Enantioselective construction of quaternary α-carbon centers on α-amino phosphonates via catalytic asymmetric allylation

Article abstract of DOI:10.1021/ol990679f

(equation presented) Asymmetric allylation of α-acetamido β-keto phosphonates was promoted, in the presence of potassium tert-butoxide as a base, by a palladium catalyst prepared from [Pd(π-allyl)(cod)]BF₄ and (R)-BINAP and gave the corresponding α-alkyl α-amino phosphonic acid derivatives with 65-88% ee. Diastereoselective reduction of the carbonyl group in the product was accomplished by NaBH₄ or Bu₄NBH₄. The diastereoselection in the reduction was reversed by choice of solvent.

Full text of DOI:10.1021/ol990679f

ORGANIC
LETTERS
1999
Vol. 1, No. 6
837-839
Enantioselective Construction of
Quaternary r-Carbon Centers on
r-Amino Phosphonates via Catalytic
Asymmetric Allylation
Ryoichi Kuwano, Ryo Nishio, and Yoshihiko Ito*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Sakyo-ku, Kyoto 606-8501, Japan
kuwano@sbchem.kyoto-u.ac.jp
Received May 19, 1999
ABSTRACT
Asymmetric allylation of r-acetamido â-keto phosphonates was promoted, in the presence of potassium tert-butoxide as a base, by a palladium
catalyst prepared from [Pd(π-allyl)(cod)]BF4 and (R)-BINAP and gave the corresponding r-alkyl r-amino phosphonic acid derivatives with
65−88% ee. Diastereoselective reduction of the carbonyl group in the product was accomplished by NaBH4 or Bu4NBH . The diastereoselection
4
in the reduction was reversed by choice of solvent.
Optically active R-amino phosphonic acids have received
much attention due to their potential biological activity1 as
well as being haptens of catalytic antibodies.2 The efficient
synthesis of optically active R-amino phosphonic acids is
one of the important topics in organic synthetic chemistry.
Although various chiral R-amino phosphonic acids have been
prepared with high enantiomeric excess by stoichiometric3
or catalytic4 asymmetric reaction,5 only one example of
stereoselective synthesis of R-amino phosphonic acids,
bearing a quaternary chiral R-carbon atom, has been, to the
best of our knowledge, reported.6,7
(4) (a) Sawamura, M.; Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30,
2247. (b) Baldwin, I. C.; Williams, J. M. J. Tetrahedron: Asymmetry 1995,
6, 679. (c) Kitamura, M.; Tokunaga, M.; Pham, T.; Lubell, W. D.; Noyori,
R. Tetrahedron Lett. 1995, 36, 5769. (d) Sasai, H.; Arai, S.; Tahara, Y.;
Shibasaki, M. J. Org. Chem. 1995, 60, 6656. (e) Gro¨ger, H.; Saida, Y.;
Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M. J. Am. Chem. Soc.
1998, 120, 3089.
(5) For reviews, see: (a) Dhawan, D.; Redmore, D. Phosphorus Sulfur
1987, 32, 119. (b) Mikolajczyk, M.; Drawbowicz, J.; Kielbasinski, P. In
StereoselectiVe Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol 9, p 5701. (c) Kukhar,
V. P.; Soloshonok, V. A.; Solodenko, V. A. Phosphorus Sulfur Silicon 1994,
92, 239.
* Alternate e-mail address: yoshi@sbchem.kyoto-u.ac.jp.
(1) For examples, see: (a) Atherton, F. R.; Hassall, C. H.; Lambert, R.
W. J. Med. Chem. 1986, 29, 29. (b) Camp, N. P.; Hawkins, P. C. D.;
Hitchcock, P. B.; Gani, D. Bioorg. Med. Chem. Lett. 1992, 2, 1047. (c)
Bird, J.; De Mello, R. C.; Harper, G. P.; Hunter, D. J.; Karran, E. H.;
Markwell, R. E.; Miles-Williams, A. J.; Rahman, S. S.; Ward, R. W. J.
Med. Chem. 1994, 37, 158.
(2) (a) Tramontano, A.; Janda, K. D.; Lerner, R. A. Science 1986, 234,
1566. (b) Pollack, S. J.; Jacobs, J. W.; Schultz, P. G. Science 1986, 234,
1570. (c) Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P.
A.; Taylor, S. D.; Yager, K. M.; Sprengeler, P. A.; Benkovic, S. J. Science
1994, 265, 234.
(3) (a) Hanessian, S.; Bennani, Y. L. Tetrahedron Lett. 1990, 31, 6465.
(b) Groth, U.; Richter, L.; Scho¨llkopf, U. Tetrahedron 1992, 48, 117. (c)
Laschat, S.; Kunz, H. Synthesis 1992, 90. (c) Yager, K. M.; Taylor, C. M.;
Smith, A. B., III. J. Am. Chem. Soc. 1994, 116, 9377. (d) Lefebvre, I. M.;
Evans, S. A., Jr. J. Org. Chem. 1997, 62, 7532.
(6) Studer, A.; Seebach, D. Heterocycles 1995, 40, 357.
(7) For examples of catalytic enantioselective construction of a quaternary
carbon center at R-position of phosphonates, see: (a) Sawamura, M.;
Hamashima, H.; Ito, Y. 65th National Meeting of the Chemical Society of
Japan; Tokyo, Japan; The Chemical Society of Japan: Tokyo, Japan, 1993;
p 4E402. (b) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996,
118, 3309.
10.1021/ol990679f CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/12/1999

A chiral carbon center is considerably difficult to construct
on prochiral nucleophiles with palladium-catalyzed asym-
metric allylation;8,9 however, a few catalyst systems have
been devised for highly enantioselective allylation.7b,10
Recently, we reported an asymmetric allylation of prochiral
nucleophiles, R-acetamido â-keto esters, introducing a chiral
carbon center to the substrate in high enantioselectivity.11
Herein, we describe an asymmetric allylation of R-acetamido
â-keto phosphonates 14c catalyzed by an optically active
BINAP12-palladium complex, which provided chiral R-
allylated R-amino â-keto phosphonates 3 with up to 88% ee
(Scheme 1). The reaction is the first catalytic enantioselective
The bulkier isopropyl group brought about a higher degree
of enantioface selection of the enolate of 1 (89% ee), but in
lower yield (34% yield for 48 h).
Other R-acetamido â-keto phosphonates 1b and 1c also
reacted with 2a, giving 3b and 3c with high stereoselectivi-
ties, respectively (entries 2 and 3). On the other hand, the
reactions of 1a with allyl acetates 2b and 2c proceeded with
79% and 65% ee, respectively (entries 4 and 5). The
γ-substituent R2 of 2 seemed to influence enantioselectivity
more than R1.
Next, trimethyl 1-(N-acetylamino)phosphonoacetate (4),16
in which a phosphonyl group replaced the ketone moiety of
R-acetamido â-keto ester, was subjected to the present
asymmetric allylation with 2a (Scheme 2). The reaction
Scheme 1
Scheme 2
proceeded slowly with lower enantioselectivity as compared
with those of 1. In comparison with the asymmetric allylation
of R-acetamido â-keto esters reported previously, the ketone
moiety may play a more important role in the stereocontrol
than the alkoxycarbonyl group.
synthesis of R-amino phosphonates with a quaternary chiral
carbon center.
The asymmetric allylation of 1 with 2 was carried out in
toluene at -30 °C with potassium tert-butoxide and 1 mol
% of the chiral catalyst prepared in situ by mixing (R)-
BINAP and [Pd(π-allyl)(cod)]BF4.13 The results are sum-
marized in Table 1. The BINAP-palladium catalyst was
(8) For reviews, see: (a) Hayashi, T. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH Publishers: New York, 1994; p 325. (b) Trost, B. M.;
Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (c) Williams, J. M. J. Synlett
1996, 705. (d) Lu¨bbers, T.; Metz, P. In StereoselectiVe Synthesis; Helmchen,
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart,
1996; Vol. 4, p 2371.
(9) (a) Fiaud, J.-C.; De Gournay, A. H.; Lacheve´que, M.; Kagan, H. B.
J. Organomet. Chem. 1978, 154, 175. (b) Hayashi, T.; Kanehira, K.;
Tsuchiya, H.; Kumada, M. J. Chem. Soc., Chem. Commun. 1982, 1162. (c)
Ito, Y.; Sawamura, M.; Matsuoka, M.; Matsumoto, Y.; Hayashi, T.
Tetrahedron Lett. 1987, 28, 4849. (d) Hayashi, T.; Kanehira, K.; Hagihara,
T.; Kumada, M. J. Org. Chem. 1988, 53, 113. (e) Sawamura, M.; Nagata,
H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 2586. (f) Sawamura,
M.; Nakayama, Y.; Tang, W.-M.; Ito, Y. J. Org. Chem. 1996, 61, 9090.
(g) Genet, J.-P.; Ferroud, D.; Juge, S.; Montes, J. R. Tetrahedron Lett. 1986,
27, 4573. (h) Genet, J.-P.; Juge, S.; Montes, J. R.; Gaudin, J. M. J. Chem.
Soc., Chem. Commun. 1988, 718. (i) Genet, J.-P.; Juge, S.; Achi, S.; Mallart,
S.; Montes, J. R.; Levif, G. Tetrahedron 1988, 44, 5263.
(10) (a) Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc.
1997, 119, 7879. (b) Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. Engl.
1997, 36, 2635.
(11) Kuwano, R.; Ito, Y. J. Am. Chem. Soc. 1999, 121, 3236.
(12) (R)-BINAP ) (R)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl: (a)
Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.;
Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (b) Takaya, H.; Mashima,
K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.; Akutagawa,
T.; Noyori, R. J. Org. Chem. 1986, 51, 629.
Table 1. Catalytic Asymmetric Allylation of R-Acetamido
â-Keto Phosphonates 1a
entry R1 (1)
R2 (2) time (h) product yieldb (%) eec (%)
1
2
3
4
5
Me (1a ) Ph (2a )
20
48
48
48
48
3a
3b
3c
3d
3e
87
72
78
27
80
87
78
88
79
65
Et (1b) Ph (2a )
Ph (1c) Ph (2a )
Me (1a ) Pr (2b)
Me (1a ) H (2c)
a All reactions were carried out in toluene (0.2 M) at -30 °C. The ratio
of 1/2/tBuOK/[Pd(π-allyl)(cod)]BF4/(R)-BINAP was 110:100:120:1:1.1.
b Isolated yield based on 2. c Determined by HPLC analysis with a chiral
stationary phase column.
(13) General Procedure for the Asymmetric Allylation of R-Acet-
amido â-Keto Phosphonates. A mixture of [Pd(π-allyl)(cod)]BF4 (1.7 mg,
5.0 µmol) and (R)-BINAP (3.3 mg, 5.3 µmol) in toluene (0.5 mL) was
stirred for 10 min at room temperature. Allyl ester 2 (0.50 mmol) was added
to the solution. After 10 min, the solution was added to a suspension of
R-acetamido â-keto phosphonate 1 (0.55 mmol) and tBuOK (67.3 mg, 0.60
mmol) in toluene (2.0 mL) at -30 °C. The reaction mixture was stirred for
20 h. The reaction was quenched by 1 N HCl aqueous (3.0 mL). The mixture
was extracted three times with EtOAc. The organic layer was washed with
brine, dried with Na2SO4, and evaporated under reduced pressure. The
residue was purified by preparative TLC (EtOAc/MeOH ) 10/1), giving
3.
effective for the asymmetric allylation of 1a with cinnamyl
acetate (2a), giving (S)-3a with 87% ee in 87% isolated yield
on the basis of 2a (entry 1).14 The allylation of 1a, which
was less reactive than the corresponding R-acetamido â-keto
ester,11 was carried out by use of an excess amount (1.1
equiv) of 1a over 2a.15 The O-substituents on the phosphonyl
group affected both the reactivity and the stereoselectivity.
838
Org. Lett., Vol. 1, No. 6, 1999

Optically active 3a can be readily converted to an R-alkyl
â-hydroxy R-amino phosphonic acid derivative 6 (Scheme
3). Diastereoselective reduction of (S)-3a was accomplished
BINAP-palladium catalyst, giving R-amino phosphonic acid
derivatives 3 bearing a quaternary chiral carbon center at
the R-position. We also succeeded in diastereoselective
reduction of 3, providing either diastereomer of the â-hy-
droxy R-amino phosphonates 6 by the appropriate choice of
solvent.
Scheme 3
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas, No. 706:
Dynamic Control of Stereochemistry, from Monbusho.
Supporting Information Available: Full characterization
and 13C NMR spectra for compounds 3, 5, and 6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL990679F
by NaBH4 in MeOH to give 6 a 74:26 syn/anti ratio of
isomers in 74% yield.17 The syn-selectivity was improved
to 82:18 (89% yield) by the use of Bu4NBH4, which does
not contain any metal cation. The improvement of the
selectivity suggests that the reduction of the ketone in MeOH
may proceed through a nonchelation transition state.18 The
stereoselectivity was significantly dependent upon reaction
solvent. The use of BuOH as a reaction solvent led to a
reverse in the diastereoselectivity, giving preferentially anti-
(2S,3R)-6 (anti/syn ) 85:15) in 78% yield.19
(17) General Procedure for the Chemoselective Reduction of 3. To a
solution of 3 (0.25 mmol) in MeOH or tBuOH (2.5 mL) was added NaBH4
or Bu4NBH4 (0.35 mmol) at the reaction temperature. After 3 disappeared
completely, saturated NH4Cl aqueous (1.0 mL) was added to the mixture,
and stirred for 5 min. The mixture was passed through a short column of
Na2SO4 (EtOAc), and the eluent was evaporated under reduced pressure.
The residue was purified by medium-pressure liquid chromatography after
passing through a short column of silica gel, giving 6.
(18) (a) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y.-D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J.
Science 1986, 231, 1108. (b) Ahn, N. T. Topics in Current Chemistry 1980,
88, 145.
(19) The relative and absolute configuration in 6 was assigned as
follows: Each diastereomer of 6 was converted into the corresponding cyclic
carbamate with bis(trichloromethyl)carbonate and diisopropylethylamine.
The relative configuration of 6 was assigned by NOE experiments of the
cyclic carbamates. The absolute configurations of 6 was determined by 1H
NMR analysis of the O-methylmandelate derivative of syn-6 according to
Trost’s procedure (see ref 20). Further details are described in the Supporting
Information.
t
In conclusion, asymmetric allylation of R-acetamido â-keto
phosphonates 1 proceeded in good enantioselectivity by
(14) The palladium catalyst prepared in situ from [Pd(π-allyl)Cl]2 was
also effective for the asymmetric reaction to give 86% ee of 3a. However,
the reaction rate was somewhat slow.
(15) The allylation of 1a with 1.5 equiv of 2a proceeded much slower
(78% yield for 48 h), and the enantiomeric excess of the product was 84%.
(16) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53.
(20) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S.
L.; Spinger, J. P. J. Org. Chem. 1986, 51, 2370.
Org. Lett., Vol. 1, No. 6, 1999
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