Novel, tunable, and efficient chiral bisdihydrobenzooxaphosphole ligands for asymmetric hydrogenation

Article abstract of DOI:10.1021/ol9025815

"Chemical Equation Presented" A series of novel, efficient, air-stable, and tunable chiral bisdihydrobenzooxaphosphole ligands (BIBOPs) were developed for rhodium-catalyzed hydrogenations of various functionalized olefins such as α-ary lenam ides, α-(acylamino)acrylic acid derivatives, β-(acylamino)acrylates, and dimethyl itaconate with excellent enantioselectivities (up to 99% ee) and reactivities (up to 2000 TON)

Full text of DOI:10.1021/ol9025815

ORGANIC
LETTERS
2010
Vol. 12, No. 1
176-179
Novel, Tunable, and Efficient Chiral
Bisdihydrobenzooxaphosphole Ligands
for Asymmetric Hydrogenation
Wenjun Tang,* Bo Qu, Andrew G. Capacci, Sonia Rodriguez, Xudong Wei,
Nizar Haddad, Bikashandarkoil Narayanan, Shengli Ma, Nelu Grinberg,
Nathan K. Yee, Dhileep Krishnamurthy, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc.,
Ridgefield, Connecticut 06877
wenjun.tang@boerhinger-ingelheim.com
Received November 6, 2009
ABSTRACT
A series of novel, efficient, air-stable, and tunable chiral bisdihydrobenzooxaphosphole ligands (BIBOPs) were developed for rhodium-catalyzed
hydrogenations of various functionalized olefins such as r-arylenamides, r-(acylamino)acrylic acid derivatives, ꢀ-(acylamino)acrylates, and
dimethyl itaconate with excellent enantioselectivities (up to 99% ee) and reactivities (up to 2000 TON).
The development of efficient chiral phosphorus ligands has
played a central role toward the rapid development in the
field of asymmetric hydrogenation.1 Structurally novel,
sterically or electronically tunable, and operationally con-
venient chiral phosphorus ligands remain of great interest
in further broadening the scope of asymmetric hydrogenation
as well as in the discovery of new efficient transition metal
catalyzed asymmetric reactions.2 We herein report a series
of novel and air-stable P-chiral bisdihydrobenzooxaphosp-
hole ligands (BIBOPs, Figure 1) and their excellent applica-
tions in rhodium-catalyzed hydrogenation of various func-
tionalized olefins. Notable features of these ligands are their
rigid and unique bisdihydrobenzo[d][1,3]oxaphosphole core
structures and the tunability by variation of the substituents
at the 4,4′-positions. Molecular modeling of their rhodium
complexes on a CAChe model3 has shown a rigid and well-
defined chiral environment as well as the potentially strong
influence of R groups at the 4,4′-positions. We predicted that
(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) Hoge, G.; Wu, H.-P.; Kissel,
W. S.; Pflum, D. A.; Greene, D. J.; Bao, J. J. Am. Chem. Soc. 2004, 126,
5966. (m) Wu, S.; Zhang, W.; Zhang, Z.; Zhang, X. Org. Lett. 2004, 6,
3565. (n) Hu, X.-P.; Zheng, Z. Org. Lett. 2004, 6, 3585. (o) Imamoto, T.;
Oohara, N.; Takahashi, H. Synthesis 2004, 1353. (p) Liu, D.; Zhang, X.
Eur. J. Org. Chem. 2005, 646. (q) Cheng, X.; Zhang, Q.; Xie, J.-H.; Wang,
L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2005, 44, 1118. (r) Imamoto,
T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, 127, 11934. (s) Chen,
W.; McCormack, P. J.; Mohammed, K.; Mbafor, W.; Roberts, S. M.;
Whittall, J. Angew. Chem., Int. Ed. 2007, 44, 4141. (t) Imamoto, T.; Saitoh,
Y.; Koide, A.; Ogura, T.; Yoshida, K. Angew. Chem., Int. Ed. 2007, 44,
8636.
(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.;
Saunders, C. P. AdV. Synth. Catal. 2004, 346, 497.
10.1021/ol9025815  2010 American Chemical Society
Published on Web 12/01/2009

was accomplished by deprotonation with nBuLi followed by
addition of I2 to form iodo compound 2 in 80% yield.
Demethylation with boron tribromide as the reagent followed
by cyclization with K2CO3 as the base in DMF afforded
racemic 3 in 90% yield over two steps. Efficient resolution
of 3 was successfully accomplished by converting to its
menthyl carbonate. The diastereomerically pure isomer 4 was
isolated in 42% yield after single crystallization, and its
absolute configuration was confirmed by its X-ray structure.4
Basic hydrolysis of carbonate 4 afforded enantiomerically
pure compound (R)-3 quantitatively. Utilizing this synthetic
route, we have prepared both (R)-3 and (S)-3 in kilogram
quantity.
With (R)-3 in hand, we were able to install different
substituents (H, OMe, Ph, or Me) at the 4 position by simple
functionalizations (Scheme 2). Thus, 6a was obtained by
Figure 1. Chiral bisdihydrobenzo[d][1,3]oxaphosphole ligands
(BIBOPs): (a) a CAChe model of the Rh-R-BIBOP complex with
the MM3 force field and (b) a tunable quadrant diagram.
Scheme 2. Syntheses of BIBOP Ligands
the steric and electronic variations of R groups could have
a great impact on the efficiencies of their rhodium complexes
when applied in asymmetric hydrogenation (Figure 1).
Synthesis of a series of BIBOP ligands (8a-d) was
derived from the same chiral intermediate, 3-tert-butyl-2,3-
dihydrobenzo[d][1,3]oxaphosphol-4-ol oxide ((R)-3, Scheme
1). Preparation of racemic 3 was accomplished from meth-
Scheme 1. Synthesis of Chiral
3-tert-Butyl-2,3-dihydrobenzo[d][1,3]oxaphosphol-4-ol
Oxide ((R)-3)
converting (R)-3 to its triflate 5 followed by hydrogenolysis
in 90% overall yield. Methylation of (R)-3 using MeI and
potassium carbonate provided 6b in 95% isolated yield. The
phenyl-substituted product 6c was formed by Suzuki coupling
from 5 and phenylboronic acid in 85% yield. Similarly, the
methyl-substituted compound 6d was prepared in 64% yield
from the triflate and trimethyl boroxine. Homocouplings of
6a-d, mediated with LDA and CuCl2 as the reagents,5
afforded 7a-d in 60-74% isolated yields as single isomeric
coupling products. It is noteworthy that the deprotonation
of 6a-d with LDA is highly selective, and the bulkiness
of the tert-butyl group only allowed deprotonation to occur
on the opposite face of the ring, which stereospecifically set
the configurations at the 2,2′-positions. Reduction of 7a-d
6
with HSiCl3 provided a series of BIBOP ligands as white
(3) Molecular simulations were performed on CAChe 6.1 with a MM3
force field.
(4) Crystallographic data for compound 4 have been deposited at the
Cambridge Crystallographic Data Centre (deposition no. CCDC-750224).
Copies of these data can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html.
(5) Maryanoff, C. A.; Maryanoff, B. E.; Tang, R.; Mislow, K. J. Am.
Chem. Soc. 1973, 95, 5839.
yldichlorophosphine in four steps. Reaction of methyldi-
chlorophosphine with t-butylmagnesium chloride and 2,6-
dimethoxyphenyllithium followed by oxidation with H2O2
provided phosphine oxide 1 in 80% yield. Iodination of 1
Org. Lett., Vol. 12, No. 1, 2010
177

solids in satisfactory yields. The air stability of these ligands in
the solid state is notable. BIBOP (8a) was exposed in air for
one month without observation of oxidation side product. This
stability provides a great deal of operational convenience.
After synthesis of the ligands, a series of rhodium
complexes Rh[(nbd)(8a-d)]BF4 were prepared. The stere-
oconfiguration of the ligand core was further confirmed by
the X-ray structure of the Rh[(nbd)((2R,2′R,3R,3′R)-BI-
BOP)]BF4 complex (Figure 2).7 The rhodium complexes
dramatically different efficiencies in hydrogenation of N-(1-
phenylvinyl)acetamide (entries 1-4). While BIBOP provided
almost perfect enantioselectivity (99% ee), MeO-BIBOP (8b)
and Ph-BIBOP (8c) led to the diminished selectivities (92%
ee and 49% ee). Surprisingly, Me-BIBOP (8d) was inef-
ficient, leading to only 4% ee. These dramatic results strongly
demonstrated the sensitivity of the substituents of the
ligand at 4,4′-positions on stereoselectivity. With the
Rh[(nbd)(8a)]BF4 complex as the catalyst, a variety of R-aryl
enamides were hydrogenated to provide very high enanti-
oselectivities (98% to >99% ee, entries 5-12). A thiophenyl
and a 2-naphthyl substrate were also reduced to afford the
products in >99% ee and 98% ee, respectively. High
enantioselectivities were also achieved on a trifluoroacetyl
enamide and a pivaloyl enamide (entries 11-12). To further
test the reactivity of the Rh-BIBOP system on hydrogena-
tion of R-arylenamides, N-(1-(4-(trifluoromethyl)phenyl)-
vinyl)acetamide (9d) was subjected to hydrogenation at
rt for 12 h under 100 psi H2 in the presence of Rh-
[(nbd)(8a)]BF4 (0.05 mol %, 2000 TON), and the desired
product (R)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide
was obtained in >99% ee and in quantitative yield.
The rhodium complexes were also applied as catalysts for
hydrogenations of R-(acylamino)acrylic acid derivatives,8 and
the results are shown in Table 2. The hydrogenations were
Figure 2. X-ray crystal structure of Rh[(nbd)((2R,2′R,3R,3′R)-
BIBOP)]BF4 (the H atoms are omitted).
Table 2. Rh-Catalyzed Asymmetric Hydrogenation of
R-(Acylamino)acrylic Acid Derivativesa
were then applied as catalysts for hydrogenation of R-aryle-
namides.8,9 The hydrogenations were run at 0 °C in dichlo-
romethane in the presence of 1 mol % rhodium complex
under 100 psi of hydrogenation for 12 h. As shown in Table
1, the rhodium complexes with different ligands provided
entry L* substrate
Ar
R, R′
tBu, Me
ee [%]b
1
8a
8b
8c
8d
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
11a
11a
11a
11a
11b
11c
11d
11e
11f
Ph
Ph
Ph
Ph
H
99
93
20
93
>99
97
97
96
98
97
99
96
98
98c
Table 1. Rh-Catalyzed Asymmetric Hydrogenation of
R-Arylenamidesa
2
3
4
5
6
7
8
9
tBu, Me
tBu, Me
tBu, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Me, Me
Ph
p-F-Ph
p-MeO-Ph
m-Br-Ph
o-Cl-Ph
2-thiophenyl Me, Me
2-naphthyl
entry
L*
substrate
Ar
R
ee [%]b
10
11
12
13
14
11g
11h
11i
11j
11k
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8a
8a
8a
8a
8a
8a
8a
8a
9a
9a
9a
9a
9b
9c
9d
9e
9f
Ph
Ph
Ph
Ph
p-MeO-Ph
p-Br-Ph
p-CF3-Ph
m-Me-Ph
3-thiophenyl
2-naphthyl
p-Br-Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CF3
tBu
99
92
49
4
99
Me, Me
N-morpholine, Me
Me, H
Ph
Ph
a Conditions: see Supporting Information for experimental details. b The
R absolute configuration was assigned by comparison of optical rotation
with reported data. The enantiometric excesses were determined by chiral
GC (Varian CP-Chiralsil-L-Val) or Chiral HPLC (chiral-AGP or chiralpak
AD-H). c The ee of acid 12k was determined on corresponding methyl ester
by treatment with TMSCHN2.
99
>99
>99
>99
98
98
99
9
10
11
12
9g
9h
9i
p-MeO-Ph
a Conditions: see Supporting Information for experimental details. b The
R 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 HPLC (chiralpak AD-H).
performed at 0 °C in methanol in the presence of 1 mol %
rhodium complex under 100 psi of hydrogenation for 12 h.
Hydrogenation of 3-phenyl-2-pivalamidoacrylate (11a) with
four chiral rhodium catalysts once again provided very
178
Org. Lett., Vol. 12, No. 1, 2010

different enantioselectivities (Table 2, entries 1-4), dem-
onstrating the importance in developing chiral ligands with
tunable electronic and steric properties. The Rh-BIBOP
catalyst led to the product with the highest enantioselectivity
(99% ee). With the same catalyst, an array of R-(acetylami-
no)acrylic acid derivatives (entries 5-12) were hydrogenated
with very good enantioselectivities (96f99% ee’s). An
excellent ee was also achieved on a urea substrate (entry
13). (Z)-2-Acetamido-3-phenylacrylic acid was hydrogenated
to provide the corresponding chiral acid in 98% ee (entry
14). Again, the reactivity of the Rh-BIBOP catalyst was
tested on hydrogenation of methyl 2-acetamido-3-(4-fluo-
rophenyl)acrylate (11d). At 0.05 mol % catalyst loading
(2000 TON), the hydrogenation product was obtained with
97% ee in quantitative yield.
excellent enantioselectivities (99% ee’s). Dimethyl itaconate
was also hydrogenated to afford the corresponding chiral
ester in 94% ee.
In conclusion, we have designed and developed a series
of novel, efficient, and tunable bisdihydrobenzooxaphosphole
ligands which have shown excellent enantioselectivities and
reactivities for rhodium-catalyzed hydrogenations of various
functionalized olefins such as R-arylenamides, R-(acylami-
no)acrylic acid derivatives, ꢀ-(acylamino)acrylates, and di-
methyl itaconate. BIBOP (8a) is proven to be a general ligand
that has provided high enantioselectivities for a range of
functionalized olefins. The ease of synthesizing both enan-
tiomers and the excellent air stability for handling make
BIBOP a practical ligand for producing chiral products such
as chiral amines, chiral R-amino acid derivatives, chiral
ꢀ-amino acid derivatives, and chiral esters by asymmetric
hydrogenation. Additionally, the substituent effect at the 4,4′-
positions of the ligand on asymmetric hydrogenation was
also demonstrated. Further applications of these ligands in
asymmetric catalysis are under investigation, and progress
will be reported in due course.
The Rh-BIBOP catalyst was also applied for hydrogenation
of methyl ꢀ-(acetylamino)acrylates and dimethyl itaconate
(Table 3).8 Both (Z)- and (E)-methyl ꢀ-(acetylamino)acrylates
Table 3. Asymmetric Hydrogenation of (Z)- or (E)-Methyl
ꢀ-(acetylamino)acrylate and Dimethyl Itaconate with
Rh[(nbd)(8a)]BF4 as the Catalysta
Acknowledgment. We thank Dr. Andre White (Boe-
hringer Ingelheim) for solving X-ray structures.
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.
entry
substrate
R, R′, R′′
ee [%]b
config
1
2
3
13a (Z)
13b (E)
13c
H, NHAc, Me
H, Me, NHAc
CH2COOMe, H, H
99
99
94
R
R
S
OL9025815
(6) Naumann, K.; Zon, G.; Mislow, K. J. Am. Chem. Soc. 1969, 91,
2788.
a The reactions were run in dichloromethane under 50 psi H2 for 12 h
in the presence of 1 mol % Rh[(nbd)(8a)]BF4 as the catalyst. b The absolute
configuration was assigned by comparison of optical rotation with reported
data. The enantiomeric excesses were determined by chiral GC (betadex-
225) or chiral HPLC (Kromasil 3-CelluCoat RP).
(7) Crystallographic data for Rh[(nbd)((2R,2′R,3R,3′R)-BIBOP)]BF4 have
been deposited at the Cambridge Crystallographic Data Centre (deposition
no. CCDC-750225). Copies of these data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html.
(8) For a recent overview on rhodium-catalyzed hydrogenation of various
functionalized olefins, see ref 1a.
(9) We have recently reported an efficient and practical method for the
synthesis of R-arylenamides, see: Tang, W.; Capacci, A.; Sarvestani, M.;
Wei, X.; Yee, N. K.; Senanayake, C. H. J. Org. Chem., DOI: 10.1021/
jo9022594.
were hydrogenated to provide the corresponding chiral
ꢀ-amino acid derivative with the same configuration and
Org. Lett., Vol. 12, No. 1, 2010
179