Conceptualization

Chemoselectivity

Regioselectivity

which functional
where it will react
group will react
Which functional group reacts first
Reaction
condition
and Reagents

How to react the less reactive group first

React both then un-react one

11/9/2016

niper_H

 Reaction of di-anions

reacts first

protecting groups

Anions that forms last

What is a protecting group?

A protecting group (PG) is a molecular framework that is introduced onto a specific
functional group (FG) in a poly-functional molecule to block its reactivity under
reaction conditions needed to make modifications elsewhere in the molecule.
e. g., Grignard reaction
Each protecting group
incorporated in a multistep synthesis increases
the synthesis by two nonproductive steps reducing
the overall yield and
efficiency of the synthesis.

Tactical Considerations

Easy & efficient

introduction
11/9/2016

Stable throughout
reaction, work-up &
purification
niper_H

Efficient and selective

removal under mild

should not create any

stereogenic centre

conditions
4

Development

11/9/2016

niper_H

Protection Of Hydroxyl group

Ethers

Methyl Ethers
Benzyl Ethers
P- Methoxy Benzyl Ethers
O- Nitro Bn Eters
P- Nitro Bn Ethers
Trityl Ethers
Alkoxy Ethers
MOM
MEM
BOM
11/9/2016

niper_H

Acetals

Esters

Tetrahydropyranyl
Ethers

Acetyl Chloride
Acetates
Pivaloates

Silyl
Ethers

t- BuDiMe Silyl
Tri IsoPro Silyl
t-Bu DiPh Silyl
6

Hydroxyl Protecting Groups

Ethers

Alkyl or Aryl ethers:

Formation:

R-OH

Methyl Ethers

Benzyl Ethers

CH2N2

BnBr, THF, NaH

MeI, NaH, THF

(MeO)2SO2
Me2SO4

BnOC(=NH)CCl3, CF3SO3H

R OH

MeI

easy on, hard off.

Usually only good
(Methyl ether) for phenols
R OMe

R OCH2Ph
(Benzyl ether)

Me3O BF4

Cleavage:
Methyl Ethers

Me3SiI or BBr3,CH2Cl2

Benzyl Ethers
PhSe-

Protects from:

HBr

Bases and weak

acids

H2-Pd/C
BuLi, B(OMe)3
Na/NH3
CrO3

11/9/2016

niper_H

Hydroxyl Protecting Groups

Ethers

p-Methoxybenzyl ether (PMB) :

Cl
MeO
R OH

Formation: KH, p-Methoxybenzyl chloride, THF

PMBOC(=NH)CCl3, CF3SO3H

O R
MeO

Cleavage: DDQ, CAN, H2/ Pd-C, Li/Na/ NH3

NBS

Protection with
(PMBOC(=NH)CCl3)

Deprotection
with NBS
Deprotection with Na/ NH3

11/9/2016

niper_H

Free radical mechanism for Deprotection with DDQ

11/9/2016

niper_H

Hydroxyl Protecting Groups

Ethers

o-Nitrobenzyl ethers:
R OH

NaH, THF

OR

p-Nitrobenzyl ethers:

NO2

Cl

R OH

Cl

Formation: o-Nitrobenzyl chloride,NaH,THF

Cleavage:Photolysis at 320 nm

Formation: p-Nitrobenzyl chloride,NaH,THF

Cleavage:Selective removal with DDQ

Trityl ethers (Tr= CPh3):

R OH

Hydrogenolysis, Electrochemically
R OCPh3

Selective for primary alcohols, stable to base

Formation:Ph3C-Cl, pyridine,DMAP, Ph3C+BF4Cleavage: Mild acid
ethers:

Methoxymethyl ethers (MOM)

R OH

R OCH2OMe

Formation: MeOCH2Cl, NaH, THF

MeOCH2Cl, CH2Cl2, i-Pr2EtN

Cleavage: Me BBr
2
HCl/ THF, reflux

CH3COCl, MeOH

Stable to base and mild acid

11/9/2016

OR
O2N

O2N

NO2

Alkoxyalkyl

NaH, THF (SN2)

niper_H

Methoxyethoxymethyl ethers (MEM)

R OH

R OCH2OCH2CH2OMe
Formation: MeOCH CH OCH Cl, NaH,THF
2 2
2
MeOCH2CH2OCH2Cl,
CH2Cl2, i-Pr2EtN
Cleavage: Lewis acids such as
ZnBr2, TiCl4, Me2BBr

Benzyloxymethyl ethers (BOM)

R OH

Formation:
Cleavage:

R OCH2OCH2Ph

PhCH2OCH2Cl, CH2Cl2, i-Pr2EtN

H2, PtO2
Na/ NH3, EtOH

10

Hydroxyl Protecting Groups

Acetals

Tetrahydropyranyl ethers (THP):

R OH

O
H+, PhH

RO

Formation: DHP, Pyridinium p-toluene sulfonate (PPTS),CH2Cl2

Cleavage: PPTS, EtOH
Drawback : Creates one more stereogenic center

Diastereomers

formation
Cleavage
Protection of OH group with THP

11/9/2016

niper_H

11

Hydroxyl Protecting Groups

Silyl ethers

R OH

R OSiR'3

Formation: R3SiCl, Pyridine, DMAP

R3SiCl, Imidazole, CH2Cl2/DMF/ CH3CN, DMAP
R3SiOTf, i-Pr2EtN, CH2Cl2

Cleavage: Acid

F- (KF, CsF, HF, n-Bu4NF)

t-Butyldimethyl silyl (TBDMS)

Triisopropyl Silyl (TIPS)

Increasing
stability towards
acids and base

t-Butlydiphenyl Silyl (TBDPS)

Cleavage
11/9/2016

niper_H

12

e. g.,

niper_H

Hydroxyl Protecting Groups

Esters

Via acid chlorides:

R'

R'

OH

R'

Cl

Cl

Acetates (Ac):

R OH

Formation: Ac2O,

R'

Formation: SOCl2 PCl (COCl)

,
5
2

R OH

OR

R OAc

pyridine

Acetyl chloride, pyridine

Cleavage: K2CO3,

MeOH, reflux

NH3, MeOH

Pivaloates (Piv):

Generation of Active Esters

O
Cl

R OH

O
OR

Selective for primaryalcohols

Formation: t-Butylacetyl chloride

t-Butylacetic anhydride
Mild base

Cleavage:
Properties:Stable to acid and mild base Not compatible with

strong nucleophiles such as organometallic reagents

14

e. g.,
Protection of OH
group with BnCl

e. g., Protection
with TBDMS

11/9/2016

niper_H

15

Hydroxyl Protecting Groups

Protection of 1,2 & 1,3-diols
O
HO

OH

R1

R2

R3

R4

Acid

Isopropylidenes (acetonides):
HO

OH

Acid

R1

R2

Acetone or
OMe

or

OMe

R1

R3

R4

R1

R2

Cycloalkylidene acetals:

O
R2

HO

OH

R1

R2

Acid
O

O
or

O
R1

O or O
R2

R1

O
R2

OMe

1,2-acetonide formation is usually favored over 1,3-acetonides

Cleavage: Mild aqueous acid
Why not acetone + H+?
Consider pKa's of protonated
ketones vs ethers

Cyclopentylidenes are slightly easier to cleave than acetonides

Cyclohexylidenes are slightly harder to cleave than acetonides

e. g.,

JACS, 100, 1978, 14, 4620

Benzylidene acetals:
Ph
HO

OH

R1

R2

Acid
CH(OMe)2

O
CHO

R1

O
R2

or

Cleavage:Acid hydrolysis or hydrogenolysis

11/9/2016

niper_H

17

p-Methoxybenzylidene acetals:

OMe

Acid

Cleavage:

HO

OH

R1

R2

CH(OMe)2

CHO
or

OMe

O
OMe

R1

Hydrolyzed about 10 times faster

than regular benzylidenes

R2

Can be oxidatively removed with CAN

Carbonates:
O
HO

OH

R1

R2

Im2CO

O
R1

O
R2

Stable to acid & more difficult to hydrolyze than esters

Formation: Im2CO or phosgene or triphosgene

Cleavage: Removed with base

11/9/2016

niper_H

18

Protection of ketones and aldehydes

O
R1

MeOH, H+
R2

R1

OMe

R2

OMe
O

R1

(CH2OH)2, H+

R2
H+

OH

R1
R2

Ketones and aldehydes

are generally
1,3-dioxolanes

Protected as cyclic
and acyclic ketals and

1,3-dioxanes

acetals

O
O
O

OH

Cleavage rate of substituted 1,3-dioxanes

R1
R2

O
O

R1
R2

O
O

Selective protection of
less hindered carbonyls
11/9/2016

niper_H

R1
R2

Stable to base

O
O

Stable
Product

19

1,3-Dithiane derivative:
O
R1

HS

SH

R2

S
R1

S
R2

or

R1

R2

Aldehydes are selectively protected in presence of ketones

Formation: HS(CH2)nSH, BF3.Et2O, DCM, 25 oC
1,3-dioxolanes and 1,3-dioxanes can be readily
converted into 1,3-dithiolanes and 1,3-dithianes

SH

SH

BF3.Et2O

Cleavage:

Hg(ClO)4, MeOH, CHCl3, 25 oC

m-CPBA, Ac2O
NBS, acetone, 0 oC
DDQ, aq. CH3CN
I , DMSO
2

11/9/2016

CAN, aq. CH3CN

Raney Ni

20

Protection of carboxylic acids

Esters

Formation: Fischer esterification (RCOOH + ROH + H+)

Acid chloride + ROH, pyridine

t-Butyl esters: Isobutylene & acid

Methyl esters: Diazomethane
Cleavage: t- Butyl esters are cleaved with aq. acids
9-Fluorenylmethyl esters (Fm):
DCC

RCOOH

OH
O

(2- Trimethyl silyl) Ethyl chloride

11/9/2016

niper_H

21

Protecting group
Carboxylic Acids
2, 2, 2- trichloroethylesters

Allyl Esters

Photoclevage

3, 5- dimethoxy bezoin acetate

2- Nitro benzyl esters

11/9/2016

niper_H

22

e. g.,
Protecting
Group

VarespladibPhospholipase
inhibitor
t-Butyl ester PG for Carboxylic acids
J. Med. Chem., 1996, 39, 5159

Silyl and Acetal or Ether

PG for Alcohols
Treprostinil- Vasodilator
P.A. Aristoff, U.S. Patent., 1987, 4, 683.
11/9/2016

niper_H

23

Org. Lett., 6, (2004), 1365

J. Org. Chem., 1998, 63, 6035

Carbohydr. Res., 1987, 162, 159.

24

Protecting Groups
Protection of amines
Carbamates

1. t-Butyl carbamate (Boc):

R NH2

Formation:

R NHBoc

Cleavage:

(Boc)2O, NaOH, H2O, 25 oC

3M HCl, EtOAc

(Boc)2O, TEA, MeOH/ DMF

TFA, PhSH, DCM

BocN3, DMSO, K2CO3

BocONH2, DMSO,DMAP
1-(tert-butoxycarbonyl) benzotriazole

AcCl, MeOH

11/9/2016

niper_H

CAN, CH3CN
P-TsOH, EtOH
25

Mechanism of
BOC protection

Mechanism of Deprotection of BOC

Lewis Acids Nonprotic acids such as AlCl3, BF3OEt2, montmorillonite (acidic
clay), celite, silica gel, and ion-exchange resins like Amberlyst 15 can also be
used for deblocking the Boc group

26

2. 9-Fluorenylmethyl carbamate (Fmoc):

R NH2

Formation:
Cleavage:

R NHFmoc

Fmoc-Cl, NaHCO3, aq. Dioxane

Fmoc-OC6F5, NaHCO3, acetone
Amine bases
Piperidine, morpholine, diisopropylethyl amine
TBAF, DMF

Fmoc protection of amines

11/9/2016

niper_H

27

Proposed mechanism for the Fmoc protection of amines

Deprotection of Fmoc:

28

3.Benzyl carbamate (Cbz or Z):

R NH2

Formation:

R NHCbz

BnOCOCl, Na2CO3, H2O

(BnOCO)2O, dioxane, H2O

Cleavage:

H2/ Pd-C
H2/ Pd-C, NH3

e. g.,

Pd-C, HCOONH4
BBr3, DCM
KOH, MeOH

Garenoxacin
11/9/2016

niper_H

Drug Res., 2002, 52, 903913.

29

4. 2,2,2-Trichloroethyl carbamate (Troc):

R NH2

R NHTroc

Formation: Cl3CCH2OCOCl, Py or aq. NaOH

Cleavage: Zn, THF, AcOH, pH= 4.2
Zn-Pb couple, 4:1 THF/ 1M NH4OAc

5. 2-Trimethylsilylethyl carbamate (Teoc):

Formation: TMSCH2CH2OCOCl (Teoc-Cl) or Teoc-N3
Teoc-OC6H4-4-NO2, NaOH
Teoc-OSu, TEA

Cleavage: Bu4NF, THF

6. Allyl carbamate (Alloc):

R NH2

R NHAlloc

Formation: CH2=CHCH2OCOCl, py
(CH2=CHCH2OCO)2O, DCM

Cleavage: Pd(Ph3P)4, TBTH, AcOH

Pd(Ph3P)4, Dimedone, THF

30

7. Phthalimides:

Other protecting group for Amines:

Benzyl (Bn)

hydrogenolysis

P-Methoxybenzyl (PMB)

3,4Dimethoxybenzyl (DMPM)

p-methoxyphenyl (PMP)

ammonium cerium(IV)
nitrate (CAN)

Tosyl (Ts)

Conc. acid (HBr, H2SO4) & strong

reducing agents (Na in liq NH3
or sodium naphthalenide

Acetyl (Ac)
Or Benzoyl (Bz)
11/9/2016

niper_H

Base(aq./gaseous ammonia or met

hylamine)
31

Gemifloxacin
Boc Protecting group

Drugs Fut., 1999, 24, 13241331.

J. Am. Chem. Soc., 2006, 128: 63106311.

11/9/2016

niper_H

Oseltamivir Phosphate

32

Protecting groups: A Necessary Evil

Protecting Group Free Synthesis

11/9/2016

niper_H

33

Nature, 2007, 446, 404-408

11/9/2016

niper_H

34

Orthogonality
Deprotection
Basic Hydrolysis

Acidic Hydrolysis

Dilute Acids
HBr-AcOH
TFA-DCM
Me3SiI, BBr3
PPTS
Dil. Acetic Acid-Temp.
Dilute Acid

Protection
Acetate Ester
Benzyl Ester
Pivaloate Ester
Trifluoro acetamide
Phthalimide
Trityl Ether/Ester
Benzyl Ether/Ester
t-Bu Ether/Ester
Alkyl Ethers
THP
MOM, MEM, BOM
Cyclic, Acyclic Acetal/Ketal

Heavy Metal
Fluoride Ion

Hg(II), NBS, I2, S-alk-H2O

TBAF-THF, HF-ACN
TBAF-THF, HF-ACN
TBAF-THF, HF-ACN
Zn-Acetic Acid-DMF

O,S/ S,S Acetal/Ketal

TES,TBDMS,TBDPS,TIPS
Me3Si Ethyl chloride
Me3Si Ethyl Carbamate
TriChloro Ethyl Ether/Ester/Carbamate

NH3, K2SO4-MeOH
NH3, K2SO4-MeOH
NH2-NH2-EtOH

Substrate
R-OH
R-NH2
R-NH2

Carbonyl
R-OH
R-COOH
R-NH2
R-OH/R-COOH/R-NH2

R-OH/R-COOH
R-OH/R-COOH
R-OH/R-COOH
R-OH
R-OH
R-OH
Carbonyl

-Elimination
Piperidine/Morpholine-DMF Fmoc
R-NH2
Hydrogenolysis [H]-Pd/C/Cyclohexene/HCOOH Benzylic ethers/Esters/Carbamate(Cbz) R-OH/R-COOH/R-NH2
H2-Pd
BOM
R-OH
Oxidation
DDQ/Ceric Amm. Nitrate
Dissolving Metal Reduction
Na-NH3
SN2
LiI,Metal cyanide/Phenyl thiolate
Transition Metal
Pd(PPh3)4-Morpholine
Wilkinson Catalyst
Photocatalysis
UV Light

11/9/2016

niper_H

p-Methoxy Benzyl Ether

Benzyl Ethers/Esters
Alkyl esters
Allylic Esters
Allylic Ethers
o-Nitro Benzyl Ester
3, 5-dimethoxy Benzoin alkanoate
2, 5-Dimethyl Phenyl Esters

R-OH
R-OH/R-COOH
R-COOH
R-COOH
R-OH
R-COOH
R-COOH
R-COOH

35

36