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Natural Products (1)

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TERPENOIDS

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TERPENOIDS
Introduction
As most of the fundamental knowledge that is common with medicinal
chemistry. The distinguishing feature is that this area involves the study
of natural products from plants, animals, or microbes. The products may
be therapeutically useful or toxic. Natural products chemistry endeavors
to examine the natural source, mechanisms whereby the source
biosynthetically constructs the product, processes whereby the product
can be isolated from the source and techniques used to identify the
product. These studies lay the groundwork for the pharmacological
evaluation of a potentially useful natural product or biochemical
investigation of a natural toxin. A plan of study in natural products
chemistry would emphasize courses in natural products and medicinal
chemistry, chemistry, botany, and microbiology with support courses in
pharmacology and pharmaceutics.
The terpenoids form a group of compounds the majority of which occur
in the plant kingdom; a few terpenoids have been obtained from other
sources. The simpler mono- and sesqui-terpenoids are the chief
constituents of the essential oils; these are the volatile oils obtained from
the sap and tissues of certain plants and trees. The essential oils have been
used in perfumery from the earliest times. The di- and tri-terpenoids
which are not steam volatile, are obtained from plant and tree gums and
resins. The tetraterpenoids form a group of compound known as the
Carotenoids. Rubber is the most important polyterpenoid.
Most natural terpenoid hydrocarbons have the molecular formula (C5H8)n,
and the value of n is used as a basis for classification.

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Number of
carbon atoms

(1)

10

Monoterpenoids (C10H16)

(2)

15

Sesquiterpenoids (C15H24)

(3)

20

Diterpenoids (C20H32)

(4)

25

Sesterterpenoids (C25H40)

(5)

30

Triterpenoids (C30H48)

(6)

40

Tetraterpenoids (carotenoids) (C40H64)

(7)

>8

> 40

Class

Polyterpenoids (C5H8)n

In addition to the terpenoid hydrocarbons, there are the oxygenated


derivatives of each class which also occur naturally, and these are mainly
alcohols, aldehydes or ketones.
The thermal decomposition of almost all terpenoids gives isoprene as one
of the products, and this led to the suggestion that the skeleton structures
of all naturally occurring terpenoids can be built up of isoprene units; this
is known as the isoprene rule, and was first pointed out by Wallach
(1887). Furthermore, Ingold (1925) pointed out that the isoprene units in
natural terpenoids were joined "head to tail" (the head being the branched
end of isoprene). This divisibility into isoprene, units, and their head to
tail union, may conveniently be referred to as the special isoprene rule.
The carbon skeletons of open-chain monoterpenoids and sesquiterpenoids
are:
C

C
Monoterpenoid

C C C C C C C C
head
tail
tail head
C

C C C C C C C C C C C C

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Sesquiterpenoid

Monocyclic terpenoids contain a six-membered ring, the monoterpenoid


open chain can give rise to only one possibility for a monocyclic
monoterpenoid, viz., the p-cymene structure. This is shown in the
following structures, the acyclic structure being written in the
conventional "ring shape". Most natural monocyclic monoterpenoids are
derivatives of p-cymene.
C

C
C
C

C
C
C
acyclic structure

C
C

C
C
C

p-cymene structure

Bicyclic monoterpenoids contain a six-membered ring and a three-, fouror five-membered ring; all three types are known.
C

C
C
C
CC C
C
C
C

C
C
C
CC C
C
C
C

C
C
C
CC C
C
C
C

Isoprene itself, a C5H8 gaseous hydrocarbon, is emitted by the leaves of


various plants as a natural byproduct of plant metabolism. Next to
methane it is the most common volatile organic compound found in the
atmosphere. Examples of C10 and higher terpenes, representing the four
most common classes are shown in the following diagram. The initial
display is of monoterpenes; larger terpenes will be shown by clicking the
"Toggle Structures" button under the diagram. Most terpenes may be
structurally dissected into isopentane segments.

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Isolation of monoterpenoids and sesquiterpenoids


There are four methods of extraction of the terpenoids: (i) expression; (ii)
steam distillation; (iii) extraction by means of volatile solvents; (iv)
adsorption in purified fats (enfleurage). Method (ii) is the one most
widely used; the plant is macerated and then steam distilled. If the
compound decomposes under these conditions, it may be extracted with
light petrol at 50C, and the solvent then removed by distillation under
reduced pressure. Alternatively, the method of adsorption in fats is used.
The fat is warmed to about 50C, and then the flower petals are spread on
the surface of the fat until the latter is saturated. The fat is now digested
with ethanol, any fat that dissolves being removed by cooling to 20C.
The essential oils so obtained usually contain a number of terpenoids, and
these are separated by fractional distillation. The terpenoid hydrocarbons
distil first, and these are followed by the oxygenated derivatives.
Distillation of the residue under reduced pressure gives the
sesquiterpenoids, and these are separated by fractional distillation. More
recently, chromatography (in its various forms) has been used both for
isolation and separation of terpenoids.

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General methods of determining structure:


(i)

A pure specimen is obtained, and the molecular formula is


ascertained by the usual methods, and also by means of mass
spectrometry. If the terpenoid is optically active, its specific rotation
is measured. Optical activity may be used as a means of
distinguishing structures.

(ii) If oxygen is present in the molecule, its functional nature is


ascertained, i.e., whether it is present as hydroxyl, aldehyde, ketone,
etc.
(iii) The presence of olefinic bonds is ascertained by means of bromine,
and the number of double bonds is determined by analysis of the
bromide, or by quantitative hydrogenation. These facts lead to the
molecular formula of the parent hydrocarbon, from which the
number of rings present in the structure may be deduced.
(iv) The preparation of nitrosochlorides and a study of their behavior.
(v) Dehydrogenation of terpenoids with sulfur, selenium, platinum, or
palladium, and an examination of the products thereby obtained.
(vi) Measurement of the refractive index leads to a value for the
molecular refraction. From this may be deduced the nature of the
carbon skeleton. Also, optical exaltation indicates the presence of
double bonds in conjugation.
(vii) Degradative oxidation. The usual reagents used for this purpose are
ozone, acidic, neutral, or alkaline permanganate, chromic acid and
sodium hypobromite. Other reagents are osmium tetroxide, nitric
acid, lead tetra-acetate, peroxy-acids, and N-bromosuccinimide for

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allylic bromination. In general, degradative oxidation has been the


most powerful tool for elucidating the structures of the terpenoids.
(viii)Ultraviolet spectroscopy has been much used in terpenoid chemistry,
its main application being the detection of conjugation.
(ix) Infrared spectroscopy is also useful in terpenoid chemistry, and is
very valuable for detecting the presence of a hydroxy group (~3400
cm-1) or an oxo group (saturated: 1750-1700 cm-1; --unsaturated:
1700-1660 cm-1). Also, infrared spectroscopy is particularly useful
for detecting the presence of the isopropenyl group, and may often
distinguish between cis- and trans-isomers.
(x) NMR spectroscopy has been used to detect and identify double
bonds, to determine the nature of end groups and also the number of
rings present, and to ascertain the orientation of methyl groups in the
molecule.
(xi) Mass spectrometry is now being increasingly used as a means of
elucidating the structure of terpenoids. Thus, it is possible to
determine molecular weights, molecular formulae, the nature of
various functional groups, and the relative positions of double
bonds. It is possible, however, to identify a terpenoid by comparison
of its mass spectrum with the reference spectrum of an authentic
specimen.
(xii) Optical rotation methods have been successfully applied to the
elucidation of the structure of terpenoids, and optical rotatory
dispersion (ORD) studies have been used to assign absolute
configurations.

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(xiii)X-ray analysis is very useful, where applicable, for elucidating


structure and stereochemistry of terpenoids.
(xiv) After the analytical evidence has led to a tentative structure (or
structures), the final proof of structure depends on synthesis.
Classification

Monoterpenoids:
The monoterpenoids may be subdivided into three groups: acyclic,
monocyclic, and bicyclic. This classification affords a convenient means
of study of the monoterpenoids.
Acyclic Monoterpenoids:

Myrcene

Myrcene, C10H16, b.p. 166-168C.


This is an acyclic monoterpenoid hydrocarbon (i.e., is a terpene) which
occurs in verbena and bay oils. Catalytic hydrogenation (platinum)
converts myrcene into a decane, C10H22; thus myrcene contains three
double bonds, and is an open-chain compound. Furthermore, since
myrcene forms an adduct with maleic anhydride, two of the double bonds
are conjugated. This conjugation is supported by the fact that myrcene
shows optical exaltation.

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Ozonolysis of myrcene produces acetone, formaldehyde and a


ketodialdehyde, C5H6O3, and the latter, on oxidation with chromic acid,
gives succinic acid and carbon dioxide.
These results can be explained by assigning structure (I) to myrcene. In
terpenoid chemistry, it is common practice to draw the carbon skeleton in
a ring fashion (the 'open' cyclohexane ring) (II).

CH2

H3C
C
H3C

CH CH2 CH2 C
6

CH CH2
2

(I)
(II)

The systematic name of the compound is obtained by the use of the rule
for acyclic polyenes. Thus, myrcene is 7-methyl-3-methyleneocta-1,6diene.
We can now represent the process of ozonolysis and oxidation of the
ketoaldehyde as shown.

O3

2CH2O
+
O

CHO

CHO

CrO3

CO2H
+

CO2

CO2H

This structure for myrcene is supported by the fact that on hydration


(under the influence of suphuric acid), myrcene forms an alcohol which,
on oxidation, gives citral. The structure of this compounds is known and
its formation is in accord with the structure given to myrcene.
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Citral

This is the most important member of the acyclic monoterpenoids, since


the structures of most of the other compounds in this group are based on
that of citral (C10H16O). Citral is widely distributed and occurs to an
extent of 60-80 percent in lemon grass oil. Citral is a liquid which has the
smell of lemons.
Citral was known to contain an oxo group, e.g., it forms an oxime, etc.
On heating with potassium hydrogen sulphate, citral forms p-cymene (II)
(Semmler, 1891). This reaction was used by Semmler to determine the
positions of the methyl and isopropyl groups in citral; Semmler realized
that the citral molecule was acyclic, and gave it the skeleton structure (I)
(two isoprene units joined head to tail).
C
C
C
C

C
C

C
C
C

(I)

(II)

Citral can be reduced by sodium amalgam to an alcohol, geraniol,


C10H18O, and is oxidized by silver oxide to geranic acid, C10H16O2; since
there is no loss of carbon on oxidation to the acid, the oxo group in citral
is therefore an aldehyde group. Oxidation of citral with alkaline
permanganate, followed by chromic acid, gives acetone, oxalic and

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laevulic acids. Thus, if citral has structure (III), the formation of these
oxidation products may be accounted for:
CO2H

CHO
(i) KMnO4
(ii) CrO3

CO2H
+
O

CO 2H

(III)

The structure is supported by the work of Verley (1897), who found that
aqueous potassium carbonate converted citral into 6-methylhept-5-en-2one (IV) and acetaldehyde. The formation of these products is readily
explained by assuming (III) undergoes cleavage at the ,-double bond;
this cleavage by alkaline reagents is a general reaction of ,-unsaturated
oxo compounds.
CHO

O
OH

(III)

CHO
CH3

(IV)

The structure of citral was confirmed by the synthesis of


methylheptenone (IV), the conversion of this into geranic ester, which
was then converted into citral by heating a mixture of the calcium salts of
geranic and formic acids.

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Stereochemistry of citral
Examination of the formula of citral shows that two geometrical isomers
are possible. The functional group (aldehyde) is trans or cis with respect
to the methylene group of the main chain. Both isomers occur in natural
citral, e.g., two semicarbazones are formed by citral; both forms of citral
itself have also been obtained: citral-a (also known as geranial) has a b.p.
118-119C/20 mm., and citral-b (also known as neral) has a b.p. 117118C/20 mm. The configuration of these two forms have been
determined from a consideration of the ring closures of the corresponding
alcohols (geraniol).
H

CHO

CHO

trans- (or E-) form;


citral-a; geranial

cis- (or Z-) form;


citral-b; neral

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Geraniol

Geraniol, C10H18O, b.p. 229-230C. This is found in many essential oils,


particularly rose oil.
Hence geraniol and nerol are geometrical isomers. Geraniol has been
assigned the trans configuration and nerol the cis on the fact that
cyclisation to -terpineol by means of dilute sulphuric acid takes place
about 9 times as fast with nerol as it does with geraniol; this faster rate
with nerol is due to the proximity of the alcoholic groups to the carbon
(*) which is involved in the ring formation. Thus:
H

CH2OH
* H

dil.
H2SO4

dil.
H2SO4

CH2OH

OH
geraniol
(trans or E)

-terpineol

nerol
(cis or Z)

Nerol occurs naturally in various essential oils, e.g., oil of neroli,


bergamot, etc.; its b.p. is 225-226C.

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Linalool

Linalool, C10H18O, b.p. 198-199C. This is an optically active


compound; the (-)-form occurs in rose oil and the (+)-form in orange oil.
The structurte of linalool has been confirmed by synthesis of linalool by
treating the sodium derivative of methylheptenone with acetylene,
followed by partial reduction of the triple bond.

Lavandulol, C10H18O, b.p. 94-95C/13 min.


This occurs in the free state and as esters in French lavender oil. It is a
particularly interesting acyclic monoterpenoid in that it does not obey the
special isoprene rule, i.e., two isoprene units are not joined head to tail.
HOH2C

Citronellal, C10H18O.
This is an optically active compound which occurs in citronella oil.
Citronellal is an aldehyde; reduction with sodium amalgam converts it
into the alcohol citronellol, C10H20O, and oxidation gives citronellic acid,

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C10H18O2. Oxidation of citronellal with chromic acid gives 3-methyladipic


acid and acetone.

CHO

CrO3
CO2H
CO2H

citronellal

Citronellol, C10H20O, b.p. 130C/5 mm.


This occurs in the (-)-form in rose and geranium oils. Its structure was
determined by oxidative degradation (to give acetone and 3-methyladipic
acid), and by the following sequence of reactions:
CHO
H2
cat.
citral

CHO

citronellal

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Na/Hg

CH2OH

citronellol

Monocyclic Monoterpenoids
Nomenclature:
For the purposes of nomenclature of the monocyclic monoterpenoids, the
fully saturated compound p-methyl-isopropyl-cyclohexane, hexahydro-pcymene or p-menthane, C10H20, is used as the parent substance; it is a
synthetic compound, b.p. 170C.
p-Menthane is (I), and (II) is a conventional method of drawing formula
(I). The positions of substituents and double bonds are indicated by
numbers, the method of numbering being shown in (I) and (II).
7 CH
3

H2C 6
H2C5
9

H3C

CH

2 CH2

3 CH
2

CH
CH
8

6
5

1
4

2
3

10

CH3

(I)

10

(II)

When a compound derived from p-menthane contains one or more double


bonds, ambiguity may arise as to the position of double bond when this is
indicated in the usual way by a number which locates the first carbon
atom joined by the double bond. To prevent ambiguity, the second carbon
atom joined to the double bond is also shown, but is placed in
parentheses.

-p-menthene;
2-p-menthene;
p-menth-2-ene;
p-methene-2

p-meth1(7)-ene

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p-mentha1,4(8)-diene

-Terpineol:
This is an optically active monoterpenoid that occurs naturally in the (+)-,
(-)- and ()-forms; it is a solid, m.p. (of the racemic modification) 35C.
The molecular formula of -terpineol is C10H18O, and the oxygen atom is
present as a tertiary alcoholic group (as shown by the reactions of terpineol). Since -terpineol adds on two bromine atoms, it therefore
contains one double bond. Thus the parent (saturated) hydrocarbon of terpineol has the molecular formula C10H20. This corresponds to CnH2n, the
general formula of the (monocyclic) cycloalkanes, and so it follows that
-terpineol is a monocyclic compound.
When heated with sulphuric acid, -terpineol forms some p-cymene.
Taking this in conjunction with the tentative proposal that -terpineol is
monocyclic, it is reasonable to infer that -terpineol contains the pcymene skeleton. Thus we may conclude that -terpineol is probably pmenthane with one double bond and a tertiary alcoholic group.
The positions of these functional groups were ascertained by Wallach
(1893, 1895) by means of graded oxidation.
Oxidation of -terpineol (1) with alkaline potassium permanganate (1%)
hydroxylates the double bond to produce the trihydroxy compound (2),
C10H20O3. This on oxidation with chromic acid (Chromium trioxide in
acetic acid) produces the compound 4 which has molecular formula of
C10H16O3. This compound was shown to contain a ketonic group and that
it was neutral. It gave no reaction with sodium carbonate solution. When
4 was refluxed with excess of standard hydroxide solution, and then back
titrated it was found that alkali had been consumed corresponding to one

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carboxyl group. Thus compound 4 appears to be the lactone of


monocarboxylic acid. On warming 4 with alkaline permanganate gave
acetic acid and compound 5 (C18H12O4). The formation of acetic acid
suggests that 4 is a methyl ketone. Thus 4 is a methyl ketone and a
lactone, it is known as homoterpenyl methyl ketone and the structure
assigned to it has been synthesized (Simonsen et al 1932).
OH
OH

KMnO4

O
COOH

CrO3

1% alkaline

CH3COOH

OH

OH

OH

COOH
HOOC
O
O
6
Terepic acid

KMnO4

O
O
5
Terpenylic acid

warm alk.
KMnO4
- CH3COOH

O
O
4

Synthesis of -terpineol starts with p-toluic acid:


The synthesis of -terpineol has been carried out by Perkin, jr with
Meldrum and Fisher (1908) starting with p-toluic acid.

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A much simpler synthesis of -terpineol has been carried out by Alder


and Vogt (1949); this makes use of the Diels-Alder reaction, using
isoprene and methyl vinyl ketone as the starting materials.

(i) MeMgBr
(ii) H+
O

OH

Two other terpineols are also known: - and -terpineol; the latter occurs
naturally.
OH

OH

-terpineol
m.p. 32-33C

-terpineol
m.p. 68-70C

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Carvone
Carvone, C10H14O, b.p. 230C/755 nm.
This occurs in various essential oils, e.g., spearmint and caraway oils, in
optically active forms and also as the racemic modification.
The structure of carvone is largely based on the fact that carvone may be
prepared from -terpineol as follows:
Cl
NOCl

NOH

isomn.

OH
(I)

Cl

NO

OH
(II)

EtONa
(-HCl)

OH
(III)
NOH

H2SO4

OH
(IV)

(V)
Carvone

The addition of nitrosyl chloride to -terpineol (I) produces -terpineol


nitrosochloride (II), the addition occurring according to Markownikoff's
rule (the chlorine is the negative part of the addendum). This
nitrosochloride rearranges spontaneously to the oxime compound (III).
Removal of a molecular of hydrogen chloride from (III) by means of
sodium ethoxide produces (IV) and this, on warming with dilute
sulphuric acid, loses a molecule of water with simultaneous hydrolysis of
the oxime to form carvone (V). Thus, according to this interpretation of
the reactions, carvone is p-menth-6,8-dien-2-one.

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Carvone oxidation and reduction

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Limonene

Limonene

Limonene, C10H16, b.p. 175.5-176.5C.


This is optically active; the (+)-form occurs in lemon and orange oils, the
(-)-form in peppermint oil, and the ()-form in turpentine oil. The racemic
modification is also produced by racemisation of the optically active
forms at about 250C. The racemic modification is also known as
dipentene; this name was given to the inactive form before its relation to
the active form (limonene) was known.
Since limonene adds on four bromine atoms, it therefore contain two
double bonds. (+)-Limonene may be prepared by dehydrating (+)-terpineol with potassium hydrogen sulphate, and limonene (or dipentene)
may be converted into -terpineol on shaking with dilute sulfuric acid.

- H2O
Or
OH
-Terpineol

The carbon skeleton and the position of one double bond in limonene are
known. The position of the other double bond, however remains uncertain
from this preparation; 1 or 2 is possible.

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Proof of position 8.
Structure 1 contains a chiral center C-4, and hence can exhibit optical
activity. Structure 2 is symmetric and so cannot be optically active.
Therefore 1 must be limonene.
Chemical proof for position 8 is afforded by the following reactions:
Limonene
1

NOCl

Limonene nitrosyl chloride


2

KOH Carvoxime
EtOH
3

Since the structure of carvoxime is known, it therefore follows that (1)


must have one double bond in position 8; thus the above reactions may be
written as:
Cl

Cl
NO

NOCl

NOH
KOH

isom.

NOH

EtOH

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Menthol and Menthone


Menthol, C10H20O.
Is an optically active compound; only (-)-form occurs naturally, e.g., in
peppermint oils. (-)-Menthol, m.p. 43C is saturated compound, and the
functional nature of the oxygen atom is alcoholic, as shown by its
reactions, e.g., menthol forms esters. Furthermore, since oxidation
converts menthol into menthone, a ketone, the alcoholic group in menthol
is therefore secondary. Also, since reduction with hydrogen iodide gives
p-menthane, menthol most probably contains this carbon skeleton.
Finally, since (+)-pulegone gives menthol on reduction, and since the
structure of pulegone is known to be (I), it therefore follows that menthol
must be (II).

[4H]
OH

O
(I)
Pulegone

(II)
Menthol

Examination of the menthol structure shows that three dissimilar chiral


centers (1, 3 and 4) are present; thus eight optically active forms (four
racemic modifications) are possible theoretically. All eight enantiomers
are known and their configurations are as follows (the horizontal lines
represent the plane of the cyclohexane ring).

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1
4

Me H

Me OH H

2
3

OH

OH

Pri

H
4

OH Pri

neomenthol

menthol

Me H
1

OH

Me OH Pri

Pri
4

OH

OH H

neoisomenthol

isomenthol

Menthone, C10H18O, b.p. 204/750 mm.


(-)-Menthone occurs in peppermint oil, and it may readily be prepared by
the oxidation of (-)-menthol with chromic acid.
[O]
O

OH
(II)
Menthol

(III)
Menthone

Synthesis of Menthone and Menthol


In 1907 Kotz and Schwartz have synthesized menthone by distillation of
the calcium salt of 2-isopropyl-5-methylpimelic acid, which was prepared
as outlined in the following scheme:
Condensation of 3-methylcyclohexanone with ethyl oxalate in the
presence of sodium followed by heating the keto ester produced then
heated under reduced pressure to give the ethyl ester of 4methylcyclohexan-2-one-1-carboxylic acid. The latter when treated with
EtONa followed by addition of isopropyl iodide gave

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isopropylcyclohexanone derivative, which on boiling with EtONa


followed by acidification gave 2-isopropyl-5-methylpimelic acid. Heating
the dicarboxylic acid on calcium salt gave the corresponding menthone.

COOEt
COOEt

heat

Na

- CO

O
COOEt
O

COOEt

1) EtONa
2) Me2CHI

COOH

1) EtONa

Ca salt
heat

COOH

2) H+

O
EtOOC

Menthone

The reduction of menthone using NaBH4 in alcohol or pulegone in the


presence of reduced catalyst gave the corresponding menthol

NaBH4

4H

EtOH
OH

Menthone

Menthol

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Pulegone

Bicyclic Monoterpenoids
The bicyclic monoterpenoids may be divided into three classes according
to the size of the second ring, the first being a six-membered ring in each
class.

Class I (6- + 3-membered ring):


10

10

1
7

7
9

9
8

thujane

carane

Class II (6- + 4-membered ring):


10

10

2
3

1
8
7

6
9

7
4
5

Pinane

Class III (6- + 5-membered ring):


10
1

1
6
5

7 9

bornane
(camphane)

2
7

norbornane
derivative
(isocamphane)

6
7

5
4

norbornane
derivative
(fenchane)

1
6
5

1
2

norbornane
derivative
(isobornylane)

7
3
4

norbornane

It is important to note that the two rings do not lie in one plane, but are
almost perpendicular to each other.
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The carane group


3
2

Car-3-ene

Car-2-ene

The thujane group


3

-thujane

(+)-sabinene

The pinane group


Pinane. The parent compound of this group, it is a synthetic substance
which may be prepared by the catalytic hydrogenation (nickel or
platinum) of either - or -pinene. Pinene exists in two geometrical
isomeric forms, cis and trans, and each of these exists as a pair of
enantiomers.
-Pinene, b.p. 156C. This is the most important member of the pinane
class. It occurs in both the (+)- and (-)-forms in all turpentine oils.

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Total synthesis of -pinene


The -pinene has been synthesized starting from trans-pinonic acid
which obtained from 2,2-dimethyl-1,3-cyclobutandicarboxylic acid
as described in the following scheme.
O

COOH

COOEt

Ac2O

COOEt

Na

i) HBr

EtOH

ii) KCN

CN

CH2OH

HOOC

i) HCl
ii) EtOH/HCl
COOEt

COOEt

COOEt

i) SOCl2
NPh2

Partial
hydrolysis

COOH

ii) Ph2NH

COOEt

H2SO4
COOH

i) SOCl2

i) KOH

ii) MeCdCl

NPh2

NPh2

ii) HCl
O

OH

trans-Pinonic acid

COOH

COOEt

H+

ClCH2COOEt
OEt

EtONa

Ethyl Pinonate

COOEt
O

140oC

CHO

COOH

KMnO4

EtOH/HCl

OH

OH

OEt
O

OH

Glycidic ester

COOEt

-30-

Na
(Dieckmann)

HCl

NH2

i) NH2OH
ii) (H)

COOEt

i) MeI
ii) AgOH

+
-Pinene

NMe3+OH-

Distillation
Reduced pressure
-Pinene

The final step gives a mixture of two compounds - and -pinene. This
was identified by the preparation of nitrosyl chloride; this proves that one
of the pinenes is but does not prove which is and which is . The
reaction of the pinenes with diazoacetic ester to form pyrazoline
derivatives which on heating alone or with cupper powder, decompose to
produce cyclopropane derivatives.
COOEt
HOOC

[O]

i) N2CHCOOEt

COOH

ii) Cu, heat


-Pinene

HOOC

-Pinene

HOOC

i) N2CHCOOEt

COOEt

ii) Cu, heat


-Pinene

[O]

COOH
HOOC

-Pinene

When the two pinenes were subjected to this treatment, and the resulting
compounds oxidized, -pinene gave 1-methylcyclopropane-1,2,3-tricarboxylic acid and -pinene gave cyclopropane-1,2,3-tricarboxylic acid.
These products are in accord with the structures assigned to - and pinenes.
-31-

The bornane (camphene)-norbornane (isocamphane) group


Bornane (camphene), C10H18. This is a synthetic compound and may be
prepared from camphor, e.g.,
(i) By the reduction of camphor to a mixture of borneols, these then
converted to the bornyl iodides which are finally reduced to bornane.
10

OH
Na/Hg
H2O

HI

Zn
CH3CO 2H

2
7

bornane

(ii) Camphor may also be converted into bornane by means of WolffKishner reduction.
O

N2H4

NHNH2

C2H5ONa
heat

Bornane is solid, m.p. 156C; it is optically inactive.

-32-

N2

Camphor

Camphor. This occurs in nature in the camphor tree of Formosa and


Japan. It is a solid, mp. 180C, and is optically active; the (+)- and (-)forms occurs naturally, and so does racemic camphor, which is the usual
form of synthetic camphor.
Bredt (1893) was the first to assign the correct formula to camphor (over
30 have been proposed). Bredt based his formula on the above facts and
also on the facts that (a) oxidation of camphor with nitric acid gives
camphoric acid, C10H16O4 (Malaguit, 1837); (b) oxidation of camphoric
acid (or camphor) with nitric acid gives camphoronic acid, C9H14O6
(Bredt, 1893).
Bredt therefore assumed that (II) was the structure of camphoric acid, and
that (I) was the structure of camphor, and proposed the following
reactions to show the relationships between camphor, camphoric acid and
camphoronic acid (III).
O

CO 2H

[O]

CO 2H

[O]

CO 2H

CO 2H
(I)

(II)

[O]
-CO2

OH

CO2H [O]
O

CO 2H
HO 2C

CO2H
(III)

-33-

Synthesis of camphor (Haller, 1896).


Haller started with camphoric acid prepared by the oxidation of camphor,
but since the acid was synthesized later by Komppa, we now have a total
synthesis of camphor.

Chemical Name of Camphor


1,7,7-Trimethylbicyclo[2.2.1]heptan-2-one

-34-

Sesquiterpenoids
The sesquiterpenoids, in general, form the higher boiling fraction of the
essential oils; this provides their chief source. Wallach (1887) was the
first to suggest that the sesquiterpenoid structure is built up of three
isoprene units; this has been shown to be the case for the majority of the
known sesquiterpenoids, but there are some exceptions.
The sesquiterpenoids are classified into four groups according to the
number of rings present in the structure. If we use the isoprene rule, then
when three isoprene units are linked (head to tail) to form an acyclic
sesquiterpenoid hydrocarbon, the latter will contain four double bonds.
Each isoprene unit contains two double bonds, but one disappears for
each pair that is connected:
C
C

C C C + C C C C + C

C
C C C C

C C

Class of sesquiterpenoids

C C C

C C C

C C C

Number of double bonds

Acyclic

Monocyclic

Bicyclic

Tricyclic

-35-

Acyclic Sesquiterpenoids
Examples of acyclic sesquiterpenoids:
1- Farnesene

-farnesene

-farnesene

Farnesene, C15H24, b.p. 128-130C/12 mm.


This is obtained by the dehydration of farnesol with potassium hydrogen
sulphate (Harries et al., 1913). This compound is the -isomer, and it has
now been shown that the -isomer occurs naturally (in oil of hops), and
Sorm et al. (1949, 1950) have assigned it the structure shown. Farnesene is also obtained by the dehydration of nerolidol.

2- Farnesol

Farnesol, C15H26O, b.p. 120C/0.3 mm.


This occurs in the oil of ambrette seeds, etc.
Its structure was elucidated by Kerschbaum (1913) as follows. When
oxidized with chromic acid, farnesol (I) is converted into farnesal (II),
C15H24O, a compound which behaves as an aldehyde. Thus farnesol is a
primary alcohol.

-36-

Conversion of farnesal into its oxime, followed by dehydration with


acetic anhydride, produces cyanide (III) which, on hydrolysis with alkali,
forms farnesenic acid (IV), C15H24O2, and a ketone, C13O22O (V).

CrO 3
CH2OH

(I)

CHO

(i) NH2OH
(ii) Ac2O

(II)

(i) KOH
(ii) H+

CN

(III)

CO 2H

+
O

(IV)

(V)

This ketone was then found to be dihydro-pseudo-ionone


(geranylacetone). In the formation of this ketone, two carbon atoms are
removed from its precursor. This reaction is characteristic of ,unsaturated carbonyl compounds, and so it is inferred that the precursor,
farnesenic acid (or its nitrile), is an ,-unsaturated compound.
Thus the foregoing facts may be formulated as follows, on the basis of the
known structure of geranylacetone.
A recent synthesis of farnesol has been carried out by Corey et al. (1967).

-37-

(i) PCl5/luitidine
(ii) NaNH2/liq. NH3 C

CH2O

CNa

(i) LAH/AlCl3
(ii) I2

trans-geranylacetone

CH2OH
Me2CuLi
I

CH2OH

CH2OH

3-Nerolidol

HO

Nerolidol, C15H26O, bp.125-127oC/4.5 mm. This occur in the oil of neroli


in the (+)- form. Nerolidol is isomeric with farnesol, and Ruzicka (1923)
showed that the relationship between the two is the same as that between
linalool and geraniol and confirmed the structure of nerolidol by
synthesis.

-38-

EtOOC

EtOOC

Cl
+

i) Bu(OH)2

EtONa

ii) HCl
O

Geranyl chloride

i) NaNH2
ii) HC CH
ii) H2O

Na
moist ether
HO

HO

(+)-Nerolidol

Diterpenoids
Vitamin A1 and A2 are monocyclic diterpenoids. They are usually
classified as belonging to the apocarotenoid group.
Vitamin A1.
Vitamin A1 influences growth in animals and also increase resistance to
disease. Night blindness is due to Vitamin A1 deficency in the human diet
and prolonged deficiency leads to xerophthalmia (hardening of the
cornea). Vitamin A1 occurs free as esters in fats, in fish, livers and in
blood. It was usually isolated as a viscous yellow oil, but later it was
-39-

obtained as a crystalline solid, mp. 63-64oC (Baxter et al. 1940). Vitamin


A1 is estimated by the blue color reaction it gives with a solution of
antimony trichloride in chloroform it is also estimated by light absorption
max 325 nm.
The IUPAC name of Vitamin A1 is retinol, that the corresponding
aldehyde is retinal and the acid is retinoic acid.
O

COOEt

i) Zn/BrCH2CH = CHCOOEt
OH

ii) H+

COOH

CH3Li

O
i) BrMg

COEt

ii) H+
CHO

(i)
(ii)

LAH

(i) H2 - Lindlar cat. (ii) H+


CH2OH

-40-

OEt
OH

Triterpenoids
Squalene, C30H50, b.p. 240-242C/4 mm.
It has been isolated from the liver oils of sharks. Other sources are olive
oil and several other vegetable oils. Squalene has also been detected in
leaves. Catalytic hydrogenation (nickel) converts squalene into
perhydrosqualene, C30H62; therefore squalene has six double bonds, and is
acyclic. Ozonolysis of squalene gives, among other products, laevulic
acid; this suggests that the group (I) is present in squalene. Since
squalene cannot be reduced by sodium and amyl alcohol, there are no
conjugated double bonds present in the molecule. Perhydrosqualene was
found to be identical with the product obtained by subjecting hexahydrofarnesyl bromide to the Wurtz reaction. This led Karrer et al. (1931) to
synthesis squalene (II) from farnesyl bromide by a Wurtz reaction.

(I)

CH2Br
2

Mg

(II)
squalene (all-trans)

-41-

Polyterpenoids
Polymeric isoprenoid hydrocarbons have also been identified. Rubber is
undoubtedly the best known and most widely used compound of this
kind. It occurs as a colloidal suspension called latex in a number of
plants, ranging from the dandelion to the rubber tree (Hevea brasiliensis).
Rubber is a polyene, and exhibits all the expected reactions of the C=C
function. Bromine, hydrogen chloride and hydrogen all add with a
stoichiometry of one molar equivalent per isoprene unit. Ozonolysis of
rubber generates a mixture of levulinic acid ( CH3COCH2CH2CO2H ) and
the corresponding aldehyde. Pyrolysis of rubber produces the diene
isoprene along with other products.

The double bonds in rubber all have a Z-configuration, which causes this
macromolecule to adopt a kinked or coiled conformation. This is reflected
in the physical properties of rubber. Despite its high molecular weight
(about one million), crude latex rubber is a soft, sticky, elastic substance.
Chemical modification of this material is normal for commercial
applications. Gutta-percha (structure above) is a naturally occurring Eisomer of rubber. Here the hydrocarbon chains adopt a uniform zig-zag or
rod like conformation, which produces a more rigid and tough substance.
Uses of gutta-percha include electrical insulation and the covering of golf
balls.
-42-

Rubber
Rubber (caoutchouc) is obtained from latex, which is an emulsion of
rubber particles in water that is obtained from the inner bark of many
types of trees which grow in the tropics and sub-tropics. When the bark of
the rubber trees is cut, latex slowly exudes from the cut. Addition of the
acetic acid coagulates the rubber, which is then separated from the liquor
and either pressed into blocks or rolled into sheets, and finally dried in a
current of warm air, or smoked.

Crude latex rubber contains, in addition to the actual rubber hydrocarbons


(90-5 percent), proteins, sugars fatty acids and resins, the amounts of
these substances depending on the source. Crude rubber is soft and sticky,
becoming more so as the temperature rises. It has a low tensile strength
and its elasticity is exhibited only over a narrow range of temperature.
When treated with solvents such as benzene, ether, light petrol, a large
part of the crude rubber dissolves; the rest swells but does not dissolve.
This insoluble fraction apparently contains almost all of the protein
impurity. On the other hand, rubber is insoluble in acetone, methanol, etc.
When un-stretched, rubber is amorphous; stretching or prolonged cooling
causes rubber to crystallize.
Structure of rubber
The destructive distillation of rubber gives isoprene as one of the main
products; this led to the suggestion that rubber is a polymer of isoprene,
-43-

and therefore to the molecular formula (C5H8)n. This molecular formula


has been confirmed by the analysis of pure rubber. Crude rubber may be
purified by fractional precipitation from benzene solution by the addition
of acetone. This fractional precipitation, however, produces molecules of
different sizes, as shown by the determination of the molecular weights of
the various fractions by osmotic pressure, viscosity and ultracentrifuge
measurements; molecular weights of the order of 300 000 have been
obtained.
The halogens and the halogen acids readily add on the rubber, e.g.,
bromine gives an addition product of formula (C5H8Br2)n, and the
hydrogen chloride the addition product (C5H9Cl)n. Pure rubber has been
hydrogenated to the fully saturated hydrocarbon (C5H10)n this is known
as hydrorubber by heating with hydrogen in the presence of platinum as
catalyst (Pummerer et al., 1922). Rubber also forms an ozonide of
formula (C5H8O3)n. All these addition reactions clearly indicate that
rubber is an unsaturated compound, and the formulae of the addition
products show that there is one double bond for each isoprene unit
present.
Ozonolysis of rubber produces laevulaldehyde and its peroxide, laevulic
acid and small amounts of carbon dioxide, formic acid and succinic acid
(Harris, 1905-1912). Pummerer (1931) showed that the laevulic
derivatives comprised about 90 percent of the products formed by the
ozonolysis.
O3

+
OHC
O

rubber
+

-44-

OHC

O
+

OHC

This observation led to the suggestion that rubber is composed of


isoprene units joined head to tail. Thus, if rubber has the following
structure, the formation of the products of ozonolysis can be explained as
in the previous scheme.
Some of the laevulaldehyde is further oxidized to laevulic and succinic
acids.
O
CO 2H

O
CHO
CO2

-45-

+ HO2C

CO 2H

Gutta-percha
Gutta-percha. (Is obtained from the bark of various trees). It is isomeric
with rubber; their structures are the same, as shown by the methods of
analysis that were used for rubber. X-ray diffraction studies (Bunn, 1942)
have shown that rubber is composed of long chains built up to isoprene
units arranged in the cis-form, whereas gutta-percha is the trans-form.
Gutta-percha is hard and has a very low elasticity.

The biosynthesis of natural rubber occurs by the indefinite linking of the


five-carbon units discussed, but each added unit must assume the cisconfiguration.

Synthetic rubbers. There are many synthetic rubbers in use, each type
possessing certain desirable properties. A great deal of work has been
-46-

done on the synthesis of natural rubber, but the difficulty has been to
obtain the isoprene units in the all cis-configuration. This has now been
achieved by means of the Ziegler-Natta catalysts, e.g., a triethylaluminium-titanium chloride complex to which has been added finely
divided lithium. The product obtained in this way is identical with natural
rubber.

-47-

STEROIDS

-48-

-49-

STEROIDS
Introduction
The important class of lipids called steroids are actually metabolic
terpenoid 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 below. 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.
Steroids are solid alcohols that are widely distributed in animal and plant
kingdoms. The basic skeleton consists of 17 carbon atoms arranged in the
form of perhydrocyclopentenophenanthrene. A steroid could be defined in
another way, as any compound which gives Diels hydrocarbon when
distilled with selenium.

Biologically, lanosterol is considered the precursor of steroids, by the loss


of the 4,4-gem-dimethyl groups and the 14 methyl group, the triterpenoid
skeleton of lanosterol is converted into the steroid skeleton.
-50-

14

HO

HO

Sterol

Lanosterol

Classification of Steroids
Steroids include many compounds of great importance to life. They could
be classified into the following groups:
I- Sterols
Such as cholesterol, the characteristic steroid of higher animals,
ergosterol which is converted to vitamin D by irradiation as well as the
common phytosterols, -sitosterol and stigmasterol.
21

20

18
19

24
23

17

22

26
25
27

14

H
HO

HO

Ergosterol

Cholesterol

H
H

HO

HO

Stigmasterol

-sitosterol

-51-

Cholesterol

Cholesterol is an extremely important biological molecule that has roles


in membrane structure as well as being a precursor for the synthesis of
the steroid hormones and bile acids. Both dietary cholesterol and that
synthesized de novo are transported through the circulation in lipoprotein
particles. The same is true of cholesteryl esters, the form in which
cholesterol is stored in cells.
The synthesis and utilization of cholesterol must be tightly regulated in
order to prevent over-accumulation and abnormal deposition within the
body. Of particular importance clinically is the abnormal deposition of
cholesterol and cholesterol-rich lipoproteins in the coronary arteries. Such
deposition, eventually leading to atherosclerosis, is the leading
contributory factor in diseases of the coronary arteries.
The Utilization of Cholesterol
Cholesterol is transported in the plasma predominantly as cholesteryl
esters associated with lipoproteins. Dietary cholesterol is transported
from the small intestine to the liver within chylomicrons. Cholesterol
synthesized by the liver, as well as any dietary cholesterol in the liver that
exceeds hepatic needs, is transported in the serum within LDLs. The liver
synthesizes VLDLs and these are converted to LDLs through the action
of endothelial cell-associated lipoprotein lipase. Cholesterol found in
-52-

plasma membranes can be extracted by HDLs and esterified by the HDLassociated enzyme LCAT. The cholesterol acquired from peripheral
tissues by HDLs can then be transferred to VLDLs and LDLs via the
action of cholesteryl ester transfer protein (apo-D) which is associated
with HDLs. Reverse cholesterol transport allows peripheral cholesterol to
be returned to the liver in LDLs. Ultimately, cholesterol is excreted in the
bile as free cholesterol or as bile salts following conversion to bile acids
in the liver.
II- Vitamin D group
They are about seven compounds (vitamin D1-D7) with the ring B being
opened. Vitamin D2 (or calciferol) is formed from ergosterol by the
sunlight irradiation.

HO

[1,7] H-shift

HO

Ergosterol

HO

Calciferol

III- Bile acids:


As their names implies, are isolated from the bile of various animals, as
well as humans. Their chief functions to facilitate the digestion of fats.

-53-

OH
COOH
H
H
HO

H
OH

Cholic acid
IV- Sex hormones
These could be divided into:
(1) Oestrogens: Characterized by ring A being aromatic, and hence
without the C-19 methyl group. They are responsible for development
and maintenance of the female secondary sex organs. An example is
-Oestradiol, main female sex hormone.
OH
H
H

HO

-Oestradiol

(2) Androgens: Are hormones which control the development of the


male genital organs and secondary sex characteristics. An example is
testosterone (male sex hormone).
OH
H
H

Testosterone

(3) Gestogens: Are hormones which are responsible for the maintenance
of pregnancy. An example is progesterone.
-54-

H
H

Progesterone

V- Adrenocortical hormones
Produced by the cortex of the adrenal glands. A lack of these hormones
leads to multiple symptoms e.g. muscular weakness, change in
carbohydrate and protein metabolism, disturbance of electrolyte balance,
etc. and eventually death. An example is cortisone.
CH2OH
C
O

O
OH

Cortisone

VI- Cardenolides
Are plant steroid which occur as glycosides. Cardiac glycosides have
powerful cardiotonic activity and can be used for treatment of heart
failure. These compounds are characterized by having a lactone group.
An example is strophanthidin.
O

23

22

21
20

OHC
OH
HO

OH

Strophanthidin

-55-

VII- Sapogenins
Are the aglycones of saponins. The first source of steroidal saponins was
Digitalis purpurea, more important as a source of the cardiac glycosides.
Sapogenins are characterized structurally by the presence of both furan
and pyran rings and spiro carbon atom (named spirostane). An example is
diosgenin.
OO

HO

Diosgenin

-56-

Mycosterol
Ergosterol: C28H44O
This occurs in yeast, Ergosterol forms an esters e.g. an acetate with acetic
anhydride, thus there is a hydroxyl group present in ergosterol.

HO

Catalytic hydrogenation (platinum) of ergosterol produces ergostanol


C28H50O, hence there are three double bonds in ergosterol.
Ozonolysis of ergosterol gives, among other products, methyl isopropyl
acetaldehyde which proves a methyl group at C24 and 22
COOH

22

21

23

20
24

26
25

O3

+ OHC

27

28

H
Ergosterol

unsaturation. The side chain must contain only one double bond, since if
more than one were present, more than one fragment would have been
removed on ozonolysis, when heated with maleic anhydride at 135C,
ergosterol forms an adduct, and so it follows that the two double bonds
(in the nucleus) are conjugated. Now ergosterol has an absorption
maximum at 282 nm. Conjugated acyclic dienes absorb in the region of
220-250 nm, but if the diene is in a ring system, then the absorption is
-57-

shifted to the region 260-290 nm. Thus the two double bonds in the
nucleus of ergosterol are in one of the rings.
The ultraviolet light effect on ergosterol resulted in the isolation of
vitamin D2 or ergocalciferol.

HO

HO

Ergosterol

Vitamin D2
(Ergocalciferol)

Ergocalciferol (Vitamin D2):


Is a crystalline solid, m.p. 115-117C, []D +130. Its molecular formula
is C28H44O, and since it forms esters, the oxygen is present as a hydroxyl
group. Furthermore, since ergocalciferol gives a ketone on oxidation, this
hydroxyl group is a secondary alcoholic group. Ozonolysis of
ergocalciferol produces, among other products, methyl isopropyl
acetaldehyde. Thus the side-chain in ergocalciferol is the same as that in
ergosterol.
Catalytic hydrogenation converts ergocalciferol into the fully saturated
compound octahydro ergocalciferol, C28H52O. This shows that there are
four double bonds present and since one is in the side-chain, three are
therefore in the nucleus.
The parent hydrocarbon of ergocalciferol is C28H52 and since this
corresponds to the general formula, CnH2n-4, the molecule therefore is
tricyclic (28+1- 52/2 = 3) therefore three rings are present.

-58-

Furthermore, ergocalciferol does not gives Diels hydrocarbon when


distilled with selenium, these fact indicate that ergocalciferol does not
contain the four-ring system of ergosterol.
Ozonolysis of vitamin D2 gave a keto acid C13H20O3 and formaldehyde,
while careful oxidation with chromium trioxide or permanganate gave the
aldehyde C21H34O.
COOH

+ CH2O

O3
O

(C13H20O3)

H
HO

Vitamin D2

CrO3
or KMnO 4
H

(C21H34O)

OHC

As a result of the addition of vitamin D to milk, deficiencies in this


vitamin are rare in this country. The main symptom of vitamin D
deficiency in children is rickets and in adults is osteomalacia. Rickets is
characterized improper mineralization during the development of the
bones resulting in soft bones. Osteomalacia is characterized by
demineralization of previously formed bone leading to increased softness
and susceptibility to fracture.

-59-

Bile Acids
The bile acids occur in bile (a secretion of the liver which is stored in the
gall bladder) of most animals combined as amides with either glycine
(NH2CH2COOH) or taurine (NH2CH2CH2SO3H), e.g. glycocholic acid (=
glycine + cholic acid), tauro-cholic acid (= taurine + cholic acid). The bile
acids are present as sodium salts.
22

21
12
19

1
2

11
9

10

18

13

23

20
17

COOH

COOH
H

16

14
15

7
4

-cholanic acid
(allo-cholanic acid)

-cholanic acid
(cholanic acid)

Most of the bile acids are hydroxy derivatives of either 5-cholanic acid
or 5-cholanic acid.
About twenty natural bile acids have been characterized and many others
are synthetic. The position of the hydroxyl group are any of the following
3, 6, 7, 11, 12 and 23 and in almost all of natural bile acids the
configuration of the hydroxyl groups are -. Some of the more important
natural bile acids are:
Name

m.p. C

Hydroxy groups

Cholic acid

195

3, 7, 12

Doexycholic acid

172

3, 12

Lithocholic acid

186

Chenodeoxy cholic acid

140

3, 7

-60-

The structures of 5-cholanic acid (cholanic acid) and 5cholanic acid (allo cholanic acid):
These acids may be derived from 5-cholestane (coprostane) and 5cholestane, respectively, as follows. At the same time, these reactions
shows the relationship between the bile acids and the sterols.

5-Cholanic acid m.p. 164C, []D +22:

H
H

oppenauer
oxid

HO

H2-pt
O

Cholest-4-en-3-one
Cholesterol
COOH

HO

CrO3

(i) CrO3
(ii) Zn-Hg/HCl

-Cholestan-3-ol
(coprostanol)

-Cholestane
(coprostane)

-Cholanic acid

5-Cholanic acid m.p. 173C, []D +22:

CrO3

H2-pt
HO

HO

Cholesterol

-Cholestan-3-ol

-Cholestan-3-one

COOH
H
CrO3

Zn/Hg
HCl
H

-Cholestane

-Cholanic acid

-61-

Structure of the bile acids:


OH
COOH

COOH
H

H
H
HO

H
HO

OH

Lithocholic acid

Cholic acid

COOH
H
H
HO

H
OH

Chenodeoxy cholic acid

Bile Acids Synthesis and Utilization


The end products of cholesterol utilization are the bile acids, synthesized
in the liver. Synthesis of bile acids is one of the predominant mechanisms
for the excretion of excess cholesterol. However, the excretion of
cholesterol in the form of bile acids is insufficient to compensate for an
excess dietary intake of cholesterol.
Synthesis of the 2 primary bile acids, cholic acid and chenodeoxycholic
acid. The reaction catalyzed by the 7-hydroxylase is the rate limiting
step in bile acid synthesis. Conversion of 7-hydroxycholesterol to the
bile acids requires several steps. Only the relevant co-factors needed for
the synthesis steps are shown. The chenodeoxycholic acid could be
prepared by the hydrolase enzyme of the chenodeoxycholyl-CoA.

-62-

Clinical Significance of Bile Acid Synthesis


Bile acids perform four physiologically significant functions:
1. their synthesis and subsequent excretion in the feces represent the only
significant mechanism for the elimination of excess cholesterol.
2. bile acids and phospholipids solubilize cholesterol in the bile, thereby
preventing the precipitation of cholesterol in the gallbladder.
3. they facilitate the digestion of dietary triacylglycerols by acting as
emulsifying agents that render fats accessible to pancreatic lipases.
4. they facilitate the intestinal absorption of fat-soluble vitamins.

-63-

Steroid hormones
Introduction:
Hormones are substances which are secreted by the ductless glands, and
only minute amounts are necessary to produce the various physiological
reactions in the body. As a group, hormones do not resemble one another
chemically, and their classification is based on their physiological
activity. The sex hormones belong to the steroid class of compounds, and
are produced in the gonads (testes in the male, and ovaries in the female).
Their activity appears to be controlled by the hormones that are produced
in the anterior lobe of the pituitary gland. Because of this, the sex
hormones are sometimes called the secondary sex hormones, and the
hormones of the anterior lobe of the pituitary (which are protein in
nature) are called the primary sex hormones.

Sex hormones:
The sex hormones are of three types: the androgens (male hormones), the
oestrogens (female hormones) and gestogens (the corpus luteum
hormones). The sex hormones are responsible for the sexual processes,
and for the secondary characteristics which differentiate males from
females.

-64-

Androgens
Androsterone: C19H30O2, m.p. 183C, []D +94
It was first isolated by Butenandt et al. (1931) from male urine (about 15
mg from 15000 litres of urine). Androsterone behaves as a saturated
compound, and since it forms mono-esters, one oxygen atom is present as
a hydroxyl group. The functional nature of the other oxygen atom was
shown to be oxo, since androsterone forms an oxime, etc. The parent
hydrocarbon of androsterone, C19H30O2, is therefore C19H32, and since this
corresponds to the general formula CnH2n-6, the molecules is tetracyclic
(D.B.E. of C19H30O2 = 19 + 1 30/2 = 5; 1 double bond due to C=O, and
so there are four rings). This led to the suggestion that androsterone
probably contains the steroid nucleus, and since it is a hydroxyketone, it
was thought that it is possibly related to oestrone. Butenandt (1932)
therefore proposed a structure which was proved correct by Ruzicka
(1934) as follows.
O
H
H
AcO

(i) CrO3
(ii) hydrolysis
HO

H
-cholestanyl -acetate

H
epiandrosterone

O
H
H
AcO

(i) CrO 3
(ii) hydrolysis
HO

H
-cholestanyl -acetate

H
H
androsterone

-65-

Ruzicka oxidized 5-cholestanyl 3-acetate with chromium trioxide in


acetic acid to epiandrosterone, a hydroxyketone with the structure
proposed for androsterone by Butenandt. When, however, 5-cholestanyl
3-acetate was oxidized, the product was androsterone. Thus the
configuration of the hydroxyl group at C-3 is and not as Butenandt
suggested. Epiandrosterone (formerly known as isoandrosterone), m.p.
174C, []D +88, has about one-eight of the activity of androsterone.
O
H
H
TsO

AcONa
AcOH-Ac2O

H
H

OH

H
H

+
AcO

H
39%

54%

OH

NaOH
O

O
H

H
H
H

HO

H
AcOH aq.

PhCO2H

H
H

O
LiAlH4

H
O

O
H

H
HO

Spondheimer et al. (1955) have converted epiandrosterone into


androsterone, starting with epiandrosterone p-toluenesulphonate (cf. tosyl
esters of sugars).
A convenient preparation of androsterone starts from
dehydroepiandrosterone (Caglioti et al., 1964).
-66-

OH
OH

H
H

TsOH, PhH

HO

O
Oppenauer
oxidn.

HO
dehydroepiandrosterone

OH
OH

(i) B2H6
(ii) Ac2O

H
H

O
H
H

TsOH, PhH
H

H
O
O

(i) B2H6
(iii) H2O2,OH

H
H

H
H

(iii) H+
HO

H
androsterone

-67-

Testosterone
Testosterone: C19H28O2, m.p. 155C, []D +109
OH
H
H

Testosterone was prepared from dehydroepiandrosterone which was


available from natural product. The dehydroepiandrosterone is the most
important and useful intermediate of sex hormones.

Synthesis of Dehydroepiandrosterone:

Synthesis of Testosterone:
-68-

OH

O
H
H

(i) Ac2O
(ii) Na-C3O7OH

(i) PhCOCl
(ii) Mild hydrolysis

AcO

HO

Dehydroepiandrosterone
OCOPh
Oppenauer
Oxid

H
H

OCOPh

HO

H
OH

H
H

Testosterone

Oestrogens

-69-

hydrolysis
KOH

H
H

Oestrone
It has been known for a long time that there are hormones which control
the uterine cycle, but it was not until that Butenandt and Doisy
independently isolated the active substance oestrone from the urine of
pregnant women. Oestrone is the first known member of the sex
hormones, and soon after its discovery two other hormones were isolated,
oestriol, and oestradiol.
(+) Oestrone, m.p. 259C, []D +170, has the molecular formula
C18H22O2. It behaves as a ketone, and contains one hydroxyl group (this
hydroxyl group is phenolic).
O
H
H

HO

Oestrone

Oestriol C18H24O3, m.p. 281C, []D +61


OH
OH
H
HO

Oestriol was isolated from human pregnancy urine by Marrian (1930).


Since oestriol forms a triacetate, three hydroxyl groups must be present in
the molecular, one was shown to be phenolic, and the other two
secondary alcoholic, since, on oxidation, a diketone is produced.
Furthermore, x-ray analysis indicates that the two alcoholic groups are in

-70-

the vicinal position. When oestriol is heated with potassium hydrogen


sulphate, one molecule of water is removed and oestrone is produced.
Oestradiol: C18H24O2
There are two stereoisomeric oestradiol, - and -;
OH

OH
H

H
H

HO

HO

Oestradiol-17

Oestradiol-17

m.p. 178C []D +81

m.p. 222C []D +54

Oestradiol-17 has been isolated from the pregnancy urine of mares.


Oestradiol-17 is much more active than oestrone, whereas oestradiol17 is much less active. It appears that oestradiol is the real hormone, and
that oestrone and oestriol are metabolic products.

Synthesis of oestrogens from dehydroepiandrosterone:


Synthesis of oestradiol:
OH

O
H
H

HO

controll
benzoylat

Na/Hg
Red.

HO

Dehydroepiandrosterone
OCOC6H5

OCOC6H5
H2

H
H
HO

H
HO

-71-

oxid

H
H

Conversion of oestradiol to oestrone:


O

OH
H

control
oxid

HO

HO

Oestrone

Oestradiol

The oestrone may be converted into oestriol as follows (Huffman et al.):


O

NOH

Zn dust
CH3COOH

H
H

CH3O

CH3O

Methyl ether of ostrone

OH

OH

OH

O
Na
(CH3)2CHOH

H
H

CH3O

CH3O

OH
OH
H
H

HO

Oestriol

-72-

H
H

Leeds et al. (1954) have converted oestrone into oestriol by simpler


method:
OAc

HO

PhCO3H

isopropenyl
acetate

H
H

AcO
OH

AcO O

AcO

LiALH4

H
H

OH

H
HO

Oestriol

-73-

(+)-Equilenin
(+)-Equilenin: C18H18O2, m.p. 258-259C, []D +87
This has been isolated from the urine of pregnant amres by Girard et al.
(1932); it is not a very potent oestrogen.
CH3

CH3

CH3O

HO
(II)

O
H

Na
C2H5OH

HO

(I)
equilenin

(III)
oestrone

The first synthesis was by Bachmann et al. (1940), but was somewhat
improved by Johnson et al. (1947). In the following chart, compound (IV)
is synthesized by the method of Bachmann, and the rest of the synthesis is
that of Johnson, who started with compound (IV) [Johnsons synthesis
involves fewer steps than Bachmanns].
NH2

NH2

(i) (CH3)2SO 4-NaOH


(ii) hydrolysis

(CH3CO)2O

KOH
HO 3S

NHCOCH3

HO

HO

Cleve's acid

CH2OH

NH2

I
(i) NaNO2-H2SO 4
(ii) KI
CH3O

CH3O

CH2Br
CH2
CH3O

CH2
(i) Mg
(ii) H2C

CH2
O

CH2
CH2

CH3O

CH2
CO 2H (i) SOCl2
(ii) SnCl4

malonic ester
synthesis
CH3O

PBr3

O
CH3O
(IV)

-74-

Johnsons synthesis starting from (IV)


CHO

(IV)
CH
OH

N
OH

N
OH

CN
-H2O

CH3
CN
O

NH2OH.HCl
O CH3CO2H

O HCO2C2H5
CH3ONa
CH3O

CH3O

CH

methyl succinate
(CH3)3COK

N (CH3)3COK

+
OK

CH3
CN
CCH2CO2CH3
CO2CH3

-75-

H3C
(Thorpe
reaction)

CH3I

NH
CO2K
CO2CH3

Artificial hormones
Many compounds with oestrogenic activity but not of steroid structure
have been prepared synthetically.

Stilboestrol: (4,4-dihydroxydiethylstilbene)
Was prepared by Dodds et al. (1939) as follows:
2CH3O

CHO

KCN

anisoin

anisaldehyde

CH3O

SnCl2

OCH3

CHOHCO

CH3O

CH2CO

C2H5

C H ONa
CH3O
OCH3 2 5
C2H5I

OCH3

CHCO

C2H5MgI

deoxyanisoin

C2H5 C2H5
CH3O

CH C

OCH3

OH

C2H5 C2H5

PBr3
CH3O
(-H2O)

OCH3

ethanolic
KOH

C2H5 C2H5
HO

stilboestrol

The above structure of stilboestrol can exist in two geometrical isomeric


forms; it is the trans-form which is the active substance, and this
configuration has been confirmed by X-ray analysis (Crowfoot et al.,
1941).
CH3
CH2
C
HO

H3C

C
CH2

trans-stilboestrol

-76-

OH

OH

Kharasch et al. (1943) have introduced a simpler synthesis of stilboestrol.


Anethole is treated with hydrobromic acid and the product, anethole
hydrobromide, is then treated with sodamide in liquid ammonia. The
resulting compound (I) gives stilboestrol on demethylation and
isomerisation in the presence of alkali. The structure of (I) is uncertain,
but it is believed to be the one given.
CH3O

CH CHCH3

HBr

CHBrCH2CH3

CH3O

NaNH2
liq. NH3

anethole

CH CH

CH3O

OCH3

alkali

HO

CH CH2

OH

C2H5 C2H5

CH2 CH3
(I)

Stilboestrol is more active than oestrone when administered


subcutaneously, and it can also be given orally.

Hexoestrol: (dihydrostilboestrol)
May be prepared from anethole hydrobromide as follows:
2 CH3O

CHBrC2H5

Na

CH CH

CH3O

OCH3

C2H5 C2H5

ethanolic
KOH

HO

CH CH

OH

C2H5 C2H5
hexoestrol

The active form is the meso-isomer (as shown by X-ray crystallography


by Crowfoot et al., 1941).

-77-

Gestogens
Progesterone

Progesterone: C21H30O2, mp. 128C, []D +192


This was first isoated in a pure form by Butenandt et al. (1934) from the
corpora lutea of pregnant sow. The chemical reactions of progesterone
show that there are two keto groups present, and since on catalytic
reduction three molecules of hydrogen are added to form the dialcohol
C21H36O2, it therefore follows that progesterone contains one double bond
(four hydrogen atoms are used to convert the two keto group to alcohol
groups) thus the parent hydrocarbon of progesterone is therefore
tetracyclic (C21H36O2 21+1 36/2= 4 rings). Furthermore, x-ray studies
have shown that progesterone contains the steroid nucleus, and this
further supported by the fact that progesterone may be prepared from e.g.
stigmasterol and cholesterol.
The absorption spectrum of progesterone, however, shows that it is an
,-unsaturated ketone (max 240 nm).

-78-

Synthesis of progesterone from ergosterol: (Shepherd et al., 1955)


This appears to be the most practical synthesis (note the enamine step).

-79-

Synthesis of progesterone from cholesterol:

-80-

Adrenocortical Hormones
Introduction:
In the adrenal glands (of mammals) there are two regions, the medulla
which produces adrenaline, and the cortex which produces steroid
hormones. The production of these adrenocortical hormones or corticoids
is controlled by the hormone produced in the anterior lobe of the pituitary,
the so-called adrenocorticortrophic hormone, ACTH. The corticoids have
many physiological functions, but their main functions are the control of
carbohydrate and protein metabolism and the control of the balance of
water and electrolytes.

Cortisone: mp. 215C, []D +209


Has been used for the treatment of rheumatoid arthritis and rheumatic
fever. Many partial syntheses are known, e.g., the following partial
synthesis starts from 3,21-diacetoxypregnane-11,20-dione (Sarett,
1948).
CH2OAc

CH2OAc

CO

C(OH)CN

O
H
H

AcO

HCN
H

H
AcO

H
CH2OH

CH2OAc

CCN

CCN
O

H
HO

O
Ac2O

(i) POCl3-C5H5N(-H2O)
(ii) KOH

OsO4

H
H

H
HO

-81-

CH2OAc
CN
C O
OsO2
O
(i) CrO3
(ii) Na2SO3

O
H
H
HO

OH
H
H

CH2OAc

CH2OH

CO

CO

OH

O
(i) -HBr
(ii) hydrolysis

Br

CO

CH2OH

H
H

H
O

cortisone

-82-

OH

(i) Ac2O
(ii) Br2