838
S.-M. Yang, W. V. Murray / Tetrahedron Letters 49 (2008) 835–839
also observed. For example, when isopropanesulfonamide
6f and benzenesulfonamide 6g were employed, comparable
yields of products (S)-9f and (S)-9g were obtained (71–
75%, entries 13 and 14). Notably, by switching the N-biaryl
mathanesulfonamide (e.g., 6c) to a N-methyl biaryl sulfon-
amide (e.g., 8), a relatively low yield of (S)-14 was obtained
under either microwave or thermal conditions presumably
due to the significantly reduced NH acidity (entries 15 and
16 vs entry 10).
After complete examination of this process, the products
(S)-9a,b and (S)-9f derived from the ring-opening reaction
were converted to the corresponding hydroxamic acids (S)-
15a–c in 73–95% yield upon treatment with hydroxylamine
hydrochloride salt and sodium methoxide (Scheme 2).9 As
previously addressed, the a-hydroxyl group is perfectly sit-
uated for installation of diverse amino groups by a SN2 dis-
placement. Activation of the hydroxyl group of (R)-9a with
triflic anhydride using 2,6-lutidine as the base provided
intermediate (R)-16, which could undergo facile displace-
ment with various amines.10 For instance, treatment of
(R)-16 with aniline or morpholine gave (S)-17a,b in excel-
lent yields (84–89%). Finally, the hydroxamic acids (S)-
18a,b were obtained by a similar transformation as men-
tioned above for (S)-15, though only a moderated yield
of (S)-18b (38%) was obtained.
The inhibitory activities of hydroxamates (S)-15a–c and
(S)-18a,b were assayed against the MMP-9 enzyme. Pre-
liminary SAR results showed that the biphenyl ether ((S)-
15a) was a suitable substituent on the nitrogen atom, giving
an IC50 of 7.8 nM, whereas the biphenyl substituent ((S)-
15b) only provided 79% inhibition at 10 lM. Increased ste-
ric influence on R1, such as isopropyl ((S)-15c), resulted ca.
35-fold loss of activity (286 nM). Instead of an a-hydroxyl
group, the a-amino substituents, including phenylamino
and morpholin-4-yl ((S)-18a,b), both gave increased
potency at low single digit nanomolar range (0.6 nM and
1.9 nM for (S)-18a and (S)-18b, respectively).
In conclusion, a facile microwave assisted epoxide ring-
opening reaction with N-biaryl sulfonamides has been
described. As illustrated by all examples examined, this
reaction is extremely efficient with good isolated yields
and general for both reaction partners. The skeleton assem-
bled by this ring-opening process could be elaborated to its
hydroxamic acid that exhibited significant binding affinity
toward MMP-9 enzyme. The optimization and detailed
SAR studies of this series as novel MMP-9 inhibitors will
be disclosed in due course.
O
O
O O
S
O O
S
HO
R1
MeO
N
R1
N
H
N
a
OH
OH
Acknowledgments
R2
(
S)-15
(
(
S
S
)-9a−b,
)-9f
R2
(
S
)-15a, R1= Me; R2= 4-methylphenoxy
S
)-15b, R1= Me; R2= phenyl
)-15c, R1= i-Pr; R2= 4-methylphenoxy
S.-M.Y. thanks Dr. Maud Urbanski for helpful discus-
sion upon preparing this manuscript and Ms. Bingbing
Wang for preparation of compound (S)-15c. The authors
also thank Dr. Robert Scannevin for the potency determi-
nation of selected compounds.
(
(S
O
O
O O
S
O O
S
MeO
N
Me
MeO
N
Me
OH
OTf
b
Supplementary data
The microwave parameters, representative procedures,
detailed reaction conditions of epoxide ring-opening reac-
tions, and 1H NMR spectra of selected compounds are
provided. Supplementary data associated with this article
O
O
(
R
)-16
(R)−9a
Me
Me
c
O
O
O O
O O
HO
S
S
N
N
Me
MeO
N
Me
H
R
R
References and notes
a
1. For representative examples, see: (a) Jacobsen, E. N.; Wu, M. H. In
Comprehensive Asymmetric Catalysis I–III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Germany, 1999;
Vol. 3, pp 1306–1326; (b) Jacobsen, E. N. Acc. Chem. Res. 2000, 33,
421–431.
2. In the design of sulfonamide-based MMP inhibitors, typically, the
biaryl ether potion was attached to the sulfonyl group instead of on
the nitrogen atom. Few exceptions, see: (a) Cherney, R. J.; Mo, R.;
Meyer, D. T.; Hardman, K. D.; Liu, R.-Q.; Covington, M. B.; Qian,
M.; Wasserman, Z. R.; Christ, D. D.; Trzaskos, J. M.; Newton, R. C.;
Decicco, C. P. J. Med. Chem. 2004, 47, 2981–2983; (b) Kim, S.-H.;
Pudzianowski, A. T.; Leavitt, K. J.; Barbosa, J.; McDonnell, P. A.;
O
O
(
S
)-18
(
S
)-17
Me
Me
(
(
S
S
)-17a, (
)-17b, (
S)-18a, R= phenylamino
)-18b, R= morpholin-4-yl
S
Scheme 2. Reagents and conditions: (a) NH2OHÁHCl (2.0 equiv), NaOMe
(6.0 equiv), MeOH, rt, 1 h, 15a (1 h, 84%), 15b (1 h, 73%), 15c (1 h, 95%),
18a (3 h, 86%), 18b (24 h, 38%); (b) Tf2O (1.2 equiv), 2,6-lutidine
(1.5 equiv), CH2Cl2, À20 to 0 °C, 1 h, 91%; (c) PhNH2 or morpholine
(4.0 equiv), CH2Cl2, 0 °C to rt, 17a (24 h, 84%), 17b (1 h, 89%).