Novel and efficient chiral bisphosphorus ligands for rhodium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/ol1000999

(Figure Presented) A series of structurally novel, operationally convenient, and efficient chiral 2-phosphino-2,3-dihydrobenzo[d][1,3] oxaphosphole ligands was developed. Applications of ligands 3a and 3b in rhodium-catalyzed asymmetric hydrogenation of α-(acylamlno)acrylates andβ-(acylamino)acrylates provided excellent enantioselectivities (up to >99% ee) and reactivities (up to 10 000 TON).

Full text of DOI:10.1021/ol1000999

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1104-1107
Novel and Efficient Chiral Bisphosphorus
Ligands for Rhodium-Catalyzed
Asymmetric Hydrogenation
Wenjun Tang,*,† Andrew G. Capacci,† Andre White,‡ Shengli Ma,†
Sonia Rodriguez,† Bo Qu,† Jolaine Savoie,† Nitinchandra D. Patel,† Xudong Wei,†
Nizar Haddad,† Nelu Grinberg,† Nathan K. Yee,† Dhileepkumar Krishnamurthy,†
and Chris H. Senanayake†
Departments of Chemical DeVelopment and Medicinal Chemistry, Boehringer
Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877
wenjun.tang@boehringer-ingelheim.com
Received January 14, 2010
ABSTRACT
A series of structurally novel, operationally convenient, and efficient chiral 2-phosphino-2,3-dihydrobenzo[d][1,3]oxaphosphole ligands was
developed. Applications of ligands 3a and 3b in rhodium-catalyzed asymmetric hydrogenation of r-(acylamino)acrylates and ꢀ-(acylamino)acrylates
provided excellent enantioselectivities (up to >99% ee) and reactivities (up to 10 000 TON).
The design of structurally novel, operationally convenient,
and efficient chiral phosphorus ligands remains of great
importance for further development in the area of asymmetric
hydrogenation as well as in the search for new efficient
metal-catalyzed asymmetric reactions.1,2 Chiral 1,1-bisphos-
phorus ligands (Structure A, Figure 1) have recently gained
increased attention3 with the development of some notable
ligands such as MiniPhos4 and trichickenfootphos.5 However,
some of these ligands are still synthetically challenging and
current methods are either applied for only one enantiomer4
or require a preparative HPLC purification.5 Additionally,
Figure 1. (A) 1,1-Bisphosphorus ligand; (B) 1-oxy-1,1-bisphos-
phorus ligand; (3a-d) novel 2-phosphino-2,3-dihydrobenzo-
[d][1,3]oxaphosphole ligand (POPs).
† Department of Chemical Development.
‡ Department of Medicinal Chemistry.
(1) For representative reviews, see: (a) Tang, W.; Zhang, X. Chem. ReV.
2003, 103, 3029. (b) Ohkuma, T.; Kitamura, M.; Noyori, R. Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: Weinheim, 2000; p 1.
(c) Brown, J. M. ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; p 121. (d) Kre´py,
K. V. L.; Imamoto, T. Top. Curr. Chem. 2003, 229, 1. (e) Guiry, P. J.;
handling of these ligands is operationally inconvenient due
to their oily or air-sensitive nature.4,5 In terms of structure,
most chiral 1,1-bisphosphorus ligands possess a methylene
group which links the two phosphorus centers.6 Interestingly,
Saunders, C. P. AdV. Synth. Catal. 2004, 346, 497
.
10.1021/ol1000999  2010 American Chemical Society
Published on Web 02/11/2010

chiral ligands containing a 1-oxy-1,1-bisphosphorus unit B
have rarely been reported.7 We herein describe the synthesis
of a series of structurally unique and operationally convenient
chiral 2-phosphino-2,3-dihydrobenzo[d][1,3]oxaphosphole
ligands 3a-d (POPs) which contain the unique substructural
unit (B) and their excellent applications in rhodium-catalyzed
asymmetric hydrogenation of R-(acylamino)acrylates and
ꢀ-(acylamino)acrylates.
We have recently reported a series of efficient BIBOP
ligands for asymmetric hydrogenation during which we
developed the scalable syntheses of chiral 3-tert-butyl-2,3-
dihydrobenzo[d][1,3]oxaphosphole intermediates (1a-b,
Scheme 1).8 This allowed us to synthesize an array of chiral
phosphine then treatment with H2O2 provided diphosphine
oxides 2a-d in 66-95% yield. No diastereomeric products
were observed during these reactions, indicating a stereospe-
cific phosphinylation at the 2 position. Reduction of 2a-d
with HSiCl3/iPr2EtN9 as the reagents in xylene provided the
desired diphosphorus ligands 3a-d in satisfactory yields.
No racemization or epimerization was observed during the
reductions. Ligand 3a (MeO-POP) was reoxidized to the
diphosphine oxide 2a with H2O2,10 showing >99% enantio-
meric purity by chiral HPLC.11 The stability of ligand 3a as
a white crystalline solid was also tested by exposure to air
at rt. No detectable oxidation was observed by 31P NMR
analysis after four hours and only ∼5% oxidation side-
product was detected after one week. The good stability of
3a in air offers great operational convenience for handling.
The rhodium complexes Rh[(3a-d)(nbd)]BF4 were also
prepared from ligands 3a-d by reacting with Rh[(nbd)2]BF4.
The absolute configuration and the relative stereochemistry
of ligands 3a-d between the chiral phosphorus center and
the adjacent chiral carbon center were unambiguously
confirmed from the X-ray structure of Rh[(ent-3a)(nbd)]BF4
(Figure 2).12 Study of the X-ray structure revealed that the
Scheme 1. Ligand Synthesis
2-phosphino-2,3-dihydrobenzo[d][1,3]oxaphosphole ligands
3a-d (POPs) in only two steps from 1a-b. Thus, depro-
tonation of 1a or 1b with LDA followed by phosphinylation
with di(tert-butyl)chlorophosphine or dicyclohexylchloro-
(2) For recent representative examples, see: (a) Imamoto, T.; Watanabe,
J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta, H.; Matsukawa, S.;
Yamaguchi, K. J. Am. Chem. Soc. 1998, 120, 1635. (b) Jiang, Q.; Jiang,
Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem., Int. Ed. 1998, 37, 1100.
(c) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de
Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000,
122, 11539. (d) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39,
3889. (e) Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425. (f)
Komarov, I. V.; Bo¨rner, A. Angew. Chem., Int. Ed 2001, 40, 1197. (g)
Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612. (h) Ostermeier,
M.; Priess, J.; Helmchen, G. Angew. Chem., Int. Ed. 2002, 41, 612. (i) Hu,
A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2002, 41, 2348. (j) Tang, W.; Wang, W.; Zhang, X. Angew.
Chem., Int. Ed. 2003, 42, 943. (k) Tang, W.; Wang, W.; Chi, Y.; Zhang,
X. Angew. Chem., Int. Ed. 2003, 42, 3509. (l) Wu, S.; Zhang, W.; Zhang,
Z.; Zhang, X. Org. Lett. 2004, 6, 3565. (n) Hu, X.-P.; Zheng, Z. Org. Lett.
2004, 6, 3585. (m) Imamoto, T.; Oohara, N.; Takahashi, H. Synthesis 2004,
1353. (nn) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646. (o) Cheng,
X.; Zhang, Q.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int.
Ed. 2005, 44, 1118. (p) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem.
Soc. 2005, 127, 11934. (q) Chen, W.; McCormack, P. J.; Mohammed, K.;
Mbafor, W.; Roberts, S. M.; Whittall, J. Angew. Chem., Int. Ed. 2007, 44,
4141. (r) Imamoto, T.; Saitoh, Y.; Koide, A.; Ogura, T.; Yoshida, K. Angew.
Chem., Int. Ed. 2007, 44, 8636.
Figure 2. X-ray structure of Rh[(ent-3a)(nbd)]BF4 [the H atoms
are omitted for clarity, selected bond lengths (Å) 2.281 (Rh-P(a)),
2.337 (Rh-P(b)); selected bond angle (deg) 73.7 (P(a)-Rh-P(b))]
rhodium atom has a stronger coordination bond with the
chiral phosphorus center (P(a)) than with the phosphorus
(6) Other than methylene group, a few chiral 1,1-bisphosphorus ligands
with carbocycle, oxygen, or nitrogen linkers were reported, see: (a) Marinetti,
A.; Le Menn, C.; Ricard, L. Organometallics 1995, 14, 4983. (b) Calabro`,
G.; Drommi, D.; Bruno, G.; Faraone, F. Dalton Trans. 2004, 81. (c) Payne,
N. C.; Stephan, D. W. J. Organomet. Chem. 1981, 221, 203.
(7) No bisphosphorus ligands containing a 1-oxy-1,1-bisphosphorus unit
B can be found on SciFinder. An unconfirmed nonchiral structure containing
1-amino-1,1-bisphosphorus unit was recently reported, see: Aluri, B. R.;
Kindermann, M. K.; Jones, P. G.; Dix, I.; Heinicke, J. Inorg. Chem. 2008,
47, 6900.
(3) (a) Jackson, M.; Lennon, I. C. Tetrahedron Lett. 2007, 48, 1831.
(b) Dai, Q.; Li, W.; Zhang, X. Tetrahedron 2008, 64, 6943.
(8) Tang, W.; Qu, B.; Capacci, A. G.; Rodriguez, S.; Wei, X.; Haddad,
N.; Narayanan, B.; Ma, S.; Grinberg, N.; Yee, N. K.; Krishnamurthy, D.;
Senanayake, C. H. Org. Lett. 2010, 12, 176.
(4) (a) Yamanio, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988. (b)
Gridnev, I. D.; Yamanoi, Y.; Higashi, N.; Tsuruta, H.; Yasutake, M.;
Imamoto, T. AdV. Synth. Catal. 2001, 343, 118.
(9) Naumann, K.; Zon, G.; Mislow, K. J. Am. Chem. Soc. 1969, 91, 2788.
(10) Oxidation of chiral phosphine with H2O2 is generally stereospecific
with retention at the P center, see ref 9 and Luckenbach, R. Tetrahedron
Lett. 1976, 24, 2017.
(5) (a) Hoge, G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.;
Bao, J. J. Am. Chem. Soc. 2004, 126, 5966. (b) Wu, H.-P.; Hoge, G. Org.
Lett. 2004, 6, 3645. (c) Gridnev, I. D.; Imamato, T.; Hoge, G.; Kouchi, M.;
Takahashi, H. J. Am. Chem. Soc. 2008, 130, 2560.
(11) See Supporting Information for details.
Org. Lett., Vol. 12, No. 5, 2010
1105

atom (P(b)) connecting with two tert-butyl groups (Figure
2). A similar coordination pattern has been observed for the
reported Rh[(trichickenfootphos)(cod)]BF4 complex.5a It is
noteworthy that the rhodium complexes Rh[(3a-d)(nbd)]BF4
have also shown great stability in air, which again provides
a great deal of operational convenience. For example, no
decomposition of Rh[(3a)(nbd)]BF4 was observed according
to NMR after exposure to air for 24 h.
the synthesis of chiral ꢀ-amino acid derivatives.14 While a
variety of effective chiral ligands have been developed for
hydrogenation of (E)-ꢀ-(acylamino)acrylates, efficient ligands
for hydrogenation of (Z)-ꢀ-(acylamino)acrylates are still
limited. We have found that the POP ligands are efficient
for both (E)- and (Z)-ꢀ-(acylamino)acrylates (Table 2). The
Rh[(3a-d)(nbd)]BF4 were applied as catalysts for hydro-
genation of R-(acylamino)acrylates. The hydrogenations were
carried out at rt in methanol under 100 psi of hydrogen (Table
1). Screening of the four chiral rhodium complexes revealed
Table 2. Asymmetric Hydrogenation of ꢀ-(Acylamino)acrylic
Acid Derivatives with the Rh-3a or Rh-3b Catalysta
Table 1. Asymmetric Hydrogenation of R-(Acylamino)acrylic
Acid Derivatives with the Rh-3a Catalysta
entry
L*
R, R’ (geometry)
eeb (%)
config
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
Me, Me ((Z)-6a)
nPr, Et ((Z)-6b)
Me, iPr ((Z)-6c)
Et, Me ((Z)-6d)
Ph, Me ((Z)-6e)
Me, Me ((E)-6a)
nPr, Et ((E)-6b)
Me, iPr ((E)-6c)
Et, Me ((E)-6d)
Me, Me ((E)/(Z)-6a 1/1)
99
98
99
98
97
95
98
98
94
94
S
S
S
S
R
S
S
S
S
S
entry
R, R′
Ph, H (4a)
Ph, H (4a)
H, Me (4b)
s/c ratiob
t (h)
ee [%]c
1
2
3
4
5
6
7
8
500
10 000
5000
2000
2000
2000
2000
2000
2000
2000
2000
1
24
6
6
6
6
6
6
6
99
99
98
Ph, Me (4c)
99
10
a Reactions were run at rt in MeOH under 100 psi H2 for 12 h in the
presence of 0.2 mol % Rh[(L*)(nbd)]BF4. b Enantiomeric excesses were
determined by chiral GC (betadex-225). See Supporting Information for
chiral GC conditions. The absolute configuration was assigned by com-
parison of optical rotation with reported data.
p-F-Ph, Me (4d)
p-MeO-Ph, Me (4e)
m-Br-Ph, Me (4f)
o-Cl-Ph, Me (4g)
1-naphthyl, Me (4h)
2-naphthyl, Me (4i)
Me, Me (4j)
>99
>99
>99
98
>99
>99
98
9
10
11
6
6
a Reactions were run at rt in MeOH under 100 psi H2, see Supporting
Information for experimental details. b s/c ratios were not fully optimized.
c S absolute configuration was assigned by comparison of optical rotation
with reported data. The enantiomeric excesses were determined by chiral
GC (Varian CP-Chiralsil-L-Val or betadex-225) or Chiral HPLC (chiralpak
AD-H). The ee of hydrogenation product 5a was determined on corre-
sponding methyl ester by treatment with TMSCHN2.
hydrogenations were carried out at rt in methanol for 12 h
under 100 psi of hydrogen at 0.2 mol % catalyst loading.
Ligand 3a was proven to be an excellent ligand for
hydrogenation of (Z)-ꢀ-(acylamino)acrylates.15 High enan-
tioselectivities (97-99% ee’s) were achieved on various (Z)-
ꢀ-(acylamino)acrylates with different substituents (entries
1-5). Notably, a ꢀ-phenyl-ꢀ-(acylamino)acrylate substrate
was hydrogenated with an excellent ee (97% ee, entry 5).
Interestingly, for hydrogenation of (E)-methyl 3-acetami-
dobut-2-enoate (entry 6), ligand 3b provided the highest ee16
and up to 98% ee’s were achieved on various (E)-ꢀ-
(acylamino)acrylates. An E/Z mixture of 6a was also
hydrogenated with the Rh-3b catalyst to provide the chiral
ꢀ-amino acid derivative in 94% ee (entry 13).
that the Rh-3a catalyst provided the best and almost perfect
enantioselectivity for hydrogenation of R-acetamidocinnamic
acid (99% ee, entry 1).13 The reactivity of this catalyst is
also notable. At a s/c ratio of 500, the hydrogenation
proceeded to completion within 1 h. High turnover, up to
10 000 TON, was also achieved without compromising the
enantioselectivity (entry 2). With Rh[(3a)(nbd)]BF4 as the
catalyst, an array of R-acetamidocinnamic acid esters were
hydrogenated to provide chiral R-amino acid derivatives in
almost perfect enantioselectivities at a very low catalyst
loading (entries 4-10). An excellent ee (98%) was also
achieved on a ꢀ-alkyl R-(acylamino)acrylate 4j (entry 11).
Asymmetric hydrogenation of ꢀ-(acylamino)acrylic acid
derivatives has become one of most efficient methods for
In summary, we have developed a series of structurally
novel and operationally convenient chiral 2-phosphino-
2,3-dihydrobenzo[d][1,3]oxaphosphole ligands (POPs) that
(14) For a recent overview on asymmetric hydrogenation of ꢀ-(acyl-
amino)acrylic acid derivatives, see: (a) Bruneau, C.; Renaud, J.-L.;
Jerphagnon, T. Coord. Chem. ReV. 2008, 252, 532. For recent examples,
see: (b) Magano, J.; Conway, B.; Bowles, D.; Nelson, J.; Nanninga, T. N.;
Winkle, D. D.; Wu, H.; Chen, M. H. Tetrahedron Lett. 2009, 50, 6329. (c)
Drexler, H.-J.; You, J.; Zhang, S.; Fischer, C.; Baumann, W.; Spannenberg,
A.; Heller, D. Org. Proc. Res. DeV. 2003, 7, 355.
(12) Crystallographic data for compound Rh[(ent-3a)(nbd)]BF4 have
been deposited at Cambridge Crystallographic Data Centre (deposition no.
CCDC-760509). Copies of these data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html.
(15) Enantioselectivities on hydrogenation of (Z)-methyl 3-acetamidobut-
2-enoate ((Z)-6a) with the Rh catalysts of different ligands: 99% ee (3a),
91% ee (3b), 94% ee (3c), and 75% ee (3d).
(13) Enantioselectivities on hydrogenation of 2-acetamido-3-phenyl-
acrylic acid (4a) with the Rh catalysts of different ligands: 99% ee (3a),
87% ee (3b), 54% ee (3c), and 92% ee (3d).
(16) Enantioselectivities on hydrogenation of (E)-methyl 3-acetamidobut-
2-enoate ((E)-6a) with the Rh catalysts of different ligands: 80% ee (3a),
95% ee (3b), 46% ee (3c), and 88% ee (3d).
1106
Org. Lett., Vol. 12, No. 5, 2010

have shown excellent enantioselectivities and reactivities
for rhodium-catalyzed hydrogenation of R-(acylamino)acry-
lates and ꢀ-(acylamino)arylates. Ligand 3a is proven to
be a very efficient and practical ligand for the synthesis
of chiral R-amino acid derivatives by asymmetric hydro-
genation. Ligands 3a and 3b have also demonstrated
excellent applications toward the synthesis of chiral
ꢀ-amino acid derivatives. Studies of these novel bisphos-
phorus ligands for other metal-catalyzed asymmetric
transformations are currently ongoing, and results will be
reported in due course.
Supporting Information Available: Experimental details
and NMR spectra of the new compounds, general hydroge-
nation procedures, and chiral separation methods of hydro-
genation products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL1000999
Org. Lett., Vol. 12, No. 5, 2010
1107