Myers Protective Groups – Silicon-Based Protection of the Hydroxyl Group Chem 115

General Reference: • In general, the stability of silyl ethers towards acidic media increases as indicated:
TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000)
4th ed. John Wiley & Sons:
Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 3rd
• In general, stability towards basic media increases in the following order:
York, 1991.
New Jersey, 2007.
TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000)

Important Silyl Ether Protective Groups: Greene, T. W.; Wuts, P. G. M. Protective Groups In Organic Synthesis, 3rd ed.
John Wiley & Sons: New York, 1991.
Half Life Half Life
CH3 Et CH3 Silyl Ether (5% NaOH–95% MeOH) (1% HCl–MeOH, 25 °C)
RO Si CH3 RO Si Et RO Si i-Pr
CH3 n-C6H13OTMS ”1 min ”1 min
Et CH3
n-C6H13OSi-i-Bu(CH3)2 2.5 min ”1 min
Trimethylsilyl (TMS) Triethylsilyl (TES) Dimethylisopropylsilyl
Isopropyldimethylsilyl (IPDMS)
n-C6H13OTBS Stable for 24 h ”1 min

n-C6H13OSiCH3Ph2 ”1 min 14 min

Et CH3 Ph n-C6H13OTIPS Stable for 24 h 55 min

RO Si i-Pr RO Si t-Bu RO Si t-Bu
n-C6H13OTBDPS Stable for 24 h 225 min
Et CH3 Ph
Davies, J. S.; Higginbotham, L. C. L.; Tremeer, E. J.; Brown, C.; Treadgold, J.
Diethylisopropylsilyl (DEIPS) t-Butyldimethylsilyl (TBS) t-Butyldiphenylsilyl (TBDPS) Chem. Soc., Perkin Trans . 1 1992, 3043.
• A study comparing alkoxysilyl vs. trialkylsilyl groups has also been done:
i-Pr R Half Life Half Life
i-Pr R O Si i-Pr O t-Bu Silyl Ether Bu4N+F– (0.06 M, 6 equiv) HClO4 (0.01 M)
RO Si i-Pr O Si
O t-Bu n-C12H25OTBS 140 h 1.4 h
i-Pr R O Si i-Pr
i-Pr R n-C12H25OTBDPS 375 h > 200 h

Di-t-butylsilylene (DTBS)
(TIPDS)Di-t-butyldimethylsilylene
Tetraisopropyldisilylene (TIPDS)
Tetraisopropyldisiloxanylidene (DTBS) n-C12H25OSiPh2(Oi-Pr) <0.03 h 0.7 h
Triisopropylsilyl (TIPS)
n-C12H25OSiPh2(Ot-Bu) 5.8 h 17.5 h

n-C12H25OPh(t-Bu)(OCH 3) 3 )
OSiPh(t-Bu)(OCH 22 h 200h
General methods for the formation of silyl ethers:
Gillard, J.W.; Fortin, R.; Morton, H. E.; Yoakim, C.; Quesnell, C. A.; Daignault, S.;
Guindon, Y. J. Org. Chem. 1988, 53, 2602.
R'3SiCl
ROH ROSiR'3 • Silyl groups are typically deprotected with a source of fluoride ion. The Si–F bond stength is
imidazole, DMF about 30 kcal/mol stronger than the Si–O bond.
Fluoride sources:
Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
Tetrabutylammonium fluoride, Bu4N+F– (TBAF)
R'3SiOTf Pyridine•(HF)x
ROH ROSiR'3 Triethylamine trihydrofluoride, Et3N•3HF
2,6-lutidine,
2,6 lutidine, CH2Cl2 Hydrofluoric acid
Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF)
Corey, E. J.; Cho, H.; Rücker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22, 3455. Ammonium fluoride, H4N+F–
P. Hogan

1
 • Monosilylation of symmetrical diols is possible, and useful.
• Selective
Selective deprotection
deprotection ofof silyl
silyl ethers
ethers is is also
also important,
important, and
and is is also
also subject
subject toto
NaH, TBSCl, THF empirical
HO OH TBSO OH empirical determination.
determination.
n n
75-97%
n = 2-6,10 TESO HO
HO
TESO
McDougal, P.G.; Rico, J.G.; Oh, Y.; Condon, B. D. J. Org. Chem. 1986, 51, 3388. H 3C H3C
CH3OBOM
CH3OBOM
CH
CH 3 CH 3 OBOM CH3 3 OBOM
TBDPSCl, i-Pr2NEt, DMF, 23 °C TBSO
TBSO pyr•HF, CH3CN TBSO
TBSO
HO OH TBDPSO OH CH
CH33 CH
CH33
n 75-86% n 0 °C, 11 h, quant.
O O H
H O
n = 2,3,5,7,9 O O AcO O
AcO O O
O O
Hu, L.; Liu, B.; Yu, C. Tetrahedron Lett. 2000, 41, 4281.
CH3 CH3 AcO
OHOH BuLi, THF; TBSCl OTBS OTBS O Ph O H3C O
HO HO HOHO CH3 CH33
88%
99% OH
CH3 CH3 N O
Roush, W. R.; Gillis, H. R.; Essenfeld, A. P. J. Org. Chem. 1983,
1984 49, 4674. H CH3
OH
• Selective protection of alcohols is of great importance in synthesis. Conditions often must be HO H
determined empirically. BzOAcO
BzO
OTIPS Taxol
Taxol O
O H
OTIPS Holton, R. A., et al. J. Am. Chem. Soc., 1994, 116, 1599.
H N O H
CH3 O H
O TESCl, 2,6-lutidine
H
H33C O H H N O H
H
OH CH2Cl2, –78 °C CH3
O
CH3 H 97% H H
H3C O H Cl2CHCO2H
CH2 OH AcO OAc
O N HO AcO OAc OAc
CH3 H OAc 90%
OTES TBSO TBSO
O O CH 2
H H O
OH • TESCl/imidazole and O N HO O
H • TESCl/imidazole O
TESOTf, 2,6-lutidine and
both OTES O
CH3 CH3
TESOTf,
gave 2,6-lutidine
the bis-silylated both
product. O O HO
HO OH
OTES OTBS
OCH3 gave the bis-silylated product. H

OH CH3
O OCH3 O
H

H N O H
H O OH
CH3 OAc
O
H O H HO2C
H3C O H O
O HO2C O
CO H CH3
CH3 H HO 2
CH2 Zaragozic acid
O N
OH CH3
OH H
O
Br Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117, 8106.
OCH3

OCH3 Phorboxazole B
• Selective deprotections in organic synthesis have been reviewed: Nelson, T. D.;
Crouch, R. D. Synthesis 1996, 1065.
Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. Engl. 2000, 39, 2536.
P. Hogan

2
 Myers Protective Groups – Protection of Hydroxyl Groups, Esters, and Carbonates Chem 115
Esters and Carbonates General methods used to form esters and carbonates:

O pyr, DMAP O
O O O O ROH
RO RO RO RO Cl R' RO R'
CH3 Cl Cl Cl
Cl Cl Cl

Acetate (Ac) Chloroacetate Dichloroacetate Trichloroacetate O O pyr, DMAP O

ROH
R' O R' RO R'

O O O O
RO RO RO RO O pyr O
F CH3 ROH
F F H3C CH3 Cl OR' RO OR'

OCH3
R O
Trifluoroacetate (TFA) Pivaloate (Piv) Benzoate (Bz) p-Methoxybenzoate
N N X–
O DMAP = 4-Dimethylaminopyridine:
O RO
RO O
O O N N
RO RO H3C CH3 H3C CH3
OCH3 O
• Proposed intermediate
Br

p-Bromobenzoate Methyl Carbonate 9-(Fluorenylmethyl) Carbonate Allyl Carbonate

(Fmoc) (Alloc) DMAP is used to accelerate reactions between nucleophiles and activated esters. Neises,
B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522.

O O • In general, the susceptibility of esters to base-catalyzed hydrolysis increases with the

O
RO RO acidity of the product acid.
RO O
O O
O RO CH3
Cl
Si(CH3)3 O CH3
Cl Cl
CH3 O O O
H3C < OCH3 < <
2,2,2-Trichloroethyl Carbonate 2-(Trimethylsilyl)ethyl Carbonate Benzyl Carbonate t-Butyl Carbonate OCH3 OCH3
H3C
(Troc) (Teoc) (Cbz) (Boc) CH3 CH3O

S
RO O O
O O
N CH3 < < Cl < F
Cl OCH3 OCH3
H3C H3C OCH3 OCH3 Cl F
Cl F
Dimethylthiocarbamate (DMTC)

P. Hogan/Seth B. Herzon

3
Acetate Esters:

• Several methods for forming and cleaving acetate esters have been developed. Lipases can often • Good selectivity can often be achieved in the selective deprotection of different esters.
be used for the enantioselective hydrolysis of acetate esters. The enantioselective hydrolysis of
meso diesters is an important synthetic transformation and racemic esters have been kinetically
resolved using lipases.

OAc OH H 3C O O
O H3 C
Acetyl cholinesterase O O
PCC H3C O H3C O
94%, 99% ee
OAc OAc OAc O
HO HO
Cl
O OH
O O
n-PrNH2
Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron Lett. 1986, O O O O
27, 1255. 71%
CH3O OH CH3O OH

• Lipases can also be effective for deprotection under very mild conditions, as in the case shown
below, where conventional methods were unsuccessful.
CH3 CH3

O O

Lipase MY OH O O
OAc O
0.1 M pH 7.2 buffer Cl CH3 O
Cl CH3 O O
O CH3 OH
CH3 28 °C, 4 days
O
O
O
Sakaki, J.; Sakoda, H.; Sugita, Y.; Sato, M.; Kaneto, C. Tetrahedron: Asymmetry, 1991, 2, 343.
CH3
O
OCH3 CH3
• A potentially general method for selectively acylating the primary hydroxyl group of a 1,2-diol O
makes use
makes use ofof stannylene
stannylene acetals
acetals as
as intermediates:
intermediates: CH3 N HO
H OH

Bu2SnO, AcCl, Neocarzinostatin Chromophore

HO OBn O OBn AcO OBn
toluene, 100 °C O CH2Cl2, 0 °C HO Myers, A. G.; Liang, J.; Hammond, M.; Wu, Y.; Kuo, E. Y. J. Am. Chem. Soc. 1998, 120,
HO
Bu Sn 5319.
Bu

Hanessian, S.;
Review: Hannessian, S.;David,
David,S.S.Tetrahedron 1985,
Tetrahedron, 41,41,
1985, 643.
643.

P. Hogan

4
• When one protective group is stable to conditions that cleave another and the converse is also true,
these groups are often said to bear an orthogonal relationship. This concept is illustrated well in the Allyl Carbonate:
context of carbonates (and carbamates).
O Pd2(dba)3, dppe, Et2NH, THF
Summary of methods for deprotecting carbonates: RO ROH
O
Methyl Carbonate:

O K2CO3, MeOH Genet, J.P.; Blart E.; Savignac, M.; Lemeune, S.; Lemaire-Audoire, S.; Bernard, J. Synlett 1993,
RO ROH 680.
OCH3
2-(Trimethylsilyl)ethyl Carbonate:

Meyers, A. I.; Tomioka, K.; Roland, D. M.; Comins, D. Tetrahedron Lett. 1978, 19, 1375.
O TBAF, THF
RO ROH
O
9-Fluorenylmethyl Carbonate:
Si(CH3)3

• The pKa of fluorene is ≈ 10.3

O Gioeli, C.; Balgobin, S.; Josephson, S.; Chattopadhyaya, J. B. Tetrahedron Lett. 1981, 22, 969.
RO H
Et3N, pyr H
O ROH
fluorene =
Benzyl Carbonate:

O H2, Pd–C, EtOH

RO ROH
O
Chattopadhyaya, J. B.; Gioeli, C. J. Chem. Soc., Chem. Comm. 1982, 672.

Trichloroethyl Carbonate:
Daubert, B. F.; King, G. C. J. Am. Chem. Soc. 1939, 61, 3328.

O Zn, AcOH Dimethylthiocarbamate (DMTC):

RO ROH
O S NaIO4 or
Cl RO ROH
Cl Cl N CH3 H2O2, NaOH
H3C

Windholz, T. B.; Johnston, D. B. R. Tetrahedron Lett. 1988, 29, 2227.

• The DMTC group is stable to a variety of reagents and reaction conditions (PCC oxidations,
Swern oxidations, chromium reagents, Grignard and alkyllithium reagents, phosphorous
ylides, LAH, HF, TBAF, and borane).

• The protecting group is introduced using thiocarbonyldiimidazole followed by treatment with

dimethylamine, or by reaction with commercially available ClCSN(CH3)2.

Barma, D. K.; Bandyopadhyay, A.; Capdevilla, J. H.; Falck, J. R. Org. Lett. 2003, 5, 4755.
P. Hogan/Seth B. Herzon

5
 Myers Protective Groups – Protection of Hydroxyl Groups, Acetals Chem 115
Cleavage of acetal protective groups:
Acetals as Protective Groups:

RO OCH3 RO O RO O CCl3 Methoxymethyl Ethers:

RO OCH3 ROH
Methoxymethyl Ether Benzyloxymethyl Ether 2,2,2-Trichloroethoxymethyl Ether

(MOM) (BOM)
1. Conc. HCl, MeOH. Weinreb, S.; Auerbach, J. J. Chem. Soc., Chem. Comm. 1974, 889.
OCH3 RO SCH3 RO O
RO O 2. Bromocatechol borane. This reagent cleaves a number of protective groups in
OCH3 approximately the following order: MOMOR ʜ MEMOR > t-BuO2CNHR > BnO2CNHR ʜ
t-BuOR > BnOR > allylOR > t-BuO2CR ʜ 2° alkylOR > BnO2CR > 1° alkylOR >>
2-Methoxyethoxymethyl Ether Methylthiomethyl Ether p-Methoxybenzyloxymethyl
p-Methoxybenzyl EtherEther alkylO2CR. Boeckman Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.

(MEM) (MTM) (PMBM) 3. LiBF4, CH3CN, H2O. Ireland, R. E.; Varney, M. D. J. Org. Chem. 1986, 51, 635.

H 3C
CH3
Si Benzyloxymethyl Ethers:
RO O CH3 O OR

RO O ROH
2-(Trimethylsilyl)ethoxymethyl Ether Tetrahydropyranyl Ether

(SEM) (THP)

1. Na, NH3. Stork, G.; Isobe, M. J. Am. Chem. Soc. 1975, 97, 6260.
General methods for forming acyclic, mixed acetals:
2. H2, Pd–C. D. Tanner, D.; Somfai, P. Tetrahedron 1987, 43, 4395.

3. Dowex 50W–X8, acidic ion exchange resin. Roush, W. R.; Michaelidies, M. R.; Tai, D. F.;
Base,
ROH R'OCH2X Chong, W. K. M. J. Am. Chem. Soc. 1987, 109, 7575.
RO OR'
Solvent

Base-solvent combinations are often diisopropylethylamine-CH2Cl2, NaH-THF, or NaH-DMF. 4-Methoxybenzyloxymethyl Ether:

Sometimes a source of iodide ion is added to enhance the reactivity of the alkylating reagent. Typical
sources include Bu4N+F
I––, ,LiI,
LiI,or
orNaI.
NaI.
RO O ROH

General methods for introducing 2-tetrahydropyranyl ethers: OCH3

TsOH 1. DDQ, H2O. Kozikowski, A. P.; Wu, J.-P. Tetrahedron Lett. 1987, 28, 5125.
ROH
O or O OR
PPTS

PPTS = Pyridinium
Pryidinium p-toluenesulfonate

Grieco, P. A.; Yoshikoshi, A.; Miyashita, M. J. Org. Chem. 1977, 42, 3772, and references
cited therein. P. Hogan

6
 2,2,2-Trichloroethoxymethyl Ether: Tetrahydropyranyl Ether:

RO O CCl3 ROH

ROH
O OR
1. Zn–Cu or Zn–Ag, MeOH. Jacobson, R. M.; Clader, J. W. Synth. Commun. 1979, 9, 57.

T. J.
2. 6% Na(Hg), MeOH, THF. Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T.J.
J. Am. Chem. Soc. 1990, 112, 7001.
1. PPTS, EtOH, 55 °C. Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem., 1977, 44, 1438.

2. TsOH, MeOH, 25 °C. Corey, E. J.; Niwa, H.; Knolle, J. J. Am. Chem. Soc. 1978, 100, 1942.
2-Methoxyethoxymethyl Ether:

OCH3 Methylthiomethyl Ether:

RO O ROH

1. ZnBr2, CH2Cl2. Corey, E. J.; Gras, J.-L.; Ulrich, P. Tetrahedron Lett. 1976, 809. RO SCH3 ROH

2. Bromocatechol borane. Refer to the section on MOM ethers.

3. PPTS, t-BuOH, heat. Monti, H.; Leandri, G.; Klos-Ringuet, M.; Corriol, C. Synth. Comm.
1983, 13, 1021. 1. HgCl2, CH3CN, H2O. Corey, E. J.; Bock, M. G. Tetrahedron Lett. 1976, 17, 3269.

2. AgNO3, THF, H2O, 2,6-lutidine. Corey, E. J.; Bock, M. G. Tetrahedron Lett. 1976, 17, 3269.

2-(Trimethylsilyl)ethoxymethyl Ether: 3. MgBr2, n-BuSH, Et2O. Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett, 1992, 183.

H 3C
CH3
Si ROH
RO O CH3

1. n-Bu4N+F–, THF. Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.

2. TFA, CH2Cl2. Jansson, K.; Frejd, J.; Kihlberg, J.; Magnusson, G. Tetrahedron Lett. 1988,
29, 361.

P.Hogan

7
 Myers Protective Groups – Protection of Hydroxyl Groups, Ethers Chem 115
Formation of trityl ethers:
Ethers as Protective Groups: HO TrO
O OCH3 Ph3CCl, DMAP O OCH3

HO OH DMF, 88% HO OH
RO OH OH
RO

Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 19, 95. In general, selective
protection of primary alcohols can be achieved.

Allyl Ether Trityl Ether Cleavage of trityl ethers:

RO 1. Amberlyst 15-H, MeOH. Malanga, C. Chem. Ind. 1987, 856.

RO
2. CF3CO2H, t-BuOH. MacCross, M.; Cameron, D. J. Carbohydr. Res. 1978, 60, 206.

OCH3 Formation of benzyl ethers:

Benzyl Ether p-Methoxybenzyl Ether RO

ROH

R'
allyl ether formation:
Allyl
R' = H or OCH3

RO 1. NaH, benzyl bromide, THF.

THF. Czernecki,
Czernecki,S.;
S.;Georgoulis,
Georgoulis,C.;
C.;Provelenghiou,
Provelenghiou,C.
C.
ROH
Tetrahedron Lett. 1976,
Tetrahedron Lett. 1976,17,
17, 3535.

2. p-CH3OC6H4CH2OC(=NH)CCl3, H+. These Theseare

areuseful
usefulconditions
conditionsfor
forbase-sensitive
base-sensitive
1. NaH, allyl bromide, benzene. Corey, E. J.; Suggs, W. J.; J. Org. Chem. 1973, 38, 3224. substrates. Yonemitsu, O.
substrates. Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
TetrahedronLett.
Lett.1988,
1988,29,
29,4139.
4139.Similar
Similar
conditions
conditionshave
havebeen
beendeveloped
developedfor
forbenzyl
benzylethers:
ethers: White, J. D.; Reddy, G. N.;
2. CH2=CHCH2OC(=NH)CCl3, H+. This procedure is useful for base-sensitive substrates. Spessard,
Spessard,G.G.O.
O.J.J.Am.
Am. Chem.
Chem. Soc.
Soc. 1988,
1988, 110,
110, 1624.
1624.
Wessel, H.-P.; Iverson, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985, 2247.
3. p-CH3OC6H4CH2Cl, NaH, THF. Marco,
Marco,J.J.L.;
L.;Hueso-Rodriguez,
Hueso-Rodriguez,J.J.A.
A.Tetrahedron
Tetrahedron
Lett.
Lett.1988,
1988,29,
29,2459.
2459.
allyl ether cleavage:
Allyl
Cleavage of benzyl ethers:
1. The use of allyl ether protective groups in synthesis has been reviewed: Guibe, F. Tetrahedron 1998, 1. H2/ Pd-C, EtOH. Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746.
54, 2967. Ammonium formate is often used as a source of H2: Bieg, T.; Szeja, W. Synthesis
1985, 76.
2. Pd(Ph3P)4, RSO2Na, CH2Cl2. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62, 8932.
Cleavage of 4-methoxybenzyl ethers:

1. DDQ, CH2Cl2. Benzyl ethers are stable to these conditions. Horita, K.; Yoshioka, T.;
Tanaka, T.; Oikawa, Y. Yonemitsu, O. Tetrahedron 1986, 42, 3021.

P. Hogan

8
 Myers Protective Groups – Protection of 1,2- and 1,3-Diols Chem 115
Protection of 1,2- and 1,3- Diols: The relative rates of hydrolysis of 1,2-O-alkylidene-_-glucofuranoses have been studied.

CH3 H3C CH3 HO H O O HO H O O CH3

O O O O O O O O O O CH3
HO HO
R' HOOH HOOH
R' n R n R R'
R' nn R R'
R' n R t1/2 = 8 h HO H O O t1/2 = 20 h HO H O O
Ethylidene Acetal Acetonide Cyclopentylidene Ketal Cyclohexylidene Ketal O O
HO HO
HOOH HOOH
OCH3 OCH3 t1/2 = 10 h t1/2 = 124 h
OCH3

Van Heeswijk, W. A. R.; Goedhart, J. B.; Vliegenthart, J. F. G. Carbohydr. Res. 1977, 58, 337.
O

O O O O O O O O General methods of cleavage:

R' n R R' n R R' n R R' n R

R' R''
H+, H2O (ROH) HO OH
Benzylidene Acetal 4-Methoxybenzylidene 3,4-Dimethoxybenzylidene Cyclic Carbonate O O
Acetal Acetal R'
R' n R
n R
• Generally, n = 0 or 1.
R' R'' R' R'' R R''
Lewis acid plus hydride donor H O OH OH O H
O O
General methods used to form acetals and ketals (illustrated for acetonides):
R' R' n R
R' n R n R
H3C CH3
R'' H O O
O HO OH O O [O]
H+ O O R'' O OH OH O R''
H 3C CH3 R' n R R' n R R' n R R' n R R' n R

H3C CH3 Selective protection of polyols:

• In general, acetonide formation with 1,2-diols occurs in preference protection to 1,3-diols;
to 1,3-diols;
CH3O OCH3 HO OH O O benzylidene acetals
benzylidene acetals display
display reversed
reversed selectivity.
selectivity. ItIt isis often
often possible
possible to
to discriminate
discriminate between
H+
between
1,2- 1,2- and of
and 1,3-diols 1,3-diols of a triol group.
a triol group.
H3C CH3 R'
R' n R n R H3C CH3
OH OH CH3
HO acetone, TsOH H 3C O OH O O
H3C
H3C CH3
CH3
O HO
OCH3 O O CH3
HO OH H+
CH3 CH3
H 3C CH2 R' 5:1
R' n R R' nn R
Williams, D.
Williams, D.R.;
R.;Sit,
Sit,S.-Y.
S.-Y.J. J.
Am. Chem.
Am. Soc.
Chem. 1984,
Soc. 106,206,
1984, 2949.
2949.

P. Hogan

9
 O O
S
CSA, H2O;
1) (CH3)2CO, CuSO4, TsOH S S H H
S OH OH O SOH p-(CH
p-(CH 3O)C
3O)C 6H
6H 4(OCH3)23)2
4CH(OCH
Cl 2) NaOH, EtOH H3C O OH CH2 O 67% over two steps O HO
HO
S OTBDPS O OTBDPS
3) CuI, HH33CC O CH2 OH
OH MgBr CSA = camphorsulfonic acid
H3C O
82% CH3
H 3C

CH3O
Mortlock, S. V.; Stacey, N. A.; Thomas, E. J. J. Chem. Soc., Chem. Comm. 1987, 880.
C 3
H3CH
O H
SO3H CH3
• In the case of a 1,2,3-triol, careful analysis must be performed to accurately predict the site of O H3C O
acetonide formation. The more substituted acetonide will be favored in cases where the substiuents
substituents H3C HH
on the resultant five-membered ring will be trans. If the substituents on the five-membered ring would H H
be oriented cis, then the alternative, less substituted acetonide may be favored.
BzO HO HO HO
OH OH HO
OH OH
Ingenol analog Ingenol

CH3 H3HC3C
H3 C CHCH
3 3 Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999,
O CH3 TsOH OO 121, 296.
HH OO
O HO
HO
HH
OH 1:10
H3HC3C

H OH OH ZnCl2, PhCHO H O O
N OH N OH
71%
N OBn N OBn

H 3C Frankowski, A.; Deredas, D.; Le Noen, D.; Tschamber, T.; Strieth, J.

CH3
O OH OTBS Helv. Chim. Acta. 1995, 78, 1837.
H CH3CN, PPTS H
O
O CH3 CH3
H 83% H CH3 CH3
O CH3 OH OH
HO OTBS
H3C
TrO N p-(CH3O)C6H4CH(OCH3)2, TrO N
OH OH N O O N
PPTS, DMF, 23 °C, 96%
MP
O N O HO CH3 O N O
H OH CH3 H
OH
MP = p-methoxyphenyl
HO
HO O O N
OH OH N
Roush, W. R.; Coe, J. W. J. Org. Chem. 1989, 54, 915. See also, Mukai, C.; Miyakawa, M.;
Hanaoka, M. J. Chem. Soc., Perkin Trans. 1 1997, 913.
O N O
H
Lampteroflavin, a source of bioluminescence.
Isobe, M.; Takahashi, H.; Goto, T. Tetrahedron Lett. 1990, 31, 717.
P. Hogan

10
 Myers Protective Groups – Selective Protection of Carbohydrates Chem 115
HO OCH3
• Selective protection methods are central to carbohydrate chemistry. The most common protective
groups in carbohydrate chemistry are acetonides, benzylidene acetals, and substituted benzylidene p-TsOH H
O OH H2 C CH3 O OH
acetals. This
This subject
subject has
has been
been reviewed:
reviewed: Calinaud,
Calinaud, P.;
P.;Gelas,
Gelas,J.J.ininPreparative
PreparativeCarbohydrate
Carbohydrate O
Chemistry. York, 1997.
Chemistry. Hanessian, S. Ed. Marcel Dekker, Inc.: New York, 1997. H 3C
HO OH 67% O OH
H3C H
OH OH
Selective Protection: thermodynamic control D-galactose

Gelas, J.; Horton, D. Carbohydr. Res. 1979, 71, 103.

HO H3C
H 3C • Note that under kinetic control the most sterically accessible
6 5 O 1 OH O H4
acetone, H2SO4 O 1 (primary) alcohol
(primary) alcohol preferentially
is preferentially attacked.
reacted.
4 O O
5 • This reaction can be applied to many hexoses, including mannose, allose, and tallose
HO 55% 3 CH3
3 2 OH 6
OH HO 2 O CH3 Kinetic vs. thermodynamic control with a pentose

D-glucose 1,2:5,6-Di-O-isopropylidene-D-glucopyranose Thermodynamic control HO

HO O
O acetone, MeOH OH
OH
Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 318. H H
2-methoxypropene, HCl
HO OH 70% O O

OCH3 H H3C CH3

OCH3 O OCH3 D-ribose
HO O
OCH3
OCH Leonard, N. J.; Carraway, K. L. J. Heterocycl. Chem. 1966, 3, 485.
O OCH3 3
p-TsOH, O OH
H Kinetic control
DMF, 64% OH HO
HO OH O 2-methoxypropene
OH O OH
OH
p-TsOH, DMF, 50% H
methyl-_-D-glucopyranoside
O HO OH O OH
O H
O O
Evans, M. E. Carbohydr. Res. 1972, 21, 473. HO H 3C
HO slow CH3
OCH3
O OH
• Note the preference for 1,3-diol protection with the methyl 4,6-benzylidene-_-D-glucopyranoside
benzylidene acetal. The phenyl group is oriented fast
exclusively as shown, in an equatorial orientation. HO OH
OH
The major isomer in solution is the pyranose form (ʜ 80%). Under
Selective Protection: kinetic control
conditions that favor kinetic control, the least sterically encumbered
alcohol in this form reacts preferentially. Isomerization is proposed to
be slower than acetonide formation. This procedure also works well
HO OCH3 with arabinose:
H
O OH H 2C CH3 O OH
O O OH 2-methoxypropene O OH
H 3C H
HO OH p-TsOH O OH
H 3C H HO OH p-TsOH, DMF, 60-70% OH
OH 95% OH O H
OH O
H3 C
D-glucose D-arabinose CH3

Gelas, J.; Horton, D. Carbohydr. Res. 1975, 45, 181.

Wolfrom, M. L.; Diwadkar, A. B.; Gelas, J.; Horton, D. Carbohydr. Res. 1974, 35, 87.
P. Hogan

11
 HO
O
Protection of cis-vicinal diols: O OCH3 (2,3-butanedione,
CH3 commercially OCH3 OH
OAc
AcO H 3C HO
available) H 3C O
O OCH3 HO OH O H3C OO
AcO
H OH
O OCH3 _,_'-dichlorotoluene, CSA, CH(OCH3)3, MeOH, reflux. OCH3 OCH3
O OH methyl-_-D-mannopyranoside 95%
H
pyr, reflux, 58% O
HO OH BF3•OEt2 is also an effective catalyst at 23 °C.
OH AcO
OAc Hense, A.; Ley, S. V.; Osborn, H. M. I.; Owen, R. D.; Poisson, J.-F.; Warriner, S. L.;
O OCH3 Wesson., K. E. J. Chem. Soc., Perkins Trans. 1 1997, 2023.
H
X Generalities concerning the selective removal of acetals and ketals:
HO O
H • Hydrolysis of the less substituted dioxane or dioxolane ring occurs preferentially in
• In general, cis-fused 5,6-systems O
substrates bearing two such groups.
are formed faster than trans-fused
5,6-systems.
OH
O H H OH
H H O
O O AcOH, H2O
Garegg, P. J.; Maron, L.; Swahn, C. G. Acta. Chem. Scand. 1972, 26, 518. O
80 °C, 85% H O
O O O
Formation of dispiroacetals as a protective group for vicinal trans diequatorial diols: H CH3O O
O
CH3O O

O
OH O Kishi, Y.; Stamos, D.P. Tetrahedron Lett. 1996, 37, 8643
HO CH3 O
OCH3 H3C
dl-camphorsulfonic acid CH3
O OO O
H 3C O H H HO H
HO O H
HO O O pH = 2, 40 °C O
76% O HO O
OCH3 CH3 CH3
methyl-_-L-fucopyranoside O 4h
HO H CH3 55% from HO O CH3
(derived from L-fucose) H
glucose

Ley, S. V.; Leslie, R.; Tiffin, P. D.; Woods, M. Tetrahedron Lett. 1992, 4767. Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 318.
• 2,2-disubstituted
2,2-disubstittued 1,3-dioxanes (6-membered rings) are generally hydrolyzed faster than the
alsobeen
A cheaper alternative has also beendeveloped:
developed: corresponding dioxolanes (5-membered rings).

OH H
O OH 1) 2-methoxypropene O OAc
CH3O OCH3 O
HO
CH3 p-TsOH H3 C
O OCH3 H3C HO OH O O
OCH3 OH 2) Ac2O, py CH3 H
CH3O OCH3 HO OH O CH3
H 3C O
HO OH H3C OO H 3C
D-mannose
OH CSA, CH(OCH3)3, MeOH, reflux OCH3 OCH3
methyl-_-D-mannopyranoside O OAc AcOH
HO CH3
91%
HO O H 2O H3C O O
74% over O O
Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org. Chem. 1996, 61, 3897. O CH3 three steps O
H3C OAc
H 3C CH3
Horton, D.; Gelas, J. Carbohydr. Res. 1978, 45, 181.
P. Hogan

12
 H
O OCH3 Lewis acid O OCH3 O OCH3
O BnO HO
Special properties of benzylidene and substituted benzylidene acetals: hydride donor
O OR' HO OR' BnO OR'
• In general, substitution of the ring of a benzylidene acetal with a p-methoxy substituent H
OR OR OR
increases the rate of hydrolysis by about an order of magnitude.
A B

R' R' Lewis acid hydride donor yield (regioisomer)

OCH3
Ac Ac TFA Et3SiH 95% (A)
Bn Bn TFA Et3SiH 80% (A)
is more rapidly hydrolyzed
hyrolyzed than
than
Bn Bn Bu2BOTf BH3•THF 87% (B)
O O O O
Bn Bn AlCl3 BH3•N(CH3)3 72% (A)
R' R' n R
n R Bn Bn HCl, THF NaBH3CN 82% (A)

Smith, M.; Rammler, D. H.; Goldberg, I. H.; Khorana, H. G. J. Am. Chem. Soc. 1962, 84, 430.
trifluoroaceticacid/triethylsilane
• The trifluroacetic acid/triethylsilanereagent
reagentwas
wasineffective
ineffectivewith
withaagalactose
galactosederivative,
derivative,
however
however thethe others
others appear
apperartotobe begeneral
generalmethods.
methods.Acetonides
Acetonides and other
and ketals
other and
ketals acetals
and acetals
• Benzylidene acetals can also
can also be cleaved
be cleaved fromfrom the reductively.
the diol diol reductively. can
can also
also bebe reduced,
reduced, so
so care
care in
in synthetic
synthetic planning
planning must
must be
be exercised.
exercised.

Trifluoroacetic acid, triethylsilane :

DeNinno, M. P.; Etienne, J. B.; Duplantier, K. C. Tetrahedron Lett. 1995, 5, 669.

Dibutylboron triflate, borane:

H2, Pd-C, AcOH Chan, T. H.; Lu, J. Tetrahedron Lett., 1998, 39, 355.
O O HO OH
or R' Aluminum trichloride, borane trimethylamine complex;
R' n R NH3, Na (Birch reduction) n R
Garegg, P. J. Pure. Appl. Chem. 1984, 56, 845.

HCl, sodium cyanoborohydride:

OCH3 Qiao, L.; Vederas, J. C. J. Org. Chem. 1993, 58, 3480.

TfOH, sodium cyanoborohydride

Kiessling, L. L.; Pohl, N. L. Tetrahedron Lett. 1997, 38, 6985.

Pd(OH)2, 25 °C, H2 Diisobutyl aluminum hydride is also an effective reagent for regioselective reduction of
O O HO OH
benzylidene acetals. This reagent gives the more hindered ether.
R' R' n R
n R Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593.

Oxidation of benzylidene and substituted benzylidene acetals:

• Methods have also been developed to cleave only one carbon-oxygen bond resulting in in • Acetals containing a methine group may be oxidized at that position resulting in the formation
the formation of a benzyl ether. This
Thisreaction
reactionhas
hasbeen
beenextensively
extensivelystudied
studiedin
inthe
thecontext
contextof
of hydroxy
of a esters.
hydroxy esters.
carbohydrate chemistry. R' R'
[O]
O O O O X

R n R R n R

• This transformation can be effected under a variety of condtions, and some

and some variants
variants can be
can be
used to further functionalize a substrate.
P. Hogan

13
 General Reactions: Proposed Mechanism:

H H
O O NBS O O Br O O NBS O O OH O OCH3 O OCH3
O NBS O
H 2O •
R n R R n R R n R R n R O OH
O OH H
H OH
OH
In the methyl 4,6-O-benzylidenehexopyranoside series, the oxidative formation of bromo
benzoates is a general reaction:
H Br2
O OCH3 NBS, BaCO3 O OCH3
O Br

O OH CCl4, 100% O OH
H Br
OH OH H
O H O OCH3
O OCH3 O
O
H O OH
O OCH3 O OCH3 O OH Br H
O NBS, BaCO3 Br H OH
OH
O OH CCl4, 67% O OH
H
OH OH
O

O OCH3
Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035, 1045, and 1053. Br

• This reaction has also been used to generate glycosylating reagents O OH

OH
H H
H H O
O
O O
O Br
Br
O O
O O
NBS, bromotrichloro-
O
O methane, then CH
H3C3 O O
O
H3C3
CH O H
H H
H O O O
O
O O
O tetrabutylammonium AcO O
AcO bromide H
H
(anomerization) AcO OAc
OAc
AcO OAc
OAc CH3 • Ozonolysis also cleaves acetals to hydroxy esters efficiently. This reaction has been
H 3C OAc
OAc O H reviewed: Deslongchamps, P.; Atlani, P.; Frehel, D.; Malaval, A.; Moreau, C.
O H Can. J. Chem. 1974, 52, 3651.
O CH3
H
O CH3
O R' O O
H H Hg(CN)2 CH3
O O H 3C
O 79% O H O O O3 R' O OH OH O R'
over two steps O H
CH
H3C O OBz
OBz O –78 °C
3 CH3 R n R R
H H n R R n R
O O CH3
AcO
AcO O O
H H
AcO OAc OH
HO
AcO
OAc
Collins, J. M.; Manro, A.; Opara-Mottah, E. C.; Ali, M. H.
J. Chem. Soc., Chem. Comm. 1988, 272. P. Hogan

14
 H
O O + – O O
O TMS DDQ, CuCl2, Bu4 NCl
NCl X TMS

O OBz or MBzO
PMPCO OBz
• Hydroxy benzoates are obtained in the presence of water. H
OBz DDQ, CuBr2, Bu4+NBr
NBr– OBz
• The axial benzoate is usually obtained. CH33O
O
X = Cl , 96%
Binkley, R. W.; Goewey, G. S.; Johnston, J. C. J. Org. Chem. 1984, 49, 992 O X = Br, 93%
NC Cl PMP = p-methoxyphenyl
OCH3 OCH3 DDQ =
CH3 O NBS, BaCO3 CH3 O NC Cl
OPiv OPiv
O
OO H2O, 72% O O OH
Zhang, Z.; Magnusson, G. J. Org. Chem. 1996, 61, 2394.
2-electron
• 2- electron oxidation
oxidation of
of 4-methoxybenzyl
4-methoxybenzyl groups
groups with
with DDQ
DDQ isis aa general
general reaction.
reaction.

• This has been used extensively to remove 4-methoxybenzyl ethers, and also to form
4-methoxybenzylidene acetals.
OCH3
OCH3 OCH3
CH3 O OPiv OCH3
OO CH3 O OPv DDQ
H2O attacks exo face OO
HO TBSO O OH TBSO O OH
H H
OCH3 OCH3

H3C CH3 H3C CH3

OTBS OTBS

OCH3 –H+

• Only this lone pair is

available for donation
into the other C-O m*
orbital. TBSO
TBSO O O
H
OCH3

H3C
CH3 CH3
OTBS

Jones, A. B.; Yamaguchi, M.; Patten, S.; Danishefsky, S. J.; Ragan, J. A.; Smith, D. B.;
King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754.
Schreiber, S. L. J. Org. Chem. 1989, 54, 17.
• Oxidation of 4-methoxybenzylidene acetals has also been studied: A useful extension of this reaction has been developed to protect diols directly:

H OCH3
O O
O TMS DDQ, AcOH, H2O O O CH3 CH3
HO TMS CH3O
OCOPh OCOPh
O OBz CH3 CH3
H MBzO OBz OH O
OBz HO 2.2 equiv DDQ O
CH3O OBz 71%
MP H
79% (19% of regioisomer)
Oikawa, Y.; Nishi, T.; Yonemitsu, O. Tetrahedron Lett. 1983, 24, 4037.
P. Hogan

15
 Myers Protective Groups – Protection of Phenols Chem 115
Phenolic Protective Groups: t-Butyl Ether Formation:

CH3 CH3
CH3
CH3
OCH3 O CH3 O O OH O
CH3

Methyl Ether t-Butyl Ether Benzyl Ether Allyl Ether

1. Isobutylene, CF3SO3H, CH2Cl2, –78 °C. Holcombe, J. L.; Livinghouse, T. J. Org. Chem.
1986, 51, 11.

O O 2. t-Butyl halide, pyr. Masada, H.; Oishi, Y. Chem. Lett. 1978, 57.
SiR3
O O R O OR O OR

t-Butyl Ether Cleavage:

Silyl Ethers Phenyl Esters Phenyl Carbonates Acetals

1. CF3CO2H, 25 °C. Beyerman, H. C.; Bontekoe, J. S. Recl. Trav. Chim. Pays-Bas.

1962, 81, 691.
Ph Ph
Si
O t-Bu • For the other phenol protective groups, the sections describing these groups in the context of
alcohols should be consulted. Most of the preparations used for alcohols are applicable to
t-Butyldiphenylsilylethyl Ether
phenols. Hydroxyl protective groups that are cleaved with base are generally more labile with
phenols.

Methyl Ether Formation:

t-Butyldiphenylsilylethyl (TBDPSE) ether formation:

DIAD, PPh3
Ph Ph
Si
OCH3 OH O t-Bu
OH Ph Ph
Si
HO t-Bu
1. MeI, K2CO3, acetone. Vyas, G. N.; Shah, N. M. Org Synth., Collect. Vol. IV 1963, 836.
• The TBDPSE group is stable to 5% TFA–CH2Cl2, 20% piperidine–CH2Cl2, catalytic
2. Diazomethane, Et2O. Bracher, F.; Schulte, B. J. Chem. Soc., Perkin Trans. 1 1996, 2619. hydrogenation, n-BuLi, and lead tetraacetate.

• The TBDPSE group has been cleaved using TBAF (2.0 equiv, 40 °C, overnight) or 50% TFA–
Methyl Ether Cleavage: CH2Cl2.

1. Me3SiI, CHCl3, 25-50 °C. This reagent also cleaves benzyl, trityl, and t-butyl ethers rapidly. Gerstenberger, B. S.; Konopelski, J. P. J. Org. Chem. 2005, 70, 1467.
Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761.

2. EtSNa, DMF, reflux. Ahmad, R.; Saa, J. M.; Cava, M. P. J. Org. Chem. 1977, 42, 1228.

3. 9-Bromo-9-borabicyclo[3.3.0]nonane, CH2Cl2. Bhatt, M. V. J. Organomet. Chem. 1978,

156, 221.
P. Hogan/Seth B. Herzon

16
 Myers Protective Groups – Protection of the Carbonyl Group Chem 115
Carbonyl protective groups:
Preparation of dimethyl acetals and ketals:
OCH3 O O
R R R O CH3O OCH3
R' OCH3 R' O R' O R R'
R R'

dimethyl acetal 1,3-dioxane 1,3-dioxolane 1. MeOH, dry HCl. Cameron, A. F. B.; Hunt, J. S.; Oughton, J. F.; Wilkinson, P. A.; Wilson,
B. M. J. Chem. Soc. 1953, 3864.
SCH3 S S O 2. MeOH, LaCl3, (MeO)3CH. Acetals are formed efficiently, but ketalization is unpredictable.
R R R R Gemal, A. L.; Luche, J.-L. J. Org. Chem. 1979, 44, 4187.
R' SCH3 R' S R' S R' S
3. Me3SiOCH3, Me3SiOTf, CH2Cl2, –78 °C. Lipshutz, B. H.; Burgess-Henry, J.; Roth, G. P.
S,S'-dimethylthioacetal 1,3-dithiane 1,3-dithiolane 1,3-oxathiolane Tetrahedron Lett. 1993, 34, 995.

General order of reactivity of carbonyl groups towards nucleophiles: 4. Sc(OTf)3, (MeO)3CH, toluene, 0 °C. Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H.
Synlett 1996, 839.
aldehydes (aliphatic > aromatic) > acylic ketones ʜ cyclohexanones > cyclopentanones >
_!`-unsaturated ketones ʜ _!_"disubstituted ketones >> aromatic ketones. • Other dialkyl acetals are formed similarly.

Cleavage of dimethyl acetals and ketals:

Approximate rates (L mol –1s–1 at 25-30 °C) for proton-catalyzed (HCl, water or dioxane-water)
cleavage of acetals and ketals. 1. TFA, CHCl3, H2O. These conditions cleaved a dimethyl acetal in the presence of a
1,3-dithiane and a dioxolane acetal. Ellison, R. A.; Lukenbach, E. R.; Chiu, C.-W.
H3C OEt H OEt
H H OEt H OPh Tetrahedron Lett. 1975, 499.
OEt OEt OEt OEt 2. TsOH, acetone. Colvin, E. W.; Raphael, R. A.; Roberts, J. S. J. Chem. Soc., Chem.
Commun. 1971, 858.
CH3O
3. 70% H2O2, Cl3CCO2H, CH2Cl2, t-BuOH; dimethyl sulfide. Myers, A. G.; Fundy, M. A.
6 X 103 5 X 103 160 41
M.; Lindstrom, Jr. P. A. Tetrahedron Lett. 1988, 29, 5609.

O O O O H
H OEt H OEt
H CH3 O O
H 3C OEt H OEt O
PvO
PvO PvO PvO
PvO
H 70% H2O2 PvO H
5 1.2 1.6 H Me2S
1.5 X 10–4 Cl3CCO2H
H OCH H OOH O
O
• In general, cyclic acetals are cleaved more slowly than their open chain analogs TBSO
TBSO 3 TBSO MeOH TBSO
TBSO
t-BuOH, CH2Cl2 TBSO 80%
• In general, dithio acetals are not cleaved by Brønsted acids. OCH33 H
OCH33
Rates of acid-catalyzed cleavage of mono thioacetals and acetals have been determined:

• Other methods resulted in cleavage of the epoxide.

H OEt H SEt H SEt H SEt
OEt OCH3 OEt SEt

160 41 1.3 3.5 X 10–4

Satchell, D. P. N.; Satchell, R. S. Chem. Soc. Rev. 1990, 19, 55.

P. Hogan

17
Cyclic acetals and ketals: • When protecting _,ß-unsaturated ketones, olefin isomerization is common.

Relative rates of ketalization with common diols: CH3 CH3 CH3

OH
HO
+
H3C CH3 O O
> OH > HO OH
OH O acid
HO OH HO O O
A B

Cleavage of 1,3-dioxolanes vs. 1,3-dioxanes: Strong acids (pKa ʜ 1) tend to favor isomerization, while weaker acids (pKa • 3)
favor isomerization much less so, or not at all.

O O acid pKa %A %B % conversion

RR R
>
R'
R' R' fumaric acid 3.03 100 0 90
O O
phthalic acid 2.89 70 30 90

Relative rates of cleavage for 1,3-dioxolanes: oxalic acid 1.23 80 20 93

0 100 100
TsOH < 1.0
CH3 CH3
R O CH3 R O R O
> > De Leeuw, J. W.; De Waard, E. R.; Beetz, T.; Huisman, H. O. Recl. Trav. Chim. Pays-Bas.
R' O R' O R' O 1973, 92, 1047.

50,000 5000 1 • Generally, methods used for formation of 1,3-dioxolanes are also useful for formation of
1,3-dioxanes.
Okawara, H.; Nakai, H.; Ohno, M. Tetrahedron Lett. 1982, 23, 1087.

Cleavage of 1,3-dioxanes and 1,3-dioxolanes:

• In general, saturated ketones can be selectively protected in the presence of _!`-unsaturated ketones.
1. PPTS, acetone, H2O, heat. Hagiwara, H.; Uda, H. J. Chem. Soc., Chem. Commun.
O 1987, 1351.
O CH3
H 3C H 3C O O
O Et 2. 1M HCl, THF. Grieco, P. A.; Nishizawa, M.; Oguri, T. Burke, S. D.; Marinovic, N.
J. Am. Chem. Soc. 1977, 43, 4178.
O OH O
HO
3. Me2BBr, CH2Cl2, –78 °C. This reagent also cleaves MEM and MOM ethers.
p-TsOH•H2O, 95% Guindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett. 1983, 24, 3969.
Bosch, M. P.; Camps, F.; Coll, J.; Guerrero, T.; Tatsuoka, T.; Meinwald, J. 4. NaI, CeCl3•7H2O, CH3CN. Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.;
J. Org. Chem. 1986, 51, 773. Sambri, L. J. Org. Chem. 1997, 62, 4183. This method is selective for
cleavage of ketals in the presence of acetals. It is also selective for ketals
• Conditions have been developed to protect _!`-unsaturated ketones selectively.
of _,ß-unsaturated ketones over ketals of saturated ketones.
O O
H 3C OTMS H 3C
TMSO CH3 O CH3 O
O H3C NaI, CeCl3•7H2O H3C
TMSOTf, CH2Cl2 O O
O CH3CN
–78 °C, 92% O H 3C H H3C H
23 °C, 2h
Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357. O H H 88% H H
O
O
P. Hogan

18
Dithioacetals:
S,S'-dialkyl
In addition to serving as a protective group, S, S'-dialkyl acetals
acetals serve
serve as
as an
an umpolung
umpolung
synthon in the construction the
of carbon-carbon bonds.
of carbon-carbon bonds.
General methods of formation of S,S''-dialkyl acetals:

O SR
see below S SR S =
O R R SR
R R R
R R R' S R' SR R' S

1. RSH, HCl, 20 °C. Zinner, H. Chem. Ber. 1950, 83, 275. CH3O O CH3 Li CH3 CH3O O CH3
O O
2. RSSi(CH3)3, ZnI2, Et2O. Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J. Am. S S
O O
Chem. Soc. 1977, 99, 5009.
CH3O CH2 CH3O CH2
3. RSH, BF3•Et2O, CH2Cl2. Marshall, J. A.; Belletire, J. L. Tetrahedron Lett. 1971, 871. See also S
Cl
Hatch, R. P.; Shringarpure, J.; Weinreb, S. M. J. Org. Chem. 1978, 43, 4172. _!`-Unsaturated 60% CH3
ketones are reported not to isomerize under these conditions. However, with any of the above S
mentioned conditions conjugate addition is a concern.

• A variety of methods has been developed for the cleavage of S,S''-dialkyl acetals, largely CH3O O CH3
due to the fact that these functional groups are often difficult to remove. O
O

CH3O
O
Cl
General methods of cleavage of S,S''-dialkyl acetals:

Radicicol dimethyl ether

1. Hg(ClO4)2, MeOH, CHCl3. Lipshutz, B. H.; Moretti, R.; Crow, R. Tetrahedron Lett. 1989, 30,
15, and references therein.
Garbaccio, R. M.; Danishefsky, S. J. Org. Lett. 2000, 2, 3127.
2. CuCl2, CuO, acetone, reflux. Stutz, P.; Stadler, P. A. Org. Synth. Collect. Vol. 1988, 6, 109.

3. m-CPBA; Et3N Ac2O, H2O. Kishi, Y.; Fukuyama, T.; Natatsuka, S. J. Am. Chem. Soc. 1973,
95, 6490.

4. (CF3CO2)2IPh, H2O, CH3CN. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.

P. Hogan

19
 Myers Protective Groups – Protection of the Carboxyl Group Chem 115
Carboxyl Protective Groups: O BOPCl, Et3N, O
R'OH
R OH CH2Cl2 R OR'
O O CH3 O O CH3 CH3
CH3
R OCH3 R O CH3 R O R O Cl
O N N O
BOPCl = P
Methyl Ester t-Butyl Ester Allyl Ester 1,1-Dimethylallyl Ester
O O O

Diago-Meseguer, J.; Palomo-Coll, A. L.; Fernandez-Lizarbe, J. R.; Zugaza-Bilbao, A.

O O O O Synthesis, 1980, 547.

R O CF3 R O R O R O
Methyl esters:
OCH3 Formation:
2,2,2-Trifluoroethyl Ester Phenyl Ester Benzyl Ester 4-Methoxybenzyl Ester
O O

R OH R OCH3
OR
O R' O R' O
R' OR
SiR3 1. TMSCHN2, MeOH, benzene. Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm.
R O OR O O O O
Bull. 1981, 29, 1475. This is considered a safe alternative to using diazomethane.
R'' 2. MeOH, H2SO4. Danishefsky, S.; Hirama, M.; Gombatz, K.; Harayama, T.; Berman, E.;
R'' Schuda, P. J. Am. Chem. Soc. 1978, 100, 6536.
Silyl Ester Ortho Ester
1,3-Dioxalone 1,3-Dioxanone
Cleavage:
Specific to !- and "-hydroxy acids
1. LiOH, MeOH, 5 °C. Corey, E. J.; Szekely, I.; Shiner, C. S. Tetrahedron Lett. 1977, 3529.
2. Pig liver esterase. This enzyme is often effective for the enantioselective cleavage of a
meso diester.
General preparations of esters:
O O
PLE
OCH3 OH
O EDC•HCl or DCC, DMAP O OCH3 pH = 6.8 OCH3
R'OH
98%, 96% ee
R OH R OR' O O

Kobayashi, S.; Kamiyama, K.; Iimori, T.; Ohno, M. Tetrahedron Lett. 1984, 25, 2557.
EDC•HCl = 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride
O
H3C O
O PLE CH3O
N N C N Et O OCH3
CH3 •HCl CH3O
OCH3 O
O O
DCC = dicyclohexylcarbodiimide O
CH3O
OH
N C N O er = 21.5

EDC•HCl is more expensive, but the urea by-product is water soluble and simplifies the Mohr, P.; Rosslein, L.; Tamm, C. Tetrahedron Lett. 1989, 30, 2513.
purification of products
P. Hogan/Seth B. Herzon

65
20
t-Butyl esters 1,1-Dimethylallyl esters

Formation:
Formation:

O O CH3
CH3 1. CH3 CH3
R OH R O CH3 Cl

O CuI, Cs2CO3 O CH3 CH3

1. Isobutylene, H2SO4, Et2O, 25 °C. McCloskey, A. L.; Fonken, G. S.; Kluiber, R. W.; Johnson,
W. S. Org. Synth., Collect. Vol. IV. 1963, 261. R OH R O
2. H2, Lindlar's cat.
2. 2,4,6-trichlorobenzoyl chloride, Et3N, THF; t-BuOH, DMAP, benzene, 20 °C. Inanaga, J.;
Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
• The 1,1-dimethylallyl ester is removed under the same conditions as an allyl ester, but is less
3. t-BuOH, EDC•HCl, DMAP, CH2Cl2. Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. J. Org. Chem. susceptible to nucleophilic attack at the acyl carbon.
1982, 47, 1962.
Sedighi, M.; Lipton, M. A. Org. Lett. 2005, 7, 1473.
4. i-PrN=C(O-tBu)NH-i-Pr, toluene, 60 °C. Burk, R. M.; Berger, G. D.; Bugianesi, R. L.; Girotra,
N. N.; Parsons, W. H.; Ponpipom, M. M. Tetrahedron Lett. 1993, 34, 975.

Benzyl esters
Cleavage:

O O
1. CF3CO2H, CH2Cl2. Bryan, D. B.; Hall, R. F.; Holden, K. G.; Huffman, W. F.; Gleason, J. G.
J. Am. Chem. Soc. 1977, 99, 2353. R OH R O
2. Bromocatechol borane. Boeckman Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.

Benzyl esters are typically prepared by the methods outlined in the general methods
section.

Allyl esters
Cleavage:
Formation:
1. H2, Pd–C. Hartung, W. H.; Simonoff, R. Org. React. 1953, 7, 263.
2. BCl3, CH2Cl2. Schmidt, U.; Kroner, M.; Griesser, H. Synthesis 1991, 294.
O O

R OH R O Phenyl esters
Formation:
1. Allyl bromide, Cs2CO3, DMF. Kunz, H.; Waldmann, H.; Unverzagt, C. Int. J. Pept. Protein
Res. 1985, 26, 493. O O
2. Allyl alcohol, TsOH, benzene, (–H2O). Wladmann, H.; Kunz, H. Liebigs Ann. Chem.
1983, 1712. R OH R O

Cleavage: Phenyl esters are typically prepared by the methods outlined in the general methods section.
They have the advantage of being cleaved under mild, basic conditions.

1. The use of allyl esters in synthesis has been reviewed. Guibe, F.: Tetrahedron 1998, 1. H2O2, H2O, DMF, pH = 10.5. Kenner, G. W.; Seely, J. H. J. Am. Chem. Soc. 1972, 94,
54, 2967. 3259.
2. Pd(Ph3P)4, RSO2Na, CH2Cl2. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997,
62, 8932.
P. Hogan/ Seth B. Herzon

21
Ortho Esters:
The synthesis of simple ortho esters has been reviewed: Dewolfe, R. H. Synthesis, 1974, 153.

OBO ester

O O 1. Esterification O
R O CH3
R OH HO 2. BF3•OEt2, CH2Cl2 O
CH3
–15 °C.

Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571.

Alternatively, ortho esters can be prepared from a nitrile:

1. HCl, MeOH O
Br CN Br O
2. OH O

HO OH
68%

Voss, G.; Gerlach, H. Helv. Chim. Acta. 1983, 66, 2294.

Special Carboxylates, !-Hydroxy and "-Hydroxy:

n n
R O R O

OH OH O O

R''
Formation:
1. Ketone or aldehyde, Sc(NTf2)3, CH2Cl2, MgSO4. Ishihara, K.; Karumi, Y.; Kubota, M.;
Yamamoto, H. Synlett 1996, 839.
2. Pivaldehyde, acid catalyst. Seebach, D.; Imwinkelried, R.; Stucky, G. Helv. Chim. Acta. 1986,
70, 448, and references cited therein.

P. Hogan

67
22
 Myers Protective Groups – Protection of the Amino Group Chem 115
Protection of amines: Formation of benzylamines:

O O O O RR'N
Base
RR'N RR'N
RO RR'N RR'N CH3 X
RR'NH
OCH3 O O O CH3
CCl3 CH3 X = Cl, Br

If primary amines are the starting materials, dibenzylamines are the products.
9-Fluorenylmethyl
Methyl 9-Fluorenylmethyl Carbamate 2,2,2-Trichloroethyl Carbamate t-Butyl Carbamate
Methyl Carbamate
Carbamate Carbamate 2,2,2-trichloroethyl Carbamate t-Butyl Carbamate O
Mix and remove water; RHN
(Fmoc) (Troc) (Boc) RNH2
H
O NaBH4, alcoholic solvent
O O O
RR'N RR'N RR'N RR'N
O O O CF3
Si(CH3)3 Formation of allylamines:

2-(Trimethylsilyl)ethyl Carbamate Allyl Carbamate Benzyl carbamate Trifluoroacetamide Base

Br RR'N
RR'NH
(Teoc) (Alloc) (Cbz)

If primary amines are the starting materials, diallylamines are the products.

RR'N RR'N RR'N

Diisopropylamine,
OAc
RR'NH RR'N
Pd(PPh
Pd(Ph 3)4
3P)

Benzylamine Allylamine Tritylamine

Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58, 6109.
General preparation of carbamates:

O Formation of tritylamines:
O
Base RR'N
RR'NH
RO Cl OR

CHCl3, DMF
O O O
Base RR'NH Br RR'N
RR'NH RR'N
RO O OR
OR

O
Base O
RR'NH RR'N
RO O–Su Mutter, M.; Hersperger, R. Synthesis 1989, 198.
OR
Su = succinimide

Bases that are typically employed are tertiary amines or aqueous hydroxide.
P. Hogan

23
Cleavage of carbamates: 2,2,2-Trichloroethyl Carbamate:

Methyl Carbamate:
O
RR'N
O O RR'NH
RR'N RR'NH CCl3
OCH3

1. Zn, H2O, THF, pH = 4.2. Just. G.; Grozinger, K. Synthesis, 1976, 457.
1. TMSI, CH2Cl2. Raucher, S.; Bray, B. L.; Lawrence, R. F. J. Am. Chem. Soc. 1987, 109, 442.
2. Cd, AcOH. Hancock, G.; Galpin, I. J.; Morgan, B. A. Tetrahedron Lett. 1982, 23, 249.
2. MeLi, THF. Tius, M.; Keer, M. A. J. Am. Chem. Soc. 1992, 114 , 5959.
2-Trimethylsilylethyl Carbamate:
9-Fluorenylmethyl Carbamate:

O O
RR'N RR'N
O O RR'NH
Si(CH3)3
RR'NH

+F–
NF, KF•H
1. Bu4N 2O,
, KF•H CH
2O, 3CN,
CH 5050
3CN, ºC. Carpino,
°C. L. A.;
Carpino, Sau,
L. A.; A.A.
Sau C.C.
J. J.
Chem. Soc.,
Chem. Chem.
Soc., Chem.
Commun. 1979, 514.
1. Amine base. The half-lives for the deprotection of Fmoc-ValOH have been studied:
studied
Atherton, E.; Sheppard R. C. in The Peptides, Udenfriend,
Udenfriend,S.
S.and
andMeienhefer
MeienheferEds.,
Eds., 2. CF3COOH, 0 °C. Carpino, L. A.; Tsao, J. H,; Ringsdorf, H.; Fell, E.; Hettrich, G. J. Chem.
Academic Press: New York, 1987, Vol. 9, p. 1. Soc., Chem. Commun. 1978, 358.

Amine base in DMF Half-Life 3. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), DMF. Roush, W. R.;
Coffey, D.S.; Madar, D. J. J. Am. Chem. Soc. 1997, 49, 2325.
20% piperidine 6s

5% piperidine 20 s t-Butyl Carbamate

carbamate:

50% morpholine 1 min

O
50% dicyclohexylamine 35 min RR'N CH3
O CH3 RR'NH
10% p-dimethylaminopyridine 85 min CH3

50% diisopropylethylamine 10.1 h

2. Bu4+NF,
F–, DMF.
DMF.Ueki,
Ueki,M.;
M.;Amemiya,
Amemiya,M.M.Tetrahedron
TetrahedronLett.
Lett.1987,
1987,28,
28,6617.
6617. 1. CF3COOH, PhSH. Thiophenol is used to scavenge t-butyl cations. TBS and TBDMS ethers
are reported to be stable under these conditions. Jacobi, P, A.; Murphree, F.;
Rupprecht, F.; Zheng, W. J . Org. Chem. 1996, 61, 2413.
F–, n-C
3. Bu4+NF, n-C88H
H17 SH. Thiols
17SH. Thiolscan
canbe
beused
usedtotoscavenge
scavengeliberated
liberatedfulvene.
fulvene.
Ueki, M.; Nishigaki, N.; Aoki, H.; Tsurusaki, T.; Katoh, T. Chem. Lett. 1993, 721. 2. Bromocatecholborane. Boeckman Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985, 26, 1411.

P. Hogan

24
Allyl Carbamate: Benzylamine:

O
RR'N
RR'N
O RR'NH
RR'NH

1. Pd(Ph
Pd(PPh3P)
3)4, Bu3SnH, AcOH, 70 – 100%yield.
70–100% yield.Dangles,
Dangles, O.;
O.; Guibe,
Guibe, F.;F.; Balavoin,
Balavoin, G.;G.; Lavielle,
Lavielle,
S.; Marquet, A. J. Org. Chem. 1987, 52, 4984. 1. Pd–C, ROH, HCO2NH4. Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.

2. Pd(Ph3P)4, (CH3)2NTMS, 89 – 100% yield. Merzouk A.; Guibe, F. Tetrahedron Lett. 1992, 2. Na, NH3. Bernotas, R. C.; Cube, R. V. Synth. Comm. 1990, 20, 1209.
33, 477.
Allylamine:

Benzyl Carbamate:
RR'N RR'NH

O
RR'N 1. Pd(Ph3P)4, RSO2Na, CH2Cl2. Most allyl groups are cleaved by this method, including
O RR'NH allyl ethers and esters. Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem. 1997, 62, 8932.

Tritylamine:

1. H2/Pd–C. Bergmann,
Bergmann,M.;
M.;Zervas,
Zervas,L.
L.Chem.
Chem.Ber.
Ber.1932,
1932,65,
65,1192.
1192.

2. H2/Pd–C, NH3. These

Theseconditions
conditionscleave
cleavethe
thebenzyl
benzylcarbamate
carbamatein
inthe
thepresence
presenceof
ofaabenzyl
benzyl RR'N RR'NH
ether. Sajiki,
Sajiki,H.
H.Tetrahedron
TetrahedronLett.
Lett.1995,
1995,36,
36,3465.
3465.

3. BBr3, CH
CH22Cl
Cl22.. Felix,
Felix,A.A.M.
M.J. J.
Org. Chem.
Org. 1974,
Chem. 39,
1974, 1427.
39, 1427.

4. Bromocatecholborane. This reagent is reported to cleave benzyl carbamates in the presence 1. 0.2% TFA, 1% H2O, CH2Cl2. Alsina, J.; Giralt, E.; Albericio, F. Tetrahedron Lett. 1996,
of benzyl ethers and TBS ethers. Boeckman
BoeckmanJr.,
Jr.,R.
R.K.;
K.;Potenza,
Potenza,J.J.C.
C.Tetrahedron
TetrahedronLett.
Lett. 37, 4195.
1985, 26, 1411.

Trifluoroacetamide:

O
RR'N RR'NH
CF3

1. K2CO3, MeOH. Bergeron, R. J.; McManis, J. J. J. Org. Chem. 1988, 53, 3108.

P. Hogan

25
 Myers Protective Groups – Protection of a Terminal Acetylene Chem 115
• Buffered TBAF was used to deprotect the silylalkynes in the
silyalkynes in the example
example shown
shown below
below to
to prevent
prevent
Alkyne protecting groups: elimination of the sensitive vinyl bromide.

Cl N Cl N
R SiR'3 H3C CH3 H3C CH3

O O O O O O
trialkylsilylalkyne TBAF, o-nitrophenol
HO OTBS HO OH
Br THF, 87% Br

• Typical silyl groups include TMS, TES, TBS, TIPS, and TBDMS.
TBDPS. Many silyl acetylenes are TBS H
commercially available, and are useful acetylene equivalents. TBS H

General preparation of silyl acetylenes:

Myers,A.
Myers, A.G.;
G.; Goldberg, S. D. Angew. Chem., Int. Ed. Engl. 2000, 15,
39, 2732.

R'3SiX
R M R SiR'3

M = Li, Mg X= Cl, OTf

• Silyl chorides are suitable for smaller silyl groups, but the preparation of more hindered silyl
acetylenes may require the use of the more reactive silyl triflate.

• In general, a strong fluoride source such as TBAF is used to cleave silylalkynes. In the case
of trimethylsilylalkynes, milder conditions can be used.

TBAF, THF
R SiR'3 R H

Cleavage of trimethysilylalkynes:

1. KF, MeOH, 50 °C. Myers, A. G.; Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc.
1991, 113, 694.

2. AgNO3 ,2,6-lutidine.
2,6-lutidine.Carreira,
Carreira,E.
E.M.;
M.;Du
DuBois,
Bois,J.J.J.J.Am.
Am.Chem
Chem.Soc.
Soc.1995,
1995,117,
117,8106.
8106.

3. K2CO3, MeOH. Cai, C.; Vasella, A. Helv. Chim. Acta. 1995, 78, 732.

P. Hogan

26