Total Synthesis Endeavors and Their Contributions to Science and Society: A Personal Account

Abstract

The advent of organic synthesis in the 19th century, serendipitous as it was, set in motion a revolution in science that continues to evolve into increasing levels of sophistication and to expand into new domains of science and technology for the benefits of science and society. Its evolution was always driven by the challenges posed by natural products, whose structures were becoming increasingly complex and diverse. In response to these challenges, synthetic organic chemists were prompted to sharpen their art to reach their target molecules, whose structures were often confirmed only after their synthesis in the laboratory through the art and science of total synthesis. The latter became the “locomotive” and the “flagship” of organic synthesis, for through this practice novel synthetic methods were discovered and invented, and also tested for their generality, applicability, and scope with regard to molecular complexity and diversity. The purpose of total synthesis has also evolved over the years to include aspects beyond the synthesis of the molecule and confirmation of its structure. In this article, we briefly review the evolution of total synthesis in terms of its power and reach and demonstrate its current state of the art that combines fundamentals with translational aspects through examples from our laboratories. The highlighted examples reflect the newly emerged paradigm of the discipline that includes—in addition to the total synthesis of the target molecule—structural elucidations, method discovery and development, design, synthesis, and biological evaluation of analogues for biology and medicine, and training of young students, preparing them for academic and industrial careers in the various disciplines that require knowledge and skills to practice the central science of chemical synthesis. Such disciplines include chemical biology, drug discovery and development, materials science and nanotechnology, and other endeavors whose fundamentals depend and rely on the structure of the molecule and its synthesis.

The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

“…The latter became the “flagship”, and the symbol of the state of the art of organic synthesis and, therefore, the locomotive driving its continuous evolution to higher and higher levels of power and performance. In addition to its advancement in terms of sophistication and reach, the purpose of total synthesis also expanded from its initial proof of principle (i.e., synthesis of urea) to the task of confirming the structure of the targeted natural product, and more recently, from demonstrating its art to applying its enabling power to facilitate biology and medicine . As we shall see below, the total synthesis of calicheamicin γ 1 I and its thioacetate analogue, calicheamicin θ 1 I , in our laboratories in the 1990s provided the first examples of the power of total synthesis in rendering readily available rare and complex natural products and their analogues as potential payloads for antibody–drug conjugates.…”

Die Bedeutung der organischen Synthese bei der Entstehung und Entwicklung von Antikörper‐Wirkstoff‐Konjugaten als gezielte Krebstherapien

“…Letztere wurde zum “Flaggschiff” und zum Symbol des aktuellsten Standes der organischen Synthese und damit zu ihrer treibenden Kraft, die ihre kontinuierliche Entwicklung auf immer höhere Leistungs‐ und Effizienzniveaus vorantreibt. Neben der Weiterentwicklung in Bezug auf Raffinesse und Reichweite hat sich der Zweck der Totalsynthese auch von ihrer ersten Machbarkeitsstudie (d. h. der Synthese von Harnstoff) auf die Aufgabe der Strukturaufklärung von Naturstoffen und in jüngster Zeit von der Demonstration ihrer künstlerischen Fähigkeiten bis zur Anwendung ihrer Befähigung zur Unterstützung von Biologie und Medizin erweitert . Wie wir später sehen werden, lieferten die Totalsynthesen von Calicheamicin γ 1 I[55] und seines Thioacetatanalogons Calicheamicin θ 1 I in unseren Laboren in den 1990er Jahren die ersten Beispiele für die Leistungsfähigkeit von Totalsynthesen, darin seltene und komplexe Naturstoffe und deren Analoga als potenzielle Wirkstoffe für Antikörper‐Wirkstoff‐Konjugate bereitzustellen.…”

Recent applications of solid-phase strategy in total synthesis of antibiotics

“…Another solution is to make the best use of the diversity of the structure of natural products in new drug discovery and pursue the essence of nature and natural products in total synthesis. 5 …”