Axially chiral electron-rich TunePhos-type ligand: synthesis and applications in asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2009.07.007

A new electron-rich TunePhos type ligand has been synthesized; excellent enantioselectivities (up to 99% ee) have been achieved in Rh-catalyzed asymmetric hydrogenation of α-dehydroamino acid methyl esters and dimethyl itaconate.

Full text of DOI:10.1016/j.tetlet.2009.07.007

Tetrahedron Letters 50 (2009) 5777–5779
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Axially chiral electron-rich TunePhos-type ligand: synthesis and applications
in asymmetric hydrogenation
Yaping Zou a, Huiling Geng b, Weicheng Zhang a, Shichao Yu a, Xumu Zhang a,
*
a Department of Chemistry and Department of Pharmaceutical Chemistry Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020 USA
b College of Science, Northwest Agriculture & Forestry University, Yangling, Shaanxi 712100, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new electron-rich TunePhos type ligand has been synthesized; excellent enantioselectivities (up to 99%
Received 6 June 2009
Accepted 2 July 2009
Available online 8 July 2009
ee) have been achieved in Rh-catalyzed asymmetric hydrogenation of
esters and dimethyl itaconate.
a-dehydroamino acid methyl
Ó 2009 Published by Elsevier Ltd.
Atropisomeric biaryl ligands are among the most valuable chiral
ligands for transition metal-catalyzed asymmetric hydrogenation.1
The prototypical ligand is BINAP 1, which was developed by Takaya
and Noyori in 1980.2 Pioneering studies on 1 by Noyori and co-
workers have led to highly efficient practical asymmetric hydroge-
nation of a diverse set of ketones, including both functionalized
and unfunctionalized (simple) ketones.3 The success of 1 also in-
spired the further development of other axially chiral biaryl type
bisphosphine ligands, such as MeO-BIPHEP 2,4 SegPhos 3,5 SynPhos
4,6 and DifluorPhos 5 (Fig. 1).7 To investigate the effect of bite angle
on enantioselectivity for biaryl ligands, we have introduced Cn-
TunePhos 6 with a tunable linking bridge.8 By systematically
changing the length of the bridge, the bite angle of 6 can be opti-
mized for the hydrogenation of different substrates. Recently,
improvement of the synthesis of TunePhos type ligands was
achieved by us9a,b as well as by Chan’s group10 in that a key step
of central-to-axial chirality transfer is devised to circumvent the
tedious resolution step involved in the original synthesis. Thus, a
Recently, an insightful method for ligand optimization was
proposed by Saito and co-workers: combined computational and
experimental studies indicated that dialkyl aryl bisphosphine 9
(R = Cy or iPr) is the ligand of choice for asymmetric hydrogenation
of
we further explored electron-rich biaryl ligand 10 for asymmetric
hydrogenation. Herein, we report the synthesis of new
a
-acetamidocinnamate.12 Inspired by these interesting results,
a
electron-rich TunePhos-type ligand and its application in highly
enantioselective Rh-catalyzed asymmetric hydrogenation of
a
-dehydroamino acid methyl esters and dimethyl itaconate (up
to 99% ee).
The synthesis of the target ligand 10 is depicted in Scheme
1.13,14 Starting from 3-bromophenol 11, protection of the hydroxyl
group afforded the carbamate 12. Regioselective ortho lithiation
followed by oxidative coupling with FeCl3 led to the formation of
the biaryl backbone of 13 in 56% yield. The labile carbamate groups
were then removed under basic condition to form the di-bromo
substituted biphenol 14, which was further subjected to Mitsun-
obu reaction condition (PPh3, DIAD, sonication) in the presence
of a chiral 2,4-diol. In this step, two diastereomers with opposite
axial chiralities were obtained, from which the desired precursor
15 was obtained through purification by column chromatography
in 22% yield. Finally, 15 was treated with nBuLi at low temperature
for Li-Br exchange; subsequent quenching with Cy2PCl afforded the
ligand 10 in moderate yield.13
*
broad series of C3 -TunePhos ligands 7 bearing different aryl sub-
stituents on the phosphine donors can be prepared by a highly
modular approach. Compared with 6c (n = 3), 7 shows enhanced
enantioselectivities toward allylphthalimides and
a
-keto esters.9b
In addition, a Ru/7 (Ar = Xylyl)/diamine catalytic system has dem-
onstrated extremely high reactivity and enantioselectivity toward
a variety of simple ketones.9c
While most biaryl ligands bearing triaryl phosphine donors
have been developed for Ru-catalyzed hydrogenation reactions,1e
some electron-rich dialkylaryl phosphine ligands (Fig. 2) have
shown potential application in Rh-catalyzed asymmetric hydroge-
nation. For example, BICHEP 8 gave much better results in the
With the new ligand 10 in hand, Rh-catalyzed asymmetric
hydrogenation was tested with the benchmark substrate methyl-
2-acetamido acrylate 16a. Solvent screening showed that the best
ees were obtained in polar solvents such as THF, ethyl acetate,
acetone, and methanol (Table 1, entries 3–6); in contrast, lower
selectivities were observed in 2,2,2-trifluoroethanol (TFE) and
weakly coordinating solvents CH2Cl2 and toluene (entries 1, 2,
and 7). Thus, methanol was selected for the following hydrogena-
tion reactions. As shown in Table 1, excellent enantioselectivities,
up to 99% ee, have been achieved in Rh-catalyzed hydrogenation
hydrogenation of ethyl (Z)-a-(benzamido)cinnamate and dimethyl
itaconate than the corresponding bis(triarylphosphine) ligand.11
* Corresponding author.
E-mail address: xumu@rci.rutgers.edu (X. Zhang).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.07.007

5778
Y. Zou et al. / Tetrahedron Letters 50 (2009) 5777–5779
O
O
O
O
PPh2
PPh2
O
O
PPh2
PPh2
PPh2
PPh2
MeO
MeO
PPh2
PPh2
O
O
BINAP 1
SynPhos 4
MeO-BIPHEP 2
SegPhos 3
O
F
F
O
(CH2)n
O
O
PPh2
PPh2
PPh2
PPh2
O
O
PAr2
PAr2
O
F
F
O
C3*-TunePhos 7
DifluorPhos 5
Cn-TunePhos 6a-6f
(n = 1-6)
Figure 1. Typical axially chiral bisphosphine ligands for asymmetric hydrogenation.
Table 1
Asymmetric hydrogenation of methyl-2-acetamido acrylate with Rh/10 catalysta
O
O
O
O
COOMe
COOMe
NHAc
Rh(COD)2BF4/10
H3C
H3C
PCy2
PCy2
PR2
PR2
*
H2 (1 bar), solvent
R
NHAc
R
16
17
Rh(COD)2BF /10
4
BICHEP 8
R-SegPhos 9 (R = Cy, iPr)
COOMe
*
19
COOMe
MeOOC
MeOOC
H2 (1 bar), THF
18
Figure 2. Electron-rich dialkylaryl bisphosphines for asymmetric hydrogenation.
Entry
Substrate
R
Solvent
ee (%)b
Configurationc
1
2
3
4
5
6
7
9
10
11
12
13
14
15d
16a
16a
16a
16a
16a
16a
16a
16c
16d
16e
16f
16g
16h
18
H
H
H
H
H
H
H
CH2Cl2
Toluene
THF
EtOAc
Acetone
MeOH
TFE
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
98
95
99
99
99
99
93
99
99
99
99
99
99
90
R
R
R
R
R
R
R
R
R
R
R
R
R
S
of a series of a-dehydroamino acid methyl esters. Substitution on
the aryl group of the substrates 16c–h has negligible effect on
enantioselectivity (entry 8 vs entries 9–14). Moreover, we found
that dimethyl itaconate 18 was also hydrogenated by Rh/10
catalyst with 90% ee in THF. These results are comparable to those
obtained by the use of other bis(dialkylarylphosphine) ligands such
as 8 and 9.
2-F–Ph
4-F–Ph
3,5-Difluoro-Ph
2-Br–Ph
4-Br–Ph
4-MeO–Ph
—
In conclusion, a new electron-rich TunePhos type ligand 10 has
been synthesized and successfully applied in Rh-catalyzed asym-
metric hydrogenation of
a-dehydroamino acid methyl esters and
dimethyl itaconate. The observed enantioselectivities (up to 99%
ee) are comparable to the results given by other bis(dialkylaryl-
phosphine) ligands. Further efforts are directed toward the expan-
sion of this synthetic strategy for the preparation of other axially
chiral ligands for asymmetric hydrogenation, as well as for other
asymmetric catalytic reactions.
a
The hydrogenation reactions were carried out with 1% Rh/10 catalyst at rt under
1 bar of H2 for 18 h. In all cases, full conversion was observed.
b
The ees were determined by chiral GC using a Chirasil-Val column.
The absolute configurations were determined by comparing the optical rota-
c
tions with the reported data.
d
The ee was determined by chiral GC using a
c
-dex 225 column.
O
a
89%
b
56%
c
91%
Et2N
Et2N
O
O
Br
Br
HO
HO
Br
Br
O
HO
Br
Et2N
O
Br
O
11
12
13
14
d
22%
O
O
Br
Br
e
57%
O
O
PCy2
PCy2
15
10
Scheme 1. Reagents and conditions: (a) (i) NaH, THF, rt; (ii) ClC(O)NEt2, rt; (b) (i) LDA, À78 °C; (ii) FeCl3, À78 °C; (c) NaOH, EtOH, reflux; (d) (2S, 4S)-pentane-2,4-diol, PPh3,
DIAD, THF, 0 °C, sonication; (e) (i) nBuLi, TMEDA, THF, À78 °C; (ii) Cy2PCl, À78 °C.

Y. Zou et al. / Tetrahedron Letters 50 (2009) 5777–5779
5779
9. (a) Zhang, X. U.S. Patent 6,521,769, 2003 (filed 1999); (b) Sun, X.; Zhou, L.; Li,
W.; Zhang, X. J. Org. Chem. 2008, 73, 1143; (c) Li, W.; Sun, X.; Zhou, L.; Hou, G.;
Yu, S.; Zhang, X. J. Org. Chem. 2009, 74, 1397; (d) Wang, C.-J.; Wang, C.-B.; Chen,
D.; Yang, G.; Wu, Z.; Zhang, X. Tetrahedron Lett. 2009, 50, 1038.
10. (a) Qiu, L.; Wu, J.; Chan, S.; Au-Yeung, T. T.-L.; Ji, J.-X.; Guo, R.; Pai, C.-C.; Zhou,
Z.; Li, X.; Fan, Q.-H.; Chan, A. S. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5815; (b)
Qiu, L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo, R.;
Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2006, 128, 5955.
Acknowledgments
Financial support by NIH (GM 58832) is greatly appreciated.
Mass spectrometry was provided by the Washington University
Mass Spectrometry Resource, an NIH Research Resource (Grant
P41RR0954).
11. Miyashita, A.; Karino, H.; Shimamura, J.-I.; Chiba, T.; Nagano, K.; Nohira, H.;
Takaya, H. Chem. Lett. 1989, 1849.
12. Shimizu, H.; Ishizaki, T.; Fujiwara, T.; Saito, T. Tetrahedron: Asymmetry 2004, 15,
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References and notes
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(b)Catalytic Asymmetric Synthesis; Ojima, I., Ed., 2nd ed.; Wiley-VCH:
Weinheim, 2000; (c)Comprehensive Asymmetric Catalysis I–III; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; (d) Tang, W.; Zhang, X.
Chem. Rev. 2003, 103, 3029; (e) Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron
2005, 61, 5405.
2. Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J.
Am. Chem. Soc. 1980, 102, 7932.
3. (a) Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 40; (b) Noyori, R. Angew. Chem.,
Int. Ed. 2002, 41, 2008.
4. Schmid, R.; Broger, E. A.; Cereghtti, M.; Crameri, Y.; Foricher, J.; Lalonde, M.;
Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure Appl. Chem. 1996, 68,
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5. Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumobayashi,
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(b) Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Genêt, J. P.; Champion, N.;
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13. Initial attempt to employ the method used for the preparation of 7 (Ref. 9b)
was found to be ineffective to synthesize the desired ligand 10.
14. Characterization data of 12–10: Compound 12: 1H NMR (500 MHz, CDCl3): d
7.30 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.15 (t, J = 8.5 Hz, 1H), 7.04 (d, J = 8.5 Hz,
1H), 3.36–3.33 (m, 4H), 1.18–1.14 (m, 6H). 13C NMR (126 MHz, CDCl3): d
153.71, 152.37, 130.44, 128.32, 125.43, 122.24, 120.87, 42.58, 42.19, 14.47,
13.56. Compound 13: 1H NMR (200 MHz, CDCl3) d 7.70 (dd, J = 8.1, 1.5 Hz, 2H),
7.65 (dd, J = 8.1, 1.5 Hz, 2H), 7.48 (t, J = 8.1 Hz, 2H), 3.40 (m, 4H), 3.18 (m, 4H),
1.26 (t, J = 7.1 Hz, 6H), 0.95 (t, J = 7.1 Hz, 6H); 13C NMR (50.3 MHz, CDCl3) d
151.74, 149.21, 130.28, 128.80, 127.65, 123.38, 121.06, 42.5, 42.2, 14.5, 13.4;
HRMS (M+H+) calcd for C22H27N2O4Br2: 541.0332, found: 541.0328. Compound
14: 1H NMR (500 MHz, CDCl3): d 7.33 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 8.0 Hz, 2H),
7.02 (d, J = 8.0 Hz, 2H), 5.13 (s, 2H). 13C NMR (126 MHz, CDCl3): d 155.09,
131.97, 125.48, 125.43, 122.92, 115.50; HRMS (M+H+) calcd for C12H9O2Br2:
342.8964, found: 342.8966. Compound 15: 1H NMR (400 MHz, CDCl3) d 7.41 (d,
J = 8.0 Hz, 2H), 7.25 (t, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.53 (m, 2H), 1.79
(m, 2H), 1.34 (d, J = 6.4 Hz, 6H); 13C NMR (100.6 MHz, CDCl3) d 158.56, 132.20,
130.16, 127.18, 125.03, 117.50, 76.68, 40.92, 22.44; HRMS (M+H+) calcd for
C17H17O2Br2: 410.9590, found: 410.9585. Compound 10: 1H NMR (400 MHz,
CDCl3) d 7.20 (d, J = 8.1 Hz, 2H), 7.05 (t, J = 8.1 Hz, 2H), 6.91 (d, J = 8.1 Hz, 2H),
4.40 (m, 2H), 2.00 (m, 2H), 1.73–0.82 (m, 50H); 13C NMR (100.6 MHz, CDCl3) d
157.93, 137.99, 137.41, 126.90, 126.13, 117.13, 74.75, 40.87, 35.83, 32.51,
30.97, 30.51, 29.81, 28.91, 28.16, 28.04, 27.58, 27.52, 27.27, 26.83. 31P
NMR(162 MHz, CDCl3): d À10.58 (s); HRMS (M+H+) calcd for C41H61O2P2:
647.4141, found: 647.4135.
8. (a) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem. 2000, 65, 6223; (b)
Wu, S.; Wang, W.; Tang, W.; Lin, M.; Zhang, X. Org. Lett. 2002, 4, 4495; (c) Tang,
W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570; (d) Lei, A.; Wu, S.; He,
M.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 1626; (e) Wang, C.-J.; Sun, X.; Zhang,
X. Angew. Chem., Int. Ed. 2005, 44, 4933; (f) Wang, C.-J.; Sun, X.; Zhang, X. Synlett
2006, 1169; For a summary of the bite angle effect on enantioselectivity, see:
Zhang, W.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278.