Organic & Biomolecular Chemistry Blog

Computational chemistry is a powerful tool for understanding real-world chemical problems. The gap between experiment and computational models is growing ever smaller. Calculated results for isolated molecules are becoming more relevant and reliable calculations for larger and larger molecular systems are becoming more accessible.

A computational study of enantioselective spiroacetalization catalyzed by phosphoric acids carried out by researchers at the Universidad de Salamanca and Oxford University effectively demonstrates the ability of advanced computational methods to elucidate key and often subtle factors that lead to different reaction outcomes.

The study uses a hybrid quantum mechanics (QM)/molecular mechanics (MM) method which makes computational simulations of large systems feasible by combining an accurate quantum mechanical description of the ‘interesting’ part of the system (i.e. the catalyst active site) with the computational efficiency of molecular mechanics applied to the surroundings. This way, one can assess the importance of environmental effects while avoiding a high computational cost. This is accomplished by partitioning the system’s total energy into inner (or active) and outer parts. The interactions within the inner part are then treated with the computationally higher quantum mechanics level and the outer parts are described using less expensive, lower level molecular mechanics methods.

The origin of greater enantioselectivity for the imidodiphosphoric acid (Figure, cat-II) over the binol phorophoric acid (Figure, cat-I) was determined through exhaustive analysis of transition state conformers using the QM/MM method. Ultimately,  it was determined that the source of chiral discrimination in catalyst II comes from a unique, bifunctional hydrogen bonding interaction between the catalyst and substrate. This confining interaction ends up limiting the accessible area to the imidodiphosphoric oxygen, resulting in an enantioselective outcome.

The significance of this work lies in the utility of theoretical models in explaining important empirical results. The ability to dissect a mechanism and identify the influential factors that determine a selective reaction outcome could not have been so easily accomplished without the use of computational analysis and will no doubt aid in the design of future organocatalysts for small, non-sterically demanding molecules.

To find out more see:

QM/MM study on the enantioselectivity of spiroacetalization catalysed by an imidodiphosphoric acid catalyst: how confinment works
Luis Simón and Robert S. Paton
DOI: 10.1039/C6OB00045B

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.

Target-based approaches to drug discovery have dominated pharmaceutical research since the early 1990s because they allow for increased screening capacity and rational drug design. Advances in combinatorial chemistry, high-throughput screening and gene expression profiling have been effective in the development of novel treatments for validated targets; however, a link between the downward trend in the number of new chemical entities reaching commercialization and the predominance of target-based drug discovery methods in the pharmaceutical industry has been suggested.

To address these issues, new technologies are constantly being developed and fragment-based drug design (FBDD) has emerged as a way to improve the quality and (most importantly) the efficiency of the drug discovery process. FBDD identifies the binding of low molecular weight ligands using techniques such as X-ray crystallography or NMR spectroscopy, and the binding information is then used to assemble potent lead compounds with drug-like properties.

In a recent publication, researchers at Astex Pharmaceuticals have noted that the success of FBDD often relies on the development of new synthetic methodologies for ligand elaboration. Despite the simplicity of fragment-like compounds, challenges lie in their design and synthesis as well as in developing the methodology to combine and grow fragments into high affinity leads. It is therefore important to identify compounds with attractive ‘fragment properties’ which are used as part of a selection process for adding new fragments into the Astex screening library. These include incorporation of diverse polar groups, multiple synthetically accessible positions for fragment growth in three dimensions and synthetic tractability among others.

Dihydroisoquinolone and some of its derivatives were identified in this study as ideal fragment-like compounds for the development of a FBDD-friendly synthetic methodology.

As proof of concept, the previously reported synthesis of dihydroisoquinolone-based compounds using Rh(III)-catalyzed C-H bond activation¹ was modified to incorporate additional potential binding groups as well as synthetic handles for efficient fragment-to-lead elaboration.

Their results illustrate an excellent example of how the application of FBDD-friendly synthetic methodology can be used to expand upon published methodologies to increase their utility in developing useful templates for fragment-based drug discovery. Although inventive ideas, such as this work, are making small contributions in pharmaceutical research, there is a need for more organic chemists to engage in these synthetic challenges if drug discovery techniques are to be fruitful in the long-run.

¹ N. Guimond et al. J. Am. Chem. Soc., 2011, 133(16), 6449–6457


To find out more see:

Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD)
Nick Palmer, Torren M. Peakman, David Norton and David C. Rees
DOI: 10.1039/C5OB02461G

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.