2-1. pg lecture 2016 ho - chemistry.syr.educhemistry.syr.edu/totah/che676/support/3b1/2.pg.pdf ·...

Protecting Groups: Additional Resources

Greene & Wuts: Protective Groups in Organic Synthesis Kocienski: Protecting Groups (see also: J. Chem. Soc., Perkin Trans. 1, 1999, 1589.) http://www.organic-chemistry.org/protectivegroups/

OHOH

OH

HOHO

OHMe

OOHO

OH

O

OH

O

OH

OHHO

OHO

OHH2N

OHOH

O

HO

OH

OHH

OH

OH

Me

OHOH

O

OH

OHHO

HO

HO

O

OHO

Me

Me Me OH

HO

O H

HOHOMeOH

OH

OH

OH

OHOH

NH

NH

Me

OH

OO

HO

palytoxin(1994, Kishi)

OH

OTBSOTBS

TBSO

TBSOTBSO

OTBSMe

OOO

OAc

O

OTBS

O

O

OTBSTBSO

OTBSO

OTBSNH

OTBSOTBS

O

TBSO

OTBS

OTBSH

OTBS

OTBS

Me

OAcOBz

O

OBz

OAcBzO

TBSO

BzO

OOBz

O

Me

Me Me OPMB

PMBO

O H

PMBOOPMBMe

OTBS

OPMB

OPMB

OPMB

OPMBOPMB

MeO

Me

OAc

O

palytoxin precursor:

OAc

TEOC

TEOC =

Me3Si O

O

Alcohol Protecting Groups: Ethers

• Methyl Ether ! ! ! ! !R-OH R-OMe

formation:

cleavage:

TBSO

OBnNaH, MeI THF, rt

OH OH

OPMB TBSO

OBnOMe OMe

OPMB

very robust, stable to strongly acid and basic conditions difficult to cleave, except in phenols

- NaH, MeI, THF - CH2N2, silica or HBF4

O

OOBz

OMe O

OOBz

OHAlBr3EtSH

- AlBr3, EtSH ! ! !- AlCl3, HSCH2CH2SH (large xs) !- BCl3, CH2Cl2, -20°C; Na2CO3 (aq) !- Me3SiI!


• Methoxymethyl Ether (MOM) ! ! ! !R-OH R-OCH2OMe

formation:

cleavage:

acetal type protecting group; stable to base and mild acid

- MeOCH2Cl, NaH, THF - MeOCH2Cl, iPr2NEt, CH2Cl2

- MeOCH2Cl, NaI, iPr2NEt, CH2Cl2 - CH2(OMe)2, P2O5, CH2Cl2

- TFA, CH2Cl2 ! ! !- Me2BBr2, CH2Cl2, -78°C!- 3% HCl, EtOH ! ! !- AcCl, MeOH, 0°C!

TBSO

OHMeOCH2Cl

iPr2NEt, CH2Cl2, 0°COMe OH

OBn TBSO

OMOMOMe OH

OBn

RO2C OMeOCH2Cl, NaI

iPr2NEt, DME, refluxOH

OSiMe3 RO2C O

OMOM

OSiMe3


• Tetrahydropyranyl Ether (THP) ! ! !R-OH R-OTHP

formation:

cleavage:

acetal type protecting group; base stable, cleaved with mild acid introduction can result in formation of diastereomers

- DHP (dihydropyran), pTsOH (cat), PhH - DHP, PPTS (cat), CH2Cl2

- HOAc/H2O ! ! !- CSA, MeOH!- PPTS, EtOH (aq) ! ! !- MgBr2, Et2O!

O OH

OAc

OPPTS, CH2Cl2

O O

OAc

OH

OTHP

N

SOTBS

MgBr2 (3 eq)Et2O OH

N

SOTBS


• Benzyl Ether (R-OBn) ! ! ! !R-OH R-OCH2Ph

formation:

cleavage:

stable to acid and base; variety of cleavage protocols

- PhCH2Br, NaH, THF - PhCH2OC(=NH)CCl3, TfOH (cat), DCM

- H2, Pd/C, EtOH (also THF or EtOAc) !- H2, Pd(OH)2, MeOH!- Li/NH3 !! ! ! !- BCl3, CH2Cl2, 0°C

SEtNaH, BnBr

Bu4NI, THF, 0°COH OH

SEtOBn OBn

SEt SEt

BnO OMeH2, Pd/C

EtOHOMe

HO OMeOMe


• p-Methoxybenzyl Ether (R-OPMB) ! ! !R-OH R-OCH2PhOMe

formation:

cleavage:

base stable; more acid labile than benzyl ether can be cleaved selectively under oxidative conditions

- p-MeOPhCH2Cl, NaH, THF - p-MeOPhCH2OC(=NH)CCl3, TfOH (cat), DCM

- H2, Pd/C, EtOH (also THF or EtOAc) !- DDQ or CAN!- Li/NH3 !! ! ! !- TFA

O

OO

OH

Cl3C OPMB

NH

TfOH (cat), Et2O O

OO

OPMB

OBn

O

O

OPMB DDQCH2Cl2-H2O OBn

O

O

OH


• Silyl Ethers ! ! ! ! !R-OH R-OSiR’3

general stability in acidic media:

general stability in basic media:

stability to acid or base depends on specific silyl ether

- TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000)

- TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000)!

RO SiMe

MeMe

trimethylsilyl (TMS)

RO SiEt

EtEt

triethylsilyl (TES)

RO SiMe

MetBu

t-butyldimethylsilyl (TBS)

RO SiPh

PhtBu

t-butyldiphenylsilyl (TBDPS)

RO SiiPr

iPriPr

triisopropylsilyl (TIPS)


• Silyl Ethers ! ! ! ! !R-OH R-OSiMe3

J. Chem. Soc., Perkin Trans. 1 1992, 3043; J. Org. Chem. 1988, 53, 2602.

formation:

- R3SiCl, imidazole, DMF (or CH2Cl2 or CH3CN)

- R3SiOTf, iPr2NEt (or 2,6-lutidine), CH2Cl2 - R3SiCl, Et3N, DMAP, CH2Cl2 (selective protection of 1° alcohols)

cleavage:

- acid: !HCl, AcOH, CSA, pTSOH, PPTS, etc. – choice will depend on specific PG!- fluoride: Bu4NF (TBAF), HF-pyridine, HF, CsF, KF, etc.



- very acid and water labile

- useful for transient protection

RO SiMe

MeMe

trimethylsilyl (TMS)

- stable to base and mild acid

- selective for 1° alcohols under controlled conditions

RO SiMe

MetBu

t-butyldimethylsilyl (TBS)

RO SiPh

PhtBu

t-butyldiphenylsilyl (TBDPS)

- stable to acid and base

- selective for 1° alcohols - also known as BPS

- TMS and TES groups can be cleaved in the presence of TBS and TBDPS - TBS can be cleaved under acide conditions in the presence of TBDPS (AcOH, THF/H2O)



- TMS and TES groups can be cleaved in the presence of TBS and TBDPS - TBS can be cleaved under acidic conditions in the presence of TBDPS (AcOH, THF/H2O)

OOOH

TBDPSO

OTES

OTBS

OHOOH

TBDPSO

OH

OTBSPPTSEtOH

AcOH-THF-H2O(3:1:1)

OPv

H

HO

OTBDPS

TBSOCO2H

OPv

H

HO

OTBDPS

HOCO2H

Alcohol Protecting Groups: Esters

• Esters ! ! ! ! ! !R-OH R-O2CR’

relative reactivity:

stable to acid and mild base not compatible with strong base or strong nucleophiles

- Pv < Bz < Ac < chloroacetate < Ac’

(reactivity largely mirrors acidity of corresponding carboxylic acid)

O CH3

O

R

acetate (Ac)

O

O

R

pivaloate (Pv)

O

O

R

benzoate (Bz)

O

O

R

chloroacetate

O

O

R

trifluoroacetate (Ac')

F

F FCl

Alcohol Protecting Groups: Esters

• Esters ! ! ! ! ! !R-OH R-O2CR’

formation:

cleavage:

- (RCO)2O or RCOCl, pyridine - (RCO)2O or RCOCl, DMAP, Et3N, CH2Cl2

- K2CO3, MeOH ! ! !- NH3, MeOH!- LiOH, THF (aq) !! ! !- DIBAL, CH2Cl2 !

OHOH

OH

tBu Cl

O(1 equiv)

pyridine, CH2Cl2OPv

OH

OH

OAc

OPv

LiOHMeOH, 3.5 h

OH

OPv

1,2- & 1,3-Diol Protecting Groups: Acetals

• Acetals !

formation:

stable to base; cleaved with mild aqueous acid

- catalysts: pTsOH, CSA, PPTS, ZnCl2, etc. - use of a Dean-Stark trap or dessicant (4Å MS or anh. CuSO4) facilitates the reaction

- silylene acetal: tBu2SiCl2, Et3N, HOBT or tBu2Si(OTf)2, 2,6-lutidene

HO OH( )n O O

( )n

R'R

O O

R R'( )n

O O

R R'( )n

O O

R R'( )n

O OSi

R R'( )n

tButBu

acetonide(isopropylidene acetal)

benzylideneacetal

p-methoxybenzylideneacetal (PMP)

di-t-butylsilyleneacetal

OMe

O O

( )n

R'R

HO OH( )nR R'

O

R R'

OMeMeO

R'

OMe

(R = Me)or or

H+ catalyst, - H2O


• Acetals ! ! !

formation:

HO OH( )n O O

( )n

R'R

• acetonide formation in 1,2-diols is generally faster than that in 1,3-diols

• benzylidene acetals typically favor protection of the 1,3-diol

HOOHOH

acetonepTsOH

OHOHO

OOO +

5 : 1

• acetal formation from PMB ethers

PhCH(OMe)2pTsOH, 4Å MS

HOOHOH OHO

HOOO

O +

1 : 9

PhPh

DDQ4Å MS, CH2Cl2

ButO2COOH

ButO2COO

PMP

OH OHOMe ButO2C

OOH

OHOMe


• Acetals ! ! ! cleavage:

- H3O+, THF ! ! !- PPTS, MeOH!- TFA-H2O ! ! ! !- AcOH!- benzylidene acetals: H2, Pd/C ! !- silylene acetals: HF•pyridine!

HO OH( )n O O

( )n

R'R

• selective cleavage of benzylidene acetals

O O

OOBn

BnO

BnO Ar LiAlH4, AlCl3or DIBAL

O OH

OOBn

BnO

BnO Ar

Ar = Ph, PMP

O O

OOBn

MeO

BnO Ar NBSCCl4 O

Br

OOBn

MeO

BnO Ar

O Ar = Ph, PMP

OO

PMP

DDQAcOH (aq)HO

OHOHO

OMeO

Aldehyde & Ketone Protecting Groups: Acetals & Ketals

• Acetals ! ! !

formation:

- 2 ROH, dry HCl ! ! !- ROTMS, TMSOTf, CH2Cl2, -78°C!!

- 1,2- or 1,3-diol, pTsOH (cat), PhH, Δ (-H2O e.g. with Dean Stark or dessicant)!

stable to base; cleaved with aqueous acid

O OR'R

O OR R'

MeO OMe

R R'

dimethyl acetal 1,3-dioxane 1,3-dioxolane

R R'

O

orORRO OO( )n

O OR'R R R'

O O OR R'

HO OHpTsOH (cat), -H2O

OHpTsOH (cat), -H2OHO

MeOHdry HCl R'R

OMeMeO

R R'

O

Aldehyde & Ketone Protecting Groups: Acetals & Ketals

• Acetals ! ! ! R R'

O

orORRO OO( )n

formation:

• selective protection of saturated ketones

• selective protection of unsaturated ketones (steric)

O

O

HO OHpTsOH (cat), -H2O

O O

O

O

O

TMSO OTMSTMSOTf, CH2Cl2, -78°C

O

OO

• migration of double bond may occur (favored by stonger acid catalysts)

O

HO OHpTsOH (cat), -H2O O

O

cleavage:

- 1M HCl, THF ! ! !- PPTS, acetone, H2O, Δ

pTsOH pKa <1 (db isomerization) fumaric acid pKa = 3.03 (no isom)

J. Org. Chem. 1985, 50, 3946.

Aldehyde & Ketone Protecting Groups: Thioacetals & Ketals

• Thioacetals ! ! !

cleavage:

- Hg(ClO4)2, MeOH (or other Hg2+ salts) !- mCPBA; Et3N, Ac2O, H2O!- IBX, DMSO (aq) !! ! !- CF3CO2)2IPh, H2O, CH3CN !

R R'

O

stable to mild acid and base; not typically cleaved with aqueous acid can be difficult to remove

S SR'R

S SR R'

1,3-dithiane 1,3-dithiolane

formation:

S SR'R

or S SR R'

O

HS SHS

SBF3•OEt2, CH2Cl2

- HS(CH2)2SH or HS(CH2)3SH, BF3•OEt2, CH2Cl2 ! !!- TMSS(CH2)2STMS or TMSS(CH2)3STMS, ZnI2, Et2O!

no isomerization

Carboxylic Acid Protecting Groups: Esters

• Esters ! ! ! ! ! !R-CO2H R-CO2R’

formation:

cleavage:

- Fisher esterification: ROH, H2SO4 (good for simple alcohols) - methyl esters: CH2N2 - t-butyl ester: isobutylene, H2SO4, Et2O - allyl ester: allyl bromide, Cs2CO3, DMF - R’OH, EDC•HCl or DCC, DMAP (very general) - 1. SOCl2, 2. ROH, pyridine (very general)

- LiOH, THF (aq) ! ! !- t-butyl ester: TFA, CH2Cl2 !!- allyl ester: Pd(PPh3)4, RSO2Na, CH2Cl2 !- benzyl ester: H2, Pd/C!

R OH

O R'OHconditions R OR'

O

R OMe

O

R OtBu

O

methyl ester t-butyl ester

R O

O

benzyl ester

Ph R O

O

allyl ester

Amine Protecting Groups: Carbamates

• Carbamates ! ! ! ! !R2-NH

formation:

cleavage:

- BOC: !HCl or TFA!or TMSI ! !!- Fmoc: !piperidine or morpholine or dicyclohexylamine!!- Cbz: !H2, Pd/C or TMSI!

R NR

O R'O

R2N OtBu

O R O

O

t-butyl carbamate(BOC)

9-fluorenylmethyl carbamate(Fmoc)

R2N O

O

benzyl carbamate(Cbz)

Ph

R2N H Cl OR'

O

R'O OR'

Oor

R2N OR'

O

Et3N, DMAP or pyridine

amines are also often protected as benzyl or allyl ethers, acetates, and tosylates. Latter two may be difficult to cleave.

2-1. pg lecture 2016 ho - chemistry.syr.educhemistry.syr.edu/totah/che676/support/3b1/2.pg.pdf ·...

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