Exploration of mild copper-mediated coupling of organotrifluoroborates in the synthesis of thiirane-based inhibitors of matrix metalloproteinases

Article abstract of DOI:10.1016/j.bmcl.2010.12.076

The copper-mediated and non-basic oxidative cross-coupling of organotrifluoroborates with phenols was applied to elaboration of the structures of thiirane-based inhibitors of matrix metalloproteinases. By revision of the synthetic sequence to allow this c

Full text of DOI:10.1016/j.bmcl.2010.12.076

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2675–2678
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Exploration of mild copper-mediated coupling of organotrifluoroborates
in the synthesis of thiirane-based inhibitors of matrix metalloproteinases
⇑
Sebastian A. Testero, Renee Bouley, Jed F. Fisher, Mayland Chang, Shahriar Mobashery
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The copper-mediated and non-basic oxidative cross-coupling of organotrifluoroborates with phenols was
applied to elaboration of the structures of thiirane-based inhibitors of matrix metalloproteinases. By revi-
sion of the synthetic sequence to allow this cross-coupling as the final step, and taking advantage of the
neutral nature of organotrifluoroborate cross-coupling, a focussed series of inhibitors showing aryloxy
and alkenyloxy replacement of the phenoxy substituent was prepared. This reaction shows exceptional
promise as an alternative to the classic copper-mediated but strongly basic Ullmann reaction, for the
diversification of ether segments within base-labile lead structures.
Received 17 November 2010
Revised 10 December 2010
Accepted 15 December 2010
Available online 29 December 2010
Keywords:
Thiirane
Ullmann reaction
Organotrifluoroborate salt
Diaryl ether synthesis
Cross-coupling
Ó 2010 Elsevier Ltd. All rights reserved.
There is a high demand for new synthetic methods for the prep-
aration of diaryl ethers and alkenyl aryl ethers, owing to their
importance as structural motifs in a wide range of molecules with
various applications. The classical reaction for preparation of diaryl
ethers is the copper-catalyzed Ullmann reaction, but this reaction
is typically carried out at high temperatures in the presence of
strong base, which significantly limits its use.1 Recently, Batey
and Quach have reported a novel protocol for ether formation from
alcohols under essentially neutral conditions, using alkenyl and
aryl trifluoroborate salts in the presence of copper.2 This method
is of interest because of its mildness, which allows application to
valuable and highly elaborated synthetics substrates.
of which 1 (also known as SB-3CT; Fig. 1) is a prototype. This inhib-
itor potently inhibits gelatinases (MMP-2 and MMP-9) in the nano-
molar range, to the virtual exclusion of the other members of the
MMP family. Compound 1 is a mechanism-based inhibitor, which
operates by a distinct mechanism that gives rise to a stable com-
plex with the gelatinases involving thiolate coordination to the
active-site zinc atom. An important feature of the inhibitor is the
biphenyl ether moiety that fits into the S10 pocket of these
gelatinases, and a thiirane ring that undergoes a gelatinase-
catalyzed ring opening to give the stable zinc–thiol interaction of
the inhibited enzyme.11
Despite its rapid metabolism in mice and other species,10
compound 1 is highly effective in animal models of several dis-
eases.12–20 This efficacy is in large measure due to the high gelatin-
ase activity of one of its major metabolites.10 Although more
potently active than compound 1, it has certain undesirable prop-
erties such as poor aqueous solubility, difficulty in formulation,
and multiple routes of metabolism that all present obstacles to
the progression of this compound in pharmacological evaluation.
SAR studies of variants of compound 1 carried out in our lab to
date have shown that the structural template can be modified to
In recent years, potassium organotrifluoroborates have become
a
promising alternative to the use of organoboronic acids.
Organotrifluoroborates are crystalline solids that show exceptional
stability toward oxygen and moisture, and they are easily pre-
pared.3 Many are now commercially available. Moreover, in many
organic reactions potassium organotrifluoroborates have shown
comparable and very often better yields compared to organobo-
ronic acids. In addition, the tetracoordinated nature of these
species allows their functionalization, increasing the molecular
complexity of the organoboron reagent, providing a unique access
to valuable organic synthons.4
O
HO
We have previously described the synthesis, inhibitory activ-
ity,5,6 mechanism7,8 and metabolism studies9,10 with a valuable
class of thiirane-containing highly selective gelatinase inhibitors,
S
S
S
S
O
O
O
O
1
2
⇑
Corresponding author.
E-mail address: mobashery@nd.edu (S. Mobashery).
Figure 1. SB-3CT (1), a potent and selective gelatinase inhibitor and intermediate
base-labile phenol 2.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.076

2676
S. A. Testero et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2675–2678
Table 1
MMPs. These results reveal the richness of the structural space for
the thiirane inhibitors, which is worthy of further exploration in
generating libraries of structurally diverse molecules.
Optimization experiment for Cu(II)-mediated etherification of the base-labile phenol
2 to produce compound 1
(i) Cu(OAc)2.H2O, DMAP,
CH2Cl2, 4Å MS, rt, 5 min.
O
In order to aggressively develop this SAR, we have focused on
the syntheses of structurally diverse libraries for biological evalua-
tion. Here, we report our efforts toward the diversification of the
phenoxy segment of 1. This ambition required a synthetic route
wherein the diversification occurs at the final step of the synthesis,
from a common intermediate, under conditions that are compati-
ble with the other functionalities present in the molecule.
We have prepared compound 2 in five synthetic steps from
4-hydroxythiophenol in the context of a focused series of sulfonate
derivatives of the thiirane inhibitors.21 The thiirane ring of 2 is
readily opened by base, by a mechanism identical to that which
occurs in matrix metalloproteinase inhibition. Consequently, 2 is
incompatible as a reagent for traditional Ullmann ether formation.
Indeed, in our hands even the milder Ullmann conditions given by
Chan and Evans22,23 (2 equiv boronic acid, 1 equiv Cu(OAc)2,
2 equiv Et3N, molecular sieves, rt) were unsuccessful.
BF3-K+
S
(ii) 2, RT, 48 h, O2
S
O
O
1
Entry
Equiv Cu(OAc)2
Equiv DMAP
Temperature
Yielda (%)
1
2
3
4
0.1
0.1
1
0.2
2
0.2
0.2
rt
rt
reflux
rt
26 (61)
0 (14)
24 (29)
72(0)
1
a
Isolated yield; data in parentheses are the recovered starting materials.
improve solubility and metabolic stability of the compound class,
concomitant with retention of selectivity and potency in inhibition
of gelatinases. Furthermore, in some cases, it was possible to tweak
the chemical structure to inhibit only MMP-2. Yet, in others the
modifications gave rise to a widening of the spectrum of inhibited
Table 2
The Cu(II)-mediated etherification of phenol 2 with different RBF3-K+ salts
(i) Cu(OAc)2.H2O (1 equiv)
DMAP(20 mol%), CH2Cl2,
O
R
4Å MS, rt, 5 min.
R-BF3 K+
2 equiv
-
S
O O
(ii) 2, RT, 48 h, O2
S
3
Entry
1
Trifluoroborate
Product
Yielda (%)
44 (33)
BF3K
O
O
O
O
O
S
S
O
O
BF3K
O
2
3
65 (0)
36 (0)
S
O O
S
BF3K
BF3K
O
S
S
S
O O
S
O
4
39 (0)
S
O O
S
NO2
NO2
BF3K
BF3K
BF3K
O
5
6
7
8
9
74 (0)
MeS
MeS
S
O O
S
O
N
O
N
N
O
N
16 (27)
53(15)
14(57)
24(33)
S
S
O
O
O
MeO
Br
MeO
Br
S
O O
S
BF3K
BF3K
O
S
S
O
O
O
Cl
Cl
S
S
O
O

S. A. Testero et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2675–2678
2677
Table 2 (continued)
Entry
Trifluoroborate
Product
Yielda (%)
BF3K
O
10
11
HO
14(41)
HO
S
O O
S
BF3K
O
N
—
—
0 (12)
0 (78)
O
12
BF3K
a
Isolated yield; data in parentheses are the recovered starting materials.
As a final effort to enable Ullmann cross-coupling diversifica-
tion from 2 as an intermediate, we explored the use of aryl triflu-
oroborates for phenol O-arylation as described by Batey and
Quach. The result from the initial reaction (Table 1, entry 1). was
encouraging. Given the modest yield for 1, and the intrinsic com-
plexity of this reaction—key variables include the choice of copper
salt catalyst, catalyst loading, catalyst ligand, reagent stoichiome-
try, solvent, temperature, oxidant, and nature of the molecular
sieves and its source—we explored many of these variables as a
prelude to library diversification. Cu(OAc)2 was chosen as the Cu(II)
source. The addition of 1,2-dimethylimidazole24 and N-methylim-
idazole25 monodentate copper ligands, as were recently used in
similar copper-catalyzed cross-couplings, gave a small increase in
the reaction yield. 1,2-Dimethylimidazole was the better ligand
of the two. DMSO and MeCN as sole solvents, or as co-solvents
(in different ratios) with dichloromethane, were compared to
dichloromethane alone. None of these changes improved the
yields. The use of 5 equiv (instead of 2 equiv) of the potassium phe-
nyltrifluorborate actually reduced the yield. This outcome may be
attributed to phenyltrifluorborate homocoupling.24 Furthermore,
we discovered that different sources for the molecular sieves, all
exhaustively activated at 200 °C under vacuum prior to use, gave
different yields. These differences may be attributed to the
variability of the constituents and the mixtures of ingredient
minerals in different molecular sieves from different origins.
As is shown in Table 1, we decided to increase the amount of
copper using DMAP as ligand. We found that 1 equiv of Cu(OAc)2,
0.2 equiv of DMAP, 2 equiv of potassium phenyltrifluoroborate in
the presence of 4 Å molecular sieves gave the best results for this
funtionalization (Table 1, entry 4). As Batey and Quach observed
previously, under these conditions, phenylboronic acid also under-
goes cross-coupling with phenol 2, although in lower yield (with
15% of cross-coupling product and 49% of starting material
recovered).
The mechanism of this copper-mediated oxidative coupling
with organotrifluoroborates is believed to go through a CuIII spe-
cies. Stahl and co-workers26 have suggested that after the initial
transmetallation, the resulting aryl-CuII species is oxidized by an-
other equivalent of CuII to yield an aryl-CuIII intermediate, which
undergoes facile C–O reductive elimination.
Notwithstanding the modesty in yields, the procedure em-
ployed in the present study allows for a single-step rapid assembly
of a series of analogs of 1 with variations in the ether moiety in the
last step on a structurally sensitive precursor. We have expanded
the mild and essentially neutral conditions developed by Batey
and Quach for the syntheses of alkenyl–aryl and aryl–aryl ethers.
The reaction was successfully applied to the base-labile thiirane
2 to generate a series of analogs of gelatinase inhibitor 1.
Acknowledgments
This research was supported by a Grant from the National
Institutes of Health (CA122417). The Mass Spectrometry
&
Proteomics Facility at the University of Notre Dame is supported
by a Grant from the National Science Foundation, (CHE-0741793).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.12.076.
References and notes
1. Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
2. Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381.
3. (a) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49; (b) Stefani, H. A.;
Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623; (c) Molander, G. A.; Ellis, N. Acc.
Chem. Res. 2007, 40, 275; (d) Darses, S.; Genet, J. P. Chem. Rev. 2008, 108, 288.
4. Molander, G. A.; Cooper, D. J. J. Org. Chem. 2008, 73, 3885. and references
therein.
5. Brown, S.; Bernardo, M. M.; Li, Z. H.; Kotra, L. P.; Tanaka, Y.; Fridman, R.;
Mobashery, S. J. Am. Chem. Soc. 2000, 122, 6799.
6. Lee, M.; Bernardo, M. M.; Meroueh, S. O.; Brown, S.; Fridman, R.; Mobashery, S.
Org. Lett. 2005, 7, 4463.
7. Forbes, C.; Shi, Q.; Fisher, J. F.; Lee, M.; Hesek, D.; Llarrull, L. I.; Toth, M.;
Gossing, M.; Fridman, R.; Mobashery, S. Chem. Biol. Drug Des. 2009, 74, 527.
8. Tao, P.; Fisher, J. F.; Mobashery, S.; Schlegel, H. B. Org. Lett. 2009, 11, 2559.
9. Celenza, G.; Villegas-Estrada, A.; Lee, M.; Boggess, B.; Forbes, C.; Wolter, W. R.;
Suckow, M. A.; Mobashery, S.; Chang, M. Chem. Biol. Drug Des. 2008, 71, 187.
10. Lee, M.; Villegas-Estrada, A.; Celenza, G.; Boggess, B.; Toth, M.; Kreitinger, G.;
Forbes, C.; Fridman, R.; Mobashery, S.; Chang, M. Chem. Biol. Drug Des. 2007, 70,
371.
11. Ikejiri, M.; Bernardo, M. M.; Bonfil, R. D.; Toth, M.; Chang, M.; Fridman, R.;
Mobashery, S. J. Biol. Chem. 2005, 280, 33992.
12. Bonfil, R. D.; Sabbota, A.; Nabha, S.; Bernardo, M. M.; Dong, Z.; Meng, H.;
Yamamoto, H.; Chinni, S. R.; Lim, I. T.; Chang, M.; Filetti, L. C.; Mobashery, S.;
Cher, M. L.; Fridman, R. Int. J. Cancer 2006, 118, 2721.
13. Kruger, A.; Arlt, M. J. E.; Gerg, M.; Kopitz, C.; Bernardo, M. M.; Chang, M.;
Mobashery, S.; Fridman, R. Cancer Res. 2005, 65, 3523.
14. Martin, M. D.; Carter, K. J.; Jean-Philippe, S. R.; Chang, M.; Mobashery, S.;
Thiolloy, S.; Lynch, C. C.; Matrisian, L. M.; Fingleton, B. Cancer Res. 2008, 68,
6251.
We realize that when the number of components for the reac-
tion is many (as is required for this reaction), many different con-
ditions could be tried. Regardless, the conditions given in Table 1,
entry 4, were satisfactory and we were poised to prepare a series
of analogs of compound 1 by this method. The results of these ef-
forts are given in Table 2.
As Batey and Quach noted, electron-rich aryl trifluoroborates
give the best results (Table 2, entries 5 and 7), whereas electron-
deficient aryl trifluoroborates with electron-withdrawing groups
at the para position and alkyl organotrifluoroborates did not react,
when treated with phenol 2 (Table 2, entries 11 and 12). However,
the electron-deficient potassium 3-nitrophenyltrifluoroborate
(Table 2, entry 4), with an electron-withdrawing group at the meta
position, furnished the desired product in a moderate yield. With
the exception of potassium trans-styryltrifluoroborate (Table 2,
entry 2), alkenyl and heterocyclic trifluoroborates were modest
cross-coupling partners (Table 2, entries 3 and 6).

2678
S. A. Testero et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2675–2678
15. Gu, Z.; Cui, J.; Borwn, S.; Fridman, R.; Mobashery, S.; Strongin, A. Y.; Lipton, S. A.
J. Neurosci. 2005, 25, 6401.
16. Ota, R.; Kurihara, C.; Tsou, T. L.; Young, W. L.; Yeghiazarians, Y.; Chang, M.;
Mobashery, S.; Sakamoto, A.; Hashimoto, T. J. Cereb. Blood Flow Metab. 2009, 29,
1547.
20. Yu, F.; Kamada, H.; Niizuma, K.; Endo, H.; Chan, P. H. J. Neurotrauma 2008, 25, 184.
21. Testero, S. A.; Lee, M.; Staran, R. T.; Espahbodi, M.; Llarrull, L. I.; Toth, M.;
Mobashery, S.; Chang, M. ACS Med. Chem. Lett. doi:10.1021/ml100254e [Epub
ahead of print].
22. Chan, D. M. T.; Monaco, K. L.; Wang, R. P. Tetrahedron Lett. 1998, 39, 2933.
23. Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.
24. Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272.
17. Luplertlop, N.; Misse, D.; Bray, D.; Deleuze, V.; Gonzalez, J. P.; Leardkamolkarn,
V.; Yssel, H.; Veas, F. EMBO Rep. 2006, 7, 1176.
18. Guo, Z.; Sun, X.; He, Z.; Jiang, Y.; Zhang, X.; Zhang, J. H. Neurol. Res. 2010, 32,
715.
25. Bolshan, Y.; Batey, R. A. Tetrahedron 2010, 66, 5283.
26. King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044.
19. He, Z. J.; Huang, Z. T.; Chen, X. T.; Zou, Z. J. Chin. Med. (Engl.) 2009, 122, 2346.