The biphenyl moiety fits in the deep hydrophobic pocket
in the active sites of gelatinases, and the inhibitor interacts
with the active-site zinc ion through the thiirane moiety. This
interaction activates the thiirane for nucleophilic attack by
the active site glutamate in these enzymes, resulting in
irreversible inhibition (Scheme 1). The mechanism of action
of this inhibitor is unique among those reported for MMPs.
which indicates that the nucleophilic attack of the thiolate
occurred exclusively at the C-3 of epichlorohydrin and the
stereocenter was not scrambeld during this step. We cannot
rule out the possibility of nucleophilic attack at C-1, and
the released Cl- subsequently attacked at C-3 epoxide
opening, though C-3 attack is the most likely route. The
enantiomeric excess was determined by chiral HPLC (Sup-
porting Information).
We also explored alternative routes to the chiral thiiranes,
starting with the same starting material 2 (Scheme 3). After
Scheme 1
Scheme 3
Whereas we have used a racemic mixture of inhibitor 1
in all previous investigations (including animal studies), we
have been curious if one or both of the enantiomers would
exhibit the biological activity. In the field of enzyme
inhibition, it is widely assumed that one enantiomer is active
while the other is not. To provide the answer to this question,
we report herein the facile syntheses of optically active (R)-
and (S)-enantiomers of compound 1, starting from com-
mercially available (R)- and (S)-epichlorohydrin, respectively
(Figure 1). We also report on the enzyme inhibitory
the thiolate was generated by the reaction of 2 with n-BuLi
and sulfur, we allowed it to react with acetyl chloride,
yielding the thioacetate 6. Compound 6 directly gives (S)-4
by treatment with epichlorohydrin. Another approach is by
the reaction of the thiolate with allyl bromide to give the
allyl sulfide 7, which could further be elaborated to the
corresponding chiral diol, (S)-8, by the Sharpless dihydroxy-
lation reaction.19 The resulting diol could be converted to
the epoxide under Mitsunobu condition.20 After careful
consideration of the yields, the need for purification, and
the issue of enantioselectivity, we opted for the original route
outlined in Scheme 2.
Figure 1. Selective gelatinase inhibitor.
The remainder of the synthetic route was similar to that
of a published method,21 which involves the formation of
the epoxide ring, sulfide oxidation, and thiirane ring forma-
tion. Throughout the synthesis, the stereocenter was intact.
The last step, conversion of the oxirane to the thiirane ring,
involves inversion of stereochemistry.22,23 This was per-
formed in the presence of thiourea to give the desired
product, which was recrystallized from 1-butanol.
properties of the enantiomers and provide answers on
interactions of these molecules within the active site of
MMP-2.
Synthesis commences with lithiation of 4-phenoxyphe-
nylbromide (2), which was then treated with sulfur to
The optical purity was determined by NMR in the presence
of the chiral shift reagent europium tris[3-(heptafluoropro-
Scheme 2
(16) Brown, S.; Bernardo, M. M.; Li, Z. H.; Kotra, L. P.; Tanaka, Y.;
Fridman, R.; Mobashery, S. J. Am. Chem. Soc. 2000, 122, 6799-6800.
(17) Gu, Z.; Cui, J.; Brown, S.; Fridman, R.; Mobashery, S.; Strongin
Alex, Y.; Lipton Stuart, A. J. Neurosci. 2005, 25, 6401-6408.
(18) Kruger, A.; Arlt, M. J. E.; Gerg, M.; Kopitz, C.; Bernardo, M. M.;
Chang, M.; Mobashery, S.; Fridman, R. Cancer Res. 2005, 65, 3523-3526.
(19) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc.
1995, 117, 10805-10816.
(20) Takano, S.; Seya, K.; Goto, E.; Hirama, M.; Ogasawara, K. Synthesis
1983, 116-117.
(21) Lim, I. T.; Brown, S.; Mobashery, S. J. Org. Chem. 2004, 69, 3572-
3573.
generate the corresponding thiolate. The thiolate was allowed
to react with (R)-epichlorohydrin (97% ee) (Scheme 2).
Optical purity of the resultant compound ((R)-3) was 97%,
(22) Sanders, M. Chem. ReV. 1966, 66, 297-339.
(23) Hauptman, E.; Fagan, P. J.; Marshall, W. Organometallics 1999,
18, 2061-2073.
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Org. Lett., Vol. 7, No. 20, 2005