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(S)-Naproxen® as a derivatizing agent to determine enantiomeric excess of cyanohydrins by HPLC
TETRAHEDRON LETTERS
Tetrahedron Letters 39 (1998) 8759-8762
Pergamon
(S)-Naproxen® as a Derivatizing Agent to Determine Enantiomeric Excess of Cyanohydrins by HPLC. Aida Soils', H~ctor Luna, Herminia L P~rez, Norberto Manjarrez, Remedios Sdnchez Depto. SistemasBiol6gicos,UniversidadAut6nomaMetropolitana-Xochimilco~Calz. del Hueso 1100, Col. Villa Quietud; Mexico,D.F., CP 04960, MEXICO
Atflano Guti6rrez Laboratoriode ResonanciaMagn6ticaNuclear, UniversidadAut6nomaMetropolitana-lztapalapa; Av. Michoacbny La Pufisima s/n, Col. Vicentina;M6xico,D.F., CP 09340, MEXICO Received 3 August 1998; revised 11 September 1998; accepted 18 September 1998 Abstract: An easy, inexpensive and accurate method to determine enantiomeric excess of cyanohydrins is described. The method consists in derivatization of cyanohydrins with (S)-naproxen® chloride and the products analyzed by HPLC. The results of enantiomeric excess so determined are similar to those obtained with [Eu(hfc)3], as a chiral shift reagent, and analysis by 1H-NMR of the cyanohydrins. © 1998 Elsevier ScienceLtd. All rights reserved. D e t e r m i n a t i o n o f o p t i c a l p u r i t y o f o r g a n i c c o m p o u n d s is v e r y i m p o r t a n t , mainly for those with b i o l o g i c a l activity. It is well k n o w n that this a c t i v i t y d e p e n d s on the s t r u c t u r e o f the substance, in such a w a y that the b i o l o g i c a l r e s p o n s e due to each e n a n t i o m e r could be different. B e c a u s e o f this, it is n e c e s s a r y to have an a d e q u a t e m e t h o d to a c c u r a t e l y determine e n a n t i o m e r i c excess. In
the
earlier
investigations,
the
optical
purity
of
cyanohydrins
was
solely
d e t e r m i n e d from the o p t i c a l r o t a t i o n , ~ but a c t u a l l y this m e t h o d is not reliable. ~ There have been e m p l o y e d s e v e r a l m e t h o d s to d e t e r m i n e e n a n t i o m e r i c e x c e s s o f c y a n o h y d r i n s , which include the f o l l o w i n g : f o r m a t i o n o f d i a s t e r e o m e r i c e s t e r s by r e a c t i o n with (R)-ctm e t h o x y - c t - t r i f l u o r o m e t h y l p h e n y l a c e t o y l c h l o r i d e and the o p t i c a l p u r i t y d e t e r m i n e d by gas
chromatography 3
or
HPLC
analysis; 4
(heptafluoropropylhydroxymethylene)-d-camphorate] chiral
shift
reagent; 5 derivatization
as a c e t a t e s ,
by
1H-NMR
europium to
(III)
prevent
using
tris-[3-
[Eu(hfc)3]
decomposition
as
a
o f the
c y a n o h y d r i n , f o l l o w e d by gas c h r o m a t o g r a p h i c analysis using a 13-cyclodextrin column; 6 derivatization
with
(+)-methoxytrifluorometylphenylacetic
acid
(MTPA)
chloride
f o l l o w e d by xgF-NMR 7 or I H - N M R analysis; I H - N M R o f m i x t u r e s o f m a n d e l o n i t r i l e and c y c l o d e x t r i n in a q u e o u s solution, s D e r i v a t i z a t i o n o f a l c o h o l s with the c o m m e r c i a l l y available (R)- and (S)- ( M T P A ) or its a n a l o g u e M P A , and f u r t h e r analysis by 19F-NMR and 1H-NMR is w i d e l y used. 9 Because o f their similar s t r u c t u r e and their a t t r a c t i v e p r i c e c o m p a r e d to the e x p e n s i v e c o m m e r c i a l MPA, r e c e n t l y ( S ) - I b u p r o f e n ® a n d ( S ) - N a p r o x e n ® have been used as chiral 0040-4039/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PiI: S0040-4039(98)01990-X
8760
derivatizing agents to assess enantiomeric excess of chiral sulfoxides by 1H-NMR.I° It is our aim to look for an accessible method to determine eaantiomeric excess of (R)-cyanohydrins. We report in this paper the use of (S)-naproxen ® as a derivatizing agent, and
analysis of the diastereomeric ester of the (R)-cyanohydrin by HPLC,
(Scheme 1) and comparison of the results with those obtained by use of [Eu(hfc)3], as a chiral shift reagent, and analysis by IH-NMR. The (S)-naproxen ® used to prepare the diastereomeric derivates of cyanohydrins was obtained by extraction with chloroform from commercially available tablets (mp. and optical activity were identical to those in literature) tl, the acid chloride was prepared by reaction with oxalyl chloride in hexane. The solid produced after evaporation of the solvent was used without any further purification to prepare the diastereoisomeric derivative of the (R)-cyanohydrin.
~ ~ , ,HmlH R,,~
"CN
+
CI
H
C,H~, j
~O~ocH
3
RI
!
v
H
/-F~-k
H3
z__ R a_
H
b
CH3
£ d e
iPr Br C1
Scheme 1 Racemic cyanohydrins were prepared by addition of KCN/AcOH buffer (pH 5.5) to an aromatic aldehyde in methanol. The mixture was stirred overnight, followed by extraction with methylenechloride; the organic phase was washed with water and dried over anhydrous sodium sulfate then the solvent was evaporated under reduced pressure. The compounds 1....an, 1...b_band l...~eare yellow oils, whereas ld and 1..&eare solids, identified by IR and NMR. The corresponding (R)-cyanohydrins were prepared from aromatic aldehydes in methanol, citrate buffer (0.02 M, pH 4.0), KCN/AcOH buffer (1N, pH 4.0),
and Capulin
(Prunnus eapuli) defatted meal as a biocatalyst. After the mixture was stirred for 4h (lb for l_~a), it was worked up as indicated in the preparation of racemic cyanohydrins, lz
8761
The
derivatization
o f the
(R)-cyanohydrin
was
made
in m e t h y l e n e c h l o r i d e
by
r e a c t i o n with the ( S ) - n a p r o x e n ® c h l o r i d e (1 eq) and p y r i d i n e (1 eq). The mixture was stirred for 1 hour, after this time the s o l u t i o n w a s e x t r a c t e d with a s o l u t i o n o f s o d i u m b i c a r b o n a t e , w a s h e d with w a t e r , and d r i e d o v e r a n h y d r o u s s o d i u m sulfate. The solvent was e v a p o r a t e d to d r y n e s s ; all the p r o d u c t s w e r e solids. The d i a s t e r e o i s o m e r s ( 2 a - 2 e ) were d i s s o l v e d in a c e t o n e and a n a l y z e d by HPLC using a ODS H y p e r s i l column, and methanol-water as mobile phase, the results are shown in T a b l e 1. T a b l e 1. E n a n t i o m e r i c e x c e s s o f ( K ) - c y a n o h y d r i n s . Product
%ee by 1H-NMRa
Product
%ee by H P L C t'
la
96.25
2a
96.40
lb
88.14
2.bb
88.32
le
79.20
2c
78.57
1._rid
81.12
2....dd
79.22
le
80.40
2_.£
75.46
a using [Eu(hfc)3] as a chiral shift reagent. b using (S)-Naproxen ® chloride as a derivatizing agent. In o r d e r to v a l i d a t e the r e s u l t s from the HPLC analysis we d e c i d e d to use a n o t h e r m e t h o d to d e t e r m i n e the o p t i c a l p u r i t y o f the c y a n o h y d r i n , p r i o r to the d e r i v a t i z a t i o n . The m e t h o d s e l e c t e d was I H - N M R using a chiral shift r e a g e n t , [Eu(hfc)3] in this case. F r o m the results shown in T a b l e 1 it can be o b s e r v e d the c l o s e s i m i l a r i t y o f the ee values o b t a i n e d from the t w o different m e t h o d s . During the ester f o r m a t i o n we o b s e r v e d some r a c e m i z a t i o n after long p e r i o d s o f r e a c t i o n , one h o u r being e n o u g h to c o m p l e t e the esterification
without
significant
racemization.
We
conclude
that
this
procedure,
d e r i v a t i z a t i o n o f the ( R ) - c y a n o h y d r i n with the c h l o r i d e o f ( S ) - n a p r o x e n ® and analysis by HPLC, is an easy, i n e x p e n s i v e and a c c u r a t e m e t h o d to d e t e r m i n e e n a n t i o m e r i c excess o f these k i n d s o f c o m p o u n d s , and it d o e s not use e x p e n s i v e chiral columns.
Acknowledgments We wish to thank the financial support o f Consejo Nacional de Ciencia y Tecnologia, M~xico, (Grant. Num. 400200-5-0491).
8762
References
1. 2.
Becker, W.; Freund, H.; Pfeil, E. Angew. Chem.,"lnt. Ed. Engl 1965, 4, 1079. Lyle, G. G.; Lyle, K.E. In Asymmetric Synthesis; Morrison, J.D., Ed.; Academic Press: New York, 1983, Vol 1, Chapter 2, p 19-26. 3. Effenberger, F.; Ziegler, T.; FOrster, S., Angew. Chem.; lnt. Ed Engl. 1987, 26, 458. 4. Brusee, J.; Roos, E.C.; Van der Gen, A., Tetrahedron Lett. 1988, 29, 4485. 5. a) Effenberger, F.; HSrsch, B.; FOrster, S.; Ziegler, T., TetrahedronLett. 1990,31, 1249;b) Ognyanov, V.I.; Datcheva, V.K.; Kyler, K.S., or. Am. Chem. Soc. 1991, 113, 6992; c) Effenberger, F.; Heid, S., Tetrahedron: Asymm. 1995, 6, 2945. 6. a) Huuhtanen T.T.; Kanerva, L.T., Tetrahedron: Asymm. 1992, 3, 1223; b) Kiljunen, E.; Kanerva, L.T., Tetrahedron: Asymm. 1994, 5, 311. 7. M6ndez,E.; Brieva, R., ReboUedo, F.; Gotor, V., J. Chem. Soc.; Chem. Commun 1995, 989. 8. Hickel, A.; Gradnig, G.; Scall, M.; Zangger, K.; Griengl, H., Spectr. Chim. Acta, Part A 1997, 53, 451. 9. Seco, J.; Latypov, Sh.; Quifio~,E.; Riguera, R., Tetrahedron Lett. 1994, 35, 2921. 10. Fauconnot, L.; Nugier, C.; Noiret, N.; Patin, H., Tetrahedron Lett. 1997 38, 7878. 11. Farmacopea de los Estados Unidos Mexicanos, 5a ed., M6xico, 1998, pp. 781. 12. Solis,A.; Luna, H.; P&ez, H.I.; Manjarrez, N.; Shnchez, R.; Submited for publication in Rev. Soc. Quire. Mex.
Tetrahedron Letters 39 (1998) 8759-8762
Pergamon
(S)-Naproxen® as a Derivatizing Agent to Determine Enantiomeric Excess of Cyanohydrins by HPLC. Aida Soils', H~ctor Luna, Herminia L P~rez, Norberto Manjarrez, Remedios Sdnchez Depto. SistemasBiol6gicos,UniversidadAut6nomaMetropolitana-Xochimilco~Calz. del Hueso 1100, Col. Villa Quietud; Mexico,D.F., CP 04960, MEXICO
Atflano Guti6rrez Laboratoriode ResonanciaMagn6ticaNuclear, UniversidadAut6nomaMetropolitana-lztapalapa; Av. Michoacbny La Pufisima s/n, Col. Vicentina;M6xico,D.F., CP 09340, MEXICO Received 3 August 1998; revised 11 September 1998; accepted 18 September 1998 Abstract: An easy, inexpensive and accurate method to determine enantiomeric excess of cyanohydrins is described. The method consists in derivatization of cyanohydrins with (S)-naproxen® chloride and the products analyzed by HPLC. The results of enantiomeric excess so determined are similar to those obtained with [Eu(hfc)3], as a chiral shift reagent, and analysis by 1H-NMR of the cyanohydrins. © 1998 Elsevier ScienceLtd. All rights reserved. D e t e r m i n a t i o n o f o p t i c a l p u r i t y o f o r g a n i c c o m p o u n d s is v e r y i m p o r t a n t , mainly for those with b i o l o g i c a l activity. It is well k n o w n that this a c t i v i t y d e p e n d s on the s t r u c t u r e o f the substance, in such a w a y that the b i o l o g i c a l r e s p o n s e due to each e n a n t i o m e r could be different. B e c a u s e o f this, it is n e c e s s a r y to have an a d e q u a t e m e t h o d to a c c u r a t e l y determine e n a n t i o m e r i c excess. In
the
earlier
investigations,
the
optical
purity
of
cyanohydrins
was
solely
d e t e r m i n e d from the o p t i c a l r o t a t i o n , ~ but a c t u a l l y this m e t h o d is not reliable. ~ There have been e m p l o y e d s e v e r a l m e t h o d s to d e t e r m i n e e n a n t i o m e r i c e x c e s s o f c y a n o h y d r i n s , which include the f o l l o w i n g : f o r m a t i o n o f d i a s t e r e o m e r i c e s t e r s by r e a c t i o n with (R)-ctm e t h o x y - c t - t r i f l u o r o m e t h y l p h e n y l a c e t o y l c h l o r i d e and the o p t i c a l p u r i t y d e t e r m i n e d by gas
chromatography 3
or
HPLC
analysis; 4
(heptafluoropropylhydroxymethylene)-d-camphorate] chiral
shift
reagent; 5 derivatization
as a c e t a t e s ,
by
1H-NMR
europium to
(III)
prevent
using
tris-[3-
[Eu(hfc)3]
decomposition
as
a
o f the
c y a n o h y d r i n , f o l l o w e d by gas c h r o m a t o g r a p h i c analysis using a 13-cyclodextrin column; 6 derivatization
with
(+)-methoxytrifluorometylphenylacetic
acid
(MTPA)
chloride
f o l l o w e d by xgF-NMR 7 or I H - N M R analysis; I H - N M R o f m i x t u r e s o f m a n d e l o n i t r i l e and c y c l o d e x t r i n in a q u e o u s solution, s D e r i v a t i z a t i o n o f a l c o h o l s with the c o m m e r c i a l l y available (R)- and (S)- ( M T P A ) or its a n a l o g u e M P A , and f u r t h e r analysis by 19F-NMR and 1H-NMR is w i d e l y used. 9 Because o f their similar s t r u c t u r e and their a t t r a c t i v e p r i c e c o m p a r e d to the e x p e n s i v e c o m m e r c i a l MPA, r e c e n t l y ( S ) - I b u p r o f e n ® a n d ( S ) - N a p r o x e n ® have been used as chiral 0040-4039/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PiI: S0040-4039(98)01990-X
8760
derivatizing agents to assess enantiomeric excess of chiral sulfoxides by 1H-NMR.I° It is our aim to look for an accessible method to determine eaantiomeric excess of (R)-cyanohydrins. We report in this paper the use of (S)-naproxen ® as a derivatizing agent, and
analysis of the diastereomeric ester of the (R)-cyanohydrin by HPLC,
(Scheme 1) and comparison of the results with those obtained by use of [Eu(hfc)3], as a chiral shift reagent, and analysis by IH-NMR. The (S)-naproxen ® used to prepare the diastereomeric derivates of cyanohydrins was obtained by extraction with chloroform from commercially available tablets (mp. and optical activity were identical to those in literature) tl, the acid chloride was prepared by reaction with oxalyl chloride in hexane. The solid produced after evaporation of the solvent was used without any further purification to prepare the diastereoisomeric derivative of the (R)-cyanohydrin.
~ ~ , ,HmlH R,,~
"CN
+
CI
H
C,H~, j
~O~ocH
3
RI
!
v
H
/-F~-k
H3
z__ R a_
H
b
CH3
£ d e
iPr Br C1
Scheme 1 Racemic cyanohydrins were prepared by addition of KCN/AcOH buffer (pH 5.5) to an aromatic aldehyde in methanol. The mixture was stirred overnight, followed by extraction with methylenechloride; the organic phase was washed with water and dried over anhydrous sodium sulfate then the solvent was evaporated under reduced pressure. The compounds 1....an, 1...b_band l...~eare yellow oils, whereas ld and 1..&eare solids, identified by IR and NMR. The corresponding (R)-cyanohydrins were prepared from aromatic aldehydes in methanol, citrate buffer (0.02 M, pH 4.0), KCN/AcOH buffer (1N, pH 4.0),
and Capulin
(Prunnus eapuli) defatted meal as a biocatalyst. After the mixture was stirred for 4h (lb for l_~a), it was worked up as indicated in the preparation of racemic cyanohydrins, lz
8761
The
derivatization
o f the
(R)-cyanohydrin
was
made
in m e t h y l e n e c h l o r i d e
by
r e a c t i o n with the ( S ) - n a p r o x e n ® c h l o r i d e (1 eq) and p y r i d i n e (1 eq). The mixture was stirred for 1 hour, after this time the s o l u t i o n w a s e x t r a c t e d with a s o l u t i o n o f s o d i u m b i c a r b o n a t e , w a s h e d with w a t e r , and d r i e d o v e r a n h y d r o u s s o d i u m sulfate. The solvent was e v a p o r a t e d to d r y n e s s ; all the p r o d u c t s w e r e solids. The d i a s t e r e o i s o m e r s ( 2 a - 2 e ) were d i s s o l v e d in a c e t o n e and a n a l y z e d by HPLC using a ODS H y p e r s i l column, and methanol-water as mobile phase, the results are shown in T a b l e 1. T a b l e 1. E n a n t i o m e r i c e x c e s s o f ( K ) - c y a n o h y d r i n s . Product
%ee by 1H-NMRa
Product
%ee by H P L C t'
la
96.25
2a
96.40
lb
88.14
2.bb
88.32
le
79.20
2c
78.57
1._rid
81.12
2....dd
79.22
le
80.40
2_.£
75.46
a using [Eu(hfc)3] as a chiral shift reagent. b using (S)-Naproxen ® chloride as a derivatizing agent. In o r d e r to v a l i d a t e the r e s u l t s from the HPLC analysis we d e c i d e d to use a n o t h e r m e t h o d to d e t e r m i n e the o p t i c a l p u r i t y o f the c y a n o h y d r i n , p r i o r to the d e r i v a t i z a t i o n . The m e t h o d s e l e c t e d was I H - N M R using a chiral shift r e a g e n t , [Eu(hfc)3] in this case. F r o m the results shown in T a b l e 1 it can be o b s e r v e d the c l o s e s i m i l a r i t y o f the ee values o b t a i n e d from the t w o different m e t h o d s . During the ester f o r m a t i o n we o b s e r v e d some r a c e m i z a t i o n after long p e r i o d s o f r e a c t i o n , one h o u r being e n o u g h to c o m p l e t e the esterification
without
significant
racemization.
We
conclude
that
this
procedure,
d e r i v a t i z a t i o n o f the ( R ) - c y a n o h y d r i n with the c h l o r i d e o f ( S ) - n a p r o x e n ® and analysis by HPLC, is an easy, i n e x p e n s i v e and a c c u r a t e m e t h o d to d e t e r m i n e e n a n t i o m e r i c excess o f these k i n d s o f c o m p o u n d s , and it d o e s not use e x p e n s i v e chiral columns.
Acknowledgments We wish to thank the financial support o f Consejo Nacional de Ciencia y Tecnologia, M~xico, (Grant. Num. 400200-5-0491).
8762
References
1. 2.
Becker, W.; Freund, H.; Pfeil, E. Angew. Chem.,"lnt. Ed. Engl 1965, 4, 1079. Lyle, G. G.; Lyle, K.E. In Asymmetric Synthesis; Morrison, J.D., Ed.; Academic Press: New York, 1983, Vol 1, Chapter 2, p 19-26. 3. Effenberger, F.; Ziegler, T.; FOrster, S., Angew. Chem.; lnt. Ed Engl. 1987, 26, 458. 4. Brusee, J.; Roos, E.C.; Van der Gen, A., Tetrahedron Lett. 1988, 29, 4485. 5. a) Effenberger, F.; HSrsch, B.; FOrster, S.; Ziegler, T., TetrahedronLett. 1990,31, 1249;b) Ognyanov, V.I.; Datcheva, V.K.; Kyler, K.S., or. Am. Chem. Soc. 1991, 113, 6992; c) Effenberger, F.; Heid, S., Tetrahedron: Asymm. 1995, 6, 2945. 6. a) Huuhtanen T.T.; Kanerva, L.T., Tetrahedron: Asymm. 1992, 3, 1223; b) Kiljunen, E.; Kanerva, L.T., Tetrahedron: Asymm. 1994, 5, 311. 7. M6ndez,E.; Brieva, R., ReboUedo, F.; Gotor, V., J. Chem. Soc.; Chem. Commun 1995, 989. 8. Hickel, A.; Gradnig, G.; Scall, M.; Zangger, K.; Griengl, H., Spectr. Chim. Acta, Part A 1997, 53, 451. 9. Seco, J.; Latypov, Sh.; Quifio~,E.; Riguera, R., Tetrahedron Lett. 1994, 35, 2921. 10. Fauconnot, L.; Nugier, C.; Noiret, N.; Patin, H., Tetrahedron Lett. 1997 38, 7878. 11. Farmacopea de los Estados Unidos Mexicanos, 5a ed., M6xico, 1998, pp. 781. 12. Solis,A.; Luna, H.; P&ez, H.I.; Manjarrez, N.; Shnchez, R.; Submited for publication in Rev. Soc. Quire. Mex.