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The mysterious time travel of chemistry: What is a "cascade reaction"?
In the field of chemistry, the efficiency and diversity of reactions are often the focus of researchers' exploration, especially when it comes to "cascade reactions". Such reactions allow chemists to carry out multiple, sequential chemical changes in a single process, often without the need to isolate intermediates. This not only improves reaction efficiency but also reduces the generation of chemical waste, representing an innovative trend in modern chemical synthesis.
A cascade reaction is a chemical process consisting of at least two consecutive reactions, whereby the proceeding of each subsequent reaction depends on the chemical functional groups generated in the previous step.
An important point in these reactions is that the reaction conditions are not changed from step to step during the cascade reaction, and no new reagents are added after the initial reaction. This approach is different from "one-pot procedures", which can perform multiple reactions without isolating intermediates, but does not exclude the addition of new reagents or changes in the reaction after the first reaction. The possibility of conditions.
The main advantages of cascade reactions include high atom economy and reduced waste generation in many chemical processes. Not only that, it also reduces the time and effort required to carry out chemical synthesis. The effectiveness and practicality of such reactions can actually be measured by several metrics, such as the number of bonds formed in the overall reaction, the degree of structural complexity that can be increased through the process, and its applicability to a wider class of substrates.
As early as 1917, Robinson's report on the synthesis of "European chamomile" was an early example of a cascade reaction.
Since then, the use of cascade reactions has grown rapidly in the field of total synthesis, facilitating the development of many new organic methodologies. Over the past few decades, the literature reviewing such responses has increased. Of particular note, there has been increasing interest in the development of asymmetric catalysis for cascade processes using chiral organocatalysts or transition metal complexes.
However, the classification of cascade reactions is often difficult due to the diversity of multi-step transformations. Renowned chemist K. C. Nicolaou classified such reactions into nucleophilic/electrophilic reactions, free radical reactions, pericyclic reactions or transition metal-catalyzed reactions, depending on the mechanisms of the steps involved. However, when multiple reaction categories are included in the same cascade, this distinction becomes quite arbitrary, and the entire process is often labeled according to a so-called “main theme.”
Among cascade reactions, almost all examples come from the total synthesis of complex molecules, highlighting their outstanding synthetic utility.
Nucleophilic/electrophilic cascade reaction
Nucleophilic/electrophilic cascade reaction refers to a cascade sequence in which the key step is a nucleophilic or electrophilic attack. One example is the short-range asymmetric synthesis of the broad-spectrum antibiotic (–)-chloramphenicol. In this process, chiral epoxy alcohols react with dichloroacetonitrile in the presence of NaH, and then further produce the corresponding products through a cascade reaction mediated by BF3·Et2O.
Another example is the total synthesis of the natural product pentalenene. This step undergoes a series of nucleophilic attack reactions to ultimately generate the target compound.
Organocatalytic cascade reactions
As a subcategory of nucleophilic/electrophilic reactions, organocatalyzed cascade reactions rely on the key nucleophilic attack driving the reaction to originate from an organic catalyst. One example is the remarkable achievement in the total synthesis of the natural product harziphilone through organic catalytic cascade reactions.Free Radical Cascade Reaction
The key step of the free radical cascade reaction is the free radical reaction, which is an excellent synthetic method due to the high reactivity of free radical species. In 1985, the total synthesis of (±)-hirsutene demonstrated the effectiveness of the free radical cascade, which involved multi-step free radical cyclization reactions.
Pericyclic cascade reaction
Pericyclic reactions are the most common in cascade transformations and include cycloadditions, electrocyclization reactions, and σ-transposition recombination. For example, in 1982, Nicolaou reported the endiandric acid cascade reaction, demonstrating the overall coherence of this process.
Transition metal catalyzed cascade reactions
Combining the novelty of organometallic chemistry with the synthetic power of cascade reactions, transition-metal-catalyzed cascade sequences offer ecological and economic advantages. For example, the synthesis of biologically active tetrahydrotryptophan products via an osmium-catalyzed cascade reaction demonstrated the potential of metal catalysis.Whether it is nucleophilic, free radical or transition metal catalyzed cascade reaction, it shows the infinite possibilities and romance of chemical synthesis. This makes us wonder, how many unknown chemical secrets are waiting for us to uncover in future scientific research?
