Bidentate camphane phosphine phosphinites as ligands in asymmetric hydrogenation of α-dehydroamino acids

Article abstract of DOI:10.1055/s-2002-31917

The rhodium(I) catalyzed asymmetric hydrogenation of methyl (Z)-N-acetamido cinnamates 5a-c in the presence of camphor-derived phosphine phosphinites 4a-c gave the corresponding phenyl alanine derivatives 6a-c with good enantioselectivities (up to 89% ee)

Full text of DOI:10.1055/s-2002-31917

LETTER
1011
Bidentate Camphane Phosphine Phosphinites as Ligands in Asymmetric
Hydrogenation of -Dehydroamino Acids
B
identate Campha
x
ne
P
hosphine Phosphini
l
tes as
L
igand
M
s
onsees,*a Sabine Laschat*b
a
Degussa AG Projekthaus Katalyse, Industriepark Höchst, G 830, 65926 Frankfurt am Main, Germany
Fax +49(69)30527338; E-mail: axel.monsees@degussa.com
b
Institut für Organische Chemie, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig, Germany
Fax +49(531)3915388; E-mail: s.laschat@tu-bs.de
Received 27 March 2002
Dedicated to Prof. L. F. Tietze, Universität Göttingen, on the occasion of his 60th birthday.
Abstract: The rhodium(I) catalyzed asymmetric hydrogenation of
methyl (Z)-N-acetamido cinnamates 5a–c in the presence of cam-
phor-derived phosphine phosphinites 4a–c gave the corresponding
phenyl alanine derivatives 6a–c with good enantioselectivities (up
to 89% ee) and high conversions.
5 steps
ref. [8]
OH
O
SO3H
PPh2
Key words: hydrogenation, rhodium, asymmetric synthesis, amino
acids, phosphines
H3B
1
2
1) n-BuLi, THF, -78 °C
2) ClPR12, rt → reflux
3) BH3 • THF, 0 °C
The asymmetric hydrogenation of -dehydroamino acids
is one of the most successful catalytic reactions and over
the last decade a plethora of novel ligands has been devel-
oped for this purpose.1 Whereas the majority of the work
in this area involves bidentate phosphine, phosphite and
phosphinite ligands, several results indicated that mixed
phosphine phosphite2 or aminophosphine phosphinite
ligands3,4 are equally or even better suited for such cata-
lytic reactions. This is in accordance with the proposal by
Achiwa, that two different donor sites can a priori lead to
a better match of the intermediates determining reactivity
and selectivity.5 In contrast to phosphine phosphites and
aminophosphine phosphinites, the corresponding phos-
phine phosphinites have only been rarely exploited.6 This
is surprising, because Saito reported excellent stereoselec-
tivities and improved n/iso ratios in hydroformylations us-
ing binaphthyl-derived phosphine phosphinites as
compared to the diphosphines.7 In addition, Börner ob-
served promising activities and selectivities of Rh(I)
diphosphinite complexes in asymmetric hydrogenations
of imines8 and enamines.9 Recently, we obtained the nov-
el bisboranato camphane phosphine phosphinite 3a by a
6-step synthesis from (1S)-(+)-camphorsulfonic acid 1.10
We were thus interested whether the corresponding bo-
rane-free ligand 4a (Scheme 1) can be used in hydrogena-
tion reactions. Furthermore, we wanted to explore
modifications of the phosphinite moiety. The preliminary
results are reported below.
DABCO
(4 equiv.)
O
R
O
PR1
PR1
THF, 85 °C
10 - 18 h
quant.
2
2
PPh2
PPh2 H3B
H3B
4a
4b
4c
1 = Ph
Mes
Cy
3a
3b
3c
53 %
57 %
55 %
Scheme 1
using hydroxyphosphine 2 as a common intermediate.10
Treatment of 2 with n-BuLi, followed by addition of the
corresponding chlorophosphine and subsequent boryla-
tion yielded compounds 3a–c in 53–57%. Removal of the
borane groups from 3 was achieved by treatment with 4
equivalents of 1,4-diazabicyclo[2.2.0]octane (DABCO)
in THF giving the desired ligands 4a–c,11 which were di-
rectly used for hydrogenation experiments. As shown in
Scheme 2 and the Table treatment of methyl (Z)-N-aceta-
midocinnamate 5a with 0.5 mol% of [Rh(COD)]2OTf and
0.6 mol% of phosphine phosphinite ligand 4a in MeOH at
ambient temperature under 5 atm of hydrogen resulted in
clean formation of the (S)-configurated phenylalanine de-
rivative 6a with good enantioselectivity (81% ee, entry
1).12 However, when using 4-methyl-substituted cinnama-
te 5b, the conversion dropped down dramatically to 20%
(entry 2). With 4-bromo-substituted cinnamate 5c again
quantitative conversion together with high enantioselecti-
tivity was achieved (entry 3). In order to avoid such large
variations of the reaction rate, the solvent was changed
In order to study the electronic and steric effects of the
phosphinite moiety of 4, three different ligands 4a–c were
prepared according to our previously described procedure
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,1011,1013,ftx,en;G07902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1012
A. Monsees, S. Laschat
LETTER
from MeOH to toluene. Indeed, the conversion for 5b to
6b could be considerably improved to 60% (entry 5). Con-
cerning the enantioselectivities the use of toluene led to an
overall increase of the ee values (entries 4–6) irrespective
of the para-substituent of the cinnamates 5a–c. This sol-
vent effect was rather unexpected because kinetic studies
and 103Rh NMR experiments by Heller and Baumann in-
dicated that aromatic solvents inhibit the catalytic activity
of cationic Rh(I) diphosphine complexes due to 6-com-
plex formation.13 When dimesitylphosphinite 4b was em-
ployed for the hydrogenations, quantitative conversions
were obtained in all cases (entries 7–9). The enantioselec-
tivities were in the same range as compared to diphe-
nylphosphinite 4a. The most surprising outcome was the
reversal of the configuration, when dicyclohexylphos-
phinite 4c was used instead (entries 10–12). A similar re-
versal of configuration was observed by Pizzano in
hydrogenations of dimethyl itaconate upon replacement
of phenyl by alkyl groups in the phosphine phosphite
ligand.14 According to mechanistic studies by Ruiz,
Claver2a,b and Landis15 we propose that the different steric
bulkiness of diarylphosphites 4a,b and dicyclohexylphos-
phite 4c results in the preferred formation of different dia-
stereomeric Rh(enamide)(H)2 complexes and thus yields
opposite enantiomers of 6.
0.5 mol%
CO2Me
NHAc
CO2Me
[Rh(COD)2]OTf
*
NHAc
0.6 mol% 4
toluene or MeOH
H2 (5 atm), rt, 18 h
R2
R2
5a
5b
5c
R
2 = H
6a
Me
Br
6b
6c
(for details see Table 1)
Scheme 2
In conclusion, the enantioselectivities obtained with
ligands 4a–c in Rh(I)-catalyzed hydrogenations of methyl
(Z)-N-acetylamidocinnamates 5a–c compare well to the
selectivities reported by Chan for an aminophosphine
phosphinite ligand derived from ketopinic acid.3 Compar-
ison with spiro diphosphinites16 and phosphine
phosphites2 indicates however, that further reduction of
the conformational flexibility of ligands 4 is required in
order to further optimize the enantioselectivity.
Acknowledgement
Generous financial support by Degussa AG and the Fonds der
Chemischen Industrie is gratefully acknowledged.
Table Catalytic Hydrogenations of Methyl (Z)-N-Acetamido Cinnamates 5a–c in the Presence of Phosphine Phosphinites 4a–ca
Entry
(1)
4
a
a
a
a
a
a
b
b
b
c
R1
5
a
b
c
R2
H
Solvent
MeOH
MeOH
MeOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
6
a
b
c
Conv. [%]b % ee
Config.c
(S)
Ph
100
20
81
73
82
85
85
87
89
85
87
50
34
29
(2)
Ph
Me
Br
H
(S)
(3)
Ph
100
100
60
(S)
(4)
Ph
a
b
c
a
b
c
(S)
(5)
Ph
Me
Br
H
(S)
(6)
Ph
100
100
100
100
100
93
(S)
(7)
Mes
Mes
Mes
Cy
Cy
Cy
a
b
c
a
b
c
(S)
(8)
Me
Br
H
(S)
(9)
(S)
(10)
(11)
(12)
a
b
c
a
b
c
(R)
(R)
(R)
c
Me
Br
c
98
a Reaction conditions: 0.3 mmol of -dehydroamino acid 4, 1.5 mol of [Rh(COD)2]OTf, 1.8 mol of ligand 4, 1.3 mL of solvent, 5 bar H2,
r.t., 18 h.
b Conversions were determined by capillary GC using a Chrompac CP-SilCB WCOT column, length 25 m, initial temperature 100 °C, rate
10 °C/min, final temperature 300 °C, carrier gas: He.
c Enantioselectivities were determined by HPLC using a Chiracel OD column with hexane/2-propanol (80:20) as solvent, flow 1 mL/min,
detection at = 220 nm.
Synlett 2002, No. 6, 1011–1013 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Bidentate Camphane Phosphine Phosphinites as Ligands
1013
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(10) Sell, T.; Laschat, S.; Dix, I.; Jones, P. G. Eur. J. Org. Chem.
2000, 4119.
(11) Selected spectroscopic data of phosphine phosphinite
ligands:
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Synlett 2002, No. 6, 1011–1013 ISSN 0936-5214 © Thieme Stuttgart · New York