An ortho-substituted BIPHEP ligand and its applications in Rh-catalyzed hydrogenation of cyclic enamides

Article abstract of DOI:10.1021/ol0258435

Matrix presented An ortho-substituted BIPHEP ligand, o-Ph-hexaMeO-BIPHEP (1), is designed and synthesized. Compared with chiral biaryl phosphines without ortho substituents such as BINAP and MeO-BIPHEP, o-Ph-hexaMeO-BIPHEP shows higher enantioselectivitie

Full text of DOI:10.1021/ol0258435

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1695-1698
An ortho-Substituted BIPHEP Ligand
and Its Applications in Rh-Catalyzed
Hydrogenation of Cyclic Enamides
Wenjun Tang, Yongxiang Chi, and Xumu Zhang*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
Received March 8, 2002
ABSTRACT
An ortho-substituted BIPHEP ligand, o-Ph-hexaMeO-BIPHEP (1), is designed and synthesized. Compared with chiral biaryl phosphines without
ortho substituents such as BINAP and MeO-BIPHEP, o-Ph-hexaMeO-BIPHEP shows higher enantioselectivities in Rh-catalyzed hydrogenation
of cyclic enamides.
Ligand design has played a central role in developing highly
efficient metal-catalyzed asymmetric reactions. Although
many effective bisphosphine ligands have been reported, the
development of new efficient phosphines remains of great
importance. Chiral biaryl bisphosphines such as BINAP,1
BIPHEMP,2 and MeO-BIPHEP2 (Figure 1) are very effective
ligands for many metal-catalyzed asymmetric reactions.
Structural variation of these ligands can lead to new chiral
catalysts with special properties. Some ligands such as
Bitianp,3 TetraMe-Bitiop,3 P-Phos,4 and Segphos5 have been
reported through modification of related biaryl phosphines.
Recently, we also developed biaryl TunaPhos ligands, a
series of BIPHEP ligands with systematic variations of bite
angles, and demonstrated that they are superior for some
asymmetric reactions.6 In this paper, we like to report a new
chiral BIPHEP ligand with ortho substituents, (3,3′-diphenyl-
4,4′,5,5′,6,6′-hexamethoxybiphenyl-2,2′-diyl)bis(diphenylphos-
phine) (abbreviated o-Ph-hexaMeO-BIPHEP, 1) and its
applications in Rh-catalyzed hydrogenation of cyclic ena-
mides. To the best of our knowledge, chiral BIPHEP ligands
with substituents at 3,3′-positions have not been systemati-
cally examined. We envision that the introduction of phenyl
groups at 3,3′-positions in 1 can have a strong influence on
the conformation of P-aryl rings and high enantioselectivity
in asymmetric hydrogenation is possible.
(1) (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345. (b)
Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 2000. (c) Noyori, R. Asymmetric Catalysis
in Organic Synthesis; Wiley: New York, 1994.
(2) (a) Schmid, R.; Cereghetti, M.; Heiser, B.; Schonholzer, P.; Hansen,
H.-J. HelV. Chim. Acta 1988, 71, 897. (b) Schmid, R.; Foricher, J.;
Cereghetti, M.; Schonhoizer, P. HelV. Chim. Acta 1991, 74, 370. (c) Schmid,
R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricehr, J.; Lalonde, M.;
Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure Appl. Chem.
1996, 68, 131.
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W. T. J. Am. Chem. Soc. 2000, 122, 11513.
The quadrant diagram has been used to describe the
effectiveness of Rh-chiral phosphine catalysts (Figure 2).1c,7
Generally, the two equatorial P-aryl rings exert the greater
(5) Saito, T.; Yokoawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.;
Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
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65, 6223.
10.1021/ol0258435 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/25/2002

calculations) shows that the two equatorial P-phenyl rings
of Rh-o-Ph-hexaMeO-BIPHEP are almost parallel to the
phenyl rings at 3,3′-positions. The two equatorial P-phenyl
rings protrude out of the two diagonal quadrants to an extent
greater than that of the Rh-hexaMeO-BIPHEP complex, in
which hydrogen atoms are at 3,3′-positions (θ ) dihedral
angle between plane C1C2P3 and plane C4C2P3; θ ) 90°
for the Rh-o-Ph-hexaMeO-BIPHEP complex; θ ) 70° for
the Rh-hexaMeO-BIPHEP complex). Consequently, a better
chiral differentiation can be achieved.
Synthesis of ligand 1 is illustrated in Scheme 1. With the
Scheme 1. Synthesis of the (S)-o-Ph-hexaMeO-BIPHEP
Ligand
Figure 1. Chiral atropisomeric bisphosphines.
steric influence on two diagonal quadrants while the two axial
P-aryl rings stay relatively open in the other two quadrants.
Hence, the orientation and rotation of the two equatorial
known iodide compound 2 as the starting material,2b (2-
phenyl-3,4,5-trimethoxyphenyl)diphenylphosphine oxide 3
was synthesized via a Suzuki coupling in 98% yield.
Deprotonation of 3 with t-BuLi followed by quenching with
I2 produced an iodination product 4 in 85% yield. Copper-
mediated Ullmann coupling of 4 led to the formation of the
bisphosphine oxide 5 in 90% yield. Resolution of racemic 5
was effectively carried out by using (+)-(2R,3R)-2,3-O-
ditoluoyltartric acid ((+)-DTTA) as the resolving agent. The
configuration of the optically pure (+)-5 was assigned as S
by comparing the hydrogenation results of ligand 1 with those
of MeO-BIPHEP and hexaMeO-BIPHEP. Reduction of the
bisphosphine oxide (S)-5 with trichlorosilane provided (S)-
1.
Figure 2. MM2 Calculations based on the CAChe program.
P-aryl rings will be crucial for chiral differentiation. We
believe that the rotation of two equatorial P-phenyl rings in
the Rh-o-Ph-hexaMeO-BIPHEP complex could be restricted
through the introduction of the two phenyl rings at 3,3′-
positions. Molecular simulation (based on the CAChe MM2
Ligand (S)-1 was used for hydrogenation of cyclic ena-
mides. Asymmetric hydrogenation of cyclic enamides is
potentially important for the synthesis of biologically active
chiral aminotetralines and aminoindanes.8 For example,
sertraline is a chiral aminotetraline compound and a major
(7) Brown. J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
1696
Org. Lett., Vol. 4, No. 10, 2002

antidepressant drug.9 However, synthesis of this drug via
asymmetric hydrogenation has not been realized. To the best
of our knowledge, only a few catalytic systems have been
efficient in the metal-catalyzed asymmetric hydrogenation
of cyclic enamides (e.g., the Rh-PennPhos10 and Rh-BPE11
systems). In our study, N-(3,4-dehydro-1-naphthyl)acetamide
was chosen as the substrate for optimizing the reaction
conditions (Table 1). The catalyst was prepared in situ by
sor, and Rh(NBD)2SbF6 was selected as the desired precur-
sor. A slight improvement of the enantioselectivity was
observed when the reaction was carried out at a lower
hydrogen pressure (entry 5 vs 6). A small solvent effect was
also found in the reaction (entries 6-10). Both THF and
CH2Cl2 proved to be good solvents for this hydrogenation
process. When the hydrogenation was carried out at 0 °C, a
further improved enantioselectivity was observed (entry 11).
The best ee (98%) was achieved when the hydrogenation
was carried out at -20 °C under 25 psi of hydrogen in CH2-
Cl2 (entry 12). This result was comparable with the best
results obtained with the Rh-PennPhos system.10 To dem-
onstrate the importance of the o-phenyl groups of (S)-1 on
the enantioselectivity of the product, we investigated the
reaction with some other chiral ligands under the same
conditions (entries 13-17). Compared with the o-Ph-
hexaMeO-BIPHEP ligand 1, significantly lower enantio-
seletivities (55-65%) were observed with other chiral biaryl
phosphines without ortho substituents, such as hexaMeO-
BIPHEP, MeO-BIPHEP, and BINAP. These results clearly
indicated the strong influence of o-phenyl groups of (S)-1
on the enantioselectivity of the reaction. When DIOP was
used as the ligand, a low ee was obtained. Under the same
reaction condition, no reaction was observed with Me-
DuPhos as the ligand.
Table 1. Optimization of the Reaction Conditions for
Rh-catalyzed Hydrogenation of a Cyclic Enamide
en-
H2
T
eeb
trya
Rh precursor
ligand
press. solvent (°C) (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Rh(COD)2SbF6 (S)-1
Rh(NBD)2BF4 (S)-1
30 atm CH3OH
30 atm CH3OH
30 atm CH3OH
30 atm CH3OH
30 atm CH3OH
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
92
81
90
50
93
94
95
90
95
93
97
98
65
Rh(COD)2PF6
[Rh(COD)Cl]2
(S)-1
(S)-1
Rh(NBD)2SbF6 (S)-1
Rh(NBD)2SbF6 (S)-1
Rh(NBD)2SbF6 (S)-1
Rh(NBD)2SbF6 (S)-1
Rh(NBD)2SbF6 (S)-1
Rh(NBD)2SbF6 (S)-1
Rh(NBD)2SbF6 (S)-1
Rh(NBD)2SbF6 (S)-1
25 psi
25 psi
25 psi
25 psi
25 psi
25 psi
25 psi
CH3OH
THF
toluene
CH2Cl2
EtOAc
CH2Cl2
CH2Cl2 -20
Rh(NBD)2SbF6 (S)-hexaMeO- 25 psi
CH2Cl2 -20
Table 2. Hydrogenation of Enamides Catalyzed by
Rh-o-Ph-HexaMeO-BIPHEP System
BIPHEP
14
Rh(NBD)2SbF6 (S)-MeO-
25 psi
CH2Cl2 -20
67
BIPHEP
15
16
Rh(NBD)2SbF6 (R)-BINAP
Rh(NBD)2SbF6 (+)-DIOP
25 psi
25 psi
25 psi
CH2Cl2 -20
CH2Cl2 -20
CH2Cl2 -20 N/A
55c
13c
17d Rh(NBD)2SbF6 (R,R)-Me-
DuPhos
a The reaction was complete in quantitative yield. The catalyst was made
in situ by stirring a solution of Rh precursor and phosphine ligand in the
solvent for 30 min [substrate/Rh/L* ) 100/1/1.1]. The configuration of the
product is S. b Enantiomeric excesses were determined by chiral GC using
Supelco chiral Select 1000 (0.25 mm × 30 m) column. c The configuration
of the major product is R. d No reaction.
mixing a solution of a Rh precursor and a phosphine ligand.
Under the initial hydrogenation pressure of 30 atm at room
temperature and with a ratio of substrate/Rh/(S)-1 of 100:
1:1.1, different Rh precursors led to different results in
enantioselectivities (entries 1-5). Cationic Rh precursors
gave better enantioselectivities than did a neutral Rh precur-
(8) Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.; Dolling, U.-
H.; Frey, L.; Karady, S.; Shi, Y.-J.; Verhoeven, T. R. J. Org. Chem. 1995,
69, 4324.
a The reaction was carried out at -20 °C under 25 psi of H2 in CH2Cl2
with catalyst [Rh((S)-1)(NBD)]SbF6/substrate ) 1:200. The reaction was
complete unless otherwise specified. The configuration of chiral amine
products is S. b Enantiomeric excesses were determined by chiral GC using
Supelco chiral Select 1000 (0.25 mm × 30 m) column. c Conversion 83%.
(9) For a racemic route to sertraline, see: William, M.; Quallich, G. Chem
Ind. (London) 1990, 10, 315. For an asymmetric route, see: (a) Quallich,
G. J.; Woodall, T. M. Tetrahedron 1992, 48, 10239. (b) Corey, E. J.; Grant,
T. G. Tetrahedron Lett. 1994, 35, 5373. (c) Lautens, M.; Rovis, T. J. Org.
Chem. 1997, 62, 5246. (d) Lautens, M.; Rovis, T. Tetrahedron 1999, 55,
8967. (d) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1,
233. (e) Chen, C.-Y.; Reamer, R. A. Org. Lett. 1999, 1, 293. (f)
Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56, 1111. (g) Yun, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 767.
(10) Zhang, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Zhang, X. J. Org. Chem.
1999, 64, 1774.
(11) Burk, M. J.; Casey, G.; Johnson, N. B. J. Org. Chem. 1998, 63,
6084.
To test the catalytic efficiency of Rh-o-Ph-hexaMeO-
BIPHEP system for hydrogenation of cyclic enamides, the
catalyst precursor [Rh((S)-1)(NBD)]SbF6 was prepared. With
this catalyst precursor, up to 2,000 turnovers for hydrogena-
Org. Lett., Vol. 4, No. 10, 2002
1697

tion of N-(3,4-dehydro-1-naphthyl)acetamide and 95% ee
were obtained. Under the optimized conditions, a variety of
enamides have been hydrogenated with the Rh-o-Ph-hex-
aMeO-BIPHEP system (Table 2). Excellent enantioselec-
tivities (96-98%) were observed on hydrogenation of cyclic
enamides derived from R-tetralones and R-indanones (entries
1-5). A tetrasubstituted five-membered cyclic enamide also
gave a high ee with complete conversion (entry 4). An
excellent ee was also achieved on the hydrogenation of an
(E)-â-dehydroamino acid ester (entry 10). However, the ee
obtained for the enamide derived from â-tetralone was low
(45%, entry 6). The system also showed only moderate ee’s
on the hydrogenation of other cyclic and acyclic enamides
(entries 7-9).
Because a cyclic carbamate substrate gave an excellent
ee (entry 5), we tested a racemic carbamate 6 for hydrogena-
tion under the same reaction conditions (Scheme 2). The
carbamate 6 was converted smoothly into the cis product 7
in 50% yield with 96% ee and the trans product epi-7 in
50% yield with 100% ee. According to the literature
procedure,12 LAH reduction of 7 can directly lead to the
formation of enantiomerically enriched sertraline.
Scheme 2. Hydrogenation of a Racemic Cyclic Carbamate
importance of the o-phenyl groups of the ligand on the
enantioselectivity of the reaction has also been demonstrated
by comparing the hydrogenation results of the corresponding
chiral ligands without ortho substituents. Further study will
be focused on the synthesis and applications of other ortho-
substituted BIPHEP or BINAP ligands and progress will be
reported in due course.
Acknowledgment. This work was supported by the
National Institute of Health.
In conclusion, we have designed and synthesized the first
BIPHEP ligand with substituents at 3,3′-positions, o-Ph-
hexaMeO-BIPHEP. This ligand has been successfully applied
in Rh-catalyzed hydrogenation of cyclic enamides and
carbamates. High ee’s and turnovers have been realized. The
Supporting Information Available: Experimental de-
tails, spectroscopic data, and analytical conditions of the
ligand and hydrogenation products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) DeNinno, M. P.; Eller, C.; Etienne, J. B. J. Org. Chem. 2001, 66,
6988.
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