Natural Products Chemistry Code: C-402 By Prof. Dr. Ahmed A. Mahmoud Department of Chemistry - Faculty of Science Minia University

By Prof. Dr. Ahmed A. Mahmoud 280 Fats, Oils, Waxes & Fats, Oils, and Fatty Acids Fatty acids: refers to long, straight-chain saturated and unsaturated acids,

typically from C12 - C20.

saturated fatty acids:

CH3(CH2)nCO2H n=10, lauric acid (C12) n=12, myristic acid (C14) n=14, palmitic acid (C16) n=16, steric acid (C ) 18 unsaturated fatty acid CO2H C18, oleic acid

polyunsaturated fatty acids (PUFA)

CO2H C18, linolenic acid 6 CO2H C18, linoleic acid 6 CO2H C20, arachidonic acid 1 Fats and Oils: Triglycerides (triaceylglycerols) are tri-esters of glycerol (1,2,3-trihydroxypropane) and fatty acids.

O The R groups can be OH H2C O C R1 fatty O saturated or unsaturated, HO OH + acids - H O HC O C R2 the same or different 2 O glycerol H2C O C R3

O O O when some of H C O C R H2C O C R1 H C O C R 2 1 the R groups are 2 1 O O unsaturated H2, catalyst O HC O C R HC O C R2 HC O C R2 2 H2, catalyst O O O H C O C R H2C O C R3 2 3 H2C O C R3 Partially hydrogenated: Hydrogenated- only saturated some cis double bond are fatty acids isomerized to trans double bonds

2 Waxes

Esters of long chain fatty acids (C16 - C36) with

long chain alcohols (C24 - C36)

CH3(CH2)nCO2–(CH2)nCH3

3 Terpenes and Terpenoids

 The terpenoids constitute the largest class of natural products.

 The great structural diversity of the terpenoids has been a challenge to the synthetic chemist and will continue to be so as more skeletal types are found.

 The rate of discovery of new terpenoids has increased over the last ten years largely as a result of the increase in the sophistication of separation and analytical techniques.

Terpene Sources

Higher Marine Fungi Plants Organisms

4 INTRODUCTION Terpenoids are: When terpenes are was given modified chemically, volatileto the compounds substances such as by oxidation whichisolated give plants from and or rearrangement of Terpentineflowers their , a the carbon skeleton, fragrance.volatile They liquid occur the resulting widelyisolated in thefrom leaves pine compounds are and fruitstrees. of higher generally referred to plants, conifers, citrus as and eucalyptus. terpenoids .

Terpene was given to the compounds isolated from Terpentine , a volatile liquid isolated from pine trees. 5 Uses of Terpenes

–Fragrances and Perfumes –Food Additives –Aroma therapy –Cleaning Products (Pinesol) –Medicines –Insecticides

6 7 8 9 Examples of Monoterpenes and their Sources

Myrcene

Myrcene Citral a Gerinol Limonene Carvon

Acyclic Monoterpenes Monocyclic Monoterpenes

Cinnamomum tamala Lemon Rose Carawya القرفة

10 Examples of Monoterpenes and their Sources

Menthol Camphor a-Pinene

Monocyclic Bicyclic Monoterpenes Monoterpenes

Camphor Tree Mentha Pine tree

11 Examples of sesquiterpenes and their Sources

Zingiberen Artemisinin Capnellene

Sesqiuterpenes

Zingiber Artemisia officinal annua Capnella الجنزبيل Anti Malrial Anti-tumor imbricata 12 Examples of Diterpenes and their Sources (Vitamin A)

Vitamin A

13 Examples of Diterpenes Examples of Triterpenes and their Sources and their Sources

Anti-oxidant Carnosic Acid Lupeol has , from Rosemary Antiinflammatory, Antitumor Properties from Senegalia visco 14 Examples of Triterpenes glycosides (Saponins) and their Sources

Saponins are a class of chemical compounds found in particular abundance in various plant species.

They are soap-like foaming they produce when shaken in aqueous solutions.

Structurally by having one or more hydrophilic glycoside moieties combined with a lipophilic triterpenederivative

16 Example of Tetra-terpenes Beta-carotene

Vitamin A

17

A TYPICAL PLANT hn Glycolysis

Photosynthesis (daytime) CO Respiration 2 (nighttime) H2O O2

N2

bacteria

TRACE METALS “N” - - + Na, Ca, K, Mg NO2 /NO3 /NH4 Fe, Cu, Co, Mo H2O The precursor to C10 terpenoids (monoterpenes) is geraniol diphosphate (diphosphate), which consists of two C5 “ units” that are joined “head-to-tail”

O O head tail PP = P O P O O O

OPP head - tail head - tail

C15 sesquiterpenoids are derived from farnesyl diphosphate, which consists of three C5 “isoprene units” that are joined “head-to-tail”

OPP

C20 diterpenoids are derived from geranylgeranyl diphosphate, which consists of four C5 “isoprene units” that are joined “head-to-tail”

OPP 18 C25 sesterpenoids are derived from geranylfarnesyl diphosphate, which consists of five C5 “isoprene units” that are joined “head-to-tail”

OPP

C30 triterpenoids and steroids are derived from squalene, which consists of two C15 farnesyl units” that are joined “tail-to-tail”

C40 tetraterpenoids are derived from phytocene, which consists of two C20 geranylgeranyl units” that are joined “tail-to-tail”

19 Isopentyl Diphosphate: The Biological Isoprene Unit.

Mevalonic acid is the biosynthetic precursor to the actual C5 “isoprene units,” which are isopentyl diphosphate (IPP, tail) and dimethylallyl diphosphate (DMAPP, head)

The Pathway from Acetate to Isopentenyl Diphosphate. Mevalonate Pathway

O acetoacetyl-CoA acetyltransferase O H C C SCoA 2 C H H2C SCoA B: acetyl CoA Claisen condensation O O SCoA

acetoacetyl CoA O O Enzyme-Cys-SH H C C S-Cys Enzyme H3C C SCoA 3 - acetyl CoA

HMG-CoA O HMG-CoA aldol synthase O condensation H3C OH O reductase H3C OH H C C SCoA 2 HO C HO2C C 2 SCoA 2 NADPH OH H H2C SCoA B: 3-Hydroxy-3-methylglutaric acid acetyl CoA Mevalonic acid (HMG-CoA) B H O O

SCoA acetoacetyl CoA 20 Conversion of mevalonic acid to IPP and DMAPP

ATP AMP ATP ADP OH O H3C 2- H3C O H3C OH OPO3 O O 3- O O - PO4 HO2C H H - OH O O P O P O- O O P O P O - - O- O- Mevalonic acid O O

H+ O CH O O O O 3 O O rearrangment O P O P O- - H - O P O P O O O P O P O - - H H O O H O- O- B: O- O- B: isopentenyl-PP dimethylallyl-PP (IPP) (DMAPP)

Carbon-Carbon Bond Formation in Terpene . Conversion of IPP and DMAPP to geraniol-PP and farnesyl-PP

electrophilic nucleophilic head group tail group - OPP - OPP 2+ OPP 2+ Mg H H Mg OPP OPP B: DMAPP OPP IPP geranyl pyrophosphate (C10)

OPP H H OPP

electrophilic B: nucleophilic OPP tail group farnesyl pyrophosphate (C15) head group 21 OPP PPO squalene synthase

Conversion of genanyl-PP to monoterpenes Limonene & a-Terpineol

C=C bond acts limonene as a nucleophile

a-terpineol 22 Examples of Monoterpenes (Acyclic & Monocyclic) Biosynthesis Pathways

23 Examples of Monoterpenes (Mono & Bi-Cyclic) Biosynthesis Pathways

24 Examples of Monoterpenes Biosynthesis Pathways

25 26 Specific methods used for structure determination of the isolated compounds

Analytical methods

MS & HR-MS  Determination of the molecular formula  Degrees of unsaturation  Optical activity

Chemical methods  Functional groups 27 Physical & Spectral Methods 1- Optical rotation [a]D 2- IR absorption 3- UV 4- 1D NMR (1H, 13C -NMR, DEPT, NOE’s) 5- 2D NMR (HMQC, HMBC, NOESY) 6- X-Ray analysis

27