Based on McMurry’s Organic Chemistry, 6th edition
©2003 Ronald Kluger
Department of Chemistry
University of Toronto

About Lipids
 Naturally materials that preferentially extract into nonpolar organic solvents


Includes fats, oils, waxes, some vitamins and hormones, some components of membrane
General types: esters (“saponifiable”) and those that can’t be hydrolyzed
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
2

27.1 Waxes, Fats, and Oils


Waxes - contain esters formed from long-chain (C16-
C36) carboxylic acids and long-chain alcohols (C24-
C36)
Triacontyl hexadecanoate is in beeswax
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
3

Fats and Oils
 Animal fats and vegetable are triacylglycerols oil
 Triesters of glycerol with three long-chain carboxylic acids
 Saponification of a fat or oil with (reaction with aqueous NaOH) yields glycerol and three fatty acids
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
4

Fatty Acids (from Fats and Oils)




Straight-chain (C
12
- C
20
) carboxylic acids
Double bonds are cis-substituted but trans-fatty acid also occur
A fat or oil in nature occurs as a mixture of many different triacylglycerols
The most abundant saturated fatty acids are palmitic
(C
16
) and stearic (C
18
)
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
5

Unsaturated and Polyunsaturated Fatty
Acids
 Oleic (C
18 with one C=C) and linolenic (C
C=C) are the most abundant unsaturated
18 with 3
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
6

27.2 Soap
 A mixture of sodium or potassium salts of long-chain fatty acids produced by alkaline hydrolysis
(saponification) of animal fat with alkali
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
7

Cleansing Action of Soap



The carboxylate end of the long-chain molecule is ionic and therefore is preferentially dissolved in water
The hydrocarbon tail is nonpolar and dissolves in grease and oil
Soaps enable grease to be dissolved into water
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
8

Detergents


“Hard” water contains Mg +2 and Ca +2 that form insoluble salts with soaps
Synthetic detergents are alkylbenzene sulfonates that dissolve dirt like soaps but do not form scums with
Mg +2 and Ca +2 .
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
9

27.3 Phospholipids



Phospholipids are diesters of H
3
PO
4
, phosphoric acid
Phosphoric acid can form monoesters, diesters and triesters
In general these are known as “phosphates”
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
10

Phosphoglycerides



Contain a glycerol backbone linked by ester bonds to two fatty acids and phosphoric acid
Fatty acid residues with C
12
–C
20
The phosphate group at C3 has an ester link to an amino alcohol
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
11

Phosphoglyceride Membranes



Phosphoglycerides comprise the major lipid component of cell membranes
Nonpolar tails aggregate in the center of a bilayer
Ionic head is exposed to solvent
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
12

Sphingolipids




The other major group of phospholipids
Sphingosine or a dihydroxyamine backbone
Constituents of plant and animal cell membranes
Abundant in brain and nerve tissue, as coating around nerve fibers.
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
13

27.4 Prostaglandins



C20 lipids that contain a five-membered ring with two long side chains
Present in small amounts in all body tissues and fluids
Many physiological effects
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
14

Prostaglandin Sources
 Biosynthesized from arachidonic acid (C20 unsaturated fatty acid)
 Catalyzed by cyclooxygenase (COX)
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
15

27.5 Terpenoids



Steam distillation of plant extracts produces
“essential oils”
Chemically related to compounds in turpentine (from pine sap) called terpenes and thus called terpenoids
Mostly hydrocarbons (some oxygens) that do not contain esters (stable to hydrolysis)
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
16

Terpenoids Are Isoprenoids


Terpenoid structures are derived from isoprene (2methyl-1,3-butadiene) units connected head-to-tail
(Isoprene Rule)
The term “head-to-tail” means that dissimilar ends are connected (you can choose which is a “head” and which is a “tail”)
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
17

Classification of Terpenoids


Classified according to the number of di-isoprenoid
(C
10
) units they contain
Monoterpenes have 10-carbons, sesquiterpenes
(sesqui = 1 1/2) have 15-carbons from three isoprene units, and so on
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
18

Some Important Terpenoids


The triterpene lanosterol is the precursor of steroid hormones
The tetraterpene b
-carotene is a source of vitamin A
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
19

27.6 Biosynthesis of Terpenoids


Isopentenyl pyrophosphate (IPP) forms higher isoprenoids in reactions catalyzed by prenyl transferase
Monoterpenoids, diterpenoids, and tetraterpoids arise from 1-deoxyxylulose 5-phosphate.
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
20

Mevalonate Pathway to
Isopentenyl Diphosphate
 Begins with the conversion of acetate to acetyl CoA followed by Claisen condensation to yield acetoacetyl
CoA
 Catalyzed by acetoacetyl-CoA acetyltransferase
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
21

Aldol Condensation Produces
HMG-CoA


Carbonyl condensation reaction of acetoacetyl CoA with acetyl
CoA
Produces 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
22

Reduction Forms Mevalonate


HMG CoA is reduced to mevalonate
Catalyzed by HMG CoA reductase utilizing NADPH
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
23

Conversion of Mevalonate to IPP


Pyrophosphorylation gives mevalonyl-PP
Addition of phosphate from ATP followed by loss of
CO
2 and phosphate
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
24

Conversion of Isopentenyl
Diphosphate to Terpenoids
 For triterpenes and larger, head-to-head coupling of farnesyl diphosphates gives squalene
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
25

Mechanism of Isomerization
 Isomerization of IPP to DMAPP is catalyzed by IPP isomerase through a carbocation pathway
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
26

Coupling Mechanism
 Nucleophilic substitution reaction in which the double bond of IPP behaves as a nucleophile in displacing diphosphate ion leaving group (PPO

)
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
27

Conversions of Monoterpenoids
 Typically involves carbocation intermediates and multistep reaction pathways catalyzed by a terpene cyclase
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
28

27.7 Steroids




Steroids,are another class of nonsaponifiable lipid, defined by structure
Has four fused rings A, B, C, and D, beginning at the lower left
Carbon atoms are numbered beginning in the A ring
The six-membered rings are in fixed chair conformations
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
29

Functions of Steroids
 In humans as hormones, steroids are chemical messengers secreted by glands and carried through the bloodstream to target tissues
 Also widely distributed as cholesterol
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
30

Male Sex Hormones
 Testosterone and androsterone are the two most important male sex hormones, or androgens
 Androstanedione is a precursor
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
31

Female Sex Hormones


Estrone and estradiol are the two most important female sex hormones, or estrogens
Progesterone is the most important progestin, steroids that function in pregnancy
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
32

Adrenocortical Hormones



Adrenocortical steroids: secreted by the adrenal glands near the upper end of each kidney
Mineralocorticoids: control tissue swelling by regulating cellular salt balance
Glucocorticoids: regulation of glucose metabolism and in the control of inflammation
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
33

Synthetic Steroids



Made in pharmaceutical laboratories as new drugs
Includes oral contraceptives and anabolic agents
Methandrostenolone is an anabolic steroid used for tissue-building
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
34

27.8 Stereochemistry of Steroids



Two cyclohexane rings can be joined in either a cis or a trans manner
In cis-decalin, both groups at the ring-junction positions are on the same side of the two rings
In trans-decalin, the groups at the ring junctions are on opposite sides
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
35

A/B Junction in Steroids


Steroids can have either a cis or a trans fusion of the
A and B ring
(B –C and C–D) are usually trans
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
36

27.9 Steroid Biosynthesis
 Enzyme-catalyzed addition of oxygen atom to squalene
 Stereospecific formation of an oxirane from an alkene
R
Squalene
R
O
2
Enzyme
O
2,3-Oxidosqualene
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003
37

Cyclization to Steroid



Stork-Eschenmoser mechanism
Enzyme-catalyzed
See Figure 27.6
R
R
E-H
O
HO
Based on McMurry, Organic Chemistry, Chapter
27, 6th edition, (c) 2003 protosteryl cation
38