DERACEMIZATION OF AXIALLY DISSYMMETRIC COMPOUNDS BY ENANTIOSELECTIVE DEHYDROHALOGENATION USING CHIRAL LITHIUM AMIDES -II-

Article abstract of DOI:10.1016/0957-4166(90)90030-E

New findings about deracemization of unsaturated carboxylic acids 1 by enantioselective dehydrohalogenation of prochiral species 2 by chiral lithium amides leading to axially dissymmetric compounds with 80percent e.e. are reported.The role of the structure of the prochiral hydrochlorinated intermediate is discussed.An example of axial to central chirality transfer is described. (1a -> 3)

Full text of DOI:10.1016/0957-4166(90)90030-E

Tetrahedron: Asymmetry Vol. 1. No.6 ,
1990
Printed in Great Britain
OF AXIALLY
COMPOUNDS BY
LITHIUM AMIDES
IVE
USING
Lncette
Ravard and J ean-Christophe Plaquevent
Sciences et de Roaen
URA D 0464,
,
BP 118 76134 Mont Saint Aignan Cedex.
(Received 17 April 1990)
Abstract : New findings about deracemlzatlon of unsaturated carboxylic
by
tlve dehydrohalogenatlon of prochlral species
by chiral lithium amides leading to axially
metric compounds wlth 80% are reported. The role of the structure of the prochiral
chlorinated intermediate is discussed. An example of axial to central chlrality transfer Is descri-
bed.
Daring oar previous stadies
the use of chiral lithium amides in asymmetric
recently reported that this class of chiral bases can exert high asymmetric
induction in enantioselective dehydrohalogenatioa of prochiral acids
leading to opti-
cally active acids
bearing a chiral
Scheme 1
ee 82 %
pr ochi r al
racemic
Scheme
Our previous communication was essentially focused on the role of the structure
of the chiral auxiliary on the enantioselectivity of the dehydrohalogenation step.
more higher
tion.
were generally observed for dehydrochlorinatlon vs
In this report, we wlsh to describe new findingsabout influence of three other
parameters on deracemization viz the sabstitaent of the cyclohexyl moiety the
figoration of the prochiral hydrochbrinated intermediate and an excess of the chiral base.
347

348
L.
al.
I n a first set of experiments, we generalized the deracemization procedure to
4-methyl cyclohexylideneacetic acid We observed that the hydrochforination of the
racemic acid
Scheme
led to a mixture
the two
prochiral acids
cis and
trans
COOH
COOH
racemic
cis
Global yield 67%
trans
trans =
2Scheme
45
ether, RT, 3
Recrystallization of this mixture led as to the pure cis isomer
recryetallizations, overall yield 43%
In the case of
acid was
and Intermediate mixtures of varioas compositions.
only the cis hydrochloriuated
cyclohexylideneacetic acid
The relative configuration of these intermediate prochiral species
was deduced from NOB difference
The hydrochlorinated compounds
were then submitted to dehydrohalogenation
Scheme 3, Table I
using
lithium amides as bases
2.5 eq.. THF, -72’C
3Scheme
optically active
T ABLE
E N T R Y
ACID
BASE
ACID
cis
trans
t -Ba
t -Ba
M e
100
100
100
83
46
0
100
5s
0
0
0
54
2
3
4
1-adamantyl
t-Bu
0
52
30
14
73
64
64
Me
17
54
100
0
t-Bn
t-Bu
M e
-13.6’
6
7
Me
M e
1-adamantyl
1-adamantyl
1-adamantyl
80
10
75
70
8
9
Me
M e
100
R ef.
[cd&-- -94.87’
Since the pure
mated by extrapolation of values reported in entries 3 to
Ref.(S)
traas isomer was not avallable, this e.e. was esti-
and 7 to 8.

Lithium amides
349
These results provide us with new informations about the deracemization reaction
the enantioseiectivity for the cis isomers is not depending on the steric hindrance of the
4 snbstitaent on the cyclohexyi ring see entries and 3
the asymmetric induction is directly related to the configuration of the prochiral
chlorinated acid Indeed, for a same chirai lithium amide, the sense of asymmetric in-
duction is reversed for the two isomeric forms of and high can be obtained
both cases. entries 3 to 6; 7 to 9 Obviously, the chiral base selects the same
tiotopic hydrogen in two prochiral species leading to
figuration of study of models rationalizing this observation is in progress and will
and 7
con-
A
be published elsewhere.
this last information demonstrates that the enantioselectivity of the
nation step is under kinetic control since a thermodynamic control would lead to the sa-
me optical activity starting from either
Finally, we performed dehydrochlorination in the presence of au excess of chiral
eq. The recovered material was a of both isomeric acids bearing the
cis or
trans see also
note 6
base
doable bond in exo or
20
position. After separation by flash chromatography
turned oat to be optically Scheme 4
petroleom
acid
We assumed
that the e.e. of
was due to the stereoselective deconjugation of optically active
e.e. only instead of 82X).
under
basic conditions, with racemization
(direct addition)
( 5 5 % )
(45%)
4Scheme
In order to decide this mechanism and to improve this decoajugation, we treated
eq. of an achiral base then added the cool reaction mixture
by
to water
instead of adding water to the reaction mixture at ca O’C
2 . 5
This procedure allowed
activity (Scheme
aqueous workup was more regio and stereoselective at low temperature
to increase the
ratio to
without any loss of optical
Obviously, the protonation step of the anionic species daring the

350
L. DUHAMEL et al.
This example of axial to central chiraiity transfer constitutes the key step of the
deracemization by enantioselective dehydrohaiogenation of the acid
since the prochiral
intermediate
can be easily obtained by hydrohalogenation of racemic
C
Scheme
References and Notes
a- L. DUHAMEL and J .C. P LAQUEVENT
L. DUHAMEL and J .C. PLAQUEVENT
Tetrahedron Letters,
Chim. Pr., II-75
2521
c- L. DUHAMEL.
A. RAVARD J .C. PLAQUEVENT and D. DAVOUST Tetrahedron Letters,
d- L. DUHAMEL, P. DUHAMEL , S. J . 0. PESCHARD J .C.
PLAQUEVENT, A. RAVARD. R. SOLLIARD, J .Y. VALNOT and H. VINCENS, Tetrahedron
5495 e- J .C. PLAQUEVENT and A. RAVARD J . Organometall. Chem.
For a recent review on
Chem. and Ind.
lithium amides in asymmetric synthesis, see N.S.
see also D. Ang. Chem. Int. Ed. Eng.,
1624
chapter 4.
This determination was performed on BRUCKER 400 and
MHz
NMR spectrome-
ters by Professor D. DAVOUST and Doctor G. PLE who are gratefully a c knowle dge d.
For experimental procedure , see ref. lc note 4 and A. RAVARD
Roaen 1990.
DUR AI S AM Y and H .M . W ALBO R S KY
a- W.H. and W.J . POPE J . Chem.
C him.
Belg.,
W.C. STILL,
-57.4’
de Doctorat,
J . Am. Chem.
,
3252
b- H. GERLACH
1291
c- H. M. WALBORSKY and R.B. BANKS, Ball.
Chim.
849
KHAN and A. MITRA, J .Org.Chem.
NMR analysis of the derived methyl eater in the presence
shown that thls compound exhibited an of
should be of S configuration according to deconjagation mechanism of a-ethylenic
acids demonstrated in the following references: a-K.I. NUNAMI, M. SUZUKI, N. YONEDA,
2923
=
of
shlft reagent
J .Chem.Soc.
1333
solution of 280mg of
solution of LDA in 17 ml of THF. After
I, 2224
c- F.L. HARRIS, L. WEILER, Tetrahedron Letters.
in 2 ml of THF was added at
at 10 ml of
b- F.L. HARRIS, L. WEILER, Tetrahedron Letters,
1939
to a
were added at this
temperature and this mixture was poured in 10 ml of cool water, then extracted twice by
20 ml of 0.1 N aqueous sodium hydroxide. Acidification and usual workup gave the crude
product
=
Acid
see note 8
was isolated by flash chromatography
petrolcam ether
0. PESCHARD,
de
Rooen 1989