Effect of amine structure and reaction additives on enantioselective deprotonations mediated by homochiral magnesium amide bases

Article abstract of DOI:10.1016/S0040-4039(01)01465-4

A series of novel, optically pure, Mg-bisamides have been prepared and, in turn, used to mediate enantioselective deprotonations of conformationally locked ketones. The new bases exhibit a wide range of selectivities, from poor to excellent (up to 95:5 e.

Full text of DOI:10.1016/S0040-4039(01)01465-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7111–7114
Effect of amine structure and reaction additives on
enantioselective deprotonations mediated by homochiral
magnesium amide bases
John D. Anderson,a Pilar Garc´ıa Garc´ıa,a Douglas Hayes,b Kenneth W. Henderson,a,*
William J. Kerr,a,* Jennifer H. Moira and Kamalesh Pai Fondekara
aDepartment of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, Glasgow G1 1XL,
Scotland, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, England, UK
Received 18 July 2001; accepted 8 August 2001
Abstract—A series of novel, optically pure, Mg-bisamides have been prepared and, in turn, used to mediate enantioselective
deprotonations of conformationally locked ketones. The new bases exhibit a wide range of selectivities, from poor to excellent (up
to 95:5 e.r.); trends between amine structure and the subsequent selectivity of the deprotonation system are detailed. In addition,
the effects on the selectivity and the reactivity of the deprotonation process on replacing the Lewis base additive HMPA for
DMPU have been investigated and found to be related to the reaction temperature. © 2001 Elsevier Science Ltd. All rights
reserved.
Magnesium bisamides, (R2N)2Mg, have recently been
highlighted as a class of reagent possessing distinctive
stability, reactivity, and selectivity characteristics1 when
compared with more traditional metal base systems. In
particular, Mg-bisamides have found good utility in the
regio- and stereoselective formation2 of synthetically
useful enolate ions, as well as, more notably, in enan-
tioselective deprotonation processes.3 Indeed, this latter
category of reaction has only very recently been devel-
oped and, to date, the sole chiral Mg-bisamide utilised
within this class of asymmetric transformation has been
that derived from the structurally simple amine (R)-N-
benzyl-a-methylbenzylamine 1. Use of this base system
in the deprotonation of conformationally locked 4-sub-
stituted and 2,6-disubstituted cyclohexanones, followed
by silyl enol ether formation, has resulted in good to
excellent levels of enantioselection and reaction conver-
sion.3 Herein, we report the effects on enantioselectivity
of systematically altering both the achiral and the chiral
sidearms of 1. In addition, the consequences of replac-
Ph
N
H
Ph
Ph
N
H
Ph
Ph
N
H
Ph
Ph
N
H
3
1
2
4
8
Ph
Ph
N
H
N
H
Ph
N
H
N
H
7
5
6
S
nPr
Et
iPr
Ph
N
H
Ph
N
H
Ph
Ph
N
H
Ph
N
H
Ph
11
10
12
9
Scheme 1.
Keywords: additives; asymmetric synthesis; chiral amines; enantioselective deprotonation; magnesium.
* Corresponding authors. Tel.: +44-141-548-2351; fax: +44-141-552-0876 (K.W.H.); tel.: +44-141-548-2959; fax: +44-141-548-4246 (W.J.K.);
e-mail: k.w.henderson@strath.ac.uk; w.kerr@strath.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01465-4

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J. D. Anderson et al. / Tetrahedron Letters 42 (2001) 7111–7114
Previously, we have shown that the use of the additive
HMPA in these systems greatly improves the reaction
rate and can also alter the selectivity of the deprotona-
tion process.3 From the results presented in Table 1, we
were also pleased to note that, over a wide range of
amine structures, HMPA (known to be a mutagen)
could be replaced by the environmentally more accept-
able substitute DMPU without any deleterious effects
on either the conversions or the selectivities of the
deprotonation reactions (with the single exception of
amine 4).6
ing the reaction additive HMPA with DMPU are
presented.
A series of chiral amines (2–12) were prepared (Scheme
1).4 Initially, the chiral methylbenzyl sidearm was
retained while the achiral portion of the amine was
systematically varied (2–9). The results of the enantiose-
lective deprotonation reactions involving the resulting
Mg-bisamides in reaction with tert-butylcyclohexanone
13 are outlined in Table 1. Some clear trends are
apparent. Firstly, for the alkyl substituted amines 2–5,
increasing the steric bulk of the achiral unit results in a
progressive rise in the selectivity of the base (from 54:46
to 91:9 e.r.). In fact, the selectivity obtained using
amine 5 is identical to the best results achieved using 1
(91:9 e.r.), although the conversion to silyl enol ether is
significantly lower (18% with 5 and 80% with 1).
Returning to our amine structure/selectivity studies and
having established that the benzyl sidearm possesses the
optimum steric properties to maximise selectivity with
good reaction conversion, when used in combination
with the a-methylbenzylamino unit, we next focused
our attention on the chiral component of the amine.
Thus, amine 10 was prepared,4 using commercially
available (R)-a-ethylbenzylamine, and subsequently
incorporated as part of the deprotonation system
(Table 2).7,8
Next, the effect of substituting the phenyl ring of the
achiral sidearm in 1 by other unsaturated units was
studied (6–9). The deprotonation reactions using the
amines incorporating allyl, naphthyl, 5-methylthio-
phenyl, or mesityl units resulted in consistently good
conversions and delivered a narrow range of efficient
selectivities (between 81:19 and 87:13 e.r.). Having
stated this, it should be noted that these amines do not
provide any improvement over the selectivity of the
reactions using 1. In this respect, on consideration of
the selectivities arising from all of the amines 1–9, and
in particular when comparing those from amines 1, 5,
and the latter allyl/aryl-possessing amines 6–9, it is
likely that the preference for the benzyl unit (in 1) arises
from steric rather than electronic reasons.5
Pleasingly, the deprotonation reactions with the ethyl-
substituted amine 10 displayed a small but reproducible
increase in selectivity compared to those with 1. In fact,
the 92:8 e.r. determined using 10 is the highest achieved
thus far for this benchmark ketone 13 using our Mg-
based strategy.10 Encouraged by this result, amines 11
and 12 were targeted to determine if an incremental rise
in selectivity would result from an increase in the steric
component at the a-position of the ligand. Both 11 and
12 were first prepared as racemates, and the optically
pure materials were isolated by fractional crystallisation
of their salts formed with (R)-mandelic acid.11 On
reaction, both amines were found to give good conver-
sions to silyl enol ether (S)-14 but with lower selectivity
than the reactions involving 10 (Table 2). In particular,
the more highly substituted amine 12 showed an appre-
ciable reduction in enantioselectivity. This indicates
that branching at the a-position of the amine has a
negative influence on the selectivity of the resultant
base.
Table 1. Enantioselective deprotonations using Mg-
bisamides derived from amines 2–9
O
OTMS
Chiral Mg-bisamide
TMSCl, HMPA or DMPU
(0.5 equiv.), THF, -78°C,1h
tBu
tBu
Throughout this study, again, HMPA and DMPU
could be exchanged without any major effects for the
reactions involving amines 10 and 11. In contrast, the
reactions using amine 12 displayed a 7% drop in selec-
tivity on replacing HMPA by DMPU.
(S)-14
13
Entry
Amine
Additive
Conv. (%)
e.r. (S):(R)
1
2
3
4
5
6
7
8
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9
9
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
40
42
73
73
87
87
18
17
80
87
76
87
85
83
76
97
54:46
55:45
77:23
75:25
72:28
80:20
91:9
In order to determine if the choice of additive plays a
role in the selectivity of the process at higher tempera-
Table 2. Enantioselective deprotonations of ketone 13
using Mg-bisamides derived from amines 10–12
88:12
82:18
81:19
87:13
87:13
86:14
87:13
85:15
84:16
9
Entry
Amine
Additive
Conv. (%)
e.r. (S):(R)
10
11
12
13
14
15
16
1
2
3
4
5
6
10
10
11
11
12
12
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
75
70
71
88
92
93
92:8
92:8
88:12
88:12
81:19
74:26

J. D. Anderson et al. / Tetrahedron Letters 42 (2001) 7111–7114
7113
critically important in determining the selectivity of the
base, with a benzyl unit achieving the optimum level of
enantioselection while maintaining good reaction con-
version. Substitution of the methyl group for an ethyl
group on the chiral sidearm of the amine results in a
small but consistent improvement in reaction selectiv-
ity. On the other hand, further increasing the size of the
alkyl unit to either an Pr group or an Pr group leads
to a drop in the selectivity of the resultant base. Fur-
thermore, in almost all of the enantioselective deproto-
nation reactions studied at −78°C, the additive HMPA
could be replaced by DMPU without any undue effect
on either selectivity or conversion.
tures, a series of reactions were conducted at −40°C
using amine 10 in conjunction with 13, as well as with
the more hindered ketone cis-2,6-dimethylcyclohex-
anone 15 (Table 3).
From Table 3 it is clear that there is indeed a relation-
ship between the selectivity of the reaction and the
additive used at −40°C.8 However, any selectivity differ-
ences between the reactions appears to be temperature
dependant, with very similar (or identical) results for
each additive at −78°C. It should also be noted from
Table 3 that increasing the reaction temperature from
−78 to −40°C only reduces selectivity of the reactions
by 2–3% when HMPA is present (entries 1, 3, 5 and 7),
but by 9–12% for the DMPU reactions (entries 2, 4, 6
and 8). Therefore, although the exchange of HMPA for
DMPU is clearly of benefit at −78°C, its utility at
−40°C must be considered against a possible reduction
in reaction selectivity.
n
i
Table 4. Enantioselective deprotonation of 4-substituted
cyclohexanones 17–19 using a Mg-bisamide derived from
10
Et
O
OTMS
Ph
N
Ph
2 Mg
Finally, to assess the wider utility of the base derived
from 10, a series of reactions were carried out on the
4-substituted cyclohexanones 17–19 (Table 4). Pleas-
ingly, the selectivities obtained in these reactions are
comparable with, or exceed those, found in the systems
using 1, confirming the general utility of 10 in the
deprotonation process, and with either HMPA or
DMPU.3,8
TMSCl, HMPA or DMPU
(0.5 equiv.), THF, -78°C,1h
R
R
(S)-20
17: R = Me
18: R = nPr
19: R = iPr
(S)-21
(S)-22
Entry
Ketone
Additive
Conv. (%)
e.r. (S):(R)
In summary, a range of chiral amines have been pre-
pared based around the systematic modification of (R)-
1
2
3
4
5
6
17
17
18
18
19
19
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
65
59
68
65
58
53
91:9
90:10
92:8
91:9
95:5
95:5
N-benzyl-a-methylbenzylamine
and
found,
on
conversion to their Mg-bisamide derivatives, to react
with 4- and 2,6-substituted cyclohexanones with good
to excellent enantioselectivities. It appears that the
steric nature of the achiral sidearm of the amine is
Table 3. Enantioselective deprotonation of ketones 13 and 15 using a Mg-bisamide derived from 10
Et
O
OTMS
R
R
R
R
Ph
N
Ph
2 Mg
TMSCl, HMPA or DMPU
(0.5 equiv.), THF
R'
R'
13: R = H, R' = tBu
15: R = Me, R' = H
(S)-14
(R)-16
Entry
Ketone
Additive
Temp. (°C)
Conv. (%)a
e.r.b
1
2
3
4
5
6
7
8
13
13
13
13
15
15
15
15
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
HMPA
DMPU
−78
−78
−40
−40
−78
−78
−40
−40
75
70
74
70
36
57
75
44
92:8
92:8
89:11
80:20
94:6
96:4
92:8
87:13
a Reaction time 1 h for entries 1–4 and 7 and 8; 6 h for entries 5 and 6.
b (S):(R) for entries 1–4 and (R):(S) for entries 5–8.

7114
J. D. Anderson et al. / Tetrahedron Letters 42 (2001) 7111–7114
followed by addition of (R)-N-benzyl-a-ethylbenzylamine
Acknowledgements
10 (0.45 g, 2 mmol). The resultant solution was heated to
reflux for 90 min and then slowly cooled to −78°C,
whereupon TMSCl (0.5 mL, 4 mmol) and DMPU (0.06
mL, 0.5 mmol) were added. After stirring for 20 min at
−78°C, 4-tert-butylcyclohexanone 13 (0.123 g, 0.8 mmol)
was added as a solution in THF (2 mL) over 1 h using a
syringe pump. The reaction was 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 vacuo. The reaction conversion was deter-
mined as 70% by GC analysis [CP SIL 19CB fused silica
capillary column; carrier gas H2 (80 kPa); 45–190°C;
temperature gradient: 45°C/min; tR=4.23 min (14); tR=
4.36 min (13)]. Flash column chromatography (eluting
with petrol/ether, 9:1) afforded (S)-4-tert-butyl-1-
trimethylsiloxy-1-cyclohexene (S)-14 (0.110 g, 61%) as a
clear oil which displayed an enantiomeric ratio of 92:8
{Chirasil-DEX CB capillary column; carrier gas H2 (80
kPa); 80°C (1 min)–120°C; temperature gradient: 1.8°C/
min; tR=19.49 min [(S)-14]; tR=19.73 min [(R)-14]}.
8. The absolute configurations of the major and minor
isomers of 14, 16, 20 and 22 were assigned by correlation
of optical rotation measurements with those of Koga and
co-workers;9 for 21 the major and minor isomer configu-
rations were tentatively assigned by comparison with the
other enol ethers.
We thank The Carnegie Trust for the Universities of
Scotland for a postgraduate studentship (J.H.M.) and
The Royal Society for a University Research Fellow-
ship (K.W.H.). We also thank the EPSRC and Glaxo-
SmithKline for a CASE award (J.D.A.), the EPSRC for
a grant (K.P.F.; GR/M12711) and the EPSRC Mass
Spectrometry Service, University of Wales, Swansea,
for analyses. Finally, thanks go to Dr. Alan R.
Kennedy (University of Strathclyde) for carrying out
the X-ray analyses.
References
1. Henderson, K. W.; Kerr, W. J. Chem. Eur. J. 2001, 7,
3430.
2. (a) Bonafoux, D.; Bordeau, M.; Biran, C.; Dunogues, J.
J. Organomet. Chem. 1995, 493, 27; (b) Bonafoux, D.;
Bordeau, M.; Biran, C.; Cazeau, P.; Dunogues, J. J. Org.
Chem. 1996, 61, 5532; (c) Bonafoux, D.; Bordeau, M.;
Biran, C.; Dunogues, J. Synth. Commun. 1998, 28, 93; (d)
Lesse`ne, G.; Tripoli, R.; Cazeau, P.; Biran, C.; Bordeau,
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3. (a) Henderson, K. W.; Kerr, W. J.; Moir, J. H. Chem.
Commun. 2000, 479; (b) Henderson, K. W.; Kerr, W. J.;
Moir, J. H. Synlett 2001, 1253; (c) Henderson, K. W.;
Kerr, W. J.; Moir, J. H. Chem. Commun. 2001, in press.
4. All amines were made by standard procedures and exhib-
ited satisfactory analytical and spectral data.
5. For more information on the structures of Mg-bisamides,
see: 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.
6. For related discussions on replacing HMPA as a reaction
additive, see: (a) O’Neil, I. A.; Lai, J. Y. Q.; Wynn, D.
Chem. Commun. 1999, 59; (b) Mukhopadhyay, T.; See-
bach, D. Helv. Chim. Acta 1982, 65, 385.
9. (a) Aoki, K.; Noguchi, H.; Tomioka, K.; Koga, K.
Tetrahedron Lett. 1993, 34, 5105; (b) Kim, H.; Shirai, R.;
Kawasaki, H.; Nakajima, M.; Koga, K. Heterocycles
1990, 30, 307.
10. For a comparison with Li-base systems, see: (a) Graf,
C.-D.; Malan, C.; Harms, K.; Knochel, P. J. Org. Chem.
1999, 64, 5581; (b) Aoki, K.; Tomioka, K.; Noguchi, H.;
Koga, K. Tetrahedron 1997, 53, 13641; (c) Busch-
Petersen, J.; Corey, E. J. Tetrahedron Lett. 2000, 41,
6941.
7. 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),
11. The absolute configurations of 11 and 12 were unambigu-
ously assigned by single-crystal X-ray diffraction analyses
of their (R)-mandelic acid salts.