A (Brief) History of the Chemistry of Natural Products

In these days, the chemistry of natural products is still a massive attraction for chemists, especially organic synthetic chemists. New substances, more or less complicated, more or less useful, are constantly discovered and investigated with all the techniques and tools that the early organic chemists could only imagine. In the course of these studies, the researchers are challenged by the preparation of the compounds which somehow drives this field forward. This time, we'll see the historical perspective of this 'ancient' research field and also future prospective that chemistry of natural products can offer.

In the early days of chemistry, there was a 'dogma' that living things are alive because of some 'vital force'. In the other words, 'organic' matter can only be made in the presence of vital force, i.e. by living things. In 1828, Friedrich Wöhler debunked this belief by synthesising an organic substance, urea, from an inorganic substance, ammonium thiocynanate (NH₄CNO). This event marks the birth of organic chemistry. Then, Hermann Kolbe in 1845 synthesised acetic acid and he used the word 'synthesis' to describe the process of assembling a chemical compound from other substances.

Selected syntheses from 19th century

From these two discoveries, more total syntheses were coming such as alizarin in 1869 and indigo in 1878 which represent landmark achievements in this field. However, probably the most spectacular total synthesis in the 19th century was E. Fischer's synthesis of (+)-glucose. This synthesis is remarkable not only for the complexity of the target but also for the stereochemical controlled that accompanied it. This amazing synthesis made him the second winner of the Nobel Prize chemistry (1902) with prize citation "in recognition of the extraordinary services he has rendered by his work on sugar and purine syntheses".

The 20th century can be dubbed as the second renaissance as massive scientific and technological advancement happened in this era. Chemistry also played as a central and decisive player in shaping the advancement in the 20th century. For example, oil has reached its potential only after chemistry allowed its analysis, fractionation, and transformation into various useful products.

Selected syntheses from the first half of 20th century

In the early 20th century, the syntheses were relatively simple and some of them were directed towards benzenoid compounds. The 20th century was destined to bring dramatic advancement in this field. This can be seen in the syntheses at the beginning of the century where more complex and sophisticated molecules were used as targets. Some of the most notable examples are tropinone (1901, 1917), camphor (1903), ɑ-terpineol (1904), haemin (1929), pyridoxine hydrochloride (1939), and equilenin (1939). It is worth noting that among those total syntheses, one-step Robinson's tropinone synthesis (1917) and Fischer's synthesis of haemin are the most impressive as both men went on to win the Nobel Prize in chemistry (Fischer in 1929 and Robinson in 1947).

In the final half of the 20th century, it saw a big leap in the field organic chemistry and total synthesis was elevated into another dimension as a powerful science and a fine art. In 1937, R. B. Woodward was appointed assistant professor in the Department of Chemistry at Harvard University. Woodward brought his towering intellect to confront some of the most fearsome molecular architecture at athat time. One after another, various structures of unprecedented complexity gave in to synthesis in the face of his ingenuity and resourcefulness. Among his accomplishment, these are some his most spectacular synthetic achievement: quinine (1944), patulin (1950), cholesterol and cortisone (1951), lanosterol (1954), lysergic acid (1954), strychnine (1954), reserpine (1958), chlorophyll a (1960), colchine (1965), cephalosporin (1966), prostaglandin F_2ɑ (1973), vitamin B₁₂, and eryhtromycin A (1981).

R. B. Woodward and selected syntheses by the Woodward Group

Besides that, Woodward  used mechanistic rationale, apart his powerful intellect, and stereochemical control as the sharp tool in his synthesis to explain his science and predict the outcome of chemical reactions, and these qualities make Woodward unique from his predecessors. Apart his mastery in the art of total synthesis, he was also master of structure determination. It is clear that his works influenced not only his students, but also his peers and colleagues such as J. Wilkinson (sandwich structure of ferrocene), K. Block (steroid biosynthesis), R. Hoffmann (Woodward-Hoffmann rules), all of whom won the Nobel Prize for chemistry.

E. J. Corey and selected syntheses by the Corey Group

During Woodward's tenure in Harvard, another master of organic synthesis, E. J. Corey, arrived as a full professor of chemistry from the University of Illinois, Urbana-Champaign in 1959. Corey's pursuit of total synthesis was marked by two distinctive elements, retrosynthetic analysis and the development of new synthetic methods as an integral of the endeavour. It was in 1961 that Corey officially introduced the principles of retrosynthetic analysis in his synthesis of longifolene. With this tools, Corey brought a highly organised and systematic approach to the field of total synthesis in which he synthesised hundreds of natural and designed products within thirty years. Besides this incredible achievement, the spin-offs from this endeavour were even more impresive: the theory of retrosynthetic analysis, new synthetic methods, asymmetric synthesis, mechanistic proposals, and important contributions to biology and medicine.

In the second half of this period was an era during which total synthesis underwent explosive growth as evidenced by inspection of the primary chemical literature. In addition to Woodward and Corey, several other groups and a number of great synthetic chemists contributed to this rich period for total synthesis where natural products became opportunities to initiate and focus major research and served as ports of entry for adventures and rewarding voyages. Among these great chemists are G. Stork, A. Eschenmoser, and Sir D. H. R. Barton, whose sweeping contributions began with Woodward era and spanned over half a century.

Left to right: Gilbert Stork, Albert Eschenmoser, and Sir Derek H. R. Barton

Stork's elegant syntheses decorated the chemical literature with his useful methodologies and similarly with Eschenmoser where his syntheses are often accompanied by profound mechanistic insight and deep-thought synthetic designs. D. H. R. Barton contributed in the use of conformational analysis and biogenetic theory which were instrumental in shaping the art and science of natural products synthesis.

The climatic productivity of the 1980s in total synthesis seemed for a moment that the efforts of the synthetic chemists had conquered most the known structural types. In some eyes, the total synthesis was dead but luckily they were wrong. The productivity in 1980s foretold the future of the science and a new explosion of the field. In the final decades of 20th century entirely new structures presented new challenges and opportunities in this field. These new challenging structures included the enediyne calicheamicin and dynemicin, the polyether neurotoxin brevetoxins A and B, the immunosuppressants cyclosporin, FK506, rapamycin, and sanglifehrin A, taxol and other tubulin binding agents, such as the epothilones eleuthrobin and sarcodictyins, ecteinascidin, the manzamines, the glycopeptide antibiotic such as vancomycin, the CP moleculs, and everninomicin 13,384-1.

Selected natural products syntheses from 1990s era

In this period, total synthesis took a more serious role in biology and medicine and a more aggressive incorporation of these area was aided by the development of new synthetic methods, such as solid-phase chemistry and combinatorial chemistry, and the new challenges posed by discoveries in genomics. Hence, synthetic chemists were moving deeper into chemical biology by taking advantage of the novel molecular architectures and bioactivity of certain natural products. A new philoshopy for total synthesis as an important component of chemical biology began to take hold.

Nowadays, the chemistry of natural products has evolved in many ways since its birth around two centuries ago. The understanding in electronic theory, the nature of chemical bonding, and the mechanistic insight aids the prediction where to break and form a bond. This is the foundation how synthetic chemists manage to incorporate pericyclic reactions, anions and cations, carbenes, and radicals in controlled ways to form or break chemical bonds in the synthesis. Besides that, a new generation of synthetic reactions based on heteroatoms and organometallic reagents have been discovered. This reactions have also revolutionised the role of catalyst in the synthesis, in particular in carbon-carbon bond formation reactions and asymmetric reactions.

Example of cascade reactions: electrocylisation cascade reaction in the synthesis of endiandric acid A

Cascade reactions also change the way synthetic chemists achieve the targets. This reactions enable several transformations to be carried in one reaction vessel in tandem; this reaction can be defined as one-pot sequences involving fleeting intermediates, each of which leads to the formation of the next until a stable product is formed. Expanding its definition, cascade reactions can include various one-pot reactions where number of reagents and/or components are added sequentially to form a final product without isolation of intermediate compounds or work-ups.

With all these advancements in hands, the science and art of organic synthesis still attract many who practice invention, discovery, and development of new synthetic reactions and reagents for wider use. New processes and engineered reactions are important for research chemists and manufacturers such in pharmaceutical industry. Others still adopt total synthesis as their main endeavour aiming to design and execute elegant strategies toward complex targets. Finally, there are who aim to incorporate biology into their total synthesis researches, thus elevating natural products to opportunities for creative science in total synthesis, synthetic methodology, and chemical biology. At the end of the day, it is up to the researchers to imagine new directions and to constantly raise the bar to higher and higher expectations for the art and science of organic and natural product synthesis.

As final remarks, surveying the total synthesis of the 19th and 20th century, one is left with amazement at its accomplishment and power. However, it is the duty of the researchers to convey the true meaning and value of the chemistry of total synthesis to society. However, most importantly perhaps, this excitement and optimism about the future of the discipline needs to be transferred to next generation of chemists. It would be interesting to see the present state-of-the-art with that at the end of the 21st century.

The largest and most complex secondary metabolite ever isolated (32 rings, 98 stereocentres, and one geometrical site).
Will we see this compound being totally synthesised at the end of 21st century? 

References
K. C. Nicolaou, D. Vourloumis, N. Wissinger, and. P. S. Baran, Angew. Chem. Int. Ed., 2000, 39, 44-122.