PROTECTINGANDBDEPROTECTING GROUPS IN ORGANIC SYNTHESIS [M.PHARM]
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Protecting groups are introduced onto reactive functional groups in organic molecules to block their reactivity during multi-step syntheses. Good protecting groups are readily introduced and removed selectively while keeping the protected group stable during other reactions. Common protecting groups discussed include silyl, acetal, ketal, ester, and carbamate groups for alcohols, aldehydes, ketones, carboxylic acids, and amines respectively. Protecting group selection and applications provide selective reactivity needed for complex molecule synthesis.
PROTECTINGANDBDEPROTECTING GROUPS IN ORGANIC SYNTHESIS [M.PHARM]
- 2. Challenges in OrganicSynthesis is anSelective functionalization of poly-functional molecules important and desirable attribute in multi-step organic synthesis. 21:56PM
- 3. Protecting Groups: A Necessary Evil 3 Note, however, that each protecting group incorporated in a multi- step synthesis increases the synthesis by two non-productive steps reducing the overall yield and efficiency of the synthesis.1:56PM
- 4. Protecting Groups in OrganicSynthesis What is a protecting group? A protecting group (PG) is a molecular framework that is introduced onto a specific functional group (FG) in a poly-functional molecule to block its reactivity under reaction conditions needed to make modifications elsewhere in the molecule.
- 5. Qualitiesof a Good Protecting Groupin Organic Synthesis A good protecting group should be suchthat: to the desired(a) It should be readily, but selectively introduced functional group in a poly-functional molecule. (b) It should be stable / resistant to the reagents employed in subsequent 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 mild conditions when its protection is nolonger required.
- 6. Protecting Groups in OrganicSynthesis The commonly encountered functional groups in organic synthesis that are reactive to nucleophilic or electrophilic reagents whose selective transformation may present challenges do regularly require deactivation by masking with a protecting group.
- 7. Protecting Groups forAlcohols The common protecting groups for alcohols are ether-protecting groups. Ethers are among the least reactive of the organic functional groups of alcohols can be grouped in theThe ether protecting groups following categories: (a) Silyl ether protectinggroups (b) Acetal protectinggroups These protections replace the acidic proton on an alcohol with an unreactive ether moiety.
- 9. Protecting Groups forAlcohols Example Tert-Butyldimethylsilyl ethers (TBDMS)
- 10. Protecting Groups forAlcohols (Silyl ProtectingGroups) Cleavage Fluoride sources: Tetrabutylammonium fluoride, Bu4N+F- (TBAF) Pyridine-HF Hydrofluoric acid (HF) Ammonium fluoride NH4 +F- 101:56PM
- 11. Protecting Groups forAlcohols (Silyl ProtectingGroups) Synthetic Applications of Silyl Protecting Groups The bulkiness of TBDMS and TBDPS ether protecting groups can be used to advantage to suppress hydrogen-bonding to the oxygen restricting any incoming reagents to approach from the least hindered side of the molecule.
- 12. Protecting Groups forAlcohols (Silyl ProtectingGroups) Synthetic Applications of Silyl Protecting Groups The bulkiness of TBDMS and TBDPS ether protecting groups can also be exploited in incorporating the protecting group on less sterically encumbered primary hydroxyl groups selectively using sub- molar amounts of the silyl chloride.
- 13. Protecting Groups forAlcohols Formation Cleavage (Benzyl ether ProtectingGroups) Rarely are alkyl ethers used as protecting groups for alcohols, but benzyl ethers are special. 15
- 14. Protecting Groups forAlcohols Cleavage (CyclicAcetal ProtectingGroups) Acetonide Protecting Groups for 1,2-Diols Formation R OH R OH + O O OR R Conditions (a) Acid catalysed hydrolysis H+, H2O (b) AcOH / H2O 161:56PM
- 15. Protecting Groups forAlcohols (Perspectives on their Synthetic Applications) Synthetic Applications of Ether Protecting Groups
- 16. Protecting Groups forAlcohols (Perspectives on their Synthetic Applications) Synthetic Applications of Cyclic Acetal ProtectingGroups
- 17. ProtectingGroups for Aldehydes and Ketones (Acetal and Ketal Protecting Groups) Acetal Protecting Group Formation Cleavage Acid catalysed hydrolysis (dilute HCl or AcOH / H2O or TFA/ H2O orp- TsOH in acetone) can be used.
- 18. ProtectingGroups for Aldehydes & Ketones 20 Because of resonance stabilization, the carbonyl of the - unsaturated ketone is less electrophilic and therefore less reactive to nucleophiles compared to an isolated ketone. (Acetal and KetalProtecting Groups) Synthetic Applications of the Acetal ProtectingGroup The Wieland-Miescher ketone is a common intermediate in the synthesis of both natural and synthetic steroids. 1:56PM
- 19. Protecting Groups for CarboxylicAcids (Esters) Cleavage R CO2H O R C OCH3 + CH3OH LiOH H2O2 21 The common ester protecting groups for carboxylic acids are methyl, ethyl and benzyl esters. Methyl Esters Formation 1:56PM
- 20. Protecting Groups for CarboxylicAcids (Esters) Ethyl and benzyl esters are prepared based on the following rationale: Best approach:
- 21. Protecting Groups for CarboxylicAcids (Esters) Mechanism of DCC coupling
- 22. Protecting Groups for CarboxylicAcids Cleavage (Esters) Ethyl Esters Formation
- 23. Protecting Groups for CarboxylicAcids (Esters) Benzyl Esters Formation R C OCH2Ph Cleavage By hydrogenolysis: A very mild method for most functional groups except with alkenes, alkynes and nitriles. O R CO2H + PhCH3 H2 Pd / C
- 24. ProtectingGroupsfor Amino Groups (Carbamate ProtectingGroups) Tert-Butyloxycarbonyl Protecting Group (BOC) Formation Example
- 25. ProtectingGroupsfor Amino Groups (Carbamate ProtectingGroups) Tert-Butyloxycarbonyl Protecting Group (BOC) Cleavage
- 26. Protecting Groups for AminoGroups Cleavage (Carbamate ProtectingGroups) Benzyloxycarbonyl Protecting Group (CBZ) Formation
- 27. Protecting Groups for CarboxylicAcids (Ester ProtectingGroups) Perspectives in the Synthetic Applications of the Ester Protecting Groups 29 Note that LiBH4 can reduce the more reactive ester functional group leaving the less reactive carboxylic acid and carbamate groups unaffected.1:56PM