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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:
O
OH
HOHO
HOOMe
1
23
4
6
Estimated order of nucleophilicity: 6-OH > 2-OH > 3-OH ~ 4-OH
O
OHHO
HOHO
OMe12
3
4
6
Estimated order of nucleophilicity: 6-OH > 3-OH > 2-OH > 4-OH
2
(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
Reagent/Condition Reference MeI, NaH in THF or DMF Tetrahedron Lett. 1989, 30, 641.
Me3O+BF4
- J. Org. Chem. 1972, 37, 912. MeOTf, DCM, py., 80°C
Protection
MeI, Ag2O J. Am. Chem. Soc. 1980, 102, 7083. BBr3, EtOAc or DCM J. Org. Chem. 1979, 44, 4863.
SiCl4, NaH, DCM, CH3CN Synthesis 1982, 1048. AlCl3, AlBr3 Chem. Lett. 1979, 97.
Deprotection
Ac2O, FeCl3, 80°C J. Org. Chem. 1974, 39, 3728 Examples:
O
O
O
OH
SPh77%
O
OH
HO
OCH3
SPh
1) CH3I, NaH, THF2) AcOH, TFA, H2O
3
(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
Reagent/Condition Reference Protection
TrCl, 3° amines, DCM Tetrahedron Lett. 1989, 30, 641. TFA, t-BuOH Carbohydr. Res. 1978, 60, 206.
HCl, CHCl3, 0°C Carbohydr. Res. 1971, 17, 439. TsOH, DCM, MeOH Tetrahedron Lett. 1977, 18, 3473.
Deprotection
BF3, Et2O Can. J. Chem. 1978, 56, 2700 Examples:
4
(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
Reagent/Condition Reference MOMCl, NaH in THF or
DMF J. Am. Chem. Soc. 1972, 94, 7827.
MOMCl, DIPEA, 0°C or r.t. - Synthesis 1975, 276. Protection
CH2(OMe)2, TsOH, LiBr, r.t. Synthesis 1985, 74. Conc. HCl, MeOH Chem. Commun. 1974, 298.
Me2BBr, DCM J. Am. Chem. Soc. 1981, 103, 3213. TFA, DCM J. Am. Chem. Soc. 1981, 103, 3210.
Deprotection
LiBF4, CH3CN, 80°C J. Org. Chem. 1986, 51, 635. Examples:
5
(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 Reference BnCl, Bu4N
+-HSO4-, KOH Tetrahedron Lett. 1975, 16, 3251.
BnBr, NaH, THF or DMF, TBAI
Tetrahedron Lett. 1976, 17, 3535.
BnBr, Ag2O, DMF, r.t. Bull. Korean Chem. Soc. 2003, 24, 163. J. Org. Chem. 1985, 50, 3940.
BnBr, Bu2SnO or (Bu3Sn)2O, toluene, reflux
J. Am. Chem. Soc. 1994, 116, 5647
Protection
BnOC(NH)CCl3, TfOH J. Am. Chem. Soc. 1988, 110, 1624. Synthesis 1987, 568.
H2, Pd/C or Pd(OH)2/C TMSI, DCM J. Org. Chem. 1977, 42, 3761.
BF3-OEt2, NaI, CH3CN J. Chem. Res. Synop. 1985, 232. Ac2O, cat.c. H2SO4, 0°C J. Org. Chem. 2004, 69, 1513.
Deprotection
FeCl3, DCM Tetrahedron: Asymmetry 1995, 857. Examples:
O
HOOMe
HO
OO
Ph 1) (n-Bu3Sn)2O2) BnBr O
BnOOMe
HO
OO
Ph
+O
HOOMe
BnO
OO
Ph
10 : 1 (Synthesis 1994, 1121)
OHO
OMe
HO
OO
Phn-Bu4N+-HSO4
-
BnBr, NaOH, DCM
+
OHO
OMe
BnO
OO
PhO
OBn
OMe
HO
OO
Ph
30% 50%
O
HOOMe
HO
OO
PhO
BnOOMe
HO
OO
Phn-Bu4N+-HSO4
-
BnBr, NaOH, DCM
50%
(Org. Lett. 2004, 6, 1365)
6
(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
Reagent/Condition Reference PMBCl, NaH, THF or DMF J. Org. Chem. 1984, 49, 51. PMBOC(NH)CCl3, TfOH Tetrahedron Lett. 1988, 29, 4139.
Tetrahedron Lett. 1983, 24, 5364. Protection
(NH3)2Ce(NO2)6, Ceric
ammonium nitrate (CAN), CH3CN, H2O
DDQ, DCM J. Am. Chem. Soc. 1985, 107, 4586. Deprotection
7
(f) R = tetrahydropyranyl (THP)
* Stability similar to glycosidic bond * Stable in basic conditions
Reagent/Condition Reference Dihydropyran, TsOH, DCM J. Org. Chem. 1979, 44, 1438. Protection Dihydropyran, PPTS, DCM J. Org. Chem. 1977, 42, 3772.
HOAc, THF, H2O J. Org. Chem. 1979, 44, 1438. PPTS, EtOH, 55°C J. Org. Chem. 1977, 42, 3772. TsOH, MeOH, r.t. J. Am. Chem. Soc. 1978, 100, 1942.
Deprotection
MgBr2, Et2O, r.t. Tetrahedron Lett. 1987, 28, 439. Examples: (ii) Silyl ether type
Sug OH Sug OSiR3R3Si X+ + NR'3 NR'3H 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) Can be cleaved with K2CO3, MeOH or citric acid Triethylsilyl (TES) Can be cleaved with HOAc Triisopropylsilyl (TIPS) Possible for selective protection of 1° OH t-Butyldimethylsilyl (TBS) Selective protection of 1° OH t-Butyldiphenylsilyl (TBDPS) Selective protection of 1° OH
Relatively stable in basic condition
8
(iii) Ester type
Sug OH + CX
O
RSug O
CR
O
+ HX
(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:
9
(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 Reference Bu4N
+OH-, r.t. Tetrahedron Lett. 1979, 20, 3561. NaOH, EtOH, H2O Tetrahedron Lett. 1973, 14, 317.
t-BuOK J. Org. Chem. 1977, 42, 918. Deprotection
DIBAL Examples:
O
OH
HOHO
HOOMe
PivCl(2 equiv.)
pyr.O
OPiv
HOHO
PivOOMe
O
OH
HOHO
HO
OMe
PivCl(2 equiv.)
pyr.O
OPiv
HOPivO
HO
OMe
O
OHHO
HOHO
SPh
PivCl(2 equiv.)
pyr.O
OPivHO
PivOHO
SPh
(J. Org. Chem. 1998, 63, 6035)
10
(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
Reagent/Condition Reference Cat. NaOMe, MeOH J. Org. Chem. 2004, 69, 1513.
LiOH, THF/H2O (3/1) J. Org. Chem. 2004, 69, 1513. K2CO3, MeOH
Deprotection
DIBAL Examples:
11
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
12
(i) For selection between 1,3-diol and trans-1,2-diol
O
Ovs.
O
HO
O
HO O
ORR
(ii) For selection between 1,3-diol and cis-1,2-diol
vs. O
HO
O
O
O
O
O
HO
R
R
vs. O
HO
O
O
O
O
O
HO
R
R
R
R
(iii) For selection between trans-1,2-diol and cis-1,2-diol
vs. O
OH
HO O
O
OHOH O
OO
13
(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:
14
(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:
O
HOOMe
HO
OO
Ph NBS, CCl4BaCO3, reflux
O
HOOMe
HO
BrBzO
O
HOOMe
HO
NBS, CCl4BaCO3, reflux
O
HOOMe
HO
BrBzOO
O
Ph
(J. Org. Chem. 1969, 34, 1035)
O
NPhth
ORBnO
OO
MeO
NaBH3CNTFA, DMF
90%
NaBH3CNTMSCl, MeCN
51%
O
NPhth
ORBnO
PMBOHO
O
NPhth
ORBnO
HOPMBO
(J. Org. Chem. 2000, 65, 2410)
15
(vi) Cyclohexane-1,2-diacetals (CDA)
O
O
MeOH, CH(OMe)3cat. H2SO4, reflux
OMe
OMe
OMe
OMe
OHO
OMe
HO
HOHO
CDA, MeOHCH(OMe)3, cat. CSA
reflux OHO
OMe
HOO
O
OMe
OMe48%
(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)
O
HO OH
HOZ O
O OH
OZSi
O
Si
iPr
iPr
iPr
iPr
16
(viii) Other examples
O
N3
HOHO
N3
N3
HOOH
N3O
Cyclohexone dimethyl ketal, TsOH-H2O, CH3CN
O
N3
HOHO
N3
N3
OO
N3O
41%
(Org. Lett. 2004, 3, 1381)
17
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:
O
O
H2N
HOHO H2N
O NH2
NH2HO
OHO
O OHO
OHNH2
H2N OH
TfN3, Et3N, CuSO4, MeOH/H2O/CH2Cl2
O
O
N3
HOHO N3
O N3
N3HO
OHO
O OHO
OHN3
N3 OH
(J. Am. Chem. Soc. 1999, 121, 6527-6541; Tetrahedron Lett. 1996, 37, 6029-6032)
R NH21) SO2Cl2, MeCN2) imidazole
NaN3 N3 S
O
N
O
N
CuSO3, K2CO3MeOH
R N3
(Org. Lett. 2007, 9, 3797–3800)
18
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,
dithiothreitol
HSSH
OH
OH etc) * Hydrogenation can be * Mechanism of Staudinger reaction
19
* Staudinger reaction can be selective (J. Am. Chem. Soc. 2002, 124, 10773-10778; J. Org. Chem. 2007, 72, 4055-4066)
O
N3
BnOBnO
N3N3
HOOBn
N3O
I
II
1
1'2'
6,3',4'-tri-O-benzyl-tetraazidoneamine
6'
O
N3
BnOBnO
H2NN3
HOOBn
N3O
I
II3
H-1 3.18H-3 3.38H-2' 3.51H-6' 3.49/3.35
proton (ppm)PMe3
O
N3
BnO
N3N3
BnOO
N3O
I
II
1
1'2'
6'
3
OBnO
N3
III
1"
2"
OBn
OBn3"
PMe3 then Cbz-Cl
O
N3
BnO
N3N3
BnOO
N3O
I
II
1
1'2'
6'
3
OBnO
HN
III
1"
2"
OBn
OBn
Cbz
H-1 3.6H-3 3.4H-2' 3.00H-6' 3.27/3.10H-3" 3.78
proton (ppm)
Per-azido per-benzyltobramycin
13
1'2'
6'
1.0 M PMe3 in toluene (1.1 eq.), Boc-ON (2.4 eq.),toluene, -78oC to 10oC
45%
OAcO
O OAcO
OAcN3
N3 OAc
O
N3
AcOAcO
N3N3
OOAc
N3O
I
II
1
4
5
III
IV
1"
6'
6"'
2"'
OAcO
O OAcO
OAcN3
N3 OAc
O
N3
AcOAcO
N3N3
OOAc
HNO
Boc
28%
1) TFA/CH2Cl22) EDC, HOBt, Et3N, NMP, DMF
OAcO
O OAcO
OAcN3
N3 OAc
O
N3
AcOAcO
N3N3
OOAc
HNO
OH
ONH
(mixed with minor N-3 Boc adduct)
H-1 3.43H-3 3.53H-2' 3.16H-6' 3.3a
H-2''' 3.3a
H-6''' 3.59/3.28
proton d (ppm)
a: approximate value
Z
HOOH
ONH
Z
20
1.0 M PMe3 in toluene (1.1 eq.), Boc-ON (2.4 eq.), toluene, -78oC to 10oC
31%OAcO
AcO OAc
O
N3
AcOAcO
N3N3
OOAc
N3O
I
II
III
OAcO
AcO OAc
O
N3
AcOAcO
N3N3
OOAc
HNO
Boc
H-1 3.4H-3 3.5H-2' 3.25H-6' 3.3
proton (ppm)
13
6'
2'
1"
NO
CN
O
O
Boc-ON:
(ii) Phthalamide (intermediate involved in Gabriel amine synthesis) Common reagents for protection: phthalic anhydride Common reagents for deprotection: acids hydrazine, EtOH, reflux Example:
21
(iii) Carbamate-type
Cl
O
R'O
R NH2 + + B
O
R'OR
HN + BH
Cl
* 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) (b) Di-tert-butyl dicarbonate , Boc anhydride (Boc2O) * Stable in basic and neutral conditions Common reagents for deprotection: acids (TFA)
Cl
O
O
O
O
O
22
(c) Benzyl chloroformate , Carbobenzoxy chloride (Cbz-Cl, Z-Cl) * Stable in acidic, basic and neutral conditions Common reagents for deprotection: hydrogenolysis (H2, Pd/C)) (d) Allyl chloroformate (Alloc-Cl) * Stable in acidic, basic and neutral conditions Common reagents for deprotection: Pd(0) reagents
Cl
O
O
Cl
O
O