Abstract
The first medicinal chemical was extracted from Australian plants in 1788. Various other products have had their ups and downs over the next two centuries.

I am here to talk about medicinal chemicals that have been isolated commercially from Australian plants and trees. I'm not going to talk about introduced species like the opium poppies they produce morphine from in Tasmania. It is Australian trees producing chemicals of medicinal use.

In 1788, soon after the English settlers arrived at Port Jackson, Dr. John White, the Surgeon General, ran out of Oil of Peppermint, which was used to treat colicky pains and disorders arising from wind. White and his assistant found an efficient substitute in the oil distilled from the leaves of a tree growing on the Port Jackson shore, a tree later named Eucalyptus piperita, or the Sydney peppermint. Later it was shown to contain a chemical called piperitone. White reported the oil to be much more useful than English peppermint oil. Later that year, a quarter of a gallon of this oil was steam-distilled from this Sydney tree which he shipped to England for testing. So, that goes back to the first year of Australia.

I want to begin talking about some alkaloids. Alkaloids are naturally occurring, basic compounds found in plants. These are alkaloids of the Duboisia species. Duboisia species were identified in eastern Australia early in the 19th century, myoporoides near Sydney in the 1800s and north along the coast in the 1860s. Wills, of Burke and Wills fame, in 1861 reported hopwoodii, and leichardtii was discovered by Ludwig Leichardt in 1867. In 1877, Joseph Bancroft, a Queensland doctor reported the midreatic properties of myoporoides extract. That is just a pupil dilator for eye examinations. He also established that the active ingredient of hopwoodii was nicotine. Aboriginal Australians called the leaves pituri and used them as a kind of chewing tobacco.

The other two species, known collectively as the corkwoods, after the nature of their bark, were soon shown to contain the tropaine alkaloids hyoscine, which is a motion-sickness drug, and hyoscyamine which is a form of atropine that doctors use for eye examinations. Because of the ready availability of the alkaloids in Europe, little more interest was shown until the onset of World War II. Russell Grimwade, who was chairman of of Felton, Grimwade and Dewardons (?), was asked if his firm could produce hyoscine to meet Australia's annual requirement, which was 11 ounces, or 300 grams. Recalling Bancroft's work on the Duboisias, Grimwade directed his lab to produce hyoscine and hyoscyamine. Within four weeks, seven ounces of pure hyoscine hydrobromide had been produced.

The company then expanded its capacity to not only make Australia self-sufficient, but to supply the Allied forces. The company was able to supply all the sea-sickness pills used by troops crossing the English Channel for the D-Day landing in France in June, 1944. I just bought some hyoscine hydrobromide the other day, I had to buy some travel-sickness pills for my kids to go down south for Easter. When you buy Quells, you are buying 0.3 mg of hyoscine hydrobromide.

After the war, the company named Drug Houses of Australia, went on producing hyoscine and atropine in expanded facilities in West Melbourne. However, after 14 years and nearly 6000 kilos of pure alkaloid salts, production ceased in 1954, largely because the embargo on the export of raw leaf was lifted. It is a common problem with Australian chemicals; we harvest the leaf, send it overseas, and they process it.

The Sydney company, Chemisee (?) Manufacturing Pty. Ltd. resumed production of the alkaloids in 1969. Keith Harrison Company began production in 1972, when Reg Smith, a friend of mine, joined the company as research manager. However, world prices fell in the mid-70s, and competition with overseas producers made it uneconomical. Production ceased once again in 1978. Reg Smith's new company, Phytex Australia, commenced production again using Queensland leaf in 1982, and he is still in that business.

The next one I want to talk about is eucalyptus oil. There is not a great range of compounds that we have produced. Three types of eucalyptus oil have been produced in Australia, medicinal oils, which have to be rich in a chemical compound called cineol, and there have been industrial and perfumery oils as well.

Medicinal oils have been produced commercially since 1854, when Joseph Bosisto set up a crude still at Dandenong Creek in Victoria. Bosisto was a young Yorkshireman who qualified as a pharmacist before being brought to Adelaide in 1848 to work for Francis Balding, another Yorkshireman, in his pharmacy on Rundell Street. In 1851, Bosisto left Victoria to join the gold rush, where he seems to have spent more time examining the local flora than digging for gold. In 1852, Bosisto opened a pharmacy in the Melbourne suburb of Richmond, where he also built a lab to investigate the chemical and medicinal properties of Australian plants. Government botanist Ferdinand von Mueller encouraged Bosisto to investigate the essential oils of eucalyptus on a commercial basis. He began operations using the leaves of what is now known to be a variety of Eucalyptus radiata.

Under the rules of the British Pharmacopoeia, which controls these things, a medicinal oil must contain at least 70% of an antiseptic chemical called guanate cineol. It has been suggested that Bosisto's oil probably contained very little, if any, cineol. Bosisto soon built distilleries at Emerald, Menzies Creek and Macclesfield, and in 1865 he began exporting to England. Alfred Felton and Frederick Grimwade saw the possibilities for trade and Felton, Grimwade and Company became the distributors of Bosisto's Oil of Eucalyptus. In about 1882, a syndicate of Felton, Grimwade and Bosisto bought a property near Dimbulah in the Wimmera in Victoria to grow mallee for distillation.

By now, Eucalyptus globulus oil, Tasmanian Blue gum oil, was also a well-established medicinal oil, and Eucalyptus cineraria was being distilled in the Goulburn district of NSW. Back in Adelaide, F. H. Faulding and Company commenced distillation of eucalyptus oil in 1887. In Western Australia, eucalyptus oil production has been very sporadic. In the year Faulding started production, Captain Forsythe (?)began producing oil at Pinjarra Park and was lauded for starting a new local industry. In July, the Daily News described his oil as being superior in strength to Bosisto's far-famed Parrot brand. But the enterprise was short-lived. I grabbed a bottle of eucalyptus oil from the bathroom cabinet, and it still is marked Bosisto's Parrot Brand Eucalyptus Oil. I think the brand actually disappeared for about 80 years and was revived.

A more sustained attempt began in 1892 when Jonah Parker built a distillery near Quairading. His factory used the leaves of young salmon gums. The family recalls that the oil was distilled three times and was sold as Parker's Treble Distilled Eucalyptus Oil. It won prizes at exhibitions in Melbourne, Paris and Glasgow before 1901.

In 1900, a chap called Louis Noak (?) also began distilling eucalyptus oil near Kellerberrin. This is an ad from the Daily News in July, 1900. The rules changed with Federation in 1901. Oil from the eastern colonies was already on sale in WA. Faulding's and Bickford's oils were widely advertised but attracted 20% import duty. With Federation, these inter-colonial tariff barriers were swept away. Both Parker and Noak went out of business. In any case, Parker's had been badly damaged in a storm and in 1901 he sold the manufacturing rights to Fauldings.

A company central to the natural products story in WA made later attempts to produce the oil. The company was Plaimarr (?) Ltd., manufacturing chemists who spent over 50 years in the essential oil, essence, fruit juice and cannon (?) business. The company was set up in West Perth in 1919 as a joint venture between confectionery manufactures Plaistowe and Horace Marr, who was their chemist. Marr was the managing director of this company from 1919 to 1960. Marr had arrived in Perth from London in 1905 at the age of 21. He is a bit of a hero of mine. He took a job as an electrode plater. In 1909 he enrolled for evening classes in chemistry at the Perth Tech. In 1916, he obtained his position with Plaistowe. While working at Plaistowes, Marr convinced himself that Western Australia's native plants could be the source of valuable natural products. In his spare time, he began experimenting with sandalwood oil.

From its early days, Plaimarrs had part-time suppliers of eucalyptus oil, and this grew during the Depression years of 1932-34 when several farmers began distilling the oil as a way of generating an income. The Plaimars 1932 headquarters building is still there in West Perth by the freeway. It has other uses; the company no longer exists.

After WWII, Plaimarr made a final attempt to establish eucalyptus oil production. A field survey showed that Eucalyptus kochii looked promising. Plaimarr selected Pinjar, which is up near Mullewa, as the site and a distillery was erected. In three months in 1951 about 400 kg of the oil was recovered, a yield of only 0.9%. You need about 2% to be profitable. Regrowth was expected to give a much higher yield, but in this dry area, regrowth was too slow and the project was abandoned in 1954.

Despite its failure in WA, the eucalyptus oil industry was generally well-established by 1900. For the next fifty years, Australia remained the largest supplier of the eucalyptus oil trade, but we no longer are. Most of it comes from China, like everything else.

Some scenes of eucalyptus oil distilling out in the bush: A still at Braidwood in NSW about 1900; one at Inglewood in Victoria which is still a production area in 1920; another one in NSW, Bedwells, from about 1930.

In 1981 it was estimated that there were about twenty-five producers of crude eucalyptus oil, most of them small-scale distillers operating on a part-time basis. Production is now confined to NSW and Victoria, with two main producers of medicinal oil: G. R. Davis and Company at West Wyalong in NSW; and Felton, Grimwade and Bickford near Inglewood, not far from Bendigo in Victoria. Both enterprises are based on plantations of Eucalyptus polybrachtea.

The next one is tea tree oil. Melaleuca alternifolia was established as a new species by botanist Edwin Chiel (?) in 1924. This attracted the attention of Arthur Penfold, another hero of mine, the economic chemist at the Museum of Applied Arts and Sciences in Sydney. Penfold had already begun to analyse the essential oil from Melaleucas, and he immediately went to Grafton to examine the new species and collect some leaf for distillation. In November, 1925, he addressed the Royal Society of NSW on his analysis, reporting that terpinene foral (?) was the major chemical component. By coincidence, Penfold was also well into a series of measurements on the disinfectant properties of essential oils and their components. In December, he was back before the Society to report on the germicidal value of alternifolia oil and terpinene foral. It was a much better antiseptic than carbolic acid.

Production of tea tree oil began as a cottage industry with distillation of oil from natural stands. It is believed that the oil was first distilled commercially at Koraki (?) near Grafton. Among the early manufacturers was Australian Essential Oil Company Ltd. in Sydney, who published a report on the medical and dental use of teatrol in 1936. Production expanded during the World War when demand exceeded supply. After the war, commercial use declined, with the availability of antibiotics and chlorinated phenol antiseptics.

Although use of the oil almost died out, production never completely stopped. In recent years, the demand for natural products instead of synthetic chemicals, even though to us chemists they are absolutely identical, has meant major resurgence for tea tree oil. Production has switched to plantation-grown Melaleuca alternifolia.

The second-last product I wanted to talk about is sandalwood oil. The sandalwood tree, Santalum spicatum, once covered much of Western Australia. The wood was first exported to Asia in 1845 for use in joss sticks. Export still continues. The oil that can be distilled from the wood is a valuable fixative for perfumes. And because of its antiseptic properties it was also, for many years, used in the treatment of cystitus and gonorrhea. The main constituents of the oil are the sesquiterpine alcohols called alpha and beta santalol.

WA sandalwood oil was first distilled experimentally in Germany in 1875, though how it got there is a bit of a mystery. By that time, sandalwood oil from India, distilled from the wood of Santalum album had a well-established market. Botanists did the WA tree no favours. Although the tree was originally known as Santalum signorum, by the time Horace Marr began production in about 1920, it had been renamed Fusanus spicatus. They were trying to compete with the Indian oil and it wasn't even a Santalum anymore.

The first plans for commercial production surfaced in 1886 when two unsuccessful attempts were made to float a public company for this purpose. The promoters planned to establish works for the manufacture of sandalwood oil and also eucalyptus oil on a site near Albany, but it failed. They couldn't raise the money. Three years later, the Great Southern Railway opened, linking Albany with Perth. Albany was chosen for a properly organised attempt to establish a sandalwood oil industry via the WA Distillery Company of London. Corrugated iron works were immediately erected on a railway siding about nine miles from Albany. By May, 1890, the company had received its first load of sandalwood, and by September of 1890, the factory was working day and night, and the first cases of sandalwood oil were shipped out. The company then disappears from the public record. The oil, basically, wasn't very good.

In 1890, Louis Noak also set up a sandalwood oil distillery at Wogolin, which I think is near York. Later he had greater success as a sandalwood dealer in Fremantle at a place near the old synagogue. Noak may well have supplied sandalwood to a Fremantle pharmacist named Edward Mayhew, who spent a considerable sum of money distilling and marketing the oil in 1894-95. He distilled the oil until about 1902 with a contract to deliver about one tonne a year to the makers of Pear's transparent soap in London. I am sure that was a lucrative contract.

The next known attempt to market sandalwood oil came from C. L Braddock, who in about 1913 moved his sandalwood oil factory from Mt Helena in the hills and began producing oil in a factory by the Swan River in Belmont. Their oil wasn't very good, either, at that time. Late in life, Edward Mayhew complained that his business was undermined by German claims that the WA oil was inferior to the Indian oil. But the Germans were right. None of the attempts that I have just mentioned had produced oil capable of meeting the requirements of the British Pharmacopoeia, that sandalwood oil contain at least 90% of those santalols.

The prosperity of newly formed Plaimarr Ltd. was founded on an earlier discovery by Marr. His experiments showed that steam distillation was inadequate for WA sandalwood. Normally, to get essential oil out of a tree, all you need to do is boil the leaves up with water and collect the oil that is distilled. But it didn't work with sandalwood oil. He found that he needed to extract the wood first. The wood is extremely hard and he had to powder it up and extract it first with petrol and then co-distill it with glycerine, and that improved the oil. He began producing good oil, as good as the Indian oil, in 1921.

Two year later, Marr discovered that Braddocks had begun using the same process. Suspecting that one of his employees had leaked information to Braddock, Marr sacked the employee and sued him and Braddock. This was the first trade secret case that was ever heard by an Australian court. The case was heard in the Supreme Court in December, 1924, but Braddock and his co-defendent won the case and were awarded costs. In delivering his judgment, the judge volunteered his opinion that no secret processes were ever developed. I think Marr just got it out of a book, we have a copy in the Curtin library. As it happened, Braddock's victory was short-lived, as Plaimarr took them over in 1931.

Getting the West Australian oil into the British Pharmacopoeia became a crusade for Marr. In 1921, he sent off samples of his improved oil for testing under clinical conditions. Reports came back from the Perth and Fremantle hospitals, the Victorian Board of Health and private practitioners, that the oil was just as good as the Indian oil. The physician in charge of the Perth VD clinic reported in 1923, that he had found, "the WA sandalwood oil is just as satisfactory as the imported article known as Santalum album." After a long campaign by Marr and the state and federal governments, during which time the botanists unhelpfully changed the name of the tree to Eucarya spicata, the WA oil was finally admitted to the B. P. in 1932. That same year, Plaimarr's production peaked at 54 tonnes per annum. Cystitus and gonorrhea sufferers took the oil in capsule form, though I suspect it didn't do them very much good.

Both sandalwood oils disappeared from the B. P. in 1948, having been supplanted by the antibiotics. By then, production was declining anyway, because wood supplies were becoming harder to maintain, and production finally ceased in about 1966.

However, production of WA sandalwood oil has recently resumed, once again at Albany. A company called Mt Romance Australia is producing the oil at their Albany works. Mt Romance produces the oil for perfumery use, but is thoroughly investigating potential pharmaceutical applications, largely based on its antimicrobial properties. Hopes are held for the treatment of Staphylococcus aureus. Tea tree oil is also being thoroughly tested for treatment of Golden Staph. Something has got to turn up soon, or we are doomed. The company is also hoping it will be useful in such things as tinea and acne.

The last compound I want to talk about is a little yellow compound called rutin. Made and found in 1887 that boiling the leaves of Eucalyptus macrorhyncha, or red stringybark, yielded copious amounts of a yellow colouring matter later identified as rutin. Ten years later, it was examined by H. G. Smith who proclaimed its potential as Australia's first natural dye stuff. Smith was Arthur Penfold's predecessor as economic chemist in Sydney and is famous for his research on eucalyptus oils and Eucalyptus smithii, the gully gum is named after him.

Rutin just couldn't compete with synthetic dye, and wasn't a commercial success. However, in 1944, rutin was shown to have Vitamin P-like properties. It is not called Vitamin P anymore. What it did is that it exerted a regulating effect on the permeability of small blood vessels. It was reported useful in the treatment of capilliary fragility. A timely paper in Nature in 1950 reminded Americans of the red stringybark source, at a time when Chinese supplies were being denied them. Within about three years, two extraction units were set up in NSW, at Rosewood in Taree with technical assistance from CSIRO. The extraction process was very simple: dried leaves were ground up and then boiled in water and the filtered extract cooled in tanks, and the yellow chemical just crystallised out, to be filtered out, dried and put in bags, with an overall yield of anywhere from 10 to 25%, which is a very high yield. Production remained steady at about 15 tonnes a year until well into the 1960s. Production ceased in about 1980. David Noel was telling me on the phone the other day that someone else has started making it again.

Q. Have you looked into the lemon-like compounds in Lemon Myrtle?

A. I had a student looking at Lemon Myrtle last year, but only with a restricted range of interests. We were looking at the acids that occur in there, like citric acid, and a little bit on the sugars. It has been around for decades. H. G. Smith was a great proponent of bush foods. There was a famous chemists' dinner in Sydney about 1920 where they served this unusual menu. He was the president. No one recognised what they were eating. He told them afterwards it was all bush food. I know the dessert was flavoured with Lemon Myrtle.