Terry T.-L. Au-Yeung

Palladium–(S,pR)‐FerroNPS‐Catalyzed Asymmetric Allylic Etherification: Electronic Effect of Nonconjugated Substituents on Benzylic Alcohols on Enantioselectivity

The development of efficient methods for enantioselective synthesis remains at the center of modern-day organic chemistry, as such methods have many important applications, from the total synthesis of natural products to the preparation of analogues of lead compounds in the pharmaceutical industry. The ability to prepare compounds by a carbon–heteroatom bond-forming process from a common intermediate is of great significance to the drug-discovery process. In particular, the stereoselective construction of an ether linkage adjacent to a stereogenic carbon center is important for the synthesis of many biologically active targets. However, this process requires further development. For example, the conventional formation of a C O bond by a direct SN2-type O alkylation (Williamson ether synthesis) is sometimes impractical synthetically owing to the strong basicity of the alkoxide anion, which may be incompatible with other functional groups present in the system. It would clearly be advantageous to construct C O bonds in a catalytic manner under mild conditions rather than through traditional organic synthesis. Enantioselective transitionmetal-catalyzed allylic substitution has become one of the most powerful tools for the generation of carbon–carbon and carbon–heteroatom bonds with various nucleophiles. The development of the synthesis of chiral compounds containing carbon–carbon or carbon–nitrogen bonds from racemic allylic electrophiles has been documented well [Eq. (1)]. In contrast, the enantioselective allylic substitution of unactivated allylic acetates with relatively hard oxygen nucleophiles has only been studied sporadically. Enantioselective iridium-catalyzed allylic substitution reactions with a broad range of phenols (relatively soft nucleophiles) have been reported. They generally proceed with good selectivity with monodentate phosphoramidite ligands. Asymmetric palladium-catalyzed C O bond formation between phenols and various allylic substrates to give ethers has also been studied. In a separate study, Kim and Lee demonstrated that the palladium-catalyzed etherification of allylic acetates with aliphatic alcohols afforded achiral ethers by using zinc alkoxides generated from diethyl zinc and an alcohol. Haight et al. reported an asymmetric variant of the protocol described by Kim and Lee. However, the more reactive allylic carbonate and harsher conditions (reflux in THF) were required, and the observed enantioselectivities were rather poor. Spurred by these findings, we undertook the challenge to develop an efficient etherification process that can proceed under mild reaction conditions with good stereoselectivity. Herein, we report a general palladiumcatalyzed asymmetric allylic substitution of racemic 1,3diphenyl-2-propenyl acetate with aliphatic alcohols in the presence of newly developed fine-tunable phosphinamidite– thioether ligands with a ferrocene motif (Scheme 1) to generate chiral ethers in high yields with excellent enantioselectivities. We recently developed a convenient synthesis of the versatile Ugi amine in optically pure form with a view to using it as a building block for the development of novel and highly modular chiral ligands. The chiral intermediate aminothioether 2 of FerroNPS was synthesized by diastereoselective ortho lithiation of the Ugi amine by treatment with sBuLi in Et2O followed by quenching with the appropriate

Bipyridyl-based diphosphine as an efficient ligand in the rhodium-catalyzed asymmetric conjugate addition of arylboronic acids to α,β-unsaturated ketones

Abstract Reactions of α,β-unsaturated ketones with excess arylboronic acids in the presence of a rhodium catalyst generated in situ from Rh(acac)(C 2 H 4 ) and ( S )-P-Phos in dioxane/water at 100°C gave high yields of the corresponding products in up to 99% ee.

Enantioselective bis-alkoxycarbonylation of styrene catalyzed by novel chiral dipyridylphosphine cationic palladium(II) complexes

Abstract The preparation of new palladium complexes that are composed of a series of chiral dipyridylphosphines [( R )-P-Phos ( 1 ), ( R )-tol-P-Phos ( 2 ) and ( R )-Xyl-P-Phos) ( 3 )] have been described. The structure of the complex [{( R )- 1 }Pd(H 2 O) 2 ](OTf) 2 was unambiguously determined by single-crystal X-ray diffractometry. These complexes were found to be effective in the asymmetric bis-methoxycarbonylation of styrene, reaching up to 84% e.e. and 79% chemoselectivity for dimethyl-2-phenylsuccinate (DMPS) under the optimal conditions. In addition, the complexes exhibited almost identical enantioselectivity on DMPS.

Studies on the rhodium- and ruthenium-catalyzed asymmetric hydrogenation of α-dehydroamino acids using a family of chiral dipyridylphosphine ligand (P-Phos)

Abstract The applications of the chiral dipyridylphosphine ligand P-Phos and its derivatives Tol-P-Phos and Xyl-P-Phos in Ru- and Rh-catalyzed hydrogenations of the methyl esters of a variety of (Z)-2-acetamido-3-arylacrylic acids have been studied systematically. The results show that the electronic and steric properties of these ligands have significant influences on the enantioselectivity of the reduction. Rh and Ru complexes of the same dipyridylphosphine ligand family exhibit different trends in enantioselectivity toward the same substrate.

Modified BINAPO ligands for Rh-catalysed enantioselective hydrogenation of acetamidoacrylic acids and esters

Abstract (S)- and (R)-2,2′-Bis[bis(3,5-dimethylphenyl)phosphinoyl]-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl (Xyl-H8-BINAPO) were synthesised by reacting chlorobis(3,5-dimethylphenyl)phosphine with (S)- and (R)-2,2′-dihydroxyl-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl, respectively. The applications of these ligands and their corresponding parent analogues in the Rh-catalysed asymmetric hydrogenation of a variety of acetamidoacrylic acids and esters provided chiral amino acid derivatives with good to excellent ees (up to 97%).