Steroid substitution

Some compounds are more difficult to derivatize than others, because of variations in the reactivity of the replaceable proton. In the case of the 17-keto steroids, substituting a solvent is adequate but such is not always the case. More powerful or... 

In 1965, Neumann and Wiechert [100] published the results of their investigations of some 150 steroids. They studied the androgenic and anabolic activity of steroids substituted in the C-1 and/or the C-2 position. Five parent compounds were chosen 1. 5a-androstan-17]3-ol 2. testosterone 3. 5a-dihydrotestosterone 4. A -5a-androsten-17j8-ol 3-one and 5. A -5a-androsten-17/3-ol. The parent compounds were further classified according to the substitution in the 17-position, i.e., l7j8-hydroxy, 17a-methyl 17j8-hydroxy, or 17/3-acetoxy compounds. 

Steroids substituted by spiro-a-methylene-7-lactones [e.g. (431)] have been synthesized as possible antitumour agents by Reformatsky reactions between ethyl 0 -(bromomethyl)acrylate and suitable steroid ketones. 

Silva, S. M., Wagner, K., Weiss, D., Beckert, R., Stevani, C. V., Baader, W. J., Studies on the Chemiexcitation Step in Peroxyoxalate Chemiluminescence Using Steroid substituted Activators, Luminescence 2002, 17, 362 369. 

On treatment in alkaline medium (KOH-EtOH), the a-oxaziran (87) gives (91), which is converted into the conjugated ketone (93) by boiling (KOH-Et0H-H20). Refluxing in methanol converts (91) into (92), which has been used to prepare a series of steroids substituted at C-18 and C-20. The circular dichroism of the nitrone chromophores of (82) and (84) and the tertiary amine chromophore of conanine has been studied. 

Steroids substituted at C-10 with carbon chains have been prepared by an apparently completely stereospecific Diels-Alder addition of but-l-en-3-one to... 

The photoisomerization of azo-compounds continues to attract attention. Evidence that photoisomerization of certain steroidal-substituted azo-compounds proceeds by way of an inversion mechanism has been described. Full details have now been reported of the photorearrangement of l,2-diaza-(Z)-cyclo-oct-l-ene (14) to the -isomer (15), and analogous transformations have been observed... 

Wright, J.N., van PT. Leersum, S.G. Chamberlin and M. Akhtar (1989). Inhibition of aromatase by steroids substituted at C-19 with halogen, sulphur, and nitrogen. J. Chem. Soc. Perkin Trans. I 1647-1655. 

Strategy Problem 1 The wrong substitution pattern . Making aromatic compounds m-substituted with two o -directing groups is always a problem. What strategies can you suggest An example (TM 412) is the alkyl hahde used in the synthesis of some steroids. 

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. 

Several substituted cyclohexane derivatives may also be obtained by the reduction of a benzenoid precursor. Partial reduction of resorcinol, for example, and subsequent methyla-tion yields 2-methylcyclohexane-I,3-dione, which is frequently used in steroid synthesis (M.S. Newman, 1960 see also p. 71f.), From lithium-ammonia reduction of alkoxybenzenes l-alkoxy-l,4-cyclohexadienes are obtained (E.J. Corey, 1968 D). 

J-Tosyloxy. d -steroids, e.g. O-tosylcholesterol, give 3,5-cyclosteroids (— /-steroids) on addition of nucleophiles. Internal hydroxyl displacement, e.g. with PClj, leads to 3fi-substituted products or overall retention of configuration at C-3 by rearrangement of the 6/5 substituent (E.M. Kosower, 1956). 

A direct, one-step aromatization of 19-substituted steroids has appeared in the Hterature, ie, cholesterol (3), dehydroisoandrosterone, androsterone, progesterone (1), and testosterone react with an electrophilic mthenium complex, C Ru , where Cp represents Tj -cyclopentadienyl, obtained through protonation of [Cp Ru(OCH2)]2 using triflic acid, to provide estrone (20) directly (46). 

The methodology used in the preparation of RU 486 (84) and other ll -steroids is shown. Conjugate addition of a cuprate reagent to the a,P-unsaturated epoxide (85) provides the liP-substituted steroid (86) stereospecificaHy (131). Subsequent steps lead to the synthesis of RU 486 (84). 

Molybdate is also known as an inhibitor of the important enzyme ATP sulfurylase where ATP is adenosine triphosphate, which activates sulfate for participation in biosynthetic pathways (56). The tetrahedral molybdate dianion, MoO , substitutes for the tetrahedral sulfate dianion, SO , and leads to futile cycling of the enzyme and total inhibition of sulfate activation. Molybdate is also a co-effector in the receptor for steroids (qv) in mammalian systems, a biochemical finding that may also have physiological implications (57). 

Steroids (1) are members of a large class of lipid compounds called terpenes that are biogenicaHy derived from the same parent compound, isoprene, C Hg Steroids contain or are derived from the perhydro-l,2-cyclopentenophenanthrene ring system (1) and are found in a variety of different marine, terrestrial, and synthetic sources. The vast diversity of the natural and synthetic members of this class depends on variations in side-chain substitution (primarily at C17), degree of unsaturation, degree and nature of oxidation, and the stereochemical relationships at the ring junctions. 

The most powerful method for stmcture elucidation of steroid compounds during the classical period of steroid chemistry (- 1940 1950s) was ir-spectroscopy. As with the ultraviolet spectra, data collected on the infrared spectra of steroids are available in several books, spectmm atiases, and review articles (265,266). Unlike ultraviolet spectroscopy, even the least substituted steroid derivatives are relatively rich in characteristic absorption bands in infrared spectroscopy (264). 

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