, starting from allyl p-keto esters 91 or allyl enol carbonates 92.

Enantioselective decarboxylative allylic alkylation was disclosed by several groups in the middle of the past decade [48]. An approach based on P-keto esters was first reported by Tunge and Burger and characterized as an asymmetric Claisen surrogate. Mainly esters with cyclic allyloxy moieties 99 were used. When the reaction was mediated by Trost s ligand R,R)-14, ketones... 

Scheme 5.31 Enantioselective decarboxylative allylic alkylation of fl-keto esters 99,...

Scheme 5.32 Enantioselective decarboxylative allylic alkylations, starting from allyl enol carbonates 101 (reported by Stoltz) and allyl enol carbonates 103 (reported by Trost).

Whereas allyl enol carbonates are prochiral starting materials, the fi-keto esters are frequently chiral but can be used as racemic compounds because the stereogenic center vanishes in the course of the decarboxylative allylic alkylation, precisely during the formation of the enolate. In general, both enantiomers of chiral fi-keto esters 91 react without enantiodifferentiation with the palladium(O) catalyst to give the enolate, a course of the reaction that was termed stereoablative... 

Scheme 5.33 Influence of the configuration at the enol double bond on the stereochemical outcome of the decarboxylative allylic alkylation, mediated by ligand R,R)-69.

In order to test this principle, Enquist and Stoltz submitted compound 107, which consisted of a 1 1 mixture of the racemate and the weso-compound to the standard decarboxylative allylic alkylation protocol. The reaction resulted in a mixture of chiral diketone 108 and the wteso-diastereomer 109 in a ratio of 81 19, the total yield amounting to 78%. More remarkably, the enantiomeric excess of the major product R,R)-108 was found to be 99% ee. The result indicates that, after the two stereogenic centers of the starting material have been subsequently bulldozed, the chiral catalyst exerts stereocontrol in the allylation of the enolate. The main diastereomer 108 was separated and served as a key intermediate in a total synthesis of the marine diterpenoid cyanthiwigin F along with the lower homolog (R = H) (Scheme 5.34) [57]. 

Scheme 5.34 Diastereoselective and enantioselective formation of diketone (fi,ft)-108 by decarboxylative allylic alkylation of a stereoisomeric mixture of 107.

Scheme 5.35 Enantioselective decarboxylative allylic alkylation of enediol-derived carbonates 110 and 111. Controlled formation of allylated a-oxy-substituted aldehydes 112 and ketones 114.

Scheme 5.38 Crossover experiment of palladium-catalyzed decarboxylative allylic alkylation reported by Stoltz et al. The authors measured the exact molecular masses by HRMS. The whole numbers are indicated here for reasons of simplification.

Scheme 5.39 Opposite topicity in the palladium-catalyzed allylic alkylation of lithium eno-late 13b and decarboxylative allylic alkylation of carbonate 103a. The same enantiomer (< )-15 forms with quasienantiomeric ligands (S,S)-14 and R,R)-69.

Scheme 5.40 Inner-sphere mechanism in the decarboxylative allylic alkylation, proposed by Stoltz.

The opposite stereochemical outcome of the reaction of the lithium enolate and the decarboxylative allylic alkylation (see Scheme 5.39) was explained by assuming an outer-sphere mechanisms in both cases. In the enolate-LDA mixed dimer. 

J ,J )-configured ligand also attacks the enolate from its 5i-face as well. The cartoons shown in Scheme 5.42 may serve to illustrate why opposite enantiomers of the palladium catalyst both lead to (/ )-allyl tetralone 15. It seems that the t-butyl-PHOX ligand is too sluggish to react with cyclic ally substrates like 127. Therefore, it remains open whether Trost s proof of the outer-sphere mechanism is restricted to the C2-symmetric bis-amide ligands. Despite the discrepancy in the stereochemistry of the mechanism, the asymmetric decarboxylative allylic alkylation enjoyed manifold applications in total synthesis [62]. 

Scheme 5.43 Enantioselective palladium-catalyzed decarboxylative allylic alkylation under ring opening of bicyclic racemic ketone 130.

Furthermore, the decarboxylative allylic alkylation was extended to cyclic dienol carbonates 132 by Cossy and coworkers. Upon treatment with the palladium complex of Trost s ligand (U,U)-14, butenolides 133 with a quaternary stereogenic center were obtained in fair chemical and optical yields (Scheme 5.44) [64]. The preferred Si-face approach of the allylpalladium cation reaction is rationalized by an outer-sphere mechanism, adapting a transition state model related to that shown in Scheme 5.42. 

Scheme 5.44 Enantioselective formation of butenolides 133 by palladium-catalyzed decarboxylative allylic alkylation of furan-derived enol carbonate 132.

Considering the fundamental mechanism of the decarboxylative allylic alkylation, as outlined in Scheme 5.30, it appears as an imaginative concept to use the enolate 95 (or 96 or 97) for an additional reaction with an electrophile before the collapse with the allyl fragment occurs. There are several conditions that need to be fulfilled the electrophile must not interfere with the oxidative addition of palladium(O) to the allyl moiety, the reaction of the enolate with... 

Scheme 5.45 Cascade of palladium-catalyzed decarboxylative allylic alkylation and trapping of the palladium enolate, assumed as O-bound tautomer 135, by Michael acceptors.

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