This video segment, adapted from NOVA uses reenactment footage to show how chemist Percy Julian completed the total synthesis of physostigmine, an alkaloid derived from the Calabar bean that could be used in the treatment of glaucoma. Julian began with very simple substances and, through a series of precise chemical reactions, arrived at the complex final natural product. The video also describes how purification and analysis are used to confirm the pathway, and how melting point can be used to provide evidence that synthesized and natural compounds are chemically the same.
Since the early 1800s, practitioners of organic chemistry have been fascinated with a group of plant-derived compounds called "alkaloids." Alkaloids contain at least one nitrogen atom among other atoms in a carbon-based ring structure, and occur naturally in vascular plants and some fungi. Notable alkaloids include caffeine, quinine, cocaine, and morphine, all of which have important medicinal qualities, and strychnine, which in excessive or continuous dosages can be poisonous.
Not much was known at first about how alkaloids form in living organisms. Yet as active agents were isolated, or extracted, from plants, and chemists tried to replicate them in the lab, it was apparent that alkaloids could be very complicated in structure. Morphine, for example, contains 40 atoms, and strychnine 47 — each one of which has a defined place in relation to the others.
Synthesizing, or assembling, organic compounds can be a long and arduous process, involving numerous steps that add, change, or remove atoms from a framework. To synthesize an alkaloid, chemists must first know — or figure out — the composition and structure of the natural molecule to be replicated. Then, starting with very small structures that chemists already know how to make, they can begin to assemble these simpler molecules into fragments, called "intermediates," of the desired compound. This may involve lots of trial and error.
To get a compound's atoms to bond in specific ways, chemists draw from several techniques. These include heating the molecule to a high temperature, which gets the atoms vibrating and makes new bonds possible; adding oxygen to the molecule, also known as "oxidation"; taking oxygen out of the molecule, which is called "reduction"; exposing the molecule to pressure; and exposing the molecule to light.
To determine whether they had indeed made what they set out to make, chemists in Percy Julian's time compared the temperature at which crystals of the compound melted with the known melting point of the natural compound. Because pure compounds having the same molecular structure melt at the same precise temperature, that melting point is like a chemical signature. Today, chemists use a technique called "spectroscopy" to measure the absorption, emission, or scattering of electromagnetic radiation by molecules. As with melting point, chemical substances produce telltale spectroscopy readings that allow them to be positively identified from a sample.