Steroids from Carvone Promotor Prof. dr. Ae. de Groot, Hoogleraar in de Bio-organische Chemie, Wageningen Universiteit Co-promotoren Prof. dr. M. B. Groen, Hoogleraar aan de Vrije Universiteit Amsterdam Dr. B. J. M. Jansen, Universitair Docent bij het Laboratorium voor Organische Chemie, Wageningen Universiteit Promotiecommissie Prof. dr. J. Wicha, Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland Prof. dr. H. Hiemstra, Universiteit van Amsterdam Dr. J.W. Scheeren, Radboud Universiteit Nijmegen Prof. dr. E. J. R. Sudhölter, Wageningen Universiteit Florence C. E. Sarabèr Steroids from Carvone Proefschrift ter verkrijging van de graad van doctor op gezag van de rector magnificus van Wageningen Universiteit, Prof. dr. ir. L. Speelman, in het openbaar te verdedigen op dinsdag 10 mei 2005 des namiddags te half twee in de aula Sarabèr, Florence C. E. Steroids from Carvone Thesis Wageningen University –with references and summaries in English, French and Dutch ISBN 90-8504-181-3 Contents Chapter 1 1 Introduction Chapter 2 31 Domino Mukaiyama reactions to polycyclic systems Chapter 3 63 New approach towards C,D-trans fused steroid and D-homo steroid skeletons Chapter 4 85 A new and short synthesis of C,D-cis fused steroid and D-homosteroid skeletons Chapter 5 99 A second new and short synthesis of C,D-trans fused steroid skeletons Chapter 6 127 Synthesis of a chiral ring D precursor for the generation of enantiomerically pure steroid skeletons Chapter 7 145 1-Phenylthio-3-vinyl-3-cyclohexenol, a new reagent for bis-annelation of silyl enol ethers Chapter 8 165 The use of b-cyanoketones for the synthesis of functionalized polycyclic compounds Chapter 9 177 Discussion Appendix 187 List of used abbreviations 188 Summary 189 Samenvatting 195 Résumé 201 Dankwoord 207 Curriculum vitae 209 Wanneer jij je ogen opent zullen wij, opnieuw, op weg gaan tussen de uren en hun uitvindingen en slenterend tussen de verschijningen zullen wij de tijd en zijn vervoegingen bevestigen. Wij zullen de deuren van de dag openen en binnentreden in het onbekende. Uit De eerste januari van Octavio Paz Introduction Introduction ______________________________________________________________________________________________ 1.1 Introduction Steroids probably form one of the most investigated groups of natural products to this date. They are related to the group triterpenes, which, in turn, belongs to a larger class of compounds known as terpenes, or isoprenoids. Many of the smaller and more volatile terpenes have been used by mankind for at least two thousand years as flavours and fragrances, although at first as components of crude plant extracts. During the Middle Ages, for example, any herbalist had many recipes for the production of medicines and essences from herbs such as rosemary, thyme, tansy, etc., all rich in terpenes1. Today, terpenes are still widely used, with applications varying from their use in perfumes, cosmetics, soaps, detergents, toothpaste, confectionery, processed meats or tinned foods, to the use of turpentine in the paint industry. The use of steroidal hormones like adrenal hormones such as cortisone, sex hormones such as estradiol and testosterone, and vitamin D is widespread in the pharmaceutical and food (supplement) industries1,2. The group of steroids includes both synthetic and natural substances, of which the latter occur in a wide variety of marine and terrestrial organic organisms3. In essence, steroids all possess a similar structural feature, the tetracyclic perhydro-1,2-cyclopentenophenanthrene ring system (see figure 1), although the group actually also includes compounds with a somewhat modified structure. Deviations from the normal skeleton are indicated by prefixes. For example, compounds missing a ring junction, leading to an opened ring system, are generally referred to as ‘seco’ steroids (e.g. vitamin D and analogues). Another example comes from compounds with an extra C-atom, indicated with the term ‘homo’ preceded by the concerned ring or atom number and placed in front of the steroid name (e.g. D-homo steroids). When a carbon atom is missing the prefix used is ‘nor’, and the prefix ‘cyclo’ refers to an extra ring formed by bonding between two C-atoms of the steroid skeleton. The peculiar numbering system used (see figure 1) originates from the early erroneous structure assigned to cholesterol. When any of the carbon atoms is missing, the numbering of the others remains unchanged4. The definitive rules for steroid nomenclature were decided in 1971 by the International Union of Pure and Applied Chemistry (IUPAC) and the International Union of Biochemistry (IUB)5. Figure 1. Steroid numbering and general stereochemistry 20 12 R 17 2 13 11 19 CD16 R 1 9 1 H 10 2 14 15 8 H H AB5 3 7 4 6 2 _______________________________________________________________________________________ Chapter 1 The initially isolated solid crystalline secondary alcohols from non-saponifiable lipid extracts of plants and animals were called sterols (~ ‘solid alcohol’, in Greek), and their name later led to the terminology “steroid”, which was introduced in 1936 for this whole class of compounds4. Early steroid research in the 19th century mainly involved isolation of the sterols, and bile acids, from natural sources. Cholesterol was one of the first sterols isolated, originally from human gallstones, but the compound was later found to be present in all animal tissues. The discovery of cholesterol is generally accredited to de Fourcroy in 17896. However, its structural elucidation had to wait until the 20th century. In 1903 this elucidation was started and it was terminated only thirty years later, when X-ray crystallographic data became available. A first steroid total synthesis of equilenin was achieved also at that time, proving the tetracyclic structure of steroidal compounds7-11. In this same period, estrone, progesterone, estradiol and testosterone were isolated and their structures elucidated10. These different developments opened the road to further academic, and from then on, also industrial research on steroids, their (bio)synthesis and their biological activity, leading to an incredible amount of publications on this subject that continues to this date1,2,4,11,12. The pharmaceutical relevance of these compounds has proven to be exceptional and nowadays around 6% of the total drug marked is covered by steroid-based preparations13. 1.2 Biological relevance The large group of steroids is subdivided into several subgroups, mainly according to the structure of the parent hydrocarbon from which they are derived. An important diversifying element in these parent hydrocarbons is the side chain attached to ring D2,3. The different subgroups that can be distinguished are sterols, sapogenins, cardiac aglycones and steroidal alkaloids, from plants, and sterols, bile acids, corticosteroids and the sex hormones estrogens, progestagens (both female) and androgens (male), from animals. The corticoids and sex hormones are known to fulfil important hormonal functions in mammals and are therefore of most interest to the pharmaceutical industry. Besides that, the cardiac aglycones, such as digitoxigenin, are known to have powerful and specific actions on the heart muscle and are for this reason also valuable agents in the treatment of heart ailments. Diosgenin, isolated from Yams (Dioscorea sp.), has proven to be a very useful sapogenin, being a valuable starting material for several steroid hormone syntheses such as cortisone and synthetic male and female sex hormones2. The majority of the sterols appear to be very long-lived and thus not metabolised. Moreover, all eukaryotes synthesise sterols, or have an absolute requirement for them in their diet. They play a vital role in maintaining structural integrity of most membraneous structures in organisms. They 3 Introduction ______________________________________________________________________________________________ Figure 2. The different steroid groups and representative compounds Sterols Sapogenins O O HO HO HO stigmasterol cholesterol diosgenin Vitamins D Steroidal Alkaloids N HO HO vitamin D ergosterol 2 solanidine (vit. D precursor) HO Cardiac aglycones or Cardenolides Bile acids O O HO CO2H OH HO HO OH H H digitoxigenin cholic acid Corticosteroids Estrogens O O CH2OH OHC CH2OH OH O OH HO O O HO cortisone aldosterone Estradiol Progestagens Androgens O OH O O progesterone testosterone further appear to assist in the regulation of permeability of these membranes for various ions1. The vitamins D form a specific group of sterols having all the same seco-steroidal structure. They play an important role in the absorption and metabolism of calcium and phosphorus in animals but originate from steroidal precursors of plant origin, such as ergosterol11. The bile acids are known for their activity in the digestion processes. The active form of these compounds is actually the bile 4 _______________________________________________________________________________________ Chapter 1 salts. They emulsify fats present in partially digested foods to make them more accessible for enzymatic cleavage leading to lipid absorption in the gut1,3,11. In the family of the steroid hormones, corticosteroids, such as cortisone and aldosterone, have a broader spectrum of activity than the sex hormones. They help to control the metabolism of carbohydrates, proteins and fats, and play an important role in the regulation of the salt and water balances in our bodies14. The sex hormones, on the other hand, are