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J.-M. Hwang et al. / Tetrahedron Letters 50 (2009) 6076–6078
tives. We have also accomplished aldol reaction of the oxaphos-
pholene intermediate with several aldehydes as electrophiles
under mild and neutral conditions to produce -hydroxy-
methoxy- -oxaphosphonates. These phosphonates, because of
c
c-
c
the ester moiety, can be easily converted into various functional
groups and in addition, this intermediate can be used for the
chain elongation in the synthesis of diverse bioactive com-
pounds.
Acknowledgments
We thank the Regional Technology Innovation Program of the
Ministry of Knowledge Economy (MKE), Korea, for financial sup-
port (Grant No. RTI05-01-02). This work was also supported by
the start-up fund provided by Roosevelt University.
Scheme 2.
the stereoselectivity; condensation between the bulkiest oxaphos-
pholene and benzaldehyde gave the best syn diastereoselectivity
(syn:anti = 4.9:1). In contrast, we found that increasing the bulki-
ness had a very little effect on the stereochemistry of our aldol
products.
Supplementary data
Supplementary data (representative experimental details for
the synthesis and the characterization data for key intermediates
are provided.) associated with this article can be found, in the on-
We presumed that the observed ratio of syn and anti isomers is
associated with the methoxy substituent at C-5 on the 1,2k5-oxa-
phospholene and with the oxygen anion in the possible enolate
intermediate after cleavage of apical P–O bond in the oxaphos-
pholene. Our postulated mechanism is that the methoxy group
at C-5 in the oxaphospholene ring allows equilibrium between
E/Z enolates which results in almost similar ratio of syn and anti
isomers. Additional experiments are in progress to examine the
influence of other phosphites and enones on the stereochemical
outcome of the phosphonate-containing aldol products. In addi-
tion, microwave-assisted condensation reaction of 1,2k5-oxaphos-
pholene intermediate and benzaldehyde appears to reduce the
reaction time dramatically. This reaction was carried out neat
and the phosphonate product could be obtained in 30 min at
120 °C (employing an average microwave power of 200 W). We
are currently improving the reaction conditions and will report
the results with other outcome soon.
Relative stereochemistry of the aldol products 3–7 were deter-
mined by comparison of their spectral data with the corresponding
product independently prepared by the use of Mukaiyama’s eno-
late of compound 1 (Scheme 2).3,8 The phosphonate-containing al-
dol compounds, 3s–5s (syn isomers), were independently
synthesized via the reaction of the 9-BBN boron enolate of 1 with
the aldehydes in question (yield 60–70%). This Mukaiyama enolate
procedure is known to produce syn aldol stereochemistry and was
utilized to compare with our syn product obtained from the con-
densation reaction. The NMR data (1H, 13C, and 31P) as well as IR
and MS were identical with the corresponding spectra for the syn
isomer.
References and notes
1. (a) Sikorski, J. A.; Logusch, E. W. In Handbook of Organophosphorus Chemistry;
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Handbook of Organophosphorus Chemistry; Engel, R., Ed.; Marcel Dekker: New
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2. (a) Kalir, A.; Kalir, H. H.. In The Chemistry of Organophosphorus Compounds;
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Engel, R. Chem. Rev. 1977, 77, 349–367; (c) Fields, S. C. Tetrahedron 1999, 55,
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Kim, C. U.; Misco, P. F.; Luh, B. Y.; Hitchcock, M. J. M.; Ghazzouli, I.; Martin, J. C. J.
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7. General procedure for the preparation of condensation products (3–7).
A
mixture of distilled enone (1 equiv) and triethylphosphite (1 equiv) was stirred
for 3–4 days at room temperature. Unreacted triethylphosphite was removed
under vacuum at 55 °C (12 mmHg). To the 2,2,2-triethoxy-5-methoxy-1,2c5
-
oxaphospholene (1.0 mmol), in a flame-dried flask under argon, was added
freshly distilled aldehyde (1.2–1.6 mmol) and stirred at ambient temperature
(0 °C for the reactions with acetaldehyde) and monitored by 1H NMR
spectroscopy. For the condensations with benzaldehyde, the oxaphospholene
was diluted with CH2Cl2 prior to addition of aldehyde. The reaction mixture was
then heated to 40 °C and monitored as mentioned above by taking aliquots from
each reaction. After disappearance of the 2,2,2-triethoxy-1,2c
5-oxaphospholene,
distilled water (10.0 mL) was added to the reaction mixture. The mixture was
allowed to stir for 8–10 h, and the crude product was extracted with CH2Cl2. The
combined organic extracts were washed with distilled water, dried over
anhydrous MgSO4, and concentrated in vacuo. After initial purification of the
crude product with flash column chromatography to remove most of unwanted
material, all of the combined mixture of diastereomers was separated with HPLC
using CH2Cl2.
In conclusion, we have been able to synthesize P(V)-2,2,2-trialk-
oxy-2,2-dihydro-5-methoxy-1,2k5-oxaphospholenes as a new type
of enolate, and have shown its application through the synthesis of
variously substituted phosphonates.
Hydrolysis of the oxaphospholene intermediate gave access to
a number of esterphosphonate and amidophosphonate deriva-
8. Mukaiyama, T.; Inoue, T. Bull. Chem. Soc. Jpn. 1980, 53, 174–178.