Introduction

Pei-Qiang Huang

Fujian Provincial Key Laboratory of Chemical Biology, Department of Chemistry and iChEM, Xiamen University, Xiamen, China

Humans rely on the Earth's resources for survival. In modern society, almost no resource except air can be used directly. The mission of chemists is to transfer natural resources from the Earth into usable materials. This task requires the understanding of structure and reactivity, and features the production/creation of natural or unnatural molecules/substances. Plants, animals, microorganisms, and fungal kingdoms both on land and in the sea are rich sources of small organic compounds called secondary metabolites or natural products.1 Very often, natural products exist in organisms in only minuscule amounts. Moreover, natural products display widespread structural diversity and important bioactivities or are potentially bioactive, which rend them ideal sources for discovering and developing medicines, agrochemicals, and many other useful chemicals.2 Thus, the chemical synthesis of natural products constitutes an important branch of science. In this context, the synthesis of structurally diverse (including the skeleton, functional group, and stereochemistry) natural products is often a challenging yet a fascinating field that has attracted numerous talented chemists for generations. Among the many books and reviews dedicated to the total synthesis of natural products,3 Selected Organic Synthesis (I. Fleming), Art in Organic Synthesis (N. Anand), The Logic of Chemical Synthesis (E. J. Corey), and Classics in Total Synthesis I-III (K. C. Nicolaou) are representative. Different from all previous literature, in this book we intend to focus on one theme: The efficiency of total synthesis.

1 The Golden Age of the Total Synthesis of Natural Products: The Era as a Dominant Field

The first chemical synthesis of a natural product can be traced back to 1828 when F. Wöhler synthesized urea.4 In an attempt to make ammonium cyanate by combining cyanic acid with ammonia, urea was obtained instead (Scheme 1a). This synthesis is the first example of the artificial production of an organic substance from inorganic materials. This serendipitous discovery not only marked the birth of organic chemistry as a branch of science, but is also celebrated as a refutation of vitalism; the hypothesis that living things are alive because of some special "vital force." According this hypothesis, "organic" compounds, so-called animal substances, could be made only by living things.

Scheme 1 Wöhler's synthesis of urea and Kolbe's synthesis of acetic acid.

The first total synthesis of a natural product by a designed synthetic route was H. Kolbe's synthesis of acetic acid reported in 18455 (Scheme 1b). This represented a singular example that an organic compound was synthesized from inorganic elements and minerals. It is this synthesis that finally put to rest the vis vitalis. Moreover, the term "synthesis" was coined for the first time to describe the process of assembling a chemical compound from other substances.

In 1965, 120 years later, Chinese scientists achieved the chemical synthesis of crystallized bovine insulin (Figure 1),6 a protein consisted of 51 amino acid residues with a molecular weight of 5733.53 Da. This work marked the first chemical total synthesis of a zoetic protein. In addition, it constituted a significant breakthrough in the field of life science and has had a substantial impact on human endeavors in finding out the secrets of life. This historic accomplishment relied on a state major science and technology program in China that started in 1958. Thanks to the cooperation of Ying-Lai Wang from the Shanghai Institute of Biochemistry (SIBC, CAS) and with the joint forces of research groups directed by Jing-Yi Niu, Cheng-Lu Zou (both from SIBC), You Wang (SIOC, CAS), and Qi-Yi Xing (Pekin University), the ambitious goal was finally achieved after 8 years' work. Note that, before this, V. du Vigneaud was awarded the 1955 Nobel Prize in Chemistry for his work on the first synthesis of polypeptide hormone oxytocin (MW 1007.19 Da.) and, by 1958, the longest peptide synthesized was a 23-residue fragment of adrenocorticotrophic hormone.

Figure 1 Structure of bovine insulin.

Since the structural determination of cholesterol and cholic acid by Windaus and Wieland in 1932, interest in the total synthesis of steroids has been widespread (e.g., Progesterone in Figure 2), and augmented as the importance of steroids in medicine and in animal physiology has grown. In particular, with the discovery of the steroids as active hormonal compounds in the 1950s, steroid chemistry blossomed. These longstanding efforts have resulted in numerous partial and total syntheses of steroids.7 Moreover, the joint efforts of many disciplines together with the pharmaceutical industry on several aspects of steroid sciences have yielded a series of steroid hormone drugs such as cortisone, cholesterol, prednisone, as well as lovastatin for the treatment of hypercholesterolemia in 1987.8 Thus, in the 1970s, when international society recognized the population explosion as one of the three challenges that threatened the survival of the human race, and hormonal contraception was the best method available for birth control,9 for once synthetic organic chemists were able to say that, with the synthetic methods developed, there was no longer any shortage of contraceptive steroids. Perhaps steroids are the sole class of natural products that have attracted the interest of so many great organic chemists and for so long (several decades). Research in this area has yielded abundant accomplishments (see Table 1 later) including a classical radical C-H functionalization reaction (the Barton reaction,10 Scheme 2a) and the first enantioselective organocatalytic reaction (Hajos-Parrish-Eder-Sauer-Wiechert reaction,11 Scheme 2b).

Figure 2 Representative accomplishments in the total synthesis of steroids, prostaglandins, and vitamins.

Table 1 Selected examples of the impact of total synthesis on science and societies.

Synthetic Target/ Contributor Achievements Quinine
W. H. Perkin (1856) Serendipitous discovery and commercialization of first industrial dye, mauveines Tropanone
R. Robinson (1917) The conception of biogenetic synthesis
Biosynthesis of alkaloids Steroids
Many distinguished synthetic organic chemists and their collaborators (biologists)8

• Control of population
• Steroid industry
• Many hormonal drugs, including anti-inflammatories
• Conformational analysis32
• The Stork-Eschenmoser hypothesis for the stereospecific biosynthesis of steroids from squalene33
• Robinson Annulation reaction34
• Birch reduction
• Barton reaction: the photocleavage of nitrite esters (an early example of C-H functionalization) (Scheme 2a)10
• Hajos-Parrish-Eder-Sauer-Wiechert reaction (the first enantioselective organocatalysis) (Scheme 2b)11

Vitamin B12
Woodward
Eschenmoser Woodward-Hoffmann rules15 and in part
the 1981 Nobel Prize in Chemistry to R. Hoffmann
Eschenmoser sulfide contraction reaction (Scheme 2c)35 Prostaglandins
Many scientists >20 drugs in clinical use Peptides
V. du Vigneaud
R. B. Merrifield
and many others The 1955 Nobel Prize in Chemistry to du Vigneaud
Solid-phase synthesis concept and technology36
the 1984 Nobel Prize in Chemistry to Merrifield
A significant contribution to modern life sciences including biology, pharmacology, and medicine A number of natural products
E. J. Corey The 1990 Nobel Prize in Chemistry to Corey
Theory (retrosynthetic analysis) of organic synthesis3c,25,37
Many named reactions, synthetic methods, and reagents

Scheme 2 Selected named reactions invented/developed during total syntheses.

Through the close collaboration between R. B. Woodward's group at Harvard (in Cambridge) and the group at the Eidgenossische Technische Hochschule (ETH, in Zurich), the total synthesis of vitamin B12 (see Figure 2) was accomplished in 1972.12 It took a period of 12 years and the efforts of more than 100 experimental chemists to achieve this challenging goal.13 This is a landmark achievement as commented on by J. W. Cornforth: "The quality of the effort needed for this extension of man's control over matter can quite fittingly be compared to the better known (and much more costly) feat of placing men on the moon.".14 Moreover, the combined efforts with R. Hoffmann to understand an unexpected stereochemical outcome of a reaction observed during the...