Synthesis of bone-targeted oestrogenic compounds for the inhibition of bone resorption

Article abstract of DOI:10.1016/S0040-4020(00)01164-9

Syntheses have been realised for several members of a new class of potential bone resorption inhibitors consisting of steroidal oestrogenic compounds linked at the 17 position to a geminal bis(phosphonic acid) moiety through an ester linkage. The approach used has the potential to allow other biologically active compounds to be coupled to the geminal bisphosphonate unit.

Full text of DOI:10.1016/S0040-4020(00)01164-9

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1837±1847
Synthesis of bone-targeted oestrogenic compounds for the
inhibition of bone resorption
Philip C. Bulman Page,a,p Jonathan P. G. Moore,a Ian Mans®eld,a Michael J. McKenzie,a
Wayne B. Bowlerb and James A. Gallagherb
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
bDepartment of Human Anatomy and Cell Biology, University of Liverpool, Liverpool L69 3GE, UK
Received 29 September 2000; revised 4 December 2000; accepted 14 December 2000
AbstractÐSyntheses have been realised for several members of a new class of potential bone resorption inhibitors consisting of steroidal
oestrogenic compounds linked at the 17 position to a geminal bis(phosphonic acid) moiety through an ester linkage. The approach used has
the potential to allow other biologically active compounds to be coupled to the geminal bisphosphonate unit. q 2001 Elsevier Science Ltd.
All rights reserved.
1. Introduction
readily cleaved would not achieve targeting. Oestrogen±
bisphosphonate conjugates are known with non-hydroly-
sable linkers,8 and with ether,9 carbonate,10 and amide11
linkers. Cortisone±bisphosphonate conjugates are known
with ester linkers.12 We reasoned that a carboxylic ester
linkage might provide an appropriate balance between
stability and ease of cleavage, and, further, that this balance
might be adjusted by, for example altering the steric
environment around the ester unit. In the case of oestradiol,
such an ester linkage might readily be positioned at either
the 3- or 17-hydroxylated positions as in 1 or 2, and this
design would in addition allow the incorporation of other
hydroxyl functionalized biologically active compounds.
Geminal bisphosphonates are stable pyrophosphate
analogues that bind ef®ciently to bone surface.1 They have
been used in the clinic to inhibit bone resorption, in most
cases with few side effects.2 Some simple examples, for
example etidronate and alendronate, are already marketed
for the treatment of osteoporosis and Paget's disease.3 It has
been suggested that bisphosphonates are general metabolic
inhibitors.4 The low level of side effects has been attributed
to the rapid absorption of the geminal bisphosphonate to the
bone surface and incorporation within the bone matrix,
thereby preventing undesired effects within other organs.2
Other clinically used treatments for osteoporosis, such as
hormone replacement threrapy, are effective, but can have
effects on other tissues.5 We are interested in using geminal
bisphosphonates as bone-targeting moieties for the treat-
ment of bone-related disease;6 our aim is to use the bone
tropism to deliver therapeutics at the desired site of action,
thus reducing unwanted side effects in other tissues. We
report here the synthesis of geminal bisphosphonic acids
functionalized with derivatives of oestradiol, an osteoclast
inhibitor known to regulate the circuitry of cytokine action
that controls bone remodelling.7
In the design of such compounds it is vital to consider the
linkage between the geminal bisphosphonate moiety and the
oestrogenic unit. A conjugate with a linker not readily
cleaved by hydrolysis or by enzyme action may not retain
oestrogenic activity, while a conjugate with a linker too
Keywords: oestrogen; bisphosphonate; targeting.
Corresponding author. Tel.: 11509-222581; fax: 11509-223926; e-mail:
p.c.b.page@lboro.ac.uk
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01164-9

1838
P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
Scheme 1. (i) DMAP, toluene, D, 4 d; 63%.
Scheme 2. (i) Et2NH, (CH2O)n, MeOH, D; (ii) cat. TsOH, toluene, D, 24 h; 88% overall.
2. Results and discussion
1,1-bisphosphonate 7, which was dehydrated under Dean±
Stark conditions to give 6 in 88% overall yield (Scheme 2).
The methylene unit of simple methylene bisphosphonates
such as 3 is readily deprotonated,13 but the anions are corre-
spondingly poorly reactive in nucleophilic substitution,14
and it was therefore necessary to add a functional group to
the geminal bisphosphonate, which could be used in a
subsequent coupling step. Our feasibility studies using
triethyl phosphonoacetate 4 showed that it is possible to
carry out a transesteri®cation selectively at the carboxylic
ester of 4 with the 17-hydroxy group of 3-O-methyl-17b-
oestradiol to give 5 in 63% yield (Scheme 1). However,
transesteri®cation of 4 did not occur with the phenolic
3-hydroxy group of oestrone under similar conditions.
A tetraethyl geminal bisphosphonate containing a diethyl
malonate unit 8a was generated in 95% yield by Michael
addition of the malonate anion to ethylidene bisphosphonate
6 induced by sodium ethoxide in ethanolic solution at
room temperature (Scheme 3).16,17 The dibenzyl analogue
8b was prepared similarly, in 58% yield, from dibenzyl
malonate.
Benzyl ether protection of the 3-hydroxy group of 17b-
oestradiol was chosen to allow for easy and selective
removal at a later stage of the synthesis. Oestrone was
converted into its methyl and benzyl ethers and the ketone
groups reduced with sodium borohydride in methanol to
give the protected 17b-oestradiols after separation from
the 17a-isomer contaminants.18 Chemoselective transesteri-
®cation of both the carboxylic esters of intermediate 8a with
3-O-benzyl-17b-oestradiol took place in toluene solution
under re¯ux in the presence of 4,4-dimethylaminopyridine
over 11 d, and led to the bis-transesteri®ed product 9 in 67%
yield. Removal of the benzyl protecting group by catalytic
hydrogenolysis over palladium on carbon gave 10 in 96%
yield. The phosphonate ester groups of 10 were selectively
hydrolysed by treatment with excess bromotrimethylsilane
over 3 d followed by addition of 1 M hydrochloric acid to
the reaction mixture;19 the product bis(phosphonic acid) 11
precipitated in excellent yield (Scheme 4). Intermediate 8a
was similarly bis-transesteri®ed with testosterone (82%)
Ethylidene bisphosphonate 6 was identi®ed as a key inter-
mediate, and was prepared in multigramme quantities from
tetraethyl methylene bisphosphonate 3 by the method of
Degenhardt.15 Treatment with paraformaldehyde and
diethylamine in methanol produced b-methoxyethylene
Scheme 3. (i) 0.1 equiv. NaOEt, diethyl or dibenzyl malonate, EtOH, rt,
15 min.
Scheme 4. (i) 8a, 0.1 equiv. DMAP, toluene, D, 11 d, 67%; (ii) H2, 10% Pd/C, THF±MeOH, 6 h, 96%; (iii) 35 equiv. TMSBr, CHCl3±CCl4, rt, 1±3 d; H3O1,
94%.

P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
1839
Scheme 5. (i) H2, Pd/C; THF, overnight, 88%; (ii) D 1308C, 3 h, 99%.
Scheme 6. (i) 13, 1.0 equiv. EDCI, 0.5 equiv. DMAP, DCM, 08C, rt overnight, 33%.
and the phosphonate ester groups hydrolysed (72%) to give
the bis(phosphonic acid).
oestrone. Coupling of 3-O-benzyl-17b-oestradiol 15 to
acid 13 to give ester 14 was successfully achieved using
EDCI as dehydrating agent in 2 h at 08C (Scheme 6).20
The analogous bis(phosphonic acid) 12, containing a single
carboxylic ester unit, is a less sterically hindered and so
potentially more readily hydrolysable conjugate. The
bisphosphonate mono-carboxylic acid 13 was produced
from 8a according to the method of Sturtz in 27% yield
by basic hydrolysis and decarboxylation induced by heat-
ing.17 In a superior procedure, hydrogenolysis of the benzyl
esters of 8b (88%) followed by decarboxylation induced
by heating (99%) led to 13 as a much cleaner material
(Scheme 5).
In order to provide a range of steroidal bisphosphonate
conjugates with a spectrum of lability towards hydrolysis
in vivo, we wished to prepare mixed malonyl derivatives of
geminal bisphosphonic acids. The need for an ef®cient and
general synthesis seemed to us to dictate an alternative
strategy involving initial generation of mixed malonates
followed by incorporation of the bisphosphonate unit
(Scheme 6).
Attempted functionalization of 3-O-benzyl-17b-oestradiol
15 with malonyl dichloride or ethyl malonyl chloride proved
unsuccessful. With a view to utilising a carbodiimide
coupling, ethyl malonic half ester 16a was prepared from
An alternative coupling procedure was next sought which
would avoid the lengthy transesteri®cation process, and
which might also allow coupling at the 3-position of
Scheme 7. (i) ROH, MeCN, D; (ii) 15, DCC, DMAP, CH2Cl2 or MeCN, rt.
Table 1. Preparation and coupling of malonic half esters
diethyl malonate by the method of Strube,21 and coupled to
3-O-benzyl-17b-oestradiol to give mixed malonate 17a
using DCC. A more ef®cient preparation of mixed malo-
nates 17b±f was realised through addition of a range of
alcohols to Meldrum's acid in acetonitrile under re¯ux to
give malonic half esters 16b±g (Scheme 7, Table 1);22
DCC-mediated coupling of 3-O-benzyl-17b-oestradiol to
16b±f took place in dichloromethane solution, providing
mixed malonates 17b±f.
Entry
ROH
Yield of 16 (%)
Yield of 17 (%)
a
a
b
c
d
e
f
EtOH
4-NO2C6H4OH
MeOH
i-PrOH
t-BuOH
PhOH
46
69
68
69
15
92
±
97
65
100b
54
34
49
g
15
a
Prepared by the method of Strube.21
Crude yield.
After some experimentation, deprotonation of 17a±d and
conjugate addition to tetraethyl ethylidene bisphosphonate
b

1840
P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
Scheme 8. (i) LHMDS, THF; 6, 608C, 18 h.
4. Experimental
Table 2. Preparation of bisphosponate conjugates
4.1. General experimental detail
Entry
ROH
Yield of 18 (%)
a
b
c
d
EtOH
30
24
57
40
Light petroleum ether (bp 40±608C) was distilled from
calcium chloride. Ethyl acetate was distilled from phos-
phorus pentoxide or calcium chloride. Dichloromethane
was distilled from phosphorus pentoxide or pentachloride.
Tetrahydrofuran was distilled under a nitrogen atmosphere
from the sodium/benzophenone ketyl radical or purchased
from the Aldrich Chemical Company in sure seal con-
tainers. Toluene was distilled from calcium hydride.
Ethanol was distilled from calcium hydride or stored over
sodium ethoxide and distilled prior to use. Methanol was
distilled from calcium hydride or stored over sodium meth-
oxide and distilled prior to use. Triethylamine, pyridine and
diethylamine were stored over potassium hydroxide pellets
and distilled prior to use. N-Bromosuccinimide was
recrystallized from water and dried under high vacuum.
Commercially available reagents were used as supplied,
without further puri®cation, unless otherwise stated.
4-NO2C6H4OH
MeOH
i-PrOH
6 was achieved to produce 18a±d, each as a ca 1:1
mixture of diastereoisomers, for example using lithium
hexamethyldisilazide as base at 608C in THF solution
(Scheme 8, Table 2). Similar transformation could not be
achieved for the other mixed malonates.
Selective hydrogenolysis of the benzyl ether of 18b did not
prove possible, but hydrogenolyses of the benzyl ethers of
18a and c to give the phenols 19a and c (80 and 79% yields,
respectively), and subsequent phosphonate ester hydrolyses
(100 and 70% yields, respectively), were carried out as
described above for bis-carboxylic ester 9, to provide the
corresponding bisphosphonic acids 20a and c (Scheme 9).
Microanalyses were performed on Carlo Erba Model 1106
or Perkin±Elmer 2400 instruments. Optical rotation values
were measured with an Optical Activity-polAAar 2001
instrument, operating at 589 nm, at the temperatures
indicated. Melting points were carried out on an Electro-
thermal-IA 9100 or a Ko¯er block apparatus and are
uncorrected.
3. Conclusions
Several members of a new class of potential bone resorption
inhibitors have been prepared, consisting of steroidal units
linked at the 17 position to a geminal bis(phosphonic acid)
moiety through ester linkages. The synthesis utilises
chemoselective reactions at a carboxylic ester and selective
phosphonate ester hydrolysis, and has the potential to allow
many oestrogen derivatives as well as other biologically
active compounds to be coupled to the geminal bis-
phosphonate unit. Investigation of the biological properties
of the steroidal bis(phosphonic acid) conjugates is in
progress.
Infrared absorption spectra were recorded on a Perkin±
Elmer Paragon 2001 or 883 LR, or Nicolet 205 FT-IR
spectrophotometers in the range 4000±600 cm21, and
were calibrated against the 1602 cm21 absorption of poly-
styrene. Liquids were run as thin ®lms, and solids as Nujol
mulls on sodium chloride plates, or as solutions in chloro-
form or methanol. Mass spectra were recorded using Kratos
MS-80, VG Analytical 7070E, or Jeol-SX102 instruments
using EI, CI, and FAB ionization techniques, a Fisons
Scheme 9. (i) H2, Pd/C, 60 psi, CH2Cl2; (ii) 8 equiv TMSBr, CH2Cl2, 2.5 d; MeOH, 30 min.

P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
1841
Instrument Trio 1000 quadrapole instrument, or by the
EPSRC National Service. 1H NMR, 13C NMR and 31P
NMR spectra were recorded on Bruker AC 200, AC 250,
AMX 400 or DPX 400 instruments.
dissolved in ethanol (100 mL) and stirred at 08C under a
nitrogen atmosphere. The mixture was allowed to reach
room temperature and stirred until all the sodium had
dissolved. The sodium ethoxide solution so prepared was
transferred via a cannula to a mixture of 6 (30.0 g,
100 mmol) and diethyl malonate (15.20 mL, 16.02 g,
100 mmol) in ethanol (50 mL). The reaction mixture was
stirred under an atmosphere of nitrogen at room temperature
for 30 min, washed with aqueous HCl (1 M, 3£100 mL) and
extracted with CH2Cl2 (200 mL). The organic layer was
dried over MgSO4, the solvent removed under reduced pres-
sure, and ®nal traces of solvent removed under high vacuum
to give 8a as a colourless oil (43.8 g, 95%). (Found: C,
43.97; H, 7.55; Cl7H34O10P2 requires: C, 44.35; H, 7.44);
nmax 3010, 1749, 1732, 1270, and 1045 cm21; dH (CDCl3)
1.28 (6H, t, Jˆ7 Hz), 1.35 (12H, t, Jˆ7 Hz), 2.33±2.75 (3H,
m), 3.97 (1H, t, Jˆ8 Hz), and 4.12±4.27 (12H, m); dC
(CDCl3) 14.48, 16.71 (d, JC±Pˆ6 Hz), 25.29 (d,
JC±Pˆ5 Hz), 34.71 (t, JC±Pˆ132 Hz), 50.51 (t, JC±Pˆ8 Hz),
61.97, 63.22 (t, JC±Pˆ8 Hz), and 169.31; dP (CDCl3) 22.33;
m/z (CI) 460.1632 (M1); C17H34O10P2 requires 460.1627.
4.2. Procedures
4.2.1. 17b-(3-Methoxy-1,3,5-oestratrienyl) 2-(diethyl-
phosphono)acetate 5. Triethyl phosphonoacetate (0.039 g,
0.175 mmol), 3-methoxy-17b-oestradiol (0.100 g, 0.349
mmol), and 4-(N,N-dimethylamino)pyridine (0.006 g,
0.052 mmol), were heated under re¯ux in toluene (10 mL)
for 4 d. The resulting mixture was washed with water
(100 mL), and the product extracted into CH2Cl2
(100 mL). The organic layer was collected and concentrated
under reduced pressure, and the crude product puri®ed by
column chromatography on silica gel, using 25±75% ethyl
acetate±petroleum ether (40±608C) as eluent to give 5 as a
colourless oil (0.05 g, 63%); nmax 2970, 1710, 1600, 1575,
1495, 1030 and 980 cm21; dH (CDCl3) 0.79 (3H, s), 1.15±
1.87 (11H, m), 1.29 (6H, t, Jˆ7 Hz), 2.05±2.34 (3H, m),
2.74±2.86 (2H, m), 2.94 (2H, d, JP±Hˆ22 Hz), 3.70 (3H, s),
4.03±4.19 (4H, m), 4.68 (1H, t, Jˆ9 Hz), 6.57 (1H, s), 6.64
(1H, dd, Jˆ9, 3 Hz), and 7.13 (1H, d, Jˆ9 Hz); m/z (EI) 464
(89) (M1), 268 (24), 179 (100), and 160 (68); Found:
464.2324. C25H37PO6 requires: 464.2328.
4.2.4. Oestrone methyl ether. Oestrone (1.00 g,
3.67 mmol) was dissolved in acetone (75 mL), and
anhydrous K2CO3 (1.53 g, 11.1 mmol) and iodomethane
(1.38 mL, 3.15 g, 22.2 mmol) were added. The reaction
mixture was stirred under a nitrogen atmosphere at room
temperature for 24 h. Aqueous HCl (1 M, 150 mL) was
added and the reaction mixture extracted into CH2Cl2. The
solvent was removed under reduced pressure and the crude
product puri®ed by ¯ash column chromatography using
20% ethyl acetate±petroleum ether (40±608C) as eluent.
The product was obtained as a colourless powder (0.89 g,
85%); nmax 2980, 1735, 1615, 1580, and 1510 cm21; dH
(CDCl3) 0.83 (3H, s), 1.26±1.68 (6H, m), 1.76±2.50 (7H,
m), 2.77±2.88 (2H, m), 3.69 (3H, s), 6.57 (1H, d, Jˆ3 Hz),
6.63 (1H, dd, Jˆ8, 3 Hz), and 7.12 (1H, d, Jˆ8 Hz); m/z
(EI) 284 (100), 199 (75), 160 (81); Found: 284.1780.
Cl9H24O2 requires 284.1776.
4.2.2. Tetraethyl ethylidene bisphosphonate 6. Tetraethyl
methylene bisphosphonate (47.4 g, 0.165 mol), para-
formaldehyde (24.75 g, 0.825 mol), and diethylamine
(17.1 mL, 12.1 g, 0.165 mol) were added to methanol
(470 mL). The reaction mixture was heated under re¯ux
until it became a colourless solution (ca 30 min), and stirred
for further 15 h at room temperature. The mixture was
concentrated under reduced pressure, and toluene
(150 mL) added. The solvent was removed under reduced
pressure, and the concentration±evaporation process
repeated a second time. This procedure was performed in
order to remove any residual methanol from the crude
viscous intermediate. The 2-methoxyethylene 1,1-bis-
phosphonate intermediate 7 was isolated as a viscous clear
oil; puri®cation at this stage was not required and the
product was used in its crude form; dH (CDCl3) 1.29
(12H, t, Jˆ8 Hz), 2.67 (1H, tt, JP±Hˆ24 Hz, JH±Hˆ5 Hz),
3.32 (3H, s), 3.86 (2H, td, JP±Hˆ17 Hz, JH±Hˆ5 Hz), and
4.15 (8H, m).
4.2.5. 3-O-Methyl-17b-oestradiol. Oestrone methyl ether
(0.50 g, 1.76 mmol) was dissolved in methanol (20 mL) and
tetrahydrofuran (20 mL). Sodium borohydride (0.10 g,
2.64 mmol) was added. The reaction mixture was stirred
for 2 h at room temperature under a nitrogen atmosphere.
Water (100 mL) was added and the mixture extracted with
CH2Cl2. The solvent was removed and the crude product
puri®ed by ¯ash column chromatography, using 50% ethyl
acetate±petroleum ether (40±608C) as eluent. The product
was obtained as a colourless powder (0.44 g, 87%); nmax
3480, 2980, 1630, 1575, 1502, and 1470 cm21; dH
(CDCl3) 0.78 (3H, s), 1.10±2.55 (14H, m), 2.81±2.99
(2H, m), 3.73 (1H, t, Jˆ8 Hz), 3.80 (3H, s), 6.63 (1H, m),
6.71 (1H, dd, Jˆ8, 3 Hz), and 7.21 (1H, d, Jˆ8 Hz); m/z
(EI) 286 (41), 268 (23), 160 (72), and 147 (100); Found:
286.1938. Cl9H26O2 requires: 286.1933.
Toluene-p-sulfonic acid (0.15 g) was added to a solution of
the crude tetraethyl 2-methoxyethylene 1,1-bisphosphonate
7 in toluene (250 mL). The reaction mixture was heated
under re¯ux overnight. The reaction mixture was washed
with water (3£100 mL), the organic layer dried over
MgSO4, and the solvent removed under reduced pressure
to yield 6 as an oil (43.16 g, 88% overall); nmax 3020,
2960, 1485, 1452, 1402, 1270, and 1050 cm21; dH
(CDCl3) 1.30 (12H, t, Jˆ8 Hz), 4.0±4.2 (8H, m), and 6.94
(2H, dd, trans JP±Hˆ40, cis JP±Hˆ36 Hz); dC (CDCl3) 16.15
(t, Jˆ3 Hz), 63.08 (d, Jˆ3 Hz), 132.58 (t, Jˆ127 Hz) and
149.11; dP (CDCl3) 11.6; m/z (CI) 301.0970 (M1H)1;
C10H22O6P2 requires 301.0970.
4.2.6. Oestrone benzyl ether. Oestrone (10.0 g, 37.0 mmol
and anhydrous K2CO3 (25.6 g, 185 mmol) were added to
acetone (150 mL). Benzyl bromide (7.79 mL, 11.2 g,
65.4 mmol) was added slowly with stirring, the reaction
mixture allowed to stir overnight at room temperature,
®ltered, and concentrated under reduced pressure. The
4.2.3. Tetraethyl 3,3-bis(ethoxycarbonyl)propylene
bisphosphonate 8a. Sodium (0.23 g, 10 mmol) was

1842
P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
concentrate was dissolved in CH2Cl2 (200 mL) and washed
with aqueous HCl (1 M, 3£100 mL). The organic layer was
dried over MgSO4 and the solvent removed under reduced
pressure. The crude product was recrystallized from metha-
nol and washed repeatedly with cold methanol to remove
traces of benzyl bromide. The product was obtained as
colourless crystals (9.47 g, 71%), mp 129±1308C; (Found:
C, 83.2; H, 7.88. C25H28O2 requires: C, 83.29; H 7.83%);
nmax 3012, 2936, 1730, 1606, and 1497 cm21; dH (CDCl3)
0.92 (3H, s), 1.39±1.73 (6H m), 1.92±2.67 (7H, m), 2.85±
2.95 (2H, m), 5.05 (2H, s), 6.75 (1H, d, Jˆ2 Hz), 6.80 (1H,
dd, Jˆ6, 2 Hz), 7.22 (1H, d, Jˆ6 Hz), and 7.33±7.46 (5H,
m); dC (CDCl3) 13.8, 21.6, 25.9, 26.5, 29.6, 31.7, 35.9, 38.3,
44.0, 48.0, 50.4, 69.9, 112.4, 114.9, 126.4, 127.4, 127.8,
128.5, 132.3, 137.2, 137.8, 156.8, and 221.0; m/z (EI) 360
(M1) and 91 (100); Found: 360.2095, C25H28O2 requires:
360.2089.
4.2.9. Tetraethyl (3,3-bis(17b-(3-hydroxyoestra-1,3,5-
trienyl)oxycarbonyl)propylidene) bisphosphonate 10.
10% Pd±C (140 mg) was added to a solution of 9
(692 mg, 0.633 mmol) in 1:1 THF±MeOH (10 mL). The
reaction mixture was shaken under an atmosphere of hydro-
gen (1 bar) for 6 h. The reaction mixture was ®ltered,
CH2Cl2 added, and the solution washed with brine. The
organic layer was collected, dried over MgSO4, and the
solvent removed under reduced pressure. The residue was
puri®ed by column chromatography on silica gel using
3±5% MeOH±CH2Cl2 as eluent to give 10 as a foam
(557 mg, 96%); (Found: C, 64.68; H, 7.76. C49H70O12P2
requires: C, 64.46; H, 7.73%); dH (CDCl3) 0.775 (3H, s),
0.781 (3H, s), 1.15±1.87 (21H, m), 1.34 (12H, t, Jˆ7 Hz),
2.09±2.33 (6H, m), 2.49 (2H, hept, Jˆ8 Hz), 2.66 (1H, tt,
JP±Hˆ24, JH±Hˆ7 Hz), 2.81 (4H, m), 4.05 (1H, t, Jˆ8 Hz),
4.16±4.24 (8H, m) 4.71 (2H, q, Jˆ9 Hz), 6.58 (2H, s), 6.66
(2H, d, Jˆ8 Hz), and 7.08 (2H d, Jˆ9 Hz); dC (CDCl3)
11.93, 12.03, 16.29 (d, Jˆ5 Hz), 23.22, 24.95, 26.16,
27.18, 27.37, 29.53, 34.17 (t, Jˆ134 Hz), 36.81, 38.56,
42.98, 43.17, 43.68, 49.64, 50.23 (t, Jˆ9 Hz), 63.06 (t,
Jˆ7 Hz), 83.95, 84.09, 112.77, 115.31, 126.22, 131.48,
131.53, 137.79, 154.23, and 168.84; dP (CDCl3) 20.7 (s);
m/z (FAB) 912.4743 (M11H); C49H70O12P2 requires
912.4343.
4.2.7. 3-O-Benzyl-17b-oestradiol 15. Sodium borohydride
(2.36 g, 62.4 mmol) was added slowly at 08C to a solution of
oestrone benzyl ether 145 (7.50 g, 20.8 mmol) in CH2Cl2
(100 mL) and methanol (100 mL). The reaction mixture
was stirred for 3 h under a nitrogen atmosphere and allowed
to reach room temperature. Water (150 mL) was added and
the mixture extracted with CH2Cl2 (200 mL) and washed
with aqueous HCl (1 M, 3£100 mL). The organic layer
was dried over MgSO4. The solvent was removed and the
crude product recrystallized from methanol to give colour-
less needles (6.70 g, 89%), mp 958C; (Found: C, 82.97; H,
8.72. C25H30O2 requires: C, 82.83; H, 8.34%); nmax 3610,
2932, 1605, and 1453 cm21; dH (CDCl3) 0.78 (3H, s), 1.10±
2.38 (14H, m), 2.81±2.88 (2H, m), 3.32 (1H, dd, Jˆ8,
9 Hz), 5.03 (2H, s), 6.71 (1H, d, Jˆ3 Hz), 6.77 (1H, dd,
Jˆ7, 3 Hz), 7.20 (1H, d, Jˆ8 Hz), and 7.28±7.46 (5H,
m); dC (CDCl3) 11.03, 23.10, 26.29, 27.20, 29.76, 30.54,
36.69, 38.82, 43.24, 43.95, 50.04, 69.96, 81.87, 112.28,
114.84, 126.32, 127.43, 127.80, 128.50, 132.95, 137.33,
138.02, and 156.72; m/z (FAB) 362.2240 (M1); C25H30O2
requires 362.2246.
4.2.10. 3,3-Bis-(17b-(3-hydroxy oestra-1,3,5-trienyl)oxy-
carbonyl)propylidene bis(phosphonic acid) 11. Tri-
methylsilyl bromide (1.24 mL, 1.47 g, 9.62 mmol) was
added to a solution of 10 (250 mg, 0.275 mmol) in 1:1
CCl4±CHCl3 (3 mL) and the reaction mixture stirred for
24 h under a nitrogen atmosphere. Water (5 mL) was
added. The off-white precipitate was removed by ®ltration,
washed with cold water and CH2Cl2, and dried under high
vacuum to give 11 as an off-white powder (206 mg, 94%);
mp 1808C (dec); dH (CD3OD) 0.85 (3H, s), 0.86 (3H, s),
1.20±2.05 (21H, m), 2.10±2.30 (5H, m), 2.38±2.50 (3H,
m), 2.70±2.81 (4H, m), 4.08 (1H, t, Jˆ7 Hz), 4.72 (2H, t,
Jˆ8 Hz), 6.47 (2H, d, Jˆ2 Hz), 6.53 (2H, dd, Jˆ9, 2 Hz),
and 7.05 (2H, d, Jˆ9 Hz); dC (CD3OD) 12.64, 12.71, 24.22,
26.37, 27.44, 28.45, 28.52, 30.63, 36.79 (t, Jˆ127 Hz),
38.16, 40.18, 44.28, 44.40, 45.10, 50.94, 52.04, 85.26,
85.34, 113.79, 116.08, 127.21, 132.36, 138.73, 155.94,
and 170.49; dP (CD3OD) 22.6; m/z (negative ion FAB)
799 (M1-H, 100).
4.2.8. Tetraethyl (3,3-bis(17b-(3-benzyloxyoestra-1,3,5-
trienyl)oxycarbonyl)propylidene) bisphosphonate 9.
4-[(N,N-Dimethylamino)pyridine (0.013 g, 0.11 mmol)
and 3-O-benzyl-17b-oestradiol (0.861 g, 2.39 mmol) were
added to a solution of 8a (0.50 g, 1.09 mmol) in toluene
(10 mL). The reaction mixture was heated under re¯ux for
11 h under an atmosphere of nitrogen. The solvent was
removed under reduced pressure and the product puri®ed
by column chromatography on silica gel using 1±3%
methanol±CH2Cl2 as eluent to give 9 as a colourless
viscous oil (0.80 g, 67%); nmax 3017, 2936, 1724, 1605,
1498, 1203, and 929 cm21; dH (CDCl3) 0.84 (3H, s), 0.88
(3H, s),1.23±1.97 (21H, m), 1.35 (12H, t, Jˆ7 Hz), 2.15±
2.36 (13H, m), 4.72±4.81 (2H, m), 5.05 (4H, s), 6.74 (2H, s),
6.80 (d, 2H, Jˆ9 Hz), 7.23 (d, 2H, Jˆ9 Hz), and 7.30±7.47
(10H, m); dC (CDCl3) 13.09, 13.20, 17.43, 17.51, 24.35,
26.19, 27.24, 28.29, 28.53, 30.82, 35.51 (t, JC±Pˆ132 Hz),
37.95, 44.15, 44.31, 44.84, 50.80, 51.38 (t, JC±Pˆ73 Hz),
63.83 (t, JC±Pˆ7 Hz), 71.00, 85.02 (d, JC±Pˆ10 Hz),
113.39, 115.92, 127.42, 128.49, 128.89, 129.59, 133.73,
138.39, 138.95, 157.84, and 169.96 (d, JC±Pˆ4 Hz); dP
(CDCl3) 20.4; m/z (FAB) 1092.5212 (M1); C63H82O12P2
requires 1092.5282.
4.2.11. Tetraethyl (3,3-bis(17b-(androst-4-en-3-onyl)oxy-
carbonyl)propylidene)bisphosphonate.
Testosterone
(0.500 g, 1.73 mmol), 8a (0.363 g, 0.788 mmol), and
4-(N,N-dimethylamino)pyridine were dissolved in toluene
(7 mL) and heated under re¯ux under an atmosphere of nitro-
gen. After 10 d, further testosterone (0.250 g, 0.86 mmol)
was added and the reaction mixture heated under re¯ux for
6 d, then washed with saturated aqueous ammonium chloride.
The mixture was extracted with CH2Cl2, and the organic
layer dried over MgSO4. The solvent was removed under
reduced pressure, and the product puri®ed by column chro-
matography on silica gel using 3% methanol±CH2Cl2 as
eluent. The product was isolated as a foam (0.61 g, 82%);
dH (CDCl3) 0.76 (3H, s), 0.78 (3H, s), 0.80±1.80 (20H, m),
1.12 (6H, s), 1.28 (12H, t, Jˆ7 Hz), 1.94±1.98 (2H, m),
2.05±2.57 (13H, m), 3.94 (1H, t, Jˆ8 Hz), 4.58 (2H, q,
Jˆ8 Hz), and 5.66 (2H, s); dC (CDCl3) 11.91, 12.02, 16.31,

P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
1843
16.42, 17.39, 20.49, 23.45, 24.82±25.02 (m), 27.31, 31.43,
32.67, 33.88, 34.34 (t, Jˆ133 Hz), 35.34, 35.69, 36.53, 38.57,
42.56±42.72 (m), 50.17, 53.61, 61.51, 62.61±62.92 (m),
83.50, 83.64, 123.97, 168.80, 168.88, 170.77, and 199.37;
dP (CDCl3) 22.98; m/z (positive ion FAB) (M11H) 946
(14), 703 (87), and 461 (100).
4.2.15. 3,3-Bis(diethoxyphosphoryl)propylene bis(car-
boxylic acid). Tetraethyl 3,3-bis(benzyloxycarbonyl)propyl-
ene bisphosphonate 8b (0.698 g, 1.19 mmol) was dissolved in
THF (10 mL), and Pd/C (0.10 g) added. The reaction mixture
was stirred under an atmosphere of hydrogen (1 bar) over-
night at room temperature, ®ltered, and saturated aqueous
ammonium chloride (50 mL) added. The mixture was
extracted with CH2Cl2 and dried over MgSO4, the solvent
removed under reduced pressure, and the product dried
under high vacuum to give a colourless solid (0.42 g, 88%);
dH (MeOD) 1.35 (12H, t, Jˆ7 Hz), 1.74 (2H, hept, Jˆ8 Hz),
2.08 (1H, tt, JP±Hˆ23, Jˆ7 Hz), 3.18 (1H, t, Jˆ7 Hz), and
3.48±3.63 (8H, m); dC (MeOD) 16.55, 16.68, 25.95 (t,
JP±Cˆ4 Hz), 35.01 (t, JP±Cˆ133 Hz), 51.10 (m), 64.45 (dd,
Jˆ9.4, 6.7 Hz), and 171.84; dP (MeOD) 22.8; m/z (positive
ion FAB) (M11D) 406 (100), and (M11H) 405 (90).
4.2.12. 3,3-Bis(17b-(androst-4-en-3-only)oxycarbonyl)-
propylidene bis(phosphonic acid). Tetraethyl (3,3-
bis(17b-(androst-4-en-3-onyl)oxycarbonyl)propylidene)bis-
phosphonate (0.129 g, 0.136 mmol) was dissolved in
CH2Cl2 (2 mL) and CCl4 (2 mL), and the mixture stirred
under an atmosphere of nitrogen. Trimethylsilyl bromide
(0.62 mL, 0.731 g, 4.77 mmol) was added slowly and the
reaction mixture stirred for 24 h. Water (25 mL) was added
and the reaction mixture stirred for 20 min, ®ltered, and the
residue washed with water and CH2Cl2. The product was
isolated by ®ltration, and dried under high vacuum (0.082 g,
72%); dH (CD3OD) 0.87 (3H, s) 0.88 (3H, s), 0.91±2.47
(41H, m), 1.23 (6H, s), 4.03 (1H, t, Jˆ6 Hz), 4.65 (2H, t,
Jˆ8 Hz), and 5.70 (2H, s); dP (CD3OD) 20.59; m/z (nega-
tive ion FAB) (M1-H) 831.5 (14), 589 (10), 152 (100).
4.2.16. 4,4-Bis(diethoxyphosphoryl)butanoic acid 13.
3,3-Bis(diethoxyphosphoryl)propylene bis(carboxylic acid)
(0.200 g, 0.495 mmol) was heated to 1308C for 3 h under a
stream of nitrogen to give 13 as a colourless oil (0.174 g,
99%); data as described above.
4.2.13. 4,4-Bis(diethoxyphosphoryl)butanoic acid 13. A
solution of potassium hydroxide (2.24 g, 40.0 mmol) in
water (5 mL) was added to a solution of 8a (9.25 g,
20.0 mmol) in THF (20 mL) at 158C. The mixture was stir-
red for 15 h at room temperature and the solvent removed
under reduced pressure. The residue was dissolved in satu-
rated aqueous potassium hydrogen sulphate (10 mL) and
extracted with ethyl acetate (3£15 mL). The organic layer
was dried over MgSO4, and the solvent removed to give the
diacid as an oil. The acid was heated at 1308C for 3 h to
afford the monoacid 13 (1.95 g, 27%); dH (MeOD) 1.35
(12H, t, Jˆ8 Hz) 2.06±2.25 (2H, m), 2.63±2.69 (1H, m),
2.81 (1H, tt, JP±Hˆ24, Jˆ7 Hz), and 4.11±4.25 (8H, m); dC
(MeOD) 16.57, 16.71, 21.82±22.10 (m), 32.53±33.07 (m),
35.87 (t, JC±Pˆ133 Hz), 64.07±64.36 (m), and 175.85; dP
(MeOD) 24.95; m/z (negative ion FAB) 361 (100) (M1-H);
Found: 363.1300. Cl2H25D2O8P2 requires: 363.1307 (posi-
tive ion FAB).
4.2.17. Tetraethyl (3-(17b-(3-benzoyloxyoestra-1,3,5-
trienyl)oxycarbonyl)propylene bisphosphonate 14. 4,4-
Bis(diethoxyphosphoryl)butanoic acid 13 (0.071 g, 0.20
mmol), 3-O-benzoyl-17b-oestradiol (0.089 g, 0.24 mmol),
and 4-(N,N-dimethylamino)pyridine (0.005 g, 0.04 mmol)
were dissolved in CH2Cl2 (5 mL), and stirred at 08C under
an atmosphere of nitrogen. EDCI (0.0455 g, 0.24 mmol)
was added, and the reaction mixture, allowed to reach
room temperature with stirring overnight, washed with
water (30 mL), and extracted with CH2Cl2. The organic
layer was dried over MgSO4, and the solvent removed
under reduced pressure. The crude product was puri®ed
by column chromatography on silica gel using 1±3% metha-
nol±CH2Cl2 as eluent to give 14 as a colourless oil (0.048 g,
33%); nmax 3053, 2983, 1729, 1601, 1243, and 1025 cm21
;
dH (CDCl3) 0.84 (3H, s), 1.25±1.93 (11H, m), 1.35 (12H, t,
Jˆ7 Hz), 1.12±2.74 (7H, m), 2.87±2.92 (2H, m), 4.12±4.28
(8H, m), 4.70 (1H, dd, Jˆ9, 7 Hz), 6.92±7.00 (2H, m), 7.33
(1H, d, Jˆ8 Hz), 7.46±7.67 (3H, m), and 8.20 (2H, dt, Jˆ8,
2 Hz); dC (CDCl3) 12.06, 16.32, 16.43, 21.04, 23.25, 26.03,
27.00, 27.59, 29.50, 35.68 (t, Jˆ132 Hz), 36.86, 38.18,
38.35, 42.87, 43.98, 49.80, 62.61 (t, Jˆ7 Hz), 82.74,
118.67, 121.58, 126.43, 128.49, 129.70, 130.10, 133.45,
137.84, 138.19, 148.68, and 172.72; dP (CDCl3) 23.2; m/z
(positive ion FAB) 719 (M11H).
4.2.14. Tetraethyl 3,3-bis(benzyloxycarbonyl)propylene
bisphosphonate 8b. Tetraethyl ethylidene bisphosphonate
6 (1.00 g, 3.33 mmol), and dibenzyl malonate (0.83 mL,
0.946 g, 3.33 mmol) were dissolved in THF (15 mL).
Lithium bis(trimethylsilyl)amide solution in THF (1 M,
0.33 mL, 0.33 mmol) was added to the reaction mixture
and stirred for 1 h at room temperature. Saturated aqueous
ammonium chloride (50 mL) was added, and the reaction
mixture extracted with CH2Cl2 (100 mL). The organic layer
was collected and dried over MgSO4, and the solvent was
removed under reduced pressure. The crude product was
puri®ed by column chromatography on silica gel using
2±3% methanol±CH2Cl2 as eluent to give 8b as a colourless
oil (1.12 g, 58%); dH (CDCl3) 1.30 (6H, t, Jˆ7 Hz), 1.31
(6H, t, Jˆ7 Hz), 2.37±2.74 (3H, m), 4.07±4.24 (9H, m),
5.14 (4H, s), and 7.24±7.35 (10H, m); dC (CDCl3) 16.10,
16.24, 24.81, 34.11 (t, JC±Pˆ132 Hz), 49.93 (t, JC±Pˆ8 Hz),
62.66 (m), 67.11, 128.03, 128.22, 128.40, 135.12, and
168.41; dP (CDCl3) 32.19; m/z (positive ion FAB)
(M11H) 585 (36), 369 (7), and 91 (100); (Found:
585.2018. C27H39P2O10 requires: 585.2019 (M11H)).
4.2.18. Ethyl malonic half ester 16a. Diethyl malonate
(10.0 g, 62.5 mmol) was dissolved in absolute ethanol
(40 mL), and a solution of potassium hydroxide (3.5 g) in
ethanol (40 mL) added dropwise over 1 h. The reaction
mixture was stirred for 2 h. and left to stand overnight.
The crude precipitated intermediate was recrystallized
from the mother liquors and washed with ether to give the
potassium salt as a colourless crystalline solid (5.0 g, 50%);
C5H7KO4 requires Cˆ35.28, Hˆ4.15; Found Cˆ34.47,
Hˆ4.13%. The potassium salt (4.45 g, 26 mmol) was
dissolved in water (3 mL) and conc. HCl (2.5 mL) added
slowly over 30 min, maintaining the temperature below
108C. The reaction mixture was ®ltered and the residue
washed with diethyl ether (5 mL). The aqueous layer was

1844
P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
extracted with diethyl ether (3£10 mL) and the combined
organic layers dried over MgSO4. The solvent was removed
under reduced pressure to give 16a as a colourless liquid
(1.9 g, 55%), nmax 3486, 1743, and 1735 cm21; dH (CDCl3)
1.29 (3H, t, JH±Hˆ7 Hz), 3.43 (2H, s), 4.23 (2H, q,
JH±Hˆ7 Hz), and 8.21 (1H, br s).
and 1462 cm21; dH (CDCl3) 0.84 (3H, s), 1.25±2.26 (16H,
m), 2.84±2.87 (2H, m), 3.45 (2H, s), 4.78 (1H, t, Jˆ7 Hz),
5.03 (2H, s), 6.70 (1H, s), 6.77 (1H, d, JH±Hˆ12 Hz), 7.18
(1H, d, JH±Hˆ8 Hz), and 7.25±7.43 (5H, m); dC (400 MHz,
CDCl3) 12.4, 23.6, 26.6, 27.6, 27.8, 30.1, 37.2, 38.9, 41.2,
43.6, 44.2, 50.1, 70.4, 84.8, 112.7, 115.3, 126.8, 127.9,
128.3, 129.0, 133.1, 137.7, 138.3, 157.2, 167.7, and 170.9;
C28H32O5 requires C, 74.96; H, 7.20. Found C, 73.65; H,
7.20%.
4.2.19. p-Nitrobenzyl malonic half ester 16b. Meldrum's
acid (1.00 g, 6.94 mmol) and p-nitrobenzyl alcohol (1.00 g,
6.53 mmol) were heated under re¯ux in acetonitrile
(3.5 mL) for 22 h under an atmosphere of nitrogen. The
solvent was removed under reduced pressure and the residue
subjected to high vacuum to give a yellow solid (1.5 g, 97%)
which was recrystallized from t-butanol±hexane (2:1) to
afford 16b as a pale yellow solid (1.00 g, 64%), mp 95±
4.2.24. 17b (3-Benzyloxyoestra-1,3,5(10)-trienyl) ethyl
malonate 17a. 3-O-Benzyl-17b oestradiol (1.0 g, 2.96
mmol), ethyl malonic half ester 16a (391 mg, 2.96 mmol)
and dicyclohexylcarbodiimide (672 mg, 3.26 mmol), and
4-(N,N-dimethylamino)pyridine (10 mol%) were stirred in
diethyl ether (35 mL) for 18 h under an atmosphere of nitro-
gen. The mixture was ®ltered, the solid washed with ether,
and the combined solvent removed under reduced pressure.
The residue was puri®ed by column chromatography on
silica gel using 10% EtOAc±petroleum ether (40±608C)
as eluent to give 17a as a colourless crystalline solid
(640 mg, 46%), nmax 1752, 1729, 1605 and 1498 cm21; dH
(CDCl3) 0.82 (3H, s), 1.28 (3H, t, JH±Hˆ8 Hz), 1.39±1.57
(9H, m), 1.8±1.9 (2H, m), 2.3±2.4 (2H, m), 2.84 (2H, m),
3.38 (2H, s), 4.17 (2H, q, JH±Hˆ8 Hz), 4.76 (1H, t,
JH±Hˆ8 Hz), 5.03 (2H, s), 6.70 (1H, s), 6.77 (1H, d,
JH±Hˆ8 Hz), 7.23 (1H, d, JH±Hˆ9 Hz), and 7.30±7.43
(6H, m); dC (CDCl3) 12.4, 14.4, 23.6, 26.6, 27.6, 27.8,
30.1, 37.2, 39.0, 41.8, 43.6, 44.2, 50.2, 61.9, 70.4, 84.2,
112.7, 115.3, 126.7, 127.8, 128.2, 128.9, 133.2, 137.8,
138.3, 157.2, 167.0, and 167.1. C32H35O5 requires C,
76.93; H, 7.06. Found C, 76.59; H, 7.43%.
988C; nmax 3500, 1747, 1727, 1605, 1522, and 1335 cm21
;
dH ((CD3)2CO) 3.50 (2H, s), 5.22 (2H, s), 7.58 (2H, d,
JH±Hˆ3 Hz), and 8.11 (2H, d, JH±Hˆ4 Hz); dC ((CD3)2CO)
40.1, 64.6, 122.8, 128.1, 166.8, and 205.2.
4.2.20. Methyl malonic half ester 16c. Meldrum's acid
(1.00 g, 6.94 mmol) and methanol (222 mg, 6.93 mmol)
were heated under re¯ux in acetonitrile (3.5 mL) for 20 h
under an atmosphere of nitrogen. The solvent was removed
under reduced pressure and the residue puri®ed by column
chromatography on silica gel using 5% MeOH±CH2Cl2 as
eluent to give 16c as a colourless oil (530 mg, 65%), nmax
2600, 1736, and 1728 cm21; dH (CDCl3) 3.48 (2H, s), 3.81
(3H, s), and 9.98 (1H, br s); dC (CDCl3) 40.7, 52.7, 167.1,
and 171.3.
4.2.21. i-Propyl malonic half ester 16d. Meldrum's acid
(2.0 g, 13.9 mmol) and isopropanol (834 mg, 13.89 mmol)
were heated under re¯ux in acetonitrile (7.0 mL) for 22 h.
The solvent was removed under reduced pressure and 16d
collected as a colourless oil essentially pure by NMR spec-
troscopy (2.03 g, 100%, nmax 1750 and 1720 cm21; dH
(CDCl3) 1.31 (6H, d, Jˆ6 Hz), 3.41 (2H, s), and 5.10 (1H,
hept, JH±Hˆ6 Hz).
4.2.25. 17b (3-Benzyloxyoestra-1,3,5(10)-trienyl) p-nitro-
benzyl malonate 17b. 3-O-Benzyl-17b oestradiol (608 mg,
1.68 mmol), p-nitrobenzyl malonic half ester 16b (400 mg,
1.68 mmol), dicyclohexylcarbodiimide (382 mg, 84.8
mmol), and 4-(N,N-dimethylamino)pyridine (10 mol%)
were stirred in CH2Cl2 (15 mL) for 4 d under an atmosphere
of nitrogen. The mixture was ®ltered, the solvent removed
under reduced pressure, and the residue puri®ed by column
chromatography on silica gel using 20% EtOAc±petroleum
ether (40±608C) as eluent to give 17b as an off-white solid
(700 mg, 69%), nmax 1750, 1731, 1607, 1519 and
1533 cm21; dH (CDCl3) 0.69 (3H, s), 1.16±1.20 (6H, m),
1.26±1.37 (1H, m), 1.71±1.74 (3H, m), 2.01±2.16 (3H, m),
3.39 (2H, s), 4.65 (1H, t, JH±Hˆ9 Hz), 4.93 (2H, s), 5.29
(2H, s), 6.6 (1H, s), 6.69 (1H, d, JH±Hˆ6 Hz), 7.09 (1H, d,
JH±Hˆ8 Hz), 7.27±7.35 (5H, m), 7.44 (2H, d, JH±Hˆ8 Hz),
and 8.13 (2H, d, JH±Hˆ8 Hz); dC (CDCl3) 11.0, 22.2, 25.1,
26.3, 26.9, 28.7, 35.8, 37.5, 40.6, 42.1, 42.7, 48.7, 64.5,
68.9, 83.0, 111.3, 113.8, 122.8, 125.3, 126.4, 126.6, 126.8,
127.3, 131.6, 136.3, 141.5, 146.8, 155.8, 165.2, and 165.2.
4.2.22. Phenyl malonic half ester 16f. Meldrum's acid
(1.84 g, 12.76 mmol) and phenol (1 g, 10.63 mmol) were
heated under re¯ux in acetonitrile (3.5 mL) for 22 h under
an atmosphere of nitrogen. The solvent was removed under
reduced pressure and the crude product puri®ed by column
chromatography on silica gel using 20±100% ethyl acetate±
petroleum ether (40±608C) as eluent to give 16f as off-white
crystals (648 mg, 34%), nmax 1754 and 1698 cm21; dH
(CDCl3) 3.68 (2H, s), 7.08±7.17 (2H, m), 7.21±7.30 (1H,
m), 7.33±7.44 (2H, m), and 9.51 (1H, br s); dC (CDCl3)
41.1, 121.2, 126.3, 129.5, 150.4, 164.9, and 171.5;
C9H8O4 requires C, 59.99; H, 4.48. Found C, 59.98; H,
4.54%.
4.2.23. 17b (3-Benzyloxyoestra-1,3,5(10)-trienyl) malo-
nic half ester 16g. Meldrum's acid (79.6 mg,
0.552 mmol) and 3-O-benzyl-17b oestradiol (200 mg,
0.552 mmol) were heated under re¯ux in acetonitrile
(1.75 mL) for 22 h under an atmosphere of nitrogen. The
solvent was removed under reduced pressure and the residue
puri®ed by column chromatography on silica gel using 5%
MeOH±CH2Cl2 as eluent, affording 16g as a colourless
solid (120 mg, 49%), nmax 3420, 2361, 1749, 1718, 1654
4.2.26. 17b (3-Benzyloxyoestra-1,3,5(10)-trienyl) methyl
malonate 17c. 3-O-Benzyl-17b oestradiol (1.00 g,
2.76 mmol), methyl malonic half ester 16c (323 mg,
2.76 mmol), dicyclohexylcarbodiimide (627 mg, 3.04
mmol), and 4-(N,N-dimethylamino)pyridine (10 mol%)
were stirred in CH2Cl2 (25 mL) for 18 h under a nitrogen
atmosphere. The solvent was removed under reduced pres-
sure and the residue puri®ed by column chromatography on
silica gel using 20% EtOAc±petroleum ether (40±608C) as

P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
1845
eluent to give 17c as a colourless crystalline solid (846 mg,
68%), nmax 1741, 1726, 1461 and 1165 cm21; dH
((CD3)2CO) 0.83 (3H, s), 1.25±1.51 (6H, m), 1.55±1.65
(2H, m), 1.85±1.95 (2H, m), 2.18±2.22 (3H, m), 2.80±
2.89 (2H, m), 3.40 (2H, s), 3.76 (3H, s), 4.77 (1H, t,
JH±Hˆ8 Hz), 5.04 (2H, s), 6.72 (1H, s), 6.78 (1H, d,
JH±Hˆ8 Hz), 7.20 (1H, d, JH±Hˆ8 Hz), and 7.30±7.44
(5H, m); dC (400 MHz, CDCl3) 11.9, 23.1, 26.1, 27.1,
27.3, 29.6, 36.7, 38.4, 42.5, 43.0, 43.7, 49.6, 52.3, 69.9,
83.8, 112.2, 114.7, 126.3, 127.3, 127.7, 128.4, 132.6,
137.2, 137.8, 156.6, 166.4, and 167.7; m/z (FAB)
462.2412 (M1); C29H34O5 requires 462.2406.
of nitrogen. The solvent was removed in vacuo and the
residue puri®ed by column chromatography on silica gel
using 1±2% MeOH±CH2Cl2 as eluent to give 18a as a
colourless oil (70 mg, 30%), nmax 1755, 1731, 1608 and
1500, 1254, and 1163 cm21; dH (CDCl3) 0.81 (3H, s),
0.82 (3H, s), 1.26±1.40 (15H, m), 1.80±2.85 (16H, m),
3.9±4.15 (1H, m), 4.19±4.24 (12H, m), 4.75±4.80 (1H,
m), 5.02 (2H, s), 6.71 (1H, s), 6.74 (1H, d, JH±Hˆ9 Hz),
and 7.20 (1H, d, JH±Hˆ8 Hz); dC (CDCl3) 11.8, 11.9,
14.1, 16.3 (t, JC±Pˆ6 Hz), 23.2, 24.8, 26.1, 27.1, 27.2,
29.7, 34.2 (t, JC±Pˆ138 Hz), 36.7, 38.4, 41.4, 41.6, 49.6,
62.6 (t, JC±Pˆ6 Hz), 69.9, 83.6, 83.9, 112.2, 114.7, 126.3,
127.4, 127.8, 128.5, 132.4, 137.0, 137.8, 156.6, 167.1,
167.2, and 167.3; dP (CDCl3) 24.15 and 24.20; m/z (FAB)
777.3797 (M1); C40H59O11P2 requires 777.3533.
4.2.27. 17b (3-Benzyloxyoestra-1,3,5(10)-trienyl) iso-
propyl malonate 17d. 3-O-Benzyl-17b oestradiol
(450 mg, 1.24 mmol), i-propyl malonic half ester 16d
(182 mg, 1.24 mmol), dicyclohexylcarbodiimide (308 mg,
1.5 mmol), and 4-(N,N-dimethylamino)pyridine (10 mol%)
were stirred in acetonitrile (4 mL) for 18 h under a nitrogen
atmosphere. The solvent was removed under reduced pres-
sure and the residue puri®ed by column chromatography on
silica gel using 5±10% EtOAc±petroleum ether (40±608C)
as eluent to give 17d as a colourless crystalline solid
(420 mg, 69%), nmax 1747, 1498, 1458, 1722, and
1376 cm21; dH (CDCl3) 0.82 (3H, s), 1.24 (6H, d,
JH±Hˆ6 Hz), 1.30±1.95 (10H, m), 2.14±2.34 (3H, m),
2.78±2.89 (2H, m), 3.35 (2H, s), 4.76 (1H, t, JH±Hˆ8 Hz),
5.02 (2H, s), 5.06 (1H, hept, JH±Hˆ6 Hz), 6.70 (1H, s), 6.75
(1H, d, JH±Hˆ9 Hz), 7.17 (1H. d. JH±Hˆ9 Hz), and 7.35 (5H,
m); dC (CDCl3) 12.0, 21.7, 21.8, 23.3, 26.2, 27.2, 27.4, 29.8,
36.9, 38.6, 42.3, 43.2, 43.8, 49.8, 52.4, 70.0, 83.8, 112.3,
114.9, 126.4, 127.2, 127.9, 128.6, 132.8, 137.4, 137.9,
156.8, 166.3, and 166.8; m/z (FAB) 491.2791 (M1H1);
C31H39O5 requires 491.2798.
4.2.30. Tetraethyl (17b (3-benzyloxyoestra-1,3,5(10)-
trienyl)oxycarbonyl) (p-nitrobenzyloxycarbonyl) pro-
pylene bisphosphonate 18b.
b (3-Benzyloxyoestra-
1,3,5(10)-trienyl) p-nitrobenzyl malonate 17b (200 mg,
0.33 mmol) was dissolved in CH2Cl2 (2 mL), diethylamine
(49 mg, 70 mL, 0.66 mmol) added, and the solution stirred
for 10 min. Tetraethyl ethylidene bisphosphonate (99 mg,
0.33 mmol) was added and the reaction mixture stirred at
room temperature overnight under an atmosphere of nitro-
gen. The solvent was removed under reduced pressure and
the residue puri®ed by column chromatography on silica gel
using 5% MeOH±CH2Cl2 as eluent to give 18b as a brown
oil (70 mg, 24%), nmax 1749, 1731, 1608, 1524, 1499, 1347,
1252, and 1163 cm21; dH (CDCl3) 0.72 (3H, s), 0.75 (3H, s),
1.35 (12H, t, JH±Hˆ7 Hz), 1.74±1.78 (2H, m), 1.80±185
(1H, m), 2.00±2.10 (1H, m), 2.17±2.22 (3H, m), 2.48±
2.55 (3H, m), 2.83±2.85 (2H, m), 3.39 (3H, s), 4.14±4.24
(8H, m), 5.03 (2H, s), 5.22±5.34 (2H, m), 6, 71 (1H, s), 6.78
(1H, d, JH±Hˆ8 Hz), 7.16 (1H, d, JH±Hˆ4 Hz), 7.31±7.44
(4H, m), 7.55 (2H, d, JH±Hˆ9 Hz), and 8.22 (2H, d,
JH±Hˆ9 Hz); dC (CDCl3) 13.0, 13.1, 17.5 (t, JH±Hˆ6 Hz),
24.4, 27.0, 28.2, 28.4, 30.8, 34.9 (t, JP±Cˆ143 Hz), 37.9,
39.5, 44.3, 44.7, 50.7, 63.9 (t, JH±Hˆ10 Hz), 66.7, 71.0,
85.0, 113.4, 115.87, 124.9, 127.4, 128.5, 128.9, 129.60,
129.61, 129.7, 133.6, 138.3, 143.2, 148.4, 157.8, 169.5,
and 169.7; dP (CDCl3) 23.49 and 23.51.
4.2.28. 17b (3-Benzyloxyoestra-1,3,5(10)-trienyl) phenyl
malonate 17f. 3-O-Benzyl-17b oestradiol (500 mg,
1.39 mmol), phenyl malonic half ester 16f (249 mg,
1.39 mmol), dicyclohexylcarbodiimide (429 mg, 2.08
mmol), and 4-(N,N-dimethylamino)pyridine (10 mol%)
were stirred in CH2Cl2 (5 mL) for 18 h under a nitrogen
atmosphere. The solvent was removed under reduced pres-
sure and the residue puri®ed by column chromatography on
silica gel using 10% EtOAc±petroleum ether (40±608C) as
eluent to give 17f as a colourless solid (670 mg, 92%), nmax
1774 and 1723 cm21; dH (CDCl3) 0.85 (3H, s), 1.19±1.50
(6H, m), 1.60±1.80 (4H, m), 2.15±2.33 (3H, m), 2.82±2.86
(2H, m), 3.61 (2H, s), 4.82 (1H, t, JH±Hˆ9 Hz), 5.01 (2H, s),
6.70 (1H, s), 6.77 (1H, d, JH±Hˆ9 Hz), and 7.11±7.42 (11H,
m); dC (CDCl3) 12.4, 23.5, 26.5, 27.5, 27.7, 30.0, 37.1, 38.8,
42.2, 43.5, 44.1, 50.0, 70.2, 84.4, 112.6, 115.1, 121.6, 126.5,
126.7, 127.7, 128.1, 128.8, 129.8, 133.0, 137.6, 138.2,
150.7, 157.1, 165.5, and 166.4; m/z (FAB) 524.2563
(M1); C34H36O5 requires 524.2563.
4.2.31. Tetraethyl (17b (3-benzyloxyoestra-1,3,5(10)-
trienyl)oxycarbonyl) (methyloxycarbonyl) propylene
bisphosphonate 18c. LHMDS (0.133 mL, 0.119 g,
0.711 mmol) was added to 17b (3-benzyloxyoestra-
1,3,5(10)-trienyl) methyl malonate 17c (300 mg,
0.66 mmol) and tetraethyl ethylidene bisphosphonate
(200 mg, 0.664 mmol) in THF (4.5 mL) solution and heated
at 608C for 18 h. The solvent was removed under reduced
pressure and the residue puri®ed by column chromato-
graphy on silica gel using 1±2% MeOH±CH2Cl2 as eluent
to give 18c as a brown oil (289 mg, 57%), dH (CDCl3) 0.80
(3H, s), 1.35 (12H, t, JH±Hˆ7 Hz), 1.85±2.05 (6H, m), 2.21±
2.35 (4H, m), 2.40±2.71 (3H, m), 2.80±2.97 (2H, m), 3.75
(3H, s), 4.14±4.26 (8H, m), 4.67±4.82 (1H, m), 5.03 (2H, s),
6.72 (1H, s), 6.78 (1H, d, JH±Hˆ8 Hz), 7.20 (1H, d,
JH±Hˆ8 Hz), and 7.30±7.45 (5H, m); dC (CDCl3) 11.9,
16.4 (t, Jˆ6 Hz), 23.3, 26.2, 27.2, 27.3, 29.8, 34.2 (t,
JC±Pˆ134 Hz), 38.5, 43.1, 49.7, 52.6, 62.7 (t, JC±Pˆ7 Hz),
69.9, 84.0, 112.4, 114.9, 126.4, 127.4, 127.8, 128.5, 131.0,
137.2, 137.8, 156.7, 168.5, and 169.8; dP (CDCl3), 24.09,
4.2.29. Tetraethyl (17b (3-benzyloxyoestra-1,3,5(10)-
trienyl)oxycarbonyl)
(ethoxycarbonyl)
propylene
bisphosphonate 18a. 17b (3-Benzyloxyoestra-1,3,5(10)-
trienyl) ethyl malonate 17a (100 mg, 0.297 mmol) was
dissolved in CH2Cl2 (2 mL). Triethylamine (120 mg,
1.186 mmol) and tetraethyl ethylidene bisphosphonate
(89 mg, 0.297 mmol) were added and the reaction mixture
stirred at room temperature overnight under an atmosphere

1846
P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
24.01; m/z (FAB) 762.3286 (M1); C39H56O11P2 requires
762.3298.
(1H, d, JH±Hˆ8 Hz), and 7.10 (1H, d, JH±Hˆ8 Hz); dC
(CDCl3) 11.9, 12.1, 16.4, 23.3, 24.8, 26.2, 27.3, 29.6, 34.1
(t, JC±Pˆ134 Hz), 36.8, 38.6, 43.1, 43.2, 43.8, 49.9 (t,
JC±Pˆ11 Hz), 52.6, 52.7, 63.0 (t, JP±Cˆ7 Hz), 83.9, 84.0,
112.87, 115.4, 126.3, 131.2, 137.8, 154.7, 168.8, and
169.5; dP (CDCl3) 24.11 and 24.07; m/z (FAB) 673.2914
(M1H1); C32H51O11P2 requires 673.2907. C32H50P2O11
requires C, 57.12; H, 7.50. Found C, 56.58; H, 7.34%.
4.2.32. Tetraethyl (17b (3-benzyloxyoestra-1,3,5(10)-
trienyl)oxycarbonyl) (i-propyloxycarbonyl) propylene
bisphosphonate 18d. Sodium hydride (9.6 mg, 0.4 mmol)
was added to a solution of 17b (3-benzyloxyoestra-1,3,5
(10)-trienyl) i-propyl malonate 17d (100 mg, 0.2 mmol)
and a solution of tetraethyl ethylidene bisphosphonate
(60.2 mg, 0.2 mmol in THF (0.5 mL) added. The reaction
mixture was stirred at room temperature for 1 h under an
atmosphere of nitrogen. The solvent was removed under
reduced pressure and the residue puri®ed by column chro-
matography on silica gel using 1±2% MeOH±CH2Cl2 as
eluent to give 18d as a brown oil (82 mg, 40%), dH
(CDCl3) 0.81 (3H, s), 1.25 (6H, d, JH±Hˆ6 Hz), 1.33
(12H, t, JH±Hˆ8 Hz), 2.10±2.13 (13H, m), 2.81±2.90 (2H,
m), 4.19 (8H, q, JH±Hˆ8 Hz), 5.03 (2H, s), 6.71 (1H, s), 6.75
(1H, d, JH±Hˆ8 Hz), 7.17 (1H, d, JH±Hˆ8 Hz), and 7.35 (4H,
m); dC (CDCl3) 11.9, 16.2 (t, JC±Pˆ6 Hz), 21.6, 23.2, 24.8,
26.0, 27.1, 27.2, 29.7, 34.2 (t, JC±Pˆ160 Hz), 38.4, 43.1,
43.7, 49.6, 52.4, 62.7 (4C, t, JC±Pˆ8 Hz), 83.6, 112.8,
115.3, 126.8, 127.9, 128.3, 129.0, 133.1, 137.7, 138.3,
157.2, 168.4, and 168.9; dP (CDCl3) 24.10 and 24.25.
4.2.35. (17b (3-Hydroxyoestra-1,3,5(10)-trienyl)oxycar-
bonyl) (ethoxycarbonyl) propylene bis(phosphonic
acid) 20a. Tetraethyl (17b (3-hydroxyoestra-1,3,5(10)-
trienyl)oxycarbonyl) (ethoxycarbonyl) propylene bis-
phosphonate 19a (457 mg, 0, 666 mmol) was stirred with
trimethylsilyl bromide (816 mg, 0.703 mL, 5.329 mmol) in
CH2Cl2 (10 mL) for 2.5 d. The solvent was removed and the
resulting concentrate stirred with MeOH (20 mL) for a
further 30 min. The solvent was removed under reduced
pressure to afford the product as an orange foam (450 mg,
100%), nmax 2683, 1752, 1730, and 1182 cm21; dH
((CD3)2CO) 0.85 (3H, s), 1.11±2.83 (20H, m), 3.90±4.14
(1H, m), 4.19±4.36 (2H, m), 4.7 (1H, q, JH±Hˆ9 Hz), 6.52
(1H, s), 6.59 (1H, d, JH±Hˆ9 Hz), and 7.09 (1H, d,
JH±Hˆ9 Hz); dC ((CD3)2CO) 11.5, 35.9, 24.9, 26.3, 27.2,
27.3, 29.8, 36.9, 44.0, 49.8, 84.0, 113.4, 115.7, 126.8,
131.5, 138.2, 156.0, 169.6, and 169.8; dP ((CD3)2CO)
28.16; m/z (FAB) 575 (M1H1), 597 (M1Na1).
4.2.33. Tetraethyl (17b (3-hydroxyoestra-1,3,5(10)-tri-
enyl)oxycarbonyl) (ethoxycarbonyl) propylene bis-
phosphonate 19a. 10% Palladium on activated charcoal
(158 mg) was added to a solution of tetraethyl (17b
(3-benzyloxyoestra-1,3,5(10)-trienyl)oxycarbonyl)) (ethoxy-
carbonyl) propylene bisphosphonate 18a (778 mg,
1 mmol) in CH2Cl2 (15 mL). The reaction mixture was stir-
red for 18 h under an atmosphere of hydrogen (60 psi). The
solvent was removed under reduced pressure and the residue
puri®ed by column chromatography on silica gel using 5%
MeOH±CH2Cl2 as the eluent to give 19a as a colourless
foam (550 mg, 80%), nmax 3276, 2982, 2930, 1745, 1731,
1611, 1503, 1246, and 1164 cm21; dH (CDCl3) 0.79 (3H, s),
1.21±1.36 (18H, m), 1.59±2.75 (15H, m), 3.95±4.09 (1H,
m), 4.20±4.25 (10H, m), 4.70±4.80 (1H, m), 6.62 (1H, s),
6.65 (1H, d, JH±Hˆ9 Hz), and 7.10 (1H, d, JH±Hˆ9 Hz); dC
(CDCl3) 13.1, 13.2, 15.28, 15.31 17.5 (t, JC±Pˆ5 Hz), 25.6,
27.0, 27.8, 28.8, 28.9, 35.8 (t, JC±Pˆ135 Hz), 38.5, 40.5,
45.4, 51.16, 51.18, 62.9, 63.1, 63.9, 64.2, 85.1, 85.3,
114.5, 116.8, 128.0, 133.9, 139.1, 156.9, 170.19, 170.21,
170.3, and 170.4; dP (CDCl3) 24.14 and 24.08; m/z (FAB)
687.3071 (M1H1); C33H52O11P2 requires 687.3063.
4.2.36. (17b (3-Hydroxyoestra-1,3,5(10)-trienyl)oxycar-
bonyl) (methyloxycarbonyl) propylene bis(phosphonic
acid) 20c. Trimethylsilyl bromide (0.102 mL, 118 mg,
0.773 mmol) was added slowly to a solution of tetraethyl
(17b (3-hydroxyoestra-1,3,5(10)-trienyl)oxycarbonyl)) (meth-
oxycarbonyl) propylene bisphosphonate 19c (65 mg,
0.0967 mmol) in dichloromethane (1.5 mL). The reaction
mixture was stirred at room temperature for 2.5 d. The
solvent was removed under reduced pressure and the result-
ing concentrate stirred with methanol (2 mL) for 30 min.
The solvent was removed under reduced pressure to afford
the product as a creamy brown foam (38 mg, 70%), dH
((CD3)2CO) 0.84 (3H, s), 1.08±1.97 (10H, m), 2.36±2.82
(5H, m), 3.74 (3H, s), 3.87±4.06 (1H, m), 4.75 (1H, q,
JH±Hˆ8 Hz), 6.53 (1H, s), 6.58 (1H, d, JH±Hˆ8 Hz), and
7.07 (1H, d, JH±Hˆ8 Hz); dC ((CD3)2CO) 16.6, 16 7, 28.2,
29.9, 31.4, 32.4, 42.0, 44.0, 48.2, 48.4, 49.0, 54.7, 55.4,
57.2, 57.3, 88.8, 88.9, 117.9, 120.2, 131.4, 136.1, 142.7,
160.2, 173.5, 173.6, 174.3, and 174.4; dP ((CD3)2CO)
28.13.
4.2.34. Tetraethyl (17b (3-hydroxyoestra-1,3,5(10)-tri-
enyl)oxycarbonyl)
(methyloxycarbonyl)
propylene
Acknowledgements
bisphosphonate 19c. 10% Palladium on activated charcoal
(41 mg) was added to a solution of tetraethyl (17b (3-
benzyloxyoestra-1,3,5(10)-trienyl)oxycarbonyl)) (methoxy-
carbonyl) propylene bisphosphonate 18c (200 mg,
0.262 mmol) in CH2Cl2 (4 mL). The reaction mixture was
stirred for 22 h under an atmosphere of hydrogen. The
solvent was removed under reduced pressure and the residue
puri®ed by column chromatography on silica gel using 5%
MeOH±CH2Cl2 as the eluent to give 19c as a colourless
foam (140 mg, 79%), dH (CDCl3) 0.79 (3H, s), 1.35 (12H,
t, JH±Hˆ8 Hz), 1.50±1.98 (10H, m), 2.08±2.70 (4H, m),
2.77±2.86 (1H, m), 3.72 (3H, s), 3.96±4.09 (2H, m),
4.10±4.33 (8H, m), 4.65±4.82 (1H, m), 6.59 (1H, s), 6.65
This investigation has enjoyed the support of the North
West Cancer Research Fund and the Medical Research
Council.
References
1. Geddes, A. D.; D'Souza, S. M.; Ebetino, F. H.; Ibbotson, K.
J. Bone Miner. Res. 1994, 9, 265. Geddes, A. D.; Bevan, J. A.;
Kasting, G. B.; Francis, M. D.; Mosekilde, L.; Hasling, C.
J. Bone Miner. Res. 1992, 7, S328. Storm, T.; Thamsborg,

P. C. B. Page et al. / Tetrahedron 57 (2001) 1837±1847
1847
G.; Steiniche, T.; Genant, H. K.; Sorensen, O. H. New Engl. J.
Med. 1990, 332, 1265. Fleisch, H. Bone 1999, 25, 158. Vitte,
C.; Fleisch, H.; Guenther, H. L. Endocrinology 1996, 137,
2324. Fleisch, H. Osteoporosis Int. 1996, 6, 166.
Cust, M. P.; Gangar, K. F.; Whitehead, M. I. In HRT and
Osteoporosis, Studd, J. W. W., Drife, J. O., Eds.; Springer:
London, 1990; pp 209.
6. Gallagher, J. A.; Bowler, W.; Moore, J. P. G.; Page, P. C. B.
UK Patent app. 9613722.9, 1996.
2. Fleisch, H. Br. J. Clin. Pract. 1994, 48, 323. Body, J. J.; Bartl,
R.; Buckhardt, P.; Delmers, P. D.; Fleisch, H.; Kanis, J. A.;
Kyle, R. A.; Mundy, G. R.; Paterson, A. H. G.; Rubens, R. D.
J. Clin. Oncol. 1998, 16, 3890. Guenther, H. L.; Fleisch, H.;
Walz, A. J. Bone Miner. Res. 1997, 12, 111. Jowsey, J.;
Hopkins, S. G. J. Lab. Clin. Med. 1970, 76, 126. Dodwell,
D. J.; Howell, A.; Ford, J. Br. J. Cancer 1990, 61, 123. Sahni,
M.; Guenther, H. L.; Fleisch, H.; Collin, P.; Martin, T. J.
J. Clin. Invest. 1993, 91, 2004.
7. Horowitz, M. C. Science 1993, 260, 626. Paci®ci, R.; Rifas,
L.; Teitelbaum, S.; Slatopolski, E.; McCracken, R.; Bergfeld,
M.; Lee, W.; Avioli, L. V.; Peck, W. A. Proc. Natl. Acad. Sci.
USA 1987, 84, 4616. Oursler, M. J.; Keeting, P. E.; Wiegand,
K. E.; Bonde, S. K.; Spielsberg, T. C.; Riggs, B. L. J. Bone
Miner. Res. 1992, 7, S111. Oursler, M. J.; Pederson, L.;
Pyffereon, J.; Osdoby, P.; FitzPatrick, L. Endocrinology
1993, 132, 1373. Oursler, M. J.; Osdoby, P.; Pyffereon, J.;
Riggs, B. L.; Spielsberg, T. C. Proc. Natl. Acad. Sci. USA
1991, 88, 6613.
3. Fleisch, H. Int. J. Clin. Pract. 1999, 2. Fleisch, H.
Scand. J. Rheumatol. 1998, 64. Russell, R. G. G.; Croucher,
P. I.; Rogers, M. J. Osteoporosis Int. 1999, 9, 66. Li, Q. N.;
Liang, N. C.; Huang, L. F.; Wu, T.; Hu, B.; Mo, L. E. Acta
Pharm. Sin. 1998, 19, 160. Kyriakidou Himonas, M.; Aloia,
J. F. Adv. Therapy 1997, 14, 281. Reginster, J. Y. L.; Halkin,
V.; Gosset, C.; Deroisy, R. Drugs Today 1997, 33, 563. Khan,
S. A.; Kanis, J. A.; Vasikaran, S.; Kline, W. F.; Matuszewski,
B. K.; McCloskey, E. V.; Beneton, M. N. C.; Gertz, B. J.;
Sciberras, D. G.; Holland, S. D.; Orgee, J.; Coombes, G. M.;
Rogers, S. R.; Porras, A. G. J. Bone Miner. Res. 1997, 12,
1700. Fleisch, H. Horm. Metab. Res. 1997, 29, 145. Black,
L. J.; Sato, M.; Rowley, E. R.; Magee, D. E.; Bekele, A.;
Williams, D. C.; Cullinan, G. J.; Bendele, R.; Kauffman,
R. F.; Bensch, W. R.; Frolik, C. A.; Termine, J. D.; Bryant,
H. U. J. Clin. Invest. 1994, 93, 63. Heaney, R. P. Am. J. Med.
1991, 91, 238.
8. Kirin, S. Japan Patent 6-100576.
9. Sugioka, T.; Inza, M. Eur Patent 0548884 A1.
10. Saari, W. S.; Rodan, G. A.; Fisher, T. A.; Anderson, P. S. Eur
Patent 0496520 A1.
11. Ueno, H.; Kadowaki, S.; Kamizono, A.; Morioka, M. Eur
Patent 0555845 A2.
12. Sturtz, G.; Guervenou, J. Phosphorus Sulfur 1994, 88, 1.
13. Quim, O. T.; Curry, J. D.; Nicholson, J. D.; Prentice, J. B.;
Roy, C. J. Organomet. Chem. 1968, 13, 199. Hutchinson,
D. W.; Semple, G. J. Organomet. Chem. 1986, 309, C7.
Seyferth, D.; Marmor, R. S. J. Organomet. Chem. 1973, 59,
257. Ebetino, F. H.; Degenhardt, C. R.; Jamieson, L. A.;
Burdsall, D. C. Heterocycles 1990, 30, 855.
14. Yuan, C.; Li, C.; Ding, Y. Synthesis 1991, 854. Neidlein, R.;
Eichinger, T. Synthesis 1991, 1228.
4. Fleisch, H.; Shinoda, H.; Adamek, G.; Felix, R.; Schenk, R.;
Hagan, P. Calcif. Tissue Int. 1983, 35, 87.
15. Degenhardt, C. R.; Burdsall, D. C. J. Org. Chem. 1986, 51,
3488.
16. Hutchinson, D. W.; Thorton, D. M. J. Organomet. Chem.
1988, 346, 341.
5. Beresford, S. A. A.; Weiss, N. S.; Voight, L. F.; McKnight, B.
Lancet 1997, 349, 458. Colditz, G. A.; Hankinson, S. E.;
Hunter, D. J.; Willet, W. C.; Manson, J. E.; Stampfer, M. J.;
Hennekens, C.; Rosner, B.; Speizer, F. E. New Engl. J. Med.
1995, 332, 1589. Colditz, G. A.; Surwell, M. A. Am. J. Obstet.
Gynecol. 1993, 168, 1473. Hiroaki, U.; Kadowaki, S.;
Kamizono, A.; Masahiko, M.; Akihisa, M. Eur. Patent app.
0555845, 1993 Bosies, E.; Esswein, A.; Bauss, F. Int. Patent
WO 92/05187, 1992 Saari, W. S.; Rodan, G. A.; Fisher, T. E.;
Anderson, P. S. Eur. Patent app. 0496520 A, 1992 Sugioka,
T.; Inazu, M. Eur. Patent app. 0548884 A, 1992 Sturtz, G.;
Guervenou, J. Fr. Patent app 2683527, 1991 Bosies, E.;
Esswein, A.; Bauss, F. Eur. Patent 0 549 645 B1, 1991
17. Sturtz, G.; Guervenou, J. Synthesis 1991, 661.
18. Levitz, M. J. Am. Chem. Soc. 1953, 75, 5352.
19. McKenna, C. E.; Schmidhauser, J. J. Chem. Soc. 1979, 35,
739. McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna,
M. C. Tetrahedron Lett. 1977, 155. Clasen, R.; Haegele, G.
J. Fluorine Chem. 1996, 77, 71.
20. Dhaon, M. K.; Olsen, R. K.; Ramsay, K. J. Org. Chem. 1982,
47, 1962. EDCI used rather than DCC as the urea side product
is water soluble, allowing for an easy work-up procedure.
21. Strube, R. E. Org. Synth. 1963, 4, 417.
22. McNab, H. Chem. Soc. Rev. 1978, 7, 345.