A new planar chiral bisphosphine ligand for asymmetric catalysis: Highly enantioselective hydrogenations under mild conditions

Full text of DOI:10.1021/ja970654g

J. Am. Chem. Soc. 1997, 119, 6207-6208
6207
Scheme 1
A New Planar Chiral Bisphosphine Ligand for
Asymmetric Catalysis: Highly Enantioselective
Hydrogenations under Mild Conditions
Philip J. Pye,* Kai Rossen,* Robert A. Reamer,
Nancy N. Tsou,† R. P. Volante, and Paul J. Reider
Department of Process Research
Merck Research Laboratories, P.O. Box 2000
Rahway, New Jersey 07065
ReceiVed March 3, 1997
The introduction of chiral bisphosphine ligands and especially
the C2 symmetric 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
(BINAP) has provided synthetic chemists with highly enanti-
oselective catalysts for a multitude of asymmetric transforma-
tions.1 BINAP is designed so that the axially chiral backbone
of the binaphthyl system is used as a scaffold for the placement
of the diphenylphosphino groups. Recently, planar chiral
molecular systems based on ferrocenes have been applied to
catalytic systems with impressive results.2 Described here is
the use of a paracyclophane backbone3 for the placement of
two diphenylphosphino groups to give a planar chiral C2
symmetric bisphosphine 1 (4,12-bis(diphenylphosphino)-[2.2]-
paracyclophane abbreviated as [2.2]PHANEPHOS). Applica-
tion of this ligand in Rh-catalyzed hydrogenations4 has led to
an exceptionally active and highly enantioselective catalytic
system.
Preparation of the active catalyst [[2.2]PHANEPHOS
Rh]+OTf- 3 was achieved by treatment of 1 with bis(1,5-
cyclooctadiene)rhodium(I) triflate to form the bright orange-
colored complex 25 (Scheme 1). Subsequent hydrogenation of
this precatalyst 2 in MeOH led to the loss of the COD
(cyclooctadiene) ligand and generated 3 as a single species.6
[[2.2]PHANEPHOS Rh]+OTf- 3 is a highly enantioselective
catalyst for the hydrogenation of dehydroamino acid methyl
esters under very mild conditions. For example, 4a, 4b, and
4e were all completely reduced in less than 10 min by simply
passing a stream of H2 through a solution of precatalyst 2 (1 to
2 mol %) and the substrate in MeOH at 23 °C. While the
unsubstituted dehydroamino acid 4a gave (R)-Ac-Ala-OMe in
excellent 99.6% enantiomeric excess (ee),7 substrates 4b and
4e gave disappointingly low ee values of 83% and 78%,
respectively. Remarkably, formation of catalyst 3 prior to
substrate addition made it possible to perform the hydrogenation
at reduced temperaturesscomplete conVersions in less than 60
min were obtained by passing H2 through the reaction mixture
at -45 °C! The high activity of 3 even made it possible to run
the hydrogenations routinely at -45 °C,8 and superb enanti-
oselectivity was obtained for a variety of substrate substitution
patterns (Table 1). Amide-protected aminoacrylic acid methyl
esters gave >94% ee under these conditions; however, geminal
substitution at the acrylic acid formed the opposite enantiomer
in up to 51% ee. The use of the free acid or the carboben-
zoxycarbonyl protecting group led to a decline in the observed
enantioselectivities.
The pronounced activity of [[2.2]PHANEPHOS Rh ]+OTf-
3 can be demonstrated by the reduction of tetrahydropyrazine
6 to afford the HIV protease inhibitor Crixivan intermediate
precursor 7 in 86% ee at -40 °C and 1.5 bar in only 6 h (100%
conversion, Scheme 2). Previous reductions of 6 using known
bisphosphine rhodium catalysts required forcing conditions (70
bar/40 °C/24 h) and proceeded with only moderate enantiose-
lectivities and incomplete conversions (e.g., BINAP, 56% ee;
Et-DuPHOS, 50% ee).9
Synthesis of [2.2]PHANEPHOS (1) began with the iron-
catalyzed bisbromination of [2.2]paracyclophane (8) (Scheme
3).10 The tedious chromatographic isolation of the desired
pseudo ortho isomer rac-9 from the complex reaction mixture
was avoided by crystallization of the highly insoluble pseudo
para isomer 10. Subsequent thermal isomerization (triglyme,
230 °C, 3 h) of the pure pseudo para isomer led to a 50:50
mixture of rac-9 and 10. The pseudo para isomer 10 crystallized
on cooling to leave the desired rac-9 in the mother liquors in
>90% purity.
Lithiation (4 equiv of tert-butyllithium) of rac-9, followed
by transmetallation (MgBr2‚Et2O) and reaction with diphe-
nylphosphinic chloride afforded rac-11 in 76% yield from rac-9
(Scheme 4). Resolution of rac-11 was performed with diben-
zoyl-D-tartaric acid to give the complex 12 in high optical purity.
After the resolving agent was removed, the phosphine oxide
(R)-11 (>99.5% ee) was reduced to the enantiomerically pure
bisphosphine ligand (R)-1 ([2.2]PHANEPHOS) with SiHCl3.11
* Authors to whom correspondence should be addressed at the follow-
ing: e-mail, philip pye@merck.com and kai rossen@merck.com.
† Department of Molecular Design and Diversity. Please direct questions
concerning the X-ray analysis to this author.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley
& Sons, Inc.: New York, 1994. (b) Ojima, I. Catalytic Asymmetric
Synthesis, VCH: New York, 1994.
(2) (a) Zhang, W.; Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron Lett.
1996, 37, 7995. (b) Burk, M. J.; Gross, M. F. Tetrahedron Lett. 1994, 35,
9363. (c) Togni, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 1475 and
references cited therein.
(3) (a) Sergeeva, E. V.; Rozenberg, V. I.; Vorontsov, E. V.; Danilova,
T. I.; Strikova, Z. A.; Yanovsky, A. I.; Belokon, Y. N.; Hopf, H.
Tetrahedron: Asymmetry 1996, 7, 3445. (b) Bodwell, G. J. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2085 and references cited therein. (c) Diederich, F.
Cyclophanes; The Royal Society of Chemistry: Cambridge, 1991. (d)
Keehn, P. M.; Rosenfeld, S. M. Cyclophanes; Academic Press: New York,
1983.
(4) (a) Kagan, H. B. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1984; Vol. 5, Chapter 1. (b) Koenig, K. E. In
Catalysis of Organic Reactions; Kosak, J. R., Ed.; Dekker: New York,
1984; Chapter 3. (c) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106.
(5) 1H NMR (399.87 MHz, CDCl3) δ 8.58 (m, 2 H), 7.85 (m, 1 H), 7.31
(m, 2 H), 7.59 (m, 1 H), 7.43 (m, 1 H), 7.36 (m, 2 H), 7.19 (m, 2 H), 6.55
(br d, J ) 8.0, 1 H), 6.43 (dd, J ) 8.0, 4.0, 1 H), 4.50 (br s, 2 H), 2.77 (m,
1 H), 2.67 (m, 1 H), 2.54 (m, 1 H), 2.48 (m, 1 H), 2.20 (o m, 3 H), 2.03
(m, 1 H); 13C NMR (100.55 MHz, CDCl3) (due to the magnetic nonequiva-
lence of the phosphorus atoms, some carbon signals are second-order
multiplets; these patterns are noted as multiplets) δ 142.2, 139.9 (m), 139.3
(m), 139.0 (t, J ) 4.0), 138.3 (m), 134.6, 133.7, 132.2 (t, J ) 4.0), 131.2
(m), 130.8 (m), 130.59, 130.58 (m), 129.2 (t, J ) 4.2), 128.9 (t, J ) 4.4),
100.5 (dt, J ) 8.8, 3.2), 91.6 (dt, J ) 8.0, 7.0), 35.1, 34.5, 32.5, 28.8; 31P
NMR (161.87 MHz, CDCl3) δ 32.7 (d, JPRh ) 146.1 Hz).
(7) The DuPHOS ligand affords an equally high ee for this substrate:
Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem.
Soc. 1993, 115, 10125.
(8) (a) Reduction of 4b with 3 between -45 and +50 °C showed an
increase of ee with decreasing temperature and a good linear dependence
of ln(ratio of enantiomers) on 1/T [ln(R/S) ) 2440/T - 5.88 (T in K; R2 )
0.9996)]. (b) Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew.
Chem. Int., Ed. Engl. 1991, 30, 477.
(6) (a) 31P NMR (161.87 MHz, CD3OD) δ 65.1 (d, JPRh ) 219.7 Hz).
(b) The hydrogenation of the analogous BINAP complex leads to the
formation of two compounds that afford different enantioselectivities in
the hydrogenation: Miyashita, A.; Takaya, H.; Souchi, T.; Noyori, R.
Tetrahedron 1984, 40, 1245.
(9) Rossen, K.; Weissman, S. A.; Sager, J.; Reamer, R. A.; Askin, D.;
Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1995, 36, 6419.
(10) Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3527.
S0002-7863(97)00654-9 CCC: $14.00 © 1997 American Chemical Society

6208 J. Am. Chem. Soc., Vol. 119, No. 26, 1997
Table 1. Asymmetric Hydrogenation of 4 to 5
Communications to the Editor
entry
R1
R2
P
ee (%)a of 5b
configg
a
b
c
d
e
f
H
H
H
H
H
H
Me
Ac
Ac
Ac
Bz
Cbz
Ac
99.6c
98d (83c)
94d
R
R
R
R
R
S
Ph
Me
Ph
H
97d
91d,e (78c)
51f
Me
a Determination of the ee with a Hewlett Packard supercritical fluid
chromatograph using two 25 cm Chiracel AD columns in tandem or
on a Hewlett-Packard 5890 GC using a Chiracel Val III 25 m column.
See the Supporting Information for separation conditions. b All reactions
went to completion in 10 to 60 min by passing H2 through the reaction
mixture at the specified temperature in MeOH. Catalyst loading was
1-2 mol %, concentration of 4 was 0.1 M. c Precatalyst (R)-2 was
mixed with 4 prior to addition of H2 at 23 °C. d Precatalyst (R)-2 was
reduced to (R)-3 at 23 °C, prior to addition of substrate at -45 °C.
e Conversion after 3 h: 50%. f Substrate added to (R)-3 at -10 °C.
g Absolute configuration determined by a comparison of the sign of
the optical rotation with literature values.
Figure 1. A drawing of the molecular structure of 12. Ellipsoids are
drawn at the 20% probability level. The dibenzoyltartaric acid and the
hydrogen atoms are omitted for clarity.
Scheme 2
Scheme 4
Scheme 3
X-ray analysis of the dibenzoyltartaric acid complex 1212
allowed the determination of the absolute stereochemistry of
the phosphine oxide and revealed the severe strain of the
paracyclophane backbone (as in the unsubstituted [2.2]paracy-
clophane the phenyl rings are bent outward with the phenyl
carbons connected to the bridges being pulled inward) (Figure
1). Additionally, the steric bulk of the diphenylphosphinyl
groups of 12 tilts the two aromatic rings at a 5.7° angle. It is
important to note that the P-P distance in 12 (and presumably
a similar distance in 1) is, at 4.8 Å, ideally suited to accom-
modate two P-Rh bond distances (2.2-2.4 Å range in similar
complexes).13
In summary, the 4,12-disubstituted [2.2]paracyclophane sys-
tem provides an excellent chiral framework for the placement
of catalytically active groups, such as the diphenylphosphino
group in [2.2]PHANEPHOS. The resulting catalyst [[2.2]-
PHANEPHOS Rh]+OTf- 3 is highly active, facilitating the
reduction of not only dehydroamino acid methyl esters but also
of the otherwise difficult to reduce tetrahydropyrazine 6 in
excellent enantioselectivity under very mild conditions. Further
extensions of the use of cyclophanes in the generation of ligands
for asymmetric catalytic reactions are currently being explored
and will be reported separately.
(11) (a) The preparation is in analogy to a synthesis of BINAP: Takaya,
H.; Akutagawa, S.; Noyori, R. Org. Synth. 1989, 67, 20. (b) The resolution
was monitored on a 25 cm Chiracel AD column using an Hewlett-Packard
SFC instrument with 15% MeOH/Supercritical-CO2, 1.0 mL/min; R t1 )
13.0 min, S t2 ) 17.8 min. (c) Reoxidation of 1 to 11 with H2O2 confirmed
that no racemization took place during the reduction of 11 to 1. (d) For a
definition of the chiral descriptor, see: Cahn, R. S.; Ingold, I.; Prelog, V.
Angew. Chem., Int. Ed. Engl. 1966, 5, 385.
(12) (a) A crystal suitable for single X-ray crystallography was obtained
from the second crop of a resolution of rac-11 with dibenzoyl-L-tartaric
acid. Chiral SFC of the dissolved crystal showed that it corresponded to
the peak eluting at 13.0 min. (b) Manuscript in preparation.
Supporting Information Available: Full experimental details for
all procedures (6 pages). See any current masthead page for ordering
and Internet access instructions.
JA970654G
(13) Tolman, C. A. Chem. ReV. 1977, 77, 313.