Structurally well-defined, recoverable C3-symmetric tris(β-hydroxy phosphoramide)-catalyzed enantioselective borane reduction of ketones

Article abstract of DOI:10.1021/ol0600584

A series of new chiral C₃-symmetric tris(β-hydroxy phosphoramide) ligands have been synthesized via the reaction of trisphosphoramide ester and Grignard reagents. The catalytic asymmetric borane reduction of ketones with these new C₃-symmetric chiral tris(β-hydroxy phosphoramide)s was investigated. Structurally well-defined, recoverable ligand 1d is an efficient catalyst for the enantioselective borane reduction of both electron-deficient and electron-rich ketones, and high enantioselectivities were achieved (up to 98% ee).

Full text of DOI:10.1021/ol0600584

ORGANIC
LETTERS
2
006
Vol. 8, No. 7
327-1330
Structurally Well-Defined, Recoverable
C -Symmetric Tris( -hydroxy
1
â
3
phosphoramide)-Catalyzed
Enantioselective Borane Reduction of
Ketones
Da-Ming Du,* Tao Fang, Jiaxi Xu, and Shi-Wei Zhang
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry and Molecular Engineering, Peking UniVersity,
Beijing 100871, P. R. China
dudm@pku.edu.cn
Received January 10, 2006
ABSTRACT
A series of new chiral C
3
-symmetric tris(
â
-hydroxy phosphoramide) ligands have been synthesized via the reaction of trisphosphoramide
-symmetric chiral tris( -hydroxy
ester and Grignard reagents. The catalytic asymmetric borane reduction of ketones with these new C
3
â
phosphoramide)s was investigated. Structurally well-defined, recoverable ligand 1d is an efficient catalyst for the enantioselective borane
reduction of both electron-deficient and electron-rich ketones, and high enantioselectivities were achieved (up to 98% ee).
C
3
symmetry is interesting, and recent reviews have il-
lustrated the importance of C symmetry and many C
symmetric compounds and their applications in asymmetric
oped tridentate trisoxazoline ligands as chiral auxiliaries in
the asymmetric allylic oxidation of cycloalkenes with moder-
ate to excellent enantioselectivities (up to 93% ee). Ahn’s
3
3
-
3
1
catalysis and chiral molecular recognition. C
3
-symmetric
3
group has reported interesting results of C -symmetric
chiral ligands in octahedral complexes also permit a reduction
in the number of possible diastereomorphous transition states
trisoxazolines in the asymmetric catalysis and the molecular
recognition of aminonium ions and sugars. Gade and co-
4
just as C
ment of new types of C
catalysis has attracted attention in recent years. For example,
the rhodium(I) complexes of enantiomerically pure tripodal
3
phosphanes with C symmetry have been reported in the
2
symmetry in asymmetric catalysis. The develop-
-symmetic ligands for asymmetric
(2) (a) Burk, M. J.; Harlow, R. L. Angew. Chem. 1990, 102, 1511-
3
1
513; Angew. Chem., Int. Ed. Engl. 1990, 29, 1462-1464. (b) Burk, M. J.;
Feaster, J. E.; Harlow, R. L. Tetrahedron: Asymmetry 1991, 2, 569-592.
(3) (a)Kawasaki, K.; Tsumara, S.; Katsuki, T. Synlett 1995, 1245-1246.
(
b) Kawasaki, K.; Katsuki, T. Tetrahedron 1997, 53, 6337-6350. (c)
Kohmura Y.; Katsuki, K. Tetrahedron Lett. 2000, 41, 3941-3945.
hydrogenation of dimethyl itachonate giving high enantio-
selectivity (95% ee). Katsuki and co-workers have devel-
(4) (a) Kim, S. G.; Ahn, K. H. Tetrahedron Lett. 2001, 42, 4175-4177.
2
(b) Ahn, K. H.; Kim, S.-G.; Jung, J.; Kim, K.-H.; Kim, J.; Chin, J.; Kim,
K. Chem. Lett. 2000, 170-171. (c) Kim, S.-G.; Kim, K.-H.; Jung, J.; Shin,
S. K.; Ahn, K. H. J. Am. Chem. Soc. 2002, 124, 591-596. (d) Kim, S.-G.;
Kim, K.-H.; Kim, Y. K.; Shin, S. K.; Ahn, K. H. J. Am. Chem. Soc. 2003,
125, 13819-13824.
(
1) (a) Moberg, C. Angew. Chem., Int. Ed. 1998, 37, 248-268. (b) Zhou,
J.; Tang Y. Chem. Soc. ReV. 2005, 34, 664-676.
1
0.1021/ol0600584 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/09/2006

3
workers also reported that chiral C -symmetric trisoxazolines
are highly efficient stereocontrolling ligands in the Cu(II)-
catalyzed enantioselective R-amination (up to 99% ee) as
well as the enantioselective Mannich reaction of prochiral
â-ketoesters (up to 91% ee).5
3
Scheme 1. Synthesis of New C -Symmetric Ligands
Enantioselective borane reduction of ketones is a standard
method for the synthesis of chiral secondary alcohol. Among
6
the catalysts which have been disclosed in the literature,
the system devised by Corey, Bakshi, and Shibata, known
7
as CBS catalyst, affords excellent enantioselectivities and
chemical yields. In this catalyst system, the formation of five-
membered oxazaborolidine ring by the reaction of NH and
OH groups with borane was important for achieving high
enantioselectivities. Various heterogeneous polymer-sup-
ported and fluorous analogues were synthesized in order to
facilitate the recovery of this useful catalyst and simplify
8
reaction conditions. Chiral phosphinamides as robust cata-
9
lysts for the reduction of ketones have also been reported.
3
One C -symmetric phosphoramide synthesized from (R)-(+)-
R-methylbenzylamine has been used in enantioselective
9
b
borane reduction of ketones, and 20% ee was obtained.
Our interest is to explore and to expand the application of
3
First, the C -symmetric ligands 1 were evaluated in the
asymmetric reduction of acetophenone using in situ generated
borane complex at room temperature for 1 h. The results
are summarized in Table 1. Ligands 1a and 1b gave only
10
C
3
-symmetric compounds in asymmetric catalysis. Herein,
we report a new series of structurally well-defined, recover-
able C -symmetric trisphosphoramides catalyzed enantiose-
lective borane reduction of prochiral ketones.
The C -symmetric ligands were obtained in two steps. The
3
3
Table 1. Enantioselective Borane Reduction of Acetophenonea
reaction of phosphorus oxychloride and L-proline methyl
ester to give the corresponding trisphosphoramide ester 2
with high yield (93%) under simple experimental conditions
(Scheme 1). Reduction of trisphosphoramide ester 2 with
LiAlH in THF afforded tris(â-hydroxy phosphoramide) 1a.
4
ligand
(mol %)
T
time yieldb eec
The reactions of the trisphosphoramide ester 2 with Grignard
reagents gave the corresponding tripodal ligands 1b-d with
moderate yields after recrystallization from a mixture of
petroleum ether and ethyl acetate.
entry
solvent (°C)
(h)
(%)
(%) confige
1
2
3
4
5
6
7
8
9
1a (10%)
1b (10%)
1c (10%)
1d (10%)
1d (10%)
1d (5%)
1d (5%)
1d (5%)
1d (5%)
1d (5%)
1d (5%)
1d (5%)
1d (5%)
1d (10%)
THF
THF
THF
THF
THF
THF
rt
rt
rt
rt
90
70
1
1
1
1
1
1
1
1
1
1
2
2
2
1
1
92
98
93
95
94
94
92
95
94
88
94
0
23
76
90
93
95
88
89
90
72
62
5
R
R
R
R
R
R
R
R
R
R
R
R
R
R
(
5) Foltz, C.; Stecker, B.; Marconi, G.; Bellemin-Laponnaz, S.; Wade-
pohl, H.; Gade, L. H. Chem. Commun. 2005, 5115-5117.
6) For reviews, see: (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int.
(
Ed. 1998, 37, 1987-2012. (b) Itsuno, S. In Organic Reactions; John
Wiley: New York, 1998; Vol. 52, p 395. (c) Deloux, L.; Srebnik, M. Chem.
ReV. 1993, 93, 763-784. (c) Wallbaum, S.; Martens, J. Tetrahedron:
Asymmetry 1992, 3, 1475-1504. (d) Singh, V. K. Synthesis 1992, 605-
CH2Cl2 70
toluene 70
THF
THF
THF
THF
THF
THF
45
rt
20
0
-20
rt
rt
6
17. (e) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475-
1
1
1
0
1
2
1
504.
(
7) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
d
81
31
94
93
1
09, 5551-5553. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.;
d
Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926.
13
4
90
92
(8) For recent examples: (a) Dalicsek, Z.; Pollreisz, F.; G o¨ m o¨ ry, A.;
f
1
1
4
5
So o´ s, T. Org. Lett. 2005, 7, 3243-3246. (b) Degni, S.; Wil e´ n, C.-E.;
Rosling, A. Tetrahedron: Asymmetry 2004, 15, 1495-1499. (c) Kell, R.
J.; Hodge, P.; Snedden, P.; Watson, D. Org. Biomol. Chem. 2003, 1, 3238-
1d (10%)g THF
a
Reaction carried out with 0.5 mmol scale in 2 mL of solvent, molar
3
2
243. (d) Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org. Chem.
002, 67, 8086-8089. (e) Hu, J.-b.; Zhao, G.; Ding, Z.-d. Angew. Chem.,
b
ratio of PhCOCH3/BH3) 1:1.2. Isolated yield by column chromatography.
c
ee determined by HPLC analysis using a Daicel Chiralcel OB column.
Int. Ed. 2001, 40, 1109-1111. (f) Schunicht, C.; Biffis, A.; Wulff, G.
Tetrahedron 2000, 56, 1693-1699. (g) Hu, J.-b.; Zhao, G.; Yang, G.-s.;
Ding, Z.-d. J. Org. Chem. 2001, 66, 303-304.
d
Yield determined by HPLC. e The absolute configuration assigned by
f
comparison with the literature; see the Supporting Information. Catalyst
was recycled once. g Catalyst was recycled twice.
(9) For examples: (a) Gamble, M. P.; Smith, A. R. C.; Wills, M. J.
Org. Chem. 1998, 63, 6068-6071. (b) Burns, B.; King, N. P.; Tye, H.;
Studley, J. R.; Gamble, M.; Wills, M. J. Chem. Soc., Perkin Trans. 1 1998,
1
027-1038. (c) Wills, M.; Gamble, M.; Palmer, M.; Smith, A.; Studley, J.
low enantioselectivity, less than 25% ee (Table 1, entries 1
and 2). A promising result (76% ee) was obtained with ligand
1c (Table 1, entry 3). When it comes to ligand 1d, the best
result (90% ee) was obtained (Table 1, entry 4). All of the
reduction products have an R configuration. It is well-known
R.; Kenny, J. J. Mol. Cat., A: Chem. 1999, 146, 139-148. (d) Li, K.; Zhou,
Z.; Wang, L.; Chen, Q.; Zhao, G.; Zhou, Q.; Tang, C. Tetrahedron:
Asymmetry 2003, 14, 95-100. (e) Basavaiah, D.; Chandrashekar, V.; Das,
U.; Reddy, G. J. Tetrahedron: Asymmetry 2005, 16, 3955-3962.
(10) Fang, T.; Du, D.-M.; Lu, S.-F.; Xu, J. Org. Lett. 2005, 7, 2081-
2
084.
1328
Org. Lett., Vol. 8, No. 7, 2006

that the enantioselectivity of borane reduction is affected
profoundly by solvent, temperature, and the amount of
catalyst. To examine these effects, the reduction of acetophe-
none was further investigated at various reaction conditions.
At high temperature, only a slight increase in enantioselec-
tivity was obtained (Table 1, entry 5). It was observed that
a decrease in the catalyst loading from 10 to 5 mol % at
room temperature resulted in a dramatic decrease in the enan-
tioselectivity with a slight loss of yield (Table 1, entries 4
and 10). Catalyst loading of 10 mol % provided the optimum
level of enantioselectivity. This is presumably because at this
loading the rate of the catalyzed reaction is sufficiently faster
Under the optimized, simple reaction conditions, ligand
1d was applied to the asymmetric borane reduction of a
variety of aromatic and aliphatic ketones. As the results
summarized in Table 3 show, high yields and enantioselec-
Table 3. Catalytic Asymmetric Reduction of Ketonesa
11
than the noncatalytic reduction with BH
3 2
‚Me S.
When the temperature exceeded 45 °C, high enantiose-
lectivities were obtained with only small variety (Table 1,
entries 5, 6, and 9). Furthermore, solvent affected the
enantioselectivity slightly (Table 1, entries 7 and 8). How-
ever, when the temperature was decreased from 20 to 0 or
-
20 °C, distinct results were obtained with obvious decreases
of both conversion and enantiomeric excess even at longer
reaction times (Table 1, entries 11-13). The recycling of
1d was investigated in borane reduction of acetophenone.
The catalyst can be simply recovered by crystallization from
reaction mixture (>70% yield) and reused with no loss of
catalytic efficiency (Table 1, entries 14 and 15).
Meanwhile, it is important to note that this catalyst system
3 2
can tolerate continuous addition of BH ‚Me S and acetophe-
none in situ at a proper interval. We tested eight continuous
additions of borane and acetophenone to the system. There
was no any distinct decrease in enantioselectivities (Table
2). These results indicate that the catalyst still has catalytic
Table 2. Tolerance of Continous Addition of Borane and
Acetophenone in Asymmetric Reductiona
BH3‚Me2S (mL)
(2 M in THF)
b
c
entry
PhCOMe (mmol) yield (%) ee (%)
1
2
3
4
5
6
7
8
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
99
99
99
99
99
99
99
99
87
95
91
93
91
93
90
89
a
Reaction carried out with 0.5 mmol scale in 2 mL of THF, molar ratio
b
c
of PhCOCH3/BH3 ) 1:1.2. Isolated yield by column chromatography. ee
determined by HPLC analysis using a Daicel Chiralcel OB column. The
absolute configurations assigned by comparison with the literature; see the
Supporting Information.
a
Reaction carried out using 5 mol % of ligand 1d in 2 mL of THF.
e
b
c
Yield determined by HPLC. ee determined by HPLC analysis using a
Daicel Chiralcel OB column.
efficiency even after the reaction was complete, and no loss
of activity nor selectivity even after eight iterative additions
of acetophenone and borane. Thus, this catalyst system can
endure in situ recycling.1 This in situ recycling of the
catalyst is very important for large-scale preparation of chiral
secondary alcohols.
tivities were obtained for prochiral ketones containing
electron-withdrawing or electron-donating groups (Table 3,
entries 1-11) unlike the CBS system, of which the enantio-
selectivity is dependent to the electronic effect of ketones.12
A slightly decreased ee was obtained with the substitution
at the ortho position, probably due to steric effects (Table
1b
3
, entries 12 and 13). It is interesting to note that ketones
(
11) (a) Xu, J.; Wei, T.; Zhang, Q. J. Org. Chem. 2003, 68, 10146-
1
2
0151. (b) Gilmore, N. J.; Jones, S.; Muldowney, M. P. Org. Lett. 2004, 6,
805-2808.
(12) Xu, J.; Wei, T.; Zhang, Q. J. Org. Chem. 2004, 69, 6860-6866.
Org. Lett., Vol. 8, No. 7, 2006
1329

containing an electron-withdrawing group give excellent
enantioselectivities (Table 3, entries 3, 4, 5, 8, and 10).
Changing linear 1-phenylbutan-1-one to branched 2-methyl-
CBS system due to absence of an active N-H group. We
assumed that the plausible transition state is one borane atom
associated with three oxygens of hydroxy groups, and Lewis
base interaction of the phosphoramide oxygen atom with
another borane will facilitate the attack of borane to carbonyl
group from the Re-face of prochiral ketone and afford the
secondary alcohol in the R configuration (Figure 2).
1-phenylpropan-1-one, the selectivity decreased greatly due
to its steric effect (Table 3, entries 14 and 15). Aliphatic
ketone 1-(trans-4-propylcyclohexyl) ethanone also gave
moderate enantioselectivity determined by HPLC analysis
after transformation to the phenyl isocyanate ester (Table 3,
entry 16).
3
To further understand the structural effect of new C -
symmetric ligands on their catalytic activity, a crystal
structure of borane complex should be useful. But all
attempts to get borane complex for XRD analysis failed. The
crystal structure of ligand 1d was determined by X-ray crystal
diffraction analysis. 1d was obtained as an air-stable,
colorless crystal upon slow evaporation in ethyl acetate-
petroleum ether. A perspective view of ligand 1d was shown
in Figure 1. From the crystal structure of 1d, we can see
Figure 2. Presumed transition state for borane reduction.
In summary, a series of new chiral C -symmetric tris(â-
3
hydroxy phosphoramide) ligands have been conveniently
synthesized from commercially available L-proline methyl
ester in two steps. Structurally well-defined, recoverable C -
3
symmetric ligand 1d was used as an efficient catalyst in the
enantioselective borane reduction of prochiral ketones con-
taining electron-withdrawing or electron-donating groups,
and high enantioselectivities were obtained (up to 98% ee).
Meanwhile, this robust catalyst can be recovered and reused
or in situ recycled. This simple catalyst system is practical
for the large-scale asymmetric synthesis of chiral secondary
alcohols. The development of other asymmetric reactions
3
using these C -symmetric ligands is ongoing in our group.
Figure 1. ORTEP diagram of ligand 1d.
Acknowledgment. This project was supported by the
National Natural Science Foundation of China (Grant Nos.
that PdO and three OH group are arranged to the same side
owing to hydrogen-bonding interaction (O(1)-HO1‚‚‚O(2)),
this conformationally restricted system was important to form
a well-defined chiral environment around the phosphorus
atom. Thus, this chiral environment in the corresponding
borane complex will result in high enantioselectivity in
borane reduction of the ketone.
20572003, 20372001, and 20521202) and Peking University.
Supporting Information Available: Experimental pro-
1
cedures, the crystal data of 1d (CIF), copies of H NMR
1
3
and C NMR spectra of 1 and 2, and HPLC spectra of
secondary alcohols. This material is available free of charge
via the Internet at http://pubs.acs.org.
Although we do not know the exact modality of this
complex, we can assume that it differs from the well-studied
OL0600584
1330
Org. Lett., Vol. 8, No. 7, 2006