+

PROTECTING GROUP
+ What is protecting group?
n  Protecting groups are groups of atoms that are attached to a
functional group to mask it from competitive undesired
reactions and later be removed from that functional group.

protecting deprotecting

n  Advantages: Allows reactions that otherwise would not be

possible

n  Disadvantages: extra steps (at least 2 - protection and

deprotection), lowered yield, low atom economy, added mass
of PG on substrate.
+
What are the best PG?

n  Considerations:
1.  protecting group and both protection / deprotection
sequences must be compatible with all other desired
steps and other functional groups.
2.  Cheap & commercially available
3.  Easy & efficient introduction
4.  Should not create any stereogenic center
Stable throughout reaction, work-up & purification
5.  Efficient removal: by-products of the removal should be
easily separated
How the
PG works ?
+
The problem of using PG
n  Ether can “protect” a hydroxyl group as an ether without
worrying about it being affected by reactions

n  there’s just one problem: ethers require very harsh

conditions in order to break (hydroiodic acid, HI)

n  Solution: instead of making a typical ether (e.g. forming an O-

C bond), we form a silyl ether (i.e. make an O-Si bond, not an
O–C bond). It’s even easier to form than a “normal” ether

n  the most common silyl ether used is trimethylsilyl (TMS)

although there are others [Generally, the bulkier the groups
around silicon, the harder it is to cleave the O–Si bond]
+
Type of Protecting Group (PG)
n  Hydroxyl PG
1.  Silyl ether (R-O-Si-R)
2.  Acetal (RO-CH2-OR)
3.  Cyclic acetal (RO-CH2-O-Cy)
4.  Ether (RO-R)
5.  Esther (RC-OR
6.  Cyclic acetal

n  Ketone and aldehyde PG

1.  Cyclic acetal
2.  thioacetal

n  Amines PG
1.  Alkyl
2.  Amide
3.  Sulfonamide

n  Amides
+Type of Hydroxyl PG
1. Silyl ether protecting group
n  The alcohol group was protected and converted into silyl
ether group

n  Few types of silyl ether group:

Trimethylsilyl Triisopropylsilyl Tert-butyldimethylsilyl [2-(trimethylsilyl)

(TMS) (TIPS) (TBS or TBDMS) ethoxy]methyl (SEM)
Silyl ether protecting group
Formation (To protect ): Cleavage (Deprotect):

(CH3)3SiCl
Example 1: Using silyl ether to protect OH group

Step 1: Protect OH group

Step 2: Perform reaction
Step 3: Deprotection OH group
Example 2

Step 1: Protect OH group

Step 2: Perform reaction
Step 3: Deprotection OH group
 CHM 624 Final exam question Dec 2014
+
Type of Hydroxyl PG
2. acetals

Formation: Cleavage:
+Type of Hydroxyl PG
3. Cyclic acetals

Tetrahydropyranyl ether (THP)

Type of Hydroxyl PG
4. Ethers

Formation: Cleavage:
+Hydroxyl PG
5. Ester
+Hydroxyl PG
6. Diol Protecting
n  All ROH protecting groups work, but 1,2- or 1,3- can be
protected in unique ways.
+
 + The stability of PG
n  When more than one alcohol exist, the primary alcohols
(least sterically hindered) will be first protected, then
secondary alcohols (more sterically hindered) and finally
tertiary alcohols

n OHExample 1:
1$equiv.$DHP THP
OH 1$equiv.$DHP
OTHP OTHP
H $$$$$$$$H+ OH
OH $$$$$$$$H+ OH

PCC PCC

H3O+ H3O+
OH OH
OTHP
OH OTHP
H OH
O O

THP
2$equiv.$DHP
n  Example 2: HO OH $$$$$$$$H+ THPO OH
OH OTHP
+
n  If the oxidation is targeted at primary alcohol, then the
secondary alcohol also should be protected.

n  protect both primary and secondary alcohol with a

different protecting group, and deprotect the primary
alcohol, followed by oxidation on primary alcohol

n  Using TMS-Cl, Et3N first and then THP. H+ allows you to
remove the TMS group easily with F-, thus allowing the THP
to stay in place:

OH 1$equiv.$TMS.Cl OTMS
OH $$$$$$$$NEt3 OH

DHP,$H+
THP

O
pcc HF
OH OTMS
H
H3O+ OTHP OTHP
OH
+
n  If the same protecting group presence on both alcohols,
deprotection occur on both group which cannot be selective

OH 2$equiv.$DHP OTHP
OH $$$$$$$$H+ OTHP

H3O+

OH
OH
+ 21

v Ease of cleavage is as follows

v  Acidic condition
TMS > TES > TBDMS > TIPS > TBDPS

v  Basic condition

TMS > TES > TBDMS = TBDPS > TIPS
+Ketone and aldehyde PG
1. Acetal

Formation:

Cleavage:

The cleavage of acyclic

acetals is easier than of
cyclic acetals
+ Examples 1:
Examples 2:

remove the
protecting group

protect the ketone

as an acetal reduce the ester to
the primary alcohol.
Examples 3:
n  If both aldehyde and ketone presence, the aldehyde will be
protected and react with 1,2 or 1,3-diol because aldehyde
are more reactive than ketone.
+Ketone and aldehyde PG
2. Thioalacetal

Formation:

Cleavage:
+Amines PG

n  The most common to protect amine is by convert it

to the carbamate formed

n  Amines also may be protected as:

Ø  N-alkylation (not commonly used)
Ø  N-acylation through formation amide
+Amines PG
1. Tert-butyl carbamates (BOC)
n  Formation:

n  Cleavage: Strong acid (3M HCl), CF3COOH

+Amines PG
2. Allyl carbamates (AllOC)
n  Formation:

n  Cleavage: Pd(0), Et3SiH

+Amines PG
3. Benzyl carbamates (CBz)
n  Formation:

n  Cleavage: Hydrogenolysis, PdCl2, Et3SiH, BBr3

+Amines PG
4. Amides

The most common,

the easiest to remove

trifluoroacetamides

•  Cleavage: NaOH
+Amines PG
5. Alkyl protecting group
n  Formation:

BnBr

n  Cleavage: H2, Pd/C, HCl

+Amines PG
6. sulfonamides
n  Formation:

n  Cleavage: Removal (typically very hard with

destroying substrates); Li/NH3
+ Examples 1:
n  Amino group can be protected by being converted to amide.
+Amides PG

Cleavage:

PBMCl =P-methoxybenzyl chloride

CAN = ceric ammonium nitrate = strong oxidant
+
Exercise 1
+
Exercise 2
Exercise 3
+ ?