terpenoids · finally, the structure of retene is confirmed by its synthesis (haworth et. al.,...

Terpenoids

Dr. Vandna Thakur

Assistant Professor

Deptt of Chemistry

HRMMV

Abeitic Acid Tricyclic diterpenoid

Chief constituent of rosin or colophony (steam distillation of

resin of Pine trees gives volatile essential oil (Terpentine oil

(source of alpha-pinene) and non-volarile substance, rosin)

Isolation: Rosin is first boiled in alcoholic soln containing HCl

and AA is obtained as Diamylamine salt.

Molecular formula: C20H30O2

Constiution:

On hydrogenation, AA gives tetrahydro abietic acid which

ensures the p/o 2 double bonds

Gives effervescences with NaHCO3 showing p/o carboxylic acid

group which does esterify easily confirming it to be 3o

carboxylic group.

➢ Herein parent HC is C19H34 (CnH2n-4) which corresponds to tricyclic

Compound

➢ AA dehydrogenates in p/o S/Se/Pd-charcoal by oxidative degradation

To give aromatic HC, retene (1-methyl-7-isopropylphenanthrene)

Degradation of Retene

(All the reaction can only be

explained by considering (I)

as the structure of retene)

To establish the position of isopropyl group:

➢ Fusing (III) with KOH followed by oxidation to give biphenyl

4-carboxylic acid (indicationg isopropyl group in retene is at position 7)

Finally, the structure of retene is confirmed by its synthesis (Haworth et. Al., (1932)

Formation of retene from AA suggests that it has retene carbon skeleton

The position of18 C has been established by retene formation, but for the exact

Structure, we must know:

➢ Position of 3o carboxylic group

➢ Position of angular methyl group

➢ Position of two double bonds

➢ Position of 3o carboxylic group:

➢ Ruzika et. al. ascertained the position of Carboxylic group by following

reactions:

The structure of Homoretene was confirmed by the chemical synthesis

(Haworth, 1932)

Homoretene on oxidation with Alkaline potassium ferricyanide gives

phenanthrene 1,7-dicarboxylic acid

Whereas, oxidation of retene also gives the same product.

Homoretene is 1-ethyl-7-iso propyl phenanthrene.

The position of ethyl group suggests that methyl and carboxyl groups are

Present on Same C (C1) in AA.

Position of angular methyl group:

Confirmed by oxidation and dehydrogenation reactions of AA.

The following reaction establish the structure of reduced AA.

Both, m-xylene and Hemimellitene have a m-methyl group, hence the angular

Methyl group must be in m-position to C1 methyl group.

Position of the double bonds:

❖ Ruzika et. al. showed that AA forms an adduct with maleic anhydride

At above 100 oC indicating the two bonds are in conjugation.

❖ Also AA shows a maximum at 238 nm in the UV region which indicates

Heteroannular conjugation i.e. the bonds are in different rings.

❖ Ring A does not contain a double bond as confirmed by oxidative study on

AA. (Slide no. 7) by Ruzika et al because p/o double bond would have

led to Rupturing of ring A. double bonds are present in ring B and C

❖ The oxidation of AA with acidic KMnO4 gives isobutyric acid which indicates

that Double bonds are present b/w C7-C8 and C13-C14.

On the basis of all the points dicussed, AA is assigned the structure

(Stereochemistry is also studied having following absolute

configuration)

On heating in p/o Pd-Charcoal (250-275 oC), AA gives Dehydroabeitic Acid

which was synthesized by Stork and Schulenberg (1956).

Reactions of Abeitic Acid: mainly Isomerization and

disproportionation occurs.

Isomerization

Disproportionation

Santonin

➢ A sesquiterpenoid lactone

➢ Found in Artemesia species

➢ Medicinal use as anthelmintic (to expel intestinal worms)

Structure:❑ Molecular formula: C15H18O3

❑ Santonin (I) dissolves in alkali to form Santoninic acid (II): this ascertain that

It is a lactone (IR studies support it to be a γ-lactone)

❑ Catalytic hydrogenation Shows the p/o two double bonds

❑ UV absorption shows it to be a a,b-unsaturated ketone (Lambda= 236 nm)

❑ Its reaction with Zn dust gives 1,4-dimethylnaphthalene, propene and

small amount of 1,4-dimethyl-2-naphthol (which suggests the p/o

Naphthalene skeleton.

❑ Reduction of santonin oxime gives santon-amine (III) which on reaction

With HNO2 gives hyposantonin (IV).

All the above reaction can be explained if we accept the structure of

santonin as (I)

Structure elucidation of Hyposantonin (IV):

❑ Hyposantonoin on oxidation with KMnO4 gives 3,6-dimethyl phthalic

Acid (V).

❑ On heating with ethanolic hydrochloride, mixture of two isometic acids

(dihydrosantinic acid (VI). Which on further heating with Ba(OH)2 gives

Product (VII).

❑ (I) and (VI) on oxidation with I2/AcOH gives Santinic Acid (vIII) which also

gives (VII) on heating with Ba(OH)2.

Other reactions of Santonin

Natural α and β-santonin has been synthesized as following

(Abe et al, 1956)

Michael addition is stereospecific, malonic ester group in XVIII takes

More stable equatorial position, following decarboxylation gives XX

( two racemic acids, alpha and Beta). After separating the two acids,

Alpha acids give alpha (+/-) santonin after oxidation and lactonization

Stereochemistry of Santonin:

α-Santonin has the following absolute configuration

β-santonin (Which also occur naturally) is the C11 epimer

Biological role (volatile and non volatile):

- Flavour, fragrance, scent

- Antibiotics

- Hormones

- Membrane lipids

- Insect attractants

- Insect antifeedants

- Mediate the electron transport processes

(in respiration and photosynthesis)

Terpenoids Biological role

Chemical and physical properties

Volatile liquids with no color

keep in amber bottles with minimum air

Odor

Asymmetric centers, isomers with optical activity

only one isomer occurs naturally

Refractive index normally high

is a means to characterize the oil

Miscible in water and soluble in organic solvents

more soluble if contains –OH fatty acids

Reasonably heat stable

can be steam distilled

Tend to be used as solvents for resins

Basic unit

•Thermal decomposition of terpenoids give isoprene as one of the

product.

•Otto Wallach pointed that terpenoids can be built up of isoprene

unit.

•Isoprene rule states that terpenoids are constructed from two or

more isoprene unit.

•Ingold suggested that isoprene units are joined in the terpenoid

via ‘head to tail’ fashion.

•Special isoprene rule states that the terpenoids are constructed of

two or more isoprene units joined in a ‘head to tail’ fashion.

But this rule can only be used as guiding principle and not as a fixed rule.

For example carotenoids are joined tail to tail at their central and there are also some

terpenoids whose carbon content is not a multiple of five.

Isoprene rule

Isoprene is the common name for 2-methylbuta-1,3-diene

CH2CHC

CH3

H2C1 2 3 4

head tail

IsopreneIsoprene unit C5

HeadTail

HeadTail

Isoprene units can be linked:

➢ Usually, head to tail to

form linear terpenes

➢ Head to head

➢ Tail to tail

➢ Cyclic terpenes also

contain links which are

called crosslinks

Head to Head

Isoprene rule linkage

Head to Tail Tail to Tail

β-Carotene

RetinolLimoneneMyrcene

In most naturally occurring terpenes, there are no head to head or tail to tail links eg.

Does not obey the isoprene rule is called an irregular terpene eg.

Cyclic terpenes also contain links that are neither of three, which are called crosslinks

Classification of TerpenoidsGeneral formula : (C5H8)n.

Classified on the basis of value of number of carbon atoms (n) present in the structure.

S.No. No. of carbons Value of n Class

1 10 2 Monoterpenoids (C10H16)

2 15 3 Sesquiterpenoids (C15H24)

3 20 4 Diterpenoids (C20H32)

4 25 5 Sesterpenoids (C25H40)

5 30 6 Triterpenoids (C30H48)

6 40 8 Tetraterpenoids (C40H64)

7 >40 >8 Polyterpenoids (C5H8)n

Biosynthesis

Formation of a chemical compound by a living

organism. It describes the experimental studies carried

out in vivo for the mode of formation of natural

products.

Biogenesis: It describes the various hypothetical

schemes proposed for the formation of natural

products.

Biogenetic Isoprene rule: The mode of arrangement of

C5 units in terpenoids differ to large extent. It has been

shown that each group of terpenoids has its own

isoprene rule, instead of Isoprene units, they are

derived from its simple hypothetical precursors such as

geraniol, farnesol, geranylgeraniol, squalene etc.

Biosynthesis of terpenoids

As discussed earlier, isoprene is precursor of all the terpenoids, but it

Was never found to be present in natural sources. Hence, the hypothesis

is not valid.

It is divided into three parts:

1). Biosynthesis of C5 units

2). Arrangement of these units to form acyclic terpenoids

3). Cyclization of Acyclic terpenoids to cyclic terpenoids

Biosynthesis of C5 units:

1) Synthesis of Mevalonic Acid:

Acetate (C2) molecule is basic precursor of terpenoids. The acetate

Is converted by CoA to active acetate or acetyl-CoA which is then

converted to mevalonic Acid (MVA) (Merck et al, 1956).

Mevalonic acid pathway

❑Formation of (S)-3-hydroxyl-3-methylglutaryl co-enzyme A (HMG-Co A)

by the condensation of acetyl co-enzyme A with acetoacetyl co-enzyme CoA.

❑Enzymatic reduction of (S)-3-hydroxyl-3-methylglutaryl co-enzyme A

(HMG-Co A) with hydrogen from nicotinamide adenine dinucleotide

phosphate (2 × NADPH) to give (R)-mevalonic acid.

Mevalonic acid pathway❑Mevalonic acid undergoes two successive phosphorylation by

adenosine triphosphate (2 × ATP) to give the 5-pyrophosphate.

❑This undergoes a trans-elimination of the tertiary hydroxyl group and

the carboxyl group to form 3-methylbut-3-enyl pyrophosphate

(isopentenyl pyrophosphate, IPP). This is in equilibrium with

dimethylallyl pyrophosphate (DMAPP).

The biosynthesis of MVA from Leucine (M. J. Moon (1946):

To support MVA as an intermediate in Terpenoid biosynthesis:

CoA Dehydrogenation

Supporting Facts for MVA pathway:

❖ MVA has been isolated from natural resources (Wolf, 1957)

❖ Introduction of 14C –labelled MVA in plants; 14C labelled Alpha-pinene

and rubber have been isolated.

❖ Use of 14C labelled acetate gave labelled Citronellal according to Acetate-MVA

Pathway.

GPP (through NPP) serves as the precursor for acyclic terpenoids

GPP serves as the precursor for monocyclic terpenoids via its Cis isomer

(*Mechanism of ring closure are not certain)

Thank you