New Chiral Diphosphine Ligands Designed to Have a Narrow Dihedral Angle in the Biaryl Backbone

Article abstract of DOI:10.1002/1615-4169(20010330)343:3<264::AID-ADSC264>3.0.CO;2-T

A series of novel optically active diphosphine ligands, (4,4′-bi-1,3-benzodioxole)-5,5′-diylbis(diarylphosphine)s (6), which are called SEGPHOS, has been designed and synthesized with dihedral angles in the Ru complexes being less than that in the corresponding BINAP-Ru complex. The stereorecognition abilities of SEGPHOS-Ru complex catalysts in the asymmetric catalytic hydrogenation of a wide variety of carbonyl compounds are superior to those observed with BINAP-Ru complex catalysts.

Full text of DOI:10.1002/1615-4169(20010330)343:3<264::AID-ADSC264>3.0.CO;2-T

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New Chiral Diphosphine Ligands Designed
to Have a Narrow Dihedral Angle
in the Biaryl Backbone
Takao Saito,* Tohru Yokozawa, Takero Ishizaki, Takashi Moroi, Noboru Sayo,
Takashi Miura, Hidenori Kumobayashi
Takasago International Corporation, Central Research Laboratory, Nishi-Yawata, Hiratsuka, Kanagawa 254-0073, Japan
Fax: (+81) 463-25-2084, E-mail: TIC00546@nifty.ne.jp
Received January 10, 2001; Accepted February 1, 2001
Abstract: A series of novel optically active diphos- stereorecognition abilities of SEGPHOS-Ru complex
phine ligands, (4,4'-bi-1,3-benzodioxole)-5,5'-diyl- catalysts in the asymmetric catalytic hydrogenation
bis(diarylphosphine)s (6), which are called SEG- of a wide variety of carbonyl compounds are super-
PHOS, has been designed and synthesized with ior to those observed with BINAP-Ru complex cata-
dihedral angles in the Ru complexes being less than lysts.
that in the corresponding BINAP-Ru complex. The
In asymmetric catalysis
using chiral transition-
metal complexes, bi-
naphthyl or biphenyl
groups have often been
bite angle in metal com-
plexes.[3] The dihedral
angles of the binaphthyl
or biphenyl systems are
expected to exert influ-
Keywords: asymmetric catalysis; homogeneous
catalysis; hydrogenation; P ligands, ruthenium
used as chiral scaffolds to produce an excellent asym- ence on the effect of the steric bulk of the diphenyl-
metric environment.[1] Among these ligands with phosphino group as illustrated in Figure 1. This
chiral binaphthyl or biphenyl bridges, the most re- working hypothesis is based on steric considerations
presentative example is the C2 symmetric 2,2'-bis(di- and does not consider the electronic properties of the
phenylphosphino)-1,1'-binaphthyl (BINAP) (1).[2] complex, or the metal's valence.
Changes in the steric and/or electronic properties of
Additionally, the following experimental results
the ligands are known to dramatically influence the support our working hypothesis. Thus, the enantio-
selectivity and the reactivity of transition-metal com- selectivities in the hydrogenation of 2-oxo-1-propanol
plexes. The framework of chiral ligands not only (2a) to (2R)-1,2-propanediol (3a) are influenced re-
sways the enantioselectivity but can also remarkably
change the reactivities of the metal complexes. Dur-
ing the course of our research on the development of
chiral diphosphine ligands, we were interested to see
if varying the dihedral angle of the chiral backbone
would have an effect on the enantioselectivity of
asymmetric hydrogenation. Additionally, in spite of a
sparsity of information in the literature concerning
the mechanism of the asymmetric control, one of the
predominant factors could be the dihedral angle in
the chiral backbone. This correlates to the natural
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/asc/ or from
the author.
Figure 1. Steric considerations based on the effect of vary-
ing the dihedral angle (q) in biaryl backbone.
264
Ó WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2001
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Adv. Synth. Catal. 2001, 343, No. 3

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Figure 3. Ketone substrates 2 and hydrogenation products 3.
(+)-O,O '-dibenzoyltartaric acid [(+)-DBT]. From the
internal comparison with (+)-DBT, the absolute con-
figuration of (+)-SEGPHOSO is defined to be R. The
X-ray structure analysis revealed that the dihedral
angle q between the least-square planes through the
two 1,3-benzodioxole rings is 71.65° [in the 1 : 1 com-
plex of (S)-Cy-BINAPO and (±)-DBT, the dihedral an-
gle of the two naphthalene rings is 79.4°].[5]
Figure 2. Structures of ligands 1, 4, 5, and 6.
markably by the choice of ligand, and increase in the
following order: BINAP 1 (89.0% ee), BIPHEMP 4
(92.5% ee), and MeO-BIPHEP 5 (96.0% ee) (Fig-
ure 2). As estimated by a CAChe MM2 calculation,
the selectivities are lineally related to the dihedral an-
gles in the Ru-complexes of these ligands: BINAP
(73.49°), BIPHEMP (72.07°), MeO-BIPHEP (68.56°).
In order to produce new diphosphine ligands with a
narrower dihedral angle than BINAP, we used the bi-
1,3-benzodioxole system as the chiral framework, be-
cause the methylenedioxy moiety could be consid-
ered to be less sterically hindered. Thus, we have de-
signed and synthesized novel optically active
diphosphine ligands, (4,4'-bi-1,3-benzodioxole)-5,5'-
diyl-bis(diarylphosphine)s (6a±c; Figure 2), which
are called SEGPHOS. Estimation of the dihedral angle
of the atropisomeric bi-1,3-benzodioxole system in
SEGPHOS 6a±Ru complex using molecular me-
chanics calculations gave a result of 64.99°.
Scheme 1. Synthesis of the (R)-(+)-SEGPHOS ligand.
The preparation of these diphosphines was
achieved using the oxidative homo-coupling of 5-di-
arylphosphinyl-1,3-benzodioxoles at the C4 position
as the key reaction.[4] The synthesis of SEGPHOS 6a
is shown in Scheme 1; ligands 6b and 6c can be also
prepared by a similar coupling reaction.
The application of the present ligands to Ru-catalyzed
hydrogenations has led to an exceptionally active and
highly enantioselective catalytic system. These SEG-
PHOS±Ru(II) complex catalysts are widely applicable
for the hydrogenation of a wide range of ketonic sub-
strates as shown in Figure 3 and Table 1.
The absolute configuration of (+)-8 was determined
by X-ray analysis of the complex of (+)-8 with (2S,3S)-
Table 1. Hydrogenation of ketone compounds 2 using the (R)-SEGPHOS-Ru(II) complex as catalyst.[a]
Compound
S/C
H2
Solvent
Temperature Time
Conversion
(%)
% ee
(kg/cm2)
(°C)
(h)
2 a
2 a
2 b
2 c
2 d
2 e
2 f
3,000
30
30
50
50
30
30
10
50
methanol
methanol
ethanol
ethanol
methanol
ethanol
ethanol
ethanol
65
65
50
70
80
90
95
50
7
7
17
17
6
2
8
100
100
100
99
100
100
100
100
99.5
98.5
93.7
98.6
97.6
98.5
99.4
99.0
10,000
1,500
1,000
10,000
2,500
10,000
1,000
2 g
20
[a] [NH2Me2][{RuCl[(R)-segphos]}2(m-Cl)3] was used as a catalyst.
Adv. Synth. Catal. 2001, 343, 264±267
265

asc.wiley-vch.de
Firstly, the excellent chiral recognition ability of a tuted b-keto esters along with a high enantioselectiv-
(R)-SEGPHOS±Ru(II) complex catalyst can be de- ity by employing the (±)-DTBM-SEGPHOS 6c±Ru(II)
monstrated by the hydrogenation of 2a to afford complex catalyst. Thus, the hydrogenation of methyl
(2R)-3a in 98.5% ee and with a substrate-to-catalyst 2-benzamidomethyl-3-oxobutanoate (9) with a (±)-
ratio of up to 10,000. Using the (R)-Tol-BINAP±Ru(II) DTBM-SEGPHOS±Ru(II) complex catalyst gave
complex catalyst, this process is now industrially op- (2S,3R)-methyl
2-benzamidomethyl-3-hydroxybu-
erating at 89% ee and with a 3,000 to 1 substrate-to- tanoate (10) almost quantitatively in 98.6% de and
catalyst ratio.[6] Hydrogenation of a-keto esters cata- 99.4% ee (cf., Tol-BINAP, 86.0% de and 99.0% ee);[10]
lyzed by
a SEGPHOS±Ru(II) complex was also this compound can be transformed to a key inter-
achieved with a high enantioselectivity. The hydroge- mediate 11 of carbapenem antibiotics (Figure 4).[11]
nation of a-keto ester 2b in the presence of the (R)- The previous diastereo- and enantioselective hydro-
SEGPHOS±Ru(II) complex catalyst gives (2R)-ethyl genation of 9 using the BINAP±Ru(II) complex cata-
4-phenyl-2-hydroxybutanoate (3b) in 93.7% ee. lyst proceeded with 86% de. Two tert-butyl groups at
When the (R)-BINAP±Ru(II) complex catalyst was the meta-position of a phenyl ring of the ligand are es-
used for this hydrogenation, the enantioselectivity de- sential for the diastereoselectivity (SEGPHOS 6a;
creased to 90.0% ee. Since BINAP±Ru(II) complexes 79.6% de, DM-SEGPHOS 6b; 93.5% de).
have been recognized to be generally efficient cata-
In conclusion, based on our working hypothesis,
lysts for the hydrogenation of the b-keto esters, the the series of SEGPHOS ligands has been shown to
enantioselectivity in the hydrogenation of methyl have high efficiency in asymmetric catalytic hydroge-
3-oxo-3-phenylpropionate (2d) with the BINAP±Ru(II)
nations. The stereorecognition abilities of SEGPHOS±
complex was disappointingly low, giving (3R)-methyl Ru complex catalysts in the hydrogenation of a wide
3-hydroxy-3-phenylpropionate (3d) with 87.0% ee variety of carbonyl compounds are superior to those
(cf., MeO-BIPHEP, 93.5% ee).[7] When the (R)-SEG- observed with BINAP±Ru complex catalysts. Other
PHOS±Ru(II) complex catalyst was employed for this potential applications of the SEGPHOS ligands in
hydrogenation, the enantioselectivity rose to 97.6% asymmetric reactions are being investigated.
ee. In the case of the hydrogenation of a b-keto ester
containing a heteroatom at the g-position, the enan-
tioselectivity is not sufficient with BINAP because the
coordination abilities of the heteroatom and the car-
Experimental Section
bonyl group of the ester are competitive. The pro-
Asymmetric Hydrogenation of 2-Oxo-1-propanol
nounced selectivity and activity of the (R)-SEG-
(2a)
PHOS±Ru(II) complex catalyst can be shown by the
[NH2Me2][{RuCl((R)-segphos)}2(m-Cl)3] (111 mg, 0.067 mmol),
2-oxo-1-propanol (100.0 g, 1.35 mol) and methanol
(200 mL) were charged to 1-L stainless steel autoclave un-
der a nitrogen stream. Hydrogen (30 kg/cm2) was intro-
duced and the mixture was stirred for 7 h at 65 °C. The con-
version and ee of (R)-1,2-propandiol (3 a) were determined
by GLC analysis (100% conversion, 98.5% ee).
hydrogenation of ethyl 4-chloro-3-oxobutanoate (2e)
to afford (3R)-ethyl 4-chloro-3-hydroxybutanoate
(3e) in 98.5% ee at 90 °C and 30 kg/cm2 in only 2 h
with 100% conversion (cf., BINAP, 95.9% ee).[8]
Furthermore, in the case of the hydrogenation of
ethyl 4-benzyloxy-3-oxobutanoate (2f), the enantio-
selectivity of (R)-3f (99.4% ee) with the (R)-SEG-
PHOS±Ru(II) catalyst is higher than that obtained
with the (R)-Tol-BINAP±Ru(II) catalyst (97.4% ee). In (R)-(+)-(4,4'-Bi-1,3-benzodioxole)-5,5'-diylbis(di-
order to investigate the efficiency and further appli- phenylphosphine oxide) (8)
cability of the SEGPHOS ligand, we attempted to hy-
drogenate g-keto esters. Hydrogenation of ethyl levu-
linate (2g) can be performed with the (R)-SEGPHOS±
Under a nitrogen atmosphere, 0.7 M LDA in THF (400 mL,
280 mmol) was added dropwise to a solution of 5-diphenyl-
phosphinyl-1,3-benzodioxole (75.22 g, 233 mmol) in THF
Ru(II) catalyst to give (R)-ethyl 4-hydroxypentanoate
(300 mL) at ±15 °C. The mixture was added to a suspension
of FeCl3 (45.79 g, 282 mmol) in THF (300 mL) at 0 °C. After
evaporation of THF, the residue was dissolved in dichloro-
methane (500 mL) and washed with 10% hydrochloric acid,
water, and then dried over Na2SO4. The solvent was evapo-
rated and the residue was washed with hot ethyl acetate
(200 mL) to give (±)-8 (yield: 56.08 g, 75%).
(3g) with up to 99% ee.[9]
Next, a dramatic improvement in diastereoselec-
tion was observed in the hydrogenation of a-substi-
A solution of (+)-DBT (11.68 g, 32.6 mmol) in methanol
(30 mL) was added to
a solution of (±)-(8) (20.73 g,
32.3 mmol) in methanol (60 mL). The mixture was stirred
at reflux for 5 min. The precipitates were washed with
methanol to give the complex (R)-(8)-(+)-DBT as colorless
crystals. The complex was stirred in a mixture of dichloro-
Figure 4. Structures of compounds 9, 10, and 11.
266
Adv. Synth. Catal. 2001, 343, 264±267

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methane (90 mL) and 1.5 N sodium hydroxide (50 mL) at
room temperature for 30 min. The organic layer was
washed with water, evaporated and dried under vacuum to
give (R)-(+)-(8); yield: 9.12 g (> 99% ee, 44%); mp: 158±
159 °C, [a]2D4: +161.9 (c 0.063, CHCl3); 1H NMR (CDCl3):
d = 5.26 (2 H, d, J = 1.5 Hz), 5.72 (2 H, d, J = 1.6 Hz), 6.65
(2 H, dd, J = 8.1, 2.1 Hz), 6.77 (2 H, dd, J = 14.1, 8.1 Hz), 7.28±
7.72 (20 H, m); 31P NMR (CDCl3): d = 29.6.
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phenylphosphine) (6a)
The mixture of (R)-(+)-(8) (1.50 g, 2.34 mmol), N,N-di-
methylaniline (3.11 g, 25.6 mmol), and trichlorosilane
(3.22 g, 23.3 mmol) was stirred in toluene (25 mL) at 110 °C
for 4 h. After the reaction mixture was cooled to 5 °C with an
ice-water bath, 15% aqueous sodium hydroxide (30 mL)
was added. The mixture was stirred at room temperature
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(CDCl3): d = 5.03 (2H, d, J = 1.6 Hz), 5.66 (2 H, d, J = 1.6 Hz),
6.51 (2 H, dd, J = 7.9, 3.1 Hz), 6.66 (2 H, d, J = 8.1 Hz), 7.11±
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