1

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