Ligand synthesis asymmetric allylation

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 aforementioned polymer-supported bis-pyridyl ligand has also been applied in microwave-assisted asymmetric allylic alkylation [140], a key step in the enantio-selective synthesis of (R)-baclofen (Scheme 7.118), as reported by Moberg and coworkers. The ( (-enantiomer is a useful agonist of the GABAb (y-aminobutyric acid) receptor, and the racemic form is used as a muscle relaxant (antispasmodic). Under microwave heating, the enantioselectivity could be improved to 89% when using toluene as solvent (see also Scheme 6.52) [140],... 

Bayardon and Sinou have reported the synthesis of chiral bisoxazolines, which also proved to be active ligands in the asymmetric allylic alkylation of l,3-diphenylprop-2-enyl acetate, as well as cyclopropanation, allylic oxidations and Diels-Alder reactions. [62] The ligands do not have a fluorine content greater than 60 wt% and so are not entirely preferentially soluble in fluorous solvents, which may lead to a significant ligand loss in the reaction system and in fact, all recycling attempts were unsuccessful. However, the catalytic results achieved were comparable with those obtained with their non-fluorous analogues. 

Scheme 17. Trost s total synthesis of pancrastatin chiral ligand 102 is utilized in a Pd-catalyzed asymmetric allylic alkylation (1995).

Asymmetric allylic substitutions are widely applied in organic synthesis, using various metal complexes, chiral ligands, nucleophiles and allyl systems [39]. Although Pd is often the metal of choice, this is not the case for monosubstituted allylic substrates, where most Pd catalysts predominantly produce the achiral linear product. In contrast. Mo, W and Ir catalysts preferentially give rise to the desired branched products and, in recent years, a number of very effective Ir catalysts for various substrates have been developed [40]. Since, to the best of our... 

As many endeavors in transition-metal catalysis, the design, synthesis and screening of chiral ligands have played a pivotal role in the development of the asymmetric allylic alkylation reaction. A series of C2-symmetric diphosphines such as DiPAMP, chiraphos, DIOP. and BINAP,... 

Recently, Trost reported an efficient Pd-catalyzed asymmetric allylic alkylation of 1-tetralones [175] and a-arylketone 83 creating a quaternary center as exemplified by the synthesis of 84 (Scheme 7) [176]. Two a-heterocyclic ketones were also alkylated with similar results. Ferrocene-based ligands are effective in pro-... 

Denmark utilized the asymmetric allylation methodology in the synthesis of the serotonin antagonist LY426965 (17), preclinical studies of which suggest its pharmacotherapy use for smoking cessation and depression-related disorders16 (Scheme 3.2m). The key intermediate alcohol (19) was prepared in 94% ee via the asymmetric addition of the silane 18 to benzaldehyde in the presence of the chiral ligand (.S, .S )-16. 

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. 

There are a number of metal-ligand systems that will provide the proper activation for nucleophile coupling, but the Pd system is by far the most well developed and useful. In recent years, asymmetric allylic alkylation reactions have received the most interest for organic synthesis apphcations (see Asymmetric Synthesis by Homogeneous Catalysis). Metals other than Pd have also received some additional attention. 

Palladium-catalyzed asymmetric allylic alkylation [529] of suitable amines with two equivalents of racemic butadiene monoxide ((-r)-411) allows for the expedient synthesis of trans-and cA-2,5-dihydropyrroles derivatives 416 and 417 that are versatile chrrons towards the s)m-thesis of a wide variety of iminosugars [530]. In the presence of 0.4% [(allyl)PdCl)2], 1.2% of enantiomerically pure diphosphine (/ ,/ )-ligand, and Na2C03 a 1 1 mixture of ( )-411 and phthalimide reacted in CH2CI2 at room temperature giving (5)-412 in 99.6% yield and... 

Bandin, M., Casolari, S., Cozzi, P. G., Proni, G., Schmohel, E., Spada, G. P., Tagliavini, E., Umani-Ronchi, A. Synthesis and characterization of new enantiopure 7,7 -disubstituted 2,2 -dihydroxy-1,1 -binaphthyls useful ligands for the asymmetric allylation reaction of aldehydes. Eur. J. Org. Chem. 2000,491-497. 

Okada, Y., Minami, T., Sasaki, Y., Umezu, Y, and Yamaguchi, M., The first synthesis of chiral phosphinocarboxyhc acid ligands, tra 5-2-(diphenylphosphino)cycloalkanecarboxyhc acids. The phosphine-palladium complexes catalyzed asymmetric allylic alkylation. Tetrahedron Lett., 31, 3905,... 

SYNTHESIS AND APPLICATION IN PALLADIUM-CATALYSED ASYMMETRIC ALLYLIC SUBSTITUTION OF ENANTIOPURE CYCLIC p-IMINOPHOSPHINE LIGANDS... 

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