Optimization in organic synthesis

Organic Synthesis, quo vadis?3 has been a phrase, perhaps in a more modern language, on the lips of the practitioners of this demanding science-art, undoubtedly from the earliest times4 but more vigorously in the last two decades.5 Comparison of achievements of yesterday6 and today7 suggests progress in our abilities to construct molecules of complexity, with higher stereocontrol, faster analysis, and greater prediction of eventual success. However, the practical aspects, on any scale, of brevity, efficiency, safety, eco-consciousness, and energyand resource-frugality remain, as noted by a major synthetic craftsman,8 crudely addressed. The Y2K symbolism is perhaps also appropriate for urgently dedicating our efforts to making headway in the solution of these interrelated goals. Our central science5a progresses on fronts of method development and total synthesis with a great deal of cross-talk and interdependency (see Fig. 1). The burgeoning literature of new methods suggests that 70% are not repeated, perhaps even in the original laboratories, a situation with dire consequences for ascertaining true yield ranges and reproducibility a la the Org. Syn. religion. Furthermore, as judged from a cursory glance of tables in recent journals, much is left to be desired in giving confidence to the user that a method has generality (substrate diversity, FG and steric tolerance, catalyst or reagent minimization, and temperature and solvent optimization). Although the beauty of judiciously modeled use of PGs is to be applauded,9 FG protection is a continuing embarrassment and annoyance. Synthetic chemists are challenging the dogma by daring the multi-FG molecules to behave in the manner desired. Ugi multicomponent reactions10 and combinatorial synthesis11 will undoubtedly soon influence the PG-expediency problem. In industry, statistical programs12 at times drive optimization of reactions thus meeting the normal intense time constraints to produce mulit-kg of commercial substances. Atom-economy, a term coined by another influential synthetic chemist,13 has brought awareness of an issue to academic scientists which their industrial process and development colleagues un-