Abstract
In this review, applications of the amide reductive functionalization methodology for the synthesis and modification of bioactive compounds are covered. A brief summary of the different protocols is presented in the introduction, followed by the synthetic application of these in late-stage functionalization, leading to known pharmaceuticals or to their derivatives, including bioisosteres, with potential higher activity as the main axis of the article. The synthetic approach to natural products based on amide reduction is also discussed; however, this is given in a condensed form focusing on recent or as yet unexplored applications due to a number of recently published excellent reviews covering this topic. The aim of this review is to illustrate the potential of reductive functionalization of amides as an elegant and useful tool in the synthesis of bioactive compounds and inspire further work in this field.
Highlights
The addition of nucleophiles to amides to obtain substituted amines represents a major challenge, and only scattered applications for particular substrates have appeared
Natural products have long been known to be an excellent source of bioactive compounds as illustrated by the fact that 28% of the drugs approved to date have a natural origin or are a derivative of such (Laraia et al, 2018)
The iridium-catalyzed chemoselective functionalization of lactam by 2-siloxyfuran in the presence of an epoxy function furnished an inseparable mixture of diastereoisomers with combined 63% yield, which was separated after the step to pure hemiacetals (47% yield for major, 32% for the minor product), which suggests the diastereoselectivity of reductive functionalization on level 1.5:1
Summary
The addition of nucleophiles to amides to obtain substituted amines represents a major challenge, and only scattered applications for particular substrates have appeared. Initial improvements were based on the activation of amides by the introduction of particular substituents, such as N-methoxy amides (Weinreb amides) or electron-withdrawing groups able to increase the carbon nucleophilicity (Pace et al, 2014) and enhance the rate of nucleophilic addition in comparison with C–N bond cleavage, which prevents daunting overaddition problem (Li and Szostak, 2020). These strategies facilitate the introduction of nucleophiles, chemoselectivity issues arise when additional electrophilic moieties (e.g., carbonyls) are present, decreasing the versatility of these methods. Relevant to this theme is the seminal example by Ganem (Schedler et al, 1993), extended later by Georg (mechanistic studies) (Spletstoser et al, 2007), Chida and Sato (acyclic amides) (Oda et al, 2012), and Furman (lactams) (Szczesniak et al, 2014) about the conversion of amides to imines
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