trans-[RuCl2(phosphane)2(1,2-diamine)] and chiral trans-[RuCl2(diphosphane)(1,2-diamine: Shelf-stable precatalysts for the rapid, productive, and stereoselective hydrogenation of ketones

Article abstract of DOI:10.1002/(SICI)1521-3773(19980703)37:12<1703::AID-ANIE1703>3.0.CO;2-I

A turnover number (TON) of 2400 000 and a turnover frequency (TOF) of 63 s^-1 are achieved with the chiral Ru(II) complex 1 (R = p-CH₃C₆H₄) in the asymmetric hydrogenation of acetophenone. Carbonyl-selective asymmetric hydrogenation of α,β-unsaturated ketones proceeds in the presence of these Ru(II) catalysts, and 4-substituted cyclohexanones are selectively converted into cis alcohols.

Full text of DOI:10.1002/(SICI)1521-3773(19980703)37:12<1703::AID-ANIE1703>3.0.CO;2-I

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Experimental Section
trans-[RuCl2(phosphane)2(1,2-diamine)] and
Chiral trans-[RuCl2(diphosphane)(1,2-dia-
mine): Shelf-Stable Precatalysts for the Rapid,
Productive, and Stereoselective Hydrogenation
of Ketones**
Typical procedure for an iodine ± magnesium exchange reaction: Prepara-
tion of 3l: A solution of ethyl 4-iodobenzoate (552 mg, 2 mmol) in THF
(20 mL) was cooled to 408C, and iPr2Mg (2.3 mL, 1.06 mmol) in tert-butyl
methyl ether was added. After 1 h at 408C, benzaldehyde (233 mg,
2.2 mmol) was added. After stirring for 3 h, the reaction mixture was
worked up as usual to give a crude yellow oil, which was purified by flash
chromatography (pentane/ether, 80/20) to give 460 mg of pure 3l (90%
yield).
Henri Doucet, Takeshi Ohkuma, Kunihiko Murata,
Tohru Yokozawa, Masami Kozawa, Eiji Katayama,
Anthony F. England, Takao Ikariya, and Ryoji Noyori*
Typical procedure for an iodine ± magnesium exchange reaction on the
solid phase: Preparation of 5a: Wang resin (100 mg) charged with 4-
iodobenzoic acid (70 mmol) was dried for 2 h under vacuum (0.1 Torr) at
508C. After cooling to room temperature under an inert atmosphere, the
resin was allowed to swell for 10 min in THF (2 mL). The heterogeneous
mixture was cooled to 358C, and a solution of iPrMgBr (0.70 mL,
0.51 mmol, 0.73m) in THF was added. After stirring for 15 min, a solution
of CuCN ´ 2LiCl (0.70 mL, 0.7 mmol, 1.0m) was added, followed, after a
further 15 min, by allyl bromide (0.30 mL, 50 equiv). After stirring for
40 min, the reaction mixture was filtered, and the resin was successively
washed with DMF, MeOH, and CH2Cl2 (six cycles) and treated with
CF3CO2H (4 mL of CF3CO2H/CH2Cl2/H2O, 9/1/1) for 20 min. After
filtration and evaporation of the volatile materials under high vacuum,
5a (10.8 mg, 95% yield) was isolated as a white solid. The HPLC purity was
98% (RP-18, MeCN/H2O, 0.1% CF3CO2H; UV detection at 254 nm).
We recently discovered that a system comprising [RuCl2-
(phosphane)n], 1,2-diamine, and an inorganic base is an
excellent catalyst for the hydrogenation of simple ketones in
2-propanol, at high substrate/catalyst molar ratios (S/C) under
mild conditions.[1] In addition to other features, this reaction is
ˆ
ˆ
characterized by high diastereo-, enantio-, and C O/C C
selectivity. However, the concentration of the catalytic species
generated in situ remains unknown. Because the quantities of
the metallic and organic components used are extremely
small, it is possible that the intermolecular reactions may be
incomplete. Furthermore, the catalytically active metal com-
plexes may not be the only complexes formed. We speculated
that the use of a pure, stable phosphane/diamine complex
would significantly increase the catalytic efficiency. We
describe here procedures for the preparation of RuII com-
plexes with phosphane and diamine ligands from commercial
or other readily available materials. As expected, these
complexes proved to be exceedingly efficient hydrogenation
precatalysts. The reaction rate and productivity were two
orders of magnitude higher than those obtained from the
complexes generated in situ.
Received: January 26, 1997 [Z11403IE]
German version: Angew. Chem. 1998, 110, 1801 ± 1804
Keywords: copper ´ Grignard reactions ´ iodine ± magnesi-
um exchange ´ magnesium ´ solid-phase synthesis
[1] Handbook of Grignard-Reagents (Eds.: G. S. Silverman, P. E. Rakita),
Marcel Dekker, New York, 1996.
[2] G. H. Posner, Org. React. 1975, 22, 253; B. H. Lipshutz, S. Sengupta,
ibid. 1992, 41, 135; T.-Y. Luh, Acc. Chem. Res. 1991, 24, 257; K. Tamao,
K. Sumitani, M. Kumada, J. Am. Chem. Soc. 1972, 94, 4374; R. J. P.
Corriu, J. P. Masse, J. Chem. Soc. Chem. Commun. 1972, 144; T.
Hayashi, M. Kumada, Acc. Chem. Res. 1982, 15, 395; E. Negishi, A. O.
King, N. Okukado, J. Org. Chem. 1977, 42, 1821; M. T. Reetz, Top. Curr.
Chem. 1982, 106; B. Weidmann, D. Seebach, Angew. Chem. 1983, 95,
12; Angew. Chem. Int. Ed. Engl. 1983, 22, 31; M. T. Reetz, Angew.
Chem. 1984, 96, 542; Angew. Chem. Int. Ed. Engl. 1984, 23, 556; G.
Cahiez, S. Marquais, M. Alami, Org. Synth. 1993, 72, 135; G. Cahiez, B.
Laboue, Tetrahedron Lett. 1992, 33, 4439.
Achiral Ru type 1 complexes with triarylphosphane, ethyl-
enediamine, and chloro ligands were prepared by the addition
of two equivalents of ethylenediamine to [RuCl2(phos-
phane)3][2] in CH2Cl2 at 258C. The mixture was stirred for
three hours (method A). Type 2 chiral complexes were most
Cl
Cl
H2
N
R1
H2
N
Ar2
P
Â
[3] Examples of halogen ± magnesium exchange reactions: J. Villieras,
R2
R3
Ar3P
Ar3P
Bull. Soc. Chim. Fr. 1967, 1520; H. H. Paradies, H. Görbing, Angew.
Chem. 1969, 81, 293; Angew. Chem. Int. Ed. Engl. 1969, 8, 279. C. F.
Smith, G. J. Moore, C. Tamborski, J. Organomet. Chem. 1971, 33, C21;
G. Cahiez, D. Bernard, J. F. Normant, ibid. 1976, 113, 107; D. Seyferth,
R. Lambert, ibid. 1973, 54, 123; N. Redwane, P. Moreau, A.
Commeyras, J. Fluorine Chem. 1982, 20, 699; N. Furukawa, T.
Shibutani, H. Fujihara, Tetrahedron Lett. 1987, 28, 5845; H. Nishiyama,
K. Isaka, K. Itoh, K. Ohm, H. Nagase, K. Matsumoto, H. Yoshiwara, J.
Org. Chem. 1992, 57, 407; C. Bolm, D. Pupowicz, Tetrahedron Lett. 1997,
38, 7349.
Ru
Ru
N
H2
P
Ar2
N
H2
Cl
1
Cl
2
[*] Prof. R. Noyori,[‡] Dr. H. Doucet, Prof. T. Ohkuma[‡]
Department of Chemistry and Molecular Chirality Research Unit
Nagoya University
[4] P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem. 1988, 53,
2390.
[5] F. Balkenhohl, C. vom dem Bussche-Hünnefeld, A. Lansky, C. Zechel,
Angew. Chem. 1996, 108, 2436; Angew. Chem. Int. Ed. Engl. 1996, 35,
2288; J. S. Früchtel, G. Jung, Angew. Chem. 1996, 108, 19; Angew.
Chem. Int. Ed. Engl. 1996, 35, 17.
[6] Supplied by Bachem Bioscience Inc., King of Prussia, PA, USA.
[7] I. Klement, K. Lennick, C. E. Tucker, P. Knochel, Tetrahedron Lett.
1993, 34, 4623.
[8] A patent covering the preparation of polyfunctional Grignard reagents
has been submitted.
Chikusa, Nagoya 464-8602 (Japan)
Fax: (‡81)52-783-4177
K. Murata, T. Yokozawa, M. Kozawa, E. Katayama,
Dr. A. F. England, Prof. T. Ikariya[‡‡]
ERATO Molecular Catalysis Project
Japan Science and Technology Corporation
1247 Yachigusa, Yakusa-cho, Toyota 470-0392 (Japan)
‡
[ ] Professors Noyori and Ohkuma were also members of the ERATO
Project.
‡‡
[
] Present address:
Department of Chemical Engineering, Faculty of Engineering
Tokyo Institute of Technology, Meguro, Tokyo 152-8552 (Japan)
[**] This work was supported by the Ministry of Education, Science,
Sports, and Culture of Japan (No. 07CE2004).
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conveniently obtained by treatment of oligomeric [RuCl2(di-
phosphane)(dmf)n][3] with 1.1 equivalents of a diamine[4] in
dmf at 258C for three hours (method B). In place of
[RuCl2(binap)(dmf)n], [NH2(C2H5)2][{RuCl(binap)}2(m-Cl)3][5]
and [RuCl(binap)(h6-arene)]Cl[6] can also be used (abbrevia-
tions are given in Figure 1). The desired mixed-ligand com-
P(C6H5)2
O
PAr2
PAr2
P(C6H5)2
P(C6H5)2
O
P(C6H5)2
(S,S)-DIOP
(S,S)-CHIRAPHOS
(S)-BINAP: Ar = C6H5
(S)-TolBINAP: Ar = p-CH3C6H4
CH3O
NH2
NH2
NH2
CH3O
NH2
(S,S)-DPEN
(S)-DIAPEN
Figure 1. Chiral diphosphanes and diamines
plex can also be obtained by the reaction of [Ru{h3-
CH2C(CH3)CH2}2(diphosphane)][7] in acetone with two
equivalents of methanolic HCl, followed by treatment of the
resulting [RuCl2(diphosphane)]n with one equivalent of a
diamine in DMF at 258C for three hours (method C). This
procedure, though somewhat tedious, provides a general
route to the preformed complexes. The diphosphane/diamine
Ru complexes thus prepared[8] are listed in Table 1. These
complexes are soluble in many common organic solvents. The
p-tolylphosphane and TolBINAP[9] complexes are more
soluble than the triphenylphosphane and BINAP analogues.
The isolated Ru complexes are fairly air- and moisture-stable
and can be stored in an ordinary vial for a long period,
preferably under an argon atmosphere.
Figure 2. ORTEP diagrams of the structures of (R),(R,R)-2d (a) and
(R),(S,S)-2e (b). All hydrogen atoms except for the amino and methine
protons of DPEN have been omitted for clarity. Selected distances[Š] and
bond angles[8]: (R),(R,R)-2d; Ru Cl1 2.421(2), Ru Cl2 2.420(2), Ru P1
2.282(3), Ru P2 2.273(2), Ru N1 2.196(7), Ru N2 2.183(7), Cl1 (H4)N2
2.74, Cl2 (H2)N1 2.77; Cl1-Ru-Cl2 162.96(8), P1-Ru-P2 92.22(8), N1-Ru-
N2 77.7(2). (R),(S,S)-2e; Ru Cl1 2.408(2), Ru Cl2 2.426(2), Ru P1
2.276(2), Ru P2 2.296(2), Ru N1 2.141(5), Ru N2 2.189(6), Cl1 (H1)N1
2.70, Cl2 (H3)N2 2.70; Cl1-Ru-Cl2 163.23(6), P1-Ru-P2 91.50(7), N1-Ru-
N2 78.0(2).
All the complexes in Table 1 have trans-dichloro geo-
metries. Single-crystal X-ray analysis[10] of (R),(R,R)-2d
indicated a distorted octahedral geometry of the Ru center
that approaches C2 sym-
metry, in which both the
TolBINAP and DPEN
chelate ligands are coor-
dinated in a l fashion
(Figure 2a). In the dia-
stereomer, (R),(S,S)-2e,
the TolBINAP ligand
forms a l seven-mem-
bered structure, while the
DPEN ligand assumes
Table 1. Synthesis and properties of the Ru complexes 1 and 2.
Complex
formula[a]
Method
Decomp [8C][b] d(31P)[c]
1a
[(OC-6-13)-RuCl2{P(C6H5)3}2(en)]
A
A
B
B
B
176
185
235
242
183
45.5 (s)
44.3 (s)
47.4 (s)
46.9 (s)
47.9 (d), 48.9
(d)[d]
1b
[(OC-6-13)-RuCl2{P(p-CH3C6H4)3}2(en)]
[(OC-6-13)-RuCl2{(R)-binap}{(R,R)-dpen}]
[(OC-6-13)-RuCl2{(R)-binap}{(S,S)-dpen}]
[(OC-6-13)-RuCl2{(S)-binap}{(S)-daipen}]
(R),(R,R)-2a
(R),(S,S)-2b
(S),(S)-2c
(R),(R,R)-2d
(R),(S,S)-2e
(S),(S)-2 f
[(OC-6-13)-RuCl2{(R)-tolbinap}{(R,R)-dpen}]
[(OC-6-13)-RuCl2{(R)-tolbinap}{(S,S)-dpen}]
[(OC-6-13)-RuCl2{(S)-tolbinap}{(S)-daipen}]
B
B
B
209
234
173
46.2 (s)
45.5 (s)
45.9 (d), 47.6
(d)[e]
a
five-membered ring
(S,S),(R,R)-2g [(OC-6-13)-RuCl2{(S,S)-diop}{(R,R)-dpen}]
(S,S),(S,S)-2h [(OC-6-13)-RuCl2{(S,S)-chiraphos}{(S,S)-dpen}]
B
C
226
204
38.9 (s)
79.1 (s)
structure with a d con-
formation (Figure 2b).
1704
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1
In these stereoisomers, the two phenyl substituents of the
N,N-ligated five-membered ring are oriented in the equatorial
direction, and the flexible P(p-H3CC6H4)2 moieties adopt
similar spatial arrangements. The Cl HN distances (2.7 ±
2.8 Š) are rather short due to intramolecular hydrogen
bonding (expected van der Waals separation, 3.0 Š). H and
31P NMR analysis of these compounds show that they exist as
a single conformer in C6D6.
The isolated Ru complexes are among the most reactive
(pre)catalysts for homogeneous hydrogenation so far report-
ed.[11] When cyclohexanone (3a) was hydrogenated in 2-
propanol (2.1 m) in the presence of 1b and (CH3)3COK
(ketone:1b:base ˆ 100000:1:450) at 10 atm H2 and 608C for
two hours, cyclohexanol (4a) was produced in 96% yield
[Eq. (a)]. The reaction was extremely rapid with an initial
H2 and 808C proceeded with an initial TOF of 259000 h
1
(72 s ), and after one hour afforded (S)-1-(1-naphthyl)etha-
nol ((S)-6g) with 91% ee in 93% yield.[13] As exemplified in
Table 2, high level enantioselectivity was obtained with
various ring-substituted acetophenones, including the o-
bromo and -methoxy derivatives 5c and 5d, and higher
1
OH
Ar
O
5
Ru catalyst
+
H2
(b)
R
R
Ar
*
6
a: R = CH3, Ar = C6H5
f: R = CH3, Ar = p-iC4H9C6H4
g: R = CH3, Ar = 1-naphthyl
h: R = C2H5, Ar = p-CH3OC6H4
b: R = CH3, Ar = o-CH3C6H4
c: R = CH3, Ar = o-BrC6H4
d: R = CH3, Ar = o-CH3OC6H4 i: R = n-C3H7, Ar = C6H5
e: R = CH3, Ar = p-C2H5C6H4 j: R = cyclo-C6H11, Ar = C6H5
OH
O
Ru catalyst
+
H2
(a)
R
R
analogues of acetophenone, with an S/C as high as 100000
[Eq. (b)].[14, 15] The degree of enantioselectivity and the
absolute configuration of the products are the same as those
obtained with the complexes generated in situ.
Asymmetric hydrogenation of 2,4,4-trimethyl-2-cyclohexe-
none (7) with (S),(R,R)-2e acts on the carbonyl group only
and gave (R)-2,4,4-trimethyl-2-cyclohexenol ((R)-8) with
94% ee and in 100% yield [Eq. (c)]. The chiral alcohol 8 is
an intermediate in the synthesis of various carotenoid-derived
bioactive terpenes and odorants.[16]
3
4
a: R = H
c: R = C6H5
b: R = (CH3)3C
1
1 [11, 12]
turnover frequency (TOF) of 563000 h or 156 s .
Hydrogenation of 4-tert-butylcyclohexanone (3b) in the
presence of 1b and (CH3)3COK (50000:1:250) at 10 atm and
608C, proceeded with a TOF of 178000 h (49 s ), and
produced the cis alcohol 4b with a cis/trans stereoselectivity of
97/3. The 4-phenyl derivative 3c was produced with a cis/trans
selectivity of 96/4.[1c]
1
1
Rapid, highly productive asymmetric hydrogenation of
ketones can be achieved with chiral precatalysts. When a
mixture of acetophenone (5a) (601 g), (S),(S,S)-2d (2.2 mg),
and (CH3)3COK (5.6 g) in 2-propanol (1.5 L) was stirred
under H2 (45 atm) at 308C for 48 h, (R)-1-phenylethanol ((R)-
6a) was obtained with 80% ee and in 100% yield (94%
(577 g) after distillation). The turnover number (TON) was
O
OH
Ru catalyst
+
H2
(c)
7
8
1
2400000, while the TOF at 30% conversion was 228 000 h
1
(63 s ).[11, 12] Hydrogenation of 1'-acetonaphthone (5g) in 2-
This new hydrogenation procedure is clean, mild, and
efficient, and offers a very practical method of chiral alcohol
synthesis.
propanol in the presence of (R),(R,R)-2d and (CH3)3COK
([ketone] ˆ 2.1 M, ketone:2d:base ˆ 50000:1:200) at 10 atm
Table 2. Ruthenium-catalyzed asymmetric hydrogenation of ketones.[a]
Ketone
Precatalyst
S/C[b]
Conditions
t [h]
Alcohol product
H2 [atm]
Yield [%][c]
ee [%][c]
Config.[d]
5a
5b
5c
5d
5e
5 f
5 f
5g
5g
5h
5i
(S),(S,S)-2d
(S),(S)-2 f
(R),(R)-2 f
(S),(S)-2 f
(R),(R)-2 f
(R),(R,R)-2d
(S),(S,S)-2d
(S),(S,S)-2d
(R),(R,R)-2d
(R),(R)-2 f
(S),(S)-2 f
2400000[e]
100000
10000
2000
10000
100000
800
100000
50000
10000
100000
100000
10000
45
10
10
4
10
10
1
10
10
10
10
10
10
48
48
6
100
94
100
98
100
99
98
99.5
93
100
87
98
100
80
99
98
82
97
96
94
98
91
95
94
92
94
R
R
S
R
S
10
21
48
24
40
S
R
R
S
1[f]
14
48
48
48
S
R
R
R
5j
7
(S),(S)-2 f
(S),(R,R)-2e
[a] Reactions were conducted at 24 ± 308C with a 2.1 ± 2.4 m solution of substrate (25 mmol) in 2-propanol in the presence of (CH3)3COK (ketone:base ˆ
220:1). [b] Substrate/catalyst molar ratio. [c] Determined by GC or HPLC analysis of the chiral phase. [d] Determined by sign of rotation. [e] Reaction with
601 g 5a (ketone:(CH3)3COK ˆ 100:1) [f] at 808C.
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were added to the residue. The mixture was degassed and stirred under
argon for 3 h. The solvent was evaporated under reduced pressure and the
residue was dissolved in CH2Cl2 (10 mL). The turbidity was removed by
filtration and the filtrate was concentrated to about 2 mL. Ether (10 mL)
was then added and the turbidity was again removed by filtration. Ether
(10 mL) was again added to the filtrate and a light brown powder
precipitated. The supernatant was removed and the resulting solid was
dried to give (S,S),(S,S)-2h (1.90 g, 78%). 1H NMR: d ˆ 0.95 (d, 6H, J ˆ
4.3 Hz, CH3), 2.77 (m, 2H, CH3CH), 3.84 (m, 2H, NHH), 4.05 (m, 2H,
NHH), 4.69 (m, 2H, NH2CH), 6.7 ± 8.1 (m, 30H, aromatic H).
Hydrogenation of cyclohexanone: (3a):[14] Conversions were determined
by gas chromatography (HP-INNOVAX (30 m), 1008C, He (55 kPa),
9.2 min (3a), 12.8 min (4a)). Correlations between reaction time (min) and
TON were as follows: (5, 12330), (10, 59280), (15, 68980), (20, 76150),
(120, 96130). 4b: cis/trans ˆ 97/3; GC: HP-INNOVAX, 1308C, 17.4 min
(cis), 20.1 min (trans). 4c: cis/trans ˆ 96/4; GC: HP-INNOVAX, 1908C,
28.6 min (cis), 30.4 min (trans).
Asymmetric hydrogenation:[14] (S),(S,S)-2d (22 mg) was dissolved in
degassed 2-propanol (20 mL), which was used as the catalyst stock solution.
Ketone 5a (601 g), 2-propanol (1.5 L), (CH3)3COK (5.6 g), and an aliquot
of the catalyst solution (2.0 mL, 0.002 mmol) (molar ratio
ketone:Ru:base ˆ 2400000:1:24000) were placed in a 10 L stainless steel
autoclave. The mixture was degassed and hydrogen was introduced to a
pressure of 45 atm. The mixture was vigorously stirred at 308C for 48 h. The
yield was determined by GC to be 100%. GC: Cyclodextrin-b-236M-19
(CHROMPAC, 50 m), 1158C, He (50 kPa), 26.7 min ((R)-6a), 28.7 min
((S)-6a), 17.8 min (5a). After the solvent was removed under reduced
pressure, the residue was passed through a silica gel column (300 g, ethyl
acetate) and then distilled (998C, 15 Torr) to give (R)-6a (577 g, 94%,
80% ee).[1a] [a]D24 ˆ ‡38.1 (c ˆ 1.02, CH2Cl2).[1a, 17]
Experimental Section
1a[8] (method A): [RuCl2{P(C6H5)3}3] (1.11 g, 1.16 mmol) was placed in a
50-mL Schlenk flask filled with argon. CH2Cl2 (10 mL) and NH2(CH2)2NH2
(0.15 mL, 2.2 mmol) were then added. The mixture was degassed and
stirred under argon at 258C for 3 h. After removal of turbidity by filtration,
the filtrate was concentrated to about 5 mL, n-hexane (20 mL) was added,
and a light brown powder was obtained. The supernatant was removed and
the resulting solid was dried under reduced pressure (1 Torr) to give
analytically pure 1a (0.55 g, 63% yield). 1H NMR (400 MHz, C6D6, 258C,
TMS): d ˆ 2.1 (m, 4H; CH2), 2.8 (m, 4H; NH2), 6.8 ± 8.0 (m, 30H; aromatic
H).
1b (method A): A light brown solid was obtained from CH2Cl2:ether (1:3)
(79%). 1H NMR: d ˆ 2.00 (s, 18H, CH3), 2.2 (m, 4H, CH2), 2.9 (m, 4H,
NH2), 6.86 (d, 12H, J ˆ 7.5 Hz, o-aromatic H), 7.9 (m, 12H, m-aromatic H).
(R),(R,R)-2a (method B): [RuCl2(C6H6)]2 (129 mg, 0.258 mmol) and (R)-
BINAP (341 mg, 0.55 mmol) were placed in a 50-mL Schlenk flask. After
the air in the flask was replaced with argon, DMF (9 mL) was added, the
mixture was degassed and stirred under argon at 1008C for 10 min to form a
reddish brown solution. After the solution was cooled to 258C,
[14]
(R,R)-
DPEN (117 mg, 0.55 mmol) was added and the mixture was stirred for 3 h.
The solvent was removed under reduced pressure (1 Torr). The residue was
dissolved in CH2Cl2 (10 mL) and turbidity was removed by filtration. The
filtrate was concentrated to about 1 mL, then ether (10 mL) was added and
a light brown powder was obtained. The supernatant was removed and the
resulting solid was dried under reduced pressure to give (R),(R,R)-2a
(0.34 g, 66% yield). 1H NMR: d ˆ 3.3 (m, 2H, NHH), 3.45 (m, 2H, NHH),
4.55 (m, 2H, NH2CH), 6.3 ± 8.8 (m, 42H, aromatic H).
(R),(S,S)-2b (method B):
CH2Cl2:ether (1:12) (62%). 1H NMR: d ˆ 3.0 (m, 2H, NHH), 4.4 (m,
2H, NHH), 4.65 (m, 2H, NH2CH), 6.3 ± 8.8 (m, 42H, aromatic H).
A light brown solid was obtained from
Hydrogenation of 5g at 808C: (S)-6g, 91% ee; GC: Chirasil-DEX CB
(25 m), 1508C, He (50 kPa), 46.8 min ((R)-6g), 42.3 min ((S)-6g), 19.1 min
(5g). Correlations between reaction time (min) and TON were as follows:
(5, 7815), (10, 29360), (15, 37870), (60, 46350).
(S),(S)-2c (method B):
A cream yellow solid was obtained from
CH2Cl2:ether (1:10) (50%). 1H NMR d ˆ 0.12 (d, 3H, J ˆ 6.8 Hz,
CH3CHCH3), 0.54 (d, 3H, J ˆ 6.8 Hz, CH3CHCH3), 1.7 (m, 1H,
(CH3)2CH), 2.75 (m, 1H, NHH((CH3)2CH)CH), 3.05 (m, 1H,
NHH((CH3)2CH)CH), 3.12 (s, 3H, CH3O), 3.31 (s, 3H, CH3O), 3.8 (m,
1H, NHH(p-CH3OC6H4)2C), 4.40 (m, 1H, NHH(p-CH3OC6H4)2C), 5.05
(m, 1H, NH2CH), 6.2 ± 8.4 (m, 40H, aromatic H).
(R)-6b: [a]2D4 ˆ ‡52.8 (neat);[1a, 18] 99% ee; Chirasil-DEX CB, 1258C,
17.1 min ((R)-6b), 20.0 min ((S)-6b).
(S)-6c: [a]2D4
1508C, 13.0 min ((R)-6c), 16.2 min ((S)-6c).
ˆ
60.5 (c ˆ 0.57, CH2Cl2);[19] 98% ee; Chirasil-DEX CB,
(R)-6d: [a]2D4 ˆ ‡59.1 (c ˆ 1.10, toluene);[20] 82% ee; Chirasil-DEX CB,
(R),(R,R)-2d: A light brown solid was obtained from CH2Cl2:ether (1:5)
(58%). 1H NMR: d ˆ 1.70 (s, 6H, CH3), 1.87 (s, 6H, CH3), 3.3 (m, 2H,
NHH), 3.5 (m, 2H, NHH), 4.55 (m, 2H, NH2CH), 6.55 ± 8.8 (m, 38H,
aromatic H).
1308C, 20.7 min ((R)- 6d), 23.5 min ((S)-6d).
(S)-6e: [a]2D4
1108C, 43.3 min ((R)-6e), 47.2 min ((S)-6e).
ˆ
48.2 (c ˆ 1.12, CHCl3);[21] 97% ee; Chirasil-DEX CB,
(S)-6 f: [a]2D5
((R)-6 f), 33.4 min ((S)-6 f).
ˆ
35.5 (neat);[22] 96% ee; Chirasil-DEX CB, 1308C, 30.1 min
(R),(S,S)-2e: A light brown solid was obtained from CH2Cl2:ether (1:5)
(51%). 1H NMR: d ˆ 1.70 (s, 6H, CH3), 1.81 (s, 6H, CH3), 3.05 (m, 2H,
NHH), 4.4 (m, 2H, NHH), 4.7 (m, 2H, NH2CH), 6.3 ± 8.8 (m, 38H,
aromatic H).
(R)-6g: [a]2D5 ˆ ‡77.0 (c ˆ 1.02, ether);[1a, 23] 98% ee.
(S)-6h: [a]2D2
1408C, 23.7 min ((R)-6h), 22.9 min ((S)-6h).
ˆ
36.1 (c ˆ 5.10, benzene);[24] 95% ee; Chirasil-DEX CB,
(S),(S)-2 f: A cream yellow solid was obtained from CH2Cl2:ether (1:14)
(60%). 1H NMR: d ˆ 0.08 (d, 3H, J ˆ 6.8 Hz, CH3(CH3)CH), 0.67 (d,
3H, J ˆ 6.8 Hz, CH3(CH3)CH), 1.66 (s, 3H, p-CH3C6H4P), 1.70 (s, 3H, p-
CH3C6H4P), 1.72 (m, 1H, (CH3)2CH), 1.99 (s, 3H, p-CH3C6H4P), 2.00 (s,
3H, p-CH3C6H4P), 2.9 (m, 1H, NHH((CH3)2CH)CH), 3.1 (m, 1H,
NHH((CH3)2CH)CH), 3.18 (s, 3H, CH3O), 3.40 (s, 3H, CH3O), 3.8 (m,
1H, NHH(p-CH3OC6H4)2C), 4.4 (m, 1H, NHH(p-CH3OC6H4)2C), 5.15 (m,
1H, NH2CH), 6.2 ± 8.8 (m, 36H, aromatic H).
(R)-6i: [a]2D3 ˆ ‡36.7 (c ˆ 1.40, CH3OH);[25] 94% ee; HPLC: CHIRALCE-
L OB (Daicel, 250 mm), 2-propanol:hexane (1:9), 308C, 254 nm,
0.5 mLmin 1, 11.2 min ((R)-6i), 9.4 min ((S)-6i).
(R)-6j: [a]2D2 ˆ ‡26.8 (c ˆ 3.29, benzene);[26] 92% ee; Chirasil-DEX CB,
1108C, 64.6 min ((R)-6j), 66.6 min ((S)-6j).
(R)-8: [a]D23 ˆ ‡87.9 (c ˆ 1.00, CH3OH);[1d, 16a] 94% ee; Chirasil-DEX CB,
908C, 49.1 min ((R)-8), 46.4 min ((S)-8).
(S,S),(R,R)-2g: Conditions: [RuCl2(C6H6)]2 (248 mg, 0.495 mmol), (S,S)-
DIOP (504 mg, 1.01 mmol), DMF (10 mL), 1008C, 2 h, and (R,R)-DPEN
(220 mg, 1.03 mmol), 258C, 3 h.[14] Isolation: removal of DMF (1 Torr,
258C !508C), extraction with CH2Cl2 (20 mL), and crystallization
(CH2Cl2:ether, 1:14, 45 mL), to give a light brown solid (530 mg, 61%
yield). 1H NMR: d ˆ 1.43 (s, 6H, CH3), 3.25 ± 3.70 (m, 6H, CH2P and
NHH), 3.95 ± 4.15 (m, 2H, NHH), 4.55 (m, 2H, NH2CH), 4.73 (m, 2H,
CHO), 6.5 ± 8.2 (m, 30H, aromatic H).
Received: February 9, 1998 [Z11454IE]
German version: Angew. Chem. 1998, 110, 1792 ± 1796
Keywords: asymmetric catalysis ´ chiral alcohols ´ N ligands
´ P ligands ´ ruthenium
(S,S),(S,S)-2h (method C): [Ru{h3-CH2C(CH3)CH2}2{(S,S)-chiraphos}]
(2.13 g, 3.0 mmol)[7] was placed in a 150-mL Schlenk flask filled with
argon. Acetone (50 mL) and HCl in CH3OH (2.27 m, 3.2 mL, 7.3 mmol)
were added and the mixture was stirred at 258C for 2 h. The turbidity was
removed by filtration, and the solvent was evaporated under reduced
pressure (1 Torr). Then dmf (20 mL) and (S,S)-dpen (632 mg, 3.0 mmol)
[1] a) T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1995, 117, 2675 ± 2676; b) T. Ohkuma, H. Ooka, T. Ikariya,
R. Noyori, ibid. 1995, 117, 10417Ð10418; c) T. Ohkuma, H. Ooka, M.
Yamakawa, T. Ikariya, R. Noyori, J. Org. Chem. 1996, 61, 4872 ± 4873;
1706
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Angew. Chem. Int. Ed. 1998, 37, No. 12

COMMUNICATIONS
d) T. Ohkuma, H. Ikehira, T. Ikariya, R. Noyori, Synlett 1997, 467 ±
468; e) T. Ohkuma, H. Doucet, T. Pham, K. Mikami, T. Korenaga, M.
Terada, R. Noyori, J. Am. Chem. Soc. 1998, 120, 1086 ± 1087.
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King, L. DiMichele in Catalysis of Organic Reactions (Eds.: M. G.
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Ohta, Y. Tonomura, K. Nozaki, H. Takaya, K. Mashima, Organo-
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Soc. Chem. Commun. 1989, 1208 ± 1210; b) K. Mashima, K. Kusano, N.
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Ishizaki, S. Akutagawa, H. Takaya, J. Org. Chem. 1994, 59, 3064 ±
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[25] B. Weber, D. Seebach, Tetrahedron 1994, 50, 7473 ± 7484.
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Organomet. Chem. 1976, 122, 83 ± 97.
Ã
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635.
Parallel Synthesis of Sialyl Lewis X Mimetics on
a Solid Phase: Access to a Library of
Fucopeptides**
[10] X-ray crystallographic analysis was performed with a Rigaku AFC
diffractometer (graphite monochromator, MoKa radiation). The
structures were solved with PATTY and DIRDIF94. (R),(R,R)-2d:
C62H56Cl2N2P2Ru, Mr ˆ 1063.06, orange crystal, 0.1  0.1  0.1 mm,
monoclinic, space group C2 (no. 5), a ˆ 24.50(1), b ˆ 20.533(9), c ˆ
Thomas F. J. Lampe, Gabriele Weitz-Schmidt, and
Chi-Huey Wong*
24.80(1) Š
b ˆ 119.20(3)8, Vˆ 10908(10) Š3,
Z ˆ 8,
1calcd
ˆ
1,
1.294 gcm 3, m(MoKa) ˆ 4.84 m
Tˆ 296 K. 9880 reflections were
independent and unique, and 6220 with I > 3.00s(I) (2qmax ˆ 508) were
used for the solution of the structure. All hydrogen atoms were
calculated from ideal geometries, fixed, and included in the calcu-
lation of the structural factor. R ˆ 0.034, Rw ˆ 0.034. (R),(S,S)-2e:
C62H56Cl2N2P2Ru, Mr ˆ 1063.06, orange crystal, 0.1  0.1  0.2 mm,
monoclinic, space group C2 (no. 5), a ˆ 24.74(2), b ˆ 20.49(1), c ˆ
In response to injury or inflammation the damaged tissue
releases cytokines, which trigger the expression of P-selectin
followed by E-selectin on the endothelium. The initial
recognition of the tetrasaccharide sialyl Lewis X (sLex) of
the terminal unit of surface glycoconjugates by the selectins
leads to leukocyte ªrollingº followed by protein ± protein
interactions (integrins CD11/18, ICAM-1 ligand) and extrav-
asation of leukocytes into the endothelium.[1] Thus, blocking
the sLex/selectin interactions at an early stage of the
inflammatory cascade, especially the P-selectin/ligand inter-
actions, has been considered to be an effective way of treating
acute and perhaps chronic inflammatory diseases.[2]
Although sLex is being clinically evaluated for the treat-
ment of reperfusion injury, it must be administered by
injection at high doses, as it binds the selectins weakly and
is orally inactive and unstable in the blood. However, the
structure of sLex has served as a useful guide for designing
simpler and better low molecular weight compounds as
25.04(1) Š
b ˆ 120.79(4)8, Vˆ 10908(11) Š3,
Z ˆ 8,
1calcd
ˆ
1,
1.294 gcm 3, m(MoKa) ˆ 4.84 m Tˆ 296 K. 12862 reflections were
independent and unique, and 7807 with I > 3.00s(I) (2qmax ˆ 558) were
used for the solution of the structure. All hydrogen atoms were
calculated from ideal geometries, fixed, and included in the calcu-
lation of the structural factor. R ˆ 0.034, Rw ˆ 0.033. Crystallographic
data (excluding structure factors) for the structures reported in this
paper have been deposited with the Cambridge Crystallographic Data
Center as supplementary publication no. CCDC-101399. Copies of the
data can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
[11] W. A. Herrmann, B. Cornils, Angew. Chem. 1997, 109, 1074 ± 1095;
Angew. Chem. Int. Ed. Engl. 1997, 36, 1048 ± 1067.
[12] The turnover number (TON) is the number of moles of product per
mole of catalyst. The turnover frequency (TOF) is the TON per hour
or second.
[13] Reaction with the diastereomeric isomer (R),(S,S)-2e, either pre-
formed or formed in situ, gave the S alcohol in 15 Æ 2%.
[*] Prof. Dr. C.-H. Wong, Dr. T. F. J. Lampe
The Scripps Research Institute
[14] Various alkaline bases, such as KOH, (CH3)2CHOK, (CH3)2CHONa,
(CH3)3COK, and K2CO3 can be used as cocatalysts. For reactions with
a high S/C, acidic impurities should be carefully removed from
substrates and solvents.
Department of Chemistry
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (‡1)619-784-2409
Dr. G. Weitz-Schmidt
Novartis Pharma AG
Preclinical Research
[15] Reaction of [RuCl2{(S)-TolBINAP}(dmf)n] and (S,S)-DPEN in
DMF at 508C (method B) gave a mixture of (S),(S,S)-2d and its cis
isomer (31P NMR, d ˆ 50.2 (d, J ˆ 38.0 Hz), 57.0 (d, J ˆ 38.0 Hz)).
Hydrogenation of 5g with the cis isomer showed comparable
reactivity to (S),(S,S)-2d, to give (R)-6 g with 97% ee.
CH-4002 Basel (Switzerland)
[**] We gratefully acknowledge financial support of our work by Novartis
Pharma AG and the NSF and the award of a DFG-Stipendium to
T.F.J.L. by the Deutsche Forschungsgemeinschaft.
[16] a) K. Mori, P. Puapoomchareon, Liebigs Ann. Chem. 1991, 1053 ±
1056; b) R. Croteau, F. Karp In Perfumes: Art, Science and Technology
Angew. Chem. Int. Ed. 1998, 37, No. 12
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