Time and Pot Economy in Total Synthesis

Abstract

Conspectus We would all like to make or obtain the materials or products we want as soon as possible. This is human nature. This is true also for chemists in the synthesis of organic molecules. All chemists would like to make their target molecules as soon as possible, particularly when their interest is in the physical or biological properties of those molecules. As demonstrated by today’s COVID-19 (SARS-CoV-2) pandemic, rapid synthesis is also crucial to enable chemists to deliver effective therapeutic agents to the community. Several concepts are currently well-accepted as important for achieving this: atom economy, step economy, and redox economy. Considering the importance of synthesizing organic molecules rapidly, I recently proposed adding the concept of time economy. In a multisep synthesis, each step has to be completed within a short period of time to make the desired molecule rapidly. The development of rapid reactions is important but also insufficient. After each step, frequent and repetitive workup operations such as quenching the reaction, extraction, separation of water and organic phases, drying the organic phase, filtration, evaporation, and purification may be required, and the time necessary for these processing operations must be taken into account. Indeed, some of the most time-consuming operations in most syntheses are the purification stages. On the other hand, one-pot reactions are processes in which several sequential reactions are conducted in a single reaction vessel, which avoids the need to purify intermediates. One-pot reactions are a useful way to shorten the total synthesis time, and the approach generally leads to an increase in the yield and a reduction in the amount of chemical waste formed. Thus, I also propose the importance of pot economy. On the basis of these concepts of time and pot economy, we have accomplished efficient syntheses of several natural products and medicines. The key to the success of these syntheses is the use of diphenylprolinol silyl ether as an effective catalyst in a one-pot reaction, in which it does not disturb the subsequent reactions. Our strategy is (1) to construct the chiral key skeletons and/or key components of natural products and medicines directly using organocatalyst-mediated one-pot reactions and (2) to conduct the subsequent transformations to the final molecules in a small number of pots utilizing the internal quench method. By means of this strategy, PGE1 methyl ester, estradiol methyl ether, and clinprost were synthesized in three, five, and seven pots, respectively. Furthermore, (−)-oseltamivir, ABT-341, baclofen, and Corey lactone were synthesized in a single reaction vessel. Further optimization of the reactions in terms of time economy allowed (−)-oseltamivir and Corey lactone to be synthesized within 60 and 152 min, respectively. These syntheses will be highlighted as case studies. Although the organocatalyst is a key compound in this Account, pot- and time-economical syntheses can be expanded to organometallic chemistry and, ind...

Is Organic Chemistry Really Growing Exponentially?

“…On am ore positive note,w ithin these newly discovered reaction types there is ag rowing fraction of complex and multicomponent transformations that can generate complex scaffolds in fewer steps and offer improved atom and pot-efficiencies. [8] These results can be considered from several perspectives.M ore narrowly, in the context of computer-aided synthesis planning, the limited rate at which chemistry expands means that expert coding of reaction rules is,atleast for the foreseeable future, scalable and can be kept au courant. Our analyses also provide clues which of the reported reactions are reliable and which ones are likely erroneous and should not be taught to the machines (and also be removed from reaction repositories).…”

Is Organic Chemistry Really Growing Exponentially?

“…Only few thousands of new reaction types are reported each year and their proportion, compared to all reported reactions, keeps decreasing. On a more positive note, within these newly discovered reaction types there is a growing fraction of complex and multicomponent transformations that can generate complex scaffolds in fewer steps and offer improved atom and pot‐efficiencies [8] . These results can be considered from several perspectives.…”

Synthesis of Natural Products by C−H Functionalization of Heterocycless

“…During the last decades, several concepts were proposed for achieving the perfect vision of total synthesis, such as atom economy, step economy, or redox economy [8–10] . Furthermore, the concepts of achieving ideality as well as time and pot economy were introduced to evaluate the efficiency of total synthesis of natural products [11,12] …”

“…In particular, many bioactive natural products feature heterocyclic architectures that are essential for their biological properties. To complete total synthesis of natural products, various synthetic methods have been developed [3–13] . Undoubtedly, the most powerful reactivity platform that has emerged over the past years is the direct functionalization of C−H bonds, empowering rapid synthesis of complex natural products as well as enabling diversification of bioactive scaffolds based on natural product architectures [14,15]…”