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
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.
JA0494398
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J. AM. CHEM. SOC. VOL. 126, NO. 13, 2004 4103