Eschenmoser began his scientific career as a graduate student in the laboratory of Leopold Ružička, at the Eidgenossische Technische Hochschule in Zurich. Ruzicka was a notable organic chemist himself having been awarded the Nobel Prize in Chemistry in 1939 for his work on the synthesis of androsterone and testosterone. Eschenmoser’s early work on the cyclization of unsaturated, conjugated hydrocarbons directly contributed to advances in the field of terpene chemistry and provided insight into steroid biosynthesis. In the early 1960s, having become Professor of General Organic Chemistry at ETH, Eschenmoser began work on what was the most complex natural product synthesized at the time—vitamin B12. In a remarkable collaboration with his colleague Robert Burns Woodward at Harvard University, a team of almost one hundred students and postdoctoral workers worked for many years on the synthesis of this molecule. At the time, a significant obstacle to the synthesis of vitamin B12 had been the difficulty in forming the macrocyclic ring closure necessary to complete the corrin ring structureat the center of the molecule. However during this time, Eschenmoser and his collaborators discovered a number reaction conditions under which this bond could be formed with a high degree of stereospecificity, including a novel photochemical process known as the “A/D variant.” The work was finally published in 1973, and it marked a landmark in the history of organic chemistry. The Eschenmoser fragmentation, the Eschenmoser sulfide contraction and Eschenmoser's salt are named after him.
A particularly vexing question in the study of the chemical origins of life is the selection of ribose, which forms the backbone of the nucleic acids found in modern biological systems. Eschenmoser’s work on a variant of the formose reaction that produces phosphorylated ribose in relatively significant concentrations has provided significant insight. Eschenmoser and colleagues demonstrated that phosphorylated glycoaldehyde when condensed with glyceraldehyde produces phosphorylated ribose differentially, providing a plausible explanation for the origin of both the sugar ribose, and the phosphate group required to polymerize monomeric nucleotides, in modern biochemistry.
TNA and Artificial Nucleic Acids
Eschenmoser developed synthetic pathways for artificial nucleic acids, specifically modifying the sugar backbone of the polymer. Having developed a number of structural alternatives to the naturally occurring nucleic acids, Eschenmoser and his colleagues were able to contrast the properties of these synthetic nucleic acids with naturally occurring ones to effectively determine the properties of RNA and DNA vital to modern biochemical processes. This work demonstrated that hydrogen-bonding interactions between the base-paring surfaces of the nucleobases alone might not have provided sufficient selection pressure to lead to the eventual rise of ribose in the structure of modern nucleic acids. He determined that pentose sugars, particularly ribose, conform to a geometry that contributes significantly to the helical structure of DNA by optimizing base-pair stacking distances in naturally occurring oligonucleotides. These base-stacking interactions orient and stabilize the base-paring surfaces of the nucleobases and give rise to the canonical Watson-Crick base-paring rules that are well understood today. Threose nucleic acid is an artificial genetic polymer invented by Eschenmoser. TNA strings composed of repeating threose sugars linked together by phosphodiester bonds. Like DNA and RNA, the molecule TNA can store genetic information in strings of nucleotide sequences. John Chaput, a professor at UC Irvine, has theorized that issues concerning the prebiotic synthesis of ribose sugars and the non-enzymatic replication of RNA may provide circumstantial evidence of an earlier genetic system more readily produced under primitive earth conditions. TNA could have been an early pre-DNA genetic system.
