T E R P E N O I D S COMPOUNDS DERIVED FROM MEVALONIC ACID

• The largest and most variable group of natural compounds (monoterpenes, sesquiterpenes, diterpenes, sesterpenes, triterpenes, polyterpenes)

• Relative both in general biosynthetic origin and reciprocal structural relationship

• Formed by multiples of five carbon unit

• Pyrolysis produces carbohydrate isoprene (2-methylbutadiene) → isoprenoids. Isoprene is not a natural compound.

TERPENOIDS - OCCURRENCE

• Prevalent majority of terpenoids is found free in plant tissues (Lamiaceae, Asteraceae, Rosaceae, Rutaceae, Apiaceae….) • Exceptionally glycosides • Esters with organic acids • Combination with proteins

• Lower members of group (C10 and C15 substances) are volatile – distillation with water steam (hydrodistillation) (essential oils – olea etherea, Etheroleum menthae)

• Higher members (C20 and more) are not volatile – extraction with organic solvents

1 ISOPRENE RULE

6 8 5 7 OH 4 3

2 OH isoprene 1 myrcene geraniol farnesol

O

camphor CO H OH 2 carvon guajol dextropimaric acid

WAYS OF C5 UNITS CONDENSATION „HEAD – HEEL“

monoterpenes sesquiterpenes diterpenes

2 WAYS OF C5 UNITS CONDENSATION

6 5 7

4 8 p-menthane type 3

2 1 type: thujane camphan head-heel 2,6-dimethyloctane pinane carane

8 6 7 5 type of cantharidine 4 3 2 1

heal-heel 2,7-dimethyloctane

6 5 7 type of fenchane 4 3 2 1

heel-side 2,3,6-trimethylheptane

BASIC SUBDIVISION OF NATURAL TERPENOIDS

LABELING NUMBER OF C5 OCCURRENCE

HEMITERPENES 1 constituent of ergot alkaloids; some C5 acids

MONOTERPENES 2 volatile constituents of essential oils (geraniol, , camphor)

SESQUITERPENES 3 constituents of essential oils (farnesol, farnesen); some bitter substances (artabsin)

DITERPENES 4 constituents of essential oils, resins, balsams (for example ); vitamin A; gibberellins (phytohormones); constituent part of some alkaloids (Aconitum); phytol (building block of chlorophylls)

TRITERPENES 6 ; pentacyclic triterpenes; ; cardioactive glycosides; some bitter substances

TETRATERPENES 8 carotenoids; xanthofylls; some lipophilic plant pigments

POLYTERPENES n cautchuc (cis) gutta-percha (trans)

3 BIOGENETIC ORIGIN

H C OH 3 C HOOCH2C CH2CH2OH

(R)-mevalonic acid

BIOGENETIC ORIGIN OF IPP (1) (takes place in cytoplasma of plant cell)

CH COCH CO SCoA CoA SH 2 CH3CO SCoA 3 2 + acetylcoenzyme A acetoacetylcoenzym A

CH3CO SCoA NADP+ HMG-CoA synthase OH NADPH OH CH C CH CO H CoA SH 3 2 2 CH3 C CH2CO2H + CH CH OH HMG-CoA reduktasa 2 2 CH2CO SCoA mevalonic acid -hydroxy--methylglutaryl-CoA 3 H C ATP 3 3 4 C CH2CH2OPP H C ADP 2 3-methyl-3-butenyldiphosphate = isopentenyldiphosphate (IPP) H3C OP -CO C 2 - HOP isomerase H2C CH2CH2OPP H C 3 C 3 2 HO O C CHCH2OPP

H3C 3-methyl-2-butenyldiphosphate = 3,3-dimethylallyldiphosphate (DAPP)

4 BIOGENETIC ORIGIN OF IPP (2) (takes place in plastides)

1 CH3 2 C=O - 1 CH COO 3 2 C=O + Pyruvic acid H + H O C H 3 3 CHO H C OH 4 H 4 C OH 5 CH2OP CH OP 5 2 1-deoxy-D-xylulose-5-phosphate GAP

HO HO 2 4 2 4 1 OP 1 3 3 OP OPP O OH OH OH IPP 2-C-methyl-D-erythritol-4-phosphate 3-methyl-3-butenyl-diphosphate

Lange B.M., Croteau R.: Biochem. Biophys. 365 (1), 170-174 (1999) Isoprenoid biosynthesis via a mevalonate-independent pathway in plants: Cloning and heterologous expression of 1-deoxy-D-xylulose-5-phosphate reductoisomerase from peppermint.

POLYMERISATION REACTIONS

CH CH3 3 C CH OPP C CH OPP PPO CH H C CH 2 CH CH 2 2 + 2 2 2 H2C CH IPP + HOPP CH C H C CH C 3 3 H C CH DMPP 3 3 geranyldiphosphate

PPO CH OPP 2 CH2 CH2 = + CH OPP + 2 CH OPP 2 CH OPP IPP 2 farnesyl-PP IPP geranyldiphosphate farnesyl-PP 2x farnesyl-PP

CH2OPP

squalene geranylgeranyl-PP

5 FORMATION OF BASIC TERPENOIDS

DAPP + IPP

H - P

C10 monoterpenes GERANYL-PP (C10) H - P IPP

C15 sesquiterpenes FARNESYL-PP (C15) H - P : condenzation "head - heel" 2x P-P P - P : kondenzation " heal - heal "

C30 PP H - P squalene

IPP

C30 triterpenes

GERANYL-GERANYL-PP (C20) C19-21 steroids (IPP) (IPP)n n H - P H - P P-P C diterpenes 20 2x gutta-percha cautchuc phytol (trans) (cis) giberillines C40 carotenoids

HEMITERPENES

2 2 1 4 3 1 4 3 CH2OH CH2OH

3-methyl-2-buten-1-ol 3-methyl-3-buten-1-ol

2 O O 2 O O 3 1 4 3 1 4 CH O P O P OH CH2 O P O P OH 2 OH OH OH OH

3-methyl-2-butenyldiphosphate 3-methyl-3-butenyldiphosphate 3,3-dimethylallyldiphosphate (DAPP) isopentenyldiphosphate (IPP)

6 MONOTERPENES

CH OH OH OPP 2 + H O + H - H2O 2 CH2OH geranyl-PP geraniol citronelol ocimene linalol

+

+ -pinene +

3-carene

GERANIOL; NEROL; LINALOL

CH CH3 3 H3C OH H 6 8 5 7 OH 4 3 H OH 2 1

Geraniol Nerol Linalol

CH CH CH CH 3 3 3 3 1 H CH OH 7 5 3 7 5 3 2 8 6 4 2 8 6 4 2 CH OH H 1 2

7 BICYCLIC MONOTERPENES

camphane linear type p-menthane

pinane fenchane carane thujane

IRIDOIDS

11 4 6 5 3 7 O 8 9 1 10 Iridane Cyclopentanotetrahydropyrane

8 IRIDOIDS

CH GERANYL - PP H O CH O O citronellal iridodial

COOCH3

HO alkaloids O

O Glc loganine

HO O O RO

O O CH2OR HOH C 2 O Glc O O aucubine O Glc valepotriates gentiopikroside

SESQUITERPENES

• THE MOST WIDESPREAD GROUP OF NATURAL COMPOUNDS

• GENERAL ORIGIN IN ORIGINAL CATIONOID PRECURSORE

• BETWEEN SINLE GROUPS SHARP DISTINCTIONS

• OCCURENCE OF SOME GROUPS CHEMOTAXONOMICALLY LIMITED TO CERTAIN PLANT SPECIES

• USEABLE FOR CHEMOTAXONOMY

9 ACYCLIC SESQUITERPENES

H

2 3 CH2OH

CH3 trans-farnesol (geraniol) CH2OH

2 3 H

CH3 cis-farnesol (nerol) OH

nerolidol (linalol)

SESQUITERPENIC CARBOHYDRATES

H H

H3C CH3

-farnesene trans--farnesene cis--farnesene

10 CYCLIC SESQUITERPENES

5 8 6 8 7 4 9 5 6 7 1 2 9 2 10 4 10 3 1 3 OPP OPP trans, trans - farnesyl-PP cis, trans - farnesyl-PP

+

OPP + carbocation carbocation OPP

14

2 1 9 10 3 8 4 5 7 6 13 bisobolane humulane 15 11 germacrane guajane ( ) cadinane ( ) caryophylane 12 ( ) eudesmane

-BISABOLENE

+ - H+

x cis-farnesyldiphosphate carbocation -bisabolene

O

CH2OH -curcumene turmerone lanceol

11 SESQUITERPENIC LACTONES (Asteraceae)

- H+ HO+ O + precursor

O

oxidation - H+

+ COOH CH2OH CH2OH

OH cyclization O C COOH O

OH

HO H O O O O O O artemisine santonine artabsine O O

ANTIFEEDANTS

Sesquiterpenic dialdehyde COH Plants of Polygonaceae, COH Canellaceae, Winteraceae families

H Mollusces (class Arthropoda) Polygodial Only once the fish try to eat…

12 DITERPENES

+C +C CH 5 5 CH2 2 CH2 OPP OPP OPP

CH2OPP

geranylgeranyldiphosphate

OH

geranyllinalol part of jasmine essential oil

DITERPENS

H3C CH2CH3

CH N CH3 H2C N Mg N

CO H3C N H H3C H COOCH3 H

CH2CH2 COO

chlorofyll a phytol

CH3

H3C O

HO -tocoferol (vitamin E) CH3

O

CH3

O

vitamin K1

13 BASIC TYPES OF CYCLIC DITERPENES

DITERPENES

ACYCLIC MONOCYCLIC BICYCLIC

20 20 20 13 15 12 12 11 14 11 14 12 14 16 15 19 19 13 19 18 13 15 5 11 1 18 18 4 6 9 1 9 10 2 10 8 2 10 8 7 3 5 7 3 5 7 3 2 9 4 4 6

17 8 6 1 16 17 retinol type 16 17 labdane type

TRICYCLIC TETRACYCLIC

15 15 14 14 16

pimarane type type caurane type

MONOCYCLIC DITERPENES

-caroten

CH2OH 2

vitamin A1 (retinol)

CH2OH

vitamin A2 (3-dehydroretinol)

14 BICYKLIC AND POLYCYCLIC DITERPENES

OH OH O HO O

O O O H CH marubiine picrosalvine OH N H OH H atisine

H

HO2C H HO2C H pimaric acid podocarpic acid

TRITERPENES

squalene

squalene-2,3-epoxide O

tetracyclic HO intermediate lanosterol HO cycloartenol

Animals lower and higher Fungi photosyntetizing plants

HO

cholesterol HO -sitosterol HO -amyrine

15 FORMATION OF AGLYCONS OF CARDIOACTIVE GLYCOSIDES

steroidal steroidal saponins alkaloids OH

20

HO HO cholesterol 20-hydroxycholesterol

CH2OH CH3 C O C O

OH HO O H progesterone 5-pregnan-3,14,21-triol-20-on O CH C 3 SCoA C3-unit

O O O O

OHC

OH OH HO HO OH H digitoxigenine hellebrigenine

BIOSYNTHESIS OF TETRATERPENS

geranylgeranyldiphosphate geranyllinaloydiphosphate

phytoene (3 conjugated double bonds, 1 x cis )

H

neurosporine (9 conjugated double bonds, all-trans)

(11 conjugated doubl bonds, all-trans)

-carotene

-carotene

16 TETRATERPENES

O OH

HO capsanthine

TETRATERPENES

OH 3' 6' 1' 1

3 HO Luteine (3R,3'R,6'R)-,-carotene-3,3'-diol 3,3'-dihydroxy--carotene

• Belongs to carotenoids of xanthophyll group • Contains the same chromophore as α-carotene, it is isomeric with zeaxanthine. • Yellow pigment, present together with carotene and chlorophyll in all green plant parts • Present in many yellow and red flowers and fruits, it was observed also in animals, for example in feathering, yolk, and in corpus luteum. • Can be present as free substance or as ester; it possesses no activity of vitamine A. • Luteine was firstly obtained in crystalline state 1907 by Willstätter from stinking nettle, later from chicken yolk. Structure was resolved by P. Karrer in 1951. • Protectum, Vitalux Plus 6, Ocuvite … macular defects of eye.

17 POLYTERPENES

H H C H H H3C 3 H3C H3C H

* n * cautchuc (all - cis) degree of polymerisation 20.000

CH3 CH3 CH3 CH3 * * n H H H H gutta-percha (all - trans) degree of polymerisation 2.000

18