Ideality in Context: Motivations for Total Synthesis.

Total synthesis-the ultimate proving ground for the invention and field-testing of new methods, exploration of disruptive strategies, final structure confirmation, and empowerment of medicinal chemistry on natural products-is one of the oldest and most enduring subfields of organic chemistry. In the early days of this field, its sole emphasis focused on debunking the concept of vitalism, that living organisms could create forms of matter accessible only to them. Emphasis then turned to the use of synthesis to degrade and reconstitute natural products to establish structure and answer questions about biosynthesis. It then evolved to not only an intricate science but also a celebrated form of art. As the field progressed, a more orderly and logical approach emerged that served to standardize the process. These developments even opened up the possibility of computer-aided design using retrosynthetic analysis. Finally, the elevation of this field to even higher levels of sophistication showed that it was feasible to synthesize any natural product, regardless of complexity, in a laboratory. During this remarkable evolution, as has been reviewed elsewhere, many of the principles and methods of organic synthesis were refined and galvanized. In the modern era, students and practitioners are still magnetically attracted to this field due to the excitement of the journey, the exhilaration of creation, and the opportunity to invent solutions to challenges that still persist. Contemporary total synthesis is less concerned with demonstrating a proof of concept or a feasible approach but rather aims for increased efficiency, scalability, and even "ideality." In general, the molecules of Nature are created biosynthetically with levels of practicality that are still unimaginable using the tools of modern synthesis. Thus, as the community strives to do more with less (i.e., innovation), total synthesis is now focused on a pursuit for simplicity rather than a competition for maximal complexity. In doing so, the practitioner must devise outside-the-box strategies supplemented with forgotten or newly invented methods to reduce step count and increase the overall economy of the approach. The downstream applications of this pursuit not only empower students who often go on to apply these skills in the private sector but also lead to new discoveries that can impact numerous disciplines of societal importance. This account traces some select case studies from our laboratory over the past five years that vividly demonstrate our own motivation for dedicating so much effort to this classic field. In aiming for simplicity, we focus on the elusive goal of achieving ideality, a term that, when taken in the proper context, can serve as a guiding light to point the way to furthering progress in organic synthesis.

Total Synthesis of (-)-Maximiscin.

A short, enantioselective synthesis of (-)-maximiscin, a structurally intriguing metabolite of mixed biosynthetic origin, is reported. A retrosynthetic analysis predicated on maximizing ideality and efficiency led to several unusual disconnections and tactics. Formation of the central highly oxidized pyridone ring through a convergent coupling at the end of the synthesis simplified the route considerably. The requisite building blocks could be prepared from feedstock materials (derived from shikimate and mesitylene). Strategies rooted in hidden symmetry recognition, C-H functionalization, and radical retrosynthesis played key roles in developing this concise route.

Decarboxylative alkenylation.

Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.