n this essay K.C. Nicolaou outlines the essence and philosophy of the art and science of total synthesis, highlighting a number of accomplishments of his group in the field. Publications from Nicolaou and his colleagues have propelled him into the top 5 most-cited chemists for the period of January 1992 to June 2002 in the ISI Essential Science Indicators Web product. Currently, Professor Nicolaou’s record in the field of Chemistry includes 247 papers cited a total of 8,732 times to date. Professor Nicolaou is the Chemistry Department Chairman, Darlene Shiley Chair in Chemistry and the Aline W. and L.S. Skaggs Professor of Chemical Biology in the Skaggs Institute at The Scripps Research Institute, and is also Professor of Chemistry at the University of California, San Diego. K.C. Nicolaou is also featured in ISIHighlyCited.com.

The Art and Science of Total Synthesis

Wöhler’s synthesis of urea in 1828 from ammonium cyanate was a milestone event, not only because it contributed to the "demystification" of nature, but more significantly because it marked the beginning of the field of organic and natural products synthesis, a scientific discipline which has since provided countless dividends for humanity. Unmoved from center stage at the dawn of the twenty-first century, the art, science, and technology of natural products total synthesis remains an intellectually challenging, exhilarating, multifaceted, and boundless field. Powerful as it is, total synthesis is being constantly pushed to new heights by the everlasting elucidation of architecturally beautiful, but often synthetically imposing, structures isolated from nature’s seemingly limitless library of molecular diversity. Through the quest to construct the most complex and challenging of nature’s molecules, total synthesis serves as a powerful engine which drives forward the more general field of organic synthesis by demanding the discovery and invention of new reagents, reactions, and strategies, while simultaneously fueling important advances in biology and medicine by providing natural and designed compounds to probe important biochemical pathways and modulate disease. At a personal level, total synthesis both cultivates and demands the very best characteristics from those who practice it: ingenuity, creativity, imagination, experimental skill, persistence, and character.

Today, problems in total synthesis are often defined by natural products possessing novel molecular architectures which have not been previously reached by chemical synthesis, and which provide new opportunities to discover and invent new science in chemistry, biology, and medicine. Having defined the target molecule according to certain criteria of complexity and relevance, a synthetic strategy, rational but not rigid, accommodating as much new chemistry as possible, is designed. The execution of the plan should be accompanied by discoveries and inventions in terms of new synthetic technologies and novel variations of the natural product for chemical biology studies.

The artistry of total synthesis lies both in the originality and elegance by which the individual steps are orchestrated within the overall synthetic strategy and in the architecture of the molecular designs of synthesized analogs with potential biological activity. Accomplishments in total synthesis of such complex molecules symbolize the state of the art of chemical synthesis and find applications in the everyday endeavors of researchers working in drug discovery, chemical biology, and materials science, among other disciplines. The impact of this work on chemistry, biology, and medicine is manifested through the synthesis of dozens of natural products and thousands of designed molecules and the design, discovery, and development of a multitude of new and enabling synthetic methods, technologies, and strategies for organic synthesis. Endiandric acids (1982), amphotericin B (1987), calicheamicin g₁^I (1992), rapamycin (1993), Taxol™ (1994), brevetoxin B (1995), epothilones A and B (1997), eleutherobin (1997), brevetoxin A (1998), vancomycin (1999), the CP-molecules (1999), trichodimerol (1999), bisorbibutenolide (1999), everninomicin (1999), colombiasin A (2001), hybocarpone (2001), and apoptolidin (2001), coleophomones A and B (2002), and diazonamide A (2002) are but some representative examples of such endeavors in our laboratories (see Figure 1).

Further Reading

1. Classics in Total Synthesis, K.C. Nicolaou and E.J. Sorensen, VCH Publishers, Weinheim, Germany, 1996.
2. The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century, K.C. Nicolaou, D. Vourloumis, N. Winssinger, P.S. Baran, Angew. Chem. Int. Ed. 39, 44 (2000).
3. The Diels-Alder Reaction in Total Synthesis, K.C. Nicolaou, S.A. Snyder, T. Montagnon, G.E. Vassilikogiannakis, Angew. Chem. Int. Ed. 41, 1668-1698 (2002).
4. The CP-Molecule Labyrinth: A Paradigm of How Endeavors in Total Synthesis Lead to Discoveries and Inventions in Organic Synthesis, K.C. Nicolaou and P.S. Baran, Angew. Chem. Int. Ed. 41, 2678-2720 (2002).

K.C. Nicolaou, Ph.D.
Department of Chemistry and the Skaggs Institute for Chemical Biology
The Scripps Research Institute
and
Department of Chemistry and Biochemistry
University of California, San Diego
La Jolla, California, USA