Direct Approach to α-Hydroxyphosphonic and α,ω-Dihydroxyalkane-α,ω-bisphosphonic Acids by the Reduction of (Bis)acylphosphonic Acids

Article abstract of DOI:10.1021/jo9803129

Acylphosphonic and bisacylphosphonic acid sodium salts were directly reduced by sodium borohydride to the corresponding hydroxyphosphonates and dihydroxyalkanebisphosphonates. The solution conformation of the (bis)hydroxyphosphonic acid sodium salts, eluc

Full text of DOI:10.1021/jo9803129

J . Org. Chem. 1998, 63, 5107-5109
5107
Dir ect Ap p r oa ch to r-Hyd r oxyp h osp h on ic a n d
r,ω-Dih yd r oxya lk a n e-r,ω-bisp h osp h on ic Acid s by th e Red u ction of
(
Bis)a cylp h osp h on ic Acid s
Ravit Chen and Eli Breuer*
Department of Pharmaceutical Chemistry, The School of Pharmacy, The Hebrew University of J erusalem,
P.O. Box 12065, J erusalem 91120, Israel
Received February 19, 1998
Acylphosphonic and bisacylphosphonic acid sodium salts were directly reduced by sodium
borohydride to the corresponding hydroxyphosphonates and dihydroxyalkanebisphosphonates. The
solution conformation of the (bis)hydroxyphosphonic acid sodium salts, elucidated from the
homonuclear and heteronuclear coupling constants of the proton adjacent to the hydroxy and the
phosphonic groups, was identical with the solid-state conformation as determined for 1-hydroxy-
2
-phenylethylphosphonic acid, a representative compound, by X-ray crystallography.
acetic acid,7a diborane in tetrahydrofuran, and by lithium
8
In previous papers it was reported from our laboratory
that R,R′-difunctionalized long-chain bisphosphonates
triethylborodeuteride.9
1
such as bisacylphosphonates 1 and R,R′-bishydroxyimi-
Attempted synthesis of R,ω-dihydroxyalkane-R,ω-bis-
phosphonic acids 3 by reduction of tetramethyl bis-
acylphosphonates to the corresponding dihydroxyalkane-
bisphosphonate tetramethyl esters, followed by bromo-
trimethylsilane-induced demethylation to the correspond-
ing bisphosphonic acids, gave rise in our hands to impure
products which were difficult to purify because of their
highly polar nature.
nophosphonates2 2 are biologically active in calcium-
We considered that since both acylphosphonic and
R-hydroxyphosphonic acids, as well as their salts, are far
more stable than the esters10 (R-hydroxyphosphonate
diesters fragment easily to the corresponding carbonyl
compound by eliminating dialkyl hydrogen phospho-
nate ), direct reduction of bisacylphosphonic acids might
lead to the desired R-hydroxy and R,R′-dihydroxyalkane-
R,ω-bisphosphonic acids more efficiently.
related disorders such as hydroxyapatite formation and
dissolution. This is in contrast to alkane-R,ω-bisphos-
phonates which are devoid of any activity.3 To elucidate
the roles of the functional groups in R positions for
biological activity, we have undertaken a systematic
study of synthesizing variously difunctionalized long-
chain bisphosphonates. This paper describes the devel-
opment of a practical method for the synthesis of R,ω-
dihydroxyalkane-R,ω-bisphosphonic acids 3 which are
also suitable for the synthesis of simple R-hydroxyphos-
phonic acids 5.
7
Resu lts
Red u ction of Acylp h osp h on a tes. Addition of so-
dium borohydride to an aqueous solution of monosodium
benzoylphosphonate or phenylacetylphosphonate gave
immediate reduction to the corresponding R-hydroxy-
phosphonic acid. The progress of the reaction could
conveniently be monitored by 31P NMR spectroscopy. In
contrast to the signal of the starting materials at ap-
proximately -1 ppm, the products resonate at around
R-Hydroxyphosphonate esters have been obtained pre-
viously by the Abramov and Pudovik reactions which
4
consist of adding phosphites to carbonyl compounds or
by the reduction of acylphosphonate diesters using vari-
ous reducing agents. Thus dialkyl acylphosphonates
have been reduced to R-hydroxyphosphonates by sodium
borohydride,5 aluminum isopropoxide, activated zinc in
,6
7
2
0 ppm in the 31P NMR spectrum. The products could
*
Corresponding author. Tel: 972-2-675-8704. Fax: 972-2-641-0740.
E-mail: breuer@cc.huji.ac.
1) (a) Golomb, G.; Schlossman, A.; Saadeh, H.; Levi, M.; Van Gelder,
be isolated in good yields by the addition of an organic
solvent, miscible with water, such as dioxane or metha-
nol. Reduction of bisacylphosphonates to R,ω-dihydroxy-
alkane-R,ω-bisphosphonic acids could be carried out
equally conveniently. The latter were isolated by the
(
J . M.; Breuer, E. Pharm. Res. 1992, 9, 143-148. (b) Van Gelder, J .
M.; Breuer, E.; Ornoy, A.; Schlossman, A.; Patlas, N.; Golomb, G. Bone
1
995, 16, 511-520. (c) Skrtic, D.; Eidelman, N.; Golomb, G.; Breuer,
E.; Eanes, E. D. Calcif. Tissue Int. 1996, 58, 347-354.
2) (a) Golomb, G.; Schlossman, A.; Eitan, Y.; Saadeh, H.; Van
(
Gelder, J . M.; Breuer, E. J . Pharm. Sci. 1992, 81, 1004-1007. (b)
Breuer, E.; Golomb, G.; Hoffman, A.; Schlossman, A.; Van Gelder, J .
M.; Saadeh, H.; Levi, M.; Eitan, Y. Phosphorus, Sulfur, Silicon 1993,
(6) O¨ hler, E.; Kotzinger, S. Liebigs Ann. Chem. 1993, 269; Synthesis
1993, 497.
(7) (a) Shahak, I.; Peretz, J . Israel J . Chem. 1971, 9, 35. (b) Horner,
L.; R o¨ der, H. Chem. Ber., 1970, 103, 2984.
7
6, 167-170.
(
3) (a) Francis, M. D.; Martodam, R. R. Chemical, biochemical, and
medicinal properties of the diphosphonates. In The Role of Phospho-
nates in Living Systems; Hilderbrand, R. L., Ed.; CRC Press: Boca
Raton, FL, 1983; pp 55-96. (b) Fleisch, H. Bone 1987, 8, S23-S28.
(8) Schlossman, A.; Breuer, E. Unpublished results.
(9) Creary, X.; Geiger, C. C.; Hilton, K. J . Am. Chem. Soc. 1983 105,
2851.
(10) Breuer, E. Acylphosphonates and their derivatives. In The
Chemistry of Organophosphorus Compounds; Hartley, F. R., Ed.; J ohn
Wiley&Sons Ltd.: New York, 1996; Vol. 4, pp 653-729.
(
4) Engel, R. Synthesis of Carbon-Phosphorus Bonds; CRC Press:
Boca Raton, FL, 1988; pp 77-136.
(5) Shahak, I.; Bergmann, E. D. Israel J . Chem. 1966, 4, 225.
S0022-3263(98)00312-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/07/1998

5
108 J . Org. Chem., Vol. 63, No. 15, 1998
Chen and Breuer
F igu r e 1.
Ch a r t 1
addition of methanol to the aqueous reaction mixtures.
The sodium salts were converted to the free acids by
passing through a cation-exchange column.
protons and, at the same time, different dihedral angles
between the R proton and the two â protons.
Similar treatment of 1-hydroxy-2-phenylethylphospho-
nic acid (5b) gave the following coupling constants:
2
3
3
3
J
HaHb,gem ) 14.4 Hz, J HbH ) 9.6 Hz, J HbP ) 7.8 Hz, J HaH
Str u ctu r es of r-Hyd r oxyp h osp h on a tes. Examina-
3.1 Hz, 3J HaP ) 3.4 Hz, J PH ) 7.5 Hz. Using these
2
)
1
tion of the H NMR spectra of both mono- and bishy-
values together with the Karplus curves, we arrive at a
conformation in which the phenyl and the phosphorus
moieties are anti and the â H-P dihedral angles are
distorted from the 60° required for the ideal staggered
structure. Compound 5b afforded high-quality crystals
which allowed a single-crystal X-ray analysis. This
confirmed the above postulated distorted staggered struc-
ture having a torsional angle of 165° for the Ph-C-C-P
group.
droxyphosphonates revealed the presence of character-
istic septets at low field as that shown for disodium 1,8-
dihydroxyoctane-1,8-bisphosphonate in Figure 1.
The septet shown clearly originates from the protons
in position R relative to the phosphorus and oxygen
atoms. Its splitting pattern indicates that the R proton
is split by the phosphorus and unequally by the two
diastereotopic protons on the adjacent methylene group.
The various coupling constants were determined by the
following decoupling techniques. Irradiation of the meth-
ylene protons in the region of 1.4-1.6 ppm caused
collapse of the septet at 3.5 ppm to a doublet which gave
Exp er im en ta l Section 12
Syn th esis of Sta r tin g Sod iu m Sa lts of Acylp h osp h o-
n a tes 1 a n d 4. Carboxylic or dicarboxylic acid chlorides were
subjected to the Arbuzov reaction with trimethyl phosphite to
yield dimethyl acylphosphonates and tetramethyl bisacylphos-
phonates, which were dealkylated using excess bromotrim-
ethylsilane to yield the corresponding trimethylsilyl esters,
which in turn were converted to the sodium salt 1 or 4 by
treatment with methanolic sodium hydroxide solution (see ref
2
the J PH ) 6.5 Hz. Irradiation of the phosphorus trans-
formed the septet at 3.5 ppm into a double doublet with
3
coupling constants of J HH ) 2.4 and 10.4 Hz. Next the
septet was irradiated causing the phosphorus signal to
3
change from a quartet to a triplet with J PH ) 6.65 Hz.
Using the Karplus curves,11 the coupling constants
determined allow to postulate the dihedral angles and
thus the conformations of the bishydroxyphosphonates
in aqueous solution. Of the three possible staggered
rotational conformations, only the structure shown in
Chart 1 satisfies all the coupling constants, which require
equal dihedral angles between the P atom and the â
1
a for bisacylphosphonates and ref 13 for acylphosphonates.
Gen er a l P r oced u r e for th e Syn th esis of r,ω-Dih y-
d r oxya lk a n e-r,ω-Bisp h osp h on ic Acid s (3). Sodium boro-
hydride (0.001 45 mol) was added to a solution of disodium
dihydrogen bisacylphosphonate (0.001 45 mol) dissolved in
distilled water (7 mL), and the reaction mixture was stirred
at room temperature for 12 h. The progress of the reaction
was monitored by 31P NMR spectroscopy to ensure complete
(
11) (a) Karplus, M. J . Chem. Phys. 1959, 30, 11. (b) Bentrude, W.
31
G.; and Setzer, W. N. Stereospecificity in P-element couplings: proton-
phosphorus couplings. In Phosphorus-31 NMR spectroscopy in stere-
ochemical analysis; Verkade, J . G., Quin, L. D., Eds.; VCH Publishers
Inc., New York, 1987; p 365.
(12) Instruments and general techniques are described in ref 1.
(13) Karaman, R.; Goldblum, A.; Breuer, E.; Leader, H. J . Chem.
Soc., Perkin Trans. 1 1989, 765-774.

Direct Approach to R-Hydroxyphosphonic Acids
J . Org. Chem., Vol. 63, No. 15, 1998 5109
conversion of the bisacylphosphonate (δ
R,R′-dihydroxyphosphonate (δ
≈ 20 ppm). If the reaction was
incomplete, an additional 0.3 equiv of NaBH was added. After
completion of the reaction, the product as sodium salt was
precipitated by the addition of methanol (50 mL) to the
reaction mixture. The free R,ω-dihydroxyalkane-R,ω-bisphos-
phonic acids could be isolated by passing the aqueous solutions
of the sodium salts through a Dowex-50W cation-exchange
column, followed by lyophilization of the eluted solutions.
P
≈ -1 ppm) to bis-
tion of the sodium salt, which was converted to the free acid
using the same method as that used for bishydroxyphospho-
P
1
4
nates: yield 57%, mp 171-173 °C; NMR (D
2
O) H, δ 4.83 (d,
2
3
1H, J (PH) ) 12.0 Hz), 7.23 (dd, 1H, J (HH) ) 5.6 Hz), 7.29 (dd,
3 3 31
2H, J (HH) ) 7.4 Hz), 7.37 (dd, 2H, J (HH) ) 7.4 Hz); P, δ 19.30
2
13
1
1
(d, J (PH) ) 11.5 Hz); C-{ H}, δ 71.52 (d, J (CP) ) 151.5 Hz),
3
126.85 (d, J (CP) ) 4.9 Hz), 127.2 (s), 128.0 (s), 139.1 (s); IR
(Nujol) ν ) 3211m, 2918s, 2855s, 2317w, 1467s, 1377m, 1287w,
7 9 4
1248m, 1218m, 1004s, 963s. Anal. Calcd for C H O P: C,
1
,6-Dih ydr oxyh exan e-1,6-bisph osph on ic acid (3a): yield
44.68; H, 4.82. Found: C, 44.41; H, 4.80.
1
9
5%, mp 160-165 °C dec; NMR (D
2
O) H, δ 1.20-1.36 (m, 2H),
1-Hyd r oxy-2-p h en yleth ylp h osp h on ic a cid (5b). So-
dium borohydride (102 mg, 0.0027 mol) was added to a solution
of sodium hydrogen phenylacetylphosphonate (0.5 g, 0.002 25
mol) dissolved in distilled water (7 mL). After completion of
the reaction, methanol (50 mL) was added to the reaction
causing precipitation of the sodium salt, which was converted
to the free acid using the same method as used for the
1
.40-1.51(m, 4H), 1.52-1.59 (m, 2H), 3.64-3.71 (septet, 2H,
2
3
3
31
J
(PH) ) 6.6 Hz, J (HaH) ) 2.4 Hz, J (HbH) ) 10.4 Hz); P, δ 25.36
2 3 13 1 2
(
)
(
)
9
)
q, J (PH) ) 6.6 Hz, J (PH) ) 6.6 Hz); C-{ H}, δ 26.5 (d, J (CP)
2
12.8 Hz), 26.6 (d, J (CP) ) 12.8 Hz), 32.5 (s), 32.5 (s), 70.36
1 1
d, J (CP) ) 155.4 Hz), 70.41 (d, J (CP) ) 155.4 Hz); IR (Nujol) ν
3193w, 2988s, 2847s, 2313w, 1463s, 1377m, 1230w, 1002m,
43m; mol wt calcd 278; FAB MS [M + H] ) 279.1, [M - H]
277.4. Anal. Calcd for C C, 25.91; H, 5.80.
Found: C, 25.41; H, 5.67.
,7-Dih ydr oxyh eptan e-1,7-bisph osph on ic acid (3b): yield
bishydroxyphosphonates: yield 75%, mp 165 °C; NMR (D
2
O)
1
3
2
3
6 16 8 2
H O P :
H, δ 2.66 (ddd, 1H, J (HaHb,gem) ) 14.4 Hz, J (HbH) ) 9.6 Hz,
2
3
J
(HbP) ) 7.8 Hz), 3.07 (dt, 1H, J (HaHb,gem) ) 14.4 Hz, J (HaH) )
3 2 3
1
3.1 Hz, J (HaP) ) 3.4 Hz), 3.77 (ddd, 1H, J (PH) ) 7.5 Hz, J (HaH)
1
3
8
1
7%, mp 170-175 °C dec; NMR (D
2
O) H, δ 1.26 (m, 4H), 1.43-
) 3.1 Hz, J (HbH) ) 9.6 Hz), 7.22-7.27 (m, 1H), 7.27-7.30 (m,
2
31
2
13
1
2
.53 (m, 4H), 1.60-1.62 (m, 2H), 3.64-3.71 (septet, 2H, J (PH)
4H); P, δ 18.22 (m, J (PH) ) 6.9 Hz); C-{ H}, δ 37.82 ( J (CP)
3
3
31
1
)
6.6 Hz, J (HaH) ) 2.4 Hz, J (HbH) ) 10.4 Hz); P, δ 24.96 (dd,
) 3.1 Hz), 70.39 (d, J (CP) ) 151.3 Hz), 126.0 (s), 128.2 (s), 128.9
2
3
13
1
2
3
J
(PH) ) 6.6 Hz, J (PH) ) 6.6 Hz); C-{ H}, δ 26.81 (d, J (CP)
)
(s), 139.73 (d, J (CP) ) 15.6 Hz); IR (Nujol) ν ) 3220m, 2921s,
2
1
(
2
2.1 Hz), 26.85 (d, J (CP) ) 12.1 Hz), 29.40 (s), 29.46 (s), 32.62
2866s, 1459s, 1378m, 1308w, 1260m, 1060m, 999s, 946s. Anal.
1
s), 70.76 (d, J (CP) ) 154 Hz); IR (Nujol) ν ) 3190w, 2924s,
Calcd for C
5.46.
8 11 4
H O P: C, 47.53; H, 5.48. Found: C, 46.64; H,
855s, 2288w, 1463m, 1377m, 1174w, 1006s, 983m, 940s; mol
wt calcd 292; FAB MS [M + H] ) 293.2, [M - H] ) 291.4.
Cr ysta lliza tion of 5b for X-r a y Cr ysta llogr a p h y. 5b
was allowed to crystallize from methanol by slow evaporation
to yield large and well-formed crystals.
Anal. Calcd for C
C, 27.58; H, 6.04.
7
H
18
O
8
P
2
2
‚H O: C, 27.11; H, 6.50. Found:
1
,8-Dih yd r oxyocta n e-1,8-bisp h osp h on ic a cid (3c): yield
1
9
1
3%, mp 180-185 °C dec; NMR (D
2
O) H, δ 1.25 (m, 6H), 1.46-
Ack n ow led gm en t. This research was supported in
part by the German-Israeli Foundation for Scientific
Research & Development. E.B. is affiliated with the
David R. Bloom Center for Pharmacy.
2
.54 (m, 4H), 1.61-1.63 (m, 2H), 3.66-3.73 (septet, 2H, J (PH)
3
3
31
)
6.6 Hz, J (HaH) ) 2.4 Hz, J (HbH) ) 10.4 Hz); P, δ 24.24 (dd,
3 13 1 2
2
J
(PH) ) 6.6 Hz, J (PH) ) 6.6 Hz); C-{ H}, δ 26.66 (d, J (CP) )
1
1
(
9
2.8 Hz), 29.52 (s), 32.45 (s), 70.55 (d, J (CP) ) 155.5 Hz); IR
Nujol) ν ) 3190w, 2925s, 2854s, 2348w, 1460m, 1224m, 1007s,
63s, 915m. Anal. Calcd for C : C, 31.37; H, 6.59.
Found: C, 31.20; H, 6.30.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data of 1-hydroxy-2-phenylethylphosphonic acid (5b)
8 20 8 2
H O P
(
10 pages). This material is contained in libraries on micro-
r-Hyd r oxyben zylp h osp h on ic Acid (5a ) Sodium boro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
hydride (362 mg, 0.0096 mol) was added to a solution of sodium
1
3
hydrogen benzoylphosphonate (2 g, 0.0096 mol) dissolved in
distilled water (10 mL). After completion of the reaction,
dioxane (150 mL) was added to the reaction causing precipita-
J O9803129