A regioselective route to 5-substituted isoxazole- And Isoxazoline- 3-phosphonates

Article abstract of DOI:10.1055/s-0028-1083343

5-Substituted 3-(diethoxyphosphoryl)isoxazoles and -2- isoxazolines were synthesized regioselectively by 1,3-dipolar cy- cloaddition of (diethoxyphosphoryl)formonitrile oxide to monosub- stituted alkynes and alkenes. By applying this methodology to an N-

Full text of DOI:10.1055/s-0028-1083343

PAPER
591
A Regioselective Route to 5-Substituted Isoxazole- and Isoxazoline-
3-phosphonates
5
-Substituted I
a
soxazole-
a
o
nd Isoxazoli
l
ne-3-ph
a
osphonates Conti,* Andrea Pinto, Lucia Tamborini, Petra Dunkel,1 Veniero Gambaro, Giacomo L. Visconti,
Carlo De Micheli
Dipartimento di Scienze Farmaceutiche ‘P. Pratesi’, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy
Fax +39(2)50319326; E-mail: paola.conti@unimi.it
Received 2 October 2008; revised 17 October 2008
tomer turned out to be the one with the S configuration at
the stereogenic center, namely (S)-ACPA [(S)-1,
Figure 1].10 A number of analogues with different substit-
uents at C-5 were prepared and tested at ionotropic and
Abstract: 5-Substituted 3-(diethoxyphosphoryl)isoxazoles and -2-
isoxazolines were synthesized regioselectively by 1,3-dipolar cy-
cloaddition of (diethoxyphosphoryl)formonitrile oxide to monosub-
stituted alkynes and alkenes. By applying this methodology to an N-
(tert-butoxycarbonyl)-substituted allylglycine methyl ester, we pre- metabotropic glutamate receptors.10,11
pared the precursors of two diastereomeric 3-phosphono-2-isoxazo-
lin-5-yl-substituted amino acids, which are bioisosteres of potent
NMDA receptor antagonists.
Recently, we took as a lead compound tricholomic acid
[(+)-2, Figure 1], a naturally occurring glutamate ana-
logue present in different species of poisonous mush-
rooms,12–14 to prepare and test its higher homologues 3a,b
and 4a,b.15,16 While the pharmacological profile of (+)-2
largely resembles that of the endogenous neurotransmit-
ter,17 the one-carbon elongation of the chain connecting
the two pharmacophoric entities, i.e. the amino acid moi-
ety and the distal carboxylate group, brought about a no-
ticeable selectivity for AMPA receptors.15 A further one-
carbon elongation of the spacer connecting the two phar-
macophoric entities resulted in a marked increase in both
affinity and selectivity for the NMDA receptors, accom-
panied by a switch in the pharmacological behavior from
agonist to antagonist.16,18
It is amply documented19 that the replacement of the distal
carboxylate group of NMDA antagonists by the bioisos-
teric phosphonate moiety significantly increases the po-
tency. As a matter of fact, such a bioisosteric modification
transforms a weak NMDA antagonist such as (R)-2-ami-
noadipic acid (5) into the quite potent (R)-2-amino-5-
phosphonopentanoic acid (6, AP-5, Figure 1).19 The same
trend is observed on passing from 4-(3-carboxypro-
pyl)piperazine-2-carboxylic acid (7) to 4-(3-phosphono-
propyl)piperazine-2-carboxylic acid (8, CPP, Figure 1),
which is a commonly used pharmacological tool to char-
acterize NMDA receptors.19
Key words: cycloadditions, regioselectivity, phosphonates, isox-
azoles, heterocycles
Isoxazole- and 2-isoxazoline-3-carboxylates are synthetic
targets of the utmost importance in the pharmaceutical in-
dustry, since such heterocyclic moieties represent the core
structures of numerous compounds provided with differ-
ent biological activities. Recent reports indicate the isox-
azole-3-carboxylate chemotype as the structural motif of
derivatives capable of inhibitory activity at the 11b-hy-
droxysteroid dehydrogenase, which could be used to treat
diabetes,2 and against enzymes involved in bacterial
lysine biosynthesis3 as well as potent serotonin reuptake
inhibitors, which could lead to novel antidepressants.4 On
the other hand, the 2-isoxazoline-3-carboxylate moiety is
present in natural compounds such as calafianin,5–7
a
spiroisoxazoline derivative produced by the marine
sponge Aplysia gerardogreeni and provided with antimi-
crobial activity. Furthermore, some 2-isoxazoline-3-car-
boxyamides linked to the piperazine nucleus have been
found to be quite potent a1a/a1d adrenoreceptor antago-
nists.8
Nevertheless, the glutamatergic field is the one where the
isoxazole- and 2-isoxazoline-3-carboxylate cores are
present with a substantial number of representatives. The
heterocyclic moiety has been used both to rigidify the
glutamate skeleton and to homologate the structure of
glutamic acid.9 The most appealing achievement has been
the discovery of 2-amino-3-(3-carboxy-5-methylisox-
azol-4-yl)propionic acid (ACPA), which turned out to be
a very potent and highly selective agonist of the AMPA
receptors, the ionotropic glutamate receptor subtypes
named after the acronym of its most selective agonist.9
Subsequently, the racemate has been resolved and the eu-
In connection with our ongoing medicinal chemistry
project aimed at the discovery of novel potent NMDA an-
tagonists, we planned the synthesis of compounds 9a,b
and 10a,b (Figure 1), the phosphonate analogues of deriv-
atives 3a,b and 4a,b.
As a preliminary exploratory investigation, we tested the
1,3-dipolar cycloaddition of (diethoxyphosphoryl)for-
monitrile oxide (12), generated in situ from the corre-
sponding oxime 11, to monosubstituted alkynes 13a–d
and alkenes 14a–d (Scheme 1). Herein we describe the
highly regioselective synthesis of 5-substituted isoxazoles
15a–d and 5-substituted 2-isoxazolines 16a–d bearing at
the 3-position the diethyl phosphonate moiety
(Scheme 1). Subsequently, we reacted the 1,3-dipole 12
SYNTHESIS 2009, No. 4, pp 0591–0596
x
x
.
x
x
.2
0
0
9
Advanced online publication: 27.01.2009
DOI: 10.1055/s-0028-1083343; Art ID: Z22308SS
© Georg Thieme Verlag Stuttgart · New York

592
P. Conti et al.
PAPER
CO2H
NH2
HO2C
HO2C
HO
HO2C
NH2
CO2H
CO2H
NH2
3a: 5S*,2S*
3b: 5R*,2S*
CO2H
NH2
N
N
N
N
O
O
O
O
Me
(S)-1
(+)-2
4a: 5S*,2'R*
4b: 5R*,2'R*
HO2C
(HO)2(O)P
CO2H
NH2
CO2H
(HO)2(O)P
HO2C
N
N
NH2
(R)-6
(R)-5
N
H
CO2H
N
H
CO2H
(R)-7
(R)-8
(HO)2(O)P
(HO)2(O)P
NH2
CO2H
CO2H
NH2
N
N
O
O
9a: 5S*,2S*
9b: 5R*,2S*
10a: 5S*,2'R*
10b: 5R*,2'R*
Figure 1 Structures of reference compounds 1, (+)-2, 3a,b, 4a,b, (R)-5, (R)-6, (R)-7, and (R)-8 and target compounds 9a,b and 10a,b
a
b
CHO
(EtO)2(O)P CH=NOH
(EtO)2(O)P CH2OH
(EtO)2(O)P
c
11
11
(EtO)2(O)P
C
N+ O–
12
(EtO)2(O)P
R
(EtO)2(O)P
c
11
+
+
R
N
N
R
O
O
17a: R = Ph
13a: R = Ph
15a: R = Ph
17b: R = CO2Me
17c: R = Bu
13b: R = CO2Me
13c: R = Bu
15b: R = CO2Me
15c: R = Bu
13d: R = CH2OH
17d: R = CH2OH
15d: R = CH2OH
(EtO)2(O)P
(EtO)2(O)P
R
c
11
+
+
R
N
N
R
O
O
14a: R = Ph
18a: R = Ph
16a: R = Ph
14b: R = CO2Me
14c: R = Bu
18b: R = CO2Me
18c: R = Bu
16b: R = CO2Me
16c: R = Bu
14d: R = CH2OH
18d: R = CH2OH
16d: R = CH2OH
(EtO)2(O)P
(EtO)2(O)P
BocHN
BocHN
NHBoc
c
11 +
+
CO2Me
CO2Me
N
N
CO2Me
O
O
( )-19
( )-20a
( )-20b
Scheme 1 Reagents and conditions: (a) (COCl)2, DMSO, Et3N, –78 °C; (b) NH2OH·HCl, CH2Cl2, –15 °C; (c) NaClO, CH2Cl2.
with a suitably protected allylglycine to yield cycload- protocol since hydroximoyl halides are usually strong ir-
ducts 20a,b, intermediates of final amino acids 10a,b.
ritants, causing severe skin allergies even when handled
with care. In addition, the competing dimerization to
furoxan prevents its application to sluggish dipolaro-
philes. This limitation can be partially overcome through
a slow generation of the nitrile oxide either by a dropwise
addition of a base or by using a solid base in a heteroge-
neous medium. According to a recent report, nitrile oxides
can be efficiently generated in situ from the corresponding
aldoximes by using bleach as the chlorinating agent,
Nitrile oxides can be generated in a variety of ways, e.g.
dehydration of primary nitroalkanes (Mukaiyama’s pro-
cedure),20 thermolysis of hydroximoyl halides,21 and oxi-
dation of oximes with a variety of oxidizing reagents.22
Usually, the most practical and scalable method is the in
situ technique based on the dehydrohalogenation of hy-
droximoyl halides by treatment with a base (Huisgen’s
procedure).23 Serious drawbacks are associated with this
Synthesis 2009, No. 4, 591–596 © Thieme Stuttgart · New York

PAPER
5-Substituted Isoxazole- and Isoxazoline-3-phosphonates
593
which also provides the basic conditions to perform the The almost unidirectional behavior observed in the cy-
dehydrochlorination step.24
cloaddition of nitrile oxide 12 to monosubstituted alkynes
13 and alkenes 14 parallels the results obtained with the
thoroughly studied benzonitrile oxide.22 As an application
of this methodology, we then prepared the two diastereo-
meric cycloadducts 20a and 20b (Scheme 1), direct pre-
cursors of amino acids 10a and 10b, which are
bioisosteres of the potent NMDA receptor antagonists 4a
and 4b. The cycloaddition reaction was carried out fol-
lowing the above described procedure and using ( )-19, a
suitably protected allylglycine, as the dipolarophile. The
two cycloadducts 20a and 20b were formed in 46% over-
all yield and in a 52:48 ratio, as established by HPLC anal-
ysis of the crude reaction mixture. Flash chromatography
allowed the recovery of the unchanged alkene and the sep-
aration of the two diastereomers 20a and 20b. The ste-
reochemistry of the cycloadducts was assigned by
comparing their 1H NMR spectra with those of the corre-
sponding 3-ethoxycarbonyl analogues.33 In particular, we
took into account the two hydrogens of the methylene
group of the side chain, which give rise to an overlapped
multiplet resonating in the region of d = 2.10–2.22, in the
case of diastereomer 20a, while they resonate as two dis-
tinct signals in the case of 20b, appearing as a multiplet in
the region of d = 1.74–2.00 and a doublet of doublets of
doublets at d = 2.16.
A careful survey of the literature shows that phosphorylni-
trile oxides have been generated both by dehydrochlorina-
tion of the (diisopropoxyphosphoryl)hydroximoyl
chloride25,26 and dehydration of diethyl (nitrometh-
yl)phosphonate.27 Nevertheless, the two reagents could
only be prepared in low yield by rather complicated pro-
cedures.28,29
Recent papers reported the synthesis of some (diethoxy-
phosphoryl)nitrones and their 1,3-dipolar cycloaddition to
an array of dipolarophiles.30,31 The procedure is based on
the Swern oxidation of the commercially available diethyl
(hydroxymethyl)phosphonate
to
yield
diethyl
formylphosphonate, which in turn was condensed with N-
alkylhydroxylamines. Diethyl formylphosphonate was
not characterized, but directly condensed with the N-
alkylhydroxylamines, since it is chemically unstable, and
at –10 °C undergoes decomposition to carbon monoxide
and diethyl phosphite.32
Following the same strategy, we prepared diethyl
formylphosphonate, which was immediately reacted with
hydroxylamine at –30 °C to give (diethoxyphosphor-
yl)formaldehyde oxime (11) in 63% yield (Scheme 1). To
a dichloromethane solution of oxime 11 and a threefold
excess of dipolarophile, bleach was added dropwise. All
the cycloaddition reactions reported in Scheme 1 were run
under comparable conditions and the reactions were al-
lowed to proceed until disappearance of the (diethoxy-
phosphoryl) formaldehyde oxime. Major isomers 15a–d
and 16a–d were isolated after column chromatography,
and fully characterized by spectroscopic and analytical
methods, whereas minor regioisomers 17a–d and 18a–d
were detected by high-resolution gas chromatography and
identified through their mass spectra. The ratios of the re-
gioisomeric pairs 15a–d/17a–d and 16a–d/18a–d were
evaluated by high-resolution gas chromatography–FID
analysis and the relative percentages are reported in
Table 1.
All reagents were purchased from Sigma. N-Boc-protected allylgly-
cine methyl ester ( )-19 was prepared according to a literature pro-
cedure.33 TLC analyses were performed on commercial silica gel 60
F
254 aluminum sheets; spots were visualized by spraying with a di-
1
lute alkaline KMnO4 soln. H NMR (300 MHz), 13C NMR (75.5
MHz), and 31P NMR (121.5 MHz) spectra were recorded on a
Varian Mercury 300 spectrometer of samples in CDCl3 soln at
20 °C. The HRGC-FID analyses were performed using an Agilent
Technologies (Palo Alto, CA) model HP 6890 series equipped with
a split–splitless injector, electronic pressure control, HP 6890 au-
tosampler, and flame ionization detector (FID). The column used
was an HP5 (5% phenyl methyl silicone) fused-silica capillary col-
umn (15 m, 0.32 mm i.d., 0.25 mm film thickness), which was also
obtained from Agilent Technologies. H2 and He were used as the
carrier and preparation gas, respectively. The flow rate of H2 was
1.3 mL/min; air He and H2 were of high-purity grade. Temperature
programming was used for the successful elution of all the peaks of
interest. The column temperature was programmed from an initial
100–280 °C at 10 °C/min; the total analysis time was 20 min. The
injector and detector temperatures were 280 and 300 °C, respective-
ly. The injector was operated in split mode with a split rate of 30:1.
The HRGC-MS analyses were performed using a Varian ion trap
Saturn 2100 with MSn-option and multi CI option coupled with a
Varian 3800 gas chromatograph. The column and the method used
were the same as that described above. The ion trap was operated in
full scan mode, detecting ions between m/z = 50 and 650. The
HPLC analysis was performed using a Varian model Prostar chro-
matograph with autosampler and UV-DAD detector (ProStar 335).
Separation was obtained on a normal-phase column (LichroCart
125-4, Lichrospher Si 60 5 mm from Merck). The injection was ef-
fected through a 10mL loop. Mobile phase: A = n-hexane, B = i-
PrOH; gradient: 20–50% of B in 10 min; flow rate: 1.0 mL/min (47
bar); column temperature 25 °C; detection at 220 nm; run time 10
min.
Table 1 Cycloaddition between (Diethoxyphosphoryl)formonitrile
Oxide 12 and Dipolarophiles 13a–d and 14a–d
Dipolarophile
13a
R
Products (ratio)a
Yieldb (%)
Ph
15a/17a (99.9:0.1)
15b/17b (96.4:3.6)
15c/17c (94.4:5.6)
15d/17d (96.4:3.6)
16a/18a (99.7:0.3)
16b/18b (98.8:1.2)
16c/18c (98.4:1.6)
16d/18d (97.6:2.4)
48
41
25
36
26
22
18
36
13b
CO2Me
Bu
13c
13d
CH2OH
Ph
14a
14b
CO2Me
Bu
14c
14d
CH2OH
a Ratio determined by HRGC-FID analysis of the crude reaction mixture.
b Yield of isolated product 15 or 16.
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P. Conti et al.
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(Diethoxyphosphoryl)formaldehyde Oxime (11)
Isoxazole 17b
HRGC: tR = 6.42 min.
DMSO (44 mmol, 3.1 mL) was added to a soln of oxalyl chloride
(22 mmol, 1.86 mL) in CH2Cl2 (90 mL), cooled at –78 °C under N2.
After 2 min, a soln of diethyl(hydroxymethyl)phosphonate (20
mmol, 2.95 mL) in CH2Cl2 (20 mL) was added dropwise. After 15
min, Et3N (170 mmol, 23.7 mL) was added dropwise. The temper-
ature was increased to –15 °C over 3.5 h. MS (7.2 g, diameter ~2
mm, pore diameter 3 Å, water adsorption capacity ≥15%) were add-
ed to the reaction flask followed by NH2OH·HCl (70 mmol, 4.86 g).
The mixture was stirred at –15 °C overnight. The white suspension
was washed with 1 N HCl (150 mL). After separation of the phases,
the aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The
combined organic phases were dried (Na2SO4), filtered, and evapo-
rated to dryness. The crude product was purified by column chro-
matography (EtOAc); this afforded compound 11.
Isoxazole 15c
Rf = 0.65 (EtOAc); HRGC: tR = 7.29 min.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 7.3 Hz, 3 H), 1.36 (t,
J = 7.0 Hz, 6 H), 1.32–1.46 (m, 2 H), 1.63–1.75 (m, 2 H), 2.75–2.85
(m, 2 H), 4.16–4.32 (m, 4 H), 6.28 (d, J = 0.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.8, 16.5 (m), 22.3, 26.4, 29.7,
63.7 (m), 103.5 (m), 155.8 (d, JC–P = 211.8 Hz), 175.0 (d, JC–P
10.5 Hz).
=
31P NMR (122 MHz, CDCl3): d = 6.30.
Anal. Calcd for C11H20NO4P: C, 50.57; H, 7.72; N, 5.36. Found: C,
50.78; H, 7.79; N, 5.11.
Yield: 2.27 g (63%); yellow oil; Rf = 0.39 (EtOAc).
1H NMR (300 MHz, CDCl3): d = 1.29 (t, J = 7.2 Hz, 6 H), 4.13 (dq,
J = 7.2, 7.2 Hz, 4 H), 7.50 (d, J = 38.5 Hz, 1 H), 11.43 (br s, 1 H).
Isoxazole 17c
HRGC: tR = 7.00 min.
13C NMR (75 MHz, CDCl3): d = 16.4 (JC–P = 6.2 Hz), 63.4 (d,
JC–P = 6.0 Hz), 141.7 (d, JC–P = 220.8 Hz).
31P NMR (122 MHz, CDCl3): d = 9.52.
Isoxazole 15d
Rf = 0.3 (EtOAc); HRGC: tR = 7.53 min.
1H NMR (300 MHz, CDCl3): d = 1.33 (t, J = 7.0 Hz, 6 H), 4.12–
4.26 (m, 4 H), 4.58 (br s, 1 H), 4.76 (s, 2 H), 6.46 (d, J = 0.9 Hz, 1
Anal. Calcd for C5H12NO4P: C, 33.16; H, 6.68; N, 7.73. Found: C,
33.42; H, 6.75; N, 7.60.
H).
13C NMR (75 MHz, CDCl3): d = 16.4 (m), 56.3 (m), 64.1 (m), 104.2
(m), 155.4 (d, JC–P = 212.7 Hz), 174.1 (d, JC–P = 10.0 Hz).
31P NMR (122 MHz, CDCl3): d = 5.83.
Cycloaddition of 11 to Alkynes 13; General Procedure
Oxime 11 (145 mg, 0.8 mmol) was added to a soln of alkyne 13 (2.4
mmol) in CH2Cl2 (3.5 mL). While the mixture was cooled in an ice
bath, a 3.5% soln of NaOCl (3.4 mL, 1.6 mmol) was added slowly,
dropwise. The reaction mixture was stirred at 25 °C for 2 h. After
separation of the phases, the aqueous phase was extracted with
CH2Cl2 (2 × 5 mL). The combined organic phases were dried
(Na2SO4). HR–GCMS analysis of the crude material, obtained after
evaporation of the solvent, showed the formation of regioisomers
15 and 17. The relative ratios of 15 and 17 were determined by
HRGC-FID analysis and are reported in Table 1. The crude material
was purified by flash column chromatography (silica gel) to give
isoxazoles 15. The yields are reported in Table 1.
Anal. Calcd for C8H14NO5P: C, 40.86; H, 6.00; N, 5.96. Found: C,
41.13; H, 6.10; N, 5.77
Isoxazole 17d
HRGC: tR = 5.17 min.
Cycloaddition of 11 to Alkenes 14; General Procedure
Oxime 11 (145 mg, 0.8 mmol) was added to a soln of alkene 14 (2.4
mmol) in CH2Cl2 (3.5 mL). While the mixture was cooled in an ice
bath, a 3.5% soln of NaOCl (3.4 mL, 1.6 mmol) was added slowly,
dropwise. The reaction mixture was stirred at 25 °C for 2 h. After
separation of the phases, the aqueous phase was extracted with
CH2Cl2 (2 × 5 mL). The combined organic phases were dried
(Na2SO4). HR–GCMS analysis of the crude material, obtained after
evaporation of the solvent, showed the formation of regioisomers
16 and 18. The relative ratios of 16 and 18 were determined by
HRGC-FID analysis and are reported in Table 1. The crude material
was purified by flash column chromatography (silica gel) to give
isoxazolines 16. The yields are also reported in Table 1.
Isoxazole 15a
Rf = 0.3 (PE–EtOAc, 1:1); HRGC: tR = 10.58 min.
1H NMR (300 MHz, CDCl3): d = 1.40 (td, J = 0.6, 7.0 Hz, 6 H),
4.22–4.35 (m, 4 H), 6.82 (d, J = 1.2 Hz, 1 H), 7.45–7.51 (m, 3 H),
7.78–7.82 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 16.5 (m), 63.9 (m), 102.2 (m),
126.3, 126.7, 129.4, 131.0, 156.6 (d, JC–P = 210.9 Hz), 171.1 (d,
JC–P = 10.2 Hz).
31P NMR (122 MHz, CDCl3): d = 5.60.
Isoxazoline 16a
Rf = 0.53 (EtOAc); HRGC: tR = 10.09 min.
1H NMR (300 MHz, CDCl3): d = 1.36 (t, J = 7.0 Hz, 3 H), 1.39 (t,
J = 7.0 Hz, 3 H), 3.19 (ddd, J = 1.5, 8.5, 17.3 Hz, 1 H), 3.62 (ddd,
J = 1.5, 11.4, 17.3 Hz, 1 H), 4.18–4.31 (m, 4 H), 5.66 (dd, J = 8.5,
11.4 Hz, 1 H), 7.26–7.41 (m, 5 H).
Anal. Calcd for C13H16NO4P: C, 55.52; H, 5.73; N, 4.98. Found: C,
55.48; H, 5.92; N, 4.73.
Isoxazole 17a
HRGC retention time: 8.94 min.
13C NMR (75 MHz, CDCl3): d = 16.5 (m), 44.9 (d, JC–P = 18.5 Hz),
Isoxazole 15b
Rf = 0.35 (PE–EtOAc, 1:1); HRGC: tR = 6.87 min.
1H NMR (300 MHz, CDCl3): d = 1.37 (t, J = 7.0 Hz, 6 H), 3.98 (s,
3 H), 4.20–4.33 (m, 4 H), 7.18 (d, J = 0.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 16.4 (m), 53.4 (m), 64.2 (m), 111.9
(m), 156.7, 157.0 (d, JC–P = 212.0 Hz), 161.0 (d, JC–P = 10.0 Hz).
63.9 (m), 83.0 (m), 126.0, 128.8, 129.1, 139.9, 151.0 (d, JC–P
=
213.5 Hz).
31P NMR (122 MHz, CDCl3): d = 6.20.
Anal. Calcd for C13H18NO4P: C, 55.12; H, 6.41; N, 4.94. Found: C,
55.01; H, 6.55; N, 4.73.
31P NMR (122 MHz, CDCl3): d = 3.49.
Isoxazoline 18a
HRGC: tR = 9.21 min.
Anal. Calcd for C9H14NO6P: C, 41.07; H, 5.36; N, 5.32. Found: C,
41.34; H, 5.46; N, 5.11.
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5-Substituted Isoxazole- and Isoxazoline-3-phosphonates
595
Isoxazoline 16b
Rf = 0.33 (EtOAc); HRGC: tR = 7.67 min.
1H NMR (300 MHz, CDCl3): d = 1.35 (td, J = 0.6, 7.0 Hz, 3 H),
1.36 (td, J = 0.6, 7.0 Hz, 3 H), 1.42 (s, 9 H), 2.10–2.22 (m, 2 H),
2.88 (ddd, J = 1.5, 7.3, 17.3 Hz, 1 H), 3.33 (ddd, J = 1.5, 10.9, 17.3
Hz, 1 H), 3.75 (s, 3 H), 4.14–4.28 (m, 4 H), 4.35 (ddd, J = 6.5, 6.5,
6.5 Hz, 1 H), 4.78 (dddd, J = 7.3, 7.3, 7.3, 10.9 Hz, 1 H), 5.34 (d,
J = 6.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 16.4 (m), 28.4, 37.6, 42.3 (d,
JC–P = 18.1 Hz), 51.2, 52.8 (m), 63.8 (m), 78.3, 80.3, 151.3 (d,
JC–P = 214.4 Hz), 155.5, 172.3.
1H NMR (300 MHz, CDCl3): d = 1.36 (t, J = 7.0 Hz, 6 H), 3.47 (m,
2 H), 3.79 (s, 3 H), 4.16–4.28 (m, 4 H), 5.08 (dd, J = 10.0, 10.0 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 16.4 (m), 41.2 (d, JC–P = 19.1 Hz),
53.2 (m), 64.1 (m), 77.8 (m), 151.0 (d, JC–P = 212.4 Hz), 169.8.
31P NMR (122 MHz, CDCl3): d = 4.87.
31P NMR (122 MHz, CDCl3): d = 6.38.
Anal. Calcd for C9H16NO6P: C, 40.76; H, 6.08; N, 5.28. Found: C,
41.05; H, 5.91; N, 5.14.
Anal. Calcd for C16H29N2O8P: C, 47.06; H, 7.16; N, 6.86. Found: C,
47.25; H, 7.23; N, 6.61.
Isoxazoline 18b
HRGC: tR = 6.63 min.
Isoxazoline 20b
Yellow oil; Rf = 0.40 (EtOAc); HPLC: tR = 7.79 min.
Isoxazoline 16c
Rf = 0.52 (EtOAc); HRGC: tR = 7.54 min.
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.0 Hz, 3 H), 1.36 (t,
J = 7.0 Hz, 3 H), 1.43 (s, 9 H), 1.74–2.00 (m, 1 H), 2.16 (ddd,
J = 4.7, 8.8, 14.0 Hz, 1 H), 2.85 (ddd, J = 1.5, 7.9, 17.3 Hz, 1 H),
3.30 (ddd, J = 1.5, 10.8, 17.3 Hz, 1 H), 3.74 (s, 3 H), 4.14–4.28 (m,
4 H), 4.38–4.50 (m, 1 H), 4.76 (dddd, J = 4.4, 7.9, 8.8, 10.8 Hz, 1
H), 5.32 (d, J = 6.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 16.4 (m), 28.4, 37.6, 42.4 (d,
JC–P = 18.1 Hz), 51.5, 52.7 (m), 63.8 (m), 78.7, 80.2, 151.4 (d,
JC–P = 214.1 Hz), 155.6, 172.5.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 7.0 Hz, 3 H), 1.20–
1.40 (m, 10 H), 1.40–1.60 (m, 1 H), 1.60–1.80 (m, 1 H), 2.79 (ddd,
J = 1.8, 8.2, 17.3 Hz, 1 H), 3.20 (ddd, J = 1.8, 10.8, 17.3 Hz, 1 H),
4.14–4.26 (m, 4 H), 4.58–4.70 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.1, 16.5 (m), 22.6, 27.6, 34.8,
41.7 (d, JC–P = 17.9 Hz), 63.8 (m), 82.1 (m), 151.1 (d, JC–P = 214.3
Hz).
31P NMR (122 MHz, CDCl3): d = 6.98.
31P NMR (122 MHz, CDCl3): d = 6.27.
Anal. Calcd for C11H22NO4P: C, 50.18; H, 8.42; N, 5.32. Found: C,
50.45; H, 8.46; N, 5.07.
Anal. Calcd for C16H29N2O8P: C, 47.06; H, 7.16; N, 6.86. Found: C,
47.32; H, 7.21; N, 6.68.
Isoxazoline 18c
HRGC: tR = 6.97 min.
Acknowledgment
Isoxazoline 16d
Rf = 0.23 (EtOAc); HRGC: tR = 6.95 min.
This work was financially supported by MIUR (PRIN 2005, Rome)
and Università degli Studi di Milano (FIRST).
1H NMR (300 MHz, CDCl3): d = 1.33 (td, J = 0.6, 7.0 Hz, 6 H),
2.90 (br s, 1 H), 3.10 (ddd, J = 1.8, 7.9, 17.3 Hz, 1 H), 3.19 (ddd,
J = 1.4, 10.8, 17.3 Hz, 1 H), 3.58 (dd, J = 4.4, 12.3 Hz, 1 H), 3.75
(dd, J = 3.5, 12.3 Hz, 1 H), 4.12–4.26 (m, 4 H), 4.76 (dddd, J = 3.5,
4.4, 7.9, 10.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 16.4 (m), 38.3 (d, JC–P = 18.5 Hz),
63.2, 63.9 (m), 82.0 (m), 151.5 (d, JC–P = 214.1 Hz).
References
(1) On leave from Semmelweis University, Budapest, Hungary
(2) Ogawa, T.; Kurose, N.; Tanaka, S.; Nishi, K. Patent
Application WO 2006132197, 2006; Chem. Abstr. 2007,
146, 62719.
(3) Sundermann, C.; Sundermann, B.; Holenz, J.; Hennies, H.-
H. Patent Application WO 2006105945, 2006; Chem. Abstr.
2006, 145, 419152.
31P NMR (122 MHz, CDCl3): d = 6.47.
Anal. Calcd for C8H16NO5P: C, 40.51; H, 6.80; N, 5.91. Found: C,
40.77; H, 6.98; N, 5.66.
(4) Caplan, J. F.; Zheng, R. J.; Blanchard, J. S.; Vederas, J. C.
Org. Lett. 2000, 2, 3857.
(5) Encarnacion, R. D.; Sandoval, E.; Malmstrom, J.;
Christophersen, C. J. Nat. Prod. 2000, 63, 874.
(6) Bardhan, S.; Schmitt, D. C.; Porco, J. A. Jr. Org. Lett. 2006,
8, 927.
Isoxazoline 18d
HRGC: tR = 5.83 min.
Diethyl (5R*,2¢S*)-5-[2¢-(tert-Butoxycarbonylamino)-2¢-(meth-
oxycarbonyl)ethyl]-4,5-dihydroisoxazole-3-phosphonate (20a)
and Diethyl (5R*,2¢R*)-5-[2¢-(tert-butoxycarbonylamino)-2¢-
(methoxycarbonyl)ethyl]-4,5-dihydroisoxazole-3-phosphonate
(20b)
Oxime 11 (1.81 g, 10 mmol) was added to a soln of 19 (4.59 g, 20
mmol) in CH2Cl2 (45 mL). While the mixture was cooled in an ice
bath, a 3.5% soln of NaOCl (42.6 mL, 20 mmol) was added slowly,
dropwise. The reaction mixture was stirred at 25 °C for 2 h. After
separation of the phases, the aqueous phase was extracted with
CH2Cl2 (2 × 5 mL). The combined organic phases were dried
(Na2SO4). The crude material was purified by flash column chroma-
tography (silica gel, cyclohexane–EtOAc, 1:1); this gave un-
changed alkene (2.20 g), 20a (0.96 g), and 20b (0.91 g).
(7) Ogamino, T.; Obata, R.; Tomoda, H.; Nishiyama, S. Bull.
Chem. Soc. Jpn. 2006, 79, 134.
(8) Baxter, E. W.; Nortey, S. O.; Reitz, A. B. Patent Application
WO 2008033513, 2008; Chem. Abstr. 2008, 148, 355825.
(9) Bräuner-Osborne, H.; Egebjerg, J.; Nielsen, E.; Madsen, U.;
Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43, 2609.
(10) Johansen, T. N.; Stensbøl, T. B.; Nielsen, B.; Vogensen, S.
B.; Frydenvang, K.; Bräuner-Osborne, H.; Madsen, U.;
Krogsgaard-Larsen, P. Chirality 2001, 13, 523.
(11) Brehm, L.; Greenwood, J. R.; Sløk, F. A.; Holm, M. M.;
Nielsen, B.; Geneser, U.; Stensbøl, T. B.; Bräuner-Osborne,
H.; Begstrup, M.; Egebjer, J.; Krogsgaard-Larsen, P.
Chirality 2004, 16, 452.
(12) Takemoto, T.; Nakajima, T. J. Pharm. Soc. Jpn. 1964, 84,
1183.
Isoxazoline 20a
Yellow oil; Rf = 0.42 (EtOAc); HPLC: tR = 6.44 min.
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596
P. Conti et al.
PAPER
(23) Christl, M.; Huisgen, R.; Sustmann, R. Chem. Ber. 1973,
(13) Takemoto, T.; Yokobe, T.; Nakajima, T. J. Pharm. Soc. Jpn.
1964, 84, 1186.
106, 3275.
(14) Lizáraga-Guerra, R.; López, M. G. J. Agric. Food Chem.
1996, 44, 2556.
(15) Conti, P.; De Amici, M.; Roda, G.; Pinto, A.; Tamborini, L.;
Madsen, U.; Nielsen, B.; Bräuner-Osborne, H.; De Micheli,
C. Tetrahedron 2007, 63, 2249.
(24) Quan, C.; Kurth, M. J. Org. Chem. 2004, 69, 1470.
(25) Sinyashin, O. G.; Romanova, I. P.; Sagitova, F. R.; Pavlov,
V. A.; Kovalenko, V. I.; Badeev, Y. V.; Azancheev, N. M.;
Ill’yasov, A. V.; Chernova, A. V.; Vandyukova, I. I.
Mendeleev Commun. 1998, 79.
(16) Conti, P.; De Amici, M.; Grazioso, G.; Pinto, A.; Roda, G.;
Stensbøl, T. B.; Madsen, U.; Nielsen, B.; Bräuner-Osborne,
H.; Pellegrini-Giampietro, F. C.; Acher, F. C.; De Micheli,
C. J. Med. Chem. 2005, 48, 6315.
(17) Pinto, A.; Conti, P.; De Amici, M.; Tamborini, L.; Madsen,
U.; Nielsen, B.; Christesen, T.; Bräuner-Osborne, H.;
De Micheli, C. J. Med. Chem. 2008, 51, 2311.
(18) Conti, P.; Caligiuri, A.; Pinto, A.; Roda, G.; Tamborini, L.;
Nielsen, B.; Madsen, U.; Frydenvang, K.; Colombo, A. H.;
De Micheli, C. Eur. J. Med. Chem. 2007, 42, 1059.
(19) Akarca, U. S. Curr. Pharm. Des. 2005, 11, 1779.
(20) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339.
(26) Al-Dulayymi, J. R.; Baird, M. S.; Pavlov, V.; Kurdjukov, A.
I. Tetrahedron 1996, 52, 8877.
(27) Zhang, R.; Chen, J. Synthesis 1990, 817.
(28) Sokolov, M. P.; Buzykin, B. I.; Pavlov, V. A. Zh. Obshch.
Khim. 1990, 60, 223.
(29) Petrov, K. A.; Chauzov, V. A.; Bogdanov, N. N.;
Pastukhova, I. V. Zh. Obshch. Khim. 1976, 46, 1242.
(30) Piotrowska, D. G. Tetrahedron 2006, 62, 12306.
(31) Piotrowska, D. G. Tetrahedron Lett. 2006, 47, 5363.
(32) Savignac, P.; Iorga, B. Modern Phosphonate Chemistry
Products; CRC Press: Boca Raton, 2003.
(33) Conti, P.; De Amici, M.; Grazioso, G.; Roda, G.;
Barberis Negra, F.; Nielsen, B.; Stensbøl, T. B.; Madsen, U.;
Bräuner-Osborne, H.; Frydenvang, K.; De Sarro, G.; Toma,
L.; De Micheli, C. J. Med. Chem. 2004, 47, 6740.
(21) Caldirola, P.; De Amici, M.; De Micheli, C. Heterocycles
1985, 23, 2479.
(22) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John
Wiley & Sons: New York, 1984.
Synthesis 2009, No. 4, 591–596 © Thieme Stuttgart · New York