Design and synthesis of matrix metalloproteinase inhibitors guided by molecular modeling. Picking the S1 pocket using conformationally constrained inhibitors

Article abstract of DOI:10.1021/jm010096n

Conformationally constrained MMP inhibitors based on a D-proline scaffold were designed using AutoDock as a modeling program. Thus a family of D-proline hydroxamic acids, having differentiated functionality at the site of binding to the S₁ pock

Full text of DOI:10.1021/jm010096n

3074
J . Med. Chem. 2001, 44, 3074-3082
Design a n d Syn th esis of Ma tr ix Meta llop r otein a se In h ibitor s Gu id ed by
Molecu la r Mod elin g. P ick in g th e S1 P ock et Usin g Con for m a tion a lly Con str a in ed
In h ibitor s
Stephen Hanessian,* D. Bruce MacKay, and Nicolas Moitessier
Department of Chemistry, Universite´ de Montre´al, C. P. 6128, Succursale Centre-Ville, Montre´al, P. Q., Canada H3C 3J 7
Received March 3, 2001
Conformationally constrained MMP inhibitors based on a D-proline scaffold were designed using
AutoDock as a modeling program. Thus a family of D-proline hydroxamic acids, having
differentiated functionality at the site of binding to the S1 pocket, was synthesized. Biological
evaluation showed low nanomolar activity and modest selectivity toward different MMP
subclasses, delineating the importance of binding to the S1 pocket for both activity and
selectivity.
In tr od u ction
The matrix metalloproteinases (MMPs) are recog-
nized as promising drug targets as evidenced by the
disclosure of several potent inhibitors in recent years.1
MMP inhibitors can be roughly organized into two
categories, namely succinate-type structures, exempli-
fied by Batimastat (1)2 and Ro32-3555 (2),3 and sulfon-
amides, including CGS 27023A (3)4 and 45 (Figure 1).
X-ray crystallography and NMR conformational studies
have been used extensively to better understand the
binding of inhibitors to these enzymes. For instance,
CGS 27023A (3) complexed with MMP-3 was studied
by NMR,6 and the tertiary structure of MMP-8 cocrys-
tallized with 1 has been elucidated by X-ray crystal-
lography.7 Although many broad spectrum MMP in-
hibitors have been disclosed, selectivity toward specific
MMP subtypes remains an important issue. We now
report the design, synthesis, and in vitro MMP inhibi-
tory activity of conformationally constrained hydroxamic
acids related to D-proline.
F igu r e 1. MMP inhibitors.
Resu lts a n d Discu ssion
Ta ble 1. Amino Acids Present in the S1′ Pocket of MMPs
Molecu la r Mod elin g a n d Design . Previous studies
MMPs
aa 1
aa 2
aa 3
have shown that selectivity can be achieved by optimiz-
ing the length of the P1′ subsite according to the
difference in depth of the S1′ pocket for different MMP
subtypes.8 As observed from X-ray crystal structures,7,9
the S1′ pocket is long and narrow for MMP-2, MMP-3,
and MMP-8, and short and narrow for MMP-1 and
MMP-9. By contrast, less information is available
concerning the exploitation the S1 pocket for selectivity
purposes.
A survey of reported X-ray crystallographic structures
of MMP-inhibitor complexes7,9 revealed that although
the tertiary structures were quite similar, a few muta-
tions of amino acids occurred at the S1 pocket (Table
1).10 For example, MMP-1 and MMP-8 featured the
same His, Phe, Ser triad of amino acids in this pocket.
Similarly, His, Phe, Tyr were found in MMP-2, MMP-
9, and MMP-13, while MMP-3 presented a distinct
MMP-1
MMP-8
MMP-2
MMP-9
MMP-13
MMP-3
His-183
His-162
His-166
His-183
His-187
His-166
Phe-185
Phe-164
Phe-168
Phe-185
Phe-189
Tyr-168
Ser-172
Ser-151
Tyr-155
Tyr-172
Tyr-176
Tyr-155
combination of amino acids (His, Tyr, Tyr). It is possible
that these differences, which are mainly related to the
aromaticity and hydrophobicity of these side chains,
could reflect on inhibitor binding and enzymatic activity.
Previous studies in our laboratories were concerned
with probing the S1, S1′, and S2′ pockets with acyclic
inhibitors such as 4 and uncovered subnanomolar
inhibition of some MMPs.5 In an effort to further
improve our understanding of the bioactive conforma-
tion of such acyclic motifs and to validate the potential
for selectivity at the S1 pocket, we turned our attention
to a constrained scaffold. Using the AutoDock suite of
molecular modeling programs,11 we designed the D-
* To whom correspondence should be addressed. Fax: (514) 343-
5728. Tel: (514) 343-6738. E-mail: stephen.hanessian@umontreal.ca.
10.1021/jm010096n CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/14/2001

Synthesis of MMP Inhibitors Guided by Molecular Modeling
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 19 3075
Sch em e 1a
a
(a) LiHMDS, PMPSO2Cl, THF, 79%; (b) LDA, THF then
PhSeBr; (c) O3, CH2Cl2, 89% (two steps); (d) (vinyl)2CuCN(MgBr)2,
TMSCl, Et2O, 71%; (e) LiHMDS, MeI, DMPU, THF (two itera-
tions), 69%; (f) LiAlH4, THF; (g) Et3SiH, BF3‚Et2O, CH2Cl2, 56%
(two steps); (h) NaClO2, NaOCl, TEMPO, CH3CN, aqueous phos-
phate buffer; (i) CH2N2, Et2O, quant. (two steps); (j) O3, CH2Cl2;
then Me2S; then NaBH4, EtOH, 69%; (k) NH2OK, NH2OH, MeOH,
65% (5b), 22% (5c).
F igu r e 2. Designed inhibitors.
had to be repeated on the crude material. Reduction of
10 with LiAlH4 then with Et3SiH in the presence of BF3‚
Et2O led to product, which was immediately desilylated
to afford 11. Oxidation14 and esterification gave 12,
which was subjected to ozonolysis followed by reductive
workup using sequential treatment with Me2S then
NaBH4 to give 13 (Scheme 1).
proline-derived analogues represented by structures
5a -i (Figure 2).12
AutoDock docking studies confirmed the expected
binding mode of 5a to be similar to that of 4 in MMP-3
(Figure 3, panels a and b). Analogues 5a , 5d , and 5f
were involved in hydrophobic interactions with the S1
pocket through the phenyl moieties. Although the side
chain of 5e was also aromatic, the presence of the
methoxy group sterically disfavored a good interaction
in this pocket.
Interestingly, AutoDock also revealed the presence of
a hydrogen bond formed between the hydroxymethyl
analogue 5c with residue Ala-165 of the protein back-
bone in MMP-3 (Figure 3, panel c). This interesting
feature led us to design compound 5g in which the
hydroxyl and the aromatic groups could interact with
the protein (Figures 3, panel d).
Syn th esis. D-Pyroglutamic acid was converted to the
known lactam 6 according to a literature procedure.13
The sulfonamide functionality was introduced as in 7,
since it was common to all targeted inhibitors and was
expected to be compatible with subsequent chemistry.
Elimination via the phenylselenyl derivative afforded
the R,â-unsaturated lactam 8, which was subjected to
conjugate addition with a vinyl magnesio cuprate to give
9 in good yield and with exclusive stereocontrol. Ini-
tially, dimethylation of 9 to give 10 proved quite
sluggish, affording the monomethyl product in prepon-
derance. To achieve complete methylation, the reaction
Conversion of the ester functionality of 12 and 13
directly to the hydroxamic acid was effected using
NH2OK in MeOH.15 Hydroxamic acid 5c proved to be
highly water soluble, and even after extensive extraction
with EtOAc from H2O, only modest amounts of product
could be recovered.
Alcohol 13 was transformed to the thioethers 15a ,
15d , and 15e (Scheme 2) by reaction of mesylate 14 with
preformed thiolates generated from reaction of thiols
with NaH in DMF. Although longer reaction times were
required compared with literature procedures,16 the
desired thioethers were nevertheless obtained in moder-
ate to excellent yield. Use of DMF was critical for the
thiolate substitution, since no reaction was observed in
other solvents such as THF, toluene, or acetonitrile.
These observations can be rationalized considering the
steric hindrance to attack of the thiolates on the
mesylate. The alkoxide generated upon treatment of 13
with NaH proved to be unstable, decomposing to a
mixture of unidentified products. Performing an in situ
quench of the reaction mixture with benzyl bromide at
low temperature to afford 16 minimized this decomposi-

3076 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 19
Hanessian et al.
F igu r e 3. Proposed docked structures for 4 (a), 5a (b), 5c (c), and 5h (d) in the MMP-3 binding site. Arrow in panel d indicates
H-bond with residue Ala-165.
Sch em e 2a
Sch em e 3a
a
(a) MsCl, Et3N, CH2Cl2, quant.; (b) RSNa, DMF, 92% (15a ),
49% (15d ), 55% (15e); (c) NH2OK, NH2OH, MeOH, 80% (5a ), 79%
(5d ), 52% (5e), 64% (5f); (d) NaH, RBr, DMF, 25%.
tion. The final hydroxamic acids 5a ,d -f were prepared
as described above.
Initially, hydroxamic acid 5g was prepared as a
mixture of diastereomers, starting from olefin 12 (Scheme
3). Dihydroxylation of 12 using OsO4 and NMO for 2
days afforded a 1.3:1 mixture of inseparable diastereo-
mers in excellent yield. As expected, selective tosylation
of the primary alcohol and subsequent reaction with
sodium benzenethiolate afforded 18 in excellent overall
a
(a) OsO4, NMO, acetone/H2O, 87%, dr 1.3:1; (b) TsCl, Et3N,
pyridine, CH2Cl2; (c) PhSNa, DMF, 84% (2 steps); (d) NH2OK,
NH2OH, MeOH, 66% (5g), 50% (5h ), 66% (5i); (e) ∆, vacuum.
yield. Conversion to hydroxamic acids 5g proceeded
smoothly to give a 1.3:1 mixture of inseparable dia-

Synthesis of MMP Inhibitors Guided by Molecular Modeling
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 19 3077
Ta ble 2. Inhibitory Activities of Compounds 4 and 5a -ia
13, which share the common His, Phe, Tyr or His, Tyr,
Tyr triads, compared to MMP-1 (His, Phe, Ser) is of
interest in the context of a preferred binding of an
arylalkylthio P1 appendage. The same trend was ob-
served with the constrained analogue 5a , which encom-
passed the acyclic skeleton of 4 and approximated its
bioactive conformation according to AutoDock modeling,
with the same arylalkylthio P1 substituent. Such a
constrained analogue has also proven to be a valuable
probe to fine-tune the nature of the S1-P1 interaction
in the quest for more potent and selective inhibitors.
Furthermore, the enhanced activity of the R-hydroxy
1-phenylthioethyl analogue 5h compared to 5i nicely
validates the value of capitalizing on observations based
on modeling and showed stereochemical dependence in
the P1 site.
IC50, nM
compd
MMP-1
MMP-2
MMP-3
MMP-9
MMP-13
4
104
198
25710
8760
654
458
1620
117
0.7
1.64
441
143
15.4
4.6
32
2.5
16.2
0.7
6.7
293
136
6.5
16.7
10.1
3.0
2.5
0.9
138
50
2.8
4.4
9.2
0.9
3.6
12
5.5
5a
5b
5c
5d
5e
5f
5h
5i
519
218
17.0
22.3
44.2
3.7
301
18.7
18.1
a
See Experimental Section for details.
stereomers. The mixture of diastereoisomeric alcohols
18 could be separated by careful flash chromatography
to afford the R-stereoisomer 18a and the S-stereoisomer
18b . Conversion of each isomer to the corresponding
hydroxamic acid afforded 5h and 5i in diastereomeri-
cally pure form, as opposed to the original 5g which
consisted of a mixture of the two. Heating 17 in vacuo
led to selective cyclization of the S-diastereomer to the
corresponding lactone 19, along with recovered 17 which
Con clu sion
Previously reported acyclic MMP inhibitor 4 was
constrained into a D-proline hydroxamic acid. Further
design of a series of analogues with the help of a
systematic docking study with MMP-3 led to analogues
with P1 appendages of different sizes, hydrophobicities,
and shapes. They were prepared from an advanced
common chiron derived from D-pyroglutamic acid and
subsequently used to probe the S1 pocket in MMPs.
These “designed” compounds exhibited nanomolar ac-
tivities with a predictable pattern of potencies. Modeling
of the complexes with MMP-3 found an extra hydrogen
bond in the case of 5c that could explain its enhanced
activity compared to 5b and was used to modulate the
activity of 5a . On the basis of this observation, we
prepared compound 5h which incorporates a new hy-
drogen bond donor on the hydrophobic phenylthioethyl
P1 side chain. Compound 5h proved to be more active
than its epimeric analogue 5i.
1
was enriched in the R-diastereomer. H NMR analysis
of 19 showed that the hydroxyl group occupied an
equatorial position, judging by the large coupling con-
stant (J ) 8.5 Hz) between the methine proton R to the
alcohol and the proton at the 3-position of the pyrroli-
dine ring. On the basis of this NMR data on the lactone
19, we were able to assign the configuration of the
epimeric alcohols 18a and 18b as R- and S- respectively.
Biologica l Assa ys. The IC50 values of analogues
5a -i compared to the acyclic counterpart 4 on five
different MMPs are listed in Table 2.
The initial goal of this work was to constrain the
acyclic carbon framework of 4 into the pyrrolidine
analogue 5a . Indeed, both were found to be roughly
equally active against four out of five MMPs. The
AutoDock model (Figure 3, panel c) showed an ad-
ditional hydrogen bond between the hydroxyl group in
5c and the protein backbone of MMP-3. It is of interest
that 5c was between two and three times more active
than 5b (Scheme 2) which lacks this hydroxyl group for
all MMPs. A loss of activity of approximately 2 orders
of magnitude in going from 5a to 5b may be due to the
absence of an aromatic P1 moiety. Lengthening the P1
subsite as in 5d resulted in a slightly different orienta-
tion of the central core, and for 5e, the exclusion of the
p-methoxyphenyl moiety out of the S1 pocket of MMP-
3. Nevertheless, these analogues did not lose significant
inhibitory activity compared to 5a . Substituting the
sulfur atom by oxygen (5a to 5f) resulted in a modest
loss of potency. The second generation compound, 5h ,
featured both the aromatic ring at the P1 subsite and
the R-hydroxyl group that, according to the proposed
binding mode (Figure 3, panel d), was involved in a
H-bond with Ala-165. Accordingly, 5h exhibited activi-
ties 3-6 times higher than the diastereomer 5i in
inhibiting MMP-3, as well as the other MMPs.
Exp er im en ta l Section
Ch em istr y. Solvents were distilled under positive pressure
of dry argon before use and dried by standard methods; THF
and ether, from Na/benzophenone; CH2Cl2 and toluene, from
CaH2. All commercially available reagents were used without
further purification. All reactions were performed under argon
atmosphere. NMR (1H, 13C) spectra were recorded on AMX-
300 and ARX-400 spectrometers in CDCl3 or CD3OD with
solvent resonance as the internal standard. Low- and high-
resolution mass spectra were recorded on VG Micromass, AEI-
MS 902, or Kratos MS-50 spectrometers using fast atom
bombardement (FAB). Optical rotations were recorded on a
Perkin-Elmer 241 polarimeter in a 1 dm cell at ambient
temperature. Analytical thin-layer chromatography was per-
formed on Merck 60F254 precoated silica gel plates. Visualiza-
tion was performed by UV or by development using KMnO4
or FeCl3 solutions. Flash column chromatography was per-
formed using (40-60 µm) silica gel at increased pressure. All
melting points are uncorrected.
(R)-5-(ter t-Bu tyl-diph en ylsila n yloxym eth yl)-1-(4-m eth -
oxy-ben zen esu lfon yl)-p yr r olid in -2-on e (7). To a solution
of lactam 6 (0.80 g, 1.93 mmol) in THF (25 mL) at -25 °C was
added LiHMDS (1.0 M in THF, 2.32 mL, 2.32 mmol). The
reaction mixture was stirred at -25 °C for 15 min. A solution
of PMPSO2Cl (0.490 g, 2.35 mmol) in THF (4 mL) was added,
and the reaction mixture was stirred at -25 °C for 1 h,
quenched with H2O (70 mL), and taken up in EtOAc (40 mL).
The phases were separated, and the organic phase was washed
with saturated NH4OH, saturated NaHCO3, and brine (50 mL
each), dried over MgSO4, filtered, and concentrated in vacuo.
While we succeeded in discovering highly active
compounds, the observed selectivity was somewhat
disappointing except that activity against MMP-1 was
much weaker compared to other MMPs. The low to
subnanomolar enzymatic inhibition of the acyclic ana-
logue 4 against MMP-2, MMP-3, MMP-9, and MMP-

3078 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 19
Hanessian et al.
0.70 (40% EtOAc in hexanes); IR (neat) 1739, 1596, 1498 cm-1
The residue was purified by column chromatography (SiO2,
20-50% EtOAc in hexanes) to afford sulfonamide 7 (0.89 g,
79%) as a colorless oil, which solidified upon standing and was
recrystallized from EtOAc to afford colorless needles: mp 110-
112 °C; [R]D +14.5 (c 1.00, CHCl3); TLC Rf ) 0.17 (20% EtOAc
;
1H NMR (300 MHz, CDCl3) δ 7.90 (d, J ) 9.0 Hz, 2H), 7.65-
7.56 (m, 4H), 7.46-7.29 (m, 6H), 6.90 (d, J ) 9.0 Hz, 2H),
5.74-5.13 (m, 1H), 4.92 (dd, J ) 16.0, 7.0 Hz, 2H), 4.12-4.07
(m, 1H), 4.04-3.82 (m, 2H), 3.78 (s, 3H), 2.93-2.82 (m, 2H),
2.22-2.13 (m, 1H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
173.02, 163.71, 138.14, 135.56, 135.45, 135.30, 135.34, 132.67,
132.28, 130.38, 129.90, 127.77, 127.70, 115.32, 113.86, 66.14,
in hexanes); IR (neat liquid): 3074, 1733, 1596, 1498 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.95 (d, J ) 9.0 Hz, 2H), 7.62-
7.55 (m, 4H), 7.46-7.33 (m, 6H), 6.88 (d, J ) 9.0 Hz, 2H),
4.47-4.38 (m, 1H), 4.02 (dd, J ) 11.0, 4.0 Hz, 1H), 3.84-3.78
(m, 1H), 3.82 (s, 3H), 2.67 (dt, J ) 20.0, 10.0 Hz, 1H), 2.36-
1.94 (m, 3H), 1.03 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 173.94,
163.59, 135.49, 135.37, 132.69, 132.30, 130.33, 130.20, 129.84,
129.80, 127.70, 127.67, 113.87, 65.50, 60.49, 55.48, 31.41,
26.68, 22.32, 19.02; HRMS calcd for C28H34NO5SiS (MH+)
524.1927, found 524.1912.
64.95, 55.52, 37.93, 36.77, 26.74, 19.09; HRMS calcd for C30H36
-
NO5SiS (MH+) 550.2084, found 550.2104.
(4R,5R)-5-(ter t-Bu tyl-d ip h en ylsila n yloxym eth yl)-1-(4-
m eth oxy-ben zen esu lfon yl)-3,3-d im eth yl-4-vin yl-p yr r oli-
d in -2-on e (10). To a solution of lactam 9 (103.8 mg, 0.189
mmol) in THF (2 mL) at -20 °C was added LiHMDS (1.0 M
in THF, 0.40 mL, 0.40 mmol). The solution was stirred for 10
min at -10 °C, DMPU (0.10 mL, 0.826 mmol) was added, and
the solution was stirred for 10 min at -10 °C. MeI (0.100 mL,
1.61 mmol) was added, and the reaction mixture was allowed
to warm to room temperature over 2.5 h. The reaction mixture
was taken up in Et2O (10 mL), washed with H2O (3 × 10 mL),
dried over MgSO4, filtered, and concentrated in vacuo. (Crude
NMR at this point shows a mixture of starting material and
products from mono- and dialkylation.) The alkylation proce-
dure was repeated exactly for the crude product. The crude
product after the second iteration was purified by column
chromatography (5-10% EtOAc in hexanes) to afford lactam
10 (74.7 mg, 69%) as a clear, colorless oil: [R]D +17.1 (c 0.97,
CHCl3); TLC Rf ) 0.48 (30% EtOAc in hexanes); IR (neat) 1739,
(R)-5-(ter t-Bu tyl-d ip h en ylsila n yloxym eth yl)-1-(4-m eth -
oxy-ben zen esu lfon yl)-1,5-d ih yd r o-p yr r ol-2-on e (8). LDA
was prepared as follows: To a solution of diisopropylamine
(0.12 mL, 0.86 mmol) in THF (10 mL) at -78 °C was added
BuLi (2.5 M in hexanes, 0.340 mL, 0.85 mmol). The solution
was allowed to warm by removal of the cooling bath for 5 min
and then cooled to -78 °C. To the LDA solution was added a
solution of lactam 7 (0.497 g, 0.851 mmol), and the reaction
mixture was stirred at -78 °C for 15 min. A solution of PhSeBr
(0.250 g, 1.06 mmol) in THF (4 mL) was added dropwise, and
the reaction mixture was stirred at -78 °C for 1 h, quenched
with H2O (15 mL), and allowed to warm to room temperature.
EtOAc (75 mL) was added, the phases were separated, and
the organic phase was washed with 2 N HCl (75 mL),
saturated NaHCO3 (75 mL), and brine (75 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
taken up in CH2Cl2 (50 mL) and cooled to -78 °C, and the
solution was sparged with O3 until a pale blue color persisted.
The reaction mixture was sparged with Ar until the blue color
was completely lost from solution, pyridine (1.5 mL) was
added, and the reaction mixture was allowed to warm to room
temperature by removal of the cooling bath. The reaction
mixture was diluted with CH2Cl2 (75 mL) and saturated
NaHCO3 (75 mL), the phases were separated, and the aqueous
phase was extracted with CH2Cl2 (2 × 75 mL). The combined
organic phases were dried over MgSO4, filtered, and concen-
trated in vacuo. The residue was purified by column chroma-
tography (10-40% EtOAc in hexanes) to afford unsaturated
lactam 8 (0.44 g, 89%) as a pale yellow foam: [R]D +70.6 (c
1.26, CHCl3); TLC Rf ) 0.51 (40% EtOAc in hexanes); IR (neat
liquid): 1730, 1595, 1490 cm-1; 1H NMR (300 MHz, CDCl3) δ
7.93 (d, J ) 9.0 Hz, 2H), 7.58-7.56 (m, 4H), 7.50-7.33 (m,
6H), 7.11 (d, J ) 6.0 Hz, 1H), 6.90 (d, J ) 9.0 Hz, 2H), 6.02 (d,
J ) 6.0 Hz, 1H), 4.79-4.75 (m, 1H), 4.24 (dd, J ) 10.0, 3.0
Hz, 1H), 3.99 (dd, J ) 10.0, 6.0 Hz, 1H), 3.83 (s, 3H), 0.99 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 169.32, 164.00, 150.90,
135.86, 135.74, 132.88, 132.83, 130.47, 130.30, 130.28, 130.21,
128.07, 128.04, 126.68, 114.31, 65.33, 63.42, 55.83, 26.97, 19.39
(1 C missing); HRMS calcd for C28H32NO5SiS (MH+) 522.1770,
found 522.1762.
1
1596, 1498 cm-1; H NMR (300 MHz, CDCl3) δ 7.79 (d, J )
9.0 Hz, 2H), 7.48-7.40 (m, 4H), 7.30-7.15 (m, 6H), 6.70 (d, J
) 9.0 Hz, 2H), 5.37 (dt, J ) 17.0, 10.0 Hz, 1H), 4.92 (d, J ) 10
Hz, 1H), 4.63 (d, J ) 10 Hz, 1H), 4.35 (dd, J ) 11.0, 3.0 Hz,
1H), 3.78 (m, 1H), 3.65 (s, 3H), 3.58 (d, J ) 9.0 Hz, 1H), 2.63
(t, J ) 9.0 Hz, 2H), 0.92 (s, 3H), 0.88 (s, 9H), 0.67 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 179.25, 163.62, 135.72, 135.68,
132.98, 132.87, 132.80, 130.46, 130.16, 129.79, 127.83, 127.69,
120.35, 113.88, 62.46, 61.07, 55.55, 48.30, 44.56, 26.89, 22.69,
20.14, 19.37; HRMS calcd for C32H40NO5SiS (MH+) 578.2396,
found 578.2400.
(2R,3R)-[1-(4-Meth oxy-ben zen esu lfon yl)-4,4-d im eth yl-
3-vin yl-p yr r olid in -2-yl]-m eth a n ol (11). To lactam 10 (55.0
mg, 0.0958 mmol) at room temperature was added LiAlH4 (1
M in THF, 0.40 mL, 0.40 mmol). The reaction mixture was
stirred at room temperature for 30 min, quenched with H2O
(5 mL), extracted with Et2O (3 × 10 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The crude lactamol was
used immediately without further purification. To a solution
of the lactamol in CH2Cl2 (2 mL) at 0 °C were added Et3SiH
(100 µL, 0.626 mmol) and BF3‚Et2O (40 µL, 0.33 mmol). The
reaction mixture was allowed to warm to room temperature
overnight and concentrated in vacuo. The residue was purified
by column chromatography (20-60% EtOAc in hexanes) to
afford alcohol 11 (17.4 mg, 56% from 10) as a clear, colorless
oil: [R]D +59.3 (c 0.76, CHCl3); TLC Rf ) 0.64 (60% EtOAc in
hexanes); IR (neat) 3501 (br), 1596, 1497 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.78 (d, J ) 9.0 Hz, 2H), 6.96 (d, J ) 9.0 Hz,
2H), 5.37 (dt, J ) 16.5, 10.0 Hz, 1H), 5.16-5.04 (m, 2H), 3.90-
3.80 (m, 1H), 3.86 (s, 3H), 3.56 (dd, J ) 12.0, 4.5 Hz, 1H), 3.30-
3.15 (m, 3H), 2.86 (br s, 1H), 2.24 (t, J ) 10.0 Hz, 1H), 0.87 (s,
3H), 0.25 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.13, 147.33,
133.20, 129.50, 120.33, 114.25, 65.59, 63.88, 62.73, 56.25,
55.61, 39.90, 24.12, 20.73; HRMS calcd for C16H24NO4S (MH+)
326.1426, found 326.1434.
(4R,5R)-5-(ter t-Bu tyl-d ip h en ylsila n yloxym eth yl)-1-(4-
m eth oxy-ben zen esu lfon yl)-4-vin yl-p yr r olid in -2-on e (9).
Caution: CuCN is highly toxic and must be handled with due
caution. Contact of reaction byproducts with acid must be
avoided. To a suspension of CuCN (3.20 g, 35.7 mmol) in Et2O
(100 mL) at -20 °C was added vinylmagnesium bromide (1 M
in THF, 73.0 mL, 73.0 mmol) over several minutes. The
reaction was stirred for 20 min and then cooled to -78 °C. A
solution of lactam 8 (4.83 g, 9.27 mmol) and TMSCl (2.6 mL,
28.0 mmol) in Et2O (35 mL) was added over 5 min, and the
reaction mixture was stirred at -78 °C for 1 h. The reaction
was quenched by addition of aqueous NH4OH (15%, 10 mL),
warmed to room temperature, and filtered through Celite. The
residue was triturated with Et2O (2 × 150 mL). The combined
organic extracts were washed with aqueous NH4OH (15%, 200
mL), dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (0-30%
EtOAc in hexanes) to afford unsaturated lactam 9 (3.59 g, 71%)
as a clear, colorless oil: [R]D +15.0 (c 0.94, CHCl3); TLC Rf )
(2R,3R)-1-(4-Meth oxy-ben zen esu lfon yl)-4,4-d im eth yl-
3-vin yl-p yr r olid in e-2-ca r boxylic a cid m eth yl ester (12).
A solution of alcohol 11 (0.670 g, 2.06 mmol) and TEMPO (22.6
mg, 0.145 mmol) in CH3CN (10 mL) and sodium phosphate
buffer (0.67 M, pH ) 6.5, 7.5 mL) was heated to 35 °C (the
heating bath was thermostated to 42 °C). Solutions of NaClO2
(tech. grade, 80%, 0.457 mg, 40.4 mmol) in H2O (2 mL) and
aqueous NaOCl (10.3% available chlorine, 0.05 mL, diluted
to 2 mL) were added dropwise over 15 min. (Note: the solutions
must not be mixed as they are unstable together.) A dark
reddish-brown color developed in the reaction mixture during

Synthesis of MMP Inhibitors Guided by Molecular Modeling
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 19 3079
addition. The reaction mixture was stirred at 35 °C overnight,
extracted with EtOAc (3 × 40 mL) from aqueous HCl (0.2 M,
40 mL), dried over MgSO4, filtered, and concentrated in vacuo.
The crude carboxylic acid was taken up in Et2O (15 mL) and
treated at room temperature with CH2N2 until a pale yellow
color was observed. The reaction mixture was stirred at room
temperature for 5 min, titrated with AcOH in Et2O until the
yellow color of CH2N2 was lost, and concentrated in vacuo. The
residue was purified by column chromatography (10-30%
EtOAc in hexanes) to afford ester 12 (0.736 g, quant.) as a
clear, colorless oil: [R]D +85.9 (c 0.80, CHCl3); TLC Rf ) 0.33
(30% EtOAc in hexanes); IR (neat) 1752, 1596, 1497 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.78 (d, J ) 9.0 Hz, 2H), 6.94 (d, J
) 9.0 Hz, 2H), 5.49 (dt, J ) 16.0, 9.0 Hz, 1H), 5.10 (d, J ) 9
Hz, 1H), 5.04 (d, J ) 16.0 Hz, 1H) 3.94 (d, J ) 10.0 Hz, 1H),
3.80 (s, 3H), 3.65 (s, 3H), 3.23-3.16 (m, 2H), 2.46 (t, J ) 9.0
Hz, 1H), 0.87 (s, 3H), 0.43 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 172.33, 163.02, 131.64, 129.80, 129.59, 120.12, 114.09, 64.46,
60.99, 58.72, 55.56, 52.32, 41.77, 23.75, 20.34; HRMS calcd
for C17H24NO5S (MH+) 354.1375, found 354.1375.
(2R,3R)-3-H yd r oxym et h yl-1-(4-m et h oxy-b en zen esu l-
fon yl)-4,4-d im eth yl-p yr r olid in e-2-ca r boxylic Acid Hy-
d r oxya m id e (5c). Hydroxamic acid 5c (4.8 mg, 22%) was
prepared from 13 according to the general procedure for
preparation of hydroxamic acids from esters, with the following
modifications: Extraction was performed using EtOAc (10 ×
20 mL EtOAc) from aqueous HCl (1 M, 10 mL), and the
product was purified by column chromatography (3-5% MeOH
in CH2Cl2). Data for 5c: white foam, [R]D +94.2 (c 0.45, CHCl3);
TLC Rf ) 0.08 (EtOAc); IR (neat) 3280 (br), 1788, 1672, 1596,
1498 cm-1; 1H NMR (300 MHz, CD3OD) δ 7.83 (d, J ) 9.0 Hz,
2H), 7.11 (d, J ) 9.0 Hz, 2H), 3.88 (s, 3H), 3.72 (d, J ) 9.5 Hz,
1H), 3.55-3.43 (m, 2H), 3.27 (d, J ) 9.0 Hz, 1H), 3.20 (d, J )
9.0 Hz, 1H), 2.25-2.17 (m, 1H), 1.84 (br s, 2H), 1.08 (s, 3H),
0.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.49, 164.98,
130.99, 130.56, 115.42, 64.34, 63.27, 60.59, 56.23, 56.16, 41.18,
25.91, 20.80; LRMS: 358 (M+), 340 (M - H2O)+, 298 (M-
CONHOH)+.
(2R,3R)-3-Met h a n esu lfon yloxym et h yl-1-(4-m et h oxy-
b en zen esu lfon yl)-4,4-d im et h yl-p yr r olid in e-2-ca r b oxyl-
ic Acid Meth yl Ester (14). To a solution of alcohol 13 (18.1
mg, 0.0504 mmol) in CH2Cl2 (1 mL) at 0 °C were added Et3N
(10 µL, 0.73 mmol) and MsCl (5.0 µL, 0.71 mmol). The reaction
was stirred at 0 °C for 1.5 h, taken up in CH2Cl2 (10 mL), and
washed quickly with saturated NH4OH (10 mL), 1 M HCl (10
mL), saturated NaHCO3 (10 mL), and brine (10 mL). The
organic phase was dried over MgSO4, filtered, and concen-
trated in vacuo. The crude mesylate 14 thus formed was used
immediately, without further purification. TLC Rf ) 0.36 (50%
EtOAc in hexanes); 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J )
9.0 Hz, 2H), 7.01 (d, J ) 9.0 Hz, 2H), 4.31-4.14 (m, 2H), 4.05
(d, J ) 9.0 Hz, 2H), 3.89 (s, 3H), 3.78 (s, 3H), 3.28 (s, 2H),
3.02 (s, 3H), 2.48-2.42 (m, 1H), 1.13 (s, 3H), 0.71 (s, 3H).
(2R,3R)-3-H yd r oxym et h yl-1-(4-m et h oxy-b en zen esu l-
fon yl)-4,4-d im eth yl-p yr r olid in e-2-ca r boxylic Acid Meth -
yl Ester (13). A solution of olefin 12 (0.736, 2.06 mmol) in
CH2Cl2 (70 mL) at -78 °C was sparged with O3 until a faint
blue color persisted in solution. The solution was sparged with
Ar at -78 °C until all blue coloration was lost from solution.
Me2S (1.0 mL, 14 mmol) was added, and the solution warmed
to room temperature over 30 min. NaBH4 (82.2 mg, 2.17 mmol)
and EtOH (75 mL) were added, and the reaction mixture was
stirred at room temperature for 2 h. The solvents were
removed in vacuo. The residue was stirred with 2 N HCl (30
mL) for 15 min, extracted with EtOAc (3 × 30 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography (40-80% EtOAc in hex-
anes) to afford alcohol 13 (0.5128 g, 69%) as a clear colorless
oil, which crystallized upon standing, and was recrystallized
(EtOAc/hexanes) to afford 13 as colorless needles: mp 115-
117; [R]D +73.8 (c 0.88, CHCl3); TLC Rf ) 0.21 (50% EtOAc in
Rep r esen ta tive P r oced u r e for Con ver sion of Mesyla te
14 t o Su lfid es. (2R,3R)-3-Ben zylsu lfa n ylm et h yl-1-(4-
m et h oxy-b en zen esu lfon yl)-4,4-d im et h yl-p yr r olid in e-2-
ca r boxylic Acid Meth yl Ester (15a ). A solution of BnSNa
in DMF was prepared as follows: To NaH (20.9 mg, 0.523
mmol), washed free of oil with hexanes (3 × 3 mL), in DMF (5
mL) was added benzyl mercaptan (50.0 µL, 0.426 mmol).
Vigorous gas evolution was observed. The reaction mixture was
stirred at room temperature for 5 min and was used im-
mediately afterward. To mesylate 14 (0.0418 mmol) was added
BnSNa in DMF (0.50 mL, 0.052 mmol). The reaction was
stirred at room temperature for 3 h, after which time TLC
indicated a small amount of starting material was still present.
A second portion of BnSNa in DMF (0.20 mL, 0.021 mmol)
was added, and the reaction mixture was stirred at room
temperature a further 30 min. The reaction mixture was taken
up in Et2O (10 mL), washed with H2O (3 × 10 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography (10-50% EtOAc in hex-
anes) to afford sulfide 15a (17.9 mg, 92% from alcohol 13) as
a clear, colorless oil: [R]D +85.9 (c 0.95, CHCl3); TLC Rf ) 0.25
(25% EtOAc in hexanes); IR (neat) 1748, 1596, 1497 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.78 (d, J ) 9.0 Hz, 2H), 7.32-7.17
(m, 5H), 6.94 (d, J ) 9.0 Hz, 2H), 3.86 (d, J ) 9.0 Hz, 1H),
3.83 (s, 3H), 3.71 (s, 3H), 3.62 (s, 2H), 3.27-3.16 (m, 2H), 2.43-
hexanes); IR (neat liquid): 3528 (br), 1741, 1595, 1497 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.79 (d, J ) 9.5 Hz, 2H), 6.96 (d,
J ) 9.5 Hz, 2H), 4.05 (d, J ) 9.0 Hz, 1H), 3.84 (s, 3H), 3.74 (s,
3H), 3.72-3.55 (m, 2H), 3.20 (s, 2H), 2.19 (ddd, J ) 9.0, 7.5,
5.0 Hz, 1H), 1.76 (br s, 1H), 1.05 (s, 3H), 0.57 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 173.46, 163.03, 129.96, 129.61, 114.09,
64.21, 61.48, 60.98, 55.86, 55.34, 52.67, 40.37, 25.15, 20.56;
HRMS calcd for C16H24NO6S (MH+) 358.1324, found 358.1325.
Rep r esen ta tive P r oced u r e for Hyd r oxa m ic Acid F or -
m a tion fr om Ester s Usin g NH2OK/NH2OH. (2R,3R)-1-(4-
Met h oxy-b en zen esu lfon yl)-4,4-d im et h yl-3-vin yl-p yr r o-
lid in e-2-ca r boxylic Acid Hyd r oxya m id e (5b). Preparation
of NH2OK/NH2OH solution (Note: a blast shield was used for
this operation): NH2OH‚HCl (0.476 mg, 6.85 mmol) was
solubilized in MeOH (2.4 mL) by heating to reflux. Most, but
not all of the salt dissolved. The solution was cooled to <40
°C, and a solution of KOH (9.98 mmol) in MeOH (1.4 mL) was
added in one portion. The resulting suspension was cooled to
room temperature before use and was used without prior
removal of precipitated material. A solution of ester 12 (22.0
mg, 0.0622 mmol) in NH2OK/NH2OH solution (2 mL) was
stirred at room temperature 3 days. The reaction mixture was
taken up in dilute aqueous HCl (pH ) 3, 20 mL), extracted
with EtOAc (3 × 15 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography (40-100% EtOAc in hexanes) to afford hy-
droxamic acid 5b (14.3 mg, 65%) as a white foam: [R]D +21.3
(c 0.30, CHCl3); TLC Rf ) 0.48 (EtOAc); IR (neat) 3331 (br),
2.33 (m, 1H), 2.30-2.12 (m, 2H), 0.95 (s, 3H), 0.46 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 172.68, 163.02, 154.78, 137.41,
129.63, 128.95, 128.51, 127.17, 114.09, 65.36, 61.42, 55.59,
52.57, 52.43, 40.90, 36.13, 28.57, 24.86, 20.74; HRMS calcd
for C23H29NO5S2 (MH+) 463.1487, found 463.1478.
(2R,3R)-1-(4-Meth oxy-ben zen esu lfon yl)-4,4-d im eth yl-
3-ph en eth ylsu lfan ylm eth yl-pyr r olidin e-2-car boxylic Acid
Meth yl Ester (15d ). Sulfide 15d (20.5 mg, 49% from alcohol
13) was prepared according to the general procedure for
preparation of sulfides from mesylate 14, modified as follows:
the reaction mixture was stirred at room temperature over-
night. Data for 15d : [R]D +101.1 (c 0.83, CHCl3); TLC Rf )
1
1748, 1693, 1595, 1497 cm-1; H NMR (300 MHz, CD3OD) δ
7.86 (d, J ) 9.0 Hz, 2H), 7.11 (d, J ) 9.0 Hz, 2H), 5.51 (dt, J
) 16.0, 9.0 Hz, 1H), 5.16-5.05 (m, 2H), 3.85 (s, 3H), 3.71 (d,
J ) 10 Hz, 1H), 3.27 (s, 2H), 2.58 (t, J ) 9.5 Hz, 1H), 0.92 (s,
3H), 0.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.58, 164.98,
133.26, 130.94, 130.70, 120.96, 115.42, 65.04, 62.53, 60.08,
56.24, 42.50, 24.10, 20.66; HRMS calcd for C16H23N2O5S (MH+)
355.1328, found 355.1332.
0.42 (40% EtOAc in hexanes); IR (neat) 1748, 1596, 1497 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.82 (d, J ) 9.0 Hz, 2H), 7.37-
7.15 (m, 5H), 7.01 (d, J ) 9.0 Hz, 2H), 3.94 (d, J ) 8.0 Hz,
1H), 3.88 (s, 3H), 3.73 (s, 3H), 3.27 (s, 2H), 2.88-2.81 (m, 2H),

3080 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 19
Hanessian et al.
2.80-2.67 (m, 2H), 2.65-2.54 (m, 1H), 2.36-2.26 (m, 2H), 1.07
(s, 3H), 0.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.64,
163.02, 140.16, 129.79, 129.64, 128.48, 128.45, 126.43, 114.09,
65.39, 61.32, 55.59, 52.98, 52.55, 40.94, 35.93, 33.98, 30.01,
24.90, 20.31; HRMS calcd for C24H32NO5S2 (MH+) 478.1722,
found 478.1714.
was added a solution of alcohol 13 (43.4 mg, 0.121 mmol) and
benzyl bromide (0.13 mL, 1.0 mmol) in DMF (4 mL). The flask
was allowed to warm to -20 °C over 20 min and was stirred
at - 20 °C for 1 h. The reaction mixture was taken up in Et2
O
(10 mL), washed with H2O (3 × 10 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified
by column chromatography (10-50% EtOAc in hexanes) to
afford ether 16f (13.7 mg, 25%) as a clear, colorless oil: [R]D
+21.3 (c 0.30, CHCl3); TLC Rf ) 0.53 (50% EtOAc in hexanes);
(2R,3R)-1-(4-Meth oxy-ben zen esu lfon yl)-4,4-d im eth yl-
3-(4-m et h oxy-ben zylsu lfa n ylm et h yl)-p yr r olid in e-2-ca r -
boxylic Acid Meth yl Ester (15e). Sulfide 15e (40.2 mg, 55%
from alcohol 13) was prepared according to the general
procedure for preparation of sulfides from mesylate 14. Data
for 15e: [R]D ) +97.6 (c 0.51, CHCl3); TLC Rf ) 0.37 (40%
EtOAc in hexanes); IR (neat) 1748, 1596, 1512 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.78 (d, J ) 9.0 Hz, 2H), 7.15 (d, J ) 9.0
Hz, 2H), 6.97 (d, J ) 9.0 Hz, 2H), 6.81 (d, J ) 9.0 Hz, 2H),
3.87 (d, J ) 10.0 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.72 (s,
3H), 3.58-3.53 (m, 2H), 3.26-3.16 (m, 2H), 2.43-2.33 (m, 1H),
2.32-2.14 (m, 2H), 0.98 (s, 3H), 0.50 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 171.43, 161.79, 157.34, 129.98, 129.57, 128.56,
114.06, 113.82, 65.33, 61.39, 55.55, 55.22, 52.51, 40.83, 35.61,
28.14, 24.82, 20.23; HRMS calcd for C24H32NO6S2 (MH+)
494.1671, found 494.1630.
1
IR (neat) 1751, 1596, 1497 cm-1; H NMR (300 MHz, CDCl3)
δ 7.81 (d, J ) 9.0 Hz, 2H), 7.39-7.22 (m, 5H), 6.94 (d, J ) 9.0
Hz, 2H), 4.42 (s, 2H), 4.01 (d, J ) 10.0 Hz, 1H), 3.86 (s, 3H),
3.68 (s, 3H), 3.51 (dd, J ) 10.0, 6.0 Hz, 1H), 3.40 (dd, J ) 9.5,
6.5 Hz, 1H), 3.28-3.20 (m, 2H), 2.40-2.30 (m, 1H), 1.10 (s,
3H), 0.61 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 172.76, 162.96,
137.84, 129.66, 128.30, 127.60, 127.40, 114.04, 73.23, 68.02,
63.80, 61.63, 55.56, 53.20, 52.40, 40.23, 25.48, 20.73; HRMS
calcd for C16H23N2O5S (MH+) 355.1328, found 355.1332.
(2R,3R)-3-Ben zyloxym eth yl-1-(4-m eth oxy-ben zen esu l-
fon yl)-4,4-d im eth yl-p yr r olid in e-2-ca r boxylic Acid Hy-
d r oxya m id e (5f). Hydroxamic acid 5f (7.7 mg, 64%) was
prepared from 16f according to the general procedure for
preparation of hydroxamic acids from esters. Data for 5f: [R]D
+49.9 (c 0.39, CHCl3); TLC Rf ) 0.60 (EtOAc); IR (neat) 3269
(2R ,3R )-3-Be n zylsu lfa n ylm e t h yl-1-(4-m e t h oxy-b e n -
zen esu lfon yl)-4,4-dim eth yl-pyr r olidin e-2-car boxylic Acid
Hyd r oxya m id e (5a ). Hydroxamic acid 5a (14.4 mg, 80%) was
prepared from 15a according to the general procedure for
preparation of hydroxamic acids from esters. Data for 5a : [R]D
+151 (c 1.08, CHCl3); TLC Rf ) 0.65 (EtOAc); IR (neat) 3331
(br), 1667, 1595, 1497 cm-1 1H NMR (400 MHz, CD3OD) δ
;
7.82 (d, J ) 9.0 Hz, 2H), 7.34-7.22 (m, 5H), 7.08 (d, J ) 9.0
Hz, 2H), 4.47-4.34 (m, 2H), 3.87 (s, 3H), 3.78 (d, J ) 6.5 Hz,
1H), 3.48-3.33 (m, 2H), 3.19 (d, J ) 10 Hz, 1H), 2.35 (m, 1H),
1.08 (s, 3H), 0.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.91,
143.65, 139.40, 130.98, 130.42, 129.30, 128.64, 128.56, 115.37,
74.10, 68.73, 64.19, 63.16, 56.19, 54.01, 41.14, 25.95, 21.04;
HRMS calcd for C22H29N2O6S (MH+) 449.1746, found 449.1735.
(br), 3202 (br), 1667, 1595, 1496 cm-1 1H NMR (400 MHz,
;
CD3OD) δ 7.80 (d, J ) 9.0 Hz, 2H), 7.31-7.25 (m, 4H), 7.25-
7.17 (m, 1H), 7.06 (d, J ) 9.0 Hz, 2H), 3.87 (s, 3H), 3.72 (d, J
) 8.5 Hz, 1H), 3.65 (s, 2H), 3.28 (d, J ) 10.0 Hz, 1H), 3.21 (d,
J ) 10.0 Hz, 1H), 2.42-2.35 (m, 2H), 2.16-2.06 (m, 1H), 0.97
(s, 3H), 0.45 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 170.78,
164.94, 149.61, 139.31, 130.91, 130.16, 129.47, 128.01, 115.43,
66.14, 62.83, 56.23, 52.51, 41.75, 36.75, 29.53, 25.48, 20.56;
HRMS calcd for C22H29N2O5S2 (MH+) 465.1518, found 465.1534.
(2R,3R)-3-(1-(R,S)-1,2-Dih yd r oxy-eth yl)-1-(4-m eth oxy-
b en zen esu lfon yl)-4,4-d im et h yl-p yr r olid in e-2-ca r b oxyl-
ic Acid Meth yl Ester (17). To a solution of olefin 12 (140.0
mg, 0.396 mmol) and NMO (58.2 mg, 0.496 mmol) in acetone/
H2O (1:1, 5 mL) at room temperature was added OsO4 (4%
aqueous solution, 0.05 mL). The solution was stirred at room
temperature 2 days, extracted with EtOAc (3 × 25 mL) from
H2O (10 mL), dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography
(20-100% EtOAc in hexanes) to afford diol (0.134 g, 87%) as
a clear, colorless oil and as a 1.3:1 mixture of diastereomers:
[R]D ) +60.0 (c 0.57, CHCl3); TLC Rf ) 0.16 (50% EtOAc in
hexanes); IR (neat) 3470 (br), 1740, 1595, 1498 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.78 (d, J ) 9.0 Hz, 2 × 0.57H), 7.72 (d,
J ) 9.0 Hz, 2 × 0.43H), 6.97 (d, J ) 9.0 Hz, 2H), 4.27 (d, J )
7.0 Hz, 0.57H), 3.91 (d, J ) 9.0 Hz, 0.43H), 3.84 (s, 3H), 3.78-
3.65 (m, 1H), 3.70 (s, 3 × 0.57H), 3.64 (s, 3 × 0.43H), 3.55-
3.40 (m, 2H), 3.08-2.83 (m, 2H), 2.22 (apparent t, J ) 9.0 Hz,
1 × 0.43H), 2.04 (dd, J ) 7.0, 4.0 Hz, 0.57H), 1.14 (s, 3 ×
0.43H), 1.04 (s, 3 × 0.57H), 0.74 (s, 3 × 0.43H), 0.73 (s, 3 ×
0.57H); 13C NMR (100 MHz, CDCl3) δ 173.90, 173.25, 162.92,
162.86, 130.29, 129.58, 129.28, 129.11, 114.00, 113.96, 71.40,
69.64, 65.37, 64.90, 62.13, 61.76, 61.36, 61.32, 55.47, 54.94,
54.48, 52.50, 41.26, 40.44, 26.38, 25.99, 21.15, 20.94; HRMS
calcd for C17H26NO7S (MH+) 388.1430, found 388.1427.
(2R,3R)-3-((R,S)-1-Hyd r oxy-2-p h en ylsu lfa n yl-eth yl)-1-
(4-m eth oxy-ben zen esu lfon yl)-4,4-d im eth yl-p yr r olid in e-
2-ca r boxylic Acid Meth yl Ester (18). To a solution of diol
17 (44.2 mg, 0.114 mmol) and p-TsCl (23.2 mg, 0.125 mmol)
in CH2Cl2 (2 mL) at 0 °C were added Et3N (16.5 µL, 0.113
mmol) and pyridine (15.5 µL, 0.112 mmol). The solution was
stirred at 0 °C for 3 h, at which time TLC indicated the
complete consumption of starting material. The reaction
mixture was extracted with CH2Cl2 (3 × 10 mL) from H2O (10
mL), dried over MgSO4, filtered, and concentrated in vacuo.
The crude tosylate was carried on without further purification.
A solution of the crude tosylate and PhSNa (29.7 mg, 0.224
mmol) in dry DMF (2 mL) was stirred at room temperature
for 2 days, taken up in Et2O (5 mL), washed with H2O (3 × 5
mL), dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (20-50%
EtOAc in hexanes) to afford sulfide 18 (44.9 mg, 84%) as a
(2R,3R)-1-(4-Meth oxy-ben zen esu lfon yl)-4,4-d im eth yl-
3-ph en eth ylsu lfan ylm eth yl-pyr r olidin e-2-car boxylic Acid
Hyd r oxya m id e (5d ). Hydroxamic acid 5d (14.2 mg, 79%) was
prepared from 15d according to the general procedure for
preparation of hydroxamic acids from esters. Data for 5d : [R]D
+108.4 (c 0.71, CHCl3); TLC Rf ) 0.81 (EtOAc); IR (neat) 3321
(br), 3207 (br), 1667, 1595, 1497 cm-1 1H NMR (400 MHz,
;
CD3OD) δ 7.83 (d, J ) 9.0 Hz, 2H), 7.28-7.10 (m, 5H), 7.09
(d, J ) 9.0 Hz, 2H), 3.88 (s, 3H), 3.73 (d, J ) 8.5 Hz, 1H),
3.30-3.19 (m, 2H), 2.86-2.80 (m, 2H), 2.75-2.66 (m, 2H), 2.54
(dd, J ) 13.0, 6.0 Hz, 1H), 2.30 (dd, J ) 8.0, 6.0 Hz, 1H), 2.21
(dd, J ) 13.0, 8.0 Hz, 1H), 1.07 (s, 3H), 0.44 (s, 3H): 13C NMR
(100 MHz, CD3OD) δ 171.04, 165.12, 142.06, 131.11, 130.64,
129.79, 129.58, 127.43, 115.61, 66.35, 62.97, 56.40, 53.38,
41.93, 37.19, 34.91, 30.87, 25.72, 20.77; HRMS calcd for
C
23H31N2O5S2 (MH+) 479.1674, found 479.1685.
(2R,3R)-1-(4-Meth oxy-ben zen esu lfon yl)-3-(4-m eth oxy-
b en zylsu lfa n ylm et h yl)-4,4-d im et h yl-p yr r olid in e-2-ca r -
boxylic Acid Hyd r oxya m id e (5e). Hydroxamic acid 5e (21.1
mg, 52%) was prepared from 15e according to the general
procedure for preparation of hydroxamic acids from esters,
modified as follows: the reaction mixture was stirred at room
temperature overnight. Data for 5e: [R]D +159.0 (c 1.05,
CHCl3); TLC Rf ) 0.69 (EtOAc); IR (neat) 3331 (br), 3197 (br),
1666, 1595, 1511 cm-1; 1H NMR (400 MHz, CD3OD) δ 7.81 (d,
J ) 9.0 Hz, 2H), 7.18 (d, J ) 9.0 Hz, 2H), 7.11 (d, J ) 9.0 Hz,
2H), 6.82 (d, J ) 9.0 Hz, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.71
(d, J ) 8.0 Hz, 1H), 3.61 (s, 2H), 3.25-3.17 (m, 2H), 2.40-
2.32 (m, 2H), 2.14-2.04 (m, 1H), 1.01 (s, 3H), 0.38 (s, 3H); 13
C
NMR (100 MHz, CD3OD) δ 170.94, 165.09, 160.34, 131.37,
131.23, 131.07, 130.70, 115.59, 114.99, 66.31, 62.99, 56.39,
55.82, 52.68, 41.89, 36.29, 29.60, 25.69, 20.73; LRMS: 495
(MH+), 434 (M-CO2NH2)+, 373 (M-PMB)+.
(2R,3R)-3-Ben zyloxym eth yl-1-(4-m eth oxy-ben zen esu l-
fon yl)-4,4-d im eth yl-p yr r olid in e-2-ca r boxylic Acid Meth -
yl Ester (16f). To NaH (60 mg, 60% dispersion in oil, 0.864
mmol), washed free of oil with hexanes (4 × 3 mL) at -78 °C,

Synthesis of MMP Inhibitors Guided by Molecular Modeling
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 19 3081
1.3:1 mixture of diastereomers: [R]D ) +39.4 (c 0.72, CHCl3);
TLC Rf ) 0.54 (50% EtOAc in hexanes); IR (neat) 3508 (br),
(s, 3 × 0.57H); HRMS calcd for C22H29N2O6S2 (MH+) 481.1467,
found 481.1478.
1
1741, 1596, 1498 cm-1; H NMR (400 MHz, CDCl3) δ 7.84 (d,
(2R,3R)-3-((R)-1-Hyd r oxy-2-p h en ylsu lfa n yl-eth yl)-1-(4-
m et h oxy-b en zen esu lfon yl)-4,4-d im et h yl-p yr r olid in e-2-
ca r boxylic Acid Hyd r oxya m id e (5i). Hydroxamic acid 5i
(2.8 mg, 66%) was prepared from 18b according to the general
procedure for preparation of hydroxamic acids from esters.
Data for 5i: [R]D ) +126 (c 0.35, CHCl3); TLC Rf ) 0.51 (6%
MeOH in CH2Cl2); 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J )
9.0 Hz, 2H), 7.45-7.04 (m, 5H), 7.03 (d, J ) 9.0 Hz, 2H), 3.88
(s, 3H), 3.81 (d, J ) 9.0 Hz, 1H), 3.68-3.62 (m, 1H), 3.25-
3.13 (m, 2H), 2.81 (dd, J ) 13.0, 10.0 Hz, 1H) 2.40 (d, J ) 7.0
Hz, 1H), 2.39 (apparent t, J ) 8.0 Hz, 1H), 0.95 (s, 3 × 0.57H),
0.46 (s, 3 × 0.57H); HRMS calcd for C22H29N2O6S2 (MH+)
481.1467, found 481.1478.
J ) 9.0 Hz, 2 × 0.43H), 7.75 (d, J ) 9.0 Hz, 2 × 0.57H), 7.37-
7.18 (m, 5H), 6.95 (d, J ) 9.0 Hz, 2H), 4.30 (d, J ) 6.5 Hz,
0.43H), 3.93 (d, J ) 9.0 Hz, 0.57H) 3.84 (s, 3H), 3.76 (s, 3 ×
0.43H), 3.70-3.55 (m, 2H), 3.60 (s, 3 × 0.57H), 3.32-3.10 (m,
2H), 3.02 (dd, J ) 14.0, 4.0 Hz, 0.43H), 2.88 (dd, J ) 14.0,
10.0 Hz, 0.43H), 2.75 (dd, J ) 14.0, 10.0 Hz, 0.57H), 2.62 (d,
J ) 4.0 Hz, 0.57H), 2.21 (apparent t, J ) 9.0 Hz, 0.57H), 1.18
(s, 3 × 0.57H), 1.09 (s, 3 × 0.43H), 0.76 (s, 3 × 0.57H) 0.75 (s,
3 × 0.43H); 13C NMR (100 MHz, CDCl3) δ 173.33, 172.76,
162.82, 134.00, 130.42, 130.19, 129.77, 129.18, 129.11, 129.07,
127.04, 126.95, 113.93, 113.80, 68.62, 66.79, 62.41, 61.77,
61.07, 60.07, 60.52, 57.04, 56.82, 55.43, 52.43, 41.67, 41.34,
41.08, 40.74, 27.27, 26.05, 21.27, 20.89; HRMS calcd for C23H30
-
Molecu la r Mod elin g. Molecular modeling studies were
performed using software programs from InsightII (Molecular
Simulations, 1995, San Diego, CA) using a modified AMBER
force field.17 The starting MMP-3 crystallographic structure,
retrieved from the Brookhaven Protein Data Bank (code 1HFS
in the PDB). Compounds 4, 5a -i were docked in the binding
site of MMP-3 using AutoDock suite of programs. Grids
surrounding the binding site were computed (61 × 61 points,
0.375 Å spacing) with AutoGrid and used for subsequent
docking study with AutoDock using Lamarckian genetic
algorithm as search protocol. The output from AutoDock was
displayed using InsightII.
NO6S2 (MH+) 480.1515, found 480.1526. Diastereomerically
pure samples were prepared by a second column chromatog-
raphy (SiO2, 40-50% Et2O in hexanes). Major diastereomer
18a : [R]D ) +45.2 (c 0.54, CHCl3); Rf ) 0.22 (60% Et2O in
hexanes); minor diastereomer 18b: [R]D ) +34.7 (c 0.49,
CHCl3); Rf ) 0.18 (60% Et2O in hexanes).
(3a R ,4R ,7a R )-4-H yd r oxy-1-(4-m e t h oxy-b e n ze n e su l-
fon yl)-3,3-dim eth yl-h exah ydr o-pyr an o[3,4-b]pyr r ol-7-on e
(19). Diol 17 (35.0 mg, 1.1:1 ratio of diastereomers) was heated
to 175 °C in vacuo. After 10 min, the oil was cooled to room
temperature. Crude NMR indicated the diastereomeric ratio
of the starting diol 17 had increased to 1.3:1. Lactone 19 was
the sole reaction product identified by NMR; integration of the
aromatic protons showed that the ratio of the major dia-
stereomer of 17 to the combined integration of the minor
diastereomer of 17 and the lactone 19 was 1.1:1. An analytical
sample of 19 was prepared by concentration of the crude
sample and heating for a further 10 min. The resulting oil was
cooled to room temperature and purified by column chroma-
tography (20-100% EtOAc in hexanes) to afford lactone 19
as a colorless oil: [R]D ) +59 (c 0.3, CHCl3); TLC Rf ) 0.33
Biologica l Assa y. Human purified MMPs were purchased
or acquired. MMP-2 gelatinase A and MMP-9 gelatinase B
were from Boehringer Mannheim (Meylan, France) and MMP-3
stromelysin 1 from Valbiotech (Paris, France). All enzymes
were activated by APMA (4-aminophenylmercuric acetate).
Inhibition of MMP-3 was quantified by using the peptido-
mimetic substrate (7-methoxycoumarine-4-yl)-Arg-Pro-Lys-
Pro-Tyr-Ala-Nva-Trp-Met-Lys(Dnp)-NH2 (Bachem, Bubben-
dorf, Switzerland) which is cleaved between Ala and Nva. For
inhibition studies of the other enzymes, the substrate Dnp-
Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(Nma)-NH2 (Bachem), which
is cleaved between amino acids Gly and Cys, was used. The
fluorescent cleavage products were measured with a cyto-
fluorometer (Cytofluor 2350, Millipore, PerSeptive Systems,
Voisins le Bretonneux, France) equipped with a combination
of 340 and 440 nm filters for excitation and emission, respec-
tively. The IC50 values were the average of at least two
determinations with a standard deviation of less than (30%.
1
(70% EtOAc in hexanes); H NMR (400 MHz, CDCl3) δ 8.04
(d, J ) 9.0 Hz, 2H), 6.99 (d, J ) 9.0 Hz, 2H), 4.43 (d, J ) 13.5
Hz, 1H), 4.26 (d, J ) 13.5 Hz, 1H), 3.89 (d, J ) 11.5 Hz, 1H),
3.88 (s, 3H), 3.60 (d, J ) 10.5 Hz, 1H), 3.20 (m, 1H), 2.98 (d,
J ) 10.5 Hz, 1H), 2.11 (dd, J ) 13.0, 8.5 Hz, 1H), 1.17 (s, 3H),
1.06 (s, 3H).
(2R,3R)-3-((R,S)-1-Hyd r oxy-2-p h en ylsu lfa n yl-eth yl)-1-
(4-m eth oxy-ben zen esu lfon yl)-4,4-d im eth yl-p yr r olid in e-
2-ca r boxylic Acid Hyd r oxya m id e (5g). Hydroxamic acid 5g
(8.4 mg, 66%) was prepared from 18 as a 1.3:1 mixture of
diastereomers, according to the general procedure for prepara-
tion of hydroxamic acids from esters. Data for 5g: TLC Rf )
0.51 (6% MeOH in CH2Cl2); 1H NMR (400 MHz, CD3OD) δ
7.83 (d, J ) 9.0 Hz, 2 × 0.43H), 7.79 (d, J ) 9.0 Hz, 2 × 0.57H),
7.45-7.04 (m, 5H), 7.03 (d, J ) 9.0 Hz, 2H), 4.21 (d, J ) 9.5
Hz, 0.57H), 3.88 (s, 3H), 3.81 (d, J ) 9.0 Hz, 0.43H), 3.68-
3.62 (m, 1H), 3.25-3.13 (m, 2H), 3.02 (dd, J ) 13.5, 6.5 Hz,
0.57H), 2.88 (dd, J ) 14.0, 7.0 Hz, 0.57H), 2.81 (dd, J ) 13.0,
10.0 Hz, 0.43H) 2.40 (d, J ) 7.0 Hz, 1H), 2.39 (apparent t, J
Ack n ow led gm en t. We thank the NSERC of Canada
for financial assistance through the Medicinal Chem-
istry Chair Program. We thank Dr. G. Tucker, Labora-
toires Servier, France, for the biological assays and
financial support. We thank Eric Therrien for compu-
tational assistance during this work.
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