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Chiral Polysiloxanes for Resolution of Optical Antipodes.

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Evidence for the intermediacy of (2) is provided (i) by
the insensitivity of the yields of (6) and (7) to addition
of a trapping agent for (2)[61, and (ii) by the fact that the
product yields according to
[5] Corresponding heterocycles metastable up to about 35°C are obtained
from ( I ) and organyl azides ( e . g . R=Ph, tolyl); they decompose by
isomerization and fragmentation like ( 4 ).
[6] The trapping agent does not react directly with ( 4 ) .
[7] According to our findings, (2) is also formed by thermolysis (ca. 90°C)
ofthe [2 +2] cycloadduct [2] accessible from ( I ) and Me3SiN=NSiMe3.
[ 8 ] At higher temperature (90"C), (3) is formed in about 20 % yield alongside
(5).
[9] Noce added in proof(Apri1 15, 1978): The efiicacy of compounds +Six as
trapping agents for (2) increases along the series (MelSiO)3 <
Me3SiNMe2 < Me3SiOMe < Me3SiC1 < Me3SiN3.
are independent of the source of (2)"'.
Like (l)lz], (2) shows an, albeit considerably lower, tendency to undergo cycloaddition to multiple bond systems.
Thus (2) reacts with itself or with benzophenone in a [2+2]
cycloaddition. Unlike ( I ) , however, (2) does not react with
bis(trimethy1)diazeneto form four-membered rings. Moreover,
[2 + 31 cycloaddition of (2) and trimethylsilyl azide to give
(3) plays only a minor role, especially at low temperatures
(O"C)[81,whereas ( 1 ) reacts quantitatively with Me3SiN3 to
form ( 4 ) . Dienes which can form Diels-Alder adducts with
( I ) could not formerly be subjected to [2+4] cycloaddition
with (2).
On the other hand, the tendency to undergo insertion into
single bonds of type >Si-X
according to
(2)
+
X-Sit
+ MezSi-NSiMe,
I
x
I
Sit
appears to be greater for (2) than for ( I ) . Thus (2) and trimethylsilyl azide give ( 5 ) in high yields, whereas the silaethene
( 1 ) does not insert at all into the Si-N bond of Me3SiN3.
Trimethylsilyl chloride also reacts with (2) mainly according
to the above equation (slight dimerization of (2) occurs),
but only to a limited extent with ( 1 ) . Hexamethylcyclotrisiloxane still gives an eight-membered ring with (2) (dimerization of (2) is the principal reaction), but not with ( 1 )['I.
Procedure
BuLi (0.79mmol) in diethyl ether (2ml), and then MesSiN3
(91 mg, 0.79 mmol) in diethyl ether (1 ml) are added dropwise
to TosOSiMeZ-CBr(SiMe3)2[2' (370 mg, 0.79 mmol) dissolved
in a mixture of diethyl ether (5 ml) and tetrahydrofuran (5 ml)
cooled to - 110°C. The reaction mixture is first warmed to
-55"C, whereupon ( 4 ) and insoluble TosOLi are formed,
and then-after addition of the desired reactant for (2)-to
room temperature.
Received: February 20, 1978 [Z 943 IE]
German version: Angew. Chem. 90. 393 (1978)
CAS Registry numbers:
( I ) , 62139-73-5; (2), 66239-89-2; ( 3 ) , 66239-88-1; ( 4 ) , 66239-874; ( 5 ) ,
66239-86-9: (61.66239-85-8; (?), 30006-66-7; (81, 2954-84-9; TosOSiMe2CBr(SiMe3)2, 621 82-97-2; Me3SiN3, 4648-54-8
Unsaturated Silicon Compounds, Part 2.-Part 1: [2]. Also Part 43 of
Compounds of Silicon and Its Group Homologs.-Part 42: [J].
[2] N . Wiberg, G. Preiner, Angew. Chem. 89, 343 (1977); Angew. Chem.
Int. Ed. Engl. 16, 328 (1977).
[3] C. M . Golino, R . D. Bush, L. H . Sommer, J. Am. Chem. SOC. 96, 614
(1974); L. H . Sommer, D. R. Parker, J . Organomet. Chem. 110, C t
(1976); A . Meller, U . Klingebiel, Angew. Chem. 88, 307 (1976); Angew.
Chem. Int. Ed. Engl. 15, 312 (1976); Cbem. Ber. 109, 2430 (1976).
[4] N . Wiberg, G. Ziegleder, Chem. Ber. 1 1 2 , No. 6 (1978).
[I]
Angew. Chem. lnt. Ed. Engl. 17 (1978) N o . 5
Chiral Polysiloxanes for Resolution of Optical Antipodes [**]
By Hartmut Frank, Graeme, J . Nicholson, and Ernst Buyer"]
Enzymes and receptors are responsible for the specific reactions and recognition of optical antipodes in nature. In the
case of synthetic drugs too, one enantiomer is usually more
active than the other. Proteins can thus undergo selective
interaction with enantiomers from an enormous variety of
substances. We have attempted to impart nature's enantiomeric selectivityto synthetic polymers with amino acid groups.
In order to study such interactions between optically active
substrate and an amino acid or peptide group as active site,
we have synthesized polymeric organosiloxanes to which an
active site, e. g. an L-amino acid, is linked with dicyclohexylcarbodiimide in the final synthetic step. Introduction of this
site at an earlier stage proved unsatisfactory owing to the
danger of racemization. Suitable polymeric backbones are
copolymers of poly[(2-carboxylpropyl)methylsiloxane], octamethylcyclotetrasiloxane, and hexamethyldisiloxane; an
amino acid or peptide group is linked as amide to the terminal
carboxylic group.
The individual chiral centers must be separated by a siloxane
chain of certain length to achieve optimum interaction and
viscosity of the polymer.
The polymer-substrate interaction has been studied by gas
chromatography. There is still no stationary phase of wide
applicability for the gas chromatographic resolution of enantiomers. Not all enantiomeric pairs of natural amino acids
can be separated with the low-molecular phases developed
for amino acids by Gil-Ad'].
The new polysiloxanes with covalently bound amino acid
or peptide groups can be used as stationary phases between
70 and 240°C. They effect direct separation of optical antipodes
from widely diverse classes of compounds such as amino
acidsiz1,hydroxy acids, alcohols, amines, and biphenyl derivatives without any need for preparation of diastereomers.
D- or L-Amino acids or their peptides can be bound as chiral
centers to the organosiloxane. N-tert-Butyl-L-valinamide
joined to the carboxyl group of the copolymeric organosiloxane by a peptide linkage has proved of great value for
optical resolutions (Scheme 1).
Glass capillaries are coated by known methods[41 with
this phase, which we designate Chirasil-Val['], containing
0.86mmol L-amino acid/g of polymer. The compounds are
converted into the volatile N,O-bis(pentafluoropropiony1)
derivative^'^] prior to gas chromatography, which is then performed under the conditions given in Figure 1. In all the
cases examined so far, the D enantiomer is eluted from an
L-amino acid phase before the L form.
[*] Prof. Df. E. Bayer, Dr. H. Frank, G. J. Nicholson
Institut fur Organische Chemie der Universitat
Auf der Morgenstelle 18, D-7400 Tiibingen (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft.
363
_----__
,.-H %.\
substances used as drugs whose enantiomeric composition
can now be established conveniently and rapidly.
120
Scheme 1
Apart from practical analytical aspects, considerable importance attaches to studies on interaction as a function of structure. Table 1 lists the separation factors of the enantiomers
of some 2-amino-I -phenylethanols which occur naturally and
are used as drugs. The following substituent effects are observed :
a) Separation factors are small for alkylated amino groups
( R =alkyl). Since there is no hydrogen atom left for hydrogen
bonding after derivatization, “three-point attachment”[61 is
impossible and the diastereomeric association complex is less
stable [norephedrine erythro-(I 2) + ephedrine erythro-(3);
norfenefrine (9) + etilefrine ( I I ] .
b) Replacement of a hydrogen atom at C-2 by a methyl
group (R=CH3) increases the difference in stability of the
diastereomeric complexes. In the case of the “parallel”
Table 1. Separation factors for N,O-per(pentafluoropropiony1)derivatives of the antipodes of compounds (1)-(13)
charged with Chirasil-Val.
R
R
160
Fig. I. Gas chromatographic separation of the enantiomeric pairs of drugs
and metabolites as N,O-per(pentafluoropropiony1) derivatives on Chirasil-Val.
20m x 0.3 mm glass capillary, hydrogen at 0.3 bar as carrier gas, temperature
of injection block and detector 250°C.
The structure of the diastereomeric association complex
is illustrated for N-cyclohexyl-0-pentafluoropropionyl-L-lactamide which elutes after the D enantiomer and whose association complex with Chirasil-L-Val is more stable than the
complex with the D enantiomer. As in the pleated sheet structure of (3-keratin,this conformation (Scheme 1)permits formation of the maximum number of hydrogen bonds. The spacefilling isopropyl and methyl groups on the asymmetric carbon
atom of the “receptor” and the “substrate”, respectively, and
the C-terminal alkylamide groups fit together as stacked layers
and stabilize the structure by van der Waals forces. No such
stacking is possible when the substrate has the D configuration;
mutual hindrance of the isopropyl and methyl groups leads
to a less stable association complex and earlier elution. The
significance of the dimethylsiloxane units is also apparent
from a model; they keep the L-valinamide units at a distance
and prevent formation of intramolecular hydrogen bonds
which would give the polymer a quasicrystalline structure.
Chirasil-Val has been used for determining the racemization
of natural amino acids, for purity checks on glycols and
biphenyl derivatives, and for separation of enantiomeric biogenic amines and hydroxy acids. The separation factors for
optical antipodes expectedly increase with decreasing separation temperature. Figure 1 shows a chromatogram of some
Cpd.
112
on a 20m x 0.3 mm glass capillary column
Separation factor a L , ~
at
at
110°C
160°C
R‘
R‘
Name
H
H
H
OH
OH
H
OH
H
OH
OH
H
OCH3
H
H
OH
OCH3
H
OCH3
H
H
H
H
H
OH
OH
OCH,
OCH3
H
Etilefrine (effortil)
“O’P-Methyl-effortiI”
Ephedrine
Metanephrine
p-Hydroxyephedrine (suprifen)
Pseudoephedrine
p-Hydroxyephedrine (suprifen)
2-Amino-1-phenylethanol
Synephrine
Norepinephrine
Norfenefrine
2-Amino-l-(3,4-dimethoxyphenyl)ethanol
“O’P-Methyl-norfenefrine”
Norephedrine
N-Cyclohexyllactamide
1.014
1.024
1.028
1.031
1.040
1.050
1.053
1.059
1.038
1.014
1.018
1.027
1.032
1.042
1.058
1.102
[a] Examined as the 0-pentafluorpropionyl derivative
364
Angew. Chem. I n t . Ed. Engl. 17 (1978) N o . 5
complex, the methyl group is directed away from the isopropyl
side chains of the valine groups; in the diastereomeric complex
they hinder each other to such a degree that optimum approach
of the N-proton of the substrate and the carbonyl group
of valine is impossible [ ( 6 ) + norephedrine erythro-(12);
synephrine (7) + p-hydroxyephedrine ( 5 ) ] .
c) The influence of substitution in the phenyl ring is less
clear-cut. A m-hydroxyl group has a deleterious effect upon
the separation of the two antipodes. A p-hydroxyl group favors
a stereospecificassociation of the secondary amines [ephedrine
erj.thr.o-(3 i + p-hydroxyephedrine ( 5 ); (2) + metanephrine
( 4 ) ] , but is unfavorable with primary amines. In the former
case, “two-point attachment” is probably stabilized by participation of the carbonyl of the 0-acyl group to give a “third
point”; in primary amines this would lead to competition
between two association conformations.
Analogies become apparent on comparison of the observed
effects with biological activities. As in gas-chromatographic
systems, the differences in the sympathomimetic effect between
the D and the L form are greater when C-2 bears an additional
methyl group (R = CH3). While the difference in the dose/action curve consists merely in a shift of the concentration
for the enantiomers of norepinephrine, an additional lowering
of the maximum efficacy of the L enantiomer compared to
that of the D enantiomer is observed with the corresponding
2-methyl compound cobefrin (and all other 2-methyl compounds)[’]. As in gas chromatography, where interaction of
the amino acid residues with secondary amines is lower, these
compounds also exhibit lower activities than primary amines
in some biological systems[’].
The use of such polymeric stationary phases facilitates investigation of the interaction between two optically active molecules over a wide range of temperature. We are now one
step closer to the synthesis of “tailored” chiral matrices, and
the requirements for the stereospecificity of catalyst systems
can be better examined. At the same time, these organosiloxanes represent yet another example of the imitation of the
properties of biopolymers by synthetic polymer^^^].
cals requires their generation by methods permitting maintenance of an adequate steady concentration of paramagnetic
particles in the ESR cavity. However, side reactions also
occurred and mixed spectra were observed.
On studying paramagnetic ion pairs with organometal
cations[*]we found that the half-lives of paramagnetic anions
can be considerably extended by complexation. We have therefore examined the oxidation of L-( +)-ascorbic acid in the
presence of diarylthallium hydroxides.
Immediately after mixing, equimolar mixtures of RzTIOH
and ascorbic acid in pyridine as solvent show distinct ESR
signals which reach maximum intensity after ca. 3h. The
concentration of the radicals formed by autoxidation can
be greatly increased by addition of lead dioxide without giving
rise to any further changes in the ESR spectra. The hyperfine
structure (cf. Fig. 1) comprises four triplets, corresponding
to coupling with two protons which are equivalent within
the linewidth, with a single proton, and with the magnetic
thallium nuclei.
Received. February 20, 1978 [Z 944 IE]
German version: Angew. Chem. 90, 396 (1978)
Fig. 1. ESR spectrum of the L-( +)-ascorbic acid radical anion-diphenylthallium complex in pyridine at room temperature.
[l] E. Gil-AD, 5. Feibush, R. Charles-Digler in A . 5.Littlewood. Gas-Chromatography 1966. Institute of Petroleum, London 1967, p. 227; W Konig,
W Parr, H . Lichtenstein, E. Bayer, J . Oro, J. Chromatogr. Sci. 8, 177
(1970).
[2] H. Frank, G. J . Nicholson, E. Bayer, J. Chromatogr. Sci. 15, 174 (1977).
[3] Chirasil-Val is available from Applied Science Laboratories, P.O. Box
440, College Station, Pennsylvania 16801 (USA).
[4] E. Schulte, Chromatographia 9, 315 (1976); P. van Hour, J . Szafranek,
C . D. Pfaflenberger, E. C . Horning, J. Chromatogr. 99, 103 (1974).
[5] E. h g g d r d , G . Seduall, Anal. Chem. 41, 1250 (1969).
[6] U . Beitler, 5.Feibush, J. Chromatogr. 123, 149 (1976).
[7] P . N . Patil, J . 5. LaPidus, D. Campbell, A . Tye, J. Pharmacol. Exp.
Ther. 155, 13 (1967).
[S] P . N . Patil, J . B. LaPidus, A . Tye, J. Pharmacol. Exp. Ther. 155, 1
(1967).
[9] E. Bayer, G. Holzbach, Angew. Chem. 89, 120 (1977); Angew. Chem.
Int. Ed. Engl. 16, 117 (1977).
We assigned the proton coupling constants (Table 1) by
analogy with earlier studied’]. The fact that the greatest coupling constant is due to the thallium nuclei follows (i) from
the unusually large temperature dependence and (ii) from
the pronounced substituent effect (Table 1).
Stable b(+)-Ascorbic Acid Radical Anions
By Hartmut B. Stegmann, Klaus Schefler, and Paul Schulerr]
The great biochemical significance of L-( +)-ascorbic acid
has induced numerous authors to undertake ESR studies on
the radicals formed on oxidation“]. The reactivity of the radi-
[‘I
Prof. Dr. H. B. Stegmann, Priv.-Doz. Dr. K. Schemer, P. Schuler
Institut fur Organische Chemie der Universitat
Auf der Morgenstelle 18, D-7400 Tiibingen 1
Angew. Chem. Int. Ed. Engi. 17 (1978) No. 5
Table 1. ESR data of paramagnetic ascorbic acid-diarylthallium complexes.
(1)
(2)
(3)
(I)
R ~ TI ’
R=
dd:
C6H5
C6H3Me2-2,5
C6H2MeJ-2,4.6
C6F5
0.245
0.250
0.270
[GI
-
:!!a
[GI
2.10
2.06
2.4
2.0
an
[GI
9
AH
[GI
9.95
5.19
6.5
61.75
2.0051
0.15
0.13
-
2.0050
~
0.2
1.O
The complexed radical anions are very stable. Thus, the
half-life of (I) is of the order of days. In order to establish
whether there is a quantitative relation between ascorbic acid
concentration and peak-to-peak signal intensities, we have
conducted preliminary studies on ( I ) at a modulation amplitude of 800mG and a microwave output of 2mW. Under
these conditions a linear dependence of the signal intensity
upon the concentration was detected, provided that comparable oxidation conditions were used. The experimental values
were reproducible within 10%. This precision and the sensitiv365
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