1
020
E. L. Carswell et al.
LETTER
Table 5 Enantioselective Deprotonations of 9 at Various Tempera- selectivity for this system was unexpectedly observed at
tures Using Base (R)-8
elevated temperatures (40 ºC). This facet of chiral magne-
sium complexes, after further careful optimisation, should
increase the applicability of these systems to a wider
range of less reactive substrates, whilst also making them
attractive for more widespread use. Moreover, it has also
been shown that both (R)-4 and (R)-8 can be used in the
absence of any Lewis basic additives to give good conver-
sions, without any substantial deleterious effect on enan-
tioselectivity. Finally, considering the critical effect of the
O
OTMS
(R)-8
TMSCl, THF
DMPU (0.5 equiv)
9
(S)-10
Temperature
Time
Conversion Enantiomeric
(
°C)
(h)
68
68
19
1
(%)
78
54
62
33
46
11
Ratio R:S
46:54
76:24
78:22
83:17
76:24
67:33
‘
spectator’ aryloxy unit found in the reactions of (R)-8, we
–
–
78
40
are now investigating the use of chiral alcohols in these
systems to further improve upon the selectivities achieved
thus far.
r.t.
4
5
6
0
Acknowledgment
0
6
1
We thank the EPSRC and GlaxoSmithKline for a CASE award
(E. L. C.). We also thank the EPSRC Mass Spectrometry Service,
1
University of Wales, Swansea, for analyses. Finally, we offer our
sincere thanks to Professor Philip Eaton (University of Chicago).
deprotonation reactions, this establishes an intriguing
practical development. Additionally, this observation
highlights the high thermal stability of these magnesium
References
(
1) Present address: Department of Chemistry and
Biochemistry, University of Notre Dame, 251 Nieuwland
Science Hall, Notre Dame, IN, 46556-5670, USA.
2) Henderson, K. W.; Kerr, W. J.; Moir, J. H. Tetrahedron
1
5
reagents.
(
(
Finally, base (R)-8 was reacted in the absence of DMPU,
to ascertain whether this system required the presence of
a strongly polar additive. To our delight, reaction at room
temperature led to a retention of the previously observed
selectivity, with only a small decrease in reaction conver-
sion (Scheme 3).
2002, 58, 4573.
3) For recent reviews, see: (a) O’Brien, P. J. Chem. Soc.,
Perkin Trans. 1 2001, 95. (b) O’Brien, P. J. Chem. Soc.,
Perkin Trans. 1 1998, 1439. (c) Simpkins, N. S. Pure Appl.
Chem. 1996, 68, 691.
(4) Henderson, K. W.; Mulvey, R. E.; Clegg, W.; O’Neil, P. A.
Polyhedron 1993, 12, 2535.
(
5) Zhang, M.; Eaton, P. E. Angew. Chem. Int. Ed. 2002, 41,
O
OTMS
2169.
(
R)-8
(6) Henderson, K. W.; Allan, J. F.; Kennedy, A. R. Chem.
Commun. 1997, 1149.
5
7
0% conversion
8:22 er
TMSCl, THF,
r.t., 19 h
(
(
7) Ashby, E. C.; Willard, G. F. J. Org. Chem. 1978, 43, 4094.
8) During the preparation of this manuscript two articles have
appeared detailing the use of chiral alkylmagnesium amides
in enantioselective alkylation of aldehydes and in the
asymmetric reduction of aryl trifluoromethylketones:
9
(S)-10
Scheme 3
(
a) Yong, K. H.; Taylor, N. J.; Chong, J. M. Org. Lett. 2002,
4, 3553. (b) Yong, K. H.; Chong, J. M. Org. Lett. 2002, 4,
139.
9) Henderson, K. W.; Kerr, W. J.; Moir, J. H. Chem. Commun.
000, 479.
In conclusion, we have developed two new classes of
enantiopure heteroleptic magnesium complexes for use in
enantioselective deprotonation reactions. Alkylmagne-
sium amide (R)-4 has been shown to be an effective base
for a range of 4-substituted cyclohexanones, displaying
enantioselectivities comparable to those of our bisamide
4
(
2
(
10) It is also worth noting that in order to access the bisamide
species, heating to reflux in THF or hexane (with two
2,9
equivalents of the chiral amine) is required.
(
R)-1, but which requires only half the quantity of chiral
(11) For related discussions on replacing HMPA as an additive
see: (a) O’Neil, I. A.; Lai, J. Y. Q.; Wynn, D. Chem.
Commun. 1999, 59. (b) Mukhopadhyay, T.; Seebach, D.
Helv. Chim. Acta 1982, 65, 385.
1
ligand. Furthermore, our H NMR spectroscopic studies
indicate that the amide residue of the reagent is most like-
ly to be responsible for the deprotonation process. If this
is indeed the case, then the development of a sub-stoichi-
ometric, catalytic, system should be possible and these
(
12) Representative experimental procedure: To a Schlenk flask,
under N , was added Bu Mg (0.79 M solution in heptane,
2
2
1.27 mL, 1 mmol). The heptane was then removed in vacuo
16
studies are currently underway in our laboratories. In ad-
dition, the aryloxymagnesium amide (R)-8 has been found
to be an efficient base for the enantioselective deprotona-
tion of ketone 9, and which interestingly displays the op-
posite selectivity to bisamide (R)-1. Also, the optimum
and replaced with THF (10 mL), followed by the addition of
(R)-N-benzyl-a-methylbenzylamine 2 (0.21 mL, 1 mmol).
The resultant solution was stirred at room temperature for 90
min and then cooled to –78 °C, whereupon TMSCl (0.5 mL,
4
mmol) and DMPU (0.06 mL, 0.5 mmol) were added. After
Synlett 2003, No. 7, 1017–1021 ISSN 1234-567-89 © Thieme Stuttgart · New York