A new and direct approach to functionalized biaryl α-ketophosphonic acids via aqueous Suzuki coupling on solid support

Article abstract of DOI:10.1016/j.tetlet.2005.10.122

A new method for the synthesis of functionalized biaryl α-ketophosphonic acids has been developed. The key step involves the use of sodium bromobenzoyl phosphonates to react with polymer-bound boronic acids via microwave-assisted aqueous Suzuki coupling. This approach provides rapid access to a wide range of diverse biaryl analogues containing an α-ketophosphonic acid moiety.

Full text of DOI:10.1016/j.tetlet.2005.10.122

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 19–22
A new and direct approach to functionalized
biaryl a-ketophosphonic acids via aqueous Suzuki
coupling on solid support
Xianfeng Li,* Anna Katrin Szardenings, Christopher P. Holmes, Liang Wang,
Ashok Bhandari, Lihong Shi, Marc Navre, Larry Jang and J. Russell Grove
Affymax, Inc., 4001 Miranda Avenue, Palo Alto, CA 94304, USA
Received 28 September 2005; revised 25 October 2005; accepted 25 October 2005
Available online 10 November 2005
Abstract—A new method for the synthesis of functionalized biaryl a-ketophosphonic acids has been developed. The key step
involves the use of sodium bromobenzoyl phosphonates to react with polymer-bound boronic acids via microwave-assisted aqueous
Suzuki coupling. This approach provides rapid access to a wide range of diverse biaryl analogues containing an a-ketophosphonic
acid moiety.
ꢀ 2005 Elsevier Ltd. All rights reserved.
a-Ketophosphonic acids (Fig. 1) exhibit a wide range of
biological activities. Kluger et al. first reported that sim-
ple aliphatic a-ketophosphonic acids were competitive
inhibitors of pyruvate dehydrogenase,1 and pyruvate
oxidase.2 Later, Tao et al. found peptidic a-ketophos-
phonic acids exhibited inhibitory activity against human
calpain I.3 Aliphatic a-ketophosphonic acids are also
biologically active in calcium-related disorders such as
hydroxyapatite formation and dissolution.4 Moreover,
a-ketophosphonic acid group represents a non-hydro-
lyzable phosphate mimetic that would be useful for
designing inhibitors to target the phosphate binding
sites of therapeutic enzymes.5 However, the papers that
have been published so far include only simple and iso-
lated examples. There is a lack of methods for the syn-
thesis of diverse and complex a-ketophosphonic acids,
which has thus far limited their utilization in biological
studies.
The precursors of a-ketophosphonic acids are the corre-
sponding diesters. Since the carbonyl group of an
a-ketophosphonate diester is highly activated, a-keto-
phosphonates containing C(O)–P bonds are known to
be highly labile and decompose readily into carboxylic
acids and dialkyl phosphonates.6–9 a-Ketophosphonates
have been shown to be susceptible to nucleophilic attack
by alcohols, thiols, amines, and enolates.6–9 These prop-
erties make them versatile intermediates, but also very
difficult to handle and purify. a-Ketophosphonates are
usually prepared by Michaelis–Arbuzov reaction be-
tween acid chlorides with trialkyl phosphites10 or by
the oxidation of a-hydroxyphosphonates.11 It has been
known that the Michaelis–Arbuzov reaction works well
only for the less complex acid chlorides. The oxidation
of a-hydroxyphosphonates tends to work well for
isolated examples, but not usually general for a range
of diverse substrates.
O
O
P
OH
R
OH
As part of our efforts to identify novel PTP inhibitors,12
we became interested in the synthesis and evaluation of
a-ketophosphonic acids. This class of compounds
contains an electron-deficient carbonyl group, which
provides an opportunity of interacting directly with
the active site cysteine residue and thus might serve as
mechanism-based inhibitors of PTPs.13 In addition, the
Figure 1. a-Ketophosphonic acids.
Keywords: a-Ketophosphonic acids; Biaryl scaffolds; Aqueous Suzuki
coupling; PTP inhibitors.
*
Corresponding author at address: Galileo Pharmaceuticals, Inc.,
Santa Clara, CA 95054, USA. Tel.: +1 408 654 5830x228; fax: +1 408
654 5832; e-mail: xli@galileopharma.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.122

20
X. Li et al. / Tetrahedron Letters 47 (2006) 19–22
Table 1. Pd(OAc)2 catalyzed aqueous Suzuki coupling reaction of
arylboronic acids and 3a–ca
inductive effect of the carbonyl group on phosphonate
acidity results in low pKa values (calcd pKa 0.8 and
5.1), indicating their good binding ability to the highly
cationic active site of PTPs. It has been shown by Breuer
et al. that a-ketophosphonic acids are far more stable
than their corresponding esters,8 presumably due to
the phosphonate dianion being a very poor leaving
group. Thus, we envisioned that a-ketophosphonic acids
(or their salts) could be used directly as precursors to
construct diverse and complex analogues. Since biaryl
scaffolds have proven to be good templates for designing
small molecule PTP inhibitors,12,14 we chose to display
a-ketophosphonic acid group on biaryl scaffolds via
Pd-assisted Suzuki coupling chemistry.15 In particular,
we wanted to develop a solid-phase approach that
would allow for the rapid synthesis of analogues with
various substituents around a biaryl scaffold.
Entry
Arylboronic acid
3a–c
Result (% conv.)b
1
2
3
4
5
6
7
8
3-MeC6H4B(OH)2
3-MeC6H4B(OH)2
3-MeC6H4B(OH)2
4-MeC6H4B(OH)2
2-MeC6H4B(OH)2
3-NO2C6H4B(OH)2
3-MeOC6H5B(OH)2
4-ClC6H5B(OH)2
a
b
c
b
b
b
b
b
>95
>95
>95
>95
77
85
>95
>95
a Reaction conditions: arylboronic acid/3a–c = 2/1, 5% Pd(OAc)2, a
mixed solvent of 10% aqueous K2CO3 and CH3CN (2:1 v/v),
microwave, 10 min.
b Conversion determined by HPLC.
solvent system. Arylboronic acids with functional
groups such as alkyl, methoxy, nitro, and halogen were
found to work well, resulting in the desired biaryl prod-
ucts (Table 1). These results indicate that 3a–c are good
substrates for Suzuki coupling, presumably due to the
electron-withdrawing effects of the a-carbonyl group.
These observations also suggest that a-ketophosphonic
acid moiety can survive the Suzuki coupling conditions
and offer additional support for its chemical stability.
As outlined in Scheme 1, sodium bromobenzoyl phos-
phonates 3a–c were prepared from the reaction of bro-
mobenzoyl chlorides 1a–c (para, meta-, and ortho-)
with trimethyl phosphite in the absence of any solvent
to give dimethyl esters 2a–c. Subsequent treatment of
the diesters with TMSBr afforded the acids. After
removal of excess TMSBr, addition of one equivalent
of sodium hydroxide in methanol precipitated 3a–c from
the reaction mixture as sodium salts. The salt forms 3a–c
are stable and easy to handle, and thus could be conve-
niently used in a parallel synthesis approach. More
importantly, the formation of sodium salts greatly sim-
plifies the purification and allows the easy preparation
of these building blocks on multi-gram scale. Com-
pounds 3a–c showed a high level of purity according
To develop solid-phase methods, we initially considered
two approaches for attaching 3a–c to solid support to
form a polymer-bound aryl bromide and then conduct
the Suzuki coupling with arylboronic acids. One was
to attach 3 to the solid support through ketone car-
bonyl, either by reacting with a hydrazine resin to form
a hydrazone linkage19 or with a diol resin to form ketal
linkage.20 The other was to tether 3 to the resin via a
phosphonate ester linkage using Mitsunobu condi-
tions.21 However, all these attempts failed to load 3 to
resins presumably due to the poor solubility of 3 in
organic solvents. Therefore, we decided to develop an
alternative approach to conduct a reversed Suzuki reac-
tion,22 by reacting a polymer-bound aryl boronic acid
with 3.
1
31
to HPLC, H, and P NMR analysis.16
With a set of building blocks 3a–c available, we investi-
gated the Suzuki coupling conditions in solution by
varying the reaction parameters (i.e., catalyst, base, sol-
vent, and temperature). This led to the identification of a
general set of conditions for the coupling reactions
(boronic acid/3a–c = 2/1, 5% Pd(OAc)2, a mixed solvent
of 10% aqueous K2CO3 and CH3CN (2:1 v/v), micro-
wave, 10 min). The combination of aqueous potassium
carbonate and acetonitrile was chosen as a solvent sys-
tem for the coupling reaction, because both reactants
are very polar in nature and have good water solubility.
Microwave irradiation17,18 was found to give good
results for Pd(OAc)2 catalyzed coupling in this aqueous
As shown in Scheme 2, ArgoPore resins (Argonaut
Technologies) were used because of their compatibility
with a wide range of solvents including polar protic
solvents such as water that is required for the Suzuki
coupling. ArgoPore Rink-NH2 resin 5 was allowed to
react with 3- or 4-carboxyphenylboronic acid to give
resin-bound boronic acids 6 (R1 = H). To introduce
R1 substituents, ArgoPore-BAL resin 4 (ArgoPore resin
functionalized with a BAL linker)23 was derivatized with
primary amines by reductive amination to give resin-
bound secondary amines 5, followed by the coupling
with 3- or 4-carboxyphenylboronic acid to give 6. Aque-
ous Suzuki coupling of 6 with the three a-ketophos-
phonic acids 3a–c generated the biaryl products 7.24
After acidic cleavage from the resin with TFA, products
8 were purified by preparative HPLC.25 Representative
examples of a-ketophosphonic acids 8a–l are shown in
Table 2. Compounds 8a–f represent six isomeric biaryl
scaffolds with different spatial orientations, and 8g–l
are biaryl analogues with substituents incorporated into
O
a
Br
Br
Cl
P(OMe)2
O
O
2a-c
b,c
1a-c
O
P
Br
OH
O- Na+
O
3a, 4-Br, 87%
3b, 3-Br, 79%
3c, 2-Br, 86%
Scheme 1. Reagents and conditions: (a) P(OMe)3, 1 h; (b) TMSBr,
CH2Cl2, overnight; (c) 1 equiv NaOH in MeOH.

X. Li et al. / Tetrahedron Letters 47 (2006) 19–22
21
group is reduced on support, the resulting amino group
could be readily derivatized into other useful functional-
ities including carboxamides, sulfonamides, and ureas.
O
b
a
OH
B
OH
NH
R1
N
CHO
R1
4
6
5
In summary, we developed a new method for the synthe-
sis of functionalized biaryl a-ketophosphonic acids
using sodium bromobenzoyl phosphonates as precur-
sors via aqueous Suzuki coupling on solid support. To
the best of our knowledge, these are the first reported
examples of palladium-catalyzed syntheses of com-
pounds incorporating a-ketophosphonic acids. This di-
rect approach provides rapid access to a wide range of
diverse biaryl a-ketophosphonic acids, which constitute
an interesting class of inhibitors of protein tyrosine
phosphatases.5
O
c
N
O
R1
P(OM)2
O
O
7 (M = K, Na)
O
d
R1HN
O
P(OH)2
8
Scheme 2. Reagents and conditions: (a) (i) R1NH2, TMOF/DMF
(1:1), 30 min; (ii) HOAc, MeOH, NaBH3CN, overnight; (b) HO2C–
C6H4–B(OH)2, PyBOP, DIEA, DMF, overnight; (c) 3a–c, Pd(OAc)2,
10% K2CO3 and CH3CN (2:1 v/v), microwave, 10 min; (d)
CF3COOH/CH2Cl2 (1:1), 20 min.
Acknowledgments
We thank Limin He for HPLC and LC/MS analysis.
We also thank Professor Ron Kluger at the University
of Toronto for helpful discussions.
Table 2. Solid-phase synthesis of biaryl a-ketophosphonic acids 8
using 3a–c via aqueous Suzuki coupling reaction
References and notes
O
6'
5
1'
5' 4
4' 3
R1HN
O
6
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O
N
8kb
8lb
b
40–3
20
N
a ArgoPore Rink-NH2 resin 5 was used with a loading of 0.60 mmol/g.
b ArgoPore BAL resin 4 was used with a loading 0.62 mmol/g.
c Isolated yields after preparative HPLC.
12. (a) Li, X.; Bhandari, A.; Holmes, C. P.; Szardenings, A. K.
Bioorg. Med. Chem. Lett. 2004, 14, 4301; (b) Holmes, C.
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the amide portion of scaffold 8b. Using the same proce-
dure, substituents could be incorporated in scaffolds 8a
and 8c–f as well.
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It is also conceivable to use this solid-phase approach to
incorporate additional sets of diversity by using boronic
acids such as (4-carboxy-2-nitrophenyl)boronic acid and
(3-carboxy-5-nitrophenyl)boronic acid. After the nitro

22
X. Li et al. / Tetrahedron Letters 47 (2006) 19–22
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24. Typical procedure for solid-phase Suzuki coupling: To a
suspension of resin 6 (50 mg, ꢁ0.6 mmol/g) in 0.6 mL of a
mixed solvent of 10% K2CO3 and CH3CN (v/v, 2/1) was
added 3 (25 mg, 0.09 mmol), and 1.0 mg of Pd(OAc)2. The
reaction mixture was irradiated in a domestic 1000 W
microwave oven for 10 min (at 20% power). The resin was
washed with water (3 · 2 mL), DMF (3 · 2 mL), and
CH2Cl2 (3 · 2 mL). Final products were cleaved from the
resin with 50% TFA in CH2Cl2.
25. HPLC purification was carried out on a preparative
Nucleosil C18 reverse phase column. The following
mobile phase gradient system was used: (solvent A:
water with 0.1% TFA; solvent B: acetonitrile with 0.1%
TFA): 0 min, 100% A; 5 min, 100% A; 20 min, 100% B;
28 min, 100% B; 30 min, 100% A. Flow rate 12 mL/min.
The yields for all the compounds were not optimized.
The low yields observed are probably due to poor
recovery of these highly polar compounds during HPLC
purification.
15. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
16. Preparation of 3c: To a stirred 2-bromobenzoyl chloride
(2.61 mL, 20 mmol, neat) at 0 ꢁC was added slowly
trimethyl phosphite (2.36 mL, 20 mmol). The mixture
was allowed to stir at rt for 1 h, and then treated with
TMSBr (5.81 mL, 44 mmol) in 100 mL of CH2Cl2 for
overnight. After concentrated in vacuo, NaOH (0.8 g,
20 mmol) in 80 mL of MeOH was added and the product
was collected by filtration to give 4.96 g of 3c as an off-
white powder (yield 86%). 1H NMR (DMSO-d6,
300 MHz) 8.30 (d, 1H), 7.58 (d, 1H), 7.32 (m, 2H). 31P
NMR (DMSO-d6, 121 MHz) ꢀ2.1. MS: m/z = 262.9
(M+ꢀ1, 100%).
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