The step count of a synthesis is a function of which reactions are used and the sequence in which they are performed. Syntheses based on reactions that provide only small increases in target-relevant complexity (TRC; Box 1) generally require more steps than those based on reactions providing greater increases in TRC. The literature is replete with examples of this, as several different research groups succeed in synthesizing a given natural product, but with greatly differing step counts29
As most reactions involve the formation of only one or two bonds, one might conclude that syntheses of very complex compounds would invariably require many reactions and therefore many steps. There are, however, two ways around this apparent problem. The first entails performing a series of reactions in one vessel so that, as the products of each reaction form, they immediately go on to take part in the next reaction of the sequence, ultimately ending up in a final isolatable product. Because the products of each individual reaction are not isolated, the sequence constitutes a single synthetic operation in which many more than two bonds are formed and much time is saved, as only a single set-up, reaction and work-up is required. The second approach to step economy is to invent new reactions that generate greater increases in TRC per step. Both strategies shorten the journey from simple commercial materials to complex targets, with the ultimate goal being to arrive at an ideal synthesis (Box 1). Both save time, while minimizing cost and especially solvent use — solvents are usually removed and discarded at each step of a synthesis, and so are the greatest source of waste in most syntheses.
Such single-operation, multiple-step processes — described variously as serial, cascade, chain, tandem, regenerative or domino reactions — are an increasingly important focus of many research groups30
, and are certainly having an impact on the ability of synthesis to produce complex targets in a step-economical fashion. This strategy draws inspiration, if not validation, from biosynthetic pathways that often proceed through such serial processes. For example, the bio-synthetic route to terpenes and steroids has been mimicked with great success through the efforts of Bill Johnson and others ()31
. Johnson’s synthesis features a biomimetic complexity-building step in which a carbocation intermediate is generated; this is used to make a bond in a way that generates a second carbocation, and the cycle is repeated until the process is terminated. This is a wonderful example of intermediate recycling (regeneration). A related process ()32
that builds on a long-standing biosynthetic hypothesis allows access to complex polyether molecules (found in many marine natural products). Similar cascades have been reported that involve other reactive intermediates, including anions, carbenes3
. Even cross-over processes, in which one reactive intermediate produces a second, different kind of intermediate34
, are emerging as innovative features of step-economical syntheses.
The use of cascade reactions to rapidly generate complexity and value
The chain reactions used to make polymers and oligomers from monomers are also obvious examples of successful cascade processes that involve the regeneration of reactive intermediates. An initiator I reacts with a monomer A to produce an intermediate I–A, which reacts with another monomer to produce I–A–A and on to the final I–[A–A]n
product. Although promising35
, this approach is not yet applicable to a broad range of targets, because of the still unsolved challenges of sequencing the reaction of different monomers (A, B, C) to make, say, I–A–B–C rather than I–A–C–B. Nature choreographs such feats through compartmentalization, proximity and templating processes. Mimicking these processes in the lab represents a priority research opportunity for chemists.
So what of the second approach for achieving greater step economy: the design or discovery of new reactions that greatly increase TRC? As we have seen, such reactions offer tremendous opportunities to move syntheses towards the ideal (). A historical example is the synthesis of cyclooctatetraene, a relatively simple-looking compound of significant theoretical interest, which originally required more than 10 steps to produce in a 1–2 % overall yield (). Although the efficiency and selectivity of this synthesis could no doubt be optimized further, the introduction of a new reaction — a nickel-catalysed process in which four acetylene (H–C
C–H) molecules react to form four bonds in one step — allowed cyclooctatetraene to be made in one step, in more than 90% yield36
. One of the more striking examples yet of a complexity-generating reaction is the arene–alkene metaphotocycloaddition, in which three new bonds and up to six chiral carbon centres are formed, an exceptional increase in complexity. This reaction has greatly shortened the syntheses of numerous natural products, underscoring the profound impact that new complexity-generating reactions can have on step economy37
Despite impressive progress in the field of synthesis, we are currently awash with complex, potentially useful natural products that cannot be made in the quantities required for scientific research or therapeutic use. In some cases, enzymes, cells, or even whole organisms can be used to produce such compounds, simple analogues of them, or precursor materials easily converted to the compound of interest38
. This approach benefits from nature’s refined pathways, but the specific nature of biosynthetic machinery means that there are limits to the range of structures it can prepare. For fields such as drug discovery, this limitation suggests that, in addition to natural products and natural-product-like compounds available through biosynthesis, one must embrace a broader range of structural (and synthetic) possibilities. New molecular scaffolds are needed if we are to truly exploit the potential of organic synthesis.