Intramolecular asymmetric allylic alkylation

Scheme 3. Pd-catalyzed intramolecular asymmetric allylic alkylation in Genet s synthesis of chanoclavine I (1994).

In an enantioselective route to the F-ring of halichondrin B, the diastereoselection with a C2-symmetric diol in intramolecular asymmetric allylic alkylation (AAA) reactions has been investigated (Equation 74) <20020L3411>. 

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]. 

A significant study of the synthesis of chiral chromans by the Pd-catalysed intramolecular asymmetric allylic alkylation of readily available phenol allyl carbonates has established the optimum conditions for this highly efficient method and demonstrated its value by the total syntheses of (+)-clusifoliol and (-)-siccanin (Scheme 6) <04JA11966>. A biomimetic enantioselective synthesis of (-)-siccanin also features this approach to the chroman moiety <04JA12565>. 

Table 6.14 Pd-catal) ed intramolecular asymmetric allylic alkylation reaction reported by Bandini and Umani-Ronchi.

Eneouraged hy Bandini s pioneering studies, You and co-workers introduced indolyl carbonates 180 into Ir-catalyzed intramolecular asymmetric allylic alkylation reactions. Interestingly, spiroindolenine derivatives 181 are obtained in 50-98% yields with up to >99/1 dr and 97% ee (Scheme 6.83). Chiral phosphoramidite ligand (/ ,/ a)-170d (Me-THQphos), newly developed by the You group, was responsible for excellent reactivity, diastereo- and enantioselectivity of this process. 

Scheme 6.83 Ir-catalyzed intramolecular asymmetric allylic alkylation reaction of indol-3-yl carbonates 180 reported by You.

Apart from reports on Ir-catalyzed intramolecular asymmetric allylic alkylation of substituted indoles with the linker attached on the C3 position,... 

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... 

Scheme 2. Pd-catalyzed asymmetric allylic alkylation of 7 is followed by a Pd-catalyzed intramolecular C-N bond formation and a Pd-catalyzed intramolecular Heck-type alkylation in Mori and Shibasaki s total synthesis of lycorane (1995).

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. 

The ABC-ring system of (—)-galanthamine has also been constructed using intramolecular Heck reactions with a particularly notable and early example being described by Trost et al. Specifically, they showed (Scheme 2) that on exposure to 15 mol% Pd(OAc)2, 15 mol% of the ligand diphenylphosphinopropane (dppp), and 3 mol equivalents of AgaCOs, the allylic ether 5, itself the product of an asymmetric allylic alkylation reaction, was converted into compound 6. This was then carried forward over a further four steps into (—)-galanthamine. 

Scheme 17 Tandem asymmetric allylic alkylation and intramolecular Heck coupling...

A few intriguing developments in the area of tetrahydro-P-carboline synthetic methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-P-carbolines from L-tryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 

This type of allylic alkylation has been applied in the asymmetric total synthesis of (—)-anatoxin-a (7) using a N-nucleophile and Pd-based bpchH2 complexes in an intramolecular reaction to form the 9-azabicyclo[4.2.1]non-2-ene system (eq 3). ... 

Seheme 6.88 Asymmetric intramolecular AFC-type allylic alkylation of phenols reported by You and by Hamada. 

High yields of 2-substituted chromans are readily attained from the asymmetric intramolecular oxa-Michael addition reaction of phenols bearing an (f -a,P-unsaturated ketone or thioester moiety mediated by a cinchona-alkaloid-urea-based bifunctional organocatalyst (140BC119). Molecular iodine-catalyzed reaction of phenols with a,P-unsaturated alcohols affords a wide range of 2,2-disubstituted chromans (14T5221). Chiral derivatives result from the intramolecular allylic alkylation of phenols bearing an... 

Naturally occurring alkaloid anatoxin-a, known to induce respiratory paralysis and possessing an unusual 9-azabicyclo[4.2.1]nonane skeleton, was recently synthesized by Trost and Oslob via an asymmetric intramolecular allylic alkylation (Scheme 39). The alcohol 179, prepared from 4-bromo-l-butene and ethylformate, was efficiently converted to functionalized cyclooctadiene 180 within six steps. Asymmetric cyclization was performed with a catalytic amount of Pd(0) and several ligands to enhance the enantioselectivity. A new chiral ligand, the (5,5)-l-(2-diphenylphosphinobenzamido)-2-(2-pico-linamido)cyclohexane, (5,5)-182, was synthesized to alleviate the unfavorable steric interaction and induced under smooth conditions the formation of cyclic 181 in 90% yield and 88% ee. The ester 181 was then converted to the methyUcetone, which was desulfonated to give (-)-anatoxin-a. 

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). 

Homillos V, van Zijl AW, Feringa BL (2012) Catalytic asymmetric synthesis of chromenes and tetrahydroquinolines via sequential allylic alkylation and intramolecular Heck coupling. Chem Commun 48 3712-3714... 

In 2011, a metal-free asymmetric intramolecular allylic alkylation promoted by a chiral A(-triflylphosphoramide 12b was achieved by Rueping et al. (Scheme 2.29). The phenol 96 was believed to undergo organic ion-pair catalytic procedure to furnish optically active 2/f-chromenes 97 in good yields and excellent enantioselectivities [40]. 

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