PROTECTING GROUPS Carey & Sundberg Chapter 13.

1 problems # 1; 2; 3a, b, c ; Smith: Chapter 7

57

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. 2 3. 4. Hydroxyl groups Ketones and aldehydes Amines 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 Formation: Cleavage: O

difficult to remove except for on phenols

CH2N2, silica or HBF4 NaH, MeI, THF AlBr3, EtSH PhSe Ph2P Me3SiI
OMe AlBr3, EtSH O OBz O OBz O OH TL 1987, 28 , 3659

Methoxymethyl ether MOM R-OH R-OCH2OMe

stable to base and mild acid

Formation: - MeOCH2Cl, NaH, THF - MeOCH2Cl, CH2Cl2, iPr2EtN Cleavage - Me2BBr2 TL 1983, 24 , 3969

PROTECTING GROUPS Methoxyethoxymethyl ethers (MEM) R-OH R-OCH2OCH2CH2OMe stable to base and mild acid TL 1976, 809

58

Formation: - MeOCH2CH2OCH2Cl, NaH, THF - MeOCH2CH2OCH2Cl, CH2Cl2, iPr2EtN Cleavage - Lewis acids such as ZnBr2, TiCl4, Me2BBr2
S MEM-O C5H11 O-Si(Ph)2tBu B Cl S O HO C5H11 O

TL 1983, 24 , 3965, 3969 O-Si(Ph)2tBu

- can also be cleaved in the presence of THP ethers Methyl Thiomethyl Ethers (MTM) R-OH R-OCH2SMe

Stable to base and mild acid

Formation: - MeSCH2Cl, NaH, THF Cleavage: - HgCl2, CH3CN/H2O - AgNO3, THF, H2O, base Benzyloxymethyl Ethers (BOM) R-OH R-OCH2OCH2Ph

Stable to acid and base

Formation: - PhOCH2CH2Cl, CH2Cl2, iPr2EtN Cleavage: - H2/ PtO2 - Na/ NH3, EtOH Tetrahydropyranyl Ether
O H
+

(THP)

R-OH

, PhH

Stable to base, acid labile

Formation Cleavage:

- DHP (dihydropyran), pTSA, PhH - AcOH, THF, H2O - Amberlyst H-15, MeOH

Ethoxyethyl ethers (EE) JACS 1979, 101 , 7104; JACS 1974, 96 , 4745.
R-OH O H+ R O O

(R-OEE)

base stable, acid labile

Benzyl Ethers (R-OBn) R-OH R-OCH2Ph Formation: Cleavage:

stable to acid and base JCS P1 1985, 2247

- KH, THF, PhCH2Cl - PhCH2OC(=NH)CCl3, F3CSO3H - H2 / PtO2 - Li / NH3

PROTECTING GROUPS 2-Napthylmethyl Ethers (NAP) JOC 1998, 63, 4172 formation: 2-chloromethylnapthalene, KH cleavage: hydrogenolysis
OH BnO O ONAP H2, Pd/C (86%) BnO OH O OH

59

p- Methoxybenzyl Ethers (PMB) Formation: - KH, THF, p-MeOPhCH2Cl - p-MeOPhCH2OC(=NH)CCl3, F3CSO3H Cleavage: H2 / PtO2 Li / NH3 DDQ Ce(NH4)2(NO3)6 (CAN) e-

TL 1988, 29 , 4139

o-Nitrobenzyl ethers Review: Synthesis 1980, 1; Organic Photochemistry, 1987, 9 , 225

NaH, THF R-OH Cl NO 2 R O O 2N

Cleavage:
HO HO HO O O

- photolysis at 320 nm
NO 2 h, 320 nm, pyrex, H2O HO HO HO O OH JOC 1972, 37 , 2281, 2282. OH

OH

p-Nitrobenzyl Ether TL 1990, 31 , 389 -selective removal with DDQ, hydrogenolysis or elctrochemically 9-Phenylxanthyl- (pixyl, px)
Formation:

TL 1998, 39, 1653

Ph Cl pyridine Ph OR

ROH

+
O O Ph h (300 nm) OH

Removal:

Ph

OR

ROH
O CH3CN,H 2O

+
O

Trityl Ethers -CPh3 = Tr R-OH R-OCPh3 - selective for 1 alcohols - removed with mild acid; base stable formation: - Ph3C-Cl, pyridine, DMAP - Ph3C + BF4Cleavage: - mild acid

PROTECTING GROUPS Methoxytrityl Ethers JACS 1962, 84 , 430 - methoxy group(s) make it easier to remove
R1 (p-Methoxyphenyl)diphenylmethyl ether 4'-methoxytrityl MMTr-OR R2 C O R Di-(p-methoxyphenyl)phenylmethyl ether 4',4'-dimethoxytrityl DMTr-OR Tri-(p-methoxyphenyl)methyl ether 4',4',4'-trimethoxytrityl TMTr-OR R3

60

Tr-OR < MMTr-OR < DMTr-OR << TMTr-OR

O HN R O O O HO OH R = Tr 48 hr. R= MMTr 2 hr. R= DMTr 15 min. R= TMTr 1 min. N 80% AcOH (aq) 20C HO HN O O HO OH N O

(too labile to be useful)

Oligonucleotide Synthesis (phosphoramidite method - Lessinger) Review: Tetrahedron 1992, 48 , 2223

S I L I C A OH OH OH S I L I C A O O O DMTrO S I L I C A DMTrO O O P O coupling S DMTrO O I2, H2O O OOB O S O S O Cl 3CCOOH O B' O HO O OO B O Repeat Cycle B' N (iPr)2 CN O B' O O O O O Si (CH 2)3 N C (CH 2)2 C O H O Cl 3CCOOH S O B HO O B Si (CH 2)3 NH 2 S I L I C A O O O O O Si (CH 2)3 N C (CH 2)2 C OH H

DMTrO O

B'

DMTrO O

B'

P O

CN B O

Base

P O

B O

P O

P O

PROTECTING GROUPS Silyl Ethers Synthesis 1985, 817 Synthesis 1993, 11 Synthesis 1996, 1031 R-OH R-O-SiR3 formation: - R3Si-Cl, pyridine, DMAP - R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAP - R3Si-OTf, iPr2EtN, CH2Cl2 Trimethylsilyl ethers Me3Si-OR TMS-OR - very acid and water labile - useful for transiant protection

61

Triethylsilyl ethers Et3Si-OR TES-OR - considerably more stable that TMS - can be selectively removed in the presence of more robust silyl ethers with with F - or mild acid
O TESO OTBS H2O/ACOH/THF (3:5:11), 15 hr (97%) OH O OTBS Liebigs Ann. Chem. 1986, 1281

Triisopropylsilyl ethers iPr3Si-OR TIPS-OR - more stabile to hydrolysis than TMS Phenyldimethylsilyl ethers J. Org. Chem. 1987, 52 , 165 t-Butyldimethylsilyl Ether tBuMe 2Si-OR TBS-OR TBDMS-OR JACS 1972, 94 , 6190 - Stable to base and mild acid - under controlled condition is selective for 1 alcohols t-butyldimethylsilyl triflate tBuMe 2Si-OTf TL 1981, 22 , 3455 - very reactive silylating reagent, will silylate 2 alcohols cleavage: - acid - F- (HF, nBu4NF, CsF, KF)
TBSO HO CO2Me HF, CH3CN (70%) O OTBS O HO JCS Perkin Trans. 1 1981, 2055 CO2Me

t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR -OR - stable to acid and base - selective for 1 alcohols - Me3Si- and iPr 3Si groups can be selectively removed in the presence of TBS or TBDPS groups. - TBS can be selectively removed in the presence of TBDPS by acid hydrolysis. TL 1989, 30 , 19

PROTECTING GROUPS cleavage - F- Fluoride sources: Me O Si tBu Me AcOH / THF/ H2O Ph O Si tBu Ph Me tBu Si Me Me O OTHP PPTS / EtOH tBu Me Si O OH JACS 1984, 106 , 3748 O Si Ph tBu Ph JOC 1981, 46 ,1506 TL 1989, 30 , 19.

62

nBu 4NF (basic reagent) HF / H2O /CH3CN HFpyridine SiF4. CH2Cl2

OH

TL 1979, 3981. Synthesis 1986, 453 TL 1992, 33 , 2289

Esters R-OH R-O2CR' Formation: - "activated acid", base, solvent, (DMAP) Activated Acids Chem. Soc. Rev. 1983, 12, 129 Angew. Chem. Int. Ed. Engl. 1978, 17, 569. RCO2H "activated acid" carboxylic acid derivative (ester, amide, etc.) Acid Chlorides
O O R OH R O Cl N acyl pyridinium ion (more reactive) N N R + N R O N + N

1. SOCl2 2. PCl5 3. (COCl)2 Anhydrides

O 2 R OH P2O 5 R O O O R

Activating Agents: Carbonyl Diimidazole

O O R OH O N N R N NH + CO + N N N

N Acyl Imidazole

PROTECTING GROUPS Dicyclohexylcarbodiimide

O O R OH C 6H11 NH O C N C 6H11 Nu: R O Nu

63

N C N

+C 6H11

N H

N H

C 6H11

Ketene formation is a common side reaction- scambling of chiral centers

O R H O C N C 6H11 C 6H11 NH R C O

"ketene"

Hydroxybenzotriazole (HOBT) - reduces ketene formation

O R O C N C 6H11 C 6H11 NH N O N N OH N R O N N

N-Hydroxysuccinimide (NHS)
O R O C N C 6H11 C 6H11 NH O O O O N O

HO

N R O

2,2'-Dipyridyl Disulfide (Aldrithiol, Corey Reagent) Aldrichimica Acta 1971, 4 , 33

O R OH Ph3P: N S S N R O S N

+
N SH

Ph3P=O

Mukaiyama's Reagent (2-Chloro-1-methyl pyridinium Iodide or 2-Fluoro-1methyl pyridinium p-toulenesulfonate) Aldrichimica Acta 1987, 20 , 54 Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575
O TsO R O O + N Me I-

+
R OH

+ N Me

Acetates R-OH R-O2CCH3 - stable to acid and mild base - not compatable with strong base or strong nucleophiles such as organometallic reagents Formation: - acetic anhydride, pyridine - acetyl chloride, pyridine

PROTECTING GROUPS Cleavage: K2CO3, MeOH, reflux KCN, EtOH, reflux NH3, MeOH LiOH, THF, H2O enzymatic hydrolysis (Lipase)
OAc Porcine Pancreatic Lipase OAc TL 1988, 30 , 6189 OH (96% ee)

64

Org. Rxns. 1989, 37, 1.

OAc

Chloroacetates - can be selectively cleaved with Zn dust or thiourea.

O Me Cl AcO Me OAc Cl O O O O OR O H2NNHCOSH Me O OR HO O AcO Me OAc O O Cl HO O JCS CC 1987, 1026 O

OH

Trifluoroacetates Formation: - with trifluoroacetic anhydride or trifluoroacetyl chloride Cleavage: - K2CO3, MeOH Pivaloate (t-butyl ester) - Fairly selective for primary alcohols Formation: - tbutylacetyl chloride or t-butylacetic anhydride Cleavage: - removed with mild base Benzoate (Bz) - more stable to hydrolysis than acetates. Formation: - benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) , benzoyl tetrazole (TL 1997, 38, 8811) Cleavage: - mild base - KCN, MeOH, reflux 1,2 and 1,3- Diols Synthesis 1981, 501
R2 OH R R1 OH O R3 H+ , -H2O R2 O R R3 O R1

Chem. Rev. 1974, 74, 581

Isopropylidenes

(acetonides)
OH R R1 OH H+ acetone or OMe MeO OMe or Me O R Me O R1

- in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored - cleaved with mild aqueous acid

PROTECTING GROUPS Cycloalkylidene Ketals - Cyclopentylidene are slightly easier to cleave than acetonides - Cyclohexylidenes are slightly harder to cleave than acetonides
O OH R R1 OH H+ , -H2O MeO OMe (CH 2)n O R (CH 2)n O R1 (CH 2)n -or-

65

Benzylidene Acetals
OH R R1 OH PhCHO -orPhCH(OMe)2 H , -H2O
+

Ph O R O R1

- in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usually favored - benzylidenes can be removed by acid hydrolysis or hydrogenolysis - benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins. p-Methoxybenzylidenes - hydrolyzed about 10X faster than regular benzylidenes - Can be oxidatively removed with Ce(NH 4)2(NO3)6 (CAN)
OBn BnO MeO O O O OMe Ce(NH 4)2(NO3)6 CH 3CN, H2O (95%) MeO O BnO OBn OH OH

Other Reactions of Benzylidenes - Reaction with NBS (Hanessian Reaction)

H Ph O O HO O O HO OMe NBS, CCl 4 Ph O HO O HO OMe Br Org. Syn. 1987, 65, 243

- if benzylidene of a 1 alcohol, then 1 bromide - Reductive Cleavage

Ph O MeO 2C
O

O CO 2Me

Na(CN)BH3, TiCl4,CH 3CN MeO 2C

OH CO 2Me OBn Synthesis 1988, 373.

O O O

Ph

TMS-CN BF3OEt2 MeO

OH Tetrahedron 1985, 41, 3867 O O H Ph CN

MeO

PROTECTING GROUPS
Ph O O DIBAL-H TL 1988, 29 , 4085 O O BnO OH

66

OMe

OMe

Carbonates
OH R R1 OH (Im)2CO O R O O R1

- stable to acid; removed with base - more difficult to hydrolyze than esters Di-t-Butylsilylene (DTBS) TL 1981, 22 , 4999 - used for 1,3- and 1,4-diols; 1,2-diols are rapidly hydrolyzed - cleaved with fluoride (HF, CH 3CN -or- Bu4NF -or- HFpyridine) - will not fuctionalize a 3-alcohol
OH OH (t-Bu)2SiCl 2, Et3N CH 3CN, HOBT O Si O tBu tBu

1,3-(1,1,3,3)-tetraisopropyldisiloxanylidene (TIPDS) - specific for 1,3- and 1,4-diols - cleaved with fluoride or TMS-I
O HN HO O O HO OH N iPr2Si(Cl)-O-Si(Cl)iPr2 pyridine

TL 1988, 29 , 1561

O HN O Si O Si O OH O O N

Ketones and Aldehydes - ketones and aldehydes are protected as cyclic and acyclic ketals and acetals - Stable to base; removed with H3O+
R O R1 (CH 2OH)2, H+ PhH, -H2O -or(CH2OSiMe 3)2, TMS-OTf, CH2Cl 2 CH 2(CH 2OH)2, H+ , PhH, -H2O MeOH, H+ R OMe OMe R1

O TL 1980, 21 , 1357

R1 O 1,3-dioxolanes R O R1 O 1,3-dioxanes

PROTECTING GROUPS Cleavage rate of substituted 1,3-dioxanes: Chem. Rev. 1967, 67 , 427.
R O > R1 O R1 O R O >> R1 O R O

67

- Ketal formation of ,-unsaturated carbonyls are usually slower than for the saturated case.
O CH 2(CH 2OH)2, H+ , PhH, -H2O O
O O O O LiBF4 O (88%) Me3Si O

O O

Fluoride cleavable ketal:

O

TL 1997, 38, 1873

Base cleavable ketal:

O R1 R2 HO OH O pTSA, C6H6 R1 O R2 R1 R2 SO2Ph SO2Ph DBU, CH2Cl 2 O

TL 1998, 39, 2401

Carboxylic Acids Tetrahedron 1980, 36, 2409. Tetrahedron 1993, 49, 3691 Nucelophilic Ester Cleavage: Organic Reactions 1976, 24, 187. Esters Alkyl Esters formation: - Fisher esterification (RCOOH +R'OH + H+) - Acid Chloride + R-OH, pyridine - t-butyl esters: isobutylene and acid - methyl esters: diazomethane Cleavage: - LiOH, THF, H2O - enzymatic hydrolysis Org. Rxns. 1989, 37, 1. - t-butyl esters are cleaved with aqueous acid - Bu 2SnO, PhH, reflux (TL 1991, 32, 4239)
OH MeO 2C CO 2Me Pig Liver Esterase pH 6.8 buffer OH MeO 2C CO 2H

O R OR'

Bu2SnO, PhH, R R= Me, Et, tBu

O OH TL 1991, 32, 4239

9-Fluorenylmethyl Esters (Fm) TL 1983, 24 , 281 - cleaved with mild base (Et2NH, piperidine)
DCC RCO 2H + OH R O O

PROTECTING GROUPS 2-Trimethylsilyl)ethoxymethyl Ester (SEM) HCA 1977, 60 , 2711. - Cleaved with Bu 4NF in DMF
DCC RCO 2H + HO O SiMe 3 R O O O SiMe 3

68

- Cleaved with MgBr2OEt2 TL 1991, 32, 3099. 2-(Trimethylsilyl)ethyl Esters JACS 1984, 106 , 3030 - cleaved with Fluoride ion
DCC RCO 2H + HO SiMe 3 O R O SiMe 3

Haloesters

- cleaved with Zn(0) dust or electrochemically

DCC RCO 2H + HO CCl 3 R O O CCl 3

Benzyl Esters RCO2H + PhCH2OH RCO2Bn Formation: Cleavage: Diphenylmethyl Esters

DCC RCO 2H + HO CHPh 2 O R O CHPh 2

DCC Acid chloride and benzyl alcohol Hydrogenolysis Na, NH3

Cleavage:

- mild H3O+ - H2, Pd/C - BF3OEt2

o-Nitrobenzyl Esters - selective removed by photolysis Orthoesters Synthesis 1974, 153 TL 1983, 24 , 5571
O RCOCl + R OH

Chem. Soc. Rev. 1987, 75

O O O

BF 3OEt2 R

O O O

- Stable to base; cleaved with mild acid

PROTECTING GROUPS

69

Amines Carbamates 9-Fluorenylmethyl Carbamate (Fmoc) Acc. Chem. Res. 1987, 20 , 401 - Cleaved with mild base such as piperidine, morpholine or dicyclohexylamine
NaHCO 3 H2O, dioxane O Cl O R2N O O

R2NH

2,2,2-Trichloroethyl Carbamate
O Cl 3C O Cl O R2NH, pyridine Cl 3C O N R R

- Cleaved with zinc dust or electrochemically.

O N EtO2C S O CCl 3 S Te Te S NaBH 4 EtO2C S NH TL 1986, 27 , 4687

2-Trimethylsilylethyl Carbamate (Teoc) - cleaved with fluoride ion.

O Me 3Si O O O N O
SiMe 3 OH Cl MeO O N O O CH 3 H O SEt SEt JACS 1979, 101 7104 OEt OTBS Bu4NF, THF (100%) MeO Cl H N O CH 3 H O SEt SEt OEt

O + R2NH Me 3Si O N R R

t-Butyl Carbamate

(BOC)
O R2NH tBuO O O O OtBu R2N OtBu

Cleavage:

- with strong protic acid (3M HCl, CF3COOH) - TMS-I

O B Cl

Allyl Carbamate (Alloc)

TL 1985, 26 , 1411 TL 1986, 27 , 3753

PROTECTING GROUPS
O R2NH O O O O R2N O O

70

- removed with Pd(0) and a reducing agent (Bu3SnH, Et 3SiH, HCO2H)

O HN O CO 2Me 1) Pd(OAc) 2, Et3N, Et3SiH 2) H3O + NH 2 CO 2Me TL 1986, 27 , 3753

Benzyl Carbanate

(Cbz)
O BnO R2NH Cl R2N O O Ph

Cleavage:

Hydrogenolysis PdCl 2, Et3SiH TMS-I BBr3 h (254 nm) Na/ NH3

m-Nitrophenyl Carbamate JOC 1974, 39 , 192

O R2N O NO 2

- removed by photolysis Amides Formamides - removed with strong acid

R2NH

HCO 2Et R2N

O H

Acetamides - removed with strong acid

R2NH

Ac2O R2N

O CH 3

Trifluoroacetamides Cleavage: - base (K2CO3, MeOH, reflux) - NH3, MeOH

R2NH

(CF3CO) 2O R2N

O CF 3

Sulfonamides p-Toluenesulfonyl

(Ts)
R2NH pTsCl, pyridine R2N SO 2

PROTECTING GROUPS Cleavage: - Strong acid - sodium Naphthalide - Na(Hg)

71

Ts

Ts

Na(Hg), MeOH Na2HPO 4 (65%)

H JOC 1989, 54 , 2992

N Ts

N H

Trifluoromethanesulfonyl
Tf N N Tf

Na, NH3

NH

HN

JOC 1992, 33, 5505

NH HN

N Tf

N Tf

Trimethylsilylethanesulfonamide (SES) TL 1986, 54 , 2990; JOC 1988, 53, 4143 - removed with CsF, DMF, 95C
R2NH Me 3Si SO 2Cl R2N O S O SiMe 3

Et3N, DMF

tert-Butylsulfonyl (Bus) JOC 1997, 62, 8604

tBuSOCl, Et3N, CH2Cl2 R 2N O S tBu mCPBA -orRuCl3, NaIO4 CF3SO3H, CH2Cl2, anisole R-NH2

R-NH2

R2N SO2tBu