Steroids reactivity

Cyclohexane was originally postulated to be non-planar by the German chemist Sachse in 1890. Definitive proof was provided in ca. 1950 by Hassel in Oslo, from analysis of X-ray structures, and by Barton in London from correlations with steroid reactivities (see also Dunitz and Weser, Further Reading). The distinction between axial and equatorial positions was also made at that time (see Barton3). 

Barton obtained his doctorate during World War II, then in 1949, serving as a sabbatical replacement at Harvard for a year, he happened to hear a talk by Louis Fieser. Fieser had written a book with his wife, Mary, on steroid chemistry, and during the lecture Fieser listed several unsolved problems in steroid reactivity. 

We shall describe a specific synthetic example for each protective group given above. Regiosdective proteaion is generally only possible if there are hydroxyl groups of different sterical hindrance (prim < sec < tert equatorial < axial). Acetylation has usually been effected with acetic anhydride. The acetylation of less reactive hydroxyl groups is catalyzed by DMAP (see p.l44f.). Acetates are stable toward oxidation with chromium trioxide in pyridine and have been used, for example, for protection of steroids (H.J.E. Loewenthal, 1959), carbohydrates (M.L. Wolfrom, 1963 J.M. Williams, 1967), and nucleosides (A.M. Micbelson, 1963). The most common deacetylation procedures are ammonolysis with NH in CH OH and methanolysis with KjCO, or sodium methoxide. 

Diene carboxylates can be prepared by the reaction of alkenyl halides with acrylates[34]. For example, pellitorine (30) is prepared by the reaction of I-heptenyl iodide (29) with an acrylate[35]. Enol triflates are reactive pseudo-halides derived from carbonyl compounds, and are utilized extensively for novel transformations. The 3,5-dien-3-ol triflate 31 derived from a 4,5-unsaturated 3-keto steroid is converted into the triene 32 by the reaction of methyl acrylate[36]. 

Carbonylation of enol triflates derived from ketones and aldehydes affords Q,/)-unsaturated esters[332]. Steroidal esters are produced via their aryl and enol triflates[328]. The enol triflate in 477 is more reactive than the aryl tritlate and the carbonylation proceeds stepwise. First, carbonylation of the enol triflate affords the amide 478 and then the ester 479 is obtained in DMSO using dppp[333]. 

Fluoropyridine is readily hydroly2ed to 2-pyridone in 60% yield by reflux in 6 Ai hydrochloric acid (383). It is quite reactive with nucleophiles. For example, the halogen mobiUty ratio from the comparative methoxydehalogenation of 2-fluoropyridine and 2-chloropyridine was 85.5/1 at 99.5°C (384). This labihty of fluorine has been utili2ed to prepare fluorine-free 0-2-pyridyl oximes of 3-oxo steroids from 2-fluoropyridine for possible use as antifertihty agents (385). 

Dimethylamino-l,3-dioxolane/cat. HOAc, CH2CI2, 83% yield. 2-Di-methylamino-l,3-dioxolane protects a reactive ketone under mild conditions it reacts selectively with a C3-keto steroid in the presence of a A -3-keto steroid. C12- and C2o-keto steroids do not react. 

The use of dimethyl sulfoxide-acetic anhydride as a reagent for the oxidation of unhindered steroidal alcohols does not appear to be as promising due to extensive formation of by-products. However, the reagent is sufficiently reactive to oxidize the hindered 11 j -hydroxyl group to the 11-ketone in moderate yield. The use of sulfur trioxide-pyridine complex in dimethyl sulfoxide has also been reported. The results parallel those using DCC-DMSO but reaction times are much shorter and the work-up is more facile since the separation of dicyclohexylurea is not necessary. Allylic alcohols can be oxidized by this procedure without significant side reactions. 

Although lead tetraacetate can attack many polar and nonpolar functions in the steroid molecule, its greatest reactivity is towards vicinal diols. These diols are generally cleaved so rapidly under stoichiometric conditions that other alcohol functions in the molecule need not be protected. Thus lead tetraacetate in acetic acid at room temperature splits the 17a,20-diol group in (9) to yield the 17-ketone (10), the allylic A -3jS-alcohol remaining intact during this oxidation. Since lead tetraacetate is solublein many anhydrous... 

In practice the 3-ketone in both 5a- and 5i -steroids is the least hindered and most reactive carbonyl group, whereas the 11-ketone is the most hindered and least reactive. The 6-ketone is less reactive than the 3-ketone but it can be selectively protected in the presence of a 17- or 20-ketone. The 7-ketone is more reactive than a 12-ketone. 

The reactivity of various steroid alcohols decreases in the order primary > secondary (equatorial) > secondary (axial) > tertiary. The only systematic investigation relating to the selective protection of steroidal hydroxyl functions has been carried out with the cathylate (ethyl carbonate) group. Since only equatorial hydroxyl groups form cathylates this ester has been used as a diagnostic tool to elucidate the configuration of secondary alcohols. 

The selective formation of the 3-monosemicarbazones of polyketonic steroids can be achieved only in the presence of 21-acetoxy-20-ketones by the use of nonbuffered conditions. Partial hydrolysis of 3,20-bissemicar-bazones can be achieved with acetic anhydride in pyridine "" to yield the 3-semicarbazone. Kinetic studies on the rates of formation of Girard hydra-zones showed that the A" -3-ketone is less reactive than the saturated 3- and 6-ketones, as reactive as the 7- and 17-ketones and more reactive than the 20- and 12-ketones. ... 

Although A" -3-keto steroids are inert to diazomethane, Fieser ° observed pyrazoline formation (24) with the more reactive cholest-4-ene-3,6-dione (23). 

While the oxidation of ketones by peracids (Baeyer-Villiger reaction) has been used in steroids mainly for ring cleavage, it has occasionally been applied to 20-ketopregnanes for conversion to 17-acetoxy- or hydroxyandros-tanes. The synthetic utility of this method is limited since reactive double bonds and other ketones are incompatible with the reagent. 

As in the case of the steroids, introduction of additional nuclear substituents yields morphine analogs of increased potency. The more important of these are derived from one of the minor alkaloids that occur in opium. Thebaine (14), present in crude opium in about one-tenth the amount of morphine, exhibits a reactive internal diene system that is well known to undergo various addition reactions in a 1,4 manner (e.g., bromination). Thus, reaction with hydrogen peroxide in acid may be visualized to afford first the 14-hydroxy-6-hemiketal (15). Hydrolysis yields the isolated unsaturated ketone (16). Catalytic reduction... 

Vinylnaphthalenes give Diels-Alder reactions more easily than styrenes and have been used to synthesize steroid-like compounds. 2-Vinylnaphthalene (61) is less reactive than 1-vinylnaphthalene (62) (Figure 2.7) it requires drastic conditions to undergo Diels-Alder reaction and the yields are low. Better results can be obtained by carrying out the reaction under high pressure (Chapter 5). Some Diels-Alder reactions of 1-vinylnaphthalene (62) are summarized in Scheme 2.23. 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

---