Step Economy & Function Oriented Synthesis
Over the past half-century, synthetic chemists have impressively demonstrated an ability to make complex molecules. The most important goal in synthesis now is to make target molecules in a practical and green if not ideal fashion. Step economy is by far the factor that most influences the practicality of a synthesis. It dictates time, cost, waste stream, scale and many other factors. Step economy in turn relies heavily on the invention or discovery of new reactions. New reactions can be used to take an otherwise long and impractical synthesis and convert it to a practical synthesis that can be conducted on scale.
The importance of new reactions to step economy: New reactions provide new ways to think about synthesis, allowing one to take a long synthesis and make it step economical. Consider the Willstatter synthesis of cyclooctatetraene (COT: 13 steps, 1-2 % yield) published in 1911 and that of Reppe based on a then new metal catalyzed reaction (1 step, 70% yield), a powerful demonstration of the importance of new reactions for achieving step economy. Other new reactions introduced by our group appear later in this document.
Step economy by function oriented design and synthesis (FOS): Most synthetic studies these days are directed at targets that have interesting structural but often even more importantly functional properties, like biological activity or value as a catalyst, probe, sensor or imaging agent. Phorbol, for example, a structurally fascinating and synthetically daunting challenge, has been one of the most studied molecules of the last century in part because of its exceptional activity (function). Its synthesis (achieved by our group) required 29 steps. By studying the structure of phorbol and molecules with similar function like DAG using computer modeling, our group proposed a simpler FOS target that could be prepared in only 7 steps. Significantly, the designed FOS target exhibited the function (activity) of phorbol. This represents a powerful strategy to achieve step economy by designing targets that have function of interest but that could be made in a practical fashion that allows synthetic innovation. Other examples of step economy achieved through function oriented design and synthesis appear below (see Bryostatin and designed bryologs).
- Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. “Function Oriented Synthesis, Step Economy, and Drug Design” Acc. Chem. Res. 2008, 41, 40-49.
- Wender, P. A.; Miller, B. L. Nature 2009, 460, 197–201.