protect - PROTECTING GROUPS Carey & Sundberg Chapter...

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PROTECTING GROUPS 57 Carey & Sundberg Chapter 13.1 problems # 1; 2; 3a, b, c ; Smith: Chapter 7 Protecting Groups T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd edition) J. Wiley & Sons, 1991. P. J. Kocienski, Protecting Groups , Georg Thieme Verlag, 1994 1. Hydroxyl groups 2 Ketones and aldehydes 3. Amines 4. Carboxylic Acids - Protect functional groups which may be incompatible with a set of reaction conditions - 2 step process- must be efficient - Selectivity a. selective protection b. selective deprotection Hydroxyl Protecting Groups Ethers Methyl ethers R-OH R-OMe difficult to remove except for on phenols Formation: - CH 2 N 2 , silica or HBF 4 - NaH, MeI, THF Cleavage: - AlBr 3 , EtSH - PhSe - - Ph 2 P - - Me 3 SiI O O OBz OMe O O OH AlBr 3 , EtSH TL 1987 , 28 , 3659 Methoxymethyl ether MOM R-OH R-OCH 2 OMe stable to base and mild acid Formation: - MeOCH 2 Cl, NaH, THF - MeOCH 2 Cl, CH 2 Cl 2 , iPr 2 EtN Cleavage - Me 2 BBr 2 TL 1983 , 24 , 3969
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PROTECTING GROUPS 58 Methoxyethoxymethyl ethers (MEM) R-OH R-OCH 2 OCH 2 CH 2 OMe stable to base and mild acid Formation: - MeOCH 2 CH 2 OCH 2 Cl, NaH, THF - MeOCH 2 CH 2 OCH 2 Cl, CH 2 Cl 2 , iPr 2 EtN TL 1976 , 809 Cleavage - Lewis acids such as ZnBr 2 , TiCl 4 , Me 2 BBr 2 O C 5 H 11 MEM-O O-Si(Ph) 2 tBu B S S Cl O C 5 H 11 HO O-Si(Ph) 2 tBu TL 1983 , 24 , 3965, 3969 - can also be cleaved in the presence of THP ethers Methyl Thiomethyl Ethers (MTM) R-OH R-OCH 2 SMe Stable to base and mild acid Formation: - MeSCH 2 Cl, NaH, THF Cleavage: - HgCl 2 , CH 3 CN/H 2 O - AgNO 3 , THF, H 2 O, base Benzyloxymethyl Ethers (BOM) R-OH R-OCH 2 OCH 2 Ph Stable to acid and base Formation: - PhOCH 2 CH 2 Cl, CH 2 Cl 2 , iPr 2 EtN Cleavage: - H 2 / PtO 2 - Na/ NH 3 , EtOH Tetrahydropyranyl Ether (THP) O O O R H + , PhH R-OH Stable to base, acid labile Formation - DHP (dihydropyran), pTSA, PhH Cleavage: - AcOH, THF, H 2 O - Amberlyst H-15, MeOH Ethoxyethyl ethers (EE) JACS 1979 , 101 , 7104; JACS 1974 , 96 , 4745. O O O R R-OH H (R-OEE) base stable, acid labile Benzyl Ethers (R-OBn) R-OH R-OCH 2 Ph stable to acid and base Formation: - KH, THF, PhCH 2 Cl - PhCH 2 OC(=NH)CCl 3 , F 3 CSO 3 H JCS P1 1985 , 2247 Cleavage: - H 2 / PtO 2 - Li / NH 3
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PROTECTING GROUPS 59 2-Napthylmethyl Ethers (NAP) JOC 1998 , 63 , 4172 formation: 2-chloromethylnapthalene, KH cleavage: hydrogenolysis BnO OH O ONAP H 2 , Pd/C (86%) BnO OH O OH p- Methoxybenzyl Ethers (PMB) Formation: - KH, THF, p-MeOPhCH 2 Cl - p-MeOPhCH 2 OC(=NH)CCl 3 , F 3 CSO 3 H TL 1988 , 29 , 4139 Cleavage: - H 2 / PtO 2 - Li / NH 3 - DDQ - Ce(NH 4 ) 2 (NO 3 ) 6 (CAN) - e - o-Nitrobenzyl ethers Review: Synthesis 1980 , 1; Organic Photochemistry , 1987 , 9 , 225 NO 2 Cl R O O 2 N NaH, THF R-OH Cleavage: - photolysis at 320 nm HO O O NO 2 HO HO OH HO O OH HO HO OH h ν , 320 nm, pyrex, H 2 O JOC 1972 , 37 , 2281, 2282. p-Nitrobenzyl Ether TL 1990 , 31 , 389 -selective removal with DDQ, hydrogenolysis or elctrochemically 9-Phenylxanthyl- (pixyl, px) TL 1998 , 39 , 1653 ROH + O Ph Cl pyridine O Ph OR Formation: Removal: O Ph OR h ν (300 nm) CH 3 CN,H 2 O ROH + O Ph OH Trityl Ethers -CPh 3 = Tr R-OH R-OCPh 3 - selective for 1° alcohols - removed with mild acid; base stable formation: - Ph 3 C-Cl, pyridine, DMAP - Ph 3 C + BF 4 - Cleavage: - mild acid
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PROTECTING GROUPS 60 Methoxytrityl Ethers JACS 1962 , 84 , 430 - methoxy group(s) make it easier to remove C O R R 2 R 1 R 3
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protect - PROTECTING GROUPS Carey & Sundberg Chapter...

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