Enantioselective deprotonation of 2,6-disubstituted cyclohexanones with a homochiral magnesium amide base and the observation of a novel kinetic resolution process

Article abstract of DOI:10.1055/s-2001-16048

A recently developed homochiral magnesium amide base has been shown to be highly effective in the asymmetric deprotonation of cis-2,6-disubstituted cyclohexanones, affording excellent levels of both conversion and enantioselection (up to >99.5:0.5 e.r.).

Full text of DOI:10.1055/s-2001-16048

LETTER
1253
Enantioselective Deprotonation of 2,6-Disubstituted Cyclohexanones with a
Homochiral Magnesium Amide Base and the Observation of a Novel Kinetic
Resolution Process
Kenneth W. Henderson,* William J. Kerr,* Jennifer H. Moir
Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, G1 1XL, Scotland, UK
Fax +44 141 548 4246; E-mail: w.kerr@strath.ac.uk
Received 9 May 2001
ture of cis-/trans-isomers. Upon optimisation of the
Abstract: A recently developed homochiral magnesium amide base
reaction between (R)-1 and 2, we were pleased to observe
a 71% conversion to silyl enol ether (R)-3 which, on anal-
ysis, exhibited an appreciable enantiomeric ratio (e.r.) of
has been shown to be highly effective in the asymmetric deprotona-
tion of cis-2,6-disubstituted cyclohexanones, affording excellent
levels of both conversion and enantioselection (up to >99.5:0.5 e.r.).
In addition, a novel kinetic resolution process has been realised with 87:13 (Scheme 1). Moreover, as well as observing a good
the corresponding trans-disubstituted substrates, allowing access to
optically enriched enol ethers and chiral ketones.
level of asymmetric induction, we were intrigued to note
that the returned and initially racemic trans-ketone 2 now
Key words: asymmetric synthesis, enantioselective deprotonation,
kinetic resolution, magnesium
exhibited a 74:26 ratio of enantiomers, thus indicating that
Mg-amide base (R)-1 had also mediated a kinetic resolu-
tion process.
In recent years considerable effort has been directed to-
wards both the preparation of novel chiral base reagents
and the subsequent scope of these species within asym-
metric synthesis. Most notably, homochiral lithium amide
bases have emerged as effective candidates for use in
enantioselective transformations, allowing direct access
to synthetically useful chiral synthons of good optical en-
richment.1 By comparison, the use of chiral magnesium
species to mediate asymmetric processes has received lit-
tle attention.2 However, when considered it appears that
magnesium amide reagents possess a series of key fea-
tures which, in combination, are central to the develop-
ment of a range of asymmetric transformations. Indeed,
two of the most important aspects of magnesium amide
chemistry are: (i) their solution aggregation is generally
simple and predictable,3 and (ii) they are highly reactive,
yet selective, bases.4 Such advantages over existing meth-
odology have therefore led us to explore both the forma-
tion and utility of this important class of chiral reagent. In
this respect, we have recently reported a convenient in situ
preparation of novel, homochiral Mg-amide base (R)-1
from the readily available and structurally very simple
chiral amine, (R)-N-benzyl- -methylbenzylamine. In
turn, this Mg-amide reagent was found to be particularly
effective in the desymmetrisation reaction of 4-substitut-
ed cyclohexanones and afforded the corresponding silyl
enol ethers with high levels of both conversion and enan-
tioselection (up to 95:5 e.r.).5,6
O
OTMS
Mg (R)-1
N
Ph
Ph 2
87:13 e.r.
TMSCl, HMPA (0.5 equiv.),
THF, –78 ºC, 65 h
71% conv.
2
(R)-3
Scheme 1
Based upon these promising initial results, we then
wished to further explore the potential of our system by
reacting each of the cis- and trans-isomers of 2 in isolation
with chiral Mg-amide base (R)-1. In this regard, when the
cis-ketone 2 was utilised at 78 °C the resulting silyl enol
ether (R)-3 registered an excellent enantiomeric ratio of
97:3 (Table 1, Entry 1). This synthetic outcome is partic-
ularly noteworthy, in that, when cis-ketone 2 was reacted
under similar conditions with the Li version of the same
chiral amide, the deprotonation process delivered a signif-
icantly lower 64.5:35.5 e.r.7 Returning to our Mg-amide
base (R)-1, whilst a reduction in the reaction time from 65
h to 6 h resulted in a drop in conversion to 25%, pleasing-
ly, increasing the reaction temperature to –60 °C, allowed
enhanced levels of conversion to be noted (67%) with
only a small drop off in enantioselection (94:6 e.r.). Upon
raising the temperature still further, to –40 °C, we were
delighted to note almost quantitative conversion (99%) of
cis-2 to (R)-3 within 6 h. Additionally, this transformation
was, again, complete without any considerable reduction
in the enantioselectivity (93:7 e.r.).
With a view to further probing the efficacy of our Mg-
based deprotonation strategy, we have now extended the
scope of our studies to encompass the enantioselective
deprotonation of alternative prochiral ketonic substrates
and more specifically, 2,6-disubstituted cyclohexanones.
In particular and to initiate this investigation, 2,6-dimeth-
ylcyclohexanone 2 was available to us as an 82:18 mix-
Reaction of (R)-1 with the trans-isomer of 2,6-dimethyl-
cyclohexanone 2, initially present as a racemic mixture,
showed that our novel chiral Mg-amide base was indeed
capable of mediating a kinetic resolution process. Follow-
ing reaction at 78 °C and after 76% conversion, the op-
Synlett 2001, No. 8, 1253–1256 ISSN 0936-5214 © Thieme Stuttgart · New York

1254
K. W. Henderson et al.
LETTER
Additional examples of 2,6-disubstituted cyclohexanones
were required to be synthesised from the corresponding
2,6-disubstituted phenols, e.g. via Raney Nickel catalysed
hydrogenation14 and subsequent oxidation of the cyclo-
hexanol intermediate with Dess-Martin reagent.15 In par-
ticular, using the phenol 6 as starting material this route
afforded quantities of both the cis- and trans-isomers of
2,6-di-iso-propylcyclohexanone 7 (Scheme 3) which
were separated and reacted with the chiral Mg-amide base
(R)-1 in isolation. More specifically, reaction of cis-2,6-
di-iso-propylcyclohexanone 7 with (R)-1 produced silyl
enol ether (S)-8 in 54% conversion after 40 h reaction time
at –78 °C. Remarkably, only one enantiomer of this prod-
uct could be observed by chiral GC, thus, allowing us to
register our highest enantiomeric ratio yet achieved of
>99.5:0.5 (Table 3, Entry 1). Pleasingly, warming the re-
action temperature sequentially to –40 °C allowed us to
observe almost quantitative conversion of cis-7 to silyl
Table 1 Enantioselective Deprotonation Reactions of cis-2 with
Mg-amide (R)-1
OTMS
O
Mg (R)-1
N
Ph
Ph 2
TMSCl, HMPA (0.5 equiv.),
THF
cis-2
(R)-3
aConversions were determined by GC analysis.
bSee ref. 8.
posite enol ether (S)-3, to that formed from the cis-isomer enol ether (S)-8 which, only upon concentration of the GC
of 2, was obtained in excess (Scheme 2).10 Additionally, sample, began to show a trace amount of the undesired
the unreacted ketone trans-2 was returned displaying an second enantiomer (98.8:1.2 e.r.).16 It is interesting and,
enantiomeric ratio of 72:28. Based on the formation of the indeed, practically relevant to note that when this depro-
known (S)-isomer of 3,9 as well as literature data,11 the tonation process with our chiral Mg-base (R)-1 was per-
predominant returned ketone was assigned as the (R,R)- formed at room temperature, high levels of
enantiomer.
enantioselection were still maintained (91:9 e.r.).17,18
OH
OH
O
O
O
OTMS
iPr
iPr
iPr
iPr
iPr
iPr
Mg (R)-1
N
Ph
Ph 2
b
a
+
TMSCl, HMPA (0.5 equiv.),
THF, –78 ºC, 65 h
76% conv.
6
cis- and trans-7
trans-2
(S)-3
79:21 e.r.
trans-2
72:28 e.r.
Scheme 3 Reagents and conditions: (a) Raney Ni, H2 (100 atm),
104 °C, 39 h, 97%; (b) Dess-Martin periodinane, CH2Cl2, r.t., 1 h,
98%.
Scheme 2
With a practically convenient method for the desymmetri-
sation of 2,6-dimethylcyclohexanone in place, we then
moved on to consider the enantioselective deprotonation
of alternative substrates using chiral Mg-amide base (R)-
1. Upon consideration of cis-2,6-diphenylcyclohexanone
4,12 reaction with (R)-1 showed a temperature window
within which acceptable yields of silyl enol ether (S)-5
were achieved. Furthermore, good levels of enantioselec-
tion were observed in each case (Table 2).
Table 3 Enantioselective Deprotonation Reactions of cis-7 with
Mg-amide (R)-1
O
OTMS
iPr
iPr
iPr
iPr
Mg (R)-1
N
Ph
Ph 2
TMSCl, HMPA (0.5 equiv.),
THF
cis-7
(S)-8
Table 2 Enantioselective Deprotonation Reactions of cis-4 with
Mg-amide (R)-1
OTMS
Ph
O
Ph
Ph
Ph
Mg (R)-1
N
Ph
Ph 2
TMSCl, HMPA (0.5 equiv.),
THF
aSee ref. 8.
bSee ref. 16.
(S)-5
cis-4
In a drive to further explore the kinetic resolution poten-
tial of our base (R)-1, we subjected trans-2,6-di-
iso-propylcyclohexanone 7 to our Mg-based deprotona-
tion strategy (Table 4). We were delighted to note that, at
aSee ref. 13.
Synlett 2001, No. 8, 1253–1256 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Enantioselective Deprotonation of 2,6-Disubstituted Cyclohexanones
Table 4 Enantioselective Deprotonation Reactions of trans-7 with
1255
Mg-amide (R)-1
O
OTMS
iPr
O
iPr
iPr
iPr
iPr
iPr
Mg (R)-1
Ph 2
N
Ph
+
TMSCl, HMPA (0.5 equiv.),
THF
trans-7
trans-7
(R)-8
–40 °C and after 66% conversion, silyl enol ether (R)-8 References and Notes
was obtained in good enantiomeric ratio (81:19). Further-
(1) For recent reviews, see: O’Brien, P. J. Chem. Soc., Perkin
more, the initially racemic trans-ketone 7 was returned
displaying a substantially increased level of one enanti-
omer over the other (94:6 e.r.). This kinetic resolution
could be further enhanced by simply performing the
deprotonation reaction at 0 °C for 19 h. Based on similar
reasoning to that used with trans-2, the predominant re-
turned ketone was assigned as the (S,S)-enantiomer.
Trans. 1 2001, 95. O’Brien, P. J. Chem. Soc., Perkin Trans. 1
1998, 1439.
(2) For relevant examples of Mg-based reagents as used in
different classes of organic transformations, see: Evans, D. A.;
Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452. Elston, C.
L.; Jackson, R. F. W.; MacDonald, S. J. F.; Murray, P. J.
Angew. Chem., Int. Ed. Engl. 1997, 36, 410. Bunnage, M. E.;
Davies, S. G.; Goodwin, C. J.; Walters, I. A. S. Tetrahedron:
Asymmetry 1994, 5, 35. Noyori, R.; Suga, S.; Kawai, K.;
Okada, S.; Kitamura, M. Pure Appl. Chem. 1988, 60, 1597.
Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J.
Am. Chem. Soc. 1979, 101, 1455.
In conclusion, we have now succeeded in extending the
scope of our enantioselective deprotonation strategy using
the chiral Mg-amide base (R)-1 to include 2,6-disubstitut-
ed cyclohexanones. More particularly, with these sub-
strates excellent levels of asymmetric induction have been
realised, up to >99.5:0.5 e.r. Indeed, this represents the
highest degree of enantioselection attained within this
specific area of chiral base chemistry.19 Additionally, we
have also observed a novel Mg-amide mediated kinetic
resolution process during the reaction of both trans-2,6-
dimethylcyclohexanone and trans-2,6-di-iso-propylcy-
clohexanone. Interestingly with respect to gaining access
to the chiral synthon of choice, with both of these sub-
strates the enantiomeric enol ether to that obtained from
the corresponding cis-ketone is formed in excess. The re-
turned ketones also display good to excellent enantiomer-
ic ratios. Overall, we believe that the practical
developments detailed here will be of general use to those
concerned with the desymmetrisation of prochiral cyclic
ketones. In addition, the further use of alternative Mg-
bisamide systems and the development of related method-
ology is currently underway in our laboratories and will
be reported in due course.
(3) Clegg, W.; Craig, F. J.; Henderson, K. W.; Kennedy, A. R.;
Mulvey, R. E.; O’Neil, P. A.; Reed, D. Inorg. Chem. 1997, 36,
6238.
(4) Allan, J. F.; Henderson, K. W.; Kennedy, A. R. Chem.
Commun. 1999, 1325. Allan, J. F.; Clegg, W.; Henderson, K.
W.; Horsburgh, L; Kennedy, A. R. J. Organomet. Chem.
1998, 559, 173. Lessène, G.; Tripoli, R.; Cazeau, P.; Biran, C.;
Bordeau, M. Tetrahedron Lett. 1999, 40, 4037. Eaton, P. E.;
Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111, 8016.
(5) Henderson, K. W.; Kerr, W. J.; Moir, J. H. Chem. Commun.
2000, 479.
(6) It should be noted that, in contrast to our initially reported
protocol which utilised hexane as solvent,5 clean formation of
(R)-1 can now be achieved using THF; this removes the
requirement for a solvent swap prior to any deprotonation
processes (vide infra).
(7) Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins, N.
S. Tetrahedron 1990, 46, 523. Simpkins, N. S. J. Chem. Soc.,
Chem. Commun. 1986, 88.
(8) Enantiomeric ratios for 3 and 8 were determined by GC
analysis (see Representative experimental procedure).
Additionally, the absolute configurations of the major and
minor enantiomers for 3 were assigned by correlation of
optical rotation measurements with those of Koga and co-
workers;9 for 8 the major and minor isomer configurations
were tentatively assigned by comparison with 3.
(9) Kim, H.; Shirai, R.; Kawasaki, H.; Nakajima, M.; Koga, K.
Heterocycles 1990, 30, 307.
(10) It is worth noting that similar deprotonation of the same
ketone trans-2 with the equivalent chiral Li-base resulted in
the formation of only completely racemic enol ether; see ref.
7.
Acknowledgement
We thank The Carnegie Trust for the Universities of Scotland for a
postgraduate studentship (J.H.M.) and The Royal Society for a Uni-
versity Research Fellowship (K.W.H.). We also thank Pfizer Global
Research and Development, Sandwich for generous funding of our
research endeavours and the EPSRC Mass Spectrometry Service,
University of Wales, Swansea, for analyses.
(11) The returned ketone trans-2 displayed a negative optical
rotation completely equivalent to and in accord with
previously reported data: Fauvre, A.; Renard, M. F.;
Synlett 2001, No. 8, 1253–1256 ISSN 0936-5214 © Thieme Stuttgart · New York

1256
K. W. Henderson et al.
LETTER
Veschambre, H. J. Org. Chem. 1987, 52, 4893. See also:
Anziani, P.; Cornubert, R.; Lemoine, M. C. R. Hebd. Seances
Acad. Sci. 1949, 229, 431.
vacuo. The reaction conversion was determined as 99% by GC
analysis [CP SIL 19CB fused silica capillary column; carrier
gas H2 (80 kPa); 45-150 °C; temperature gradient: 5 °C/min;
tR = 11.9 min (cis-7); tR = 12.2 min (8)]. Flash column
chromatography (eluting with petrol/ether 19:1) afforded
(6S)-2,6-di-iso-propyl-1-trimethylsiloxy-1-cyclohexene (S)-8
(184 mg, 90%) as a clear oil which displayed an enantiomeric
ratio of 98.8:1.2 {Chirasil-DEX CB capillary column; carrier
gas H2 (40 kPa); 75 °C (1 min)-115 °C; temperature gradient:
1.3°C/min; tR = 27.4 min [(S)-8]; tR = 27.8 [(R)-8]}.
IR (film): 1664 cm-1 (s, C=C). 1H NMR (CDCl3, 400 MHz):
3.04 (1H, septet, J = 6.9 Hz, CH), 2.22-2.15 (1H, m, CH),
2.03-1.80 (3H, m, CH and CH2), 1.70-1.60 (2H, m, CH2),
1.36-1.27 (2H, m, CH2), 0.90 (3H, d, J = 6.9 Hz, CH3), 0.89
(6H, t, J = 7.3 Hz, 2 CH3), 0.74 (3H, d, J = 6.8 Hz, CH3),
0.17 ppm (9H, s, Si(CH3)3). 13C NMR (CDCl3, 100 MHz):
143.9, 123.8, 45.0, 28.2, 26.5, 23.4, 22.4, 22.25, 21.3, 20.9,
20.4, 16.9, 0.8. HRMS: C15H30OSi, M+ requires 255.2144;
found 255.2143. Analysis calculated for C15H30OSi: C, 70.80,
H, 11.88; found: C, 70.80, H, 12.03. [ ]D20 -4.1°, c 1.4, CHCl3.
All other compounds gave satisfactory spectral and analytical
data.
(12) Commercially available 2,6-diphenylcyclohexanone 4
afforded <1% of the trans-ketone upon isomer separation
using column chromatography. As such, deprotonation was
performed on the cis-ketone only.
(13) Enantiomeric ratios for 5 were determined by HPLC analysis:
Chirasil OD-H column; (254 nm); eluant: 0.5% iPrOH in
heptane; 0.2 ml/min; tR = 22.7 min [(S)-5], tR = 25.0 min [(R)-
5]. Additionally, the absolute configurations of the major and
minor enantiomers for 5 were tentatively assigned by
correlation with 3.
(14) Coffield, T. H.; Filbey, A. H.; Ecke, G. G.; Kolka, A. J. J. Am.
Chem. Soc. 1957, 79, 5019.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(16) It should be noted that GC analyses for Table 3, Entries 2, 3,
and 4 were performed using a sample concentration of 10 mg/
mL c.f. Table 3, Entry 1 where a more standard concentration
of 1 mg/mL was adopted.
(17) Representative experimental procedure: To a Schlenk
flask, under N2, was added Bu2Mg (0.79 M solution in
heptane, 1.27 mL, 1 mmol). The heptane was then removed in
vacuo and replaced with THF (10 mL), followed by addition
of (R)-N-benzyl- -methylbenzylamine (0.42 mL, 2 mmol).
The resultant solution was heated to reflux for 90 min and then
slowly cooled to –40 °C, whereupon TMSCl (0.5 mL, 4
mmol) and HMPA (0.09 mL, 0.5 mmol) were added. After
stirring for 20 min at –40 °C, cis-2,6-di-iso-propylcyclo-
hexanone 7 (146 mg, 0.8 mmol) was added as a solution in
THF (2 mL) over 1 h using a syringe pump. The reaction was
allowed to stir at –40 °C for a further 5 h and then quenched
by the addition of saturated aqueous NaHCO3 (5 mL). After
warming to room temperature the reaction mixture was
extracted with ether (50 mL) and washed with saturated
aqueous NaHCO3 (2 20 mL). The combined aqueous phase
was extracted with ether (2 20 mL), the combined organic
phase was then dried (Na2SO4) and the solvent removed in
(18) It is worth noting that cis-2,6-di-tert-butylcyclohexanone was
also prepared by Raney Ni catalysed hydrogenation of the
corresponding phenol.14 However, all attempts to deprotonate
this substrate with a range of (achiral) bases proved
unsuccessful.
(19) For a comparison with Li-base systems which employ
appreciably more complex amides, see: Graf, C.-D.; Malan,
C.; Harms, K.; Knochel, P. J. Org. Chem. 1999, 64, 5581.
Aoki, K.; Tomioka, K.; Noguchi, H.; Koga, K. Tetrahedron
1997, 53, 13641. See also ref. 9 and Busch-Petersen, J.;
Corey, E. J. Tetrahedron Lett. 2000, 41, 6941.
Article Identifier:
1437-2096,E;2001,0,08,1253,1256,ftx,en;D12201ST.pdf
Synlett 2001, No. 8, 1253–1256 ISSN 0936-5214 © Thieme Stuttgart · New York