STEROIDS

1
STEROIDS
2
STEROIDS
Compounds with the four-ring pattern A-B-C-D are
called steroids.
C
D
A
B
22
The numbering system is historic and is shown
here for later reference.
21
23
20
26
18
12
17
24
25
11
13
19
16
1
27
9
14
2
Most steroids also have a side chain on ring D
and angular methyl groups at the junctions of
rings A/B and C/D. Frequently there is an
oxygenated group at C3 (arrow).
10
15
8
3
7
5
6
4
.. in this section we will see how steroids arise
3
FORMATION OF SQUALENE
IPP
C5
C10
B
C5
C5
DMAPP
C15
C15 C15
Squalene is the precursor of all steroids in
both plants and animals.
C30
squalene
4
SQUALENE FOLDING CONFORMATION
CHAIR-BOAT-CHAIR-BOAT FOLDING
5
CHAIR-BOAT-CHAIR-BOAT FOLDING
CHAIR
BOAT
BOAT
TAIL
CHAIR
Squalene has to be folded in a specific fashion
when it binds to the cyclase enzyme that converts
it to a steroid. This folding is called a
chair-boat-chair-boat conformation.
If squalene cannot adopt this conformation, it
cannot form a steroid and will form some other
type of triterpene.. (DISCUSSED LATER).
6
CHAIR-BOAT-CHAIR-BOAT FOLDING
CHAIR-BOAT-CHAIR-BOAT FOLDING
CHAIR
BOAT
BOAT
TAIL
CHAIR
Squalene has to be folded in a specific fashion
when it binds to the enzyme that converts it to a
steroid. This folding is called a
chair-boat-chair-boat conformation.
If squalene cannot adopt this conformation, it
cannot form a steroid and will form some other
type of triterpene.. (DISCUSSED LATER).
7
FORMATION OF LANOSTEROL
MAMMALS
.. action of a mammalian cyclase enzyme
- a remarkable biosynthetic sequence
8
EPOXIDATION OF SQUALENE BY A FLAVOPROTEIN MONOOXYG
ENASE
flavoprotein
NADPH
H2O
O2


squalene
squalene-2,3-epoxide
Enz-BH
enzyme-catalyzed ring opening
..


..

CARBOCATION
tertiary !
9
CYCLIZATION OF SQUALENE
FORMATION OF A STEROID - LANOSTEROL (MAMMALS)
OH
..


..
squalene

elimination
B

9

yellow groups rearrange by 1,2-shifts
The proton at C9 is lost in an elimination
double bond from C8 to C9
9
8
lanosterol
10
RING CLOSURES





All the orbitals are perfectly aligned for these
internal polymerizations.
11
THE ORBITALS ARE ALL ALIGNED PERFECTLY
B-H
..






1
1
new bond is numbered and highlighted yellow
12
2
1

2

1
3
2

4
1
3
13
THE REARRANGING GROUPS ARE ANTI IN EVERY CASE
B
H
CH3
H


C
C
C
C
C
C
H
CH3
This is set up to be a concerted (or nearly
concerted) process.
14
ELIMINATION TO FORM A DOUBLE BOND
B
CARBOCATION REARRANGEMENTS ON SKELETON
MAMMALS
(WAGNER-MEERWEIN)
IN THREE DIMENSIONS

15
B-Enz

ANOTHER VIEW
16
ALL OTHER STEROIDS IN MAMMALS ARE
DERIVED FROM LANOSTEROL
cholesterol
lanosterol
estrone
pregnenolone
estradiol
progesterone
testosterone
corticosterone
17
squalene
RADIOACTIVE LABELLING EXPERIMENT
lanosterol
Agrees perfectly with the biosynthetic sequence.
cholesterol
18
FORMATION OF CYCLOARTENOL
PLANTS
19
CYCLIZATION OF SQUALENE
FORMATION OF A STEROID - CYCLOARTENOL (PLANTS)
OH
..


..
squalene

B

9
8
10

The proton at C9 migrates to C8 , a proton
is lost from the methyl at C10 forming a
cyclo- propane ring.
cycloartenol
20
B
FORMATION OF CYCLOPROPANE RING
CARBOCATION REARRANGEMENTS ON SKELETON
PLANTS
(WAGNER-MEERWEIN)

21
SOME OTHER PLANT STEROIDS
diosgenin
sigmasterol
(mexican yams)
(soy beans)
Used by Marker to synthesize the first birth
control pills.
SYNTEX
digitoxigenin
(Digitalis spp , foxglove)
norethindrone
22
b-sitosterol
wheat germ oil, corn oil
strophanthidin
Strophanthus spp
sapogenin, arrow poison
ouabain
Strophanthus spp
sapogenin, arrow poison
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OTHER FOLDINGS OF SQUALENE
OTHER STEROIDS OTHER TRITERPENOIDS
24
OTHER TRITERPENOIDS FROM SQUALENE
The particular cyclase enzyme in a given
plant can bring about variations in the folding
of squalene, resulting in different types of
natural products being formed.
Not every plant cyclizes squalene to steroids.
There is a hugh variety of other
triterpenoids found in different plant sources,
each of which act on squalene differently.
25
CHAIR-CHAIR-CHAIR-CHAIR-CHAIR
OH
OH
attack from both ends
a-onocerin
26
CHAIR-CHAIR-CHAIR-BOAT
OH

dammarenediols
27
CHAIR-BOAT-CHAIR-BOAT FOLDING
CAN PRODUCE OTHER TYPES OF COMPOUNDS THAN
CYCLOARTENOL IN PLANTS
lupeol
euphol
b-amyrin
cycloartenol
28
DIFFERENT PLANTS DO DIFFERENT THINGS !

..
OH

OH
There are many other possibilities which we do
not have time to cover.
malabaricol
29
STEROIDAL ALKALOIDS
Sometimes different pathways combine, for
instance, steroids and alkaloids.
Different parts of a molecule can originate from
different sources.
30
solanidine
rubijervine
green potato tubers
Veratrum album , European hellebore
insecticide
conessine
Holarrhena spp
(-)-solasodine
used in India to treat amoebic dysentery