Late‐Stage Functionalization by Chan–Lam Amination: Rapid Access to Potent and Selective Integrin Inhibitors

Abstract

A late‐stage functionalization of the aromatic ring in amino acid derivatives is described. The key step is a copper‐catalysed diversification of a boronate ester by amination (Chan–Lam reaction) that can be carried out on a complex β‐aryl‐β‐amino acid scaffold. This not only considerably extends the substrate scope of amination partners, but also delivers an array of potent and selective integrin inhibitors as potential treatment agents of idiopathic pulmonary fibrosis (IPF). This versatile chemical strategy, which is amenable to high‐throughput‐array protocols, allows the installation of pharmaceutically valuable heteroaromatic fragments at a late stage by direct coupling to NH heterocycles, leading to compounds with drug‐like attributes. It thus constitutes a useful addition to the medicinal chemist's repertoire.

Chlorinated Solvents: Their Advantages, Disadvantages, and Alternatives in Organic and Medicinal Chemistry

“…The University of Nottingham (UoN) has been hosting drug discovery activities analogous to those undertaken in pharmaceutical companies for 10 years as part of both its teaching and learning (T&L) activities − and also as part of its R&D portfolio. − As of September 2019, the GSK Carbon Neutral Laboratory for Sustainable Chemistry, University of Nottingham project laboratory (which hosts 16 organic and medicinal research chemists and graduate and undergraduate students when at full capacity) has ceased its use of chlorinated solvents for all chromatographic applications except for rare cases involving solubility issues. On average, 20–25 flash chromatographic separations are conducted each week using a Biotage SP4 to purify new investigational medicinal chemistry drug molecules, synthetic natural products, and their intermediates.…”

“…More recently, copper-based methodologies such as the Chan–Evans–Lam reaction have been employed as a late stage functionalization tool in medicinal chemistry by Robinson et al Developments by Ma and co-workers have led to new Cu-catalyzed C–N and C–O bond forming methodologies that have been applied in organic and medicinal chemistry. − A review on the topic is also available …”

Selective Carbon‐Carbon Bond Amination with Redox‐Active Aminating Reagents: A Direct Approach to Anilines†

“…[4] Despite the significance of the developed methods, site-selective amination of simple hydrocarbons or complex molecules via late-stage modification is still highly desired. [5] Carbon skeletons exist ubiquitously in bulk chemicals, biomass and chemical synthetics. [6] Direct skeleton modification of alkylarenes via C-C bond amination would facilitate access to valueadded amines, especially anilines.…”

Iridium-catalysed C–H borylation of β-aryl-aminopropionic acids

“…25 The Chan-Lam coupling was also an effective methodology to access N-linked heteraraomatic β-aryl-aminopropionic acid derivatives, the 1,3-dimethylpyrazole derivates 10 and 11 were accessed in 74 and 68% yield respectively over two steps. 26 These transformations are further examples of the Chan-Lam coupling as a viable sustainable alternative to Pdcatalysed etherification and amination and are compatible with tandem iridium borylation. Bromination of 2i with CuBr 2 provided the 3-bromo-5-tert-butyl derivative 12, this motif is featured in recently reported selective integrin antagonists.…”