ESSAY One Hundred Years Lock-and-Key Principle ** Albert Eschenrnoser* When we look at modern organic chemistry and ask ourselves where we are going. then the spirit of no other organic chemist of thc past appears to be nearer to our present-day thinking than that of Emil Fischer. In saying this, I refer, of course, to Fischer’s legacy of the “lock-and-key” concept, an idea which together with Pauling’s later extension to transition states constitutes the foundation on which all our modern structural modeling of the selectivity of intermolecular communication in chemistry and biology rests. Rightly, therefore, this symposium commemorates the concept’s centenary, and the organizers are to be congratulated for their insight and initiative. By the spirit of Emil Fischer, however, I also mean (and perhaps above all) Fischer’s attitude as an organic chemist towards biology. It is the attitude that made and continues to make the biological world the major and deepest source of inspiration for research in organic chemistry, be it in a direct or an indirect way, or just as a reference for achievement. Organic chemistry has returned to this attitude only relatively recently after :i period of splendid isolation in organo-chemical self-complacency for more than half ;Icentury after Emil Fischer’s time. Today. we marvel at Fischer’s foresight in choosing the research fields in which he decided to spend his lifetime as a scientist. fields in which he created an oeuvre that makes hiin today the unique pioneering figure for organic chemistry, biochemistry, and molecular biology alike. His focus on the basic structural a n d synthetic chemistry of carbohydrates, nucleotides. and polypeptides, the three families of organic matter that later were recognized as the three pillars on which the living world is built, his interest in and practical use of enzymes as chemical catalysts, and his concern about their mode of action all differentiate him from the natural-products chemists of the self-complacency period, when the recurring pleasures of successful constitutional analyses and syntheses of nicely crystallizing low molecular weight objects, beautiful colors of pigments, fine odors of terpenes, and interesting biomedical properties of alkaloids lured the chemists away from proteins and nucleic acids. from those constitutionally repetitive and ”nasty” materials that later revealed themselves as the most important part of (*I [**I Prot I h . A. Ewhenmoser Lahot-,itorium fur Orgamsche Chemir ETI I-Zcnti-um Uni\ ersititstrassr 16. CH-XOY2 Zurich (Switzerland) Int. code + ( l ) 632-1043 Intr,ductor? i-cmarks at the symposium “Supramolecular Chemistry: 100 Yeal-s L.ock-nnd-Key Principle” in Mainr o n August 17, 1994, organired by F. Diedei-tch and H. Ringsdorf. the task originally assigned to the chemistry that was named organic, namely, the task of studying the substances produced by living organisms. If Emil Fischer lived in our time, and if he happened not to be a biologist, he would quite probably be a practitioner of what today is called supramolecular chemistry, judging by the pronounced flair he had for structure and synthesis. In this field of chemical enterprise chemists set out to systematically conquer through synthesis new domains of the structure space of organic matter. Let us call to mind that the portion of sequence space occupied by DNA and proteins during biological evolution is infinitesimally small compared to the overall size of these structure spaces; and the structure space of organic matter as 21 whole is infinitely greater than the space within which living matter is evolving. Clearly, moving within a structure space, be it by Nature herself or by synthetic chemists, demands the process of srlecrion-selection of structures based on specific criteria. In this context we can distinguish two types of selection: post-synthesis and pre-synthesis selection. Darwinian selection is the prototypical example of the first. but also a chemist’s discovery of an unexpected structure with an unexpected property that is put to good use is an example. The second type of selection represents-at least in traditional thinking the molecular scientist’s dream: it is the construction of a specific object based on theory; that is, the scientist selects the object to be synthesized in advance. Selection criteria are always utilitarian. be it fitness for survival, or for technological. scientific. or cultural application. In the supramolecular chemist’s space walks. utility is connected with a given structure’s specific properties; such properties manifest themselves in the transfer of information from the structure to a receiver, most often another niolecular or supramolecular structure. And thus, mutual and strictly selective molecular recognition-Fischer’s lock and key is the central issue. Therein lies that underlying dichotomy in structure space exploration in chemical research: post-synthesis selection (discovery) versus pre-synthesis selection (design). The recent sudden rise of encoded combinatorial synthesis within chemistry should make us reflect: we witness the transplant of a principle of synthesis from the heart of biology into the center of chemistry. An exciting period is ahead of us in which we shall be able to watch and compare the power of the two selection modes in chemical synthesis and their impact on the evolution of chemistry.