1. Chapter 10 Protective Groups
Organic Synthesis
Spring 1999
Chapter 10 Protective Groups
strategy of using protecting groups ?
OCFC-Chap10
Chap9&10

2. Requirements for Ideal Protecting Groups:  223
Organic Synthesis
Spring 1999
Requirements for Ideal Protecting Groups:  223
quantitative protection under mild conditions
stable under the reaction conditions
quantitative deprotection under mild conditions
orthogonal protection: inert to deprotection conditions of other protecting groups
references: (1) P. G. M. Wuts & T. W. Greene, ‘Greene’s Protective Groups in Organic Synthesis’ 4th ed., Wiley, (2) P. J. Kocienski, ‘Protecting Groups’, Thieme, 3rd ed
OCFC-Chap10
Chap9&10

3. Protection of Alcohols (R-OH) (I)
Organic Synthesis
Spring 1999
Protection of Alcohols (R-OH) (I)
ether formation: R-O-R’;  225 Table 10.1
stable under neutral/basic conditions & to oxidations
1. RO-CH3 / RO-CH2CH3: alkyl ethers
2. RO-CH2CH=CH2: allyl ethers
OCFC-Chap10
Chap9&10

4. Protection of Alcohols (R-OH) (II)
Organic Synthesis
Spring 1999
Protection of Alcohols (R-OH) (II)
ether formation: R-O-R’;  225 Table 10.1
3. RO-CH2Ph (Bn): benzyl ethers; RO-CH2Ph-p-OMe (PMB)
4. RO-CPh3 (Tr): trityl ethers, selective for 1o alcohols
OCFC-Chap10
Chap9&10

5. Protection of Alcohols (R-OH) (III)
Organic Synthesis
Spring 1999
Protection of Alcohols (R-OH) (III)
ether formation: R-O-R’;  225 Table 10.1
5. RO-CH2OMe (MOM); RO-CH2SMe (MTM); RO-MEM
6. RO-CMe3 (RO-tBu): tert-butyl ethers, stable & bulky
OCFC-Chap10
Chap9&10

6. Protection of Alcohols (R-OH) (IV)
Organic Synthesis
Spring 1999
Protection of Alcohols (R-OH) (IV)
ether formation: R-O-R’;  225 Table 10.1
7. RO-THP: tetrahydropyranyl ethers; RO-EE (1-ethoxyethyl)
8. RO-SiR’3 (RO-TMS): trimethylsilyl ethers;  226 Table 10.2
TMS: unstable in acid, TBDMS: rather stable, TBDPS: bulky & very stable, TIPS: bulky & stable, SEM: orthogonal deprotection
OCFC-Chap10
Chap9&10

7. Protection of Alcohols (R-OH) (V)
Organic Synthesis
Spring 1999
Protection of Alcohols (R-OH) (V)
ester formation: R-O-CO-R’;  226 Table 10.3
stable under mild acidic conditions & to oxidations
examples:  227; (3)  (4)
OCFC-Chap10
Chap9&10

8. Protection of 1,2- / 1,3-Diols
Organic Synthesis
Spring 1999
Protection of 1,2- / 1,3-Diols
acetals: stable under basic conditions,  231 bot
reagents: ArCHO / ketones or PhCH(OMe)2 / Me2C(OMe)2
carbonates: stable under mild acidic conditions; R=R’=O
reagents: COCl2, (RO)2C=O, (Cl3CO)2C=O, CDI (19)
OCFC-Chap10
Chap9&10

9. Protection of Thiols (R-SH)
Organic Synthesis
Spring 1999
Protection of Thiols (R-SH)
thioether (sulfide) formation: R-S-R’;  230 top
thioester formation: R-S-C(O)R’; similar to alcohols
OCFC-Chap10
Chap9&10

10. Protection of Aldehydes & Ketones
Organic Synthesis
Spring 1999
Protection of Aldehydes & Ketones
acetals / thioacetals:  230 bot – 231 top
Y = W = O; stable to bases, deprotection with acids
(TMSOCH2)2 & cat. TMS-triflate: under neutral conditions by Noyori
Y = W = S; stable to acids & bases, deprotection with HgO, F3B•OEt2
Y =O, W = S; intermediate between acetals & thioacetals
OCFC-Chap10
Chap9&10

11. Protection of Carboxylic Acids (RCO2H)
Organic Synthesis
Spring 1999
Protection of Carboxylic Acids (RCO2H)
ester formation: RC(O)-O-R’; similar to alcohols
esterification with alcohols, CH2N2, or SN2 reaction
orthoester formation: RC(OR’)3, acid labile;  229
OCFC-Chap10
Chap9&10

12. Deprotection of Carboxylic Esters
Organic Synthesis
Spring 1999
Deprotection of Carboxylic Esters
OCFC-Chap10
Chap9&10

13. Protection of Amines (I)
Organic Synthesis
Spring 1999
Protection of Amines (I)
amides/imides: rather stable;  232 bottom
less basic/nucleophilic N & more acidic H
alkylamines: similar to alcohols (Bn, SEM);  232 top
OCFC-Chap10
Chap9&10

14. Protection of Amines (II)
Organic Synthesis
Spring 1999
Protection of Amines (II)
carbamates:  233 Table 10.4 & top (23-24)
R-NH-Troc
R-NH-Boc
R-NH-Fmoc
R-NH-Teoc
OCFC-Chap10
Chap9&10