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Determination of the Enantiomeric Ratio of Unprotected Amino Acids by NMR Spectroscopy with C2-Chiral Palladium Compounds.

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fore, in our future preparative-scale studies with 2, we will apply
the electrochemical regeneration of the oxidized flavin under
anaerobic conditions"] in order to complete the catalytic cycle.
These studies with 2, which has been prepared in gram quantities, will also explore the interesting catalytic oxidation of aldehydes into carboxamides. In parallel, we are investigating the
monooxygenase activity of the novel flavo-cyclophane 24 in the
hydroxylation of phenolic compounds.["J
Received: January 31, 1996 [Z87111E]
German version: Angnr. Chem. 1996, /OX, 1434-1437
Keywords: cyclophanes
*
enzyme mimetics
- pyruvate oxidase
[ I ] S.-W Tam-Chang, L. Jimenez, F. Diederich. Hrlv. Chim. Actu 1993, 76, 26162639.
(21 a) B. Sedewitz. K. H. Schleifer. F Gotz. J Bucteriol. 1984, 160. 273-278; b) F.
Gotz. B. Sedewitz in Biochetnistr? rind Physiology of' Thiamine Diphospkute
Enq~me.~,
(Eds.: H. Bisswanger, J. Ullrich), VCH, Weinheim, 1991, pp. 286293.
131 a) Y. A. Muller. G. E.Schulz, Science (Washington, D. C.) 1993,259.965-967;
b) Y A. Muller. G . Schumacher, R. Rudolph, G . E. Schulz. J Mol. Bioi. 1994.
237,315-335.
[4] a) J. Castells. H. Llitjos, M. Moreno-Maiias. li.truher/ron Letr. 1977, 205-206;
b) J. Castells, F. Pujol. H. Llitjos, M Moreno-Mafias. Terruhwlron 1982. 38,
337 -346; C) H Inoue. K . Higdshiurd, J. Cheni. Soc. Chrrn. Con?rnurt. 1980,
549-550, d) H. Inoue, S. Tamura, ihid. 1985. 141 -142; e) Y. Yano. Y Tsukagoshi. J Chem. Res. is) 1984.406-407.
[5] a) Y. Ymo, Y Hoshino. W. Tagaki, Chern. Lett. 1980. 749-752; b) S. Shinkai,
T. YdmdShita. Y Kusano, 0 . Manabe, 7iclr-uhedronLett. 1980,2f. 2543-2546;
c) S. Shinkai, T. Yamashita. Y. Kusano, 0. Manabe, J. Org. Chrnt. 1980. 45,
4947-4952; d) J. Am. Chem. So?. 1982, 104, 563 -568.
[6] D. Hilvert, R. Breslow, Bioor;p. Clien~.1984. 12. 206-220.
171 a) For a discussion of the reaction of thiazohum salts with benzaldehyde see:
Y:T. Chen. G. L. Barletta, K. Hagjoo, J. T. Cheng. F. Jordan, J Org. Chein.
1994. S9, 7714-7722; b) R. Breslow, J. A m C h m . Soc. 1951, 79, 1762-1763;
c) ihirl. 1958. XO, 3719-3726.
[8] This redox reaction has been investigated in detail on a model system: C. C.
Chiu, K. Pan. F. Jordan. J Am. Chem. Soc. 1995. 117, 7027-7028.
[9] a) F. Diederich, Cdophunes, The Royal Society of Chemistry, Cambridge.
1991; b) F. Diederich, K. Dick. D. Griebel. Chem. Ber. 1985. I / & 3588-3619:
c) D R. Carcanague. F. Diederich, Angew. Chent. 1990. 102. 836 -838; Angew.
Chem. I n ! . Ed. EngI. 1990, 29, 769-711.
(10) All new compounds described were fully characterized by 'H and I3C NMR,
FT-IR, UVjVIS, and fluorescence spectroscopy, mass spectrometry (FAB' o r
EI), and elemental analysis o r high-resolution mass spectrometry.
[I I] D. R. Carcanague. Ph.D. Thesis. University of California. Los Angeles, 1991
[12] B. Amit, E. Hazum, M. Fridkin, A. Patchornik. Inr. J. Prpr. Protpin Res 1977.
9, 91 -96.
1131 a) N. Miyaura, T. Yanagi, A. Suzuki. Synih. Contmun. 1981. I f , 513-519:
b) N. Miyaura, A. Suzuki. Chenr. Rev. 1995. 95, 2457-2483.
[14] a) F. Yoneda. Y Sakuma, M. Ichiba, K. Shinomura, J. Ani. Chmi. Soc. 1976.
9X. 830-835; b) F Yoneda, Y. Sakuma. K. Shinomura. J. Chem. Soc. Perkrn
Truns 1 1978, 348-351; c) F. Yoneda, K. Shinozuka. K. Hiromatsu. R. Matsushita, Y. Sakuma, M Hamana, Chenz. Phurm. Bull. 1980, 2X. 3576-3583.
[15] Experiments were run in triplicate in a 0.2 cm U V cuvette at T = 300 K and
[Et,N] = 50mM. Eadie-Hofstee plots (vvs. ~/[2-naphthaldehyde])and nonlinear least-squares curve-fitting of the saturation kinetics data gave k,,, and K ,
values identical to those determined in the Lineweaver-Burk plot. The wavelength 7. For the monitoring of the disappearance of the visible flavin absorption
was chosen in such a manner that the initial absorbance was A , =1.0:
[2] = 0 . 5 m ~ . i.= 455.0 nm; [3] = 2 m ~ .>. = 505.2 nm: [4] = 10mM. and
[S] = 2 m ~j. , = 510.4 nm. In the reaction with (4 + 5 ) . k , was found to be zero
order in [S]. The reaction velocity for the catalyst system ( 1 +26) had been
measured under similar conditions at T = 303 K . L. S. Jimenez. Ph.D. Thesis.
University of California, Los Angeles. 1989 [I]
[16] A. Fersht, Enzyme Structurc uwd Mechuriisn?. 2nd ed., Freeman. New York.
1985.
[17] H . Dugas, Bioorgunic Cherni.stry.3rd ed., Springer. New York, 1995. and references therein.
I181 T C. Bruice, N. G. Kundu, J. Ant. Cliem. Soc. 1966, 88. 4097--4098.
.
[19] Reactions were run For 1 h at room temperature and [Et,N] = 5 0 m ~ [alde, 121 = 5 m ~ .
hyde] = 5 O m ~and
[20] A widely studied enzyme performing this reaction is the FAD-dependent
monooxygenase 4-hydroxybenzoate hydroxylase, see B. Entsch. W. J. H. van
Berkel, FASEE J. 1995, 9,476-483.
1344
0 VCH
Verlagsgesellschuft mhH, 0-69451 Wetnherrn, 1996
Determination of the Enantiomeric Ratio of
Unprotected Amino Acids by NMR Spectroscopy
with C,-Chiral Palladium Compounds
Bernd Staubach and Joachim Buddrus*
a-Amino acids are important compounds in chemistry and
biochemistry. Current syntheses focus on compounds with S- or
R-configuration and with additional substituents in a- o r other
In most cases, for the determination of the enantiomeric ratio the chiral amino acid is chemically modified and
subjected to N M R spectroscopy or chromatography. N M R
is carried out by reacting the amino acid with chiral
carboxylic acid chlorides under Schotten - Baumann condit i o n ~ [or
~ ] with chiral phosphonates;[61in each case a workup
procedure of the diastereomeric mixture is necessary prior to
N M R analysis. N M R analysis is also feasible with water-soluble
chiral lanthanoid shift reagents, however, line broadening due
For gas chroto paramagnetic relaxation is often
matographic analysis the amino acid is converted in two steps to
its corresponding N-acyl ester and investigated on a chiral stationary p h a ~ e . [ ~Liquid
. ~ l chromatographic analysis is carried
out with diastereomeric derivatives (from chiral isothiocyanate[Io1)under normal phase conditions on an achiral stationary phase, or with free amino acids under reversed-phase
conditions in the presence of chirdl auxiliaries either in the mobile["] o r in the stationary phase;['21analysis with free amino
acids by liquid chromatography may suffer from problems concerning UV detection." Ibl Analysis by capillary electrophoresis
is accomplished after derivdtization with o-phthaldialdehydel
cysteine.r'31Here we report on a N M R spectroscopic method
that permits determination of the enantiomeric ratio of the unprotected amino acid by using chiral palladium compound~.['~1
[Pd(H2NCH,CH,NH2)(H20)2(N03)2](1 a) is known to react with a-amino acids 2 in water to yield the square-planar
bicyclic compounds 3a.[l51Starting from optically active C,-chiral 1,2-diamines, we prepared aqueous solutions of the chirdl
palladium compounds 1 b - e and subsequently treated them
with amino acids to give the diastereomeric palladium complexes 3 b - e (cislfrans isomers). The N M R analysis of the
diastereomeric complexes yielded the enantiomeric ratio of the
amino acid directly.
The equilibrium (a) lies predominantly but not completely to
the right, and is slow on the N M R time scale, as indicated by
N M R signals of both the free and the complexed amino
acid.However, complexation is completed by adding NaOD (ca.
0.75 equiv). The addition of larger amounts was avoided to
1
2
1 0
0
NO:
2 NO?
1
a
b
c
d
e
R
H
CH3
C6H5
CH2CH2CD20CH3
2
3 a-e
[*] Prof. Dr. J. Buddrus, DipLChem. B. Staubach
Institut Fur Spektrochemie und Angewandte Spektroskopie an der Universitit
Postfach 101352. D-44013 Dortmund (Germany)
Fax: Int. code + (231)1392-120
0570-0833/9613512-1344 .t 15.00f ,2510
Angen. Chijm. In!. Ed. Engl. 1996. 35, No. 12
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prevent dimerization of
o r ring opening of 3I"I in alkaline
solution. The N M R signals of the two diastereomers are separated both in the 'H and I3C N M R spectra. The amino acid
residue yields two sets of N M R signals, whereas the diamine
residue leads to four sets of signals (two pairs of diastereomeric
atoms). Figure l a and I b show the I3C and 'H N M R spectrum
of 3d, which is obtained from DL-alanine and Id. To test the
ability of the chiral palladium compounds 1 as suitable auxiliaries, alanine with different R/S ratios was prepared by weighing the pure enantiomers and examining the products of the
reaction with I d . N M R spectroscopic analysis gives the same
ratio within the experimental error ( & 1 %; Fig. Ic). Evidently,
kinetic resolution (if any) is below the N M R detection limit.
15.2
55.5/
l b + proline
18.0,
Id + tryptophane
I d + threonine
l e + valine
--192.5
192.0
1.35
1.30
1.25
1.35
1.30
I
1.25
'96
l e + serine
\-,
-6
-8
-8
-L460
Id + histidine Ic]
Fig. I . NMR spectra of3d (R' = CH,) in D,O; a) "C N M R spectrum (100 MHz.
carbonyl region). b) and c) 'H N M R spectrum (400 MHz, methyl region) from
ui-alanine and L-alanine with 80% ee. respectively.
-
11.6'
Ib + methylphenylglycine Id1
l b + 0-aminobutyric acid
,23.0
/-I90
To investigate the influence of the substituent R in 3b-e on
the magnitude of the N M R signal separation, several optically
active 1.2-diamines were tested :[lS1 (2&3S)-2,3-diaminobutane,
(1 R,2R)-1,2-diphenylethylenediamine, (1 R,2R)-1,2-diaminocyclohexane, (2 R,3R)-2,3-diamino-l ,I ,4,4-tetradeuterio-I ,4-dimethoxybutane, and in addition to these C2-chiral diamines
(R)-l,2-propylenediamine.
The results obtained with DL-alanine
as analyte are presented in Table 1. The largest signal separation
Table 1. ' H NMR signal separation of the diastereomeric mixture of type 3, obtained from the auxiliaries Ib-f and m-alanine.
Auxiliary
Ad [Hz][a]
lc
22.4
Id
Ib
le
14.0
10.8
8.2
If1
J
l e + a-thienylglycine lel
Scheme 1. Diastereomeric 'H (400 MHz) and "C (100 MHz) signal separations
(in Hz) of some palladiumpL-amino acid complexes (')C NMR signal separations
in italics). a) Separation arbitrarily assigned to one of the two constitutopic groups;
b) separation arbitrdriliy assigned to one of the diastereomeric protons; c) structure
proposed according to ref. [20]; d)-f) compounds kindly provided by Prof. M.
Schneider. Prof. H. J. Altenbach, Wuppertal, and Prof. G. Haufe. Munster. respectively; g) I9F N M R at 360 MHz.
1 f Ibl
7.0
[a] Separation of the CH, signals in the alanine residue at 400 MHz. [b] Obtained
from (R)-l.2-diaminopropane [19].
was observed with 1c (R = phenyl), which can be explained by
the magnetic anisotropy of the benzene ring. Unfortunately,
compound I c is only sparingly soluble in D,O, necessating
longer N M R measuring time. Most experiments were performed with the auxiliary 1 b, because this compound is sufficiently water-soluble and gives simple 'H N M R spectra. Several
natural sc-amino acids, three artificial a-amino acids (one of
them alkylated in 1-position), and one /?-amino acid, all of them
unprotected, were investigated; selected 'H and 13CN M R signal separations are given in Scheme 1.
In summary. the enantiomeric ratio of a chiral 2- or ,&amino
acid can be easily determined: The free amino acid is simply
added to an aqueous solution of one of the optically active
palladium compounds I b-e. and the diastereomeric mixture is
An,prw. C'ht~in l i i r . Ed. EngI. 1996. 35, No. 12
'H
Id + y-fluoraminobutyric acid
directly analyzed by 'H o r I3C N M R spectroscopy. In contrast
to line widths obtained with paramagnetic lanthanoid shift
reagents, the line width of all compounds of type 3 is less than
1 Hz. We are currently preparing further auxiliaries of type 1
with a view to increasing the magnitude of the separations of the
N M R signals. Even larger separation of the N M R signals are
obtained with the C,-chiral compound l a (NH, replaced by
(R)-NHCH(CH,)C,H,): 98 Hz (400 MHz) for the protons of
the methyl group in DL-alanine.
E.xperimental Procedure
The chiral diamines [lX] were treated with [K,PdCI,] to give the corresponding
[Pd(diamine)CI,] complexes [21]. [Pd(diamine)CI,] (0.02 mmol) and AgNO,
(0.04 mmol) were suspended in D,O (1 mL) and stirred for 30 minutes. After removal of the precipitated AgCl by centrifugation, a clear yellow solution of [Pd(diamine)(D,O),(NO,),] (1). which is stable at room temperature for several months,
was obtained [16]. Free amino acid 2 (0.017 mmol) and NaOD (0.01Smmol)
were added and the mixture was stirred until it became clear (1 to 10 minutes).
The solution was analyzed by ' H NMR spectroscopy. For analysis by "C NMR
c,VCH YerlagsgrsellsrhuffmbH. 0.69451
Weinl7eim. 1996
0570-0833/96/3512-1345S 15.00+ 25 0
1345
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spectroscopy the concentrations of the reactants were chosen 15 times higher
(about 0 . 3 ~ ) ,which is the upper limit of solubility for the compounds I b. Id.
and l e .
Received: December 15. 1995 [Z86481E]
German version- Angeir. Chen7. 1996. 108, 144-1445
Keywords: amino acids * chiral auxiliaries - NMR spectroscopy
palladium compounds
-
[l] a) R. M. Williams, Synthesis q/ Opticrrllr Acriiv a-Amino Arid& Pergamon,
Oxford. 1989; b) J. Mulzer, H. J. Altenbach. M. Braun, K. Krohn. H. U.
Reissig Organic Synthesis Highlights, VCH, Weinheim. 1991.p. 300.
[2] J. Kamphuis, W. H . J. Boesten, B. Kaptein, H. F. M. Hermes, T. Sonke. Q. B.
Broxterman. W. J. J. van den Tweel, H. E. Schoemaker in Chrralifj,in 1ndustr.r
(Eds.: A. N. Collins, G. N. Sheldrake, J. Crosby). Wiley, 1992,p. 187.
[3] J. W. Scott. Top. Strreorhem. 1989,19,209.
[4] For reviews concerning NMR spectroscopic determination of enantiomeric
purity of organic compounds including amino acids see: a ) D. Parker. Ci~en7.
Rei'. 1991. 91. 1441; b) R. Hulst, R. M. Kellogg. B. L. Feringa, Red. Trur.
Chim. Puys-Bus 1995. 114. 115.
[S] a) W. H. Kruizinga, J. Bolder, R. M . Kellogg, J. Org. Cheri7. 1988.53,1826; b)
W. Breuer. I. Ugi. J. Chem. Res. Miniprint 1982. 2901
[6] a) R. Hulst, R. W. J. Zijlstrd, N. Koen de Vries, B. L. Feringa. Ti~troherlron:
Asymmetry 1994,5.1701; b) R. Hulst, N. Koen de Vries, B. L. Feringa, Angew
Cliem. 1992. 104, 1089; Angeir. Chem. In/. Ed. Engl. 1992. 31, 1092.
[7] a) K. Kabuto, Y Sasaki, J. Chein. S<JC.Cllem. C o m m 1984.316: b) R. Hulst,
N. K. deVries. B. L. Feringa. J. Or-g. Cheri?. 1994, 59, 7453; c) J. Kido. Y.
Okamoto, H. G. Brittain, J. Orx. Clzen?. 1991. 56. 1412. d) J.A. Peters,
C. A. M. Vijverberg. A. P. G . Kieboom, H. van Bekkum. Tetroheilron Lett.
1983.24. 3141.
[XI E. Gil-Av, B. Feibush, R Charles-Sigler, Tetruhedron Lett. 1966,1009.
191 V. Schurig, Asymmetric Synrh. 1983. I . 59.
[lo] M. Lobell, M. P. Schneider, J Chromurogr. 1993,633,287.
I l l ] a) V Davanakov, Y. Zolototarev. A. Kurganov. J Liy. Chrori7utograpliy 1979,
2,1191 ; b) W H. Pirkle. Asymmetric Synth. 1983. I, 87.
[I21 a) T. Shinbo, T. Yamaguchi, K. Nishimura, M. Sugiura, J. Chromurogrcrpli.
1987.405.145;b) A.Shibukawa. T. Nakagawa in Chrrul Sepurutions & HPLC
(Ed.. A. M. Krstulovic). Wiley. 1989. p. 476.
[13] H. J. Issaq. K . C. Chan, Elec~rophorests1995,16. 467.
[14] For NMR analysis of chiral aminophosphonic acids with [K,PdCI,] see: 2.
Glowacki. M. Topolski. E. Matczdk-Jon, M. Hoffmann. Mugn. Res. Chern.
1989.27. 922.
[15] M. C. Lim. J. Chem. SOC.Dalton Trans. 1978. 726.
[16] M. C . Lim. R. B. Martin, J lnorg Nucl. Cheni. 1976,38. 1911.
[17] T G. Appleton, A. J. Bailey. D. R. Bedgood, Jr.. J. R. Hall. lnorg. Chern. 1994.
33. 217.
[lS] (1 R.2R)-1,2-diphenylethylenediamineand (1 R.2R)-1,2-diaminocyclohexane
were purchased from Fluka. Buchs. Switzerland. (R)-1.2-diaminopropdne was
prepared according to ref. [19]. (2S,3S)-2,3-diaminobutane was prepared starting from (2R,3R)-2,3-butandio1 [22]. (2R.3R)-2,3-diamino-l,l,4.4-tetradeuterio-1.4-dimethoxybutanewas prepared according to the corresponding undeuterated compound [23] starting from (2R,3R)-dirnethyltartrate acetonide.
total yield over six steps 21 YO.'H N M R (as bishydrochloride in [DJDMSO):
6 = 8.74 ( s , 6 H , 2 N H 3 1, 3.67 (s, 2H. CH), 3 53 (s. 6H. 20CH,); "C{'H}
N M R ([DJDMSO): 6 = 66.1 (quint.. CD,; J(C,D) = 22 Hz), 58.5 (OCH,).
49.8 (CH).
[19] F P. Dwyer. E L . Grawan, A. Shulman, J. Am. Chem. SOC.1959,H I , 290.
[20] N. N. Chernovd, V. V. Strukov. G . B. Avetikyan, V. N. Chernonozhkin. Russ.
J. lnorg. Chem. 1980. 25,872.
[21] B. J. McCornick E. N . Jaynes, Jr.. R. I. Kaplan. Inorg. Swrh. 1972,13. 216.
1221 S. Y. M. Chooi, P.-H. Leung, S:C. Ng. G. H. Quek, K. Y. Sim. Tetrahedron:
Asyrnmetry 1991, 2. 981.
[23] D. Seebach, H. 0. Kalinowski. B. Bastani, G. Crass, H. Daum, H. Dorr. N. P.
DuPreez, V. Ehrig. W. Langer, C. Nussler, H.-A. Oei. M. Schmidt, H e h . Chim.
Arta 1917.60. 301
Chiral Catalytic Membranes**
Ivo F. J. Vankelecom,* Diedrik Tas, Rudy F. Parton,
Valtrie Van de Vyver, and Pierre A. Jacobs
The easy separation of a solid catalyst from the reaction mixture is one of the main advantages offered by heterogeneous
catalysts and an essential prerequisite for their regeneration.
Since the cost of most chiral homogeneous catalysts is very high,
their heterogenization is highly desirable. Chiral complexes are
the most important class of homogeneous enantioselective
catalysts.['] Typical examples are the Ru-BINAP complex
[2,2'-bis(diphenylphosphanyl-1,l '-binaphtyl]chloro( p-cymene)ruthenium['] (1) and the Jacobsen catalyst N,N'-bis(3,5-di-tertbu tylsalicylidene)chloro-l,2-~yclohexanediaminemanganese~~~
(2), which catalyze hydrogenation and epoxidation reactions,
respectively. For the Jacobsen catalyst (2). no successful hetero-
1
2
'CH3
genization procedure has been published, and regeneration does
not seem possible. In only one case was a homogeneous chromium-containing Jacobsen catalyst successfully recycled 5 timesf4]
However, this was in the enantioselective ring opening of epoxides, a reaction that involves no oxidants and thus avoids oxidative destruction of the complex, a major deactivation route for
salen complexes. In the case of BINAP-based catalysts, only a
triphasic system consisting of a solid support, the sulfonated
form of the complex dissolved in an ethyleneglycol phase, and
an immiscible phase containing the substrate has been reported.[']
Here we present the preparation, catalytic characterization,
and regeneration of the heterogeneous chiral catalysts by means
of a new, versatile, and generally applicable method for complex
immobilization. The above-mentioned BINAP complex 1 and
[*] Dr. I. F. J. Vankelecom, D. Tas. Dr. R. F. Parton, V. Van de Vyver.
Prof. P. A. Jacobs
Centrum voor Oppervlaktechemie en Katalyse
Katholieke Universiteit Leuven
Kardinaal Mercierlaan 92, B-3001 Leuven (Belgium)
Fax: Int. code +(16)32199S
e-mail: ivo.vankelecom(a agr.kuleuven.ac.be
[**I This work was supported by the Belgian Federal Government (IUAP-PA1
V. acknowledges a post-doctoral
grant on Supramolecular Catalysis). I. F. .I.
fellowship from the Katholieke Universiteit Leuven. D . T. and R. F. P thank
the Belgian National Fonds voor Wetenschappelijk Onderzoek (N. F. W 0.)
for research grants.
1346
0 VCH
Verlugsgesell.whaffrmbH. 0-69451 Wemheim. 1996
0570-083319613512-1346 $ 15.00+ ,2510
Angen. Chem. I n t . Ed. Engl. 1996. 35, No. I2
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acid, chiral, spectroscopy, enantiomers, nmr, compounds, palladium, amin, determination, unprotected, ratio
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