Steroids Stereochemistry

The steroids are modified triterpenoids containing the tetracyclic ring system of lanos-terol (Figure 5.55), but lacking the three methyl groups at C-4 and C-14. Cholesterol (Figure 5.76) typifies the fundamental structure, but further modifications, especially to the side-chain, help to create a wide range of biologically important natural products, e.g. sterols, steroidal saponins, cardioactive glycosides, bile acids, corticosteroids, and mammalian sex hormones. Because of the profound biological activities encountered, many natural steroids together with a considerable number of synthetic and semi-synthetic steroidal compounds are routinely employed in medicine. The markedly different biological activities observed emanating from compounds containing a common structural skeleton are in part ascribed to the functional groups attached to the steroid nucleus, and in part to the overall shape conferred on this nucleus by the stereochemistry of ring fusions.

Ring systems containing six-membered or five-membered rings can be trans-fused as exemplified by trans-decalin or cis-fused as in cis-decalin (Figure 5.76). The trans-fusion produces a flat-tish molecule when two chair conformations are present. The only conformational mobility allowed is to less favourable boat forms. Both bridgehead hydrogens (or other substituents) are axial to both of the rings. In contrast, the cis-fused decalin is basically a bent molecule, and is found to be flexible in that alternative conformers are possible, both rings still being in chair form. However, this flexibility will be lost if either ring is then trans-fused to a third ring. Bridgehead substituents are axial to one ring, whilst being equatorial to the other, in each conformer.

In natural steroids, there are examples of the A/B ring fusion being trans or cis, or having unsaturation, either A4 or A5. In some compounds, notably the oestrogens, ring A can even be aromatic; clearly there can then be no bridgehead substituent at C-10 and the normal C-10 methyl (C-19) must therefore be lost. All natural steroids have a trans B/C fusion, though cis forms can be n n

21 22

21 22

Testosterone Decalin

steroid numbering

irans-decalin

irans-decalin

all-irans H

A5-unsaturation steroid numbering

cis-decalin cis-decalin

all-irans H

Testosterone Stereochemistry

A ring aromatic

A ring aromatic

A5-unsaturation

A4-unsaturation

Figure 5.76

A5,7-unsaturation

A4-unsaturation

Figure 5.76

A5,7-unsaturation made synthetically. The C/D fusion is also usually trans, though there are notable exceptions such as the cardioactive glycosides. Of course, such comments apply equally to some of the triterpenoid structures already considered. However, it is in the steroid field that the relationship between stereochemistry and biological activity is most marked. The overall shapes of some typical steroid skeletons are shown in Figure 5.76.

Systematic steroid nomenclature is based on a series of parent hydrocarbons, including estrane, androstane, pregnane, cholane, cholestane, ergostane, campestane, stigmastane and poriferastane (Figure 5.77). The triterpenoid hydrocarbons lanostane and cycloartane are similarly used in systematic nomenclature and are also included in Figure 5.77. It is usual to add only unsaturation (ene/yne) and the highest priority functional group as suffixes to the root name; other groups are added as prefixes. Stereochemistry of substituents is represented by a (on the lower face of the molecule when it is drawn according to customary conventions as in Figure 5.77), or p (on the upper face). Ring fusions may be designated by using a or p for the appropriate bridgehead hydrogen, particularly those at positions 5 and 14, which will define the A/B and C/D fusions respectively, e.g. 5p-cholestane has the A/B rings cis-fused. Since the parent hydrocarbon assumes that ring fusions are trans, the stereochemistry for ring fusions is usually only specified where it is cis. Cholesterol is thus cholest-5-en-3P-ol or 5-cholesten-3P-ol. The term nor is affixed to indicate loss of a carbon atom, e.g. 19-norsteroids (see page 274) lack C-19 (the methyl at C-10).

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