Synthesis and evaluation of a broad range of new chiral (aminoalkyl)phosphane ligands for asymmetric hydrogen-transfer reduction of prochiral ketones

Article abstract of DOI:10.1002/ejoc.200300131

Twenty new chiral (aminoalkyl)phosphane ligands have been prepared from four enantiomerically pure advanced chiral compounds. We describe their use for asymmetric hydrogen-transfer reduction of three prochiral ketones. Enantioselectivities up to 90% were

Full text of DOI:10.1002/ejoc.200300131

FULL PAPER
Synthesis and Evaluation of a Broad Range of New Chiral
(Aminoalkyl)phosphane Ligands for Asymmetric Hydrogen-Transfer Reduction
of Prochiral Ketones
[a]
[a]
[a]
´
Matthieu Leautey, Philippe Jubault,* Xavier Pannecoucke, and
Jean-Charles Quirion[a]
Keywords: Amines / Asymmetric catalysis / Hydrogen transfer / Phosphanes
Twenty new chiral (aminoalkyl)phosphane ligands have
been prepared from four enantiomerically pure advanced
chiral compounds. We describe their use for asymmetric hy-
drogen-transfer reduction of three prochiral ketones.
the influence on the enantioselectivity of each part of these
new (aminoalkyl)phosphane ligands.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Enantioselectivities up to 90% were obtained. We investigated Germany, 2003)
Introduction
ketones; in fact, though, it is highly desirable to have access
to a variety of catalysts in order to optimize the reaction
when applied to a wide range of substrates.
Catalytic asymmetric reduction of prochiral ketones to
produce chiral secondary alcohols is an important reaction
in organic synthesis.[1] This enantioselective transformation
can be carried out in several ways, including hydride re-
duction with an oxazaborolidine catalyst,[2] hydrogenation
with chiral diphosphane ligands,[3] and transfer hydrogen-
ation.[4] In view of the low cost of the reducing agent and
its operational simplicity, transition-metal-catalyzed trans-
fer hydrogenation either with 2-propanol or with an
HCO2H/Et3N mixture[5] as a hydride source has emerged
as an attractive alternative to asymmetric hydrogenation
with H2. Numerous catalytic systems of varying levels of
efficiency have been developed involving, for example, ru-
thenium complexes modified by various di- or tridentate
ligands such as diamines,[5] amino alcohols,[6] amidates,[7]
oxazolines/amines,[8] phosphanes/amines,[9] or phosphane
oxides.[10] One of the most efficient systems is based on the
RuIIϪTsDPEN complex reported by Noyori,[11] who sug-
gested that the presence of an NH moiety in the ligand
structure may promote a cyclic transition state through hy-
drogen bonding to the ketone substrate. Moreover, it ap-
peared that the formation of a metalϪligand bifunctional
complex might induce high enantioselectivity because of a
greater affinity of the substrate to the active site of the cata-
lyst. Despite these developments, there is as yet no universal
catalyst for the transfer hydrogenation of all prochiral
We have recently[12] described the synthesis of chiral α-
substituted [β-(aminocarbonyl)alkyl]phosphaneϪboranes
2
by diastereoselective alkylation of [β-(amino-
carbonyl)alkyl]phosphaneϪboranes 1, using classical O-
benzylated phenylglycinol as a chiral inducer (Scheme 1).
Hydrolysis of these compounds afforded the advanced chi-
ral pool compound 3.
Scheme 1
The promising yields and diastereoselectivities obtained
encouraged us to test these precursors (and related variants)
in asymmetric catalytic processes. Here we present the syn-
thesis and evaluation of a broad range of new chiral (ami-
noalkyl)phosphane ligands for asymmetric hydrogen-trans-
fer reduction of prochiral ketones.
[a]
´ ´
´
Laboratoire d’Heterochimie Organique associe au CNRS,
Results and Discussion
´
IRCOF, INSA et Universite de Rouen,
`
1 rue Tesniere, 76821 Mont-Saint-Aignan Cedex, France
Fax: (internat.) ϩ 33-2/35522959
Ligand Synthesis
E-mail address: philippe.jubault@insa-rouen.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Our divergent approach to the design of new (amino-
alkyl)phosphane ligands involved the generation of ad-
Eur. J. Org. Chem. 2003, 3761Ϫ3768
DOI: 10.1002/ejoc.200300131
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3761

´
M. Leautey, P. Jubault, X. Pannecoucke, J.-C. Quirion
FULL PAPER
vanced chiral intermediates and their subsequent trans- ation from cyclohexane/ethyl acetate. The absolute configu-
formation into a series of functionalized chiral (aminoalkyl)- ration of the chiral center next to the phosphane was deter-
phosphanes 5Ϫ24. We were then able to determine which mined by X-ray diffraction analysis of 23. (R)-(ϩ)-(2-
part of the catalyst is essential for asymmetric transfer Carboxy-1-phenylethyl)diphenylphosphaneϪborane
(3d)
hydrogenation of prochiral ketones, as illustrated in was also obtained by semi-preparative chiral HPLC separ-
Scheme 2.
ation,[16] its configuration being correlated to that of amide
23 after the coupling reaction between 3d and α-methylben-
zylamine. All the structures of the ligands 6Ϫ24 are shown
in Schemes 4Ϫ6.
Scheme 2
Specifically, we investigated the stereochemical influences
of the chiral center next to the phosphane, the oxygen func-
tionality, and the nature of R1, R2, and R3.
The new (aminoalkyl)phosphane ligands were synthe-
sized by the general procedure depicted in Scheme 3.
Scheme 4
Scheme 3
Scheme 5
Racemic compounds 3b, 3c, and 3d were prepared by a
general procedure involving reaction between the α,β-
unsaturated
ester
and
the
sodium
salt
of
diphenylphosphaneϪborane, followed by saponification of
the resulting esters. For all the ligands, the two final steps
involved amide reduction and removal of borane. Ligand 5
was directly synthesized by a diastereoselective alkylation
of 1.[12] Eight ligands (6Ϫ13) were prepared by coupling of
(S)-(ϩ)-[2-carboxy-1-(methyl)ethyl]diphenylphosphaneϪ
borane (3a) with various amines. Five ligands (14Ϫ18) were
synthesized from (2-carboxyethyl)diphenylphosphaneϪ
borane (4) through the coupling of 4 with (R)-phenyl-
glycinol or (R)-aminobutanol derivatives. Ligands 19 and
20 were prepared by coupling of α-methylbenzylamine with
(S)-(ϩ)-(2-carboxy-1-ethylethyl)diphenylphospaneϪborane
(3b), which was obtained by semi-preparative chiral HPLC
separation.[13] Ligands 21 and 22 were obtained from (R)-
(ϩ)-(2-carboxy-1-isopropylethyl)diphenylphosphaneϪ
Scheme 6
In most cases, both the coupling reaction and the re-
duction of the amide moiety proceeded in moderate to very
good yields. Removal of the borane protection (DABCO,
toluene, reflux) in the final step gave the (aminoalkyl)phos-
phane ligands 5Ϫ24 in quantitative yields.
Optimization of the Asymmetric Hydrogen-Transfer
Reduction of Prochiral Ketones
Three prochiral ketones
Ϫ
acetophenone, propi-
borane (3c), also obtained by semi-preparative chiral HPLC ophenone, and isobutyrophenone Ϫ were investigated as
separation.[14] Ligands 23 and 24 were prepared by dia- asymmetric hydrogenation substrates. Ligand 17, which was
stereoselective 1,4-addition,[15] followed by separation by the most convenient to synthesize, was chosen for a more
flash chromatography through silica gel and recrystallis- thorough study of the transfer hydrogenation conditions be-
3762
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Eur. J. Org. Chem. 2003, 3761Ϫ3768

Asymmetric Hydrogen-Transfer Reduction of Prochiral Ketones
FULL PAPER
cause this catalyst/ligand combination displayed a broad the phosphane had a dramatic effect on the stereochemical
range of enantioselectivity for the three substrates course of the reaction. Moreover, if we compare the ees for
(acetophenone 27.9% ee; propiophenone 56.2% ee; isobu- ligands 5 and 6, since the inversion was not complete this
tyrophenone 80.9% ee). Under the standard conditions, we result does actually represent a match mismatched effect,
used a ligand/metal ratio of 2:1, 6 equiv. of base, and 100 although not a large one.
equiv. of substrate. We then studied various parameters,
It also seems that, for this type of ligand, the chiral center
first comparing the two bases iPrOK and KOH. Although adjacent to the amine has the major influence on the sense
the enantiomeric excesses were very similar for the three of induction. Ligand 18 gave lower ees than ligand 17 for
substrates (∆ee Ͻ 2%), iPrOK was selected as it gave faster the reactions with propiophenone and isobutyrophenone,
reaction rates.[17]
indicating that the presence of an aromatic group on the
We next studied the influence of base stoichiometry (4, 6 chiral center has a beneficial effect, probably due either to
or 8 equiv.), finding that the use of 6 equiv. iPrOK provides π-stacking interactions (between the prochiral ketone and
a modest improvement in enantioselectivity. (∆ee Ͻ 10%). the ligand) or steric effects. It therefore appears that ligand
The reaction temperature appeared to have little effect upon 17 is an efficient ligand for the reduction of the most hin-
ee, although reaction rates were greatly improved at 60 and dered prochiral ketone tested (isobutyrophenone) but a less
80 °C. We then studied the influence of the number of li- efficient one for the other two ketones.
gand equivalents relative to the metal (namely, 1, 2, or 4).
We next investigated the influence on the enantioselectiv-
Use of 1 equiv. gave very low enantiomeric excesses, while ity of the group adjacent to the chiral center of ligand 17
the best results were obtained with the use of 4 equiv. of (alcohol, ether, or hydrogen). Table 2 shows the results from
ligand. Finally, we tested two different ‘‘ruthenium’’ species: a small screen of ligands 14, 15, and 16. Replacement of the
p-cymene and hexamethylbenzene. [RuCl2(p-cymene)]2 gave ether moiety in 17 by an alcohol reduced the ees obtained in
higher ees (∆ee ϭ 24%) when, for example, ligands 17 and the reduction of isobutyrophenone (80.9% ee for 17 vs.
18 were tested.
35.7% for 15) and propiophenone (56.2% for 17 vs. 34.8%
After numerous assays, standard conditions were defined for 15) and inverted the sense of induction. In the case of
with a substrate/catalyst ratio (S/C) of 100 as follows: the the acetophenone reduction, it appeared that the presence
chiral catalysts were prepared by heating 2 mol % of ligand of an alcohol moiety has a beneficial influence (still with
with 0.5 mol % of [RuCl2(p-cymene)]2 at reflux in 2-propa- an inversion of induction), which could be due to modifi-
nol for 30 min, and iPrOK (6 mol %) was added to the cation of the chelating mode between the metal and the
solution, which was then diluted with 2-propanol (in order ligand giving rise to a mixture of amino alcohol, (hydroxy-
to obtain [ketone] ϭ 0.1 ). Finally, the prochiral ketone alkyl)phosphane, and (aminoalkyl)phosphane-type species.
(100 equiv.) was added to the reaction mixture, and the Indeed, ligand 15 gave the best ee for the reduction of ace-
transfer hydrogenations were performed at 60 °C.[18]
tophenone in this series [48.7% ee, (R) major]. On the other
hand, removal of the oxygen atom (in case 14, for example)
resulted in very low ee. Likewise, introduction of a second
oxygen atom as a MEM function (16) produced only mod-
erate ees. It therefore appeared that in the absence of a chi-
ral center next to the phosphane, the best functional group
on the opposite part of the catalyst is an alkoxy group; li-
gand 17 was the best catalyst for the reduction of isobutyro-
phenone, but was less efficient for less hindered ketones
such as acetophenone and propiophenone.
Scheme 7
In a first set of experiments, we examined the importance
of the presence of a chiral center next to the phosphane
moiety. Table 1 shows the results from a small screen of four
ligands. In terms of the enantiopurity of the product, the
best ligand for this first series was 17. These initial results
indicated that the introduction of a chiral center next to
Table 2. Asymmetric hydrogen transfer reduction of prochiral
ketones
Ligand
ee (%)
R6 ϭ Me
R6 ϭ Et
R6 ϭ iPr
17
15
14
16
27.9 (S)
48.7 (R)
11.5 (S)
20.2 (R)
56.2 (S)
34.8 (R)
10.7 (S)
45.1 (R)
80.9 (S)
35.7 (R)
5.8 (S)
63 (R)
Table 1. Asymmetric hydrogen transfer reduction of prochiral
ketones
Ligand
ee (%)
R6 ϭ Me
R6 ϭ Et
R6 ϭ iPr
As shown in Table 1, it appeared that the presence of a
chiral center next to the phosphane group had a detrimen-
tal influence on the magnitude of asymmetric induction, so
we went on to investigate the effect of modifying the group
connected to the ‘‘right arm’’ of the catalyst through the
amine. Table 3 shows the results of a small screening to de-
17
18
5
27.9 (S)
30.7 (S)
4.5 (S)
56.2 (S)
50.6 (S)
14.9 (S)
01 (R)
80.9 (S)
73.6 (S)
27.6 (S)
18.8 (R)
6
12.9 (R)
Eur. J. Org. Chem. 2003, 3761Ϫ3768
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´
M. Leautey, P. Jubault, X. Pannecoucke, J.-C. Quirion
FULL PAPER
termine the best compromise between the functionality on
either side of the ligand. All the catalysts in Table 3 have a
methyl group next to the phosphane. Removal of the chiral
center connected to the amine moiety resulted in very low
levels of enantioselectivity regardless of the group on the
amine (hydrogen in 12, benzyl in 11, O-benzyloxyethyl in
10, ethyl in 8). Condensation of 3 with (R)-α-methylben-
zylamine afforded ligand 9, which induced poor levels of ee.
In contrast, ligand 7 [obtained from (S)-α-methylbenzyla-
mine] is an efficient ligand for the reduction of aceto-
phenone (82.9% ee) and propiophenone (77.5% ee), but a
poor one for the asymmetric reduction of isobutyro- 24
phenone. Comparison of the results obtained for ligands 7
and 9 clearly demonstrates a ‘‘match-mismatched effect’’.
Moreover, in this case, the chiral center adjacent to the
phosphane governs the sense of induction.
Table 4. Asymmetric hydrogen transfer reduction of prochiral
ketones
Ligand
ee (%)
R6 ϭ Me
R6 ϭ Et
R6 ϭ iPr
9
7
19
20
21
22
23
30.5 (S)
82.9 (S)
75.5 (S)
84.8 (S)
44.2 (S)
59.4 (S)
7.7 (R)
32.6 (S)
77.5 (R)
75.3 (S)
90.1 (S)
54.2 (S)
64.8 (S)
22.8 (R)
16.7 (R)
10.4 (S)
4.5 (R)
12.8 (S)
12 (S)
7.6 (S)
7.4 (R)
30.3 (R)
7.7 (R)
21.5 (R)
stereoisomeric ligands 19 and 20 are indeed similar, no mat-
ter whether (R)- or (S)-α-methylbenzylamine is used. How-
ever, the chiral center next to the amine moiety is a tertiary
center, which seems to be necessary for the reaction to be
selective. The results obtained with benzylamine 11 and
ethylamine 8 are indeed very weak (Table 3; maximum ee:
23%). The results obtained with the ligands possessing a
methyl group (7 and 9), an ethyl group (19 and 20), or an
isopropyl group (21 and 22) on the chiral center next to the
phosphane moiety are very similar. This implies that these
ligands constitute a ‘‘specific family’’ for which the enanti-
omeric excesses are similar for acetophenone and propi-
ophenone, and weaker for isobutyrophenone. With a phenyl
group on the chiral center next to the phosphane moiety
(23 and 24), however, the results were quite different, and
low enantiomeric excesses were obtained. In this case the
sense of induction is governed by the chiral center next to
the amine moiety. This is probably due to electronic effects
(π-stacking with the substrate, which also has an aromatic
group) and/or a change in the three-dimensional structure
of the ligand.
Table 3. Asymmetric hydrogen transfer reduction of prochiral
ketones
Ligand
ee (%)
R6 ϭ Me
R6 ϭ Et
R6 ϭ iPr
12
8
20.2 (S)
0
13.2 (S)
23.3 (S)
30.5 (S)
82.9 (S)
20.1 (S)
7.6 (R)
6.3 (S)
17.9 (S)
32.6 (S)
77.5 (S)
3.9 (S)
14.4 (R)
26 (S)
19 (R)
10.4 (S)
4.5 (S)
10
11
9
7
Of this limited screening of 13 ligands, two exhibited pro-
mising levels of asymmetric induction: ligand 17 for the
asymmetric reduction of isobutyrophenone (80.9% ee), and
ligand 7 for acetophenone (82.9% ee) and propiophenone
(77.5% ee).
Finally, ligand 13 was synthesized [from (S)-phenylglyci-
nol] in order to determine the influence on the enantioselec-
tivity of a combination of a methyl group adjacent to the
phosphane and an alcohol next to the amine. This combi-
nation produced poorer ees and an inversion of the sense
of induction (11% ee for acetophenone, 16% for propi-
ophenone, and 7% for isobutyrophenone). This result prob-
ably means that a mixture of an (aminoalkyl)phosphane-
type ligand and an amino alcohol ligand linked to the ru-
thenium metal was present during the reduction process.
We finally studied the influence of the nature of the sub-
stituent R3 connected to the chiral center next to the phos-
phane moiety (Table 4). We first noticed that enantiomeric
excesses were increased when the methyl group was replaced
by an ethyl group (from 9 and 7 to 19 and 20), no matter
whether there was a matched or a mismatched effect
(Table 4). The presence of an isopropyl group, however, did
not produce any further increase in the enantiomeric excess:
selectivity decreased with ligands 21 and 22.
Conclusion
In conclusion, we have investigated a small library of new
(aminoalkyl)phosphane for asymmetric transfer hydrogen-
ation of prochiral ketones. Two types of ligands have em-
erged from this study; the first, exemplified by ligand 17,
is effective for the reduction of isobutyrophenone, and the
second (20) is better for the asymmetric reduction of aceto-
phenone and propiophenone.
Further investigations, especially concerning X-ray struc-
tures of the complexes, mechanistic information, and appli-
cation to other prochiral ketones are currently in progress
in our laboratory and will be reported in due course.
Experimental Section
The chiral center next to the phosphane moiety shows
correlation to the sense of the asymmetric induction ob-
served, while it seems that the chiral center next to the am-
ine moiety has little influence on the sense of asymmetric
General: Solvents were purified by conventional methods prior to
use. TLC was performed on Merck 60F-250 silica gel plates and
column chromatography on silica gel SI 60 (230Ϫ240 mesh). Melt-
induction. The enantiomeric excesses obtained with dia- ing points were taken with a Kofler apparatus and were uncor-
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Eur. J. Org. Chem. 2003, 3761Ϫ3768

Asymmetric Hydrogen-Transfer Reduction of Prochiral Ketones
FULL PAPER
rected. Elemental analyses were carried out with a CarloϪErba EA
propanol (in order to obtain [ketone] ϭ 0.1 ). Finally the prochi-
1100 analyzer. NMR spectra were recorded with a Bruker DXP
ral ketone (100 equiv.) was added to the reaction mixture. After
1
300 spectrometer operating at 300 MHz for H, 75.4 MHz for 13C completion of the reaction, the degree of conversion was deter-
and 121.5 MHz for 31P. This probe is equipped with pulsed-field
mined by gas chromatography, and the product was recovered by
filtration of the reaction solution on a plug of silica to remove
the catalyst. The determination of the enantiomeric excesses was
determined with a Varian 3300 capillary gas chromatograph with
a Supelco β-Dex column (15 m ϫ 0.25 mm i.d.), nitrogen as carrier
gas, and a flame ionization detector. The GC separation was cali-
brated with the racemic material: for acetophenone T ϭ 110 °C,
(z) gradients. Chemical shifts (δ) are expressed in ppm relative to
1
TMS for H and 13C nuclei and to H3PO4 for 31P nuclei; coupling
constants (J) are given in Hertz; coupling multiplicities are reported
as conventional abbreviations. All hydrogenation experiments were
performed by use of standard Schlenk techniques under nitrogen.
General Procedure for the Coupling Reaction between O-Protected
Amino Alcohols, Amino Alcohols, Amines, or α-Methylbenzylamine
and 3a, 3b, 3c, 3d, or 4: Oxalyl chloride (1.4 g, 11 mmol) was added
dropwise under nitrogen to a stirred, cooled (0 °C) solution of (2-
carboxyethyl)diphenylphosphaneϪborane (4, 1.5 g, 5.5 mmol)
or enantiomeric pure [2-carboxy-1-alkyl (or -1-phenyl)]-
diphenylphosphaneϪborane (3a, 3b, 3c, or 3d) (5.5 mmol) in di-
chloromethane (30 mL). The reaction mixture was stirred at room
temperature for 4 h. Removal of solvent and excess of oxalyl chlo-
ride under reduced pressure (0.05 Torr) afforded the corresponding
acid chloride in quantitative yield as a red oil. Sodium hydroxide
(0.176 g, 4.39 mmol), dissolved in water (0.5 mL), was added
slowly, at room temperature, to a stirred solution of 3-(diphenyl-
R
t1 ϭ 12.1, Rt1 ϭ 12.8; for propiophenone Tϭ 110 °C, Rt1 ϭ 17.7,
Rt1 ϭ 18.3; for isobutyrophenone T ϭ 110 °C, Rt1 ϭ 23.8, Rt1
24.1. The optical rotation of the product was compared to a litera-
ture value to assign the absolute configuration.[19]
ϭ
(S)-(2-Carboxy-1-ethylethyl)diphenylphospane؊Borane (3b): Separ-
ation was by chiral HPLC (ref.[13]): White powder; m.p. ϭ 98 °C;
Rf ϭ 0.5 (cyclohexane/ethyl acetate, 7:3). [α]2D0 ϭ ϩ47.7 (c ϭ 1.06,
1
CHCl3). H NMR: δ ϭ 0.5Ϫ1.5 (m, 3 H), 0.9 (t, J ϭ 7 Hz, 3 H),
2.4Ϫ2.7 (m, 2 H), 3.0Ϫ3.2 (m, 1 H), 7.4Ϫ7.6 (m, 6 H), 7.7Ϫ7.9
(m, 4 H) ppm. 31P NMR: δ ϭ 24.6 ppm. 13C NMR: δ ϭ 13 (d,
J ϭ 10.3 Hz), 23.8 (d, J ϭ 3.4 Hz), 31.4 (d, J ϭ 37.1 Hz), 34.4 (d,
J ϭ 5.7 Hz), 128Ϫ129.4, 131.9Ϫ133.1, 178.5 (d, J ϭ 13.1 Hz) ppm.
C17H22BO2P (300.15): calcd. C 68.03, H 7.39; found C 68.08, H
7.43.
phosphanyl)propanoyl
chloride
(1.06 g,
3.9 mmol)
or
(boranatoϪdiphenylphosphanyl)acetyl chloride (1.12 g, 3.9 mmol)
and O-protected amino alcohol, amino alcohol, amine, or α-meth-
ylbenzylamine (3.9 mmol) in dichloromethane (30 mL). The reac-
tion mixture was stirred at room temperature for 4 h and was then
washed with water (3 ϫ 10 mL). The organic layer was dried
(MgSO4) and the solvents were evaporated under reduced pressure
to afford [(aminocarbonyl)alkyl]phosphaneϪboranes. The crude
product was purified by chromatography (each eluent is specified
in the Supporting Information).
(R)-3-(2-Carboxy-1-isopropylethyl)diphenylphospane؊Borane (3c):
Separation was by chiral HPLC (ref [14]):White powder; m.p. ϭ 109
°C; Rf ϭ 0.35 (cyclohexane/ethyl acetate, 7:3). [α]2D0 ϭ ϩ27.8 (c ϭ
1.0, CHCl3). 1H NMR: δ ϭ 0.5Ϫ1.5 (m, 3 H), 0.85 (d, J ϭ 6.7 Hz,
3 H), 0.91 (d, J ϭ 6.7 Hz, 3 H), 1.9Ϫ2.1 (m, 1 H), 2.4Ϫ2.7 (m, 2
H), 3.1Ϫ3.3 (m, 1 H), 7.2Ϫ7.5 (m, 6 H), 7.6Ϫ7.8 (m, 4 H) ppm.
31P NMR: δ ϭ 23.8 ppm. 13C NMR: δ ϭ 17.5 (d, J ϭ 2.8 Hz),
22.5 (d, J ϭ 10.3 Hz), 26.7 (d, J ϭ 4 Hz), 29 (d, J ϭ 5.7 Hz), 33.9
(d, J ϭ 34.8 Hz), 126.9Ϫ127.7, 129.5Ϫ133.7, 177.2 (d, J ϭ 12 Hz)
ppm. C18H24BO2P (314.18): calcd. C 68.82, H 7.70; found C 68.63,
H 7.50.
General Procedure for the Reduction of the [(Amino-
carbonyl)alkyl]phosphane؊Boranes to (Aminoalkyl)phosphane؊
Boranes: A THF/BH3 solution (1 , 4 mmol) was added dropwise
under nitrogen to
a stirred, cooled (0 °C) solution of
(R)-3-(2-Carboxy-1-phenylethyl)diphenylphospane؊Borane
(3d):
[(aminocarbonyl)alkyl]phosphaneϪboranes (1 mmol) in tetra-
hydrofuran (18 mL). The reaction mixture was stirred at room tem-
perature for 1 h and then heated at reflux overnight. The reaction
mixture was then cooled to 0 °C and hydrolyzed with HCl (6 ,
12 mL). Stirring was continued for 15 min, and sodium hydroxide
(15 , 12 mL) was then added. The mixture was stirred for 2 h and
then extracted with ethyl acetate (3 ϫ 15 mL). The organic layer
was dried (MgSO4) and the solvents were evaporated under re-
duced pressure to afford (aminoalkyl)phosphaneϪboranes. The
crude product was purified by chromatography (each eluent is
specified in the Supporting Information).
Separation was by chiral HPLC (ref. [16]):White powder; m.p. ϭ
179 °C; Rf ϭ 0.52 (cyclohexane/ethyl acetate, 5:5). [α]2D0 ϭ ϩ197.1
1
(c ϭ 1.0, CHCl3). H NMR: δ ϭ 0.5Ϫ1.5 (m, 3 H), 2.7Ϫ2.9 (m, 1
H), 3.1Ϫ3.3 (m, 1 H), 4.1Ϫ4.3 (m, 1 H), 6.9Ϫ7.4 (m, 10 H),
7.4Ϫ7.6 (m, 3 H), 7.8Ϫ8 (m, 2 H) ppm. 31P NMR: δ ϭ 25.6 ppm.
13C NMR: δ ϭ 35.6 (d, J ϭ 7.4 Hz), 39.2 (d, J ϭ 32.4 Hz),
128Ϫ134.9, 178.2 (d, J ϭ 15.3 Hz) ppm. C21H22BO2P (348.19):
calcd. C 72.44, H 6.37; found C 71.92, H 6.02.
[(1R)-2-Benzyloxy-1-phenylethyl][(3S)-3-(diphenylphosphanyl)-
butyl]amine (5): White oil; Rf ϭ 0.56 (cyclohexane/ethyl acetate,
1
6:4). H NMR: δ ϭ 0.83 (dd, J ϭ 6.9, J ϭ 15.1 Hz, 3 H), 1.1Ϫ1.3
General Procedure for the Reduction of the (Amino-
alkyl)phosphane؊Boranes to (Aminoalkyl)phosphane Ligands 5؊24:
1,4-Diazabicyclo[2.2.2]octane (6 mmol) was added under nitrogen
to a stirred solution of (aminoalkyl)phosphaneϪborane (0.5 mmol)
in toluene (7.5 mL). The reaction mixture was stirred at 40 °C for
8 h. The reaction solvents were evaporated under reduced pressure
to afford (aminoalkyl)phosphane. The crude product was purified
by chromatography (each eluent is specified in the Supporting In-
formation).
(m, 1 H), 1.5Ϫ1.7 (m, 1 H), 1.8 (s, 1 H), 2.3Ϫ2.5 (m, 3 H), 3.34
(dd, J ϭ 9.2, J ϭ 9.2 Hz, 1 H), 3.40 (dd, J ϭ 3.9, J ϭ 9.5 Hz, 1
H), 3.75 (dd, J ϭ 3.8, J ϭ 9.0 Hz, 1 H), 4.38 (d, J ϭ 15.9 Hz, 1
H), 4.43 (d, J ϭ 15.9 Hz, 1 H), 7.1Ϫ7.3 (m, 16 H), 7.3Ϫ7.5 (m, 4
H) ppm. 31P NMR: δ ϭ 0.58 ppm. 13C NMR: δ ϭ 14.9 (d, J ϭ
16.0 Hz), 26.3 (d, J ϭ 9.1 Hz), 32.3 (d, J ϭ 16.6 Hz), 43.8 (d, J ϭ
12.6 Hz), 61.6, 72.2, 74.5, 126.3, 126.5, 126.6, 126.7, 127.15 (d, J ϭ
6.8), 127.2 (d, J ϭ 6.8 Hz), 127.21, 127.4, 127.5 (d, J ϭ 4.0 Hz),
132.5 (d, J ϭ 18.8 Hz), 132.6 (d, J ϭ 18.8 Hz), 136.2 (d, J ϭ
15.0 Hz), 136.3 (d, J ϭ 15.0 Hz), 137.0, 139.7 ppm.
Catalytic Hydrogenation: The standard procedure was as follows:
[RuCl2(p-cymene)]2 (1 equiv.) and the ligand (2 equiv.) were dis-
solved in 2-propanol (5 mL) under nitrogen. The solution was
stirred at 80 °C for 30 min, and then cooled to 60 °C. iPrOK (6
equiv.) was added to the solution, which was then diluted with 2-
[(1S)-2-Benzyloxy-1-phenylethyl][(3S)-3-(diphenylphosphanyl)-
butyl]amine (6): White oil; Rf ϭ 0.56 (cyclohexane/ethyl acetate,
1
6:4). H NMR: δ ϭ 0.88 (dd, J ϭ 6.7, J ϭ 14.8 Hz, 3 H), 1.2Ϫ1.4
(m, 1 H), 1.5Ϫ1.7 (m, 1 H), 1.88 (s, 1 H), 2.2Ϫ2.3 (m, 1 H), 2.3Ϫ2.4
Eur. J. Org. Chem. 2003, 3761Ϫ3768
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3765

´
M. Leautey, P. Jubault, X. Pannecoucke, J.-C. Quirion
FULL PAPER
(m, 1 H), 2.5Ϫ2.6 (m, 1 H), 3.35 (dd, J ϭ 9.0, J ϭ 9.2 Hz, 1 H),
6.3 Hz), 130.72 (d, J ϭ 4.6 Hz), 130.75, 131.1 (d, J ϭ 4.6 Hz), 135.9
3.43 (dd, J ϭ 3.8, J ϭ 9.4 Hz, 1 H), 3.78 (dd, J ϭ 3.8, J ϭ 8.7 Hz, (d, J ϭ 18.3 Hz), 135.1 (d, J ϭ 19.4 Hz), 139.5 (d, J ϭ 13.7 Hz),
1 H), 4.37 (d, J ϭ 15.6 Hz, 1 H), 4.42 (d, J ϭ 15.9 Hz, 1 H),
7.15Ϫ7.25 (m, 16 H), 7.3Ϫ7.4 (m, 4 H) ppm. 31P NMR: δ ϭ 0.20
ppm. 13C NMR: δ ϭ 15.3 (d, J ϭ 16.0 Hz), 27.0 (d, J ϭ 10.3 Hz),
32.8 (d, J ϭ 16.6 Hz), 44.6 (d, J ϭ 12.6 Hz), 61.9, 72.2, 74.4, 126.3,
126.5, 126.6, 126.7, 127.2 (d, J ϭ 6.3 Hz), 127.3, 127.4, 127.6 (d,
J ϭ 8.6), 132.4 (d, J ϭ 21.7 Hz), 132.7 (d, J ϭ 21.7 Hz), 136.0 (d,
J ϭ 14.8 Hz), 136.2 (d, J ϭ 14.3 Hz), 137.0, 139.7 ppm.
139.6 (d, J ϭ 13.7 Hz), 142.7 ppm.
[(3S)-3-(Diphenylphosphanyl)butyl]amine (12): White oil; Rf ϭ 0.15
1
(methanol). H NMR: δ ϭ 0.97 (dd, J ϭ 6.9, J ϭ 16.9 Hz, 3 H),
1.3Ϫ1.5 (m, 1 H), 1.5Ϫ1.7 (m, 3 H), 2.2Ϫ2.4 (m, 1 H), 2.5Ϫ2.6
(m, 1 H), 2.6Ϫ2.7 (m, 1 H), 7.1Ϫ7.3 (m, 6 H), 7.3Ϫ7.5 (m, 4 H)
ppm. 31P NMR: δ ϭ 0.1 ppm. 13C NMR: δ ϭ 16.8 (d, J ϭ
15.4 Hz), 28.5 (d, J ϭ 10.3 Hz), 34.2 (d, J ϭ 17.1 Hz), 47.7 (d, J ϭ
12.6 Hz), 128.6 (d, J ϭ 7.4 Hz), 128.8 (d, J ϭ 6.3 Hz), 129.1 (d,
J ϭ 5.7 Hz), 133.9 (d, J ϭ 18.8 Hz), 134.2 (d, J ϭ 18.8 Hz), 137.4
(d, J ϭ 13.1 Hz), 137.6 (d, J ϭ 13.1 Hz) ppm.
[(3S)-3-(Diphenylphosphanyl)butyl][(1S)-1-phenylethyl]amine
(7):
White oil; Rf ϭ 0.46 (cyclohexane/ethyl acetate, 7:3). 1H NMR: δ ϭ
0.85 (dd, J ϭ 6.9, J ϭ 15.1 Hz, 3 H), 1.23 (d, J ϭ 6.6 Hz, 3 H),
1.25Ϫ1.4 (m, 1 H), 1.5Ϫ1.7 (m, 2 H), 2.2Ϫ2.4 (m, 2 H), 2.5Ϫ2.6
(m, 1 H), 3.58 (q, J ϭ 6.6 Hz, 1 H), 7.1Ϫ7.3 (m, 11 H), 7.4Ϫ7.5
(m, 4 H) ppm. 31P NMR: δ ϭ 0.40 ppm. 13C NMR: δ ϭ 16.6 (d,
J ϭ 16.0 Hz), 24.8, 28.1 (d, J ϭ 9.7 Hz), 34.0 (d, J ϭ 17.1 Hz),
45.8 (d, J ϭ 12.6 Hz), 58.5, 127.0, 127.3, 128.7 (d, J ϭ 6.8 Hz),
128.8 (d, J ϭ 8.0 Hz), 128.83, 129.4 (d, J ϭ 4.6 Hz), 134.0 (d, J ϭ
18.8 Hz), 134.0 (d, J ϭ 19.4 Hz), 137.5 (d, J ϭ 14.3 Hz), 137.7 (d,
J ϭ 13.7 Hz), 145 ppm.
2-[(3S)-3-(Diphenylphosphanyl)butylamino]-2-(2R)-phenylethanol
(13): White oil; Rf ϭ 0.5 (ethyl acetate). H NMR: δ ϭ 0.86 (dd,
1
J ϭ 6.9, J ϭ 14.8 Hz, 3 H), 1.2Ϫ1.4 (m, 1 H), 1.5Ϫ1.7 (1 H), 2.32
(s, 2 H), 2.4Ϫ2.6 (m, 3 H), 3.3Ϫ3.45 (m, 1 H), 3.5Ϫ3.6 (m, 2 H),
7.1Ϫ7.3 (m, 11 H), 7.3Ϫ7.5 (m, 4 H) ppm. 31P NMR: δ ϭ 0.26
ppm. 13C NMR: δ ϭ 16.6 (d, J ϭ 15.4 Hz), 28.2 (d, J ϭ 9.7 Hz),
34.0 (d, J ϭ 16.6 Hz), 45.4 (d, J ϭ 12.0 Hz), 64.8, 67.1, 127.6,
128.0, 128.7 (d, J ϭ 6.8 Hz), 128.8 (d, J ϭ 6.8 Hz), 129.0, 129.1 (d,
J ϭ 4.0 Hz), 134.0 (d, J ϭ 18.8 Hz), 134.1 (d, J ϭ 19.4 Hz), 137.4
(d, J ϭ 14.8 Hz), 137.6 (d, J ϭ 14.8 Hz) ppm.
[(3S)-3-(Diphenylphosphanyl)butyl]ethylamine (8): Colorless oil;
Rf ϭ 0.37 (methanol/dichloromethane, 6:4). 1H NMR: δ ϭ 0.87 (t,
J ϭ 7.1 Hz, 3 H), 0.95 (dd, J ϭ 6.9, J ϭ 14.6 Hz, 3 H), 1.18 (s, 1
H), 1.2Ϫ1.4 (m, 1 H), 1.5Ϫ1.7 (m, 1 H), 2.1Ϫ2.3 (m, 1 H), 2.7Ϫ2.9
(m, 1 H), 2.9Ϫ3.2 (m, 2 H), 7.1Ϫ7.3 (m, 6 H), 7.3Ϫ7.6 (m, 4 H)
ppm. 31P NMR: δ ϭ Ϫ0.57 ppm. 13C NMR: δ ϭ 13.0, 16.2 (d,
J ϭ 14.9 Hz), 27.9 (d, J ϭ 12.6 Hz), 31.4 (d, J ϭ 17.7 Hz), 42.6,
45.6 (d, J ϭ 13.7 Hz), 128.2 (d, J ϭ 6.8 Hz), 128.3 (d, J ϭ 5.7 Hz),
128.7 (d, J ϭ 6.3 Hz), 129.2 (d, J ϭ 9.7 Hz), 133.3 (d, J ϭ 18.8 Hz),
133.6 (d, J ϭ 19.4 Hz), 136.8 (d, J ϭ 13.7 Hz), 137.1 (d, J ϭ
13.7 Hz) ppm.
[(3S)-3-(Diphenylphosphanyl)propyl][(1R)-1-phenylethyl]amine (14):
White oil; Rf ϭ 0.4 (cyclohexane/ethyl acetate, 5:5). 1H NMR: δ ϭ
1.4Ϫ1.5 (m, 2 H), 1.8Ϫ2.0 (m, 2 H), 2.4Ϫ2.6 (m, 2 H), 2.96 (s, 2
H), 3.4 (dd, J ϭ 8.7, J ϭ 10.5 Hz, 1 H), 3.51 (dd, J ϭ 4.1, J ϭ
10.5 Hz, 1 H), 3.58 (dd, J ϭ 4.1, J ϭ 8.5 Hz, 1 H), 7.0Ϫ7.2 (m, 11
H), 7.2Ϫ7.3 (m, 4 H) ppm. 31P NMR: δ ϭ Ϫ15.0 ppm. 13C NMR:
δ ϭ 26.8 (d, J ϭ 11.4 Hz), 27.6 (d, J ϭ 16.0 Hz), 49.5 (d, J ϭ
13.7 Hz), 65.8, 67.8, 128.6, 128.8, 129.6 (d, J ϭ 6.8 Hz), 129.8,
133.9 (d, J ϭ 18.8 Hz), 139.9 (d, J ϭ 12.6 Hz), 141.75 ppm.
[(3S)-3-(Diphenylphosphanyl)butyl][(1R)-1-phenylethyl]amine
(9):
White oil; Rf ϭ 0.4 (cyclohexane/ethyl acetate, 7:3). 1H NMR: δ ϭ
0.88 (dd, J ϭ 6.9, J ϭ 14.8 Hz, 3 H), 1.2 (d, J ϭ 6.4 Hz, 3 H),
1.1Ϫ1.4 (m, 1 H), 1.5Ϫ1.7 (m, 1 H), 1.96 (s, 1 H), 2.2Ϫ2.3 (m, 1
H), 2.3Ϫ2.5 (m, 1 H), 2.5Ϫ2.6 (m, 1 H), 3.58 (q, J ϭ 6.4 Hz, 1 H),
7.1Ϫ7.3 (m, 11 H), 7.3Ϫ7.5 (m, 4 H) ppm. 31P NMR: δ ϭ 0.00
ppm. 13C NMR: δ ϭ 18.9 (d, J ϭ 16.0 Hz), 26.5, 30.5 (d, J ϭ
9.7 Hz), 36.2 (d, J ϭ 16.6 Hz), 48.1 (d, J ϭ 12.0 Hz), 60.5, 129.0,
129.4, 130.7 (d, J ϭ 6.8 Hz), 130.8 (d, J ϭ 6.8 Hz), 130.9, 131.1 (d,
J ϭ 6.3 Hz), 135.9 (d, J ϭ 18.3 Hz), 136.2 (d, J ϭ 18.9 Hz), 139.5
(d, J ϭ 14.8 Hz), 139.7 (d, J ϭ 14.8 Hz), 147.9 ppm.
2-[(3S)-3-(Diphenylphosphanyl)propylamino]-2-(2R)-phenylethanol
(15): Colorless oil; Rf ϭ 0.15 (cyclohexane/ethyl acetate, 7:3). 1H
NMR: δ ϭ 1.4 (d, J ϭ 6.6 Hz, 3 H), 1.5Ϫ1.6 (m, 1 H), 1.6Ϫ1.8
(m, 2 H), 2.0Ϫ2.2 (m, 2 H), 2.6Ϫ2.8 (m, 2 H), 3.8 (q, J ϭ 6.6 Hz,
1 H), 7.3Ϫ7.5 (m, 11 H), 7.5Ϫ7.56 (m, 4 H) ppm. 31P NMR: δ ϭ
Ϫ14.7 ppm. 13C NMR: δ ϭ 24.9, 26.2 (d, J ϭ 11.4 Hz), 27.2 (d,
J ϭ 16.0 Hz), 49.3 (d, J ϭ 13.7 Hz), 58.6, 127.1, 127.4, 128.85,
128.88 (d, J ϭ 6.8 Hz), 128.95, 128.97 (d, J ϭ 9.7 Hz), 133.2 (d,
J ϭ 18.3 Hz), 133.3 (d, J ϭ 18.3), 139.3 (d, J ϭ 13.1 Hz), 139.3 (d,
J ϭ 13.1 Hz), 146.2 ppm.
[(3S)-3-(Diphenylphosphanyl)propyl][(1R)-1-(ethoxymethoxy-
methyl)propyl]amine (16): White oil; Rf ϭ 0.48 (cyclohexane/ethyl
acetate, 5:5). H NMR: δ ϭ 0.81 (t, J ϭ 7.4 Hz, 3 H), 1.1 (t, J ϭ
[2-(Benzyloxy)ethyl][(3S)-3-(diphenylphosphanyl)butyl]amine (10):
White oil; Rf ϭ 0.25 (cyclohexane/ethyl acetate, 7:3). 1H NMR: δ ϭ
0.92 (dd, J ϭ 6.9, J ϭ 14.6 Hz, 3 H), 1.3Ϫ1.4 (m, 1 H), 1.5Ϫ1.7
(m, 1 H), 2.3Ϫ2.4 (m, 1 H), 2.5Ϫ2.8(m, 2 H), 2.66 (t, J ϭ 5.1 Hz,
2 H), 3.15 (s, 1 H), 3.48 (t, J ϭ 5.1 Hz, 2 H), 4.4 (s, 2 H), 7.1Ϫ7.3
(m, 11 H), 7.3Ϫ7.5 (m, 4 H) ppm. 31P NMR: δ ϭ Ϫ0.07 ppm. 13C
NMR: δ ϭ 16.7 (d, J ϭ 16.0 Hz), 28.3 (d, J ϭ 9.7 Hz), 33.5 (d,
J ϭ 17.1 Hz), 47.9 (d, J ϭ 12.6 Hz), 49.4, 69.6, 73.6, 128.1, 128.2,
128.8, 128.9 (d, J ϭ 7.4 Hz), 129.0 (d, J ϭ 6.3 Hz), 129.1 (d, J ϭ
5.7 Hz), 134.0 (d, J ϭ 21.1 Hz), 134.1 (d, J ϭ 21.7 Hz), 137.4 (d,
J ϭ 13.7 Hz), 137.6 (d, J ϭ 13.7 Hz), 138.6 ppm.
1
7.0 Hz, 3 H), 1.25Ϫ1.5 (m, 2 H), 1.5Ϫ1.7 (m, 3 H), 1.9Ϫ2.1 (m, 2
H), 2.4Ϫ2.6 (m, 1 H), 2.6Ϫ2.7 (m, 2 H), 3.3 (dd, J ϭ 6.4, J ϭ 9.7,
1 H), 3.5 (q, J ϭ 7.1 Hz, 2 H), 3.6 (dd, J ϭ 3.8, J ϭ 10.0 Hz, 1
H), 4.58 (s, 2 H), 7.2Ϫ7.3 (m, 6 H), 7.3Ϫ7.5 (m, 4 H) ppm. 31P
NMR: δ ϭ Ϫ14.9 ppm. 13C NMR: δ ϭ 10.7, 15.6, 24.6, 26.2 (d,
J ϭ 12.0 Hz), 27.2 (d, J ϭ 16.0 Hz), 48.6 (d, J ϭ 13.7 Hz), 59.0,
63.6, 69.7, 95.7, 128.8 (d, J ϭ 6.8 Hz), 133.1 (d, J ϭ 18.3), 139.1
(d, J ϭ 12.6 Hz) ppm.
Benzyl[(3S)-3-(diphenylphosphanyl)butyl]amine (11): White oil; Rf ϭ
0.26 (cyclohexane/ethyl acetate, 7:3). H NMR: δ ϭ 0.93 (dd, J ϭ
6.9, J ϭ 15.1 Hz, 3 H), 1.2Ϫ1.4 (m, 1 H), 1.5Ϫ1.7 (m, 1 H), 1.51
[(1R)-2-Benzyloxy-1-phenylethyl][(3S)-3-(diphenylphosphanyl)-
propyl]amine (17): White oil; Rf ϭ 0.30 (cyclohexane/ethyl acetate,
7:3). H NMR: δ ϭ 0.75 (t, J ϭ 7.4 Hz, 3 H), 1.2Ϫ1.4 (m, 2 H),
1
1
(s, 1 H), 2.3Ϫ2.4 (m, 1 H), 2.5Ϫ2.65 (m, 1 H), 2.65Ϫ2.8 (m, 1 H), 1.4Ϫ1.67 (m, 3 H), 1.9Ϫ2.0 (m, 2 H), 2.5Ϫ2.7 (m, 3 H), 3.23 (dd,
3.6 (d, J ϭ 15.9 Hz, 1 H), 3.64 (d, J ϭ 15.6 Hz, 1 H), 7.1Ϫ7.3 (m, J ϭ 6.9, J ϭ 9.2 Hz, 1 H), 3.37 (dd, J ϭ 4.3, J ϭ 9.2 Hz, 1 H),
11 H), 7.3Ϫ7.5 (m, 4 H) ppm. 31P NMR: δ ϭ 0.17 ppm. 13C NMR: 4.38 (s, 2 H), 7.1Ϫ7.25 (m, 11 H), 7.3Ϫ7.45 (m, 4 H) ppm. 31P
δ ϭ 18.7 (d, J ϭ 16.0 Hz), 30.2 (d, J ϭ 9.7 Hz), 35.9 (d, J ϭ
NMR: δ ϭ Ϫ14.8 ppm. 13C NMR: δ ϭ 10.7, 24.7, 26.2 (d, J ϭ
17.1 Hz), 49.5 (d, J ϭ 12.6 Hz), 56.2, 129.3, 130.5, 130.65 (d, J ϭ 12.0 Hz), 27.2 (d, J ϭ 16.0 Hz), 48.7 (d, J ϭ 13.7 Hz), 59.0, 72.6,
3766
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 3761Ϫ3768

Asymmetric Hydrogen-Transfer Reduction of Prochiral Ketones
FULL PAPER
73.6, 128.1, 128.8, 128.85 (d, J ϭ 6.3 Hz), 128.9, 129.0, 133.2,
138.9, 139.2 (d, J ϭ 13.1 Hz), 139.3 (d, J ϭ 12.6 Hz) ppm.
[(3S)-3-(Diphenylphosphanyl)-3-phenylpropyl][(1R)-1-phenylethyl]-
amine (24): White powder; Rf ϭ 0.40 (cyclohexane/ethyl acetate/
triethylamine, 8.5:1.5:0.5). 1H NMR: δ ϭ 1.7Ϫ2.0 (m, 2 H),
2.0Ϫ2.4 (m, 3 H), 3.3Ϫ3.5 (m, 1 H), 3.5Ϫ3.7 (m, 1 H), 6.8Ϫ7.9
(m, 20 H) ppm. 31P NMR: δ ϭ 1.36 ppm. 13C NMR: δ ϭ 28.5,
32.1 (d, J ϭ 9.4 Hz), 42.1 (d, J ϭ 12.6 Hz), 44.4 (d, J ϭ 11.4 Hz),
56.5, 125.1Ϫ135.9, 144.2, 144.5 ppm.
[(1R)-1-Benzyloxymethylpropyl][(3S)-3-(diphenylphosphanyl)-
propyl]amine (18): Colorless oil; Rf ϭ 0.56 (cyclohexane/ethyl acet-
ate, 6:4). 1H NMR: δ ϭ 1.5Ϫ1.7 (m, 2 H), 1.9Ϫ2.1 (m, 3 H),
2.5Ϫ2.6 (m, 2 H), 3.4 (dd, J ϭ 9.2, J ϭ 9.2 Hz, 1 H), 3.5 (dd, J ϭ
4.0, J ϭ 9.5 Hz, 1 H), 3.85 (dd, J ϭ 3.9, J ϭ 9.0 Hz, 1 H), 4.48 (d,
J ϭ 16.1 Hz, 1 H), 4.54 (d, J ϭ 15.9 Hz, 1 H), 7.1Ϫ7.3 (m, 16 H),
7.3Ϫ7.4 (m, 4 H) ppm. 31P NMR: δ ϭ Ϫ14.6 ppm. 13C NMR: δ ϭ
26.2 (d, J ϭ 11.4 Hz), 27.0 (d, J ϭ 16.0 Hz), 49.1 (d, J ϭ 13.7 Hz),
63.3, 73.8, 76.0, 128.0, 128.2, 128.25, 128.3, 128.85, 128.9, 128.92
(d, J ϭ 6.3 Hz), 128.95, 128.97 (d, J ϭ 5.1 Hz), 133.2 (d, J ϭ
Supporting Information Available (see footnote on the first page of
this article): Yields, spectroscopic and analytical data for the
amides and amines precursors of ligands (PDF).
18.3 Hz), 138.6, 139.3 (d, J ϭ 13.1 Hz), 139.4 (d, J ϭ 13.1 Hz), Acknowledgments
141.3 ppm.
This work is part of the RINCOF/PUNCHORGA program, and
´
we thank the Conseil Regional de Haute-Normandie for their
financial support (Grant to M. L.). We also warmly thank Dr.
Francine Agbossou, University of Lille, for helpful discussions and
for providing us with the opportunity to investigate some of the
hydrogenation experiments in her laboratory.
[(3S)-3-(Diphenylphosphanyl)pentyl][(1R)-1-phenylethyl]amine (19):
White oil; Rf ϭ 0.42 (cyclohexane/ethyl acetate/triethylamine,
8.5:1.5:0.5). H NMR: δ ϭ 0.82 (t, J ϭ 7.2 Hz, 3 H), 1.2 (d, J ϭ
6.4 Hz, 3 H), 1.0Ϫ1.6 (m, 5 H), 2.0Ϫ2.2 (m, 1 H), 2.3Ϫ2.5 (m, 2
H), 3.55 (q, J ϭ 6.6 Hz, 1 H), 7.0Ϫ7.5 (m, 15 H) ppm. 31P NMR:
δ ϭ Ϫ 5.45 ppm. 13C NMR: δ ϭ 10.8 (d, J ϭ 11.4 Hz), 22.1 (d,
J ϭ 14.8 Hz), 23.3, 29.2 (d, J ϭ 14.3 Hz), 33.8 (d, J ϭ 11.4 Hz),
44.7 (d, J ϭ 10.3 Hz), 57.0, 125.4Ϫ136.3, 144.6 ppm.
1
[1]
[1a]
Reviews, see:
I. Ojima (Ed.), in Catalytic Asymmetric Syn-
[1b]
thesis, VCH Publishers, Weinheim, 1993.
R. Noyori, Asym-
metric Catalysis in Organic Synthesis, John Wiley & Sons, New
York, 1994. [1c] E. N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.),
[(3S)-3-(Diphenylphosphanyl)pentyl][(1S)-1-phenylethyl]amine (20):
White oil; Rf ϭ 0.42 (cyclohexane/ethyl acetate/triethylamine,
in Comprehensive Asymmetric Catalysis, Springer-Verlag,
[1d]
Berlin, 1999.
R. Noyori, T. Ohkuma, Angew. Chem. 2001,
1
8.5:1.5:0.5). H NMR: δ ϭ 0.82 (t, J ϭ 7.2 Hz, 3 H), 1.2 (d, J ϭ
113, 41Ϫ75, Angew. Chem. Int. Ed. 2001, 40, 40Ϫ73.
[2] [2a]
6.4 Hz, 3 H), 1.0Ϫ1.6 (m, 5 H), 2.1Ϫ2.3 (m, 1 H), 2.3Ϫ2.4 (m, 2
H), 3.55 (q, J ϭ 6.6 Hz, 1 H), 7.0Ϫ7.5 (m, 15 H) ppm. 31P NMR:
δ ϭ Ϫ 5.29 ppm. 13C NMR: δ ϭ 10.8 (d, J ϭ 11.4 Hz), 22.1 (d,
J ϭ 14.8 Hz), 23.3, 29.2 (d, J ϭ 14.3 Hz), 33.8 (d, J ϭ 11.4 Hz),
44.7 (d, J ϭ 10.3 Hz), 57.0, 125.4Ϫ136.3, 144.6 ppm.
E. Corey, R. K. Bakshi, S. Shibata, C. Chen, V. K. Singh,
[2b]
J. Am. Chem. Soc. 1987, 109, 7925Ϫ7926.
S. Wallbaum, J.
Martens, Tetrahedron: Asymmetry 1992, 3, 1475Ϫ1504.
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R. Noyori, H. Takaya, Acta Chem. Scand. 1996, 50,
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380Ϫ390.
M. J. Burk, Acc. Chem. Res. 2000, 33, 363Ϫ372.
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R. Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem.
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Chem. Soc. 1998, 120, 3817Ϫ3818.
Y. Jiang, Q. Jiang, X. Zhang, J. Am.
[4c]
M. Bernard, V. Guiral,
[(3R)-3-(Diphenylphosphanyl)-4-methylpentyl][(1R)-1-phenylethyl]-
amine (21): White oil; Rf ϭ 0.72 (cyclohexane/ethyl acetate/triethyl-
F. Delbecq, F. Fache, P. Sautet, M. Lemaire, J. Am. Chem. Soc.
1998, 120, 1441Ϫ1446. [4d] M. J. Palmer, M. Wills, Tetrahedron:
1
amine, 8:2:0.5). H NMR: δ ϭ 0.82 (t, J ϭ 7.4 Hz, 3 H), 0.85 (t,
[4e]
Asymmetry 1999, 10, 2045Ϫ2061.
H. Brunner, F. Henning,
J ϭ 7.4 Hz, 3 H), 1.04 (s, 1 H), 1.1 (d, J ϭ 6.7 Hz, 3 H), 1.3Ϫ1.6
(m, 2 H), 1.7Ϫ1.8 (m, 1 H), 1.9Ϫ2.0 (m, 1 H), 2.0Ϫ2.2 (m, 2 H),
3.4 (q, J ϭ 6.6 Hz, 1 H), 7.0Ϫ7.5 (m, 15 H) ppm. 31P NMR: δ ϭ
Ϫ 6.75 ppm. 13C NMR: δ ϭ 17.4 (d, J ϭ 10.8 Hz), 21 (d, J ϭ
8.6 Hz), 23.3, 27.0 (d, J ϭ 15.4 Hz), 27.9 (d, J ϭ 16 Hz), 38.4 (d,
J ϭ 14.6 Hz), 46.8 (d, J ϭ 6.8 Hz), 57.0, 125.4Ϫ136.9, 144.7 ppm.
[4f]
M. Weber, Tetrahedron: Asymmetry 2002, 13, 37Ϫ42.
Pastor, P. Västilä, Chem. Commun. 2002, 2046Ϫ2047.
I. M.
[4g]
S. J.
M. Nordin, P. Roth, T. Tarnai, D. A. Alonso, P. Brandt, P. G.
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[5b]
J. Am. Chem. Soc. 1996, 118, 2521Ϫ2522.
L. Schwink, T.
Ireland, K. Püntener, P. Knochel, Tetrahedron: Asymmetry
1998, 9, 1143Ϫ1163. [5c] A. Aranyos, G. Csjernyik, K. J. Szabo,
[(3R)-3-(Diphenylphosphanyl)-4-methylpentyl][(1S)-1-phenylethyl]-
amine (22): White oil; Rf ϭ 0.72 (cyclohexane/ethyl acetate/triethyl-
[5d]
J. E. Bäckvall, Chem. Commun. 1999, 351Ϫ352.
J. E.
Bäckvall, R. L. Chowdhury, U. Karlsson, J. Chem. Soc., Chem.
Commun. 1991, 473Ϫ475.
1
amine, 8:2:0.5). H NMR: δ ϭ 0.82 (t, J ϭ 7.4 Hz, 3 H), 0.85 (t,
[6] [6a]
M. J. Palmer, T. Walsgrove, M. Wills, J. Org. Chem. 1997,
J ϭ 7.4 Hz, 3 H), 1.04 (s, 1 H), 1.1 (d, J ϭ 6.7 Hz, 3 H), 1.3Ϫ1.6
(m, 2 H), 1.7Ϫ1.8 (m, 1 H), 1.9Ϫ2.0 (m, 1 H), 2.0Ϫ2.2 (m, 2 H),
3.4 (q, J ϭ 6.6 Hz, 1 H), 7.0Ϫ7.5 (m, 15 H) ppm. 31P NMR: δ ϭ
Ϫ 6.72 ppm. 13C NMR: δ ϭ 17.4 (d, J ϭ 10.8 Hz), 21 (d, J ϭ
8.6 Hz), 23.3, 27.0 (d, J ϭ 15.4 Hz), 27.9 (d, J ϭ 16 Hz), 38.4 (d,
J ϭ 14.6 Hz), 46.8 (d, J ϭ 6.8 Hz), 57.0, 125.4Ϫ136.9, 144.7 ppm.
[6b]
62, 5226Ϫ5228.
D. A. Alonso, D. Guijarro, P. Pinho, O.
Temme, P. G. Andersson, J. Org. Chem. 1998, 63, 2749Ϫ2751.
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D. A. Alonso, S. J. M. Nordin, P. Roth, T. Tarnai, P. G.
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T. Ohta, S. I. Nakahara, Y. Shigemura, K. Hattoti, I. Furu-
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[8]
[9] [9a]
J.-X. Gao, T. Ikariya, T. Noyori, Organometallics 1996, 15,
[(3R)-3-(Diphenylphosphanyl)-3-phenylpropyl][(1R)-1-phenylethyl]-
amine (23): White powder; Rf ϭ 0.40 (cyclohexane/ethyl acetate/
triethylamine, 8.5:1.5:0.5). 1H NMR: δ ϭ 1.7Ϫ2.0 (m, 2 H),
2.0Ϫ2.4 (m, 3 H), 3.3Ϫ3.5 (m, 1 H), 3.5Ϫ3.7 (m, 1 H), 6.8Ϫ7.9
(m, 20 H) ppm. 31P NMR: δ ϭ 1.15 ppm. 13C NMR: δ ϭ 28.5,
32.1 (d, J ϭ 9.4), 42.1 (d, J ϭ 12.6), 44.4 (d, J ϭ 11.4), 56.5,
125.1Ϫ135.9, 144.2, 144.5.
[9b]
1087Ϫ1089.
Y. Jiang, Q. Jiang, G. Zhu, X. Zhang, Tetra-
hedron Lett. 1997, 38, 6565Ϫ6568.
A. M. Maj, K. M. Pietrusiewicz, I. Suisse, F. Agbossou, A.
[10]
Morteux,, Tetrahedron: Asymmetry 1999, 10, 831Ϫ835.
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K. Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori, J.
[11b]
Am. Chem. Soc. 1997, 119, 8738Ϫ8739.
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K. J. Haack, S.
Eur. J. Org. Chem. 2003, 3761Ϫ3768
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3767

´
M. Leautey, P. Jubault, X. Pannecoucke, J.-C. Quirion
FULL PAPER
1997, 109, 300Ϫ303, Angew. Chem. Int. Ed. Engl. 1997, 36,
Pannecoucke, J.-C. Quirion, Tetrahedron Lett. 2002, 43,
9237Ϫ9240.
Chiralcel OJ-H Column 250 ϫ 20 mm; flow: 6 mL/min., 19 °C,
UV detector (250 nm), eluent: heptane/2-propanol/formic acid,
80:20:0.5. Retention times: (S)-(Ϫ): Rt ϭ 22.4 min, (R)-(ϩ):
Rt ϭ 27.0 min.
A slow background epimerization of the product was observed;
short reaction times were therefore highly advantageous.
In 93% of the experiments, conversion rates of 80% or more
are obtained in less than 9 h (all the conversions rates (for each
ketone) and for each ligand are collected in the Supporting In-
formation).
[11c]
288Ϫ290.
S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya,
[16]
R. Noyori, J. Am. Chem. Soc. 1995, 117, 7562Ϫ7563.
[12]
[13]
´
M. Leautey, G. Castelot-Deliencourt, P. Jubault, X. Pannec-
oucke, J.-C. Quirion, J. Org. Chem. 2001, 66, 5566Ϫ5571.
Chiralcel OJ-H Column 250 ϫ 20 mm; flow: 8 mL/min., 19 °C,
UV detector (250 nm), eluent: heptane/2-propanol/formic acid,
93:7:0.5. Retention times: (R)-(Ϫ): Rt ϭ 25.3 min, (S)-(ϩ):
Rt ϭ 29.2 min.
[17]
[18]
[14]
[15]
Chiralcel OJ-H Column 250 ϫ 20 mm; flow: 8 mL/min, 19 °C,
UV detector (250 nm), eluent: heptane/2-propanol/formic acid,
93:7:0.5. Retention times: (S)-(Ϫ): Rt ϭ 22.4 min, (R)-(ϩ):
Rt ϭ 26.5 min.
[19]
T. Langer, G. Helmchen, Tetrahedron Lett. 1996, 37,
1381Ϫ1384.
´
M. Leautey, G. Castelot-Deliencourt, P. Jubault, X.
Received March 4, 2003
3768
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3761Ϫ3768