CHAPTER 6

Steroids
P.S. Kalsi

CHAPTER OBJECTIVES
After reading this chapter, you will be able to understand:
Introduction, definition and classification of steroids
" Chemical and stereochemical aspects of steroids
" Biological significance of steriods
Synthetic approaches
Biogenetic approaches to various classes of steroid

6.1 INTRODUCTION
The lipid fractions isolated from plants and animals contain an important group of compounds called
steroids, which are important "biological regulators" and almost always show dramatic physiological
effects when administered to living organis1ms. The steroids include compounds: male and female sex
hormones, adrenocortical hormones, D vitamins, the bile acids, and certain cardiac active principles.
Steroids arce tetracyclic natural products related to the terpenes and both classes are biosynthesized
by a similar route. An important example is cholesterol, the major component of human gall stones
(Gk., chole, bile).
Cholesterol is present in some amount in all normal animal tissues, however, large amounts are
present in the brain and in the spinal cord. The total amount present in a180 Ib person is 240 g, about 0.5
1b! It is present partly as the frec alcohol and partly esterified with fatty acids.
There are close similarities in chemical structures and stereochemistry, even then each class of steroids
denonstrates unique and distinctively different biologic activities. Adrenocorticoids have two classes,
glucocorticoids which regulate carbohydralc, lipid, and protein metabolism and the mineralocorticoids,
which regalate salt balance, and water retention. The sex hormones include the female sex hormones,
progestins and estrogens, and the male sex hormones, androgens. Structural modifications may be any
minor to the steroid nucleus, such as changes in or insertion of functional groups at different positions,
lead to marked changes in physiologic activity.

6.2 DEFINITION AND STRUCTURE

Steroids consist of four fused rings (A, B, C, and D). Chemically, these hydrocarbons are
cyclopentanoperhydrophenanthrenes; they contain a five-membered cyclopentane (D) ring, plus the
completely saturated
three rings of phenanthrene. A perhydrophenanthrene (rings A, B, and C) is the
derivative of phenanthrene (Scheme 6.1).
6.2 Pharmaceutical Medicinal and Natural Product Chemistry

12
13 17
11
D 16
1 9
10
2 14 15
A B
3 7
5
4 6
The basic steroiod skeleton Phenanthrene 1,2-cyclopentenophenanthrene

The basic steroid skeleton, which is that of hydrogenated 1, 2-cyclopentenophenanthrene having two methyl sub
stituents at C-10 and C-13 and an additional side chain at C-17 (See Scheme 6.2).
Scheme 6.1

Many aspects of the chemistry of cholesterol (Scheme 6.2) and the common steroid structure were
determined during the nineteeth and early-twentieth centuries. Heinrich Wieland and Adolf Windaus
related the structural features between cholesterol and the bile acids and were awarded Nobel prizes
for chemistry in 1927 and 1928, respectively, for their contributions to steroidchemistry. X-ray data
reported in 1932 deduced the correct structure of steroids. The structure of cholesterol was confirmed in
1955 by Woodward's total synthesis.
Steroids have, generally, the same absolute configuration as cholesterol has. The methyl substituents
at position 10and 13 are often called angular methyl groups (Scheme 6.2). They serve as areference point
for stereochemical designations. Substituents that are on the same side as the angular methyl groups, i.e.,
above the plane of the steroid structure, are designated as B. Those below the steroid plane are a. Both
the hydroxy group at position 3 and the side chain (R) at 17 are Bsubstituents in cholesterol.
18
12 CH, R
13 Angular methyl groups (B) placed
1911 17
18
H,Ç H
J14 16 19 CHa
CH, 11 R
10 8 15 12
H 2
5 1 13 17
HO 9 14 15
16
6
4 H 6 3 5 7
General steroid ring structure Cholesterol (chair structure)
The stereochemistry at the various stereocenters is almost
invariably as shown
Scheme 6.2

All the steroids e.g., cholestrol give,

with selenium at 360°C (Diels, 1927). Inamong
fact,
other products, Diels' hydrocarbon on
a steroid may be defined as any dehydrogenation
Diels' hydrocarbonwhen distilled with selenium
(Scheme 6.3). compound which gives
 Steroids 6.3

H,C CH, CH,

H,C
CH,
H,C
Se
Distil

HO Diels' hydrocarbon
Cholesterol

Scheme 6.3

When a and ß designations are applied to the hydrogen atom at position 5, the ring system in which
the A, B ring junction is trans becomes the 50. series; the ring system in which the A, B ring junction
is cis becomes the 5ß series (Scheme 6.4). Moreover, in all natural steroids the B, C ring junctions are
trans (See Scheme 6.2) the A, Bring junction, however, may be either cis or trans, and this possibility
gives rise to two general groups of steroids having the three-dimensional structures shown in (Scheme
6.4). The C/D ring fusion is also normally trans, though there are notable examples when this fusion is
cis e.g., in the case of cardiac glycosides.

AB trans ringjunction Me
Me H

B
HÌ.
H H Cholesterol
H
Equatorial hydroxy 5o. Series of steroids
(All ring junctions are trans.)
(cholestanol)
Cis ring junction
Me
Me H
D
H
H H

HO.

5ß Series of steroids
(A,B ring junction is cis all other ring
Axial hydroxyl junctions are trans)
- (coprostanol)
Scheme 6.4
64 Pharmaceutical Medicinal and Natural Product Chemistry

6.3 STEREOCHEMICAL ASPECTS

The following points may be noted:
"The absolute stereochemistry of the steroid and any substituents is shown with solid (8) and
dashed () bonds as shown in the general ring structure of a steroid (See, Scheme 6.2). Most
carbons have one Bbond and onc x bond, with the Bbond lying closer to the "top'" or C18 and
C19 methylside of the molecule, both a and Bsubstituents may be axial or cquatorial.
" Atroom temperature cyclohexanc interconverts rapidly to a miror image chair conformation.
As one chair form converts to the other (ring flip) all the cquatorial hydrogen atoms become
axial and all the axial hydrogens becomes equatorial without losing their identity as up or down
(Scheme 6.5).

H H H
Ring flip H H
H
H
H

Axial and equatorial hydrogens interconvert, however, an up bond remain up and a down bond remains down.
Scheme 6.5

" Decalin has two cyclohexane rings fused at a common C-C bond. Two diastereoisomers are
possible, depending on whether the hydrogen atoms at the ring junction are cis or trans. One
may view trans decalin as a four carbon chain joined to a cyclohexane via its two equatorial
bonds (Scheme 6.6). While this union involves one axial and one equatorial bond to make cis
decalin.

Decalin

This bond is like an equatorial

substituent on ring B
H H This bond is an equatorial
substituent on ring B
B H
A B

B
H
Trans
decalin This bond is also similar
to an equatorial This bond is an axial
substituent on ring B H substituent on ring B
Cis-decalin

Scheme 6.6
 Steroids 6.5

" When a cyclohexane ring flips the substituents that were cquatorial become axial and vice versa
(Sec, Schenme 6.5). This is so for cis-decalin, which has an axial-cquatorial junction. Ring fip
is not possible for trans-decalin. For trans-decalin to invert, the junction would have to become
axial-axial, and one cannot link the axial positions to form a six-membered ring. Cis-decalin, on
the other hand, ring inverts just as fast as cyclohexane (Scheme 6.7).
Axial
H
H

B Ring flip
Equatorial( A

H in a square starts axial on

ring B while H in a circle After ingfip this hydrogen now
starts equatorial on ring B becomes equatorial to ringB
(cis Decalin)
H
For trans decalin, no ring
Not possible to join two
flip is possible axial positions into six
H membered ring

(Trans Decalin)
Scheme 6.7

than cis decalin

Trans-decalin with both substituents i.e. ring residues equatorial is more stable
in which one ring residue is axial.
becomes slightly more stable than the
When an angular methyl group is introduced the cis-form 9-mehtyl decalin system. The
trans-form. Steroids and several other natural products contain the energy between the decalins
introduction of an angular methylgroup reduces the differences in compressed by four
group is sterically
since in the trans-compound (I, Scheme 6.7a) the methylreduced to two in the case of cis-isomer
axial hydrogen atoms (on C, C4, Cg, and C,) which is
(II, C, and C4).
CH, H
H
H CH, H
H 9 H
2
H8
7
H 10 H
6I 5 10 3
7-H H
H H
H 5H
6
() ()
Scheme 6.7(a)
 6.6 Pharmaceutical Medicinal and Natural Product Chemistry
" Like a decalin system each ring junction in a steroid could be either cis or trans. However,
allsteroids have all trans-junctions except where rings Aand Bjoin which is sometimes cis.
Examples are cholestanol (all trans) and coprostanol (A and Bfused cis).
" The steroids are rigid molecules and cannot undergo ring flip. Importantly even in the case
of steroids where one has a cis-A/B decalin type junction, there are other trans decalin type
junctions which do not allowany flip. Consequently a steroid 'molecule is remarkably stable,
and thus the hydroxyl group in cholestanol (Scheme 6.4) is held equatorial on ring Awhile the
hydroxyl group in coprostanol is held axial on ring A.
Thus in summary all natural steroids have B/C ring fusion trans, C/D fusion is also mostly trans
but exceptions are in cardiac glycosides where it is cis. The A/B fusion could be cis or trans (Scheme
6.7b).

H H H

A
H
|A,B
H H H
H
H
All-trans A/B cis A/B cis, C/D cis

H H
D
A
B /B
AB H
H H

AB with Aunsaturation A/B with A`-unsaturation A ring aromatic

Scheme 6.7(b)

6.4 NOMENCLATURE
Common names e.g., testosterone and cortisone are much easier to use than the long systematic names.
Substituents must always have their position and stereochemistry clearly indicated with common names
(c-g., 17a:-methyltestosterone, 9a-fluorocortisone).
Systematic nomenclature of a steroid depends on its basic hydrocarbon framework which depends on
the nature of the group R at C17(Table 6.1)and also on the precise stereochemistry at C3.

Stereochemistry at C5
The stereochemistry of the H at C5 must be indicated in the name. The stereochemistry of the
H atoms is not indicated unless it differs from that in 5a-cholestane. Changing the other
stereochemistry of
any of the ring juncture or backbone carbons with a heavy line on Sa-cholestane) greatly changes the
shape of the steroid. The names of different steroid hydrocarbons as defined (Table 6.1) are given in
(Scheme 6.8).
 Steroids 6.7

Table 6.1 Names of basic steroid hydrocarbon framework

18 R
H
H,C
19 17
CH,
H 5a. 5p

H H H

When the stereochemistry is not

known, a wavy line is üsed in
|the drawing

Group R Name
-H Androstane
19
-H (with -H also replacing-CH) Estrane
20 21
CH,CH Pregnane
2022 23 24
CHCH,CH,CH, Cholane

21CH3
20 22 23 24 25 26
CHCH,CH,CH,CHCH, Cholestane

21CH, 27CH,
Stereochemistry the terms cis, trans and syn, anti.
The terms cis and trans in steroid nomenclature depict the backbone stereochemistry between rings.
Thus 5a-steroids are A/B trans and Sß-steroids are A/B cis (see,Schemes 6.4 and 6.8). The terms syn
and antiare used analogously to trans and cis for indicating stereochemistry in bonds connecting rings
(e.g., the C9:C10 bond that connects rings A and C) (Scheme 6.9).

21 22 24
20 26
18
12H,C 23 25
17
19 11 G13 27
1H,C H D 16
14
2 I
8. 15
A H
3 B
4 H 5a-Cholestane

Contd.
6.8 Pharnaceutical Medicinal and NaturalProduct Chemistry

H,C H,C Hreplaces CH, H,ç

H,C H,C H H H

H H H H H

H H H
5a-Pregnane 5a-Androstane 5a-Estrane
The names of basic hydrocarbon groups of steroids
Scheme 6.8

HC Anti H,C

Trans) Trans
HCAnti H,C
trans
TransAnt Cis H
H

Anti
H Trans
Trans-anti-trans-anti-trans 5ß-Cholestane has
system in a steroidal skeleton Cis-anti-trans-anti-trans system
Scheme 6.9

It is significant to note that no naturally occuring (biologically active) steroid has syn
When one considers the three rings (A-C) of a steroid. The most stable of these is the type geometry.
form, an all-chair conformation. The trans-syn-trans form is the least stable as this trans-anti-trans
realized only when the middle ring has the energetically unfavorable boat conformationstructure can be
(Scheme 6.10).

H H
H H
A/B
H
H
Trans-anti-trans Trans-syn-trans
Scheme 6.10
 Steroids 6.9

Fusidie acid a steroid like microbinl product with unusual structural and
stereochemical feantures
An extremely potent antibiotic which has a steroid liko structure and has a broad
is most unusual
spectrunm of biological activity in fusidic acid. Its molecular shapemethods which
and has given important clucs to researchers investigating thetrans-fused. by The boat
steroids are synthesized in nature. In fusidic acid all rings are
ike cyclohexane ring is indeed most unusual since most steroids have it only in chair
conformation. Consequently in this "steroid like" structure one has syn type geometry
and 6.10). In a steroid
(C9 and Ci0) which indeed is very unusual (See, Schemes 6.7bposition,
normally one has two angular methyl groups at C10 and C13 in fusidic acid
position
there is not only an unusual number of methyl groups but also their different
at C4, C8, C10, and C14.

H,C cO,H
-CH, H
HO.
CHa H
10 9
OAc
11 H
4
8
HoC COH HO"
5 14
3 CH,
HO
H CH,
16
oçCHs
Fusidic acid Fusidic acid

the fusidium fungus antibiotic

In 1953 from monkey dung which contains the strain of staphylococcus. In 1962,
fusidic acid was isolated which was found active against theinfections in humans were
the first reports of the successful treatment of staphylococcus become resistant
published of which the treatment of certain skin disorders (that had
particularly interesting. Fusidic
to other antibiotics) with fusidic acid derivatives are protein synthesis without getting
acid acts by penetrating into the bacterial cell to stop synthetic steroids have a great
inactivated (unlike penicillin) by counter enzymes. Thus
future to act as alternate antibiotics.

The Position of Double Bond

carbon-carbon double bond is
Position of unsaturation is shown by suffix '-cnc'. The location of the
the double bond and then changing
specified by giving the lesser of the two numbers of the carbon inScheme
the terminal -ane' in the parent hydrocarbon to "-ene' (I and II, 6.11). When a double bond
given, the greater
lies between two carbons, which are not consecutively numbered, both numbers are
number is given inparenthesis (III). steroid. If the CC is
The symbol Ais generally used to designate the position of a C=Cbond in abetween position5 and
between the 4 and 5 position, the compound is called a A"-steroid; if the C=C is
10, the compound is designated a A0-steroid.
6.10 Pharmaceutical Medicinal and Natural Product Chemistry

H,C H,C H,C

H,C H H,c H,C

H H

5-Androstene or H
A-Androstene or 5a-Androst-8-ene or 5a-Androst-8(14)-ene or
Androst-5-ene 5a-a-Androstene 5a-AA814-Androstene
(1) (1) (11)
Scheme 6.11

Cholesterol (cholest-5-en-3B-ol) is a A steroid or, more specifically, a A-sterol because it is an

unsaturated alcohol (See Scheme 6.3 and II and III, Scheme 6.11).

Position of Substituents
The nature and position of a substituent is indicatedby adding prefixes and suffixes to the parent
hydrocarbon (Table 6.2), the following points may be noted:
Location of the double bond in a steroid has been discussed above.
" In case more than one substituents are present in the steroid molecule, only one is indicated by
suffix and others as prefixes. The substituent to be chosen by a suffix is from the priority order
carboxylic acid >lactone >estet >aldehyde >ketone >alcohol >amine >ether. Halogen, allkyl
and nitro are always idicated by prefixes. An example is from bile acids (Scheme 6.12).
Table 6.2 Prefixes and Suffixes for steroidal nomenclature

Group Prefix Suffix

Olefinic double bond
ene
Triple bond yne
Acetate
Acetoxy acetate
Hydroxy Hydroxy ol
Benzoate
Benzoyloxy yl benzoate
Carbony Oxo one
Carboxylic acid Carboxy oic acid
Carboxylic ester as Methyl ester Methoxy carbonyl methyl oate
Epoxide Epoxy
Halogen as chloro Chloro
Amine Amino amine
 example, cholic acid, whick:.
Thebile acids, contain no C=C and belong to the 5ß series. For5B-cholestane backbone andi
has the
an important cholesterol metabolite in man and animals,
named 3a., 7a, 12a-trihydroxy 5ß-cholan-24-oic acid.

OH
COOH

HO* OH
H
Cholic acid

3c, 7x, 12a,-trihydroxy-5 B-cholan-24-oic acid

Scheme 6.12

OH
HCH
OH
H,C LH H,G H

H H

H H
Testosterone
HO (178-Hydroxyandrost-4-en-3-one)
17B-Estradiol or

(Estra-1, 3, 5(10)-triene-3,17B-diol) 17B-hydroxy-4-androsten-3-one

OH
21

20 OAc
H,C
13 OH
-OH
17
19 H
H,C H

Cortisone Cortisone acetate

(17,21-Dihydroxypregn-4-ene 17, 21-Dihydroxypregn4-ene 3,11, trve
3, 11, 20-trione) 21-ucetate

Scheme 6.13
6.12 Pharnaceutical Medicinaland Natural Product Chemistry
"In adding the suffix to the stem name of the parent system, the terminal -e' of '-ane' or -ene' is
deleted when the suffix begins with a vowel(Scheme 6.13).
Consider the example of the male sex hormones (androgens) which are based on the structure of
Sa-androstane. Testosterone, an important naturally occurring androgen, is named 17ß-hydroxy
4-androsten-3-one. Note the droping of the terminal e' from adrostene since the suffix 'one'
begins with a vowel. Also look to the names of cholic acid and cholesterol. Further examples are
in (Scheme 6.14).
OH
CH,CH,
-H
H
CH, H
I-\
1

H H H
5
H
17a-Estradiol A
Progesterone
(pregn-4-ene-3,20-dione) 5a-Pregnan-3-one

CH,OH
H,Ç =0
H,C
HO -OH
CH,
CH, H I-:
2
H
5 H
H
A
H
5a-Cholest-1-en-3-one Cortisol
11B,17a,21-trihydroxy-4
pregnene-3,20-dione)
Scheme 6.14

Deviation from Normal Prefixes and Special Prefixes

Consult Table 6.3 and examples are given in (Scheme 6.15).

6.5 CLASSIFICATION AND BIOLOGICAL ACTIVITY

One may classify steroids depending on the nature of the group present at C-17 on a steroidal skeleton.
One has already seen as to how the name of a steroid depends on the basic hydrocarbon framework
(see Table 6.1).
 Steroids 6.13

Table 6.3 Special prefixes

Prefix Modified group
Nor Omission of a-CHor other group e.g., a CHg, group
Homo Addition of a-CH-or other group
Cyco Additional ring formation
Seco Fission of a ring
Anhydro Loss of hydrogen and thydroxyl groups from adjacent carbon atoms with formation of adouble bond.
Dehydro Loss of two hydrogen atoms from adjacent carbon atoms with formation of a double bond.
Deoxo Replacement of the oxygen atom of aketo group by two hydrogen atoms.
Deoxy Replacement of a hydroxylgroup by hydrogen atom.
Dihydro Addition of two hydrogen atoms to a double bond.

23

H H

H H
5 Becomes 5

H H
5p-Cholane 23-nor-5ß-cholane

I
H H
I
A
H H
B

H H
A-nor-5a-androstane
B-homo-5-pregnane

1 H
2
HO,C H H
5
HO 4 H
2,3-Seco-5ß-androstane-2,3-dioic acid
Scheme 6.15
6.14 Pharmaceutical Medicinal and Natural Product Chemistry
It may be mentioncd that trivial names are still retaincd for the commnon steroids. Howevcr, some
names uscd in the carlier literature are replaced by new names e.g., coprostanol is now named correctly
under the IUPAC rule as Sß-cholestan-3B-ol. The steroids may be broadly classified in to the following
five categerics:
M. Syols
.2. Sex hormones
3. Bile acids
4. Cardiac glycosides
5. Sapogenins and
6. Adrenocortical hormones

(A) Sterols
C-27, C-28, and C-29 Steroids
" Have a 8-, 9,or 10-carbon side chain at C-17
" Have one or more hydroxyl groups on ring system of the steroid
Cholesterol is the typical 27-carbon steroid which is abundantly available and can be isolated from
vertebrates and invertebrates and has also been reported to occur in plants. Several sterols have their
origin in marine invertebrates and they suggest a relationship between the stage of evolution and the
nature of the steroid formed. The steiols of marine invertebrates, as compared with the 8-carbon side
chain of cholesterol at C17, contain a C-9 or C-10 unit in the form of methyl or an ethyl group at C-24.
Stigmasterol (Scheme 6.16) is among the most abundant sterols of plants while among yeast sterols
mention is made of ergosterol (Scheme 6.17).

24

H H
HO
Stigmasterol
Scheme 6.16

Cholesterol may be regarded as the principal but not the only sterol of mammalian tissue. In humans it
occurs in particularly high concentrations in brain, spinal cord, and adrenal glands. In most of the tissues
it is accompanied by small quantities of several other sterols and among these mention may be made of
5a-cholestanol, 7-dehydrocholesterol, and 5a-cholest-7-en-3ß-ol. Significantly in the large intestine it is
 Steroids 6.15

the form of
Cholesterol occurs both in the free as well as in
converted into 5B-chlocstanol (coprostanol). biological membranes and is probably responsible
esters with higher fatty acids. This is a component ofMoreover, cholesterol is important as the precursor
for permitting the steroid hormone to enter the celI.
hormones.
of the bile acids, sex and adrenocortical
proved to have any spccific or direct physiological
It may be mentioned that cholesterol has never beenmention may be made of vilarnin-D, the precursor
role. Among the more important 27-carbon steroids
of which is 7-dehydrocholesterol.

Vitamin D
shown (1919) that sunlight helped cure rickets--a childhooddisease characterized by poor bone
It was foodstuffs increased their antirachitic properties and, in
growth. It was found that iradiation of certain
steroid ergosterol was isolated from yeast. Irradiation of ergosterol was found to produce a highly
1930 a
reaction that takes place is one in which the dienoid ring
active material vitamin D,. The photochemical
Bof ergosterol opens to producea conjugated triene:
CH,
CH, H,C.
H
H,C
H
HC UV light
Room temp.
CH, CH,
H

H
HO
HO Vitamin D,
Ergosterol
Scheme 6.17

Ecdysone Molting Hormone

molecule which is only found in thc orthopods and plants is ecdysone. Two hormones
Adistinctly different
the moulting hormones (MH) present in insects play vital roles in their
i.e, juvenile hormones (JH) and and
and reproduction. The MH initiates the deposition of new layers of cuticle
growth, development of metamorphosis.
of the old at each stage of development while the JH controls the process steriods.
shedding
ecdysone with interesting structural features when compared with other
MH is a steroid,
(B) Sex Hormones
Steroids
" C-18, C-19, and C-21 group (androgens) or a two
(estrogens), or a hydroxyl
" Have a keto group at C-17 gestogins)
carbon chain (progestins or