Matthew O. Kitching

Palladium‐Catalyzed Cross‐Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize

In 2010, Richard Heck, Ei-ichi Negishi, and Akira Suzuki joined the prestigious circle of Nobel Laureate chemists for their roles in discovering and developing highly practical methodologies for C-C bond construction. From their original contributions in the early 1970s the landscape of the strategies and methods of organic synthesis irreversibly changed for the modern chemist, both in academia and in industry. In this Review, we attempt to trace the historical origin of these powerful reactions, and outline the developments from the seminal discoveries leading to their eminent position as appreciated and applied today.

Goldberg Active Template Synthesis of a [2]Rotaxane Ligand for Asymmetric Transition-Metal Catalysis

We report on the active template synthesis of a [2]rotaxane through a Goldberg copper-catalyzed C-N bond forming reaction. A C2-symmetric cyclohexyldiamine macrocycle directs the assembly of the rotaxane, which can subsequently serve as a ligand for enantioselective nickel-catalyzed conjugate addition reactions. Rotaxanes are a previously unexplored ligand architecture for asymmetric catalysis. We find that the rotaxane gives improved enantioselectivity compared to a noninterlocked ligand, at the expense of longer reaction times.

Copper‐Catalyzed Cross‐Coupling Interrupted by an Opportunistic Smiles Rearrangement: An Efficient Domino Approach to Dibenzoxazepinones

The construction of C O and C N bonds by palladiumand copper-mediated cross-coupling approaches has undergone a renaissance in the last decade. Although the utility of these coupling approaches to effect a single-bond construction event has now been established, the quest to improve efficiency has driven the further exploration of one-pot procedures for effecting multiple transformations, often by a domino approach. Success in this area has come from impressive examples of ligand control, finely tuned multicatalyst systems, and exploitation of established multicomponent reactions. Based on our previous experience with Ullmann couplings of 2-halobenzamides, combined with the established Goldberg N-arylation methods, 8] we envisaged that a copper-catalyzed one-pot annulation between 2-iodobenzamides 2 and 2-bromophenols 3 would allow access to dibenzoxazepinones 1 by selective C O and C N bond forming events (Scheme 1).

Cancer, Chemistry, and the Cell: Molecules that Interact with the Neurotensin Receptors

The literature covering neurotensin (NT) and its signalling pathways, receptors, and biological profile is complicated by the fact that the discovery of three NT receptor subtypes has come to light only in recent years. Moreover, a lot of this literature explores NT in the context of the central nervous system and behavioral studies. However, there is now good evidence that the up-regulation of NT is intimately involved in cancer development and progression. This Review aims to summarize the isolation, cloning, localization, and binding properties of the accepted receptor subtypes (NTR1, NTR2, and NTR3) and the molecules known to bind at these receptors. The growing role these targets are playing in cancer research is also discussed. We hope this Review will provide a useful overview and a one-stop resource for new researchers engaged in this field at the chemistry-biology interface.

A Machine‐Assisted Flow Synthesis of SR48692: A Probe for the Investigation of Neurotensin Receptor‐1

Here we report the direct comparison of a conventional batch mode synthesis of Meclinertant (SR48692, 1), a neurotensin receptor-1 antagonist, with its machine-assisted flow chemistry alternative. By using these enabling tools, combined with solid-supported reagents and scavengers, many process advantages were observed. Care, however, must be taken not to convert these techniques into expensive solutions to problems that do not exist.

Sequence-Specific β-Peptide Synthesis by a Rotaxane-Based Molecular Machine

We report on the synthesis and operation of a three-barrier, rotaxane-based, artificial molecular machine capable of sequence-specific β-homo (β3) peptide synthesis. The machine utilizes nonproteinogenic β3-amino acids, a class of amino acids not generally accepted by the ribosome, particularly consecutively. Successful operation of the machine via native chemical ligation (NCL) demonstrates that even challenging 15- and 19-membered ligation transition states are suitable for information translation using this artificial molecular machine. The peptide-bond-forming catalyst region can be removed from the transcribed peptide by peptidases, artificial and biomachines working in concert to generate a product that cannot be made by either machine alone.

The synthesis of neurotensin antagonist SR 48692 for prostate cancer research.

An improved synthesis of the molecule SR 48692 is presented and its use as a neurotensin antagonist biological probe for use in cancer research is described. The preparation includes an number of enhanced chemical conversions and strategies to overcome some of the limiting synthetic transformations in the original chemical route.

Ruthenium-Catalyzed Dehydrative Benzofuran Synthesis via C–H Activation

Significance: Reported is the ruthenium-catalyzed dehydrative ortho-functionalization of phenols 1 with diols 2 affording benzofurans 4. When simple alcohols were employed, only ortho-functionalized phenols were obtained (not shown). When diols 2 were employed, the cyclized benzofurans 4 were the preferred products. Inclusion of an excess of a simple alkene (cyclopentene) promoted the coupling reaction. An impressive array of substrates were shown to undergo the transformation (4a–x), including more complex diols (4u) and structurally elaborate phenols (4s,4v,4w). A cursory investigation of the reaction mechanism is also reported. Comment: The present report represents a highly convenient and robust method for the synthesis of substituted benzofurans, which are medicinally relevant heterocycles with a diverse range of biological activities (see Review below). The sheer scope and high yields of the reported process appear to make this method highly attractive for the synthesis of 2-substituted benzofurans. It would be interesting to know if the process performed as well on scale (10 g and above) as it does on more standard quantities (1 mmol).