Steroids substituents

Three stereoisomers are possible in the cholestanylindene-derived zir-conocene complexes illustrated in Scheme 67. Two are racem-like, and the other is meso-like depending on the geometry of the metallocene moiety. The stereochemistry of the reaction is controlled by both the structure of the metallocene skeleton and steroidal substituent. Polymerization of propylene with 0-C activated with MAO gave polypropylene of 240,000, about 40% mmmm approximately 70% is due to enantiomorphic site control and the rest is due to chain-end control. Use of the catalyst derived from a /3-A-B mixture produced a mixture of polymers. The a-A and a-B/MAO catalysts afforded isotactic poly-... 

In synkinesis steroids are useful in solution as spacers between two reactive. sites bound to steroid substituents and as matrices on solid. surfaces. The magic of the steroidal skeleton lies in its extreme variability of stiffness and flexibility accompanied by consistent intramolecular distances (Fig. 3.1.1). Steroids also form hydrophobic and amphiphilic domains with pronounced stereochemical control and selective solubility in membrane structures. 

The bulkiness and stereochemistry of large steroid substituents allows stereoselective hydrolyses of unnatural enantiomers. Cholesterol together with cholesterol esterase have been used to resolve binaphtols and other diols into their enantiomers the diasteromeric dicholesteryl-diesters are hydrolyzed selectively by the crude enzyme in two steps and the final diol is a pure enantiomer. 

Connection between the anellated rings in both groups of compounds may be cis or trans, i.e., the substituents at the anellated C-atoms either are located at the same side or at different sides of the molecule. Table 38 shows the type of anella-tion with respect to some representatives of the different groups of steroids. Substituents have a so-called jff-position if their spatial location relative to the plane of the ring system is the same as that of the C-10 methyl group, i.e., in front of the plane in the projection used in this book. They have an x-position in the opposite case, i.e., behind the plane of projection. 

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. 

A major difficulty with the Diels-Alder reaction is its sensitivity to sterical hindrance. Tri- and tetrasubstituted olefins or dienes with bulky substituents at the terminal carbons react only very slowly. Therefore bicyclic compounds with polar reactions are more suitable for such target molecules, e.g. steroids. There exist, however, several exceptions, e. g. a reaction of a tetrasubstituted alkene with a 1,1-disubstituted diene to produce a cyclohexene intermediate containing three contiguous quaternary carbon atoms (S. Danishefsky, 1979). This reaction was assisted by large polarity differences between the electron rich diene and the electron deficient ene component. 

The most difflcult pharmaceutically relevant oxidation of steroids is the introduction of a 14 -hydroxyl group. This functional group is found in heart-active steroids (cardenolides) such as digitoxigenin, which also contain a 17/J-butenolide substituent. The 14/ -hydroxyl group is easily cleaved off by dehydration and must therefore not be treated with Lewis or... 

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). 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

A typical steroid skeleton is shown along with the numbenng scheme used for this class of compounds Specify in each case whether the designated substituent is axial or equatorial... 

The 1950s and 1960s saw the development of orally active progestins based on the synthesis of steroids that lack the C19-angular methyl substituent (19-norsteroids). The commercial production of these compounds for the regulation of menstmal disorders began in 1957, and for oral contraception in 1960. 

Interest in the synthesis of 19-norsteroids as orally active progestins prompted efforts to remove the C19 angular methyl substituent of readily available steroid precursors. Industrial applications include the direct conversion of androsta-l,4-diene-3,17-dione [897-06-3] (92) to estrone [53-16-7] (26) by thermolysis in mineral oil at about 500°C (136), and reductive elimination of the angular methyl group of the 17-ketal of the dione [2398-63-2] (93) with lithium biphenyl radical anion to form the 17-ketal of estrone [900-83-4] (94) (137). 

Besides the aforementioned chemical methods, microbial degradations have been used to remove the C19 angular methyl substituent of readily available steroid precursors. For example, 19-hydroxysterols, such as 3P-acetoxy-19-hydroxy-5-cholestene [750-59-4] (107), can be converted to estrone by Mocardia sp. in yields up to 70% (120,145,146). 

Catalytic hydrogenation of the 14—15 double bond from the face opposite to the C18 substituent yields (196). Compound (196) contains the natural steroid stereochemistry around the D-ring. A metal-ammonia reduction of (196) forms the most stable product (197) thermodynamically. When R is equal to methyl, this process comprises an efficient total synthesis of estradiol methyl ester. Birch reduction of the A-ring of (197) followed by acid hydrolysis of the resultant enol ether allows access into the 19-norsteroids (198) (204). 

Other, removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a sdyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. The key step, treatment of (257) with methyl aluminum chloride in methylene chloride at —78° C, followed by acylation and chromatographic separation, affords (258) in 55% yield (two steps). When this cyclization was attempted on similar compounds that did not contain the C7P-silicon substituent, no tetracycHc products were observed. Steroid (258) is converted to lanosterol (77) in three additional chemical steps (225). 

Hydrogenation of unsubstituted or 3/ -substituted-A -steroids (25a) over platinum gives, almost exclusively, the 5a-product (26a). With 3a-substituents (25b) the 5j5-product (24b) is formed preferentially. Hydrogenation of A" -steroids (23a or b) gives product mixtures in which the 5a/5j5 ratio is dependent on the nature and stereochemistry of the sub-... 

The hydrogenation of ring A aromatic steroids over ruthenium occurs, almost invariably, from the a side and all substituents on the original aromatic ring are cis in the resulting cyclohexane. Estrone (62) is hydrogenated over ruthenium to 5a,10a-estrane-3/3,17j6-diol (63) in 85-90% yield. 

With the 4-, 6-" and 15- ° keto steroids the degree of epimerization at C-5 and C-14 depends on the presence of other functional groups and substituents. Exchange of the 16- " and 20- keto pregnanes yields the 17/5-epimer as the main product. 

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