An important structural feature of any steroid is recognition of the presence of asymmetric carbon atoms and designation in the formal nomenclature of the structural isomer that is present. Thus, reduction of pregnan-3-one to the corresponding 3-alcohol will produce two epimeric steroids (see Figure 1). The resulting hydroxyl may be above the plane of the A ring and is so designated on the structure by a bold solid line; it is referred to as a 3 β-ol. The epimer, or 3α-ol, has the hydroxyl below the plane of the A ring and is so designated by a dotted line for the C ⋯ OH bond. If the α- or β-orientation of a substituent group is not known, it is designated with a wavy line (C ~OH).
Fig1. Structural consequences resulting from the reduction of of the 3-keto group of pregnan-3-one to a hydroxyl group (see Row 1). As shown in Row 2, the orientation of the hydroxyl group is not designated (see the green wavy bond of the C3 hydroxyl group). As shown in Row 3, there are two structural options for the orientation of the hydroxyl goup on C-3. The hydroxyl can be either “above” the plane of the page (see the solid blue hydroxyl group) or below the plane of the page (see the dashed red hydroxyl group). Thus, in Row 3, application of steroid nomenclature rules designates that the red hydroxyl below the plane of the page is a 3α-hydroxyl while the blue hydroxy above the plane of the page is a 3β-hydroxyl. Row 4 presents the chair presentation for the A/B rings of the two pregnane isomers; this further emphasizes that the alpha and beta 3- hydroxyl groups each have a distinctly different orientation in space.
Another locus where asymmetric carbon atoms play an important role in steroid structure determination is the junction between each of the A, B, C, and D rings. Figure 2 illustrates these relationships for cholestanol and coprostanol. Thus, in the 5α-form, the 19-methyl and α-hydrogen on carbon-5 are on opposite sides of the plane of the A:B ring; this is referred to as a trans fusion. When the 19-methyl and β-hydrogen on car bon-5 are on the same side of the A:B ring fusion, this is denoted cis fusion. In the instance of cis fusion of the A:B rings, the steroid structure can no longer be drawn in one plane. Thus, in all 5β-steroid structures that have cis fusion between rings A and B, the A ring is bent into a second plane that is at approximately a right angle to the B:C:D rings (see Figure 2).
Fig2. Comparison of structural relationships resulting from cis or trans A:B ring fusion in 5α-cholestane versus 5β-cholestane (top row) and cholestanol versus coprostanol (second row). In 5α-cholestane and cholestanol (left side of rows 1 and 2) the A:B ring fusion is trans (C-19-methyl-C-5H) while in 5β-cholestane and coprostanol (right side of rows 1 and 2) the A:B ring fusion is cis (C-19-methyl-C-5H). The orientation of substituents around carbon-5 for the cis and trans circumstances are illustrated in the bottom row (•–• indicates carbon–carbon bonds). Finally, with respect to the hydroxyl on C-3, its beta orientation is maintained for both cholestanol and coprostanol in spite of their different A/B ring fusions.
Thus, each of the ring junction carbons is potentially asymmetric, and the naturally occurring steroid will have only one of the two possible orientations at each ring junction. Although there are two families of naturally occurring steroids with either cis or trans fusion of the A:B rings, it is known that the ring fusions of B:C and C:D in virtually all naturally occurring steroids are trans. Consideration of the estrogen steroid series (see Figure 3) is a special case in which the A ring is aromatic; thus there is no cis–trans isomerism possible at carbons-5 and -10.
Fig3. Family tree of the seven principal classes of steroids (bottom row) that are structurally derived from the parent cholestane (top row). Cholestane has 10 additional carbons added to sterane; these include two methyl groups, C-18 and C-19, added respectively to C-13 and C-10 and an eight-carbon side chain (C-20 to C-27) attached to C-17 of the D-ring.
The side chain is a third domain of the steroid structure where asymmetry considerations are important. Historically, interest first centered on carbon-20 of the cholesterol side chain, although side chain asymmetry is also now known to be crucial for the insect steroid hormoneecdysterone, for a number of vitamin D metabolites (see Figure3), and in the production of many bile acids (see cholic acid in Figure 3). While the α or β notation is satisfactory for the designation of substituents of the A, B, C, and D ring structures, this terminology is not applicable to the side chain. This is because there is free rotation of the side chain at the carbon-17 carbon-20 bond; thus, the side chain may assume a number of orientations in relation to the ring structure.
Figure 4 identifies for cholesterol the eight asymmetric carbon atoms. Introduction of the Δ5,6-double bond in cholesterol deletes one asymmetric center, whereas addition of the eight-carbon side chain adds one asymmetric carbon at position 17. Carbon-20 of the side chain is also asymmetric. Finally, introduction of a hydroxyl group on carbon-3 creates still another asymmetric center. Thus, there are a total of eight asymmetric carbons or 28 = 256 possible structural isomers. Considering that cholesterol is the most prevalent naturally occurring steroid, it is an impressive testament to the precision of evolutionary events and to the specificity of the many enzymes involved in the biosynthesis of cholesterol that only one major sterol product is present in mammalian systems.
Fig4. Asymmetric carbons of cholesterol. The eight asymmetric carbons of cholesterol are indicated by the magenta dots (●). There are 28 or 256 structural isomers of cholesterol. Only one structural isomer is produced in higher animals.
