2006 Phosphonate Nitrone
2006 Phosphonate Nitrone
Abstract—A convenient method for the synthesis of N-substituted C-phosphorylated nitrones 2 from hydroxymethylphosphonates
via successive Swern oxidation and treatment with respective hydroxylamines is reported for the first time. Moderate (20%) to excel-
lent (up to 90%) diastereoselectivities in cycloadditions of nitrone 2a and terminal alkenes were observed with trans C5-substituted
isoxazolidines predominating. In ZnCl2-catalysed cycloadditions, mixtures enriched in cis diastereoisomers were produced.
2006 Elsevier Ltd. All rights reserved.
Cycloaddition reactions are among the most powerful for the synthesis of a wide range of substituted a-amino-
chemical transformations available to organic chemis- phosphonates, after reductive cleavage of the isoxazol-
try, because the regio- and stereochemistry of cyclo- idine ring (Scheme 2).
adducts are often controlled by both steric and electronic
effects.1–4 1,3-Dipolar cycloadditions of nitrones to Previously, attempts at synthesizing nitrones 2 from
alkene dipolarophiles are of special interest, since substi- formylphosphonates 3 had failed. Dialkyl formyl-
tuted isoxazolidines have found numerous applications phosphonates are chemically unstable and at 10 C
as enzyme inhibitors,5,6 furanoside ring mimics,7–10 as undergo decomposition to carbon monoxide and a di-
well as key intermediates in the synthesis of a variety alkyl phosphite.20 To overcome this problem, Vasella
of compounds after cleavage of the N–O bond.1 accomplished a multi-step synthesis of N-glycosyl-C-
dialkoxyphosphorylated nitrones 4 (Scheme 3),21 which
C-Alkoxycarbonyl nitrones 1 are easily available by without isolation were subjected to 1,3-dipolar cyclo-
condensation of the corresponding N-hydroxylamines addition with ethylene.
and alkyl glyoxylates and consequently they have been
employed in the syntheses of several amino acids as well Prompted by a recent letter by Chiacchio et al.22
as other biologically important compounds (Scheme which utilised the N-methyl nitrone obtained from
1).11–19
R R
It was reasoned that analogous N-substituted C-phos- NH OH R N O R'
5 N
3 4 O
phorylated nitrones 2 would be useful intermediates (R"O)2(O)P R'
(R"O)2(O)P P(O)(OR")2
2
R
O N O Scheme 2. Retrosynthesis of substituted a-aminophosphonates from
HC COOR" O HC P(O)(OR")2 nitrones 2.
R'
1 R'=COOR" 3
2 R'=P(O)(OR")2 O O
1. NH2OH
O O O O 2. HCHO O O O O
Scheme 1. Synthetic approaches to C-alkoxycarbonyl- and C-phos- OH
3.(R"O)2P(O)H N
phorylated nitrones. 4. p-benzoquinone O
P(O)(OR")2
4
* Tel.: +48 42 677 92 35; fax: +48 42 678 83 98; e-mail: dorota@
ich.pharm.am.lodz.pl Scheme 3. Synthesis of the N-chiral Vasella nitrone 4.
0040-4039/$ - see front matter 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.104
ARTICLE IN PRESS
2 D. G. Piotrowska / Tetrahedron Letters xxx (2006) xxx–xxx
signals between the H3–H4a, H5–H4a and H3–H5 pairs in The relative configurations of the other isoxazolidines
isoxazolidine 8a unambiguously supported the cis rela- (trans-7 and cis-8) were established by comparison of
tionship between the H3, H4a and H5 protons. The their spectral data with those of 7a and 8a. Similar vic-
observation of a positive NOE signal for the H5–H4b inal coupling constant values were observed in all the cis
and H3–H4a pairs in adduct 7a clearly identified their and trans isomers.
trans relationship.
The cis/trans ratios of the isoxazolidines produced in
The presence of the diethoxyphosphoryl group at C3 in thermal cycloadditions were influenced by Lewis acids
compounds 7 and 8 provides new opportunities in the (e.g., ZnCl2), especially in those cases where chelation
conformational analysis of substituted isoxazolidines, of both alkenes and nitrones by the acid could be effi-
since vicinal coupling constants between H4CCP and cient.3 Nitrone 2a (R = Me) was treated with allyl alco-
C5CCP can be applied in addition to 3J(H3CCH4) hol in the presence of an equimolar amount of ZnCl2 at
and 3J(H4CCH5). After extraction of all the vicinal room temperature to give a 20:80 mixture of isoxazol-
couplings available, the conformational homogeneity idines 7a and 8a in 90% total yield. In addition, the
of isoxazolidines 8h, 8g and 7f could be proved ZnCl2-catalysed cycloaddition of nitrone 2a to allyltri-
(Fig. 2). methylsilane afforded a 55:45 mixture of isoxazolidines
7d and 8d, respectively, in 89% yield. As expected, based
From the 1H and 13C NMR spectra of isoxazolidine on the results obtained earlier with nitrone 1,3,28 the ob-
3,5-diphosphonate 8h, the following couplings were served mixtures were enriched in cis isomers 8a and 8d.
extracted: J(H3–H4a) = 7.0 Hz, J(H3–H4b) = 10.3 Hz, These observations further support the stereochemistries
J(H4a–P3) = 7.0 Hz, J(H4a–P5) = 3.3 Hz, J(H4b–P3) = of isomers 7 and 8, which have already been established.
18.0 Hz, J(H4b–P5) = 16.5 Hz, J(H4a–H5) = 7.0 Hz, From these mixtures, additional amounts of 8a as well
J(H4b–H5) = 10.3 Hz and J(CCCP) = 9.8 Hz. These val- as pure 8d were isolated.
ues26,27 clearly showed that the isoxazolidine ring in 8h
exists in a single 4E conformation having both bulky In conclusion, a general procedure for the synthesis of
diethoxyphosphoryl groups in pseudoequatorial posi- N-substituted C-phosphorylated nitrones 2 based on
tions (Fig. 2) and thus reveal the cis relationship of H3 Swern oxidation of hydroxymethylphosphonates and
and H5. Similarly, the cis configuration of the minor low temperature addition of hydroxylamines was elabo-
isomer 8g was also established from corresponding rated. Cycloadditions of nitrone 2a (R = Me) and termi-
couplings [J(H3–H4a) = 8.1 Hz, J(H3–H4b) = 9.3 Hz, nal alkenes led almost exclusively to the formation of
J(H4a–P3) = 6.6 Hz, J(H4b–P3) = 18.6 Hz, J(H4a– C5-substituted isoxazolidines 7 and 8 with moderate
H5) = 6.6 Hz, J(H4b–H5) = 8.7 Hz and J(CCCP) = (20%) to excellent (up to 90%) trans to cis diastereoselec-
8.3 Hz], indicating the analogous 4E conformation of tivities. In ZnCl2-catalysed cycloadditions, mixtures
the isoxazolidine ring with both diethoxyphosphoryl enriched in cis diastereoisomers were produced. Further
and phenyl groups in pseudoequatorial positions. studies on cycloadditions of nitrones 2 to more substi-
Furthermore, the vicinal couplings found for 7f tuted alkenes are underway.
[J(H3–H4a) = 6.6 Hz, J(H3–H4b) = 12.0 Hz, J(H4a–P) =
3.0 Hz, J(H4b–P) = 17.4 Hz, J(H4a–H5) = 0 Hz, These findings pave the way for new syntheses of, for
J(H4b–H5) = 4.5 Hz and J(CCCP) = 9.5 Hz] support example, enantiomerically pure phosphonate analogues
the 4E conformation of the isoxazolidine ring, in which of homoserine, polyoxamic acids, 4-substituted glutamic
the P(O)(OEt)2 and OAc groups occupy the pseudoequ- acid and other a-aminophosphonates as analogues of
atorial and axial positions, respectively (Fig. 2). The biologically important compounds using a variety of
anomeric effect of the AcO–C5 group additionally stabi- N-chiral nitrones 2. This chemistry is currently under
lizes this conformation. investigation in this laboratory and will be disclosed in
due course.
Me N O OH Me N O OH Acknowledgements
H5 H
(EtO)2(O)P H4β (EtO)2(O)P H The author is grateful to Professor Andrzej E. Wróblew-
H 3 H4α H H
ski for support, fruitful discussions and helpful sugges-
7a 8a tions. Mrs. Jolanta Płocka and Mrs. Małgorzata
Pluskota are acknowledged for their skilled experimen-
Figure 1. Observed NOEs for 7a and 8a. tal contributions. This work was supported by the Med-
ical University of Łódź (502-13-332 and 503-3014-1).
3. Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, Sciortino, M. T.; Valveri, V.; Mastino, A.; Romeo, G.
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Soc., Perkin Trans. 1 2002, 2419–2438. 1243, 1185, 1054, 1022, 966, 854, 784 cm 1. 1H NMR
5. Ding, P.; Miller, M. J.; Chen, Y.; Helquist, P.; Oliver, A. (CDCl3, 300 MHz): 6.99 (d, J = 22.2 Hz, 0.15 · 1H, CH-P,
J.; Wiest, O. Org. Lett. 2004, 6, 1805–1808. E), 6.82 (d, J = 25.8 Hz, 0.85 · 1H, CH–P, Z), 4.32–4.12
6. Wess, G.; Kramer, W.; Schubert, G.; Enhsen, A.; Barin- (m, 4H, CH2OP, E + Z), 4.08 (d, J = 1.2 Hz, 0.15 · 3H,
ghaus, K.-H.; Globmik, H.; Müller, S.; Bock, K.; Kleine, CH3N, E), 3.84 (s, 0.85 · 3H, CH3N, Z), 1.38 (t,
H.; John, M.; Neckermann, G.; Hoffmann, A. Tetrahedron J = 7.0 Hz, 0.15 · 6H, CH3CH2OP, E), 1.36 (t,
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7. Procopio, A.; Alcaro, S.; De Nino, A.; Maiuolo, L.; 300 MHz): 6.90 (d, J = 22.2 Hz, 0.15 · 1H, E), 6.11 (d,
Ortuso, F.; Sindona, G. Bioorg. Med. Chem. Lett. 2005, J = 26.4 Hz, 0.85 · 1H, Z), 4.30–4.15 (m, 0.85 · 4H, Z),
15, 545–550. 3.81 (d, J = 0.6 Hz, 0.15 · 3H, E), 3.75–3.50 (m, 0.15 · 4H,
8. Chiacchio, U.; Genovese, F.; Iannazzo, D.; Piperno, A.; E), 2.70 (s, 0.85 · 3H, Z), 1.12 (t, J = 6.9 Hz, 0.85 · 6H, Z),
Quadrelli, P.; Antonino, C.; Romeo, R.; Valveri, V.; 0.88 (t, J = 7.1 Hz, 0.15 · 6H, E); 13C NMR (CDCl3,
Mastino, A. Bioorg. Med. Chem. 2004, 12, 3903–3909. 75.46 MHz): 127.30 (d, J = 209.9 Hz, CH–P, E + Z), 63.33
9. Richichi, B.; Cicchi, S.; Chiacchio, U.; Romeo, G.; (d, J = 6.0 Hz, CH2OP, Z), 63.17 (d, J = 6.0 Hz, CH2OP,
Brandi, A. Tetrahedron 2003, 59, 5231–5240. E), 55.33 (d, J = 11.5 Hz, CH3N, Z), 52.17 (s, CH3N, E),
10. Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. J. Org. 16.40 (d, J = 6.3 Hz, CH3CH2OP, Z), 16.32 (d, J = 5.7 Hz,
Chem. 2000, 65, 5575–5589. CH3CH2OP, E); 31P NMR (CDCl3, 121.47 MHz): 5.61 (Z)
11. Chiacchio, U.; Saita, M. G.; Crispino, L.; Gumina, G.; and 5.36 (E); 31P NMR (C6D6, 121.47 MHz): 7.02 (E) and
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13. Chiacchio, M. A.; Borrello, L.; Di Pasquale, G.; Pollicino, 6.70 (d, J = 25.8 Hz, 0.86 · 1H, CH–P, Z), 5.52 (s,
A.; Bottino, F. A.; Rescifina, A. Tetrahedron 2005, 61, 0.14 · 2H, CH2Ph, E), 4.98 (s, 0.86 · 2H, CH2Ph, Z),
7986–7993. 4.29–4.23 (m, 0.86 · 4H, Z), 4.20–4.05 (m, 0.14 · 4H, E),
14. Machetti, F.; Cordero, F. M.; De Sarlo, F.; Brandi, A. 1.31 (t, J = 7.0 Hz, 3H, E + Z), 1.30 (t, J = 7.0 Hz, 3H,
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