Design and synthesis of a novel three-hindered quadrant bisphosphine ligand and its application in asymmetric hydrogenation

Article abstract of DOI:10.1039/c0cc02620d

A novel three hindered quadrant bisphosphine ligand has been synthesized. The ligand shows excellent enantioselectivities and reactivities for rhodium-catalyzed hydrogenations of various functionalized olefins.

Full text of DOI:10.1039/c0cc02620d

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Design and synthesis of a novel three-hindered quadrant bisphosphine
ligand and its application in asymmetric hydrogenationw
Kexuan Huang,a Xiaowei Zhang,ab Thomas J. Emge,a Guohua Hou,a Bonan Caoa and
Xumu Zhang*a
Received 16th July 2010, Accepted 17th August 2010
DOI: 10.1039/c0cc02620d
A novel three hindered quadrant bisphosphine ligand has been
synthesized. The ligand shows excellent enantioselectivities and
reactivities for rhodium-catalyzed hydrogenations of various
functionalized olefins.
acid. We predicted that the chiral cyclohexane structure of the
ligand would facilitate the ortho-lithiation step to afford one
single stereoisomer so that a preparative HPLC purification
would not be necessary for the ligand synthesis. The
application of the ligand in rhodium-catalyzed asymmetric
hydrogenation will also be described in this communication.
Over recent decades, tremendous effort has been devoted to
the design and synthesis of chiral phosphorus ligands that can
provide high enantioselectivities and high reactivities in
transition-metal-mediated
asymmetric
hydrogenation.1
Although the substrate scope of asymmetric hydrogenation
has been largely broadened and excellent enantioselectivities
have been obtained by using historically successful ligands
such as DIPAMP,2 BINAP3 and Duphos,4 the search for
novel and unique chiral phosphine ligands still remains an
important goal because of the increasingly demand for efficient
catalysts by the pharmaceutical industry.5 As a result of
the huge success of ligands such as DIPAMP and BINAP,
C2-symmetry has remained a popular design for chiral
bisphosphine ligands. On the other hand, the development of
C1-symmetrical bisphosphine ligands and their corresponding
hydrogenation catalysts has been delayed to some extent.6
Recently, Hoge reported the synthesis of a bisphosphine
ligand 1(trichickenfootphos) with a three hindered quadrant
diagram feature.7 The corresponding rhodium complex
showed good enantioselectivity and activity towards a variety
of prochiral alkenes in asymmetric hydrogenation. However,
the ligand synthesis relies on HPLC chiral separation, which
could limit its large scale production and application in
industry.
The synthesis of ligand 8 started from the reduction of
commercially available (1S,2S)-1,2-cyclohexanedicarboxylic
acid 3 to give enantiopure chiral diol 4 (Scheme 1). Cyclic
sulfate 5 was formed in high yield according to the literature
procedure.11 Treatment of 5 with tert-butylphosphane in the
presence of nBuLi, followed by in situ oxidation with sulfur
powder, provided enantiomerically pure phosphane sulfide 6 in
excellent yield.12 Subsequent ortho-lithiation with tBuLi/TMEDA
at ꢀ78 1C in HMPA/THF, followed by phosphinylation with
di(tert-butyl)chlorophosphine provided 7 as a single diastereomer.
The stereospecific phosphinylation was due to the induction of
the chiral cyclohexane ring structure. The di-tert-butyl
phosphine group is stable to air in this case. The absolute
configuration of 7 was confirmed by its X-ray crystallographic
structure (Fig. 1).z Desulfurization of 7 with hexachlorodisilane13
in toluene provided ligand 8 in 91% yield.
In order to examine the catalytic properties of 8, a cationic
Rh complex Rh[(8)(nbd)]BF4 (nbd = norbornadiene) was
prepared and used as the catalyst precursor in the hydrogenation
of various prochiral alkenes. a-(Acylamino)acrylic acids and
esters were hydrogenated at rt in methanol under 50 psi of
hydrogen (Table 1).
Our group has been dedicated to the design and synthesis of
P-chiral bisphosphine ligands with a rigid electron-rich
phosphocyclic motif, such as TangPhos8 and DuanPhos.9
The five-membered phospholane rings restrict the conformational
flexibililty, which can lead to better enantioselectivity in
asymmetric reaction. We think that three-blocked quadrant
bisphosphorus ligands based on the P-chiral phosphocyclic
motif could also be a good C1-symmetric design.10 Herein, we
report the synthesis of a new rigid three-quadrant-hindered
bisphosphine ligand starting from 1,2-cyclohexanedicarboxylic
a Department of Chemistry and Chemical Biology & Department of
Pharmaceutical Chemistry, Rutgers, The State University of New
Jersey, Piscataway, NJ 08854, USA. E-mail: xumu@rci.rutgers.edu;
Fax: +1 732 445 6312; Tel: +1 732 445 1454
b Department of Chemistry, The Pennsylvania State University,
University Park, PA 16802, USA
Scheme 1 Synthesis of ligand 8. Reagents and conditions: (a) LiAlH4,
98%; (b) i. SOCl2, NEt3, ii. RuCl3ꢁXH2O, NaIO4, 88%; (c) tBuPH2,
nBuLi, S, 81%; (d) tBuLi, TMEDA, tBu2PCl, 52%, (e) Si2Cl6, toluene,
91%.
w Electronic
supplementary
information
(ESI)
available:
Characterization data for new compounds. CCDC 784696. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc02620d
c
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Chem. Commun., 2010, 46, 8555–8557 8555

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Table 2 Rh-catalyzed asymmetric hydrogenation of b-(acetylamino)-
acrylates and itaconic acid derivativesa
Entry Substrate R1, R2 (geometry)
eeb [%] Config
1
2
3
4
5
6
Me, Me ((E)-11a)
Me, Me((Z)-11a)
Me, Et((Z)-11b)
Ph, Me((E/Z)-11c)
4-F-Ph, Me((E/Z)-11d)
98
97
97
95
94
S
S
S
R
R
R
4-Me-Ph, Me ((E/Z)-11e) 94
H, H (12a)
97
98
98
R
R
R
7
8
Me, H (12b)
Me, Me (12c)
9
a
The reactions were carried out at rt under 50 psi H2 in MeOH for
12 h in the presence of 0.2 mol% Rh[(8)(nbd)]BF4 as the catalyst
precursor. Conversions were 100%. For the E/Z ratio of 11c–e, see
b
ref. 14. The ee values were determined by chiral GC (betadex-390 or
Fig. 1 ORTEP view (50% probability thermal ellipsoids) of 7.
Hydrogen atoms have been omitted for clarity.
gamadex-225). The absolute configurations of the products were
determined by comparison of their retention times of two enantiomers
with reported data.
Excellent enantioselectivities and full conversion were
achieved for an array of a-acetamidocinnamic acids and their
esters with different substitutedgroups (entry 5–13). To further
test the catalytic reactivity of Rh-8, methyl a-(acetamido)-2-
phenylacrylate (9a) was hydrogenated with 0.02 mol% complex
Rh-8 under the same reaction conditions without compromising
the enantioselectivity (entry 3). High turnover (10 000 TON)
was also achieved with an excellent ee (98%) for the same
substrate (entry 4). Moreover, the hydrogenation of 9a
proceeded to completion within 30 min at a S/C ratio of
500 under the same reaction conditions (entry 1).
obtain unnatural enantiomerically enriched b-amino acids.
But it still remains much less successful compared to the
hydrogenation of their a-analogues.15 The hydrogenation with
Rh-8 complex was carried out at rt in methanol for 12 h under
50 psi of hydrogen with a 0.2 mol% catalyst loading.
High enantioselectivities (97–98% ee) were achieved for both (Z)
and (E)-methyl b-(acetylamino)acrylates (Table 2, entry 1–2).
An E/Z mixture of b-phenyl-b-(acylamino)acrylate substrate
was also hydrogenated with the Rh-8 catalyst to provide the
chiral b-amino acid derivative in 95% ee (entry 4). Itaconic
acid and its methyl esters were also hydrogenated under the
same reaction conditions to afford excellent ee values (up to
98%, entry 7–9).
Asymmetric hydrogenation of b-(acetamido)acrylate
derivatives is one of the most efficient and practical ways to
Table 1 Rh-catalyzed asymmetric hydrogenation of a-(acylamino)-
acrylic acids and estersa
In conclusion, we have designed and synthesized a new rigid
three hindered quadrant bisphosphine ligand based on the
phosphocyclic motif. Ligand 8 is proved to be a practical
ligand for the Rh-catalyzed asymmetric hydrogenation of
various functionalized olefins, with high enantioselectivities
(up to 99% ee) and reactivities (up to 10 000 TON). Further
studies to explore its applications in other metal-catalyzed
asymmetric catalytic reactions will be reported in due course.
We thank Dr Tom Emge for crystallographic analysis. This
work was supported by the National Institutes of Health
(GM58832) and National Center for Research Resources
(NCRR, No. 1S10RR023698-01A1).
Entry
R1, R2
S/C ratio
t/h
ee [%]b
1
2
3
4
5
6
7
8
Ph, Me (9a)
Ph, Me (9a)
Ph, Me (9a)
Ph, Me (9a)
Ph, H (9b)
4-F-Ph, Me (9c)
4-Cl-Ph, Me (9d)
4-Br-Ph, Me (9e)
4-MeO-Ph, Me (9f)
3-Br-Ph, H (9g)
3-Br-Ph, Me (9h)
3,5-F2-Ph, Me (9i)
2-Cl-Ph, Me (9j)
2-Thienyl, Me (9k)
H, H (9l)
500
0.5
12
12
24
12
12
12
12
12
12
12
12
12
12
12
12
>99
>99
99
1000
5000
10 000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
98
>99
>99
>99
>99
>99
>99
>99
>99
99
9
10
11
12
13
14
15
16
Notes and references
z The compound 7 (C21H41Cl3P2S) crystallizes in the orthorhombic
space group P212121 with a = 8.4109(5) A, b = 15.8263(10) A,
c = 39.840(3) A, V = 5303.3(6) A3, Z = 8, d(calcd) = 1.237 g cmꢀ3
and m(Mo Ka) = 0.551 mmꢀ1. A Bruker Smart APEX CCD
diffractometer with graphite monochromatized Mo Ka radiation
(l = 0.71073 A) was used to collect 58 982 reflections (16 069 unique)
in the range 2.74 to 30.541 at 100(2) K giving final residual values of
Rf 0.0651 (all data) and Rf 0.0593 ([I > 2s(I)]).
>99
>99
99
n-Pr, Me (9m)
a
The reactions were carried out at rt under 50 psi H2 in MeOH.
b
Conversions were 100%. The ee values were determined by chiral
GC (Chiralsil-VAL III FSOT). The ee values of the acids were
determined on the corresponding methyl ester by treatment with
TMSCHN2. The absolute configurations of the products were determined
as S by comparison of their retention times of two enantiomers with
reported data.
1 (a) W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029;
(b) T. C. Clark and C. R. Landis, Tetrahedron: Asymmetry,
2004, 15, 2123.
2 (a) W. S. Knowles, Acc. Chem. Res., 1983, 16, 106;
(b) W. S. Knowles, Angew. Chem., Int. Ed., 2002, 41, 1998.
c
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3 (a) A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito,
T. Souchi and R. Noyori, J. Am. Chem. Soc., 1980, 102, 7932;
(b) R. Noyori, Chem. Soc. Rev., 1989, 18, 187; (c) R. Noyori,
Science, 1990, 248, 1194; (d) R. Noyori and H. Takaya, Acc. Chem.
Res., 1990, 23, 345.
4 (a) W. A. Nugent, T. V. RajanBabu and M. Burk, Science, 1993,
259, 479; (b) M. Burk, Acc. Chem. Res., 2000, 33, 363.
5 (a) I. Ojima, Catalytic Asymmetric Synthesis, Wiley-VCH,
New York, 2000, pp. 1–110; (b) E. N. Jacobsen, A. Pfaltz and
H. Yamamoto, Comprehensive Asymmetric Catalysis, Springer,
Berlin, New York, 1999, vol. I, pp. 121–182.
6 (a) H. Blaser, W. Brieden, B. Pugin, F. Spindler, M. Studer and
A. Togni, Top. Catal., 2002, 19, 3; (b) K. Matsumura, H. Shimizu,
T. Saito and H. Kumobayashi, Adv. Synth. Catal., 2003, 345, 180;
(c) A. Ohashi, S. Kikuchi, M. Yasutake and T. Imamoto, Eur. J.
Org. Chem., 2002, 2535.
7 (a) G. Hoge, H. -P. Wu, W. S. Kissel, D. A. Pflum, D. J. Greene
and J. Bao, J. Am. Chem. Soc., 2004, 126, 5966; (b) H.-P. Wu and
G. Hoge, Org. Lett., 2004, 6, 3645; (c) D. Gridnev, T. Imamato,
G. Hoge, M. Kouchi and H. Takahashi, J. Am. Chem. Soc., 2008,
130, 2560.
8 For applications of TangPhos in asymmetric hydrogenation, see:
(a) W. Tang and X. Zhang, Angew. Chem., Int. Ed., 2002, 41, 1612;
(b) W. Tang and X. Zhang, Org. Lett., 2002, 4, 4159; (c) W. Tang,
D. Liu and X. Zhang, Org. Lett., 2003, 5, 205; (d) Q. Dai, W. Yang
and X. Zhang, Org. Lett., 2005, 7, 5343; (e) Q. Yang, W. Gao,
J. Deng and X. Zhang, Tetrahedron Lett., 2006, 47, 821;
(f) C. Wang, H. Tao and X. Zhang, Tetrahedron Lett., 2006, 47,
1901; (g) Q. Yang, G. Shang, W. Gao, J. Deng and X. Zhang,
Angew. Chem., Int. Ed., 2006, 45, 3832; (h) G. Shang, Q. Yang and
X. Zhang, Angew. Chem., Int. Ed., 2006, 45, 6360; (i) J. Chen,
Q. Liu, W. Zhang, S. Spinella, A. Lei and X. Zhang, Org. Lett.,
2008, 10, 3033; (j) J. Chen, W. Zhang, H. Geng, W. Li, G. Hou,
A. Lei and X. Zhang, Angew. Chem., Int. Ed., 2009, 48, 800. For
applications of TangPhos in other asymmetric catalysis, see:
(k) M. P. Watson and E. N. Jacobsen, J. Am. Chem. Soc., 2008,
130, 12594; (l) A. S. Tsai, R. M. Wilson, H. Harada,
R. G. Bergman and J. A. Ellman, Chem. Commun., 2009, 3910;
(m) D. Noh, H. Chea, J. Ju and J. Yun, Angew. Chem., Int. Ed.,
2009, 48, 6062; (n) J. Sun and G. C. Fu, J. Am. Chem. Soc., 2010,
132, 4568.
9 For applications of DuanPhos in asymmetric hydrogenation, see:
(a) D. Liu and X. Zhang, Eur. J. Org. Chem., 2005, 646; (b) D. Liu,
W. Gao and C. Wang andX. Zhang, Angew. Chem., Int. Ed., 2005,
44, 1687; (c) X. Sun, L. Zhou, C. Wang and X. Zhang,
Angew. Chem., Int. Ed., 2007, 46, 2623; (d) H. Geng, W. Zhang,
J. Chen, G. Hou, L. Zhou, Y. Zou, W. Wu and X. Zhang,
Angew. Chem., Int. Ed., 2009, 48, 6052; (e) W. Li, G. Hou,
M. Chang and X. Zhang, Adv. Synth. Catal., 2009, 351, 3123.
For applications of DuanPhos in other asymmetric catalysis, see:
(f) J. L. Zigterman, J. C. S. Woo, S. D. Walker, J. S. Tedrow,
C. J. Borths, E. E. Bunel and M. M. Faul, J. Org. Chem., 2007, 72,
8870; (g) D. H. Phan, B. Kim and V. M. Dong, J. Am. Chem. Soc.,
2009, 131, 15608.
10 For recent examples of C1-symmetric ligand design, see: (a) Q. Dai,
W. Li and X. Zhang, Tetrahedron, 2008, 64, 6943; (b) W. Tang,
A. G. Capacci, A. White, S. Ma, S. Rodriguez, B. Qu, J. Savoie,
N. D. Patel, X. Wei, N. Haddad, N. Grinberg, N. K. Yee,
D. Krishnamurthy and C. H. Senanayake, Org. Lett., 2010, 12, 1104.
11 (a) Y. Gao and K. B. Sharpless, J. Am. Chem. Soc., 1988, 110,
7538; (b) B. M. Kim and K. B. Sharpless, Tetrahedron Lett., 1989,
30, 655.
12 X. Zhang, K. Huang, G. Hou, B. Cao and X. Zhang,
Angew. Chem., Int. Ed., 2010, DOI: 10.1002/anie.201002990.
13 G. Zon, K. E. DeBruin, K. Naumann and K. Mislow, J. Am.
Chem. Soc., 1969, 91, 7023.
14 G. Zhu, Z. Chen and X. Zhang, J. Org. Chem., 1999, 64, 6907.
15 H.-J. Drexler, J. You, S. Zhang, C. Fischer, W. Baumann,
A. Spannenberg and D. Heller, Org. Process Res. Dev., 2003, 7,
355.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8555–8557 8557