“Total synthesis,” explains the Introduction of Classics in Total Synthesis, “is the chemical synthesis of a molecule, usually a natural product, from relatively simple starting materials and is to be distinguished from partial synthesis or semisynthesis which designates the synthesis of a given molecule from an advanced precursor related to it, which may or may not be a natural product itself.” Total synthesis marks the complete chemical mastery of a complex molecule; if the molecule is of biological provenance, it shows how chemistry can take over the process of creating it. The biological molecule can now be synthesized in the laboratory, then redesigned to fit new functions as needed, and dealt in the same way as chemists deal with inorganic matter.

The modern history of total synthesis begins in the early nineteenth century with the synthesis of urea by Friedrich Wöhler in 1828. It was the first synthesis of an organic substance using only inorganic reagents. The synthesis of acetic acid in 1845 and glucose in 1890 were other nineteenth-century milestones. Throughout the latter half of that century, almost all organic chemists tried their hand at total synthesis, typically of dyes and small organic molecules of biological provenance and economic interest.

In the twentieth century, total synthesis became a Holy Grail of organic chemistry with attempts directed at increasingly complex molecules including organic substances. Toward the end of the twentieth century, the editors of Classics in Total Synthesis estimated that more than 20 Nobel Prizes were earned through this enterprise. The list of recipients reads like a Who's Who of chemistry, including Emil Fischer (1902), Adolf von Baeyer (1905), Otto Wallach (1910), Hans Fischer (1930), Leopold Ruz̆ic̆ka (1939), Robert Robinson (1947), Alexander Todd (1957), Vladimir Prelog (1975), and Elias J. Corey (1990), among many others besides Har Gobind Khorana (1968).

Khorana was unique among organic chemists because he directed his whole research focus on total syntheses of biologically salient macromolecules of increasing complexity ending with the synthesis of a complete functional gene in 1979. In the process, he perfected methodologies that were widely recognized as major technical breakthroughs in organic chemistry and in the emerging discipline of molecular biology.