Controlling diastereoselectivity in the reactions of enantiomerically pure α-bromoacyl-imidazolidinones with nitrogen nucleophiles: Substitution reactions with retention or inversion of configuration

Article abstract of DOI:10.1039/b417954d

Diastereoselective substitution reactions of α-bromoacyl- imidazolidinones with nitrogen nucleophiles can be promoted with either retention or inversion of configuration by carrying out reactions under epimerising or non-epimerising conditions. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b417954d

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Controlling diastereoselectivity in the reactions of enantiomerically
pure a-bromoacyl-imidazolidinones with nitrogen nucleophiles:
substitution reactions with retention or inversion of configuration{{
N. R. Treweeke,a P. B. Hitchcock,a D. A. Pardoeb and S. Caddick*c
Received (in Cambridge, UK) 30th November 2004, Accepted 26th January 2005
First published as an Advance Article on the web 8th February 2005
DOI: 10.1039/b417954d
acid derivatives. The most obvious is that if access to both
diastereoisomers of a substitution product is required then, in
general, access to both enantiomers of the chiral auxiliary is
required. In this paper we describe a method which avoids this
limitation, providing a simple route to either diastereomer (and
hence enantiomer) of an amine-substituted carboxylic acid
derivative. This solution is a result of the differing, (and
stereocomplementary) effects of the auxiliary on an incoming
halide when enolate chemistry is used, and on an outgoing halide
when nucleophilic substitution is used. We demonstrate this
concept by application to the synthesis of aromatic containing
a-amino acids.
Diastereoselective substitution reactions of a-bromoacyl-imida-
zolidinones with nitrogen nucleophiles can be promoted with
either retention or inversion of configuration by carrying out
reactions under epimerising or non-epimerising conditions.
The preparation of enantiomerically pure a-amino acid derivatives
has always been a challenge for the organic chemist and a number
of different catalytic and stoichiometric strategies have been
employed.1 Over a number of years we2 and others3 have been
interested in the development of dynamic kinetic resolution
(DKR), particularly for the synthesis of a-amino-acids. Dynamic
kinetic resolution is a conceptually appealing approach as it
involves the conversion of a mixture of stereoisomers into a single
product isomer.4,5
We had previously described a stereocomplementary approach
to a-amino acids using
a crystallisation induced dynamic
resolution (CIDR)/DKR approach.8 However reliance on the
CIDR method is limited, principally because of the lack of
certainty associated with such a crystallisation approach. It is never
clear which epimer will selectively crystallise from the rapidly
epimerising mixture.9 Thus an alternative general strategy was
sought (Fig. 2). We envisaged that substitution of the (29R)-
bromide 1 with a nucleophile under epimerising conditions should
lead to a product 2 with overall retention of configuration via
DKR in which the (29S)-isomer would be most reactive. This
would be complemented by classical inversion providing access to
3 under non-epimerising conditions (Fig. 2).
In previous studies we have investigated substitution reactions
of a-haloacyl-imidazolidinones with amines and other nucleophiles
under DKR conditions. These reactions provide access to
diastereomerically enriched products by employing a chiral
auxiliary to control the stereochemical outcome of the substitution
reaction. Molecular modelling by Santos et al.6 indicates that the
selective reaction of one epimer can be attributed to the ease with
which the halide can depart without suffering an undesirable steric
interaction with the stereocontrolling group on the chiral auxiliary
(Fig. 1 A versus B). This is in contrast to the majority of chiral
auxiliary controlled reactions using acyl-imidazolidinones and
oxazolidinones in which the key interaction is between the
incoming group and the stereodirecting group.7
In order to test this hypothesis we needed to prepare a variety of
2-bromo-derivatives (4a–4e). In our hands, and after considerable
experimentation, we identified bromination conditions utilising
LHMDS for enolate generation, using bromine as an electrophile.
From a synthetic perspective there are still limitations to the
aforementioned DKR method for making a-substituted carboxylic
Fig. 1 Transition state assemblies for substitution reactions of a-bro-
moacyl-imidazolidinones.
{ Electronic supplementary information (ESI) available: representative
procedures and characterisation data for all compounds. See http://
www.rsc.org/suppdata/cc/b4/b417954d/
{ This paper is dedicated with admiration and respect to Professor Steven
V. Ley on the occasion of his 60th birthday.
*s.caddick@ucl.ac.uk
Fig. 2 Strategy for complementary stereochemical approach to a-amino
acid derivatives from a single bromide.
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Using this protocol we were able to isolate the (29R)-bromo-
derivatives (4a–4e) as single diastereomers (.95% by NMR) in
isolated yields in excess of 70%. The other by-products observed in
the reactions were either dibrominated species (,10%) or, in the
cases of 4d and 4e, the (29S)-bromide. The relative (and hence)
absolute stereochemistry of the bromides was unambiguously
established by X-ray analysis of the epimer of 4b§ (also see ESI{).
Substitution of the diastereomerically pure bromides (4a–4e)
with benzylamine under DKR conditions (using Bu4NI as an
epimerising reagent) was examined and shown to proceed with a
high level of stereocontrol (1H NMR) and with retention of
configuration. The sense of diastereoselectivity was confirmed by
X-ray analysis of 5b§ (also see ESI{). This is consistent with a
reaction involving initial conversion of the (29R) bromide into a
mixture of (29S)/(29R) halides and thence selective reaction of the
(29S) product with inversion of configuration. Yields and
diastereoselectivities are sufficiently high to be synthetically useful
(Table 1).
Table 2 Auxiliary cleavage protocols
Entry
Nu
Method
Product
Yield (Auxiliary)
1
2
3
4
5
6
7
8
9
10
NaOMe
LiOOH
NaOMe
LiOOH
NaOMe
LiOOH
NaOMe
LiOOH
NaOMe
LiOOH
A
B
A
B
A
B
A
B
A
B
7a, n = 1
8a, n = 1
7b, n = 2
8b, n = 2
7c, n = 3
8c, n = 3
7d, n = 4
8d, n = 4
7e, n = 5
8e, n = 5
78% (77%)
96% (90%)
92% (85%)
95% (96%)
86% (90%)
91% (93%)
97% (90%)
75% (92%)
85% (100%)
99% (64%)
Substitution of the (29R) bromides (4a–4e) with a nitrogen
nucleophile under non-epimerising conditions required careful
experimentation. Initial work using benzylamine was promising
but difficulties in avoiding epimerisation with a concomitant
compromise in diastereoselectivity were encountered. However
success was achieved using the nucleophile tetramethylguanidi-
nium azide (TMGA).10 Exposure of the (29R) bromides (4a–4e).
cleavage could be confirmed at this stage, in the case of 7b, by
correlation with a sample prepared by independent synthesis,
starting from R-homophenylalanine (see ESI{). Hydrogenolysis of
the a-benzylamino group could be achieved in good yields and
without significant racemisation (see ESI{) using Pearlman’s
catalyst (.95% yields). Hydrogenation of the a-azido species
was most effective using Pd/C provided the a-amino acids in good
yields (.85%). The stereochemical integrity of the a-amino esters
or acid derivatives resulting from these procedures were judged to
have retained high levels of optical purity (.90%) by comparison
with literature data, where available (see ESI for details{).
In summary we have shown that a-amino-substituted carboxylic
acid derivatives can be prepared using substitution reactions of
a-bromoacyl-imidazolidinones. The stereodirecting group on the
auxiliary controls the facial selectivity in the reaction of an enolate
with an electrophile to give a single diastereomeric bromide. The
resulting (29R) bromides can be converted into the desired
substitution product with inversion of configuration (under non-
epimerising conditions). Substitution of the (29R) bromides can
also be achieved with retention of configuration via a DKR
pathway. The latter results are consistent with the model involving
stereochemical control by the interaction of the bromide as it
departs with the stereodirecting group on the auxiliary. The ability
to prepare either diastereomer (and hence enantiomer, after
auxiliary cleavage) of a substitution product from the same
substrate using a single chiral auxiliary offers a complementary
approach to the majority of other auxiliary based protocols for the
asymmetric synthesis of a-amino acid derivatives.
to TMGA in dichloromethane at
0 uC led to excellent
yields and diastereoselectivities of products (6a–6e, Table 1).
Diastereoselectivities were estimated by careful analysis of 1H
NMR spectra and the relative (and hence absolute) stereochemical
assignments confirmed by X-ray analysis of 6b.
As expected and by analogy with prior reports in the literature
auxiliary cleavage could be readily achieved using either sodium
methoxide11 (a-methylbenzylamino-products (5a–5e)) or lithium
peroxide (a-azido-products) (6a–6e).12 Both procedures proceeded
with excellent recovery of the chiral auxiliary (Table 2). The
stereochemical integrity of the products derived from auxiliary
Table 1 Complementary DKR and substitution approach to a-azido/
amino carboxylic acid derivatives
Entry
Nucleophile
Product
Yield (de)
1
2
3
4
5
6
7
8
9
10
BnNH2
TMGA
BnNH2
TMGA
BnNH2
TMGA
BnNH2
TMGA
BnNH2
TMGA
5a, n = 1
6a, n = 1
5b, n = 2
6b, n = 2
5c, n = 3
6c, n = 3
5d, n = 4
6d, n = 4
5e, n = 5
6e, n = 5
77% (80%)
94% (95%)
98% (80%)
92% (95%)
93% (80%)
93% (95%)
97% (86%)
91% (95%)
90% (81%)
89% (95%)
We gratefully acknowledge EPSRC, GSK, Key Organics,
AstraZeneca, Novartis, CEM (UK) and BBSRC for financial
support of our programme. We are grateful to Tony Avent and
Ali Abdul-Sada at the University of Sussex for their valuable
contributions to the work. Provision of high-resolution mass
spectra by the EPSRC Mass Spectrometry Service in Swansea is
acknowledged.
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N. R. Treweeke,a P. B. Hitchcock,a D. A. Pardoeb and S. Caddick*c
aDepartment of Chemistry, University of Sussex, Brighton, UK BN1 9QJ
bGlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow,
Essex, UK CM19 5AW
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cDepartment of Chemistry, University College London, 20 Gordon
Street, London, UK WC1H OAJ. E-mail: s.caddick@ucl.ac.uk
Notes and references
§ Structure corroboration for the epimer of 4b, for 5b and 6b were obtained
and full details are available in the ESI.{ Summarised data are provided
below.
Epimer of 4b (29S)-isomer, C21H23BrN2O2: M 5 415.3, monoclinic, P21
˚
(no. 4), a 5 10.3839(12), b 5 6.2094(4), c 5 15.9554(18) A, b 5 108.513(4)u,
3
V 5 975.5(2) A , Z 5 2, m(Mo–Ka) 5 2.12 mm21. 3198 Unique reflections,
˚
2534 with I . 2s(I). R1 5 0.050 for I . 2s(I), wR2 5 0.104 for all data.
CCDC 261877.
5b, C27H39N3O2: M 5 441.6, orthorhombic, P212121 (no. 19),
3
˚
˚
a 5 9.5902(3), b 5 10.3216(4), c 5 24.9928(10)A, V 5 2473.9(2) A ,
Z 5 4, m(Mo–Ka) 5 0.08 mm21. 4434 Unique reflections, 3264 with I .
2s(I). R1 5 0.046 for I . 2s(I), wR2 5 0.112 for all data. CCDC 261878.
6b, C21H23N5O2: M 5 377.4, monoclinic, C2 (no. 5), a 5 19.2790(16),
3
˚
˚
b 5 6.0518(8), c 5 17.189(2) A, b 5 99.200(8)u, V 5 1979.7(4) A , Z 5 4,
m(Mo–Ka) 5 0.08 mm21. 2477 Unique reflections, 2118 with I . 2s(I).
R1 5 0.086 for I . 2s(I), wR2 5 0.254 for all data. CCDC 261879. See
http://www.rsc.org/suppdata/cc/b4/b417954d/ for crystallographic data in
.cif or other electronic format.
8 S. Caddick and K. Jenkins, Tetrahedron Lett., 1996, 37, 1301.
9 E. Eliel and H. W. Samuel, Stereochemistry of Organic Compounds,
1993, Wiley-Interscience, New York.
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11 A. J. Papa, J. Org. Chem., 1966, 31, 1426–1430.
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1 R. M. Williams, Synthesis of Optically Active a-Amino Acids, 1989,
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2 S. Caddick, C. A. M. Afonso, S. X. Candeias, P. B. Hitchcock,
K. Jenkins, L. Murtagh, D. Pardoe, A. G. Santos, N. R. Treweeke and
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1870 | Chem. Commun., 2005, 1868–1870
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