The document discusses protecting groups in organic synthesis. It defines protecting groups and lists criteria for effective protecting groups. It then discusses specific protecting groups for alcohols, including acetals like THP and MEM groups, alkyl ethers like benzyl and t-butyl ethers, and silyl ethers like trimethylsilyl ether. More bulky silyl protecting groups like TIPS, TBDMS, and TBDPS are also introduced to overcome issues with nucleophilic attack on trimethylsilyl ethers.

1. RETROSYNTHETIC APPROCH TO ORGANIC SYNTHESIS PROTECTING GROUPS Dr. Shaikh S. Nizami Department of Chemistry University of Karachi

2. PROTECTING GROUPS

3. CONTENTS Definition of Protecting Groups Criteria for Protecting Groups Protection of alcohols Protection of amines Protection of aldehydes & ketones

4. Definition NaBH 4 LiAlH 4 The ester cannot be directly reduced leaving the ketone unaffected

5. Solution of problem The problem may be circumvented in two ways: a) By the use of protecting groups b) By changing the synthetic strategy to the TM

6. Solution of problem If it is necessary to reduce an ester in presence of a ketone then First the ketone must be converted to a function which is stable to the reducing agent/ The ester then be reduced and ketone subsequently regenerated .

7. Protection of a ketone during reduction of an ester overall HOCH 2 CH 2 OH/H + LiAlH 4 H 3 O +

8. Criteria for protecting groups Simple to introduce in a molecule, in good yield Stable to the reaction conditions for the next step Easy to remove to get back same functional group, in good yield

9. PROTECTION OF ALCOHOLS Following methods have been used to protect alcoholic group 1. Use of acetals 2. Use of alkyl ethers 3. Use of silyl ethers

10. PROTECTION OF ALCOHOLS 1. Use of acetals It includes Tetrahydropyranyl (THP) derivatives Methoxyethoxymethyl (MEM) derivatives

11. Acetals as protecting groups for alcohols (THP) + Tetrahydropyran (THP) H + or RCH 2 OTHP is stable to oxidation, reduction & base H 2 O/H + Deprotection Protection

12. Acetals as protecting groups for alcohols (MEM) + or Methoxethoxymethyl (MEM) RCH 2 OMEM is stable to oxidation, reduction & base H + Protection Deprotection

13. PROTECTION OF ALCOHOLS 2. Use of ethers It includes benzyl ethers t-butylethers

14. Benzyl ethers as protecting groups for alcohols + pyridine H 2 /Pd Benzyl ether is stable to base, mild acid, oxidation & reduction Protection Deprotection

15. t- Butyl ethers as protecting groups for alcohols + or H + Protection H 3 O + Deprotection t-Butyl ether is stable to base, mild acid, oxidation & reduction

16. PROTECTION OF ALCOHOLS 3. Use of silyl ethers + pyridine Protection or H + Deprotection Trimethylsilyl ether is stable to base, oxidation & reduction

17. PROTECTION OF ALCOHOLS 3. Use of silyl ethers Trimethylsilyl ethers are attacked by certain nucleophiles. To overcome this problem a number of more bulky trialkylsilyl protecting groups have been developed

18. Bulky trialkylsilyl protecting groups I II III I, Triisopropylsilyl ether (TIPSOR) II, t-Butyldimethylsilyl ether (TBDMSOR) III, t-Butyldiphenylsilyl ether (TBDPSOR)