Goals of an Organic Synthesis

The role of organic synthesis in science and in practice is not easily defined in an unambiguous way. To answer the question about the goals of an organic synthesis, one cannot simply refer directly to the application or usefulness of the target compound, even if the term 'usefulness' is understood in the broadest sense. Nevertheless, we would like to start this chapter with just this obvious case — the synthesis of unquestionably useful organic compounds.

1.1 GOAL UNAMBIGUOUS AND UNQUESTIONABLE

From ancient times, mankind was enchanted by the marvelous colors arising from the treatment of cloth with the natural dyes extracted from various animals or plants. As early as the 13th century B.C., Phoenicians knew how to manufacture indigoid dyes (Tyrian purple) from the secretions of certain Mediterranean Sea mollusks. To produce 1 gram of the dye, 10000 animals were required for a lengthy and laborious procedure. Its price was up to 10–20 times its weight in gold.

In ancient Rome, the skill of producing this dye became one of the most closely guarded state secrets. By Nero's decree, the right to wear garments dyed in purple was granted exclusively to the emperor himself (Royal Purple). This romantic aura persisted up to the second half of the 19th century, when a rationalistic approach in an emerging science, organic chemistry, mercilessly removed the curtain of mystery and identified the individual components responsible for the dying properties of the natural material (indigo 1 and 6,6'-dibromoindigo 2, Scheme 1.1).

Shortly thereafter, an inexpensive procedure for the industrial production of 1 from readily available starting materials was elaborated (Bayer, 1878). In related efforts, chemists identified another compound, alizarine 3, which was isolated from a certain species of plants (Rubia tinctoria). It was used for centuries as a natural dye. Originally very expensive, it soon became an inexpensive product owing to the ease of its synthesis from the aromatic hydrocarbon anthracene, present in coal tar (Grebe and Lieberman, 1868).

These were truly triumphal achievements and they produced a deep impression, not only on chemists, but on the general public as well. It was convincing proof of the power and promise of this rapidly blossoming and daring newborn infant, organic synthesis.

The thread of life, DNA, codes hereditary information for all living creatures. The well-known double helix structure of this molecule was proposed by Watson and Crick in 1953. As Khorana acknowledged later, 'Synthetic work related to this structure immediately began to be my ambition'. The accomplishment of this dream required nearly two decades of intense work by a large group, but culminated in a brilliant success (and a Nobel Prize). Khorana's total synthesis of a biologically active gene, a fragment of DNA, coding the biosynthesis of tyrosine messenger RNA was a benchmark achievement. Its synthesis confirmed the fundamental principles of molecular genetics and provided a tremendous impact on the development-of genetic engineering.

Ascorbic acid 4 is one of a set of essential vitamins. The consequences of a deficiency of this simple (but then unknown) ingredient in the diet were first encountered in the era of great geographical discoveries. Deaths among sailors, caused by the mysterious illness scurvy, were heavier than those by all other natural disasters taken together. Elucidation of the structure of ascorbic acid in 1928, followed by its laboratory synthesis (Rechstein, 1934) and shortly thereafter by its industrial synthesis from D-glucose, forever eliminated this threat. According to Pauling, it provided us as well with reliable protection against a number of other diseases, including the common cold.

Prostaglandins (PGs) such as PGE1, 5 (Scheme 1.2), first identified in the 1950s, were immediately recognized as extremely important bioactive substances. These regulators, present in nearly all tissues and fluids of mammals, powerfully affect the functioning of their respiratory, digestive, reproductive, and cardiovascular systems. PGs are produced in minute amounts (the human organism produces as little as 1 milligram per day), and there are no natural sources available for the isolation of PGs in substantial amounts. Additional complications in the study and collection of prostaglandins arise because of the high lability of these compounds.

Both the progress gained in the in-depth understanding of the mechanism of their action, and the achievements in the practical application of prostaglandins (in medicine and veterinary science), were made possible only by the success of synthetic chemists in developing efficient routes for the total synthesis of these compounds and their numerous analogs. Because of the exceptional activity of PGs and some of their more stable synthetic analogs, their production on a laboratory scale (hundred milligram quantities to several kilograms per year) is sufficient to satisfy the demands of an entire country. As a result, a synthetic program initially aimed at purely fundamental goals led directly to the development of a synthetic protocol useful for applied purposes.

'Is a tree worth a life?' — an article under this headline was published in Newsweek (August 5, 1991). 'Tree' refers to the evergreen Pacific yew tree, Taxus brevifolia, which grows in the forests of the western USA and Canada. A peculiar and rather fateful feature of the yew tree is its unique ability to produce the complicated molecule taxol 6 (Scheme 1.2), a significantly efficient anti-cancer drug. This drug passed phase III clinical trials and became one of the most promising medicines for the treatment of ovarian and breast cancer, especially those cases incurable by other forms of treatment.

Every year, breast cancer will kill about 45 000 women in the USA while an additional 12000 will be victims of ovarian cancer. Treatment for one cancer patient requires the sacrifice of three 100-year-old trees to obtain 60 pounds of bark to produce a few grams of 6. The Bristol-Myers pharmaceutical company alone needs 25 kilograms of pure taxol to broaden their clinical studies — a harvest of about 38 000 trees. With the survival of the Pacific yew at risk, the expression of great concern among the environmentalists is not surprising: 'Is a tree worth a life?' Fortunately it need not be a 'your money or your life' dilemma. Several options are in fact available which can save life without unacceptable sacrifices of the environment. Not surprisingly, the search for more abundant and renewable natural sources of taxol are carried out with extreme vigor. Efforts spent on the total synthesis of taxol and related compounds have been no less. The unique pattern of the carbon framework coupled with the extensive functionalization made the total synthesis of 6 a truly challenging goal. The first two total syntheses, reported independently in 1994 by Holton's and...