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Direct Enantiomer Resolution of Hydroxy and Carbonyl Compounds by Gas Chromatography on Chirasil-Val.

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Direct Enantiomer Resolution of Hydroxy and
Carbonyl Compounds by Gas Chromatography on
By Bernhard Koppenhoefer*, Hans Allmendinger. and
Graeme Nicholson
New methods for the chemical and biotechnological
synthesis of chiral active substances"] have led to extraordinarily high enantiomeric excesses (ee), which can be accurately determined only by sensitive, direct methods. Gas
chromatography o n chiral stationary phases[*] such as Chir a ~ i l - V a l [is~ ~the method of choice, providing the substances are sufficiently volatile and have favorable chromatographic properties (retention time, separation factor
u, peak shape).
Polar compounds are, as a rule, derivatized in order to
shorten the time of analysis and avoid peak tailing. Recourse to acylation of hydroxy compounds[41leads to small
separation factors, since the donor functions for hydrogen
bonding with the stationary phase are eliminated. A complete separation on Chirasil-Val is only observed if at least
two ester carbonyl groups are present; aromatic n-systems
additionally promote the separation. Arylethanediols,
which are formed in high enantiomeric yields (ee = 99.4%)
by reduction with bakers' yeast[51, and the atropisomeric
chiral reagent"'] 2,2'-dihydroxy-l,l '-binaphthyl are chromatographed as diperfluoropropionates 1 and 2 , respectively[']. (The respective separation factor u, the column
temperature, and the more strongly retained enantiomers
are given in brackets under the formulas; in some cases,
however, the order of elution of the enantiomers has not
been determined.) Cyclic carbonates obtained from diols
and phosgene have only one carbonyl group and are separable only under carefully optimized conditions[71.
The derivatization of hydroxy groups with nitrogen-con-
W. Francke, Hamburg, and Dr. D.A . Schooley, Palo-
Alto, CA (USA), for kindly supplying reference substances.
3 (1.129, 5 0 ° C )
4 (1.036, 5 0 ° C )
5 (1.067, 8 0 ° C )
From these findings, we can derive a model of the separation mechanism. In the thin-film capillary (film thickness
ca. 0.1 km) there are about lo2 superjacent chiral polymer
chains (selectors of the order of magnitude of 1 nm).
Hence, there is a stationary liquid phase which completely
surrounds the substrate. By rapid reversible inclusion of
the enantiomeric selectands from the gas phase in the chiral cavities of the condensed phase (which are already
present or are formed by a change in conformation), the
entropy is reduced at the expense of the (more favorable)
enthalpy"'. Moreover, since the changing shape of the cavities is averaged over all orientations of the selectands accomodated within them, usually only small differences in
free energies of interaction of the enantiomers result
( -AAG333 = 0. I J/mol for 4). The mobility, however, is already sufficiently restricted by one hydrogen bridge, for
even on rotation about this axis the enantiomers of 4 always differ regarding the sum of the various van der Waals
interactions (attractive and repulsive) with the boundaries
of the virtual chiral cavities. In combination with the high
efficiency of the capillary columns employed ( lo5 theoretical plates), even such an unspecific mechanism enables the
clean separation of a large variety of enantiomeric pairs on
the same stationary phase. For instance, I-menthen-4-01 5
was detected in the pheromone bouquet of bark beetles['"].
lnstitut fur Organische Chemie der Universitat
Auf der Morgenstelle 18, D-7400 Tubingen 1 (FRG)
Prof. Dr.
0 VCH Verlagsgesellschaft mbH, 0-6940 Weinheim. 1985
[*] Dr. B. Koppenhoefer, DipLChem. H. Allmendinger, G. Nicholson
We thank
2 (1.O38,18O0C, R )
taining reagents also has disadvantages : Admittedly, the
separation factors are increased by N-H donor functions,
but the volatility is considerably reduced. Furthermore, the
conversion into urethanes[*] includes the danger of side
reactions and racemization (e.g. in the case of mandelic
acid), often accompanied by an unsatisfactory conversion.
By using suitably deactivated glass capillaries (e.g. with
diphenyltetramethyldisilazane), the functionalization of
the hydroxy groups can be dispensed with in a number of
classes of compounds, since the peak tailing caused by absorption on the column wall is largely suppressed. Thus,
enantiomeric alcohols[91can now be resolved on amide
phases without recourse to derivatization. This method is
applicable to primary (3), secondary (4), and tertiary ( 5 )
alcohols. The surprising resolution of 4 demonstrates that
one strong attractive interaction (e.g. hydrogen bridges of
the type 0 - H . . .O=C) can lead to a satisfactory discrimination of the enantiomers, since 4 contains neither a hetero atom like 3 nor a n system like 5.
6a, R
6b, R
612, R
6d, R
Me (1.034, 5 0 ° C .
E t (1.040, 5 0 ° C ,
iPr (1.031, 5 0 " C ,
tBu (1.074, 5OoC,
7a, K
7b, R
7c, R
(1.034, 5 0 T , R )
iPr (1.061, 7 0 " C , S )
tBu (1.130, 7 0 " C , S )
The enantiomers of the phenyl-substituted alcohols 6
and 7 have been obtained by asymmetric synthesis""] from
the corresponding ketones. In addition, we have been able
to assign the absolute configuration by reduction with bakers' yeast. In 6 , the preference given by the stationary
phase for the R-enantiomers increases with the size of the
alkyl groups (see also Fig. 1). The homologous benzyl derivatives 7 show an analogous trend (in both series, the Lconfigurated alcohol is eluted later["]). The average relative retention time of 7c is only 0.09 at llO"C, referred to
the corresponding isopropylurethane['*I.
Also in the case of the mesityl derivative 8 (hindered rotation), the separation factor u is astonishingly high. The
corresponding naphthyl and anthryl derivatives behave
similarly to 6a. Even dihydroxy compounds, e.g. the phe-
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Angew. Chem. I n l . Ed. Engl. 24 (1985) N o . I
Polyfunctional hydroxycarboxylic acids such as threo2,3-dihydroxybutanoic acid or 2-hydroxyglutaric acid lactone are separated as 3-pentyl esters 15 and 16, respectively; the preparatively useful enantiomers of tartaric acid are
best separated by way of the bisacetonide 17. As was demonstrated some years ago['], even diketones can be completely resolved into the enantiomers without resorting to
derivatization. O n the basis of theoretical considerations,
the 3,4-diphenyl-2,5-hexanedione18 with C2 symmetry
has been chosen as example.
Fig. I . Uerivatization-free enantiomer resolution of hydroxy compounds on
Chirdsil-Val. carrier gas 0.6 bar H,, Duran glass capillary 37 nm x 0.25 nm,
number of theoretical plates 1.3 x lo5. Top: suicide substrate lZc, 110°C isotherm; bottom: increasing separation factors in the phenyl alkanols 6b-6d,
60°C isotherm.
OH 0
15 (1.133, 8 0 ° C , 2 S , 3 R )
16 (1.Ob9, 8 0 ° C , S )
17 (1.040, 8 0 " C , 2 S , 3 s )
18 (1.031, 1 3 0 ° C )
no1 9 or truns-l,2-~yclohexanediol10, can be separated.
The same applies for lactones containing one hydroxy
8 (1.064, 8 0 ° C )
9 (1.035, 1 0 0 ° C )
10 (1.036, 6 0 ° C )
group, e.g. pantolactone 11 or mevalonolactone 12a.
Compounds 12a and 12b are key building blocks in the
biosynthesis of juvenile hormones in insects. The fluorocompound 12c (see Fig. 1) has been employed as suicide
substrate for the inhibition of hormone production in parasites (e.g. the tobacco horn worm Manduca s e ~ t a ) " ~this
is an interesting alternative to biological pest control with
0 0
11 (1.158, 8O"C, R )
13a, K
13b, K
13c, It
Received: August 14, 1984:
revised: September 18, 1984 [Z 966 IE]
German version: Angew. Chem. 97 (1985) 46
Thus, the scope of application of peptide phases partially overlaps that of complexation gas chromatography["],
which is still indispensable in the case of less polar compounds, e.g. pheromones with a spiroketal s t r ~ c t u r e " ~O] n.
the other hand, the thermally stable polymeric phase Chirasil-Val has also proven useful for many polar, less volatile compounds.
1Za, R
12b, R
IZc, R
E t (1.033, 7 0 " C , S)
rPr (1.044, 7 0 " C , R )
P h (1.041, 12O"C, R )
(1.033, llO"C, S )
(1.033, l l O " C , S)
C H , F (1.043, 1 1 0 ° C )
OH 0
14 (1.039, l O O " C , S )
Consequently, open-chain hydroxy acids require only a
simple racemization-free['41 esterification of the carboxy
group. Similarly, as in the case of the 2-hydroxy
3pentanol proves to be the most suitable alcohol component
in the case of 3-hydroxy acids with regard to separation
factor, volatility, and polarity of the derivatives. The separation factors a increase with the size of the main chain. In
contrast to the 2-hydroxy acid esters, however, the L-enantiomer of the 3-hydroxy esters (e.g. S-13a or R-13b)
usually undergoes the stronger interaction with L-ChirasilVal. Tropanoic acid, a 3-hydroxy acid with an asymmetry
center on C-2 (cf. 14), is the chiral component of the alkaloids atropine and hyoscyamine.
Angew. Chem. Inr. Ed Engl. 24 (1985) No. 1
[ l ] a) J. D. Morrison: Asymmetric Synlhesic. Academic Press, New York
1983; b) Biotechnology, Science 219 (1983) 609-746: c) T. H. Maugh,
&id. 221 (1983) 351; d ) H. S . Mosher, J. D. Morrison, h i d . 221 (1983)
1013; e) R. Noyori, 1. Tomino, Y . Tanimoto, J. Am. Chent. Soc. IOI
(1979) 3129.
[2] V. Schurig, Angew. Chem. 96 (1984) 733; Angew. Chem. I n t . E d Engl. 23
(1984) 747.
[3] H. Frank, G. J. Nicholson, E. Bayer, Angew. Chem. YO (1978) 396; Angew. Chem. I n / . Ed. Enql. 17 (1978) 363; E. Bayer, Z . Nafurfi,rsch. 8 3 8
(1983)- I28 I .
[4] a) N. Oi, R. Tdkai, H. Kitahara, J . Chromarogr. 256 (1983) 154; b) W. A.
Konig, 1. Benecke, ibid. 269 (1983) 19.
[5] B. Koppenhoefer, W. Winter, E. Bayer, Liebigs Ann. Chem. 1983. 1986.
[6] B. Koppenhoefer, Dissertation, Universitat Tiibingen 1980.
[7] W. A. Konig, E. Steinbach, K. Ernst, Angew. Chem. 96 (1984) 516; Angew. Chem. I n t . Ed. Engl. 23 (1984) 527.
IS] W. A. Konig, W. Francke, 1. Benecke, J. Chromatogr. 239 (1982) 227.
[9] V. Schurig, R. Weber, Angew. Chem. 95 (1983) 797; Angew. Chem. I n / .
Ed. Engl. 22 (1983) 772.
[lo] W. Francke, P. Sauerwein, J . P. Vite, D. Klimetzek, Narurwisrenschafen
67 (1980) 147.
[ I 11 The CIP nomenclature is less helpful for describing the uniform elution
behavior of the alcohols 6 and 7;due to the priority sequence ethyl <
benzyl < isopropyl, the descriptor of the absolute configuration is interchanged within the homologous series. The D/L nomenclature is more
consistent in describing the fact that the substituents phenyl (benzyl), alkyl, and H are always arranged in a clockwise manner in the more
strongly retained enantiomer when viewed from the direction of the OH
group (referred to L-Chirasil-Val).
1121 Prepared from 1 mg of 7c with 100 FI of isopropylisocyanate in 200 PI of
dichloromethane (1 h, 110°C); yield 40%.
[I31 G. B. Quistad, D. C. Cerf, D. A. Schooley, G. B. Staal, Nafrrre (Lundon)
289 (1981) 176.
[I41 B. Koppenhoefer, H. Allmendinger, G . J. Nicholson, E. Bayer, J. Chromalogr. 260 (1983) 63.
[I51 B. Koppenhoefer, K. Hintzer, R. Weber, V. Schurig, Angew. Chem. 92
(1980) 473: Angew. Chem. Inr. Ed. Engl. 19 (1980) 471.
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enantiomers, resolution, carbonyl, compounds, chirasil, direct, chromatography, gas, val, hydroxy
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