Lecture n.

THE TERPENES part II

 use of valerian. The reactive epoxide group is likely to be responsible for 212 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition

THE TERPENES – sesquiterpenes i

H
guaiyl cation
e.g. matricin, thapsigargin
H
E 10 germacryl cation ii
e.g. parthenolide
E
he termi- OPP
one and geranyl PP E,E-farnesyl cation
11 eudesmyl cation
e.g. α-santonin

olved in E1 humulyl cation

e.g. humulene
for the E

thesized caryophyllyl cation

her than OPP ≡
e.g. caryophyllene
W–M

GPP in allylic cation HR H S E 1,3-hydride

shift
electrophilic addition
ure 5.9) giving tertiary cation
H

farnesyl nerolidyl cation bisabolyl cation amorphyl cation

e.g. bisabolene, α-bisabolol e.g. artemisinic acid
n initial OPP a

ost from
6

HR HS
t lost in E1 stereospecific E
a

7
loss of proton a carotyl cation
W–M
Z b 1,3-hydride
esquiter- b
shift
10
d an ad- OPP E,Z-farnesyl cation
H
farnesyl PP
clization (FPP) 11
b
cis-germacryl cation cadinyl cation
e.g. α-cadinene
bi-, and E1: farnesyl diphosphate synthase
own nat-
n natural Figure 5.29 n n = ring size generated

cis-humulyl cation

Figure 5.31
 O hydrolysis of ring expansion, and Dai valori di distribuzione dimensionale dei
primi lotti, sembrerebbe che la composizio- photooxidation
.5 (continued) H hemiketal H quenching of carbocation
ne lipidica influenziH direttamente le dimen- to hydroperoxide H
THE TERPENES – sesquiterpenes HO
Cananga odorata
sioni particellari: i lotti SLN 2YY e SLN 4YY,

H2O
Tab 4 -Tabella riassuntiva dei risultati ottenuti dall’analisi elementare GC-MS
aventi composizione lipidica identica, pre- dell’olio essenziale di Ylang Ylang.
OTempi
an chamomile is usually taken as an aqueous infusion (chamomile tea) to aid digestion, curb flatulence, etc., but extracts
The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 213
sentano dimensioni inferiori rispetto ai lotti 2/hν di Indice Indice Attribuzione Quantità %
ture in mouthwashes, shampoos, and many pharmaceutical preparations. It has mild antiseptic and anti-inflammatory rimanenti. Conseguentemente si è pensato Ritenzione di Ritenzione di ritenzione composto incognito nell’olio

es. The flower-heads yield 0.4–1.5% of volatile oil, which contains over 75% of aliphatic esters of angelic, tiglic,
ic, and isobutyric acids (Figure 5.33), products from metabolism of the amino acids isoleucine, leucine, and valine (see O (ylang ylang) di modificare il metodo di produzione delle
nanoparticelle solide lipidiche allo scopo di
O
(min)
5,06
calcolato
935
tabulato
939 alfa pinene 0,01
H H
H
O H H ottenere una buona distribuzione dimensio- limonene H
– H+
6, 79, 316), with small amounts of monoterpenes and sesquiterpenes. – H+ H nale. La fase lipidica del lotto, su cui sono
7,19 1030
O 1168O
1029
Hacetato di benzile
0,08

HO state effettuate tutte le modifiche, è costitu-

HO C
10,75 1162 0,13

E1 HO
H 2C OH HO2C 2 e Crovol Maracuja 1:1
ita da Cetyl Palmitate 13,09 1258 HO
1257 Clinalil acetato
2
0,08

O v/v (tab. 3). I risultati migliori sono stati ot- 15,25 1342 1338 elemene delta 0,10

11-carbon ring of the humulyl carbocation Another type of decalin-containing sesquiterpene dihydroartemisinic acid
tenuti con i lotti SLN 12YY e SLN 13YY, pro-
dotti utilizzando l’Ultraturrax per 3 minuti;
15,56
dihydroartemisinic
1354 1351 alfa cubebene
acid 0,15

5.31) may be retained, of is cation

as in the formationbisabolyl seen in the structures of cadinenes and amorpha-
γ-bisabolene air oxidation to hydroperoxide
16,13 1376 1375 alfa ylangene 0,08

lene (Figure
(–)-β-bisabolene
214 5.37),
Medicinal Natural +to
or modified Products:
give theA Biosynthetic Approach. (Figure
4,11-diene. α-Cadinene 3rd Edition
5.38) is one of the many
O2 hydroperoxide
(–)-α-bisabolol oxide B
la fase lipofila del lotto SLN 12YY è costituita
da Cetyl Palmitate/Tegosoft MM 1/1, mentre
16,25 1381 1377 copaene alfa 1,44
–H b la fase lipofila del lotto SLN 13YY è formata 16,36 1385 1381 geranil acetato 0,68
yllyl cation containing a nine-membered ring E1terpenoids H2O found in juniper berries (Juniperus communis;
OH formation of da Cetyl Plamitate/Crodamazon Castanha do 16,59 1395 1388 beta cubebene 0,19
a four-membered ring, as in β-caryophyllene Cupressaceae) used in making gin, and this compound is
hemiacetal, Brasil 1/1. Le dimensioni particellari di que- 16,63 1396 1391 beta elemene 0,57
5.37). Humulene
H H OH H OH
Box 5.4is found in hops (Humulus derived from the 10-carbon ring-containing cis-germacryl O H
hemiketal sti ultimi lotti sono molto inferiori rispetto ai 17,36 1426 1419 trans cariofillene 6,15
a HO H then lactone H
lotti precedenti e che il valore di uniformità
Cannabaceae), and β-caryophyllene is found in a cation. The double bonds in the b
cis-germacryl cation formation è addirittura inferiore a 1.
17,57 1435 1434 beta gurjunene 0,39
Feverfew
of plants, e.g. in the oils from cloves (Syzygium are unfavourably placed for a cyclization reaction, O O 17,92 1449 1446 trans cinnamyl acetato 0,70
a Analisi chimica dell’olio essenziale di 18,05 1455 1451 trans isoeugenolo 0,11
um; Myrtaceae) and cinnamon (Cinnamomum as observed with the germacryl Ocation, and available HOO
(–)-α-bisabolol oxide A
evidence points to an initial 1,3-shift of hydride to the difficulties. The plant is a O O
Ylang Ylang 18,09 1456 1454 muurola-3,5-diene trans 0,53
Feverfew is a traditional herbal remedy for
um; Lauraceae). the relief of arthritis, migraine, toothache, and menstrual HO O
Lo Spettrometro di Massa costituisce un 18,18 1460 1455 humulene alfa 2,32
(–)-α-bisabolene
perennial, (–)-α-bisabolol
strongly aromatic herb of the E1: γ-bisabolene
Compositae/Asteraceae family, and has been classified synthase
variously as Tanacetum parthenium
valido rivelatore per tecniche analitiche
18,40 1469 1467 Muurola-4(14),5-diene cis 0,25
(FPP is substrate) H H H
strumentali di separazione quali la gas- the conversion of dihydroartemisinic
(which is currently favoured), Chrysanthemum parthenium, Leucanthemum parthenium, or Pyrethrum O parthenium. Studies have O O
cromatografia, la cromatografia liquida e 18,64
acid 18,73
1479
into artemisinin
1477 Cadina-1(6),4-diene trans 0,18
1483 1480is thought
muurolene gamma to 1,59
confirmed that feverfew is an effective prophylactic – H+ for migraine in about 70% of sufferers. It reduces the frequency
treatment HO2C l’elettroforesi capillare. I suoi pregi sono
Figure 5.32 HO2C soprattutto la sensibilità e la capacità di
be a 18,88
non-enzymic
1489
autooxidation
1485 Germacrene D 21,65
and severity of attacks and the vomitingb associated with athem. The herb has been shown to inhibit blood platelet aggregation,
≡ identificare i composti chimici anche in as- 19,26 1500 1500 Muurolene alfa 1,00
the release of 5-hydroxytryptamine (5-HT, serotonin) fromE1platelets, the release of histamine from mast cells, and the production O
senza di standard, in particolare quando il
a HOf a range of sesquiterpene lactones of the germacrane and guianane groups
19,43 1508 1506 Farnesene alfa 19,66
metodo di ionizzazione del campione è del
of prostaglandins, thromboxanes, and leukotrienes.
E1: amorpha-4,11-diene synthase artemisinin
tipo a impatto elettronico (EIMS). In que- 19,61 1516 1514 Cadinene gamma 1,07
characterized
humulylincation
the leaf material, the principal constituent
1% in driedHleaves). The powerful
O
and major active component is parthenolide
H pungent odour of the plant arises α-humulene
from the volatile (FPP is
HO oil constituents, substrate)
of which the monoterpene
Artemisia annua
(Figure 5.34) (up to about sto caso la gascromatografia, accoppiata
(qinghaosu)
alla spettrometria di massa (GC-MS), è una
19,82
20,03
1526
1535
1523
1535
Cadinenedelta
Cadina-1(2),4-diene trans
3,85
0,22
E2 b O tecnica analitica particolarmente efficace
camphor (Figure 5.14) is a major constituent. Feverfew may be taken
O E2: eaten
as the fresh leaf, often CYPwithsesquiterpene
bread in the formoxidase
of nell’analisi delle sostanze volatili in miscele
20,15
20,63
1541
1563
1539
1561
Cadinene alfa
Germacrene B
0,28
0,08
a sandwich to minimize the bitter taste, or it can be obtained in commercial dosage forms as tablets or capsules of the dried complesse, a causa della elevata risoluzione
O 21,53 1600 1601 Guaiol 0,13
– H+
powdered leaf. The parthenolide content of dried leaf deteriorates O on storage, and many commercial preparations of feverfew cromatografica delle colonne capillari e del-
la considerevole riproducibilità degli spettri 21,92 1619 1619 Cubenol-1,10-di-epi 0,16
have been shown to contain little H parthenolide, or to O
E2
Figure 5.39
O
be well below the stated content. This
O may be a consequenceO of complexation di frammentazione EIMS. L’ingrediente scel- 22,21 1633 1629 Cubenol-1-epi 0,40
withα-humulene
plant thiols via Michael addition. Consumers of fresh leaf can be troubled O
H by sore mouth or mouth ulcers, caused by the to in questo specifico progetto è l’olio essen-
(–)-zingiberene (–)−β-sesqui- O 22,52 1647 1642 Muurololo-epi-alfa 0,87
O e.g. contact α-santonin
E1: synthase H ziale di Ylang Ylang e l’obiettivo principale è
sesquiterpenes.
E2: β-caryophylleneParthenolide is also known to be capable of causing some allergic
synthase phellandrene effects,
parthenin dermatitis. The proposed stato quello di quantificare, tramite GC-MS,
22,60 1651 1646 Muurolol alfa 0,67
(FPP is substrate
mechanism of for both of
action enzymes)
parthenolide via O
O alkylation of thiol groups in proteins is shown in Figure 5.35. la percentuale di incapsulazione nelle na- 22,80 1661 1654 Cadinol alfa 2,67
O caryophyllyl cationelephantopin β-caryophyllene noparticelle solide lipidiche di ogni singolo 24,15 1726 1725 Farnesolo-2E,6E 2,10

O H O isopropyl side-chain to generate a new cation, and thus followed by transformation into artemisinin
componente dell’olio essenziale, e non la
25,13 1772 1760 by
percentuale di incapsulazione dell’olio “in
a disequence
Benzoato benzile 11,02

.37 O O2 CO2H CO2H 26,60 1846 1847 Farnesil Acetato-2E,6E 9,14

– H+ NADPH allowingNADP cyclization
+ to the cadinyl cation (Figure 5.31). of reactions that is currently 27,23 regarded
1877 as non-enzymic,
toto”. Per queste ragioni, l’olio essenziale di
1866
Ylang Ylang è stato sottoposto ad analisi chi-
Salicilato di benzile 7,90
O O O angelic acid tiglic acid % totale 98,61
E1 OH
HOH E2 H
δ-Cadinene E3 is an alternative deprotonation product; it is and broughtTheabout byandan
Mevalonate oxygen-mediated
mica qualitativa e quantitativa percentuale
Methylerythritol photochem-
Phosphate Pathways: Terpenoids and Steroids 22
−H +
O −H +
further
CHCO2OH2 Helaborated to gossypol
CHO in cotton (see page 220). ical oxidation
Kosmetica marzo under
2012 conditions that might normally be 55
germacryl cation (+)-germacrene A CO2H
H
E1
thapsigargin
O
H H
Amorpha-4,11-diene
sequential
of alcohol
isovaleric
oxidation
acid to acidisobutyric
E3 acidNADP+ (Figure 5.39) is structurally re-
Box 5.7 (continued)
present in the plant. An intermediate in this process, also
Figure δ-cadinene
5.33
lated to the O2 cadinenes, but the different stereochemistry found naturally in OHC
A. annua,
OH
is the hydroperoxide
KOS_2012_002_INT@052-057.indd 55

HO CHO
of dihy- 14/02/12 15.35

cadinyl cation − H2O

α-cadinene NADPH
of ring fusion and the position of the second double bond droartemisinic acid. The further HO OH modifications
HO postulated
OH
E1: δ-cadinene synthase E4 E4
biological Oactivity;PPindeed,
(FPP or nerolidyl
O is substrate) O
is a consequence
activity is typically lost if agents may irreversibly
OH CO2H
alkylate critical enzymes of athat
CO2H
different cyclization mechanism HO in Figure 5.39 include ring expansion by cleavage of this OH
either the double bond or the carbonyl group is chemi- lactone control cell division, whilst allergenic compounds may
.38 cally reduced.
O
In some structures, additional
parthenolide
O formation operating
electrophilic conjugate with proteins to form to produce
antigens the initial Gossypium
which trigger barbadense
decalin ring system. In hydroperoxide
HO CHO
OH
and a second oxygen-mediated hydroper- HO
(+)-costunolide OHC OH
centres offer further scope for alkylation reactions. In the allergic response. thisThe case, a six-membered
beneficial effects of partheno- ring is formed first to give the oxidation. The 1,2,4-trioxane system in artemisinin
(+)-gossypol (–)-gossypol can
parthenolide (Figure A5.35),
E1: (+)- germacrene an electrophilic
synthase epoxideA hydroxylase
E2: (+)-germacrene lide and structurally related compounds
E4: (+)-costunolide synthase in feverfew
group(FPP
is isalso
substrate for E1)
present, E3: dehydrogenase
allowing transannular bisabolyl
cyclization have been demonstrated cation;
to relate to alkylationagain,
of thiola 1,3-hydride shift is implicated be viewed more simply as a combination of hemiketal,
Figure 5.43
and generation of a second alkylation site. Cytotoxic groups.
Figure 5.34 prior to forming the decalin system of the amorphyl cation hemiacetal, and lactone functions, and the later stages of
 (GGPP), which is formed by addition of a further
s are by no means restricted to this cyclization by
proton lost in alkene formation is
IPP molecule to FPP in the electrophilic
same manner as described used to protonate another double
tae/Asteraceae undoubtedly provides
THE TERPENES – diterpenes addition electrophilic
protonation additionbond gives tertiary
of double bond and give tertiary cation
for the lower terpenoids (Figure 5.46).
giving tertiary cationOne of the tertiary
giving
carbocation; thiscation
allows a series
H of concerted
E
cyclizations terminating in proton loss
E
H H H
H H OPP
E E1 a
OPP OPP E1 ≡ H
farnesyl PP OPP OPP
(FPP) GGPP verticillyl cation H
electrophilic
GGPP H cyclization (–)-copalyl PP
E1 OH OH
10 O 18
10 acetyl-
OH 11 9 O2 CoA O2
12 16
19 OPP
NADPH NADPH – H+ OPP OPP
HO 13 15 H
OPP H 14
17
3
8 7
6
b ≡ H
allylic cation IPP E4 E3 E2 4 5
E1
1 2
HO several steps; HH H E2 H
Oelectrophilic addition H H H H
O O hydroxylations H OAc 5 a-hydroxylation H H
gives
AcO tertiary cation 20 via allylic radical;
and esterifications
232 Medicinal Natural5 Products: A Biosynthetic Approach. 3rd Edition
taxadien- GGPP a-acetylation; taxadiene taxenyl cation (+)-copalyl PP
5α-acetoxy-10β-ol 10b-hydroxylation (labdadienyl PP)
10-deacetyl- E1: (−)-copalyl diphosphate synthase (ent-kaurene synthase A)
OPP baccatin III Box E2:
5.10(+)-copalyl
(continued)
diphosphate synthase (part of bifunctional abietadiene synthase)
HR HS postulated oxetane ring formation:
stereospecific
E1 loss of proton
acetyl-CoA E5 Figure 5.51
5
O OAc O
β-phenylalanoyl-CoA E6 further O
O O
esterifications O AcO O
plus side-chain HO O O O O
OOPP
2, NADPH E7 R2 O CHHO
3
hydroxylation H O
geranylgeranyl PP
benzoyl-CoA E8
(GGPP) O O O OH ≡
AcO O O OH OH
O R3 Gingko biloba
E1: geranylgeranyl diphosphate synthase O O H
R1 O H O
O
O
O HO bilobalide
O OH
O 1
R2 O HR3
O NH O
OH Ph NH OR O OH
2′ ginkgolide A OH H O
H
O Ph O Ph AcO
H HO O
H ginkgolide B OH OH H R
OH OH paclitaxel
HO ginkgolide C OH (taxol) OH
OH
O O O O OH
Taxus brevifolia ginkgolide J OH H OH OH O
O phenylalanine aminomutase reaction:
ginkgolide M H OH OH NH2 R = H, kaempferol
paclitaxel R = OH, quercetin
(taxol) CO2H CO2H
Although many examples of this group of natural ter-
TRITERPENES (C30 )
THE TERPENES – sesterpenes
penoids are now known, they are found principally in
fungi and marine organisms, and span relatively few struc- Triterpenes are not formed by an extension of the now
tural types. The origins of ophiobolene and ophiobolin familiar process of adding IPP to the growing chain. In-
A (Figure 5.58) from cyclization of geranylfarnesyl PP stead, two molecules of FPP are joined tail-to-tail to yield

W–M 1,5-hydride shift generates allylic cation;

concerted cyclizations cyclization onto this cation follows;
initiated by allylic cation the cation is eventually quenched by water
H
H

OPP H2O O
geranylfarnesyl PP
H H
(GFPP) Helminthosporium maydis
H H
OHC O O H
H H O
O
O
H H
HO HO ophiobolene
ophiobolin A (ophiobolin F)

Figure 5.58

Sesterpenes are a rareOPPclass of isoprenoids.

HO They are produced mainly by fungi and marine
AcO O
H
organisms, but some exemples in plant kingdom O also exist.
H

H H
THE TERPENES – triterpenes OGly2
HO
squalene H 20
H

E1 O2, FAD sequence of W–M 1,2-hydride

NADPH H+
and 1,2-methyl shifts 3 H
The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 235 Gly1O HO
H
H H H H ginsenoside
FPP (panaxoside)
cyclizations H
1′ 3′ Gly1 Gly2
E1 * 2′
PPO ≡ β1→2 β1→6 b
w
FPP 3 H H ginsenoside Rb1 Glc–Glc– –Glc–Glc
1 2 b
* HO HO β1→2 β1→6 e
O H H ginsenoside Rb2 Glc–Glc– –Ara–Glc H
electrophilic addition (pyranose)
allylic cation giving tertiary cation (3S)-2,3-oxidosqualene protosteryl cation protosteryl cation C
β1→2 β1→6
(squalene oxide) ginsenoside Rc Glc–Glc– –Ara–Glc
OPP animals plants (furanose)
H H * fungi β1→2
ginsenoside Rd Glc–Glc– Glc
*
loss of proton with formation loss of proton loss of proton leads
of cyclopropane ring gives alkene H to cyclopropane H OGly2
HO
H H 20
H
loss of diphosphate E1: squalene epoxidase
H * OPP gives primary cation * H
H+
HO HO H
* * H H HO 6 HO
H
H H 1,3-alkyl shift generates lanosterol cycloartenol OGly1
presqualene PP W–M new cyclopropane ring 244 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition ginsenoside
1,3-alkyl and more favourable (panaxoside)
Figure
shift 5.61 tertiary cation Panax ginseng Gly1 Gly2

* * H Box 5.11 (continued) β1→2

cation quenched by
attack of hydride
(NADPH) H
NADPH
E1: squalene synthase
Figure 5.60
ginsenoside Re Rha–Glc– Glc
* * protonation of epoxide electrophilic addition electrophilic addition β1→2
allows ring opening to gives tertiary cation CO2Hcation
gives tertiary
H ginsenoside Rf Glc–Glc– H
H tertiary cation + 6-membered ring + 6-membered ring
ginsenoside Rg1 Glc Glc
bond cleavage produces alkene CO2
and favourable allylic cation O β1→2
E1 D-glucuronic acid H ginsenoside Rg2 Rha–Glc– H
CO2H O
O H
H H HO H
HO O H
* H O
HO CO2H HO HO H
* O O H H
HO 2Na
O O2C O
2,3-oxidosqualene HO H Figure 5.72
squalene H OH β1→2
electrophilic addition
gives tertiary cation
D-glucuronic acid glycyrrhetic acid carbenoxolone sodium
+ 5-membered ring
Glycyrrhiza glabra electrophilic addition
glycyrrhizic acid
W–M rearrangement;
H
H gives tertiary cation ring expansion at expense of
Figure 5.70 tertiary → secondary cation H
 THE TERPENES – triterpenes
238 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition
cyclization is initiated by
protonation of double bond
to give tertiary cation

H H H squalene
O E1 E2
HO H
E1
E2 H
chair – boat – chair – boat H
2,3-oxidosqualene

H H
2 10 9
1

HO 3 HO
4 6 7 H H
5 8
H H
H sequence of W–M H
protosteryl cation 1,2-hydride and
1,2-methyl shifts hopanyl cation
E1 sequence of W–M
1,2-hydride and E2
1,2-methyl shifts E1 E1
H H OH
H H H
H H H H H H H H H
2 1 10 9
252 Medicinal Natural
OH Products: A Biosynthetic Approach. 3rd Edition
HO 3 H H
4 6 7 H
HO H 5 8
H the side-chain, attached at C-24. These substituent car- side-chain, a trans-!22 double bond, a feature seen i
H
protosteryl cation
H Hbon atoms are numbered 241 andH242 (Figure 5.74); some H sterols, but
many plant ≡ never in mammalian
H ones. The in
cyclopropane ring E1 older publications may use 28 and 29. The widespread HO troduction of methyl and ethyl groups at C-24 generates
formation and loss of loss of H-9 creates H H H H
double bond E2 hopan-22-ol
plant hopene
sterols campesterol and sitosterol (Figure 5.81) are tetrahymanol
new chiral centre, and the 24-alkyl groups in campestero
proton from C-10 methyl (diplopterol)
H H respectively 24-methyl and 24-ethyl analogues of choles- sitosterol, and stigmasterol are designated α. The predom
E1: squalene:hopene cyclase
terol. Stigmasterol contains additional unsaturation in the inant sterol found in fungi is ergosterol (Figure 5.81)
H E2: squalene:tetrahymanol cyclase
HO H HO H 242
Figure 5.68 241
H H 22 H H E
≡ ≡
24 24
S R
H H Alicyclobacillus acidocaldarius (Figure 5.68). On which, even at low concentrations, produce a frothin
the other hand, tetrahymanol H from the protozoan inH aqueous solution, because theyH have surfactant and
H The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 249
Tetrahymena pyriformis,H because H of its symmetry, H soap-like H properties. The nameH comes H
from the Lati
might appearHOto have a 3-hydroxyl group, HO but this sapo, meaning soap, HO
and plant materials containin
HO HO is derived from water and not
stigmasterol
H molecular oxygen, as saponins
sitosterol
H were originally used for cleansing
fucosterol clothes, e.g
H H would be the case if oxidosqualene were involved. soapwort (Saponaria officinalis; Caryophyllaceae) and
cycloartenol lanosterol H H
As in formation of 9the 8 protosteryl
14
cation (page 237), quillaia or soapbark (Quillaja saponaria; Rosaceae)
E1: oxidosqualene:cycloartenol cyclase (cycloartenol synthase) H H Markovnikov additions followed by Wagner–Meerwein These materials also cause haemolysis, lysing re
4 H
E2: oxidosqualene:lanosterol cyclase (lanosterol synthase) HO 5
6
ring expansions
HO (rather than anti-Markovnikov
HO additions) blood cells by increasing the permeability of th
H H
cholesterol may occur during thelanosterol
cyclization
H H mechanisms shown in plasma
H
cycloartenol H membrane, and thus they are highly toxic whe
Figure 5.63 Figure 5.68. HO HO injected into the bloodstream. Some saponin-containin
Figure 5.75 ergosterol campesterol
 terol. Stigmasterol
respectively contains
24-methyl and additional
24-ethyl unsaturation
analogues in thesitosterol, and stigmasterol are designated α. The predom-
of choles-
terol. Stigmasterol contains additional unsaturation in the inant sterol found in fungi is ergosterol (Figure 5.81),
THE TERPENES – triterpenes
266 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition 22
241
242H
242

H E
24 24
241
22
24
HS 24
R
H E
O S R
H H H
O 24
O O HH HH H
23 H H H H
21 23
21
22 HO HO HO
20 20 22 H H H H H H
stigmasterol sitosterol fucosterol
17 17 HO HO HO
stigmasterol sitosterol fucosterol
H 14 OHC H 14

10
3 H OH 3 5 H OH H
HO HO O H H HH H
H OH O
H HO HO
digitoxigenin hellebrigenin H H H H
ergosterol campesterol
cardenolide bufadienolide HO HO
OH H
Figure 5.81 ergosterol campesterol
H
Characteristic features of cardiac glycosides:
• cis-fused A/B and C/D rings H Figure 5.81
• 14β-hydroxyl HO electrophilic addition; W–M 1,2-hydride shift
Ad
digitoxigenin Ad C-methylation using SAM
• unsaturated lactone at C-17β followed by loss of proton Me S
272 Medicinal Natural Products: A Biosynthetic Approach. 3rd Edition Me S H
• sugar residues on 3β-hydroxyl electrophilic addition; 1
24W–M 1,2-hydride shift
AdR
Ad RC-methylation using SAM Me S second electrophilic
followed by loss of proton
Me S 26 H 241 R addition involving
Figure 5.98 Box 5.18 (continued) 24
R 25 SAM
E1 H second electrophilic
26
27 E1 addition involving
e.g. 24
lanosterol, cycloartenol
25 SAM
O O
E1 H E1 E3
created at this stage. An intermediate malonate ester is and d-cymarose; Figure 5.101). In plants, cardiac 27
allylic NADPH
OH E2
involved, and ring formation probably occurs via the glycosides are confined to the angiosperms, but are e.g. lanosterol, cycloartenol H isomerization
E3 NADPH
aldol addition process shown in Figure 5.100 to give O
found in both monocotyledons andH dicotyledons. The E2
allylic
NADPH
R1O isomerization
the cardenolide digitoxigenin, the carboxyl carbon of Ocardenolides O are more common, and H
the
OH
plant families H
O
the malonate ester being lost by decarboxylation OR O
during the Apocynaceae (e.g. Strophanthus), Liliaceae (e.g. E2 E3
2
O NADPH
OH H e.g. fucosterol e.g. campesterol
the process (compare the role of malonate in the acetate Convallaria), andOHScrophulariaceae (e.g. Digitalis) yield
R1 = R2 = H, digoxin allylic E2 E3
pathway). Digitoxigenin is the precursor of digoxigenin 1medicinal agents [Box 5.18]. The rarer bufadienolides are E3 NADPH dehydrogenation E4 O2
R = Me, R2 = H, medigoxin (metildigoxin) isomerization
e.g. fucosterol NADPH
e.g. campesterol
and gitoxigenin by specific hydroxylations (Figure 5.99). R1found = Glc, R2in some
= Ac, members
lanatoside C of the Liliaceae (e.g. Urginea) dehydrogenation
5.18] and Ranunculaceae (e.g. Helleborus),allylic
1 = Glc, R2 = H, deslanoside (desacetyl-lanatoside C)
Oxaloacetate is the source of the extra carbon atoms R [Box as NADPH dehydrogenation E4 O2
isomerization E3 O2
NADPH
22 22 NADPH
in bufadienolides; a similar esterification/aldol reaction well as in toads. Monarch butterflies and their larvae NADPH
dehydrogenation
Figure 5.105
sequence may be proposed (Figure 5.100). This would are known to accumulate in their bodies a range of
a The
produce bufalin (Figure 5.99), those
bufadienolide
Digitalis
total cardenolide content ofpurpurea
structure up to 1% is two to three times that found in D. purpurea. The main constituents resemble
cardenolides which they ingest from their food plant, the NADPH
E3 O2 E4
NADPH
22 22
of D. purpurea, but contain an acetyl ester function on the third digitoxose, that furthest from the aglycone. This acetyl e.g. sitosterol e.g. stigmasterol e.g. ergosterol
found in the skin of toad (Bufo spp.),
group makes from which easier
the compounds common
this to isolate from themilkweed
plant material(Asclepias more Asclepiadaceae).
syriaca;
and they crystallize readily. Drying of the leaf is E3 E4
similarly accompanied
class of compound was originally isolated byand somehaspartial hydrolysis
This makes of the original
themfreshunpalatable
leaf constituents to
through enzymic action,
predators suchandas both E1:
the sterol C-24 methyltransferase E3: ∆24 sterol reductase
terminal glucose and the acetyl group may be hydrolysed off, extending the range of compounds isolated. The D. lanata cardiac e.g. sitosterol
E2: 24-methylenesterol C-methyltransferase e.g. stigmasterol e.g. ergosterol
subsequently taken the generalglycosides
name. are Note birds. Endogenous compounds have and E4 sterol C-22 desaturase
based that,
on five in the digitoxigenin,
aglycones: Digitalis-like
gitoxigenin and gitaloxigenin, as found in D. purpurea, plus digoxigenin
subsequent formation of hellebrigenin (Figure
diginatigenin (Figure which do notalso
5.103),5.99), occur been detected,
in D. purpurea. albeitglycosides
The primary in very smallthe quantities,
containing in
E1: sterol C-24 methyltransferase
acetylated tetrasaccharide E3: ∆24 sterol reductase
unit glucose–acetyldigitoxose–(digitoxose)2 – are called lanatosides. Lanatosides A and C (Figure 5.103) constituteFigure the
E2:major5.82
24-methylenesterol C-methyltransferase
hydroxylation at C-5 occurs with the expected retention mammalian tissues. Ouabain (see below, Figure 5.106),
components in the fresh leaf (about 50–70%) and are based on the aglycones digitoxigenin and digoxigenin respectively.
E4 sterol C-22 desaturase
 estriol
(oestriol)
Characteristic features of oestrogens:
THE TERPENES – hormones
The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 279
• C18 estrane skeleton
The Mevalonate and Methylerythritol Phosphate Pathways: Terpenoids and Steroids 279 • aromatic A ring (consequently no methyl at C-10)
21
17α-hydroxylation
• no side-chain
O O O
21
17 OH 5.131
Figure
O O 17α-hydroxylation O
H O2 H H O2 H
NADPH NAD+ 17 NADPH OH
H O2 H H H H H H O2 H H H H H
E1 NAD+ E2 E3 oxidative removal of
HO NADPH HO O NADPH
O
O 17a-hydroxylation O
side-chain (Figure 5.133) O
H H H H
E1 cholesterol H H
E2pregnenolone progesterone
E3 H H17a-hydroxyprogesterone 17 OH
HO HO side-chain degradation via O O H O2 H O2 H
cholesterol 20,22-dihydroxycholesterol
pregnenolone progesterone O2 17a-hydroxyprogesterone O2 NADPH NADPH
(see Figure 5.99) NADPH E4 21-hydroxylation E4 NADPH
side-chain degradation via H H H H H H
20,22-dihydroxycholesterol O2 OH O2 OH E1 E2
E1: cholesterol
(see Figure 5.99) monooxygenase (side-chain cleaving) NADPH E4 21-hydroxylation E4 NADPH HO E3 HO E3 HO
E2: ∆5-3β-hydroxysteroid dehydrogenase O O pregnenolone 17α-hydroxypregnenolone dehydroepiandrosterone
5-∆4 -isomerase OH OH
/3-oxosteroid ∆ OH oxidation of 3-hydroxyl
E1: cholesterol monooxygenase (side-chain cleaving) 11 11
E3: steroid 17α-hydroxylase
E2: ∆5-3β-hydroxysteroid dehydrogenase O H O H NAD+ E4 and tautomerism to
(steroid 17α-monooxygenase) conjugated system
/3-oxosteroid ∆5-∆4E4:
-isomerase
steroid 21-hydroxylase OH sequential oxidation of
E3: steroid 17α-hydroxylase(steroid 21-monooxygenase) 11 H H 11 H H O C-10 methyl to aldehyde O O
H H
(steroid 17α-monooxygenase)
E5: steroid 11β-hydroxylase O O
E4: steroid 21-hydroxylase (steroid 11β-monooxygenase) O HO O2
H H 11-deoxycorticosterone H H 11-deoxycortisol H O2 H H
(steroid 21-monooxygenase)
E6: corticosterone 18-hydroxylase NADPH NADPH
E5: steroid 11β-hydroxylase(corticosterone 18-monooxygenase) O O2 O O2
E5 11b-hydroxylation E5 H H H H H H
(steroid 11β-monooxygenase) 11-deoxycorticosteroneNADPH 11-deoxycortisol NADPH E5 E5
E6: corticosterone 18-hydroxylase OH OH O
OH O O
(corticosterone 18-monooxygenase) O2 O2 androstenedione
NADPH E5 11b-hydroxylation E5 oxidative loss of C-10
O sequential oxidation 18 O NADPH O O2
OHC of 18-methyl E5 formyl and aromatization
OH HO OH HO OH HO OH NADPH NADH/ E6
O2 of ring A (Figure 5.134) NADPH
H NADPH H H
O sequential oxidation 18 O O O OH OH
OHC of 18-methyl
HO H H HO H H HO OH H H
O2 E6
H H O H H O2 H
O NADPH H O
NAD(P)H NADPH
aldosterone corticosterone hydrocortisone
H H E6 H H H H (cortisol) H H H H H H
E6 E5
O O O HO HO O
Figure 5.112
aldosterone corticosterone hydrocortisone estrone estradiol testosterone
(cortisol) (oestrone) (oestradiol)

E1: steroid 17α-hydroxylase E4: ∆5-3β-hydroxysteroid dehydrogenase

Figure 5.112 OH OH
E2: steroid C-17/C-20 lyase /3-oxosteroid ∆5-∆4-isomerase
O O E3: steroid 17α-hydroxylase-17,20-lyase (CPY17) (bifunctional) E5: cytochrome P-450 aromatase (P450arom; CPY19)
OH OH E6: 17β-hydroxysteroid dehydrogenase
O HO
OH E1 OH
H H
O
NADPH
O Figure 5.132
O OH H H HO + OH H H
E1 NAD
H O HO
NADPH E2
cortisone hydrocortisone
H H H H (cortisol)
E1: 11β-hydroxysteroid +
dehydrogenase 1
NAD
O E2: 11β-hydroxysteroid E2 O
dehydrogenase 2
cortisone hydrocortisone
THE TERPENES
300 Medicinal Natural Products: A – tetraterpenes
Biosynthetic Approach. 3rd Edition

β-carotene β-carotene
GGPP

E1
PPO
GGPP
α-carotene
α-carotene OH
electrophilic addition OH
allylic cation giving tertiary cation

OPP
H H loss of proton
HO zeaxanthin
with formation of
cyclopropane ring HO zeaxanthin OH
OH O
O
O
loss of diphosphate O HO violaxanthin
H OPP gives primary cation H OH
HO violaxanthin
OH

H H
HO lutein
prephytoene PP O
W–M 1,3-alkyl shift generates
new cyclopropane ring and HO OH
lutein
more favourable tertiary cation O
H
H OH
apart from the final proton H
loss, this sequence is exactly
analogous to that seen with HO astaxanthin
presqualene PP (Figure 5.60) H H O OH

loss of proton bond cleavage produces alkene HO astaxanthin O

generates alkene E1 and favourable allylic cation
O OH

Z O
capsanthin
OH
capsanthin
Z-phytoene (plants/fungi)
(E-phytoene in bacteria) OH O
HO fucoxanthin OAc
sequence of desaturation E2 OH
reactions; in plants and fungi, plants E3 E5 bacteria/fungi O
E4
the central double bond is also HO
isomerized Z → E fucoxanthin OAc
OH
E γ-carotene

lycopene
E1: phytoene synthase E3: ζ-carotene desaturase
E2, E5: phytoene desaturase E4: carotene isomerase γ-carotene
δ-carotene