ASSIGNMENT

Topic: Synthetic applications of protecting groups of the

carboxylic acid group

Submitted to: Dr. Tahir Mahmood

Submitted by: Zunaira
Roll number: 21422 (137)
Semester: 8th morning
Protecting groups of the carboxylic acid group

Protecting Groups for Carboxylic Acids (Esters) The common ester protecting groups for
carboxylic acids are methyl, ethyl, and benzyl esters. Methyl Esters.
 Ethyl and benzyl esters are prepared based on the following rationale:

Preparation:

HCl H2
R CO2H + ROH R C OR + H2O

DCC O
+ DCHU
R CO2H + ROH R C OR

DCC= 1,3-Dicyclohexyl carbodiimide

N C N

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Mechanism of DCC coupling

O O
N C N + R C O H N C N
H
+ R C O

O
O O C R
R C O + N C N N C
H
N
H
O O
R C O O
R H
C N + N C N
R O H + N
R O

H H

O
O
O O
R H H
H R N C N
R O N C N +
+ R O
H

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Ethyl esters

Formation

DCC O
R CO2H + CH3CH2OH R C OCH2CH3

Cleavage
O LiOH
R C OCH2CH3 R CO2H + CH3CH2OH
H2 O2

Synthetic applications of Protecting groups for carboxylic acids

Protecting groups for carboxylic acids are used to avoid reaction of the acidic -COOH
hydrogen with bases and nucleophiles or to prevent nucleophilic additions at the carbonyl
carbon.
The most common group for the protection of acid is an ester. The total synthesis of complex
organic architectures is often complicated by the presence of several different functional
groups in the target molecule. These groups often present significant synthetic challenges,
particularly if the reactions in a preparative sequence may affect one or more of these
functional groups.

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Typically, protecting groups are employed to temporarily render the reactive functionalities
inert while transformations are performed at other sites in the molecule. The protecting
groups are then unmasked at strategic points later in the synthetic route. The choice of
protecting group is often a key decision, as problems with their introduction or removal may
affect the viability of the synthetic sequence.

Alternatively, protecting groups can become a liability should they decompose at undesired
times or contribute to the instability of intermediates. Therefore, efforts have been focused on
developing reliable systems that have sufficient stability to withstand many common
transformations but that can still be removed under mild conditions when desired. These
efforts have resulted in the development of many different blocking groups for a variety of
functionalities.

In the search for the optimal protecting group, predicting which one will perform best in a
complex system can be difficult. One approach to address this challenge is to use protecting
groups that can be installed and removed under a variety of conditions, ensuring that options
will be available if the planned installation or removal leads to unforeseen substrate
decomposition.

The generation of PMB esters has also been reported from the reaction of carboxylic acids
with commercially available 4-methoxybenzyl-2,2,2-trichloro-acetamide. The use of the
dichloroacetamide for esterification does not require an acid catalyst because the carboxylic
acid itself promotes the transformation. This method was successful over a wide range of
substrates, including electron-rich and electron-poor benzoic acids and carboxylic acids
bearing halogens, alkenes, and alkynes. Esters such as, which have a free alcohol group, were
also formed in excellent yields. The mild nature of these conditions is demonstrated by the

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formation of the PMB ester of naproxen with no racemization of the nearby chiral center.

Ph O Ph O
NH
72% no isomerization
OH
PMB
O CCl3 OPMB

CH2Cl2,rt MeO
MeO 80% no isomerization

CO2H
CO2H

Additionally, PMB ester was formed with no detectable isomerization of the Z-alkene to the

more stable E-isomer. Preliminary mechanistic studies showed that the addition of strong
amine bases hampered this reaction. This implies that the carboxylic acid first protonates the
imidate (which has a pKa of approximately 11); the imidate group is then displaced by the
carboxylate anion, leaving trichloro acetamide as the only by-product of the transformation.
The presence of an amine was found to be detrimental to the transformation because the
basic amine protects the imidate from protonation, thus suppressing the esterification in these

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cases.

NH

Cl3C O
O O
OMe
R OH R OPMB
DCM,rt

MeO
Ph CO2PMB Ph

CO2PMB
OH
34 CO2PMB
37 38
79% 80% 72%

1. To protect the carboxylate group, the 4-methoxybenzyl (PMB) ester has become known
as an inexpensive “workhorse” protecting group. This ester may be readily introduced in
high yield under several mild reaction conditions. The PMB ester possesses excellent
stability under many reaction conditions; therefore, it can be used in a variety of settings.
Also, when the removal of a PMB ester is desired, many orthogonal methods may be
employed to induce cleavage. This review discusses conditions for installing and
removing PMB esters and presents many complex examples in which the PMB ester is
featured. Rather, this manuscript will focus on the most interesting and useful examples
that may prove beneficial for planning multi-step syntheses of complex molecules that
require protection of the carboxylate function. However, this review will provide a more
thorough discussion of the PMB ester protecting group than other sources that provide
general overviews of protecting groups
PMB esters have found extensive use in total syntheses and have proven to be

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 particularly valuable to synthetic organic chemists. More recently, these applications
have been expanded into investigations in organic methodology and bio-organic
chemistry.

2.

3. Because of the ability of PMB esters to be formed and cleaved under a variety of mild
conditions from inexpensive starting materials, the PMB group has become one of the
“workhorses” protecting groups when working with complex organic molecules that
require carboxylate protection.

4. 1. Examples of the Use of PMB Esters in Total Syntheses

5. PMB esters were useful in the synthesis of the diene-containing histone deacetylase
inhibitor trichostatin A. The major carbon-carbon bond-forming reaction in this synthetic
sequence was the palladium-catalyzed coupling of ketone with vinyl bromide. The
removal of the PMB group from the ester followed by coupling of the newly formed
carboxylic acid with a hydroxylamine equivalent provided trichostatin A in excellent
yield. The palladium-catalyzed coupling was equally efficient with the methyl ester, but
hydrolysis of the methyl ester with hydroxide led to isomerization of the trisubstituted
alkene, forming a mixture of E- and Z-alkene isomers.

6. The removal of the PMB group with TFA provided a useful solution to this problem, with
no alkene isomerization being observed under these conditions. In the case of ester,
triethyl silane is added to the reaction as a cation scavenger to reduce the 4-
methoxybenzyl cation, forming 4-methyl anisole and triethyl silyl trifluoroacetate as side
products while protecting the diene and the aromatic ring from side reactions with the 4-
methoxybenzyl cation.

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7.

O O
O LTMP,Zncl 2
107 OPMB
N
Pd(dba)(4 mol %)
109
N 82%
O
Br OPMB
108

O O O O
OH
ClC(O)OET,Et 3N
OH N
110
H2NOTBS 111 H
N 96% N 71%

THF/MeOH.0oC
then CSF

Theodorakis and his group used a PMB ester in their synthesis of borrelia in. Aldehyde was
utilized in an acetate aldol reaction with the silyl enol ether of 4-methoxybenzyl acetate to
provide β-hydroxy ester in 71% yield (the other diastereomer of the alcohol was also
produced in 14% yield). The stereoselectivity of this reaction is attributed to the chiral center
that is present adjacent to the aldehyde in the compound.

The protection of alcohol as a methoxymethyl (MOM) ether followed by deprotection of the

TBS ethers and the PMB ester led to the hydroxy acid which was then used in a macro
lactonization. The PMB ester was stable under the HF•pyridine conditions used to remove
the TBS group due to the pyridine acting as a buffer, protecting the acid-sensitive PMB ester.
Notable in this example is the stability of the acid-sensitive MOM and 2 methoxy ethoxy

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methyl (MEM) ethers under the deprotection conditions of the PMB ester. After some
subsequent steps, the natural product (−)-borrelia in was accessed from hydroxy acid.

O OH

O O
OTMS O

OPMB OMEM OPMB

OMEM +

H H

OTBS OTBS

A PMB ester fragment was also used in the formal synthesis of (−)-borrelia in. Here,
aldehyde was used in a samarium iodide-promoted Reformatsky reaction with 4-
methoxybenzyl 2-bromoacetate. A mixture of isomers resulted from this reaction, but both
alcohols could be oxidized to the identical ketone and then reduced selectively utilizing a

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chiral ruthenium catalyst to access a single stereoisomer of the β-hydroxy ester.

THPO H SmI2 HTPO

117 O 119 O
90%
+ OPMB

O
Br
O
118
OMe

A PMB ester was critical in a synthetic study by Liu and co-workers on the C19 diterpenoid
alkaloids. Essential to this endeavor was the preparation of the lactone as a key intermediate.
An intramolecular Diels-Alder reaction of triene afforded the bicyclic system. At this point in
the sequence, the PMB ester required cleavage without opening the lactone ring, and the
resulting acid needed to be reduced to the alcohol. The removal of the PMB ester with TFA
followed by activation of the resulting carboxylic acid as the mixed carbonate and reduction
with sodium borohydride provided primary alcohol in 90% overall yield without any
undesired opening of the lactone ring.

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 H H
O
(i) TFA,DCM
BHT O O
O
(ii) ClCO2ET,Et 3N,THF
129
xylene,130 oC PMBO H O then NaBH4
CO2PMB HO H O
O
130 131
97% 90%

Winkler and co-workers utilized a PMB ester to advantage in their synthetic studies on
taxane diterpenes PMB ester was treated with TFA and trifluoroacetic anhydride in acetone
to provide acetonide, which was then subjected to photocyclization. While not explicitly
stated, attempts to hydrolyze the ester under basic conditions likely resulted in
decarboxylation, thus leading to the employment of the PMB ester, which could be converted
to the desired heterocycle under acidic conditions. After photocyclization, the opening of the
cyclobutane with aqueous sodium hydroxide provided the desired taxane-like ring system

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 O
CO2PMB O O
CF3CO2H 161
(CF3CO)2O hv
O
OMe
H acetone OMe acetone/CH3CN
H
160
O O
H
O
O 1) NaOH
H
MeOH/H2O

163
2) CH2N2
H OMe Et2O
H H H
OMe
162

References
1. Wuts PGM. In: Protective Groups in Organic Synthesis. 5th. Greene TW, editor. John
Wiley & Sons; Hoboken, NJ: 2014.

2.
https://profiles.uonbi.ac.ke/andakala/files/sch_504_protecting_groups_in_organic_synt
hesis.pdf

3. Kocienski PJ. Protecting Groups. 3rd. Thieme Verlag; Stuttgart: 2005.

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