protecting groupskpk/pg.pdf · methoxymethyl ethers (mom): formation: meoch 2cl, nah, thf cleavage:...

CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan

Protecting Groups

Tactical Considerations

Cheap & commercially available Easy & efficient introduction

Should not create any stereogenic center

Stable throughout reaction, work-up & purification

Efficient removal

By-products of the removal should be easily separated

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Protecting Groups Hydroxyl Protecting Groups

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Ethers 1. Methyl ethers:

Formation: CH2N2

BBr3, CH2Cl2 Cleavage:

NaH, MeI, THF

PhSe-

Ph2P-

Me3SiI

Difficult to remove except for phenols

R OH R OMe



3

Ethers 2. Methoxymethyl ethers (MOM):

Formation: MeOCH2Cl, NaH, THF

Me2BBr Cleavage:

MeOCH2Cl, CH2Cl2, i-Pr2EtN

HCl/ THF, reflux

CH3COCl, MeOH

Stable to base and mild acid

R OH R OCH2OMe



4

Ethers 3. Methoxyethoxymethyl ethers (MEM):

Formation: MeOCH2CH2OCH2Cl, NaH, THF

Lewis acids such as ZnBr2, TiCl4, Me2BBr2 Cleavage:

MeOCH2CH2OCH2Cl, CH2Cl2, i-Pr2EtN


R OH R OCH2OCH2CH2OMe



5

Ethers 4. Benzyloxymethyl ethers (BOM):

Formation:

H2, PtO2 Cleavage:

PhCH2OCH2Cl, CH2Cl2, i-Pr2EtN


R OH R OCH2OCH2Ph

Na/ NH3, EtOH



6

Ethers 5. Tetrahydropyranyl ethers (THP):

Formation:

PPTS, EtOH Cleavage:

DHP, PPTS, CH2Cl2

Stable to base

Amberlyst H-15, MeOH

Creates one more stereogenic center

R OHORO

OH+, PhH



7

Ethers 6. Benzyl ethers (Bn):

Formation:

H2/ PtO2 Cleavage:

NaH, BnBr, THF/ DMF/ DME

Li/ NH3

R OH R OCH2Ph

KH, BnCl, THF

BnOC(=NH)CCl3, CF3SO3H

H2/ Pd-C



8

Ethers 7. p-Methoxybenzyl ethers (PMB):

Formation:

DDQ Cleavage:

KH, p-Methoxybenzyl chloride, THF

CAN

PMBOC(=NH)CCl3, CF3SO3H

H2/ Pd-C Li/ NH3

R OH

MeOCl

MeOO R

OH

R

OPMBDDQ

MS R

OO

PMP

R

OHPMBODIBAL-H



9

Ethers 8. Silyl ethers:

Formation:

Acid Cleavage:

R3SiCl, Pyridine, DMAP

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

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

R OH R OSiR3



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Properties: Acid and water labile

Useful for transient protection

8.1. Trimethylsilyl ethers (TMS):



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Properties: Considerably more stable than TMS

Can be selectively removed in presence of more robust silyl ethers with F- or mild acids

8.2. Triethylsilyl ethers (TES):



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Properties: More stable to hydrolysis than TMS

8.3. Triisopropylsilyl ethers (TIPS):



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Properties: Stable to bases and mild acids

8.4. t-Butyldimethylsilyl ethers (TBS/ TBDMS):

Under controlled condition it is selective for primary alcohols

Formation: t-Butyldimethylsilyl triflate, base

t-Butyldimethylsilyl chloride, base

O

OTBS

OH

TESO

OTBS

O

H2O/ AcOH/ THF



14


Properties: Stable to bases and mild acids

8.5. t-Butyldiphenylsilyl ethers (TBDPS):

Selective for primary alcohols

Me3Si & i-Pr3Si groups can be selectively removed in presence of TBS or TBDPS

TBS group can be selectively removed in presence of TBDPS by acid hydrolysis

OTBSOTBDPS

OHOTBDPS

AcOH/ H2OTHF



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Cleavage:

8.5. t-Butyldiphenylsilyl ethers (TBDPS):

F-, n-Bu4F

HF/ H2O/ CH3CN

HF.pyridine

SiF4. CH2Cl2



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Ethers 9. o-Nitrobenzyl ethers:

Formation:

Cleavage:

R OHCl

NO2

OR

NO2

NaH, THF

o-Nitrobenzyl chloride, NaH, THF

Photolysis at 320 nm



17

Ethers 10. p-Nitrobenzyl ethers:

Formation:

Cleavage:

p-Nitrobenzyl chloride, NaH, THF

Selective removal with DDQ

R OH

Cl

ORNaH, THF

O2N O2N

Hydrogenolysis

Electrochemically



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Ethers 11. Trityl ethers (Tr= CPh3):

Formation:

Cleavage:

Ph3C-Cl, pyridine, DMAP

Mild acid

Selective for primary alcohols, stable to base

R OH R OCPh3

Ph3C+BF4-



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Esters

Formation: “Activated acid”, base, solvent Chem. Soc. Rev. 1983, 12, 129

R OH RO

O

R'

Angew. Chem. Int. Ed. Engl. 1978, 17, 569



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1. Via acid chlorides:

Formation: SOCl2 PCl5 (COCl)2

O

R' OH

O

R' Cl

O

R' N

N

Cl R OH O

R' OR

Esters



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Properties: Stable to acid and mild base

Not compatible with strong nucleophiles such as organometallic reagents

R OH R OAc

Esters 2. Acetates (Ac):

Formation: Ac2O, pyridine

Acetyl chloride, pyridine

Cleavage: K2CO3, MeOH, reflux KCN, EtOH, reflux

NH3, MeOH LiOH, THF, H2

Enzyme hydrolysis (Lipase)



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Selective for primary alcohols

Esters 3. Pivaloates (Piv):

Formation: t-Butylacetyl chloride

t-Butylacetic anhydride

Cleavage: Mild base

R OH

O

Cl O

OR



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Protection of 1,2 & 1,3-diols

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

Cleavage: Mild aqueous acid

OO

R1 R2

R3 R4OHHO

R1 R2

O

R3 R4

Acid

1. Isopropylidenes (acetonides):

OO

R1 R2

OHHO

R1 R2

Acid

Acetone orOMe

orOMe

OMe



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Cyclopentylidenes are slightly easier to cleave than acetonides

2. Cycloalkylidene acetals:

OO

R1 R2

OHHO

R1 R2

Acid OO

R1 R2O O

or

or

Cyclohexylidenes are slightly harder to cleave than acetonides



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1,3-Benzylidene formation is usually favored over 1,2-Benzylidene

3. Benzylidene acetals:

Benzylidenes are usually hydrogenolyed slower than benzyl ethers or olefins

OO

R1 R2

OHHO

R1 R2

Acid

CHO

Ph

CH(OMe)2

or

Cleavage: Acid hydrolysis or hydrogenolysis



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4. p-Methoxybenzylidene acetals:

Cleavage: Hydrolyzed about 10 times faster than regular benzylidenes

OO

R1 R2

OHHO

R1 R2

Acid

CHOCH(OMe)2

or

OMe OMe

OMe

Can be oxidatively removed with CAN



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5. Carbonates:

Cleavage: Removed with base

Stable to acid & more difficult to hydrolyze than esters

OO

R1 R2

OHHO

R1 R2

O

Im2CO

Formation: Im2CO or phosgene or triphosgene


Protecting Groups

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Protection of ketones and aldehydes

Ketones and aldehydes are generally protected as cyclic and acyclic ketals and acetals

Stable to base

O

R1 R2

R1

R2

OMe

OMe

MeOH, H+

OH OH

H+

O

OR1

R21,3-dioxanes

(CH2OH)2, H+ O

O

R1

R21,3-dioxolanes

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Protecting Groups


Cleavage rate of substituted 1,3-dioxanes

O

OR1

R2 O

OR1

R2 O

OR1

R2

Ketal formation of α,β-unsaturated carbonyls are usually slower than for the saturated case

O

O

O

OO

(CH2OH)2H+


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Protecting Groups


1. Fluoride cleavable ketal:

O

O

O

O

Me3Si

O

O

O

LiBF4

2. Base cleavable ketal:

O

R1 R2R1 R2

OO

HO SO2PhOH

pTSA

SO2PhDBU, DCM O

R1 R2


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Protecting Groups


3. 1,3-Dithiane derivative:

O

R1 R2 R1 R2SS

SHHSS S

R1 R2

or

Formation: HS(CH2)nSH, BF3.Et2O, DCM, 25 oC

Aldehydes are selectively protected in presence of ketones

In α,β-unsaturated ketones, double bond does not migrate to the β,γ-positions

OO

O

S

S


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Protecting Groups


3. 1,3-Dithiane derivative:

1,3-dioxolanes and 1,3-dioxanes can be readily converted into 1,3-dithiolanes and 1,3-dithianes

OO SSSHSH

BF3.Et2O

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

NBS, acetone, 0 oC

I2, DMSO

CAN, aq. CH3CN

m-CPBA, Ac2O

DDQ, aq. CH3CN


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Protecting Groups Protection of carboxylic acids


Esters 1. Alkyl esters:

Cleavage:

Formation: Fischer esterification (RCOOH + R’OH + H+) Acid chloride + ROH, pyridine

t-Butyl esters: Isobutylene & acid

Methyl esters: Diazomethane

LiOH, THF, H2O

Enzyme hydrolysis

t-Butyl esters are cleaved with aq. acid

Bu2SnO, PhH, reflux

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Protecting Groups Protection of carboxylic acids


Esters 2. 9-Fluorenylmethyl esters (Fm):

OH

RCOOH

O

O R

DCC

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Protecting Groups Protection of amines


Carbamates 1. t-Butyl carbamate (Boc):

R NH2 R NHBoc

Cleavage:

Formation: (Boc)2O, NaOH, H2O, 25 oC (Boc)2O, TEA, MeOH/ DMF

BocN3, DMSO

3M HCl, EtOAc TFA, PhSH, DCM

AcCl, MeOH

CAN, CH3CN

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Carbamates 2. Allyl carbamate (Alloc):

R NH2 R NHAlloc

Cleavage:

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

Pd(Ph3P)4, TBTH, AcOH

Pd(Ph3P)4, Dimedone, THF

37



Carbamates 3. Benzyl carbamate (Cbz or Z):

Cleavage:

Formation: BnOCOCl, Na2CO3, H2O

(BnOCO)2O, dioxane, H2O

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

R NH2 R NHCbz

Pd-C, HCOONH4

BBr3, DCM

KOH, MeOH

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Carbamates 4. 9-Fluorenylmethyl carbamate (Fmoc):

R NH2 R NHFmoc

Cleavage:

Formation: Fmoc-Cl, NaHCO3, aq. Dioxane Fmoc-OC6F5, NaHCO3, acetone

Amine bases Piperidine, morpholine, diisopropylethyl amine

TBAF, DMF

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Carbamates 5. 2,2,2-Trichloroethyl carbamate (Troc):

R NH2 R NHTroc

Cleavage:

Formation: Cl3CCH2OCOCl, Py or aq. NaOH

Zn, THF, H2O, pH= 4.2 Zn-Pb couple, 4:1 THF/ 1M NH4OAc

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Carbamates 6. 2-Trimethylsilylethyl carbamate (Teoc):

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

Teoc-OSu, TEA

protecting groupskpk/pg.pdf · methoxymethyl ethers (mom): formation: meoch 2cl, nah, thf cleavage:...

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