Asymmetric Hydrogenation of Nonaromatic Cyclic Substrates.

Chiral cyclic structures are found in numerous natural products, pharmaceutical compounds, and important synthetic intermediates. Asymmetric hydrogenation, allowing for the preparation of these complex targets in an environmentally benign and efficient manner, has received much attention over the past few years. This review summarizes the advances in the construction of chiral heterocycles and carbocycles (including cyclic amines, ethers, alcohols, and alkanes) via the asymmetric hydrogenation of nonaromatic cyclic substrates (including prochiral cyclic imines, ketones, and alkenes) using appropriate transition-metal complexes.

Allylic Alkylations with Enamine Nucleophiles.

Allylic alkylation reactions are some of the most important carbon-carbon bond forming reactions in organic synthesis. In particular, the alkylation of carbonyl substrates provides an efficient pathway to structurally diverse molecules. Such reactions predominantly rely on the in situ generation of a nucleophilic enamine intermediate. This brief personal account describes research carried out in our group concerning the Pd-catalyzed allylic alkylation of carbonyl compounds using these species. Our methodology combines Pd-catalysis with metallocene ligands to carry out these transformations.

Pd(II)-Catalyzed Asymmetric Addition of Arylboronic Acids to Isatin-Derived Ketimines.

A Pd(II)/Pyrox-catalyzed enantioselecitve addition of arylboronic acids to 3-ketimino oxindoles was developed, providing chiral 3-amino-2-oxindoles with a quaternary stereocenter in high yields and with good enantioselectivities. A variety of functionalized 3-ketimino oxindoles can be used, and the method tolerates some variation in arylboronic acid scope. This asymmetric arylation provides an alternative efficient catalytic method for the preparation of chiral 3-aryl-3-amino-2-oxindoles, which also represents the first example of a Pd(II)-catalyzed addition of arylborons to exocyclic ketimines.

Transition metal-catalyzed allylic substitution reactions with unactivated allylic substrates.

The transition metal-catalyzed allylic substitution of unactivated allylic substrates (allylic alcohols, allylic ethers and allylic amines) is rapidly becoming an important area of research. There are several advantages to using these substrates in allylic substitution reactions: the use of unactivated alcohols minimizes the production of waste by-products and reaction steps; and allylic ethers and allylic amines are useful substrates because of their stability and their presence in numerous biologically active compounds. Research in this field has therefore gained widespread attention for promoting the development of efficient and environmentally benign procedures for the formation of C-C, C-N and C-O bonds.

Asymmetric tandem reactions of N-sulfonylimines and α,ß-unsaturated aldehydes: an alternative reaction pathway to that of using saturated aldehydes.

An organocatalyzed asymmetric tandem reaction of cyclic N-sulfonylimines and α,ß-unsaturated aldehydes was developed. These substrates follow an alternative reaction pathway to that of reactions involving saturated aldehydes, affording similar piperidine derivatives.

Asymmetric domino reaction of cyclic N-sulfonylimines and simple aldehydes with trans-perhydroindolic acid as an organocatalyst.

An asymmetric domino reaction was developed utilizing readily available cyclic N-sulfonylimines and simple aldehydes to construct biologically important and synthetically challenging piperidine derivatives consisting of three contiguous stereocenters. trans-Perhydroindolic acid proved to be an efficient organocatalyst in this reaction (up to 89% yield, 80:20 dr, and 99% ee). The absolute configuration of the catalytic product was determined by X-ray crystallography studies. The product could be conveniently converted to synthetically useful intermediates, such as (3R,4S)-4-ethyl-3-methyl-6-phenylpiperidinyridin-2-one (8), via a simple transformation.

The synthesis of chiral ß-aryl-α,ß-unsaturated amino alcohols via a Pd-catalyzed asymmetric allylic amination.

Chiral ß-aryl-α,ß-unsaturated amino alcohols were synthesized via a Pd-catalyzed asymmetric allylic amination of 4-aryl-1,3-dioxolan-2-one using planar chiral 1,2-disubstituted ferrocene-based phosphinooxazolines as ligands. Under the optimized reaction conditions, a series of substrates were examined and the products were obtained in good to excellent yields (up to 92%) and enantioselectivities (up to 98% ee) under mild reaction conditions. The desired products were determined to be of (R)-configuration and could subsequently be transformed into compounds with interesting biological activity using simple transformations.

Palladium-catalyzed asymmetric hydrogenation of α-acyloxy-1-arylethanones.

First hand: The first example of a palladium-catalyzed asymmetric hydrogenation of α-acyloxy ketones (1) was accomplished to give the hydrogenated products 2 with by far the highest catalytic efficiency in up to quantitative conversions and excellent enantioselectivities. The hydrogenated products could serve as important intermediates for the preparation of many drug candidates. TFE=2,2,2-trifluoroethanol.

Synthesis of spirotetramates via a Diels-Alder approach.

A study toward the unusual spirotetramate core of the pyrroindomycin antibiotics employing an intermolecular Diels-Alder reaction of an exo-methylene tetramic acid dienophile is described. The exo-methylene tetramate is readily synthesized from S-methylcysteine, and its reactivity as a dienophile is compared with that of related dehydroalanine derivatives. An alternative approach to spirotetramates using a nitroalkene dienophile is also reported.