Tetrahedron Letters
Roof shape chiral alcohol: auxiliary for asymmetric synthesis
of
a-halo acid derivatives
⇑
Nilesh Jain, Ashutosh V. Bedekar
Department of Chemistry, Faculty of Science, M. S. University of Baroda, Vadodara 390 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Roof shape chiral enantiopure alcohol, obtained by bio-catalytic separation of isomers, was used as a new
Received 4 November 2015
Revised 26 December 2015
Accepted 2 January 2016
Available online 6 January 2016
auxiliary for asymmetric synthesis of
a-halo acid derivatives. Esterification reaction of roof shape chiral
enantiopure alcohol and racemic -halo acids in the presence of DCC, DMAP furnished diastereomers of
a
ester in non-racemic manner. Diastereoselectivity up to 90% was observed, the absolute configuration of
newly generated chiral center was established by the single crystal X-ray diffraction analysis.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Roof shape chiral alcohol
Chiral auxiliary
a-Halo acid derivative
Diastereoselective synthesis
Dynamic kinetic resolution
Asymmetric synthesis of optically active products using a vari-
ety of chiral auxiliaries, natural and artificial, is an established tool
in modern synthetic organic chemistry. For a number of years nat-
solvating agents for the discrimination of the signals of optically
active acids in NMR spectroscopy.
6
1
Optically pure a-substituted alkanoic acids and their number of
urally occurring chiral auxiliaries remained the preferred choice for
such studies. However, due to some limitations, such as unavail-
ability of both isomers, inability to obtain optically pure com-
pounds in large quantities, other structural limitations. There is a
continuous need to search new artificial chiral molecules to utilize
as auxiliaries for asymmetric synthesis.2 The design of molecules
suitable for the use as chiral auxiliary requires some specific struc-
tural arrangement. The shape, size, and arrangement of functional
groups in chiral molecules play a crucial role in the efficiency of
their use as auxiliary for asymmetric synthesis. Hence, molecules
with unique shape and arrangement of aromatic rings which offer
stereocontrol can be examined as auxiliaries. Synthetically pre-
pared chiral molecules have advantages over the naturally avail-
able compounds of chiral pool as their structures can be fine
tuned and their both enantiomers can be easily obtained. Weber
introduced a novel class of compounds resembling the shape of a
roof and studied their applications as clathrate hosts with inclusion
derivatives are an important class of natural and synthetic com-
pounds. Many strategies have been developed for their enantiose-
lective synthesis. The approach involving the selective alkylation of
7
a
the enolate of chiral esters is widely investigated. This includes
7
b,c
the use of chiral auxiliaries, utilizing hydroxy pentolactone,
7d
7e
carvone derives alcohols, 2-oxoimidazolidine 4-carboxylate,
cyclohexanol based auxiliaries, carbohydrate based alcohols,
and sultam based amides . Besides these, other strategies includ-
-alkylation by
phase-transfer catalysis, etc. have also been investigated. Separa-
tion of enantiomers of the easily available -substituted acids and
7
f
7g
7
h
8
ing asymmetric hydrogenation of acrylates,
a
9
a
their straightforward conversion to functionalized derivatives is
another attractive option to access such molecules. This may be
achieved by fractional crystallization of its salt with chiral resolv-
1
0
11
ing agents or by enzymatic kinetic resolution methods. Both
these classical approaches can furnish maximum 50% yield of the
desired isomer. To overcome this limitation dynamic kinetic reso-
lution (DKR) and dynamic thermodynamic resolution (DTR) have
been developed where the unreacted isomer of the starting mate-
rial is interconverted to the more reactive one or stable one, hence
3
properties. Such molecules also find many applications in differ-
4
ent areas ranging from material to medicinal chemistry. In our
continuing work, we have presented synthesis, resolution of roof
shape alcohols 1 and 2, and their derivatives.5 The roof shape
alcohols were also converted to amines to be scanned as chiral
,6
12
effectively increasing the yields to acceptable level. In this work
we explore the roof shape chiral alcohol 1 as a new auxiliary to
access optically enriched a-halo esters. These are important inter-
⇑
mediates for the synthesis of other functionalities by suitable
substitution reactions (see Fig. 1).
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0