One-pot synthesis of γ-hydroxy-γ-oxaphosphonates using pentacovalent oxaphosphorane chemistry

Article abstract of DOI:10.1016/j.tetlet.2009.08.059

P(V)-2,2,2-triethoxy-2,2-dihydro-5-methoxy-1,2λ⁵-oxaphospholene was synthesized as a new type of enolate which was hydrolyzed to give a series of phosphonates. In addition, aldol reaction of the oxaphospholene intermediate with several aldehyde

Full text of DOI:10.1016/j.tetlet.2009.08.059

Tetrahedron Letters 50 (2009) 6076–6078
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Tetrahedron Letters
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One-pot synthesis of
c
-hydroxy-
c-oxaphosphonates using pentacovalent
oxaphosphorane chemistry
a,
Jae-Min Hwang a, Tasneem Islam b, , Kang-Yeoun Jung
*
*
a Department of Environmental & Applied Chemistry, College of Engineering, Kangnung-Wonju National University, Gangneung 210-702, Republic of Korea
b Department of Biological, Chemical and Physical Sciences, Roosevelt University, IL 60173, USA
a r t i c l e i n f o
a b s t r a c t
P(V)-2,2,2-triethoxy-2,2-dihydro-5-methoxy-1,2k5-oxaphospholene was synthesized as a new type of
enolate which was hydrolyzed to give a series of phosphonates. In addition, aldol reaction of the oxaphos-
pholene intermediate with several aldehydes as electrophiles under mild and neutral conditions pro-
duced phosphonate-containing aldol compounds through a two-step one-pot reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 25 July 2009
Revised 19 August 2009
Accepted 20 August 2009
Available online 23 August 2009
Keywords:
Phosphonates
Oxaphospholene
Enolate
Aldol product
Phosphonate analogues have been extensively studied in recent
years due to their applications as antibiotics and anti-viral agents
as well as insecticides and herbicides.1,2 They show much greater
stability to hydrolysis and resistance to proteases than phosphates
and have been used as isosteric mimics of carboxylic acids or phos-
phate esters. Thus, new or improved methods for phosphonate
synthesis continue to attract much attention.
In our attempt to develop new methodology for the synthesis of
biologically active phosphonate derivatives, we have previously re-
ported the synthesis of carbon analogues of Ramirez’s 1,3,2k5-
dioxaphospholenes.3 These oxaphospholenes were prepared from
trialkylphosphite and methyl vinyl ketone and were reacted with
a series of aldehydes to make phosphonate-containing aldol com-
pounds under mild conditions. We subsequently applied this
methodology to efficiently synthesize antifungal agent, ( )-trans
and cis-neocnidilides.4
Herein we report our success in overcoming this aforemen-
tioned problem by synthesizing pentacovalent 2,2,2-trialkoxy-
2,2-dihydro-5-methoxy-1,2k5-oxaphospholenes. Reaction of these
oxaphospholenes with various aldehydes resulted in an ester
group in the final aldol compounds which can be easily functional-
ized and more importantly allow extension of C–C bond.
Trimethyl and triethyl phosphites were reacted with methyl
acrylate to give the corresponding pentacovalent 2,2,2-trimethoxy
or triethoxy-2,2-dihydro-5-methoxy-1,2k5-oxaphospholenes as a
new type of enolate (Scheme 1). However, both oxaphospholene
intermediates started to decompose when exposed to air. Triethyl
phosphite adduct proved to be more stable and resulted in higher
Despite our success in the development of a new methodology
for the synthesis of phosphonate-containing aldol compounds and
its application toward the synthesis of antifungal agent, this strat-
egy has a major limitation. It did not allow us to manipulate the
keto functional group and further extend the C–C bond. Thus,
transformation of the keto group on the final aldol compounds into
the corresponding carbonyl derivatives proved to be challenging to
make highly functionalized phosphonate derivatives.
* Corresponding authors. Tel.: +82 33 640 2403; fax: +82 33 641 2410 (K.-Y.J.).
E-mail addresses: tislam@roosevelt.edu (T. Islam), kyjung@kangnung.ac.kr (K.-Y.
Jung).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.059

J.-M. Hwang et al. / Tetrahedron Letters 50 (2009) 6076–6078
6077
yield compared to the outcome of trimethyl phosphite reaction.
Because of the instability, only the triethoxyoxaphospholene inter-
mediate was prepared and used for further reaction without
purification.5
product, 2:2a = 9:1.5 The unalkylated product 2 can then be further
modified to give the N-substituted phosphonates.6
The
P(V)-2,2,2-triethoxy-2,2-dihydro-5-methoxy-1,2k5-oxa-
phospholene intermediate synthesized was also reacted with a ser-
ies of aldehydes to afford compounds 3–77 in a two-step one-pot
approach.
A
new P(V)-2,2,2-triethoxy-1,2k5-oxaphospholene was ob-
tained from the reaction of freshly distilled triethyl phosphite with
methyl acrylate at room temperature which was hydrolyzed
immediately with water to give b-methylesterphosphonate 1, in
82% yield. Triethylphosphite was also treated with acrylamide at
room temperature, however, no reaction was observed. Carrying
out the reaction at room temperature and slowly increasing to
80 °C gave the corresponding P(V)-1,2k5-oxaphospholene which
after hydrolysis yielded a mixture of two products, amidophosph-
onate 2 and N-alkylated amidophosphonate 2a, respectively. These
mixtures were separated by column chromatography and the ratio
was determined to be 2:2a = 1:5 (yield 83%). We, then, attempted
to control the ratio of products by changing the reaction conditions
such as amount of phosphite and reaction temperature. Varying
the amount of trialkylphosphites did not affect the ratio of the
products. However, when we carried out the reaction at 80 °C,
we observed that unalkylated product 2 was obtained as the major
Our initial condensation reaction with benzaldehyde was per-
formed neat at ambient temperature and afforded only 60% of 3s
and 3a along with hydrolyzed product 1, after 3 days (Table 1, en-
try 1). Improved result was obtained when the reaction was con-
ducted in CH2Cl2 and refluxed at 40 °C (entry 2). However, in all
other cases, optimal yields were achieved when the condensation
reaction was carried out neat at 0 °C (only for entry 3) and at room
temperature (entries 4–6). Condensation reaction of P(V)-2,2,2-tri-
ethoxy-2,2-dihydro-5-methoxy-1,2k5-oxaphospholene intermedi-
ate with aldehydes at various temperatures resulted in
approximately 1:1 ratio of syn and anti isomers, which varied from
the previously published results (approximately syn:anti = 1.3–
4.9:1).3 Previous report where triethylphosphite was reacted with
methyl vinyl ketone demonstrated that the steric bulk of the li-
gands on the phosphorus and/or around the aldehydes influences
Table 1
Ratio of isomers and yields of the phosphonate-containing aldol products
Entry
Aldehydes (R0CHO)
Solvent
Temperature
Reaction time
Phosphonate products
Yielda (%)
Ratiob (syn:anti)
1
Neat
rt
3 days
60
1:1.1
2
3
4
5
6
CH2Cl2
Neat
Neat
Neat
Neat
rt ? 40 °C
24–26 h
32–36 h
24–26 h
24–26 h
24–26 h
81
75
77
77
78
1:1.2
1:1.1
1:1.1
1:1.1
1:1.1
CH3CHO
0 °C
rt
rt
rt
a
Isolated yields after HPLC purification.
Syn:anti ratio determined by HPLC and confirmed by 1H NMR spectroscopy.
b

6078
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-
line version, at doi:10.1016/j.tetlet.2009.08.059.
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;
Engel, R., Ed.; Marcel Dekker: New York, 1992; pp 739–805; (b) Eto, M. In
Handbook of Organophosphorus Chemistry; Engel, R., Ed.; Marcel Dekker: New
York, 1992; pp 807–873.
2. (a) Kalir, A.; Kalir, H. H.. In The Chemistry of Organophosphorus Compounds;
Hartley, F. R., Ed.; Wiley and Sons: New York, 1996; Vol. 4, pp 767–780; (b)
Engel, R. Chem. Rev. 1977, 77, 349–367; (c) Fields, S. C. Tetrahedron 1999, 55,
12237–12273; (d) Knowles, J. R.; Orr, G. A. Biochem. J. 1974, 141, 721–723; (e)
Kim, C. U.; Misco, P. F.; Luh, B. Y.; Hitchcock, M. J. M.; Ghazzouli, I.; Martin, J. C. J.
Med. Chem. 1991, 34, 2286–2294; (f) Varki, A. Glycobiology 1993, 3, 97–130.
3. McClure, C. K.; Jung, K. Y. J. Org. Chem. 1991, 56, 2326–2332.
4. McClure, C. K.; Jung, K. Y.; Grote, C. W.; Hansen, K. Phosphorus, Sulfur Silicon
Relat. Elem. 1993, 75, 23–26.
5. Hwang, J. M.; Kwon, H. B.; Lee, S. B.; Jung, K. Y. Bull. Korean Chem. Soc. 2009, 30,
239–241.
6. (a) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899–931; (b)
Couture, A.; Deniau, E.; Woisel, P.; Grandclaudon, P. Tetrahedron Lett. 1995, 36,
2483–2486; (c) Zamova, A. M.; Molodykh, Zh. V.; Kudryavtseva, L. A.;
Teplyakova, L. V.; Fedorov, S. B.; Ivanov, B. E. Pharm. Chem. J. 1986, 20, 774–777.
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.