Synthesis and application of C2-symmetric diamino FERRIPHOS as ligands for enantioselective Rh-catalyzed preparation of chiral α-amino acids

Article abstract of DOI:10.1016/S0957-4166(99)00002-6

C₂-Symmetrical ferrocenyl diamino diphosphines (diamino FERRIPHOS ligands) proved to be excellent ligands for the rhodium-catalyzed enantioselective reduction of methyl α-acetamidoacrylates. The straightforward synthesis, their air stability an

Full text of DOI:10.1016/S0957-4166(99)00002-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 375–384
Synthesis and application of C -symmetric diamino FERRIPHOS
2
as ligands for enantioselective Rh-catalyzed preparation of chiral
α-amino acids
Juan J. Almena Perea, Matthias Lotz and Paul Knochel
a
b
b,∗
a
Degussa AG, Specialty Chemicals Division, Rodenbacher Chaussee 4, D-63403 Hanau (Wolfgang), Germany
Fachbereich Chemie der Philipps-Universität Marburg, Hans-Meerwein-Str, D-35032 Marburg, Germany
b
Received 23 November 1998; accepted 31 December 1998
Abstract
C2-Symmetrical ferrocenyl diamino diphosphines (diamino FERRIPHOS ligands) proved to be excellent ligands
for the rhodium-catalyzed enantioselective reduction of methyl α-acetamidoacrylates. The straightforward synthe-
sis, their air stability and the easy modification of their structure makes these ligands especially interesting for
transition metal-catalyzed hydrogenations. α-Amino acids with enantioselectivities greater than 95% (and up to
9
9.3% ee) were obtained with no need of further recrystallization. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Homogeneous asymmetric catalysis using transition metal complexes has attracted a great deal of
interest because of its high efficiency and economic feasibility in producing a broad range of optically
1
active compounds. Many chiral bisphosphines have been prepared since the late 1960s to induce
enantioselective catalytic reactions, and several industrial processes use chiral phosphine transition metal
1
a
2
complexes as catalysts, for instance, in the production of L-DOPA, L-menthol, or the herbicide (S)-
3
metolachlor (the largest process using an asymmetric hydrogenation catalyst in quantities of over 10 000
tons per year), the latter being an example of the application of ferrocene-based ligands.
Ferrocenyl diphosphine ligands are a versatile class of compounds because they can be easily modified,
benefitting from the special reactivity of the benzylic position, which allows the introduction of different
4
nucleophiles with retention of configuration. Ferrocene-based ligands incorporating both central and
planar chirality is a well developed area that has found successful application in numerous asymmetric
3,5
catalytic processes. Although a great number of C -symmetrical diphosphine ligands have been
2
∗
Corresponding author. E-mail: knochel@ps1515.chemie.uni-marburg.de
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00002-6

376
J. J. Almena Perea et al. / Tetrahedron: Asymmetry 10 (1999) 375–384
6
reported to catalyze the asymmetric hydrogenation of prochiral olefins, few examples of synthesis and
application of C -symmetrical ferrocenyl diphosphine ligands in metal-catalyzed processes have been
2
described. Hayashi et al. have obtained ligand 1 via resolution of the racemic mixture and applied it
to the palladium-catalyzed asymmetric cross-coupling reaction between vinylic bromides and Grignard
7
reagents; Ikeda et al. have synthesized ligands of type 2 and 3 and used them for the palladium-catalyzed
8
asymmetric allylic substitutions. To our knowledge only two examples of C -symmetrical ferrocenyl
2
9
diphosphine ligands have been applied to the asymmetric hydrogenation of prochiral enamides.
Recently, we have developed the synthesis of several new optically active ferrocenyl derivatives.4b–d,11
Now we wish to report the application of some easily prepared C -symmetrical ferrocenyl diphosphine
2
12
ligands to the synthesis of optically active amino acids.
2. Results and discussion
2.1. Synthesis of ligands 9a–c
Syntheses of ligands 9a,b have already been described and will not be discussed in the present work.12
In order to prepare ligand 9c, a similar procedure was employed. Friedel–Crafts acylation of ferrocene
(
4) with propionyl chloride (2 equiv.) in the presence AlCl (2 equiv.) in CH Cl at 0°C afforded diketone
3 2 2
5
c in 74% yield. Asymmetric reduction of diketone 5c with BH ·SMe in THF at 0°C in the presence of
3
2
60 mol% of B-methyl oxazaborolidine [prepared from (S)-2-(diphenylhydroxymethyl)pyrrolidine and
13
†
methyl boronic acid; CBS-catalyst from now on] yielded diol 6c in a 95:5 dl:meso ratio and ee
8%. Conversion to the acetate (pyridine, acetic anhydride, rt) followed by reaction with Me NH in
9
2
a mixture of 1:1 MeOH:H O furnished the desired diamine 8c in 64% yield (3 steps). Lithiation of
2
8
c with t-BuLi in ether at 0°C and quenching with ClPPh produced diphosphine 9c in 40% yield
2
as a single diastereoisomer (de 100%; no other isomer was detected by NMR analysis) due to the
15
well known diastereoselective ortho directing effect of the dimethylamino group, and with an ee
‡
>
98%. These phosphines 9a–c (alkyl dimethylamino FERRIPHOS ligands) are all crystalline, air stable
solids (no oxidation products were observed after 3 months of air exposure) and are easily purified by
recrystallization in acetone or diethyl ether/pentane (Scheme 1).
In order to obtain other ligands with a different amino group than the dimethylamino one, compound
9a was transformed into the corresponding acetate 10a (acetic anhydride, 100°C), and was reacted with
pyrrolidine or N-cyclohexyl-N-methyl amine affording the corresponding diamino diphosphines 9d,e
in 65 and 87% yield as single diastereoisomers (no racemization was detected during these reactions)
(Scheme 2).
†
‡
14
CBS≡Corey–Bakshi–Shibata, the authors who improved the method discovered by S. Itsuno for the reduction of ketones.
Dimethylamino alkyl FERRIPHOS is the nomenclature that we propose for a C -symmetrical ferrocenyl diphosphine ligand,
2
in which the 2 position has an alkyl group and the alpha position has a dimethylamino group.

J. J. Almena Perea et al. / Tetrahedron: Asymmetry 10 (1999) 375–384
377
Scheme 1.
Scheme 2.
2.2. Application of the FERRIPHOS ligands 9a–e to the synthesis of α-amino acid derivatives
For the evaluation of the efficiency of ligand 9a for catalysis, rhodium-catalyzed hydrogenation of
different methyl α-acetamido acrylates 11a–e was performed. The hydrogenation reaction proceeded
under very mild conditions (ca. 1 bar H ; rt) in the presence of 1 mol% of the catalyst prepared in situ [1
2
1
mol% of Rh(COD) BF ; 1 mol% of 9a]. Reactions were monitored by H NMR (reaction times being
2
4
2–6 h). The results obtained are summarized in Table 1.
Concerning the hydrogenation of compound 11a, the results obtained are better than the ones reported
1
0
16
with other ferrocenyl ligands for the same substrate (BPPFA, 21% ee; JOSIPHOS, 96% ee) and better
6
f
or very close to the best results obtained with other ligands ([2.2]PHANEPHOS, 83% ee; DUPHOS
derivatives, 85–>99% ee; DIOP, 82% ee). Hydrogenation of (Z)-α-acetamidocinnamic acid was also
attempted, but the corresponding amino acid derivative was only obtained in 73% ee. Addition of 2%
6
e
17
of CF COOH to the reaction mixture previous to the hydrogenation step improved the ee up to 89%.
3
Although these are only moderate results, they are still better than others previously reported for other
1
7
17
ferrocenyl ligands (BPPFA-IP, 52% ee; BPPFA-Ph, 52% ee) and very close to the results obtained
6
a
18
16
19
with other diphosphines (DIOP, 72% ee; BPPM, 78% ee; JOSIPHOS, 84% ee; PPFA, 76% ee).
The reaction described in Table 1 entry 2, was also performed with only 0.2% of rhodium complex and
0.2% of ligand 9a, the enantiomeric excess being 97.1%. This reaction is not affected by the substrate
concentration either. Repetition of the reaction in Table 1, entry 2 with a 1 M concentration of substrate
afforded the expected phenylalanine derivative 17a in 97.0% ee.

378
J. J. Almena Perea et al. / Tetrahedron: Asymmetry 10 (1999) 375–384
Table 1
Hydrogenation of methyl (Z)-α-acetamidoacrylates with ligand 9aa
Table 2
a
Hydrogenation of methyl (Z)-α-acetamidocinnamate with different ligands
Ligands 9b–e were also tested in the hydrogenation of methyl (Z)-α-acetamidocinnamate. The results
are shown in Table 2. Good enantioselectivities were also obtained with the other ligands.

J. J. Almena Perea et al. / Tetrahedron: Asymmetry 10 (1999) 375–384
379
2.3. Synthesis of (S)-α-amino acid derivatives
To demonstrate the versatility of the chemistry described in this paper, preparation of the other
enantiomer of compound 9a was performed (Scheme 3). The only difference resides in the choice of the
other enantiomer of the CBS-catalyst [the one derived from (R)-proline for performing the CBS-catalyst
synthesis].
Scheme 3.
This new ligand was tested for the hydrogenation of the same α-acetamido dehydroamino acids 11a–e
as in the case of ligand 9a. The results are included in Table 3.
Table 3
Hydrogenation of methyl (Z)-α-acetamidoacrylates with ligand 16a

380
J. J. Almena Perea et al. / Tetrahedron: Asymmetry 10 (1999) 375–384
The fact that the other enantiomer of our ligands is also active in hydrogenation reactions and can be
easily prepared, offers access to both enantiomers of the hydrogenated products.
3. Conclusion
In summary, we have found a new application for the previously reported diamino diphosphine ligands
obtained in our group. We have also demonstrated that this wide family of FERRIPHOS ligands are
excellent ligands for the asymmetric reduction of alkyl α-acetamido acrylates. Further extension to other
transition metal-catalyzed reactions and to the hydrogenation of other substrates are in progress in our
laboratory.
4. Experimental
4.1. General
Melting points are uncorrected. Proton and carbon nuclear magnetic resonance spectra ( H and 13
1
C
NMR) were recorded at room temperature in CDCl (unless otherwise indicated) on a Bruker AC 300
3
spectrometer (300 MHz for proton; 75 MHz for carbon), using TMS as an internal reference. Phosphorus
31
nuclear magnetic resonance spectra ( P NMR) were recorded at room temperature in CDCl on a
3
Bruker AM 400 spectrometer (162 MHz for phosphorus), using H PO 85% as an external reference.
3
4
Chemical shifts are given relative to the reference (TMS or H PO 85%); coupling constants are given
3
4
in hertz. Optical rotations were measured on a Perkin–Elmer 241 polarimeter. Fourier transformation IR
spectra were recorded on a Nicolet 510 FTIR spectrometer. Electron impact (EI, 70 eV) mass spectra
were recorded on a Varian CH 7A instrument. Enantiomeric excesses were determined by HPLC. A
Chiralcel OD column (Daicel Chemical Industries) was used at 30°C (unless otherwise indicated) with
n-heptane:2-propanol, 9:1 (unless otherwise indicated) as a mobile phase and detection by a diode
array UV–vis detector at 215 nm. Alternatively, enantiomeric excesses were measured by GC on a 25
m×0.2 mm fused silica WCOT Chirasil-L-Val (0.12 µm) using hydrogen (100 kPa) as the mobile phase.
Racemic compounds were used as references to choose the operating conditions for the resolution of the
enantiomer and/or diastereomer peaks.
4.2. Materials
THF, Et O and methyl t-butyl ether (MTBE) were distilled from sodium; CH Cl was distilled from
2
2
2
CaH ; pyridine was dried over KOH. Commercial reagents were used without further purification.
2
MeOH of technical degree (<0.1% H O) was used without degassing. t-BuLi was obtained from
2
Chemetall GmbH as 15% solution in hexanes. Compounds 11a–d were prepared according to literature
20
procedures. Compound 11e was purchased from Aldrich. Compounds 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a,
1
2
9
b were prepared as previously reported with the same enantiopurities. Physical and spectroscopical
12
data of compounds 13–16 were in accordance with the ones reported for their enantiomers, except
for the sign of the optical rotation. (S)-α,α-Diphenylprolinol21 and CBS-catalyst were prepared as
previously reported.
13

J. J. Almena Perea et al. / Tetrahedron: Asymmetry 10 (1999) 375–384
381
4.3. General procedure for the hydrogenation of dehydroamino acids
In a 25 mL Schlenk tube under argon, Rh(COD) BF (0.01 mmol, 4.1 mg) and the corresponding
2
4
ligand 9a–e, 16 (0.01 mmol) were dissolved in MeOH or MeOH/toluene mixture. After complete
solubilization of the rhodium complex, the corresponding dehydroamino acid (1 mmol) was added
dissolved in MeOH. The Schlenk tube was connected to a hydrogen balloon and the inert atmosphere was
1
replaced by hydrogen. The reactions were monitored by H NMR. When full conversion was obtained,
the solvent was removed, and the crude reaction was filtered through a short silica gel column using
MTBE as eluent. Enantiomeric excesses and absolute configurations were assigned by comparison with
2
2
literature data. N-Acetylphenylalanine methyl ester (12a, 17a): GC (140°C): t (min)=10.13 (R), 11.67
(
(
R
2
2
S). N-Acetyl-3-(2-naphthyl)alanine methyl ester (12b, 17b): HPLC (flow rate of 0.6 mL/min): tR
min)=20.09 (R), 23.61 (S). N-Acetyl-p-chlorophenylalanine methyl ester (12c, 17c):23 HPLC (flow rate
of 0.8 mL/min): t (min)=13.14 (R), 17.46 (S); GC (160°C): t (min)=11.82 (R), 13.32 (S). N-Acetyl-
R
R
23
p-fluorophenylalanine methyl ester (12d, 17d): HPLC (flow rate of 0.8 mL/min): t (min)=12.81 (R),
5.72 (S); GC (140°C): t (min)=11.29 (R), 13.25 (S). N-Acetylalanine methyl ester (12e, 17e): GC
R
22
1
R
(
80°C): t (min)=6.14 (R), 8.09 (S).
R
0
4
.4. 1,1 -Dipropanoylferrocene 5c
To a suspension of aluminum(III) chloride (14.67 g, 110.0 mmol) in CH Cl (60 mL) at 0°C under
2
2
argon was added propanoyl chloride (9.5. mL, 110.0 mmol). Ferrocene (9.30 g, 50.0 mmol) in CH Cl2
2
(50 mL) was added dropwise within 30 min. The reaction was warmed to room temperature and stirred
overnight. Work-up was done at 0°C by dropwise addition of ice-cold water (50 mL; caution: gas
evolution!). The reaction mixture was diluted with CH Cl (100 mL) and washed twice with saturated
2
2
aqueous K CO (50 mL) and brine (50 mL). The organic layer was dried (MgSO ) and concentrated
2
3
4
to afford a red solid which was washed with MTBE. A yield of 74% (11.0 g, 37.0 mmol) was obtained
without further purification. Mp 50–51°C; IR (KBr): νmax=3096 (w), 2934 (w), 1674 (vs), 1458 (s), 1242
1
(
s), 1102 (m), 1048 (m), 807 (m); H NMR δ=4.88–4.85 (m, 4H), 4.59–4.56 (m, 4H), 2.84–2.71 (m, 4H),
13
+
1
1
6
.34–1.23 (m, 6H); C NMR δ=203.68, 79.90, 72.92, 70.17, 32.68, 7.82; MS (EI, 70 eV) m/z: 298 (M ,
00%), 269 (24), 213 (27), 186 (6), 121 (27). Anal. calcd for C H FeO : C, 64.45; H, 6.08. Found: C,
16
18
2
4.25; H, 6.05.
0
4
.5. (R,R)-1,1 -Bis(α-hydroxypropyl)ferrocene 6c
Under argon, the CBS-catalyst (2.49 g, 9.0 mmol) was dissolved in THF (10 mL) and cooled to 0°C.
From a syringe charged with BH ·SMe (1 M in THF, 37.5 mL) 20% of the final amount (7.5 mL)
3
2
was added to the catalyst solution. After 5 min of stirring, the remaining BH ·SMe and a solution
3
2
of the diketone 5c (4.50 g, 15.0 mmol) in THF (30 mL) were simultaneously added within 2 h. The
red color of the ketone turns to yellow upon reduction. After 5 min at 0°C the excess BH ·SMe was
3
2
quenched by dropwise addition of methanol (10 mL; caution: gas evolution!). After gas evolution had
ceased, the mixture was poured onto saturated aqueous NH Cl (150 mL) and extracted with MTBE (200
4
mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried (MgSO ) and
4
then concentrated to give an oil which was purified by column chromatography (hexanes:MTBE, 1:1).
Yield: 80% [3.62 g, 12.0 mmol; dl:meso=92:8; ee >98%; HPLC, 5% i-PrOH, flow rate of 0.6 mL/min,
2
2
T=20°C, t /min=8.35 (SS), 9.12 (RS), 11.09 (RR)]. Yellow oil; [α]D =−92.4 (c=1.31, benzene); IR
R
1
(
neat): νmax=3320 (s, br), 3080 (w), 2930 (m), 2860 (m), 1460 (m), 1380 (m), 1030 (s), 810 (s); H NMR

382
J. J. Almena Perea et al. / Tetrahedron: Asymmetry 10 (1999) 375–384
δ=4.42 (t, J=6.2, 2H), 4.26–4.12 (m, 10H), (m, 6H), 1.69–1.50 (m, 4H), 0.89 (t, J=7.4, 6H); 13C NMR
+
δ=93.45, 71.29, 67.34, 67.31, 66.32, 66.30, 32.69, 9.79; MS (EI, 70 eV) m/z: 302 (M , 22%), 284 (44),
2
66 (100), 255 (12), 226 (15), 178 (24), 160 (68), 91 (75). Anal. calcd for C H FeO : C, 63.59; H,
16 22 2
7.34. Found: C, 63.43; H, 7.41.
0
4
.6. (R,R)-1,1 -Bis(α-acetoxypropyl)ferrocene 7c
Diol 6c (0.60 g, 2 mmol) was dissolved in pyridine (4 mL) and acetic anhydride (2 mL) and stirred
for 12 h at room temperature. Volatile matter was removed under vacuum (1 mmHg, 5 h) to yield
quantitatively the acetate 7c as a yellow oil which was already >98% pure as indicated by NMR analysis.
2
2
1
(
dl:meso=95:5; ee >98%); [α]D =−40.3 (c=2.06, CHCl ); IR (neat): ν =1732 (vs), 1236 (vs); H
3
max
NMR δ=5.69–5.65 (m, 2H), 4.19 (s, 2H), 4.11–4.08 (m, 6H), 2.09 (s, 6H), 1.88–1.72 (m, 4H), 0.91
13
(
(
t, J=7.3, 6H); C NMR δ=170.61, 88.57, 73.15, 68.31, 68.51, 67.90, 67.24, 28.45, 21.16, 10,16; MS
+
EI, 70 eV) m/z: 380 (M , 10%), 326 (7), 266 (25), 220 (50), 221 (12), 161 (15). Exact mass calcd for
C H FeO : 386.1180. Observed: 386.1176.
20
26
4
0
4
.7. (R,R)-1,1 -Bis(α-N,N-dimethylaminopropyl)ferrocene 8c
The diacetate 7c (0.97 g, 2.5 mmol) was dissolved in a CH OH/water mixture (20 mL). Dimethylamine
3
(40% in water, 10 mL) was added. After stirring for 12 h at room temperature, the reaction was poured
into saturated aqueous NH Cl (50 mL) and extracted with MTBE (100 mL). After washing with water
4
(
2×50 mL) and brine (50 mL), the organic layer was dried and concentrated to give an oil which
was purified by column chromatography (hexanes:MTBE, 2:1 with 2% NEt ) to yield diamine 8c in
8
CHCl ); IR (KBr): ν =3092 (m), 1471 (s), 1450 (s), 986 (s), 827 (s); H NMR δ=4.05–3.98 (m, 8H),
3
NMR δ=85.81, 70.04, 68.09, 67.86, 67.64, 64.90, 40.54, 24.43, 12.29; MS (EI, 70 eV) m/z: 356 (M ,
3
3
22
1% yield (0.72 g, 2.0 mmol; dl:meso=>99:<1) as a brown solid; mp 86–89°C; [α] =−21.3 (c=1.43,
D
1
3
max
13
.24 (dd, J=10.9, 3.3, 2H), 2.07–1.94 (m, 2H), 1.99 (s, 12H), 1.80–1.66 (m, 2H), 1.09 (t, J=7.3, 6H);
C
+
4%), 327 (12), 311 (29), 282 (16), 268 (33), 267 (20), 239 (100), 178 (56). Anal. calcd for C H FeN :
20 32 2
C, 67.41; H, 9.05; N, 7.86. Found: C, 67.55; H, 8.95; N, 7.84.
0
0
0
4
.8. (αR,α R)-2,2 -Bis(α-N,N-dimethylaminopropyl)-(S,S)-1,1 -bis(diphenylphosphino)ferrocene 9c
Diamine 8c (0.97 g, 2.9 mmol) was dissolved under argon in Et O (10 mL), cooled to 0°C and t-BuLi
2
(c=1.5 M; 5.8 mL, 8.7 mmol) was added within 5 min. The solution was stirred at the same temperature
for 0.5 h (the color changed from yellow to deep red). After quenching with ClPPh (2.1 mL, 11.8 mmol)
2
at 0°C and stirring at rt for 3 h, the mixture was poured onto a saturated solution of NaHCO (20 mL)
3
and extracted with CH Cl . After drying with MgSO and filtration, the residue was purified by column
2
2
4
chromatography (hexanes:MTBE, 3:1 and then 1:1 with 1% of Et N) and recrystallized in hexanes. A
3
yellow solid was isolated in 40% yield (0.84 g, 1.1 mmol) as a single diastereomer (de 100%; ee >98%).
2
2
Mp 185–187°C; [α]D =−566.8 (c=0.66, CHCl ); IR (KBr): νmax=3068 (w), 3051 (w), 3026 (w), 1584
3
−1 1
(
w), 738 (s), 697 (s) cm ; H NMR δ=7.32–7.04 (m, 20H), 4.29, 4.13 (2×br s, 2×2H), 3.81–3.78 (m,
13
2
H), 3.02 (br s, 2H), 2.09–2.01 (m, 2H), 1.94–1.85 (m, 2H), 1.81 (s, 12H), 1.13 (t, J=7.4, 6H); C NMR
δ=140.54 (d, J=7.2), 138.47 (d, J=9.3), 135.01 (d, J=22.2), 132.11 (d, J=18.7), 128.55, 127.98, 127.28,
1
27.19, 126.99, 98.19 (d, J=23.6), 76.16 (d, J=8.9), 73.01, 72.04 (d, J=5.4), 70.47, 62.55 (d, J=7.0),
31
+
39.73, 23.55, 13.65; P NMR δ=−23.45; MS (EI, 70 eV) m/z: 724 (M , 39), 679 (30), 665 (44), 664

J. J. Almena Perea et al. / Tetrahedron: Asymmetry 10 (1999) 375–384
383
(
100), 636 (20), 635 (24), 634 (22), 339 (22), 183 (18). Anal. calcd for C H FeN P : C, 72.93; H, 6.95;
44 50 2 2
N, 3.87. Found: C, 72.83; H, 7.08; N, 3.60.
0
0
0
4
.9. (αR,α R)-2,2 -Bis(α-acetoxyphenylmethyl)-(S,S)-1,1 -bis(diphenylphosphino)ferrocene 10a
Diamine 9a (0.82 g, 1.0 mmol) was dissolved in acetic anhydride (4 mL) and heated at 100°C for 2.5
h. The volatiles were then removed under vacuum (1 mmHg, 3 h), affording in quantitative yield the
corresponding acetate (>95% pure, NMR). Further purification could be achieved by recrystallization in
2
2
diethyl ether/hexanes. Brown solid; mp 184°C (decomp.); [α] =−169.6 (c=0.46, CHCl ); IR (KBr):
D
3
−1 1
νmax=1736 (vs), 1231 (vs), 737 (vs), 702 (s) cm ; H NMR δ=7.27–7.03 (m, 30H), 6.58 (d, J=2.8,
H), 4.61 (t, J=2.3, 2H), 3.96 (br s, 2H), 3.25–3.24 (m, 2H), 1.27 (s, 6H); 13C NMR δ=169.03, 139.49
d, J=10.0), 139.07, 136.29 (d, J=9.0), 134.90 (d, J=22.1), 132.61 (d, J=18.8), 129.24, 128.25, 128.22,
28.15, 128.05, 127.92, 127.84, 127.78, 127.41, 93.06 (d, J=22.9), 74.26, 73.95, 73.87, 73.75, 72.32 (d,
2
(
1
31
+
J=4.2), 20.12; P NMR δ=−23.75; MS (EI, 70 eV) m/z: 851 (M 1, 5), 733 (55), 394 (22), 339 (17), 338
(
69), 337 (100), 183 (38). Anal. calcd for C H FeO P : C, 73.42; H, 5.21. Found: C, 73.26; H, 5.29.
52 44 4 2
0
0
0
4
.10. (αR,α R)-2,2 -Bis(α-pyrrolidinophenylmethyl)-(S,S)-1,1 -bis(diphenylphosphino)ferrocene 9d
Diacetate 10a (300 mg, 0.35 mmol) was treated with pyrrolidine (1.46 mL, 17.5 mmol) in CH CN
3
(
2 mL)/H O (0.2 mL) at 90°C for 12 h. The solvents were removed under vacuum and the residue
2
dissolved in MTBE and washed with brine. After removal of solvents, the residue was purified by column
chromatography (hexanes:MTBE, 5:1) to yield the corresponding product in 65% yield (198 mg, 0.23
mmol) as an orange solid; mp 242°C (decomp.); [α]D22=−317.7 (c=0.53, CHCl ); IR (KBr): νmax=3067
3
−1 1
(
w), 3024 (w), 1601 (w), 1585 (w), 737 (s), 698 (s) cm ; H NMR δ=7.30–6.88 (m, 30H), 4.65 (d,
J=4.6, 2H), 4.26, 3.09, 2.95 (3×br s, 3×2H), 1.97–1.93 (m, 4H), 1.81–1.77 (m, 4H), 1.28–1.19 (m,
1
3
4
1
H), 1.08–1.03 (m, 4H); C NMR δ=142.81, 139.93 (d, J=7.5), 138.07 (d, J=10.3), 135.03 (d, J=23.2),
32.45 (d, J=18.9), 128.80, 128.58, 128.19, 128.08, 127.92, 127.65, 127.57, 127.42, 126.51, 99.62 (d,
31
J=23.5), 75.44 (d, J=10.0), 73.23, 72.06, 71.45, 65.74 (d, J=11.2), 51.43, 22.73; P NMR δ=−23.46;
MS (EI, 70 eV) m/z: 872 (M , 30), 803 (19), 802 (100), 734 (48), 733 (69), 732 (72), 724 (28), 464 (31),
+
463 (62), 401 (19), 395 (76), 394 (72), 393 (24), 337 (30), 239 (30), 183 (77), 160 (53). Exact mass calcd
for C H FeN P : 872.3112. Observed: 872.3133.
56
54
2 2
0
0
0
4
.11. (αR,α R)-2,2 -Bis[α-(N-cyclohexyl-N-methylamino)phenylmethyl]-(S,S)-1,1 -bis(diphenyl-
phosphino)ferrocene 9e
Diacetate 10a (160 mg, 0.18 mmol) was treated with N-cyclohexyl-N-methylamine (1.2 mL, 9.3
mmol) in CH CN (2 mL)/H O (0.2 mL) at 90°C for 12 h. The solvents were removed under vacuum and
3
2
the residue taken up in MTBE and washed with brine. After removal of solvents, the residue was purified
by column chromatography (hexanes:MTBE, 5:1) to yield the corresponding product in 87% yield (150
mg, 0.16 mmol) as a pale yellow solid; mp 224°C (decomp.); [α]D22=−290.2 (c=0.57, CHCl ); IR (KBr):
3
−1 1
νmax=3071 (w), 3053 (w), 3001 (w), 1600 (m), 1584 (w), 741 (s), 701 (s) cm ; H NMR δ=7.24–7.03
m, 30H), 4.95 (d, J=4.7, 2H), 4.34, 3.31, 3.06 (3×br s, 3×2H), 2.12–2.05 (m, 2H), 1.51–1.47 (m, 4H),
.43 (s, 6H), 1.34–1.31 (m, 4H), 0.91–0.66 (m, 12H); 13C NMR δ=142.77, 139.95 (d, J=7.8), 138.34 (d,
J=10.2), 135.58 (d, J=23.4), 132.58 (d, J=18.8), 128.60, 128.50, 128.12, 128.01, 127.42, 127.33, 127.17,
(
1
1
3
26.37, 98.75 (d, J=23.4), 76.10 (d, J=11.4), 73.74, 72.92 (d, J=5.5), 71.18, 64.28 (d, J=11.2), 60.07,
2.02, 29.22, 26.22, 26.04, 26.00; 31P NMR δ=−24.80; MS (EI, 70 eV) m/z: 958 (M 1, 17), 845 (51),
+

384
J. J. Almena Perea et al. / Tetrahedron: Asymmetry 10 (1999) 375–384
764 (25), 763 (52), 762 (100), 735 (32), 733 (27), 506 (20), 395 (29), 183 (20). Exact mass calcd for
C H FeN P : 956.4051. Observed: 956.4064.
62
66
2 2
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (SFB 260, Graduiertenkolleg,
Leibniz Program) and the Fonds der Chemischen Industrie. We thank BASF AG (Ludwigshafen),
Chemetall (Frankfurt) and Degussa AG (Hanau) for the generous gift of chemicals. J.J.A.P. was an
Alexander von Humboldt Foundation Fellow before moving to Degussa AG.
References
1. (a) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106–112. (b) Ojima, I. Catalytic Asymmetric Synthesis; VCH: New York,
1993. (c) Sheldon, R. A. Chirotechnology; Marcel Dekker: New York, 1993. (d) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; John Wiley & Sons: New York, 1994.
2
3
4
. Noyori, R. Acc. Chem. Res. 1990, 23, 345–350.
. Togni, A. Angew. Chem. 1996, 108, 1581–1583; Angew. Chem., Int. Ed. Engl. 1996, 35, 1475–1477.
. (a) Gokel, G. W.; Marquarding, D.; Ugi, I. K. J. Org. Chem. 1972, 37, 3052–3058. (b) Schwink, L.; Knochel, P. Tetrahedron
Lett. 1996, 37, 25–28. (c) Almena Perea, J. J.; Ireland, T.; Knochel, P. Tetrahedron Lett. 1997, 38, 5961–5964.
. (a) Hayashi, T.; Kumada, M. Acc. Chem. Res. 1982, 15, 395–401. (b) Hayashi, T. Pure Appl. Chem. 1988, 60, 7–12.
. (a) Kagan, H. B.; Dang, T. P. J. Am. Chem. Soc. 1972, 94, 6429–6433. (b) Knowles, W. S.; Sabacky, M. J.; Vineyard, B.
D.; Weinkauff, D. J. J. Am. Chem. Soc. 1975, 97, 2567–2568. (c) Fryzuk, M. D.; Bosnich, B. J. Am. Chem. Soc. 1977,
5
6
99, 6262–6267. (d) Mayashita, A.; Yasuda, A.; Takaya, H.; Totiumi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc.
1980, 102, 7932–7934. (e) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518–8519. (f) Pye, P. J.; Rossen, K.; Reaner, R. A.;
Tsou, N. N.; Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 119, 6207–6208.
. Hayashi, T.; Yamamoto, A.; Hojo, M.; Ito, Y. J. Chem. Soc., Chem. Commun. 1989, 495–596.
. (a) Zhang, W.; Hirao, T.; Ikeda, I. Tetrahedron Lett. 1996, 37, 4545–4548. (b) Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda, I.
Tetrahedron Lett. 1996, 37, 7995–7998.
7
8
9. (a) Kang, J.; Lee, J. H.; Ahn, S. H.; Choi, J. S. Tetrahedron Lett. 1998, 39, 5523–5526. (b) Almena Perea, J. J.; Börner, A.;
Knochel, P. Tetrahedron Lett. 1998, 39, 8073–8076.
1
1
1
1
1
0. Hayashi, T.; Mise, T.; Mitachi, S.; Yamamoto, K.; Kumada, M. Tetrahedron Lett. 1976, 1133–1134.
1. Schwink, L.; Ireland, T.; Püntener, K.; Knochel, P. Tetrahedron: Asymmetry 1998, 9, 1143–1163.
2. Schwink, L.; Knochel, P. Chem. Eur. J. 1998, 4, 950–968.
3. Wright, J.; Frambes, L.; Reeves, P. J. Organomet. Chem. 1994, 476, 215–217.
4. (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Chem. Commun. 1983, 469–470. (b) Corey, E. J.; Bakshi,
R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553.
1
1
1
1
1
2
2
5. Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J. Am. Chem. Soc. 1970, 92, 5389–5393.
6. Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062–4066.
7. Yamamoto, K.; Wakatsuki, J.; Sugimoto, R. Bull. Chem. Soc. Jpn. 1980, 53, 1132–1137.
8. Inoguchi, K.; Sakuraba, S.; Achiwa, K. Synlett 1992, 169–178.
9. Cullen, W. R.; Woollins, J. D. Can. J. Chem. 1982, 60, 1793–1799.
0. Herbst, R. M.; Shemin, D. Org. Synth. Coll. Vol. II 1943, 1–3.
1. Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Turner Jones, E. T.; Hoogsteen, J.
K.; Baum, M. W.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751–762.
2
2
2. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115, 10125–10138.
3. Chan, A. S.; Hu, W.; Pai, C.-C.; Lau, C.-P. J. Am. Chem. Soc. 1997, 119, 9570–9571.