Asymmetric synthesis of β-phosphono malonates via Fe2O3-mediated phospha-Michael addition to Knoevenagel acceptors

Article abstract of DOI:10.1021/ol016591v

(matrix presented) The first asymmetric P-C bond formation under heterogeneous conditions was achieved via a Fe₂O₃-mediated conjugate addition of a chiral phosphite to alkylidene malonates. The easy cleavage of the chiral auxiliary f

Full text of DOI:10.1021/ol016591v

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3515-3517
Asymmetric Synthesis of â-Phosphono
Malonates via Fe2O3-Mediated
Phospha-Michael Addition to
Knoevenagel Acceptors
Livio Tedeschi and Dieter Enders*
Institut fu¨r Organische Chemie, Rheinisch Westfa¨lische Technische Hochschule,
Professor-Pirlet-Strasse 1, 52074 Aachen, Germany
enders@rwth-aachen.de
Received August 15, 2001
ABSTRACT
The first asymmetric P−C bond formation under heterogeneous conditions was achieved via a Fe2O -mediated conjugate addition of a chiral
3
phosphite to alkylidene malonates. The easy cleavage of the chiral auxiliary from the addition products leads to optically active â-substituted
â-phosphono malonates in good yields and high enantiomeric excesses.
The pioneering work on P-C bond formation was carried
out by Arbusov in the early 20th century, culminating in
the well-known Michaelis-Arbuzov reaction.1 In the fol-
lowing decades the chemistry of phosphonates has developed
relatively slowly because of the difficulty of forming the
C-P bond. Its renaissance came after 1959 with the
discovery of natural occurring aminophosphonic acids2 and
new biologically active phosphonates.3
Phosphonoacetic acid,4 for example, has been shown to
inhibit the replication of cytomegalovirus and herpes virus
by interacting directly with the virus-induced DNA poly-
merase. Phosphonoformate5 has shown activity in cell
cultures against HTLV-III (the virus implicated in AIDS),
and a derivative of â-phosphonomalonic acid6 was used as
an inhibitor of ras farnesyl protein transferase in studies
directed to the development of new antitumor agents.
The need for testing new optically active highly function-
alized phosphonates with different substitution patterns for
biological activity has made their synthesis of increasing
interest.7 However, only a few methods have been developed
so far for the asymmetric P-C bond formation, generally
limited to the asymmetric additions of phosphites to imines
or aldehydes8 in the presence of organometallic bases or
catalysts.
(1) (a) Michaelis, A.; Kaehne, R. Ber. Dtsch. Chem. Ges. 1898, 31,
1048-1055. (b) Arbusov, B. A. Pure Appl. Chem. 1964, 9, 307-335.
(2) (a) Horiguchi, M.; Kandatsu, M. Nature 1959, 184, 901-902. (b)
Fields, S. C. Tetrahedron 1999, 55, 12237-12273.
(3) (a) Hildebrand, R. The Role of Phosphonates in LiVing Systems; CRC
Press: Boca Raton, 1983. (b) Engel, R. Chem. ReV. 1977, 77, 349-367.
(c) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur, Silicon Relat. Elem. 1991,
63, 193-215.
(4) (a) Shipkowitz, N. L.; Bower, R. R.; Appell, R. N.; Nordeen, C. W.
Appl. Microbiol. 1973, 26, 264-267. (b) Mao, J. C. H.; Robishaw, E. E.
Biochemistry 1975, 14, 5475-5479. (c) Sabourin, C. L. K.; Reno, J. M.;
Boezi, J. A. Arch. Biochem. Biophys. 1978, 187, 96-101. (d) Mao, J. C.
H.; Otis, E. R.; von Esch, A. M.; Herrin, T. R. Antimicrob. Agents
Chemother. 1985, 27, 197-202.
(5) Sandstrom, E. G.; Kaplan, J. C.; Byington, R. E.; Hirsch, M. S. Lancet
1985, 1, 1480-1482.
(6) Patel, V. D.; Schmidt, R. J.; Biller, S. A.; Gordon, E. M.; Robinson,
S. S.; Manne, V. J. Med. Chem. 1995, 38, 2906-2921.
(7) Dhawan, B.; Redmore, D. Phosphorus Sulfur 1987, 32, 119-144.
(8) (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem. 1997, 109, 1290-
1310; Angew. Chem., Int. Ed. Engl. 1997, 36, 1236-1246. (b) Sasai, H.;
Bougauchi, M.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1997, 38, 2717-
2720. (c) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995,
60, 6656-6657. (d) Hanessian, S.; Bennani, Y. L.; Herve´ Y. Synlett 1993,
35-36. (e) Blazis, V. J.; Koeller, K. J.; Spilling, C. D. Tetrahedron:
Asymmetry 1994, 5, 499-502. (f) Devitt, P. G.; Kee, T. P. Tetrahedron
1995, 40, 10987-10996.
10.1021/ol016591v CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/11/2001

In a previous communication9 we reported the first general
asymmetric Michael addition10 of a phosphorus nucleophile
to nitroalkenes. Herein we describe the conjugate addition
of the enantiopure phosphite (R,R)-1 to R,â-unsaturated
malonates 2 as a key step in the synthesis of optically active
â-substituted â-phosphono malonates 5 (Scheme 1). This
triple bonds using a solid base was first shown by Koenig
and co-workers,13 who used an Al2O3/KOH system in the
Pudovik reaction of various secondary phosphines and
phosphites.
In recent years other research groups were also involved
in the study of C-C bond formation via Michael addition
using MgO14 or Mg-Al-O-t-Bu hydrotalcite15 as solid base
catalysts.16 In the latter case the activity of the solid base
catalyst was shown to be strongly dependent on the prepara-
tion method of the oxide and the pretreatment temperature.
As heterogeneous reactions can be performed under
particularly mild conditions, we decided to develop a new
solid base for the asymmetric conjugate addition of phos-
phorus nucloephiles to R,â-unsaturated malonates.
Metal oxides can activate P(O)H groups so that deproto-
nation of the P-H bond occurs in the presence of weaker
bases than organolithium reagents such as, for example,
KOH.
Scheme 1. Asymmetric Synthesis of â-Substituted
â-Phosphono Malonatesa
In our study we first examined the effect of different metal
oxides as solid supports for KOH on the stereoselectivity of
the Michael addition of (R,R)-1 to malonate 2a (Scheme 2).
Scheme 2. Case Study for the Screening of the Solid Base
a (a) Fe2O3/KOH, CH2Cl2, rt. (b) TMSCl, NaI, CH3CN, reflux.
(c) CH2Cl2/H2O. (d) CH2N2, MeOH/H2O.
reaction constitutes the first example of asymmetric P-C
bond formation under heterogeneous conditions.
Phosphite (R,R)-1 was prepared from TADDOL11
(R,R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyl-1,3-di-
oxo-lane in a two-step procedure as previously reported.9
The conjugate addition of (R,R)-1 to the alkylidene
malonates 2a-e in the presence of Fe2O3/KOH as a solid
base led to chiral â-phosphono malonates 3a-e in good
yields and high diastereomeric excesses.
The TADDOL auxiliary was easily cleaved9,12 without
detectable epimerization or racemization, by refluxing the
addition products in acetonitrile in the presence of TMSCl/
NaI and subsequently hydrolyzing the resulting bistrimeth-
ylsilyl ester.
The solid bases for the initial screening were prepared by
dissolving KOH in methanol and adding the solution to a
stirred suspension of the desired metal oxide in methanol.
The solvent was then removed under reduced pressure, and
the residue dried under vacuum at room temperature. A 1:5
ratio of phosphite/solid support and a 1:1.7 molar ratio of
phosphite/base were initially used.
Formation of the phosphonate 3a could be observed in
all cases with a diastereoselectivity depending on the metal
oxide. The best value was achieved in the case of Fe2O3
(Table 1).
The very polar acids (S)-4a-e were not isolated but
directly esterified with CH2N2 to the corresponding methyl
esters (S)-5a-e, which could be easily purified by flash
column chromatography on silica gel (n-hepane/isopropyl
alcohol 9:1).
The presence of the solid support appeared to be essential
for the activation of the P-H bond toward deprotonation.
No reaction could be observed when only KOH in the
absence of metal oxide was used.
The solvent effect was also studied, and among those
examined, CH2Cl2 led to the best diastereoselectivity com-
The possibility of performing the addition of a phosphorus
compound, containing a labile P-H bond, to double and
(9) Enders, D.; Tedeschi, L.; Bats, J. W. Angew. Chem. 2000, 112, 4774-
4776; Angew. Chem., Int. Ed. 2000, 39, 4605-4607.
(10) (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061.
(b) Leonard, J.; D´ıez_Barra, E.; Merino, S. Eur. J. Org. Chem. 1998, 63,
2051-2061. (c) Rossiter, B. E.; Swingle, N. Chem. ReV. 1992, 92, 771-
806.
(11) (a) Beck, A. K.; Bastani, B.; Plattner, D. A.; Petter, W.; Seebach,
D.; Braunschweig, H.; Gysi, P.; La Vecchia, L. Chimia 1991, 45, 238-
244. (b) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem. 2001, 113,
96-142; Angew. Chem., Int. Ed. 2001, 40, 92-138.
(12) Morita, T.; Okamoto, Y.; Sakurai, H Tetrahedron Lett. 1978, 28,
2523-2526.
(13) (a) Semenzin, D.; Etemad-Moghadam, G.; Albouy, D.; Diallo, O.;
Koenig, M. J. Org. Chem. 1997, 62, 2414-2422. (b) Albouy, D.; Laspe´ras,
M.; Etemad-Moghadam, G.; Koenig, M. Tetrahedron Lett. 1999, 40, 2311-
2314.
(14) Kabashima, H.; Tsuji, H.; Hattori, H. Appl. Catal., A 1997, 165,
319-325.
(15) Choudary, B. M.; Kantam, M. L.; Reddy, C. V.; Figueras, F.
Tetrahedron 2000, 56, 9357-9364.
(16) (a) Tanabe, K.; Ho¨lderich, W. F. Appl. Catal., A 1999, 181, 399-
434. (b) Hattori, H. Chem. ReV. 1995, 95, 537-538. (c) Ono, Y.; Baba, T.
Catal. Today 1997, 38, 321-337. (d) Tungler, A.; Fodor, K. Catal. Today
1997, 37, 191-208. (e) Barteau, M. A. Chem. ReV. 1996, 96, 1413-1430.
3516
Org. Lett., Vol. 3, No. 22, 2001

conjugate addition of (R,R)-1 to variously substituted aro-
matic R,â-unsaturated malonates 2. Optically active â-sub-
stituted â-phosphono malonates 3a-e could thus be obtained
in good chemical yields (61-75%) and high de (82-94%)
(Table 2).
Table 1. Screening of Different Solid Bases for the Michael
Addition of Phosphite (R,R)-1 to Malonate 2a to Form the
Adduct 3a (Scheme 2)
entrya
solid base
yield [%]b
de [%]c
Aliphatic substituents were also employed (cyclohexyl,
isopropyl), and they showed even higher reactivity leading
to improved yields (85-87%) but only unsatisfactory de
values (15-30%).
Separation of small quantities of minor diastereoisomer
in the addition products 3a-e could be achieved by HPLC
or recrystallization to obtain optically pure compounds.
1
2
3
4
5
6
Al2O3/KOH
ZnO/KOH
Cu2O/KOH
MnO2/KOH
Fe2O3/KOH
MgO/KOH
88
81
77
72
85
85
65
43
41
58
77
67
a All reaction were carried out in CH2Cl2 (1 mL/mmol) at room
temperature. b Yields of isolated products. c Determined via 31P NMR
spectroscopy of the crude product.
The absolute configuration of the new stereogenic center
generated by the conjugate addition was unambiguously
established as S by X-ray crystallography of 3e.18
pared to oxygen-containing solvents such as methanol,
acetone, THF, diethyl ether, or dimethoxyethane.
The diastereoselectivity was also strongly dependent on
the molar ratio of base adsorbed on the solid support, and
the best results could be obtained in the case of a 1:2.5 molar
ratio phosphite/KOH.
The cleavage of the chiral auxiliary under nonracemizing
conditions in the final step led to the title products (S)-5a-e
in good yields (Table 3).
As already mentioned pretreatment of the solid base plays
a crucial role on its activity. The most effective system was
obtained by drying the solid base under high vacuum for 72
h at 140 °C and performing the addition reaction in the
presence of small amounts of water.
Curiously, in the presence of water the diastereoselectivity
of the addition proved to be time dependent, increasing with
longer reaction times.
Table 3. Cleavage of TADDOL Auxiliary to Yield
â-Phosphono Malonates (S)-5a-e
entry
product
yield [%]a
ee [%]b
δ
31P [ppm]
1
2
3
4
5
5a
5b
5c
5d
5e
72
86
77
74
82
84
92
94
84
90
27.8
27.9
27.8
28.0
27.8
The inexpensive and readily accessible Fe2O3/KOH system
could be now applied under optimized conditions17 to the
a Yields of isolated products. b Determined via HPLC over chiral
stationary phase (Daicel OD, Daicel AD, n-heptane/isopropyl alcohol, 9:1).
Table 2. Michael Addition of Phosphite (R,R)-1 to
R,â-Unsaturated Malonates 2a-e (Scheme 1)
In summary, we have succeeded in developing a general
and efficient asymmetric synthesis of â-substituted â-phospho-
no malonates in good yields and very good enantiomeric
excesses via a Fe2O3-mediated P-C bond forming Michael
addition under mild conditions. The title compounds are of
chemical and medicinal interest.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Sonderforschungs-bere-
ich 380) and the Fonds der Chemischen Industrie. We thank
Degussa AG, BASF AG, Bayer AG, and Aventis for the
donation of chemicals. We also thank Dr. J. W. Bats for the
X-ray structure analysis and Stephan Noll for his contribution
to the experimental part of this work.
OL016591V
(17) General procedure for the phospha-Michael addition to R,â-
unsaturated malonates. Phosphite (R,R)-1 (1 mmol), malonate 2 (1 mmol),
and solid base (2.7 g, containing 2.5 mmol KOH) were stirred together in
a minimum quantity of CH2Cl2 (1 mL), containing 5 mmol of water. The
solid base was then filtered off and washed with CH2Cl2, and the solvent
was evaporated under reduced pressure to give colorless solids, which were
purified by flash chromatography on silica gel (pentane/diethyl ether).
(18) Details of the X-ray structure analysis will be described in a full
paper.
a Yields of isolated products. b Determined via 31P NMR spectroscopy
of the crude product. Values in parentheses after chromatographic epimer
separation (Merck Fertigsa¨ule LiChrosorb, pentane/diethyl ether).
Org. Lett., Vol. 3, No. 22, 2001
3517