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Deracemization of axially dissymmetric compounds by enantioselective dehydrohalogenation using chiral lithium amides -II-
Vol. 1. No.6 , pp.347-350, Printed in Great Britain
Tetrahedron: Asymmetry
1990
0957-4166/90 $3.Wc.O0 Pergan1on PK!ss plc
DERACEMIZATION OF AXIALLY DISSYMMETRIC ENANTIOSELEC 1 IVE OEHYDROHALOGENATION
COMPOUNDS BY
USING CHIRAL LITHIUM AMIDES -II-
Lncette Dnhamel*, Alain Ravard and Jean-Christophe Plaquevent
URA D 0464, UFR Sciences et Techniqaes , Universite de Roaen BP 118 E 76134 Mont Saint Aignan Cedex.
(Received 17 April 1990)
Abstract : New findings about deracemlzatlon of unsaturated carboxylic acids 1 by enantloselectlve dehydrohalogenatlon of prochlral species 2 by chiral lithium amides leading to axially dlssymmetric compounds wlth 80% e.e. are reported. The role of the structure of the prochiral hydrochlorinated intermediate is discussed. An example of axial to central chlrality transfer Is described. f & -2 1
Daring oar previous stadies about the use of chiral lithium amides in asymmetric syathesis1*2.we recently reported that this class of chiral bases can exert high asymmetric induction in enantioselective dehydrohalogenatioa of prochiral acids 2, leading to optically active acids 1 bearing a chiral axi@ t Scheme 1 ):
12 r a c e m i c
23
12 (S) ee 82 %
prochiral
Scheme 1
Our previous communication was essentially focused on the role of the structure of the chiral auxiliary on the enantioselectivity of the dehydrohalogenation step. Fnrthermore higher e.e.‘s were generally observed for dehydrochlorinatlon vs dehydrobromination. In this report, we wlsh to describe new findingsabout influence of three other parameters on deracemization viz : the 4- sabstitaent of the cyclohexyl moiety , the configoration of the prochiral hydrochbrinated intermediate and an excess of the chiral base. 347
348
L. DUHAMEL ef al.
In a first set of experiments, we generalized the deracemization procedure to 4-methyl cyclohexylideneacetic acid _Q. We observed that the hydrochforination of the racemic acid &J led to a mixture ot the two isomeric prochiral acids & cis and & trans ( Scheme 2 1 :
lb racemic
COOH
COOH
2_b trans
2& cis
2Scheme
(2_
c’
Global yield 67% ; a cls / Z& trans = 55 / 45
Recrystallization of this mixture led as to the pure cis isomer ( petrolearn ether, RT, 3 recryetallizations, overall yield 43% 1 and Intermediate mixtures of varioas compositions. In the case of 4-tert-butyl cyclohexylideneacetic acid &, only the cis hydrochloriuated acid & was obtainedic. The relative configuration of these intermediate prochiral species was deduced from NOB difference datafcB3. The hydrochlorinated compounds 2 were then submitted to dehydrohalogenation using chiral lithium amides as bases 4 t Scheme 3, Table I 1: R’ I
Ph,,;_Rz
2.5 eq.. THF, -72’C
L
3Scheme
optically active 1
T A B L E I : ENANTIOSELECTIVE DEHYDROCHLORINATION ’ E N T R Y PROCHIRAL ACID 2
1 2 3 4 5 6 7 8 9
R’
cis
/
t-Ba t-Ba Me Me Me Me Me Me Me
100 100 100 83 46 0 100 5s 0
/ / / / / / / / /
trans
0 0 0 17 54 100 0 45 100
BASE R2
t-Bu 1-adamantyl t-Bu t-Bn t-Bu t-Bu 1-adamantyl 1-adamantyl 1-adamantyl
CHIRAL
ACID
[til$
o.p. X (conf .)
+SO.9’ +77.3’ +49.8’ +29.1’ -13.6’
54 (S) 02 (S) 52 is) 30 (S) 14 ( Ri >75q) (R) 80 (S) 10 (ISi >75=‘tRf
(a) (a) tb) tb) (b)
+76.8’ (b) +9.7’ ib) -
1 Yield X
88’C 84rc 73 64 64 75 70 -
(a) EtOH, c=l Ref. (R), [cd&-- -94.87’ tc=O.98, EtOHIS; (b) EtOH, c=O.9 Ref.(S) Culs4s=+95.8 ic=O.87, EtOH )6 (c) Since the pure a traas isomer was not avallable, this e.e. was esti-
mated by extrapolation of values reported in entries 3 to 5 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 I and 3 ; 2 and 7 j. - the asymmetric induction is directly related to the configuration of the prochiral hydrochlorinated acid a. Indeed, for a same chirai lithium amide, the sense of asymmetric induction is reversed for the two isomeric forms of a, and high e.e.‘s can be obtained in both cases. I see entries 3 to 6; 7 to 9 j. Obviously, the chiral base selects the same enantiotopic hydrogen in t.hr two isomeric prochiral species 2b, t,hus leading to opp0sit.e configuration of a. A study of models rationalizing this observation is in progress and will be published elsewhere. - this last information demonstrates that the enantioselectivity of the dehydrohalogenation step is under kinetic control since a thermodynamic control would lead to the same optical activity starting from either a cis or a trans ( see also ref.lc, note 6 j. Finally, we performed dehydrochlorination in the presence of au excess of chiral base ( 5 eq. 1. The recovered material was a mixtare of both isomeric acids bearing the doable bond in exo or endo position. After separation by flash chromatography t petroleom ether/EtzO= 80/ 20 j’, acid 3 turned oat to be optically active*( Scheme 4 ). We assumed that the e.e. of 2 was due to the stereoselective deconjugation of optically active Jo under basic conditions, with racemization ( SZX e.e. only instead of 82X).
+ COOH ( d i r e c t
addition)
4Scheme
2 ( 5 5 % ) ee=52:5%
12 ( 4 5 % )
In order to decide this mechanism and to improve this decoajugation, we treated (S) & by 2.5 eq. of an achiral base (LIlAI, then added the cool reaction mixture I-72’Cj to water ( instead of adding water to the reaction mixture at ca O’C j.
2 . 5 eq. LOA L LiO
\P /
LiO
-J
3(90X)
ee-50%
This procedure allowed us to increase the 3/h ratio to 90110, without any loss of optical activity (Scheme S). Obviously, the protonation step of the anionic species daring the aqueous workup was more regio and stereoselective at low temperature ld*‘o.
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 3, since the prochiral intermediate & can be easily obtained by hydrohalogenation of racemic 3.
C
Scheme 5
References and Notes (1) a- L. DUHAMEL and J.C. PLAQUEVENT , Tetrahedron Letters, 21 , 2521 (1980); bL. DUHAMEL and J.C. PLAQUEVENT , Ball. Sot. Chim. Pr., II-75 (19821; c- L. DUHAMEL. A. RAVARD , J.C. PLAQUEVENT and D. DAVOUST , Tetrahedron Letters, a $517 (1987); d- L. DUHAMEL, P. DUHAMEL , S. POUQUAY, J. JAMAL EDDINE, 0. PESCHARD , J.C. PLAQUEVENT, A. RAVARD. R. SOLLIARD, J.Y. VALNOT and H. VINCENS, Tetrahedron , &, 5495 (1988); e- J.C. PLAQUEVENT and A. RAVARD , J. Organometall. Chem. , MI CSl (1989) (2) For a recent review on chiral lithium amides in asymmetric synthesis, see N.S. Simpkins, Chem. and Ind. ,387 (1988) ; see also D. Seebach , Ang. Chem. Int. Ed. Eng., a, 1624 (1988) chapter 4. (3) This determination was performed on BRUCKER 400 and SO0 MHz ‘H NMR spectrometers by Professor D. DAVOUST and Doctor G. PLE who are gratefully acknowledged. (4) For experimental procedure , see ref. lc note 4 and A. RAVARD , These de Doctorat, Roaen 1990. (5) H. DURAISAMY and H.M. WALBORSKY , J. Am. Chem. Sot. , 10s . 3252 (1983). (6) a- W.H. PERKIN and W.J. POPE , J. Chem. Sot. , lSl0 (1911) ; b- H. GERLACH , Helv. Chim. Acta, B , 1291 (1966); c- H. M. WALBORSKY and R.B. BANKS, Ball. Sot. Chim. Belg., fl, 849 (1980). (7) W.C. STILL, M. KHAN and A. MITRA, J.Org.Chem. ,a , 2923 (1978). (8)Coll& = -57.4’ (0.7,EtOH). jH NMR analysis of the derived methyl eater in the presence of chlral shlft reagent Eu(hfc)a shown that thls compound exhibited an e.e. of 522 5%; (-1 3 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, J.Chem.Soc. Perkin I, 2224 (1978); b- F.L. HARRIS, L. WEILER, Tetrahedron Letters, 25, 1333 (1984); c- F.L. HARRIS, L. WEILER, Tetrahedron Letters. Zp, 1939 (1985). (9)A solution of 280mg of (S) b leeSO%) in 2 ml of THF was added at -72-C to a 3.Smmoi solution of LDA in 17 ml of THF. After 18hrs at -72-C, 10 ml of Et20 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 ( 2 /h=90/10). Acid 2 was isolated by flash chromatography ( petrolcam ether / EtoO = 80/20 1 ( 70X, see note 8 1. (101 0. PESCHARD, Th4se de Doctorat , Rooen , 1989
Tetrahedron: Asymmetry
1990
0957-4166/90 $3.Wc.O0 Pergan1on PK!ss plc
DERACEMIZATION OF AXIALLY DISSYMMETRIC ENANTIOSELEC 1 IVE OEHYDROHALOGENATION
COMPOUNDS BY
USING CHIRAL LITHIUM AMIDES -II-
Lncette Dnhamel*, Alain Ravard and Jean-Christophe Plaquevent
URA D 0464, UFR Sciences et Techniqaes , Universite de Roaen BP 118 E 76134 Mont Saint Aignan Cedex.
(Received 17 April 1990)
Abstract : New findings about deracemlzatlon of unsaturated carboxylic acids 1 by enantloselectlve dehydrohalogenatlon of prochlral species 2 by chiral lithium amides leading to axially dlssymmetric compounds wlth 80% e.e. are reported. The role of the structure of the prochiral hydrochlorinated intermediate is discussed. An example of axial to central chlrality transfer Is described. f & -2 1
Daring oar previous stadies about the use of chiral lithium amides in asymmetric syathesis1*2.we recently reported that this class of chiral bases can exert high asymmetric induction in enantioselective dehydrohalogenatioa of prochiral acids 2, leading to optically active acids 1 bearing a chiral axi@ t Scheme 1 ):
12 r a c e m i c
23
12 (S) ee 82 %
prochiral
Scheme 1
Our previous communication was essentially focused on the role of the structure of the chiral auxiliary on the enantioselectivity of the dehydrohalogenation step. Fnrthermore higher e.e.‘s were generally observed for dehydrochlorinatlon vs dehydrobromination. In this report, we wlsh to describe new findingsabout influence of three other parameters on deracemization viz : the 4- sabstitaent of the cyclohexyl moiety , the configoration of the prochiral hydrochbrinated intermediate and an excess of the chiral base. 347
348
L. DUHAMEL ef al.
In a first set of experiments, we generalized the deracemization procedure to 4-methyl cyclohexylideneacetic acid _Q. We observed that the hydrochforination of the racemic acid &J led to a mixture ot the two isomeric prochiral acids & cis and & trans ( Scheme 2 1 :
lb racemic
COOH
COOH
2_b trans
2& cis
2Scheme
(2_
c’
Global yield 67% ; a cls / Z& trans = 55 / 45
Recrystallization of this mixture led as to the pure cis isomer ( petrolearn ether, RT, 3 recryetallizations, overall yield 43% 1 and Intermediate mixtures of varioas compositions. In the case of 4-tert-butyl cyclohexylideneacetic acid &, only the cis hydrochloriuated acid & was obtainedic. The relative configuration of these intermediate prochiral species was deduced from NOB difference datafcB3. The hydrochlorinated compounds 2 were then submitted to dehydrohalogenation using chiral lithium amides as bases 4 t Scheme 3, Table I 1: R’ I
Ph,,;_Rz
2.5 eq.. THF, -72’C
L
3Scheme
optically active 1
T A B L E I : ENANTIOSELECTIVE DEHYDROCHLORINATION ’ E N T R Y PROCHIRAL ACID 2
1 2 3 4 5 6 7 8 9
R’
cis
/
t-Ba t-Ba Me Me Me Me Me Me Me
100 100 100 83 46 0 100 5s 0
/ / / / / / / / /
trans
0 0 0 17 54 100 0 45 100
BASE R2
t-Bu 1-adamantyl t-Bu t-Bn t-Bu t-Bu 1-adamantyl 1-adamantyl 1-adamantyl
CHIRAL
ACID
[til$
o.p. X (conf .)
+SO.9’ +77.3’ +49.8’ +29.1’ -13.6’
54 (S) 02 (S) 52 is) 30 (S) 14 ( Ri >75q) (R) 80 (S) 10 (ISi >75=‘tRf
(a) (a) tb) tb) (b)
+76.8’ (b) +9.7’ ib) -
1 Yield X
88’C 84rc 73 64 64 75 70 -
(a) EtOH, c=l Ref. (R), [cd&-- -94.87’ tc=O.98, EtOHIS; (b) EtOH, c=O.9 Ref.(S) Culs4s=+95.8 ic=O.87, EtOH )6 (c) Since the pure a traas isomer was not avallable, this e.e. was esti-
mated by extrapolation of values reported in entries 3 to 5 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 I and 3 ; 2 and 7 j. - the asymmetric induction is directly related to the configuration of the prochiral hydrochlorinated acid a. Indeed, for a same chirai lithium amide, the sense of asymmetric induction is reversed for the two isomeric forms of a, and high e.e.‘s can be obtained in both cases. I see entries 3 to 6; 7 to 9 j. Obviously, the chiral base selects the same enantiotopic hydrogen in t.hr two isomeric prochiral species 2b, t,hus leading to opp0sit.e configuration of a. A study of models rationalizing this observation is in progress and will be published elsewhere. - this last information demonstrates that the enantioselectivity of the dehydrohalogenation step is under kinetic control since a thermodynamic control would lead to the same optical activity starting from either a cis or a trans ( see also ref.lc, note 6 j. Finally, we performed dehydrochlorination in the presence of au excess of chiral base ( 5 eq. 1. The recovered material was a mixtare of both isomeric acids bearing the doable bond in exo or endo position. After separation by flash chromatography t petroleom ether/EtzO= 80/ 20 j’, acid 3 turned oat to be optically active*( Scheme 4 ). We assumed that the e.e. of 2 was due to the stereoselective deconjugation of optically active Jo under basic conditions, with racemization ( SZX e.e. only instead of 82X).
+ COOH ( d i r e c t
addition)
4Scheme
2 ( 5 5 % ) ee=52:5%
12 ( 4 5 % )
In order to decide this mechanism and to improve this decoajugation, we treated (S) & by 2.5 eq. of an achiral base (LIlAI, then added the cool reaction mixture I-72’Cj to water ( instead of adding water to the reaction mixture at ca O’C j.
2 . 5 eq. LOA L LiO
\P /
LiO
-J
3(90X)
ee-50%
This procedure allowed us to increase the 3/h ratio to 90110, without any loss of optical activity (Scheme S). Obviously, the protonation step of the anionic species daring the aqueous workup was more regio and stereoselective at low temperature ld*‘o.
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 3, since the prochiral intermediate & can be easily obtained by hydrohalogenation of racemic 3.
C
Scheme 5
References and Notes (1) a- L. DUHAMEL and J.C. PLAQUEVENT , Tetrahedron Letters, 21 , 2521 (1980); bL. DUHAMEL and J.C. PLAQUEVENT , Ball. Sot. Chim. Pr., II-75 (19821; c- L. DUHAMEL. A. RAVARD , J.C. PLAQUEVENT and D. DAVOUST , Tetrahedron Letters, a $517 (1987); d- L. DUHAMEL, P. DUHAMEL , S. POUQUAY, J. JAMAL EDDINE, 0. PESCHARD , J.C. PLAQUEVENT, A. RAVARD. R. SOLLIARD, J.Y. VALNOT and H. VINCENS, Tetrahedron , &, 5495 (1988); e- J.C. PLAQUEVENT and A. RAVARD , J. Organometall. Chem. , MI CSl (1989) (2) For a recent review on chiral lithium amides in asymmetric synthesis, see N.S. Simpkins, Chem. and Ind. ,387 (1988) ; see also D. Seebach , Ang. Chem. Int. Ed. Eng., a, 1624 (1988) chapter 4. (3) This determination was performed on BRUCKER 400 and SO0 MHz ‘H NMR spectrometers by Professor D. DAVOUST and Doctor G. PLE who are gratefully acknowledged. (4) For experimental procedure , see ref. lc note 4 and A. RAVARD , These de Doctorat, Roaen 1990. (5) H. DURAISAMY and H.M. WALBORSKY , J. Am. Chem. Sot. , 10s . 3252 (1983). (6) a- W.H. PERKIN and W.J. POPE , J. Chem. Sot. , lSl0 (1911) ; b- H. GERLACH , Helv. Chim. Acta, B , 1291 (1966); c- H. M. WALBORSKY and R.B. BANKS, Ball. Sot. Chim. Belg., fl, 849 (1980). (7) W.C. STILL, M. KHAN and A. MITRA, J.Org.Chem. ,a , 2923 (1978). (8)Coll& = -57.4’ (0.7,EtOH). jH NMR analysis of the derived methyl eater in the presence of chlral shlft reagent Eu(hfc)a shown that thls compound exhibited an e.e. of 522 5%; (-1 3 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, J.Chem.Soc. Perkin I, 2224 (1978); b- F.L. HARRIS, L. WEILER, Tetrahedron Letters, 25, 1333 (1984); c- F.L. HARRIS, L. WEILER, Tetrahedron Letters. Zp, 1939 (1985). (9)A solution of 280mg of (S) b leeSO%) in 2 ml of THF was added at -72-C to a 3.Smmoi solution of LDA in 17 ml of THF. After 18hrs at -72-C, 10 ml of Et20 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 ( 2 /h=90/10). Acid 2 was isolated by flash chromatography ( petrolcam ether / EtoO = 80/20 1 ( 70X, see note 8 1. (101 0. PESCHARD, Th4se de Doctorat , Rooen , 1989