Chiral tricarbonyl(η6-arene)chromium complexed diphosphanes. Highly enantioselective rhodium-mediated hydrogenation of ketones

Article abstract of DOI:10.1016/S0040-4039(01)00325-2

Arenechromium complexed diastereomeric aminophosphine-phosphinite ligands derived from tetrahydroisoquinoline have been synthesised and examined as chiral auxiliaries in the hydrogenation of functionalised ketones. A cyclopentyl-substituted anti-stereoisomer is providing the highest enantioselectivities (up to >99% ee).

Full text of DOI:10.1016/S0040-4039(01)00325-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2809–2812
Chiral tricarbonyl(h6-arene)chromium complexed diphosphanes.
Highly enantioselective rhodium-mediated hydrogenation
of ketones
Corinne Pasquier, Lydie Pe´linski, Jacques Brocard, Andre´ Mortreux and
Francine Agbossou-Niedercorn*
Laboratoire de Catalyse de Lille, UPRESA 8010, ENSCL, BP 108, 59652 Villeneuve d’Ascq Cedex, France
Received 15 February 2001; revised 21 February 2001; accepted 23 February 2001
Abstract—Arenechromium complexed diastereomeric aminophosphine–phosphinite ligands derived from tetrahydroisoquinoline
have been synthesised and examined as chiral auxiliaries in the hydrogenation of functionalised ketones. A cyclopentyl-substituted
anti-stereoisomer is providing the highest enantioselectivities (up to >99% ee). © 2001 Elsevier Science Ltd. All rights reserved.
Chiral chelating phosphines containing a ferrocene
have encountered great success in asymmetric cataly-
sis.1 On the contrary, and although the tricarbonyl
chromium unit has proven its utility as a stereodirecting
group in chiral catalysts,2 the use of arenechromium
based chiral phosphines has obtained increased interest
only in recent years.3
As part of an ongoing exploration of various synthetic
approaches to aminophosphine–phosphinite ligands
(AMPP),4 we previously utilised the tricarbonyl
chromium moiety to vary the stereo-electronic proper-
ties during ligand tuning.5 In our example, the nitrogen
atom of the AMPP was directly connected to the
complexed ortho-substituted arene ring. Consequently,
O
O
1) SOCl2, EtOH
1) BH3
.
Me2S
OH
OEt
OH
N
N
N
2) NaOH
2) (CF3CO)2O,
pyridine
0 ºC, CH2Cl2
80% overall
O
COCF3
H
H
4
3
1) Cr(CO)6
2) chromatography
60%
ClPR2
NEt3, Et2O
O
(OC)3Cr
OPR2
PR2
OEt
COCF3
OEt
N
+
anti-5
syn-5
N
N
COCF3
(OC)3Cr
R = Ph, 1
R = Cp, 2
1) NaBH4, MeOH
2) PR2Cl, NEt3
70 - 80%
70 - 80%
Cp: cyclopentyl
(OC)3Cr
OPR2
PR2
OPR2
PR2
N
(OC)3Cr
N
R = Ph anti-Ph-6
R = Cp anti-Cp-7
R = Ph syn-Ph-6
R = Cp syn-Cp-7
Scheme 1.
Keywords: enantioselective hydrogenation; rhodium; ketones; aminophosphine–phosphinites; tricarbonylarenechromium.
* Corresponding author. Fax: 33 (0)3 20 43 65 85; e-mail: francine.agbossou@ensc-lille.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00325-2

2810
C. Pasquier et al. / Tetrahedron Letters 42 (2001) 2809–2812
the Cr(CO)3 unit brought about steric and electronic
control onto the corresponding AMPP ligands and a
beneficial effect was observed in several cases.
diastereomers, the protons on the carbons connected to
the complexed arene ring and lying on the side of the
chromium tripod were deshielded (average Dl=0.2
ppm) compared to the uncomplexed ligand. The
remaining protons, opposite to the Cr(CO)3 were not or
only slightly deshielded (Dl<0.1 ppm). Next, the anti
and syn compounds, anti-5 and syn-5, were reduced
with NaBH4 providing the corresponding amino-alco-
hols, which were converted through the standard proce-
dure into the anti (anti-Ph-6 and anti-Cp-7) and syn
(syn-Ph-6 and syn-Cp-7) complexed AMPP ligands in
70–80% overall yields.7
Considering the steric crowding provided by the
Cr(CO)3 when complexed on an aromatic precursor
and taking into account the beneficial outcome
expected while varying judiciously only the steric char-
acteristic of chiral ligands, we thought to utilise the
Cr(CO)3 unit to accomplish specifically a steric tuning
of AMPP ligands. The ligand precursor derived from
tetrahydroisoquinoline carboxylic acid, which eludes
the immediate proximity of the complexed arene and
the nitrogen atom of the future AMPP ligand, appears
particularly relevant for such a study. In addition, the
uncomplexed ligands (S)-Cp,Cp-QuinoNOP and (S)-
Cy,Cy-QuinoNOP induced already high enantioselec-
These new ligands were then evaluated in the rhodium
catalysed hydrogenation of 5 typical ketones possessing
various functionalities, i.e. 4,4-dimethyl-2,3-furandione
8, ethyl pyruvate 9, ethyl phenylglyoxylate 10, N-ben-
zylbenzoylformamide 11, and 2-(N,N-dimethyl)-
aminoketone hydrochloride 12 (Scheme 2). The results
of the hydrogenation are summarised in Table 1.
Earlier results are also reported in Table 1 for com-
parison.
tivities
in
ketone
hydrogenation.5
In
this
communication, we report the synthesis of isoquinoline
based diastereomeric diphosphanes bearing a Cr(CO)3
moiety and their use in asymmetric hydrogenation of
functionalised ketones.
The parent ligands (S)-Ph,Ph-QuinoNOP 1 and (S)-
Cp,Cp-QuinoNOP 2 (Scheme 1) have already been
synthesised previously starting from (S)-1,2,3,4-tetra-
hydro-3-isoquinolinecarboxylic acid 3.5b In order to
synthesise and separate the corresponding Cr(CO)3
complexed diastereomeric precursors possessing oppo-
site face aromatic chiralities, the methodology devel-
oped earlier by us and others did not apply.2a,5b We
have therefore devised the strategy given below. First,
acid 3 was converted into its ethyl ester followed by a
reaction with trifluoroacetic anhydride providing com-
pound 4 in 80% overall yield. The latter was then
thermolysed in the presence of hexacarbonylchromium
in dibutylether/tetrahydrofuran producing the mixture
of diastereomers anti-5 and syn-5 as a result of the
Cr(CO)3 complexation below and above the arene plane
with nevertheless no diastereoselectivity (anti/syn: 54/
46). Both diastereomers could be separated through
silica gel chromatography (60% overall yield). Assign-
ments of all protons of both isolated complexes were
obtained easily by use of standard NMR techniques.
Hence, the pairs of methylene protons attached to a
given carbon atom were identified. The protons posi-
tioned to the side of the carbonyl ligands of Cr(CO)3
can be markedly deshielded.6 Consequently, in both
First, the phenyl-substituted ligands 1, anti-6 and syn-6
were examined in the hydrogenation of 8 (entries 1–3).
As usual, the phenyl substituted AMPPs required more
severe reaction conditions than the cycloalkyl substi-
tuted ones (entries 1–6). We noticed clearly a beneficial
effect due to the Cr(CO)3 moiety of the anti-Ph-6
auxiliary as the hydrogenation product, pantolactone,
was produced with 72% ee compared to 37% ee for the
uncomplexed ligand (entry 2 versus 1). This is the
highest enantioselectivity ever reached for the hydro-
genation of
8 with Rh-based phenyl substituted
AMPPs.8 This value corresponds to an improvement of
the enantiodifferenciation of 35% ee for the produced
pantolactone compared to the uncomplexed ligand 1
and of 17% ee when compared to the best previously
reported (S)-Ph,Ph-oxo-ProNOP ligand.9 Nevertheless,
a small decrease of enantioselectivity was obtained with
anti-Cp-7 as 87% ee were measured compared to 95%
for the uncomplexed ligand 2 (entry 5 versus 4).
For the other four substrates, a beneficial effect (or
clean conservation of the very high enantioselectivities)
could be attributed to the presence of Cr(CO)3 in the
matched diastereomer anti-Cp-7 mentioned above. For
example, for substrate 9, on going from uncomplexed 2
O
OH
[Rh(L*2)X]2
+ H2
1
R2
1
R
R2
8-12
R
L*2: AMPP; X: Cl or TFA
O
O
H
CH3
O
O
H3C
.
NMe2
HCl
CH3
N
O
R
O
O
O
O
R = CH3 9
11
12
8
R = Ph 10
Scheme 2.

C. Pasquier et al. / Tetrahedron Letters 42 (2001) 2809–2812
Table 1. Asymmetric hydrogenation of functionalised ketonesa
2811
Entry
Substrate
Chiral ligand
Rhb complex
Solvent
PH (bar)
T (°C)
Time (h)c
Conv. (%)d
Ee (%)e
2
(confign)
1
2
3
4
5
6
7
8
8
1f
Rh-TFA
Rh-TFA
Rh-TFA
Rh-TFA
Rh-TFA
Rh-TFA
Rh-TFA
Rh-Cl
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
MeOH
MeOH
MeOH
PhCH3
PhCH3
MeOH
PhCH3
MeOH
PhCH3
MeOH
PhCH3
PhCH3
PhCH3
EtOH
50
50
50
50
50
50
50
50
50
50
50
50
50
30
30
30
30
30
30
30
50
50
50
50
50
50
50
50
50
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
89
69
69
0.33
0.5
0.5
1
6
3
6
6
6
6
3
4
3
20
3
3
7
94
90
85
100
61
98
100
97
100
93
100
100
100
51
37 (R)
72 (R)
17 (R)
95 (R)
87 (R)
85 (R)
80 (R)
70 (R)
86 (R)
76 (R)
83 (R)
95 (R)
78 (R)
5 (S)
11 (S)
4 (S)
5 (S)
22 (S)
4 (S)
10 (S)
\99 (S)
\99 (S)
94 (S)
\99 (S)
\99 (S)
95 (S)
anti-Ph-6
syn-Ph-6
2
anti-Cp-7
syn-Cp-7
2f
9
2
9
anti-Cp-7
syn-Cp-7
2
anti-Cp-7
syn-Cp-7
2f
Rh-TFA
Rh-Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Rh-TFA
Rh-TFA
Rh-TFA
Rh-TFA
Rh-Cl
Rh-Cl
Rh-Cl
Rh-Cl
Rh-Cl
Rh-Cl
Rh-Cl
Rh-Cl
Rh-Cl
Rh-Cl
Rh-Cl
Rh-Cl
10
2
2
68
35
100
34
49
anti-Cp-7
anti-Cp-7
syn-Cp-7
syn-Cp-7
2
anti-Cp-7
syn-Cp-7
2f
20
11
12
19
18
18
18
18
18
100
100
100
100
100
100
anti-Cp-7
syn-Cp-7
EtOH
EtOH
a Hydrogenations were carried out in a 50 mL stainless steal autoclave using recrystallised 8, 11, and 12 and distilled 9 and 10; substrate/Rh=200/
1.
b Catalyst precursors: Rh-Cl:[Rh(COD)Cl]2, Rh-FTA:[Rh(COD)(OCOCF3]2.
c Reaction times were not necessarily optimised.
d Determined by 1H NMR for 11 and 8 and capillary GC, FS-cyclodextrine b-I/P (25 m×0.32 m) for 8, 9 and 10.
e Determined on the basis of the specific rotation value [h]D26=+82.2 (c 1.09, CHCl3) for (S)-(+)-N-benzylmandelate10 for the hydrogenation of 11,
by capillary GC, FS-cyclodextrine b-I/P (25 m×0.32 m) for 8, 9, and 10, and HPLC analysis (chiralcel OD (Daicel)) of the free amine for 12.
f Taken from Ref. 5a.
to anti-Cp-7 with a parallel switch from toluene to
methanol as the solvent, an increase of 15% ee was
obtained (entry 12 versus 7). For the second ketoester
10, an identical trend was observed even if the selectiv-
ity remained low (entries 14–20). For substrate 12, for
which reactions are carried out in ethanol, no loss of
enantioselectivity was observed with anti-Cp-7 (entry 25
versus 24) and a slight decrease was noted with syn-Cp-
7 (entry 26 versus 24).
In summary, this study shows how enantioselectivity
benefits from the presence of the Cr(CO)3 moiety in the
matched diastereomer anti-Cp-7. Nevertheless, only an
increase of an average of 15% ee is achieved. Due to the
C1 and C3 spacers between the complexed arene ring
and the NP and OP functions of the ligand, respec-
tively, a steric control is essentially effective. In addi-
tion, this study has shown that even if generally basic
AMPP ligands are best examined in apolar aprotic
solvents for ketones hydrogenation, switching to more
polar and protic solvents can be beneficial to the enan-
tioselective process. This approach is currently applied
to the tuning of other ligands as well and extended to
other enantioselective catalyses.
We have already proposed that when hydrogenation of
ketones is carried out in toluene, the non chiral ligand
X (Cl or TFA) most probably remains on the rhodium
during catalysis.10 This of course is inhibiting substrate
chelation onto the metal in the key catalytic hexacoor-
dinate intermediates Rh(P2)(H)2(X)(RCOR%). However,
this limitation is not an obstacle to very high enantiose-
lectivities for the hydrogenation of substrates 8 and 11.
For the latter, the previously proposed hydrogen bond
between HN and the chlorine might contribute to the
high enantiodifferenciation observed. On the other side,
when alcohols are used as solvents, the catalytic inter-
mediates are most probably cationic allowing a benefi-
cial chelation of substrates 9, 10, and 12.6c,10
Acknowledgements
The authors gratefully thank the ‘Ministe`re de la
Recherche et de la Technologie’ and the ‘Centre
National de la Recherche Scientifique’ for financial
support.

2812
C. Pasquier et al. / Tetrahedron Letters 42 (2001) 2809–2812
4. (a) Agbossou, F.; Carpentier, J.-F.; Hapiot, F.; Suisse, I.;
References
Mortreux, A. Coord. Chem. Rev. 1998, 178–180, 1615 and
references cited therein; (b) Pasquier, C.; Eilers, J.; Reiners,
I.; Martens, J.; Agbossou, F.; Mortreux, A. Synlett 1998,
1162; (c) Mortreux, A.; Petit, F.; Buono, G.; Peiffer, G.
Bull. Soc. Chim. Fr. 1987, 631.
1. (a) Hayashi, T. In Ferrocenes; Togni, A.; Hayashi, T., Eds.;
VCH: Weinheim, 1995; p. 105; (b) Togni, A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1475.
2. (a) Jones, G. B.; Heaton, S. B.; Chapman, B. J.; Guzel, M.
Tetrahedron: Asymmetry 1997, 8, 3625; (b) Uemura, M.;
Miyake, R.; Hayashi, Y. J. Chem. Soc., Chem. Commun.
1991, 1696; (c) Uemura, M.; Miyake, R.; Nakayama, K.;
Hayashi, Y. Tetrahedron: Asymmetry 1992, 3, 713; (d)
Jones, G. B.; Guzel, M.; Chapman, B. J. Tetrahedron:
Asymmetry 1998, 9, 901; (e) Heaton, S. B.; Jones, G. B.
Tetrahedron Lett. 1992, 33, 1693; (f) Jones, G. B.; Heaton,
S. B. Tetrahedron: Asymmetry 1993, 4, 261; (g) Jones, G.
B.; Guzel, M.; Heaton, S. B. Tetrahedron: Asymmetry 2000,
11, 4303; (h) Malfait, S.; Pe´linski, L.; Brocard, J. Tetra-
hedron: Asymmetry 1996, 7, 653.
3. For a recent review, see: (a) Bolm, C.; Muniz, K. Chem.
Soc. Rev. 1999, 28, 51. For representative contributions,
see: (b) Uemura, M.; Miyake, R.; Nishimura, H.; Mat-
sumoto, Y.; Hayashi, T. Tetrahedron: Asymmetry 1992, 3,
213; (c) Hayashi, Y.; Sakai, H.; Kaneta, N.; Uemura, M.
J. Organomet. Chem. 1995, 503, 143; (d) Vasen, D.; Salzer,
A.; Gerhards, F.; Gais, H.-J.; Stu¨rmer, R.; Bieler, N. H.;
Togni, A. Organometallics 2000, 19, 539; (e) Han, J. W.;
Jang, H.-J.; Chung, Y. K. Tetrahedron: Asymmetry 1999,
10, 2853; (f) Son, S. U.; Jang, H.-Y.; Lee, I. S.; Chung, Y.
K. Organometallics 1998, 17, 3236; (g) Nelson, S. G.;
Hilfiker, M. A. Org. Lett. 1999, 1, 1379.
5. (a) Pasquier, C.; Naili, S.; Pe´linski, L.; Brocard, J.;
Mortreux, A.; Agbossou, F. Tetrahedron: Asymmetry 1998,
9, 193; (b) Pasquier, C.; Naili, S.; Mortreux, A.; Agbossou,
F.; Pe´linski, L.; Brocard, J.; Eilers, J.; Reiners, I.; Peper,
V.; Martens, J. Organometallics 2000, 19, 5723.
6. The anti and syn assignment of the isolated complexed
compounds was made according to: (a) Mailvaganam, B.;
Perrier, R. E.; Sayer, B. G.; McCarry, B. E.; Bell, R. A.;
McGlinchey, M. J. J. Organomet. Chem. 1988, 354, 325;
(b) Persson, M.; Hacksell, U.; Cso¨regh, I. J. Chem. Soc.,
Perkin Trans. 1 1991, 1453.
7. The ligands have been fully characterised. 31P NMR
characteristics of the new ligands (121 MHz, CDCl3, all
singlets): anti-6 116.3 (PO), 65.8 (PN); syn-6 116.1 (PO), 56.8
(PN); anti-7 146 (PO), 63.8 (PN); syn-7 145.5 (PO), 57.1 (PN).
8. Roucoux, A.; Thieffry, L.; Carpentier, J.-F.; Devocelle,
M.; Me´liet, C.; Agbossou, F.; Mortreux, A.; Welch, A. J.
Organometallics 1996, 15, 2440.
9. (a) Tani, K.; Suwa, K.; Tanigawa, E.; Ise, T.; Yamagata,
T.; Tatsuno, Y.; Otsuka, S. J. Organomet. Chem. 1989, 370,
203; (b) Roucoux, A.; Agbossou, F.; Mortreux, A.; Petit,
F. Tetrahedron: Asymmetry 1993, 4, 2279.
10. Hatat, C.; Karim, A.; Kokel, N.; Mortreux, A.; Petit, F.
New J. Chem. 1990, 14, 141.
.