Expand the Universe!

Figure 1. Diversity-Oriented Synthesis (DOS). Taken from Ref. [3].

The world of chemical compounds has a parallel to the field of astronomy. The curious ones are never happy about having one universe. The question they always ask is: are there any other universes out there?

The world of chemical compounds resembles that of a chemical ‘space’. Our universe is ‘Nature’. So we are living in a ‘chemical universe’ that includes all the natural products generated from Nature. We rely on these natural products to survive. Organic chemists undertake the challenges of synthesizing these complex molecules. We use these compounds as inspirations to make better drugs. But is that enough? Well, we have taken a step further – we develop analogues of these compounds to improve their biological activities. The next question would be: can we make compounds that are not present in the ‘Natural Product’ Space? Can we expand the ‘chemical space’ using chemistry?

The answer is a resounding ‘yes’, and the way we do it is through the strategy called ‘diversity-oriented synthesis’ (DOS), which is pioneered by Prof. Schreiber at Harvard [1,2]. This week, we have an article in NATURE by Spring et. al. [3]. In the article, they describe and emphasize the potential of using DOS to expand the chemical space. Figure 1 [3] illustrates the promise of DOS. From a common ‘intermediate’, which is densely functionalized, we can use a number of distinct strategies (chemical reactions) to arrive at a number of different ‘drug-like compounds’. The example shown in Figure 1 is indeed an exemplary one. As we will notice, the 3 ‘drug-like compounds’ that are generated from the common ‘intermediate’ have very distinct chemical structures (skeletons), which is exactly the promise DOS offers. Even in a non-DOS setting, it is still possible to generate chemical structures which are distinct to each other - if they are formed via mechanistically different reaction pathways. What DOS stresses about is the promise that chemical structures (skeletons) which are not present in the 'natural-product' world can be synthesized.

On the other hand, the Fragment-based screening (FBS) strategy in the diagram is not at all problematic – that is something that we have been adopting all the time when we are developing new reactions. The fact is just that when both strategies are placed side-by-side, DOS seems to offer a more diverse repertoire of chemical structures. While the retrosynthetic strategy is about a logical analysis of a synthetic problem towards a starting precursor, DOS is working in the opposite direction: we are working form the starting precursor to a diverse array of possible chemical structures.

Diversity-oriented synthesis (DOS) is an engagement in creativity and imagination, with the ultimate aim to explore and expand the ‘chemical space’ we are yet to discover. Expand your universe!

-by Ed Law 4/2/2011


To see an impressive example of DOS by Schreiber et. al., see the following Wikipedia page [4,5]:

http://en.wikipedia.org/wiki/Divergent_synthesis

Reference:

1. In this article I would like to focus on the potential of generating novel chemical structures by diversity-oriented synthesis (DOS). In the perspective of the pharmaceutical industry, DOS is not the most common way of generating lead compounds for screening. This is due to the vast variety of distinct chemical structures that will render the compound libraries less systematic and organized for screening studies. Nevertheless, DOS is a strategy that calls for further exploration in the industry, because we can generate compounds with novel biological properties not present in ‘natural product-like’ compounds.

2. (a)A Planning Strategy for Diversity-Oriented Synthesis. Martin D. Burke and Stuart L. Schreiber Angew. Chemie. Int. Ed. 2003, 43, 1, 46–58. (b) For some recent examples, see: (i)Expanding Stereochemical and Skeletal Diversity Using Petasis Reactions and 1,3-Dipolar Cycloadditions Giovanni Muncipinto, Taner Kaya, J. Anthony Wilson, Naoya Kumagai, Paul A. Clemons, and Stuart L. Schreiber. Org. Lett., 2010, 12 (22), P. 5230–5233; (ii) Gold(I)-Catalyzed Coupling Reactions for the Synthesis of Diverse Small Molecules Using the Build/Couple/Pair Strategy. Tuoping Luo and Stuart L. Schreiber. J. Am. Chem. Soc., 2009, 131 (15), P. 5667–5674

3. Drug discovery: A question of library design. Philip J. Hajduk, Warren R. J. D. Galloway & David R. Spring. Nature 2011, 470, 42–43.

4. http://en.wikipedia.org/wiki/Divergent_synthesis

5. The original reference: Short Synthesis of Skeletally and Stereochemically Diverse Small Molecules by Coupling Petasis Condensation Reactions to Cyclization Reactions Naoya Kumagai, Giovanni Muncipinto, Stuart L. Schreiber. Angew. Chemie. Int. Ed. 2006, 45, 22, 3635-3638.