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Protecting Groupskpk/pg.pdf · Methoxymethyl ethers (MOM): Formation: MeOCH 2Cl, NaH, THF Cleavage:...
Transcript of 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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CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
2
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
4
Ethers 3. Methoxyethoxymethyl ethers (MEM):
Formation: MeOCH2CH2OCH2Cl, NaH, THF
Lewis acids such as ZnBr2, TiCl4, Me2BBr2 Cleavage:
MeOCH2CH2OCH2Cl, CH2Cl2, i-Pr2EtN
Stable to base and mild acid
R OH R OCH2OCH2CH2OMe
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
5
Ethers 4. Benzyloxymethyl ethers (BOM):
Formation:
H2, PtO2 Cleavage:
PhCH2OCH2Cl, CH2Cl2, i-Pr2EtN
Stable to base and mild acid
R OH R OCH2OCH2Ph
Na/ NH3, EtOH
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
10
Ethers 8. Silyl ethers:
Properties: Acid and water labile
Useful for transient protection
8.1. Trimethylsilyl ethers (TMS):
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
11
Ethers 8. Silyl ethers:
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):
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
12
Ethers 8. Silyl ethers:
Properties: More stable to hydrolysis than TMS
8.3. Triisopropylsilyl ethers (TIPS):
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
13
Ethers 8. Silyl ethers:
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
14
Ethers 8. Silyl ethers:
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
15
Ethers 8. Silyl ethers:
Cleavage:
8.5. t-Butyldiphenylsilyl ethers (TBDPS):
F-, n-Bu4F
HF/ H2O/ CH3CN
HF.pyridine
SiF4. CH2Cl2
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
16
Ethers 9. o-Nitrobenzyl ethers:
Formation:
Cleavage:
R OHCl
NO2
OR
NO2
NaH, THF
o-Nitrobenzyl chloride, NaH, THF
Photolysis at 320 nm
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
18
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-
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
19
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
20
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
21
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)
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
22
Selective for primary alcohols
Esters 3. Pivaloates (Piv):
Formation: t-Butylacetyl chloride
t-Butylacetic anhydride
Cleavage: Mild base
R OH
O
Cl O
OR
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
23
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
24
Protection of 1,2 & 1,3-diols
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
25
Protection of 1,2 & 1,3-diols
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
26
Protection of 1,2 & 1,3-diols
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups Hydroxyl Protecting Groups
27
Protection of 1,2 & 1,3-diols
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
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Protecting Groups
28
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
29
Protecting Groups
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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+
Protection of ketones and aldehydes
30
Protecting Groups
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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
Protection of ketones and aldehydes
31
Protecting Groups
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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
Protection of ketones and aldehydes
32
Protecting Groups
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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
Protection of ketones and aldehydes
33
Protecting Groups Protection of carboxylic acids
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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
34
Protecting Groups Protection of carboxylic acids
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
Esters 2. 9-Fluorenylmethyl esters (Fm):
OH
RCOOH
O
O R
DCC
35
Protecting Groups Protection of amines
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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
36
Protecting Groups Protection of amines
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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
Protecting Groups Protection of amines
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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
38
Protecting Groups Protection of amines
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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
39
Protecting Groups Protection of amines
CH-‐423 Course on Organic Synthesis; Course Instructor: Krishna P. Kaliappan
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