Steroids double bond activation

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketonesfl 13], The Michael addition of 2-methyl-1,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (5)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidi2ed with PdCl2-CuCl2-02 to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

It is also used ia the preparation of biologically active steroids where the fluorine is added in a cis configuration to the double bond (13,14). 

The steroid hormones are mainly inactivated in the liver, where they are either reduced or further hydroxylated and then conjugated with glucuronic acid or sulfate for excretion (see p. 316). The reduction reactions attack 0X0 groups and the double bond in ring A. A combination of several inactivation reactions gives rise to many different steroid metabolites that have lost most of their hormonal activity. Finally, they are excreted with the urine and also partly via the bile. Evidence of steroids and steroid metabolites in the urine is used to investigate the hormone metabolism. 

The adrenal glands secrete over 50 different steroids, the most important of which are aldosterone and hydrocortisone. Aldosterone causes salt retention in the body. It is not commercially available. Hydrocortisone is useful for its anti-inflammatory and antiallergic activity. Cortisone and its derivatives have similar activity and it is reduced in vivo to hydrocortisone. The two substances are used to treat rheumatoid arthritis. The 11-P-hydroxyl of hydrocortisone is believed to be of major importance in binding to the receptors of enzymes. Anti-inflammatory activity is significantly Increased by various substituents 6a-fluoro, 9a-fluoro, 21-hydroxy, 2a-methyl, 9a-chloro, and a double bond at C-1. 

Within the basic structure of the steroid molecule (Fig. 60.4), a 4,5 double bond and a 3-ketone group are needed for typical steroid activity. A hydroxyl group on Cll is needed for glucocorticoid activity (corticosterone) but is not required for sodium-retaining activity (desoxycorticosterone). The addition of a hydroxyl group on C17, which converts corticosterone to cortisol, also increases glucocorticoid activity. 

Vitamin D. The term vitamin D refers to a group of seco-steroids that possess a common conjugated triene system of double bonds. Vitamin I), (10a) and vitamin D, (10b) are the best-known examples (Fig. 2). Vitamin D (10a) is found primarily in vertebrates, whereas vitamin 11 (10b) is found primarily in plants. The term vitamin is a misnomer. Vitamin I) is a prohormonc that is converted into physiologically active form, primarily 1.25-dihydroxy vitamin D3 (11), by successive hydroxylalions in the liver and kidney. This active form is part of a hormonal system that regulates calcium and phosphate metabolism in the target tissues. 

In 1953, G. D. Searle and Co. patented a related compound, norethynodrel. This steroid is also an active contraceptive when taken orally. This fact is not at all surprising to an experienced organic chemist because it is well known that a CC double bond such as the one in norethynodrel is readily isomerized into conjugation with a carbonyl group. This acid-catalyzed isomerization occurs via an enol intermediate, and the equilibrium favors the more stable, conjugated compound. The acidic conditions in the human gastric system are quite sufficient to accomplish the transformation of norethynodrel to norethindrone. It seems that chemical reactions do not care much about patents ... 

The synthesis of modified cortical steroids has received particular interest since the report of greatly enhanced activity in the series of 9-halogen derivatives of hydrocortisone [23]. Further modifications have included the introduction of the C-l double bond [24] and the 2-methyl group [25]. The increased activity due to these latter changes has been attributed to protection of A-ring against inactivation via enzymatic reduction. [26] It seemed reasonable to suppose that a 6a-meth-yl group would be similarly effective. 

The initial breakthrough came with the introduction of a 1,2-double bond in the A-ring of the steroid nucleus, giving prednisone and prednisolone which have enhanced activity (three- to five-times that of cortisone) and reduced mineralocor-ticosteroid activity at the projected therapeutic dose. 

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