Water soluble phosphines: Part XIII. Chiral phosphine ligands with amino acid moieties

Article abstract of DOI:10.1016/S0022-328X(99)00689-0

Nucleophilic phosphination of the potassium or sodium salt of the fluorophenylalanines (1a, 2a) or -glycines (3a, 4a) with potassium phosphides Ph(R)PK (R=Me, Ph) yields chiral phosphine ligands (1-7) with amino acid moieties. The X-ray structure of 3·2H₂O (space group Pbca) has been determined showing a betaine type structure for the amino acid moiety. The α-methyl derivatives of the phosphinophenylglycines (10, 11) were obtained in an analogous manner as 1-7. ortho- and para-Fluoroacetophenones have been employed as starting material for the syntheses of α-[4-fluorophenyl]-α-methylglycine (9c) and its ortho-isomer (8c), the X-ray structure of its monohydrate has been determined (space group P1?). The N-acetyl (3b, 8e) and ester derivatives (3d, 8d) of 3 and 8c are accessible using standard procedures. Resolution of the diastereomeric salt 12 obtained from (S)-(+)-2-hydroxymethylpyrrolidine and racem-8e by fractionated crystallization yielded the (S,R)-isomer. The absolute configuration of (S,R)-12 was determined by X-ray structural analysis (space group P2₁2₁2₁). Cleavage of (S,R)-12 with hydrochloric acid gave enantiopure (R)-8e [α]_D²⁰=-30.9° (c=1, CH₃OH).

Full text of DOI:10.1016/S0022-328X(99)00689-0

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Journal of Organometallic Chemistry 598 (2000) 116–126
Water soluble phosphinesꢀ
Part XIII. Chiral phosphine ligands with amino acid moieties
David J. Brauer a, Stefan Schenk a, Stefan Roßenbach a, Michael Tepper a,
Othmar Stelzer a,*, Thomas Ha¨usler b, William S. Sheldrick b
a Fachbereich 9, Anorganische Chemie, Bergische Uni6ersita¨t-Gesamthochschule Wuppertal, Gaußstraße 20, D-42097 Wuppertal, Germany
b Lehrstuhl fu¨r Analytische Chemie, Ruhr-Uni6ersita¨t Bochum, Uni6ersita¨tsstraße 150, D-44780 Bochum, Germany
Received 7 July 1999; accepted 17 October 1999
Abstract
Nucleophilic phosphination of the potassium or sodium salt of the fluorophenylalanines (1a, 2a) or -glycines (3a, 4a) with
potassium phosphides Ph(R)PK (R=Me, Ph) yields chiral phosphine ligands (1–7) with amino acid moieties. The X-ray structure
of 3·2H2O (space group Pbca) has been determined showing a betaine type structure for the amino acid moiety. The a-methyl
derivatives of the phosphinophenylglycines (10, 11) were obtained in an analogous manner as 1–7. ortho- and para-Fluoroace-
tophenones have been employed as starting material for the syntheses of a-[4-fluorophenyl]-a-methylglycine (9c) and its
(
ortho-isomer (8c), the X-ray structure of its monohydrate has been determined (space group P1). The N-acetyl (3b, 8e) and ester
derivatives (3d, 8d) of 3 and 8c are accessible using standard procedures. Resolution of the diastereomeric salt 12 obtained from
(S)-(+)-2-hydroxymethylpyrrolidine and racem-8e by fractionated crystallization yielded the (S,R)-isomer. The absolute configu-
ration of (S,R)-12 was determined by X-ray structural analysis (space group P212121). Cleavage of (S,R)-12 with hydrochloric acid
gave enantiopure (R)-8e [h]2D0= −30.9° (c=1, CH3OH). © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Nucleophilic phosphination; Fluorophenyl a-amino acids; a-Methylated; Phosphine derivatives; Resolution; X-ray structures
1. Introduction
Unnatural and non-proteinogenic a-amino acids con-
taining functionalized aromatic substituents are of con-
siderable interest as enzyme inhibitors [2a] and chiral
synthons [2b]. They have been employed as building
blocks for the syntheses and the design of new types of
proteins and peptidomimetic drugs [2c] with unusual
properties [2d]. Phosphono and phosphonomethyl
derivatives of phenylglycine and alanine (A [3a], B [3c]
and C [3d]) were tested as glutamate and aspartate
antagonists. While compounds of type A–C have been
known for more than 1 decade [3], preliminary reports
on the analogous phosphino derivatives D appeared only
very recently in the literature [4,5]. Due to their metal
Prior reports from this laboratory have documented
the utility of nucleophilic phosphination of fluoroaro-
binding capacity these biologically based phosphine
matic compounds as a straightforward synthetic strategy
ligands are of potential use in medical imaging and in
for the preparation of hydrophilic functionalized phos-
homogeneous catalysis.
phine ligands [6]. The successful implementation of this
nucleophilic phosphination strategy necessarily depends
on the availability of suitable fluorophenyl derivatives
of the amino acids. Some of them are commercially-
ꢀ For Part XII, see Ref. [1].
* Corresponding author. Tel.: +49-202-439-2517; fax: +49-202-
439-3053.
0022-328X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(99)00689-0

D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
117
The phosphines 1 and 2 show singlets in the 31P{1H}-
NMR spectrum in a range typical for tertiary phosphines
[11] with a high field shift of lP for the ortho-isomer 1
(lP= −13.0 ppm) as compared to that of 2 (lP= −5.4
ppm). The protons of the CH2 units are inequivalent in
both cases. Typical eightline patterns are obtained in the
1H-NMR spectrum (AB part of an ABM spin system (A,
B=CH2, M=CH). Asymmetric substitution at the
a-carbon atom of the amino acid moiety renders the
phenyl groups of the Ph2P unit in 1 inequivalent, two sets
of resonances being observed for the aromatic carbon
atoms in the 13C{1H}-NMR spectrum.
available (e.g. 2-, 3- or 4-fluorophenylalanine and 2-
fluorophenylglycine) or may be prepared using standard
synthetic procedures [7] as will be shown below.
In this paper we concentrate on the synthesis of
phenylglycine and -alanine derivatives bearing phos-
phino substituents in the ortho or para position to the
amino acid moieties (CH(NH2)COOH or CH2CH(NH2)-
COOH) within the aromatic ring systems by nucleophilic
phosphination. Preliminary results of this work have
been published elsewhere [5]. The synthetic principle
outlined here may be used for a modular approach [8]
to a great variety of chiral mono- or bidentate (P- or
P,N-donors) phosphine ligands which may find applica-
tion in combinatorial catalysis [9].
The phosphine ligands 3–5 with glycine moieties have
been obtained by the same synthetic procedure as em-
ployed for 1 and 2 (Eqs. (3 and 4)). Due to the greater
nucleophilicity of Ph(Me)PK [12] its reaction with 3a
(Eq. (4)) proceeds much faster than the corresponding
reaction of 3a with Ph2PK. If enantiomerically pure 4a
2. Synthesis of 2- and 4-diphenylphosphino derivatives
of phenylalanine and -glycine
(4-fluoro-
-a-phenylglycine, [h]2D0= −138°; c=1, 1 m
D
Nucleophilic phosphination of fluoroaromatic systems
either with PH3, primary or secondary phosphines in the
superbasic medium [6a–c] or with alkali metal phos-
phides in anhydrous solvents normally requires activa-
tion of the CꢀF bond by electron withdrawing
substituents like SO3M, PO3M2, CN or COOM (M=
Na, K) [6d,e]. This is, however, not a necessary prere-
quisite since it has been shown by us in previous work
[6d] that phosphino derivatives of phenylacetic acid and
benzylamine (F) are accessible by nucleophilic phosphi-
nation of the corresponding fluoroaromatic compounds
E with CH2ꢀZ substituents (Z=NH2, COOH) in high
yields (Eq. (1)).
HCl) was employed for the nucleophilic phosphination
according to Eq. (3), the product 4 obtained showed no
optical activity. Under the reaction conditions obviously
a complete racemization occurred via equilibrium depro-
tonation at the a-carbon atom of 4 [13]. Racemization
of optically active amino acids is known to occur
preferably in alkaline media and is accelerated by groups
stabilizing the negative charge created in a-position [13c].
Racemization at the a-carbon atom was also observed
during the phosphination of NH2 and COOH protected
(S)-b-bromoalanine with the less nucleophilic copper(I)
phosphides [14].
The extension of this synthetic strategy to fluorophenyl
substituted amino acids was expected to yield the corre-
sponding phosphino derivatives. Thus, when 2- or 4-
fluorophenylalanine were reacted with potassium
diphenylphosphide in DME at reflux temperature the
phosphinophenyl amino acids 1 and 2 are formed in
satisfying yields (Eq. (2)). Both isomers of fluorophenyl-
alanine (1a (ortho) and 2a (para)) [10a] are commercially
available. 1a was prepared from 2-fluorobenzyl chloride
using the classical procedure first published by Marvel
[10c].
The phosphine ligand 5 (R=Me) is obtained as a
mixture of two diastereoisomers (erytho and threo iso-
mer) as indicated by two 31P{1H}-NMR resonances
(lP= −38.6, −39.5 ppm, intensity ratio 1:1) and the
observation of two sets of lines for the aromatic carbon
atoms in the 13C{1H}-NMR spectrum. One diastereoiso-
mer (lP= −39.5 ppm) could be obtained almost pure
by recrystallization of 5 from a 3:1 methanol–water

118
D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
mixture. The solubility of 3–5 in water is very low. As
for amino acids [15] it increases; however, significantly
in the acid or basic range. The phenyl groups of the
Ph2P unit in 3 are inequivalent two sets of resonances
being observed in the 13C{1H}-NMR spectrum.
Thus on oxidation of 3 with H2O2 the phosphine oxide
3c is formed (Eq. (8)). N-acetylation of 3 was achieved
by reaction with acetic acid anhydride in the presence
of a catalytic amount of CF3COOH (Eq. (7a)). Esterifi-
cation of 3 (Eq. (7b)) with orthoformate in methanol
and equimolar amounts of trifluoro acetic acid gave the
methyl ester 3d as its trifluoro acetate salt. It shows a
singlet in the 19F-NMR spectrum at −73.1 ppm. The
quartet at lC=118.1 ppm (1J(CF)=292.6 Hz) in the
13C{1H}-NMR spectrum may be assigned to the CF3
group of the trifluoro acetate anion. For the two CO
groups of 3b separate resonances (lC=175.0, 176.7
ppm) are observed in the 13C{1H}-NMR spectrum in a
lC range typical for carboxylic acids
Attempts to synthesize the secondary phosphine
derivative of phenylglycine 6 (R=H) selectively by
reaction of the potassium salt of 3a with PhPHK were
not sucessful (Eq. (4)). A mixture of 6 and the tertiary
phosphine 7 with two phenylglycine moieties was ob-
tained (Eqs. (4 and 6)). If the potassium salt of 3a is
treated with a 2:1 molar ratio of PhPH2–KOtBu, bi-
functional 7 is formed as the main product. It is
obtained as a mixture of three diastereoisomers (two
meso forms, lP= −24.7, −25.9 ppm, and a racemate,
lP= −24.9 ppm) (Eq. (5)), which could be separated
by stepwise changing the pH value of the aqueous
solution in the range between 0 and 7. The racemate
shows two inequivalent CH groups as indicated by two
resonances at 4.98 ppm (4J(PH)=7.9 Hz) and 4.88
ppm (4J(PH)=7.6 Hz).
3. X-ray structure of 3·2H2O
In order to get detailed information about the influ-
ence of the amino acid moiety on the geometrical
parameters of the triphenylphosphine skeleton of 3, a
crystal structure investigation was performed. The
structure determination described in this paper is the
first reported for a phosphino substituted amino acid.
Crystals of composition 3·2H2O suitable for X-ray
structural analysis were obtained by recrystallization of
3 from water–methanol. The isolated molecule with the
labeling scheme together with selected bond distances
and bond angles is shown in Fig. 1. Crystallographic
data are collected in Table 1.
The unit cell contains the R- and the S-enantiomer
of 3 (space group Pbca). The amino acid substituent
has a betaine type structure, the CꢀO distances with-
in the CO2 group being almost identical (O(121)ꢀ
The phosphine ligands 3–5 show reactions typical for
amino acids and tervalent phosphorus compounds.
,
C(122) 1.249(4), O(122)ꢀC(122) 1.247(4) A) with a
O(121)ꢀC(122)ꢀO(122) bond angle of 117.2(4)°. The
,
CꢀN bond distance C(121)ꢀN(121) (1.504(4) A) is in a
range typical for amino acids in their betaine form [16].
The molecules in 3·2H2O are held together by a hydro-
gen bonding network involving the NH+3 , carboxylate
groups and the water molecules. A detailed analysis of
hydrogen bridging in the solid state of amino acids has
been performed by Jo¨nsson and Kvick [17] using neu-
tron diffraction.
As a result of the steric interaction between the
amino acid unit and the phenyl ring [C(3n)] (n=1–6)
,
the PꢀC distances P(1)ꢀC(11) (1.849(4) A) and
,
P(1)ꢀC(31) (1.848(4) A) and the C(11)ꢀP(1)ꢀC(31) bond
angle (104.4(2)°) are widened up. They are somewhat
larger than the corresponding average values in Ph3P
,
,
Fig. 1. Molecular structure of 3·2H2O. Selected bond lengths (A) and
angles (°): P(1)ꢀC(11) 1.849(4), P(1)ꢀC(21) 1.839(4), P(1)ꢀC(31)
(1.831 A or 102.8°, respectively) [18]. The repulsion
between Ph ring [C(3n)] (n=1–6) and the amino acid
moiety in 3 is also reflected by the extension of the
1.848(4),
C(122)ꢀO(121)
1.249(4),
C(122)ꢀO(122)
1.247(4),
C(122)ꢀC(121) 1.545(5), C(121)ꢀN(121) 1.504(4); C(21)ꢀP(1)ꢀC(31)
100.6(2), C(21)ꢀP(1)ꢀC(11) 101.6(2), C(11)ꢀP(1)ꢀC(31) 104.4(2),
O(121)ꢀC(122)ꢀO(122) 127.7(5), N(121)ꢀC(121)ꢀC(122) 108.8(3),
O(122)ꢀC(122)ꢀC(121) 115.1(4), O(121)ꢀC(122)ꢀC(121) 117.2(4).
,
bond length C(11)ꢀC(12) (1.400(5) A) and by the values
obtained for the bond angles C(32)ꢀC(31)ꢀP(1)
(114.6(4)°) or C(36)ꢀC(31)ꢀP(1) (125.1(4)°), respec-

D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
119
Table 1
Crystal data
Compound
3·2H2O
8c·H2O
12·H2O
Empirical formula
Formula weight
Crystal system
Space group
C20H22NO4P
371.37
Orthorhombic
Pbca
9.687(2)
10.629(3)
37.856(7)
90
90
90
3898(2)
4
1.266
Mo–Ka
C9H12FNO3
201.20
Triclinic
C16H25FN2O5
344.38
Orthorhombic
P212121
6.8070(10)
10.647(2)
24.297(4)
90
90
90
1760.8(5)
4
1.299
Mo–Ka
(
P1
,
a (A)
6.0819(12)
,
b (A)
6.815(2)
11.645(3)
79.82(2)
77.90(2)
86.50(2)
464.4(2)
2
,
c (A)
h (°)
i (°)
k (°)
3
,
V (A )
Z
Dcalc (g cm−3
Radiation
)
1.439
Mo–Ka
,
Wavelength (A)
Temperature (K)
Diffractometer
0.71073
293(2)
Siemens P4
0.71073
293(2)
Siemens P3
0.71073
295(2)
Siemens P3
Crystal size (mm)
0.26×0.40×0.72
0.165
0.40×0.40×0.34
0.120
0.44×0.40×0.24
0.103
v (mm−1
)
Transmission
q Range (°)
Limiting indices
Reflections
Unique
–
0.9650–0.9547
2–30.06
05h58, −95k59, −165l516
4785
0.9771–0.9605
2–27.50
−85h58, −135k513, −315l531
9350
4520550
05h511, 05k512, 05l545
3463
3463
2736
4049
Rint
0.0
897
0.045
0.0164
2182
0.048
0.0216
3389
0.034
Observed (I\2|I)
R1 (obs)
wR2 (all data)
Goodness-of-fit
0.126
0.803
0.1310
0.961
0.0896
1.001
Parameters
236
177
263
−3
,
DF (e A
)
0.223 to −0.212
None
0.518 to −0.484
None
0.218 to −0.161
−0.4(7)
Flack parameter
tively. The triarylphosphine fragment has a propeller
conformation with the three aromatic ring systems be-
ing rotated in the same sense.
ligands of type 3 or 4 as cocatalysts in enantioselective
catalysis.
The starting materials 8c, 9c for the preparation of
a-methyl derivatives of the ortho- and para-phos-
phinophenylglycines (10, 11) have not yet been re-
ported in the literature so far. They were obtained by
hydrolysis of the hydantoines 8b, 9b obtained by the
reaction of ortho- or para-fluoroacetophenone (8a, 9a)
with ammonium carbonate and potassium cyanide
(Bucherer reaction [19,20]) (Eqs. (9 and 10)). For the
hydantoines 8b, 9b and the a-methylfluorophenyl-
glycines 8c, 9c singlets are observed in the 19F{1H}-
NMR spectrum in a range typical for lF (−110 to
−115 ppm) of fluorophenyl compounds [21,22]. Two
resonances at 156.5 and 177.3 or 156.8 and 177.4 ppm,
respectively, are obtained in the 13C{1H}-NMR spec-
trum for the carbonyl groups of the hydantoine system
in 8b or 9b.
4. Synthesis of a-methyl derivatives of
phosphinophenylglycine
Amino acids are prone to racemization at the a-car-
bon atoms in acid and especially in basic media. The
implication of this process for the syntheses of enan-
tiopure phosphine ligands containing amino acid moi-
eties according to Eqs. (2–5) has been shown above for
4. In order to use this synthetic strategy for enantio-
selective syntheses of these ligands, the hydrogen at the
C(a) carbon atom of the starting materials 3a, 4a had
to be replaced by alkyl groups. The racemization pro-
cess would also limit the application of optically pure

120
D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
lution of the racemate of 8c by enzymatic methods or
fractional crystallization of diastereoisomers formed
with enantiopure organic bases (see below).
Nucleophilic phosphination of the potassium salts of
the a-methylfluorophenyl glycines with Ph2PK in DME
yields the phosphino derivatives 10 and 11 in satisfying
yields (Eq. (11)). In the 31P{1H}-NMR spectrum 10 and
11 show signals in the typical lP range found for tertiary
aromatic phosphines [11] with a high field shift of lP for
the ortho isomer (10: lP= −13.7; 11: lP= −1.7 ppm).
As in the case of 1 and 3 the Ph groups of the Ph2P
moieties are inequivalent, two sets of signals being
observed in the 13C{1H}-NMR spectrum for the ipso and
ortho carbon atoms.
5. X-ray structure of 8c·H2O
In order to evaluate the structural effect of a methyl
group introduced in the a-position of ortho-fluoro-
phenylglycine, an X-ray structural analysis of 8c was
performed. Suitable crystals of composition 8c·H2O were
obtained by recrystallization of 8c from water–methanol
mixtures. The results of the X-ray structural analysis are
shown in Fig. 2, crystallographic data are collected in
Table 1, selected bond lengths and angles are given in the
caption to Fig. 2. The unit cell contains the R- and
S-enantiomer of 8c with a betaine type structure.
The plane of the fluorophenyl group is oriented
roughly orthogonal to that of the C(1), C(2), O(1), O(2)
fragment, the dihedral angle being 86.65(6)°. A similar
orientation is found in ortho-fluorophenylglycine (3a),
for which a dihedral angle of 105.5° was reported [23].
In 8c, the methyl substituent (C(3)) lies in the plane of
the fluorophenyl group, and this fact accounts for the
relatively large C(3)ꢀC(1)ꢀC(4) angle (114.1(1)°). As
shown by the C(5)ꢀC(4)ꢀC(1)ꢀC(3) torsion angle of
179.0(1)°, the rotamer found in the crystal is that which
avoids a short F···C(3) contact. Interestingly, a 28° value
can be calculated for the corresponding torsion angle in
3a, and this conformational difference between 8c and 3a
is the most conspicuous effect attributable to quaterniza-
tion of the a carbon of 3a. The only other statistically
significant substitution effects on the structure of 8c are
the elongation of the C(1)ꢀC(2) bond length by 0.043(6)
The methyl ester hydrochloride 8d and the N-acetyl
derivative 8e have been obtained by reaction of 8c with
SOCl2–MeOH or acetic acid anhydride in the presence
of NaHCO3, respectively, according to Eqs. (12 and 13)
[20]. Both derivatives have been employed for the reso-
,
A and the compression of the NꢀC(1)ꢀC(2) and
NꢀC(1)ꢀC(4) bond angles on the average by 2.5°.
The conformation assumed by the fluorophenyl group
1
,
in 8c leads to a F···H(NC) contact of 2.17 A , which
,
Fig. 2. Molecular structure of 8c·H2O. Selected bond lengths (A) and
1 In order to correct the hydrogen coordinates for the systematic
shortening of XꢀH bonds as determined by X-ray diffraction, the
hydrogen atoms were pushed along their XꢀH bond vector to a
distance of 0.967 A for X=O and 1.033 A for X=N, which are
typical values for such bonds as determined by neutron diffraction
[24].
angles (°): C(1)ꢀC(2) 1.563(2), C(1)ꢀC(3) 1.521(2), C(1)ꢀC(4) 1.522(2),
C(1)ꢀN 1.502(2), C(2)ꢀO(1) 1.235(2), C(2)ꢀO(2) 1.249(2); Nꢀ
C(1)ꢀC(2) 108.1(1), NꢀC(1)ꢀC(3) 107.1(1), NꢀC(1)ꢀC(4) 109.0(1),
C(2)ꢀC(1)ꢀC(3) 108.4(1), C(2)ꢀC(1)ꢀC(4) 109.9(1), C(3)ꢀC(1)ꢀC(4)
114.1(1).
,
,

D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
121
ral auxilliary base (Eq. (14)). Selective crystallization of
diastereoisomeric salt 12 from acetone yielded one iso-
mer [h]2D0= +2.3° (c=1, acetone), the absolute
configuration (S,R) of which was determined by an
X-ray structural analysis (see below). The chiral amine
was cleaved from (S,R)-12 with hydrochloric acid, opti-
cally active (R)-8e [h]2D0= −30.9° (c=1, CH3OH) be-
ing obtained by extraction with ethylacetate (Eq. (15)).
The enantiomeric purity of (R)-8e was determined by
derivatization with (S)-(+)-a-methoxy-a-(trifluoro-
methyl)phenyl acetyl chloride ((S)-(+)-MTPACl) [29].
19F-NMR was employed for the detection of the
diastereomeric derivatives. The amino acid derivative
(R)-(−)-8e showed a negative Cotton effect at 260 and
215 nm [30]. The enantiomeric purity of the free acid 8c
was determined by liquid chromatography after deriva-
,
Fig. 3. Molecular structure of 12·H2O. Selected bond lengths (A) and
angles (°): C(1)ꢀC(2) 1.555(2), C(1)ꢀC(3) 1.535(2), C(1)ꢀC(4) 1.524(2),
C(1)ꢀN(1) 1.471(2), C(2)ꢀO(1) 1.255(2), C(2)ꢀO(2) 1.236(2);
N(1)ꢀC(1)ꢀC(2) 107.0(1), N(1)ꢀC(1)ꢀC(3) 110.3(1), N(1)ꢀC(1)ꢀC(4)
109.8(1), C(2)ꢀC(1)ꢀC(3) 106.0(1), C(2)ꢀC(1)ꢀC(4) 110.2(1),
C(3)ꢀC(1)ꢀC(4) 113.3(1).
tization with 2,3,4,6-tetra-O-benzoyl-b-D-glucopyra-
nosyl isothiocyanate (BGIT) [31] to be better than 98%.
The (S)-(+)-2-hydroxymethyl pyrrolidine hydro-
chloride obtained on cleavage of diastereomeric 12
according to Eq. (15) was collected. On deprotonation
with NaOH in the two-phase system water–CH2Cl2 the
free base could be recovered in about 90% yield and
reintroduced into the resolution process.
Parallel syntheses [9] of different enantiopure phos-
phine ligands of type 10 with amino acid moieties using
(R)-(−)-8e as starting material are presently studied.
might be a weak, bent (F···H(NC)ꢀN, 120°) intramolec-
ular hydrogen bond [25]. Intermolecular hydrogen
bonding is more important in 8c. First, dimers with
centrosymmetric ten-membered rings are formed, the
H(NB)···O(2) (−x, 1−y, 2−z) separation calculating
,
to 1.79 A. Second, a H(NA)···O(1) (1+x, y, z) contact
,
of 1.78 A links the dimers to chains (Fig. 2). Third, the
water oxygen atom O(3) donates its proton H(O3C) to
the O(2) atom, and also acts as a weak acceptor
,
[O(3)···H(NC) (x−1, y, z), 2.27 A], but these contacts
are apparently not sufficient to prevent the disorder of
the solvent.
7. X-ray structure of 12·H2O
The results of the X-ray determination are shown in
Fig. 3. Since the structural solution was chosen to be
consistent with the known S-conformation of the
pyrrolidinium cation, the absolute configuration of the
anion of 8e in the crystal is found to be R. As in 8c, the
fluorophenyl group in 12 is oriented roughly perpendic-
ular to the C(1), C(2), O(1), O(2) fragment, dihedral
angle 80.02(6)°, and nearly parallel to the C(1)ꢀC(3)
bond with the fluorophenyl group again oriented so as
to avoid a short C(3)···F contact, the C(5)ꢀC(4)ꢀ
C(1)ꢀC(3) torsion angle being 175.4(1)°. While this
rotamer might have been stabilized in 8c by the
F···H(NC) contact, we note that no F···H(N1) hydro-
6. Resolution of racemic derivatives of 8c
In contrast to the glycine derivative 3a its a-methyl-
ated analog 8c must be stable towards the racemization
process [13] induced by strong bases like the nucleo-
philic phophido anions employed for the syntheses of
the respective phosphino derivatives according to Eqs.
(3–5 and 11). For the synthesis of optically active
phosphine ligands with amino acid moieties enantio-
pure 8c or its derivatives, e.g. 8d or 8e, were necessary.
Attempts to achieve the resolution of the ester hy-
drochloride 8d by enzymatic ester hydrolysis [26,27]
using lipases from different sources in two phase sys-
tems have been unsuccessful so far [28]. This may be
due to the shielding of the COOMe group by the
a-methyl group and the bulky ortho-fluorophenyl
substituent.
,
gen bond is present in 12 as this separation is 3.00 A.
,
The C(5)ꢀF bond length of 12·H2O, 1.362(2) A,
,
compares well with that of 8c, 1.364(2) A, and neither
differs significantly from that of the corresponding
,
bond in 3a, 1.354(6) A. The endocyclic bond angles of
the fluorophenyl groups in these three compounds ex-
hibit deviations from the ideal 120° value which are
typical for fluorine substitution [32–34]; thus the aver-
age CꢀCꢀC angle at the fluorinated carbon is spread to
124.3(2)° while the average endocyclic angles at the
C(4) and C(6) atoms, which are in b position to the
fluorine substituent, are compressed to 116.3(5) and
Resolution of the N-acetylated derivative 8e by salt
formation and selective crystallization of the dia-
stereomeric salts formed with cinchonin and cin-
chonidine in different solvents were not successful. Res-
olution of racem-8e could finally be achieved, however,
using (S)-(+)-2-hydroxymethyl pyrrolidine as the chi-

122
D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
118.1(4)°, respectively. Another effect which might
possibly be attributed to fluorine substitution is the
asymmetry of the exocyclic bond angles of the C(4)
atom. In 8c, 12 and 3a, the angle involving the
fluorinated carbon atom (i.e. C(1)ꢀC(4)ꢀC(5)) is on the
average 2.8(1)° smaller than the other angle.
mixtures were heated at reflux temperature for 18–24 h.
Thereafter, the solvent was removed in vacuo (20°C,
0.01 mbar). The residue obtained was dissolved in
water (50 or 20 ml) and conc. HCl was added until the
solutions showed a pH value of 5. 1 was precipitated as
a colorless solid, which was filtered off and washed with
a 1:3 methanol–water mixture. For further purification
it was recrystallized from 2:1 methanol–water mixture.
On acidification, 2 was obtained as a viscous material,
which after addition of 5 ml of methanol and heating to
60°C for 5 min gave a white solid, which was further
purified by recrystallization from a 2:1 methanol–water
mixture. Yields: 7.6 g (70%) 1, 3.16 g (56%) 2.
With C(10)ꢀN(1) and C(10)ꢀO(3) bond lengths of
,
1.345(2) and 1.230(2) A, respectively, the geometry of
the amino acid group in 12 is unexceptional, and the
,
0.031(3) A shortening of the C(1)ꢀN(1) distance
compared to that of the corresponding bond in 8c is
probably due to differences in the hybridization of the
nitrogen atoms in these two compounds.
Fig. 3 shows how hydrogen bonding between anion
and cation in the asymmetric unit of 12·H2O leads to
formation of a nine-membered ring. The cation is also
linked to a screw related anion by an H(N2B)···O(1)
contact (1−x, y−0.5, 1.5−z). The water oxygen
atom O(5) donates not only a proton to the O(3) atom
of the anion but also a proton to the O(4) atom of a
screw-related cation. Since the O(1) atom participates
in more hydrogen bonds than does the O(2) atom, it is
not surprising that the C(2)ꢀO(1) is somewhat longer
1. Anal. Calc. for C21H20NO2P·CH3OH·H2O (399.4):
C, 66.15; H, 6.56; N, 3.51. Found: C, 66.05; H, 6.46; N,
3.67%. H-NMR (CD3OD, l, ppm): 3.59, 3.18, 4.02,
1
6.8–7.5 (arom. H); 13C{1H}-NMR (CD3OD, l, ppm):
173.7, 141.9 (J=25.5), 137.9 (J=13.6), 137.4 (J=9.5),
137.3 (J=9.4), 135.1, 135.0 (J=19.4), 131.5 (J=5.1),
130.7, 130.1, 130.0, 129.8 (J=7.0), 129.7 (J=6.9),
128.7, 57.0 (J=4.1), 36.9 (J=19.3 Hz); 31P{1H}-NMR
(CD3OD, l, ppm): −13.0.
2. Anal. Calc. for C21H20NO2P·2H2O (385.4): C,
65.45; H, 6.27; N, 3.63. Found: C, 64.80; H, 6.72; N,
,
(0.019(3) A) than the C(2)ꢀO(2) valency.
1
3.37%. H-NMR (CD3OD, NH3, l, ppm): 3.31, 3.41
(CH2), 3.86 (CH), 7.2–7.8 (arom. H); 13C{1H}-NMR
(CD3OD, NH3, l, ppm): 181.4, 141.1, 138.2 (J=9.1),
135.5 (J=8.4), 134.8 (J=19.3), 134.5 (J=19.3), 130.9
(J=7.3), 130.1, 129.7 (J=7.1 Hz), 58.7, 42.1; 31P{1H}-
NMR (CD3OD, NH3, l, ppm): −5.4.
8. Experimental
For experimental details see Part XII of this series
[1]. Phenylphosphine, diphenylphosphine [35a,b],
phenylmethylphosphine [35c], 2- and 4-fluorophenylala-
nine as well as 2- and 4-fluorophenylglycine were pur-
chased from Aldrich GmbH or synthesized by known
methods [2a,27]. The sodium or potassium salts of the
fluorophenyl amino acids have been prepared by addi-
tion of equivalent amounts of NaOH, KOH or KOtBu
to the aqueous or methanol solutions, evaporating the
solvent and drying the salts obtained in vacuo (20–
60°C, 0.01 mbar). Starting materials were characterized
8.2. Synthesis of the phosphino deri6ati6es 3–5 of
phenylglycine
To the solution of 3.07 g (16.5 mmol) or 4.90 g (26.3
mmol) Ph2PH or 2.11 g (17.0 mmol) Ph(Me)PH, re-
spectively, in 50 ml of DME, 0.64 g (16.5 mmol) or 1.02
g (26.2 mmol) or 0.66 g (17.0 mmol) of potassium metal
was added. After completion of the metalation reac-
tions the sodium salts of 3.0 g (17.7 mmol) 2-
1
by H-, 13C{1H}- and 31P{1H}-NMR spectroscopy and
1
mass spectrometry. H-, 19F-, 13C{1H}- and 31P{1H}-
NMR spectra were recorded on a Bruker AC 400 or
AM 250 and a Jeol FX90 Q Fourier transform spec-
trometer. Mass spectra were obtained on a Varian
MAT 311A.
fluorophenylglycine or 4.67
g
(27.6 mmol) 4-
fluorophenylglycine were added. The reaction mixtures
were heated at reflux for 3 h (3), 72 h (4) or 15 min (5),
respectively. The residues obtained after removal of the
solvent in vacuo (20–80°C, 0.02 mbar) were dissolved
in 50 or 100 or 30 ml of water. To these solutions 10%
HCl was added until a pH value in the range 4–5 was
reached. The precipitates formed were filtered off and
washed with three aliquots of a 1:3 methanol–water
mixture. Further purification was achieved by recrystal-
lization from water–methanol. Yields: 3.61 g (60%) 3,
6.80 g (68%) 4, 3.82 g (77%) 5.
8.1. Synthesis of the phosphino deri6ati6es 1, 2 of
phenylalanine
Solutions of Ph2PK in DME were prepared by reac-
tion of 1.13 g (29.0 mmol) or 0.59 g (15.0 mmol) of
potassium with 5.40 g (29.0 mmol) or 2.79 g (15.0
mmol) of Ph2PH dissolved in 60 or 100 ml of DME. To
these solutions 6.00 g (27.1 mmol) of the potassium salt
or 3.00 g (14.6 mmol) of the sodium salt of ortho- or
para-fluorophenylalanine were added and the reaction
3. Anal. Calc. for C20H18NO2P·2H2O (371.4): C,
64.68; H, 5.97; N, 3.77. Found: C, 64.74; H, 5.95; N,
3.84%. 1H-NMR (CD3OD, l, ppm): 5.72, 7.0–7.7

D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
123
(arom. H); 13C{1H}-NMR (CD3OD, l, ppm): 179.8,
142.4 (J=27.2), 138.4 (J=13.7), 137.8 (J=9.7), 137.4
(J=8.9), 136.1 (J=1.3), 134.9 (J=19.2), 134.6
(J=18.8), 131.2, 130.1, 130.0, 129.8, 129.7 (J=6.8),
129.6 (J=6.7), 128.6 (J=4.7), 57.6 (J=27.7 Hz);
31P{1H}-NMR (CD3OD, l, ppm): −9.6.
4. Anal. Calc. for C20H18NO2P·C2H5OH (381.4): C,
69.28; H, 6.34; N, 3.67. Found: C, 69.58; H, 6.02; N,
3.99%. 1H-NMR (CD3OD, l, ppm): 4.36, 7.1–7.6
(arom. H); 13C{1H}-NMR (CD3OD, l, ppm): 179.6,
145.8, 138.8 (J=10.9), 137.1 (J=10.5), 135.0
(J=20.0), 134.8 (J=19.6), 130.1, 129.8 (J=6.9), 128.6
(J=7.2 Hz), 62.1; 31P{1H}-NMR (CD3OD, l, ppm):
−1.3.
129.4 (J=5.1), 129.4 (J=4.8), 60.1 (J=23.7), 59.9
(J=22.0 Hz); 31P{1H}-NMR (D2O, KOH, l, ppm):
racemate: −24.9; meso forms: −24.7, −25.9.
8.4. Synthesis of deri6ati6es of 3
8.4.1. Synthesis of the N-acetyl deri6ati6e 3b
A 1.00 g (2.86 mmol) sample of 3 was suspended in
excess acetic acid anydride. After addition of a small
quantity (ca. 0.01 g) of trifluoroacetic acid the reaction
mixture was heated to 40°C for 30 min. The precipitate
formed, on cooling the reaction mixture to 0°C, was
collected on a suction funnel and washed with diethyl
ether. After drying in vacuo (20°C, 0.01 mbar) 3b was
obtained as a colorless solid. Yield: 0.85 g (75%).
3b. Anal. Calc. for C22H20NO3P·0.5H2O (386.4): C,
68.38; H, 5.48; N, 3.62. Found: C, 68.89; H, 5.60; N,
3.22%. 1H-NMR (CD3OD, l, ppm): 1.58, 6.39;
13C{1H}-NMR (CD3OD, l, ppm): 176.7 (J=1.7),
175.0, 145.1 (J=27.4), 141.2 (J=14.4), 140.3 (J=
10.0), 140.1 (J=9.6), 138.2, 137.7 (J=20.4), 137.3
(J=19.5), 133.2, 132.5, 132.3, 132.1 (J=7.3), 132.1
(J=6.7), 131.5 (J=4.6), 58.6 (J=26.5 Hz), 24.3;
31P{1H}-NMR (CD3OD, l, ppm): −11.8.
5. Anal. Calc. for C15H16NO2P·H2O (291.3): C,
61.85; H, 6.23; N, 4.81. Found: C, 62.43; H, 6.55; N,
1
4.75%. H-NMR (CD3OD, l, ppm): 1.64, 1.68, 5.37,
5.42; 13C{1H}-NMR (CD3OD, l, ppm): 180.2, 179.9,
150.8 (J=26.4), 150.6 (J=26.4), 143.3 (J=11.2), 142.9
(J=11.2), 140.7 (J=13.2), 140.6 (J=13.2), 133.9
(J=2.1), 133.2 (J=18.3), 133.2 (J=2.0), 132.8
(J=17.3), 130.7, 130.5, 129.7 (J=5.1), 129.5 (J=6.1),
129.3, 128.8, 128.6, 128.5, 128.3 (J=6.1), 127.8
(J=5.1), 59.8 (J=22.4), 59.2 (J=25.4), 13.2
(J=14.2), 13.1 (J=13.2 Hz); 31P{1H}-NMR (CD3OD,
l, ppm): −38.6, −39.5.
8.4.2. Synthesis of the ester 3d
To the solution of 0.86 g (2.6 mmol) of 3 and 0.53 g
(5.0 mmol) of trimethylorthoformate in 5.0 ml of
methanol, 0.30 g (2.6 mmol) of trifluoroacetic acid was
added at 0°C. The reaction mixture was stirred at
ambient temperature for 12 h. After removal of all
volatiles in vacuo (20°C, 0.001 mbar) 3d was obtained
as a colorless solid. Yield: 1.10 g (93%).
3d. Anal. Calc. for C23H21F3NO4P (463.4): C, 59.62;
H, 4.57; N, 3.02. Found: C, 58.92; H, 4.65; N, 2.91%.
1H-NMR (CD3OD, l, ppm): 3.34, 6.10; 13C{1H}-NMR
(CD3OD, l, ppm): 170.9, 163, 139.4 (J=27.6), 137.7
(J=19.5), 138.9 (J=14.8), 137.3 (J=8.7), 136.6 (J=
1.2), 136.5 (J=8.9), 134.8 (J=19.6), 131.5, 131.0,
130.2, 130.1, 129.8 (J=6.9), 129.6 (J=7.1), 128.1,
118.1 (1J(CF)=292.6), 54.6 (J=32.0 Hz), 49.8;
31P{1H}-NMR (CD3OD, l, ppm): −13.3; 19F-NMR
(CD3OD, l, ppm): −73.1.
8.3. Synthesis of the phosphine 7 with two amino acid
moieties
A 9.86 g (58.3 mmol) sample of 2-fluorophenyl-
glycine was dissolved in 50 ml of MeOH and 6.55 g
(58.4 mmol) of KOtBu was added. After stirring for 2 h
the solvent was removed in vacuo (20°C, 0.1 mbar).
The residue obtained was suspended in 90 ml of DME.
6.87 g (61.2 mmol) of KOtBu and 3.3 g (30.6 mmol) of
PhPH2 was added to this suspension. The reaction
mixture was stirred at 80°C for 7 days. After addition
of 20 ml of water, all volatiles were removed in vacuo.
The residue obtained was dissolved in 80 ml of water.
Thereafter, conc. HCl was added to this solution until
a pH value of 0 was reached. On addition of NaOH a
precipitate was formed at pH 4.0 (4.95 g, racemate). It
was filtered off and dried in vacuo. On addition of
NaOH to the filtrate, until a pH value of 7 was reached,
a further amount of 7 (3.84 g, meso forms) was ob-
tained. Yield: 8.8 g (74%).
8.4.3. Synthesis of the oxide 3c
To a suspension of 0.50 g (1.43 mmol) of 3 in 1 ml of
water, 0.16 ml 30% H2O2 (1.5 mmol) was added with
cooling in an ice bath. For the isolation of the oxide all
volatiles were evaporated from the clear solution leav-
ing 3c as a colorless solid. Yield: quantitative.
3c. Anal. Calc. for C20H18NO3P·H2O (369.4): C,
65.03; H, 5.46; N, 3.79. Found: C, 64.63; H, 5.34; N,
3.59%. 1H-NMR (CD3OD, l, ppm): 5.12, 7.0–7.8
(arom. H); 13C{1H}-NMR (CD3OD, l, ppm): 174.3
(J=0.9), 141.4 (J=6.9), 135.3 (J=12.8), 134.6 (J=
2.5), 134.2 (J=3.2), 133.5 (J=10.1), 133.1 (J=10.5),
132.8 (J=108.1), 132.7 (J=100.7), 132.6 (J=9.1),
7. Anal. Calc. for C22H21N2O4P·4H2O (408.4): C,
55.00; H, 6.08; N, 5.83. Found: C, 55.62; H, 5.64; N,
1
5.96%. H-NMR (D2O, KOH, l, ppm): racemate: 4.98
(J=7.9), 4.88 (J=7.6), 6.6–7.4 (arom. H); meso forms:
4.92 (J=7.4), 4.87 (J=7.2 Hz), 6.6–7.4 (arom. H);
13C{1H}-NMR (D2O, KOH, l, ppm): racemate: 181.6,
181.5, 150.2 (J=18.1), 150.0 (J=17.0), 138.0 (J=9.0),
137.0 (J=10.7), 136.8 (J=9.4), 136.3 (J=20.1), 135.8,
135.5, 132.7, 132.3, 131.4, 131.0 (J=7.0), 129.7, 129.6,

124
D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
9c. Anal. Calc. for C9H10FNO2 (183.2): C, 59.01; H,
5.50; N, 7.64. Found: C, 59.25; H, 5.56; N, 7.72%.
1H-NMR (D2O, l, ppm): 1.45, 6.7–7.4 (arom. H);
13C{1H}-NMR (D2O, l, ppm): 169.1, 163.7 (J=242.0),
144.3, 129.4 (J=8.2), 117.3 (J=21.3 Hz), 63 (br), 28.6;
19F-NMR (D2O, l, ppm): −114.2.
131.8 (J=104.5), 130.3 (J=12.6), 130.1 (J=12.7),
130.1 (J=12.6), 57.8 (J=4.9 Hz); 31P{1H}-NMR
(CD3OD, l, ppm): 42.7.
8.5. Synthesis of 2- and 4-fluoro-h-methylphenylglycine
(8c, 9c)
8.6. Syntheses of h-(2-diphenylphosphinophenyl)-h-
methylglycine (10) and h-(4-diphenylphosphinophenyl)-
h-methylglycine (11)
8.5.1. 5-(2-fluorophenyl)-5-methylhydantoine and
5-(4-fluorophenyl)-5-methylhydantoine (8b, 9b)
An 80.1 g (1.23 mol) or a 13.0 g (0.20 mol) sample of
potassium cyanide and 237.3 g (2.47 mol) or 38.4 g
(0.40 mol) of (NH4)2CO3 were dissolved in a 1.5 l or 0.4
l of a 1:1 mixture of water–ethanol. To this solution,
85.5 g (0.62 mol) or 13.8 g (0.1 mol) of 2- or 4-
fluoroacetophenone, respectively, was added. After
heating the reaction mixture to 40°C for 2 h its volume
was reduced to about one-half by evaporation in vacuo
(20°C, 0.1 mbar). The precipitate formed was filtered
off and dried in vacuo. A further charge may be
obtained on acidification of the filtrate with HCl until
the solution shows a pH value of 5. Yields: 98.5 g (77%)
8b, 14.2 g (68%) 9b.
8b. Anal. Calc. for C10H9FN2O2 (208.2): C, 57.69; H,
4.36; N, 13.46. Found: C, 57.90; H, 4.48; N, 13.52%.
1H-NMR (DMSO-d6, l, ppm): 1.74, 7.2–7.6 (arom. H),
8.32, 10.9; 13C{1H}-NMR (DMSO-d6, l, ppm): 177.3,
160.6 (J=248.0), 156.5, 130.8 (J=8.9), 128.6 (J=3.3),
126.5 (J=11.6), 124.5 (J=3.3 Hz), 116.2 (J=21.9),
61.4, 23.2; 19F-NMR (DMSO-d6, l, ppm): −113.1.
9b. 1H-NMR (DMSO-d6, l, ppm): 1.74, 7.2–7.6
(arom. H), 8.7; 13C{1H}-NMR (DMSO-d6, l, ppm):
177.4 (J=0.7), 162.2 (J=244.7), 156.8, 136.4 (J=3.1),
127.9 (J=8.4), 115.6 (J=21.5 Hz), 64.1, 25.4; 19F-
NMR (DMSO-d6, l, ppm): −110.3.
To a solution of 23.0 mmol of Ph2PK prepared by
reaction of 4.28 g (23.0 mmol) of Ph2PH with 0.90 g
(23.0 mmol) of potassium in 40 ml of dimethoxyethane,
4.03 g (22.0 mmol) of 8c or 4.14 g (22.6 mmol) of 9c,
respectively, were added and the reaction mixtures were
heated for 24 or 48 h. The residue obtained after all
volatiles had been removed in vacuo was dissolved in
40 ml of water, and conc. HCl was added until the pH
of the solution reached a value of 4.5. The precipitate
formed was filtered off, washed with three aliquots of
water–methanol mixtures and was finally recrystallized
from a 5:1 methanol–water mixture. Yields: 4.4 g
(55%) 10, 6.2 g (75%) 11.
10. Anal. Calc for C21H20NO2P·H2O (367.4): C,
68.65; H, 6.04; N, 3.81. Found: C, 67.94; H, 5.99; N,
1
3.59%. H-NMR (D2O, l, ppm): 6.3–7.4 (arom. H),
1.45 (CH3); 13C{1H}-NMR (D2O, l, ppm): 186.0 (J=
1.4), 154.2 (J=25.8), 139.8 (J=10.6), 139.8 (J=10.1),
139.5, 136.5 (J=16.6), 135.3 (J=18.8), 135.3 (J=
18.4), 132.0, 130.7 (J=6.1), 130.6, 129.2, 128.7 (J=
7.2), 65.3 (J=7.0), 30.5 (J=4.4 Hz); 31P{1H}-NMR
(D2O, l, ppm): −13.7.
11. Anal. Calc. for C21H20NO2P·H2O (367.4): C,
68.65; H, 6.04; N, 3.81. Found: C, 68.54; H, 6.09; N,
1
3.84%. H-NMR (DMSO-d6, l, ppm): 7.1–7.6 (arom.
8.5.2. Syntheses of 8c and 9c
H), 1.71 (CH3); 13C{1H}-NMR (DMSO-d6, l, ppm):
170.4, 142.3, 136.7 (J=11.4), 136.7 (J=11.3), 135.2
(J=11.1), 133.2 (J=19.5), 133.2 (J=19.4), 132.9 (J=
19.9), 129.0, 128.8 (J=6.9), 126.2 (J=7.1 Hz), 61.9,
23.4; 31P{1H}-NMR (DMSO-d6, l, ppm): −1.7.
A 95.8 g (0.46 mol) sample of 8b or 14.2 g (0.068
mol) of 9b was suspended in 250 or 150 ml of water. On
addition of 76.8 g (1.165 mol) of KOH (85%) or 6.0 g
(0.15 mol) of NaOH clear solutions were obtained
which were heated for 2 days under reflux. For the
isolation of the amino acids, conc. HCl was added until
the solutions showed a pH of 5. After cooling of the
reaction mixtures to 20°C the precipitate was filtered
off using a Buchner funnel. The products thus obtained
were recrystallized from water. Yields: 64.1 g (72%) 8c,
8.9 g (71%) 9c.
8.7. Synthesis of N-acetyl-h-(2-fluorophenyl)-h-
methylglycine (8e)
To a suspension of 9.17 g (109.2 mmol) of NaHCO3
in 300 ml of a 1:1 water–dioxane mixture, 10.0 g (54.6
mmol) of 8c and 1.3 equivalents of acetic anhydride
were added. The reaction mixture was stirred at 50°C
for 4 h. Thereafter, all volatile materials were removed
in vacuo using a rotary evaporator. The residue ob-
tained was dissolved in 200 ml of water. Half concen-
trated hydrochloric acid was added until a pH value of
1.5 was reached. The N-acetyl derivative 8e precipitated
was filtered off and recrystallized from ethanol. Yield:
10.8 g (88%).
8c. Anal. Calc. for C9H10FNO2·0.5H2O (192.2): C,
56.24; H, 5.77; N, 7.29. Found: C, 56.68; H, 5.19; N,
1
8.14%. H-NMR (CD3OD–D2O, l, ppm): 1.71, 7.0–
7.7 (arom. H); 13C{1H}-NMR (CD3OD–D2O, l, ppm):
185.2, 164.9 (J=244.5), 138.9 (J=12.9), 131.9 (J=
8.8), 131.0 (J=5.0), 127.4 (J=3.2), 118.9 (J=22.8
Hz), 63.0, 28.9; 19F-NMR (CD3OD–D2O, l, ppm):
−111.2.

D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
125
8e. Anal. Calc. for C11H12FNO3 (225.2): C, 58.66; H,
5.37; N, 6.22. Found: C, 58.49; H, 5.65; N, 6.11%.
1H-NMR (DMSO-d6, l, ppm): 6.94–7.57 (arom. H), 1.94
(CH3), 1.89 (CH3); 13C{1H}-NMR (DMSO-d6, l, ppm):
173.1, 168.9, 160.1 (J=247.2), 129.4 (J=9.2), 128.8
(J=4.1), 128.6 (J=11.2), 123.7 (J=3.1), 115.8 (J=23.4
Hz), 59.6, 23.2, 23.0; 19F-NMR (DMSO-d6, l, ppm):
−111.4.
sulfate. After evaporation of the extracts in vacuo, 8e was
obtained as a colorless solid. Yield: 5.57 g (96%).
[h]2D0= −30.9° (c=1, CH3OH).
8.10. X-ray structure analyses of 3·2H2O, 8c·H2O and
12·H2O
8.10.1. X-ray structure of 3·2H2O
A crystal (0.26×0.40×0.72 mm) was sealed in a
capillary. X-ray data were measured with a Siemens P4
diffractometer equipped with a graphite monochromator
and employing Mo–Ka radiation. The structure was
solved by direct methods using SHELXS-86 and refined
against F2 with SHELXL-93.
8.8. Synthesis of h-(2-fluorophenyl)-h-methylglycine-
methyl ester hydrochloride (8d)
A 30.2 g (0.254 mol) sample of thionylchloride was
added to 100 ml of methanol at 0°C within a period of
30 min and the reaction mixture was stirred for another
30 min at this temperature. A 15.5 g (84.6 mmol) sample
of the amino acid 8c was dissolved in this solution and
the reaction mixture was stirred for 4 days. After
completion of the reaction (control by 19F-NMR spec-
troscopy) all volatiles were removed in vacuo using a
rotary evaporator (20°C, 20 mbar). The solid obtained
was washed with 300 ml of ether and dried in vacuo.
Yield: 19.4 g (95%).
8.10.2. X-ray structure of 8c·H2O
A block-shaped crystal (0.34×0.40×0.40 mm) was
glued to a glass fiber. X-ray data were measured with a
Siemens P3 diffractometer equipped with a graphite
monochromator and employing Mo–Ka radiation. A
hemisphere of data (4°52q560°) was collected with the
q–2q scan technique, reflections with 2q below 50° being
measured twice. Intensities were derived by profile anal-
ysis and were corrected for absorption and the drift of
the three standards. The positions of the non-hydrogen
atoms were located by direct methods. Subsequently the
hydrogen atoms were revealed by a difference Fourier
synthesis, which showed that the hydrogen atoms of the
water molecule were disordered over three sites. The
structure was refined with a SHELXTL program package
(version 5.03) with non-hydrogen atoms anisotropic and
hydrogen atoms isotropic, and crystal data are given in
Table 1.
8d. Anal. Calc. for C10H13ClFNO2·0.5H2O (242.7): C,
49.49; H, 5.81; N, 5.77. Found: C, 49.25; H, 5.42; N,
1
5.64%. H-NMR (D2O, l, ppm): 7.2–7.65 (arom. H),
3.79 (CH3), 2.02 (CH3); 13C{1H}-NMR (D2O, l, ppm):
174.2, 162.2 (J=246.2), 135.2 (J=9.2), 130.4 (J=2.0),
127.7 (J=3.0), 124.4 (J=12.2), 118.6 (J=21.4 Hz),
60.9, 56.7, 23.3; 19F-NMR (D2O, l, ppm): −114.1.
8.9. Syntheses and resolution of diastereomeric 12,
preparation of (R)-(−)-8e
To a suspension of 16.53 g (73.4 mmol) of racemic 8e
in 110 ml of acetone, 7.42 g (73.4 mmol) of (S)-(+)-2-hy-
droxymethylpyrrolidine was added. The reaction mixture
was heated at reflux until all 8e had been dissolved. On
cooling the solution to ambient temperature, 12 was
precipitated as colorless needles which were collected by
filtration through a suction funnel. A further crop of 12
was obtained on concentration of the filtrate to 50 ml and
cooling to −10°C. Yield: 8.41 g (35%).
12. Anal. Calc. for C16H23FN2O4 (326.4): C, 58.89; H,
7.10; N, 8.58. Found: C, 58.89; H, 7.06; N, 8.47%.
1H-NMR (D2O, l, ppm): 6.94–7.58 (arom. H), 3.52–
3.73, 3.11–3.16, 1.95, 1.89; 13C{1H}-NMR (D2O, l,
ppm): 178.9, 170.9, 162.0 (J=247.2), 132.1 (J=11.2),
130.7 (J=5.1), 129.4 (J=9.2), 124.3 (J=3.1), 116.2
(J=22.4 Hz), 62.6, 61.5, 46.3, 27.1, 24.8, 23.6, 22.7;
19F-NMR (D2O, l, ppm): −114.7.
8.10.3. X-ray structure of 12·H2O
A crystal (0.24×0.40×0.44 mm) was glued to a glass
fiber, and intensity data (4°52q555°) comprising two
octants and their Friedel equivalents were measured with
a Siemens P3 diffractometer using the ꢀ-scan technique.
Intensities were derived by profile fitting, and they were
corrected for absorption and the fluctuations of the three
standard reflections. The structure was solved by direct
methods with the hydrogen atoms being located by a
difference Fourier calculation. This showed that the
methyl group of C(11) is disordered. While the hydrogen
atoms which are bonded to the nitrogen and oxygen
atoms were refined isotropically, those bonded to the
carbon atoms were placed in idealized positions. The
refinement converged, and crystal data are given in Table
1.
The crystals obtained above were suspended in 20 ml
of water. Half concentrated hydrochloric acid was added
until a pH value of 1.5 was reached. The reaction mixture
was extracted with three aliquots of 30 ml of ethylacetate.
The collected organic phases were dried over magnesium
9. Supplementary material
Further details of the crystal structure investigation on
3 are available from the Fachinformationszentrum Karls-

126
D.J. Brauer et al. / Journal of Organometallic Chemistry 598 (2000) 116–126
Tetrahedron Lett. 37 (1996) 6475. (d) K. Severin, R. Bergs, W.
Beck, Angew. Chem. 110 (1998) 1723; Angew. Chem. Int. Ed.
Engl. 37 (1998) 1634.
ruhe, D-76344 Eggenstein-Leopoldshafen, Germany, on
quoting the depository number CSD 405956. Details of
the crystal structures of 8c·H2O and 12·H2O may be
obtained from the Cambridge Crystallographic Data
Centre, 12 Union Rd, Cambridge CB2 1EZ, UK, by
quoting the respective depository numbers CCDC
134136 and 134137, the authors and the literature
reference.
[10] (a) D.N. Wheatley, J.Y. Henderson, Nature 247 (1974) 281. (b)
G.L. Goodsen, I.L. Honigberg, J.J. Lehmann, J. Org. Chem. 25
(1960) 1920. (c) C.S. Marvel, Org. Synth. 21 (1941) 60. (d) C.S.
Marvel, Org. Synth. Coll. III (1955) 495.
[11] L. Maier, in: G.M. Kosolapoff, L. Maier (Eds.), Organic Phos-
phorus Compounds, vol. 1, Wiley-Interscience, New York, 1972,
p. 4.
[12] K. Issleib, R. Ku¨mmel, J. Organomet. Chem. 3 (1965) 84.
[13] (a) M. Bodanczky, C.A. Bickheimer, Chimia 14 (1960) 368. (b)
E. Wu¨nsch, in: Houben-Weyl (Ed.), Methoden der Organischen
Chemie, vol. 15, Georg Thieme Verlag, Stuttgart, 1974. (c) D.S.
Kamp, S.W. Wang, J. Am. Chem. Soc. 92 (1970) 1053.
[14] C. Meyer, H. Gru¨tzmacher, H. Pritzkow, Angew. Chem. 109
(1997) 2576; Angew. Chem. Int. Ed. Engl. 36 (1997) 2471.
[15] (a) M.S. Dunn, L.B. Rockland, Adv. Protein Chem. 3 (1947)
295. (b) Houben-Weyl (Ed.), Methoden der Organischen
Chemie, vol. XI/2, Georg Thieme Verlag, Stuttgart, p. 295.
[16] R.E. Marsh, Acta Crystallogr. 11 (1958) 654.
Acknowledgements
This work was supported by Deutsche Forschungsge-
meinschaft and Fonds der Chemischen Industrie.
Celanese GmbH and Aventis Research Technologies
(Hoechst AG) are thanked for financial support.
[17] P.G. Jo¨nsson, A. Kvick, Acta Crystallogr. Sect. B 28 (1972)
1827.
References
[18] (a) J.J. Daly, J. Chem. Soc. (1964) 3799. (b) B.J. Dunne, A.G.
Orpen, Acta Crystallogr. Sect. C 47 (1991) 345.
[19] (a) S.N. Rastogi, J.S. Bindra, N. Anand, Indian J. Chem. (1971)
1175. (b) E. Ware, Chem. Rev. 46 (1950) 403. (c) J. Taillades, A.
Rousset, M. Lasperas, A. Commeyras, Bull. Soc. Chim. Fr.
(1986) 650.
[20] (a) D. Obrecht, C. Spiegler, P. Scho¨nholzer, K. Mu¨ller, H.
Heimgartner, F. Stierli, Helv. Chim. Acta 75 (1992) 1666. (b) D.
Obrecht, H. Karajiannis, C. Lehmann, P. Scho¨nholzer, C.
Spiegler, K. Mu¨ller, Helv. Chim. Acta 78 (1995) 703.
[21] H.O. Kalinowski, S. Berger, 19F-NMR Spektroskopie, Georg
Thieme Verlag, Stuttgart, 1984.
[22] J.W. Emsley, J. Feeney, L.H. Surcliffe, High Resolution Nuclear
Magnetic Resonance Spectroscopy, vol. 2, Pergamon, Oxford,
1966, p. 871.
[1] P. Machnitzki, M. Tepper, K. Wenz, O. Stelzer, E. Herdtweck,
J. Organomet. Chem., submitted for publication.
[2] (a) G.C. Barret, Chemistry and Biochemistry of the Amino
Acids, Chapman and Hall, London, 1985. (b) G.M. Koppala,
H.F. Schuster, Asymmetric Synthesis: Construction of Molecules
using Amino Acids, Wiley-Interscience, New York, 1987. (c) A.
Giannis, T. Kolter, Angew. Chem. 105 (1993) 1303; Angew.
Chem. Int. Ed. Engl. 32 (1993) 1244. (d) Y. Hayashi, N.
Sekiyama, S. Nakanishi, D.E. Jane, D.C. Sunter, E.F. Birse,
P.M. Udvarhelyi, J.C. Watkins, Neuroscience 14 (1994) 3370.
[3] (a) J. Gomeza, S. Mary, I. Brabet, M.L. Parmentier, S. Restitu-
ito, J. Bockaert, J.P. Piu, Mol. Pharmacol. 50 (1996) 923. (b)
D.E. Jane, K. Pittaway, D.C. Sunter, N.K. Thomas, J.C.
Watkins, Neuropharmacology 34 (1995) 851. (c) M. Bayle-La-
coste, J. Moulines, N. Collignon, A. Boumekouez, E. deTinguy-
Moreaud, E. Neuzil, Tetrahedron 46 (1990) 7793. (d) K. Baczko,
W.Q. Liu, B.P. Roques, C. Garbay-Jaureguiberry, Tetrahedron
52 (1996) 2021. (e) A.A. Cordi, M.L. Vazquez (Searle and Co.),
EP 364996 (25 April 1990) [C.A. 114 (1990) 24 192].
[23] J.H. Burns, E.W. Hagaman, Acta Crystallogr. Sect. C 49 (1993)
1393.
[24] F.H. Allen, O. Kennard, D.G. Watson, L. Brammer, A.G.
Orpen, R. Taylor, J. Chem. Soc. Perkin Trans. 2 (1987) S1.
[25] J.D. Dunitz, R. Taylor, Chem. Eur. J. 3 (1997) 89.
[26] R.A. Sheldon, Chirotechnology — Industrial Synthesis of Opti-
cally Active Compounds, Marcel Dekker, New York, 1993.
[27] R.O. Duthaler, Tetrahedron 50 (1994) 1540.
[28] These experiments were performed by Dr A. Liese and M. de
Oliviers Villela Filho, Forschungszentrum Ju¨lich, Germany.
[29] (a) Y.F. Li, F. Hammerschmidt, Tetrahedron: Asymmetry 4
(1993) 109. (b) W. Breuer, I. Ugi, J. Chem. Res. (M) (1982) 2901.
[30] (a) O. Cantin, C. Cativiela, M.D. Diaz-de-Villegas, R. Navarro,
E.P. Urriolabeitia, Tetrahedron: Asymmetry 7 (1996) 2695. (b)
L.C. Lo, N. Berova, K. Nakanishi, G. Schlingmann, G.T.
Carter, B.D. Borders, J. Am. Chem. Soc. 114 (1993) 7371.
[31] M.P. Schneider, M. Lobell, J. Chromatogr. 633 (1993) 287.
[32] G. Portalone, G. Schultz, A. Domenicano, I. Hargittai, J. Mol.
Struct. 118 (1984) 53.
[33] H.M. Frey, D.C. Marshall, R.F. Skinner, Trans. Faraday Soc.
(1965) 61.
[34] A. Domenicano, P. Murray-Rust, A. Vaciago, Acta Crystallogr.
Sect. B 39 (1983) 457.
[35] (a) F. Pass, H. Schindlbaur, Monatsh. Chem. 90 (1959) 148. (b)
W. Gee, R.A. Shaw, B.C. Smith, Inorg. Synth. 9 (1967) 19. (c)
N. Roberts, S.B. Wild, J. Am. Chem. Soc. 101 (1979) 6254.
[4] S.R. Gilbertson, G.W. Starkey, J. Org. Chem. 61 (1996) 434,
2922.
[5] (a) M. Tepper, O. Stelzer, T. Ha¨usler, W.S. Sheldrick, Tetrahe-
dron Lett. 38 (1997) 2257. (b) O. Stelzer, M. Tepper (Celanese
GmbH), DE 19704491 (2 March 1997) [C.A. 129 (1998) 149 099].
[6] (a) F. Bitterer, O. Herd, A. Heßler, M. Ku¨hnel, K. Rettig, O.
Stelzer, W.S. Sheldrick, S. Nagel, N. Ro¨sch, Inorg. Chem. 35
(1996) 4103. (b) O. Herd, K.P. Langhans, O. Stelzer, N. Wefer-
ling, W.S. Sheldrick, Angew. Chem. Int. Ed. Engl. 32 (1993)
1058. (c) O. Herd, A. Heßler, K.P. Langhans, O, Stelzer, W.S.
Sheldrick, N. Weferling, J. Organomet. Chem. 475 (1994) 99. (d)
M. Hingst, M. Tepper, O. Stelzer, Eur. J. Inorg. Chem. (1998)
73. (e) P. Machnitzki, T. Nickel, O. Stelzer, C. Landgrafe, Eur.
J. Inorg. Chem. (1998) 1029.
[7] Y. Izumi, I. Chibata, T. Itoh, Angew. Chem. 90 (1978) 187;
Angew. Chem. Int. Ed. Engl. 17 (1978) 176.
[8] B.M. Trost, D.L. Van Vranken, C. Bingel, J. Am. Chem. Soc.
114 (1992) 9327.
[9] (a) K.D. Shimizu, B.M. Cole, C.A. Krueger, K.W. Kuntz, M.L.
Snaper, A.H. Hoveyda, Angew. Chem. 109 (1997) 1782; Angew.
Chem. Int. Ed. Engl. 36 (1997) 1704. (b) A.M. LaPointe, J.
Comb. Chem. 1 (1999) 101. (c) S.R. Gilbertson, X. Wang,
.