Lithiated alkylidenebis(phosphonates): Reactive phosphorus intermediates in the synthesis of 3-amino-1-alkenylphosphonates

Article abstract of DOI:10.1002/hc.20450

An efficient and stereoselective-synthesis of 3-amino-1-alkenylphosphonates by a direct procedure involving alkylidene diphosphorylation of nucleophiles followed by a Horner-Emmons olefination of aminoaldehydes is reported. The versatility of the method is illustrated by the preparation of P-monoglycosyl-, P-diglycosyl 3-aminoalkenyl-, and alkylphosphonates.

Full text of DOI:10.1002/hc.20450

Heteroatom Chemistry
Volume 19, Number 5, 2008
Lithiated Alkylidenebis(phosphonates):
Reactive Phosphorus Intermediates in the
Synthesis of 3-Amino-1-alkenylphosphonates
Claude Grison1 and Tomasz Krzysztof Olszewski2
1Universite´ Montpellier 2, ENSCM, 8 rue de l’Ecole Normale, 34296 Montpellier Ce´dex 5, France
2Faculty of Chemistry, Wroclaw University of Technology, Wybrzeze Wyspianskiego 27, 50–370,
Wroclaw, Poland
Received 20 December 2007; revised 3 March 2008
Thus 3-aminoalkenyl- and 3-aminoalkyl phos-
ABSTRACT: An efficient and stereoselective-
phonates have been the subject of recent stud-
synthesis of 3-amino-1-alkenylphosphonates by a
ies, and they have been prepared as analogues of
direct procedure involving alkylidene diphosphoryla-
sphingosine-1-phosphate [2], dihydrosphingosine-1-
tion of nucleophiles followed by a Horner–Emmons
phosphate [3], and sphingomyelin [4]. Sphingosine
olefination of aminoaldehydes is reported. The versa-
(or 4-sphingenine), dihydrosphingosine (or sphinga-
tility of the method is illustrated by the preparation
nine), and phytosphingosine (or 4-hydroxy sphinga-
of P-monoglycosyl-, P-diglycosyl 3-aminoalkenyl-,
nine) are the major long-chain bases of ceramide,
ꢀ
C
and alkylphosphonates.
2008 Wiley Periodicals, Inc.
sphingomyelin, and glycosphingolipids [5].
Heteroatom Chem 19:461–469, 2008; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20450
These sphingolipid metabolites act both intra-
cellularly and extracellularly to cause numerous
and significant biological responses [6]. The bioac-
tivity of the sphingolipid metabolites is regulated
by the presence of the phosphate group. Indeed,
the phosphorylated form is often antagonistic to
the unphosphorylated form. For example, sphingo-
sine is an essential regulatory component of stress
responses associated with cell growth arrest, apop-
tosis, inhibition of protein kinase C, and calcium
releasing and decreasing of thermotolerance. In con-
trast, sphingosine-1-phosphate has been implicated
in cellular proliferation and survival with stimu-
lation of growth, suppression of apoptosis, regu-
lation of motility, and calcium, and increasing of
thermotolerance [7]. It has been suggested that
the control of the dynamic balance between in-
tracellular sphingosine-1-phosphate and sphingo-
sine may provide the basis for the development of
novel therapeutics. The understanding of the cat-
alytic mechanism of the hydrolysis of the phospho-
ester linkage of sphingosine-1-phosphate or other
INTRODUCTION
Many aminophosphonate derivatives have attracted
particular interest, and they have found broad appli-
cations in many areas of medicine and agriculture
[1]. For some of these compounds, biological activ-
ity seems to be linked to the presence of a metabol-
ically stable aminophosphorylated residue within
their structure. For instance, 3-aminophosphonates
are the analogues of 2-aminoethyl phosphates in
which the scissile O P bond is replaced by a C P
bond and therefore, they are resistant to the phos-
phohydrolase action.
Correspondence to: Claude Grison; e-mail: cgrison@univ-
montp2.fr.
c
ꢀ
2008 Wiley Periodicals, Inc.
461

462 Grison and Olszewski
sphingolipids such as sphinganine-1-phosphate,
phytosphingosine-1-phosphate, and sphingomyelin
has inspired recent extensive studies [2–4].
Also, 3-aminophosphonate analogues of other
lipid mediators such as lysophosphatidic acids have
recently attracted considerable attention because of
their potential as LPA (lysophosphatidic acid or 2-
O-acyl-sn-glycero-3-phosphate) receptor agonists or
antagonists [8].
In addition, aminophosphonic acids are the
most important substitutes for the corresponding
amino acids and there is considerable interest
in the chemical modification of amino acids
to better understand the biological significance
of their derivatives. It has been shown that 3-
aminophosphonic derivatives were interesting as
peptidomimetics of D-Ala-D-Ala [9], D-alanyl phos-
phate [10], 3-amino-2-mercapto-carboxylic acids
[11], (S)-glutamic [12], and pyroglutamic acids
[13]. Several 3-aminoalkenylphosphic acids and
their analogues have been described as inhibitors
of D-Ala-D-Ala-ligase [9,10], metallopeptidase [11],
NMDA (N-methyl-D-aspartic acid)-receptor ligands
[13], and human rhinovirus 3C protease [14].
Owing to the biological importance of the
3-aminophosphonate moiety, a versatile strategy,
which allows the introduction of a large variety of
substituents is of a particular interest.
rived from diethyl ethynyl phosphonate, to an ala-
nine Schiff base [20].
Finally, several examples of (E)-(3-amino-1-
alkenyl)phosphonates have been prepared by the
Horner-Emmons reaction between N-protected
aminoaldehydes and the carbanion derived from
tetraethyl methylenebisphosphonate. However, this
strategy has not been investigated extensively and
only a few reports are available in the literature de-
scribing the design of novel enzymatic inhibitors
[2a–2d, 8–11,13,14].
In continuation of our studies on the
Horner type-reactions [21] and on chiral alkyli-
dene diphosphorylated derivatives [22], here we
present a rapid and simple access to 3-amino-1-
alkenylphosphonates 1.
The strategy involves a one-pot sequence based
on a regioselective Horner-Emmons olefination in-
volving alkylidene bis(phosphonic) anions 2 and
aminoaldehydes 3. As previously described [22], the
intermediates 2 were generated in situ by a se-
lective phosphonomethylation of chlorophosphory-
lated substrates 4 using the carbanions derived from
diethyl alkylphosphonates 5 (Scheme 1).
The detailed mechanism of the process depends
on the nature of the Z group (Scheme 2). When Z =
OEt, the intermediate anions 2 were formed directly
by the successive addition of a solution of LDA (2
equivalents/base 2) onto diethyl alkylphosphonates
5 and diethyl phosphorochloridate 4 (R3 = OEt) in
THF at −70◦C (route A).
Herein, we report an efficient and rapid method
for the preparation of 1-, 3-substituted 3-amino-1-
alkenyl- and 3-amino-1-alkylphosphonates and P-
mono- or P-diglycosyl 3-amino-1-alkenyl- and 3-
amino-1-alkylphosphonates.
When Z = Cl, the intermediate anions 2 were
obtained after the alcoholysis of the chlorine atom
of the intermediates 6 and addition of one supple-
mentary equivalent of base (route B). The anions 6
were generated by successive addition of a solution
of BuLi (2 equivalents/base 1) onto diethyl alkylphos-
phonates 5 and ethyl phosphorochloridate 4.
For both routes, aminoaldehydes were intro-
duced onto the nonisolated intermediates 2, which
reacted via a Horner-Emmons carbonyl olefination
RESULTS AND DISCUSSION
Common methods for the synthesis of (3-amino-1-
alkenyl)phosphonates involve the acid-catalyzed re-
arrangement of allylic α-hydroxyphosphonates [15]
with secondary amines, the Pd(0) and Ni(II) cat-
alyzed intermolecular allylic amination of α-acetoxy-
2-alkenylphosphonates [16], the thermal rearrange-
ment of trichloroacetimidic esters of allylic α-
hydroxy phosphonates [17], or allylic α-azido phos-
phonates [18]. These strategies cannot be applied
to substituted (3-amino-1-alkenyl) phosphonates be-
cause of the difficulties relating to the preparation of
the starting reagents, severe reaction conditions, and
the lack of the ability to control the regioselectivity,
stereoselectivity, and stereospecificity of rearrange-
ments. Another route to these compounds involves
the addition of imines to the alkynylphosphonate
titanium(II) complexes [19]. A similar process to
prepare unsubstituted aminoalkenylphosphonates is
based on the addition of the lithiated carbanion, de-
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

Lithiated Alkylidenebis(phosphonates) 463
Route A
The addition of an aminoaldehyde 3 onto the gener-
ated in situ lithiated anions 2 led to the formation of
the expected amino-1-alkenylphosphonates 1 when
room temperature was attained. After the removal
of the salts and chromatography, 1 was obtained
in satisfactory yield and purity (Table 1). This syn-
thesis starting from the easily available substrates,
diethyl alkylphosphonates 5, and the diethyl phos-
phorochloridate (4, R3 = OEt) worked well with a
wide range of aminoaldehydes, and in addition a
substituent on the R2 position (1b, R2 = Me) was tol-
erated under the reaction conditions. The simplicity
of the experimental procedure should be noted; this
one-pot synthesis that proceeds by sequential metal-
lation, substitution, metallation, and carbonylolefi-
nation represents a significant improvement for the
preparation of 3-amino-1-alkenylphosphonates 1.
All compounds 1 were fully characterized on the
basis of their 1H, 13C, and 31P NMR, IR, and MS spec-
1
tra. Characteristic signals in the H NMR spectrum
of 1a–1d are the signals corresponding to the CH
alkene with a typical downfield shift for an E config-
uration (δ = 6.76–6.34 ppm).
SCHEME 2
In every case, the preferential configuration of
the newly formed double bond was E. The formation
of only one isomer is typical of the Horner-Emmons
to give the desired 3-amino-1-alkenylphosphonates
1. The results are summarized in Table 1.
TABLE 1 Synthesis of 3-amino-1-alkenylphosphonates 1 via a Horner-Emmons carbonyl olefination of aminoaldehydes 3
Compound 1
R1
R2
R3
R4
Z
Route
Base 1
Base 2
E/Z ratio
Yield%
1a
1a
1a
1b
1c
1d
Et
CF3CH2
CF3CH2
Et
EtO
Cl
Cl
EtO
EtO
EtO
A
B
B
A
A
A
LDA
BuLi
BuLi
LDA
LDA
LDA
LDA
LDA
KH
LDA
LDA
LDA
>99a
>95b
>95b
>99a
>99a
>99a
60
60
30
57
70
63
Me
H
Et
Me
Bn
Me
H
H
Et
Et
Et
Et
Et
i Bu
1e
Me
Bn
Me
H
H
H
Et
Cl
Cl
Cl
B
B
B
BuLi
BuLi
BuLi
LDA
LDA
LDA
>99a
>99a
>99a
45
50
42
1f
Et
1g
aOnly E-aminophosphonates 1 were detected in 1H-NMR.
b Traces of Z-aminophosphonates 1 were detected in 1H-NMR.
Heteroatom Chemistry DOI 10.1002/hc

464 Grison and Olszewski
reactions with aminoaldehydes and diethyl phos-
phonates [21d].
SCHEME 3
Route B
In preliminary attempts to tailor Z-selectivity, we in-
troduced a trifluoroethoxy group on a phosphorus
atom (1a, R4 = CF3CH2). It appeared that 2 behaved
very specifically and the E-stereoselectivity was con-
served, despite the presence of the trifluoroethoxy
group. The use of potassium hydride in THF led to
1a in only poor yield and did not modify the E/Z
ratio. Thus, the traditional parameters (cation and
electronic effect) did not affect the stereoselectivity
of the Horner reaction. As a result, the reaction was
generally studied with BuLi as base 1 and LDA as
base 2.
The
synthesis
of
the
saturated
α-
aminophosphonates 7 can also be achieved in
excellent yields, by catalytic hydrogenation of the
3-amino-1-alkenylphosphonates 1 (Scheme 3 and
Table 2). In sharp contrast with the hydrogenation
of the vinylogous aminoester Boc NH CHMe
CH CMe COOMe [23], no diastereoselectivity was
observed with the analogous aminophosphonate
Boc NH CHMe CH CMe P(O)(OEt)2 7b. This
result is quite surprising, because it could be
supposed that the (S) configuration of the N-α-
ethyl carbon would involve a diastereoselective
hydrogenation of the aminophosphonate 7b. As
a consequence, it appeared that the concept of
1,3-allylic strain could not be applied to the hydro-
genation of the 3-aminobutenyl phosphonate 7b.
Because the natural metabolites of the sphin-
gomyelin cycle include either a carbohydrate moi-
ety or a phosphorylated group linked to a sphingo-
sine unit, the synthesis of aminophosphonates with
a glycosyl moiety represents an interesting possibil-
ity. With this aim, we have also studied the catalytic
hydrogenation of 1e and 1f, a priori the most diffi-
cult examples, having steric hindrance on the phos-
phorus atom. It is noteworthy that these hydrogena-
tions carried out in the presence of palladium on
charcoal (10%), in EtOH, at room temperature were
The various compounds summarized in Table 1
demonstrated the generality of the method. 3-amino-
1-alkenylphosphonates bearing linear (1a and 1b
R1 = Me; 1a–1d, R2 = H, Me; 1a–1d, R3 = Et) and
i
ramified (1c, R1 = Bn; 1d, R1 = Bu) substituents
were compatible with the procedure. The product
1 was obtained satisfactorily with 57%–70% overall
yield after chromatography.
With the complete one-pot synthesis of 3-amino-
1-alkenylphosphonates 1 in hand, our attention
was turned to the possible preparation of the
first P-mono and then P,P-diglycosyl 3-amino-1-
alkenylphosphonates 1e–1g in this way.
The methodology used ethyl or D-ribosyl phos-
phorodichloridate as dichlorophosphorylated sub-
strate 4 (R3 = Et, rib, Z = Cl) and subsequently pro-
tected D-galactose as nucleophile (R4 = gal). The in-
corporation of one or two glycosyl residues smoothly
modified the efficiency of the procedure. The sequen-
tial in situ reaction led to 1e–1g with reasonable
yields (50%–42%). The regioselectivity of the reac-
tion was shown to be in favor of alkenes 1e–1g:
clearly the steric hindrance of the glycosyl residues
oriented the regioselectivity of the olefination and
allowed the exclusive removal of the diethyl phos-
phono group.
The reaction led to the creation of a phospho-
rus stereogenic center, and both diastereomers were
observed by 31P and 13 C NMR (ratio 1/1).
This sequential in situ reaction proved to be
an efficient synthetic method for the preparation of
functional aminoalkenylphosphonates 1.
TABLE
alkenylphosphonates 1
2 Catalytic hydrogenation of the 3-amino-1-
Diastereomeric
ratio
Compound R1 R2
R3
Yield%
7a
7b
7c
7d
Me
H
Et
Et
Et
Et
–
1/1
–
96
95
97
96
Me Me
Bn
H
H
i Bu
–
7e
Me
Bn
H
1/1
1/1
95
In addition, the preparation of aminoalkenyl-
phosphonates 1e–1g with a chiral phosphorus atom
confirmed the synthetic potential of the method and
the obtained compounds are of particular interest
for further biological applications.
7f
H
93
Heteroatom Chemistry DOI 10.1002/hc

Lithiated Alkylidenebis(phosphonates) 465
very efficient (93%–95%). 31P NMR of the galactosyl
aminophosphonates 7e and 7f indicated the pres-
ence of two diastereomers (diastereomeric ratio 1/1).
In summary, we developed a rapid and efficient
one-step synthesis of various aminoalkenylphos-
phonates starting from readily available phos-
phonates and phosphorochloridates. In addition,
the presented methodology allowed the prepara-
tion of the P-mono and P,P-diglycosyl-3-amino-1-
alkenylphosphonates.
Moreover, the saturated α-aminophosphonates
can be obtained easily by the catalytic hydrogenation
of aminoalkenylphosphonates. These compounds
are important building blocks in organic synthesis
and in the preparation of biologically active com-
pounds.
After that time, the reaction was again cooled down
to −70◦C and then the appropriate aminoaldehyde 3
(3.6 mmol, in 10 mL of dry THF) was added drop-
wise. After the addition was complete, the reaction
was left to warm slowly to r.t. and then stirred at that
temperature over a period of 12 h. After that time, the
reaction was quenched with water (20 mL). The or-
ganic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 30 mL). The combined
organic phases were dried (Na2SO4) and filtered, and
the solvent was removed on the rotary evaporator af-
fording the crude product that was further purified
by column chromatography.
Route B. To a dry 100-mL four-necked flask
equipped with a thermometer and dropping funnel,
dry THF (10 mL) was added and after cooling down
to −50◦C an n-BuLi (6.0 mL, 9.0 mmol, 1.5 M in hex-
ane) was gradually injected. This mixture was cooled
down to −78◦C before adding dropwise the solution
of (EtO)2P(O)CH3 5 (1.32 mL, 9.0 mmol, in 10 mL of
dry THF). After stirring, the reaction mixture for 30
min. at −78◦C, the solution of ZP(O)Cl2 4 (4.5 mmol,
in 10 mL of dry THF) was added dropwise, and the
stirring was continued for 2.5 h at that temperature.
After that time, a solution of appropriate alcohol (4.5
mmol, in 10 mL of dry THF) was added dropwise
and after stirring for 15 min at −78◦C the reaction
mixture was allowed to warm slowly to r.t. over a
period of 4 h. Then the reaction mixture was again
cooled down to −78◦C and LDA (3.6 mmol) was
gradually injected and after 20 min the appropriate
aminoaldehyde 3 (3.6 mmol, in 10 mL of dry THF)
was added dropwise. The reaction mixture was left
to warm to r.t. and then stirred at that temperature
over a period of 12 h. After that time, the reaction was
cooled down to −50◦C and quenched with water (15
mL). The organic layer was separated, and the aque-
ous layer was extracted with CH2Cl2 (3 × 30 mL).
The combined organic phases were dried (Na2SO4)
and filtered, and the solvent was removed on the
rotary evaporator affording the crude product that
was further purified by column chromatography.
EXPERIMENTAL
NMR experiments were recorded on Bruker spec-
trometers (AM 400, DRX 400). Chemical shifts (δ)
are reported in ppm and referenced to initial TMS (δ
1
0.0) for H NMR and CDCl3 (δ 77.0) for 13C NMR;
coupling constants (J) are quoted in hertz; two-
dimensional techniques were also used to assist in
structural elucidation. Diastereomer ratios were de-
termined on the basis of 31P NMR of the crude prod-
ucts. IR spectra were recorded on a Nicolet 210 FT-
IR spectrometer, and only the most representative
frequencies (cm−1) are reported. Mass spectra (ESI)
were obtained with LCM Waters-Micromass/zq spec-
trometer. Merck silica gel 60 (230–400 mesh) was
used as stationary phase for column chromatogra-
phy. TLC (Merck Kieselgel 60, F254) was viewed us-
ing a UV light (254 nm). Optical rotations were mea-
sured on Bellingham-Stanley ADP 220 polarimeter.
All reactions were conduced in oven-dried glassware
under inert atmosphere of nitrogen. All solvents were
purified according to standard procedures.
Preparation of γ -Aminovinylphosphonates 1
Route A. A 100-mL four-necked flask equipped
with a thermometer and dropping funnel, was
charged with a solution of (EtO)2P(O)CH2R2 5 (3.6
mmol in 10 mL of dry THF) and after cooling down
to −78◦C an LDA (7.2 mmol) was gradually injected.
The reaction mixture was allowed to warm to −70◦C
and stirred at that temperature for 1h. After that time
a solution of (EtO)2P(O)Cl 4 (0.52 mL, 3.6 mmol, in
10 mL of dry THF) was added dropwise. The mix-
ture was stirred for 2 h at −70◦C, then allowed to
warm to −50◦C and stirred, for 1 h at that tem-
perature before warming to room temperature (r.t.),
where the mixture was stirred for an additional 1 h.
Compound 1a. Colourless oil; Rf (0.21
1
AcOEt/hexane 8:1); [α]23D = −22.0 (c 0.5, CH2Cl2) H
NMR (CDCl3) δH (ppm): 6.73–6.62 (m, 1H, CH ),
5.73 (m, 1H, P(O)CH ), 4.63 (bs, 1H, NH), 4.34 (bs,
1H, CH), 4.08–4.01 (m, 4H, (OCH2CH3)2, 1.41 (s, 9
3
H, C(CH3)3), 1.29 (t, 6 H, (OCH2CH3)2, JHH = 8.7
4
Hz), 1.29 (d, 3 H, CH3, JHH = 4.5 Hz). 13C NMR
(CDCl3; 100 MHz) δC (ppm): 154.86 (s, NHCO),
153.63 (d, CH , 2 JCP = 5.1 Hz), 116.58 (d, CH , 1 JCP
3
= 187 Hz), 61.77 (s, OCH2), 48.27 (d, CH, JCP
=
21.8 Hz), 28.29 (s, C(CH3)3), 20.04 (s, CH3), 16.35 (d,
Heteroatom Chemistry DOI 10.1002/hc

466 Grison and Olszewski
CH2CH3, 3 JCP = 6.4 Hz). 31P NMR (CDCl3; 170 MHz)
δP (ppm): 19.1 (s). IR, νmax (film) cm−1: 3283 (NH),
1716 (C O), 1634 (C C), 1029 (P O), 973 (P O).
SM (ESI > 0.40V): 330.3 [M + Na]+.
3272 (NH), 1721 (C O), 1629 (C C), 1024 (P O),
963 (P O). SM (ESI > 0.40V): 372.3 [M + Na]+.
Compound 1e (diastereomers). Colourless oil;
Rf (0.45 AcOEt/hexane 4:1), [α]23D = −37.50 (c 0.8,
1
CH2Cl2), H NMR (CDCl3) δH (ppm): 6.69–6.55 (m,
Compound 1b. Colourless oil; Rf (0.38 AcOEt/
1H, CH ), 5.67–5.57 (m, 1H, P(O)CH ), 5.52 (d,
1
Hexane 4:1); [α]23D = −6.0 (c 1.0, CH2Cl2) H NMR
3
1H, H1, JHH = 5.2 Hz), 4.90 (bs, 1H, NH), 4.62–
3
(CDCl3) δH (ppm): 6.34 (dd, 1H, CH , JHH
=
4.59 (m, 1H, CH), 4.56–4.53 (m, H2, 1H), 4.28–3.91
(m, 7H, H3, H4, H5, OCH2CH3, OCH2Gal), 1.48 (s,
3H, CH3), 1.36 (s, 3H, CH3), 1.34 (s, 9H, C(CH3)3),
1.25 (s, 3H, CH3), 1.24 (s, 3H, CH3), 1.22–1.19 (m,
3H, OCH2CH3), 1.10–1.07 (m, 3H, CH3). 13C NMR
(CDCl3; 100 MHz) δC (ppm): diastereomer 1: 155.62
5.25 Hz), 4.97 (bs, 1H, NH), 4.47 (bs, 1H, CH), 4.03–
3.92 (m, 4H, (OCH2CH3)2), 1.82 (d, 3H, CH3 C ,
4 JHH = 9.25 Hz), 1.35 (s, 9H, C(CH3)3), 1.26–1.21 (m,
6H, (OCH2CH3)2), 1.15 (d, 3H, CH3, 4 JHH = 4.25 Hz).
13C NMR (CDCl3; 100 MHz) δC (ppm): 154.98 (s,
2
NHCO), 147.43 (d, CH , JCP = 8.0 Hz), 125.74 (d,
2
(s, NHCO), 151.97 (d, CH , JCP = 5.2 Hz), 117.81
1
CH , JCP = 175.5 Hz), 61.66 (s, OCH2), 48.46 (d,
(d, CH , 1 JCP = 182 Hz), 109.74 (s, C(CH3)2), 108.83
(s, C(CH3)2), 96.24 (s, C1), 70.67 (s, C4), 70.45 (s, C3),
70.32 (s, C2), 67.37 (d, C5, 3 JCP = 5.8 Hz), 64.65 (d, C6,
2 JCP = 5.0 Hz), 61.90 (m, OCH2), 47.05 (bs, CH), 28.40
(s, C(CH3)3), 26.00 (s, CH3), 25.90 (s, CH3), 24.95
(s, CH3), 24.47 (s, CH3), 21.30 (s, CH3), 16.42 (m,
CH2CH3). diastereomer 2: 155.50 (s, NHCO), 151.95
3
CH, JCP = 21.6 Hz), 28.26 (s, C(CH3)3), 20.28 (s,
3
CH3), 16.25 (d, CH2CH3, JCP = 6.1 Hz), 12.59 (d,
CH3 C , 2 JCP = 9.6 Hz). 31P NMR (CDCl3; 170 MHz)
δP (ppm): 21.2 (s). IR, νmax (film) cm−1: 3200 (NH),
1705 (C O), 1639 (C C), 1000 (P O), 970 (P O).
SM (ESI > 0.40V): 344.3 [M + Na]+.
2
1
(d, CH , JCP = 4.9 Hz), 117.78 (d, CH , JCP = 184
Hz), 109.74 (s, C(CH3)2), 108.83 (s, C(CH3)2), 96.24
(s, C1), 70.67 (s, C4), 70.45 (s, C3), 70.32 (s, C2), 67.67
Compound 1c. Colourless oil; Rf (0.35
AcOEt/hexane 2:1), [α]23D = −6.0 (c 0.5, CH2Cl2),
1H NMR (CDCl3) δH (ppm): 7.24–7.08 (m, 5H,
ArH), 6.70–6.60 (m, 1H, CH ), 5.65–5.60 (m, 1H,
P(O)CH ), 4.53 (bs, 2H, NH, CH), 3.98–3.89 (m,
4H, (OCH2CH3)2), 2.82 (bs, 2H, CH2Ph), 1.32 (s,
9H, C(CH3)3), 1.23–1.18 (m, 6H, (OCH2CH3)2).
13C NMR (CDCl3; 100 MHz) δC (ppm): 154.92 (s,
3
2
(d, C5, JCP = 6.0 Hz), 65.47 (d, C6, JCP = 5.5 Hz),
61.25 (m, OCH2), 47.07 (bs, CH), 28.40 (s, C(CH3)3),
26.00 (s, CH3), 25.90 (s, CH3), 24.95 (s, CH3), 24.47 (s,
CH3), 21.30 (s, CH3), 16.42 (m, CH2CH3). 31P NMR
(CDCl3; 170 MHz) δP (ppm): 18.7 (s) and 18.3 (s)
(in ratio 1:1). IR, νmax (film) cm−1: 3207 (NH), 1720
(C O), 1578 (C C), 1254 (P O), 978 (P O). SM (ESI
>0.40V): 544.2 [M + Na]+.
2
NHCO), 151.87 (d, CH , JCP = 5.4 Hz), 136.37,
1
129.41, 128.55, 126.85 (Carm), 117.96 (d, CH , JCP
= 185 Hz), 61.81 (s, OCH2), 53.65 (bs, CH), 40.61 (s,
CH2Ph), 28.26 (s, C(CH3)3), 16.34 (d, CH2CH3, 3 JCP
=
Compound 1f (diastereomers). Colourless oil;
Rf (0.47 AcOEt/hexane 4:1), [α]23D = −29.28 (c 1.4,
5.8 Hz). 31P NMR (CDCl3; 170 MHz) δP (ppm): 18.1
(s). IR, νmax (film) cm−1: 3277 (NH), 1721 (C O),
1634 (C C), 1024 (P O), 963 (P O). SM (ESI >
0.40V): 406.4 [M + Na]+.
1
CH2Cl2), H NMR (CDCl3) δH (ppm): 7.24–7.08 (m,
5H, ArH), 6.70–6.59 (m, 1H, CH ), 5.70–5.56 (m, 1H,
P(O)CH ), 5.46 (d, 1H, H1, 3 JHH = 5.2 Hz), 4.76–4.72
(m, 1H, NH), 4.54–4.51 (m, 1H, CH), 4.25–4.23 (m,
H2, 1H), 4.20–3.90 (m, 7H, H3, H4, H5, OCH2CH3,
OCH2Gal), 2.82–2.77 (m, 2H, CH2Ph), 1.45 (s, 3H,
CH3), 1.44 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.31 (s,
9H, C(CH3)3), 1.25 (s, 3H, CH3), 1.22–1.17 (m, 6H,
OCH2CH3). 13C NMR (CDCl3; 100 MHz) δC (ppm):
diastereomer 1: 154.96 (s, NHCO), 151.96 (d, CH ,
2 JCP = 5.0 Hz), 136.37, 129.38 128.83, 126.77 (Carm),
117.80 (d, CH , 1 JCP = 185 Hz), 109.74 (s, C(CH3)2),
108.83 (s, C(CH3)2), 96.22 (s, C1), 70.66 (s, C4), 70.60
Compound 1d. Colourless oil; Rf (0.44
AcOEt/hexane 2:1), [α]23D = −18.0 (c 0.5, CH2Cl2), 1H
NMR (CDCl3) δH (ppm): 6.64–6.53 (m, 1H, CH ),
5.75–5.65 (m, 1H, P(O)CH ), 4.51 (bs, 1H, NH),
4.24 (bs, 1H, CH), 4.01–3.98 (m, 4H, (OCH2CH3)2),
1.64–1.59 (m, 1H, CH(CH3)2), 1.36 (s, 9H, C(CH3)3),
1.20–1.25 (m, 2H, CHCH2), 1.26 (t, 6H, (OCH2CH3)2),
3
3 JHH = 9.0 Hz), 0.87 (d, 6H, CH(CH3)2, JHH = 4.25
Hz). 13C NMR (CDCl3; 100 MHz) δC (ppm): 155.05
2
3
(s, NHCO), 153.40 (d, CH , JCP = 5.0 Hz), 116.72
(s, C3), 70.38 (s, C2), 67.06 (d, C5, JCP = 6.6 Hz),
1
(d, CH , JCP = 186 Hz), 61.69 (s, OCH2), 51.11
64.35 (d, C6,2 JCP = 5.6 Hz), 61.75 (m, OCH2), 53.53
(bs, CH), 40.61 (bs, CH2Ph), 28.24 (s, C(CH3)3), 25.99
(s, CH3), 25.91 (s, CH3), 24.92 (s, CH3), 24.42 (s,
CH3), 16.30 (m, CH2CH3). diastereomer 2: 154.96
3
(d, CH, JCP = 21.5 Hz), 43.41 (s, CHCH2), 28.24
(s, C(CH3)3), 24.66 (s, CH(CH3)2), 22.71 (s, (CH3)2),
3
16.29 (d, CH2CH3, JCP = 6.3 Hz). 31P NMR (CDCl3;
170 MHz) δP (ppm): 18.7 (s). IR, νmax (film) cm−1:
(s, NHCO), 152.12 (d, CH , JCP = 5.0 Hz), 136.37,
2
Heteroatom Chemistry DOI 10.1002/hc

Lithiated Alkylidenebis(phosphonates) 467
1
ing material), and after 12 h under H2 (30 bars) the
mixture was filtered through a celite and evaporated
to give crude product that did not required any fur-
ther purification.
129.38 128.83, 126.77 (Carm), 117.40 (d, CH , JCP
=
184 Hz), 109.74 (s, C(CH3)2), 108.83 (s, C(CH3)2),
96.22 (s, C1), 70.66 (s, C4), 70.60 (s, C3), 70.38 (s,
C2), 67.41 (d, C5, JCP = 6.4 Hz), 64.83 (d, C6,2 JCP
3
= 5.4 Hz), 61.97 (m, OCH2), 53.53 (bs, CH), 40.61
(bs, CH2Ph), 28.24 (s, C(CH3)3), 25.99 (s, CH3), 25.91
(s, CH3), 24.92 (s, CH3), 24.42 (s, CH3), 16.30 (m,
CH2CH3). 31P NMR (CDCl3; 170 MHz) δP (ppm): 18.9
(s) and 18.4 (s) (in ratio 1:1). IR, νmax (film) cm−1:
3257 (NH), 1715 (C O), 1582 (C C), 1031 (P O),
976 (P O). SM (ESI > 0.40V): 620.6 [M + Na]+.
Compound 7a. Colourless oil; [α]23D = −6.36 (c
1
1.1, CH2Cl2) H NMR (CDCl3) δH (ppm): 4.44 (bs,
1H, NH), 4.07–3.97 (m, 4H, (OCH2CH3)2), 3.59
(bs, 1H, CH), 1.80–1.50 (m, 4H, CH2CH2), 1.36 (s,
3
9H, C(CH3)3), 1.27 (t, 6H, (OCH2CH3)2), JHH
=
8.0 Hz), 1.08 (d, 3H, CH3, JHH = 4.0 Hz). 13C NMR
4
(CDCl3; 100 MHz) δC (ppm): 155.40 (s, NHCO), 61.54
3
(s, OCH2), 46.94 (d, CH, JCP = 17.8 Hz), 29.88
Compound 1g (diastereomers). Colourless oil;
Rf (0.35 AcOEt/hexane 4:1), [α]23D = −51.67 (c 0.6,
2
(d, CH2, JCP = 4.5 Hz), 28.35 (s, C(CH3)3), 23.12
(d, CH2P(O)1 JCP = 141 Hz), 21.09 (s, CH3), 16.44
1
CH2Cl2), H NMR (CDCl3) δH (ppm): 6.76–6.62 (m,
(d, CH2CH3, JCP = 5.9 Hz). 31P NMR (CDCl3; 170
3
1H, CH ), 5.81–5.70 (m, 1H, P(O)CH ), 5.49–5.46
(m, 1H, H1), 4.88 (s, 1H, H1Rib), 4.70 (bs, 1H, NH),
4.67–4.62 (m, 2H, H2, H4Rib), 4.55–4.50 (m, 1H,
H3Rib), 4.34 (bs, 1H, CH), 4.26–4.20 (m, 1H, H2Rib),
4.219–3.90 (m, 7H, H3, H4, H5 OCH2Rib, OCH2Gal),
3.23 (s, 3H, OCH3), 1.47 (s, 3H, CH3), 1.46 (s, 3H,
CH3), 1.40 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.37 (s,
9H, C(CH3)3), 1.26 (s, 3H, CH3), 1.24 (s, 3H, CH3),
1.98–1.18 (m, 3H, CH3). 13C NMR (CDCl3; 100 MHz)
δC (ppm): diastereomer 1: 154.90 (s, NHCO), 154.36
MHz) δP (ppm): 32.2 (s). IR, νmax (film) cm−1: 3288
(NH), 1710 (C O), 1055 (P O), 958 (P O). SM (ESI
> 0.40V): 332.3 [M + Na]+.
Compound 7b (diastereomers). Colourless oil;
[α]23D = −3.0 (c 1.0, CH2Cl2) 1H NMR (CDCl3) δH
(ppm): 4.63 (bs, 1H, NH), 4.44 (bs, 1H, CHP(O)),
4.83–3.98 (m, 4H, (OCH2CH3)2), 3.73 (bs, 1H, NCH),
1.85–1.65 (m, 2H, CH2), 1.3 (s, 9H, C(CH3)3),
1.27–1.23 (m, 6H, (OCH2CH3)2), 1.2–1.1 (m, 3H,
CHCH3P(O) diastereomer 1), 1.00–1.05 (m, 3H,
2
1
(d, CH , JCP = 5.0 Hz), 116.13 (d, CH , JCP = 182
Hz), 112.57 (s, C(CH3)2), 109.62 (s, C1Rib), 109.74
(s, C(CH3)2), 108.83 (s, C(CH3)2), 96.22 (s, C1), 85.09
(s, C2Rib), 81.66 (s, C3Rib), 79.66 (s, C4Rib), 70.69 (s,
C4), 70.64 (s, C3), 70.36 (s, C2), 67.17 (s, C5Rib), 67.38
CHCH3P(O) diastereomer 2), 1.04 (d, 3H, CH3, 4 JHH
=
4.0Hz). 13C NMR (CDCl3; 100 MHz) δC (ppm): di-
astereomer 1: 155.57 (s, NHCO), 61.70 (s, OCH2),
3
3
(d, C5, JCP = 5.7 Hz), 65.23 (d, C6,2 JCP = 5.3 Hz),
44.73 (bs, CHP(O)), 48.70 (d, CH, JCP = 15.5 Hz),
55.02 (s, OCH3), 48.10 (bs, CH), 28.35 (s, C(CH3)3),
25.99 (s, CH3), 24.95 (s, CH3), 24.42 (s, CH3), 20.17
(s, CH3). diastereomer 2: 154.90 (s, NHCO), 154.36
37.45 (s, CH2), 28.37 (s, C(CH3)3), 20.14 (s, CH3),
3
16.47 (d, (OCH2CH3)2, JCP = 6.0 Hz), 13.51 (d,
2
CH3CP(O), JCP = 9.0 Hz). diastereomer 2: 155.12
2
1
(d, CH , JCP = 5.0 Hz), 116.13 (d, CH , JCP = 182
Hz), 112.57 (s, C(CH3)2), 109.62 (s, C1Rib), 109.74
(s, C(CH3)2), 108.83 (s, C(CH3)2), 96.22 (s, C1), 85.09
(s, C2Rib), 81.66 (s, C3Rib), 79.66 (s, C4Rib), 70.69 (s,
C4), 70.64 (s, C3), 70.36 (s, C2), 67.17 (s, C5Rib), 67.19
(s, NHCO), 61.70 (s, OCH2), 44.73 (bs, CHP(O)),
3
48.70 (d, CH, JCP = 15.5 Hz), 37.30 (s, CH2), 28.37
(s, C(CH3)3), 20.14 (s, CH3), 16.47 (d, (OCH2CH3)2,
3 JCP = 6.0 Hz), 12.94 (d, CH3CP(O), 2 JCP = 9.0 Hz). 31
P
NMR (CDCl3; 170 MHz) δP (ppm): 35.1 (s) and 35.32
(s) (in ratio 1:1). IR, νmax (film) cm−1: 3288 (NH), 1710
(C O), 1055 (P O), 958 (P O). SM (ESI > 0.40V):
346.3 [M + Na]+.
(d, C5, JCP = 6.0 Hz), 64.97 (d, C6,2 JCP = 6.1 Hz),
3
55.02 (s, OCH3), 48.10 (bs, CH), 28.35 (s, C(CH3)3),
26.39 (s, CH3), 25.99 (s, CH3), 24.95 (s, CH3), 24.42
(s, CH3), 20.17 (s, CH3). 31P NMR (CDCl3; 170 MHz)
δP (ppm): 19.8 (s) and 19.2 (s) (in ratio 1:1). IR, νmax
(film) cm−1: 3157 (NH), 1721 (C O), 1557 (C C),
1070 (P O), 1004 (P O). SM (ESI > 0.40V): 702.6
[M + Na]+.
Compound 7c. Colourless oil; [α]23D = −1.92 (c
0.52, CH2Cl2), 1H NMR (CDCl3) δH (ppm): 7.23–
7.09 (m, 5H, ArH), 4.39 (bs, 1H, NH), 4.04–3.94
(m, 4H, (OCH2CH3)2), 3.75 (bs, 1H, CH), 2.73–2.64
(m, 2H, CH2Ph), 1.80–1.50 (m, 4H, CH2CH2), 1.32
(s, 9H, C(CH3)3), 1.25–1.21 (m, 6H, (OCH2CH3)2).
13C NMR (CDCl3; 100 MHz) δC (ppm): 155.53 (s,
NHCO), 137.66, 129.42, 128.44, 126.48 (Carm), 61.64
(s, OCH2), 53.25 (bs, CH), 41.45 (s, CH2Ph), 28.34
(s, C(CH3)3), 23.20 (s, CH2), 21.79 (s, CH2), 16.47 (d,
General Procedure for the Hydrogenolysis of the
Aminoalkenylphosphonates 1
Hydrogenolysis was carried out in standard condi-
tions using Pd/C 10% and H2 (30 bars). The starting
material was dissolved in dry EtOH (15 mL). Pd/C
was added (10% with respect to the mass of the start-
3
(OCH2CH3)2, JCP = 5.0 Hz). 31P NMR (CDCl3; 170
MHz) δP (ppm): 32.20 (s). IR, νmax (film) cm−1: 3283
Heteroatom Chemistry DOI 10.1002/hc

468 Grison and Olszewski
(s, 3H, CH3), 1.21–1.17 (m, 3H, OCH2CH3). 13C NMR
(CDCl3; 100 MHz) δC (ppm): diastereomer 1: 155.66 (s,
NHCO), 129.51, 129.41 128.43, 126.47 (Carm), 109.74
(s, C(CH3)2), 108.83 (s, C(CH3)2), 96.24 (s, C1), 70.77
(NH), 1710 (C O), 1034 (P O), 963 (P O). SM (ESI
> 0.40V): 408.1 [M + Na]+.
Compound 7d. Colourless oil; [α]23D = −16.36 (c
1
(s, C4), 70.69 (s, C3), 70.34 (s, C2), 67.30 (d, C5, 3 JCP
=
1.1, CH2Cl2), H NMR (CDCl3) δH (ppm): 4.33 (bs,
6.2 Hz), 64.76 (d, C6,2 JCP = 5.5 Hz), 61.70 (m, OCH2),
52.50 (bs, CH), 41.47 (bs, CH2Ph), 28.38 (s, C(CH3)3),
25.96 (s, CH3), 25.93 (s, CH3), 24.88 (s, CH3), 24.45
(s, CH3), 23.18 (s, CH2), 21.77 (s, CH2), 16.46 (m,
CH2CH3). diastereomer 2: 155.58 (s, NHCO), 129.51,
129.41 128.43, 126.47 (Carm), 109.74 (s, C(CH3)2),
108.83 (s, C(CH3)2), 96.24 (s, C1), 70.77 (s, C4), 70.69
1H, NH), 4.07–4.04 (m, 4H, (OCH2CH3)2), 3.62 (bs,
1H, CH), 1.76–1.52 (m, 5H, CH2CH2P(O), CH(CH3)2),
1.40 (s, 9H, C(CH3)3), 1.33 (t, 6H, (OCH2CH3)2),
3 JHH = 9.0 Hz), 1.26–1.20 (m, 2H, CHCH2), 0.89
(d, 6H, CH(CH3)2, 3 JHH = 4.25 Hz). 13C NMR (CDCl3;
100 MHz) δC (ppm): 155.64 (s, NHCO), 61.52 (s,
3
OCH2), 49.24 (d, CH, JCP = 21.0 Hz), 44.77 (s,
3
CHCH2), 28.35 (s, C(CH3)3), 24.71 (s, CH(CH3)2),
23.02 (s, (CH3)2), 22.18 (s, CH2), 21.50 (s, CH2), 16.46
(s, C3), 70.34 (s, C2), 67.37 (d, C5, JCP = 6.4 Hz),
64.20 (d, C6,2 JCP = 5.3 Hz), 61.70 (m, OCH2), 52.50
(bs, CH), 41.47 (bs, CH2Ph), 28.38 (s, C(CH3)3), 25.96
(s, CH3), 25.93 (s, CH3), 24.88 (s, CH3), 24.45 (s, CH3),
3
(d, (OCH2CH3)2, JCP = 6.0 Hz). 31P NMR (CDCl3;
170 MHz) δP (ppm): 32.58 (s). IR, νmax (film) cm−1:
3283 (NH), 1716 (C O), 1034 (P O), 968 (P O). SM
(ESI > 0.40 V): 374.2 [M + Na]+.
23.18 (s, CH2), 21.77 (s, CH2), 16.46 (m, CH2CH3). 31
P
NMR (CDCl3; 170 MHz) δP (ppm): 33.4 (s) and 32.6
(s) (in ratio 1:1). IR, νmax (film) cm−1: 3303 (NH), 1716
(C O), 1173 (P O), 986 (P O). SM (ESI > 0.40V):
622.6 [M + Na]+.
Compound 7e (diastereomers). Colourless oil;
1
[α]23D = −27.50 (c 0.4, CH2Cl2), H NMR (CDCl3) δH
3
(ppm): 5.52 (d, 1H, H1, JHH = 5.2 Hz), 4.93 (bs,
1H, NH), 4.56–4.53 (m, H2, 1H), 4.28–3.91 (m, 7H,
H3, H4, H5, OCH2CH3, OCH2Gal), 3.58 (bs, 1H, CH),
1.89–1.55 (m, 4H, CH2CH2), 1.47 (s, 3H, CH3), 1.37
(s, 3H, CH3), 1.36 (s, 9H, C(CH3)3), 1.28 (s, 3H, CH3),
1.26 (s, 3H, CH3), 1.25–1.22 (m, 3H, OCH2CH3), 1.08–
1.06 (m, 3H, CH3). 13C NMR (CDCl3; 100 MHz) δC
(ppm): diastereomer 1: 155.63 (s, NHCO), 109.71 (s,
REFERENCES
[1] For
recent
book
and
reviews
on
α-
aminophosphonates see: (a) Kuhkhar, V. P.;
Hudson, H. R. (Eds.). In Aminophosphonic and
Aminophosphinic Acids. Chemistry and Biological
Activity; Wiley: Chichester, UK, 2000; (b) Kafarski,
P.; Lejczak, B. Cur Med Chem: Anti-Cancer Agents
2001, 1, 301–312; (c) Grembecka, J.; Kafarski, P.
Mini-Rev Med 2001, 1 133–144. For reviews on
γ -aminophosphonates, see: (a) Kafarski, P.; Lejczak,
B. Phosphorus, Sulfur, Silicon Relat Elem 1991, 63,
193–215; (b) Hoagland, R. E. Am Chem Soc Symp
Ser 1988, 380, 182; (c) Issleib, K. Nachr Chem Tech
Lab 1987, 35, 1037.
C(CH3)2), 108.79 (s, C(CH3)2), 96.26 (s, C1), 70.66 (s,
3
C4), 70.43 (s, C3), 70.34 (s, C2), 67.34 (d, C5, JCP
=
6.0 Hz), 64.70 (d, C6,2 JCP = 5.2 Hz), 61.96 (m, OCH2),
47.07 (bs, CH), 28.44 (s, C(CH3)3), 26.02 (s, CH3),
25.95 (s, CH3), 24.93 (s, CH3), 24.44 (s, CH3), 23.53
(s, CH2), 23.09 (s, CH2), 21.37 (s, CH3), 16.45 (m,
CH2CH3). diastereomer 2: 155.48 (s, NHCO), 109.71
(s, C(CH3)2), 108.79 (s, C(CH3)2), 96.26 (s, C1), 70.66
[2] For selected significant references, see: (a) Foss, F.
W.; Snyder, A. H.; Davis, M. D.; Rouse, M.; Okusa,
M. D.; Lynch, K. R.; Macdonald, T. L. Bioorg Med
Chem 2007, 15, 663–677; (b) Yan, L.; Hale, J. J.;
Lynch, C. C.; Budhu, R.; Gentry, A.; Mills, S. G.;
Hajdu, R.; Keohane, C. A.; Rosenbach, M. J.; Milligan,
J. A.; Shei, G-J; Chrebet, G.; Bergstrom, J.; Card, D.;
Rosen, H.; Mandala, S. M. Bioorg Med Chem Lett
2004, 14, 4861–4866; (c) Hale, J. J.; Neway, W.; Mills,
S. G.; Hajdu, R.; Keohane, C. A.; Rosenbach, M. J.;
Milligan, J. A.; Shei, G-J; Chrebet, G.; Bergstrom,
J.; Card, D.; Koo, G. C.; Koprak, S. L.; Jackson, J.
J.; Rosen, H.; Mandala, S. Bioorg Med Chem Lett
2004, 14, 3351–3355; (d) Sun, C.; Bittman, R. J Org
Chem 2004, 69, 7694–7699; (e) Schick, A.; Kolter, T.;
Giannis, A.; Sandohoff, K. Tetrahedron 1995, 51, 41,
11207–11218.
[3] Lu, X.; Byun, H-S.; Bittman, R. J Org Chem 2004, 69,
5433–5438.
[4] (a) Hakogi, T.; Monden, Y.; Taichi, M.; Iwama, S.;
Fujii, S.; Ikeda, K.; Katsumara, S. J Org Chem 2002,
67, 4839–4846; (b) Hakogi, T.; Monden, Y.; Iwama, S.;
Fujii, S.; Katsumara, S. Org Lett 2000, 2(17), 2627–
2629.
(s, C4), 70.43 (s, C3), 70.34 (s, C2), 67.83 (d, C5, 3 JCP
=
6.2 Hz), 65.49 (d, C6,2 JCP = 5.3 Hz), 61.12 (m, OCH2),
47.07 (bs, CH), 28.44 (s, C(CH3)3), 26.02 (s, CH3),
25.95 (s, CH3), 24.93 (s, CH3), 24.44 (s, CH3), 23.53
(s, CH2), 23.09 (s, CH2), 21.85 (s, CH3), 16.11 (m,
CH2CH3). 31P NMR (CDCl3; 170 MHz) δP (ppm): 33.4
(s) and 32.7 (s) (in ratio 1:1). IR, νmax (film) cm−1:
1716 (C O), 1250 (P O), 1004 (P O). SM (ESI >
0.40V): 546.5 [M + Na]+.
Compound 7f (diastereomers). Colourless oil;
1
[α]23D = −27.00 (c 1.0, CH2Cl2), H NMR (CDCl3) δH
(ppm): 7.23–7.09 (m, 5H, ArH), 5.47 (d, 1H, H1, 3 JHH
= 5.0 Hz), 4.60–4.55 (m, H2, 1H), 4.53 (bs, 1H, NH),
4.26–3.95 (m, 7H, H3, H4, H5, OCH2CH3, OCH2Gal),
4.77 (bs, 1H, CH), 2.70–2.68 (m, 2H, CH2Ph), 1.80–
1.47 (m, 4H, CH2CH2), 1.36 (s, 3H, CH3), 1.32 (s, 9H,
C(CH3)3), 1.25 (s, 3H, CH3), 1.24 (s, 3H, CH3), 1.22
Heteroatom Chemistry DOI 10.1002/hc

Lithiated Alkylidenebis(phosphonates) 469
[5] (a) Merrill, A. H.; Sandhoff, K. In: Biochemistry of
Lipids and Membranes; Vance, D. E.; Vance, J. E.
(Eds.); Elsevier: Amsterdam, the Netherlands 2002;
pp. 373–407; (b) Sweeley, C. C. In Biochemistry of
Lipids and Membranes; Vance, D. E.; Vance, J. E.
Eds.; Elsevier: Amsterdam, the Netherlands 1991;
pp. 327–361.
[6] (a) Doherty, G. A.; Forrest, M. J.; Hajdu, R.; Hale,
Je J.; Li, Z.; Mandala, S. M.; Mills, S G.; Rosen,
H.; Scolnick PCT Int. Appl. 2003 WO 2003061567
A2 20030731; Chem Abs 2003, 139, 149413; (b) Van
Brocklyn, J. R.; Lee, M-J.; Menzeleev, R.; Olivera, A.;
Edsall, L.; Cuvillier, O.; Thomas, D. M.; Coopman, P.
J. P.; Thangada, S.; Liu, C. H.; Hla, T.; Spiegel, S. J
Cell Biol 1998, 142, 1, 229–240 and references cited
therein.
E. L.; Binford, S. L.; Harr, J. E. V.; DeLisle, D. M.;
Worland, S. T. J Med Chem 1998, 41, 2806–2818.
[15] (a) Ohler, E.; Zbiral, E. Chem Ber 1991, 124, 175; (b)
Ohler, E.; Zbiral, E. Synthesis 1991, 357–361.
[16] (a) De la Cruz, A.; He, A.; Thanavaro, A.; Yan, B.;
Spilling, C. D.; Rath, N. P. J Organomet Chem 2005,
690, 2577–2592; (b) Oehler, E.; Kanzler, S. Phospho-
rus, Sulfur Silicon 1996, 112, 71–90; (c) Zhu, J.; Lu,
X. J Chem Soc Chem Commun 1987, 17, 1318–1319.
[17] Ohler, E.; Kotzinger, S. Synthesis 1993, 5, 497–502
and references cited therein.
[18] Ohler, E.; Kotzinger, S. Liebigs Ann Chem 1993, 269.
[19] Al Quntar, A. A. A.; Dembitsky, V. M.; Srebnik, M.
Org Lett 2003, 5, 357–359.
[20] Tabcheh, M.; Pappalardo, L.; Roumestant, M. L.;
Viallefont, P. Amino Acids 1992, 2, 191–193.
[7] For a recent review, see Spiegel, S.; Milstien, S. J. Biol
Chem 2002, 277, 29, 25851–25854.
[8] Heasley, B. H.; Jarosz, R.; Carter, K. M.; Van, S. J.;
Lynch, K. R.; Macdonald, T. L. Biorg Med Chem Lett
2004, 14, 4069–4074.
[9] (a) Vo-Quang, Y.; Gravey, A. M.; Simonneau, R.; Vo-
Quang, L.; A.M. Lacoste, A.M.; Le Goffic F. Tetrahe-
dron Lett 1987, 28, 6167–6170.
[21] (a) Grison, C.; Coutrot,P.; Gene`ve, S.; Didierjean,
C.; Marraud, M. J Org Chem 2005, 70(26), 10753–
10764; (b) Grison, C.; C. Comoy, C.; Chatenet, D.;
Coutrot, P. J Organomet Chem 2002, 662, 83–97;
(c) Grison, C.; Geneve, S.; Coutrot, P. Tetrahe-
dron Lett 2001, 3831–3834; (d) Grison, C.; Gene`ve,
S.; Halbin, E.; Coutrot, P. Tetrahedron 2001, 57,
4903–4923; (e) Coutrot, P.; Grison, C.; Gene`ve, S.;
Didierjean, C.; Aubry, A.; Vicherat, A.; Marraud, M.
Lett Peptide Sci 1997, 4, 415–422; (f) Coutrot, P.;
Grison, C.; Lecouvey, M. Phosphorus Sulfur Silicon
1994, 97, 47–56; (g) Coutrot, P.; Grison, C.; Gerardin-
Charbonnier, C.; Lecouvey, M. Tetrahedron Lett
1993, 34, 2767–2770; (h) Coutrot, P.; Boulliung,
N.; Grison, C. M. Eur Pat Appl 1993, 521752 A1
19930107; Chem Abs 1993, 119, 160985; (i) Coutrot,
P.; Boulliung, N.; Grison, C. Synthesis 1991, 23–25;
(j) Coutrot, P.; Grison, C.; Sauvetre, R. J.
Organometal Chem 1987, 332, 1–8; (k) Coutrot, P.;
Grison, C.; Youssefi-Tabrizi, M. Synthesis 1987, 2,
169–170.
[22] (a) Grison, C.; Chibli, H.; Barthes, N.; Coutrot, P. J.
Org Chem 2006, 71, 7978–7988; (b) Grison, C.; Joliez,
S.; De Clercq E.; Coutrot, P. Carbohydr Res 2006, 341,
1117–1129; (c) Grison, C.; Letondor; C., Chibli, H.; P.
Coutrot, P. Tetrahedron Lett 2005, 46, 6525–6528.
[23] (a) Pihko, P. M.; Koskinen, A. M. P. J Org Chem
1998, 63, 92–98; (b) Grison, C.; Geneve, S.; Claudel,
S.; Coutrot, P.; Marraud, M. Tetrahedron Lett 2003,
2297–2300.
[10] Chakravarty, P. K.; Greenlee, W. J.; Parsons, W. H.;
Patchett, A. A.; Combs, P.; Roth, A.; Bush, R. D.;
Mellin, T. N. J. Med Chem 1989, 32, 1886–1890.
[11] (a) Niestroj, A. J.; Feussner, K.; Heiser, U.; Dando,
P. M.; Barrett, A. Gerhatz, B.; Demuth, H. U. Biol
Chem 2002, 383, 1205–1214; (b) David, C.; Bischoff,
L.; Roques, B. P.; Fournie´-Zaluski, M-C. Tetrahe-
dron 2000, 56, 209–215; (c) David, C.; Bischoff, L.;
Meudal, H.; Mothe´, A.; De Mota, N.; DaNascimento,
S.; Liorens-Cortes, C.; Roques, B. P.; Fournie´-Zaluski,
M-C. J Med Chem 1999, 42, 5197–5211.
[12] (a) Evans, R. H.; Francis, A. A.; Jones, A. W.; Smith,
D. A. S.; Watkins, J. C. Br J Pharmacol 1982, 75, 65;
(b) Davies, J.; Francis, A. A.; Jones, A. W.; Watkins, J.
C. Neurosci Lett 1981, 21, 77.
[13] Langlois, N.; Rojas-Rousseau, A.; Decavallas, O.
Tetrahedron: Asymmetry 1996, 7, 1095–1100.
[14] Dragovich, P. S.; Webber, S. E.; Babine, R. E.;
Fuhrman, S. A.; Patick, A. K.; Matthews, D. A.; Lee,
C. A.; Reich, S. H.; Prins, T. J.; Marakovits, J. T.;
Littlefield, E. S.; Zhou, R.; Tikhe, J.; Ford, C. E.;
Wallace, M. B.; Meador, J. W.; Ferre, R. A.; Brown,
Heteroatom Chemistry DOI 10.1002/hc