Enantioselective deprotonation reactions using polymer-supported chiral magnesium amide bases

Article abstract of DOI:10.1039/b104417f

Novel and readily accessible polymer-supported chiral magnesium amide reagents have been prepared and shown to be effective in the asymmetric deprotonation of a series of prochiral cyclohexanones, affording good to excellent levels of both conversion and

Full text of DOI:10.1039/b104417f

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Enantioselective deprotonation reactions using polymer-supported
chiral magnesium amide bases†
Kenneth W. Henderson,* William J. Kerr* and Jennifer H. Moir
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow,
Scotland, UK G1 1XL. E-mail: w.kerr@strath.ac.uk
Received (in Cambridge, UK) 18th May 2001, Accepted 25th July 2001
First published as an Advance Article on the web 28th August 2001
Novel and readily accessible polymer-supported chiral
magnesium amide reagents have been prepared and shown
to be effective in the asymmetric deprotonation of a series of
prochiral cyclohexanones, affording good to excellent levels
of both conversion and enantiomeric ratio (up to 93+7); the
2
Scheme 2 Reagents and conditions: i, (R)-2 (2 eq.), Bu Mg (1 eq.), THF,
reflux, 90 min; ii, TMSCl (4 eq.), DMPU (0.5 eq.), THF, 278 °C, 4 h.
Merrifield-based chiral amine species has been shown to be
readily recyclable.
amine resin (R)-2 (Table 1). At 278 °C the 4-substituted
cyclohexanones 3a–d all showed good levels of conversion and
gave enol ethers (S)-4a–d with enantiomeric ratios of up to
The application of chiral lithium amide base reagents within
1
asymmetric organic synthesis is widespread. Additionally we
have recently disclosed the preparation of a novel homochiral
magnesium amide base and have shown it to be particularly
effective in the desymmetrisation of both 4-substituted and
7
5+25. With the 2,6-disubstituted substrates, higher tem-
peratures were required to achieve acceptable levels of
conversion. However, when all ketones (3a–f) employed here
are considered, it should be noted that at room temperature
higher conversions were achieved in almost every instance
with, at worst, only small reductions in the recorded enantio-
meric ratios. Indeed, the enantioselection observed upon
reaction of cis-3e and cis-3f appears largely independent of
temperature. Furthermore reaction of cis-diisopropylcyclohex-
2
,6-disubstituted cyclohexanones; the initially reported proc-
esses afforded the corresponding silyl enol ethers in up to 95+5
2
er. Consequently, with a view to gaining the practical and
3
economic advantages offered by solid phase chemistry, we
envisioned that tethering the chiral amine, and ultimately the
4
Mg-amide, to a polymer support would provide a convenient
and potentially recyclable enantioselective reaction source.
Furthermore and at least as importantly, based on our drive to
alter the nature of the base itself, we believed that this approach
would also allow the establishment of a library of supported
chiral amines and, in turn, resin-bound Mg-amides, which
would enable an effective assessment of the key structural
requirements for the optimisation of such enantioselective
reagents. Herein, we report our initial studies in this area and,
more specifically, the first use of a polymer-supported chiral
Mg-amide base to mediate enantioselective deprotonation
processes.
Table 1 Enantioselective deprotonations using Merrifield-based amine (R)-
a
2
c
Ketone
Product
Temp.
t/h
Conversion er
(%)
b
2
78 °C
4
2
78
91
74+26
65+35
rt
At the outset of this programme, the simple and readily
5
accessible Merrifield resin 1 formed an attractive starting point
2
78 °C
4
2
74
94
68+32
64+36
for direct functionalisation with (R)-a-methylbenzylamine. The
process shown in Scheme 1 cleanly afforded the supported
chiral amine (R)-2.‡
rt
Having established a practically efficient approach to the
preparation of (R)-2, its use as a Mg-amide derivative was then
evaluated in the enantioselective deprotonation of 3a. Optimum
formation of the requisite Mg-amide species occurred following
reflux of (R)-2 with dibutylmagnesium for 90 min in THF.§ On
cooling the resin-bound base to 278 °C, we were pleased to
observe the first asymmetric deprotonations with our new
supported reagent. As shown in Scheme 2, in the presence of 0.5
mol equiv. of DMPU and excess TMSCl, good levels of both
conversion of 3a to (S)-4a (78%) and enantiomeric ratio (74+26
er) were achieved.†
278 °C
4
2
85
91
74+26
68+32
rt
278 °C
rt
4
2
89
88
75+25
69+31
Based on this experimental protocol, we moved on to
consider the desymmetrisation reaction of a series of alternative
prochiral cyclohexanones 3 using our Merrifield-based chiral
278 °C 43
240 °C 24
rt 2
7
86
98
76+24
73+27
75+25
278 °C 19
240 °C 68
rt 2
2
69
97
—
91+9
93+7
Scheme 1 Reagents and conditions: i, (R)-a-methylbenzylamine (3 eq.),
NaI (1 eq.), DMF, 48 h.
a
2
Reagents and conditions: i, (R)-2 (2 eq), Bu Mg (1 eq.), THF, reflux, 90
min; ii, TMSCl (4 eq), DMPU (0.5 eq.), ketone (0.8 eq.), THF.†
†
Electronic supplementary information (ESI) available: representative
b
Conversions were determined by GC analysis. c See footnote¶.
experimental procedure. See http://www.rsc.org/suppdata/cc/b1/b104417f/
1722
Chem. Commun., 2001, 1722–1723
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104417f

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Table 2 Enantioselective deprotonation of 3a using recycled amine (R)-2
Table 3 Enantioselective deprotonations using soluble supported amine
(
R)-5a
Conversion
(%)
Ketone
Product
(S)-4a
(S)-4d
(S)-4f
Temp.
t/h
er
3
a
278 °C
rt
278 °C
rt
240 °C
rt
4
2
4
2
24
2
91
> 99
82
96
67
83+17b
70+30
80+20
71+29
93+7
Cycle
Temp.
t/h
Conversion (%) er (S)+(R)
3
d
1
2
3
4
5
6
rt
rt
rt
rt
2
2
2
2
2
4
91
97
86
91
92
71
65+35
65+35
65+35
66+34
66+34
73+27
cis-3f
> 99
93+7
a
2
Reagents and conditions: i, (R)-2 (2 eq.), Bu Mg (1 eq.), THF, reflux, 90
min; ii, TMSCl (4 eq.), DMPU (0.5 eq.), ketone (0.8 eq.), THF. b This result
is comparable with that observed in our unsupported base studies (278 °C,
6
rt
278 °C
h; 89% conv., 90+10 er); see ref. 2.
anone cis-3f gives a 97% conversion and an outstanding er of
deprotonation protocols. Indeed, it is envisaged that this facet of
the supported Mg-amide chemistry disclosed here will be of
considerable benefit when employing more precious chiral
amines, which are either commercially unavailable or have
required multi-step generation. The application of this method-
ology to the preparation of a library of chiral Mg-amide reagents
and the use of other resins is underway and will be reported in
due course.
93+7 even at room temperature. As such, this method affords us
a practically convenient method by which to generate high
levels of asymmetric induction in the deprotonation of specific
2
,6-disubstituted cyclohexanones.¶
In addition to establishing the initial deprotonation strategies
using our Merrifield-based Mg-amide, we were also keen to
develop an efficient recycling protocol. In this respect,
following completion of reaction, the parent polymer-bound
chiral amine (R)-2 was readily regenerated by consecutively
We gratefully acknowledge The Carnegie Trust for the
Universities of Scotland for a postgraduate studentship
washing the resin with a 2+1 mixture of THF–HCl (1 M) and
(
J. H. M.) and The Royal Society of a University Research
i
then, to liberate the amine from the HCl salt, with 10% Pr
2
NEt
Fellowship (K. W. H.). We also thank Dr J. Cai and Dr W. B.
Wathey at Organon Laboratories, for many helpful discussions
and the generous donation of materials, and the EPSRC Mass
Spectrometry Service, University of Wales, Swansea for
analyses.
in DMF. This process opened up the possibility of re-using the
supported chiral amine and, as such, we can now report that (R)-
2
can, indeed, be recycled up to and over 5 times. More
specifically, in a series of deprotonations of 3a to afford (S)-4a,
no appreciable drop in conversion was noted and the enantio-
meric ratio remained consistent throughout (Table 2). Fur-
thermore, after 5 cycles at room temperature, the resin was also
able to show a return to the enhanced levels of asymmetric
induction observed at 278 °C (Cycle 6), thus demonstrating the
durability of the tethered amine.∑
Notes and references
‡
The amine loading level was established by derivatisation with FmocCl,
6
followed by UV analysis of the subsequent cleavage reaction. This
routinely showed an amine loading of 1.30–1.40 mmol g for (R)-2 and
1
2
1
2
1
.00 mmol g for (R)-5.
Having successfully optimised our deprotonation strategy
using the accessible and readily recyclable Merrifield-based
chiral amine resin (R)-2, we moved on to explore the effects of
alternative polystyrene supports on the enantioselective poten-
tial of the resin-bound Mg-amide, In this respect, a soluble
§
It should be noted that whilst the production of a resin-bound Mg-
bisamide reagent is supposed, the possible formation of some alkyl(Bu)-
Mg-amide species must also be recognised. A control experiment
performed between Bu Mg and 3a gave no reaction, even at room
2
temperature. Based on this observation, it is believed that the presence of
such an alkyl–Mg intermediate would have no adverse affect on the
deprotonation process.
8
polystyrene resin was prepared and, subsequently, function-
alised with (R)-a-methylbenzylamine to afford the supported
amine (R)-5 (Scheme 3).‡ With this material in hand, we went
on to assess the performance of (R)-5, as the Mg-amide, in the
enantioselective deprotonation reaction of a selection of
ketones. Pleasingly, as can be seen in Table 3, with 3a and 3d
this new soluble resin-bound species provided excellent
reaction conversions and, moreover, delivered enhanced levels
of enantiomeric ratio at both room temperature and at 278 °C.
One again, (S)-4f was formed in excellent er and with no
appreciable difference in enantioselection being observed
between room temperature and 240 °C.
¶
Enantiomeric ratios were determined by GC analysis. Additionally, the
absolute configuration of the major and minor enantiomers for 4a, 4b, 4d,
and 4e were assigned by correlation of optical rotation measurements with
those of Koga and co-workers (ref. 7); for 4c and 4f the major and minor
isomer configurations were tentatively assigned by comparison with 4a, b,
and d, and 4e, respectively. All compounds also exhibited satisfactory
analytical and spectral data.
∑ It should be noted that resin (R)-2 was also effectively recycled following
the initial reaction of cis-3f at room temperature, and afforded a > 99%
conversion and 93+7 er.
1
2
3
For recent reviews, see: P. O’Brien, J. Chem. Soc., Perkin Trans. 1, 2001,
5; P. O’Brien, J. Chem. Soc., Perkin Trans. 1, 1998, 1439.
K. W. Henderson, W. J. Kerr and J. H. Moir, Chem. Commun., 2000,
79.
S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach, D. A.
Longbottom, M. Nesi, J. S. Scott, R. I. Storer and S. J. Taylor, J. Chem.
Soc., Perkin Trans. 1, 2001, 3815; R. H. Drewry, D. M. Coe and S. Poon,
Med. Res. Rev., 1999, 19, 97; S. J. Shuttleworth, S. M. Allin and P. K.
Sharma, Synthesis, 1997, 1217.
9
4
Scheme 3 Reagents and conditions: i, AIBN, toluene, 70 °C, 40 h; ii, (R)-a-
methylbenzylamine (3 eq.), NaI (1 eq.), DMF, 48 h.
4
M. Majewski, A. Ulaczyk and F. Wang, Tetrahedron Lett., 1999, 40,
8755.
In conclusion, we have successfully prepared two distinct
polymeric species posessing chiral amino functionality and, in
turn, chiral Mg-amide units and both of these have been shown
to be effective in the enantioselective deprotonation reaction of
a variety of 4-substituted and, more particularly, 2,6-di-
substituted cyclohexanones. Moreover, moderate to high levels
of asymmetric induction (up to 93+7 er) were observed, even
during reactions performed at room temperature. In addition,
the supported chiral amine derived from Merrifield resin was
found to be efficiently recycled for further use within the
5 Polymer Laboratories Ltd, Essex Road, Church Stretton, Shropshire, UK
2
1
SY6 6AX; loading: 1.88 mmol g ; 1% cross-linking.
6
7
E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis, A
Practical Approach, IRL Press, Oxford, 1989.
K. Aoki, H. Noguchi, K. Tomioka and K. Koga, Tetrahedron Lett., 1993,
3
4, 5105; H. Kim, R. Shirai, H. Kawasaki, M. Nakajima and K. Koga,
Heterocycles, 1990, 30, 307.
8
M. Narita, Bull. Chem. Soc. Jpn., 1978, 51, 1477. For a review on soluble
polymer-supported reagents in organic synthesis, see: P. H. Toy and
K. D. Janda, Acc. Chem. Res., 2000, 33, 546.
Chem. Commun., 2001, 1722–1723
1723