Skip to main content
Chemistry LibreTexts

27.8: How Steriods Are Chemical Messengers

The important class of lipids called steroids are actually metabolic derivatives of terpenes, but they are customarily treated as a separate group. Steroids may be recognized by their tetracyclic skeleton, consisting of three fused six-membered and one five-membered ring, as shown in the diagram to the right. The four rings are designated A, B, C & D as noted, and the peculiar numbering of the ring carbon atoms (shown in red) is the result of an earlier misassignment of the structure. The substituents designated by R are often alkyl groups, but may also have functionality. The R group at the A:B ring fusion is most commonly methyl or hydrogen, that at the C:D fusion is usually methyl. The substituent at C-17 varies considerably, and is usually larger than methyl if it is not a functional group. The most common locations of functional groups are C-3, C-4, C-7, C-11, C-12 & C-17. Ring A is sometimes aromatic. Since a number of tetracyclic triterpenes also have this tetracyclic structure, it cannot be considered a unique identifier.

1.jpg

Steroids are widely distributed in animals, where they are associated with a number of physiological processes. Examples of some important steroids are shown in the following diagram. Norethindrone is a synthetic steroid, all the other examples occur naturally. A common strategy in pharmaceutical chemistry is to take a natural compound, having certain desired biological properties together with undesired side effects, and to modify its structure to enhance the desired characteristics and diminish the undesired. This is sometimes accomplished by trial and error.
The generic steroid structure drawn above has seven chiral stereocenters (carbons 5, 8, 9, 10, 13, 14 & 17), which means that it may have as many as 128 stereoisomers. With the exception of C-5, natural steroids generally have a single common configuration. This is shown in the last of the toggled displays, along with the preferred conformations of the rings.

http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/Images3/steroid1.gif

http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/Images3/steroid2.gif

http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/Images3/steroid3.gif

http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/Images3/steroid4.gif

Chemical studies of the steroids were very important to our present understanding of the configurations and conformations of six-membered rings. Substituent groups at different sites on the tetracyclic skeleton will have axial or equatorial orientations that are fixed because of the rigid structure of the trans-fused rings. This fixed orientation influences chemical reactivity, largely due to the greater steric hindrance of axial groups versus their equatorial isomers. Thus an equatorial hydroxyl group is esterified more rapidly than its axial isomer.

It is instructive to examine a simple bicyclic system as a model for the fused rings of the steroid molecule. Decalin, short for decahydronaphthalene, exists as cis and trans isomers at the ring fusion carbon atoms. Planar representations of these isomers are drawn at the top of the following diagram, with corresponding conformational formulas displayed underneath. The numbering shown for the ring carbons follows IUPAC rules, and is different from the unusual numbering used for steroids. For purposes of discussion, the left ring is labeled A (colored blue) and the right ring B (colored red). In the conformational drawings the ring fusion and the angular hydrogens are black.

http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/Images3/decalin1.gif

http://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/Images3/decalin2.gif

The trans-isomer is the easiest to describe because the fusion of the A & B rings creates a rigid, roughly planar, structure made up of two chair conformations. Each chair is fused to the other by equatorial bonds, leaving the angular hydrogens (Ha) axial to both rings. Note that the bonds directed above the plane of the two rings alternate from axial to equatorial and back if we proceed around the rings from C-1 to C-10 in numerical order. The bonds directed below the rings also alternate in a complementary fashion.

Conformational descriptions of cis- decalin are complicated by the fact that two energetically equivalent fusions of chair cyclohexanes are possible, and are in rapid equilibrium as the rings flip from one chair conformation to the other. In each of these all chair conformations the rings are fused by one axial and one equatorial bond, and the overall structure is bent at the ring fusion. In the conformer on the left, the red ring (B) is attached to the blue ring (A) by an axial bond to C-1 and an equatorial bond to C-6 (these terms refer to ring A substituents). In the conformer on the right, the carbon bond to C-1 is equatorial and the bond to C-6 is axial. Each of the angular hydrogens (Hae or Hea) is oriented axial to one of the rings and equatorial to the other. This relationship reverses when double ring flipping converts one cis-conformer into the other.

Cis-decalin is less stable than trans-decalin by about 2.7 kcal/mol (from heats of combustion and heats of isomerization data). This is due to steric crowding (hindrance) of the axial hydrogens in the concave region of both cis-conformers, as may be seen in the model display activated by the following button. This difference is roughly three times the energy of a gauche butane conformer relative to its anti conformer. Indeed three gauche butane interactions may be identified in each of the cis-decalin conformations, as will be displayed by clicking on the above conformational diagram. These gauche interactions are also shown in the model.
 

Steroids in which rings A and B are fused cis, such as the example on the right, do not have the sameconformational mobility exhibited by cis-decalin. The fusion of ring C to ring B in a trans configuration prevents ring B from undergoing a conformational flip to another chair form. If this were to occur, ring C would have to be attached to ring B by two adjacent axial bonds directed 180º apart. This is too great a distance to be bridged by the four carbon atoms making up ring C. Consequently, the steroid molecule is locked in the all chair conformation shown here. Of course, all these steroids and decalins may have one or more six-membered rings in a boat conformation. However the high energy of boat conformers relative to chairs would make such structures minor components in the overall ensemble of conformations available to these molecules.

8.jpg

Contributors

William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry