STEROIDS

 A family of lipids found in plants and animals derived from one of the multitude of C30
triterpenes.
lipids are loosely defined as biological substances that are generally hydrophobic in
nature and in many cases soluble in organic solvents

 First isolated along with fats by extracting plant and animal tissues with chloroform or ether.
Like other lipids, steroids are insoluble in water but soluble in organic solvents

 The fundamental structure of every steroid molecule contains a phenanthrene skeleton

(saturated) with a fused cyclopentane ring.

cyclopenta[a]phenanthrene skeleton

All steroid molecules are formed from the above steroid ring system by replacing ring hydrogens
with hydrocarbon chains or functional groups or by introducing carbon-carbon double bonds into
one or more of the cyclohexane rings , or by bond scissions or ring expansions or contractions.
Methyl groups are normally present at C-10 and C-13. An alkyl side chain may also be present at
C-17.

 Steroid molecules containing a hydroxy function and no carboxyl or aldehyde groups are
called sterols, cholesterol, a waxy solid, is an example
Class No Example MF
of C
Cholestanes 27 Cholesterol C27H46O

Class No Example MF IUPAC approved numbering

of C
Cholanes 24 Cholic acid C24H40O5

Class No Example MF
of C
Pregnanes 21 Progesterone C21H30O2

Gonane, MF =C17H28
is the basic
Class No Example MF Steroid nucleus:
of C No methyl group at
C10 & C13,
Androstanes 19 Testosterone C19H28O2
No side chain at C17
No side chain at C17
Class No Example MF
of C
Estranes 18 Estrone C18H22O2 No methyl group at
C10, No side chain at C17
 Steroid biosynthesis

Isopentenyl pyrophosphate Head to Tail coupling

IPP
IPP

FPP
DMAPP GPP
Dimethylallyl pyrophosphate Geranyl pyrophosphate Farnesyl pyrophosphate

Tail to Tail coupling

of 2 FPP units gives
Squalene

Triterpene Oxidation of terminal db to epoxide

Squalene Opening of epoxide leads to a
Found in shark liver oil domino ring closure
Symmetrical about Steroid biosynthesis scheme
the new bond same in plants & animals till this point
 Tail to Tail coupling of two FPP to give Triterpene Squalene

Enzyme squalene synthase catalyses the reductive Squalene

Dimerisation of two FPP units Found in shark liver oil
Symmetrical about
mechanism the new bond
 Mechanisms for the Conversion of Presqualene
Diphosphate to Squalene

J. Am. Chem. Soc. 2002, 124, 30, 8846-8853

  Squalene is oxidized to squalene epoxide

Squalene monooxygenase (squalene epoxidase) uses NADPH and molecular oxygen to

oxidize squalene to squalene epoxide .
 squalene epoxide is converted to a protosterol cation and
finally to lanosterol
Enzyme Lanosterol synthase catalyses this process

Lanosterol

A discreet carbocation mechanism is

proved (not concerted)
 A series of further transformations take place in animals to transform
C30 lanosterol to C27 cholesterol (lanosterol  zymosterol  cholesterol)
• First by removal of methyl group at C14 by an oxidative process
• Then a similar removal of the two methyl groups at C4 to give zymosterol
• Then db on the side chain reduced and db in ring B moved position to give
cholesterol

Lanosterol

removal of methyl group at C14 removal of the two methyl groups at C4

db on the side chain reduced

and db in ring B moved
position to give cholesterol
Zymosterol
Cholesterol an intermediate in Cholesterol biosynthesis
 Cycloartenol is formed in plants
In animals the methyl group at C8 cyclopropyl group
migrates to give lanosterol fused to ring B at
carbon 9 ,10

Lanosterol Cycloartenol
 a tetracyclic triterpenoid  a triterpenoid of the sterol class
 the compound from which all found in plants.
animal and fungal steroids are  the starting point for the
derived. synthesis of almost all
plant steroids

IUPAC approved numbering scheme

 Nomenclature
Structural Bases for Naming Steroids

 The four rings are commonly denoted by the

capital letters A, B, C and D reading from left to
right. The ring letter designation is used only in
discussion sections of publications as they have
no role in formal nomenclature.

 The numbering system used to denote

steroid carbon atoms traces back to the
days of the major structure determination
work and reflects the then uncertainty
(Finar) about the overall structure

At all C-atoms of the steroid skeleton the H-atoms

can be replaced by other atoms or groups of atoms.
These atoms or groups are the substituents and
each has its own name, place, direction and
function.
IUPAC approved numbering scheme
 Nomenclature
Structural Bases for Naming Steroids
Gonanes
C17H28

IUPAC approved numbering scheme

(8S,9R,10S,13S,14R)-
2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17-
hexadecahydro-1H-cyclopenta[a]phenanthrene
5( or )- gonanes C19 methyl group at C10 and the C18 methyl
group at C13 are absent in this skeleton

If stereochemistry at C5 is unknown
then called 5()- gonanes

1H-cyclopenta[a]phenanthrene
Estrane C18H30
Estrane is a C18 steroid derivative, with a gonane core. It is hydrocarbon with a
methyl group at C-13 but without a methyl group at C-10 and no carbon
substitution at C-17

5( or )-estrane

Estrane is a 19-nor steroid

Here “nor” indicates the angular “methyl “ group is missing
C19 methyl group at C10 absent in this skeleton
IUPAC approved numbering scheme
Androstane C19H32 , C19 steroid with a gonane core.

It is a hydrocarbon with methyl groups at C-10 and C-13,

but without carbon substitution as a side chain at C-17

Androstane can also exist as either of two isomers, IUPAC approved numbering scheme
known as 5α-androstane and 5β-androstane

the shape of the steroid is important for its interaction with the receptor
and thus for its biological activity
Pregnane C21H36

It is a hydrocarbon with methyl groups at C-10 and C-13, with

a side chain at C-17 upto C-21 substitution

5α-pregnane and 5β-pregnane

IUPAC approved numbering scheme

Cholane C24H42

The hydrocarbon with methyl groups at C-10 and C-13, with

a side chain at C-17 upto Carbon chain 24 is named Cholane

5( or )-cholane
Cholestane C27H48
The hydrocarbon with methyl groups at C-10 and
C-13, with a side chain at C-17 upto Carbon chain
C-27 is named Cholestane
5( or )-cholestane

IUPAC approved numbering scheme

5()-cholestane

Cholesterol
Ergostane, C28H50, 24S-methylcholestane

It is a hydrocarbon with methyl groups at C-10 and C-13, with a side chain at C-
17 upto C-27 (as in cholestane) and a methyl group at C-24

IUPAC approved numbering scheme

 Use of the prefix “nor-”
When a methylene group is missing from side chain, it indicated by the prefix-nor-
preceded by the number of carbon that disappeared

IUPAC approved numbering scheme

5β-Cholane 24-Nor-5β-Cholane
When a ring has been contracted indicated by prefix “nor” (for loss of one unsubstituted
methylene group); “dinor” for loss of two such methylene groups), preceded by (a small)
capital letter indicating the ring affected

Or 4-nor-5  -androstane, where

methylene group(s) lost is considered
to include the highest numbered
unsubstituted atom of the ring involved,
5-Androstane A-nor-5-Androstane and the locant of that lost methylene group
Or precedes the prefix nor
4-nor-5  -androstane
Use of the prefix des-

IUPAC approved numbering scheme

5-Androstane Des- A-androstane

removal of a terminal ring, with addition of a hydrogen atom at each

junction atom with the adjacent ring, is indicated by the prefix “des-”,
followed by the italic CAPITAL letter designating that ring

5β,10-Dimethyl-13,14-epoxy-des-A-18-nor-androstane
Use of the prefix homo-

When a ring has been enlarged, indicated by prefixe “homo” (or dihomo for two methylene
groups) , preceded by (a small) capital letter indicating the ring affected

IUPAC approved numbering scheme

5β-Pregnane B-homo-5β-Pregnane
 Use of the prefix seco-

5-Cholane 3,4-seco-5-Cholane

When ring fission has occurred with addition of a H atom to each new terminal group,
This is indicated by the number showing the position of the bond broken, followed by
the prefix ‘seco’

2,3-seco-5-Androstane-2,3-dioic acid
5-Androstane
Use of the prefix cyclo-

5-cholestane 3  ,5-cyclocholestane

The prefix ‘cyclo’ preceded by the number of positions concerned is used to indicate
a three membered ring in this case
 Illustration of biogenic origin of steroids

squalene epoxide protosterol cation

lanosterol

lanosterol

Cholesterol Zymosterol
 Cholesterol has 8 stereocenters & so
256 stereoisomers possible,
but only two of the stereoisomers are of biochemical
significance (nat-cholesterol and ent-cholesterol,
for natural and enantiomer, respectively), and only
(nat-cholesterol) one occurs naturally (nat-cholesterol)

 Cholesterol often has a bad reputation, due to its role in heart disease.
Excess cholesterol in the bloodstream is a key contributor to accumulation of artery-
clogging plaque that can set the stage for a heart attack.

 But cholesterol is also vital to our health and well-being.

 It is a crucial building block in cell membranes.

 It's also used to make vitamin D, steroid hormones (adrenal steroids and sex
hormones; testosterone and estrogen), and fat-dissolving bile acids.

 our liver and intestines make about 80% of the cholesterol we need to stay healthy
and only about 20% comes from the foods we eat.
Häggström M, Richfield D (2014). "Diagram of the pathways of human steroidogenesis".
 Vitamin D: a group of fat- soluble secosteroids (steroids in which one of the bonds
in the steroid rings is broken)
responsible for increasing absorption of Ca, Mg and phosphate

Vitamin D2 Vitamin D4
Vitamin D3
Ergocalciferol, 22-Dihydroergocalciferol
Cholecalciferol,
Calciferol

Deficiency of vitamin D results in bone damage and to bone-softening diseases

The natural vitamin D3 is produced in skin upon ultraviolet irradiation of 7-
dehydrocholesterol (provitamin D3) (believed to be a purely photochemical process, not
requiring enzymes)
or natural vitamin D3 is absorbed from the diet.
7-Dehydrocholesterol A very important [1,7] thermal
(provitamin D3) is sigmatropic rearrangement that
photolyzed by the occurs in the human body
ultraviolet light of
sunlight to
previtamin D3, which
spontaneously
isomerizes to
vitamin D3
(cholecalciferol) .
VitaminD3 is
converted
into calcitriol(1,25-
dihydroxycholecalcife
rol) the active
hormone (active
form of vitamin D),
by hydroxylation cholecalciferol
reactions in the liver
and kidneys. It binds
to and activates the
Vitamin D receptor, in
the cell nucleus. calcitriol
A biomimetic total synthesis of progesterone (W. S. Johnson, 1971)
 A synthesis inspired by the polyene cyclization of squalene oxide to dammaradienol
in the biosynthesis of lanosterol.
 Displayed a synthetically useful domino reaction and demonstrated the utility of the
Johnson– Claisen rearrangement.
A biomimetic total synthesis of progesterone (W. S. Johnson, 1971)

Retrosynthetic Analysis
Progesterone: Right Half

Methacrolein (Methacrylaldehyde) 3-pentynyl magnesium bromide

Johnson–Claisen rearrangement sets the Johnson–Claisen

γ,δ-unsaturation rearrangement

allylic alcohol is heated with trialkyl

orthoacetate under midly acidic
conditions to produce a γ,δ-
unsaturated ester
Progesterone: Left Half

1,4-diketo relationship installed from Furan starting material

Progesterone: Converging Two Halves

Schlosser modification of the Wittig provides the requisite E-olefin.

Allows the selective formation of E-alkenes through the use of excess lithium salts
during the addition step of the ylide and subsequent deprotonation/protonation steps.

Deprotection and cyclization installs the final unsaturation

Progesterone: Cation-π-Cylization

Ethylene carbonate
(1,3-dioxolan-2-one)
Cation-π-cylization forges all six stereocenters in a tandem operation from the
crude tertiary alcohol
Diels–Alder Reactions in Steroid Synthesis

There are 14 different ways reported in which a single DA reaction can be used to
install the six-membered rings of the typical 6,6,6,5 steroid ring system,

Synthesis 2015, 47, 1–21

 Cohen and Warren’s 1937 synthesis of the steroid skeleton –
construction of C ring

1-vinylnaphthalene
Synthesis of Adrenosterone through Diels Alder pathway (Stork)
A nonskeletal ring is installed first by the DA reaction which then ozonolysed

• keto acid 22 and 4 molar equivalents of isopropenyllithium gave 23

• upon dehydration with Burgess reagent 23 gave 24
• on exposure to TFA in CH2Cl2 24 gave DA adduct 25
configuration of the stereocenter at C8 in 24, controls the stereoselectivity by placing
the dienophile on the lower face of the diene.
Burgess reagent
methyl N-(triethylammoniumsulfonyl)carbamate
Dehydration of secondary
and tertiary alcohols
Mild and selective reagent
DA reaction of a Furano Diene in the formal Total Synthesis of ()-Estrone

2-(3-methoxyphenethyl)furan

A formal synthesis involves beginning to

a midpoint (i.e, to a precursor from
which known synthetic methods avalible
to arrive at the target molecule)
Torgov Diene is synthesised here)

J. Org. Chem. 2011, 76, 57–64

 DA reaction in the synthesis of a progesterone

Electrocyclic ring
opening
DA reactions in the synthesis of a steroid like skeleton

16-oxasteroid
A 0 ABCD Strategy for Steroids framework
Domino Intramolecular Diels Alder Reaction:
Marck Nörret and Michael S. Sherburn
This domino sequence generates four rings, four C-C bonds, and eight contiguous
stereocenters in a single operation and, as such, represents a new 0 -ABCD
strategy for the synthesis of steroids and related compounds

Retro synthesis scheme

Angew. Chem. Int. Ed. 2001, 40, No. 21

Steroid frameworks through a double DA reaction

Processes in which two cycloadditions are carried out without isolation of the first
DA cycloadduct. Steroid frameworks can be formed in one synthetic operation
through double dehydro-DA sequences involving 1,5-dien-3-ynes