Nicholas Butt

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.

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.

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.

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.

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

Chiral β-aryl-α,β-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.

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.

Recent advances of remote selective C–H activation: Ligand and template design

Regioselective (site selective) control is one of the major aims of research directed towards the development of novel organic methodologies. Regioselective control is especially important for C−H activation reactions because most organic compounds contain a large number of C−H bonds and it can therefore be difficult to differentiate between similarly reactive C−H bonds. Traditional approaches for controlling the regiose‐ lectivity of C−H activation reactions involve the use of an ortho directing group, which results in an ortho‐selective functional‐ ization process, and ortho‐C–H functionalization reactions of this type have been studied extensively [1–7]. In contrast, re‐ ports pertaining to remote selective C–H activation using an existing functional group remain scarce because of the inability of functional groups to strongly direct the activation of a single remote C–H bond. Many examples have been reported for me‐ ta‐selective C–H functionalization reactions by virtue of the steric or electronically biased properties of the arene sub‐ strates, however these usually suffer from limited substrate types and scope [8–22]. In contrast, remote C–H bond activa‐ tion reactions that override the intrinsic electronic and steric properties of the substrate as well as the ortho‐directing effects via a more general method, are less‐well developed. Yu’s pio‐ neering work towards the use of an end‐on template strategy for the activation of C–H bonds has inspired research involving template‐ and ligand‐controlled (mono‐protected amino acid ligands) remote site selective activation of C–H bonds [23–28]. A variety of different nitrile templates have been developed to promote the meta‐selective C–H functionalization reactions of a wide range of substrates, including toluenes, phenols, anilines and carboxylic acids etc. [23–32]. In addition, the research groups of Yu and Dong recently described the development of a novel and elegant meta‐C–H activation strategy using a ligand and norbornene‐type transient mediator (not discussed in this highlight) [33–35]. Herein, we provide a brief overview of re‐ cent developments in the design and application of ligands and templates for the remote site selective C–H activation of aro‐ matic compounds. Yu/Movassaghi and co‐workers [27] have developed sever‐ al sulfonyl‐type templates for the meta‐selective C–H function‐ alization of indoline and indole derivatives (Scheme 1). The focus of this particular study was to develop a robust method for the preparation of the TS2 template for the meta‐selective C–H activation of indoline and indole substrates. Interestingly, however, they also discovered that the TS3 template exhibited enhanced para‐selectivity towards indoline compared with control experiments using the TS1 template. Although the selec‐ tive para C–H functionalization of indolines is not particularly challenging, Yu’s results show that template‐directed para‐C–H bond activation is possible and that this strategy could poten‐ tially be used for the activation of para‐C–H bonds in other systems. The regioselective para‐C–H activation of toluene can be dif‐ ficult compared with indole and indoline substrates. Maiti’s group [36] recently reported the preparation of an interesting template that could direct the Pd‐catalyzed para‐C–H activation of toluene‐type substrates with excellent selectivity. Maiti’s template design strategy differed from Yu’s in the sense that it was dependent on the occurrence of a larger metallacycle pre‐transition state (Scheme 2). Inspired by the cyclophane structure, Maiti’s group employed a biphenyl skeleton for the

Synthesis of Heterocycles via Palladium-Catalyzed Wacker-Type Oxidative Cyclization Reactions of Hydroxy- and Amino-Alkenes

Oxygen and nitrogen containing heterocyclic compounds are some of the most important and prominent structures found in biologically active natural and synthetic products, thus their synthesis is of paramount importance to the chemical community. One particularly important route to the synthesis of these structures is that of Wacker-type oxidative cyclizations. Palladium-catalyzed oxidative cyclizations represent an efficient and simple procedure for the synthesis of a variety of heterocyclic structures. The catalytic system can be fine-tuned to promote different oxidative transformations and to induce asymmetry in to the cyclized products, either via the use of chiral ligands or by manipulating chirality present in the starting substrate.