Development of DIOP derivatives as efficient ligands for asymmetric hydrogenation: Factors controlling the reactivities and enantioselectivities

Article abstract of DOI:10.1016/j.tetasy.2004.05.042

Several DIOP derivatives have been developed as efficient ligands for Rh and Ir-catalyzed asymmetric hydrogenations. The conformational mobility of the backbone in this type of ligand plays an important role in governing both the reactivity and enantioselectivity. Isolation of pure pre-catalyst is another key factor to obtain high catalytic activity.

Full text of DOI:10.1016/j.tetasy.2004.05.042

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2181–2184
Development of DIOP derivatives as efficient ligands for
asymmetric hydrogenation: factors controlling the reactivities
and enantioselectivities
Duan Liu, Wenge Li and Xumu Zhang*
Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
Received 30 April 2004; accepted 19 May 2004
Abstract—Several DIOP derivatives have been developed as efficient ligands for Rh and Ir-catalyzed asymmetric hydrogenations.
The conformational mobility of the backbone in this type of ligand plays an important role in governing both the reactivity and
enantioselectivity. Isolation of pure pre-catalyst is another key factor to obtain high catalytic activity.
Ó 2004 Published by Elsevier Ltd.
1. Introduction
cant role in the asymmetric induction. Based on Kagan’s
pioneering work, thousands of chiral phosphine com-
pounds have been synthesized with diverse chiral back-
bones with many being proven to be efficient ligands for
asymmetric catalysis.2
DIOP 1 (Fig. 1), developed by Kagan in the 1970’s, is
one of the earliest and most extensively explored chiral
phosphine ligands in asymmetric hydrogenation, albeit
with only moderate to good enantioselectivities.1 It has
shown synthetic chemists that the chirality does not
have to be on the phosphorus centers for a phosphine
compound to be a highly selective ligand for asymmetric
catalysis, while the chiral backbone can play a signifi-
Recently, several modifications on the backbone of
DIOP ligands have been reported leading to new 1,4-
bisphosphine ligands with improved enantioselectivities
in Rh-catalyzed asymmetric hydrogenations.3 For
example, we introduced (R,S,S,R)-DIOP* 2 (Fig. 1)
with excellent results in the Rh-catalyzed hydrogenation
of aryl-enamides.4 Such high enantioselectivities were
attributed to the increased conformational rigidity of the
chiral backbone of the ligand.4a Based on a similar
conformational analysis, we successfully applied an-
other structurally related type of ligands 35 (Fig. 1) with
a 1,4-dioxane backbone, which showed comparable re-
sults to 2 in the Rh-catalyzed hydrogenation of aryl-
enamides.3j Interestingly, we found that while Rh-3
complex formed in situ catalyzed the hydrogenation of a
more electron-rich substrate MOM-protected b-hydr-
oxyl enamide 4a to 5a with full conversion and high
enantioselectivity,3j Rh-2 complex showed no reactivity
under the same reaction conditions. These unexpected
results prompted us to extend the conformational
studies of this particularly important and interesting
type of 1,4-bisphosphine. Herein, we report the exten-
sion of this ligand family, leading to the synthesis of two
new ligands 6 and 7 (Fig. 1) with acyclic backbones, and
the discussion of the influence of conformational
O
O
O
O
PPh2
PPh2
PPh2
PPh2
1 DIOP
2 DIOP*
OR
H
RO
RO
PAr2
PAr2
PPh2
PPh2
OR
H
3
6 R = H
7 R = Bn
Figure 1. Structures of DIOP type ligands.
* Corresponding author. Tel.: +1-814-865-4221; fax: +1-814-863-8403;
e-mail: xumu@chem.psu.edu
0957-4166/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2004.05.042

2182
D. Liuet al. / Tetrahedron: Asymmetry 15 (2004) 2181–2184
Table 1. Ligand comparison in asymmetric hydrogenation of an
electron-rich substrate 4a with in situ Rh complexesa
mobility of ligands on the reactivities and enantioselec-
tivities based on the results of Rh-catalyzed asymmetric
hydrogenation of MOM-protected b-hydroxyl ena-
mides. Some preliminary results of Ir-catalyzed hydro-
genation of a cyclic imine substrate with this type of
ligands are reported as well.
OMOM
NHAc
OMOM
NHAc
[Rh(NBD)2]SbF6/L*, 1 mol%,
MeOH, H2 (10 bar), 25 oC, 12 h
4a
(S)-5a
Lꢀ
Conversion (%)
Ee (%)b
2. Results and discussion
Entry
1
2
3
2
6
7
0
100
100
––
In general, increasing the conformational flexibility of
ligand should enhance the reactivity of the metal cata-
lyst. Ligand 2 was less reactive than 3 in Rh-catalyzed
hydrogenation probably due to the two methyl groups
at the a-position to the diphenylphosphine groups,
which rigidified the seven membered metal–ligand che-
late ring. One way to reduce the rigidity of this chelate
ring is opening the five membered ketal ring on the
backbone. The resulting ligands should be able to form
reactive metal complexes easily. Thus, we envisioned
that ligand 6 and 7 should form more reactive Rh cat-
alysts than 2. The syntheses of 6 and 7 are outlined in
Scheme 1. Ligand 6 was prepared directly from the
hydrolysis of DIOP*6 with methanesulfonic acid, while
ligand 7 was synthesized from the known epoxide 87 via
reduction, mesylation, and phosphination.
80.2
84.6
a The reactions were carried out at rt under 10 bar of H2 for 12 h. The
catalyst was prepared in situ by mixing [Rh(NBD)2]SbF6 (1 mol %)
and ligand (1.1 mol %) in MeOH.
b The enantiomeric excesses were determined by chiral HPLC using a
(S,S)-Whelk-01 column. The (S)-configurations of the products were
determined by comparing the retention times of two enantiomers with
reported data.
verify if this principle applied to DIOP* and enhance
catalyst,
the
reactivity
of
its
Rh
pure
[Rh(DIOP*)(NBD)]SbF6 10 was isolated and used as a
catalyst precursor. It was found that complex 10 pro-
vided the best catalytic system of this ligand family for
the hydrogenation of 4a, affording 5a quantitatively
with 98.1% ee under very mild conditions within 1 h
(entry 1 in Table 2). Such a dramatic increase in reac-
tivity was apparently due to the isolation of pure Rh-
DIOP* complex 10. It is noteworthy that DIOP* pro-
vided higher enantioselectivity (98.1% ee) than ligand 6
and 7 (80.2% ee and 84.6% ee, respectively) in this
reaction, which is actually quite reasonable. The con-
formational rigidity of a chiral ligand is an important
factor governing not only the reactivity, but also the
enantioselectivity in asymmetric catalysis.9 Bidentate
chiral ligands with a more rigid backbone between the
two coordinating sites can form a more rigid metalo-
cycle with fewer available conformations, and thus en-
hance the enantioface differentiation leading to chiral
product with higher ee value. Although the Rh-DIOP*
complex is less reactive than Rh complexes with 6 and 7,
it should be more enantioselective due to its more rigid
backbone. Ligand 7 was slightly more enantioselective
than 6, which was in consistence with the trend of their
In order to verify our hypothesis, substrate 4a was
hydrogenated with Rh-complexes formed in situ with
ligand 2 (DIOP*), 6, and 7, respectively, under the same
reaction conditions. As we expected, while DIOP*
showed no reactivity for this transformation (entry 1 in
Table 1), both 6 and 7 provided full conversions of 4a to
5a with good enantioselectivities (entries 2 and 3 in
Table 1). These results strongly supported our hypoth-
esis that the conformational mobility of a ligand plays a
significant role in governing the catalytic activity of its
transition-metal complex. More flexible metal–ligand
chelates, such as in Rh-6 and Rh-7, provided higher
reactivities than less flexible chelates, such as in Rh-2.
On the other hand, it was shown for different types of
ligands that the isolated pure Rh-ligand complex per-
formed with higher reactivity than the Rh complex
generated in situ due to the existence of small amounts
of less reactive metal species in the latter.8 In order to
HO
HO
O
O
i
PPh2
PPh2
PPh2
PPh2
85%
2 DIOP*
6
O
O
BnO
BnO
BnO
BnO
BnO
BnO
ii
84%
OMs
OMs
iii
PPh2
PPh2
30%
8
7
9
Scheme 1. Reagents and conditions: (i) MeOH, H2O, MeSO3H, refluxing; (ii) (a) LiHB(Et)3, THF, 0 °C–rt; (b) MsCl, Et3N, CH2Cl2, 0 °C;
(iii) LiPPh2, THF, )78 °C–rt.

D. Liuet al. / Tetrahedron: Asymmetry 15 (2004) 2181–2184
2183
Table 2. Asymmetric hydrogenation of MOM-protected b-hydroxyl
enamides with [Rh(DIOP*)(NBD)]SbF6 (10) as a catalyst precursor
Table 3. Ir-catalyzed asymmetric hydrogenation of a cyclic imine with
DIOP derivatives as ligandsa
OMOM
NHAc
OMOM
NHAc
[Ir(COD)Cl]2/ L*, I2
1 mol% of 10,
solvent, 1000 psi H2, 1 d
N
N
11
H
MeOH, H2 (15psi), 25 oC, 1h
12
Conversion
(%)
R
R
4
(S)-5
Entry
Lꢀ
Solvent
Temp.
(°C)
Ee
(%)b
Entry
Substrate
Conversion
(%)
Ee
(%)a
1
2
3
4
5
6
7c
8
9
2
2
2
6
7
7
7
7
7
MeOH
Toluene
CH2Cl2
CH2Cl2
MeOH
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
25
25
25
0
20.0
95.4
90.9
31.0
13.0
39.3
96.6
96.4
98.4
6.0
20.0
29.3
11.0
6.4
1
2
4a R ¼ H
100
100
100
100
100
100
100
98.1
4b R ¼ o,p-2F
4c R ¼ p-F
4d R ¼ p-Cl
4e R ¼ CH3
4f R ¼ Ph
95.8
99.4
95.7
99.1
99.6
97.7
3
4
5
6
7
77.8
85.0
81.6
41.1
4g R ¼ OMe
25
60
4h
= 2-Naphthyl
8
100
>99.9
a The reactions were carried out at the indicated temperature under
1000 psi of H2 for 1 d. The catalyst was prepared in situ by mixing
[Ir(COD)Cl]2 (0.5 mol %) and ligand (1.1 mol %) in solvent followed
by addition of I2 (10 mol %).
b The enantiomeric excesses were determined by chiral GC using a
chiral select 1000 column.
c The reaction time was 3 d.
R
a The enantiomeric excesses were determined by chiral HPLC using an
(S,S)-Whelk-01 column. The (S)-configurations of the products were
determined by comparing the retention times of two enantiomers with
reported data.
backbone rigidities. All these results clearly indicate that
conformational analysis of the backbone rigidity could
be an effective tool for designing good ligands in terms
of both reactivity and enantioselectivity.
3. Conclusion
In conclusion, several DIOP derivatives16 have been
developed as efficient ligands for Rh and Ir-catalyzed
asymmetric hydrogenations. The results of the Rh-cat-
alyzed hydrogenation of MOM-protected b-hydroxyl
enamides strongly support our conformational analysis
about the influence of the ligand backbone flexibility on
the reactivities and enantioselectivities. Isolation of the
pure catalyst precursor is also necessary to provide the
most active catalytic species.
Chiral amino alcohols have been widely used as phar-
maceutical components,10 chiral ligands11 and auxilia-
ries.12 Although many synthetic methods have been
well-documented,13 developing new and practical cata-
lysts for the preparation of such important chiral
building blocks via simple asymmetric hydrogenation of
4 to 5 is still attractive. To further demonstrate its
generality in high reactivity and enantioselectivity for
this potentially useful transformation, Rh-DIOP* com-
plex 10 was used to catalyze the hydrogenation of a
series of MOM-protected b-hydroxyl enamides 4a–h
under very mild conditions. As shown in Table 2, all
the reactions went to completion within 1 h with
the enantioselectivities being excellent for all the
substrates with different substituents on the phenyl ring
(100% conversion, 96%–99% ee), providing a very
selective and efficient catalytic system for the synthesis
of nearly enantiomerically pure amino alcohol
derivatives.
Acknowledgements
This work was supported by NIH. We gratefully
acknowledge the generous loan of precious metals from
Johnson Matthey Inc.
References and notes
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effective for the Ir-catalyzed hydrogenation of imi-
nes.2d;14 DIOP was among the earliest ligands explored
for imine reduction, although only moderate ee values
were obtained.15 Thus, we were also interested in
investigating imine reduction with those DIOP deriva-
tives for comparison. Some of the preliminary results of
Ir-catalyzed hydrogenation of a cyclic imine 11 with
ligands 2, 6, and 7 are summarized in Table 3. With Ir-7
complex generated in situ as a catalyst and 10 mol % I2
as an additive, 85% ee was obtained at 0 °C in CH2Cl2
(entry 7 in Table 3), which is better than those previ-
ously reported with DIOP.15
2. For recent reviews, see: (a) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; Wiley-Interscience: New
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Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
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Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907; (f) Cao, P.; 13. Bergmeier, S. C. Tetrahedron 2000, 56, 2561, and refer-
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4. (a) Li, W.; Zhang, X. J. Org. Chem. 2000, 65, 5871; (b)
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independently, see: Yan, Y.-Y.; RajanBabu, T. V. J. Org.
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Org. Lett. 2000, 2, 199; (d) Yan, Y.-Y.; RajanBabu, T. V.
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3,4-Dihydroxy-2,5-bis(diphenylphosphanyl)hexane 6:
20
D
½aŠ ¼)15.2 (c 0.40, CHCl3); 1H NMR (CD2Cl2,
360 MHz) d 7.58–7.55 (m, 8H), 7.39–7.34 (m, 12H),
3.60–3.54 (m, 2H), 2.61–2.54 (m, 2H), 2.47 (br s, 2H),
0.84 (d, J ¼ 7:0 Hz, 3H), 0.80 (d, J ¼ 7:0 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) d 137.1 (dd, J ¼ 14; 7 Hz,
J ¼ 51:7 Hz), 134.3 (dd, J ¼ 8:0 Hz, J ¼ 20:4 Hz), 129.7
(d, J ¼ 28:2 Hz), 129.0 (dd, J ¼ 7:2 Hz, J ¼ 11:7 Hz), 72.3
(dd, J ¼ 7:1 Hz, J ¼ 11:4 Hz), 33.9 (d, J ¼ 11:4 Hz), 10.3
(d, J ¼ 17:4 Hz); 31P NMR (CDCl3, 145 MHz) d )7.68;
HRMS (Mþ+1) m=z calcd for C30H33O2P2 487.1950,
found 487.1916.
6. For the synthesis of DIOP* 2, see Ref. 4.
7. Merrer, Y. L.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.;
Geoffroy, S.; Foglietti, M.-J. Bioorg. Med. Chem. 1997, 5,
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C.; Heller, D. J. Organomet. Chem. 2001, 621, 89.
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3,4-O-Dibenzyl-3,4-dihydroxy-2,5-bis(diphenylphosphan-
20
D
yl)hexane 7: ½aŠ ¼ +74.6 (c 0.50, CHCl3); 1H NM R
(CDCl3, 360 MHz) d 7.48–7.07 (m, 30H), 4.54 (s, 4H),
3.49–3.43 (m, 2H), 2.44–2.37 (m, 2H), 0.89–0.83 (m, 6H);
13C NMR (CDCl3, 90 MHz)
d
138.1, 136.4 (d,
J ¼ 16:0 Hz), 136.0 (d, J ¼ 15:8 Hz), 133.5–132.4 (m),
128.3–126.8 (m), 79.0 (t, J ¼ 9:3 Hz), 74.0 (d, J ¼ 4:0 Hz),
33.4 (d, J ¼ 11:6 Hz), 9.52 (d, J ¼ 17:9 Hz); 31P NM R
(CDCl3, 145 MHz) d )8.24; HRMS (Mþ+1) m=z calcd for
C44H45O2P2 667.2889, found 667.2858.
[Rh(DIOP*)(NBD)]SbF6 10: 1H NMR (CDCl3, 360 MHz)
d 8.04–7.99 (m, 4H), 7.64–7.56 (m, 6H), 7.41–7.40 (m, 6H),
7.01–7.00 (m, 4H), 4.49 (br s, 2H), 4.15 (br s, 2H), 4.06 (m,
2H), 3.77 (br s, 2H), 2.60–2.57 (m, 2H), 1.39 (s, 2H), 1.20
(s, 6H), 1.10–1.04 (m, 6H); 31P NMR (CDCl3, 145 MHz) d
32.89 (d, J ¼ 152:1 Hz 6H); 31P NMR (CDCl3, 145 MHz)
d 32.89 (d, J ¼ 152:1 Hz).