Organic & Biomolecular Chemistry Blog

It comes as no surprise to those with a background in organic or medicinal chemistry that one of the most important and often-overlooked synthetic transformations is the formation of amide bonds.

Amide linkages are one of the most prolific moieties in the synthesis of pharmaceuticals and biologically active molecules. However, despite their prevalence there remain synthetic challenges, as even the simplest amides can be difficult to make.

A group at the University of Southern Denmark led by Prof. Trond Ulven has developed a protocol for amide coupling through in situ formation of acyl fluorides.

Initially, the researchers were working toward the synthesis of a molecular inhibitor for the free fatty acid receptor 2 (FFA2/GPR43), which has recently generated some interest as a target for treating various metabolic disorders.

While attempting the synthesis of an intermediate, coupling between their sterically hindered and sensitive carboxylic acid with an electron deficient and hindered amide understandably led to unsatisfactory results using standard coupling procedures.

Given the multiple steps required to generate both intermediates, the group decided to explore alternative methods to solve their problem. Indeed, acyl fluorides proved to be ideal as they behave like activated esters due to the unique nature of the carbonyl-fluoride bond while also minimizing steric hindrance between the two coupling partners.

Literature protocols are available for the generation of acyl fluorides and there are disadvantages associated with some. In recent years however, a number of alternative fluorinating agents have been reported that are capable of generating the acyl fluoride in situ under mild reaction conditions.

Prof. Ulven’s group was able to further improve the efficiency of this methodology by utilizing an alternative fluorinating agent, BTFFH, which is normally used in solid-phase peptide synthesis. This reagent reduces byproduct formation observed with reagents such as DAST, Deoxo-Fluor and XtalFluor-E. High conversions and isolated yields were obtained as a result and Ulven’s method was also successfully applied to amide coupling reactions previously reported as low yielding.

There is still a need for chemists to develop better ways to synthesize complex amide-containing structures without the need for external reagents. In the meantime, solutions such as these overcome synthetic challenges and are critical to further development and understanding in organic reaction design.


To find out more see:

A protocol for amide bond formation with electron deficient amines and sterically hindered substrates
Maria E. Due-Hansen, Sunil K. Pandey, Elisabeth Christiansen, Rikke Andersen, Steffen V. F. Hansen and Trond Ulven
DOI: 10.1039/C5OB02129D

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

For centuries, natural products have been linked to medicine through traditional remedies and since played an important role in drug discovery.

New tagetitoxin structure based on 2D NMR correlations

Despite competition from other drug discovery methods, natural products have provided their fair share of clinical candidates and commercial drugs. Furthermore, the isolation, synthesis and biological evaluation of natural products often lead to lasting impressions in science.

In a recent study lead by Dr Abil Aleiv of the University College London, the structure of the known natural product tagetitoxin has been revised based on a detailed analysis of newly acquired NMR and MS data. The group employed 2D ¹H–¹³C HMBC correlations and long-range J_CH couplings in conjunction with computational analysis to correlate J_CH couplings with predicted values.

For several years, the structure of tagetitoxin remained a mystery. First identified in 1981 by Mitchell, the structure was only partially characterized by MS and was proposed to be an 8-membered heteroatomic ring.  Revised structures have since been published by Mitchel (1989), Vassylyev (2005) and Gronwald (2005). Despite all these efforts, conflicting results and incomplete analyses resulted in the absolute configuration remaining undetermined.

Structures of tagetitoxin previously published by Mitchel (1989), Vassylyev (2005) and Gronwald (2005)

Early analysis of complex structures was generally difficult as spectrometers were relatively insensitive and experiments were performed at low-fields strengths. Through the increasing prevalence and utility of modern 2D NMR experiments in the past decade, NMR has become a powerful and enabling tool for structure elucidation and confirmation.

In addition, the key to Dr Aliev’s findings lies in confirming the purity of the tagetitoxin sample the group had acquired. They noted that the compound gradually decomposed in aqueous solutions if left for prolonged periods of time, which they suspect led to additional peaks being observed in previously reported NMR spectra.

This exciting work showcases the importance of technical advances in determining the structure of biologically active natural products with greater ease and confidence. As a result, advances in lead development and the identification of important families of pharmacophores for drug discovery can be attained with greater efficiency, which may contribute to a revival of interest in natural products for drug discovery purposes.

To find out more see:

The structure of tagetitoxin
Abil E. Aliev, Kersti Karu, Robin E. Mitchell and Michael J. Porter
DOI: 10.1039/c5ob02076j

Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.