Ranking of Synthesis Plans

Abstract

Hendrickson's definition of the "ideal synthesis" serves as a benchmark to assess synthesis plans. Criteria such as convergency, increase in complexity, and ro-bustness are presented to rank synthesis plans and to pinpoint weaknesses therein. Any ranking of plans for the synthesis of a given target compound depends on benchmarks which must be defined. Possible criteria may be • the shortest route (time involved), • the cheapest route (cost of materials), • the novelty of the route (patentability), • the greenest route (avoidance of problematic waste), • the healthiest route (avoidance of toxic intermediates and side products), • the most reliable route (lowest risk approach). Aside from these external criteria, ranking of synthesis proposals could also follow systematic criteria, e.g., the step count. A synthesis that reaches the target in fewer steps than another one is considered superior. Every synthesis consists of obligatory steps, i.e., those by which the skeleton is made. When focusing on this aspect, the bond-set would give a lower limit to the number of steps involved in a projected synthesis, because any refunction-alization steps and protecting group management steps count in addition to the skeleton forming steps. Because of this, the bond-set does not reveal too much about a step count and the quality of a projected synthesis. For instance, the differences between the bond-sets of Woodward's [1] and Muxfeldt's [2] tetracycline syntheses are minimal (Scheme 8.1). Comparison of the bond-sets does not reveal that in Muxfeldt's synthesis three bonds are formed in one operation rendering this synthesis significantly shorter-22 steps in Woodward's synthesis versus 17 in Muxfeldt's.