Synthesis of functionalized alkoxyalkylidene gem-bisphosphonates

Article abstract of DOI:10.1016/j.tet.2008.04.052

We report the synthesis of a series of new functionalized bisphosphonates and bisphosphonic acids with an alkoxy group fixed at the geminal carbon, which is proposed to increase their lipophilicity and so their bioavailability. Subsequently, the alkylation of these alkoxy bisphosphonates with allyl bromide is reported. The reactivity of the allyl group has been studied to give access to alkoxy bisphosphonates functionalized by diverse groups including alcohol, aldehyde, carboxylic acid, epoxide and amine.

Full text of DOI:10.1016/j.tet.2008.04.052

Tetrahedron 64 (2008) 6537–6543
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of functionalized alkoxyalkylidene gem-bisphosphonates
,
a
a
a
Jean-Pierre Haelters a , Helene Couthon-Gourves , Alan Le Goff , Gaelle Simon ,
*
´ `
`
a
b
`
Bernard Corbel , Paul-Alain Jaffres
a
´ ´
Laboratoire de Chimie Hetero-Organique, U.F.R. Sciences et Techniques, 6. av. Le GorgeudC.S. 93837, 29238 Brest Cedex 3, France
b CEMCA, UMR CNRS 6521, U.F.R. Sciences et Techniques, 6. av. Le GorgeudC.S. 93837, 29238 Brest Cedex 3, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the synthesis of a series of new functionalized bisphosphonates and bisphosphonic acids with
an alkoxy group fixed at the geminal carbon, which is proposed to increase their lipophilicity and so their
bioavailability. Subsequently, the alkylation of these alkoxy bisphosphonates with allyl bromide is re-
ported. The reactivity of the allyl group has been studied to give access to alkoxy bisphosphonates
functionalized by diverse groups including alcohol, aldehyde, carboxylic acid, epoxide and amine.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 26 January 2008
Received in revised form 10 April 2008
Accepted 14 April 2008
Available online 18 April 2008
Keywords:
Bisphosphonates
Bisphosphonic acids
Aminobisphosphonates
Alkoxy methylene bisphosphonates
1. Introduction
triggerable group like esters or amides. In this paper, we describe
the synthesis of new alkoxy bisphosphonates and we report their
Bisphosphonates represent an important class of pharmaco-
logically active molecules, which are widely used in the treatment
of various bone diseases, such as osteoporosis,1 Paget’s disease,2
hypercalcaemia3 and bone metastases secondary to breast cancer4
and prostate cancer.5 Recent studies have shown that anti-tumour
properties of bisphosphonates included inhibition of tumour cell
proliferation and invasion,6 inhibition of tumour cell adhesion to
bone,7 inhibition of angiogenesis8 or induction of apoptosis.9 Some
bisphosphonates also activate the gd T cell population, which
shows potential cytotoxic activity towards a broad spectrum of
tumours.10 Some others possess anti-inflammatory properties and
may be effective in the treatment of rheumatoid arthritis11 or ex-
hibit anti-parasitic activity.12
Due to their exceptional bone affinity, bisphosphonates can
serve also as drug carriers or prodrugs for bone diseases. For several
years, our laboratory has been studying this concept by developing
the chemistry of 1,1-gem-bisphosphonates functionalized de-
rivatives and their conjugation with different drugs.13
However, bisphosphonic acids and their conjugates are suffering
from their very low oral bioavailability14 due to their high hydro-
philicity. Consequently, to improve the lipophilic character of these
compounds, some authors15 have converted hydroxy or/and amino
group or phosphonic acid groups into an enzyme- or acid-
alkylation with allylbromide. Based on the reactivity of the allyl
group, the introduction of several functionalities, including alcohol,
aldehyde, carboxylic acid, epoxide and amine, is reported.
2. Results and discussion
In our laboratory, Sturtz and Ollivier16 synthesized alkoxy
bisphosphonate derivatives 2, and interestingly showed that the
increasing lipophilicity of the substituent R1 (R1¼Me, Bu) does not
reduce the osteotropism of these compounds. Following this
reported methodology, we have prepared (Scheme 1) a series of
compounds 2, including four new compounds (2c–2f), with dif-
ferent R1 substituents and have submitted them to deprotonation/
alkylation sequences.
O
O
(C2H5O)2P
R1O
(C2H5O)2P
(C2H5O)2P
R1O
(C2H5O)2P
OR1
i
ii
(C2H5O)2P
O
O
2
O
3
1
R1 = CH3
R1 = C10H21
R1 = C16H33
R1 = C6H5-CH2
R1 = C4H9
R1 = C6H13
Scheme 1. (i) LDA, THF, (C2H5O)2P(O)Cl, ꢀ78 ꢁC to 0 ꢁC and (ii) NaH, allyl bromide,
* Corresponding author.
E-mail address: jean-pierre.haelters@univ-brest.fr (J.-P. Haelters).
DMF, rt.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.052

6538
J.-P. Haelters et al. / Tetrahedron 64 (2008) 6537–6543
Alkylation of compounds 2 with allyl bromide (NaH, DMF) gives
O
(C2H5O)
R1O
the expected bisphosphonates 3 in good yields (60–80%). But
attempts to alkylate compounds 2 with other alkyl bromides in-
cluding benzyl bromide, ethyl bromoacetate or bromoacetonitrile
failed whatever the conditions employed (solvent, temperature).
These observations could be explained by a nucleophilic sub-
stitution that could take place in the case of allyl bromide, probably
at the allylic carbon and with an allylic rearrangement, following an
SN20 reaction. The alkylation with a Michael acceptor as electrophile
(e.g., ethyl acrylate, acrylonitrile) did not produce better results,
indicating that the steric hindrance could inhibit this alkylation
reaction. However, the introduced allyl group offers a great po-
tential for the incorporation of different functionalities to produce
a wide range of products as reported in Scheme 2.
2P
11c
NH2
(C2H5O)2P
O
ii
O
O
O
(C2H5O)2P
(C2H5O)2P
i
R1O
10c
H
R1O
NH-Bn
NH2Bn
(C2H5O)2P
(C2H5O)2P
O
O
4c : R1 = C6H13
iii
O
O
P
HO
R1O
HO
12c
P
HO
O
O
O
Scheme 4. (i) BnNH2, 4 Å sieves, Pyr–BH3, MeOH, rt, 7 h; (ii) 20% Pd(OH)2, H2, MeOH,
(C2H5O)2P
(C2H5O)2P
15 h; and (iii) (CH3)3SiBr, CH2Cl2, rt, 15 h then MeOH.
R
R1
O
R1
O
(C2H5O)2P
(C2H5O)2P
Another strategy has been investigated to produce the alkoxy
methylene bisphosphonate functionalized by an amino group as
depicted in Scheme 5. The alcohol 6d, which is synthesized fol-
lowing a hydroboration–oxidation procedure22 starting from 3d
(Scheme 2), reacts with mesylchloride to give compound 13d. In
a second step, 13d reacts with sodium azide to produce compound
14d, which is subsequently reduced in 15d with triphenylphos-
phine, according to a modified Staudinger procedure.23 The corre-
sponding phosphonic acid 16d was then obtained in an overall
yield of 25% by treatment with an excess of bromotrimethylsilane
as previously described.
O
O
3
a
4
R = CHO
b
c
d
e
5
6
7
8
R = CH2OH
R = CH2-CH2-OH
R = CO2H
R = HC CH2
O
Scheme 2. (a) O3, CH2Cl2, ꢀ78 ꢁC then (CH3)2S, rt; (b) O3, CH2Cl2, ꢀ78 ꢁC then BH3–
(CH3)2S, rt; (c) BH3–THF, THF, 0 ꢁC, 1.5 h, then MeOH, 3 M NaOH, 30% H2O2, 50 ꢁC, 1 h;
(d) NaIO4, RuCl3, CCl4, CH3CN, H2O, rt; and (e) m-CPBA, CH2Cl2, rt.
O
O
O
(C2H5O)2P
(C2H5O)2P
(C2H5O)2P
ii
i
Compounds 3c and 3f have been treated with ozone in
dichloromethane at ꢀ78 ꢁC to afford the ozonides 9c and 9f, which
have not been isolated. The ozonide 9c was slowly decomposed
with dimethylsulfide17 at room temperature to give, after 4 days, as
monitored by 31P NMR, the aldehyde 4c in a quantitative yield. In
a different way, the ozonide 9f was reduced with BH3–DMS18 giving
rise to the alcohol 5f in 76% yield (Scheme 3).
The aldehyde 4c was then treated with benzylamine and
methanolic pyridine–borane in the presence of 4 Å molecular
sieves to effect reductive amination19 to afford 10c (Scheme 4). This
compound was isolated in moderate yield (32%) and all attempts to
get the debenzylated compound 11c (H2/P–C, Pd(OH)220) failed.
Then, the corresponding phosphonic acid 12c was obtained almost
quantitatively by treatment with an excess of bromo-
trimethylsilane21 followed by the methanolysis of the resulting
trimethylsilyl ester.
C10H21
(C2H5O)2
O
(CH2)3-N3
C10H21
(C2H5O)2
O
(CH2)3-O-Ms
C10H21
(C2H5O)2
O
(CH2)3-OH
O
P
P
P
O
14d
O
O
6d
13d
O
P
O
P
O
O
(C2H5O)2P
iii
HO
iv
C10H21
(CH2)3-NH3
C10H21
(C2H5O)2
O
(CH2)3-NH2
HO
P
HO
O
15d
16d
Scheme 5. (i) CH3SO2Cl, Et3N, CH2Cl2, rt, 2 h; (ii) NaN3, DMF, rt, 6 h; (iii) Ph3P, THF,
H2O, rt; and (iv) (CH3)3SiBr, CH2Cl2, rt, 15 h then MeOH.
The oxidative cleavage of the double bond of 3b is accomplished
with RuCl3–NaIO4 under Sharpless conditions24 producing the
carboxylic acid 7b in a quantitative yield. This acid was then con-
verted into the amine 18b (Scheme 6) by a Curtius reaction using
the Yamada reagent25 (diphenylphosphonic azidedDDPA). First,
the azide group is transferred by the reaction of the carboxylic acid
7b with DDPA. Benzyl alcohol is then added to the isocyanate in-
termediate, to afford the carbamate 17b in 76% yield. The removal of
the benzyl group by catalytic hydrogenolysis with 10% Pd–C under
H2 atmosphere gives quantitatively the amino compound 18b. The
phosphonic acid 19b was isolated after the classical silylation
(Me3SiBr)/alcoholysis procedure.
Epoxidation of 3a with m-chloroperoxybenzoic acid in CH2Cl2
affords quantitatively the epoxide 8a. Treatment of 8a with tri-
phenylphosphine and bromine26 in dichloromethane at room
temperature affords, before the purification by chromatography on
silica gel, a mixture of triphenylphosphine oxide and bromohydrin
20a (Scheme 7). After chromatography, a mixture of compounds
20a and 200a in the ratio of 1/9 is isolated. The formation of 200a
results from an intramolecular cyclization of 20a. Of note, this kind
O
(C2H5O)2P
3c : R1 = C6H13
R1O
3f : R1 = C6H5-CH2
(C2H5O)2P
O
O
O
(C2H5O)2P
R1O
(C2H5O)2P
ii
9c
H
O
O
O
O
4c
(C2H5O)2P
R1O
(C2H5O)2P
O
O
(C2H5O)2P
R1O
(C2H5O)2P
iii
O
9f
OH
9c, 9f
5f
O
Scheme 3. (i) O3, CH2Cl2, ꢀ78 ꢁC; (ii) (CH3)2S, rt, 96 h; and (iii) BH3–(CH3)2S, rt, 48 h.

J.-P. Haelters et al. / Tetrahedron 64 (2008) 6537–6543
6539
O
O
O
P
P
(C2H5O)2
(C2H5O)2
P
(C2H5O)2
C4H9O
(C2H5O)2
O
i, ii
iii
CH2Ph
C4H9O CH2-NH2
C4H9O CH2-CO2H
CH2-NH
O
P
P
P
(C2H5O)2
(C2H5O)2
O
18b
O
O
17b
7b
O
P
O
HO
iv
C4H9O
HO
CH2-NH3
P
HO
O
19b
Scheme 6. (i) N3–P(O)(OPh)2, Et3N, benzene, reflux; (ii) PhCH2OH; (iii) H2, Pd–C, MeOH; and (iv) (CH3)3SiBr, CH2Cl2, rt, 15 h then MeOH.
of cyclization has been previously reported in the literature.27
Compound 200a exists in a mixture of two diastereoisomers in
a ratio 70/30. Treatment of the mixture of 20a and 200a with bro-
motrimethylsilane has completed the cyclization and gives only the
acid 210a as two diastereoisomers in a 70/30 ratio. The addition of
an aqueous solution of trimethylamine on 210a gives rise to the
product of substitution 220a in a quantitative yield.
a solution of Mo/MoO3 staining reagent.28 Liquid chromatographies
were carried out on silica gel (Merck 60, 70–230 mesh).
4.2. General procedure for the synthesis of alkoxy methylene
bisphosphonates 2
The following compounds have been prepared as described by
Ollivier et al.16
To a solution of diisopropylamine (10.5 g, 104 mmol) in dry THF,
under nitrogen, cooled to ꢀ78 ꢁC, was added a 2.5 M solution of
BuLi in hexane (40 mL, 100 mmol). Then, phosphonate 1 (50 mmol)
was introduced in the mixture and diethyl chlorophosphate
(10.35 g, 60 mmol) was added dropwise. The reaction mixture was
allowed to warm up to 0 ꢁC, hydrolyzed with water and extracted
with CH2Cl2 (3ꢂ100 mL). The extract was dried over MgSO4, filtered
and concentrated to give the crude bisphosphonate 2, which is
purified by fractional distillation under vacuo or by chromatogra-
phy on silica gel.
O
(C2H5O)2P
CH3O
O
O
P
C2H5O
O
(C2H5O)2P
CH3O CH2
(C2H5O)2P
OH
Br
i
+
CH2
C
H2
CH
Br
CH2
CH3O
O
(C2H5O)2P
(C2H5O)2P
O
O
O
20'a
8a
20a
O
P
O
P
O
HO
(CH3)3NH
O
O
ii
iii
Br
CH2
CH3O
N(CH3)3
CH3O
CH2
(HO)2P
O P
O
21'a
O
(CH3)3NH
O
22'a
4.2.1. Tetraethyl 1-methoxymethylene-1,1-bisphosphonate 2a
Yield: 87%. 1H NMR (CDCl3)
d 4.32–4.18 (m, 8H), 3.79 (t, 1H,
Scheme 7. (i) Ph3PBr2, SiO2, 99/1: ethyl acetate/ethanol; (ii) (CH3)3SiBr, CH2Cl2, rt, 15 h
then MeOH; and (iii) N(CH3)3 40 wt % in H2O.
2JHP¼17), 3.62 (s, 3H), 1.34 (t, 3H, 3JHH¼7); 31P NMR (CDCl3)
d 15.1;
13C NMR (CDCl3)
d
74.7 (t, 1JCP¼157), 63.2, 62.3, 16.2; Anal. Calcd for
3. Conclusion
C
10H24O7P2 (318.2): C 37.7, H 7.6, P 19.5. Found: C 37.4, H 7.7, P 19.3.
In this paper, the alkylation of alkoxy methylene bisphospho-
nate 2 with allyl bromide is reported. The introduced allyl group
has been chemically transformed in order to incorporate new
functionalities including alcohol, aldehyde, carboxylic acid, epoxide
and amine. The resulting bisphosphonate have been hydrolyzed to
give access to a wide family of new functionalized alkoxy
bisphosphonic acids. We expect, for these new bisphosphonic
acids, a decrease of their hydrophilic character and therefore
a better bioavailability by oral administration. The evaluations of
their biological activities are currently in progress. Furthermore,
the functionalities introduced could be useful for the synthesis of
conjugate of alkoxy methylene bisphosphonates.
4.2.2. Tetraethyl 1-butoxymethylene-1,1-bisphosphonate 2b
Yield: 87%; 1H NMR (CDCl3)
d 4.32–4.12 (m, 8H), 3.9 (t, 1H,
3
3
2JHP¼18), 3.74 (t, 2H, JHH¼7), 1.56 (qt, 2H, JHH¼7), 1.44–1.20 (m,
14H), 0.87 (t, 3H, 3JHH¼7); 31P NMR (CDCl3)
d
17.0; 13C NMR (CDCl3)
d
74.7, 73.1 (t, 1JCP¼158), 63.2, 63.0, 31.5, 18.7, 16.2, 13.5; Anal. Calcd
for C13H30O7P2 (360.3): C 43.3, H 8.4, P 17.2. Found: C 43.1, H 8.5, P
17.0.
4.2.3. Tetraethyl 1-hexoxymethylene-1,1-bisphosphonate 2c
Yield: 82%; 1H NMR (CDCl3)
d 4.29–4.16 (m, 8H), 3.9 (t, 1H,
2JHP¼18), 3.74 (t, 2H, 3JHH¼7), 1.6 (qt, 2H, 3JHH¼7), 1.38–1.18 (m, 6H),
3
3
1.34 (t, 12H, JHH¼7), 0.87 (t, 3H, JHH¼7); 31P NMR (CDCl3)
d 16.5;
13C NMR (CDCl3)
d
75.0, 73.1 (t, 1JCP¼157), 63.1, 62.0, 31.2, 29.3, 25.2,
4. Experimental section
4.1. General
22.2, 16.1, 13.6; Anal. Calcd for C15H34O7P2 (388.4): C 46.4, H 8.8, P
15.9. Found: C 46.2, H 8.9, P 15.8.
4.2.4. Tetraethyl 1-decoxymethylene-1,1-bisphosphonate 2d
1H (300 MHz), 13C (75 MHz) and 31P NMR (120 MHz) spectra
were recorded on a Bruker AC 300 spectrometer using chloroform
as an internal reference in CDCl3 solutions (7.24 ppm) for 1H NMR
spectra and (77.0 ppm) for 13C NMR spectra, and phosphoric acid
Yield: 80%; 1H NMR (CDCl3)
d
4.29–4.14 (m, 8H), 3.90 (t, 1H,
3
3
2JHP¼18), 3.74 (t, 2H, JHH¼7), 1.6 (qt, 2H, JHH¼7), 1.39–1.16 (m,
14H), 1.38 (t, 12H, JHH¼7), 0.87 (t, 3H, JHH¼7); 31P NMR (CDCl3)
3
3
d
16.5; 13C NMR (CDCl3)
d
75.0, 73.1 (t, 1JCP¼157), 63.0, 62.8, 31.5,
(85%) for 31P NMR spectra. Chemical shifts (
d
) are given in parts per
29.4, 29.2, 28.9, 25.5, 22.3, 16.1, 13.7; Anal. Calcd for C19H24O7P2
(444.5): C 51.3, H 9.5, P 13.9. Found: C 51.0, H 9.6, P 13.7.
million; multiplicities are indicated by s (singlet), br s (broad sin-
glet), d (doublet), dd (double-doublet), t (triplet), q (quadruplet), qt
(quintuplet), m (multiplet) or st (sextuplet). Coupling constants (J)
are reported in hertz. Analytical TLCs were performed on silica gel
plates (Merck, 60F254) and bisphosphonates were visualized with
4.2.5. Tetraethyl 1-hexadecoxymethylene-1,1-bisphosphonate 2e
Yield: 75%; 1H NMR (CDCl3)
d 4.30–4.10 (m, 8H), 3.90 (t, 1H,
3
3
2JHP¼18), 3.75 (t, 2H, JHH¼7), 1.57 (qt, 2H, JHH¼7), 1.40–1.15 (m,

6540
J.-P. Haelters et al. / Tetrahedron 64 (2008) 6537–6543
3
3
26H), 1.34 (t, 12H, JHH¼7), 0.87 (t, 3H, JHH¼7); 31P NMR (CDCl3)
4.3.6. Tetraethyl 1-benzyloxybut-3-enylidene-1,1-bisphos-
phonate 3f
d
16.5; 13C NMR (CDCl3)
29.6, 29.3, 25.8, 22.7, 16.4, 14.1; Anal. Calcd for C25H54O7P2 (528.6):
C 56.8, H 10.3, P 11.7. Found: C 56.4, H 10.5, P 11.9.
d
75.5, 73.5 (t, 1JCP¼157), 63.3, 63.2, 31.9,
Yield: 60%; 1H NMR (CDCl3)
d
7.2–7.4 (m, 5H), 6.1 (m, 1H), 5.1–
3
3
5.2 (2dd, 2H, 1JHH¼1.6, JHHcis¼10.0, JHHtrans¼17.1), 4.9 (s, 2H), 4.8
(td, 2H, 2JHP¼14.1, 3JHH¼7.0), 4.1–4.3 (m, 8H), 1.3 (m, 12H); 31P NMR
4.2.6. Tetraethyl 1-benzyloxymethylene-1,1-bisphosphonate 2f
(CDCl3) d d 132.2, 127.7, 117.5, 80.3 (t,
16.6; 13C NMR (CDCl3)
Yield: 78%; 1H NMR (CDCl3)
d
7.41–7.26 (m, 5H), 4.83 (s, 2H),
JCP¼150), 69.7, 62.2, 35.9,16.0; Anal. Calcd for C19H32O7P2 (434.4): C
4.30–4.08 (m, 8H), 4.06 (t, 1H, 2JHP¼17), 1.34 (t, 6H, 3JHH¼7), 1.33 (t,
52.5, H 7.4, P 14.3. Found: C 52.2, H 7.5, P 14.1.
6H, JHH¼7); 31P NMR (CDCl3)
d d 135.6,
16.4; 13C NMR (CDCl3)
3
1
127.9, 127.5, 74.9, 70.8 (t, JCP¼157), 62.6, 62.5, 15.6; Anal. Calcd
for C16H28O7P2 (394.3): C 48.7, H 7.2, P 15.7. Found: C 48.4, H 7.3, P
15.5.
4.4. Tetraethyl 1-hexoxy-3-oxopropylidene-1,1-
bisphosphonate 4c
A solution of alkene 3d (0.48 g, 1 mmol) in CH2Cl2 (20 mL) was
cooled to ꢀ78 ꢁC. The effluent stream of an ozone generator was
bubbled into the methylene chloride solution until the blue col-
our of unreacted ozone was noticeable. Then, dry nitrogen was
bubbled through the reaction mixture for 10 min and 5 mL of
methylsulfide was added. The reaction mixture was allowed to
warm up to room temperature and was stirred until the entire
4.3. General procedure for the synthesis of tetraethyl 1-
alkoxybut-3-enylidene-1,1-bisphosphonate 3
To a solution of NaH (8 mmol) in dry DMF (30 mL) was added
bisphosphonate (6 mmol) at room temperature, under N2. After
45 min, allyl bromide (10 mmol) was added and the mixture was
stirred at room temperature for 12 h. Then, the mixture was con-
centrated in vacuo, diluted with CH2Cl2 (30 mL) and washed with
brine (20 mL). The organic layer was dried (MgSO4), concentrated
in vacuo and the residue was purified by chromatography to yield
compounds 3.
disappearance of the ozonide 9c followed by 31P NMR (9c:
d
31P
18.25, 17.9 (dd, AB, JPP¼40 Hz) (4 days)). The solution was evap-
orated in vacuo to give quantitatively the aldehyde 4c. 1H NMR
3
(CDCl3)
d
9.87 (t, 1H, JHH¼3), 4.31–4.16 (m, 8H), 3.91 (t, 2H,
3
3
3
3JHH¼7), 2.96 (dt, 2H, JHH¼3, JHP¼14), 1.57 (qt, 2H, JHH¼7),
1.42–1.18 (m, 6H), 1.33 (t, 12H, JHH¼7), 0.87 (t, 3H, JHH¼7); 31P
3
3
3
NMR (CDCl3)
d
17.7; 13C NMR (CDCl3)
d
198.7 (d, JCP¼29), 77.1 (t,
4.3.1. Tetraethyl 1-methoxybut-3-enylidene-1,1-bisphosphonate 3a
1JCP¼151), 66.8, 62.9, 62.6, 44.2, 30.7, 29.2, 24.6, 21.6, 15.5, 13.1;
Anal. Calcd for C17H36O8P2 (430.4): C 47.4, H 8.4, P 14.4. Found: C
47.1, H 8.5, P 14.3.
Yield: 75%; 1H NMR (CDCl3)
d 6.0 (m, 1H), 5.1–5.2 (m, 2H), 4.1–
4.3 (m, 8H), 3.6 (s, 3H), 2.9 (m, 2H), 1.3 (m, 12H); 31P NMR (CDCl3)
d
19.2; 13C NMR (CDCl3)
d
131.6, 116.0, 77.3 (t, 1JCP¼151), 62.3, 53.5,
34.7, 15.6; Anal. Calcd for C13H28O7P2 (358.1): C 43.6, H 7.9, P 17.3.
Found: C 43.4, H 8.0, P 17.1.
4.5. Tetraethyl 3-benzylamino-1-hexoxypropylene-1,1-
bisphosphonate 10c
4.3.2. Tetraethyl 1-butoxybut-3-enylidene-1,1-bisphosphonate 3b
Yield: 70%; 1H NMR (CDCl3)
d 6.0 (m, 1H), 5.1 (m, 2H), 4.2 (m,
To MeOH (15 mL) containing 71 mg of 4 Å molecular sieves was
added sequentially the aldehyde 4c (0.43 g, 1 mmol), benzylamine
(0.107 g, 1 mmol) and pyridine–borane (0.08 mL, 0.8 mmol). After
7 h, the resulting mixture was treated with 2 mL of 1 N HCl for
5 min and then pH adjusted to 14 using 2 N NaOH. Three extrac-
tions were performed with CH2Cl2, and the combined organic ex-
tracts were washed with brine, dried over MgSO4 and concentrated
in vacuo. The resulting residue was purified by chromatography
(silica, ethyl acetate/ethanol: 5/1) to give the pure compound 10c as
8H), 3.8 (t, 2H, 3JHH¼7), 2.9 (m, 2H), 1.5 (m, 16H), 0.9 (t, 2H, 3JHH¼7);
31P NMR (CDCl3)
d d 132.3, 117.4, 80.2 (t,
19.0; 13C NMR (CDCl3)
1JCP¼151), 65.7, 63.0, 62.7, 35.5, 32.0, 18.8, 16.1, 13.6; Anal. Calcd
for C16H34O7P2 (400.4): C 48.6, H 8.6, P 15.5. Found: C 48.3, H 8.7, P
15.3.
4.3.3. Tetraethyl 1-hexoxybut-3-enylidene-1,1-bisphosphonate 3c
Yield: 80%; 1H NMR (CDCl3)
d 6.0 (m, 1H), 5.1 (m, 2H), 4.2 (m,
8H), 3.8 (t, 2H, 3JHH¼7), 2.9 (td, 2H, 3JHP¼14.2, 3JHH¼7), 1.5 (m, 2H),
an uncoloured oil. Yield: 32%; 1H NMR (CDCl3)
d 7–7.4 (m, 5H),
3
1.3 (m, 18H), 0.9 (t, 3H, JHH¼7); 31P NMR (CDCl3)
d
19.1; 13C NMR
3
4.25–4.04 (m, 8H), 3.80 (s, 2H), 3.75 (t, 2H, JHH¼7), 2.93 (t, 2H,
(CDCl3)
d
132.4, 117.3, 80.2 (t, 1JCP¼151), 66.0, 63.0, 62.6, 35.5, 31.3,
3JHH¼7), 2.33 (tt, 2H, 3JHH¼7, 3JHP¼14), 1.68 (qt, 2H, 3JHH¼7), 1.14 (m,
18H), 0.87 (t, 3H, 3JHH¼7); 31P NMR (CDCl3)
d
19.3; 13C NMR (CDCl3)
29.8, 25.2, 22.2,16.1,13.6; Anal. Calcd for C18H38O7P2 (428.4): C 50.5,
H 8.9, P 14.5. Found: C 50.3, H 9.0, P 14.3.
d
139.6, 128.3, 127.2, 80.1 (t, 1JCP¼150), 66.3, 63.3, 63.0, 53.3, 43.9,
40.9, 31.4, 25.6, 22.4, 16.4, 13.8; Anal. Calcd for C24H45NO7P2 (521.6):
C 55.3, H 8.7, N 2.7, P 11.9. Found: C 55.0, H 8.8, N 2.6, P 11.7.
4.3.4. Tetraethyl 1-decoxybut-3-enylidene-1,1-bisphosphonate 3d
Yield: 77%; 1H NMR (CDCl3)
d 6.0 (m, 1H), 5.1 (m, 2H), 4.2 (m,
8H), 3.8 (t, 2H, 3JHH¼7), 2.9 (m, 2H), 1.5 (m, 2H), 1.3 (m, 12H), 1.2 (m,
14H), 0.9 (t, 3H, 3JHH¼7); 31P NMR (CDCl3)
d
19.1; 13C NMR (CDCl3)
4.6. 3-Benzylamino-1-hexoxypropylene-1,1-bisphosphonic
acid 12c
1
d
132.4, 117.3, 80.3 (t, JCP¼151), 66.0, 63.0, 62.6, 35.5, 31.6, 29.9,
29.2, 29.0, 25.6, 22.3, 16.2, 13.7; Anal. Calcd for C22H46O7P2 (484.5):
C 54.5, H 9.6, P 12.8. Found: C 54.2, H 9.8, P 12.6.
A solution of 10c (0.15 g, 0.29 mmol) and bromotrimethylsilane
(0.26 mL, 2 mmol) in CH2Cl2 (5 mL) was stirred under N2 at room
temperature for 15 h and then evaporated. The residue was dis-
solved in 5 mL of MeOH and evaporated to give quantitatively the
4.3.5. Tetraethyl 1-hexadecoxybut-3-enylidene-1,1-bisphos-
phonate 3e
Yield: 72%; 1H NMR (CDCl3)
d
6.08 (m, 1H), 5.11 (m, 2H), 4.2 (m,
acid 12c as a viscous oil. 1H NMR (CD3OD)
d 7.6–7.4 (m, 5H), 4.20 (s,
3
3
3
8H), 3.8 (t, 2H, 3JHH¼7), 2.9 (td, 2H, 3JHP¼14.2, 3JHH¼7), 1.5 (m, 2H),
2H), 3.95 (t, 2H, JHH¼7), 3.43 (t, 2H, JHH¼7), 2.51 (tt, 2H, JHH¼7,
1.3 (m, 12H), 1.2 (m, 26H), 0.8 (t, 3H, JHH¼7); 31P NMR (CDCl3)
3JHP¼14), 1.68 (qt, 2H, 3JHH¼7), 1.15 (m, 6H), 0.85 (t, 3H, 3JHH¼7); 31
P
3
d
19.1; 13C NMR (CDCl3)
62.9, 35.8, 31.9, 30.2, 29.7, 29.5, 29.3, 25.9, 22.7, 16.5, 14.1; Anal.
Calcd for C28H58O7P2 (568.7): C 59.1, H 10.3, P 10.9. Found: C 59.2, H
10.3, P 10.9.
d
132.8, 117.6, 80.6 (t, 1JCP¼151), 66.3, 63.3,
NMR (CD3OD)
d
19.6; 13C NMR (CD3OD)
d
130.5, 128.7, 128.1, 76.7 (t,
1JCP¼145), 66.4, 50.3, 43.2 (t, JCP¼8), 31.5, 29.65, 28.0, 25.6, 22.5,
13.8; Anal. Calcd for C16H29NO7P2 (409.35): C 46.95, H 7.14, N 3.42,
O 27.36, P 15.13. Found: C 47.0, H 7.2, N 3.5, P 14.9.
3

J.-P. Haelters et al. / Tetrahedron 64 (2008) 6537–6543
6541
4.7. Tetraethyl 1-benzyloxy-3-hydroxypropylene-1,1-
bisphosphonate 5f
a colourless oil. 1H NMR (CDCl3)
d
4.11–4.34 (m, 8H), 3.76 (t, 2H,
3
3JHH¼7), 3.3 (t, 2H, JHH¼7), 2.0–2.23 (m, 2H), 2.79–2.94 (m, 2H),
3
3
1.56 (qt, 2H, JHH¼7), 1.18–1.46 (m, 26H), 0.87 (t, 3H, JHH¼7); 31P
A solution of alkene 3f (0.43 g, 1 mmol) in CH2Cl2 (20 mL) was
cooled to ꢀ78 ꢁC. The effluent stream of an ozone generator was
bubbled into the methylene chloride solution until the blue colour
of unreacted ozone was noticeable. The reaction mixture was
allowed to warm up to room temperature, and dry nitrogen was
bubbled through it for 10 min. Borane–dimethyl sulfide complex
(3.5 mmol) was added by syringe over several minutes, and the
reaction mixture was allowed to stand at room temperature for
48 h. Aqueous 5% HCl (0.3 mL) was added, and the resulting mix-
ture was vigorously stirred for 1 h. Solid NaHCO3 was added until
the aqueous layer was basic, and anhydrous MgSO4 was added as
drying agent. The reaction mixture was filtered and concentrated
with a rotary evaporator to give the desired alcohol 5f as a colour-
NMR (CDCl3)
d
19.4; 13C NMR (CDCl3)
d
80.5 (t, 1JCP¼150), 66.2, 63.2,
62.9, 45.9, 32.8, 30.7, 30.2, 29.3, 26.4, 23.5, 23.0, 16.4, 13.6; Anal.
Calcd for C22H47N3O7P2 (527.6): C 50.1, H 9.0, N 8.0, P 11.7. Found: C
49.8, H 9.1, N 8.1, P 11.6.
4.11. Tetraethyl 4-amino-1-decoxybutylene-1,1-
bisphosphonate 15d
To a solution of 14d (0.9 g, 1.7 mmol) in THF cooled to 0 ꢁC was
added Ph3P (0.44 g, 1.7 mmol). The reaction mixture was allowed to
warm up to room temperature and stirred for 2 h. Then, H2O
(0.045 g, 2.5 mmol) was added and stirring was maintained for 16 h.
THF was removed under reduced pressure and the crude product
was diluted with a mixture 1/1 of diethyl ether and petroleum ether
to precipitate Ph3P(O). After filtration, the solvents were removed in
vacuo. The residue was partitioned between diethyl ether (60 mL)
and 3 M HCl (20 mL). The organic layer was discarded and the
aqueous layer was basified with 4 M NaOH (20 mL) at 0 ꢁC. Then, the
solution was extracted with CH2Cl2, dried over MgSO4, filtered and
evaporated to give 15d as a viscous oil. Yield: 78%; 1H NMR (CDCl3)
less oil. Yield: 76%; 1H NMR (CDCl3)
d 7.14–7.39 (m, 5H), 4.92 (s, 2H),
3
3
4.11–4.34 (m, 8H), 3.94 (t, 2H, JHH¼7), 2.47 (tt, 2H, JPH¼15,
3
3
3JHH¼7), 1.34 (t, 6H, JHH¼7), 1.33 (t, 6H, JHH¼7); 31P NMR (CDCl3)
d
19.5; 13C NMR (CDCl3)
67.9, 62.7, 51.1, 33.8, 15.6; Anal. Calcd for C18H32O8P2 (438.4): C 49.3,
H 7.4, P 14.1. Found: C 49.1, H 7.5, P 14.0.
d
137.0, 127.4, 126.9, 79.3, (t, 1JCP¼150 Hz),
4.8. Tetraethyl 1-decoxy-4-hydroxybutylene-1,1-
bisphosphonate 6d
d
4.1–4.3 (m, 8H), 3.75 (t, 1H, 3JHH¼7), 3.65 (t, 1H, 3JHH¼7), 2.9–3.15
(m, 2H), 2.38 (br s, 2H), 2.05–2.25 (m, 2H), 1.85–2.05 (m, 2H), 1.53
(qt,1H, 3JHH¼7),1.45 (qt,1H, 3JHH¼7),1.18–1.36 (m, 26H), 0.87 (t, 3H,
To a solution of 3d (2.2 g, 4.5 mmol) in dry THF (12 mL) cooled
with an ice-water bath was added a 1 M solution of BH3THF in THF
(7.4 mL) under nitrogen. After stirring for 1.5 h, the reaction mix-
ture was quenched with methanol followed by the addition of
aqueous 3 M NaOH (2.5 mL) and 30% H2O2 (2.4 mL). The solution
was heated at 50 ꢁC for 1.5 h, then it was stirred at room temper-
ature for 15 h. Aqueous saturated sodium chloride solution was
added, and the product was extracted with diethyl ether and then
chloroform. The extracts were combined, dried over MgSO4, filtered
and the solvents were removed under reduced pressure, leaving
the desired alcohol 6d as a colourless oil, which was used in the
3JHH¼7); 31P NMR (CDCl3)
d 19.4, 19.0.
4.12. 4-Amino-1-decoxybutylene-1,1-bisphosphonic acid 16d
A solution of 15d (1.7 mmol) and bromotrimethylsilane (1.6 mL,
12.2 mmol) in CH2Cl2 (20 mL) was stirred under N2 at room tem-
perature for 15 h and then evaporated. The residue was dissolved in
10 mL of MeOH and evaporated to give the crude acid 19b as
a viscous oil. Addition of CH2Cl2 gave a precipitate, which is filtered
and dried in a desiccator. Product was re-crystallized from meth-
anol to give a white powder. Yield: 80%;1H NMR (CD3OD)
d 3.90 (t,
next step without further purification. 1H NMR (CDCl3)
d
4.08–4.24
2H, JHH¼7), 2.99 (t, 2H, JHH¼7), 2.23–2.1 (m, 2H), 2.04 (qt, 2H,
3
3
(m, 8H), 3.77 (t, 2H, 3JHH¼7), 3.65 (t, 2H, 3JHH¼7), 2.07–2.27 (m, 3H),
3JHH¼7), 1.62 (t, 2H, JHH¼7), 1.45–1.22 (m, 14H), 0.90 (t, 3H,
3
3
1.77–1.93 (m, 2H), 1.56 (qt, 2H, JHH¼7), 1.1–1.30 (m, 26H), 0.87 (t,
3JHH¼7); 31P NMR (CD3OD)
d d 79.8 (t,
21.1; 13C NMR (CD3OD)
3
3H, JHH¼7); 31P NMR (CDCl3)
d
19.7; 13C NMR (CDCl3)
d
80.7 (t,
1JCP¼145), 67.9, 41.1, 33.0, 31.5, 30.7, 30.4, 29.8, 27.0, 23.7, 23.4, 14.4;
Anal. Calcd for C14H33NO7P2 (389.4): C 43.2, H 8.5, N 3.6, P 15.9.
Found: C 43.1, H 8.6, N 3.5, P 15.8.
1JCP¼151), 66.2, 63.2, 62.8, 62.6, 31.8, 30.1, 29.4, 29.2, 27.7, 26.7, 25.9,
22.5, 16.4, 14.0.
4.9. Tetraethyl 1-decoxy-4-[(methylsulfonyl)oxy]butylene-
1,1-bisphosphonate 13d
4.13. 3-Butoxy-3,3-bis(diethoxyphosphoryl)propanoic acid 7b
To a mixture of alkene 3b (1 g, 2.5 mmol) and sodium periodate
(2.19 g, 4.1 equiv) in 5 mL of carbon tetrachloride, 5 mL of aceto-
nitrile and 7.5 mL of water was added 14 mg (5.5 mol %) of ruthe-
nium trichloride hydrate. The mixture was then stirred vigorously
for 24 h at room temperature. Then, 25 mL of CH2Cl2 was added and
the mixture was filtered through a Celite pad, and the aqueous
phase was extracted three times with CH2Cl2. The combined or-
ganic extracts were dried over MgSO4 and concentrated to give
0.95 g (90% yield) of the crude acid 7b as a dark oil. 1H NMR (CDCl3)
To a solution of 6d and Et3N (0.5 g, 5 mmol) in dry CH2Cl2
(20 mL) cooled with an ice-water bath was added dropwise a so-
lution of CH3SO2Cl (0.51 g, 4.5 mmol) in CH2Cl2 (10 mL). After stir-
ring at room temperature for 2 h, the mixture was poured into H2O
and extracted with CH2Cl2. The extract was dried over MgSO4, fil-
tered and evaporated to give 13d, which is used in the next step
without further purification. 1H NMR (CDCl3)
d 4.09–4.34 (m, 10H),
3.77 (t, 2H, 3JHH¼7), 3.0 (s, 3H), 1.95–2.32 (m, 4H), 1.57 (qt, 2H, 3JHH
¼
7), 1.11–1.31 (m, 26H), 0.87 (t, 3H, 3JHH¼7); 31P NMR (CDCl3)
d
19.3.
d
4.14–4.34 (m, 8H), 3.98 (t, 2H, JHH¼7), 3.17 (t, 2H, JHP¼15), 1.57
3
3
(qt, 2H, JHH¼7), 1.25–1.4 (m, 14H), 0.9 (t, 3H, JHH¼7); 31P NMR
3
3
4.10. Tetraethyl 4-azido-1-decoxybutylene-1,1-
bisphosphonate 14d
(CDCl3)
d
18.0; 13C NMR (CDCl3)
d
168.7, 76.9 (t, 1JCP¼154), 66.7, 63.2,
36.3, 31.3, 18.0, 15.5, 12.9; Anal. Calcd for C15H32O9P2 (418.4): C 43.1,
H 7.7, P 14.8. Found: C 42.9, H 7.8, P 14.6.
To a solution of 13d in anhydrous DMF (20 mL) was added NaN3
(0.31 g, 4.5 mmol), and the mixture was stirred at room tempera-
ture for 6 h. After evaporation of the DMF under reduced pressure,
the residue was dissolved in CH2Cl2, washed with H2O, dried over
MgSO4, concentrated and purified by chromatography (silica, 2/1:
ethyl acetate/hexane) to give 950 mg (40% overall yield) of 14d as
4.14. Tetraethyl 2-[(benzyloxycarbonyl)amino]-1-
butoxyethylene-1,1-bisphosphonate 17b
Acid 7b (0.95 g, 2.25 mmol) was refluxed in benzene (20 mL)
with an equimolar mixture of diphenylphosphonic azide and

6542
J.-P. Haelters et al. / Tetrahedron 64 (2008) 6537–6543
triethylamine for 1 h. Then, a slight excess of benzyl alcohol (2 mL)
was added and the mixture was refluxed for 17 h. The mixture was
concentrated in vacuo, diluted with CH2Cl2 (30 mL), washed five
times with 20 mL of saturated aqueous solution of NaHCO3, dried
over MgSO4, filtered and evaporated. Then, the residue was purified
by chromatography (silica, ethyl acetate) to give 0.9 g (76% yield) of
3,4-epoxy-1-methoxybutylene-1,1-bisphosphonate
8a
(0.5 g,
1.32 mmol) in a solution of CH2Cl2 (2 mL) was added also in one
portion. After stirring for 15 min, the reaction mixture was poured
into cold 1 N aq NaHCO3 (100 mL) and extracted three times with
CH2Cl2 (30 mL). The extracts were combined, dried and evaporated
to give quantitatively a mixture of compound 20a and Ph3PO. The
chromatography of this mixture on silica gel with ethyl acetate as
eluent to eliminate Ph3PO gave 300 mg of a mixture of compounds
20a and 200a in the ratio 10/90. Product 200a appeared as two di-
17b as a colourless oil. 1H NMR (CDCl3)
d 7.27–7.41 (m, 5H), 5.88 (t,
3
3
1H, JHH¼5), 5.1 (s, 2H), 4.11–4.32 (m, 8H), 3.89 (dt, 2H, JHH¼5,
3
3
3JHP¼13), 3.79 (t, 2H, JHH¼7), 1.50 (qt, 2H, JHH¼7), 1.20–1.41 (m,
14H), 0.87 (t, 3H, 3JHH¼7); 31P NMR (CDCl3)
d
17.9; 13C NMR (CDCl3)
astereoisomers in the ratio 70/30. 1H NMR (CDCl3) 20a
d 4.35–4.29
2
d
156.1, 136.7, 128.4, 128.0, 79.3 (t, 1JCP¼151), 66.5, 63.6, 41.2, 32.2,
(m, 1H), 4.29–4.20 (m, 8H), 3.66 (s, 3H), 3.46 (dd, 2H, JHH¼2,
19.0, 16.4, 13.8; Anal. Calcd for C22H39NO9P2 (523.5): C 50.5, H 7.5, N
2.7, P 11.8. Found: C 50.2, H 7.6, N 2.6, P 11.6.
3JHH¼5), 2.49–2.28 (m, 2H), 1.39 (t, 12H); 31P NMR (CDCl3) 20a
d
19.2, 19.6 (dd AB, 2JPP¼34); 1H NMR (CDCl3) 200a
d 4.77–4.46 (m,
1H), 4.46–4.16 (m, 6H), 3.62 (s, 3H), 3.62–3.39 (m, 2H), 3.0–2.29 (m,
31
2
4.15. Tetraethyl 2-amino-1-butoxyethylene-1,1-
bisphosphonate 18b
2H), 1.51–1.28 (m, 9H); P NMR (CDCl3) 200a
d
34.3 (d, JPP¼51,
diast 1), 32.7 (d, 2JPP¼48, diast 2), 18.0 (d, 2JPP¼48, diast 2), 17.4 (d,
2JPP¼51, diast 1).
A
mixture of tetraethyl 2-[(benzyloxycarbonyl)amino]-1-
butoxyethylene-1,1-bisphosphonate 17b (360 mg, 0.65 mmol) and
10% Pd–C (30 mg) in absolute EtOH (15 mL) was stirred under
a hydrogen atmosphere (1 atm) at room temperature for 15 h. After
removal of the catalyst by filtration, the filtrate was evaporated to
dryness in vacuo, to give quantitatively the amino compound. 1H
4.19. 5-(Bromomethyl)-2-hydroxy-3-methoxy-2-oxido-1,2-
oxaphospholan-3-ylphosphonic acid 210a
To a mixture of 20a and 200a (0.3 g) in anhydrous CH2Cl2 (15 mL)
was added bromotrimethylsilane (1 mL). After stirring for 20 h, the
solution was evaporated in vacuo and MeOH (1 mL) was added.
After stirring for 15 min, the solution was evaporated again to give
compound 210a in a quantitative yield as a viscous oil. 1H NMR
NMR (CDCl3)
d 5.07 (br s, 2H), 4.09–4.32 (m, 8H), 3.92 (t, 2H,
3
3
3JHH¼7), 3.43 (t, 2H, JHP¼13), 1.56 (qt, 2H, JHH¼7), 1.20–1.41 (m,
14H), 0.88 (t, 3H, 3JHH¼7); 31P NMR (CDCl3)
d
17.8; 13C NMR (CDCl3)
d
77.8 (t, 1JPC¼148), 66.6, 62.7, 41.4, 31.2, 18.0, 15.4, 12.9; Anal. Calcd
(CD3OD)
d 5.99 (s, 3H, OH), 4.64–4.46 (m, 1H), 3.68, 3.67 (2s, 3H),
3.67–3.37 (m, 2H), 3.03–2.39 (m, 2H); 31P NMR (CD3OD)
d 34.9 (d,
for C14H33NO7P2 (389.4): C 43.2, H 8.5, N 3.6, P 15.9. Found: C 43.0,
H 8.7, N 3.5, P 15.8.
2JPP¼46, diast 1), 33.9 (d, 2JPP¼45, diast 2), 15.9 (d, 2JPP¼45, diast 2),
2
15.1 (d, JPP¼46, diast 1); 13C NMR (CD3OD)
d
77.5 (dd, 1JCP¼163.6,
4.16. 2-Amino-1-butoxyethylene-1,1-bisphosphonic acid 19b
JCP¼127, diast 1), 77.0 (dd, JCP¼158, JCP¼127, diast 2), 75.8 (diast 2),
75.6 (diast 1), 56.6 (diast 2), 56.1 (diast 1), 38.9, 35.2 (diast 1), 34.5
(diast 2); Anal. Calcd for C5H11BrO7P2 (324.0): C 18.5, H 3.4, Br 24.6,
P 19.1. Found: C 18.3, H 3.6, Br 24.4, P 19.2.
A
solution of tetraethyl 2-amino-1-butoxyethylene-1,1-
bisphosphonate 18b (0.65 mmol) and bromotrimethylsilane
(0.61 mL, 4.7 mmol) in CH2Cl2 (20 mL) was stirred under N2 at room
temperature for 15 h and then evaporated. The residue was dis-
solved in 10 mL of MeOH and evaporated to give the crude acid 19b
4.20. Hydrogen 2-hydroxy-3-methoxy-2-oxido-
5-[(trimethylammonio)methyl]-1,2oxaphospholan-
3-ylphosphonate 220a
as a viscous oil. 1H NMR (CD3OD)
d
4.1 (t, 2H, 3JHH¼7), 3.5 (m, 2H),
3
3
3
1.6 (qt, 2H, JHH¼7), 1.41 (st, 2H, JHH¼7), 0.9 (t, 3H, JHH¼7); 31P
1
NMR (CD3OD)
d
15.2; 13C NMR (CD3OD)
d
76.1 (t, JCP¼142), 69.3,
A mixture of 210a (0.2 g) and trimethylamine solution 40% in
water (4 mL) was stirred for 5 h. Then, the solution was evaporated
to give quantitatively compound 220a as a viscous oil. 1H NMR
43.2, 33.3, 19.8, 14.2; Anal. Calcd for C6H17NO7P2 (277.1): C 26.0, H
6.2, N 5.0, P 22.3. Found: C 25.8, H 6.3, N 4.8, P 22.1.
(CD3OD)
d
2.32 (m, 1H), 2.66 (m, 1H), 2.91 (s, 27H), 3.61 (m, 5H),
37.2 (
, JPP¼30,
4.17. Tetraethyl 3,4-epoxy-1-methoxybutylene-1,1-
bisphosphonate 8a
4.46 (m, 1H), 4.80 (br s, OH); 31P NMR (CD3OD)
d
d
diast 1), 35.2 (d, JPP¼23, diast 2), 12.3 (d, JPP¼23, diast 2), 10.6 (d,
JPP¼30, diast 1); 13C NMR (CD3OD)
d
76.5 (t, JCP¼148), 73.4, 71.7,
A mixture of alkene 3a (3.58 g, 10 mmol) and 70% 3-chloroper-
oxybenzoic acid (3.15 g, 14 mmol) in CH2Cl2 (50 mL) was stirred for
2 days at room temperature. Aqueous 10% Na2SO3 was added and
the organic phase was extracted, washed with satd aqueous
NaHCO3, dried (MgSO4) and evaporated to give 3.7 g (100% yield) of
64.3, 45.2, 45.0, 37.9; Anal. Calcd for C14H37N3O7P2 (421.4): C 39.9, H
8.9, N 10.0, P 14.7. Found: C 39.1, H 8.8, N 9.9, P 14.9.
References and notes
8a as a colourless oil. 1H NMR (CDCl3)
d 4.29–4.20 (m, 8H), 3.64 (s,
1. (a) Fleish, H. Ann. Med. 1997, 29, 55–62; (b) Harris, S. T.; Watts, N. B.; Jackson, H.
K.; Genant-Wasnish, R. D.; Ross, P.; Miller, P. D.; Licata, A. A.; Chesnut, C. H. Am. J.
Med. 1993, 95, 557–567.
2. (a) Smith, R.; Russell, R. G. G.; Bishop, M. Lancet 1971, i, 945; (b) O’Doherty, D. P.;
Bickerstoff, D. R.; McCloskey, E. V.; Hamdy, N. A. T.; Beneton, M. N. C.; Harris, S.;
Mian, M.; Kanis, J. A. J. Bone Miner. Res. 1990, 5, 483–491; (c) Roux, C.; Gennari,
C.; Farrerons, J.; Devogelaer, J. P.; Mulder, H.; Kruse, H. P.; Picot, C.; Titeux, L.;
Reginster, J. Y. Arthritis Rheum. 1995, 38, 851–858; (d) Miller, P. D.; Brown, J. P.;
Siris, E. S.; Hoseyni, M. S.; Axelrod, D. W.; Bekker, P. J. Am. J. Med. 1999, 106, 513–
520.
3H), 3.32 (m, 1H), 2.80 (t, 1H, 3JHH¼5), 2.63–2.45 (m, 1H), 2.58 (dd,
1H, 3JHH¼5, 2JHH¼3), 2.14–2.01 (m,1H),1.38–1.28 (m,12H); 31P NMR
2
(CDCl3)
d
18.9, 18.6 (dd AB, JPP¼35); 13C NMR (CDCl3)
d 78.6 (t,
1JCP¼151), 62.6, 62.3, 54.0, 47.3, 33.6, 15.6; Anal. Calcd for
C
13H28O8P2 (374.3): C 41.7, H 7.5, P 16.5. Found: C 41.5, H 7.6, P 16.4.
4.18. Tetraethyl 4-bromo-3-hydroxy-1-methoxybutylene-1,1-
bisphosphonate 20a and diethyl 5-(bromomethyl)-2-ethoxy-
3-methoxy-2-oxido-1,2-oxaphospholan-3-ylphosphonate 200a
3. (a) Fleish, H. Drugs 1991, 42, 919–944; (b) Coleman, R. E. Rev. Contemp. Phar-
macother. 1998, 9, 147–164; (c) Major, P. P.; Lortholary, A.; Hon, J.; Abdi, T.; Mills,
G.; Mensen, H. D.; Yunus, F.; Bell, R.; Body, J.; Fehling, E.; Seaman, J. J. Clin. Oncol.
2001, 19, 558–567.
4. (a) Paterson, A. H. G.; Powles, T. J.; Kanis, J. A.; McCloskey, E.; Hanson, J.; Ashley,
S. J. Clin. Oncol. 1993, 11, 59–65; (b) Hortobagyi, G. N.; Theriault, R. L.; Porter, L.;
Blayney, D.; Lipton, A.; Sinoff, C.; Wheeler, H.; Simeone, J. F.; Seaman, J.; Knight,
R. D. N. Engl. J. Med. 1996, 335, 1785–1791; (c) Diel, I. J.; Solomayer, E. F.; Costa,
S. D.; Gollan, C.; Goerner, R.; Wallwiener, D.; Kaufmann, M.; Bastert, G. N. Engl. J.
To
a magnetically stirred solution of bromine (0.074 mL,
1.45 mmol) in anhydrous CH2Cl2 (25 mL), triphenylphosphine
(0.38 g, 1.45 mmol) was added in one portion. The brown solution
turned immediately to a pale yellow colour and then, tetraethyl

J.-P. Haelters et al. / Tetrahedron 64 (2008) 6537–6543
6543
Med. 1998, 339, 357–363; (d) Theriault, R. L.; Lipton, A.; Hortobagyi, G. N.; Leff,
R.; Glu¨ck, S.; Stewart, J. F.; Costello, S.; Kennedy, I.; Simeone, J.; Seaman, J. J.;
Knight, R. D.; Mellars, K.; Heffernan, M.; Reitsma, D. J. J. Clin. Oncol. 1999, 17,
846–854.
5. (a) Sasaki, A.; Boyce, B. F.; Story, B.; Wright, K. R.; Chapman, M.; Boyce, R.;
Mundy, G. R.; Yoneda, T. Cancer Res. 1995, 55, 3551–3557; (b) Sasaki, A.; Kita-
mura, K.; Alcalde, R. E.; Tanaka, T.; Suzuki, A.; Etoh, Y.; Matsumura, T. Int. J.
Cancer 1998, 77, 279–285.
6. (a) Boissier, S.; Ferreras, M.; Peyruchaud, O.; Magnetto, S.; Ebetino, F. H.;
Colombel, M.; Delmas, P.; Delaisse´, J.-M.; Clezardin, P. Cancer Res. 2000, 60,
2949–2954; (b) Virtanen, S.; Va¨a¨na¨nen, H. K.; Ha¨rko¨nen, P. L.; Lakkakorpi, P. T.
Cancer Res. 2002, 62, 2708–2714.
7. (a) van der Pluijm, G.; Vloedgraven, H.; van Beck, E.; van der Wee-Pals, L.;
Lowik, C.; Papapoulos, S. J. Clin. Invest. 1996, 98, 698–705; (b) Boissier, S.;
Magnetto, S.; Frappart, L.; Cuzin, B.; Ebetino, F. H.; Delmas, P. D.; Clezardin, P.
Cancer Res. 1997, 57, 3890–3894.
13. (a) Sturtz, G.; Guillamot, G.; Bourdeaux, M.; Chauvet, M. Eur. J. Med. Chem. 1984,
19, 274–276; (b) Sturtz, G.; Guervenou, J. Synthesis 1991, 661–662; (c) Sturtz, G.;
Appere, G.; Breistol, K.; Fodstad, O.; Schwartsmann, G.; Hendriks, H. R. Eur. J.
Med. Chem. 1992, 27, 825–833; (d) Sturtz, G.; Couthon, H.; Fabulet, O.; Mian, M.;
Rosini, S. Eur. J. Med. Chem. 1993, 28, 899–903; (e) Gourves, J.-P.; Couthon, H.;
Sturtz, G. Phosphorus Sulfur Silicon 1997, 132, 219–229; (f) Couthon, H.; Gourves,
J.-P.; Guervenou, J.; Corbel, B.; Sturtz, G. Synth. Commun. 1999, 29, 4241–4260.
14. (a) Hannuniemi, R.; Lauren, L.; Puolijoki, H. Drugs Today 1991, 27, 375–390; (b)
Lin, J. H. Bone 1996, 18, 75–85; (c) Vepsa¨la¨inen, J. J. Curr. Med. Chem. 2002, 9,
1201–1208.
15. (a) Turhanen, P. A.; Vepsa¨la¨inen, J. J. Beilstein J. Org. Chem. 2006, 2, 2; (b) Tur-
hanen, P. A.; Vepsa¨la¨inen, J. J. Synthesis 2005, 13, 2119–2121; (c) Vepsa¨la¨inen, J. J.
Tetrahedron Lett. 1999, 40, 8491–8493; (d) Vachal, P.; Hale, J. J.; Lu, Z.; Streck-
fuss, E. C.; Mills, S. G.; MacCoss, M.; Yin, D. H.; Algayer, K.; Manser, K.; Kesi-
soglou, F.; Ghosh, S.; Alani, L. L. J. Med. Chem. 2006, 49, 3060–3063; (e) Monteil,
M.; Guenin, E.; Migianu, E.; Lutomski, D.; Lecouvey, M. Tetrahedron 2005, 61,
7528–7537; (f) Turhanen, P. A.; Vepsa¨la¨inen, J. J. Synthesis 2005, 18, 3063–3066;
(g) Niemi, R.; Turhanen, P.; Vepsa¨la¨inen, J.; Taipale, H.; Ja¨rvinen, T. Eur. J. Pharm.
8. (a) Perez-Atayde, A.; Sallan, S.; Tedrow, U.; Connors, S.; Allred, E.; Folkman, J.
Am. J. Pathol. 1997, 150, 815–821; (b) Fournier, P.; Boissier, S.; Filleur, S.;
´
¨ ¨
Guglielmi, J.; Cabon, F.; Colombel, M.; Clezardin, P. Cancer Res. 2002, 62, 6538–
Sci. 2000, 11, 173–180; (h) Ahlmark, M.; Vepsalainen, J.; Taipale, H.; Niemi, R.;
Ja¨rvinen, T. J. Med. Chem. 1999, 42, 1473–1476; (i) Niemi, R.; Vepsa¨la¨inen, J.;
Taipale, H.; Ja¨rvinen, T. J. Med. Chem. 1999, 42, 5053–5058.
16. Ollivier, R.; Sturtz, G.; Legendre, J.-M.; Jacolot, G. Eur. J. Med. Chem. 1986, 21,
103–110.
6544; (c) Wood, J.; Bonjean, K.; Ruetz, S.; Bellahcene, A.; Devy, L.; Foidart, J. M.
J. Pharmacol. Exp. Ther. 2002, 302, 1055–1061; (d) Hamma-Kourbali, Y.; Di
Benedetto, M.; Ledoux, D.; Oudar, O.; Leroux, Y.; Lecouvey, M.; Kraemer, M.
Biochem. Biophys. Res. Commun. 2003, 310, 816–823.
9. (a) Shipman, C. M.; Rogers, M. J. Br. J. Haematol. 1997, 98, 665–672; (b) Lee,
M. V.; Fong, E. M.; Singer, F. R.; Guenette, R. S. Cancer Res. 2001, 15, 2602–2608;
(c) Riebeling, C.; Forsea, A. M.; Raisova, M.; Orfanos, C. E.; Geileu, C. C. Br. J. Cancer
2002, 87, 366–371; (d) Fromigue, O.; Lagneaux, L.; Body, J. J. J. Bone Miner. Res.
2000, 15, 2211–2221; (e) Nishida, S.; Kikuichi, S.; Haga, H.; Yoshioka, S.; Tsubaki,
M.; Fujii, K.; Irimajiri, K. Biol. Pharm. Bull. 2003, 26, 96–100; (f) Dumon, J.-C.;
Journe´, F.; Kheddoumi, N.; Lagneaux, L.; Body, J.-J. Eur. Urol. 2004, 45, 521–529.
10. Miyagawa, F.; Tanaka, Y.; Yamashita, S.; Minato, N. J. Immunol. 2001, 166, 5508–
5514.
17. Pappas, J. J.; Keaveney, W. P.; Gancher, E.; Berger, M. Tetrahedron Lett. 1966, 7,
4273–4278.
18. Flippin, L. A.; Gallagher, D. W.; Jalali-Araghi, K. J. Org. Chem. 1989, 54, 1430–1432.
19. Boman, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem. 1995, 60, 5995–5996.
20. Fadel, A. J. Org. Chem. 1999, 64, 4953–4955.
21. (a) McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M. C. Tetrahedron Lett.
1977, 18, 155–158; (b) McKenna, C. E.; Schmidt-Hauser, J. J. Chem. Soc., Chem.
Commun. 1979, 739.
22. Kultyshev, R. G.; Liu, J.; Liu, S.; Tjarks, W.; Soloway, A. H.; Shore, S. G. J. Am.
11. (a) Dunn, C. J.; Galinet, L. A.; Wu, H.; Nugent, R. A.; Schlachter, S. T.; Staite, N. D.;
Aspar, D. G.; Elliott, G. A.; Essani, N. A.; Rokloff, N. A. J. Pharmacol. Exp. Ther. 1993,
226, 1691–1698; (b) Schlachter, S. T.; Galinet, L. A.; Shields, S. K.; Aspar, D. G.;
Dunn, C. J.; Staite, N. D.; Nugent, R. A. Bioorg. Med. Chem. Lett. 1998, 8, 1093–
1096; (c) Flora, L. Arthritis Rheum. 1979, 22, 340–346; (d) van Offel, J. F.;
Shuerwegh, A. J.; Bridts, C. H.; Bracke, P. G.; Stevens, W. J.; De Clerck, L. S. Clin.
Exp. Rheumatol. 2001, 19, 13–20.
12. Martin, M. B.; Grimley, J. S.; Lewis, J. C.; Heath, H. T.; Bailey, B. N.; Kendrick, H.;
Yardley, V.; Caldera, A.; Lira, R.; Urbina, J. A.; Moreno, S. N. J.; Docampo, R.;
Croft, S. L.; Oldfield, E. J. Med. Chem. 2001, 44, 909–916.
Chem. Soc. 2002, 124, 2614–2624.
23. Knouzi, N.; Vaultier, M.; Carrie´, R. Bull. Soc. Chim. Fr. 1985, 5, 815–819.
24. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46,
3936–3938.
25. Yamada, S.-I.; Ninomiya, K.; Shiori, T. Tetrahedron Lett. 1973, 26, 2343–2346.
26. Palumbo, G.; Ferreri, C.; Caputo, R. Tetrahedron Lett. 1983, 24, 1307–1310.
27. (a) Pondaven-Raphalen, A.; Sturtz, G. Phosphorus Sulfur 1987, 29, 329–339; (b)
Kirchmayr, R.; Illy, H. Ger. Offen. 1976, 2555452; (c) Machida, Y.; Saito, I. J. Org.
Chem. 1979, 44, 865–866.
28. Stillway, L. W.; Harmon, S. J. A. J. Lipid Res. 1980, 21, 1141–1143.