ORGANIC SYNTHESIS - University Of Nairobi Personal Websites

PART BORGANIC SYNTHESIS2:14 PM1

What is Synthesis?Synthesis involves combining two or more chemical entitiesthrough covalent bonds to generate a more complex molecule.The covalent bonds formed between these chemical entitiescould be based on: a substitution reaction, an addition reactionSince the new bonds formed during synthesis occur atfunctional groups inherent in polyfunctional molecules, it isusually necessary to use protecting groups to minimize the2:14 PMformation of side-products.2

Is Synthesis of Any Value?Synthesis is important to the food and cosmetics industry, butalso finds wide application in medicine.Although nature can provide the source of cinnamaldehyde(occurs in the cinnamon plant), its wide application as aflavouring agent requires that it be readily available in largequantities.Synthesis has served to supplement the natural source.2:14 PM3

Of What Value is Synthesis?Synthesis of Moisturizers and SweetenersEnzymatic hydrolysis of starch provides glucose, which whenreduced provides sorbitol, a moisturizer and sweetner.2:14 PM4

Organic SynthesisWhat are the Essentials in Synthesis?Since organic synthesis is applied organic chemistry, to stand arealistic chance of succeeding in any synthesis, the studentought to have a good knowledge-base of organic chemistry inthe following areas: Protecting group chemistry Asymmetric synthesis Functional group transformations (SCH 202 & SCH 206) Substitution reactions (SCH 102) Addition reactions (SCH 202 and SCH 206)2:14 PM Strategies for synthetic planning (Retrosynthetic analysis)5

Protecting Groups in OrganicSynthesis2:14 PM6

Challenges in Organic SynthesisChemoselectivity can be Elusive2:14 PMSelective functionalization of poly-functional molecules is animportant attribute in multi-step organic synthesis.7

Protecting Groups: A Necessary EvilNote that the introduction of each protecting group in a multi-stepsynthesis increases the synthesis by two non-productive steps reducing theoverall yield and efficiencyof the synthesis.82:14 PM

Protecting Groups in Organic SynthesisWhat is a protecting group?A protecting group (PG) is a molecular unit that is introducedonto a specific functional group (FG) in a poly-functionalmolecule to block its reactivity under reaction conditionsneeded to make modifications elsewhere in the molecule.2:14 PM9

Protecting Groups in Organic SynthesisThe Qualities of a Good Protecting GroupA good protecting group should be such that:(a)It should be readily and selectively introducedto thedesired functional group in a poly-functional molecule.(b) It should be resistant (inert) to the reagents employed in thesubsequent reaction steps in which the group being masked(protected) is desired to remain deactivated (protected).(c) It should be capable of being selectively removed under mildconditions when its protection is no longer required.2:14 PM10

Protecting Groups in Organic Synthesis2:14 PMThe common functional groups that are reactive to nucleophilicor electrophilic reagents whose selective transformation maypresent challenges do regularly require deactivation by maskingwith a protecting group.11

Protecting Groups for AlcoholsWhy Ethers?As derivatives of alcohols, ethers are among the least reactive ofall classes of organic compounds.No wonder, the common protecting groups for alcohols areether-protecting groups.To achieve the desired protection, the conversion of alcohols toethers replace the acidic proton on an alcohol with anunreactive alkyl moiety.2:14 PM12

Protecting Groups for AlcoholsWhat Kind of Ethers?Except for benzyl ethers, hadly are alcohols protected as alkylethers. The ether protecting groups of alcohols can be groupedinto the following categories:(a) Silyl ether protecting groups(b) Acetal protecting groups2:14 PM13

Protecting Groups for AlcoholsSilyl Ether Protecting GroupsSilicon ethers are the most commonly used alcohol protectinggroups. The O-Si bond formed is strong and less reactive tostrong bases compared to the O-H bond in the parent alcohol.Moreover, the bulkier silicon prevents easy access byelectrophiles to the lone pairs of electrons on the oxygen atom.2:14 PM14

Protecting Groups for AlcoholsTert-Butyldimethylsilyl Ether Protecting GroupFormationImidazole neutralizes the HCl produced in the reaction tosuppress side-reactions that could arise from it.Example2:14 PM15

Protecting Groups for Alcohols(Deprotection of Silyl Protecting Groups)CleavageThis takes advantage of the selective siliphilic property offluoride ions.Fluoride sources: Hydrofluoric acid (HF)2:14 PM Tetrabutylammonium fluoride, Bu4N F- (TBAF)16

Protecting Groups for Alcohols(Synthetic Applications using Silyl Protecting Groups)The bulkiness of TBDMS and TBDPS ether protecting groups canbe used to advantage to direct it to the least hindered primaryhydroxyl group leading to selective protection of a primaryhydroxyl group in the presence of a secondary hydroxyl group.2:14 PM17

Protecting Groups for Alcohols(Benzyl ether Protecting Groups)FormationCleavageAlthough alkyl ethers are not commonly used as protectinggroups for alcohols due to the harsh conditions required fortheir deprotection, benzyl ethers are unique since they can beeasily be cleaved through hydrogenolysis.2:14 PM19

Protecting Groups for Alcohols(Perspectives in Synthesis)Benzyl ether protecting groups can be used along with silylether protecting groups to protect poly alcohols duringsynthesis.Note that whereas one can selectively protect a primary alcoholas a silylether in the presence of a secondary alcohol, such2:14 PMselectivity is not possible with benzyl ethers.20

Protecting Groups for Diols(Cyclic Acetal Protecting Groups)Acetonide Protecting Groups for 1,2-DiolsThe formation of thermodynamically stable five membered ringsystems is feasible.FormationCleavageExploits the reversibility of the acid-catalysed equilibrium.2:14 PM21

Protecting Groups for Alcohols(Perspectives in Synthesis)Synthetic Applications of Cyclic Acetal Protecting Groups2:14 PM22

Protecting Groups for Aldehydes and Ketones(Acetal and Ketal Protecting Groups)Acetal Protecting GroupFormationCleavageAcid catalysed hydrolysis (dilute HCl/ H2O or TFA/ H2O)2:14 PM23

Protecting Groups for Aldehydes(Synthetic Perspectives)Apart from the use of PCC, selective oxidation of an alcohol maybe challenging to achieve in the presence of an aldehyde.2:14 PM24

Protecting Groups for Carboxylic Acids(Esters)The common ester protecting groups for carboxylic acids aremethyl, ethyl and benzyl esters.Methyl EstersFormationCleavageOR C OCH32:14 PMLiOHH2O2R CO2H CH3OH25

Protecting Groups for Carboxylic Acids(Esters)Methyl, ethyl and benzyl esters can be prepared based on thefollowing rationale:Best approach:2:14 PM26

Protecting Groups for Carboxylic Acids(Esters)Mechanism of DCC coupling N C NOR C O OR2:14 PMOHR' OHN C N OR C OOO C RN CNHHN C NOR C OC NNHR' O H HN C NOR C O HOROHR'OHN C N OROR' OHHN C N27

Protecting Groups for Carboxylic Acids(Esters)Ethyl EstersFormationCleavageOR C OCH2CH3LiOHR CO2H CH3CH2OHH2O22:14 PM28

Protecting Groups for Carboxylic Acids(Esters)Benzyl EstersFormationCleavage: By hydrogenolysis2:14 PM29

Protecting Groups for Amino Groups(Carbamate Protecting Groups)Carbamates combine half of the stability of amides and half ofthe reactivity of esters.Tert-Butyloxycarbonyl Protecting Group (BOC)Formation2:14 PM30

Protecting Groups for Amino Groups(Carbamate Protecting Groups)Tert-Butyloxycarbonyl Protecting Group (BOC)Cleavage: Accomplished under acidic conditions2:14 PM31

Protecting Groups for Amino Groups(Carbamate Protecting Groups)Benzyloxycarbonyl Protecting Group (CBZ)FormationCleavage2:14 PM32

Protecting Groups for Carboxylic Acids(Ester and Carbamate Protecting Groups)Perspectives in the Synthetic Applications of the Ester andCarbamate Protecting Groups2:14 PMLiBH4 reduces the more reactive ester functional group leavingthe less reactive carboxylic acid and carbamate groups33unaffected.

Organic Synthesis What are the Essentials in Synthesis? 5 Since organic synthesis is applied organic chemistry, to stand a realistic chance of succeeding in any synthesis, the student ought to have a good knowledge-base of organic chemistry in the following areas: Protecting group chemistry Asymmetric synthesis