Enantioselective synthesis of α-hydroxy and α-amino phosphonates via catalytic asymmetric hydrogenation

Article abstract of DOI:10.1021/ol9906099

(equation presented) Cationic rhodium catalysts of the C₂ symmetric DuPHOS (1) and BPE (2) ligands have demonstrated the ability to asymmetrically hydrogenate a novel series of enol phosphonates (3) in good to excellent enantiomeric excess unde

Full text of DOI:10.1021/ol9906099

ORGANIC
LETTERS
1999
Vol. 1, No. 3
387-390
Enantioselective Synthesis of r-Hydroxy
and r-Amino Phosphonates via
Catalytic Asymmetric Hydrogenation
,†
Mark J. Burk,* Timothy A. Stammers,‡ and Judith A. Straub§
Department of Chemistry, Duke UniVersity, P. M. Gross Chemical Laboratory,
Durham, North Carolina 27706
markburk@chirotech.com
Received April 21, 1999
ABSTRACT
Cationic rhodium catalysts of the C symmetric DuPHOS (1) and BPE (2) ligands have demonstrated the ability to asymmetrically hydrogenate
2
a novel series of enol phosphonates (3) in good to excellent enantiomeric excess under mild conditions. Initial studies toward the catalytic
asymmetric hydrogenation of enamido phosphonates (6 and 7) using the DuPHOS−Rh+ catalysts are also reported.
R-Amino phosphonates and R-hydroxy phosphonates are
useful compounds for the inhibition of enzymes due to their
ability to mimic hydrolysis transition states.1,2 These func-
tionalities have been employed in compounds designed to
inhibit enzymes such as renin, EPSP synthase, and HIV
protease.3 The stereochemistry of the R-amino phosphonates
or R-hydroxy phosphonates can effect the enzyme inhibition,3b
thus providing the impetus for examining the asymmetric
synthesis of these compounds. Cationic rhodium catalysts
with DuPHOS (1) and BPE (2) ligands (Figure 1) have been
used to perform asymmetric hydrogenations on a wide variety
enamido4 and enol esters.4a,5 Herein we describe the first
catalytic asymmetric hydrogenation of a series enolbenzoate
phosphonates as well as some initial studies directed toward
the asymmetric hydrogenation of enamido phosphonates
using the DuPHOS-Rh and BPE-Rh catalysts. To date there
† Present address: Chirotech Technology Ltd., Cambridge Science Park,
Milton Rd. Cambridge CB4 4WE, England.
‡ Present address: Department of Chemistry, University of Toronto,
Toronto, Ontario, Canada, M5S 3H6.
§ Present address: Pharmacopeia, Inc., CN 5350, Princeton, NJ 08543-
5350.
(1) Dhawan, B.; Redmore, D. Phosphorus Sulfur 1987, 32, 119.
(2) Kafarski, P.; Lejczak, B. Phosphorus Sulfur Silicon Relat. Elem. 1991,
63, 193.
(3) (a) Sikorski, J. A.; Miller, M. J.; Braccolino, D. S.; Cleary, D. G.;
Corey, S. D.; Font, J. L.; Gruys, K. J.; Han, C. Y.; Lin, K.-C.; Pansgrau, P.
D.; Ream, J. E.; Schnur, D.; Shah, A.; Walker, M. C. Phosphosphorus,
Sulfur Silicon 1993, 76, 115. (b) Stowasser, B.; Budt, K.-H.; Jian-Qi, L.;
Peyman, A.; Ruppert, D. Tetrahedron Lett. 1992, 33, 6625. (c) Patel, D.
V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett. 1990, 31, 5587. (d)
Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron Lett. 1990, 31,
5591.
(4) (a) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518. (b) Burk, M. J.;
Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem. Soc. 1993, 115,
10125. (c) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc.
1995, 117, 9375. (d) Burk, M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg,
C. S.; Lee, J. R.; Martinez, J. P. Pure Appl. Chem. 1996, 68, 37. (e) Burk,
M. J.; Allen, J. G.; Keisman, W. F. J. Am. Chem. Soc. 1998, 120, 657.
(5) Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc. 1998,
120, 4345.
Figure 1. The DuPHOS and BPE Ligands.
10.1021/ol9906099 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/03/1999

have been two published examples of the catalytic asym-
metric synthesis of R-hydroxy phosphonates.6 The catalytic
asymmetric synthesis of R-amino phosphonates has received
recent attention, including asymmetric hydrogenation7 and
hydrophosphonylation8 strategies.
Table 1. Ligand Optimization for the DuPHOS/
BPE-Rh-Catalyzed Asymmetric Hydrogenation of Enolbenzoate
Phosphonates 3
I. r-Hydroxy Phosphonates. Enolbenzoate phosphonate
substrates 3 were readily synthesized as shown in Scheme
1. Acyl chlorides were treated with trimethyl phosphite to
Scheme 1
subst
R
ligand
conva
% eeb
configc
3a
3a
3a
3a
3a
3b
3b
3b
H
H
H
H
(R,R)-2a
(S,S)-1a
(R,R)-1b
(R,R)-1c
(R,R)-1d
(R,R)-2a
(S,S)-1a
(R,R)-1b
27
100
100
100
40
45
100
9
64
84
96
92
85
60
86
ND
S-(-)
R-(+)
S-(-)
S-(-)
R-(+)
S-(+)
R-(-)
ND
H
CH3
CH3
CH3
form R-keto phosphonate intermediates9 which were then
reacted with benzoic anhydride and DBU to form enolben-
zoates 3 in yields that ranged from 43 to 86% after
purification. Only the E isomer of the olefin was observed
for 3b-h.10 To the best of our knowledge the enolbenzoate
phosphonates 3 are novel.
a Conversion determined by 1H or 31P NMR. b Enantiomeric excess
determined by chiral HPLC on a Daicel Chiralcel OJ column for 6a and a
Chiralpak OT column for 4b.11 c Configuration assigned on the basis of
correlation between HPLC elution order, optical rotation, and catalyst
configuration relative to the known compound 5.
To obtain optimum enantioselectivities for the asymmetric
hydrogenation of enolbenzoate phosphonates, the various
DuPHOS-Rh and BPE-Rh catalysts were screened against
model substrates 3a-b. Reactions were carried out in
methanol with an initial hydrogen pressure of 4 atm and the
results are shown in Table 1. In the case of 3a, Et-DuPHOS-
Rh (1b-Rh) provided the highest enantioselectivity. However,
when the hydrogenation of 3b was attempted with Et-
DuPHOS-Rh, the conversion dropped to only 9% after 2
days. Hydrogenation of 3b with Me-DuPHOS-Rh (1a-Rh)
and Me-BPE-Rh (2a-Rh) were then examined and Me-
DuPHOS-Rh effected complete conversion to 4b after 48 h
with 86% ee.
catalysts. In the present case however, the R/S assignment
is reversed by replacing a carboxylate ester with a phospho-
nate ester.
Pressure and solvent effects for catalytic asymmetric
hydrogenations can be quite dramatic in terms of reaction
rates and enantioselectivity.12 In the case of enolbenzoate
phosphonates, methanol was found to be the superior solvent
based on enantioselectivity and reaction rate (complete in
<12 h under the conditions given in Table 2). For the
hydrogenation of 3a, ethanol, CH2Cl2, hexane, diethyl ether,
and DME yielded enantioselectivities above 90% using the
Et-DuPHOS-Rh catalyst but required more than 12 h to go
to completion. Performance of the hydrogenation reaction
with 3a was particularly poor in benzene and toluene. Recent
studies have shown that these aromatic solvents can form
stable complexes with the cationic DuPHOS-Rh catalysts in
solution and that some classes of substrates are slow to
displace the arene ligands thereby resulting in poor conver-
sions and compromised enantioselectivities.5,13 The influence
of initial hydrogen pressure upon the asymmetric hydrogena-
tion of 3a was tested in a range of 1-6 atms. All reactions
were complete in less than 24 h with no observable effect
on the enantioselectivity. The effect of higher H2 pressure
It should be noted that the stereochemical sense of the
reduction is consistent with results obtained for the hydro-
genation of enamido esters4b and enol esters5 using these
(6) (a) Arai, T.; Bougauchi, M.; Sasai, H.; Shibasaki, M. J. Org. Chem.
1996, 61, 2926. (b) Wynberg, H.; Smaardijk, A. A. Tetrahedron Lett. 1983,
24, 5899.
(7) Examples of the catalytic asymmetric hydrogenation of enamido
phosphonates include: (a) Schmidt, U.; Oehme, G.; Krause, H. Synth.
Commun. 1996, 26, 777. (b) Talley, J. J. US 5,321,153 14.6.94; Appl.
898,253 15.6.92. (c) Schollkopf, U.; Hoppe, I.; Thiele, A. Liebigs Ann.
Chem. 1985, 555. Analogous enamido phosphinic acid esters: Dwars, T.;
Schmidt, U.; Fischer, C.; Grassert, I.; Kempe, R.; Frohlich, R.; Drauz, K,
Oehme, G. Angew. Chem., Int. Ed. Engl. 1998, 37, 2851.
(8) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995,
60, 6656.
(9) R-Keto phosphonate intermediates of 3a-h proved to be unstable,
decomposing over several days at room temperature.
(10) E/Z assignment was based on JPH coupling constants: JPHa ) ∼11
Hz, JPHb ) ∼35 Hz(Bentrude, W. D.; Setzer, W. N. In 31P NMR in
stereochemical Ananlysis; Verkade, J. G., Quin, L. D., Eds.; VCH Publishers
Inc.: Deerfield Beach, FL, 1987; p 379).
(11) Enantiomeric excess determined by comparison to racemate. Race-
mates for 4a, 8, and 9 were prepared by hydrogenation of the precusor
olefins with the [(DiPFc)Rh(COD)]OTf catalyts (DiPFc ) 1,1′-bis-
(diisopropylphosphino)ferrocenyl). Racemic mixtures for 4b-h were
prepared through the hydrogenation of the precursor olefins with 10% Pd/
C.
(12) Halpern, J. In Asymmetric Catalysis; Morrison, J. D., Ed.; Academic
Press: New York, 1985; Vol. 5, p 41. (b) Sawamura, M.; Kuwano, R.; Ito,
Y. J. Am. Chem. Soc. 1995, 117, 9602. (c) Ojima, I.; Kogure, T.; Yoda, N.
J. Org. Chem. 1980, 45, 4728.
(13) Burk, M. J.; Bienewald, S.; Challenger, S.; Derrick, A.; Ramsden,
J. A. J. Org. Chem. 1999, 64, 3290.
388
Org. Lett., Vol. 1, No. 3, 1999

was not examined. However, in previous studies involving
the DuPHOS-Rh and BPE-Rh catalysts, only minor effects
on enantioselectivity were observed for the asymmetric
hydrogenation of other substrates at elevated H2 pressures
(up to 100 atm).4 The effect of temperature was not examined
for the reaction involving 3.
h to afford the corresponding R-hydroxy phosphonates 5.
An example is shown in Scheme 2, where 4d is converted
to the previously reported compound 5d6a with no apparent
loss of optical purity.
Results of the catalytic asymmetric hydrogenation involv-
ing a series enolbenzoate phosphonates 3 are shown in Table
2. For the aliphatic substituents, enantioselectivities were
Scheme 2
Table 2. Enolbenzoate Phosphonates 3 Hydrogenated with the
DuPHOS/BPE-Rh Catalystsa
II. r-Amino Phosphonates. N-acetyl and N-Cbz enamido
phosphonates 6 and 7a were synthesized as described in the
literature.14 A practical route to a variety of substituted
enamido phosphonates has yet to be demonstrated despite
several strategies published in the literature.7,14 Ligand
optimization studies were performed on the N-acetyl and
N-Cbz enamido phosphonates 6 and 7a. The Et-DuPHOS-
Rh catalyst provided optimum enantioselectivities for both
the N-acetyl 6 and N-Cbz 7a enamido phosphonate substrates
as illustrated in Table 3.
Table 3. Ligand Optimization for the DuPHOS/
BPE-Rh-Catalyzed Asymmetric Hydrogenation of N-acetyl 6
and N-Cbz 7 Enamido Phosphonates
subst
R
ligand
conva
% eeb
configc
6
6
6
6
7a
7a
7a
7a
7a
Ac
Ac
Ac
Ac
Cbz
Cbz
Cbz
Cbz
Cbz
(S,S)-1a
(S,S)-1b
(S,S)-1c
(R,R)-1d
(S,S)-2a
(S,S)-1a
(S,S)-1b
(S,S)-1c
(R,R)-2b
100
100
90
6
88
93
95
68
ND
88
90
94
81
57
R-(-)
R-(-)
R-(-)
ND
R-(-)
R-(-)
R-(-)
R-(-)
S-(+)
a Conditions: [(ligand)Rh(COD)]OTf, S/C 125, MeOH, 4 atm H2, 25
°C, 12-48 h. b Enantiomeric excess determined by chiral HPLC on a Daicel
Chiralcel OJ column for 6a, Chiralpak OT column for 6b-f and a Chiracel
OB for 6h.11 c 57% conversion.
72
100
100
93
good, ranging from 86 to 96%. The highest stereoselectivity
for the unsubstituted 3a was obtained with Et-DuPHOS-Rh
catalyst. Alkyl-substituted enolbenzoate substrates 3b-g
were reduced with optimum ee’s using the less bulky Me-
DuPHOS-Rh, consistent with the ligand optimization studies
shown in Table 1. In the case of the more sterically
demanding p-methoxyphenyl substituent on 3h, the reaction
did not proceed with Me-DuPHOS-Rh but did go to partial
conversion using the less rigid Me-BPE-Rh catalyst after 2
days, although only modest enantioselectivity was observed.
The R-benzoyloxy phosphonates 4 can be simply depro-
tected using K2CO3 in methanol at room temperature for 2
a Conversion determined by 1H or 31P NMR. b Enantiomeric excess
determined by chiral GC on a Chirasil-L-Val column.11 c Absolute
configuration assigned based on data supplied by Talley.7b
Ligand optimization reactions were performed in MeOH,
however, further studies of the solvent effects showed that
in the hydrogenation of 7a using Et-DuPHOS-Rh, i-PrOH
gave a marginally higher ee (95%). Hydrogenation reactions
involving 7a did not proceed well in benzene and toluene,
presumably analogous to what was observed for the hydro-
genation of 3a in these solvents.
Org. Lett., Vol. 1, No. 3, 1999
389

Initial studies involving the catalytic asymmetric hydro-
genation of substituted enamido phosphonates include the
Et-DuPHOS-Rh reduction of (E)-3-methyl-1-benzyloxycar-
bonylamino-1-dimethylphosphonylbut-1-ene 7b (not shown)
to produce 9b (Figure 2), a compound previously reported
Scheme 3
pected in light of previous observations for the catalytic
asymmetric hydrogenation of various classes of substrates
employing the DuPHOS-Rh and BPE-Rh catalysts where E-
and Z-substituted olefins allowed for comparable selectivi-
ties.4b-c,5,15
Figure 2. N-Cbz R-amino phosphonates.
The catalytic asymmetric hydrogenation of enolbenzoate
phosphonates using the DuPHOS-Rh and BPE-Rh catalysts
provides an efficient route to enantiomerically enriched alkyl-
substituted R-hydroxy phosphonates. Given the ease with
which substrates 3 are prepared this method is likely to find
broad application for the preparation of R-hydroxy phos-
phonate derivatives. Preliminary studies also have shown that
the Et-DuPHOS-Rh catalysts can hydrogenate enamido
phosphonates effectively and with moderate to high enan-
tioselectivity, potentially providing a convenient route to
R-amino phosphonates in high enantiomeric purity.
by Talley.7b The reaction was complete after 12 h at room
temperature in MeOH with an initial H2 pressure of 4 atm,
resulting in an enantiomeric excess of 95%. Consistent with
results from the enol phosphonate series, aryl-substituted
enamido phosphonates appear to give lower enantioselec-
tivities compared to their alkyl counterparts. Reduction of
(E)-phenyl-substituted N-Cbz enamido phosphonate7b 7c (not
shown) with Me-DuPHOS-Rh provided 9c in 76% ee.
The (Z)-methyl enamido phosphonate 7d was prepared in
poor yield (11%) in a condensation reaction between
dimethylpropionylphosphonate and benzylcarbamate as shown
in Scheme 3, conditions similar to those used in the
preparation of the unsubstituted parent substrate 7a.14 After
a failed attempt to hydrogenate 7d with Et-DuPHOS-Rh, the
reduction was attempted with Me-DuPHOS-Rh which al-
lowed complete conversion to afford 9d in 71% ee. The
lower ee achieved in the reduction of (Z)-enamide 7d
represents a significant compromise in selectivity compared
to the result for 9b which was obtained from the (E)-enamide.
This dependence on substrate geometry is somewhat unex-
Acknowledgment. Thanks to Steve Truckenbrod and
George Dubay for acquiring HRMS data. This research was
funded by a grant from Pew Charitable Trusts. T.A.S. was
supported by a fellowship established by Burroughs-
Wellcome. We thank Dr. John Talley of Monsanto for
providing substrate 7b.
Supporting Information Available: Preparations and
1
characterization for 3, 4, 8, and 9a including H, 13C, and
31P spectra, optical rotations, HRMS, and chiral HPLC and
GC data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Zon, J. Synthesis 1981, 324.
(15) (a) Burk, M. J.; Bienewald, F.; Harris, M.; Zanotti-Gerosa, A. Angew.
Chem., Int. Ed. Engl. 1998, 37, 1931. (b) Burk, M. J.; Casy, G.; Johnson,
N. J. Org. Chem. 1998, 63, 6084.
OL9906099
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Org. Lett., Vol. 1, No. 3, 1999