A new and expedient diastereoselective synthesis of α-(hydroxyamino)phosphonates and α-aminophosphonates by silyl trifiate promoted diethyl phosphite addition to chiral N-benzyl nitrones

Article abstract of DOI:10.1002/ejoc.200200698

An efficient methodology for the synthesis of α-aminophosphonates has been developed taking advantage of the tertbutyldimethylsilyl triflate activated addition of diethyl phosphite to N-benzyl nitrones derived from chiral α-alkoxy and α-(Boc-amino) aldehy

Full text of DOI:10.1002/ejoc.200200698

FULL PAPER
A New and Expedient Diastereoselective Synthesis of
α-(Hydroxyamino)phosphonates and α-Aminophosphonates by Silyl Triflate
Promoted Diethyl Phosphite Addition to Chiral N-Benzyl Nitrones
Carmela De Risi,[a] Daniela Perrone,[b] Alessandro Dondoni,*[b] Gian Piero Pollini,*[a] and
Valerio Bertolasi[c]
Keywords: Asymmetric synthesis / Enzyme inhibitors / Nitrones / Peptidomimetics / Phosphonates
An efficient methodology for the synthesis of α-aminophos-
phonates has been developed taking advantage of the tert-
butyldimethylsilyl triflate activated addition of diethyl phos-
phite to N-benzyl nitrones derived from chiral α-alkoxy and
α-(Boc-amino) aldehydes. The stereoselective carbon−
phosphorus bond-forming reaction proceeded smoothly to
give α-(hydroxyamino)phosphonate intermediates as the
primary adducts, which were subsequently converted into
the corresponding polyhydroxylated α-amino- and α,β-diami-
nophosphonates by conventional reductive processes.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
man collagenase, and as haptens for the generation of cata-
lytic antibodies. Aminophosphonic acids also have been
proved to act as anti-thrombotic agents.[3]
The biological importance of aminophosphonic acids
was recognized over 40 years ago.[1] Since then, a great
number of papers dealing with their chemistry and biologi-
cal activity have provided evidence for the growing and con-
tinuous interest in this promising and somewhat undiscov-
ered class of potential drugs.[2] Despite the well-known
structural differences between the phosphonic and car-
boxylic functional groups (e.g., size, shape, acidity, and the
pseudo-tetrahedral array about the P atom vs. trigonal ar-
ray about the C atom), the phosphonic acid moiety has long
been established as a bioisostere of a carboxyl unit. Conse-
quently, α-aminophosphonic acids are considered impor-
tant surrogates of α-aminocarboxylic acids and a variety of
physiological responses can be obtained by using them in
medicinal and pharmaceutical chemistry. Moreover, be-
cause of their ability to mimic transition states of hydrolysis,
phosphonic acid derivatives having heteroatoms at the α-
and/or β-positions have been shown recently to be inhibi-
tors of various enzymes, including HIV-protease and hu-
Therefore, in recent years the synthesis of phosphonic
acid analogues of proteinogenic and non-proteinogenic α-
amino acids has gained increasing importance, leading to
the elaboration of numerous synthetic methods for amino-
phosphonates. In many cases, the absolute configuration at
the α-position of the substituted phosphonic acids can af-
fect their biological properties. As a result, the obvious need
for enantiomerically homogeneous α-aminophosphonates
with established absolute configuration at their stereogenic
carbon atom has been realized by the development of sev-
eral asymmetric syntheses of these compounds.
Results and Discussion
As a part of our ongoing interest in this field,[4] we de-
cided to develop a new synthetic approach to chiral polyhy-
droxylated α-amino- and α,β-diaminophosphonates. Our
project was based on the synthesis of protected α-(hydroxy-
amino)phosphonates as the key intermediates, followed by
the unmasking of the amino group. Interestingly, these pri-
mary adducts also belong to a class of biologically impor-
tant compounds, since they are phosphorus isosters of α-
(hydroxyamino)carboxylic acids.[5] Thus, we envisioned a
synthetic scheme that relied on the formation of the
carbonϪphosphorus bond through nucleophilic addition of
a dialkyl phosphite to the iminium-like moiety of N-benzyl
nitrones derived from chiral α-alkoxy and N-protected α-
amino aldehydes (Scheme 1).[6]
[a]
`
Dipartimento di Scienze Farmaceutiche, Universita di Ferrara
Via Fossato di Mortara 17Ϫ19, 44100 Ferrara, Italy
Fax: (internat.) ϩ 39-0532/291296
E-mail: pol@unife.it
[b]
[c]
Dipartimento di Chimica, Laboratorio di Chimica Organica,
`
Universita di Ferrara
Via L. Borsari 46, 44100 Ferrara, Italy
Fax: (internat.) ϩ 39-0532/291167
E-mail: adn@unife.it
Dipartimento di Chimica, Centro di Strutturistica
`
Diffrattometrica, Universita di Ferrara
Via L. Borsari 46, 44100 Ferrara, Italy
E-mail: m38@unife.it
1904
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200200698
Eur. J. Org. Chem. 2003, 1904Ϫ1914

Diastereoselective Synthesis of α-(Hydroxyamino)phosphonates and α-Aminophosphonates
FULL PAPER
successfully in earlier additions of diethyl phosphite to α,β-
unsaturated carbonyl compounds, alkenenitriles, aldehydes,
ketones, and imines.[4a]
These observations suggested that the conjugate base of
the phosphite is still too weak a nucleophile toward the
nitrone, suggesting that activation of the latter is required
for it to function as an acceptor in the carbonϪphosphorus
bond-forming reaction. Low yields (5Ϫ10%) of adduct were
isolated by precomplexation of the nitrone with Lewis acids
(BF3·Et2O or TMSCl) in THF or CH2Cl2, but using 1.1
equiv. of tert-butyldimethylsilyl triflate (TBDMSOTf)[11] at
Ϫ20 °C for 10 min remarkably facilitated the addition of
the phosphorus reagent to give the α-(hydroxyamino)phos-
phonate 2 as a single product in 70% isolated yield
(Scheme 2).
Scheme 1
The addition reaction of nucleophiles to nitrones[7] for
the synthesis of nitrogen-containing compounds has several
advantages over that employing more traditional CϭN elec-
trophiles, particularly imines. These include: a) the ease of
the preparation, manipulation, and storage of nitrones be-
cause of their high stability and, quite often, crystallinity; b)
the high reactivity determined by the superior electrophilic
character of nitrones; c) the internal asymmetric induction
by chiral substituents on the carbon or nitrogen atom; d)
the control of the diastereofacial selectivity by pre-com-
plexing agents. While various carbon nucleophiles have
been employed by us and others,[8] the use of heteronucleo-
philes appears to be quite rare.[9] Vasella and co-workers[10]
reported the addition of phosphorus nucleophiles to
N-glycosyl nitrones as the key step in synthetic routes to
α-aminophosphonic acids.
Scheme 2
The configuration at the newly formed stereocenter was
established unequivocally by single-crystal X-ray analysis of
2 (Figure 1), which shows an anti relationship between the
hydroxyamino group and the pre-existing alkoxy group.
Guided by this observation, next we examined the ad-
dition of diethyl phosphite to N-benzyl nitrones derived
from other chiral alkoxy aldehydes (Scheme 3).
The reactions of nitrones 3a[8a] and 3b,[8b] derived from
protected -threose and -galactose respectively, proceeded
smoothly under the same conditions as above
Addition Reactions
A set of experiments was carried out using the readily (TBDMSOTf, THF or CH2Cl2, Ϫ20 °C, 10 min) to give the
available -glyceraldehyde-derived nitrone 1[8b] as the model corresponding adducts 4a and 4b in very good yields. The
compound. The results are collected in Table 1.
structures of these compounds also were established by X-
We observed that no reaction occurred when 1 was ray crystallography (Figures 2 and 3).
treated with diethyl phosphite in anhydrous CH2Cl2 or
The observed diastereoselectivity is in agreement with the
THF at room temperature, even in the presence of either a stereochemical outcomes of earlier Lewis acid promoted
catalytic or stoichiometric amount of a base, such as addition reactions of various nucleophiles to nitrone 1.[8b,12]
1,1,3,3-tetramethylguanidine (TMG), that has been used Transition state models have been postulated that involve
Table 1. Addition of diethyl phosphite to nitrone 1
Entry
Reactants (equiv.)
Conditions (solvent/temp.)
Yield (%)[a]
1
2
3
4
5
6
7
8
HP(O)(OEt)2 (1)
HP(O)(OEt)2 (2)
HP(O)(OEt)2 (3)
THF or CH2Cl2/room temp.
THF or CH2Cl2/room temp.
THF or CH2Cl2/room temp.
THF or CH2Cl2/room temp.
THF or CH2Cl2/room temp.
THF or CH2Cl2/0 °C
THF or CH2Cl2/room temp.
THF or CH2Cl2/room temp.
THF or CH2Cl2/Ϫ20 °C
THF or CH2Cl2/0 °C
THF or CH2Cl2/room temp.
THF or CH2Cl2/Ϫ20 °C
Ϫ[b]
Ϫ[b]
Ϫ[b]
Ϫ[b]
Ϫ[b]
Ϫ[b]
5
HP(O)(OEt)2 (1), TMG[c] (cat)
HP(O)(OEt)2 (1), TMG (1)
HP(O)(OEt)2 (1), BF3·Et2O (1)
HP(O)(OEt)2 (1), BF3·Et2O (1.1)
HP(O)(OEt)2 (1), BF3·Et2O (2.2)
HP(O)(OEt)2 (1), TMSCl (1.1)
HP(O)(OEt)2 (1), TMSCl (1.1)
HP(O)(OEt)2 (1), TMSCl (1.1)
HP(O)(OEt)2 (1), TBDMSOTf (1.1)
10
10
9
10
11
12
5
Ϫ[b]
70
[a]
[b]
[c]
Isolated yield. Unchanged 1 was recovered totally. 1,1,3,3-Tetramethylguanidine.
Eur. J. Org. Chem. 2003, 1904Ϫ1914
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1905

C. De Risi, D. Perrone, A. Dondoni, G. P. Pollini, V. Bertolasi
FULL PAPER
Figure 2. ORTEP view of compound 4a displaying the thermal
ellipsoids at 30% probability
Figure 1. ORTEP view of compound 2 displaying the thermal
ellipsoids at 30% probability
Scheme 3
the participation of the Lewis acid to give chelate structures
through coordination to the nitrone and alkoxy oxygen
atoms.[8b] Hence, it is likely that the silicon atom of the tri-
alkylsilyl group coordinates to both the nitrone oxygen
Figure 3. ORTEP view of compound 4b displaying the thermal
ellipsoids at 30% probability
atom and one of the oxygen atoms of the dioxolane ring. from N-benzylhydroxylamine[14] and the corresponding α-
Hence, two transition state structures A and B are postu- amino aldehydes 5bϪd, which in turn were easily prepared
lated, arising from coordination to the nitrone oxygen atom by literature procedures.[15]
and to the α-alkoxy (α-chelation) or β-alkoxy (β-chelation)
Nitrones 6bϪd are all solids that were purified by flash
1
groups, respectively (Figure 4). The formation of the anti chromatography. Careful H NMR analysis revealed that
isomer suggests that the addition of the nucleophile occurs the (Z) isomer was obtained in all cases, since the nuclear
preferentially to the si face of the nitrone in the β-chelate Overhauser effect observed between the azomethine hydro-
model B.
gen atom (HCϭNϩ) and the methylene group of the N-
As an extension of our method, next we focused attention benzyl moiety (N-CH2Ph) is diagnostic of the (Z) configu-
on the addition of diethyl phosphite to α-amino nitrones ration.[8b] The experiments using α-amino nitrones 6aϪd as
6aϪd derived from natural α-amino acids, namely serine, substrates for the nucleophilic addition of diethyl phosphite
threonine, cysteine, and proline, respectively (Table 2). gave results that were in marked contrast with those ob-
While the synthesis of -serine-derived nitrone 6a has been served in the reactions of chiral α-alkoxy nitrones. Indeed,
described already,[13] the hitherto unreported α-amino when these N,N-diprotected α-amino nitrones were treated
nitrones 6bϪd were readily prepared (Scheme 4) starting with TBDMSOTf and then diethyl phosphite in THF or
1906
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Diastereoselective Synthesis of α-(Hydroxyamino)phosphonates and α-Aminophosphonates
FULL PAPER
similar features to those of the syn-hydroxylamines derived
from the reaction of nitrones 6a and 6d with various nucleo-
philes.[16] According to the model formulated by Merino et
al.,[16] these adducts exist in a rigid conformation because
of hydrogen bonding between the hydroxyamino oxygen
atom and the carbamate group (Figure 5).
Figure 5. Conformations of hydroxylamines 7aϪd
1
Indeed, the H NMR spectra of 7a and 7d did not show
Figure 4. Proposed models for the addition of diethyl phosphite to
any changes in the range of temperatures between 25 and
Ϫ55 °C, and showed a low-field chemical shift for the
hydroxyamino proton in the range between δ ϭ 7.6 and
7.9 ppm at various concentrations. Moreover, consistent
with an antiperiplanar disposition of the hydrogen atoms
linked to the two adjacent stereocenters, the 1H NMR spec-
tra at low temperature (from Ϫ40 to Ϫ55 °C) showed values
the nitrone 1
Table 2. Addition of diethyl phosphite to nitrones 6
3
of JH,H coupling constants between these atoms of
10.37 Hz for 7a and 10.20 Hz for 7d. The relative stereo-
chemistry of derivatives 7b and 7c was assigned by analogy
to those of 7a and 7d.
We also examined the silyl triflate promoted diethyl phos-
phite addition to N-monoprotected α-amino nitrones 8aϪc,
whose progenitors were alanine, phenylalanine, and leucine,
respectively. Compounds 8a and 8b have been reported in
the literature,[13b,17] whereas the new compound 8c was pre-
pared from the corresponding aldehyde[18] under the usual
conditions (N-benzylhydroxylamine, MgSO4, CH2Cl2,
room temp.).
When TBDMSOTf-precomplexed nitrones 8aϪc were
treated with diethyl phosphite in THF or CH2Cl2 at Ϫ20
°C, 95:5 mixtures of diastereoisomeric hydroxylamines 9
and 10 were obtained in very good yields (80%) (Scheme 5).
Only the major anti isomers 9aϪc were isolated by flash
chromatography.
Scheme 4
CH2Cl2 at Ϫ20 °C, the syn adducts 7aϪd were obtained in
good yields after flash chromatography (Table 2).
Being unable to obtain any compound 7aϪd as a single
crystal suitable for X-ray analysis, their relative stereochem-
istries were attributed on the basis of spectroscopic data.
The 1H NMR spectra of the syn adducts 7a and 7d showed Scheme 5
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C. De Risi, D. Perrone, A. Dondoni, G. P. Pollini, V. Bertolasi
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X-ray crystallography of compound 9c showed an anti
relationship between the NHBoc and N(OH)Bzl groups
(Figure 6).
Figure 7. Proposed models for the addition of diethyl phosphite
to N,N-disubstituted α-amino nitrones and N-monosubstituted α-
amino nitrones
tected α-amino nitrones derived from natural α-amino
acids, such as alanine and phenylalanine.[17]
Synthesis of α-Amino- and α,β-Diaminophosphonates
Figure 6. ORTEP view of compound 9c displaying the thermal
We anticipated that the α-(hydroxyamino)phosphonates
described in the previous section could serve as the precur-
sors to chiral polyhydroxylated α-amino- and α,β-diamino-
phosphonates. This concept called for a reductive operation
to transform the hydroxyamino group into the correspond-
ing amine. Various methods for the reduction of N,N-di-
alkylhydroxylamines have been reported, including catalytic
hydrogenation,[19] reduction with SmI2,[19] Zn/HCl,[19]
ellipsoids at 30% probability
These result are in agreement with the stereochemical
outcome that we observed for the addition reaction of 2-
lithiothiazole to the nitrone derived from N-monoprotected
serinal.[13a] This result confirms the tunable syn/anti stereo-
selectivity of the nucleophilic addition reactions to α-amino
nitrones of bis- and monoprotected amino groups.
Raney
Ni,[19,20]
aqueous
TiCl3,[21,22]
and
Zn/
Cu(OAc)2.[8d,23]
Since compounds 9aϪc showed identical spectroscopic
data, the same relative stereochemistry of 9c was assigned
In our hands, the method of choice was strictly depen-
dent on the nature of the hydroxylamine to be reduced. In
particular, reduction of the hydroxyamino function of
polyhydroxylated α-(hydroxyamino)phosphonates was
easily achieved through both the zinc/copper() acetate
system and catalytic hydrogenation, while the reduction of
β-amino-α-(hydroxyamino)phosphonates took place con-
veniently only by catalytic hydrogenation. Other methods
led to considerable decomposition of the starting materials.
Thus, when compound 2 was treated with a mixture of
Zn/Cu(OAc)2 according to our earlier procedure,[8d] the re-
sulting α-(benzylamino)phosphonate 11 was isolated in 60%
yield after flash chromatography (Scheme 6).
1
to the products 9a and 9b. Indeed, the H NMR spectra of
compounds 9aϪc displayed a typical double doublet in the
range between δ ϭ 3.25 and 3.34 ppm for the hydrogen
atom linked to the carbon atom bearing the hydroxyamino
moiety and the phosphonate group (2JHϪP ϭ 17.0Ϫ17.5 Hz
3
and JH,H ϭ 4.0Ϫ4.6 Hz).
To explain the observed syn/anti stereoselectivity in the
addition reaction to chiral α-amino nitrones, we postulate
two reactive conformations C and D (Figure 7), in which
the silicon atom of the trialkylsilyl group coordinates to
both the nitrone oxygen atom and the carbamate group.
The difference between these conformations exists on the
outside and inside positions of the medium-sized substitu-
ent.
The addition to N,N-disubstituted α-amino nitrones 6
should take place from the less-hindered side of the cyclic
chelate C (Re attack) to give the syn adducts 7, while the
addition of diethyl phosphite to the N-monosubstituted de-
rivatives 8 should occur from the less-hindered side of the
cyclic chelate D leading to the anti products 9, as assumed
for the reaction of Grignard reagents with N-monopro- Scheme 6
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Diastereoselective Synthesis of α-(Hydroxyamino)phosphonates and α-Aminophosphonates
FULL PAPER
The same protocol was applied to derivatives 4a and 4b amino moiety with the concomitant protection of the free
to give α-(benzylamino)phosphonates 12a and 12b in satis- amino group to give derivatives 16aϪd, in satisfactory
factory yields (Scheme 7).
yields after purification by silica gel column chromatogra-
phy (40Ϫ63%) (Table 4).
Table 4. Catalytic hydrogenation of β-amino-α-(hydroxyamino)-
phosphonates
Scheme 7
Alternatively, the α-(hydroxyamino)phosphonates 2 and
4a,b were elaborated through concomitant deoxygenation
and debenzylation. This process was achieved in one step
by catalytic hydrogenation using palladium hydroxide
[Pd(OH)2] on charcoal as a catalyst, in the presence of di-
tert-butyl dicarbonate (Boc2O), to give the N-Boc-protected
derivatives 13Ϫ15 in very good yields after purification by
flash chromatography (Table 3). It is noteworthy that the
reduction of 4a proceeded with accompanying removal of
the O-benzyl protecting group and protection of the so-
formed primary hydroxy function to give the N,O-Boc-di-
protected derivative 14 in 60% yield.
Finally, the reductive deprotection/reprotection sequence
was applied to the pure anti-α-(hydroxyamino)phosphon-
ates 9aϪc to furnish the derivatives 17aϪc in good yields
(Scheme 8).
Table 3. Catalytic reduction of polyhydroxylated α-(hydroxy-
amino)phosphonates
Scheme 8
Conclusion
In summary, chiral alkoxy and N-protected amino
nitrones have been conveniently used in a Lewis acid stereo-
controlled addition reaction with diethyl phosphite to ob-
tain non-racemic α-(hydroxyamino)phosphonates in good
yields and with high diastereoselectivity. These intermediate
adducts represent the key intermediates in the synthesis of
α-amino- and α,β-diaminophosphonates, a significant class
All attempts to convert phosphonates 7aϪd to their cor- of biologically active compounds to act as phosphorus iso-
responding N-benzyl-protected amines by means of the Zn/ steres of their parent carboxylic acids. The ready accessi-
Cu(OAc)2 reducing system proved to be unsatisfactory, fur- bility of the starting materials and the simplicity of all the
nishing the expected products in very low yields. On the synthetic steps make our method very practical for the syn-
contrary, catalytic hydrogenation under the same conditions thesis of phosphonate-containing molecules, stressing once
as above [H2, Pd(OH)2/C, Boc2O] allowed us to remove more the versatility of nitrone-based chemistry in the syn-
both the benzyl and hydroxy groups from the hydroxy- thesis of biologically active compounds.
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C. De Risi, D. Perrone, A. Dondoni, G. P. Pollini, V. Bertolasi
FULL PAPER
m.p. 117Ϫ120 °C, [α]2D0 ϭ Ϫ7.0 (c ϭ 0.78, CHCl3). IR (KBr): ν˜ ϭ
Experimental Section
1690, 1592 cmϪ1 1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.29
.
(s, 9 H, tBuO), 1.72 (s, 3 H, OCCH3), 1.75 (s, 3 H, OCCH3),
3.05Ϫ3.30 (m, 2 H, SCH2), 4.83 (s, 2 H, NCH2Ph), 5.26 (br., 1 H,
HCNBoc), 6.82 (d, J ϭ 5.30 Hz, 1 H, HCϭN), 7.30Ϫ7.50 (m, 5
H, arom.) ppm. C18H26N2O3S (350.2): calcd. C 61.69, H 7.48, N
7.99; found C 61.75, H 7.55, N 7.95.
General Remarks: Melting points were determined with
a
BüchiϪTottoli apparatus and are uncorrected. Infrared (IR) spec-
tra were recorded with an FT-IR Paragon 500 spectrometer. 1H
nuclear magnetic resonance (NMR) spectra were taken both with
a Bruker AC-200 spectrometer at 200 MHz and a Varian 300 Unity
spectrometer at 300 MHz, while 31P NMR spectra were recorded
with a Varian 300 Unity spectrometer at 121 MHz. Chemical shifts
are given in ppm downfield from tetramethylsilane as the internal
standard and coupling constants are given in Hz. Optical rotations
were measured with a PerkinϪElmer 241 MC Polarimeter. Organic
solutions were dried with anhydrous magnesium sulfate and the
solvents evaporated with a rotary evaporator. Light petroleum re-
fers to petroleum ether with boiling range 40Ϫ60 °C and ether to
diethyl ether. Reactions were monitored by TLC on silica gel 60
F254 with detection by charring with alcoholic solutions of nin-
hydrin or aqueous potassium permanganate solutions. Flash chro-
matography was carried out with Merck silica gel 60 (230Ϫ400
mesh). All moisture-sensitive reactions were performed under N2
or Ar using oven-dried glassware. Elemental analyses were deter-
mined by the microanalytical laboratory of the Dipartimento di
Chimica, University of Ferrara. α-Alkoxy nitrones 1,[8b] 3a,[8a] and
3b,[8b] and α-amino nitrones 6a,[13] 8a, and 8b,[13b,17] were prepared
according to the cited literature procedures.
(Z)-N-{[(2S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]methylidene}-
benzylamine N-Oxide (6d): This compound was obtained from
5d,[15c] by using the aforementioned general procedure, as a white
solid after flash chromatography (eluent: EtOAc/MeOH, 97:3),
yield: 2.43 g (80%), m.p. 65Ϫ68 °C, [α]2D0 ϭ Ϫ24.0 (c ϭ 1.0, CHCl3).
1
IR (KBr): ν˜ ϭ 1690, 1592 cmϪ1. H NMR (200 MHz, CDCl3, 25
°C): δ ϭ 1.43 (s, 9 H, tBuO), 1.70Ϫ2.10 (m, 3 H), 2.20Ϫ2.50 (m,
1 H), 3.30Ϫ3.50 (m, 2 H), 4.77Ϫ4.85 (m, 1 H, HCNBoc), 4.86 (s,
2 H, NCH2Ph), 6.70 (br., 1 H, HCϭN), 7.30Ϫ7.50 (m, 5 H, arom.)
ppm. C17H24N2O3 (304.2): calcd. C 67.08, H 7.95, N 9.20; found
C 67.15, H 7.88, N 9.15.
General Procedure for the Synthesis of α-(Hydroxyamino)phosphon-
ates: A cooled (Ϫ20 °C) solution of the appropriate nitrone
(1 mmol), in anhydrous THF or CH2Cl2 (3 mL) containing
TBDMSOTf (1.1 mmol), was treated with diethyl phosphite
(1 mmol). The reaction mixture was stirred at the same temperature
for 10 min, and then saturated aqueous NaHCO3 (2 mL) and
EtOAc (5 mL) were added. The organic phase was separated, dried,
and the solvent evaporated. The residue was purified by flash chro-
matography or crystallization to afford pure α-(hydroxyamino)-
phosphonates.
General Procedure for the Synthesis of N-Benzyl Nitrones 6b؊d and
8c: N-Benzylhydroxylamine (10 mmol) and anhydrous magnesium
sulfate (10 mmol) were added successively to a well-stirred solution
of the aldehyde (10 mmol) in dichloromethane (75 mL). Stirring
was continued at room temperature for 5 h, the reaction mixture
was filtered, and the filtrate concentrated. Nitrones 6bϪd were
purified by flash chromatography or crystallization, while nitrone
8c was used in the next step as obtained, since its purification by
flash chromatography led to considerable decomposition.
Diethyl {(1S,2R)-1-[Benzyl(hydroxy)amino]-2,3-(isopropylidene-
dioxy)propyl}phosphonate (2): This compound was obtained from
1, by using the aforementioned general procedure, as a white solid,
yield: 261 mg (70%), m.p. 113Ϫ114 °C (ether), [α]2D0 ϭ ϩ20.0 (c ϭ
0.9, CHCl3). IR (KBr): ν˜ ϭ 3207, 1220 cmϪ1. 1H NMR (200 MHz,
CDCl3, 25 °C): δ ϭ 1.30Ϫ1.50 [m, 12 H, P(OCH2CH3)2 and
3
2
(Z)-N-{[(2S)-2-(N-tert-Butoxycarbonyl)-4-methyl]pentylidene}-
benzylamine N-Oxide (8c): This compound was obtained from the
corresponding aldehyde,[18] by using the aforementioned general
procedure, as a yellow syrup, which was used in the addition reac-
tion without further purification. Yield: 2.56 g (80%). IR (neat):
OC(CH3)2], 3.27 (dd, 1 H, JH,H ϭ 7.7 Hz, JH,P ϭ 15.3 Hz,
HCNOH), 4.00Ϫ4.30 (m, 7 H, OCH2CH, P(OCH2CH3)2 and
NCHPh), 4.37 (d, 1 H, part of an AB system, J ϭ 13.4 Hz,
NCHPh), 4.42Ϫ4.55 (m, 1 H, OCH2CH), 6.13 (br., 1 H, NOH),
7.20Ϫ7.40 (m, 5 H, arom.) ppm. 31P NMR (121 MHz, CDCl3, 25
°C): δ ϭ 24.85 ppm. C17H28NO6P (373.2): calcd. C 54.68, H 7.56,
N 3.75; found C 54.75, H 7.60, N 3.83.
ν˜ ϭ 1690, 1592 cmϪ1 1H NMR (300 MHz, CDCl3, 25 °C): δ ϭ
.
0.94 [m, 6 H, HC(CH3)2], 1.42 (s, 9 H, tBuO), 1.54Ϫ1.70 (m, 3 H,
HC(CH3)2 and H2CCH), 4.50 (br., 1 H, HCNBoc), 4.87 (s, 2 H,
NCH2Ph), 5.92 (br., 1 H, NHBoc), 6.85 (br., 1 H, HCϭN),
7.25Ϫ7.60 (m, 5 H, arom.) ppm. C18H28N2O3 (320.2): calcd. C
67.47, H 8.81, N 8.74; found C 67.55, H 8.75, N 8.82.
Diethyl
{(1S,2R,3S)-1-[Benzyl(hydroxy)amino]-4-benzyloxy-2,3-
(isopropylidenedioxy)butyl}phosphonate (4a): This compound was
obtained from 3a, by using the aforementioned general procedure,
as a white solid, yield: 345 mg (70%), m.p. 115Ϫ118 °C (EtOAc),
[α]2D0 ϭ Ϫ6.1 (c ϭ 1.1, CHCl3). IR (KBr): ν˜ ϭ 3262, 1229 cmϪ1
.
(Z)-N-{[(4S,5R)-3-(tert-Butoxycarbonyl)-2,2,5-trimethyl-1,3-oxa-
zolidin-4-yl]methylidene}benzylamine N-Oxide (6b): This compound
was obtained from 5b,[15a] by using the aforementioned general pro-
cedure, as a white solid after flash chromatography (eluent: diethyl
ether/light petroleum, 9:1), yield: 2.78 g (80%), m.p. 65Ϫ67 °C,
1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.32 (s, 3 H, OCCH3),
1.36 [m, 6 H, P(OCH2CH3)2], 1.42 (s, 3 H, OCCH3), 3.27 (dd, 1
H, 3JH,H ϭ 7.6 Hz, 2JH,P ϭ 15.1 Hz, HCNOH), 3.73 (d, J ϭ 4.8 Hz,
2 H, CH2OBn), 4.10Ϫ4.50 [m, 8 H, P(OCH2CH3)2, OCHCHO,
and NCH2Ph], 4.57 (s, 2 H, OCH2Ph), 6.00 (br., 1 H, NOH),
7.20Ϫ7.40 (m, 10 H, arom.) ppm. 31P NMR (121 MHz, CDCl3):
δ ϭ 24.62 ppm. C25H36NO7P (493.2): calcd. C 60.84, H 7.35, N
2.84; found C 60.90, H 7.40, N 2.90.
[α]2D0 ϭ ϩ15.6 (c ϭ 1.0, CHCl3). IR (KBr): ν˜ ϭ 1690, 1592 cmϪ1
.
1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.33 (s, 3 H, OCCH3),
1.45 (d, J ϭ 7.0 Hz, 3 H, CH3CHO), 1.47 (s, 9 H, tBuO), 1.61 (s,
3 H, OCCH3), 4.13 (q, J ϭ 6.1 Hz, 1 H, CH3CHO), 4.60Ϫ4.80 (m,
1 H, HCNBoc), 4.89 (s, 2 H, NCH2Ph), 6.67 (br., 1 H, HCϭN),
7.25Ϫ7.60 (m, 5 H, arom.) ppm. C19H28N2O4 (348.2): calcd. C
65.49, H 8.10, N 8.04; found C 65.53, H 7.98, N 8.10.
Diethyl {(R)-[Benzyl(hydroxy)amino](5-deoxy-1,2:3,4-di-O-isopro-
pylidene-α-D-galactopyranos-5-yl)methyl}phosphonate (4b): This
compound was obtained from 3b, by using the aforementioned
general procedure, as a white solid, yield: 441 mg (88%), m.p.
176Ϫ179 °C (EtOAc), [α]2D0 ϭ Ϫ59.3 (c ϭ 0.5, CHCl3). IR (KBr):
(Z)-N-{[(4R)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-1,3-thiazolidin-
4-yl]methylidene}benzylamine N-Oxide (6c): This compound was
obtained from 5c,[15b] by using the aforementioned general pro-
cedure, as a yellowish solid (light petroleum), yield: 2.63 g (75%),
ν˜ ϭ 3236, 1218 cmϪ1 1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ
.
1.30Ϫ1.45 [m, 15 H, P(OCH2CH3)2, 3 OCCH3], 1.54 (s, 3 H,
1910
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1904Ϫ1914

Diastereoselective Synthesis of α-(Hydroxyamino)phosphonates and α-Aminophosphonates
FULL PAPER
3
2
OCCH3), 3.68 (dd, 1 H, JH,H ϭ 10.0 Hz, JH,P ϭ 13.4 Hz, 4JH,P ϭ 3.7 Hz, P(OCH2CH3)2], 1.51 (s, 9 H, tBuO), 1.70Ϫ2.20 (m,
3
2
HCNOH), 4.10Ϫ4.40 [m, 7 H, P(OCH2CH3)2, NCHPh, 4Ј-H and 4 H), 2.77 (dd, 1 H, JH,H ϭ 10.3 Hz, JH,P ϭ 13.4 Hz, HCNOH),
5Ј-H], 4.43 (d, 1 H, part of an AB system, J ϭ 13.6 Hz, NCHPh), 3.10Ϫ3.50 (m, 2 H), 4.10Ϫ4.50 [m, 6 H, P(OCH2CH3)2, NCHPh
4.62 (s, 2 H, 2Ј-H and 3Ј-H), 5.51 (d, J ϭ 4.9 Hz, 1 H, 1Ј-H), and CHNBoc], 4.64 (d, 1 H, part of an AB system, J ϭ 13.9 Hz,
6.01 (br., 1 H, NOH), 7.20Ϫ7.48 (m, 5 H, arom.) ppm. 31P NMR NCHPh), 7.20Ϫ7.40 (m, 5 H, arom.), 7.88 (s, 1 H, NOH) ppm. 31
P
(121 MHz, CDCl3, 25 °C): δ ϭ 26.31 ppm. C23H36NO9P (501.2): NMR (121, MHz, CDCl3, 25 °C): δ ϭ 27.51 ppm. C21H35N2O6P
calcd. C 55.08, H 7.24, N 2.79; found C 55.15, H 7.32, N 2.75.
(442.2): calcd. C 57.00, H 7.97, N 6.33; found C 57.15, H 8.10,
N 6.40.
Diethyl {(S)-[Benzyl(hydroxy)amino][(4S)-3-(tert-butoxycarbonyl)-
2,2-dimethyl-1,3-oxazolidin-4-yl]methyl}phosphonate (7a): This
compound was obtained from 6a, by using the aforementioned
general procedure, as a yellowish syrup after flash chromatography
Diethyl {(1R,2S)- and (1S,2S)-1-[Benzyl(hydroxy)amino]-2-(tert-
butoxycarbonylamino)propyl}phosphonates (9a and 10a): These
compounds were obtained from 8a, by using the aforementioned
general procedure (333 mg, 80% overall yield). Flash chromatog-
raphy (eluent: EtOAc/light petroleum, 1:1) of the crude reaction
mixture furnished pure 9a and a mixture of 9a and 10a. Data for
9a: Yellowish syrup, [α]2D0 ϭ Ϫ25.0 (c ϭ 0.8, CHCl3). IR (neat):
(eluent: EtOAc/light petroleum, 2:1), yield: 378 mg (80%), [α]2D0
ϭ
1
ϩ4.4 (c ϭ 1.9, CHCl3). IR (neat): ν˜ ϭ 3341, 1667, 1220 cmϪ1. H
NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.30Ϫ1.45 [m, 9 H,
P(OCH2CH3)2 and OCCH3], 1.50 (s, 12 H, OCCH3 and tBuO),
1
ν˜ ϭ 3341, 1667, 1215 cmϪ1. H NMR (200 MHz, CDCl3, 25 °C):
3
2
3.13 (dd, 1 H, JH,H ϭ 10.4 Hz, JH,P ϭ 12.5 Hz, HCNOH), 3.94
(dd, 2 H, J ϭ 5 and 9.4 Hz, OCH2CH), 4.05Ϫ4.32 [m, 5 H,
P(OCH2CH3)2 and NCHPh], 4.38Ϫ4.52 (m, 1 H, CHNBoc), 4.67
(d, 1 H, part of an AB system, J ϭ 13.8 Hz, NCHPh), 7.20Ϫ7.40
(m, 5 H, arom.), 7.59 (s, 1 H, NOH) ppm. 31P NMR (121, MHz,
CDCl3, 25 °C): δ ϭ 26.72 ppm. C22H37N2O7P (472.2): calcd. C
55.92, H 7.89, N 5.93; found C 55.98, H 7.80, N 5.88.
δ ϭ 1.20Ϫ1.50 (m, 18 H, CH3CH, P(OCH2CH3)2 and tBuO), 3.25
3
2
(dd, 1 H, JH,H ϭ 4.2 Hz, JH,P ϭ 17.5 Hz, HCNOH), 4.00Ϫ4.30
[m, 6 H, P(OCH2CH3)2, NCHPh and CHNH), 4.38 (d, 1 H, part
of an AB system, J ϭ 13.3 Hz, NCHPh), 5.25 (d, J ϭ 10 Hz, 1 H,
NHBoc), 6.48 (br., 1 H, NOH), 7.20Ϫ7.40 (m, 5 H, arom.) ppm.
31P NMR (121 MHz, CDCl3, 25 °C):
δ ϭ 26.37 ppm.
C19H33N2O6P (416.2): calcd. C 54.80, H 7.99, N 6.73; found C
54.85, H 8.10, N 6.65. Selected spectroscopic data for 10a: 1H
Diethyl
{(S)-[Benzyl(hydroxy)amino][(4S,5R)-3-(tert-butoxycar-
3
bonyl)-2,2,5-trimethyl-1,3-oxazolidin-4-yl]methyl}phosphonate (7b):
This compound was obtained from 6b, by using the aforementioned
general procedure, as a yellowish syrup after flash chromatography
(eluent: diethyl ether/light petroleum, 6:1), yield: 340 mg (70%),
[α]2D0 ϭ ϩ11.8 (c ϭ 0.2, CHCl3). IR (neat): ν˜ ϭ 3341, 1667, 1218
NMR (200 MHz, CDCl3, 25 °C): δ ϭ 2.78 (dd, 1 H, JH,H
ϭ
2
8.2 Hz, JH,P ϭ 14.7 Hz, HCNOH), 4.58 (d, 1 H, part of an AB
system, J ϭ 10.5 Hz, NCHPh), 4.81 (d, J ϭ 10.0 Hz, 1 H, NHBoc),
7.00 (br., 1 H, NOH), 7.20Ϫ7.40 (m, 5 H, arom.) ppm. 31P NMR
(121 MHz, CDCl3, 25 °C): δ ϭ 25.09 ppm.
cmϪ1 1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.22 (s, 3 H,
.
Diethyl {(1R,2S)- and (1S,2S)-1-[Benzyl(hydroxy)amino]-2-(tert-bu-
toxycarbonylamino)-3-phenylpropyl}phosphonates (9b and 10b):
These compounds were obtained from 8b by using the aforemen-
tioned general procedure (394 mg, 80% overall yield). Flash chro-
matography (eluent: EtOAc/light petroleum, 1:1) of the crude reac-
tion mixture furnished pure 9b and a mixture of 9b and 10b. Data
for 9b: Yellowish syrup, [α]2D0 ϭ Ϫ23.3 (c ϭ 0.2, CHCl3). IR (neat):
OCCH3), 1.30Ϫ1.40 [m, 9 H, P(OCH2CH3)2, CH3CHO], 1.48 (s, 9
H, tBuO), 1.61 (s, 3 H, OCCH3), 3.13 (dd, 1 H, JH,H ϭ 10.4 Hz,
3
2JH,P ϭ 12.9 Hz, HCNOH), 4.10 (d, 1 H, part of an AB system,
J ϭ 13.6 Hz, NCHPh), 4.15Ϫ4.40 [m, 5 H, P(OCH2CH3)2 and
OCHCH3], 4.45 (m, 1 H, CHNBoc), 4.65 (d, 1 H, part of an AB
system, J ϭ 13.6 Hz, NCHPh), 7.20Ϫ7.40 (m, 5 H, arom.), 7.52 (s,
1 H, NOH) ppm. 31P NMR (121, MHz, CDCl3, 25 °C): δ ϭ
26.88 ppm. C23H39N2O7P (486.2): calcd. C 56.78, H 8.08, N 5.76;
found C 56.70, H 8.15, N 5.70.
1
ν˜ ϭ 3336, 1691, 1220 cmϪ1. H NMR (200 MHz, CDCl3, 25 °C):
δ ϭ 1.20Ϫ1.50 [m, 15 H, P(OCH2CH3)2 and tBuO], 3.00Ϫ3.30 (m,
3
2
2 H, PhCH2), 3.34 (dd, 1 H, JH,H ϭ 4.6 Hz, JH,P ϭ 17.0 Hz,
HCNOH), 4.02 (d, 1 H, part of an AB system, J ϭ 13.2 Hz,
Diethyl {(S)-[Benzyl(hydroxy)amino][(4R)-3-(tert-butoxycarbonyl)-
2,2-dimethyl-1,3-thiazolidin-4-yl]methyl}phosphonate (7c): This
compound was obtained from 6c, by using the aforementioned
general procedure, as a colourless syrup after flash chromatography
NCHPh), 4.10Ϫ4.30 [m,
6 H, P(OCH2CH3)2, CHNH and
NCHPh], 5.33 (d, J ϭ 9.4 Hz, 1 H, NHBoc), 6.16 (br., 1 H, NOH),
7.10Ϫ7.50 (m, 10 H, arom.) ppm. 31P NMR (121 MHz, CDCl3, 25
°C): δ ϭ 25.55 ppm. C25H37N2O6P (492.2): calcd. C 60.96, H 7.57,
N 5.69; found C 61.10, H 7.60, N 5.60. Selected spectroscopic data
(eluent: EtOAc/light petroleum, 1:2), yield: 342 mg (74%), [α]2D0
ϭ
1
Ϫ8.8 (c ϭ 1.2, CHCl3). IR (neat): ν˜ ϭ 3341, 1667, 1228 cmϪ1. H
NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.35 [dt, 6 H, 3JH,H ϭ 6.9 Hz,
4JH,P ϭ 2.9 Hz, P(OCH2CH3)2], 1.45 (s, 9 H, tBuO), 1.55 (s, 3 H,
OCCH3), 1.79 (s, 3 H, OCCH3), 3.10Ϫ3.30 (m, 2 H, SCH2), 3.64
1
for 10b: H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 2.85 (ddd, 1 H,
3
2
4JH,H ϭ 1.7, JH,H ϭ 5.7 Hz, JH,Pϭ 13.0 Hz, HCNOH), 4.50 (d,
part of an AB system, J ϭ 13.0 Hz, NCHPh), 5.50 (d, J ϭ 9.4 Hz,
1 H, NHBoc) ppm. 31P NMR (121 MHz, CDCl3, 25 °C): δ ϭ
25.94 ppm.
2
(dd, 1 H, 3JH,H ϭ 10.2 Hz, JH,P ϭ 13.3 Hz, HC-NOH), 4.04 (d, 1
H, part of an AB system, J ϭ 13.8 Hz, NCHPh), 4.10Ϫ4.35 [m, 4
H, P(OCH2CH3)2], 4.76 (d, 1 H, part of an AB system, J ϭ
13.8 Hz, NCHPh), 4.87Ϫ5.00 (m, 1 H, CHNBoc), 7.10Ϫ7.40 (m,
6 H, arom. and NOH) ppm. 31P NMR (121, MHz, CDCl3, 25 °C):
δ ϭ 26.88 ppm. C22H37N2O6PS (488.2): calcd. C 54.08, H 7.63, N
5.73; found C 54.15, H 7.70, N 5.82.
Diethyl {(1R,2S)- and (1S,2S)-1-[Benzyl(hydroxy)amino]-2-(tert-bu-
toxycarbonylamino)-4-methylpentyl}phosphonates (9c and 10c):
These compounds were obtained from 8c by using the aforemen-
tioned general procedure (367 mg, 80% overall yield). Flash chro-
matography (eluent: EtOAc/light petroleum, 1:1) of the crude reac-
Diethyl
{(S)-[Benzyl(hydroxy)amino][(S)-1-(tert-butoxycarbonyl)- tion mixture furnished pure 9c and a mixture of 9c and 10c. 9c:
pyrrolidin-2-yl]methyl}phosphonate (7d): This compound was ob-
tained from 6d, by using the aforementioned general procedure, as
a colourless syrup after flash chromatography (eluent: EtOAc/light
petroleum, 1:1), yield: 363 mg (82%), [α]2D0 ϭ ϩ7.2 (c ϭ 0.9,
White solid, m.p. 73Ϫ75 °C (EtOAc/cyclohexane), [α]2D0 ϭ Ϫ50.0
(c ϭ 0.5, CHCl3). IR (KBr): ν˜ ϭ 3336, 1691, 1220 cmϪ1. 1H NMR
(200 MHz, CDCl3, 25 °C): δ ϭ 0.90 (d, J ϭ 5.9 Hz, 3 H, HCCH3),
0.91 (d, J ϭ 5.9 Hz, 3 H, HCCH3), 1.20Ϫ1.80 [m, 18 H,
CHCl3). IR (neat): ν˜ ϭ 3320, 1668, 1220 cmϪ1
.
1H NMR
P(OCH2CH3)2, tBuO, HC(CH3)2 and H2CCH], 3.27 (dd, 1 H,
(200 MHz, CDCl3, 25 °C): δ ϭ 1.34 [dt, 6 H, JH,H ϭ 7.1 Hz, 3JH,H ϭ 4.0 Hz, JH,P ϭ 17.0 Hz, HCNOH), 4.04 (d, 1 H, part of
3
2
Eur. J. Org. Chem. 2003, 1904Ϫ1914
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1911

C. De Risi, D. Perrone, A. Dondoni, G. P. Pollini, V. Bertolasi
FULL PAPER
an AB system, J ϭ 13.5 Hz, NCHPh), 4.08Ϫ4.28 [m, 5 H,
(d, J ϭ 5.0 Hz, 1 H, 1Ј-H), 7.20Ϫ7.40 (m, 5 H, arom.) ppm. 31P
P(OCH2CH3)2 and CHNH], 4.36 (d, 1 H, part of an AB system, NMR (121 MHz, CDCl3, 25 °C): δ ϭ 27.77 ppm. C23H36NO8P
J ϭ 13.5 Hz, NCHPh), 5.26 (d, J ϭ 10.0 Hz, 1 H, NHBoc), 6.31
(485.22): calcd. C 56.90, H 7.47, N 2.88; found C 57.10, H 7.52,
(br., 1 H, NOH), 7.27Ϫ7.40 (m, 5 H, arom.) ppm. 31P NMR N 2.90.
(121 MHz, CDCl3, 25 °C): 25.31 ppm. C22H39N2O6P (458.3): calcd.
General Procedure for the Synthesis of Compounds 13؊15, 16a؊d,
C 57.63, H 8.57, N 6.11; found C 57.70, H 8.65, N 6.00. Selected
and 17a؊c: A solution of protected α-(hydroxyamino)phosphonate
(1 mmol) and (Boc)2O (1.5 mmol) in EtOH (10 mL) was hydrogen-
ated at room temperature for the appropriate time under 5 atm
in the presence of 20% palladium hydroxide on activated charcoal
(Pearlman’s catalyst). The reaction mixture was filtered through a
plug of Celite, the solvent was evaporated under reduced pressure,
and the residue was purified by flash chromatography.
spectroscopic data for 10c: 1H NMR (200 MHz, CDCl3, 25 °C):
3
2
δ ϭ 2.82 (dd, 1 H, JH,H ϭ 7.7 Hz, JH,P ϭ 14.8 Hz, HCNOH),
4.04 (d, 1 H, part of an AB system, J ϭ 10.5 Hz, NCHPh), 4.61
(d, 1 H, part of an AB system, J ϭ 10.5 Hz, NCHPh), 4.70 (d,
J ϭ 10.0 Hz, 1 H, NHBoc) ppm. 31P NMR (121 MHz, CDCl3, 25
°C): 26.34 ppm.
General Procedure for the Synthesis of N-Benzyl-Protected α-
Aminophosphonates: Zn dust (5 mmol) was added to a solution of
Cu(OAc)2·H2O (0.2 mmol) in AcOH (4 mL) and the resulting sus-
pension was stirred at room temperature for 15 min. A solution of
N-benzylhydroxylamine (1 mmol) in AcOH/H2O (3:1, 4 mL) was
added. The reaction mixture was stirred at 70 °C overnight, then
filtered through Celite. The filtrate was neutralized with an aqueous
solution of 3  NaOH, extracted with EtOAc (3 ϫ 5 mL), and
washed with a saturated aqueous solution of EDTA. The organic
phase was dried and concentrated, and the residue was purified by
flash chromatography to furnish pure benzylamines.
Diethyl [(1S,2R)-1-(tert-Butoxycarbonylamino)-2,3-(isopropylidene-
dioxy)propyl]phosphonate (13): This compound was obtained from
2 by using the aforementioned general procedure. Reaction time:
48 h. Yield: 257 mg (70%). White amorphous solid (eluent: EtOAc/
cyclohexane, 1:1, containing 0.1% Et3N), m.p. 54Ϫ55 °C, [α]2D0
ϭ
1
ϩ3.8 (c ϭ 0.9, CHCl3). IR (KBr): ν˜ ϭ 3400, 1691, 1225 cmϪ1. H
NMR (300 MHz, DMSO, 120 °C): δ ϭ 1.28 [dt, 6 H, 4JH,P ϭ 2 Hz,
3JH,H ϭ 7.0 Hz, P(OCH2CH3)2], 1.30 (s, 3 H, OCCH3), 1.36 (s, 3
H, OCCH3), 1.43 (s, 9 H, tBuO), 3.87 and 3.98 (AB system, 1 H,
4JH,P ϭ 1 Hz, 3JH,H ϭ 6.5 Hz, OCHCHO), 3.90 and 3.95 (AB sys-
4
3
tem, 1 H, JH,P ϭ 1 Hz, JH,H ϭ 6.5 Hz, OCHCHO), 4.00Ϫ4.17
[m, 5 H, P(OCH2CH3)2 and NCH], 4.35 (m, 1 H, OCH2CH), 6.40
(d, J ϭ 8 Hz, 1 H, NH) ppm. 31P NMR (121 MHz, DMSO, 120
°C): δ ϭ 22.78 ppm. C15H30NO7P (367.2): calcd. C 49.04, H 8.23,
N 3.81; found C 49.10, H 8.16, N 3.90.
Diethyl {(1S,2R)-1-(Benzylamino)-2,3-(isopropylidenedioxy)-
propyl}phosphonate (11): This compound was obtained from 2, by
using the aforementioned general procedure, as a yellowish oil after
flash chromatography (eluent: EtOAc/light petroleum, 2:1), yield:
214 mg (60%), [α]2D0 ϭ ϩ20.0 (c ϭ 1.0, CHCl3). IR (neat): ν˜ ϭ 3435,
Diethyl [(1S,2R,3S)-1-(tert-Butoxycarbonylamino)-4-(tert-butoxy-
carbonyloxy)-2,3-(isopropylidenedioxy)butyl]phosphonate (14): This
compound was obtained from 4a by using the aforementioned gen-
eral procedure. Reaction time: 48 h. Yield: 298 mg (60%). Yellow
1242 cmϪ1
.
1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.20Ϫ1.40
[m, 9 H, P(OCH2CH3)2 and OCCH3], 1.43 (s, 3 H, OCCH3), 2.10
3
2
(br., 1 H, NH), 3.23 (dd, 1 H, JH,H ϭ 4.5 Hz, JH,P ϭ 14.4 Hz,
HCNH), 3.94 (d, 1 H, part of an AB system, J ϭ 13.0 Hz,
NCHPh), 4.00Ϫ4.30 [m, 7 H, P(OCH2CH3)2, NCHPh, OCH2CH],
4.40 (m, 1 H, OCH2CH), 7.20Ϫ7.40 (m, 5 H, arom.) ppm. 31P
NMR (121 MHz, CDCl3, 25 °C): δ ϭ 25.87 ppm. C17H28NO5P
(357.2): calcd. C 57.13, H 7.90, N 3.92; found C 57.20, H 7.80,
N 4.05.
oil (eluent: EtOAc/cyclohexane, 2:1, containing 0.1% Et3N), [α]2D0
ϭ
Ϫ10.1 (c ϭ 0.9, CHCl3). IR (neat): ν˜ ϭ 3400, 1691, 1220 cmϪ1. 1H
4
NMR (300 MHz, DMSO, 120 °C): δ ϭ 1.29 [dt, 6 H, JH,P
ϭ
3
4.5 Hz, JH,H ϭ 7.0 Hz, P(OCH2CH3)2], 1.41 (s, 9 H, tBuO), 1.48
(s, 3 H, OCCH3), 1.50 (s, 12 H, tBuO and OCCH3), 3.96Ϫ4.24 [m,
9 H, P(OCH2CH3)2, NCH, 2 HCOC(CH3)2 and CH2OBoc], 5.40
(br., 1 H, NH) ppm. 31P NMR (121 MHz, DMSO, 120 °C): δ ϭ
22.79 ppm. C21H40NO10P (497.2): calcd. C 50.70, H 8.10, N 2.82;
found C 50.80, H 7.95, N 2.90.
Diethyl {(1S,2R,3S)-1-(Benzylamino)-4-benzyloxy-2,3-(isopropyl-
idenedioxy)butyl}phosphonate (12a): This compound was obtained
from 4a, by using the aforementioned general procedure, as a yel-
lowish oil after flash chromatography (eluent: EtOAc), yield:
286 mg (60%), [α]2D0 ϭ Ϫ5.0 (c ϭ 1.3, CHCl3). IR (neat): ν˜ ϭ 3436,
Diethyl [(R)-(tert-Butoxycarbonylamino)(5-deoxy-1,2:3,4-di-O-iso-
propylidene-α-D-galactopyranos-5-yl)methyl]phosphonate (15): This
1240 cmϪ1 1H NMR (200 MHz, CDCl3, 25 °C): δ ϭ 1.20Ϫ1.50
.
compound was obtained from 4b by using the aforementioned gen-
eral procedure. Reaction time: 48 h. Yield: 396 mg (80%). Colorless
syrup (eluent: EtOAc/cyclohexane, 3:1, containing 0.1% Et3N),
[α]2D0 ϭ Ϫ52.2 (c ϭ 0.9, CHCl3). IR (neat): ν˜ ϭ 3400, 1691, 1218
cmϪ1. 1H NMR (300 MHz, DMSO, 120 °C): δ ϭ 1.27 [t, J ϭ 5 Hz,
6 H, P(OCH2CH3)2], 1.32 (s, 6 H, 2 ϫ OCCH3), 1.42 (s, 12 H,
tBuO and OCCH3), 1.47 (s, 3 H, OCCH3), 4.00Ϫ4.20 [m, 6 H,
P(OCH2CH3)2, 5Ј-H and HCNH], 4.33 (dd, 1 H, J ϭ 2.5 and 5 Hz,
2Ј-H), 4.40 (d, J ϭ 8 Hz, 1 H, 4Ј-H), 4.62 (dd, 1 H, J ϭ 2.5 and
8 Hz, 3Ј-H), 5.46 (d, J ϭ 5 Hz, 1 H, 1Ј-H), 6.38 (d, J ϭ 8 Hz, 1 H,
NH) ppm. 31P NMR (121 MHz, DMSO, 120 °C): δ ϭ 23.37 ppm.
C21H38NO10P (495.2): calcd. C 50.90, H 7.73, N 2.83; found C
50.98, H 7.60, N 2.92.
[m, 12 H, P(OCH2CH3)2 and OC(CH3)2], 1.89 (br., 1 H, NH), 3.15
(dd, 1 H, 3JH,H ϭ 6.4 Hz, 2JH,P ϭ 18.0 Hz, HCNH), 3.50Ϫ4.30 [m,
10 H, P(OCH2CH3)2, PhCH2, OCHCHO and NCH2Ph], 4.60 (AB
system, 2 H, J ϭ 12.1 Hz, PhCH2O), 7.20Ϫ7.40 (m, 10 H, arom.)
ppm. 31P NMR (121 MHz, CDCl3, 25 °C): δ ϭ 26.78 ppm.
C25H36NO6P (477.2): calcd. C 62.88, H 7.60, N 2.93; found C
63.00, H 7.75, N 2.88.
Diethyl {(R)-(Benzylamino)(5-deoxy-1,2:3,4-di-O-isopropylidene-α-
D-galactopyranos-5-yl)methyl}phosphonate (12b): This compound
was obtained from 4b, by using the aforementioned general pro-
cedure, as a as a colourless oil after flash chromatography (eluent:
EtOAc/light petroleum, 1:3), yield: 267 mg (55%), [α]2D0 ϭ Ϫ24 (c ϭ
1.0, CHCl3). IR (neat): ν˜ ϭ 3430, 1245 cmϪ1. 1H NMR (300 MHz,
Diethyl
{(S)-(tert-Butoxycarbonylamino)[(4S)-3-(tert-butoxycar-
CDCl3, 25 °C): δ ϭ 1.25Ϫ1.40 [m, 12 H, P(OCH2CH3)2 and 2 bonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]methyl}phosphonate (16a):
OCCH3], 1.45 (s, 3 H, OCCH3), 1.58 (s, 3 H, OCCH3), 3.35 (dd, 1 This compound was obtained from 7a by using the aforementioned
H, 3JH,H ϭ 8.0 Hz, 2JH,P ϭ 12.0 Hz, HCNH), 4.00 (s, 2 H, PhCH2),
general procedure. Reaction time: 72 h. Yield: 290 mg (62%). Yel-
4.08Ϫ4.28 [m, 6 H, P(OCH2CH3)2, NH and 4Ј-H), 4.31 (dd, J ϭ lowish syrup (eluent: EtOAc/cyclohexane, 1:1, containing 0.1%
1.0, 5.0 Hz, 1 H, 5Ј-H), 4.60Ϫ4.72 (m, 2 H, 2Ј-H and 3Ј-H), 5.55 Et3N), [α]2D0 ϭ Ϫ45.8 (c ϭ 0.5, CHCl3). IR (neat): ν˜ ϭ 3400, 1690,
1912
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 1904Ϫ1914

Diastereoselective Synthesis of α-(Hydroxyamino)phosphonates and α-Aminophosphonates
FULL PAPER
1
1225 cmϪ1. H NMR (300 MHz, DMSO, 120 °C): δ ϭ 1.29 [dt, 6 J ϭ 10 Hz, 1 H, HNCHP) ppm. 31P NMR (121 MHz, DMSO, 120
4
3
H, JH,P ϭ 4.5 Hz, JH,H ϭ 7 Hz, P(OCH2CH3)2], 1.41 (s, 9 H,
°C): δ ϭ 23.87 ppm. C17H35N2O7P (410.2): calcd. C 49.75, H 8.60,
tBuO), 1.48 (s, 3 H, OCCH3), 1.49 (s, 12 H, OCCH3 and tBuO), N 6.83; found C 49.90, H 8.45, N 7.00.
3.86Ϫ4.26 [m,
8 H, P(OCH2CH3)2, HNCH, HCNBoc and
Diethyl
[(1R,2S)-1,2-Bis(tert-butoxycarbonylamino)-3-phenylpro-
CH2OC(CH3)2], 5.40 (br., 1 H, NH) ppm. 31P NMR (121, MHz,
DMSO, 120 °C): δ ϭ 22.81 ppm. C20H39N2O8P (466.2): calcd. C
51.49, H 8.43, N 6.00; found C 51.55, H 8.53, N 5.95.
pyl]phosphonate (17b): This compound was obtained from 9b by
using the aforementioned general procedure. Reaction time: 72 h.
Yield: 301 mg (62%). Yellowish syrup (eluent: EtOAc/cyclohexane,
3:1, containing 0.1% Et3N), [α]2D0 ϭ Ϫ15.5 (c ϭ 0.6, CHCl3). IR
Diethyl {(S)-(tert-Butoxycarbonylamino)[(4S,5R)-3-(tert-butoxy-
carbonyl)-2,2,5-trimethyl-1,3-oxazolidin-4-yl]methyl}phosphonate
(16b): This compound was obtained from 7b by using the afore-
mentioned general procedure. Reaction time: 72 h. Yield: 303 mg
(63%). Yellowish syrup (eluent: EtOAc/cyclohexane, 1:1, containing
0.1% Et3N), [α]2D0 ϭ Ϫ26.8 (c ϭ 0.4, CHCl3). IR (neat): ν˜ ϭ 3400,
(neat): ν˜ ϭ 3400, 1691, 1218 cmϪ1. H NMR (300 MHz, DMSO,
1
140 °C): δ ϭ 1.27Ϫ1.36 [m, 15 H, P(OCH2CH3)2 and tBuO), 1.45
(s, 9 H, tBuO), 2.74 (dd, J ϭ 10 and 14 Hz, 1 H, CHPh), 3.07 (dd,
J ϭ 4, 14 Hz, 1 H, CHPh), 3.98Ϫ4.28 [m, 6 H, P(OCH2CH3)2,
HCNHBoc and HCP], 5.88 (d, J ϭ 8.0 Hz, 1 H, HNCHCH2), 6.20
(d, J ϭ 8.0 Hz, 1 H, NHCHP), 7.10Ϫ7.50 (m, 5 H, arom.) ppm. 31
P
1690, 1220 cmϪ1. H NMR (300 MHz, DMSO, 120 °C): δ ϭ 1.29
1
NMR (121 MHz, DMSO, 120 °C): δ ϭ 23.91 ppm. C23H39N2O7P
(486.2): calcd. C 56.78, H 8.08, N 5.76; found C 56.80, H 8.15,
N 5.60.
[m, 6 H, P(OCH2CH3)2], 1.39 (d, J ϭ 7 Hz, 3 H, CH3CHO), 1.41
(s, 9 H, tBuO), 1.48 (s, 3 H, OCCH3), 1.49 (s, 12 H, OCCH3 and
tBuO), 3.86Ϫ4.26 [m, 6 H, P(OCH2CH3)2, HNCH, HCNBoc],
4.34Ϫ4.44 (m, 1 H, OCHCH3), 5.40 (br., 1 H, NH) ppm. 31P NMR
(121, MHz, DMSO, 120 °C): δ ϭ 22.92 ppm. C21H41N2O8P
(480.3): calcd. C 52.49, H 8.60, N 5.83; found C 52.60, H 8.48,
N 6.00.
Diethyl {(1R,2S)-1,2-Bis(tert-butoxycarbonylamino)-4-methyl-
pentyl}phosphonate (17c): This compound was obtained from 9c by
using the aforementioned general procedure. Reaction time: 72 h.
Yield: 300 mg (66%). Yellowish syrup (eluent: EtOAc/cyclohexane,
1:1, containing 0.1% Et3N), [α]2D0 ϭ Ϫ23.2 (c ϭ 1.3, CHCl3). IR
Diethyl
{(S)-(tert-Butoxycarbonylamino)[(4R)-3-(tert-butoxycar-
1
(neat): ν˜ ϭ 3400, 1691, 1215 cmϪ1. H NMR (300 MHz, DMSO,
bonyl)-2,2-dimethyl-1,3-thiazolidin-4-yl]methyl}phosphonate (16c):
This compound was obtained from 7c by using the aforementioned
general procedure. Reaction time: 10 d. Yield: 193 mg (40%). Col-
orless syrup (eluent: EtOAc/cyclohexane, 1:1, containing 0.1%
Et3N), [α]2D0 ϭ Ϫ56.0 (c ϭ 1.9, CHCl3). IR (neat): ν˜ ϭ 3400, 1690,
1220 cmϪ1. 1H NMR (300 MHz, DMSO, 120 °C): δ ϭ 1.29 [q, J ϭ
5 Hz, 6 H, P(OCH2CH3)2], 1.41 (s, 9 H, tBuO), 1.50 (s, 9 H, tBuO),
1.67 (s, 3 H, OCCH3), 1.78 (s, 3 H, OCCH3), 3.20 (d, J ϭ 12.5 Hz,
120 °C): δ ϭ 0.88 (d, J ϭ 7.0 Hz, 3 H, HCCH3), 0.91 (d, J ϭ
7.0 Hz, 3 H, HCCH3), 1.24Ϫ1.33 [dt, 6 H, 4JH,P ϭ 5.0 Hz, 3JH,H ϭ
7.0 Hz, P(OCH2CH3)2], 1.41 (s, 9 H, tBuO), 1.43 (s, 9 H, tBuO),
1.59Ϫ1.73 [m, 3 H, HC(CH3)2 and H2CCH(CH3)2], 3.78Ϫ3.92 (m,
1 H, CH2CHNH), 4.00Ϫ4.12 [m, 4 H, P(OCH2CH3)2], 4.15 (ddd,
3
3
2
1 H, JH,H ϭ 5.0, JH,N ϭ 10.0, JH,P ϭ 18.0 Hz, HCP), 4.30 (m,
1 H, HNCHCH2), 5.91 (d, J ϭ 7.0 Hz, 1 H, HNCH), 6.03 (d, J ϭ
10 Hz, 1 H, HNCHP) ppm. 31P NMR (121 MHz, DMSO, 120 °C):
δ ϭ 23.86 ppm. C20H41N2O7P (452.3): calcd. C 53.08, H 9.13, N
6.19; found C 53.15, H 9.00, N 6.25.
4
3
2
1 H, SCH), 3.34 (ddd, 1 H, JH,P ϭ 1.0, JH,H ϭ 5.5, JH,H
ϭ
12.5 Hz, SCH), 4.02Ϫ4.18 [m, 4 H, P(OCH2CH3)2], 4.37 (dt, 1 H,
2
3JH,H ϭ 10.5 Hz, JH,P ϭ 14 Hz, HCNBoc), 4.66Ϫ4.76 (m, 1 H,
CHNH), 5.33 (br. s, 1 H, NH) ppm. 31P NMR (121, MHz, DMSO,
120 °C): δ ϭ 23.06 ppm. C20H39N2O7PS (482.2): calcd. C 49.78, H
8.15, N 5.81; found C 49.95, H 8.00, N 6.00.
X-ray Structure Determinations: X-ray diffraction data for com-
pounds 2, 4a, 4b, and 9c were collected at 295 K with a Nonius
Kappa CCD diffractometer using graphite-monochromated Mo-
˚
Kα radiation (λ ϭ 0.7107 A). The structures were solved by direct
Diethyl {(S)-(tert-Butoxycarbonylamino)[(S)-1-(tert-butoxycarbon-
yl)pyrrolidin-2-yl]methyl}phosphonate (16d): This compound was
obtained from 7d by using the aforementioned general procedure.
Reaction time: 72 h. Yield: 266 mg (61%). Colorless syrup (eluent:
EtOAc/cyclohexane, 1:1, containing 0.1% Et3N), [α]2D0 ϭ Ϫ38.0
(c ϭ 1.3, CHCl3). IR (neat): ν˜ ϭ 3400, 1690, 1220 cmϪ1. 1H NMR
methods (SIR97)[24] and refined (SHELXL-97)[25] by a full-matrix
least-squares method with anisotropic non-hydrogen and hydrogen
atoms included in calculated positions riding on their carrier atoms,
except for OH and NH hydrogen atoms in compounds 2, 4a, and
4b, which were refined isotropically. ORTEP[26] views are shown
in Figures 1Ϫ3, and 6, respectively. Crystal Data: 2: C17H28NO6P;
4
(300 MHz, DMSO, 120 °C): δ ϭ 1.29 [dt, 6 H, JH,P ϭ 2.6 Hz,
monoclinic, space group P21, a ϭ 9.5358(6), b ϭ 10.1850(3), c ϭ
3JH,H ϭ 7.0 Hz, P(OCH2CH3)2], 1.42 (s, 9 H, tBuO), 1.47 (s, 9 H,
tBuO), 1.78Ϫ2.16 (m, 4 H, 3Ј-CH2 and 4Ј-CH2), 3.13Ϫ3.22 (m, 1
3
˚
˚
11.4938(7) A, β ϭ 110.621(2)°, V ϭ 1044.8(1) A , Z ϭ 2, Dc ϭ
1.187 g·cmϪ3. Intensity data collected with θ Յ 27.5°; 2508 inde-
pendent reflections measured; 1877 observed [I Ͼ 2σ(I)]. Final R
index ϭ 0.041 (observed reflections). The molecules possess inter-
molecular hydrogen bonds between N-hydroxy and phosphonate
H, 5Ј-H), 3.28Ϫ3.40 (m,
1 H, 5Ј-H), 3.89Ϫ4.15 [m, 6 H,
P(OCH2CH3)2, HCNHBoc and HCNBoc], 5.51 (d, J ϭ 8 Hz, 1 H,
NH) ppm. 31P NMR (121, MHz, DMSO, 120 °C): δ ϭ 23.80 ppm.
C19H37N2O7P (436.2): calcd. C 52.28, H 8.54, N 6.42; found C
52.35, H 8.40, N 8.90.
˚
groups, O1ϪH···O4 (Ϫx, 1/2 ϩ y, 2 Ϫ z) [O1···O4 ϭ 2.633(4) A,
O1ϪH···O4 ϭ 177(4)°]. 4a: C25H36NO7P; monoclinic, space group
˚
Diethyl
[(1R,2S)-1,2-Bis(tert-butoxycarbonylamino)propyl]phos-
P21, a ϭ 11.750(1), b ϭ 10.1491(7), c ϭ 12.346(1) A, β ϭ
3
phonate (17a): This compound was obtained from 9a by using the 107.147(4)°, V ϭ 1406.8(2) A , Z ϭ 2, Dc ϭ 1.165 g·cmϪ3. Intensity
˚
aforementioned general procedure. Reaction time: 72 h. Yield:
246 mg (60%). Yellowish syrup (eluent: EtOAc/cyclohexane, 1:1,
data collected with θ Յ 27.5°; 3341 independent reflections meas-
ured; 2466 observed [I Ͼ 2σ(I)]. Final R index ϭ 0.064 (observed
containing 0.1% Et3N), [α]2D0 ϭ Ϫ21.6 (c ϭ 0.4, CHCl3). IR (neat): reflections). The molecules possess intermolecular hydrogen bonds
ν˜ ϭ 3400, 1690, 1220 cmϪ1. 1H NMR (300 MHz, DMSO, 120 °C):
δ ϭ 1.15 (d, J ϭ 7 Hz, 3 H, CH3CH), 1.28 [dt, 6 H, 4JH,P ϭ 5.0 Hz,
between N-hydroxy and phosphonate groups, O1ϪH···O4
˚
[O1···O4 ϭ 2.685(5) A, O1ϪH···O8 ϭ 175(5)°]. 4b: C23H36NO9P;
3JH,H ϭ 7.0 Hz, P(OCH2CH3)2], 1.41 (s, 9 H, tBuO), 1.44 (s, 9 orthorhombic, space group P212121, a ϭ 9.9495(2), b ϭ 14.1008(4),
3
Ϫ3
˚ ˚
H, tBuO), 3.79Ϫ3.94 (m, 1 H, CH3CHNH), 4.00Ϫ4.12 [m, 4 H,
c ϭ 19.3015(6) A, V ϭ 2707.9(1) A , Z ϭ 4, Dc ϭ 1.230 g·cm .
P(OCH2CH3)2], 4.17 (ddd, 1 H, 3JH,H ϭ 5.0, 3JH,N ϭ 10.0, 2JH,P ϭ Intensity data collected with θ Յ 27°; 3269 independent reflections
18.0 Hz, HCP), 5.98 (d, J ϭ 7.0 Hz, 1 H, HNCHCH3), 6.15 (d, measured; 2470 observed [I Ͼ 2σ(I)]. Final R index ϭ 0.069 (ob-
Eur. J. Org. Chem. 2003, 1904Ϫ1914
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1913

C. De Risi, D. Perrone, A. Dondoni, G. P. Pollini, V. Bertolasi
FULL PAPER
served reflections). The molecules possess intermolecular hydrogen
bond between N-hydroxy and phosphonate groups, O1ϪH···O8
(1/2 ϩ x, 1/2 Ϫ y, 1 Ϫ z) [O1···O8 ϭ 2.648(6) A, O1ϪH···O8 ϭ
[7]
For a recent and exhaustive review on nucleophilic addition
reactions to nitrones, see: M. Lombardo, C. Trombini, Syn-
thesis 2000, 759Ϫ774.
˚
[8] [8a]
A. Dondoni, F. Junquera, F. L. Merchan, P. Merino, T.
167(5)°]. 9c: C22H39N2O6P; orthorhombic, space group P212121,
Tejero, Synthesis 1994, 1450Ϫ1456. [8b] A. Dondoni, S. Franco,
F. Junquera, F. L. Merchan, P. Merino, T. Tejero, V. Bertolasi,
3
˚
˚
a ϭ 9.8171(4), b ϭ 11.0010(5), c ϭ 49.372(2) A, V ϭ 5332.1(4) A ,
Z ϭ 8, Dc ϭ 1.142 g·cmϪ3. Intensity data collected with θ Յ 25°;
3771 independent reflections measured; 2638 observed [I Ͼ 2σ(I)].
Final R index ϭ 0.073 (observed reflections). The asymmetric unit
comprises two independent molecules, which form a complex net-
work of hydrogen bonds: O1AϪH···O2B (x, y, z) [O1A···O2B ϭ
[8c]
Chem. Eur. J. 1995, 1, 505Ϫ520.
Aldrichim. Acta 1997, 30, 35.
A. Dondoni, D. Perrone,
A. Dondoni, S. Franco, F.
[8d]
Junquera, F. L. Merchan, P. Merino, T. Tejero, J. Org. Chem.
1997, 62, 5497Ϫ5507. [8e] A. Dondoni, D. Perrone, M. Rinaldi,
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A. Dondoni, D. Per-
˚
2.783(6) A, O1AϪH···O2B ϭ 146°]; N2AϪH···O5B (x, y, z)
[9]
For some examples of a dialkyl phosphite/nitrone approach to
the synthesis of α-deoxy-α-hydroxyamino sugar phosphonates,
see: [9a] J. M. J. Tronchet, D. Schwarzenbach, E. Winter-Mihaly,
C. Diamantides, U. Likic, G. Galland-Barrera, C. Jorand, K.
D. Pallie, J. Ojha-Poncet, J. Rupp, G. Moret, M. Geoffroy, Helv.
Chim. Acta 1982, 65, 1404Ϫ1411. [9b] J. M. J. Tronchet, E. Win-
ter-Mihaly, J. Rupp, F. Barbalat-Rey, M. Geoffroy, Carbohydr.
Res. 1985, 136, 375.
˚
[N2A···O5B ϭ 2.916(6) A, N2AϪH···O5A ϭ 134°]; O1BϪH···O2A
˚
(x, y, z) [O1B···O2A ϭ 2.669(6) A, O1BϪH···O2A ϭ 128°];
˚
N2BϪH···O5A (x
ϩ
1, y, z) [N2B···O5A
ϭ
2.995(7) A,
N2BϪH···O5A ϭ 157°]. CCDC-165735 (2), -165736 (4a), -199534
(4b), and -199535 (9c) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
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A. Vasella, R. Voeffray, Helv. Chim. Acta 1982, 65,
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Acknowledgments
We gratefully acknowledge MIUR (PRIN 2000) for financial sup-
port and the high-field NMR center of the University of Ferrara
for collection of the NMR spectra.
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For earlier and recent reports of nitrone activation by O-silyl-
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