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Organic Synthesis
The Science behind the Art
By W. A. Smit, A. F. Bochkov, R. Caple The Royal Society of Chemistry
Copyright © 1998 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-544-0
CHAPTER 1
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 Nicolaou's teams,' were properly acclaimed as brilliant successes of modern synthetic chemistry. Both preparations are rather lengthy and may seem to be of purely academic interest. Yet these and related studies pave the way for further exploration of structure–activity relationships aimed at elucidating more available and active taxol analogs of practical value.
The fascinating success of transplantation surgery is among the most spectacular achievements of modern medicine. Undoubtedly the development of ingenious surgery skills and carefully refined techniques was a necessary prerequisite for these achievements. Of no less importance was the discovery of drugs capable of modifying and controlling the reactions of a patient's immune system to prevent the rejection of grafted organs. One of the most efficient immunosuppressant agents, FK-506 7, was isolated from the fermentation broth of the microorganism Streptomyces tsukubaensis in 1987.
Despite its formidable complexity, the total synthesis of this compound was completed in less than two years by Shinkai's group at Merck Sharpe & Dohm. Certainly this synthesis is not suggested as an alternative route to the rather inexpensive microbiological process. However, elaboration of synthetic approaches toward 7 opened an entry into the preparation of its derivatives bearing isotope labels as well as analogs of 7 required for the study of the interactions of the drug with its receptors, an extremely difficult problem. These studies are of utmost importance and very promising since they may lead ultimately to the rational design of immune modulators which are simpler and more useful than the original compound 7.
It is easy to put together a long list summarizing the achievements of organic synthesis that supply virtually every field of science and touch all aspects of our everyday life. The complexity of these syntheses, their scale (from a fraction of a milligram to a million tons) and the methods used vary tremendously. They differ as well in their ultimate significance for mankind. Whatever the targets are, however, synthetic rubbers and fibers, drugs and dyes, high octane gasoline and detergents, vitamins and hormones, or numerous reagents, they share one thing in common: in all cases the target possessed a set of useful properties warranting its synthesis. This direction of synthetic studies seems to be of unquestionable value and it corresponds exactly to the wishes of the taxpayers who want to see a quick reward for the investment of their money.
1.2 GOAL UNAMBIGUOUS BUT QUESTIONABLE
The importance of science, however, cannot be directly assessed using the criteria of immediate 'usefulness'. As organic chemistry has evolved, synthetic chemists have striven to synthesize any compound that could be isolated from natural sources, especially from living organisms, often without any obvious relevance to the possible utilitarian value of these compounds. Some of these syntheses took decades to accomplish. At present, the gap between the discovery of a new natural compound (and such discoveries are made, in the true sense of the word, every day) and its synthesis is reduced to a very few years, or even months. However, why spend so much effort for the preparation of a compound already synthesized in nature?
It is true that quite often the challenging complexity of the target per se serves as a powerful driving force to exercise the synthetic chemist's skill. Yet, the principal motivation stems from the perception that Mother Nature does nothing in vain. Everything she makes serves the essential needs of living organisms and, consequently, is of vital importance for mankind. This confidence continually finds credibility in both general as well as specific aspects in the course of the evolution of knowledge. Consider the following examples.
Among the multitude of natural compounds there exists a large class known as the isoprenoids (or terpenoids), composed of thousands of structurally diverse compounds related by a common biosynthetic origin. Some of these compounds, such as vitamins A and D or the steroidal hormones, have been known for a long time to be essential regulators for the normal functioning of a mammalian organism. In addition, there are compounds that, without doubt, are of practical value (camphor, natural rubber, menthol, carotene, etc.). Until the early 1950s the prevailing view was that the majority of isoprenoids were superfluous, devoid of both biological activity and applied usefulness. The reasons why living organisms took the trouble and consumed the energy to make these complicated structures remained obscure. It was commonly accepted that they were inert materials (secondary metabolites), their only destination being the removal of the end products of metabolism. It might have appeared that merely professional pedantry and the lack of any imagination compelled chemists to pursue endless and time consuming studies in the search to isolate ever-increasing numbers of natural isoprenoids from all imaginable sources, to establish their structures, and then to synthesize them. For decades, the only observable results of these studies were additional, yet seemingly meaningless, contributions to the inventory of the products created and stored in nature for unknown purposes.
In the 1960s, however, these views underwent truly dramatic changes. Doubts regarding the usefulness of terpenoids, both for the producing organisms and for us as customers, had to be abandoned. For instance, it became obvious that not only mammals, but insects as well, widely use various isoprenoids as hormones. Thus, one of the most amazing biological phenomena, insect metamorphosis (the emergence of an adult from a larval stage via periodic molting), is controlled by a carefully tuned interplay of a set of hormones released by several glands. A small gland known as the corpora allata releases a juvenile hormone (JH) 8 (Scheme 1.3), which is essential for the development of the larvae. At a certain moment the release of 8 is stopped. Molting into an adult then occurs, induced by a secretion of another hormone, ecdyson 9, by the prothoracic gland.
This aging process can be completely stopped if, at this very moment, a fresh amount of 8 is introduced. As a result, a giant but not viable larva appears. Both 8 and 9 (Scheme 1.3) are modified terpenoids. The richest natural source of JH (adult male abdomens of the silk moth Hyalphora cecropia) gives no more than a couple of micrograms of 8 per insect. Nevertheless, 8 became a relatively available compound due to the tremendous efforts spent upon its total synthesis. Elucidation of the role and successful synthesis of JH triggered an avalanche of studies aimed at the creation of simpler and convenient analogs of this compound. These efforts ultimately led to the appearance of a new generation of pest-control chemicals.
In plants, some terpenoids are produced as vitally important hormones involved in the regulation of growth and development. Thus, the diterpenoid gibberellic acid 10, widely distributed in the plant kingdom, is known to exercise numerous physiological functions. This compound was first identified as a metabolite of the fungus Gibberella fujikuroi, a fungus shown to cause abnormal growth and eventual death of afflicted rice seedlings. A later study discovered that 10 and its numerous analogs are produced by various plants as endogenous growth regulators. Synthesis of this compound by Corey's group stands as one of the top achievements that attests to the power of modern organic chemistry.
Another terpenoid, abcisin 11, which was isolated from a variety of plants, functions as a sort of antagonist to 10. In fact, 11 was shown to be responsible for the inhibition of the growth of seedlings and induction of the formation of resting buds. Thus the changes from the state of active growth during long-day conditions to the dormancy period under short-day conditions are controlled by the balance in the production of these hormones.
Microorganisms and fungi are an especially rich source of isoprenoids of the most diverse structures. Among these products one may find powerful toxins, compounds with antitumor and anti-inflammatory activity or antibiotics. Very little is known about their role in the host organisms. However, the broad spectrum of the observed biological activity could be taken as at least circumstantial evidence to indicate the existence of some function mediated by these products and essential to their producers.
Nowhere in Nature can an individual live isolated, not participating in the intricate interactions between other members of the biological community (biocenosis). Therefore, a truly comprehensive understanding of the functions of natural compounds requires an in-depth investigation of their possible involvement as mediators in the interactions between organisms belonging to the same, or even entirely different, species. As a community we are at the very beginning of the studies of these aspects of chemical ecology. At the same time, numerous facts have already been accumulated which attest to the generality and vital importance of chemical communication channels at all levels of biological organization.
A special term, pheromones (exohormones, or more generally semiochemicals), was coined for compounds which fulfill the role of chemical signals transferring information from one organism to another. The isoprenoids described earlier are not the only group of compounds specifically designated to serve as chemical signals. Nature has no special preference in its choice of a particular group of organic chemicals for these purposes. It can choose a suitable compound to fulfill the required function from a broad array of products without any obvious limitation to the gross structure, complexity, or functionality of the candidates. The following examples exemplify the diversity of functions and chemical structures of semiochemicals used by various species.
It appears that insects have achieved the most spectacular results in elaborating an extremely intricate and ingenious system of chemical communication. With the help of pheromones they can pass information about species of the same type (recognition and classification signals), about the location of male or female species (sex attractants), about the closeness of an enemy (alarm pheromones) or the shortest route to the food source (route indicators), and many others.
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Excerpted from Organic Synthesis by W. A. Smit, A. F. Bochkov, R. Caple. Copyright © 1998 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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