Cycloadditions of 1-phosphono-1,3-butadienes with nitroso heterodienophiles: A versatile synthetic route for polyfunctionalized aminophosphonic derivatives

Article abstract of DOI:10.1021/jo100230r

The hetero-Diels-Alder (HDA) reaction of 1-(diethoxyphosphonyl)-1,3- butadiene, 1-(dibenzyloxyphosphonyl)-1,3-butadiene, and 1-(diethoxyphosphonyl)- 3-tert-butyldimethylsilyloxy-1,3-butadiene with various nitroso heterodienophiles has been investigated as a new synthetic route for aminophosphonic derivatives. The HDA cycloadditions regioselectively led to the proximal isomers, i.e., presenting the NR³ group in the meta position regarding the phosphonate substituent. From the resulting 6-phosphono-3,6- dihydro-1,2-oxazine cycloadducts, a limited number of chemical steps were allowed to obtain a significant variety of aminophosphonic compounds of potential interest in medicinal chemistry. This has been illustrated through the synthesis of (Z)-4-(o-tolylamino)-1-hydroxybut-2-enylphosphonic acid, diethyl 3,4-dihydroxy-1-o-tolylpyrrolidin-2-yl-2-phosphonate, 4-(o-tolylamino)-1,2,3- trihydroxybutylphosphonic acid, diethyl 3-(2-(o-tolylamino)-1-hydroxyethyl) oxiran-2-yl-2-phosphonate, and diethyl 4,5-dihydroxymorpholin-6-yl-6- phosphonate.

Full text of DOI:10.1021/jo100230r

pubs.acs.org/joc
[4 þ 2] Cycloadditions of 1-Phosphono-1,3-butadienes with Nitroso
Heterodienophiles: A Versatile Synthetic Route for Polyfunctionalized
Aminophosphonic Derivatives
Jean-Christophe Monbaliu,‡ Bernard Tinant,§ and Jacqueline Marchand-Brynaert*,‡
‡
§
Unite de Chimie organique et medicinale and Unite de Chimie structurale et des mecanismes reactionnels,
ꢀ
Institut de la matieꢁre condenseꢀe et des nanosciences, Universiteꢀ catholique de Louvain, Ba^timent Lavoisier,
ꢀ
ꢀ
ꢀ
ꢀ
Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
jacqueline.marchand@uclouvain.be
Received February 16, 2010
The hetero-Diels-Alder (HDA) reaction of 1-(diethoxyphosphonyl)-1,3-butadiene, 1-(dibenzyloxyphos-
phonyl)-1,3-butadiene, and 1-(diethoxyphosphonyl)-3-tert-butyldimethylsilyloxy-1,3-butadiene with
various nitroso heterodienophiles has been investigated as a new synthetic route for aminophosphonic
derivatives. The HDA cycloadditions regioselectively led to the proximal isomers, i.e., presenting the NR3
group in the meta position regarding the phosphonate substituent. From the resulting 6-phosphono-
3,6-dihydro-1,2-oxazine cycloadducts, a limited number of chemical steps were allowed to obtain a
significant variety of aminophosphonic compounds of potential interest in medicinal chemistry. This has
been illustrated through the synthesis of (Z)-4-(o-tolylamino)-1-hydroxybut-2-enylphosphonic acid,
diethyl 3,4-dihydroxy-1-o-tolylpyrrolidin-2-yl-2-phosphonate, 4-(o-tolylamino)-1,2,3-trihydroxybutyl-
phosphonic acid, diethyl 3-(2-(o-tolylamino)-1-hydroxyethyl)oxiran-2-yl-2-phosphonate, and diethyl
4,5-dihydroxymorpholin-6-yl-6-phosphonate.
Introduction
compounds despite the increasing interest in Fosmidomycin
and Rhizocticin families, for example (Figure 1).3,4
Recent discoveries of natural organophosphonate com-
pounds with promising activities in both agricultural and
medicinal fields have stimulated the development of syn-
thetic analogues. In particular, aminophosphonic deriva-
tives constitute an important class of pharmacologically
active molecules.1 Although displaying fundamental differ-
ences (in terms of pKa, geometry, and shape), the phospho-
nate moiety is considered an analogue of the carboxylic
group (i.e., bioisoster) in medicinal chemistry.2 R-Amino-
phosphonic compounds and their diesters (phosphonates),
as direct analogues of the natural R-amino acids, occupy a special
place among diverse structures of aminophosphonic deriva-
tives. Less attention is paid to β-, γ-, and δ-aminophosphonic
As part of a research program dedicated to the synthesis
of aminophosphonic compounds based on the Diels-Alder
(DA) reaction,5 we became interested in the hetero-Diels-Alder
(HDA) reaction of phosphonodienes (1) and nitroso dienophiles
(2) as a versatile route toward 6-phosphono-3,6-dihydro-1,2-
oxazine derivatives, precursors of δ-aminophosphonic com-
pounds (Figure 2). Dienes possessing a dialkoxyphosphonyl
substituent in the C(1) position are known to display a poor
reactivity in [4 þ 2] cycloadditions, as a consequence of their
(3) Palacios, F.; Alonso, C.; de Los Santos, J. M Chem. Rev. 2005, 105,
899–931.
(4) Han, L.; Hiratake, J.; Kamiyama, A.; Sakata, K. Biochemistry 2007,
46, 1432–1447.
(5) (a) Marchand-Brynaert, J.; Defacqz, N.; Robiette, R. Recent Res.
Dev. Org. Chem. 2001, 5, 207–223. (b) Robiette, R.; Defacqz, N.; Peeters, D.;
Marchand-Brynaert, J. Curr. Org. Synth. 2005, 2, 453 and references therein.
(c) Monbaliu, J.-C.; Tinant, B.; Peeters, D.; Marchand-Brynaert, J. Tetra-
hedron Lett. 2010, 51, 1052–1055. (d) Monbaliu, J.-C.; Marchand-Brynaert,
J. Synthesis 2009, 11, 1876–1880. (e) Monbaliu, J.-C.; Marchand-Brynaert, J.
Tetrahedron Lett. 2008, 49, 1839–1842.
(1) Kukhar, V. P.; Hudson, H. R. Aminophosphonic and Aminophosphinic
Acids, Chemistry and Biological Activity; J. Wiley & Sons, Ltd.: New York,
2000.
(2) Wermuth, C. The Practice Of Medicinal Chemistry; Elsevier Academic
Press: New York, 2006.
5478 J. Org. Chem. 2010, 75, 5478–5486
Published on Web 07/21/2010
DOI: 10.1021/jo100230r
r
2010 American Chemical Society

Monbaliu et al.
JOCArticle
SCHEME 1. Synthesis of Dienes (TBDMS = tert-
Butyldimethylsilyl)
FIGURE 1. Some aminophosphonic compounds of interest.
2-oxazines, have been further considered as synthons for the
preparation of δ-aminophosphonic derivatives in the aliphatic
series and in the pyrrolidine family.
Results and Discussion
Synthesis of the Precursors. 1-(Diethoxyphosphonyl)-1,3-
butadiene (1a), obtained in two steps from 1,4-trans-dichloro-
butene according to a modified protocol of the literature,5d is
the precursor of 1-(dibenzyloxyphosphonyl)-1,3-butadiene
(1b) (Scheme 1). The recently described phosphonyl dichloride
intermediate 35c reacted directly with 2 equiv of freshly distilled
benzyl alcohol and pyridine. Dienes 1a and 1b are easily
purified by column chromatography on silica gel; they are
stable under storage at 4 °C during several months.
FIGURE 2. General strategy toward δ-aminophosphonic com-
pounds.
weak dienyl activation. Even with activated CdC dienophiles,
the DA cycloaddition yields remain modest.5b We have recently
reported that 2-nitrosotoluene (2a) is able to react quantitatively
with 1-diethoxyphosphonyl-1,3-butadiene (1a) under micro-
wave (MW) heating.5e This HDA reaction provides the first
example of an efficient cycloaddition using a phosphonodiene.
Theoretical studies by Leach and Houk6a reported that the
cycloadditions of inactivated or poorly activated dienes with
nitroso dienophiles led to mixtures of proximal and distal
regioisomers.6b Similarly, we investigated the HDA reaction
of 1-diethoxyphosphonyl-1,3-butadiene (1a) with nitroso
dienophiles (model compounds and reagents used in this
work) by computational methods and concluded that the
phosphonate moiety prevents the formation of the more
constrained distal cycloadduct, leading to complete proxi-
mal regioselectivity (theoretical results not shown). This is
experimentally shown below.
Three different phosphonodienes 1 were considered in our
study. As phosphonic acids are particularly awkward to handle,
due to their low solubility in common organic solvents, the
release of free acids has to be performed in the last synthetic step,
preferably avoiding purification. Accordingly, dienes 1a and 1b
were used as simple C(1)-substituted 1,3-butadienes with two
different P-protecting groups (1a, R1 = Et and R2 = H; 1b
R1 = Bn and R2 = H) which could be cleaved under selective
conditions, nucleophilic substitution and catalytic hydrogena-
tion, respectively. A third phosphonodiene 1c (R1 = Et, R2 =
OTBDMS) was synthesized in order to increase the butadienyl
reactivity toward dienophiles. Various nitroso dienophiles were
considered as partners, from a stable one (2a) to transient
species (acylnitroso derivatives 2d-g), covering some molecular
diversity. Particular nitroso substituents (R3) were used because
of their convenient deprotection into free amines (e.g., 2b-d).
The HDA cycloadditions of dienes 1a-c with nitroso
dienophiles 2a-g (Figure 2) are fully discussed in this article,
in continuation of our preliminary investigations already
published.5e Some cycloadducts, i.e., 6-phosphono-3,6-dihydro-1,
1-Diethoxyphosphonyl-3-(tert-butyldimethylsilyloxy)-1,3-
butadiene (1c) was obtained from the known vinylphospho-
nate 4.7 Under the usual conditions for the synthesis of silyl
enol ethers (TBDMSCl, NaI, Et3N),8 cleavage of the diethyl
phosphonate moiety was observed due to the in situ formation of
TBDMSI. In the absence of NaI, no reaction occurred. Optimal
conditions were found using DBU in THF with 1 equiv of tert-
butyldimethylsilyl chloride. Conversion of 4was complete within
1
1 h (monitoring by H NMR 500 MHz), but the purification
induced loss of final pure product (50% isolated yield).
The C(1) typical 13C NMR signals and JC-P coupling
constants are quite similar for dienes 1a-c (δ = 115-
1
118 ppm; J=189-191 Hz). However, the chemical shift
belonging to C(4) appears significantly different for 1c
(δ=102 ppm) compared to 1a,b (δ=124-125 ppm) because
of an increase in electron density.
The most reactive nitroso dienophiles are those where the
NdO group is directly linked to an electron-withdrawing
substituent.6,9 In contrast, arylnitroso dienophiles are stable
(6) (a) Leach, G. L.; Houk, K. N. J. Org. Chem. 2001, 66, 5192–5200.
(b) Boger, D.; Patel, M.; Takusagawa, F. J. Org. Chem. 1985, 50, 1911–1916.
(for proximal/distal nomenclature).
(7) McClure, C. K.; Grote, C. W. Tetrahedron Lett. 1991, 32, 5313–5316.
(8) (a) Cazeau, P.; Duboudin, F.; Moulines, F.; Badot, O.; Dunogues, J.
Tetrahedron 1987, 43, 2075–2088. (b) Cazeau, P.; Duboudin, F.; Moulines,
F.; Babot, O.; Dunogues, J. Tetrahedron 1987, 43, 2089–2100.
(9) (a) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595.
(b) Yamamoto, Y.; Yamamoto, H. Eur. J. Org. Chem. 2006, 2031–2043.
(c) Kawasaki, M.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 16482–
16483. (d) Yamamoto, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44,
7082–7085. (e) Comins, D. L.; Kuethe, J. T.; Miller, T. M.; Fevrier, F. C.;
Brooks, C. A. J. Org. Chem. 2005, 70, 5221–5234. (f) Vogt, P. F.; Miller, M. J.
Tetrahedron 1998, 54, 1317–1348. (g) Streith, J.; Defoin, A. Synthesis 1994,
1107–1117.
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SCHEME 2. Cycloaddition of 1a-c to o-Nitrosotoluene
SCHEME 3. Cycloaddition of 1a to R-Chloronitroso Dieno-
philes
entities, and some of them are commercially available.
Despite their stability, they are good dienophiles.9 R-Chloro
nitroso dienophiles react slowly with dienes, are poorly
stable, and are light sensitive.10 Nevertheless, their use in
alcoholic solvent is of particular interest since the initial
cycloadducts are solvolyzed in situ to give the corresponding
N-deprotected oxazines.11 Nitroso formate and acylnitroso
dienophiles also offer the possibility of further deprotection
of the cycloadducts, but these reagents are highly reactive
and prone to rapid degradation. For this work, o-nitrosoto-
luene (2a) was purchased as its dimeric form, while the
R-chloro (2b,c) and acylnitroso (2d-g) dienophiles were in
situ prepared from their respective precursors (i.e., hydro-
xamic acids and 9,10-dimethylanthracenyl cycloadducts)
according to established procedures.12-15
useful for the structural assignments.16-18 The oxazines 5a,b
could be easily purified by column chromatography and
stored for a long time without degradation. Unfortunately,
cycloadduct 5c was poorly stable and degraded quite rapidly
under purification and storage, even at -20 °C. Attempts to
directly deprotect or hydrolyze the silylenol ether function
of crude 5c led disappointingly to untractable mixtures.
Consequently, 5c could not be exploited as a useful synthon
toward aminophosphonic derivatives, and its precursor,
i.e., diene 1c, was not further considered in the present
study.
A freshly prepared solution of 2-chloro-2-nitrosopropane
(2b) was engaged under mild HDA conditions with diene 1a
in chloroform at room temperature in the dark (Scheme 3).
The reaction was monitored by NMR analysis. After 5 days,
a mixture of several products was observed, containing
mainly 1a and the desired cycloadduct 6b (e20% of the
crude material), easily identified by the typical 1JC-P value of
164.7 Hz observed in 13C NMR for the C(6) peak at 74.3 ppm
and an additional singlet at 207.1 ppm, characteristic of the
imminium quaternary carbon.
A similar behavior has been observed in diethyl ether as
solvent or when 1-chloro-1-nitrosocyclohexane (2c) is used as
the dienophile. Complete degradation of the corresponding
cycloadducts 6b,c during solvolysis with ethanol, aqueous
workup, or direct chromatography was observed. Hence, we
were unable to isolate the N-deprotected oxazine 7. Therefore,
we considered the acylnitroso dienophiles.
Using standard conditions for the generation of acylni-
troso species 2d-g from the corresponding hydroxamic acids
(i.e., oxidation with commercial butylammonium (meta)-
periodate), we never observed cycloadditions with diene 1a.
After complete consumption of the hydroxamic acids, phos-
phonodiene 1a was recovered in more than 95% yield. Alter-
natively, the modified Moffatt-Swern protocol was used, but
no cycloadducts were observed. This prompted us to consider
another source of acylnitroso species, and we put our attention
on anthracenyl acylnitroso cycloadducts 8, well-known for their
thermal instability. Modified protocols from the literature were
applied to produce compounds 8d-g (Scheme 4).12 Treatment
of a chloroform solution of 9,10-dimethylanthracene and butyl-
ammonium (meta)periodate with a dimethylformamide solution
HDA Cycloadditions of Dienes 1a-c and Dienophiles
2a-g. The reactivity of dienes 1a-c was first evaluated
versus commercial o-nitrosotoluene (2a), used as a reference
reagent, under classical thermal activation (reflux in dichloro-
ethane (DCE)) and microwave (MW) heating. Although
(chiral) catalysts have been shown to activate the HDA
reactions of nitroso dienophiles,9 we did not consider cata-
lytic systems here because of the particular nature of the
dienyl partners 1. The phosphonate group behaves as a good
Lewis base, trapping the Lewis acid catalysts and preventing
from efficient complexation-decomplexation equilibria.5a,b
Similarly to diene 1a,5e diene 1b led to the cycloadduct 5b
within a short reaction time (1 h) and in high yield under MW
heating (Scheme 2). As expected, the 3-silyloxy diene 1c was
more reactive than 1a,b in DCE at reflux, yielding the
corresponding cycloadduct 5c within 4 h (100% conversion)
instead of 12-17 h for dienes 1a,b.
1H, 13C,and 31P NMR spectroscopy allowed us to unam-
biguously confirm the proximal regioisomer of the cycload-
ducts 5 (see the Experimental Section). In particular, 13C
NMR chemical shifts and JC-P coupling constants were very
(10) (a) Riddell, F. Tetrahedron 1975, 31, 523–525. (b) Riddell, F.;
Labaziewicz, H. J. Chem. Soc., Perkin Trans. 1 1979, 2926–2929.
(11) (a) Gupta, A. K.; Acharya, J.; Pardasani, D.; Dubey, D. K. Tetra-
hedron Lett. 2007, 48, 767–770. (b) Kumar, V.; Kaushik, M. P. Tetrahedron
Lett. 2005, 46, 8121–8123.
(12) (a) Keck, G.; Webb, R.; Yates, J. Tetrahedron 1981, 37, 4007–4016.
(b) Mulvihill, M.; Cage, J.; Miller, M. J. Org. Chem. 1998, 63, 3357–3363.
(13) Monbaliu, J.-C.; Marchand-Brynaert, J.; Peeters, D. Tetrahedron
Lett. 2009, 50, 2555–2558.
(14) (a) Quadrelli, P.; Mella, I.; Carosso, S.; Bovio, B.; Caramella, P. Eur.
J. Org. Chem. 2007, 6003–6015. (b) Quadrelli, P.; Invernizzi, A.; Caramella,
P. Tetrahedron Lett. 1996, 37, 1909–1912.
(15) (a) Adamo, M. F. A.; Bruschi, S. J. Org. Chem. 2007, 72, 2666–2669.
(b) Chow, C.; Shea, K. J. Am. Chem. Soc. 2005, 127, 3678–3679.
(16) Savignac, P.; Iorga, B. Modern Phosphonate Chemistry; CRC Press:
Boca Raton, 2003.
(18) (a) Dieltiens, N.; Stevens, C. V.; Masschelein, K.; Hennebel, G.; Van
der Jeught, S. Tetrahedron 2008, 64, 4295–4303. (b) Vanderhoydonck, B.;
Stevens, C. V. Tetrahedron 2007, 63, 7679–7689.
(17) (a) Yu, J.; Huang, S. Phosphorus, Sulfur, Silicon 1997, 131, 107–127.
(b) Pamies, O.; Backvall, J. J. Org. Chem. 2003, 68, 4815–4818.
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SCHEME 4. Cycloaddition of 1a to Acylnitroso Dienophiles
Generated in Situ from Their 9,10-DMA Adducts
FIGURE 3. Conformers of cycloadduct 5a and their relative
energies (B3LYP/6-31G**).
SCHEME 5. Reductive Cleavage of 5a and Further Functiona-
lizations
TABLE 1. 13C NMR (75 MHz, CDCl3) Data of Cycloadducts 9
(δ Values (ppm) and JC-P Values (Hz) in Parentheses)
d
e
f
g
C(3) 46.3
C(4) 125.1
C(5) 121.5
(0)
42.0
(0)
43.4
(0)
42.3
(0)
(9.6)
(3.8)
(9.4) 124.7
(5.5) 120.9
(9.6) 124.8
(3.6) 121.0
(9.5) 124.6
(5.7) 121.0
C(6) 73.9 (159.4) 75.8 (160.0) 75.5 (160.7) 76.0 (160.4)
of hydroxamic acids quantitatively led to the corresponding
anthracenyl adducts 8. After reductive workup (aqueous Na2-
S2O3) to remove the excess of periodate, the precursors 8 were
isolated with satisfying purity. They are stable under storage
at -20 °C but degraded under chromatography conditions.
Several conditions for the reaction of 1a and crude 8d-g
have been investigated. Complete transformation of diene 1a
(NMR analysis) occurred using a 8/1a ratio between 1 and 2
in refluxing DCE overnight (Scheme 4). After purification,
the cycloadducts 9d-g were isolated in moderate to good
yields. NMR analyses of the crude cycloadducts 9 were
consistent with the formation of single regioisomers. The
proximal regioselectivity was confirmed by comparison with
the other series (see above, cycloadducts 5) and further
assessed by X-ray data from a functionalized derivative
(see below, structure 23d).
Our experimental data are in good agreement with the com-
puted more stable conformer II (ΔE = 4.2 kcal mol-1).
3
Chemical Modification of the 3,6-Dihydro-1,2-oxazine De-
rivatives. Four diversification sites are identified on our
cycloadducts, namely the N-O bond, the CdC double
bond, the phosphonate, and the NR3 groups. Accordingly,
reductive cleavage, oxidation, functional group interconver-
sion, or combinations of these reactions could provide a
versatile synthetic route for aminophosphonic compounds in
both aliphatic and heterocyclic series.
Typical 13C NMR features are summarized in Table 1. For
all of the cycloadducts, the experimental coupling constants
are quite similar, in particular 3JC-P (9-10 Hz). This could
be interpreted in terms of conformational behavior of het-
erocycles 5 and 9 and explained using the relevant Karplus
curve.19 Two stable conformers were computed for the
3,6-dihydro-1,2-oxazine 5a at the B3LYP/6-31G** level of
theory.20 Conformer I presents the phosphonate substituent
in a pseudoaxial position, while for conformer II, this group
is in a pseudoequatorial position (Figure 3). Interestingly,
both conformers show the 2-tolyl substituent in a pseudo-
axial position, releasing the nitrogen lone pair in a pseudo-
equatorial position. In the most stable conformer II, the
φP-C(6)-C(5)-C(4) dihedral angle is 137° and 73° for the other
A first synthetic application of the 3,6-dihydro-1,2-oxazine
framework is the selective reductive cleavage of the N-O bond
to generate a 1,4-bifunctional 2-butene derivative with pre-
served (Z)-configuration (Scheme 5). In our case, reduction by
zinc powder in acetic acid was the most efficient method for
preparing (Z)-diethyl 4-(o-tolylamino)-1-hydroxy-2-butenyl-
1-phosphonate (10) from 5a in quantitative yield5e (structure
confirmed by X-ray data; see Supporting Information).
Classically, the diethyl phosphonate group is deprotected
with hot 6 N HCl, KOHaq, or TMSX (X = Br or I),21
trimethylsilylbromide being the most common method. The
diester 10 was thus deprotected using TMSBr followed by
the alcoholysis of the intermediate bis(trimethylsilyl) ester,
leading to the desired (Z)4-(o-tolylamino)-1-hydroxy-2-bu-
tenyl-1-phosphonic acid (11) in high yield.
3
conformer I. These values correspond to JP-C coupling
Compound 10 can be used as an intermediate for the
synthesis of azaheterocyclic phosphonates. Indeed, ring
closure into the pyrrolidine derivative 12 was realized
constants of 10 and 0 Hz from the Karplus curve, respectively.
(19) (a) Gorenstein, D. G. Phosphorus-31 NMR, Principles and Applica-
tions; Academic Press: New York, 1984. (b) Quin, L. S. A Guide to
Organophosphorus Chemistry; John Wiley & Sons: New York, 2000.
(20) Gaussian 98 suite of programs, Revision A.11: Frisch, M. J. et al.
Gaussian, Inc., Pittsburgh, PA, 1998.
(21) (a) Kocienski, P. Protecting Groups; Thieme Verlag: Stuttgart, 2004.
(b) Greene, T.; Wuts, P. Protective Groups in Organic Synthesis; John Wiley
& Sons: New York, 1999.
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Monbaliu et al.
SCHEME 7. N-Deprotection of Oxazine Derivatives
JOCArticle
SCHEME 6. Dihydroxylation of 5a,b and Further Functionali-
zations
TMSBr/MeOH, yielding quantitatively to acid 16. Hydrogena-
tion of 14b directly yielded the same aminophosphonic com-
pound 16 with concomitant cleavage of the 1,2-oxazine pattern
and benzyl ester moieties.
The syn-diol 14a has also been considered as a valuable
intermediate for the synthesis of R-epoxy δ-aminophospho-
nates 20 and 21 (Scheme 6). Addition of tert-butyldimethyl-
silyl chloride to a solution of 14a and imidazole led to the
C(4)-protected compound 17 with a total chemoselectivity
due to the steric effect of the phosphonate group. Mesylation
of the remaining C(5)-OH proceeded smoothly under stan-
dard conditions. The intermediate 18 crystallized from an
ether/hexane mixture, allowing the unambiguous assign-
ment of the relative stereochemistry by X-ray diffraction
analysis (see the Supporting Information). Reductive clea-
vage of 18 under catalytic hydrogenation conditions gave
1-(diethoxyphosphonyl) 4-(o-tolylamino)-1-hydroxy-2-
methanesulfonatobutan-3-yl-tert-butyldimethylsilane (19).
This intermediate cyclized intramolecularly, upon K2CO3
treatment, to give the epoxide 20 in good yield. The oxirane
structure was confirmed by NMR analysis: the signal of the
C(1)-P carbon atom of 20 is strongly shielded (δ = 48.2 ppm)
regarding the corresponding carbon of the precursor 19 (δ =
67.9 ppm, JC-P = 160.6 Hz) and the large JC-P value of
203.1 Hz are typical for 1,2-epoxyalkyl phosphonates.16
Finally, deprotection of the silylated alcohol using tetrabu-
tylammonium fluoride allowed the isolation of compound
21, with an overall yield of 66% after column chromato-
graphy on silica gel (five steps from diol 14a), as a single
stereoisomer (one 31P NMR signal).
Similar functionalizations have also been considered start-
ing from the N-acylated cycloadducts 9 (see Scheme 4).
Unfortunately, the N-O bond cleavage failed under stan-
dard conditions. Compounds 9 were unreactive with Zn
in HCl or Mo(CH3CN)3(CO)3, and complete degradation
occurred in the presence of SmI2.
by first converting the hydroxyl group into a leaving
group with CBr4 and polymer-supported PPh3. In the
presence of imidazole, the intramolecular nucleophilic
substitution by the aniline moiety led to diethyl 2,5-dihydro-
1-o-tolyl-1-pyrrol-2-yl-2-phosphonate (12), recovered in good
yield after filtration of the polymeric reagent (Scheme 5).
Further treatment of 12 with osmium oxide and N-methylmor-
pholine oxide (NMO) gave the syn-diol 13 in high yield.
The observation of a single peak in the 31P NMR spectrum
indicates that the dihydroxylation has proceeded with complete
facial selectivity, leading to the formation of one stereoisomer,
most probably with the trans relationship between P and O
substituents for steric reasons. This suggests an efficient
control of the relative stereochemistry by the bulky phospho-
nate group.
A second synthetic application of the 3,6-dihydro-1,2-
oxazine starts with the selective oxidation of the CdC double
bond. A syn-dihydroxylation, followed by N-O reductive
cleavage and phosphonate deprotection provided a practical
entry to polyhydroxylated δ-aminophosphonates (Scheme 6).
Treatment of 5a and 5b under standard syn-dihydroxyla-
tion conditions (see above) gave the corresponding diols
14a5e and 14b as single stereoisomers from 31P NMR spectra
of the crude products (e.g., one signal observed). The trans
relationship of the phosphonate group regarding the two
hydroxyl groups was attributed on the basis of X-ray data
recorded previously for a crystalline derivative of compound
14a, namely the benzoyl bis-ester.5e Treatment of 14a,b with
Zn/AcOH led to complete degradation of the heterocycles.
Fortunately, the reductive cleavage of 14a was effective under
catalytic hydrogenation conditions and gave the diethyl tris-
(hydroxyamino)phosphonate 15 in 98% yield. Deprotection of
the diethoxyphosphonyl ester was then accomplished with
1
1
Lastly, N-Boc deprotection of the oxazine 9d was considered
as the first step of a sequence of functionalization. Treatment
of cycloadduct 9d with trifluoroacetic acid (TFA) in dichlor-
omethane at room temperature yielded the salt 22 (Scheme 7).
Upon neutralization (aqueous NaHCO3), complete degrada-
tion occurred, and the major product was the diene 1a due
to the retro-DA process.5d This result, consistent with the
observed instability of cycloadducts 6 during workup, imposes
5482 J. Org. Chem. Vol. 75, No. 16, 2010

Monbaliu et al.
JOCArticle
modification of the CdC double bond first (reduction or
dihydroxylation) before cleavage of the N(2) substituent.
Hence, we prepared the syn-diols 23d and 23e as previously
described (Scheme 7). Here again, single stereoisomers were
formed according to the 31P NMR data.
X-ray diffraction analysis of a monocrystal 23d confirmed
both the trans relationship of the phosphonate group regard-
ing the syn-hydroxyl groups and the proximal regioselecti-
vity of the key HDA step (see the Supporting Information).
Finally, 23d was readily deprotected with TFA, yielding the
stable oxazidine 24.
The reagents were purchased from commercial sources and
used without further purification. The solvents (anhydrous grade;
H2O < 0.001%) were purchased from commercial sources and
stored under argon atmosphere over molecular sieves. The vessel
was flame dried under high vacuum and then cooled under argon
atmosphere. TLC analyses were performed on aluminum plates
coated with silica gel 60 F254 and visualized with UV (254 nm) or
KMnO4 solution.
Compounds 1a, 5a, 10, 12, 14a, and 15 have been previously
reported.5d,e
1-(Dibenzyloxyphosphonyl)-1,3-butadiene (1b). To a stirred
solution of 1a (2 g, 10.5 mmol) in dry dichloromethane (10 mL)
at room temperature was added dropwise TMSBr (4 mL, 34.88
mmol) for 15 min. After complete consumption of 1a (about 2 h,
NMR control), the volatiles were removed under reduced pressure.
The intermediate bis(trimethylsilyl) ester was dissolved in dry
dichloromethane (10 mL) with a few drops of dry DMF. The
resulting solution was treated dropwise with oxalyl chloride
(3.55 mL, 42 mmol) under vigorous magnetic stirring at 20 °C.
After 1 h, the crude material was concentrated under reduced
pressure. The (E)-buta-1,3-diene 1-phosphonyl dichloride residue 3
was dissolved in anhydrous THF (20 mL) and treated with pyridine
(2.21 mL, 27.4 mmol) and with freshly distilled benzyl alcohol
(2.4 mL, 23.1 mmol) at 0 °C for 1 h. The mixture was allowed to
slowly warm to room temperature and stirred overnight. After-
ward, the crude material was concentrated under reduced pressure,
diluted with ethyl acetate (20 mL), washed with aqueous saturated
NH4Cl (20 mL), dried over MgSO4, filtered, and concentrated. The
oily residue was purified by column chromatography on silica gel
(toluene/ethyl acetate 5:2) to give 1b as a pale yellow oil (4.6 g,
62%): Rf (toluene/ethyl acetate 5:2) = 0.6; 1H NMR (300 MHz,
CDCl3) δ 7.32 (m, 10H), 7.06 (m, 1H), 6.36 (m, 1H), 5.72 (dd,
Conclusion
A few HDA reactions with unsaturated phosphonates
have been reported in the previous literature, such as the
[4 þ 2] cycloadditions of vinyl acyl phosphonates with enol
ethers leading to dihydropyranphosphonates.22 Here, we
have further documented this domain of heterocyclic chem-
istry with the synthesis of dihydrooxazinephosphonates.
The 6-phosphono-3,6-dihydro-1,2-oxazine synthon result-
ing from the HDA reaction of 1-phosphonodienes and
nitroso dienophiles offers a versatile synthetic route for the
synthesis of polyfunctionalized aminophosphonic deriva-
tives, with complete control of the regio- and stereoselecti-
vities. Some compounds prepared from the precursors 5 and
9 are structurally related to natural products or analogues of
potential interest in medicinal chemistry. For instance, com-
pounds 10 and 11 possess the same skeleton as rhizocticin
A,23 and the pyrrolidine 13 can be considered as a bioisoster
of dihydroxyproline (Scheme 5).24 The triols 15 and 16 are
related to xylose25 and monomers for modified nylons26
(Scheme 6). The 1,2-epoxyalkyl-1-phosphonate motif of 20
and 21 is similar to an antibiotic (Fosfomycin) isolated from
Streptomyces fradiae, which has stimulated many synthetic
efforts.27 Hence, our HDA methodology can efficiently
contribute to the current search of molecular diversity and
offers new opportunities for the discovery of biologically
active compounds.28
J
H,H = 19.4 Hz, JH,P = 17.2 Hz, 1H), 5.46 (m, 2H), 5.03 (d, JH,P
=
=
8.0 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 149.2 (d, JC,P
5.9 Hz), 136.2, 136.1, 135.6 (d, JC,P = 27.4 Hz), 128.6, 128.4, 128.3,
128.0, 126.8, 125.3, 117.6 (d, JC,P = 191.8 Hz), 67.4 (d, JC,P = 5.4
Hz); 31P NMR (121 MHz, CDCl3) δ20.47; IR (NaCl) ν 2972, 2908,
1613, 1525, 1220, 1072 cm-1; HRMS (ESI) calcd for C18H19O3PNa
[M þ Naþ] 337.0970, found 337.0974.
1-(Diethoxyphosphonyl)-3-tert-butyldimethylsiloxy-1,3-buta-
diene (1c). A solution of 1-(diethoxyphosphonyl)but-1-en-3-one 47
(2 g, 10 mmol) and TBDMSCl (1.6 g, 10 mmol) in anhydrous THF
(50 mL) was treated dropwise by DBU (1.5 mL, 10 mmol) at 20 °C.
After 1 h, the crude material was concentrated under reduced
pressure, diluted with petroleum ether (30 mL), and filtered
through a short silica gel pad to give pure diene 1c as a yellow oil
Experimental Section
All melting points are uncorrected. 1H (300 or 500 MHz) and
13C (75 or 125 MHz) NMR spectra were recorded on a 300 or a
500 MHz NMR spectrometer in CDCl3 (with TMS for 1H and
CDCl3 for 13C as the internal reference) or D2O. 31P (121 MHz)
NMR spectra were recorded on a 300 MHz NMR spectrometer
in CDCl3 or D2O (with H3PO4 as the internal reference).
1
(1.6 g, 50%): Rf (EtOAc/cyclohexane 75:25) = 0.5; H NMR
(300 MHz, CDCl3) δ 6.91 (dd, JH,P = 21.2 Hz, JH,H = 16.7 Hz,
1H), 5.98 (dd, JH,P = 20.0 Hz, JH,H = 16.7 Hz, 1H), 4.60 (2 s, 2H),
4.08 (dq, JH,P = 7.2 Hz, JH,H = 7.1 Hz, 4H), 1.32 (t, JH,H = 7.1
Hz, 6H), 0.96 (s, 9H), 0.18 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
153.8 (d, JC,P = 23.8 Hz), 146.8 (d, JC,P = 7.5 Hz), 115.0 (d, JC,P
=
190.1 Hz), 102.2, 62.1 (d, JC,P = 5.4 Hz), 26.0, 18.6, 16.7 (d, JC,P
=
6.4 Hz), -4.4; 31P NMR (121 MHz, CDCl3) δ 20.51; IR (NaCl)
ν 2957, 2931, 2902, 2858, 1252 cm-1; HRMS (ESI) calcd for
C14H29O4PSiNa [M þ Naþ] calcd 343.1470, found 343.1482.
Dibenzyl 3,6-Dihydro-2-o-tolyl-1,2-oxazin-6-yl-6-phosphonate
(5b). A solution of diene 1b (2.1 g, 6.58 mmol) in dichloroethane
(10 mL) and o-tolylnitroso 2a (0.82 g, 6.58 mmol) was stirred
in a microwave oven under 500 W irradiation at 100 °C for 1 h.
The reaction mixture was concentrated under reduced pressure
and purified by column chromatography on silica gel (toluene,
then toluene/EtOAc 5:2) to give 5b as a brown oil (2.57 g, 90%):
(22) (a) Telan, L. A.; Poon, C.-D.; Evans, S. A., Jr. J. Org. Chem. 1996,
61, 7455–7462. (b) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc. 1998, 120,
4895–4896.
(23) (a) Wiemer, D. F. Tetrahedron 1997, 53, 16609–16644. (b) Fregenhagen,
A.;Angst, C.;Peter, H. H.J. Antibiot. 1995, 48, 1043–1045. (c) Rapp, C.; Jung, G.;
Kluger, M.; Loeffler, W. Liebigs Ann. Chem. 1988, 655–661.
(24) (a) Kaname, M.; Mashige, H.; Yoshifyji, S. Chem. Pharm. Bull. 2001,
49, 531–536. (b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.;Eur. J.
2006, 12, 3636–3646.
(25) Wroblewski, A.; Glowacka, I. Tetrahedron 2005, 61, 11930–11938.
(26) Falentin, C.; Beaupere, D.; Demailly, G.; Stasik, I. Carbohydr. Res.
2007, 342, 2807–2809.
1
ꢀ
ꢀ
(27) (a) Wroblewski, A. E.; Ba-k-Sypien, I. I. Tetrahedron: Asymmetry
Rf (toluene/EtOAc 5:2) = 0.4; H NMR (500 MHz, CDCl3)
ꢀ
ꢀ
2007, 18, 2218–2226. (b) Wroblewski, A. E.; Ba-k-Sypien, I. I. Tetrahedron:
Asymmetry 2007, 18, 520–526. (c) Hwang, J.-M.; Jung, K.-Y. Bull. Korean
Chem. Soc. 2002, 23, 1841–1850. See also ref.1.
δ 7.25-7.05 (m, 15H), 6.06 (broad s, 2H), 5.1-4.99 (m, 5H), 3.76
(m, 1H), 3.49 (m, 1H), 2.24 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 147.8, 136.3 (d, JC,P = 6.2 Hz), 136.2 (d, JC,P = 5.9 Hz), 133.1,
130.9, 128.6, 128.6, 128.6, 128.4, 128.0, 126.7 (d, JC,P = 10.2 Hz),
(28) Moonen, K.; Laureyn, I.; Stevens, C. Chem. Rev. 2004, 104, 6177–
6215.
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Monbaliu et al.
JOCArticle
126.5, 125.9, 122.4 (d, JC,P = 5.0 Hz), 118.8, 75.9 (d, JC,P = 59.9
Hz), 68.7 (d, JC,P = 6.7 Hz), 68.1 (2 d, JC,P = 6.7 Hz), 52.4, 18.2;
31P NMR (121 MHz, CDCl3) δ 19.28; IR (NaCl) ν 2940, 1488,
1421, 1237, 1027, 972 cm-1; HRMS (ESI) calcd for C25H26NO4-
PNa [M þ Naþ] 458.1497, found 458.1491.
7.72-7.69 (m, 2H), 7.44-7.40 (m, 3H), 6.06 (broad s, 2H),
4.85 (broad d, JH,P = 19.9 Hz, 1H), 4.62 (m, 1H), 4.14-3.89 (m,
5H), 1.22 (td, JH,P = 17.2 Hz, JH,H = 7.1 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 170.3, 136.1, 133.5, 131.3, 128.8, 124.8 (d,
J
C,P = 9.5 Hz), 121.0 (d, JC,P = 5.7 Hz), 75.5 (d, JC,P = 160.7
Diethyl 3,6-Dihydro-5-tert-butyldimethylsiloxy-2-o-tolyl-1,2-
oxazin-6-yl-6-phosphonate (5c). A solution of diene 1c (0.26 g,
0.7 mmol) and nitrosotoluene 2a (0.1 g, 0.7 mmol) in refluxing
dichloroethane (10 mL) was stirred 4 h. The reaction mixture
was concentrated and purified by column chromatography on
silica gel (toluene, then toluene/EtOAc 5:4) to give 5c as a brown
oil (0.28 g, 78%): Rf (toluene/EtOAc 5:4) = 0.5; 1H NMR (300
MHz, CDCl3) δ 7.16 (m, 4H), 5.16 (d, JH,H = 5.3 Hz, 1H), 5.02
(ddd, JH,P = 13.4 Hz, JH,H = 5.3 Hz, JH,H = 2.1 Hz, 1H),
4.27-4.08 (m, 4H), 3.75 (ddd, JH,H = 15.3 Hz, JH,P = 4.6 Hz,
JH,H = 2.1 Hz, 1H), 3.43 (d, JH,H = 15.3 Hz, 1H), 2.35 (s, 3H),
1.31 (t, JH,H = 7.1 Hz, 6H), 0.95 (s, 9H), 0.24 (s, 3H), 0.23 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 149.9 (d, JC,P = 11.5 Hz), 147.3,
133.4, 131.2, 126.6, 126.1, 118.6, 97.9 (d, JC,P = 5.5 Hz), 73.6 (d,
JC,P = 162.6 Hz), 63.4 (d, JC,P = 6.8 Hz), 63.0 (d, JC,P = 6.8 Hz),
55.5 (d, JC,P = 2.3 Hz), 25.9, 18.5, 18.3, 16.8 (d, JC,P = 5.3 Hz),
-4.0, -4.4; 31P NMR (121 MHz, CDCl3) δ 19.02; HRMS (ESI)
calcd for C21H37NO5PSi [M þ Hþ] 442.2179, found 442.2194.
General Cycloaddition Procedure toward N-Acylated 1,2-Oxa-
zine Compounds 9d-g. A solution of 9,10-dimethylanthracene
(1 g, 4.8 mmol) and tert-butylammonium metaperiodate (3.1 g,
7.2 mmol) in dry chloroform (30 mL) was treated dropwise by a
DMF solution (10 mL) of hydroxamic acid (7.2 mmol) over 2 h at
0 °C. After complete addition, the ice bath was removed, and
the mixture was allowed to slowly warm up to 20 °C for 1 h. The
reaction mixture was concentrated under reduced pressure. The
residue was diluted in ethyl acetate (30 mL) and washed with
saturated aqueous sodium thiosulfate (3 ꢀ 10 mL), brine (2 ꢀ
10 mL), and water (1 ꢀ 10 mL). The organic layer was dried over
MgSO4, filtered, and then concentrated. The yellow solid residue
(8d-g) was dissolved in a mixture of dichloroethane (10 mL) and
1a (in the molar ratios given in Scheme 4). After 15 h at reflux, the
solvent was removed under reduced pressure. The residue was
diluted in cold ethanol (30 mL), and the resulting suspension was
filtered to remove 9,10-dimethylanthracene. Further purification
was carried out by column chromatography on silica gel.
Hz), 63.9 (d, JC,P = 6.7 Hz), 63.0 (d, JC,P = 6.4 Hz), 43.4, 16.5
(d, JC,P = 6.1 Hz); 31P NMR (121 MHz, CDCl3) δ 15.38; IR
(NaCl) ν 1662, 1647, 1448, 1394, 1369, 1259, 1161, 1022, 976
cm-1; HRMS (ESI) calcd for C15H20NO5PNa [M þ Naþ]
348.0977, found 348.0986.
Diethyl 3,6-Dihydro-2-(2-phenylacetyl)-1,2-oxazin-6-yl-6-phos-
phonate (9g). Chromatography (EtOAc/cyclohexane 75:25) gives
9g as a yellow oil (1.73 g, 71%): Rf (EtOAc/cyclohexane 75:25) =
0.2; 1H NMR (500 MHz, CDCl3) δ 7.35-7.32 (m, 5H), 6.03 (m,
2H), 4.74 (broad d, JH,P = 16.2 Hz, 1H), 4.35 (dd, JH,H = 18.1 Hz,
J
H,P = 2.9 Hz, 1H), 4.24-4.12 (m, 5H), 3.96 (d, JH,H = 14.5 Hz,
1H), 3.83 (d, JH,H = 14.5 Hz, 1H), 1.39 (t, JH,H = 7.1 Hz, 3H), 1.35
(t, JH,H = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.3,
134.8, 129.7, 128.8, 127.1, 124.6 (d, JC,P =9.6 Hz), 120.9 (d, JC,P
3.8 Hz), 76.0 (d, JC,P = 160.4 Hz), 64.0 (d, JC,P = 6.7 Hz), 63.3 (d,
C,P = 6.7 Hz), 39.9, 16.8 (d, JC,P = 5.5 Hz); 31P NMR (121 MHz,
=
J
CDCl3) δ 16.48; IR (NaCl) ν 2982, 2384, 17118, 1437, 1394, 1022,
970 cm-1; HRMS (ESI) calcd for C16H22NO5PNa [M þ Naþ]
362.1133, found 362.1135.
(Z)-4-(o-Tolylamino)-1-hydroxybut-2-enylphosphonic Acid (11).
To a solution of 10 (0.1 g, 0.32 mmol) in dry dichloromethane
(2 mL) was added dropwise TMSBr (0.14 mL, 1 mmol) at 20 °C.
After complete consumption of 10, MeOH (5 mL) was added and
the mixture stirred for 1 h. The volatiles were removed under
reduced pressure. The oily residue was washed several times with
ethyl acetate and then diethyl ether, yielding pure 11 as a yellow oil
(0.08 g, >95%): 1H NMR (500 MHz, D2O) δ 7.43-7.39 (m, 4H),
5.99 (ddd, JH,P = 12.5 Hz, JH,H = 8.5 Hz, JH,H = 5.0 Hz, 1H),
5.87 (m, 1H), 4.71 (dd, JH,P = 13.4 Hz, JH,H = 8.5 Hz, 1H), 4.17
(m, 2H), 2.44 (s, 3H); 13C NMR (125 MHz, D2O) δ 135.4 (d,
JC,P = 3.4 Hz), 133.3, 133.0, 132.1, 130.6, 128.3, 123.7, 122.6 (d,
JC,P = 11.8 Hz), 66.2 (d, JC,P = 158.4 Hz), 48.2, 17.0; 31P NMR
(121 MHz, D2O) δ 20.92; IR (NaCl) ν 3334, 2928, 2771, 1576,
1170, 1084 cm-1; HRMS (ESI) calcd for C11H17NO4P [M þ Hþ]
258.0895, found 258.0890.
Diethyl 3,4-Dihydroxy-1-o-tolylpyrrolidin-2-yl-2-phosphonate
(13). A solution of 12 (2.78 g, 9.4 mmol) in acetone (30 mL)
was treated successively with water (20 mL), NMO (2.42 g,
20.68 mmol), and K2OsO2(OH)4 (0.17 g, 0.47 mmol) at 20 °C.
After 24 h, toluene (30 mL) was added, and the mixutre was
concentrated under vacuum. The resulting dark oil was purified
by column chromatography on silica gel (ethyl acetate/iP-rOH
9:1) to give 13 as a yellow oil (2.9 g, >95%): Rf (ethyl acetate/
iP-rOH 9:1) = 0.2; 1H NMR (300 MHz, CDCl3) δ 7.2-7.24 (m,
4H), 4.57 (ddd, JH,P = 10.9 Hz, JH,H = 4.6 Hz, JH,H = 4.6 Hz,
1H), 4.38 (dd, JH,H = 9.2 Hz, JH,H = 4.6 Hz, 1H), 4.13 (m, 1H),
3.87 (m, 4H þ OH), 3.68 (dd, JH,H = 9.8 Hz, JH,H = 4.9 Hz,
1H), 2.88 (dd, JH,H = 9.8 Hz, JH,H = 4.5 Hz, 1H), 2.28 (s, 3H),
1.09 (dt, JH,P = 9.9 Hz, JH,H = 7.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 148.9, 134.1, 126.8, 124.0, 121.3, 73.7 (d, JC,P = 3.6
Hz), 71.9 (d, JC,P = 6.9 Hz), 63.0 (d, JC,P = 168.2 Hz), 62.9 (d,
Diethyl 3,6-dihydro-2-(tert-butoxycarbonyl)-1,2-oxazin-6-yl-
6-phosphonate (9d). Chromatography (toluene/EtOAc 5:4) gives
9d as a yellow oil (1.85 g, 85%): Rf (toluene/EtOAc 5:4) = 0.2;
1H NMR (500 MHz, CDCl3) δ 6.05 (broad s, 2H), 5.00 (broad d,
J
H,P = 17.1 Hz, 1H), 4.22 (m, 5H), 4.04 (m, 1H), 1.50 (s, 9H),
1.38 (t, JH,H = 6.9 Hz, 3H), 1.34 (t, JH,H = 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 154.9, 125.1 (d, JC,P = 9.4 Hz),
121.5 (d, JC,P = 5.5 Hz), 82.2, 73.9 (d, JC,P = 159.4 Hz), 63.9 (d,
J
C,P = 6.6 Hz), 63.2 (d, JC,P = 6.6 Hz), 45.2, 28.4, 16.6 (d, JC,P
=
4.9 Hz); 31P NMR (121 MHz, CDCl3) δ 16.37; IR (NaCl)
ν 2980, 1707, 1394, 1367, 1261, 1234, 1164, 1024, 972 cm-1
;
HRMS (ESI) calcd for C13H24NO6PNa [M þ Naþ] 344.1239,
found 344.1243.
Diethyl 2-Acetyl-3,6-dihydro-1,2-oxazin-6-yl-6-phosphonate
(9e). Chromatography (EtOAc) gives 9e as a yellow oil (1.46 g,
77%): Rf (EtOAc) = 0.2; 1H NMR (300 MHz, CDCl3) δ 6.04
(broad s, 2H), 4.86 (broad d, JH,P = 16.6 Hz, 1H), 4.17 (m, 6H),
J
C,P = 7.3 Hz), 62.5 (d, JC,P = 6.8 Hz), 59.4 (d, JC,P = 9.3 Hz),
18.9, 16.4 (d, JC,P = 5.7 Hz); 31P NMR (121 MHz, CDCl3) δ
2.21 (s, 3H), 1.34 (td, JH,P = 11.4 Hz, JH,H = 7.1 Hz, 6H); 13
C
27.75; IR (NaCl) ν 3325, 2929, 1492, 1225, 1049, 1028 cm-1
;
NMR (75 MHz, CDCl3) δ 170.7, 124.7 (d, JC,P = 9.6 Hz), 120.9
(d, JC,P = 3.6 Hz), 75.8 (d, JC,P = 160.0 Hz), 64.0 (d, JC,P = 6.8
Hz), 63.2 (d, JC,P = 6.8 Hz), 41.2, 20.1, 16.7 (d, JC,P = 5.7 Hz);
31P NMR (121 MHz, CDCl3) δ 16.51; IR (NaCl) ν 2984, 1670,
1649, 1394, 1256, 1215, 1022, 970 cm-1; HRMS (ESI) calcd for
C10H18NO5PNa [M þ Naþ] 286.0820, found 286.0815.
HRMS (ESI) calcd for C15H24NO5PNa [M þ Naþ] 352.1290,
found 352.1280.
General Procedure for the syn-Hydroxylation of 5. A solution
of 5a or 5b (9.4 mmol) in acetone (30 mL) was treated successively
with water (20 mL), NMO (2.42 g, 20.68 mmol) and K2OsO2-
(OH)4 (0.17 g, 0.47 mmol) at rt. After 24 h, toluene (30 mL) was
added, and the mixture was concentrated under reduced pressure.
The resulting dark oil was directly purified by column chromato-
graphy on silica gel to give the pure diols 14.
Diethyl 3,6-Dihydro-2-benzoyl-1,2-oxazin-6-yl-6-phosphonate
(9f). Chromatography (EtOAc) gives 9f as a yellow oil (1.31 g,
56%): Rf (EtOAc) = 0.6; 1H NMR (300 MHz, CDCl3) δ
5484 J. Org. Chem. Vol. 75, No. 16, 2010

Monbaliu et al.
JOCArticle
Dibenzyl syn-4,5-Dihydroxy-2-o-tolyl-3,4,5,6-tetrahydro-1,2-
oxazin-6-yl-6-phosphonate (14b). The crude product was puri-
fied by column chromatography on silica gel (ethyl acetate/
i-PrOH 95:5) to give 14b as a yellow oil (85%): Rf (ethyl acetate/
i-PrOH 94:5) = 0.5; 1H NMR (300 MHz, CDCl3) δ 7.31-7.14
(m, 15H), 5.07 (m, 4H), 4.67 (dd, JH,P = 10.0 Hz, JH,H = 8.5 Hz,
1H), 4.32 (m, OH), 4.2 (broad s, 1H), 4.01 (m, 1H þ OH),
3.48-3.36 (m, 2H), 2.27 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
147.3, 136.1 (d, JC,P = 5.7 Hz), 135.9 (d, JC,P = 6.0 Hz), 133.6,
131.2, 131.1, 129.1, 128.9, 128.8, 128.4, 128.3, 126.6, 126.4, 118.8,
20 °C. After complete consumption of 17 (5 h, NMR control),
water (5 mL) was added. The organic layer was washed with
10% aqueous NH4Cl (1 ꢀ 5 mL), brine (1 ꢀ 5 mL), and water
(2 ꢀ 5 mL), dried over MgSO4, filtered, and concentrated. The
residue was purified by column chromatography on silica gel
(dichloromethane/EtOAc 3:1) and could be recrystallized from
an acetone/hexane 1:10 mixture to give 18 as colorless crystals
(0.73 g, 70%): Rf (toluene/AcOEt 5:4) = 0.4; mp 98-99 °C; 1H
and 13C NMR spectra were not exploitable due to low rotational
equilibria; 31P NMR (121 MHz, CDCl3) δ 17.86; IR (NaCl)
ν 2930, 1489, 1362, 1254, 1177, 1026, 970; HRMS (ESI) calcd for
C22H40NO8PSiSNa [M þ Naþ] 560.1879, found 560.1898.
1-(Diethoxyphosphonyl)-4-(o-tolylamino)-3-tert-butyldimethyl-
silyloxy-1-hydroxybutan-2-yl Methanesulfonate (19). A solution
of 18 (0.53 g, 0.93 mmol) in ethyl acetate (5 mL) with a few drops
of AcOH was stirred for 15 h at 20 °C under H2 atmosphere in the
presence of Pd-C as catalyst (5 mol %). The reaction mixture
was concentrated under reduced pressure and further purified by
column chromatography on silica gel (dichloromethane/EtOAc
3:1) to give 19 as a brown solid (0.48 g, 95%). Compound 19
could be recrystallized from an acetone/hexane/ether 10:5:5 mix-
ture affording brown crystals (0.31 g, 61%): Rf (dichloromethane/
EtOAc 3:1) = 0.4; mp99-100 °C;1H NMR (300 MHz, CDCl3) δ
7.15-7.08 (m, 2H), 6.79-6.73 (m, 2H), 5.04 (m, 1H), 4.71 (m,
1H), 4.38 (dd, JH,P = 12.8 Hz, JH,H = 4.8 Hz, 1H), 4.18 (m, 4H),
75.8 (d, JC,P = 156.9 Hz), 69.2 (d, JC,P = 6.9 Hz), 68.7 (d, JC,P
=
6.4 Hz), 67.1, 66.4 (d, JC,P = 11.3 Hz), 58.0, 18.2; 31P NMR (121
MHz, CDCl3) δ 20.86; IR (NaCl) ν 3393, 2957, 2926, 1734, 1718,
1489, 1456, 1215, 1049, 1009, 997 cm -1; HRMS (ESI) calcd for
C25H28NO6PNa [M þ Naþ] 492.1552, found 492.1541.
4-(o-Tolylamino)-1,2,3-trihydroxybutylphosphonic Acid (16).
To a solution of compound 15 (0.5 g, 1.4 mmol) in dry
dichloromethane (10 mL) was added dropwise TMSBr (1.17
mL, 8.6 mmol) at rt. After complete consumption of compound
15 (about 2 h, NMR control), MeOH (5 mL) was added and the
mixture stirred for 1 h. The volatiles were removed under
reduced pressure. The oily residue was washed with ethyl acetate
(2 ꢀ 10 mL) and diethyl ether (2 ꢀ 10 mL) to give pure 16 as a
1
yellow oil (0.39 g, 95%): H NMR (500 MHz, D2O) δ (major
rotamer) 7.61-7.16 (m, 4H), 4.40-4.15 (m, 1H), 4.06-3.91 (m,
2H), 3.73 (dd, JH,H = 12.9 Hz, JH,H = 3.0 Hz, 1H), 3.55 (dd,
JH,H = 12.9 Hz, JH,H = 9.4 Hz, 1H), 2.43 (s, 3H); 13C NMR
(125 MHz, D2O) δ (major rotamer) 133.6, 133.2, 132.1, 130.7,
128.4, 123.8, 73.7 (d, JC,P = 5.6 Hz), 69.6 (d, JC,P = 155.6 Hz),
67.2 (d, JC,P = 5.5 Hz), 53.4, 16.7; 31P NMR (121 MHz, D2O) δ
20.9; MS (ESI) calcd for C11H19NO6P [M þ Hþ] 292.24, found
292.17.
Alternative Synthesis of Compound 16. A solution of 14b
(0.5 g, 1.1 mmol) in ethanol (25 mL) with a drop of acetic acid
was stirred for 15 h at rt under H2 atmosphere in the presence of
Pd-C as catalyst (5 mol %). Afterward, the reaction mixture
was concentrated in vacuo and purified by column chromato-
graphy on silica gel to give 16 as a yellow oil (>90%).
Diethyl syn-4-tert-Butyldimethylsilyloxy-5-hydroxy-2-o-tolyl-
3,4,5,6-tetrahydro-1,2-oxazin-6-yl-6-phosphonate (17). To a solu-
tion of 14a (4.27 g, 12.37 mmol) and imidazole (0.93 g, 13.61
mmol) in dry dichloromethane (20 mL) was added dropwise a
solution of tert-butyl(chloro)dimethylsilane (1.97 g, 12.37 mmol)
in dichloromethane (5 mL) over 30 min at 0 °C. After complete
addition, the mixture was allowed to slowly warm to 20 °C and
stirred overnight. The reaction mixture was washed with brine
(1 ꢀ 10 mL) and water (2 ꢀ 10 mL). The organic layer was dried
over MgSO4, filtered, and concentrated. The oily residue was
purified by column chromatography on silica gel (toluene/ethyl
acetate 5:4) to give 17 as a colorless oil (5.2 g, 92%): Rf (toluene/
EtOAc 5:4) = 0.4; 1H NMR (500 MHz, CDCl3) δ (major
3.49 (dd, JH,H = 12.2 Hz, JH,H = 6.9 Hz, 1H), 3.22 (dd, JH,H
=
12.3 Hz, JH,H = 3.5 Hz, 1H), 3.12 (broad s, 3H), 2.22 (broad s,
3H), 1.36 (t, JH,H = 6.9 Hz, 3H), 1.25 (t, JH,H = 6.9 Hz, 3H), 0.93
(s, 9H), 0.18 (s, 3H) and 0.12 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 145.1, 130.6, 127.4, 124.8, 119.8, 112.6, 89.9 (d, JC,P = 10.9 Hz),
71.2 (d, JC,P = 3.3 Hz), 67.8 (d, JC,P = 160.6 Hz), 62.9 (d, JC,P
=
7.5 Hz), 62.3 (d, JC,P = 6.8 Hz), 46.1, 38.9, 26.1, 18.3, 17.9, 16.7
(d, JC,P = 5.3 Hz), -4.6, -4.7; 31P NMR (121 MHz, CDCl3) δ
21.05;IR (NaCl) ν 3246, 2930, 1607, 1508, 1473, 1362, 1256, 1227,
1177, 1051, 974 cm-1; HRMS (ESI) calcd for C22H42NO8PSiSNa
[M þ Naþ] 562.2036, found 562.2024.
Diethyl 3-tert-Butyldimethylsilyloxy-1,2-epoxy-4-o-tolylami-
nobutane-1-phosphonate (20). A solution of 19 (0.19 g, 0.35
mmol) in anhydrous dichloromethane (2 mL) with K2CO3
(0.24 g, 1.75 mmol) was stirred overnight at reflux. The reaction
mixture was quenched with saturated aqueous NH4Cl and
extracted several times with dichloromethane. The organic layer
was dried over MgSO4, filtered, and concentrated. The oily
residue was purified by column chromatography on silica gel
(dichloromethane/EtOAc 3:1) to give 20 as a colorless oil
(0.13 g, 82%): Rf (dichloromethane/EtOAc 3:1) = 0.7; 1H
NMR (300 MHz, CDCl3) δ 7.18-7.07 (m, 2H), 6.68-6.55
(m, 2H), 4.17 (m, 4H), 3.93 (m, NH), 3.78 (td, JH,H = 5.6 Hz,
J
H,H = 5.5 Hz, 1H), 3.42 (ddd, JH,H = 5.5 Hz, JH,P = 5.4 Hz,
JH,H = 2.5 Hz, 1H), 3.30 (m, 2H), 2.98 (dd, JH,P = 29.8 Hz,
H,H = 2.5 Hz, 1H), 2.15 (s, 3H), 1.33 (dt, JH,H = 7.1 Hz, JH,P
J
=
rotamer) 7.48-6.64 (m, 4H), 4.60 (dd, JH,P = 11.8 Hz, JH,H
6.3 Hz, 1H), 4.50 (m, 1H), 4.30-3.92 (m, 5H), 3.22 (broad d,
H,H = 4.4 Hz, 2H), 2.33 (s, 3H), 1.30 (t, JH,H = 7.0 Hz, 3H), 1.19
(t, JH,H = 7.0 Hz, 3H), 0.93 (s, 9H), 0.16 (s, 3H), 0.12 (s, 3H);
13C NMR (125 MHz, CDCl3) δ (major rotamer) 148.4, 131.7,
130.8, 126.6, 125.8, 119.0, 77.1 (d, JC,P = 158.3 Hz), 67.3 (d,
=
5.2 Hz, 6H), 0.93 (s, 9H), 0.12 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 145.9, 130.5, 127.4, 122.8, 117.7, 109.9, 71.5, 63.4, 63.2
(d, JC,P = 6.4 Hz), 59.0, 48.2 (d, JC,P = 203.1 Hz), 47.2, 26.1,
18.3, 17.8, 16.7 (d, JC,P = 5.7 Hz), -4.5, -4.7; 31P NMR (121
MHz, CDCl3) δ 18.59; IR (NaCl) ν 2930, 1607, 1508, 1473, 1257,
1101, 1053, 1024, 974 cm-1; HRMS (ESI) calcd for C21H38-
NO5PSiNa [M þ Naþ] 466.2155, found 466.2160.
J
JC,P = 6.7 Hz), 63.3 (d, JC,P = 6.6 Hz), 62.3 (d, JC,P = 6.5 Hz),
62.4, 58.9, 26.0, 18.8, 18.4, 17.8 (d, JC,P = 5.6 Hz), 17.8 (d,
Diethyl 1,2-Epoxy-3-hydroxy-4-o-tolylaminobutane-1-phos-
phonate (21). A solution of 20 (0.31 g, 0.7 mmol) in anhydrous
THF (5 mL) was treated dropwise with tetrabutylammonium
fluoride (1.05 mL, 1 M in THF, 1.05 mmol). After 2 h, the sol-
vent was evaporated under reduced pressure and the residue
dissolved in ethyl acetate (10 mL). The organic layer was then
washed with brine (2 ꢀ 5 mL) and water (1 ꢀ 5 mL), dried over
MgSO4, filtered, and concentrated. The crude product was
purified by column chromatography on silica gel (dichloromethane/
EtOAc 3:1), affording pure 21 (0.22 g, 97%) as a yellow oil: Rf
J
C,P = 3.1 Hz), -4.4; 31P NMR (121 MHz, CDCl3) δ 20.82; IR
(NaCl) ν 3366, 2927, 1489, 1252, 1103, 1047, 972 cm-1; HRMS
(ESI) calcd for C21H38NO6PSiNa [M þ Naþ] 482.2104, found
482.2108.
Diethyl syn-4-tert-Butyldimethylsilyloxy-5-methanesulfonato-
2-o-tolyl-3,4,5,6-tetrahydro-1,2-oxazin-6-yl-6-phosphonate (18).
A solution of 17 (0.84 g, 1.92 mmol), DMAP (cat.), and pyridine
(0.23 mL, 2.89 mmol) in anhydrous dichloromethane (5 mL)
was treated dropwise by mesyl chloride (0.22 mL, 2.87 mmol) at
J. Org. Chem. Vol. 75, No. 16, 2010 5485

Monbaliu et al.
JOCArticle
(dichloromethane/EtOAc 3:1) = 0.4; 1H NMR (300 MHz,
CDCl3) δ 7.12-7.05 (m, 2H), 6.6-6.65 (m, 2H), 4.17 (m, 4H),
4.00 (m, 2H), 3.48 (m, 2H), 3.32 (dd, JH,H = 12.9 Hz, JH,H = 7.0
Hz, 1H), 3.18 (dd, JH,P = 30.4 Hz, JH,H = 2.5 Hz, 1H), 3.00
(broads, OH), 2.16 (s, 3H), 1.34 (t, JH,H = 7.1Hz, 6H);13CNMR
(75 MHz, CDCl3) δ 150.0, 130.6, 127.4, 123.1, 118.1, 110.3, 67.8,
63.6 (d, JC,P = 6.4 Hz), 63.3 (d, JC,P = 6.3 Hz), 58.3, 47.5 (d,
JC,P = 202.7 Hz), 47.7, 17.8, 16.7 (d, JC,P = 5.7 Hz); 31P NMR
(121 MHz, CDCl3) δ 18.68; IR (NaCl) ν 3384, 2984, 2908, 1607,
1516, 1448, 1319, 1244, 1051, 1022, 978 cm-1; HRMS (ESI) calcd
for C15H24NO5PNa [M þ Naþ] 352.1290, found 352.1296.
Trifluoroacetate Salt of Diethyl 3,6-Dihydro-1,2-oxazin-6-yl-
6-phosphonate (22). A solution of 9d (1 g, 3.11 mmol) in
anhydrous dichloromethane (10 mL) at rt was treated dropwise
with trifluoroacetic acid (0.46 mL, 6.23 mmol) over 10 min. After
15 h, the volatiles were removed under reduced pressure giving 22
(0.33 g, >90%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ
12.28 (broad s, 2H), 6.21 (m, 2H), 5.14 (broad d, JH,P = 17.3 Hz,
1H), 4.17 (m, 6H), 1.38 (t, JH,H = 7.1 Hz, 6H); 13C NMR
64.2 (d, JC,P = 7.1 Hz), 64.0 (d, JC,P = 6.4 Hz), 51.2, 28.4, 16.6
(d, JC,P = 9.9 Hz), 16.6 (d, JC,P = 6.6 Hz); 31P NMR (121 MHz,
CDCl3) δ 19.14; IR (NaCl) ν 3394, 2979, 1720, 1392, 1367, 1283,
1155, 1143, 1026 cm-1; HRMS (ESI) calcd for C13H26NO8PNa
[M þ Naþ] 378.1294, found 378.1291.
Diethyl 2-acetyl-4,5-dihydroxymorpholin-6-yl-6-phosphonate
(23e): Rf (EtOAc/i-PrOH 8:2) = 0.3; 1H NMR (300 MHz,
CDCl3) δ 4.57 (d, JH,H = 13.7 Hz, 1H), 4.48-3.92 (m, 7H),
3.32 (d, JH,H = 13.7 Hz, 1H), 2.16 (s, 3H), 1.38 (t, JH,H = 7.0,
6H); 13C NMR (75 MHz, CDCl3) δ 171.0, 76.1 (d, JC,P = 160.4
Hz), 67.0, 64.8 (d, JC,P = 9.4 Hz), 63.8 (d, JC,P = 6.3 Hz), 63.5
(d, JC,P = 5.2 Hz), 47.0, 20.0, 16.5 (d, JC,P = 4.9 Hz); 31P NMR
(121 MHz, CDCl3) δ 18.41; IR (NaCl) ν 3362, 1636, 1456, 1418,
1238, 1051, 1022, 980 cm-1; HRMS (ESI) calcd for C10H20-
NO7PNa [M þ Naþ] 320.0875, found 320.0886.
Diethyl 4,5-Dihydroxymorpholin-6-yl-6-phosphonate (24). A
solution of 23d (1.11 g, 3.11 mmol) in anhydrous dichloro-
methane (10 mL) at rt was treated dropwise with trifluoroacetic
acid (0.46 mL, 6.23 mmol) over 10 min. After 15 h, the volatiles were
removed under reduced pressure affording 24 (0.79 g, >90%) as a
(75 MHz, CDCl3) δ 160.8 (q, JC,F = 40.8 Hz), 121.4 (d, JC,P
10.3 Hz), 120.0 (d, JC,P = 4.3 Hz), 115.3 (q, JC,F = 286.3 Hz),
=
1
yellow oil: H, 13C, and 31P NMR spectra were not exploitable;
74.0 (d, JC,P = 160.0 Hz), 66.7 (d, JC,P = 7.3 Hz), 66.0 (d, JC,P
=
HRMS (ESI) calcd for C8H18NO6PNa [M þ Naþ] 278.0769, found
7.8 Hz), 44.2 (d, JC,P = 2.6 Hz), 16.3 (d, JC,P = 4.6Hz); 31P NMR
(121 MHz, CDCl3) δ 14.3; IR (NaCl) ν 2991, 1780, 1636, 1209,
1164, 1030, 982 cm-1; HRMS (ESI) calcd for C8H17NO4P
[M þ Hþ] 222.0895, found 222.0889.
278.0762.
Acknowledgment. This work was supported by the F.R.
S.-FNRS (Fonds National de la Recherche Scientifique,
Belgium), the F.R.I.A.-FNRS (Fonds pour la Formation
General Procedure for the Bishydroxylation of 9. A solution of
9d or 9e (2.4 mmol) in acetone (12 mL) was treated successively with
water (6 mL), NMO (5.28 mmol), and K2OsO2(OH)4 (0.12 mmol)
at 20 °C. After 24 h, toluene (10 mL) was added, and the mixture
was concentrated under reduced pressure. The resulting dark oil
was directly purified by column chromatography on silica gel to
give 23d (0.6 g, >70%) and 23e (0.64 g, >90%) as yellow oils.
tert-Butyl 6-(diethoxyphosphonyl)-4,5-dihydroxymorpho-
line-2-carboxylate (23d): Rf (EtOAc/i-PrOH 9:1) = 0.3; mp
122-123 °C; 1H NMR (300 MHz, CDCl3) δ 4.50 (m, 1H þ OH),
4.29 (m, 5H), 4.04 (m, 2H), 3.46 (broad d, JH,H = 14.5 Hz, 1H),
ꢁ
a la Recherche dans l’Industrie et dans l’Agriculture,
Belgium), and the ARC (Action de Recherche Concertee of
ꢀ
UCL) no. 08/13-009. J.M.-B. is senior research associate of
F.R.S.-FNRS, and J.-C.M. is a F.R.I.A.-FNRS fellow. We
thank Prof. D. Peeters, Dr G. Dive, and Prof. R. Robiette for
stimulating discussions.
1
Supporting Information Available: H and 13C NMR spectra
3.13 (broad s, OH), 1.50 (s, 9H), 1.40 (dt, JH,P = 7.6 Hz, JH,H
7.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 156.1, 82.3, 72.1 (d,
C,P = 155.6 Hz), 66.8 (d, JC,P = 1.7 Hz), 64.9(d, JC,P = 10.3 Hz),
=
for all new compounds and X-ray data for compounds 10, 18, 19,
and 23d. This material is available free of charge via the Internet at
http://pubs.acs.org.
J
5486 J. Org. Chem. Vol. 75, No. 16, 2010