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I. Terpenes
Many naturally occurring compounds, including fragrances, have carbon skeletons that contain n 5 carbons, where n = integer. These compounds, terpenes, are comprised of a common structural unit known as an isoprene.

H 2C CH H 2C CH2 CH 2

Realize however, that the actual compound isoprene is not present in the terpene; it only forms the characteristic structure of the carbon skeleton. This is because once the isoprene units are linked together, they can undergo a variety of chemical transformations, including reduction, hydration, cyclization, etc. What is important is the way the units are linked together. There are isoprene rules that specify the proper and necessary linkages.

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1. Isoprene Rules Although terpenes consist of C5 units, they are for historical reasons named and classified according to the number of C10 units.

# Carbons 10 15 20 30 40

Classification Monoterpene Sesquiterpene Diterpene Triterpene Tetraterpene

# Isoprenes 2 3 4

Must have 1 head-to-tail linkage 2 head-to-tail linkages 3 head-to-tail linkages

Derived from two sesquiterpenes (2 C15) Derived from two diterpenes (2 C20)

How are the two sesquiterpenes and diterpenes joined in the C30 and C40 compounds, respectively? Important: other linkages may be present, but the above rules must be obeyed in order for a compound to be classified as a terpene.

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2. Examples of Terpenes Monoterpenes (C10 = 2 isoprenes) must have one HT linkage (shown in blue). Other linkages maybe be present (shown in red).

OH

CHO

Myrcene (bayberry)

Limonene (lemon/orange)

Menthol (peppermint)

Citronella (lemon grass)

Cyclizations, oxidations, etc. can be done, but the isoprene rules are obeyed.

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Sesquiterpenes have three isoprene units and two HT linkages

Bisabolene (termite pheromone)

Turmeron (tumeric)

Caryophyllene (misc essential oils)

Diterpenes have four isoprene units and three HT linkages

OH OH Steviol (from the sweet-tasting Stevia shrub) COOH COOH

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Triterpenes are two sesquiterpenes linked TT (with 4 total HT)

OH

HO
Dammarenediol (ginseng)

Tetraterpenes are two diterpenes linked TT (with 6 total HT)

Lycopene (red colour of tomatoes)

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3. Biosynthesis of Terpenes The precursors for terpene biosynthesis are C5 units: dimethylallyl pryrophosphate and isopentenyl pyrophosphate. While the reaction occurs somewhere between SN1 and SN2, it is helpful to analyze it as though it proceeded entirely by SN1.

OPP DMA-OPP (electrophile)

Both are resonance-stabilized, but we need to add a Nu to the primary in order to link the tail

OPP

unstable E

IPP-OPP OPP E (nucleophile) Ionization forms unstable CC, but the addition of E+ forms
a much more stable tertiary, so IPP-OPP acts as a Nu instead

DMA-OPP easily loses OPP to make a stable carbocation; hence, DMA-OPP will behave as an electrophile. IPP-OPP, on the other hand, will not ionize, because it does not give a stable carbocation. Thus, IPP-OPP acts as a nucleophile.

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The reaction between the DMA-OPP and IPP-OPP is better shown as follows:

OPP

OPP

OPP OPP H new double bond is trans OPP Geranyl-OPP (C10 with one H-T link)

The C10 Geranyl-OPP (GPP) can be used to make monoterpenes, or, because the pink portion resembles DMA-OPP, it can act as an electrophile and be elongated.

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If geranyl pyrophosphate is diverted to the biosynthesis of monoterpenes, various reactions can occur. These are just some of the many possibilities:
H OPP OPP
resonance and rotation

= H2O H

Geranyl-OPP

OH

limonene

geraniol

myrcene

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If the elongation route is taken, then a maximum of C20 is achieved. The C15 and C20 products can be used to make sesqui- and diterpenes.
Geranyl-OPP Farnesyl-OPP (C15 with two H-T)

OPP OPP

OPP

OPP

Geranylgeranyl-OPP (C20 with three H-T)

OPP

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If elongation stops at C20, where do the C30 and C40 terpenes come from? They arise from the reductive dimerization of two C15 or C20 units. The reaction uses NADPH, but its mechanism still remains a mystery.
O O O O O

O P O P O O O O

Farnesyl pyrophosphate

O P O P O

NADPH

Squalene

Squalene is subsequently used for the biosynthesis of other triterpenes and steroids.

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4. Origin of DMA-OPP and IPP-OPP The branched C5 compounds used for terpenes are made from acetoacetyl thioester, an intermediate in fatty-acid biosynthesis. o Recall that this -keto thiolester is formed from the Claisen condensation between malonyl thioester and acetyl thioester. A critical reaction that initiates the biosynthesis of the C5 compounds is an aldol reaction between acetoacetyl thioester and acetyl thioester. o In the aldol, acetyl thioester is used, and not malonyl thioester, because the equilibrium constant for an aldol condensation is much more favourable (unlike the Claisen condensation). o This reaction forms a branched C6 compound, a -hydroxy dithioester, where the beginnings of an isoprene skeleton are recognizable.
O CH3 O + O CH3 C SR
H

O SR

OH
N

C CH2 C SR

CH3

C CH2 C SR O CH2 C SR
T

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If we compare the aldol condensation product to IPP-OPP, we can predict the reactions that need to occur.
H

OH
N

CH3

C CH2 C SR O CH2 C SR
T

IPP-OPP CH3 C CH2 CH2 CH2 OPP

o The extra C attached to one of the heads needs to be lost. o The tail needs to be reduced to an alcohol, and then phosphorylated. o The OH on the neck needs to be removed. o A double bond between the neck and a head needs to be formed. The intermediate relating the aldol condensation product and IPP-OPP is a compound called mevalonic acid.

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First, one of the thioesters is hydrolyzed by an enzyme to a carboxylic acid. The starting material is achiral, but the product is chiral. However, the enzyme ensures that only one stereoisomer is formed. A couple of enzyme-catalyzed reductions then take us to mevalonic acid.
OH CH3 O H2O CH3 OH C CH2 COO * O CH2 C SR NADH OH CH3 C CH2 COO NADH CH3 OH C CH2 COO CH2 CHO

C CH2 C SR O CH2 C SR

CH2 CH2OH Mevalonic acid

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The primary alcohol of mevalonic acid is then phosphorylated twice, to give a pyrophosphate. The alcohol on the neck is also phosphorylated. Why phosphorylate the neck OH? Instead of a -keto group, a -phosphate leaving group accepts the electrons generated during the decarboxylation reaction.
OH O P O OH CH3 C CH2 COO CH2 CH2OH 3 ATP 3 ADP O CH3 O C CH2 C O CH2 CH2 OPP

OPP Isopentenyl pyrophosphate

CH3

C CH2 CH2 CH2 OPP

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The biosynthesized IPP-OPP can then be converted to DMA-OPP by an isomerization reaction.

H OPP Isopentenyl pyrophosphate OPP H OPP Dimethylallyl pyrophosphate

As we have seen, in the biosynthesis of terpenes, IPP-OPP DMA-OPP And the reaction joins them together in a head-to-tail manner. Try and see if you can determine how many ATP and NADH are required to synthesize IPP-OPP or DMA-OPP using acetyl CoA as the starting material.

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J. Steroids
These compounds are plant and animal lipids that consist of a characteristic tetracyclic fused-ring system: three 6-membered rings and one five-membered ring.
11 1 17
CH3

C
10 9

13 14

D
15

H CH3

A 5

B
6

H H H

Usually, the rings are fused in a trans manner. The H and CH3 groups are also trans to each other, and they are also in the axial positions. Such an arrangement results in a planar, rigid structure, and this flatness is important as cell-membrane components flat molecules take up less space. Steroids are synthesized from terpenes (and not fatty acids), and they usually also have axial methyl groups at C-10 and C13.

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1. Biosynthesis of Lanosterol: an Intermediate to Cholesterol Cholesterol is biosynthesized from the triterpene (C30) squalene. If we redraw squalene, we can notice where the cyclization reactions need to occur so that new carbon-carbon bonds are formed.

Squalene

The green dashes are to-be-made bonds that will form the rings.

The necessary C-C bonds are formed by the reaction of a carbocation with an alkene, similar to the acid-catalyzed self-polymerization reaction observed in the synthesis of alkylbenzene sulfonate detergents.

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First, squalene is enzymatically oxidized to an epoxide. Because of its strained nature, epoxides open very easily in the presence of an acid (review the acidcatalyzed opening of epoxides). The Nu is the electron-rich alkene.

H O H O

HO

HO

HO

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H H H = HO HO HO H A rearragement caused by a series of 1,2-hydride and 1,2-alkyl shifts occurs. These involve the movement of H atoms and CH3 groups, along with their bonding electrons. H H H H

HO

Lanosterol

These reactions lead to lanosterol, an intermediate in cholesterol biosynthesis. Note that there are 7 chiral centres in lanosterol, and none in squalene. Although there are 27 = 128 possible stereoisomers, only one is formed. This is because the enzymes that perform these cyclization and rearrangement reactions place the starting materials in the proper orientation.

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HO

This is the "side view" of the same reaction, and it shows the ring conformations H H

Chair

Boat
H

Chair HO Lanosterol

HO H H

H H

HO H

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The product formed from these cyclization and rearrangement reactions is lanosterol, which is a principle component of lanolin (lana = wool, oleum = grease). Various (complicated) transformations to lanolin result in cholesterol.

H Lanosterol C30 H Cholesterol C27

H H

HO

HO

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K. Fat-Soluble Vitamins
Vitamins are divided into two broad classes, those that are water-soluble and those that are fat-soluble, which are considered to be lipids (A, D, E, K). 1. Vitamin A (Retinol) Vitamin A is formed only in animals, but it arises from the metabolism of a provitamin found in plants: -carotene.
cleave at T-T carotene CH2OH Retinol (stored in liver as ester)

Because vitamin A is fat-soluble, it can also be accumulated in the body just like other fat-soluble compounds. These include PCBs, dioxins, DDT, and methyl-Hg.

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The best understood role of vitamin A is its participation in the visual cycle (rod cells). Retinol is oxidized to retinal (vitamin A aldehyde) in the body, which forms an imine with an NH2 group in the protein opsin. This retinal-opsin complex is responsible for the vision process.
enzyme
H

Light absorption causes double-bond isomerization and release of 11-transretinal from the enzyme

imine formation

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2. Vitamin E Vitamin E is a terpenoid (a compound derived from a terpene).

O HO terpenoid (isoprenoid)

It possesses a sterically hindered phenolic OH group that is responsible for the antioxidant action of vitamin E. It loses H atoms (proton + electron) to give a resonance-stabilized free radical. The H quenches other free radicals that may damage biomolecules. The vitamin E radical is stable and hindered, so it does not cause damage.

OH
Synthetic antioxidants such as butylated hydroxy toluene (BHT) are used as food preservatives.

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3. Vitamin K The name of vitamin K comes from the German word koagulation, which signifies its importance in the blood-clotting process. Vitamin K is synthesized by bacteria living in the intestine. Menadione is a synthetic compound with vitamin K activity.
O
Vitamin K 1

O
Menadione

4. Vitamin D Vitamin D is prepared from 7-dehydrocholesterol in a multistep process. The first step is photochemical and requires UV light.

HO

HO

vitamin D3

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Summary up to now Textbook Chapter 21: o Pages covered: 758 763, 766 768 o Suggested problems: 23, 26, 27, 28, 35, 41 Lab manual: o Practice problems: 39 65 o 2009 Final Exam: 29 35