Magnesium amide base-mediated enantioselective deprotonation processes

Article abstract of DOI:10.1016/S0040-4020(02)00364-2

A novel homochiral magnesium bisamide has been readily prepared and, following careful optimisation, this species has been shown to react efficiently with a series of prochiral 4-substituted cyclohexanones in the presence of TMSCl to give the corresponding silyl enol ethers in enantiomeric ratios of up to 95:5. Additionally, the same chiral base system has been shown to be highly effective in the desymmetrisation of cis-2,6-disubstituted cyclohexanones, providing excellent levels of both conversion and enantioselection (up to >99.5:0.5 er). Furthermore, the magnesium bisamide has also been shown to mediate a kinetic resolution process with the corresponding trans-disubstituted substrates, allowing access to enantioenriched enol ethers and ketones.

Full text of DOI:10.1016/S0040-4020(02)00364-2

TETRAHEDRON
Pergamon
Tetrahedron 58 12002) 4573±4587
Magnesium amide base-mediated enantioselective
deprotonation processes
²
Kenneth W. Henderson,p William J. Kerrp and Jennifer H. Moir
Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, Glasgow G1 1XL, UK
Received 4 January 2002; accepted 11 February 2002
AbstractÐA novel homochiral magnesium bisamide has been readily prepared and, following careful optimisation, this species has been
shown to react ef®ciently with a series of prochiral 4-substituted cyclohexanones in the presence of TMSCl to give the corresponding silyl
enol ethers in enantiomeric ratios of up to 95:5. Additionally, the same chiral base system has been shown to be highly effective in the
desymmetrisation of cis-2,6-disubstituted cyclohexanones, providing excellent levels of both conversion and enantioselection 1up to
.99.5:0.5 er). Furthermore, the magnesium bisamide has also been shown to mediate a kinetic resolution process with the corresponding
trans-disubstituted substrates, allowing access to enantioenriched enol ethers and ketones. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
ment and ®rst use of a homochiral magnesium amide base in
the enantioselective deprotonation of prochiral ketones.7
Over recent years, the widespread and continued requirement
for access to enantioenriched organic products and synthons
has driven the explosion of interest in both the preparation of
novel chiral base reagents and the subsequent application of
such species in asymmetric synthesis. Notably, homochiral
lithium amides have emerged as effective synthetic tools for
use in a range of enantioselective transformations.1 In
comparison to their Li-counterparts, the use of chiral magne-
sium reagents within asymmetric organic synthesis and, in
particular, as mediators of enantioselective deprotonation
processes has received scant attention. Indeed, in a more
general sense, only relatively rarely have Mg compounds,
other than Grignard-type reagents,2 been employed within
asymmetric synthesis,3 and even then they are most usually
only present as the Lewis acid promoter in the presence of a
chiral additive. However, when Mg-amide reagents are
considered, it appears that they possess several key features
which, in combination, are central to the development of a
range of asymmetric transformations. In particular, and in
contrast to the Li-systems, their solution aggregation state is
generally simple and predictable.4 Furthermore, Mg-amides
are more thermally stable5 and, in a racemic sense, it has
already been noted that they are reactive yet selective
bases.5,6 Such advantages over existing methodology have
therefore led us to explore the formation and utility of chiral
reagents of this class. Herein, we report in full the develop-
2. Results and discussion
2.1. Preparation of a homochiral magnesium amide base
Aided by the commercial availability of dibutylmagnesium,
the synthesis and isolation of Mg-bisamides has now become
a generally facile process. Indeed, heating a combination of a
secondary amine 12 equiv.) and Bu2Mg to re¯ux in hexane,
heptane, or toluene oftenresults in the formation of a crystalline
bis1amido)Mg-product upon cooling.4,5 To initiate this pro-
gramme of study, and based on our structural study of the Li-
amide 1R)-1,8 we chose to utilise the readily available, rela-
tively inexpensive, and structurally simple amine, 1R)-N-
benzyl-a-methylbenzylamine 1R)-2. As such, 2 equiv. of
amine 1R)-2 were added to a solution of Bu2Mg in hexane,
followed by heating to re¯ux for 90 min. On removal of solvent,
pleasingly, 1H NMR spectroscopy showed clean formation of
the novel chiral Mg-amide reagent 1R)-3. Attempts to form 1R)-
3 at room temperature led to incomplete reaction. It should also
be noted that, to date and despite a series of attempts, we have
yet to realise successful precipitation of our new Mg-bisamide.
Keywords: asymmetric synthesis; chiral amines; enantioselective deproto-
nation; kinetic resolution; magnesium.
Corresponding authors. Tel.: 144-141-548-2351; fax: 144-141-552-
p
0876; e-mail: k.w.henderson@strath.ac.uk; Tel.: 144-141-548-2959;
fax: 144-141-548-4246; e-mail: w.kerr@strath.ac.uk
Present address: Research and Development, Organon Laboratories Ltd.,
²
Newhouse, Lanarkshire ML15SH, UK.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020102)00364-2

4574
K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
Scheme 1.
2.2. Development of an enantioselective deprotonation
protocol with homochiral magnesium amide R)-3 and
4-substituted cyclohexanones
At this stage the choice of solvent was reconsidered and
preliminary deprotonation studies in THF were performed.
The ®rst interesting observation on attempting the transfor-
mations in this alternative solvent was that it was possible to
form silyl enol ether 5a from ketone 4a without the addition
of HMPA. At room temperature, using chiral Mg-amide
base 1R)-3 under external or internal quench conditions,
conversions of 94±97% were achieved with the enol ether
5a displaying enantiomeric ratios in the region of 58:42. On
the other hand, upon lowering the reaction temperature to
2788C, no apparent change in the enantioselection was
observed.
Based on extensive studies as reported in the chemical
literature,1 ketone 4a was the substrate on which we chose
to perform our initial deprotonation attempts. At the outset,
using an external quench protocol, ether was employed as the
reaction solvent, both with and without the addition of 1equiv.
of HMPA. All reactants were added at 2788C, with the result-
ant mixtures then being allowed to warm to room temperature
overnight in order to effect maximum conversion. The reaction
carried out in the absence of HMPA afforded none of the
desired silyl enol ether product 5a. However, in the presence
of 1equiv. of HMPA, chiral Mg-amide base 1 R)-3 was shown
to deprotonate ketone 4a, to afford silyl enol ether 5a, in a
moderate 53% yield and in an enantiomeric ratio of 58:42 in
favour of the 1S)-enantiomer.9 In turn, using the same external
quench technique and maintaining the reaction temperature at
2788C for 7 h delivered a similar 60:40 er and a signi®cantly
lower isolated yield of 12%.
Despite being able to perform these deprotonations of
prochiral ketone 4a in the absence of HMPA, only low
levels of asymmetric induction were recorded. Therefore,
the introduction of HMPA to the THF-based processes was
probed. Furthermore, in a similar approach to that taken
with ether as solvent, an internal quench procedure was
combined with the slow addition of the ketone at low
temperature. In this respect, adding the ketone in THF
over 1h appeared to be optimal for this system. Indeed, as
can be seen from Table 11entry 1), the use of 1equiv. of
HMPA gave a conversion of 96% and provided enol ether
5a with an er of 75:25. Moreover, when the stoichiometry of
HMPA was varied from 1to 0.5 equiv. the enantiomeric
ratio of 5a was further enhanced to 82:18 1entry 3). In
contrast, increasing the amount of HMPA is obviously dele-
terious to the asymmetric induction 1entry 2), as is lowering
the level to 0.1equiv 1entry 4). It should also be noted at this
stage that small variations in the stoichiometry of the
HMPA, above and below 0.5 equiv., led to no further
enhancement in selectivity. The processes also appeared to
be largely indifferent to any increases in reaction dilution.11
In attempts to improve upon the poor levels of enantio-
selection observed thus far with ether as solvent, an internal
quench protocol was examined.10 Furthermore, a slow addi-
tion strategy for introducing the ketone to the base system
was also adopted. These techniques proved somewhat bene-
®cial in that an enantiomeric ratio of 63:37 for 5a was
observed at room temperature and at 2788C a further
improved er of 70:30 was recorded 1Scheme 1). Despite
the relatively low levels of enantioselection, these initial
results showed that this simple homochiral Mg-bisamide
base system was, indeed, capable of mediating an enantio-
selective deprotonation process with the conformationally
locked ketone 4a.
Having optimised the deprotonation system to this stage it is
worth noting that the levels of selectivity being observed in
reactions of 4a with the enantiomerically pure Mg-amide
base 1R)-3 182:18 er) are already signi®cantly higher than
those achieved using the corresponding chiral Li-amide
base 1R)-1 175.5:24.5).9a,b On the other hand and, in parti-
cular, due to the ambiguities present in the chemical litera-
ture,9 the use of optical rotation measurements to establish
the enantiomeric ratios of the product enol ethers was of
some concern. In this regard, during the course of this
work, the disclosure of a series of results, including some
careful chiral GC analysis, by Knochel and co-workers
provided a rapid chromatographic technique for the accurate
determination of the levels of enantioselection being
attained in our asymmetric deprotonation processes.
Furthermore, correlation with Knochel's results allowed
con®rmation of the assignment of the absolute stereo-
chemistry for the enol ether 5a.12
Table 1. Enantioselective deprotonation reactions of ketone 4a with Mg-
bisamide 1R)-3 and varying levels of HMPA
Entry HMPA 1equiv.) Conversion 1%) Enantiomeric ratioa 1S)/1R)
11 96
75:25
2
3
4
2
0.5
0.172
38
8 8182:1
76:24
57.5:42.5
a
Enantiomeric ratios were established using optical rotation.9

K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
Table 2. Enantioselective deprotonation reactions of ketone 4a with Mg-bisamide 1R)-3
4575
Entry
Solvent
HMPA 1equiv.)
Conversion 1%)
Enantiomeric ratioa 1S)/1R)
1Et
2
3
4
5
2O
CH2Cl2
THF
THF
THF
THF
THF
183
140
0
1494
2
80:20
72:28
33
86:1
26
82
90:10
84:16
91:9
6
7
0.5
0.:1953
91
a
Enantiomeric ratios were determined by GC analysis; see Section 4.
In due course and having established a chiral GC separation
protocol, a series of key experiments were repeated 1Table
2). Firstly, it should be noted that each of the reactions did
show an enhanced level of enantioselection in comparison
to the equivalent reactions which were analysed using
polarimetry. Having stated this, it is clear that the overall
trend remained consistent, with reaction in THF 1entry 4)
being superior with regards to both conversion 194%) and
enantioselection 186:14 er) to the directly comparable reac-
tion in ether 1entry 1). Reaction in DCM 1entry 2) also
displayed lower overall ef®ciency.
tions, on the factors which affect enantioselectivity in the
deprotonation reaction of ketone 4a by chiral Mg-amide
base 1R)-3, were indeed accurate. Additionally, it is now
clear that the true level of selection being achieved in
these Mg-based processes is appreciably higher than that
originally recorded. It is also worth noting here that chiral
amine 1R)-2 could be recovered from the reaction mixture
with no loss in optical purity 1in 90% yield following
alumina column chromatography).
Ongoing efforts to further improve upon the results achieved
to date prompted us to lower the deprotonation reaction
temperature from 278 to 2988C. However, this afforded
no appreciable change in either the conversion of 4a
180%) or the enantiomeric ratio displayed by 5a 191:9)
after 6 h reaction time.
Upon further consideration of the results obtained using
THF as the reaction solvent, once again, it became clear
that an optimum level of the Lewis base additive HMPA
was required in order to effect both high conversion and
maximum enantioselection. In its absence 1entry 3), reaction
was slow, with only 33% conversion of 4a to 5a being
observed after 6 h, although it should be noted that the
enantiomeric discrimination 190:10 er) was comparable
with the highest levels achieved thus far. As already
mentioned, reaction in the presence of 1equiv. of HMPA
1entry 4) afforded high levels of both conversion and
enantioselectivity, and, as expected, doubling the quantity
of HMPA 1entry 5) was detrimental to both enantioselection
and, more signi®cantly, to conversion. Once again, reducing
the number of equivalents of HMPA from 1to 0.5 1entry 6)
afforded the optimum result with respect to enantioselection
191:9 er) whilst giving a good 82% conversion. Any further
reduction in the quantity of HMPA 1entry 7) had a negative
effect on the reaction conversion.
In addition to these studies, the requirement for the speci®c
Lewis base additive HMPA was explored. Pleasingly, we
found that this toxic co-solvent could be replaced by the
more practically acceptable DMPU, without signi®cant
loss in either the reactivity or selectivity of chiral Mg-
amide base 1R)-3. As shown in Scheme 2, reaction of 1R)-
3 with ketone 4a in the presence of 1equiv. of DMPU
afforded silyl enol ether 5a in 93% conversion and with
an enantiomeric ratio of 86:14. In concordance with the
HMPA reactions, halving the quantity of DMPU to
0.5 equiv. resulted in improved enantioselection 190:10
er), whilst a high level of conversion 189%) was maintained.
With these initial studies in hand and in order to investigate
the wider applicability of our Mg-based strategy, a series
of equivalent ketone substrates were then subjected to our
Overall, it was concluded that our initial series of observa-
Scheme 2.

4576
K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
Table 3. Enantioselective deprotonation reactions of ketones 4a±e with Mg-bisamide 1R)-3
Entry
Ketone
R
Product
Conversion 1%)
Enantiomeric ratioa 1S)/1R)
1
2
3
4
5
4a
4b
4c
4d
4e
tBu
Me
nPr
Ph
1S)-5a
1S)-5b
1S)-5c
1S)-5d
1S)-5e
82
91:9
:9
8191
88
79
88:12
87:13
95:5
iPr
77
a
Enantiomeric ratios were determined by GC analysis; see Section 4.
optimised reaction conditions with chiral Mg-amide 1R)-3.
As shown in Table 3, using ketones 4a±e the developed
protocol consistently delivered the corresponding enol
ethers 5a±e with good ef®ciency and enantioselection.13
Indeed, the enantiomeric ratio displayed upon the desym-
metrisation of 4-iso-propylcyclohexanone 4e 195:5) is
already approaching the optimum levels achievable for
such transformations.
again being minimal 1at 23%). As anticipated, the introduc-
tion of HMPA to the reaction solution had no effect upon
enolate concentration. However, upon the addition of
4 equiv. of TMSCl a 58% conversion of ketone 4a to 5a
was observed. This result indicates that the reaction of the
formed Mg-enolate with TMSCl, to yield silyl enol ether, is
clearly driving the reaction on and encouraging further Mg-
enolate formation.
2.3. 1H NMR spectroscopic study for probing Mg-
enolate formation
In summary, these NMR spectroscopic studies have allowed
us to propose that HMPA has little in¯uence over the reac-
tivity of Mg-amide base 1R)-3 in the absence of TMSCl. On
the other hand, with regards to the rate of the reaction over-
all, HMPA is believed to be in¯uencing the reactivity of the
Mg-enolate intermediate, with addition of HMPA being
necessary in order to induce high conversion of 4a to 5a
1as shown in Tables 1and 2). It is also important to note that
the presence of TMSCl is required from the outset of the
reaction, in order to effect high levels of conversion of
ketone to silyl enol ether. With respect to enantioselectivity,
the presence of HMPA does not appear to signi®cantly in¯u-
ence the asymmetric potential of our system, at least until
higher equivalents of this Lewis base additive are employed.
As this study progressed it became increasingly important
for us to attempt to ascertain the degree of Mg-enolate
formation under a series of appropriate reaction conditions,
with and without the co-solvent, HMPA, and the electro-
philic trap, TMSCl. In order to achieve this goal, we chose
1
to conduct a H NMR spectroscopic study in THF-d8. This
allowed us to recreate our deprotonation reaction condi-
tions, whilst also providing us with a suitable sample for
direct analysis. In this regard, chiral Mg-amide base 1R)-3
was suspended in THF-d8 at room temperature and ketone
4a was added as a solution in THF-d8. The resultant mixture
was allowed to stir for 30 min before an aliquot was
1
removed via cannula and the H NMR spectrum obtained.
2.4. Some practical improvements
The resulting spectral analysis indicated only a relatively
small degree of enolate formation 122%). Furthermore,
when the reaction was allowed to continue at room tempera-
ture for a total of 16 h this low level of enolate formation
remained constant at 22%. In an effort to increase the extent
of deprotonation of 4a, 1equiv. of HMPA was then added to
Having further developed our understanding of the Mg-
amide mediated deprotonation process, attempts were
made to more closely monitor reaction progress and, indeed,
establish the times required for formation of elevated quan-
tities of silyl enol ether 5. Interestingly, following a series of
GC monitoring studies, using ketone 4a as an exemplar, it
was established that conversion to the silyl enol ether was
consistently high 1and in the region of 80%) immediately
after addition of the ketone over 1h. Importantly, we
observed no signi®cant change in the enantiomeric ratio
of product 5a after this 1h reaction time.
1
the THF-d8 reaction solution. However, H NMR spectro-
scopy revealed no increase in the enolate concentration
after 30 min. Indeed, this level remained unchanged over
a 5-day period. It can be concluded, therefore, that depro-
tonation of ketone 4a is minimal in the presence of Mg-
base 1R)-3 alone. This study also suggests that the Lewis
base additive, HMPA, plays no part in facilitating further
enolate formation.
With a view to increase the overall practical utility of our
deprotonation strategy, we also attempted the synthesis of
chiral Mg-amide base 1R)-3 directly in THF. This would
allow the deprotonation process to be performed without
the inconvenience of having to remove the hexane solvent
in vacuo, followed by the re-suspension of 1R)-3 in THF.
Pleasingly, following heating to re¯ux for 90 min, chiral
In an effort to further investigate the enolisation process and,
more speci®cally, to establish the in¯uence of TMSCl, a
second H NMR spectroscopic experiment was conducted.
1
Initially, similar measurements were taken in THF-d8, with
enolate formation in the absence of both HMPA and TMSCl

K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
4577
selective deprotonation reaction of 2,6-dimethylcyclo-
hexanone 6, chiral Mg-amide base 1R)-3 is also capable of
mediating a kinetic resolution process.
Based on these promising initial results and to further
explore the potential of this reaction system, the cis- and
trans-isomers of ketone 6 were then separated and reacted
in isolation. More speci®cally, when cis-ketone 6 was
subjected to the Mg-amide base 1R)-3 at 2788C for 40 h,
54% conversion was achieved and the resulting silyl enol
ether registered an excellent enantiomeric ratio of 97:3
1Table 4, entry 1). This outcome is particularly noteworthy,
in that, when cis-ketone 6 was reacted with the Li-version of
the same chiral amide, the resulting enol ether was delivered
with a signi®cantly lower er of 64.5:35.5.9a,14 Furthermore,
this result is at least equivalent to those obtained for the
desymmetrisation of ketone 6 using much more structurally
complex Li-amide bases.13b,14
Scheme 3.
Mg-amide base 1R)-3 was cleanly synthesised in THF solu-
tion. Importantly, subsequent use of this base in deprotona-
tion reactions allowed silyl enol ether formation with almost
identical levels of conversion and enantioselection to those
registered previously.
2.5. Enantioselective deprotonation reactions of 2,6-
disubstituted cyclohexanones with homochiral
magnesium amide R)-3
Returning to our Mg-amide base 1R)-3, we remained un-
satis®ed at the length of time required to achieve an accept-
able level of conversion of cis-6 to 7. In this regard, whilst a
reduction in the reaction time to 6 h at 2788C resulted in a
drop in conversion to 25% 1Table 4, entry 2), we were
pleased to ®nd that increasing the reaction temperature to
2608C, afforded a signi®cant rise in reaction conversion
167%) with only a small drop off in enantioselection 194:6
er; entry 3). Upon increasing the temperature yet further to
2408C 1entry 4), we were delighted to observe almost quan-
titative conversion of cis-6 within 6 h, with silyl enol ether
1R)-7 exhibiting a minimal reduction in enantioselectivity
1to 93:7 er).
In an effort to further establish and, moreover, widen the
scope of our novel Mg-amide mediated enantioselective
deprotonation process, our attention was turned to consider
the desymmetrisation reactions of alternative prochiral
cyclic ketones and, more speci®cally, 2,6-disubstituted
cyclohexanones. In particular and to initiate this investiga-
tion, 2,6-dimethylcyclohexanone 6 was available commer-
cially as an 82:18 mixture of cis-/trans-isomers; the trans-
ketone exhibited a 50:50 ratio of enantiomers. The cis/trans
mixture of ketone 6 was subjected to reaction with chiral
Mg-amide base 1R)-3 using our optimised deprotonation
strategy. After 6 h reaction time, the corresponding silyl
enol ether was obtained in a low 27% conversion. Upon
consideration of the increased steric bulk around the
site of deprotonation in ketone 6, relative to that of the 4-
substituted cyclohexanones 4, it is perhaps not surprising
that a lower conversion was noted for this transformation
over a period of 6 h at 2788C. Therefore, in an effort to
improve upon this, the reaction time was increased from 6 to
65 h. Pleasingly, this afforded 1R)-7 with an increased level
of conversion 171%) and with an enantiomeric ratio of 88:12
1Scheme 3).13 Moreover, as well as observing a good level
of asymmetric induction, we were intrigued to note that the
returned and initially racemic trans-ketone displayed an
optical activity 174:26 er). This would suggest that as well
as being particularly effective at performing an enantio-
Moving on to consider reaction of trans-2,6-dimethylcyclo-
hexanone, trans-6, initially present as a racemic mixture, at
2788C this isomer afforded a good 53% isolated yield of
silyl enol ether 7 which displayed an enantiomeric ratio of
72:28 in favour of the 1S)-enantiomer 1Scheme 4). Interest-
ingly, this is the enantiomeric silyl enol ether to that
obtained in excess from reaction of cis-6 with chiral Mg-
amide base 1R)-3, thereby providing us with a convenient
route into either the 1R)- or 1S)-form of 7. With regards to
the unreacted trans-ketone, trans-6 was returned displaying
an enantiomeric ratio of 77:23, thus re-af®rming our initial
observation that a kinetic resolution reaction had, indeed,
taken place. Based on the formation of the known 1S)-
isomer of 7,13b as well as literature data,15 the predominant
Table 4. Enantioselective deprotonation reactions of cis-6 with Mg-bisamide 1R)-3
Entry
Temperature 18C)
Time 1h)
Conversion 1%)
Enantiomeric ratioa 1R)/1S)
1
2
3
4
278
278
260
240
40
6
6
54
25
67
99
97:3
97:3
94:6
93:7
6
a
Enantiomeric ratios were determined by GC analysis; see Section 4.

4578
K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
Scheme 4.
Scheme 5. Reagents and conditions: 1i) Raney Ni, H2 196 atm), 1048C, 39 h, 97%; 1ii) Dess±Martin periodinane, CH2Cl2, rt, 1h, 98%.
returned ketone was assigned as the 1R,R)-enantiomer.
Interestingly, and although chiral Li-amide bases have,
indeed, been used to good effect in the kinetic resolution
of certain racemic ketones,16 when the equivalent Li-base to
chiral Mg-amide base 1R)-3 was used in the desymmetrisa-
tion reaction of trans-6, completely racemic silyl enol ether
7 was observed.9a
est level of asymmetric induction observed during this study
on the deprotonation of cis-2,6-diphenylcyclohexanone 8
with chiral Mg-amide base 1R)-3 1entry 3).13
Additional examples of 2,6-disubstituted cyclohexanones
were required to be synthesised from the corresponding
2,6-disubstituted phenols. In particular, Raney Nickel cata-
lysed hydrogenation of 2,6-di-iso-propylphenol 10 afforded
the fully saturated ring product, cyclohexanol 11 1as a
mixture of isomers), upon optimisation of the reaction con-
ditions 1Scheme 5).17 In turn, a suitable method for the
oxidation of alcohol 11 to afford cis- and trans-ketone 12
was required. As such, using the Dess±Martin periodinane
reagent18 we were delighted to observe complete reaction of
the crude alcohol 11 to afford cyclohexanone 12 in 98%
yield within 1h. GC analysis allowed the ratio of cis/
trans-isomers of 12 to be determined as 82:18 in favour of
the cis-compound, with the trans-isomer exhibiting a 50:50
ratio of enantiomers. Subsequent silica column chromato-
graphy permitted the separation and isolation of the cis- and
trans-isomers.
Following on from these encouraging results, we then
decided to investigate the behaviour of chiral Mg-amide
base 1R)-3 in the desymmetrisation reaction of alternative
2,6-disubstituted cyclohexanones. Upon consideration of
2,6-diphenylcyclohexanone 8, the commercial sample
afforded ,1% of the trans-ketone upon isomer separation
by column chromatography. As such, a deprotonation study
was performed on the cis-ketone only.
With regards to the effect of temperature on the selectivity
of the reaction to form enol ether 9 from cis-8, it was not
surprising to view the lowest enantiomeric ratio at the
highest reaction temperature of 2208C 1Table 5, entry 1).
Similar yields of silyl enol ether 1S)-9 were observed at both
2208C 1entry 1) and 2408C 1entry 2) with only a small
increase in the enantioselectivity of the reaction being
observed at the lower temperature. Further temperature
reduction to 2608C afforded a drop in yield, even with an
increased reaction time. On the other hand, the enol ether
1S)-9 obtained from this latter reaction did display the high-
In due course, cis-ketone 12 was reacted with chiral Mg-
amide base 1R)-3 to afford silyl enol ether 1S)-13 in 54%
conversion after 39 h reaction time at 2788C. Remarkably,
in this example, only one enantiomer of the product enol
ether could be observed by chiral GC, allowing us to register
our highest enantiomeric ratio yet achieved of .99.5:0.5
Table 5. Enantioselective deprotonation reactions of cis-8 with Mg-bisamide 1R)-3
Entry
Temperature 18C)
Time 1h)
Yield 1%)
Enantiomeric ratioa 1S)/1R)
1
2
3
220
240
260
8
8
24
83
86
39
79:21
82:18
87:13
a
Enantiomeric ratios were determined by GC analysis; see Section 4.

K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
Table 6. Enantioselective deprotonation reactions of cis-12 with Mg-bisamide 1R)-3
4579
Entry
Temperature 18C)
Time 1h)
Conversion 1%)
Enantiomeric ratioa 1S)/1R)
1
2
3
4
5
278
278
260
240
rt
39
6
6
6
2
54
9
66
99
100
.99.5:0.5
99.7:0.3
99.4:0.6
98.8:1.2
91:9
a
Enantiomeric ratios were determined by GC analysis; see Section 4.
1entry 1, Table 6). Pleasingly, warming the reaction from
2788C through 2608C 1entry 3), to 2408C 1entry 4),
allowed us to view almost quantitative conversion of cis-
12 to silyl enol ether 1S)-13 after only 6 h reaction time.13
Furthermore, a trace of the undesired second enantiomer of
the enol ether 13 only began to show upon a tenfold concen-
tration of the GC sample. It is also encouraging, from a
practical point of view, to note the high level of enantio-
selection observed when the desymmetrisation reaction is
carried out at room temperature 1entry 5).
deprotonation study with homochiral Mg-amide base 1R)-
3. However, all attempts to deprotonate this material with a
range of 1achiral) bases proved unsuccessful.
3. Conclusions
In conclusion, we have been successful in developing a
straightforward preparative route to a novel homochiral
Mg-bisamide reagent, from a structurally simple, readily
available, and relatively inexpensive chiral amine. Follow-
ing this, we have gone on to demonstrate, for the ®rst time,
that such a species can successfully mediate enantio-
selective deprotonation reactions. Indeed, having explored
a series of reaction conditions, a standard and optimum
protocol has now been established. Importantly, these
methods allow the desymmetrisation of a variety of 4-
substituted cyclohexanones to be realised in high conver-
sion and with good to excellent levels of asymmetric induc-
tion. Furthermore, we have also succeeded in extending the
scope of our desymmetrisation strategy using chiral Mg-
amide base 1R)-3 to encompass the enantioselective depro-
tonation reactions of 2,6-disubstituted cyclohexanones.
More particularly, these substrates have afforded us excel-
lent levels of asymmetric induction 1up to .99.5:0.5 er). To
date, these values represent the highest degree of enantio-
selection to have been attained within this speci®c area of
chiral base chemistry.
Furthermore, in the anticipation that we would again
observe a kinetic resolution process similar to that noted
with trans-2,6-dimethylcyclohexanone 6, we subjected
trans-2,6-di-iso-propylcyclohexanone 12 to our Mg-based
deprotonation strategy 1Table 7). In turn, we were delighted
to note that, at 2408C silyl enol ether 1R)-13 was afforded in
a good enantiomeric ratio of 81:19 1entry 1). Furthermore,
the initially racemic ketone 12 was returned displaying a
substantially increased level of one enantiomer over the
other 194:6 er). This kinetic resolution could be further
enhanced by simply performing the deprotonation reaction
at 08C. Based on similar reasoning to that used previously
with trans-6, the predominant returned ketone was assigned
as the 1S,S)-enantiomer.
Finally, it is worth noting that the alternative 2,6-disubsti-
tued ketone, 2,6-di-tert-butylcyclohexanone,17 was also
accessed with a view to exploring the reactivity of this
even more hindered substrate within our enantioselective
In addition to these desymmetrisation studies, we have also
Table 7. Enantioselective deprotonation reactions of trans-12 with Mg-bisamide 1R)-3
Entry
Temperature
18C)
Time
Conversion
1%)
Enantiomeric ratio
of 13a 1R)/1S)
Enantiomeric ratio of
trans-12a 1S,S)/1R,R)
1
2
3
240
0
0
67 h
100 min
19 h
66
59
99
81:19
76:24
53:47
94:6
80:20
99:1
a
Enantiomeric ratios were determined by GC analysis; see Section 4.

4580
K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
established a novel Mg-amide mediated kinetic resolution
process in the reactions of both trans-2,6-dimethyl- and
trans-2,6-di-iso-propylcyclohexanone. Interestingly with
respect to gaining access to the chiral synthon of choice,
with both of these substrates the enantiomeric enol ether to
that obtained from the corresponding cis-ketone is formed in
excess. Additionally and importantly, the returned ketones
also display good to excellent levels of optical enrichment.
Mineralight UVGL-25 lamp or developed using potassium
permanganate, vanillin, and/or Brady's reagent 12,4-DNP).
Flash column chromatography was carried out using
Prolabo silica gel 1230±400 mesh). Gravity column
chromatography was carried out using Merck aluminium
oxide 90 1activity grade II±III, 70±230 mesh). This was
neutralised by standing in ethyl acetate for 7 days, followed
by ®ltration and washing with ethanol, water, and ethanol
before drying at 1208C overnight. The alumina was deacti-
vated to activity grade IV prior to use. This involved shak-
ing with 10% 1w/w) of water.
With regards the more general utility of these methods, it is
worth stressing that the practical developments and enantio-
selective processes detailed here have been realised by the
application of a very simple and readily accessible amide
base system. We believe that this feature, coupled with the
relatively robust nature of Mg-amides in general, will
impact positively on the more widespread use and adoption
of these techniques. Furthermore, it is also envisaged that
Mg-based reagents of this type have considerable scope for
further development. In this respect, the application of
alternative Mg-bisamide systems and the establishment of
related methodology are currently underway in our labora-
tories and will be reported in due course.
Gas chromatography was carried out using a Carlo Erba
HRGC 5300 gas chromatograph ®tted with: 1i) a DB 179
column, 1ii) a CP-SIL 19CB column, or 1iii) a CP-Chirasil-
DEX CB column. Detection was by ¯ame ionisation and
the chromatograph was interpreted using JCL 6000
computer software. HPLC was carried out on a Chirasil
OD-H column using a Waters 501HPLC pump, a Waters
484 tuneable absorbance detector 1set at 254 nm unless
otherwise speci®ed), and processed using a Waters 746
data module.
IR spectra were obtained on a Nicolet Impact 400D FTIR
1
spectrometer. H and 13C NMR spectra were obtained on a
4. Experimental
4.1. General
Bruker DPX 400 spectrometer at 400 and 100 MHz, respec-
tively. Chemical shifts are reported in ppm. Coupling con-
3
stants are reported in hertz and refer to JH±H interactions
unless otherwise speci®ed. Where 13C jmod NMR spectra
have been recorded, up 1u) indicates CH or CH3 groups and
down 1d) indicates C or CH2 groups.
Diethyl ether, tetrahydrofuran, THF-d8, and hexane were
dried by heating to re¯ux over sodium wire, benzophenone
ketyl being used as an indicator, and then distilled under N2.
Dichloromethane was distilled from calcium hydride under
N2. Light petroleum was distilled prior to use and refers to
the fraction of bp 30±408C.
High resolution mass spectra were obtained on a Finnigan
MAT 900XLT double focussing mass spectrometer at the
EPSRC National Mass Spectrometry Services Centre,
University of Wales, Swansea, UK. Elemental analyses
was obtained using a Carlo Erba 1106 CHN analyser.
Polarimetry was carried out on a Perkin Elmer 341polari-
meter using a cell with a path length of 1dm. Concentra-
n-Butyllithium, obtained as a 1.6 M solution in hexane, was
standardised using diphenylacetic acid19 or salicylaldehyde
phenylhydrazone.20 Dibutylmagnesium, obtained as a 1M
solution in heptane, was standardised using sec-butanol with
phenanthroline being used as an indicator21 or salicylalde-
hyde phenylhydrazone.20
tions are expressed in g dm23
.
Air-sensitive reactions were carried out using Schlenk
apparatus. This was initially evacuated and ¯ame dried,
followed by purging with N2 1£3).
1R)-11)-N-Benzyl-a-methylbenzylamine 1R)-2, HMPA,
and DMPU were dried by heating to re¯ux over calcium
hydride, distilled under vacuum, and stored over molecular
sieves. Di-iso-propylamine was dried by heating to re¯ux
over calcium hydride, distilled under N2, and stored over
molecular sieves.
4.2. Preparation of bis{ R)-N-benzyl-a-methylbenzyl-
amido}magnesium R)-3
4.2.1. Preparation in hexane. To a solution of Bu2Mg
10.91mL of a 1.1M solution in heptane, 1mmol) in hexane
18 mL), was added 1R)-N-benzyl-a-methylbenzylamine 1R)-
2 10.42 mL, 2 mmol). The solution was heated to re¯ux
under a N2 atmosphere for 90 min, and allowed to cool to
room temperature assuming quantitative formation of chiral
Mg-amide 1R)-3 11mmol). If subsequent reactions were not
to be performed in hexane, this was removed in vacuo, to
afford a pale yellow oil, and replaced with the solvent of
choice. dH 1400 MHz, C6D6): 1.17 1d, Jˆ6.6 Hz, 3H, CH3),
3.35±3.40 1m, 1H, CH), 3.48±3.57 1m, 2H, CH2), 7.02±
7.22 ppm 1m, 10H, ArH).
4-Methylcyclohexanone 4b, 4-n-propylcyclohexanone 4c,
4-iso-propylcyclohexanone 4e, 2,6-dimethylcyclohexanone
6, and 2,6-di-iso-propylcyclohexanone 12 were dried by
heating to re¯ux over fused CaCl2, distilled under vacuum,
and stored over molecular sieves. 4-tert-Butylcyclohexanone
4a, 4-phenylcyclohexanone 4d, cis-2,6-diphenylcyclohexa-
none 8, and cis-2,6-di-tert-butylcyclohexanone, were recrys-
tallised from dry hexane at 48C. TMSCl was distilled under N2
and stored over molecular sieves.
Thin layer chromatography was carried out using Camlab
silica plates coated with ¯uorescent indicator UV254 or
Merck aluminium oxide 60 1neutral) plates coated with
¯uorescent indicator F254. These were analysed using a
4.2.2. Preparation in THF. To a solution of Bu2Mg
11mmol; NB heptane was removed in vacuo prior to

K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
4581
the addition of THF) in THF 110 mL), was added 1R)-N-
benzyl-a-methylbenzylamine 1R)-2 10.42 mL, 2 mmol).
The solution was heated to re¯ux under a N2 atmosphere
for 90 min, and allowed to cool to room temperature
assuming quantitative formation of chiral Mg-amide 1R)-3
11mmol).
15) 1a) 1R)-3, 1 mmol, 1b) THF 110 mL), 1c) 123 mg,
0.8 mmol, 1d) 0.5 mL, 4 mmol, 1e) ±, 1f) 2788C, 1g) 24 h,
1h) reaction conversion was determined as 31% by GC
analysis 1see Section 4.4.1); puri®cation was carried out
by gravity column chromatography using neutral, deacti-
vated 1grade IV) alumina 1petrol), 1i) ±, 1j) [a]Dˆ211.6
1cˆ0.4, CHCl3), 57:43.
4.3. Enantioselective deprotonation reactions of
cyclohexanones using an external quench protocol
4.4. Enantioselective deprotonation reactions of
cyclohexanones using an internal quench protocol
4.3.1. Typical procedure. A solution of chiral Mg-amide
base 1R)-3 11mmol, see Section 4.2.1) in ether 110 mL) was
cooled to 2788C under N2. The Schlenk ¯ask was then
charged with 4-tert-butylcyclohexanone 4a 1123 mg,
0.8 mmol) as a solution in ether 12 mL) over 5 min. After
stirring for 20 min at 2788C, TMSCl 10.5 mL, 4 mmol) was
added, followed by HMPA 10.18 mL, 1 mmol). The result-
ing solution was allowed to warm to room temperature over
a period of 20 h, and was then quenched by the addition of
saturated aqueous NaHCO3 15 mL). The reaction mixture
was extracted with ether 150 mL) and washed with saturated
aqueous NaHCO3 12£20 mL). The combined aqueous phase
was then extracted with ether 12£20 mL), the combined
organic phase was dried over Na2SO4, followed by removal
of the solvent in vacuo. Flash silica column chromatography
1petrol/ether 9:1) afforded 4-tert-butyl-1-trimethylsiloxy-1-
cyclohexene 5a9a,b 196 mg, 53%) as a colourless oil. The
enantiomeric ratio of 5a was determined as 58:42 1S)/1R)
using polarimetry; [a]Dˆ212.2 1cˆ1.8, CHCl3). Rf 1silica:
petrol/ether 9:1): 0.90; Rf 1alumina: petrol): 0.46; nmax
1®lm): 1677 cm21; dH 1400 MHz, CDCl3): 0.18 1s, 9H,
Si1CH3)3), 0.88 1s, 9H, C1CH3)3), 1.21±1.29 1m, 2H,
CH2), 1.79±1.84 1m, 2H, CH2), 1.98±2.09 1m, 3H,
CHC1CH3)3 and CH2), 4.84±4.86 ppm 1m, 1H, CvCH).
4.4.1. Typical procedure. A solution of chiral Mg-amide
base 1R)-3 11mmol, see the procedure given in Section
4.2.1) in THF 110 mL) was cooled to 2788C under N2.
The Schlenk ¯ask was then charged with TMSCl 10.5 mL,
4 mmol) and HMPA 190 mL, 0.5 mmol). After stirring for
20 min at 2788C, 4-tert-butylcyclohexanone 4a 1123 mg,
0.8 mmol) was added as a solution in THF 12 mL) over
1h using a syringe pump. The resulting solution was
allowed to stir at 2788C for a further 5 h 1overall reaction
time, 6 h), and was then quenched by the addition of
saturated aqueous NaHCO3 15 mL). After warming to
room temperature, the reaction mixture was extracted with
ether 150 mL), and washed with saturated aqueous NaHCO3
12£20 mL). The combined aqueous phase was then
extracted with ether 12£20 mL) and the combined organic
phase was dried over Na2SO4. The reaction conversion was
determined as 82% by GC analysis 1DB 179 fused silica
capillary column; carrier gas H2 180 kPa); 60±1908C;
temperature gradient: 458C/min; tRˆ3.1min 1 4a), 3.3 min
15a)). Following removal of the solvent in vacuo, the
resultant yellow oil was then puri®ed by gravity column
chromatography on neutralised, deactivated alumina
1petrol) to afford afforded 4-tert-butyl-1-trimethylsiloxy-1-
cyclohexene 5a9a,b 1115 mg, 64%) as a colourless oil. The
enantiomeric ratio of 5a was determined as 91:9 1S)/1R) by
GC analysis [Chirasil DEX CB capillary column; carrier gas
H2 140 kPa); 808C 11min)±120 8C; temperature gradient:
1.88C/min; tRˆ25.4 min [1S)-5a], 25.7 min [1R)-5a].
4.3.2. Preparation of S)-4-tert-butyl-1-trimethylsiloxy-
1-cyclohexene, S)-5a.9a,b The following experiments
were carried out according to the typical procedure given
in Section 4.3.1. Data are reported as: 1a) chiral Mg-amide
base, 1b) deprotonation reaction solvent, 1c) ketone 4a,
added as a solution in the reaction solvent 12 mL) over
5 min, 1d) TMSCl, 1e) HMPA, 1f) temperature, 1g) time,
1h) conversion, 1i) isolated yield, 1j) [a]D, er 1S)/1R).
4.4.2. Preparation of S)-4-tert-butyl-1-trimethylsiloxy-
1-cyclohexene, S)-5a.9a,b The following experiments
were carried out according to the typical procedure given
in Section 4.4.1; in entries 11)±17) polarimetry was used to
determine the enantiomeric ratio of each sample. Data are
reported as: 1a) chiral Mg-amide base, 1b) deprotonation
reaction solvent, 1c) TMSCl, 1d) Lewis base additive, 1e)
ketone 4a, 1f) volume of addition solvent and addition
time of 4a, 1g) temperature, 1h) overall reaction time, 1i)
conversion, 1j) isolated yield, 1k) er 1S)/1R).
11) 1a) 1R)-3, 1 mmol, 1b) ether 110 mL), 1c) 123 mg,
0.8 mmol, 1d) 0.5 mL, 4 mmol, 1e) ±, 1f) 2788C to rt, 1g)
20 h, 1h) n/a, 1i) 0%, 1j) n/a.
12) See the typical procedure given in Section 4.3.1.
13) 1a) 1R)-3, 1 mmol, 1b) ether 110 mL), 1c) 123 mg,
0.8 mmol, 1d) 0.5 mL, 4 mmol, 1e) 0.18 mL, 1 mmol, 1f)
2788C, 1g) 7 h, 1h) n/a, 1i) 22 mg, 12%, 1j) [a]Dˆ215.6
1cˆ1.1, CHCl3), 60:40.
11) 1a) 1R)-3, 1mmol, 1b) ether 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 0.18 mL, 1 mmol, 1e) 123 mg,
0.8 mmol, 1f) 1mL ether, 1h, 1g) rt, 1h) 16 h, 1i) 100%,
1j) ±, 1k) [a]Dˆ222.11 cˆ1.5, CHCl3), 63:37.
14) 1a) 1R)-3, 1 mmol, 1b) THF 110 mL), 1c) 123 mg,
0.8 mmol, 1d) 0.5 mL, 4 mmol, 1e) ±, 1f) rt, 1g) 16 h, 1h)
reaction conversion was determined as 94% by GC analysis
1see Section 4.4.1); puri®cation was carried out by gravity
column chromatography using neutral, deactivated 1grade
IV) alumina 1petrol), 1i) ±, 1j) [a]Dˆ213.9 1cˆ1.5,
CHCl3), 58:42.
12) 1a) 1R)-3, 1mmol, 1b) ether 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 0.18 mL, 1 mmol, 1e) 123 mg,
0.8 mmol, 1f) 4 mL ether, 4 h, 1g) 2788C, 1h) 8 h, 1i) 62%,
1j) ±, 1k) [a]Dˆ233.6 1cˆ1.1, CHCl3), 70:30.
13) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) ±, 1e) 123 mg, 0.8 mmol, 1f) 1mL THF, 1h,

4582
K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
1g) rt, 1h) 16 h, 1i) 97%, 1j) [a]Dˆ212.8 1cˆ1.5, CHCl3),
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i) 93%,
1j) ±, 1k) 86:14.
57.5:42.5.
14) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 0.18 mL, 1 mmol, 1e) 123 mg,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i) 96%,
1j) ±, 1k) [a]Dˆ242.4 1cˆ1.5, CHCl3), 75:25.
117) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) DMPU, 60 mL, 0.5 mmol, 1e) 124 mg,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i) 89%,
1j) ±, 1k) 90:10.
15) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 0.36 mL, 2 mmol, 1e) 123 mg,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i) 38%,
1j) ±, 1k) [a]Dˆ212.7 1cˆ1.2, CHCl3), 57.5:42.5.
118) 1a) 1R)-3, 0.5 mmol, 1b) THF 15 mL), 1c) 0.25 mL,
2 mmol, 1d) HMPA, 45 mL, 0.5 mmol, 1e) 61mg,
0.4 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 1h, 1i) 81%
11h); 80% 1after quenching at 1h), 1j) 65 mg, 72%, 1k)
88:12.
16) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 90 mL, 0.5 mmol, 1e) 123 mg,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i) 81%,
1j) ±, 1k) [a]Dˆ254.2 1cˆ1.5, CHCl3), 82:18.
119) 1a) 1R)-3, 0.5 mmol 1prepared in THF according to the
procedure given in Section 4.2.2), 1b) THF 15 mL), 1c)
0.25 mL, 2 mmol, 1d) HMPA, 45 mL, 0.25 mmol, 1e)
62 mg, 0.4 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 1h,
1i) 81% 11 h); 75% 1after quench at 1 h), 1j) 57 mg, 63%, 1k)
87:13.
17) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 18 mL, 0.1mmol, 1e) 123 mg,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i) 72%,
1j) ±, 1k) [a]Dˆ244.0 1cˆ1.4, CHCl3), 76:24.
4.4.3. Preparation of S)-4-methyl-1-trimethylsiloxy-1-
cyclohexene, S)-5b.12,22 The following experiment was
carried out according to the typical procedure given in
Section 4.4.1using chiral Mg-amide base 1 R)-3 11mmol)
in THF 110 mL), TMSCl 10.5 mL, 4 mmol), HMPA 190 mL,
0.5 mmol), and ketone 4b 198 mL, 0.8 mmol) in THF
12 mL) added over 1h. The reaction conversion was deter-
mined as 81% by GC analysis 1DB 179 fused silica capillary
column; carrier gas H2 180 kPa); 60±1908C; temperature
gradient: 458C/min; tRˆ1.9 min 14b), 2.2 min 15b)). The
resultant yellow oil was then puri®ed by gravity column
chromatography using neutral, deactivated alumina 1petrol)
to afford 5b 1100 mg, 68%) as a colourless oil. The
enantiomeric ratio was determined as 91:9 by GC analysis
{Chirasil-DEX CB capillary column; carrier gas H2
130 kPa); 608C 11min)±100 8C; temperature gradient:
1.08C/min; tRˆ24.5 min [1S)-5b], 25.1min [1 R)-5b]}. Rf
1silica: petrol/ether 9:1) 0.88; Rf 1alumina: petrol) 0.45;
nmax 1®lm): 1670 cm21; dH 1400 MHz, CDCl3): 0.19 1s,
9H, Si1CH3)3), 0.95 1d, Jˆ6.3 Hz, 3H, CH3), 1.10±2.10
1m, 7H, CH and 3£CH2), 4.82±4.83 ppm 1m, 1H,
CvCH); [a]Dˆ217.0 1cˆ0.7, CHCl3).
18) 1a) 1R)-3, 1mmol, 1b) ether 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 0.18 mL, 1 mmol, 1e) 123 mg,
0.8 mmol, 1f) 2 mL ether, 1h, 1g) 2788C, 1h) 6 h, 1i) 83%,
1j) ±, 1k) 80:20.
19) 1a) 1R)-3, 1mmol, 1b) CH 2Cl2 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 0.18 mL, 1 mmol, 1e) 126 mg,
0.82 mmol, 1f) 2 mL CH2Cl2, 1h, 1g) 2788C, 1h) 6 h, 1i)
40%, 1j) ±, 1k) 72:28.
110) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) ±, 1e) 122 mg, 0.79 mmol, 1f) 2 mL THF, 1 h,
1g) 2788C, 1h) 6 h, 1i) 33%, 1j) ±, 1k) 90:10.
111) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 0.18 mL, 1 mmol, 1e) 123 mg,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i) 94%,
1j) ±, 1k) 86:14; NB chiral amine 1R)-2 was recovered from
the reaction mixture following alumina column chromato-
graphy 190% yield).
112) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 0.36 mL, 2 mmol, 1e) 125 mg,
0.81mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i)
26%, 1j) ±, 1k) 84:16.
4.4.4. Preparation of S)-4-n-propyl-1-trimethylsiloxy-1-
cyclohexene, S)-5c. The following experiment was carried
out according to the typical procedure given in Section 4.4.1
using chiral Mg-amide base 1R)-3 11mmol) in THF
110 mL), TMSCl 10.5 mL, 4 mmol), HMPA 190 mL,
0.5 mmol), and ketone 4c 1113 mg, 0.81 mmol) in THF
12 mL) added over 1h. The reaction conversion was deter-
mined as 88% by GC analysis 1DB 179 fused silica capillary
column; carrier gas H2 180 kPa); 60±1908C; temperature
gradient: 458C/min; tRˆ2.9 min 14c), 3.1min 1 5c)). The
resultant yellow oil was then puri®ed by gravity column
chromatography using neutral, deactivated alumina 1petrol)
to afford 5c 198 mg, 58%) as a colourless oil. The enantio-
meric ratio was determined as 88:12 by GC analysis
{Chirasil-DEX CB capillary column; carrier gas H2
130 kPa); 808C 11min)±120 8C; temperature gradient:
1.38C/min; tRˆ22.8 min [1S)-5c], 23.0 min [1R)-5c]}; NB:
the major and minor isomer con®gurations for 5c were
tentatively assigned by comparison with 5a-b and 5d-e. Rf
113) See the typical procedure given in Section 4.4.1.
114) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 18 mL, 0.1mmol, 1e) 122 mg,
0.79 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i)
53%, 1j) ±, 1k) 91:9.
115) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) HMPA, 90 mL, 0.5 mmol, 1e) 123 mg,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2988C, 1h) 6 h, 1i) 80%,
1j) ±, 1k) 91:9.
116) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) DMPU, 0.12 mL, 1 mmol, 1e) 123 mg,

K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
4583
1silica: petrol/ether 9:1) 0.90; Rf 1alumina: petrol) 0.47; nmax
1®lm): 1670 cm21; dH 1400 MHz, CDCl3): 0.18 1s, 9H,
Si1CH3)3), 0.89 1t, Jˆ7.1, 3H, CH3), 1.21±1.73 1m, 9H,
CH and 4£CH2), 1.99±2.11 1m, 2H, CH2), 4.82±4.85 ppm
1m, 1H, CvCH); dc 1100 MHz, CDCl3): 0.5, 14.6, 20.5,
29.5, 29.9, 30.6, 33.3, 38.5, 103.8, 150.5 ppm; HRMS
1CH2Cl2) m/z calcd for C12H24OSi 1M1): 212.1596.
Found: 212.1604; [a]Dˆ235.2 1cˆ1.2, CHCl3).
determined as 50:50 by GC analysis {Chirasil-DEX CB
capillary column; carrier gas H2 140 kPa); 708C 11min)±
1108C; temperature gradient: 1.38C/min; tRˆ14.8 and
15.0 min [1S,S)- and 1R,R)-trans-6]}.
The cis- and trans-isomers of 2,6-dimethylcyclohexanone 6
were separated using ¯ash silica column chromatography
1petrol/ether 9:1). This afforded each isomer as a clear
liquid. cis-6:23 Rf 0.30; nmax 1®lm): 1715 cm21; dH
1400 MHz, CDCl3): 0.99 1d, Jˆ6.5 Hz, 6H, 2£CH3),
1.28±1.39 1m, 2H, CH2), 1.70±1.83 1m, 2H, CH2), 2.06±
2.12 1m, 2H, CH2), 2.34±2.42 ppm 1m, 2H, 2£CH); trans-
6:23 Rf 0.25; nmax 1®lm): 1715 cm21; dH 1400 MHz, CDCl3):
1.06 1d, Jˆ7.0 Hz, 6H, 2£CH3), 1.49±1.58 1m, 2H, CH2),
1.70±1.76 1m, 2H, CH2), 1.87±1.95 1m, 2H, CH2), 2.50±
2.59 ppm 1m, 2H, 2£CH).
4.4.5. Preparation of S)-4-phenyl-1-trimethylsiloxy-1-
cyclohexene, S)-5d.12,22 The following experiment was
carried out according to the typical procedure given in
Section 4.4.1using chiral Mg-amide base 1 R)-3 11mmol)
in THF 110 mL), TMSCl 10.5 mL, 4 mmol), HMPA 190 mL,
0.5 mmol), and ketone 4d 1138 mg, 0.79 mmol) in THF
12 mL) added over 1h. The reaction conversion was deter-
mined as 79% by GC analysis 1DB 179 fused silica capillary
column; carrier gas H2 180 kPa); 60±1908C; temperature
gradient: 458C/min; tRˆ5.1min 1 4d), 5.3 min 15d)). The
resultant yellow oil was then puri®ed by gravity column
chromatography using neutral, deactivated alumina 1petrol)
to afford 5d 194 mg, 48%) as a colourless oil. The enantio-
meric ratio was determined as 87:13 by GC analysis
{Chirasil-DEX CB capillary column; carrier gas H2
140 kPa); 1108C 11min)±150 8C; temperature gradient:
1.88C/min; tRˆ20.5 min [1S)-5d], 20.8 min [1R)-5d]}. Rf
1silica: petrol/ether 9:1) 0.88; Rf 1alumina: petrol) 0.44;
nmax 1®lm): 1670 cm21; dH 1400 MHz, CDCl3): 0.25 1s,
9H, Si1CH3)3), 1.98±2.32 1m, 6H, 3£CH2), 2.75±2.89 1m,
1H, PhCH), 4.98±5.00 1m, 1H, CvCH), 7.23±7.36 ppm
1m, 5H, ArH); [a]Dˆ233.5 1cˆ2.3, CHCl3).
The following experiments were carried out according to the
typical procedure given in Section 4.4.1, with the exception
that in some instances the base was prepared in THF by the
procedure given in Section 4.2.2. Data are reported as: 1a)
chiral Mg-amide base 1prepared by the procedure given in
Section 4.2.1or 4.2.2), 1b) deprotonation reaction solvent,
1c) TMSCl, 1d) HMPA, 1e) ketone 6, 1f) volume of addition
solvent and addition time of 6, 1g) temperature, 1h) overall
reaction time, 1i) conversion, 1j) isolated yield following ¯ash
silica column chromatography 1petrol/ether 9:1), 1k) er 1R):1S).
11) 1a) 1R)-3, 1 mmol 1Section 4.2.1), 1b) THF 110 mL), 1c)
0.5 mL, 4 mmol, 1d) 90 ml, 0.5 mmol, 1e) cis/trans-6,
0.11 mL, 0.8 mmol, 1f) 2 mL THF, 1 h, 1g) 2788C, 1h)
6 h, 1i) reaction conversion was determined as 27% by GC
analysis 1DB 179 fused silica capillary column; carrier gas
H2 180 kPa); 60±1908C; temperature gradient: 108C/min;
tRˆ1.9 min 1cis-6), 2.1min 1 trans-6), 2.4 min 17)); NB:
unreacted ketone 6 showed a 78:22 cis/trans ratio, 1j) ±,
1k) enantiomeric ratio was determined as 88:12 by GC
analysis {Chirasil-DEX CB capillary column; carrier gas
H2 140 kPa); 708C 11 min)±1108C; temperature gradient:
1.38C/min; tRˆ13.1 min 1cis-6), 14.8 min and 15.0 min
[1S,S)- and 1R,R)-trans-6], 17.3 min [1R)-7], 17.9 min [1S)-
7]}; NB: unreacted trans-6 exhibited a 57:43 er in favour of
the 1R,R)-isomer.15 Rf 1silica: petrol/ether 9:1) 0.91; Rf
4.4.6. Preparation of S)-4-iso-propyl-1-trimethylsiloxy-
1-cyclohexene, S)-5e.12,22 The following experiment was
carried out according to the typical procedure given in
Section 4.4.1using chiral Mg-amide base 1 R)-3 11mmol)
in THF 110 mL), TMSCl 10.5 mL, 4 mmol), HMPA 190 mL,
0.5 mmol), and ketone 4e 1113 mg, 0.81 mmol) in THF
12 mL) added over 1h. The reaction conversion was deter-
mined as 77% by GC analysis 1DB 179 fused silica capillary
column; carrier gas H2 180 kPa); 60±1908C; temperature
gradient: 458C/min; tRˆ2.9 min 14e), 3.1min 1 5e)). The
resultant yellow oil was then puri®ed by gravity column
chromatography using neutral, deactivated alumina 1petrol)
to afford 5e 133 mg, 39%) as a colourless oil. The enantio-
meric ratio was determined as 95:5 by GC analysis
{Chirasil-DEX CB capillary column; carrier gas H2
140 kPa); 808C 11min)±120 8C; temperature gradient:
1.38C/min; tRˆ24.3 min [1S)-5e], 24.8 min [1R)-5e]}. Rf
1silica: petrol/ether 9:1) 0.90; Rf 1alumina: petrol) 0.46;
nmax 1®lm): 1670 cm21; dH 1400 MHz, CDCl3): 0.19 1s,
9H, Si1CH3)3), 0.88 1d, Jˆ6.7 Hz, 3H, CH3), 0.89 1d,
Jˆ6.7 Hz, 3H, CH3), 1.20±1.34 1m, 4H, 2£CH2), 1.47±
1.52 1m, 1H, CH), 1.75±1.80 1m, 1H, CH), 2.00±2.08 1m,
2H, CH2), 4.84±4.86 ppm 1m, 1H, CvCH); [a]Dˆ249.0
1cˆ1.5, CHCl3).
1alumina: petrol) 0.50; nmax 1®lm): 1683 cm21
; dH
1400 MHz, CDCl3): 0.18 1s, 9H, Si1CH3)3), 1.04 1d,
Jˆ6.9 Hz, 3H, CHCH3), 1.33±1.49 1m, 3H, CH and CH2),
1.56 1s, 3H, CvCCH3), 1.59±1.64 1m, 1H, CH), 1.75±1.80
1m, 1H, CH), 1.93±1.96 1m, 1H, CH), 2.10±2.14 ppm 1m,
1H, CH); [a]Dˆ114.3 1cˆ2.2, CHCl3).
12) 1a) 1R)-3, 1 mmol 1Section 4.2.1), 1b) THF 110 mL), 1c)
0.5 mL, 4 mmol, 1d) 90 ml, 0.5 mmol, 1e) cis/trans-6,
0.11 mL, 0.8 mmol, 1f) 2 mL THF, 1 h, 1g) 2788C, 1h)
65 h, 1i) 71%; NB: unreacted ketone 6 showed a 72:28
cis/trans ratio, 1j) ±, 1k) 88:12; NB: unreacted trans-6
exhibited a 74:26 er in favour of the 1R,R)-isomer.15
4.4.7. Preparation of R)-2,6-dimethyl-1-trimethylsiloxy-
1-cyclohexene, R)-7.9a,13b,14 The ratio of cis-6/trans-6 was
determined as 82:18 using GC analysis 1DB 179 fused silica
capillary column; carrier gas H2 180 kPa); 60±1908C;
temperature gradient: 108C/min; tRˆ1.9 min 1cis-6),
2.1min 1 trans-6)); the enantiomeric ratio of trans-6 was
13) 1a) 1R)-3 1mmol 1Section 4.2.2), 1b) THF 110 mL), 1c)
0.5 mL, 4 mmol, 1d) 90 ml, 0.5 mmol, 1e) cis-6, 0.11 mL,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 40 h, 1i)
54%, 1j) 83 mg, 53%, 1k) 97:3.
14) 1a) 1R)-3, 1mmol 1Section 4.2.2), 1b) THF 110 mL), 1c)

4584
K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
0.5 mL, 4 mmol, 1d) 90 ml, 0.5 mmol, 1e) cis-6, 0.11 mL,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i) 25%,
1j) 41mg, 25%, 1k) 97:3.
dH 1400 MHz, CDCl3): 20.29 1s, 9H, Si1CH3)3), 1.59±1.65
1m, 1H, CH), 1.70±1.80 1m, 2H, CH2), 2.07±2.14 1m, 1H,
CH), 2.39±2.45 1m, 1H, CH), 2.51±2.57 1m, 1H, CH),
3.44±3.50 1m, 1H, PhCH), 7.17±7.44 ppm 1m, 10H, ArH);
[a]Dˆ15.11 cˆ1.6, CHCl3).
15) 1a) 1R)-3, 1mmol 1Section 4.2.2), 1b) THF 110 mL), 1c)
0.5 mL, 4 mmol, 1d) 90 ml, 0.5 mmol, 1e) cis-6, 0.11 mL,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2608C, 1h) 6 h, 1i) 67%,
1j) 85 mg, 54%, 1k) 94:6.
12) 1a) 1R)-3, 0.5 mmol, 1b) THF 15 mL), 1c) 0.25 mL,
2 mmol, 1d) 45 ml, 0.25 mmol, 1e) recrystallised cis-8,
98 mg, 0.39 mmol, 1f) 2 mL THF, 1h, 1g) 2408C, 1h) 8 h,
1i) 108 mg, 86%, 1j) 82:18.
16) 1a) 1R)-3, 1mmol 1Section 4.2.2), 1b) THF 110 mL), 1c)
0.5 mL, 4 mmol, 1d) 90 ml, 0.5 mmol, 1e) cis-6, 0.11 mL,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2408C, 1h) 6 h, 1i) 99%,
1j) 147 mg, 92%, 1k) 93:7.
13) 1a) 1R)-3, 0.5 mmol, 1b) THF 15 mL), 1c) 0.25 mL,
2 mmol, 1d) 45 ml, 0.25 mmol, 1e) recrystallised cis-8,
104 mg, 0.42 mmol, 1f) 2 mL THF, 1 h, 1g) 2608C, 1h)
24 h, 1i) 52 mg, 39%, 1j) 87:13.
4.4.8. Preparation of S)-2,6-dimethyl-1-trimethylsiloxy-
1-cyclohexene, S)-7.9a,13b,14 The following experiment was
carried out according to the typical procedure given in
Section 4.4.1, with the exception that the base was prepared
in THF by the procedure given in Section 4.2.2. Data are
reported as: 1a) chiral Mg-amide base, 1b) deprotonation
reaction solvent, 1c) TMSCl, 1d) HMPA, 1e) ketone 6, 1f)
volume of addition solvent and addition time of 6, 1g)
temperature, 1h) overall reaction time, 1i) 7, isolated yield,
er 1S)/1R), 1j) recovered 6, isolated yield, er 1R,R)/1S,S); NB:
isolated yields were obtained following ¯ash silica column
chromatography 1petrol/ether 9:1); for GC conditions and
analysis, see above.
4.4.10. Preparation of S)-2,6-di-iso-propyl-1-trimethyl-
siloxy-1-cyclohexene, S)-13. The following experiments
were carried out according to the typical procedure given
in Section 4.4.1, with the exception that the base was
prepared in THF by the procedure given in Section 4.2.2.
Data are reported as: 1a) chiral Mg-amide base, 1b) depro-
tonation reaction solvent, 1c) TMSCl, 1d) HMPA, 1e) ketone
12, 1f) volume of addition solvent and addition time of 12,
1g) temperature, 1h) overall reaction time, 1i) conversion, 1j)
isolated yield following ¯ash silica column chromatography
1petrol), 1k) er 1S)/1R).
11) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) 90 ml, 0.5 mmol, 1e) trans-6, 88 mg,
0.7 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 65 h, 1i)
74 mg, 53%; 72:28, [a]Dˆ29.7 1cˆ1.8, CHCl3), 1j) 5 mg,
6%; 77:23, [a]Dˆ259.2 1cˆ0.1, MeOH).15
11) 1a) 1R)-3, 0.5 mmol, 1b) THF 15 mL), 1c) 0.25 mL,
2 mmol, 1d) 45 ml, 0.25 mmol, 1e) cis-12, 85 ml,
0.4 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 39 h, 1i) reac-
tion conversion was determined as 54% by GC analysis 1DB
179 fused silica capillary column; carrier gas H2 180 kPa);
458C 11min)±150 8C; temperature gradient: 58C/min;
tRˆ16.0 min 1cis-12), 16.4 min 113)), 1j) 35 mg, 34%, 1k)
enantiomeric ratio was determined as .99.5:0.5 by GC
analysis 1sample concentration 1mg/mL) {Chirasil-DEX
CB capillary column; carrier gas H2 140 kPa); 758C
4.4.9. Preparation of S)-2,6-diphenyl-1-trimethylsiloxy-
1-cyclohexene, S)-9.24 2,6-Diphenylcyclohexanone 8 was
puri®ed using ¯ash silica column chromatography 1petrol/
ether 20:1). This afforded cis-8 as a white solid which was
further puri®ed by recrystallisation using hexane. Cis-8:25 Rf
0.34; nmax 1CH2Cl2): 1715 cm21; dH 1400 MHz, CDCl3):
1.99±2.19 1m, 4H, 2£CH2), 2.38±2.42 1m, 2H, CH2),
3.78±3.82 1m, 2H, 2£CH), 7.15±7.33 ppm 1m, 10H,
ArH); dC 1100 MHz, CDCl3): 26.5 1d), 37.8 1d), 58.4 1u),
127.3 1u), 128.6 1u), 129.2 1u), 138.9 1d), 208.5 ppm 1d): mp
121±1228C 1lit. mp25 1248C).
11 min)±1158C;
temperature
gradient:
1.38C/min;
tRˆ26.4 min 1S)-13, 26.9 min 1R)-13}.13 1Found: C, 70.80;
H, 12.03%. C15H30OSi requires C, 70.80; H, 11.88%) Rf
;
1silica; petrol): 0.64; nmax 1®lm): 1664 cm21
dH
1400 MHz, CDCl3): 0.17 1s, 9H, Si1CH3)3), 0.74
1d, Jˆ6.8 Hz, 3H, CvCCH1CH3)2), 0.89 1t, Jˆ7.3 Hz,
6H, CHCH1CH3)2), 0.90 1d, Jˆ6.9 Hz, 3H, CvCCH1CH3)2),
1.27±1.36 1m, 2H, CH2), 1.60±1.70 1m, 2H, CH2), 1.80±
2.02 1m, 3H, CH and CH2), 2.15±2.22 1m, 1H, CH), 3.00±
3.07 ppm 1septet, Jˆ6.9 Hz, 1H, CvCCH1CH3)2); dc
1100 MHz, CDCl3): 0.8 1u), 16.9 1u), 20.4 1u), 20.9 1u),
21.3 1u), 22.3 1d), 22.4 1d), 23.4 1d), 26.5 1u), 28.2 1u),
45.0 1u), 123.8 1d), 143.9 ppm 1d); HRMS 1CH2Cl2) m/z
Calc. for C15H30OSi 1M1): 255.2144. Found: 255.2143;
[a]Dˆ24.11 cˆ1.4, CHCl3).
The following experiments were carried out according to
typical procedure in Section 4.4.1. Data are reported as:
1a) chiral Mg-amide base, 1b) deprotonation reaction
solvent, 1c) TMSCl, 1d) HMPA, 1e) cis-ketone 8, 1f) volume
of addition solvent and addition time of cis-8, 1g) tempera-
ture, 1h) overall reaction time, 1i) isolated yield following
gravity column chromatography using neutral, deactivated
alumina 1petrol), 1j) enantiomeric ratio, determined using
HPLC and reported as 1S)/1R) {Chirasil OD-H column; l
1254 nm); eluant: 0.5% i-PrOH in heptane; 0.2 mL/min;
tRˆ22.7 min [1S)-9], 25.0 min [1R)-9]}.13
12) 1a) 1R)-3, 0.5 mmol, 1b) THF 15 mL), 1c) 0.25 mL,
2 mmol, 1d) 45 ml, 0.25 mmol, 1e) cis-12, 82 ml,
0.4 mmol, 1f) 2 mL THF, 1h, 1g) 2788C, 1h) 6 h, 1i) 9%,
1j) 5 mg, 5%, 1k) 99.7:0.3 1sample concentration 10 mg/
mL).
11) 1a) 1R)-3, 0.5 mmol, 1b) THF 15 mL), 1c) 0.25 mL,
2 mmol, 1d) 45 ml, 0.25 mmol, 1e) recrystallised cis-8,
105 mg, 0.42 mmol, 1f) 2 mL THF, 1 h, 1g) 2208C, 1h)
8 h, 1i) 111 mg, 83%, 1j) 79:21. Rf 1silica: petrol/ether 9:1)
13) 1a) 1R)-3, 0.5 mmol, 1b) THF 15 mL), 1c) 0.25 mL,
2 mmol, 1d) 45 ml, 0.25 mmol, 1e) cis-12, 82 ml,
0.4 mmol, 1f) 2 mL THF, 1h, 1g) 2608C, 1h) 6 h, 1i) 66%,
0.91; Rf 1alumina: petrol) 0.41; nmax 1CHCl3): 1645 cm21
;

K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
4585
1j) 57 mg, 56%, 1k) 99.4:0.6 1sample concentration 10 mg/
mL).
was added and an aliquot of the resultant solution again
removed after both 30 min and 5 days. H NMR spectro-
1
scopy revealed no increase in Mg-enolate formation 118 and
19%, respectively). dH 1400 MHz, C4D8O): 0.92 1s, br,
C1CH3)3 for Mg-enolate and 4a), 4.82±4.87 ppm 1m,
CvCH for Mg-enolate).
14) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) 90 ml, 0.25 mmol, 1e) cis-12,
0.8 mmol, 1f) 2 mL THF, 1h, 1g) 2408C, 1h) 6 h, 1i) 99%,
1j) 184 mg, 90%, 1k) 98.8:1.2 1sample concentration 10 mg/
mL).
1 6m4l,
1ii) To a solution of chiral Mg-amide base 1R)-3 10.5 mmol,
prepared by the procedure given in Section 4.2.1) in THF-d8
12 mL) at room temperature, was added 4-tert-butylcyclo-
hexanone 4a 162 mg, 0.4 mmol) as a solution in THF-d8
10.5 mL). An aliquot of the resultant mixture was then
removed via cannula after 16 h, 1H NMR spectroscopy indi-
cating 23% formation of the Mg-enolate intermediate.
HMPA 190 ml, 0.5 mmol) was then added, and an aliquot
15) 1a) 1R)-3, 0.5 mmol, 1b) THF 15 mL), 1c) 0.25 mL,
2 mmol, 1d) 45 ml, 0.25 mmol, 1e) cis-12, 78 mg,
0.43 mmol, 1f) 2 mL THF, 1h, 1g) rt, 1h) 2 h, 1i) 100%, 1j)
104 mg, 95%, 1k) 91:9 1sample concentration 1 mg/mL).
4.4.11. Preparation of R)-2,6-di-iso-propyl-1-trimethyl-
siloxy-1-cyclohexene, R)-13. The following experiments
were carried out according to the typical procedure given
in Section 4.4.1, with the exception that the base was
prepared in THF by the procedure given in Section 4.2.2.
Data are reported as 1a) chiral Mg-amide base, 1b) deproto-
nation reaction solvent, 1c) TMSCl, 1d) HMPA, 1e) ketone
12, 1f) volume of addition solvent and addition time of 12,
1g) temperature, 1h) overall reaction time, 1i) conversion, 1j)
13, isolated yield, er 1R)/1S),13 1k) recovered 12, isolated
yield, er 1S,S)/1R,R); NB: isolated yields were obtained
following ¯ash silica column chromatography 1petrol).
1
of the reactant solution again removed after 30 min. H
NMR spectroscopy revealed no increase in the Mg-enolate
concentration 123%). TMSCl 10.25 mL, 2 mmol) was added
and the resultant mixture was then stirred at room tempera-
ture for 16 h. 1H NMR spectroscopy revealed a 58% conver-
sion of ketone 6a to silyl enol ether 7a. dH 1400 MHz,
C4D8O): 0.83 1s, C1CH3)3), 4.74±4.75 ppm 1m, CvCH).
4.6. Preparation of 2,6-di-iso-propylcyclohexanol, 1117
A 50 mL autoclave vessel was charged with aqueous Raney
nickel 1440 mg), followed by 2,6-di-iso-propylphenol 10
13.7 mL, 20 mmol). The vessel was placed under H2 pres-
sure 196 atm), and heated to 1048C over a period of 4 h.
During this time, the pressure inside the autoclave vessel
was increased to 108 atm. Reaction was continued at 1048C
and 108 atm for a total of 39 h, before the heat was discon-
tinued. Once the vessel had cooled to room temperature the
remaining H2 gas was blown off and the vessel opened to
allow ®ltration of the reactant mixture through a pad of
kieselguhr 1eluant: EtOH/EtOAc). The resulting solution
was dried 1Na2SO4) and the solvent was removed in vacuo
to afford the desired product 11 13.59 g, 97%) as a mixture
of isomers. Rf 1silica: petrol/ether 9:1) 0.41 and 0.32; nmax
1®lm): 3406 cm21; dH 1400 MHz, CDCl3): 0.80±0.96 1m,
12H, 4£CH3), 1.10±1.26 1m, 4H, 2£CH2), 1.52±1.63 1m,
3H, CH and CH2), 1.70±1.78 1m, 1H, CH), 2.18±2.22
1m, 1H, CH), 3.18±3.19 1m, 1H, CH), 3.67±3.72 1m, 1H,
CH), 4.07±4.10 ppm 1m, 1H, OH).
11) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) 90 ml, 0.5 mmol, 1e) trans-12, 134 mg,
0.74 mmol, 1f) 2 mL THF, 1h, 1g) 2408C, 1h) 67 h, 1i)
reaction conversion was determined as 66% by GC analysis
1CP SIL 19CB fused silica capillary column; carrier gas
H2 180 kPa); 458C 11min)±190 8C; temperature gradient:
108C/min; tRˆ13.6 min 1trans-12), 14.0 min 113)),
1j) 93 mg, 49%, enantiomeric ratio was determined as
81:19 by GC analysis, [a]Dˆ11.8 1cˆ1.4, CHCl3), 1k)
43 mg, 32%, enantiomeric ratio was determined as 94:6
by GC analysis {Chirasil-DEX CB capillary column; carrier
gas H2 140 kPa); 758C 11min)±115 8C; temperature gradi-
ent: 1.38C/min; tRˆ26.6 min 1S,S)-12, 27.7 min 1R,R)-12},
[a]Dˆ273.3 1cˆ1.2, MeOH).
12) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) 90 ml, 0.5 mmol, 1e) trans-12, 150 mg,
0.82 mmol, 1f) 2 mL THF, 1h, 1g) 0 8C, 1h) 100 min,
1i) 59%, 1j) 100 mg, 48%, 76:24, 1k) 58 mg, 39%, 80:20.
4.7. Preparation of Dess±Martin periodinane26;27
To a solution of Oxonew 1353 g, 0.57 mol) in H2O 11.3 L),
was added 2-iodobenzoic acid 1100 g, 0.40 mol). The reac-
tion was warmed to 708C over 50 min and then mechani-
cally stirred at this temperature for 3 h, during which time
the initially thick slurry became a ®nely dispersed suspen-
sion. This suspension was then cooled to 08C for 2 h with
very slow stirring. The resulting precipitate was ®ltered,
washed with H2O 15£200 mL), acetone 12£100 mL), and
ether 12£100 mL) to afford a white, crystalline solid, 1-hy-
droxy-1,2-benziodoxol-311H)-one-1-oxide 1IBX) 1101 g,
89%). This solid was then suspended in acetic anhydride
1400 mL), and p-toluenesulfonic acid 10.75 g, 4.8 mmol)
was added. The ¯ask was then equipped with a drying
tube, and the reaction was stirred at 808C for 2 h whereupon
partial dissolution was observed. The resulting suspension
was then cooled to 08C for 4 h, ®ltered, and rinsed with
13) 1a) 1R)-3, 1mmol, 1b) THF 110 mL), 1c) 0.5 mL,
4 mmol, 1d) 90 ml, 0.5 mmol, 1e) trans-12, 146 mg,
0.80 mmol, 1f) 2 mL THF, 1h, 1g) 0 8C, 1h) 19 h, 1i) 98%,
1j) 181 mg, 89%, 53:47, 1k) 4 mg, 2%, 99:1.
1
4.5. H NMR spectroscopic study
1i) To a solution of chiral Mg-amide base 1R)-3 10.5 mmol,
prepared by the procedure given in Section 4.2.1) in THF-d8
12 mL) at room temperature, was added 4-tert-butylcyclo-
hexanone 4a 162 mg, 0.4 mmol) as a solution in THF-d8
10.5 mL). An aliquot of the resultant mixture was then
removed via cannula into a N2 ®lled NMR spectroscopy
1
tube, after both 30 min and 16 h. H NMR spectroscopy
indicated 22% formation of the intermediate Mg-enolate
in both cases. Subsequently, HMPA 190 ml, 0.5 mmol)

4586
K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
anhydrous ether 15£50 mL) to afford the Dess±Martin
periodinane as a white crystalline solid which was dried
under vacuum for 6 h 1134 g, 88%). dH 1400 MHz,
CDCl3): 1.91 1s, 9H, 3£CH3), 7.82±7.86 1m, 1H, ArH),
8.00±8.04 1m, 2H, ArH), 8.13±8.16 ppm 1m, 1H, ArH);
mp 1338C 1lit. mp18 124±1268C).
References
1. For review articles, see: O'Brien, P. J. Chem. Soc., Perkin
Trans. 1 2001, 95. O'Brien, P. J. Chem. Soc., Perkin Trans.
1 1998, 1439. Simpkins, N. S. Pure Appl. Chem. 1996, 68,
691. Koga, K. Pure Appl. Chem. 1994, 66, 1487. Cox, P. J.;
Simpkins, N. S. Tetrahedron: Asymmetry 1991, 2, 1 . Simpkins,
N. S. Chem. Soc. Rev. 1990, 19, 335. See also: Jones, S. J. Chem.
Soc., Perkin Trans. 1 2002, 1 .
4.8. Preparation of 2,6-di-iso-propylcyclohexanone, 12
2. Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki, K. J.
Am. Chem. Soc. 1979, 101, 1455. Baggett, N.; Simmonds, R. J.
J. Chem. Soc., Perkin Trans. 1 1982, 197. Nakajima, M.;
Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 9751. Weber,
B.; Seebach, D. Tetrahedron 1994, 50, 6117 and references
cited therein. See also: Bunnage, M. E.; Davies, S. G.;
Goodwin, C. J.; Walters, I. A. S. Tetrahedron: Asymmetry
1994, 5, 35.
A solution of Dess±Martin periodinane 1891mg, 2.2 mmol)
in CH2Cl2 110 mL) was added to a solution of alcohol 11
1368 mg, 2 mmol) in CH2Cl2 18 mL). The initially yellow
solution turned cloudy upon stirring at room temperature for
1h, after which time the reaction was diluted with ether
150 mL) and the resulting suspension hydrolysed with
1.3 M NaOH solution 120 mL). After stirring for 10 min,
the ether layer was extracted with NaOH 120 mL), washed
with H2O 125 mL), and dried 1Na2SO4), before the solvent
was removed in vacuo. This afforded ketone 12 as a crude
yellow oil 1358 mg, 98%).
3. Bolm, C.; Beckmann, O.; Cosp, A.; Palazzi, C. Synlett 2001,
1461. 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, 41 0.
Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am
Chem. Soc. 1999, 121, 7559. Ichiyanagi, T.; Shimizu, M.;
Fujisawa, T. J. Org. Chem. 1997, 62, 7937. Takacs, J. M.;
Lawson, E. C.; Reno, M. J.; Youngman, M. A.; Quincy,
D. A. Tetrahedron: Asymmetry 1997, 8, 3073. Desimoni, G.;
Faita, G.; Righetti, P. P. Tetrahedron Lett. 1996, 37, 3027.
OrdonÄez, M.; Guerrero-de la Rosa, V.; Labastida, V.; Llera,
J. M. Tetrahedron: Asymmetry 1996, 7, 2675. Fujisawa, T.;
Ichiyanagi, T.; Shimizu, M. Tetrahedron Lett. 1995, 36, 5031.
Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807.
Gothelf, K. V.; Jùrgensen, K. A. Chem. Commun. 2000, 1449.
Yamamoto, H.; Watanabe, S.; Kadotani, K.; Hasegawa, M.;
Noguchi, M.; Kanemasa, S. Tetrahedron Lett. 2000, 41, 3131.
Crosignani, S.; Desimoni, G.; Faita, G.; Filippone, S.;
Mortoni, A.; Righetti, P.; Zema, M. Tetrahedron Lett. 1999,
40, 7007. Desimoni, G.; Faita, G.; Mortoni, A.; Righetti, P.
Tetrahedron Lett. 1999, 40, 2001. Gothelf, K. V.; Hazell,
R. G.; Jùrgensen, K. A. J. Org. Chem. 1998, 63, 5483. Gothelf,
K. V.; Hazell, R. G.; Jùrgensen, K. A. J. Org. Chem. 1996, 61,
346. Corey, E. J.; Li, W.; Reichard, G. A. J. Am. Chem. Soc.
1998, 120, 2330. Corey, E. J.; Wang, Z. Tetrahedron Lett.
1993, 34, 4001. Noyori, R.; Suga, S.; Kawai, K.; Okada, S.;
Kitamura, M. Pure Appl. Chem. 1988, 60, 1597.
The ratio of cis-12/trans-12 was determined as 82:18 using
GC analysis 1DB 179 fused silica capillary column; carrier
gas H2 180 kPa); 458C 11min)±190 8C; temperature gradi-
ent: 208C/min; tRˆ7.0 min 1cis-12), 7.3 min 1trans-12)); the
enantiomeric ratio of trans-12 was determined as 50:50 by
GC analysis {Chirasil-DEX CB capillary column; carrier
gas H2 140 kPa); 758C 11 min)±1158C; temperature gradi-
ent: 1.38C/min; tRˆ26.6 min 1S,S)-12, 27.7 min 1R,R)-12}.
Flash silica column chromatography 1petrol/ether 20:1)
afforded cis-2,6-di-iso-propylcyclohexanone, cis-12, and
trans-2,6-di-iso-propylcyclohexanone, trans-12, as yellow
oils.
cis-12: 1Found: C, 78.88; H, 12.17%. C12H22O requires C,
79.06; H, 12.16%) Rf 0.31; nmax 1®lm): 1715 cm21; dH
1400 MHz, CDCl3): 0.83 1d, Jˆ6.7 Hz, 6H, 2£CH3), 0.87
1d, Jˆ6.5 Hz, 3H, 2£CH3), 1.26±1.36 1m, 2H, CH2), 1.59±
1.70 1m, 1H, CH), 1.88±1.94 1m, 1H, CH), 2.03±2.14 ppm
1m, 6H, 2£CH and 2£CH2); dc 1100 MHz, CDCl3): 19.4 1u),
22.0 1u), 26.3 1d), 26.7 1u), 31.7 1d), 58.5 1u), 214.4 ppm 1d);
HRMS 1CH2Cl2) m/z Calc. for C12H22O 1M1): 183.1749.
Found: 183.1752.
4. 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. Henderson, K. W.; Allan, J. F.; Kennedy, A. R. Chem.
Commun. 1997, 1149. Westerhausen, M. Inorg. Chem. 1991,
30, 96.
trans-12: 1Found: C, 78.86; H, 12.38%. C12H22O requires C,
79.06; H, 12.16%) Rf 1petrol/ether 20:1) 0.22; nmax 1®lm):
1715 cm21; dH 1400 MHz, CDCl3): 0.85 1d, Jˆ6.3 Hz, 6H,
2£CH3), 0.90 1d, Jˆ6.4 Hz, 6H, 2£CH3), 1.66±1.72 1m, 4H,
2£CH2), 1.83±1.90 1m, 2H, CH2), 2.01±2.10 ppm 1m, 4H,
4£CH); dc 1100 MHz, CDCl3): 19.9 1u), 21.2 1d), 21.3 1u),
5. Allan, J. F.; Henderson, K. W.; Kennedy, A. R. Chem.
Commun. 1999, 1325.
Á
6. Lessene, G.; Tripoli, R.; Cazeau, P.; Biran, C.; Bordeau, M.
27.11u), 30.7 1d), 56.9 1u), 216.7 ppm 1d); HRMS 1CH Cl2)
2
m/z Calc. for C12H22O 1M1): 183.1749. Found: 183.1751.
Tetrahedron Lett. 1999, 40, 4037. Allan, J. F.; Clegg, W.;
Henderson, K. W.; Horsburgh, L.; Kennedy, A. R. J. Organo-
met. Chem. 1998, 559, 173. Bonafaux, D.; Bordeau, M.; Biran,
Acknowledgements
Á
C.; Dunogues, J. Synth. Commun. 1998, 28, 93. Kondo, Y.;
We thank The Carnegie Trust for the Universities of
Scotland for a postgraduate studentship 1J. H. M.) and The
Royal Society for a University Research Fellowship 1K. W.
H.). We also thank P®zer Global Research and Develop-
ment, Sandwich for generous funding of our research
endeavours and the EPSRC Mass Spectrometry Service,
University of Wales, Swansea, for analyses.
Yoshida, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
1996, 2331. Bonafoux, D.; Bordeau, M.; Biran, C.; Cazeau,
Á
P.; Dunogues, J. J. Org. Chem. 1996, 61, 5532. 1f) Bonafoux,
Á
D.; Bordeau, M.; Biran, C.; Dunogues, J. J. Organomet. Chem.
1995, 493, 27. Eaton, P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem.
Soc. 1989, 111, 8016. For a recent review see: Henderson, K. W.;
Kerr, W. J. Chem. Eur. J. 2001, 7, 3430.

K. W. Henderson et al. / Tetrahedron 58 +2002) 4573±4587
4587
7. For preliminary communication of part of this work, see:
Henderson, K. W.; Kerr, W. J.; Moir, J. H. Chem. Commun.
2000, 479. Henderson, K. W.; Kerr, W. J.; Moir, J. H. Synlett
2001, 1253.
co-workers: 1a) Aoki, K.; Tomioka, K.; Noguchi, H.; Koga,
K. Tetrahedron Lett. 1993, 34, 5105. 1b) Kim, H.; Shirai, R.;
Kawasaki, H.; Nakajima, M.; Koga, K. Heterocycles 1990, 30,
307. For 5c, 9, and 13 the major and minor isomer
con®gurations were tentatively assigned by comparison with
5a/b/d/e and 7.
8. Armstrong, D.; Henderson, K. W.; Kennedy, A. R.; Kerr,
W. J.; Mair, F. S.; Moir, J. H.; Moran, P. H.; Snaith, R. J.
Chem. Soc., Dalton Trans. 1999, 4063.
14. Simpkins, N. S. J. Chem. Soc., Chem. Commun. 1986, 88.
15. The returned ketone trans-6 displayed a negative optical rota-
tion completely equivalent to and in accord with previously
reported data: Fauvre, A.; Renard, M. F.; 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.
9. In the initial experiments, optical rotation measurements were
used to ascertain the enantiomeric composition of the silyl
enol ether 5a. Simpkins and Koga have disagreed on the maxi-
mum value for the optical rotation of enantiomerically pure
5a, in this study the maximum value as calculated by Simpkins
was used to correlate our results. See: 1a) Cain, C. M.;
Cousins, R. P. C.; Coumbarides, G.; Simpkins, N. S. Tetra-
hedron 1990, 46, 523. Cousins, R. P. C.; Simpkins, N. S.
Tetrahedron Lett. 1989, 30, 7241. Shirai, R.; Tanaka, M.;
Koga, K. J. Am. Chem. Soc. 1986, 108, 543. Aoki, K.;
Nakajima, M.; Tomioka, K.; Koga, K. Chem. Pharm. Bull.
1993, 41, 994.
16. Bambridge, K.; Clark, B. P.; Simpkins, N. S. J. Chem. Soc.,
Perkin Trans. 1 1995, 2535. Kim, H.; Kawasaki, H.;
Nakajima, M.; Koga, K. Tetrahedron Lett. 1989, 30, 6537.
Eleveld, M. B.; Hogeveen, H. Tetrahedron Lett. 1986, 27, 631.
17. Cof®eld, T. H.; Filbey, A. H.; Ecke, G. G.; Kolka, A. J. J. Am.
Chem. Soc. 1957, 79, 5019.
18. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
19. Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41,
1879.
10. Bunn, B. J.; Simpkins, N. S.; Spavold, Z.; Crimmin, M. J. J.
Chem. Soc., Perkin Trans. 1 1993, 3113. Bunn, B. J.;
Simpkins, N. S. J. Org. Chem. 1993, 58, 533. Sugasawa, K.;
Shindo, M.; Noguchi, H.; Koga, K. Tetrahedron Lett. 1996,
37, 7377.
20. Love, B. E.; Jones, E. G. J. Org. Chem. 1999, 64, 3755.
21. Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9,
165.
11. It should be noted that in all experiments employing 4-tert-
butylcyclohexanone, for optimum results the ketone should be
puri®ed by recrystallisation from hexane at 48C. See: Perrin,
D. D.; Armarego, W. L. F. Puri®cation of Laboratory Chemi-
cals; 3rd ed.; Pergamon: Oxford, 1998.
22. Graf, C.-D.; Malan, C.; Harms, K.; Knochel, P. J. Org. Chem.
1999, 64, 5581.
23. Corey, E. J.; Enders, D. Chem. Ber. 1978, 111, 1337.
24. Choi, T.; Cizmeciyan, D.; Khan, S. I.; Garcia-Garibay, M. A.
J. Am. Chem. Soc. 1995, 117, 12893.
12. Graf, C.-D.; Malan, C.; Knochel, P. Angew. Chem., Int. Ed.
Engl. 1998, 37, 3014.
25. Betts, B. E.; Davey, W. J. Chem. Soc. 1961, 3340.
26. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537.
13. The absolute con®guration of the major and minor enanti-
omers for 5b, 5d, 5e, and 7 were assigned by correlation of
optical rotation measurements with those of Koga and
27. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.