Intellectual curiosity has always been one of the major driving forces leading to new advances in chemistry. At the onset of the 20th century, the fact that biaryls could be optically active even if lacking asymmetrically substituted carbon atoms arose interest, hinting at a novel type of stereomerism. It took quite a while (and some bizarre explanations)1 until in 1922 Christie and Kenner2 first correctly recognized that the phenomenon was the consequence of a hindered rotation about the aryl-aryl single bondshence termed atropisomerism by Kuhn. Still, no particular attention was initially paid to this class of stereoisomers until enantiomerically pure biaryls, such as BINAP (1),3 were found to be excellent ligands in asymmetric catalysis and until the chiral biaryl unit was recognized as the decisive structural element of many natural products (Figure 1).4,5 With the modern screening techniques and the bioassayguided search for novel compounds, the number of isolated axially chiral natural biaryls is steadily increasing.4 This class of secondary metabolites is characterized by a broad structural diversity, reaching from relatively simple molecules like the C2-symmetric biphenyl 2, which solely contains the element of axial chirality,6 to more complex compounds, like, e.g., the dimeric naphthylisoquinoline alkaloids michellamine A [(P,P)-3] and its axial epimer (i.e., its atropodiastereomer), michellamine B [(P,M)-3],7,8 which possess even three biaryl axes, of which the two outer ones are stereogenic, while * To whom correspondence should be addressed. E-mail: bringmann@ chemie.uni-wuerzburg.de; breuning@chemie.uni-wuerzburg.de. † These authors contributed equally to this work. ‡ Present address: Institute of Organic Chemistry, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany. § Present address: Kekulé Institute of Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk Str. 1, 53121 Bonn, Germany. Gerhard Bringmann was born in 1951 and studied chemistry in Gie en and Münster, Germany. After his Ph.D. with Prof. B. Franck in 1978 and postdoctoral studies with Prof. Sir D. H. R. Barton in Gif-sur-Yvette (France), he passed his habilitation at the University of Münster in 1984. In 1986, he received offers for full professorships of Organic Chemistry at the Universities of Vienna and Würzburg, of which he accepted the latter in 1987. In 1998, he was offered the position of director at the Leibniz Institute of Plant Biochemistry in Halle, which he declined. His research interests focus on the field of analytical, synthetic, and computational natural product chemistry, i.e., on axially chiral biaryls. He received several prizes and awards, among them the Otto-Klung Award in chemistry (1988), the Prize for Good Teaching of the Free State of Bavaria (1999), the Adolf-Windaus Medal (2006), the Honorary Doctorate of the University of Kinshasa (2006), the Paul-J.-Scheuer Award (2007), and the Honorary Guest Professorship of Peking University (2008). Chem. Rev. 2011, 111, 563–639 563

Atroposelective total synthesis of axially chiral biaryl natural products.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/jps.2600780902

Enantioselective Aspects of Drug Action and Disposition: Therapeutic Pitfalls

Following clinical trials conducted in China in the 1970s, gossypol was proposed as a drug for male contraceptive use This review summarizes the extensive investigations on formal animal toxicology and on the recovery of fertility in men after stopping gossypol treatment which led to the decision by the Special Programme of Research, Development and Research Training in Human Reproduction (HRP) at the World Health Organization (WHO), that gossypol would not be acceptable as an antifertility drug It is concluded that the assessment of gossypol reinforces the mandatory requirement that future contraceptive drugs must be developed by the established routes of appropriate animal toxicology and phased clinical studies

Gossypol: reasons for its failure to be accepted as a safe, reversible male antifertility drug.

Gossypol is a sesquiterpene that occurs naturally in seed and other parts of the cotton plant. Because of restricted rotation around the binaphthyl bond, it occurs naturally as enantiomeric mixtures with (+)-gossypol to (-)-gossypol ratios that vary between 97:3 and 31:69. Commercial cotton varieties (Gossypium hirsutum) normally exhibit an approximate 3:2 ratio. (+)-Gossypol is significantly less toxic than (-)-gossypol to nonruminant animals; thus, cottonseed containing high levels of (+)-gossypol might be safely fed to nonruminants. Gossypol, however, is an important component in the cotton plant's defense against insect herbivores, but it is not known how cotton plants that exhibit high levels of (+)-gossypol in the foliage might be affected by insect herbivory. To address this question, 1-d-old Helicoverpa zea larvae were fed diets with 0.16, 0.20, and 0.24% racemic, (+)-, and (-)-gossypol. Larval pupal weights, days-to-pupation, and survival were adversely affected by all gossypol diets compared with the control diet. Statistical differences were determined by comparing the compounds among themselves at the three levels and between the three compounds at the same level. When the compounds were compared among themselves, no large differences were observed in pupal weights or in days-to-pupation among any of the diets. Among the three compounds, at the 0.16% level, the diet containing racemic gossypol was the most effective at reducing survival. At the 0.20 and 0.24% levels of racemic (+)- and (-)-gossypol, survival was not statistically different. The overall results indicate that (+)-gossypol is as inhibitory to H. zea larvae as racemic or (-)-gossypol, and thus, cotton plants containing predominantly the (+)-enantiomer in foliage may maintain significant defense against insect herbivory.

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Effect of Racemic and (+)- and (−)-Gossypol on the Survival and Development of Helicoverpa zea Larvae

Gossypol, a pigment present in various parts of the cotton plant , was first discovered by Longmore in 1886 and subsequently isolated in pure crystalline form in 1899 by Marchlewski. During the ensuing decades, extensive investigation of this compound focused on methods of identifying or eliminating it from cotton seed, which was used as a livestock feed, and its toxicity in animals consuming cotton seed. The structure of gossypol (fig. I), 2,2'-bi-8-formyl-l ,6,7-trihydroxy-5-isopropyl-3methylnaphthyl , was first formulated by Adams et al. (1938), and was confirmed when Edwards (1958) totally synthesised the molecule. The chemistry, metabolism and toxicology of gossypol have been extensively reviewed (Abou-Donia 1976; Adams et al. 1960). It was not until the late 1960s that attention began to be paid to the antifertility activity of gossypol, when farmers in some rural areas of China, particularly in Hubei and Hebei provinces , developed fatigue and a burning sensation on the face, hands and other exposed parts of the body. This disease entit y was given the name 'Hanchuan fever' because it was first recognised in Hanchuan county by the Hubei ProvincialEpidemic Prevention Station in 1967 (Wu, unpublished data). The farmers called their disease 'the burning fever' (Huang 1985; Wu 1972). Epidemiologists showed that patients with this 'burning fever' had consumed homemade unheated cotton seed oil containing gossypol, which is largelydestroyed by moist heat treatment during processing of commercial cotton seed oil (Dowell & Menaul 1923). Cessation of the use of the raw cotton seed oil led to remission of the burning symptoms. However, many couples from these rural areas were found to be infertile; the women had amenorrhoea and the men had oligospermia or azoospermia. Most of the men and women recovered if a lower total amount of raw cotton seed oil was consumed. This led to consideration of whether gossypol, at an appropriate dosage, would be effective as a male contraceptive or a therapeutic agent for some gynaecological diseases (Qian 1972; Wu 1972).

An overview of the clinical pharmacology and therapeutic potential of gossypol as a male contraceptive agent and in gynaecological disease.

Summary

The enantiomers of gossypol have been tested as male oral anti-fertility agents in hamsters. As determined by fertility tests the (-) isomer was fully active at half the effective dose of the racemate, whereas the (+) isomer exerted no anti-fertility effect.

S. A. Matlin

Papers

Comparative anti-fertility effects of gossypol enantiomers in male hamsters.