Albert S. C. Chan

Advances and Applications in Organocatalytic Asymmetric aza‐Michael Addition

The stereocontrolled construction of chiral carbon–carbon bonds and carbon–heteroatom bonds are topics of paramount importance in modern organic synthesis. The importance has been driven predominantly by optically active compounds in natural products and pharmaceuticals. The success of asymmetric organocatalysis can be attributed to the advantages of their availability and their capacity to perform asymmetric transformations in a metal-free environment, under mild and non-inert reaction conditions. Asymmetric organocatalysis, using small chiral organic molecules as enantioselective catalysts, has experienced an impressive growth and is now considered the “third pillar” of enantioselective catalysis together with biocatalysis and metal catalysis. Among the great variety of organocatalytic asymmetric transformations, Michael additions occupy a very important position and have received widespread attention for accessing a variety of chiral synthetically useful building blocks. In particular, the Michael addition of nitrogen-based nucleophiles to a,b-unsaturated carbonyl systems, also termed the aza-Michael reaction, represents an especially interesting variant since it is a versatile method for constructing a new C N bond and constitutes; an important step in the synthesis of bioactive natural compounds. During the past decade, a number of elegant organocatalysts have been developed for enantiocontrol in a large variety of reactions. Accordingly, the organocatalytic asymmetric aza-Michael addition has been a very active field of research, the previous progress of which has also been the subject to some excellent reviews. The majority of organocatalytic reactions are amine catalystbased and proceed via enamine or iminium intermediates, or the amine acts as a base. Therefore, a possible competition between the catalyst and the nitrogen-based nucleophile exists in the organocatalytic aza-Michael addition. This could compromise the enantioselectivity of the reaction and remains as one of the difficulties in developing organocatalytic asymmetric aza-Michael addition. Consequently, the appropriate choices of the nitrogen-based nucleophile and the catalyst system represent a critical factor in the organocatalytic asymmetric azaMichael addition. Encouragingly, significant progress has been made in the past several years towards achieving organocatalytic asymmetric aza-Michael additions during the rapid development of asymmetric organocatalysis. Many new substrates have been applied accordingly in this transformation, together with the new approaches developed for the purpose of targetand diversity-oriented asymmetric synthesis. Based on the comprehensive work of Enders, the process made in organocatalytic asymmetric aza-Michael addition between 2010 and early 2012 are surveyed in this review. The review is also organized according to the catalyst system used.

Ligand-Controlled Enantioselective [2 + 2] Cycloaddition of Oxabicyclic Alkenes with Terminal Alkynes Using Chiral Iridium Catalysts

The first catalytic asymmetric [2 + 2] cycloaddition of oxabicyclic alkenes and terminal alkynes has been developed. This iridium-catalyzed enantioselective [2 + 2] cycloaddition allows the formation of four stereocenters in a single step with excellent enantioselectivity (94-->99% ee).

Rhodium-Catalyzed Asymmetric Addition of Arylboronic Acids to β-Phthaliminoacrylate Esters toward the Synthesis of β-Amino Acids

Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to beta-phthaliminoacrylate esters took place efficiently to give high yields of beta-aryl-beta-amino acid esters with 96-99% enantioselectivity, which was realized by use of a hydroxorhodium/chiral diene complex.

Copper(II)-catalyzed hydrosilylation of ketones using chiral dipyridylphosphane ligands: highly enantioselective synthesis of valuable alcohols.

In the presence of PhSiH(3) as the reductant, the combination of enantiomeric dipyridylphosphane ligands and Cu(OAc)(2)·H(2)O, which is an easy-to-handle and inexpensive copper salt, led to a remarkably practical and versatile chiral catalyst system. The stereoselective formation of a selection of synthetically interesting β-, γ- or δ-halo alcohols bearing high degrees of enantiopurity (up to 99.9% enantiomeric excess (ee)) was realized with a substrate-to-ligand molar ratio (S/L) of up to 10,000. The present protocol also allowed the hydrosilylation of a diverse spectrum of alkyl aryl ketones with excellent enantioselectivities (up to 98% ee) and exceedingly high turn-over rates (up to 50,000 S/L molar ratio in 50 min reaction time) in air, under very mild conditions, which offers great opportunities for the preparation of various physiologically active targets. The synthetic utility of the chiral products obtained was highlighted by the efficient conversion of optically enriched β-halo alcohols into the corresponding styrene oxide, β-amino alcohol, and β-azido alcohol, respectively.

CuII‐Catalyzed Asymmetric Hydrosilylation of Diaryl‐ and Aryl Heteroaryl Ketones: Application in the Enantioselective Synthesis of Orphenadrine and Neobenodine

With certain amounts of sodium tert-butoxide and tert-butanol as additives, catalytic amounts of an inexpensive and easy-to-handle copper source Cu(OAc)(2)⋅H(2)O, a commercially available and air-stable non-racemic dipyridylphosphine ligand, as well as the stoichiometric desirable hydride donor polymethylhydrosiloxane (PMHS), formed a versatile in situ catalyst system for the enantioselective reduction of a broad spectrum of prochiral diaryl and aryl heteroarylketones in air, in high yields and with good to excellent enantioselectivities (up to 96 %). In particular, the practical viability of this process was evinced by its successful applications in the asymmetric synthesis of optically enriched potent antihistaminic drugs orphenadrine and neobenodine.

Silver‐Catalyzed Hydrogenation of Aldehydes in Water

The hydrogenation of organic compounds is one of the most important classes of reactions for the synthesis of biorenewable chemicals and fuels, commodity chemicals, fine chemicals, and pharmaceuticals. Since the widely known Wilkinson catalyst was prepared and used for the hydrogenation of alkenes in the 1960s, a vast number of rhodium, ruthenium, palladium, and iridium catalysts have shown excellent activity in homogeneous hydrogenation. Recently, there has also been significant progress in hydrogenation by using cheaper and more abundant metals (Fe, Co etc.) as catalysts, as well as frustrated Lewis pairs in metal-free systems. Surprisingly, homogeneous complexes of silver, one of the most important metals throughout history, have never shown any practical catalytic organotransformation through activating molecular hydrogen, even though Halpern and Webster reported that inorganic substrates such as [Cr2O7] 2

Preparation of 8-hydroxyquinoline derivatives as potential antibiotics against Staphylococcus aureus.

This work describes the preparation of quinoline compounds as possible anti-bacterial agents. The synthesized quinoline derivatives show anti-bacterial activity towards Staphylococcus aureus. It is interesting to observe that the synthetic 5,7-dibromo-2-methylquinolin-8-ol (4) shows a similar minimum inhibitory concentration of 6.25μg/mL as compared to that of methicillin (3.125μg/mL) against Staphylococcus aureus.

Asymmetric ring-opening of oxabenzonorbornadiene with amines promoted by a chiral iridium-monophosphine catalyst.

A new iridium-monophosphine catalyst is found to be efficient for asymmetric ring-opening of benzonorbornadiene with amines, providing a series of chiral substituted dihydronaphthalenes in high yields (up to 98%) and excellent enantioselectivities (>99%).

Synthesis of β-Amino Acid Derivatives via Copper-Catalyzed Asymmetric 1,4-Reduction of β-(Acylamino)acrylates

A new set of reaction conditions has been established to facilitate the copper-catalyzed enantioselective 1,4-reduction of β-(acylamino)acrylates toward a selection of β-alkyl-β-amino acid derivatives in high yields and with uniformly high ee values (up to 99%) irrespective of the use of (E)- or (Z)-substrates.

Nickel(II)-Dipyridylphosphine-Catalyzed Enantioselective Hydrosilylation of Ketones in Air

Out of thin air: Catalytic amounts of nickel(II) salt and non-racemic dipyridylphosphine ligand, as well as the stoichiometric hydride source PhSiH(3), formed an effective catalyst system for the Ni(II)-catalyzed asymmetric hydrosilylation of a diverse range of electron-deficient aryl alkyl ketones with enantioselectivities up to 90% ee. The practical potential of the protocol was evinced by its good air-stability.