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

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, 2007. (2) P. J. Kocienski, ‘Protecting Groups’, Thieme, 3rd ed. 2004. OCFC-Chap10 Chap9&10

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

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

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

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

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

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

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

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

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

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

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

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