Chapter 3: Protecting Groups I. Protecting Groups of Hydroxyl Groups Consider the stability and effect of anomeric group! Consider the solubility of starting material (the choice of solvent)! Consider the reactivity of different hydroxyl groups! * DCM is common for pyranoses with 2-3 OH’s. For pyranose with more than 4 OH’s, use DMF or pyridine. * Nucleophilicity of OH groups on pyranoses (chair conformation) (Carbohydr. Res. 1987, 162, 159.) 1° OH > 2° OH Equatorial OH > axial OH Equatorial OH with vicinal axial OH (or OR) > Equatorial OH without vicinal axial OH (or OR) Examples: 6
OH
4
O
HO HO
1 2
3
HO
OMe
Estimated order of nucleophilicity: 6-OH > 2-OH > 3-OH ~ 4-OH
HO
6
OH O
4
OMe
HO 3
2
HO
1
Estimated order of nucleophilicity: 6-OH > 3-OH > 2-OH > 4-OH
1
(i) Alkyl ether type Sug
OH
Sug
OR
Advantages: * Relatively stable in harsh conditions (acidic, basic, reflux, etc.) * Enhance the reactivity of glycosylation due to electron-donating effect * More compatible to the conditions needed for deoxygenation or amino (azido) substitution * Selective protection is possible Disadvantages: * Relatively harder to remove (deprotect) * Conditions for protection and deprotection may not be compatible to other types of protecting groups (a) R = methyl (CH3, Me) * Not commonly used due to the difficulty of deprotection * Methoxy group can be found in naturally occurring unusual sugars
Protection
Deprotection
Reagent/Condition MeI, NaH in THF or DMF Me3O+BF4MeOTf, DCM, py., 80°C MeI, Ag2O BBr3, EtOAc or DCM SiCl4, NaH, DCM, CH3CN AlCl3, AlBr3 Ac2O, FeCl3, 80°C
Reference Tetrahedron Lett. 1989, 30, 641. J. Org. Chem. 1972, 37, 912. J. Am. Chem. Soc. 1980, 102, 7083. J. Org. Chem. 1979, 44, 4863. Synthesis 1982, 1048. Chem. Lett. 1979, 97. J. Org. Chem. 1974, 39, 3728
Examples: OH
O O SPh
O
1) CH3I, NaH, THF 2) AcOH, TFA, H2O
O SPh
HO
77%
OCH3
OH
2
(b) R = trityl, triphenylmethyl (Ph3C, Tr) * Excellent for selective protection of primary OH * Stable in basic but very labile in acidic conditions * Easy to observe with TLC * Deprotection can be tricky Protection Deprotection
Reagent/Condition TrCl, 3° amines, DCM TFA, t-BuOH HCl, CHCl3, 0°C TsOH, DCM, MeOH BF3, Et2O
Examples:
3
Reference Tetrahedron Lett. 1989, 30, 641. Carbohydr. Res. 1978, 60, 206. Carbohydr. Res. 1971, 17, 439. Tetrahedron Lett. 1977, 18, 3473. Can. J. Chem. 1978, 56, 2700
(c) R = methoxymethyl (CH3OCH2, MOM) * Can be incorporated at relatively weak basic conditions (3° amine) but needs relatively strong acid (TFA) to remove * Stable in basic conditions * The reagent, MOMCl, is considered carcinogenic
Protection
Deprotection
Reagent/Condition MOMCl, NaH in THF or DMF MOMCl, DIPEA, 0°C or r.t. CH2(OMe)2, TsOH, LiBr, r.t. Conc. HCl, MeOH Me2BBr, DCM TFA, DCM LiBF4, CH3CN, 80°C
Examples:
4
Reference J. Am. Chem. Soc. 1972, 94, 7827. Synthesis 1975, 276. Synthesis 1985, 74. Chem. Commun. 1974, 298. J. Am. Chem. Soc. 1981, 103, 3213. J. Am. Chem. Soc. 1981, 103, 3210. J. Org. Chem. 1986, 51, 635.
(d) R = benzyl (C6H5CH2, Bn) * Can be traceless removed using hydrogenolysis * Stable in basic conditions * Relatively stable in acidic conditions * Quenching excess reagent (BrBr) with MeOH can be tricky Reagent/Condition BnCl, Bu4N+-HSO4-, KOH BnBr, NaH, THF or DMF, TBAI BnBr, Ag2O, DMF, r.t.
Protection
Reference Tetrahedron Lett. 1975, 16, 3251. Tetrahedron Lett. 1976, 17, 3535. Bull. Korean Chem. Soc. 2003, 24, 163. J. Org. Chem. 1985, 50, 3940. J. Am. Chem. Soc. 1994, 116, 5647
BnBr, Bu2SnO or (Bu3Sn)2O, toluene, reflux BnOC(NH)CCl3, TfOH
J. Am. Chem. Soc. 1988, 110, 1624. Synthesis 1987, 568.
H2, Pd/C or Pd(OH)2/C TMSI, DCM BF3-OEt2, NaI, CH3CN Ac2O, cat.c. H2SO4, 0°C FeCl3, DCM
Deprotection
J. Org. Chem. 1977, 42, 3761. J. Chem. Res. Synop. 1985, 232. J. Org. Chem. 2004, 69, 1513. Tetrahedron: Asymmetry 1995, 857.
Examples: Ph
O O HO
1) (n-Bu3Sn)2O 2) BnBr
O HO
O O HO
Ph
Ph
O + BnO
OMe
O O BnO
O HO
OMe 10
:
OMe
1
(Synthesis 1994, 1121)
Ph
O O HO
HO
n-Bu4N+-HSO4BnBr, NaOH, DCM
O
O
Ph
HO
Ph
O
O BnO
OBn O
O O HO
+
OMe 30%
Ph
O O HO
n-Bu4N+-HSO4BnBr, NaOH, DCM
O HO
OMe
Ph
50%
O O HO
OMe
50%
O BnO
(Org. Lett. 2004, 6, 1365)
5
OMe
OMe
(e) R = p-methoxybenzyl (CH3OC6H4CH2, PMB) * More prone to oxidative cleavage than Bn but less prone to reductive cleavage than Bn * Stable in basic conditions * Relatively stable in acidic conditions
Protection
Deprotection
Reagent/Condition PMBCl, NaH, THF or DMF PMBOC(NH)CCl3, TfOH (NH3)2Ce(NO2)6, Ceric ammonium nitrate (CAN), CH3CN, H2O DDQ, DCM
6
Reference J. Org. Chem. 1984, 49, 51. Tetrahedron Lett. 1988, 29, 4139. Tetrahedron Lett. 1983, 24, 5364.
J. Am. Chem. Soc. 1985, 107, 4586.
(f) R = tetrahydropyranyl (THP) * Stability similar to glycosidic bond * Stable in basic conditions Reagent/Condition Dihydropyran, TsOH, DCM Dihydropyran, PPTS, DCM HOAc, THF, H2O PPTS, EtOH, 55°C TsOH, MeOH, r.t. MgBr2, Et2O, r.t.
Protection
Deprotection
Reference J. Org. Chem. 1979, 44, 1438. J. Org. Chem. 1977, 42, 3772. J. Org. Chem. 1979, 44, 1438. J. Org. Chem. 1977, 42, 3772. J. Am. Chem. Soc. 1978, 100, 1942. Tetrahedron Lett. 1987, 28, 439.
Examples:
(ii) Silyl ether type Sug
OH
+
R3Si
X
+
NR'3
Sug
OSiR3
+ H
NR'3 X
* Stability varies General reagents for protection: R3SiX with 3° amines (DIPEA, TEA, immidazole, lutidine, pyridine, etc) Common reagents for deprotection: TBAF, BF3, KF, or pyridine-HF Trimethylsilyl (TMS) Triethylsilyl (TES) Triisopropylsilyl (TIPS) t-Butyldimethylsilyl (TBS) t-Butyldiphenylsilyl (TBDPS)
Can be cleaved with K2CO3, MeOH or citric acid Can be cleaved with HOAc Possible for selective protection of 1° OH Selective protection of 1° OH Selective protection of 1° OH Relatively stable in basic condition
7
(iii) Ester type O O Sug
OH +
C
C R
Sug
O
R
+
HX
X
(a) R = trifluoroacetyl (TFA) General reagent for protection: trifluoroacetic anhydride with 3° amines (DIPEA, TEA, immidazole, lutidine, pyridine etc), DMAP as catalyst Common reagent for deprotection: weak acids or bases
(b) R = acetyl (Ac) General reagents for protection: Ac2O with 3° amines (DIPEA, TEA, immidazole, lutidine, pyridine etc) or Ac2O with cat. acids. Common reagents for deprotection: K2CO3, MeOH, cat. NaOMe in MeOH, or LiOH, THF, H2O (J. Org. Chem. 2004, 69, 1513) * anomeric acetyl group can be selectively removed with H2NNH2-HOAc or BnNH2 Examples:
8
(c) R = trimethylacetyl (Piv) * Can be used for selective protection General reagent for protection: pivaloyl chloride (PivCl) with 3° amines (DIPEA, TEA, pyridine etc) Reagent/Condition Bu4N+OH-, r.t. NaOH, EtOH, H2O t-BuOK DIBAL
Deprotection
Reference Tetrahedron Lett. 1979, 20, 3561. Tetrahedron Lett. 1973, 14, 317. J. Org. Chem. 1977, 42, 918.
Examples: OH
PivCl (2 equiv.) pyr.
O HO HO HO
OH HO
OPiv O HO HO PivO
OMe
PivCl (2 equiv.) pyr.
O
HO HO
OPiv HO
OMe
O
HO PivO OMe
OMe HO
HO
OH O SPh
HO
PivCl (2 equiv.) pyr.
OPiv O SPh
PivO HO
HO
(J. Org. Chem. 1998, 63, 6035)
9
(d) R = Benzoyl (Bz) * Can be used for selective protection General reagent for protection: benzoyl chloride (BzCl) with 3° amines (DIPEA, TEA, pyridine etc) * Less common method for protection: Benzoic acid, DEAD, PPh3
Deprotection
Reagent/Condition Cat. NaOMe, MeOH LiOH, THF/H2O (3/1) K2CO3, MeOH DIBAL
Examples:
10
Reference J. Org. Chem. 2004, 69, 1513. J. Org. Chem. 2004, 69, 1513.
II. Protecting Groups of 1,2- or 1,3-Dihydroxyl Groups Consider the formation of acetal (ketal) from diol and aldehyde (ketone)! Consider the solubility of ring or fused ring for selectivity! Six-membered ring: thermodynamically favored Five-membered ring: kinetically favored General Mechanism
11
(i) For selection between 1,3-diol and trans-1,2-diol O
HO O
O R
O
O
vs.
HO
O
R
(ii) For selection between 1,3-diol and cis-1,2-diol R HO
O
O
O vs.
O
R
O O
HO
R HO
O
R O
R
O O
vs.
O
R HO
O
(iii) For selection between trans-1,2-diol and cis-1,2-diol OH
OH OH O O
O
vs.
O HO O
O
12
(iv) Acetonide (isopropylidene) Common reagents for protection: acetone or Me2C(OMe)2 and acids (TsOH, PPTS, ZnCl2 etc) with removal of water Common reagents for deprotection: acids (TsOH, TFA, HCl etc) with addition of water Examples:
13
(v) Benzylidene Common reagents for protection: PhCHO or PhCH(OMe)2 and acids (TsOH, PPTS, ZnCl2 etc) with removal of water Common reagents for deprotection: acids (TsOH, TFA, HCl etc) with addition of water * Can be selectively converted into Bn or Bz Examples: Ph
O O HO
HO Ph
Br BzO HO
NBS, CCl4 BaCO3, reflux
O
O HO
OMe
OMe
O BzO
O NBS, CCl4 BaCO3, reflux
O HO HO
Br O
HO HO
OMe
OMe
(J. Org. Chem. 1969, 34, 1035) NaBH3CN TFA, DMF 90%
MeO
O O BnO
PMBO HO BnO
O OR NPhth
O OR NPhth NaBH3CN TMSCl, MeCN 51%
(J. Org. Chem. 2000, 65, 2410)
14
HO PMBO BnO
O OR NPhth
(vi) Cyclohexane-1,2-diacetals (CDA) OMe OMe
MeOH, CH(OMe)3 cat. H2SO4, reflux
O
OMe OMe
O
HO HO HO
HO
OMe
CDA, MeOH CH(OMe)3, cat. CSA reflux
O
OMe
HO O O
48%
HO
OMe
OMe
(Angew. Chem. Int. Ed. Engl. 1994, 33, 2290) Similar reagent: CH3C(OMe)2C(OMe)2CH3, or 2,3-butanedione
(vii) Silyl-based protecting group Triisopropyldisilyl (TIPDS) iPr
HO O
Z
iPr
O Si
O
Z
O HO
OH
Si
iPr
O
iPr
15
O
OH
(viii) Other examples N3 HO HO
N3 O
N3
Cyclohexone dimethyl ketal, TsOH-H2O, CH3CN
N3
HO HO
O N3
O HO
N3
N3 O
N3
O
OH
41%
(Org. Lett. 2004, 3, 1381)
16
O
III. Protecting Groups of Amino Groups (i) Masking NH2 (amino) as N3 (azido) * Organoazides can be explosive ([C+O]/N ≥ 3) ((a) P. A. S. Smith, Open-Chain Nitrogen Compounds, vol. 2, Benjamin, New York, 1966, 211 – 256; (b) J. H. Boyer, R. Moriarty, B. de Darwent, P. A. S. Smith, Chem. Eng. News 1964, 42, 6.) Examples: H2N HO
HO
HO
HO H2N O O O HO
NH2 NH2
O
N3 O O HO
N3 OH
O OH
O OH O
O H 2N
HO
HO
TfN3, Et3N, CuSO4, MeOH/H2O/CH2Cl2
NH2 OH
O
N3
O
OH
N3
OH
(J. Am. Chem. Soc. 1999, 121, 6527-6541; Tetrahedron Lett. 1996, 37, 6029-6032)
NaN3
1) SO2Cl2, MeCN 2) imidazole
O N3
S
N N
O
(Org. Lett. 2007, 9, 3797–3800)
17
R
NH2
CuSO3, K2CO3 MeOH
R
N3
N3 N3
The azido group can be converted (reduced) to amino group using the following methods: (1) H2, Pd/C; (2) PR3, THF, H2O; (3) LiAlH4; (4) thiols (HSCH2CH2SH, HSCH2CH2OH, OH HS
dithiothreitol
SH OH
etc)
* Hydrogenation can be * Mechanism of Staudinger reaction
18
* Staudinger reaction can be selective (J. Am. Chem. Soc. 2002, 124, 10773-10778; J. Org. Chem. 2007, 72, 4055-4066) N3
6'
O I
BnO BnO
1'
2'
N3
proton (ppm)
6'
H-1 3.18 H-3 3.38 H-2' 3.51 H-6' 3.49/3.35
N3
O HO
3
II
O I
BnO BnO
PMe3
1
N3
H2N
OBn
6'
1'
2'
N3
N3
O BnO
1
II
3
1
N3
BnO
1'
2'
N3
N3
O BnO
III
1"
H-1 3.6 H-3 3.4 H-2' 3.00 H-6' 3.27/3.10 H-3" 3.78
O I
PMe3 then Cbz-Cl
O
1
BnO
3
N3
4
N3
II 1
O
5
O
1.0 M PMe3 in toluene (1.1 eq.), Boc-ON (2.4 eq.), toluene, -78oC to 10oC
N3
OAc proton d (ppm)
III
45%
O OAc
OAc
AcO
N3
O
O OAc
OAc
N3 O
AcO AcO Z
N3
N3 O AcO
28% OAc
O O
N3 O OAc O
N3
OAc
(mixed with minor N-3 Boc adduct)
1) TFA/CH2Cl2 2) EDC, HOBt, Et3N, NMP, DMF
N H
O
H N
O
: approximate value
HO
O
N3
a
OH
N3
N3 O
OAc
H-1 3.43 H-3 3.53 H-2' 3.16 H-6' 3.3a H-2''' 3.3a H-6''' 3.59/3.28
O 6"'
HN Cbz
O
AcO AcO
1"
IV
2"
N3
N3 2"'
OBn OBn
O
Per-azido per-benzyl tobramycin
N3 O AcO
III
1"
O I
AcO AcO
N3
O
N3
6'
II
3
OBn OBn
O 2" 3"N
N3
N3
BnO
proton (ppm)
OAc
II
3
OBn
O I
BnO
N3
O HO
6,3',4'-tri-O-benzyltetraazidoneamine
N3
6'
1'
2'
N3
OAc
19
OH
H N OAc
O
N H
Z
Boc
N3
6'
N3 O I
AcO AcO
2'
N3
N3 O
II
3
1
O
AcO
O
1.0 M PMe3 in toluene (1.1 eq.), Boc-ON (2.4 eq.), toluene, -78oC to 10oC
N3
N3
N3 O AcO
31%
OAc
1"
O
AcO AcO
O O
III AcO OAc
AcO OAc
proton (ppm) H-1 H-3 H-2' H-6'
Boc-ON:
3.4 3.5 3.25 3.3
CN O
O
N O
(ii) Phthalamide (intermediate involved in Gabriel amine synthesis) Common reagents for protection: phthalic anhydride Common reagents for deprotection: acids hydrazine, EtOH, reflux Example:
20
H N OAc
Boc
(iii) Carbamate-type Cl R
NH2
O R'
+
+
B
R
H N
O
+
H
R' O O
* Solvent selection is important. (a) 9-Fluorenylmethoxycarbonyl chloride (Fmoc-Cl) * Stable in acidic and neutral conditions * Easy to observe with strong UV absorption Common reagents for deprotection: amines (piperidine)
Cl
O O
(b) Di-tert-butyl dicarbonate , Boc anhydride (Boc2O) O
* Stable in basic and neutral conditions
O O
Common reagents for deprotection: acids (TFA)
21
B Cl
(c) Benzyl chloroformate , Carbobenzoxy chloride (Cbz-Cl, Z-Cl) Cl
* Stable in acidic, basic and neutral conditions
O O
Common reagents for deprotection: hydrogenolysis (H2, Pd/C))
(d) Allyl chloroformate (Alloc-Cl)
Cl
* Stable in acidic, basic and neutral conditions Common reagents for deprotection: Pd(0) reagents
22
O O
