Lecture 8- Terpenoids

Question 1

What are terpenoids structure

Answer 1

1. Terpenoids derive from 5-carbon isoprene
2. Hydrocarbons, sometimes with oxygenation
3. Often polycyclic
4. Can contain unsaturation

Question 2

What are terpenoids used for

Answer 2

1. Essential oils and flavours - pine, ginger, menthol
2. Colours- sunflowers, tomatoes, turmeric
3. Pharmacologically active - cannabinoids, ginkgolide, bilobalide

Question 3

What are names for terpenoids with increasing isoprene units 1-6, 8

Answer 3

1. 1= hemiterpenoid - 5C
2. 2= Monoterpenoid- 10C
3. 3= Sesquiterpenoid- 15C
4. 4= diterpenoid- 20C
5. 5= Sesterpenoid- 25C
6. 6=Triterpenoid- 30C
7. 8=Tetraterpenoid- 40C
8. Polyterpenoid

Question 4

What are the two derivatives of terpenes that nature uses

Answer 4

1. IPP- isopentenylpyrophosphate
2. DMAPP- dimethylallylpyrophosphate
3. Used to construct all terpenes

Question 5

What is produced when DMAPP reacts with IPP

Answer 5

1. Form geranyl pyrophosphate
2. Direct attack of IPP on non-ionised DMAPP does not occur
3. DMAPP is ionised to give carbocation - di
4. Proton drops off and double bond of IPP attacks carbocation

Question 6

What does geranyl pyrophosphate do after formation

Answer 6

1. Ionises and cyclises to give a tertiary cation
2. From this cation the other monoterpenes arise by rearrangement reactions, eliminations, addition of water and oxidations

Question 7

What is formed if geranyl pyrophosphate loses a proton after formation of carbocation

Answer 7

1. Forms myrcene- non cyclic

Question 8

How does geranyl pyrophosphate form limonene

Answer 8

1. If double bond attacks carbocation- forms cyclic structure
2. If new carbocation deprotonates- limonene

Question 9

How is pinene formed

Answer 9

1. If double bond attacks carbocation- forms cyclic structure
2. If double bond acts as a nucleophile to carbocation
3. Then proton eliminated- determines if alpha or beta

Question 10

What are other monoterpene derivatives of geranyl pyrophosphate

Answer 10

1. Menthol
2. R-carvone
3. Camphor
4. All oxidised by water acting as nucleophile to carbocation- OH can then be oxidised to =O

Question 11

Describe properties of monoterpenes

Answer 11

1. Low molecular weight (C10) and low polarity- often volatile
2. Have characteristic odours
3. Opposite enantiomers have different scents

Question 12

How do you form sesquiterpenes

Answer 12

1. A C15 precursor is needed
2. This is derived from the reaction of geranylpyrophosphate with another molecule of IPP to give Farnesyl pyrophosphate

Question 13

How do you form diterpenes

Answer 13

1. A C20 precursor is needed
2. Formed from reaction of farnesyl pyrophosphate with IPP to give geranylgeranyl pyrophosphate
3. geranylgeranyl pyrophosphate undergoes electrophilic cyclisation to produce polycyclic structures

Question 14

How are triterpenes formed

Answer 14

1. Synthesised by squalene
2. Squalene is made from 2 farnesyl units head to head

Question 15

How do you synthesise steroids from squalene

Answer 15

1. Oxidise to form 2,3-oxidosqualene
2. Then undergoes electrophilic cyclisation and rearrangement to access the steroidal nucleus

Question 16

How can terpenes be used to make polyester

Answer 16

1. Beta-pinene multistep synthesis
2. Produce 4-isopropyl-cyclohexanone which is oxidised using mCPBA, CH2CI2 to produce 4-isopropylcaprolactone
3. This undergoes ring opening polymerisation to produce polyester

Question 17

What are steroids

Answer 17

1. Organic compounds with 4 rings organised in a specific molecular configuration
2. Steroids core structures are composed of 17 carbon atoms bonded in 4 fused rings
3. 3 6-Member cyclohexane ring
4. 1 5-member cyclopentane ring
5. e.g. cholesterol, estradiol, testosterone

Question 18

What are the two principal biological functions of steroids

Answer 18

1. Important component in cell membranes which alters membrane fluidity
2. Signalling molecules which activate hormone receptors

Question 19

What are all steroids manufactured from

Answer 19

1. Ianosterol (animal and fungi)
2. Cycloartenol (plants)
3. Both are derived from cyclisation of the triterpene squalene

Question 20

What are polyketides

Answer 20

1. Diverse range of highly oxygenated secondary metabolites - contain ketones
2. Biosynthesis vai thio-Claisen condensation of acyl-coenzyme A units by PKS (polyketides synthases)
3. Type 1 - macrolides
4. Type 2- often aromatic molecules
5. Type 3 - Often small aromatic molecules

Question 21

How are polyketides formed from terpenoids

Answer 21

1. Epoxidation
2. Followed by ring opening and closing

Question 22

What are examples of type 1 polyketides

Answer 22

1. Glycosylated macrolides
2. Erythromycin
3. clarithromycin
4. Amphotericin B

Question 23

What are prostaglandins

Answer 23

1. PG’s are a group of physiologically active lipid compounds which have diverse hormone-like effects in animals
2. PG’s are derived enzymatically from the fatty acid, arachidonic acid
3. Every PG contains 20 carbon atoms including a 5-carbon ring
4. Prostaglandins are powerfulling acting vasodilators and inhibit the aggregation of blood platelets
5. Also have a role in inflammation

Question 24

What is an example of a prostaglandin

Answer 24

1. Alprostadil

Question 25

Describe how aspiring works

Answer 25

1. Aspiring blocks an enzyme called cyclooxygenase, COX-1 and COX-2 which is involved with the ring closure and addition of oxygen to arachidonic acid which forms prostaglandins 2. The acetyl group on aspirin is hydrolysed and linked to the alcohol group of serien as an ester 3. This blocks the channel in the enzyme so arachidonic cannot enter the active site

Question 26

What are alkaloids

Answer 26

1. Natural products that usually contain a basic nitrogen 2. Alkaloids are produced by a large variety of fungi, plants and microorganisms 3. Generally have a better taste 4. Biological roles vary e.g. protective (predators or parasites), neurotransmitters (serotonin, dopamine) 5. Many are pharmacologically active - antimalarial, antibacterial, anticancer, psychotropic 6. Biosynthesis pathways complex, but begin with amino acids

Question 27

What are some examples of alkaloids

Answer 27

1. Aconitine 2. Ephedrine 3. morphine 4. Caffeine 5. Cocaine

Question 28

Describe classification of alkaloids

Answer 28

1. No uniform classification 2. Most recent classifications based on similarity of- carbon skeleton (indole-, isoquinoline-, pyridine-like) and biochemical precursor (which amino acid) 3. Used to be based on the common natural source e.g. type of plant

Question 29

What is cocaine

Answer 29

1. Stimulating, appetite supressing local anesthetic 2. High addictive due to interactions with the mesolimbic reward pathway which increases dopamine production in the brain 3. First derived from tropinone

Question 30

Describe biosynthesis of cocaine

Answer 30

1. Start with L-glutamine which is decarboxylated by PLP enzyme producing putrescine 2. N-methylation by SAM enzyme to produce N-methylputrescine 3. Diamine oxidase oxidises NH2 to =O 4.

Question 30

Describe first part of biosynthesis of cocaine

Answer 30

1. Start with L-glutamine which is decarboxylated by PLP enzyme producing putrescine 2. N-methylation by SAM enzyme to produce N-methylputrescine 3. Diamine oxidase oxidises NH2 to =O 4. Shiff base formation to form iminium species

Question 31

Describe second part of the biosynthesis of cocaine

Answer 31

1. React iminium with Coenzyme A- Happens twice 2. Hydroxylated by hydroxylase enzyme 3. elimination to generate another iminium 4. Aminolate attack of iminium 5. Then remove coenzyme to get OMe 6. Then reduction steps to get to cocaine

Question 32

What did Willstatter do

Answer 32

1. synthesised cocaine over many many steps 2. Proved cocaine had tropane core structure

Question 33

What did Robinson do

Answer 33

1. Different method to build tropinone core 2. Did retrosynthetic approach 3. Dialdehyde, H2NMe, acetone are basic components - starting materials

Question 34

Describe double Mannich reaction

Answer 34

1. One-pot -refined to have 90% yield