Thiourea-Catalyzed Enantioselective Hydrophosphonylation of Imines: Practical Access to Enantiomerically Enriched α-Amino Phosphonic Acids

Article abstract of DOI:10.1021/ja0494398

Chiral thiourea 1b catalyzes the highly enantioselective hydrophosphonylation of a wide range of N-benzyl imines. The hydrophosphonylation products are readily deprotected by hydrogenolysis, providing access to free α-amino phosphonic acids in highly enantioenriched form. Copyright

Full text of DOI:10.1021/ja0494398

Published on Web 03/13/2004
Thiourea-Catalyzed Enantioselective Hydrophosphonylation of Imines:
Practical Access to Enantiomerically Enriched r-Amino Phosphonic Acids
Guy D. Joly and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received January 30, 2004; E-mail: jacobsen@chemistry.harvard.edu
R-Amino phosphonic acids, their phosphonate esters, and short
peptides incorporating this unit are excellent inhibitors of a wide
range of proteolytic enzymes.1 In addition, R-amino phosphonate
derivatives have broad application due to their antibacterial2 and
antifungal3 activity, and as inhibitors of phosphatase activity.4 The
biological activity of compounds incorporating the R-amino phos-
phonic acid moiety depends on their absolute configuration.
Figure 1. Thiourea catalysts.
Therefore, the synthesis of enantiomerically enriched R-amino
phosphonates has received considerable attention, and there are
numerous reports of resolution and chiral auxiliary-based ap-
proaches.5 However, there are few catalytic enantioselective
methods available to access this class of compounds.6,7 Of these
methods, the most direct approach involves the addition of
phosphites to imines. While significant advances have been made
in the development of asymmetric hydrophosphonylation methodol-
ogy, the highest selectivities are generally restricted to cyclic imine
substrates, and an excess of the nucleophilic phosphite is required.8
Furthermore, there have been no reports of the asymmetric catalytic
synthesis of R-aryl-R-amino phosphonates. Herein, we describe a
highly enantioselective hydrophosphonylation of N-benzyl imines
promoted by a chiral thiourea catalyst (Figure 1). A mild procedure
for the global deprotection of the hydrophosphonylation products
is also demonstrated, providing straightforward access to enantio-
merically enriched R-amino phosphonic acids.
Chiral ureas and thioureas have recently emerged as highly
enantioselective catalysts for the addition of carbon nucleophiles
to activated π-systems.9 Preliminary exploratory experiments with
phosphorus-based nucleophiles revealed that thiourea catalyst 1a
(10 mol %) promoted the addition of dimethyl phosphite 3a to aryl
imine 2a at 23 °C with promising enantioselectivity (80% ee) but
poor reaction rate (35% conversion in 22 h).10 Attempts to improve
yield by raising the reaction temperature or increasing the concen-
tration of the nucleophile 3a led to dramatically reduced enanti-
oselectivities.
Table 1. Phosphite Optimizationa
1
phosphite
R
imine
time (h)
conv (%)b
ee (%)c
3bd
phenyl
2a
2bg
2a
2b
2ad
2be
2a
2b
2a
2b
2a
2b
2a
2b
1
1
1
1
2
2
8
8
32
8
100
100
100
100
83
85
89
91
50
65
86
90
99
77
80f
72f
53f
68
77
90
84
43
59
78
73
93
90
3cd
3d
3e
2,2,2-trifluoroethyl
2-cyanoethyl
2-chloroethyl
2-methoxyethyl
p-nitrobenzyl
o-nitrobenzyl
3f
3gh
3hi
24
18
26
24
100
a Reactions were carried out with 0.13 mmol of imine and phosphite in
100 µL of toluene. b Determined by 1H NMR. c Determined by chiral HPLC.
d Slow addition of phosphite over 1 h. e Slow addition of phosphite over 2
h. f Product is not configurationally stable and slowly racemizes upon
standing at 23 °C. g Reaction carried out using 100 µL of EtOAc as solvent.
h Reactions carried out using 600 µL of EtOAc as solvent. i Reactions carried
out using 300 µL of EtOAc as solvent.
Variation of catalyst structure revealed that 1b, which provides
the highest enantioselectivities in the asymmetric hydrocyanation
of imines,9d is also optimal for imine hydrophosphonylation.11,12
In addition, the electronic nature of the nucleophilic phosphite was
identified as a key parameter, with electron-withdrawing ester
substituents providing superior reaction rates (Table 1). Although
diphenyl phosphite 3b and bis-(2,2,2-trifluoroethyl) phosphite 3c
underwent rapid and moderately enantioselective reaction, the
resulting products were found to be configurationally unstable.13
Further optimization of the nucleophile revealed that slightly less
electron-deficient phosphites provided configurationally stable
adducts, albeit at the expense of reaction rate. In particular, the
additions of di-(2-chloroethyl) phosphite 3e and di-(2-nitrobenzyl)
phosphite 3h proceeded with high enantioselectivity. The reactivity
of phosphite 3h was investigated further, with the expectation that
its addition products would be susceptible to hydrogenolysis and
thereby serve as convenient precursors to unprotected R-amino
phosphonic acids.14
The addition of phosphite 3h to N-benzyl imines 2 catalyzed by
1b proved to be remarkably general under optimized conditions
(Table 2).15 High enantioselectivities were obtained across a wide
range of both aliphatic and aromatic substrates.16 Only imine 2f
bearing an alkenyl side chain and pyrrole derivative 2r afforded
modest ee’s (81-82%). However, the optical purity of addition
product 4f was enhanced to 99% ee after two recrystallizations (64%
overall yield from 2f). In general, the best reaction rates were
realized with aliphatic imines, while electron-poor aromatic sub-
strates required longer reaction times and, in certain cases, elevated
temperatures. The absolute configuration of products 4 obtained
using catalyst 1b was found to be consistent with the sense of
stereoinduction observed in the asymmetric Strecker and Mannich
reactions.9a-e
9
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J. AM. CHEM. SOC. 2004, 126, 4102-4103
10.1021/ja0494398 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Hydrophosphonylation of Iminesa
Current efforts are directed toward developing synthetic applications
and a mechanistic understanding of this promising hydrophosphon-
ylation reaction.
Acknowledgment. This work was supported by the NIH
(GM43214) and by a predoctoral fellowship from the National
Science Foundation to G.D.J.
Supporting Information Available: Representative experimental
procedures, characterization data, and chiral chromatographic analyses
of racemic and enantiomerically enriched products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
product
R
temp (°C)
time (h)
yield (%)b
ee (%)c
98
96
90
90
93
82 (99)
98
96
96
92
96
98
99
98
96
92
4ad
4b
4c
Ph
4
4
4
4
4
4
4
4
23
4
4
23
4
4
23
4
72
24
24
24
72
7
72
48
48
72
72
48
72
72
48
72
48
18
87
90
93
91
83
91 (64)
89
90
78
81
52
83
87
86
77
89
89
3-pentyl
i-Pr
c-hex
t-Bu
4d
4e
References
4fe,f
4g
4h
4i
(CH3)2CdCH
p-FC6H4
p-OMeC6H4
p-CO2CH3C6H4
o-MeC6H4
o-ClC6H4
m-ClC6H4
p-ClC6H4
2-naphthyl
3-pyridyl
2-furyl
(1) For reviews of the biological activity of R-amino phosphonic acids, see:
(a) Hiratake, J.; Oda, J. Biosci. Biotechnol. Biochem. 1997, 61, 211. (b)
Kafarski, P.; Lejczak, B. Phosphorus, Sulfur, and Silicon 1991, 63, 193.
For a fM inhibitor of carboxypeptidase A, see: (c) Kaplan, A. P.; Bartlett,
P. A. Biochemistry 1991, 30, 8165.
(2) (a) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassall, C. H.; Holmes, S.
W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S. Nature 1978, 272, 56.
(b) Pratt, R. F. Science 1989, 246, 917.
(3) Maier, L.; Diel, P. J. Phosphorus, Sulfur, and Silicon 1991, 57, 57.
(4) Beers, S. A.; Schwender, C. F.; Loughney, D. A.; Malloy, E.; Demarest,
K.; Jordan, J. Bioorg. Med. Chem.1996, 4, 1693.
(5) For reviews, see: (a) Dhawan, B.; Redmore, D. Phosphorus and Sulfur
1987, 32, 119. (b) Kukhar, V. P.; Soloshonok, V. A.; Solodenko, V. A.
Phosphorus, Sulfur, and Silicon 1994, 92, 239. (c) Kolodiazhnyi, O. I.
Tetrahedron: Asymmetry 1998, 9, 1279.
4j
4kg
4l
4m
4n
4o
4p
4q
4r
2-thienyl
2-pyrrolyl
23
4
94
81
86
(6) For a review, see: Gro¨ger, H.; Hammer, B. Chem.-Eur. J. 2000, 6, 943.
(7) (a) Burk, M. J.; Stammers, T. A.; Straub, J. A. Org. Lett. 1999, 1, 387.
(b) Schmidt, U.; Krause, H. W.; Oehme, G.; Michalik, M.; Fischer, C.
Chirality 1998, 10, 564. (c) Schmidt, U.; Oehme, G.; Krause, H. Synth.
Commun. 1996, 26, 777. (d) Scho¨llkopf, U.; Hoppe, I.; Thiele, A. Liebigs
Ann. Chem. 1985, 555. (e) Kitamura, M.; Tokunaga, M.; Pham, T.; Lubell,
W. D.; Noyori, R. Tetrahedron Lett. 1995, 36, 5769. (f) Sawamura, M.;
Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30, 2247.
(8) (a) Schlemminger, I.; Saida, Y.; Gro¨ger, H.; Maison, W.; Durot, N.; Sasai,
H.; Shibasaki, M.; Martens, J. J. Org. Chem. 2000, 65, 4818. (b) Gro¨ger,
H.; Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M. J.
Am. Chem. Soc. 1998, 120, 3089. (c) Gro¨ger, H.; Saida, Y.; Arai, S.;
Martens, J.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 9291.
(d) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995, 60,
6656.
a Reactions were carried out on a 0.5 mmol scale unless noted otherwise
using unpurified commercial diethyl ether under ambient atmosphere.
b Isolated yield after silica gel chromatography; yield in parentheses was
obtained after recrystallization. c Determined by chiral HPLC; ee in
parentheses was obtained after recrystallization (see Supporting Information).
d Absolute configuration determined by conversion to the known R-amino
phosphonic acid 5a. e Absolute configuration determined by conversion to
the known R-amino phosphonic acid 5f. The absolute configurations of all
other products 4 were assigned by analogy. f Reaction carried out on a 2.19
mmol scale. g Reaction employed 20 mol % 1b.
Scheme 1. Synthesis of R-Amino Phosphonic Acids
(9) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
(b) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2000, 39, 1279. (c) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867.
(d) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. (e)
Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. (f)
Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E. N. Synlett 2003, 1919. (g)
Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672.
(10) Other nucleophilic phosphorus reagents examined included diethyl phos-
phite (6% conversion, 22 h), trimethyl phosphite (0% ee), and dimethyl
tert-butyldimethylsilyl phosphite (no reaction, 16 h). The poor reactivity
of dimethyl tert-butyldimethylsilyl phosphite implies a critical role for
the proton of the dialkyl phosphites. This is further supported by the
somewhat counterintuitive increase in reaction rate with less electron-
rich dialkyl phosphite nucleophiles. A correlation between reactivity and
the acidity of the phosphite proton is suggested.
(11) For example, 1a catalyzes the addition of diphenyl phosphite 3b to imine
2a in 59% ee under the same conditions employed using 1b to provide
product in 77% ee (Table 1). Also, catalyst 1a affords 4c in 85% ee as
compared to 90% ee using catalyst 1b under the conditions described in
Table 2. Additional urea and thiourea catalysts were examined. See the
Supporting Information.
Hydrophosphonylation products 4 were examined as candidates
for global deprotection under mild hydrogenolytic conditions.
Treatment of adduct 4b with 20 mol % Pd/C under an atmosphere
of hydrogen afforded enantiomerically enriched R-amino phospho-
nic acid 5b (Scheme 1). Deprotection of phenyl glycine derivative
4a yielded 5a via selective hydrogenolysis of the three protecting
groups with no detectable cleavage of the more sterically demanding
phosphorus-substituted benzylic position. Finally, R-amino phos-
phonate 4f was prepared on a one-gram scale and recrystallized to
99% ee. Subjecting adduct 4f to the deprotection conditions resulted
in concomitant hydrogenation of the olefin to provide (R)-LeuP 5f,
the R-amino phosphonic acid analogue of leucine and a known
inhibitor of leucine amino peptidase.17
(12) These studies were guided by the hypothesis that catalysts 1 activate imines
to nucleophilic addition via hydrogen bonding to the thiourea protons.
See ref 9d.
(13) A crossover experiment revealed that racemization occurred via a retro-
addition pathway.
(14) For the preparation of 3h, see the Supporting Information.
(15) Optimization revealed very little solvent dependence; nonpolar ethereal
solvents give the highest enantioselectivities, with diethyl ether providing
optimal results. The reaction also displays a minimal dependence upon
concentration, but best results are achieved at 0.4 M. When possible,
lowering the temperature to 4 °C has a beneficial effect upon enantiose-
lectivity.
This new methodology provides general and convenient access
to a wide range of highly enantiomerically enriched R-amino
phosphonates. The deprotection of these products under mild
conditions yields the corresponding R-amino phosphonic acids.
(16) Unbranched aliphatic imines are not useful substrates due to their rapid
decomposition under the reaction conditions.
(17) Giannousis, P. P.; Bartlett, P. A. J. Med. Chem. 1987, 30, 1603.
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