A highly efficient and enantioselective synthesis of EEHP and EMHP: intermediates of PPAR agonists

Article abstract of DOI:10.1016/j.tetlet.2016.06.093

Glycolate alkylation reactions of (S)-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one auxiliary has been optimised with high yields and diastereoselectivity on substituted benzyl and allyl bromides. The standardised reaction condition was employed for the stereoselective synthesis of EEHP and EMHP intermediates of PPAR agonists.

Full text of DOI:10.1016/j.tetlet.2016.06.093

Accepted Manuscript
A highly efficient and enantioselective synthesis of EEHP and EMHP: Inter-
mediates of PPAR agonists
Mukesh Gangar, M. Harikrishnan, Sandeep Goyal, Maulik N. Mungalpara,
Vipin A. Nair
PII:
S0040-4039(16)30762-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.093
TETL 47820
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 May 2016
13 June 2016
21 June 2016
Please cite this article as: Gangar, M., Harikrishnan, M., Goyal, S., Mungalpara, M.N., Nair, V.A., A highly efficient
and enantioselective synthesis of EEHP and EMHP: Intermediates of PPAR agonists, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.093
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Graphical Abstract
A highly efficient and enantioselective synthesis of
EEHP, EMHP: intermediates of PPAR agonists
Leave this area blank for abstract info.
Mukesh Gangar, Harikrishnan M., Sandeep Goyal, Maulik N. Mungalpara, Vipin A. Nair

1
Tetrahedron Letters
A highly efficient and enantioselective synthesis of EEHP and EMHP: intermediates of PPAR
agonists
Mukesh Gangar, Harikrishnan M., Sandeep Goyal, Maulik N. Mungalpara, Vipin A. Nair
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar, Punjab 160062, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
.
© 2013 Elsevier Ltd. All rights reserved.
Glycolate alkyation reactions of (S)-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one auxiliary
has been optimized with high yields and diastereoselectivity on substituted benzyl and allyl
bromides. The standardised reaction condition was employed for the stereoselective synthesis of
EEHP and EMHP intermediates of PPAR agonists.
Available online
Keywords:
.
Chiral auxiliary
Glycolate alkylation
Stereoselectivity
EEHP
PPAR agonists
———
 Corresponding author. Tel.: +91-172-229-2045; fax: +91-172-221-4692; e-mail: vn74nr@yahoo.com

2
(S)-Ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (EEHP), (S)-
ethyl 2-methoxy-3-(4-hydroxyphenyl)propanoate (EMHP),
investigated some of the crucial factors which govern the
stereoselectivity of C-C bond formation in aldol reactions on
various substrates.7 This led us to further explore an
imidazolidinone based chiral auxiliary for the glycolate alkylation
reaction.
isopropyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (IEHP) and
their corresponding acids are pharmaceutically active compounds as
they form the core of a series of anti-diabetic drugs such as
ragaglitazar, saroglitazar, tesaglitazar, navaglitazar, broadly named
as glitazars, and other peroxisome proliferator activated receptor
(PPAR) agonists (Fig. 1).1 The potential of these intermediates to
provide biologically active compounds and drug molecules is of
immense importance, and so is their synthesis. Many viable
strategies have been developed over the years for their synthesis in
enantiomerically pure form.2 However most of the reported methods
are based on chiral resolution of racemic mixtures using enzymatic
and chemical methods.2d-e,3 Chiral resolution is substrate selective
and is difficult to employ when synthesising a library of molecules
due to significant loss of yield. The other strategies employed make
use of metal catalyzed asymmetric hydrogenation of α-ethoxy
cinnamic acid derivatives.2h,2i Even then the optical purity is not
satisfactory and often expensive catalysts are used. Organocatalyzed
asymmetric glycolate alkylation reactions suffer from poor
enantioselectivity, require stoichiometric excess of substrate, harsh
conditions, low overall yield and tedious purification steps making it
unfavourable.4 All these factors necessitate a cost effective and
stereoselective strategy for accessing this class of molecules.
Scheme 1. Retrosynthetic analysis of 2
Result and discussion:
The N-acylation reaction was carried out by the deprotonation of the
chiral auxiliary (S)-4-isopropyl-1-((R)-1-phenylethyl)imidazolidin-2-
one 3 with NaH in freshly dried THF followed by the treatment with
benzyloxyacetyl chloride to afford the acylated chiral auxiliary (4).
The efficacy of benzyloxy acylated chiral auxiliary was examined in
the glycolate alkylation reaction using benzyl bromide as
electrophile. A preliminary experiment involving the formation of
lithium enolate of 4 generated using LiHMDS at -78 °C and its
subsequent alkylation with benzyl bromide either at -78 °C or 0 °C
did not afford the product (Table 1). Furthermore, the corresponding
sodium and potassium enolates were also not successful. The use of
the Lewis acid TiCl4 along with DIPEA also failed to give the
product.
Literature survey led us to the conclusion that a major problem
associated with many of the reported strategies are ineffective
protocols for the installation of chiral center and alkylation of the
secondary hydroxyl group which leads to partial racemisation.5
Based on our interests in stereoselective C-C bond forming reactions
we decided to explore a chiral auxiliary mediated alkylation for the
synthesis of the EEHP and EMHP.
Scheme 2. Synthesis of (S)-3-((R)-2-(benzyloxy)-3-phenylpropanoyl)-4-isopropyl-
1-((R)-1-phenylethyl)imidazolidin-2-one 5a
Later attempts were to enhance the deprotonation by chelating the
lithium cation using TMEDA so that the hexamethyldisilylamide
anion is sufficiently basic for the proton abstraction. To our delight,
the addition of equimolar amount of LiHMDS and TMEDA to a
solution of 4 in THF at -78 °C followed by the addition of benzyl
bromide and thereafter increasing the temperature to -40 °C resulted
in a dramatic improvement in the reaction (Scheme 2). The reaction
mixture was purified using column chromatography to give the
product 5a in high yield. A diastereomeric ratio of >99:01 was
determined from the 1H NMR spectrum of the reaction mixture. The
absolute configuration was confirmed by cleaving the auxiliary using
NaOH in THF:water under reflux condition to give the (R)-2-
(benzyloxy)-3-phenylpropanoic acid 6 (Scheme 3). Based on the
correlation of the optical rotation value with the literature [observed
[α]D +80.5 (c 0.8 in EtOH), reported [α]D +72.5 (c 0.8 in EtOH)], an
R configuration was unambiguously assigned.8 The chiral auxiliary
was recovered in 88% yield after the hydrolysis.
Figure 1. PPAR α/γ agonists
A retrosynthetic analysis (Scheme 1) of the intermediate 2 indicates
asymmetric glycolate alkylation as the key step. To obtain the
enantiomerically pure alkylated adduct, the acetylated auxiliary was
treated with benzyl bromides. The reported chiral auxiliaries for the
glycolate alkylation reaction suffer from various disadvantages like
low yield, longer reaction time, costly reagents and also endocyclic
cleavage.6 Asymmetric glycolate alkylation reactions of an
imidazolidinone based chiral auxiliary in solid phase resulted in
only moderate enantiomeric excess. Also the use of large excess of
electrophiles, long reaction time, costly solid resins and low yields
makes this procedure less appealing.6a Glycolate alkylation had
been attempted for the synthesis of various natural products but the
procedure relies mainly on the use of allylic iodides.6b
Pseudoephedrine has been used as a chiral auxiliary for the
glycolate alkylation reactions with protected and unprotected
hydroxyl group, however low diastereoselectivity and longer
reaction time were major drawbacks.6d We had recently

3
Table 1: Standardisation of reaction condition for the glycolate alkylation reaction
Table 2. Glycolate alkylation reactions of (S)-4-isopropyl-1-(R)-1-
phenylethyl]imidazolid- in-2-one (4)
No.
Condition
Time
(h)
4
4
4
4
4
3
Temp.
Yield
(%)
NA
Trace
10
NA
NA
92
dra
(0C)
1
2
3
4
5
6
n-BuLi
LiHMDS
NaHMDS
KHMDS
TiCl4, DIPEA
LiHMDS, TMEDA
-78 to 0
-78 to 0
-78 to 0
-78 to 0
-78 to 0
-78 to -40
-
-
-
-
-
No.
1
Starting material
C6H5CH2Br
Product Yielda (%)
dr (R:S)b
>99:01
99:01
5a
5b
92
86
2
4-F-C6H4CH2Br
>99:01
3
4
5
6
7
8
4-Cl-C6H4 CH2Br
4-Br-C6H4 CH2Br
4-Me-C6H4 CH2Br
2-Br-C6H4 CH2Br
3-Bromoprop-1-ene
5c
5d
5f
88
88
82
75
92
90
99:01
99:01
99:01
99:01
99:01
99:01
a: diastereomeric ratio was determined from the 1H NMR spectrum of the reaction
mixture
5g
5h
5i
1-Bromo-3-methyl
but-2-ene
a: isolated yields; b: diastereomeric ratios were determined from the 1H NMR
spectra of the reaction mixtures.
Scheme 3. Hydrolysis of the alkylated adduct 5a
A plausible mechanism for the stereoselectivity in glycolate
alkylation is proposed in fig. 2. The generation of the enolates with
lithium base at –78 °C occurs with high stereoselectivity. The (Z)
selectivity can be understood by the sterically controlled six
membered transition state formed from the imidazolidinone based
chiral auxiliary and the lithium base. In transition state B the
imidazolidine ring would face a 1,2 diequatorial steric interaction
with the benzyloxy group, which is prohibitively high. Therefore, a
Scheme 4. Synthesis of (4-(bromomethyl)phenoxy)(tert-butyl)diphenylsilane 9
deprotonation via transition state
A occures inspite of the
The reaction conditions were then generalized with substituted
benzyl bromides bearing electron donating and -withdrawing groups
and also with allyl bromides (Table 2, entries 1-8). The scope of the
glycolate alkylation reaction was further illustrated in the synthesis
of EEHP and MEHP. The synthesis of the TBDPS protected benzyl
bromide commenced with the protection of 4-hydroxy benzaldehyde
using TBDPSCl in the presence of imidazole in DCM giving 7
(Scheme 4). It was then reduced using NaBH4 and taken to the next
step without purification. The primary hydroxyl group was converted
to bromide quantitatively using PBr3 in Et2O.9 The alkylation
reaction was performed on the benzyloxy acetylated chiral auxiliary
with p-OTBDPS protected benzyl bromide (9) giving the alkylated
product 10 with a diastereoselectivity of >99:01 (Scheme 5). This
product, without further purification, was further subjected to
deprotection using DBU in acetonitrile-water medium. The desired
product 11 was isolated and then hydrolysed using the NaOH and the
corresponding acid 12 was obtained after acid-base work up. It was
then esterified to give the essential synthetic intermediate 13. An
enantiopurity of 99.7% was recorded by HPLC.
repulsive1,3-interaction. The alkylation reaction is thought to
proceed through the chelation enforced transition state of the (Z)
enolate as depicted in fig. 2. Herein the Re face attack is favored over
the Si face by the enolate due to the steric hindrance imparted by the
resident endocyclic isopropyl group.
Employing the standardised conditions, the synthesis of EEHP and
EMHP
was
initiated.
(R)-4-isopropyl-1-((S)-1-
phenylethyl)imidazolidin-2-one 3ꞌ was employed for acetylation
using two different alkyloxyacetyl chlorides giving the
corresponding acylated auxiliaries (14a, 14b) in high yields (Scheme
6). Alkylation was carried out using LiHMDS as base and TMEDA
as additive at -78 °C and to our delight excellent yields of 15a, 15b
were obtained in diastereomeric ratios of >99:01. The TBDPS group
in the alkylated product was then cleaved using DBU in acetonitrile-
water medium at room temperature to obtain the free phenolic group.
The absolute stereochemistry was ascertained by single crystal X-ray
analysis (Fig. 3).10
Figure 2. Plausible transition state for the glycolate alkylation reaction

4
Conclusion
The synthesis of PPAR agonist intermediates, EEHP and EMHP,
was standardised in 5 steps employing an imidazolidinone based
chiral auxiliary in high yields and excellent stereoselectivity. The
nature of the procedure being general, can be applied to the synthesis
of various molecules involving these intermediates.
Acknowledgement
Financial assistance in the form of a Senior Research Fellowship
from CSIR to M.G. is gratefully acknowledged. We are thankful to
Dr. Angshuman Roy Choudhury, IISER Mohali for the X-ray
crystallographic data.
Supporting Information
Crystallographic data for the compound 16a has been deposited with
the Cambridge Crystallographic Data Centre, CCDC No. 1452339.
Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-
(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Scheme 5. Synthesis of (R)-ethyl 2-(benzyloxy)-3-(4-hydroxyphenyl)propanoate 13
Cleavage of the chiral auxiliary was done with NaOH as base in
THF-H2O medium under reflux conditions. The corresponding acids
(17a, 17b) were purified by acid-base workup, and without the
necessity for column chromatography. Alternatively the cleavage of
the auxiliary can be carried out at room temperature in the presence
of H2O2-LiOH.H2O in THF-H2O medium also. After cleavage, the
carboxylic acid was converted to ester in the presence of catalytic
amount of H2SO4 in ethanol with excellent enantioselectivity.
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5
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7
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10 Crystals were developed in Ethanol-Hexane (1:1) medium.

6
Graphical Abstract
A highly efficient and enantioselective synthesis of EEHP, EMHP: intermediates of PPAR agonists
Mukesh Gangar, Harikrishnan M., Sandeep Goyal, Maulik Mungalpara, Vipin A. Nair*
A highly efficient and enantioselective synthesis of
EEHP, EMHP: intermediates of PPAR agonists
Leave this area blank for abstract info.
Mukesh Gangar, Harikrishnan M., Sandeep Goyal, Maulik N. Mungalpara, Vipin A. Nair

7
Highlights
 Chiral auxiliary mediated glycolate alkyation reactions.
 High yields and diastereoselectivities compared to the reported strategies.
 Efficient enantioselective synthesis of the intermediates of PPARα/ agonists.
 Transition state model for the glycolate alkylation reaction.
 Wide scope of the synthetic protocol for accessing similar intermediates.