Design, synthesis, and evaluation of matrix metalloprotease inhibitors bearing cyclopropane-derived peptidomimetics as P1′ and P2′ replacements

Article abstract of DOI:10.1021/jo0110698

We have previously used trisubstituted cyclopropanes as peptide replacements to induce conformational constraints in known pseudopeptide inhibitors of a number of important enzymes. Cyclopropane-derived peptide mimics are novel in that they are among the few replacements that locally orient the peptide backbone and the amino acid side chain in a predefined manner. Although these dipeptide isosteres have been employed to orient amino acid side chains mimicking the gauche(-) conformation of _χ1-space, their ability to project the side chains into an anti orientation has not been evaluated. As a first step toward this goal, the conformationally constrained pseudopeptides 8 and 10 and their corresponding flexible analogues 9 and 11 were prepared and tested as inhibitors of matrix metalloproteinases (MMPs). These compounds are analogues of 4 and 5, which were known to be potent MMP inhibitors. The anti orientations of the isopropyl side chain in 8 and the aromatic ring in 10 relative to the peptide backbone substituents on the cyclopropane were predicted to correspond to the known orientations of the P1′ and P2′ side chains of 5 when bound to MMPs. Hence, 8 and 10 were designed explicitly to probe topological features of the S1′ or the S2′ binding pockets of the MMPs. They were also designed to explore the importance of the P1′-P2′ amide group, which is known to form highly conserved hydrogen bonds in several MMP-inhibitor complexes, and the viability of introducing a retro amide linkage between P2′ and P3′. Pseudopeptides 8 and 9 were found to be weak competitive inhibitors of a series of MMPs. Any entropically favorable conformational constraints that were induced by the cyclopropane in 8 were thus overwhelmed by the loss of the hydrogen bonding capability associated with the P1′-P2′ amide group. On the other hand, compounds 10 and 11, which contain a P2′-P3′ retro amide group, were modest competitive inhibitors of a series of MMPs. The results obtained for 10 and 11 suggest that there may be a loss of hydrogen bonding capability associated with introducing the P2′-P3′ retro amide group. However, because the conformationally constrained pseudopeptide 10 was significantly more potent than its flexible analogue 11, trisubstituted cyclopropanes related to 3 may serve as useful rigid dipeptide replacements in some biologically active pseudopeptides.

Full text of DOI:10.1021/jo0110698

4062
J . Org. Chem. 2002, 67, 4062-4075
Design , Syn th esis, a n d Eva lu a tion of Ma tr ix Meta llop r otea se
In h ibitor s Bea r in g Cyclop r op a n e-Der ived P ep tid om im etics a s P 1′
a n d P 2′ Rep la cem en ts
Andreas Reichelt, Christoph Gaul, Robin R. Frey, April Kennedy, and Stephen F. Martin*
Department of Chemistry and Biochemistry and the Institute for Cellular and Molecular Biology,
The University of Texas, Austin, Texas 78712
sfmartin@mail.utexas.edu
Received November 13, 2001
We have previously used trisubstituted cyclopropanes as peptide replacements to induce confor-
mational constraints in known pseudopeptide inhibitors of a number of important enzymes.
Cyclopropane-derived peptide mimics are novel in that they are among the few replacements that
locally orient the peptide backbone and the amino acid side chain in a predefined manner. Although
these dipeptide isosteres have been employed to orient amino acid side chains mimicking the gauche-
(-) conformation of ø1-space, their ability to project the side chains into an anti orientation has not
been evaluated. As a first step toward this goal, the conformationally constrained pseudopeptides
8 and 10 and their corresponding flexible analogues 9 and 11 were prepared and tested as inhibitors
of matrix metalloproteinases (MMPs). These compounds are analogues of 4 and 5, which were known
to be potent MMP inhibitors. The anti orientations of the isopropyl side chain in 8 and the aromatic
ring in 10 relative to the peptide backbone substituents on the cyclopropane were predicted to
correspond to the known orientations of the P1′ and P2′ side chains of 5 when bound to MMPs.
Hence, 8 and 10 were designed explicitly to probe topological features of the S1′ or the S2′ binding
pockets of the MMPs. They were also designed to explore the importance of the P1′-P2′ amide
group, which is known to form highly conserved hydrogen bonds in several MMP-inhibitor
complexes, and the viability of introducing a retro amide linkage between P2′ and P3′. Pseudo-
peptides 8 and 9 were found to be weak competitive inhibitors of a series of MMPs. Any entropically
favorable conformational constraints that were induced by the cyclopropane in 8 were thus
overwhelmed by the loss of the hydrogen bonding capability associated with the P1′-P2′ amide
group. On the other hand, compounds 10 and 11, which contain a P2′-P3′ retro amide group, were
modest competitive inhibitors of a series of MMPs. The results obtained for 10 and 11 suggest that
there may be a loss of hydrogen bonding capability associated with introducing the P2′-P3′ retro
amide group. However, because the conformationally constrained pseudopeptide 10 was significantly
more potent than its flexible analogue 11, trisubstituted cyclopropanes related to 3 may serve as
useful rigid dipeptide replacements in some biologically active pseudopeptides.
In tr od u ction
few mimics of an extended conformation,2 which is
important for pseudopeptide-like enzyme inhibitors. Con-
trolling backbone conformation is not sufficient to opti-
mize binding interactions because the amino acid side
chains also contribute critical recognition elements for
binding and specificity. Hence, a conformationally con-
strained dipeptide isostere capable of orienting the side
chains while simultaneously constraining the backbone
in an extended conformation would be a useful tool for
drug discovery.
Toward addressing this critical need, we have devel-
oped novel replacements for a dipeptide array in which
the backbone and the side chain of an amino acid residue
are fixed in predetermined orientations by a cyclopropane
ring.3 The first type of these isosteres was obtained
The design of small rigid molecules that replicate the
essential features of oligopeptide secondary structure is
a central goal in efforts to identify peptide-like ligands
having high affinity for biological targets. However,
determining the conformation that a peptide adopts upon
binding to its receptor, namely the biologically active
conformation, is a major challenge. One general strategy
that has been successfully used to gain insights regarding
the structure of the bound peptide involves introducing
conformational restraints into specific sites of the mol-
ecule and correlating the resultant biological activity with
structure.1 Most of the conformationally restricted re-
placements of peptide secondary structure reported to
date are capable of controlling the organization of the
backbone by imitating turns or helices, but there are only
(2) (a) Hagihara, M.; Anthony, N. J .; Stout, T. J .; Clardy, J .;
Schreiber, S. L. J . Am. Chem. Soc. 1992, 114, 6568-6570. (b) Smith,
A. B., III; Keenan, T. P.; Holcomb, R. C.; Sprengeler, P. A.; Guzman,
M. C.; Wood, J . L.; Carroll, P. J .; Hirschmann, R. J . Am. Chem. Soc.
1992, 114, 10672-10674. (c) Chen, L.; Trilles, R. V.; Tilley, J . W.
Tetrahedron Lett. 1995, 36, 8715-8718. (d) Boumendjel, A.; Roberts,
J . C.; Hu, E.; Pallai, P. V.; Rebek, J ., J r. J . Org. Chem. 1996, 61, 4434-
4438. (e) J anetka, J . W.; Raman, P.; Satyshur, K.; Flentke, G.; Rich,
D. H. J . Am. Chem. Soc. 1997, 119, 441-442.
(1) For some recent reviews of peptide mimics, see: (a) Giannis, A.;
Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244-1267. (b)
Liskamp, R. M. J . Recl. Trav. Chim. Pays-Bas 1994, 113, 1-19. (c)
Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699-1720. (d)
Schneider, J . P.; Kelly, J . W. Chem. Rev. 1995, 95, 2169-2187. (e)
Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789-12854.
10.1021/jo0110698 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/22/2002

Matrix Metalloprotease Inhibitors
J . Org. Chem., Vol. 67, No. 12, 2002 4063
operationally by forming a bond between the â-carbon
atom of an amino acid side chain in the peptide 1 to the
N-terminal side of the R-carbon atom and replacing the
amide nitrogen with a carbon atom (path a). The result-
ing pseudopeptides have the general structure 2. The
second type of replacement arises from forming a bond
between the â-carbon and the carbonyl carbon atom on
the C-terminal side of the R-carbon atom and replacing
the carbonyl carbon atom with a tetrahedral carbon (path
b). These conformationally constrained peptide mimics
have the general structure 3. When the backbone sub-
stituents on the cyclopropane ring are trans as shown in
2 and 3, the backbone will be locally constrained in an
extended conformation. Depending on the stereochemis-
try at the remaining cyclopropane carbon, the amino acid
side chain can be positioned relative to the backbone in
orientations that approximate ø1-angles in 1 of gauche(-)
(-60°), gauche(+) (+60°), or anti ((180°). Thus, the
spatial position of the R2 group in 2 corresponds closely
to that found in the gauche(-) conformation, whereas
that in 3 mimics an anti conformation.
also been used by others as peptide mimics.10 That
cyclopropane-derived replacements actually stabilize or
enforce the predicted structural properties was verified
in a significant study in which truncated analogues of 2
were incorporated in conformationally restricted inhibi-
tors of HIV-1 protease.6 More recently, we have found
that such replacements mimic bound conformations of
the phosphotyrosine residue in high-affinity SH2 binding
antagonists.11
Some years ago, we became interested in the possibility
of introducing cyclopropane replacements into 4 and 5,
which were known to be nanomolar inhibitors of several
matrix metalloproteases (MMPs).12 The MMPs are a
group of zinc-dependent enzymes that degrade the pro-
teins of the extracellular matrix.13 These enzymes are
normally responsible for the turnover and destruction of
tissues in processes such as growth, wound healing, and
embryonic development. When the MMPs are not prop-
erly regulated, however, they are involved in a variety
of pathological conditions including cancer,14 arthritis,15
and periodontal disease,16 and inhibition of matrix metallo-
proteases has thus been of considerable interest in drug
development. Numerous inhibitors of MMPs have been
reported, and the best ones contain a functional group
capable of chelating the zinc(II) ion in the active site, with
the hydroxamic acid moiety providing the best potency;17
however, few MMP inhibitors incorporate conformational
constraints.18
Sch em e 1
In our first experiments directed toward evaluating
conformationally constrained analogues of 4, we prepared
the cyclopropane-derived hydroxamates 6 and 7 in which
the leucine side chain was simply joined to the peptide
backbone by forming a carbon-carbon bond.19 The cy-
clopropane ring at the P1′ subsite in each of these
(10) (a) Melnick, M. J .; Bisaha, S. N.; Gammill, R. B. Tetrahedron
Lett. 1990, 31, 961-964. (b) Bovy, P. R.; Tjoeng, F. S.; Rico, J . G.;
Rogers, T. E.; Lindmark, R. J .; Zablocki, J . A.; Garland, R. B.;
McMackins, D. E.; Dayringer, H.; To´th, M. V.; Zupec, M. E.; Rao, S.;
Panzer-Knodle, S. G.; Noicholson, N. S.; Salyers, A.; Taite, B. B.; Herin,
M.; Miyano, M.; Feigen, L. P.; Adams, S. P. Bioorg. Med. Chem. 1994,
2, 881-895. (c) Hanessian, S.; Griffin, A.; Devasthale, P. V. Bioorg.
Med. Chem. Lett. 1997, 7, 3119-3124. (d) Mart´ın-Vila`, M.; Muray, E.;
Aguado, G. P.; Alvarez-Larena, A.; Branchadell, V.; Minguillo´n, C.;
Giralt, E.; Ortun˜o, R. M. Tetrahedron: Asymmetry 2000, 11, 3569-
3584.
To evaluate 1,2,3-trisubstituted cyclopropane deriva-
tives of 2 and 3 as peptide isosteres, we developed a
number of efficient methods for the enantioselective
syntheses of cyclopropanes bearing functionally diverse
substituents.4 Cyclopropanes, primarily those related to
2, were then incorporated as rigid replacements into
biologically active inhibitors of renin,5 HIV-1 protease,6
and Ras farnesyltransferase,7 as well as enkephalin
analogues8 and SH2 antagonists.9 Cyclopropanes have
(11) Davidson, J . P.; Lubman, O.; Rose, T.; Waksman, G.; Martin,
S. F. J . Am. Chem. Soc. 2002, 124, 205-215.
(12) (a) Dickens, J . P.; Donald, D. K.; Kneen, G.; McKay, W. R. U.S.
Patent 4,599,361, J uly 8, 1986. (b) Dickens, J . P.; Donald, D. K.; Kneen,
G.; McKay, W. R. U.S. Patent 4,743,587, May 10, 1988.
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Schwartz, M. A.; Van Wart, H. E. Prog. Med. Chem. 1992, 29, 271-
334. (c) Hagmann, W. K.; Larkk, M. W.; Becker, J . W. Annu. Rep. Med.
Chem. 1996, 31, 231-240.
(3) Martin, S. F.; Austin, R. E.; Oalmann, C. J . Tetrahedron Lett.
1990, 31, 4731-4734.
(4) (a) Doyle, M. P.; Pieters, R. J .; Martin, S. F.; Austin, R. E.;
Oalmann, C. J .; Mueller, P. J . Am. Chem. Soc. 1991, 113, 1423-1424.
(b) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin, A.
B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. J .; Pieters,
R. J .; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.;
Martin, S. F. J . Am. Chem. Soc. 1995, 117, 5763-5775. (c) Martin, S.
F.; Hom, R. K. Tetrahedron Lett. 1999, 40, 2887-2890. (d) Martin, S.
F.; Hom, R. K.; Dwyer, M. P. Tetrahedron Lett. 1999, 40, 6721-6724.
(5) (a) Martin, S. F.; Austin, R. E.; Oalmann, C. J .; Baker, W. R.;
Condon, S. L.; deLara, E.; Rosenberg, S. H.; Spina, K. P.; Stein, H. H.;
Cohen, J .; Kleinert, H. D. J . Med. Chem. 1992, 35, 1710-1721. (b)
Baker, W. R.; J ae, H. S.; Martin, S. F.; Condon, S. L.; Stein, H. H.;
Cohen, J .; Kleinert, H. D. Bioorg. Med. Chem. Lett. 1992, 2, 1405-
1410.
(14) DeClerck, Y. A.; Imren, S. Eur. J . Cancer 1994, 30A, 2170-
2180.
(15) Bernstein, P. R.; Edwards, P. D.; Williams, J . C. Prog. Med.
Chem. 1994, 31, 59-120.
(16) Lee, W.; Aitken, S.; Sodek, J .; McCulloch, C. A. J . Periodont.
Res. 1995, 30, 23-33.
(17) (a) Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359-
1472. (b) Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J . H.
Chem. Rev. 1999, 99, 2735-2776.
(18) (a) Cherney, R. J .; Wang, L.; Meyer, D. T.; Xue, C.-B.;
Wasserman, Z. R.; Hardman, K. D.; Welch, P. K.; Covington, M. B.;
Copeland, R. A.; Arner, E. C.; DeGrado, W. F.; Decicco, C. P. J . Med.
Chem. 1998, 41, 1749-1751. (b) Steinman, D. H.; Curtin, M. L.;
Garland, R. B.; Davidsen, S. K.; Heyman, H. R.; Holms, J . H.; Albert,
D. H.; Magoc, T. J .; Nagy, I. B.; Marcotte, P. A.; Li, J .; Morgan, D. W.;
Hutchins, C.; Summers, J . B. Bioorg. Med. Chem. Lett. 1998, 8, 2087-
2092. (c) Smith, A. B., III; Nittoli, T.; Sprengeler, P. A.; Duan, J . J .
W.; Liu, R.-Q.; Hirschmann, R. F. Org. Lett. 2000, 2, 3809-3812. (d)
Decicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001, 3, 1029-1032.
(19) Martin, S. F.; Oalmann, C. J .; Liras, S. Tetrahedron 1993, 49,
3521-3532.
(6) Martin, S. F.; Dorsey, G. O.; Gane, T.; Hillier, M. C.; Kessler,
H.; Baur, M.; Mathae, B.; Erickson, J . W.; Bhat, T. N.; Munshi, S.;
Gulnik, S. V.; Topol, I. A. J . Med. Chem. 1998, 41, 1581-1597.
(7) Hillier, M. C.; Davidson, J . P.; Martin, S. F. J . Org. Chem. 2001,
66, 1657-1671.
(8) Martin, S. F.; Dwyer, M. P.; Hartmann, B.; Knight, K. S. J . Org.
Chem. 2000, 65, 1305-1318.
(9) Davidson, J . P.; Martin, S. F. Tetrahedron Lett. 2000, 41, 9459-
9464.

4064 J . Org. Chem., Vol. 67, No. 12, 2002
Reichelt et al.
Sch em e 2
corresponding flexible analogue 9 as a control so that the
effects of introducing the conformational constraint could
be reliably assessed. This is important because both 8
and 9 lack the P1′-P2′ amide linkage that was known
to form highly conserved hydrogen bonds with Leu-181
and Pro-238 of the enzyme.20 The pseudopeptides 8 and
9 would thus also probe the importance of these hydrogen
bonds to binding affinity.
The X-ray crystallographic investigations of 5 bound
to MMP-1 revealed that the aromatic ring of the P2′
residue was oriented in an anti conformation.20 Even
though these structural studies show that the P2′-P3′
amide functional group forms two hydrogen bonds with
the Tyr-240 and Gly-179 residues of the enzyme, substi-
tutions involving this amide linkage appear to be better
tolerated in MMP inhibitors than those on the P1′-P2′
amide.22 On the basis of these considerations, the cyclo-
propane containing pseudopeptide 10 emerged as a
second intriguing target for evaluation. The N-acetyl
group at the C-terminus of 10 forms a retro amide that
maintains the amide character of this nitrogen, thereby
allowing the formation of a hydrogen bond to Gly-179.
Compound 11 would then serve as the appropriate
control. The syntheses of the cyclopropane-containing
peptide mimics 8 and 10 as well as their flexible
analogues 9 and 11 and their inhibitory activities against
several MMPs are described in this paper.
Resu lts a n d Discu ssion
Syn th esis of MMP In h ibitor s w ith P 1′ Rep la ce-
m en ts. The first step toward the synthesis of 8 entailed
preparing the cyclopropyl lactone 13 (90% yield, 92% ee)
by the enantioselective intramolecular cyclopropanation
of the known allylic diazoacetate 12 using the chiral
dirhodium catalyst Rh2[5(R)-MEPY]4.4b,19 The absolute
stereochemistry of the enantiomer of 13 had been previ-
ously established by the crystal X-ray structure of a
protected tyrosine derivative.4b The lactone ring 13 was
opened by reaction with N-methoxy-N-methylamine in
the presence of Me3Al according to the Weinreb protocol,23
and the intermediate primary alcohol was oxidized with
PCC to give 14 in 85% overall yield. Epimerization of the
aldehyde group was achieved by heating 14 with an
excess of triethylamine in methanol to give 15 in which
the backbone substituents are trans.
The one-carbon homologation of the aldehyde group in
15 was achieved via a Peterson olefination using 2-lithio-
2-trimethylsilyl-1,3-dithiane,24 and hydrolysis of the hy-
droxamic acid group furnished 16 in 67% overall yield.
Mercuric ion-promoted methanolysis of the ketene thio-
acetal moiety in 16 gave the desired methyl ester 17 in
73% yield.25 It was necessary to monitor the progress of
this reaction carefully, because prolonged reaction times
led to formation of the dimethyl ester as a byproduct. The
carboxylic acid group in 17 was transformed into a
protected amino group in 53% yield by the stepwise
pseudopeptides enforces a locally extended conformation
on the backbone while orienting the isopropyl group in a
gauche(-) orientation in 6 and a gauche(+) orientation
in 7. There were no structures of an MMP-inhibitor
complex at the time 6 and 7 were prepared, so these
ligands were designed to serve as preliminary probes of
the biologically active conformation at the P1′ site of 4.
Because 6 and 7 exhibited only micromolar activities
toward various MMPs, we concluded that the resident
cyclopropanes in 6 and 7 were poor mimics of the bound
conformation of 4. We further speculated that the iso-
propyl group in 4 occupied an anti orientation in the
bound conformation of 4 and related MMP inhibitors.
This conjecture was subsequently verified by crystal-
lographic and NMR studies of 5 bound to human fibro-
blast collagenase (MMP-1).20,21
The arena of MMP inhibitors thus offered an excellent
opportunity to explore the properties of replacements
generally related to 3 wherein the amino acid side chain
would be projected in an anti conformation. The pseudo-
peptide 8 emerged as an attractive target because model-
ing suggested that the cyclopropane ring would nicely
mimic the biologically active conformation at the P1′
subsite of 5 by positioning the isopropyl group in an anti
orientation relative to the extended backbone of the
inhibitor. It would then be necessary to prepare the
(22) (a) Levy, D. E.; Lapierre, F.; Liang, W.; Ye, W.; Lange, C. W.;
Li, X.; Grobelny, D.; Casabonne, M.; Tyrrell, D.; Holme, K.; Nadzan,
A.; Galardy, R. E. J . Med. Chem. 1998, 41, 199-223. (b) Chen, J . J .;
Zhang, Y.; Hammond, S.; Dewdney, N.; Ho, T.; Lin, X.; Browner, M.
F.; Castelhano, A. L. Bioorg. Med. Chem. Lett. 1996, 6, 1601-1606.
(23) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
48, 4171-4174.
(24) (a) Seebach, D.; Kolb, M.; Groebel, B. T. Chem. Ber. 1973, 106,
2277-2290. (b) Kolb, M. Synthesis 1990, 171-190.
(25) Boger, D. L.; Takahashi, K. J . Am. Chem. Soc. 1995, 117,
12452-12459.
(20) (a) Spurlino, J . C.; Smallwood, A. M.; Carlton, D. D.; Banks,
T. M.; Vavra, K. J .; J ohnson, J . S.; Cook, E. R.; Falvo, J .; Wahl, R. C.;
Pulvino, T. A.; Wendoloski, J . J .; Smith, D. L. Proteins: Struct., Funct.,
Genet. 1994, 19, 98-109. (b) Stams, T.; Spurlino, J . C.; Smith, D. L.;
Wahl, R. C.; Ho, T. F.; Qoronfleh, M. W.; Banks, T. M.; Rubin, B. Struct.
Biol. 1994, 1, 119-123.
(21) Ghose, A. K.; Logan, M. E.; Treasurywala, A. M.; Wang, H.;
Wahl, R. C.; Tomczuk, B. E.; Gowravaram, M. R.; J aeger, E. P.;
Wendoloski, J . J . J . Am. Chem. Soc. 1995, 117, 4671-4682.

Matrix Metalloprotease Inhibitors
J . Org. Chem., Vol. 67, No. 12, 2002 4065
Sch em e 3
from the corresponding hydroxy acid, gave the amine 21
in 54% yield.8,28 The ester moiety of 21 was transformed
into an N-methyl amide using methylamine in the
presence of a catalytic amount of NaCN,27b and hydro-
genolysis of the O-benzyl group using Pd-BaSO4 as the
catalyst gave 8 in 86% overall yield. The choice of the
catalyst is crucial for this transformation, as it is known
that Pd-C and other palladium catalysts may lead to
extensive N-O bond cleavage.29
Remaining was the preparation of compound 9, which
is the flexible analogue of 8, and our initial plan was to
join the P1′ and P2′ subunits by a reductive amination
of the aldehyde 24. Thus, the known oxazolidinone imide
2230 was converted into the corresponding thioester 23,
which was reduced to aldehyde 24 with triethylsilane on
Pd-C.31 Although reductive amination of aldehydes with
amino acid derivatives is well-known,32 we found that the
secondary amine formed from reaction of aldehyde 24
with H-Phe-NHMe was invariably contaminated with
a diastereomer epimeric at the carbon bearing the
isobutyl group. For example, reaction of the aldehyde 24
with H-Phe-NHMe in the presence of sodium triace-
toxyborohydride gave an inseparable mixture (ca. 3:1) of
the desired amine 27 and its epimer in 90% combined
yield.33
All attempts to avoid epimerization during this reduc-
tive amination sequence were unsuccessful, so we turned
our attention to preparing 27 by N-alkylation of H-Phe-
NHMe. Toward this end, the oxazolidone imide 22 was
converted to the corresponding alcohol 25 by reduction
with lithium borohydride in the presence of MeOH.34 Our
initial plan was to react 25 with the dinitrobenzene-
sulfonamide of H-Phe-NHMe under Mitsunobu condi-
tions to give a product in which the secondary amine
functionality was already protected as an arylsulfona-
mide.35 Unexpectedly, the 2,4-dinitrobenzenesulfonamide
of H-Phe-NHMe was unstable under the coupling
conditions, and the desired alkylation product was ob-
tained in only 16% yield. Reaction of H-Phe-NHMe with
a triflate, prepared in situ from alcohol 25, did not give
the desired amine 27 either. After considerable experi-
mentation, we found that prolonged heating of the
bromide 26, which was prepared in 89% yield by treating
25 with CBr4 and Ph3P, with H-Phe-NHMe in the
Curtius procedure developed by Weinstock.26 Preliminary
experiments to effect the conversion of the methyl ester
group in 18 to a protected hydroxamic acid group using
O-benzylhydroxylamine in the presence of a variety of
catalysts such as Me3Al or NaCN were unsuccessful, even
at elevated temperatures.27 However, a two-step proce-
dure involving saponification of the methyl ester followed
by coupling of the derived mixed anhydride with O-
benzylhydroxylamine gave the desired O-benzylhydrox-
amic acid 19 in 79% overall yield. The synthesis of the
P1′ cyclopropylamine fragment 20 was completed by
removing the Boc-protecting group from 19 by reaction
with 4 N HCl in dioxane.
We had originally considered preparing a cyclopropane
derivative of 4 by alkylating 20 with the triflate derived
from D-3-(4-methoxyphenyl)lactate. However, it was not
possible to convert O-methyl-D-tyrosine directly to methyl
D-3-(4-methoxyphenyl)lactate using nitrous acid without
partial racemization, so we decided to prepare the des-
methoxy analogue 8 instead. Deletion of the aromatic
methoxy group was not expected to have a significant
effect upon the biological activity because the hydrox-
amates 4 and 5 have similar inhibitory activities toward
several MMPs.12 In the event, reaction of 20 with the
triflate of D-phenyl lactate, which was prepared in situ
(26) Weinstock, J . J . Org. Chem. 1961, 26, 3511.
(27) (a) Pirrung, M. C.; Chau, J . H. L. J . Org. Chem. 1995, 60,
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Chem. 1987, 52, 2033-2036.
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(29) Nikam, S. S.; Kornberg, B. E.; J ohnson, D. R.; Doherty, A. M.
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(30) Beckett, R. P.; Crimmin, M. J .; Davis, M. H.; Spavold, Z. Synlett
1993, 137-138.
(31) (a) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990, 31,
2849-2852. (b) Evans, D. A.; Black, W. C. J . Am. Chem. Soc. 1993,
115, 4497-4513. (c) Fukuyama, T.; Lin, S. C.; Li, L. J . Am. Chem.
Soc. 1990, 112, 7050-7051.
(32) (a) Kaltenbronn, J . S.; Hudspeth, J . P.; Lunney, E. A.;
Michniewicz, B. M.; Nicolaides, E. D.; Repine, J . T.; Roark, W. H.; Stier,
M. A.; Tinney, F. J .; Woo, P. K. W.; Essenburg, A. D. J . Med. Chem.
1990, 33, 838-845. (b) Bravo, A.; Go´mez-Monterrey, I.; Gonza´lez-
Mun˜iz, R.; Garc´ıa-Lo´pez, M. T. J . Chem. Soc., Perkin Trans. 1 1991,
3117-3120.
(33) Han, Y.; Chorev, M. J . Org. Chem. 1999, 64, 1972-1978.
(34) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307-312.
(35) (a) Fukuyama, T.; J ow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373-6374. (b) Fukuyama, T.; Cheung, M.; J ow, C.-K.; Hidai,
Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831-5834.

4066 J . Org. Chem., Vol. 67, No. 12, 2002
Reichelt et al.
Sch em e 4
acid-catalyzed isomerization of the double bond. When
the diazoacetate 32 was heated in the presence of the
chiral catalyst Rh2[5(S)-MEPY]4, the cyclopropyl lactone
33 was obtained in 62% yield (85% ee).4a,b
The lactone ring in 33 was then opened with N-
methoxy-N-methylamine using the Weinreb protocol,23
and the resulting primary alcohol was protected to give
34 in 80% overall yield. Hydrolysis of the hydroxamide
moiety with anhydrous hydroxide in Et2O proceeded with
concomitant epimerization to give 35 in 89% yield.38 The
absolute stereochemistry at each of the cyclopropyl
carbon atoms in 35 corresponded to that found in the
pseudopeptide target 10, and it remained to introduce
the requisite nitrogen substituents via Curtius reactions.
Although initial attempts to induce the Curtius reaction
of 35 using diphenylphosphoryl azide were inefficient,39
the stepwise procedure developed by Weinstock proved
to be superior.26 Thus, sequential reaction of 35 with
ethyl chloroformate and NaN3 afforded an intermediate
acyl azide that underwent a Curtius rearrangement upon
heating in the presence of allyl alcohol to give the
allyloxycarbonyl (Alloc)-protected amine 36 in 80% yield.
Sch em e 5
presence of potassium carbonate and catalytic amounts
of tetrabutylammonium iodide gave the amine 27 in 42%
yield.
Prior to converting the tert-butyl ester group in 27 to
the requisite hydroxamic acid function, it was necessary
to protect the secondary amine in order to prevent
cyclization of an activated carboxylic acid to give a
γ-lactam. Hence, 27 was converted to its carbamate 28
in 92% yield. Subsequent deprotection of the tert-butyl
ester in 28 with trifluoroacetic acid gave the correspond-
ing acid that was then activated with isobutyl chloro-
formate. Reaction of the mixed anhydride thus formed
with O-(trimethylsilyl)hydroxylamine gave hydroxamic
acid 29 in 84% overall yield from 28. Deprotection of the
amine functionality by hydrogenolysis employing Pd-
BaSO4 as the catalyst gave 9 in 94% yield. Although
compound 9 tends to undergo lactamization at elevated
temperatures, it is stable at room temperature in solution
for several weeks.
Syn th esis of MMP In h ibitor s w ith P 2′ Rep la ce-
m en ts. The opening move in the synthesis of the cyclo-
propane-derived pseudopeptide 10 involved the prepa-
ration of the requisite cyclopropyl lactone 33, which
would then be elaborated into 36, the constrained P2′
subunit of 10. p-Iodoanisole (30) was first coupled with
propargyl alcohol via a Sonogashira reaction36 to give an
intermediate aryl propargyl alcohol that was reduced by
catalytic hydrogenation over P-2 nickel to provide the
allylic alcohol 31 in 71% overall yield. Transformation
of 31 into the allylic diazoacetate 32 according to the
standard Corey-Myers protocol37 proceeded in 65% yield.
It was necessary to use a slight excess of N,N-dimethyl-
aniline (DMA) to avoid complications associated with
At this juncture, the synthetic plan called for append-
ing the P1′ subunit by acylation of 36 with an activated
derivative of the known carboxylic acid 37.30 Thus, 37
was first converted into the pentafluorophenyl ester 38
that was then coupled with the N-protected cyclopropane
36 in the presence of (Ph3P)4Pd and Bu3SnH using a one-
pot deprotection-acylation sequence reported by Speck-
amp to give 39 in 84% yield.40 Preliminary experiments
directed toward converting the protected primary alcohol
of 39 into a carboxylic acid that would be subjected to
(38) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J . J . Am.
Chem. Soc. 1976, 98, 1275-1276.
(36) Tretyakov, E. V.; Tkachev, A. V.; Rybalova, T. V.; Gatilov, Y.
V.; Knight, D. W.; Vasilevsky, S. F. Tetrahedron 2000, 56, 10075-
10080.
(37) Corey, E. J .; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559-
3562.
(39) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30,
2151-2157.
(40) Roos, E. C.; Bernabe, P.; Hiemstra, H.; Speckamp, W. N.;
Kaptein, B.; Boesten, W. H. J . J . Org. Chem. 1995, 60, 1733-1740.

Matrix Metalloprotease Inhibitors
J . Org. Chem., Vol. 67, No. 12, 2002 4067
Sch em e 6
reagents, proceeded in poor yields, a two-step procedure
involving sequential oxidation with Dess-Martin perio-
dinane and then sodium chlorite under buffered condi-
tions furnished the acid 43 in 92% yield.42 The transfor-
mation of 43 into the Alloc-protected amine 44 was
achieved in 81% yield via the two-step Curtius procedure
described previously. N-Acetylation of 44 according to the
Speckamp protocol as before afforded 45 in 84% yield.
At this point, it was necessary to effect the regioselec-
tive opening of the succinimide ring in 45 to deliver the
linear pseudopeptide 10. The reaction of hydroxylamine
with succinimides related to 45 had been reported to
proceed with good to complete regioselectivity with attack
on the less hindered carbonyl group.43 We found, how-
ever, that reaction of 45 with recrystallized hydroxy-
lamine hydrochloride under basic conditions provided a
regioisomeric mixture (ca 2:1) of the hydroxamic acids
10 and 46, respectively. Hence, the N-substituent in such
imides plays an important role in directing the regio-
chemistry of imide cleavage. Although it was difficult to
separate the major product 10 from 46, pure 10 could be
isolated by preparative thin-layer chromatography. The
structure of 10 was assigned using a combination of
COSY, NOESY, HMQC, and HMBC experiments on pure
10 and on a mixture of 10 and 46 that was enriched in
46; we were unable to isolate 46 in pure form.
Sch em e 7
the second Curtius reaction were not encouraging. Namely,
we were unable to cleanly oxidize the alcohol 40. Al-
though we did not rigorously identify the cause of the
difficulty, we reasoned that the intermediate aldehyde
was unstable as amino cyclopropanes bearing electron-
withdrawing groups are known to suffer ring opening.41
To make the amide nitrogen in 39 less electron
donating, we attempted to acylate it under a number of
conditions but discovered that it was resistant to a
bimolecular acylation. We were then attracted to the
possibility that this nitrogen atom might undergo an
intramolecular acylation to give a succinimide. Toward
this end, 39 was treated with formic acid to give 41,
followed by cyclization to the succinimide in acetyl
chloride. Subsequent removal of the formate ester in
refluxing methanol provided the alcohol 42 in 66% overall
yield from 39. Although direct oxidation of the alcohol
group in 42 to a carboxylic acid using a variety of
oxidizing agents, including chromium and ruthenium
Preparation of the hydroxamic acid 11, which is the
flexible analogue of 10, was a far simpler task. N-Boc-
O-methyl-L-tyrosinol44 (47) was converted in two steps
into the azide 48. Reduction of the azide by catalytic
hydrogenation in acetic anhydride, followed by removal
of the N-Boc group with methanolic HCl, gave the
monoprotected diamine 49 as its hydrochloride salt
together with small amounts (<3%) of a compound that
(41) (a) Rynbrandt, R. H.; Dutton, F. E. Tetrahedron Lett. 1972,
1937-1940. (b) Cannon, J . G.; Garst, J . E. J . Org. Chem. 1975, 40,
182-184. (c) Paulini, K.; Reissig, H. U. Liebigs Ann. Chem. 1994, 549-
554.
(42) Dalcanale, E.; Montanari, F. J . Org. Chem. 1986, 51, 567-569.
(43) Devlin, J . P.; Ollis, W. D.; Thorpe, J . E.; Wood, R. J .; Broughton,
B. J .; Warren, P. J .; Wooldridge, K. R. H.; Wright, D. E. J . Chem. Soc.,
Perkin Trans. 1 1975, 830-841.

4068 J . Org. Chem., Vol. 67, No. 12, 2002
Reichelt et al.
was tentatively identified as the transacylated amine
hydrochloride 50. Reaction of 49 with the mixed anhy-
dride derived from 37 and isobutyl chloroformate fur-
nished 51 in 81% yield. The carboxylic acid obtained upon
treating 51 with trifluoroacetic acid was then converted
into the desired hydroxamic acid 11 in 80% overall yield
via sequential reaction with isobutyl chloroformate and
O-(trimethylsilyl)hydroxylamine.
interactions apparently do contribute significantly to the
overall binding affinity. However, it is also important to
recognize that the removal of the amide functional group
also changes the hybridization and basicity of the nitro-
gen atom in the P1′-P2′ link. This nitrogen atom is
approximately planar in the flexible inhibitor 5, whereas
it is tetrahedral in both 8 and 9. The biological assays
were typically conducted in the pH range of 6.5-7.4, so
the nitrogen atoms in 8 and 9 should be protonated in
bulk solvent. Hence, the ionic and polar character of 8
and 9 is very different from 5.
Pseudopeptides 10 and 11 were considerably more
potent than 8 and 9, but they were still weaker inhibitors
than the parent 5. That the flexible analogue 11 was
400-1000 times less potent than 5 demonstrates that
introduction of a retro amide replacement at the P2′-
P3′ amide linkage is detrimental to activity. Modeling
suggests that even though the NH group of 11 could be
suitably positioned for forming a hydrogen bond with the
carbonyl group of Gly-179 of the MMP, the C-terminal
carbonyl group in 11 is probably displaced to the extent
that it is no longer able to serve effectively as a hydrogen
bond acceptor with the enzyme, especially to the Tyr-
240 residue. What was particularly striking is that the
conformationally constrained pseudopeptide 10 was sig-
nificantly more potent (about 5-35-fold) than its flexible
analogue 11. Thus, despite the fact that introducing a
retro amide moiety into the P2′-P3′ subsite of MMP
inhibitors reduces potency, this loss can be at least
partially restored by constraining the backbone and
projecting the aromatic ring at the P2′ subsite in an
approximately anti orientation.
Biologica l Activities of 8-11. The cyclopropane-
containing inhibitors 8 and 10, their respective flexible
analogues 9 and 11, and the parent pseudopeptide 5 were
tested for inhibitory activity against a number of MMPs
using established assays.45 Briefly, the matrilysin and
stromelysin-1 assays were performed at pH 6.5, whereas
the human fibroblast collagenase (HFC) and gelatinase
A assays were performed at pH 7.4. Enzyme inhibition
was measured using a flourimetric assay in which MMP-
catalyzed cleavage of the peptide substrate Gly-Glu-
(EDANS)-Gly-Pro-Leu-Gly-/-Leu-Tyr-Ala-Lys(DABCYL)-
Gly (10 µM) was monitored using a concentration of
enzyme that resulted in a 40-fold increase in fluorescence.
The concentration of inhibitor ([Inh]) that resulted in 50%
inhibition was determined by plotting the log[Inh] vs the
log function of the % inhibition. The IC50 values were
determined from a single assay using a regression
analysis of the concentration/inhibition data with seven
dilutions over a 1000-fold concentration range. The
results of these bioassays are summarized in Table 1. For
reference purposes, the hydroxamate 5, which lacks the
aryl methoxy group, is approximately equipotent with 4
against MMP-1.12 Hence, an aryl methoxy group does not
seem to have a significant impact on inhibitor potency,
and 5 would thus appear to be a reasonable control for
10 and 11.
Con clu sion s
The cyclopropane-derived pseudopeptides 8 and 10 and
their flexible analogues 9 and 11 were prepared as
derivatives of the corresponding MMP inhibitors 5 and
4. These compounds were designed to test whether the
introduction of a conformational constraint mimicking
the biologically active conformation at the P1′ or P2′
subsites of 5 and 4 would enhance MMP binding affinity.
Replacing the P1′-P2′ amide group of MMP inhibitors
with a basic amino ethylene group is tremendously
detrimental to enzyme binding. Indeed, the low biological
activities of 8 and 9 do not allow any conclusions
regarding whether substituted cyclopropanes of the
general type 3 mimic the bound conformation of MMP
inhibitors related to 5. Although the introduction of a
retro amide at P2′-P3′ of 4 was detrimental to potency,
comparing the activities of 10 and 11 demonstrates for
the first time that cyclopropane-containing pseudopep-
tides can have significantly higher activities than their
flexible analogues. We previously found that rigidified
pseudopeptides incorporating replacements derived from
2 were either equipotent or less active than their flexible
derivatives.5-8,11 The present results thus clearly signal
that further investigations are necessary to understand
the basis of these differences and to establish the scope
and utility of cyclopropane-derived isosteres related to
3.
Ta ble 1. IC50 Va lu es (µM) for MMP In h ibitor s
MMP-1
HFC
MMP-2
MMP-3
MMP-7
matrilysin
compd
gelatinase A stromelysin-1
5
8
9
0.0025
26% @100 µM
36% @10 µM
0.0007
6.0
6.15
0.016
124
inactive
@10 µM
0.0065
2.5% @100 µM
40% @10 µM
10
11
0.054
1.9
0.064
0.26
1.0
6.9
0.78
6.7
Inspection of the results for the flexible pseudopeptide
9 clearly indicates that deleting the carbonyl carbon atom
of the P1′-P2′ amide linkage in 5 had a dramatic and
deleterious effect upon biological activity. Compound 9
was four orders of magnitude less potent an inhibitor of
a series of MMPs than the parent hydroxamate 5. Indeed,
the IC50 values for HFC (MMP-1), stromelysin-1 (MMP-
3), and matrilysin (MMP-7) were beyond the detection
limit of the assay. The observation that 8 and 9 were
approximately equipotent in these assays suggests that
introducing a conformational constraint into 9 was insuf-
ficient to rescue activity. Inasmuch as the carbonyl
oxygen atom and the amide N-H of the P1′-P2′ amide
group form two highly conserved hydrogen bonds with
the Leu-181 and Pro-238 residues of the MMP active
site,20 this loss of potency is perhaps not surprising. These
(44) J urczak, J .; Gryko, D.; Kobrzycka, E.; Gruza, H.; Prokopowicz,
P. Tetrahedron 1998, 54, 6051-6064.
(45) Marcotte, P. A.; Davidsen, S. K. Characterization of Matrix
Metalloproteinase Inhibitors: Enzymatic Assays. In Current Protocols
in Pharmacology; Enna, S. J ., Williams, M., Ferkany, J . W., Kenakin,
T., Porsolt, R. D., Sullivan, J . P., Eds.; J ohn Wiley & Sons: New York,
2001; pp 3.7.1-3.7.14.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, all solvents and reagents
were reagent grade and used without purification. Tetrahy-
drofuran (THF) was distilled from potassium/benzophenone

Matrix Metalloprotease Inhibitors
J . Org. Chem., Vol. 67, No. 12, 2002 4069
ketyl under nitrogen, and dichloromethane (CH2Cl2) was
distilled from calcium hydride prior to use. Reactions involving
air- or moisture-sensitive reagents or intermediates were
performed under an inert atmosphere of argon in glassware
that had been oven- or flame-dried. Reaction temperatures are
reported as the temperature of the bath surrounding the
vessel. Flash chromatography was performed using silica gel
60 (230-400 mesh ASTM) according to Still’s protocol,46
eluting with solvents as indicated. Melting points are uncor-
rected. Infrared (IR) spectra were recorded either neat on
sodium chloride plates or as solutions in CHCl3 and are
reported in wavenumbers (cm-1) referenced to the 1601.8 cm-1
absorption of a polystyrene film. 1H and 13C NMR spectra were
obtained as solutions in CDCl3 unless otherwise indicated, and
chemical shifts are reported in parts per million (ppm, δ)
downfield from Me4Si (TMS). Coupling constants are reported
in hertz (Hz). The following are the designations for the
spectral splitting patterns: s, singlet; br, broad; d, doublet; t,
triplet; q, quartet; m, multiplet; comp, complex multiplet; and
app, apparent. Percent yields are given for compounds that
were g95% pure as judged by NMR.
[1S-(1r,2r,3r)]-2-Hyd r oxym eth yl-3-isop r op ylcyclop r o-
p a n e-1-ca r boxylic Acid N-Meth oxy-N-m eth yl Am id e. A
solution of Me3Al (2.0 M in hexane) (50 mL, 100 mmol) was
added to a suspension of N,O-dimethylhydroxylamine hydro-
chloride (8.35 g, 86 mmol) in CH2Cl2 (320 mL) at 0 °C. After
the mixture was stirred for 25 min, a solution of 134b,19 (2.00
g, 14 mmol) in CH2Cl2 (120 mL) was added at 0 °C, and stirring
was continued at room temperature for 6 h. The reaction
mixture was cooled to 0 °C, and 2 N aqueous HCl (75 mL)
was slowly added. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 75 mL). The
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by
flash chromatography eluting with EtOAc/hexane (2:1) to give
2.68 g (95%) of a colorless oil: 1H NMR δ 4.05-3.95 (m, 2 H),
3.72 (s, 3 H), 3.18 (s, 3 H), 2.72 (br s, 1 H), 2.19-2.03 (m, 1 H),
1.93-1.84 (m, 1 H), 1.64 (app tt, J ) 6.8, 8.9 Hz, 1 H), 1.21
(app dt, J ) 8.9, 10.7 Hz, 1 H), 0.93 (d, J ) 6.6 Hz, 3 H), 0.90
(d, J ) 6.6 Hz, 3 H); 13C NMR δ 173.7, 61.3, 58.4, 33.6, 32.6,
25.9, 22.9, 22.6, 19.0; IR ν 3501, 2962, 1636, 1463, 1384, 1097
cm-1; MS m/z 202.1430 [C10H19NO3 + H requires 202.1443],
184 (base), 154, 141.
[1S-(1r,2r,3r)]-2-F or m yl-3-isop r op ylcyclop r op a n e-1-
ca r boxylic Acid N-Meth oxy-N-m eth yl Am id e (14). A
mixture of pyridinium chlorochromate (6.03 g, 28 mmol) and
Celite (4.00 g) was added to a solution of the alcohol from the
preceding experiment (2.82 g, 14 mmol) in CH2Cl2 (150 mL).
The reaction mixture was stirred at room temperature for 2 h
and then concentrated under reduced pressure. The residue
was suspended in Et2O (150 mL) and filtered through a Celite
pad. The filtrate was concentrated under reduced pressure,
and the crude product was purified by flash chromatography
eluting with hexane/EtOAc (3:1) to give 2.48 g (89%) of 14 as
a colorless oil: 1H NMR δ 9.81 (d, J ) 6.1 Hz, 1 H), 3.70 (s, 3
H), 3.16 (s, 3 H), 2.79-2.71 (m, 1 H), 2.43-2.32 (m, 1 H), 2.00-
1.92 (m, 1 H), 1.54 (app dt, J ) 8.9, 10.9 Hz, 1 H), 0.99 (app
t, J ) 7.1 Hz, 6 H); 13C NMR δ 201.0, 170.5, 61.5, 36.3, 33.0,
32.6, 27.7, 22.7, 22.5, 22.4; IR ν 3018, 2965, 1693, 1649, 1462,
1392, 1094 cm-1; MS m/z 200.1285 [C10H17NO3 + H requires
200.1286] (base), 156, 139, 111.
[1S-(1r,2â,3r)]-2-F or m yl-3-isop r op ylcyclop r op a n e-1-
ca r boxylic Acid N-Meth oxy-N-m eth yl Am id e (15). Neat
Et3N (23 mL, 165 mmol) was added to a solution of 14 (2.25 g,
11 mmol) in MeOH (570 mL), and the mixture was stirred at
70 °C for 72 h. The mixture was concentrated under reduced
pressure to give 2.25 g (quantitative) of 15 as a colorless oil.
Compound 15 could be used without purification: 1H NMR δ
9.50 (d, J ) 3.2 Hz, 1 H), 3.73 (s, 3 H), 3.18 (s, 3 H), 2.90-2.84
(m, 1 H), 2.57-2.54 (m, 1 H), 1.73-1.67 (m, 1 H), 1.65-1.60
(m, 1 H), 0.99 (d, J ) 6.6 Hz, 3 H), 0.88 (d, J ) 6.6 Hz, 3 H);
13C NMR δ 199.4, 169.5, 61.6, 38.7, 35.0, 32.7, 26.8, 25.6, 22.4,
21.9; IR ν 3155, 2962, 1710, 1652, 1464, 1383, 1097 cm-1; MS
m/z 200.1283 [C10H17NO3 + H requires 200.1286] (base), 182,
170, 142, 139, 111.
[1S-(1r,2â,3r)]-2-([1,3]-Dit h ia n e-2-ylid en em et h yl)-3-
isop r op ylcyclop r op a n e-1-ca r boxylic Acid N-Meth oxy-N-
m eth yl Am id e. A solution of n-BuLi (1.52 M in hexane, 4.3
mL, 6.5 mmol) was added to a solution of 2-(trimethylsilyl)-
1,3-dithiane (1.43 g, 7.4 mmol) in THF (40 mL) at 0 °C. The
mixture was stirred at 0 °C for 15 min and cooled to -78 °C,
and a solution of 15 (0.92 g, 4.7 mmol) in THF (25 mL) was
added. The reaction mixture was stirred at -78 °C for 0.5 h,
and then H2O (40 mL) was added. The layers were separated,
and the aqueous layer was extracted with Et2O (3 × 60 mL).
The combined organic layers were dried (MgSO4) and concen-
trated under reduced pressure. The crude product was purified
by flash chromatography eluting with hexane/EtOAc/CH2Cl2
(5:1:1) to yield 0.99 g (70%) of a colorless oil: (Note: the
compound decomposes within hours in CDCl3.) 1H NMR δ 5.43
(d, J ) 9.1 Hz, 1 H), 3.69 (s, 3 H), 3.16 (s, 3 H), 2.85-2.79
(comp, 4 H), 2.47 (ddd, J ) 4.9, 6.1, 9.1 Hz, 1 H), 2.23-2.08
(comp, 3 H), 1.79-1.66 (m, 1 H), 1.05 (app dt, J ) 6.1, 9.8 Hz,
1 H), 0.98 (d, J ) 6.6 Hz, 3 H), 0.81 (d, J ) 6.6 Hz, 3 H); 13C
NMR δ 171.7, 134.7, 125.7, 61.5, 38.5, 32.8, 30.3, 29.5, 26.6,
25.7, 25.6, 25.1, 22.5, 22.2; IR ν 3020, 2956, 1715, 1494, 1367,
1210, 1167 cm-1; MS m/z 302.1243 [C14H23NO2S2 + H requires
302.1248], 272, 241 (base), 135.
[1S-(1r,2â,3r)]-2-([1,3]-Dit h ia n e-2-ylid en em et h yl)-3-
isop r op ylcyclop r op a n e-1-ca r boxylic Acid (16). A solution
of 10% aqueous KOH (20 mL) was added to a solution of the
N-methoxy-N-methyl amide from the preceding experiment
(721 mg, 2.4 mmol) in EtOH (20 mL), and the mixture was
heated under reflux for 26 h. The EtOH was removed under
reduced pressure, and the resulting aqueous solution was
washed with Et2O (8 mL). The aqueous layer was acidified to
pH ) 4 by adding 4 N aqueous HCl and extracted with CH2Cl2
(4 × 25 mL). The combined organic layers were dried (MgSO4)
and concentrated under reduced pressure to give 595 mg (96%)
of 16 as a white foam that was used without further purifica-
tion: (Note: the compound decomposes within hours in
CDCl3.) 1H NMR δ 5.36 (d, J ) 9.1 Hz, 1 H), 2.90-2.82 (comp,
4 H), 2.42 (ddd, J ) 4.8, 6.6, 9.1 Hz, 1 H), 2.18-2.11 (comp, 2
H), 1.83-1.76 (m, 1 H), 1.74 (dd, J ) 4.8, 9.4 Hz, 1 H), 1.11
(app dt, J ) 6.6, 9.4 Hz, 1 H), 1.01 (d, J ) 6.6 Hz, 3 H), 0.88
(d, J ) 6.6 Hz, 3 H); 13C NMR δ 178.4, 132.7, 127.1, 39.1, 30.1,
29.4, 28.8, 27.5, 26.1, 24.9, 22.4, 22.0; IR ν 3018, 2964, 1695,
1522, 1424, 1216 cm-1; MS m/z 259.0820 [C12H18O2S2 + H
requires 259.0826] (base), 241, 213, 135, 107.
[1R-(1r,2r,3â)]-2-Isop r op yl-3-m eth oxylca r bon ylm eth -
ylcyclop r op a n e-1-ca r boxylic Acid (17). Mercury(II) chlo-
ride (1.50 g, 5.5 mmol) was added to a solution of 16 (0.65 g,
2.5 mmol) in MeOH/H2O (9:1, 120 mL), and the mixture was
heated at 70 °C for 2 h. The mixture was concentrated under
reduced pressure, and the crude product was purified by flash
chromatography eluting with hexane/EtOAc/AcOH (75:25:1)
1
to give 0.37 g (73%) of 17 as a white solid: mp 70-72 °C; H
NMR δ 3.66 (s, 3 H), 2.45 (dd, J ) 6.4, 15.9 Hz, 1 H), 2.15 (dd,
J ) 8.0, 15.9 Hz, 1 H), 1.74-1.63 (comp, 2 H), 1.55 (dd, J )
4.8, 9.1 Hz, 1 H), 1.01 (d, J ) 6.6 Hz, 3 H), 1.00-0.93 (m, 1
H), 0.87 (d, J ) 6.6 Hz, 3 H); 13C NMR δ 178.6, 172.2, 51.7,
38.2, 37.7, 26.3, 25.0, 23.6, 22.2, 22.1; IR ν 3515, 2960, 1733,
1697, 1456, 1177 cm-1; MS m/z 200.1036 [C10H16O4 requires
200.1049], 183 (base), 169, 155, 141, 127, 109.
[1R-(1r,2r,3â)]-2-Isop r op yl-3-m eth oxylca r bon ylm eth -
ylcyclop r op a n e-1-ca r ba m ic Acid ter t-Bu tyl Ester (18).
Isobutyl chloroformate (263 µL, 2.0 mmol) was added to a
solution of 17 (290 mg, 1.5 mmol) and Et3N (263 µL, 1.9 mmol)
in acetone/H2O (10:1, 5 mL) at -10 °C. The reaction mixture
was stirred at -10 °C for 0.5 h, and a solution of sodium azide
(151 mg, 2.3 mmol) in H2O (0.4 mL) was added. The reaction
mixture was stirred at -10 °C for 1 h and then partitioned
between CH2Cl2 (8 mL) and H2O (2 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 8 mL). The combined organic
layers were dried (MgSO4) and concentrated under reduced
pressure. The residual oil was dissolved in t-BuOH (8 mL);
(46) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

4070 J . Org. Chem., Vol. 67, No. 12, 2002
Reichelt et al.
the reaction mixture was heated under reflux for 16 h, and
the solvent was removed under reduced pressure. The yellow
solid was purified by flash chromatography eluting with
hexane/EtOAc (5:1) to give 215 mg (53%) of 18 as a white
solid: mp 83-87 °C; 1H NMR δ 4.64 (br s, 1 H), 3.66 (s, 3 H),
2.57 (dd, J ) 6.1, 15.8 Hz, 1 H), 2.36-2.50 (m, 1 H), 2.03 (dd,
J ) 8.2, 15.8 Hz, 1 H), 1.43 (s, 9 H), 1.25-1.19 (m, 1 H), 1.02
(d, J ) 6.6 Hz, 3 H), 0.98 (d, J ) 6.6 Hz, 3 H), 0.88-0.78 (m,
1 H), 0.59-0.49 (m, 1 H); 13C NMR δ 172.9, 156.6, 79.4, 51.5,
37.2, 34.0, 32.6, 28.3, 27.5, 22.4, 21.0; IR ν 3020, 2956, 1715,
1494, 1367, 1210, 1167 cm-1; MS m/z 272.1860 [C14H25NO4 +
H requires 272.1862], 256, 244, 216 (base), 172.
[1R-(1r,2r,3â)]-3-Ca r boxym eth yl-2-isop r op ylcyclop r o-
p a n e-1-ca r ba m ic Acid ter t-Bu tyl Ester . A solution of 1 N
aqueous NaOH (1.1 mL, 1.1 mmol) was added to a solution of
18 (202 mg, 0.75 mmol) in EtOH (6 mL), and the mixture was
heated at 75 °C for 1 h. The solution was concentrated under
reduced pressure, and the resulting semisolid was dissolved
in H2O (3 mL) and EtOAc (6 mL). The aqueous layer was
acidified to pH ) 4 by adding 1.5 N aqueous HCl, and the
layers were separated. The aqueous layer was extracted with
EtOAc (2 × 6 mL). The combined organic layers were washed
with brine (5 mL), dried (MgSO4), and concentrated under
reduced pressure to give 185 mg (96%) of a white solid, mp
132-134 °C, which was used in the next step without further
purification: 1H NMR (CD3OD) δ 2.48-2.40 (comp, 2 H), 2.10
(dd, J ) 8.0, 15.9 Hz, 1 H), 1.44 (s, 9 H), 1.27-1.13 (m, 1 H),
1.03 (d, J ) 6.4 Hz, 3 H), 0.96 (d, J ) 6.4 Hz, 3 H), 0.91-0.82
(m, 1 H), 0.49 (ddd, J ) 6.0, 7.1, 10.0 Hz, 1 H); 13C NMR
(CD3OD) δ 176.4, 159.4, 80.2, 38.3, 35.2, 34.1, 28.7, 28.4, 22.9,
22.8, 20.6; IR ν 3019, 2977, 1716, 1694, 1505, 1216 cm-1; MS
m/z 258.1705 [C13H23NO4 + H requires 258.1705], 242, 230,
202 (base), 184, 158.
[1R-(1r,2r,3â)]-3-Ben zoxyca r b a m oylm et h yl-2-isop r o-
p ylcyclop r op a n e-1-ca r ba m ic Acid ter t-Bu tyl Ester (19).
Isobutyl chloroformate (111 µL, 0.85 mmol) was added drop-
wise to a solution of the acid from the preceding reaction (183
mg, 0.71 mmol) and Et3N (139 µL, 0.99 mmol) in THF (4 mL)
at -10 °C. The mixture was stirred for 20 min, whereupon
O-benzylhydroxylamine (175 µL, 1.4 mmol) was added drop-
wise at -10 °C. The mixture was stirred at room temperature
for 12 h; the solvent was partially removed under reduced
pressure, and EtOAc (5 mL) was added. The organic layer was
washed with 0.5 N aqueous HCl (1 × 3 mL), and the aqueous
layer was extracted with EtOAc (2 × 4 mL). The combined
organic layers were dried (MgSO4) and concentrated under
reduced pressure. The resulting crude product was purified
by flash chromatography eluting with hexane/EtOAc (1:1) to
yield 211 mg (82%) of 19 as a white solid: mp 119-123 °C; 1H
NMR δ 12.05 (br s, 1 H), 7.44-7.26 (comp, 5 H), 4.99 (d, J )
11.4 Hz, 1 H), 4.96 (d, J ) 11.4 Hz, 1 H), 4.76 (br s, 1 H), 2.78
(dd, J ) 2.7, 17.7 Hz, 1 H), 2.24 (dd, J ) 2.9, 7.5 Hz, 1 H),
1.65 (dd, J ) 11.3, 17.7 Hz, 1 H), 1.43 (s, 9 H), 1.29-1.21 (m,
1 H), 1.01 (d, J ) 6.6 Hz, 3 H), 0.96 (d, J ) 6.6 Hz, 3 H), 0.77-
0.72 (m, 1 H), 0.40 (ddd, J ) 5.8, 7.5, 10.2 Hz, 1 H); 13C NMR
δ 168.1, 158.2, 136.2, 128.9, 128.2, 128.1, 80.8, 77.5, 38.5, 33.8,
32.2, 28.3, 27.1, 22.6, 22.3, 20.5; IR ν 3442, 3172, 2993, 1701,
1666, 1498, 1161 cm-1; MS m/z 363.2278 [C20H30N2O4 + H
requires 363.2284], 335, 307 (base), 257, 217, 201, 156, 140.
[1R-(1r,2r,3â)]-3-Ben zoxyca r b a m oylm et h yl-2-isop r o-
p ylcyclop r op yla m in e Hyd r och lor id e (20). A solution of 19
(85 mg, 0.23 mmol) in 4 N HCl in dioxane (1 mL) was stirred
at room temperature for 10 min, and the solvent was removed
under reduced pressure. The resulting white foam was tritu-
rated with Et2O (2 × 2 mL) to afford 69 mg (quantitative) of
20 as a white solid, mp 65 °C (dec). This material was used in
the next step without further purification: 1H NMR (CD3OD)
δ 7.43-7.33 (comp, 5 H), 4.85 (s, 2 H), 2.53 (dd, J ) 3.7, 7.8
Hz, 1 H), 2.19 (dd, J ) 6.8, 15.0 Hz, 1 H), 2.03 (dd, J ) 7.2,
15.0 Hz, 1 H), 1.40-1.26 (m, 1 H), 1.17-1.08 (m, 1 H), 1.09
(d, J ) 6.6 Hz, 3 H), 1.06 (d, J ) 6.6 Hz, 3 H), 0.81-0.73 (m,
1 H); 13C NMR (CD3OD) δ 170.6, 136.9, 130.2, 129.7, 129.5,
79.1, 35.4, 33.8, 31.4, 28.0, 22.9, 22.6, 20.5; IR (CH2Cl2) ν 3054,
2986, 1662, 1422, 1264 cm-1; MS m/z 263.1771 [C15H22N2O2
+ H requires 263.1760] (base), 246, 157, 140, 107.
N-{[1R-(1r,2r,3â)]-3-Ben zoxyca r b a m oylm et h yl-2-iso-
p r op ylcyclop r op yl}-L-p h en yla la n in e Meth yl Ester (21).
Freshly distilled trifluoromethanesulfonic anhydride (57 µL,
0.35 mmol) was slowly added to a solution of methyl D-3-
phenyllactate (63 mg, 0.35 mmol) in CH2Cl2 (1 mL) at 0 °C.
The mixture was stirred at 0 °C for 10 min, and 2,6-lutidine
(41 µL, 0.35 mmol) was added. Stirring at 0 °C was continued
for an additional 15 min, whereupon i-Pr2NEt (72 µL, 0.41
mmol) was added. A mixture of 20 (35 mg, 0.12 mmol) and
i-Pr2NEt (31 µL, 0.18 mmol) in CH2Cl2 (0.5 mL) was added,
and the mixture was stirred at room temperature for 12 h. A
portion of CH2Cl2 (3 mL) was added, and the solution was
washed with brine (2 mL) and saturated aqueous NaHCO3 (2
mL). The combined aqueous layers were extracted with CH2Cl2
(2 mL), and the combined organic layers were dried (MgSO4)
and concentrated under reduced pressure. The resulting crude
product was purified by flash chromatography eluting with
hexane/EtOAc (2:1) to yield 28 mg (54%) of 21 as a colorless
oil: 1H NMR (CD3OD) δ 7.41-7.31 (comp, 5 H), 7.24-7.13
(comp, 5 H), 4.82 (s, 2 H), 3.63 (s, 3 H), 3.56 (app t, J ) 6.9
Hz, 1 H), 2.90 (dd, J ) 6.4, 13.4 Hz, 1 H), 2.82 (dd, J ) 7.4,
13.4 Hz, 1 H), 2.02 (dd, J ) 3.2, 7.5 Hz, 1 H), 1.91 (dd, J )
6.8, 14.3 Hz, 1 H), 1.81 (dd, J ) 7.8, 14.3 Hz), 1.42-1.34 (m,
1 H), 0.93 (d, J ) 6.6 Hz, 3 H), 0.92 (d, J ) 6.6 Hz, 3 H), 0.53-
0.48 (m, 1 H), 0.35 (ddd, J ) 5.6, 7.5, 10.0 Hz, 1 H); 13C NMR
(CD3OD) δ 176.9, 172.0, 139.1, 137.0, 130.4, 130.1, 129.6, 129.5,
129.2, 127.5, 79.1, 64.2, 52.1, 41.2, 40.6, 37.0, 35.8, 27.9, 23.1,
22.9; IR ν 3401, 2955, 1731, 1689, 1456, 1174 cm-1; MS m/z
425.2444 [C25H32N2O4 + H requires 425.2440] (base), 319, 301,
274.
N-{[1R-(1r,2r,3â)]-3-Ben zoxyca r b a m oylm et h yl-2-iso-
p r op ylcyclop r op yl}-L-p h en yla la n in e N′-Meth yl Am id e. A
solution of 21 (25 mg, 0.059 mmol) in 33% ethanolic MeNH2
(2 mL) containing NaCN (0.5 mg, 0.010 mmol) was heated in
a closed vial at 55 °C for 17 h. The solvent was removed under
reduced pressure, and the resulting crude product was purified
by flash chromatography eluting with CHCl3/MeOH (100:1)
to give 23 mg (90%) of a white solid: mp 126-130 °C; 1H NMR
(CD3OD) δ 7.42-7.33 (comp, 5 H), 7.26-7.14 (comp, 5 H), 4.84
(d, J ) 10.9 Hz, 1 H), 4.80 (d, J ) 10.9 Hz, 1 H), 3.34-3.29
(m, 1 H), 2.86 (dd, J ) 7.1, 13.4 Hz, 1 H), 2.74 (dd, J ) 7.4,
13.4 Hz, 1 H), 2.63 (s, 3 H), 2.00-1.86 (comp, 2 H), 1.80 (dd,
J ) 7.9, 14.4 Hz, 1 H), 1.38-1.21 (m, 1 H), 0.92 (d, J ) 6.7
Hz, 3 H), 0.91 (d, J ) 6.7 Hz, 3 H), 0.52-0.43 (m, 1 H), 0.34
(ddd, J ) 5.6, 7.5, 10.0 Hz, 1 H); 13C NMR (CD3OD) δ 177.4,
172.2, 139.4, 136.9, 130.4, 130.3, 129.7, 129.5, 129.3, 127.5,
79.1, 65.4, 41.2, 40.6, 36.8, 35.6, 28.0, 26.0, 23.1, 22.8; IR ν
3226, 2957, 1652, 1461, 1406, 1124 cm-1; MS m/z 424.2590
[C25H33N3O3 + H requires 424.2600], 333, 318, 273, 259, 179
(base), 164, 140, 120.
N-{[1R-(1r,2r,3â)]-3-H yd r oxyca r b a m oylm et h yl-2-iso-
p r op ylcyclop r op yl}-L-p h en yla la n in e N′-Meth yl Am id e
(8). A solution of the O-benzyl hydroxamate from the preceding
experiment (16 mg, 0.038 mmol) in MeOH (1 mL) containing
5% Pd-BaSO4 (16 mg) was shaken under a H2 atmosphere
(40 psi) for 15 h. The catalyst was removed by vacuum
filtration through a Celite pad, which was then washed with
MeOH (4 mL). The combined filtrates were concentrated under
reduced pressure, and the resulting yellow oil was triturated
with hexane (2 × 1 mL) to afford 12 mg (95%) of 8 as a pale
yellow solid: mp 48 °C dec; 1H NMR (CD3OD) δ 7.27-7.15
(comp, 5 H), 3.33-3.28 (m, 1 H), 2.85 (dd, J ) 7.5, 13.4 Hz, 1
H), 2.75 (dd, J ) 7.5, 13.4 Hz, 1 H), 2.67 (s, 3 H), 2.02 (dd, J
) 6.3, 14.5 Hz, 1 H), 1.93 (dd, J ) 3.2, 7.5 Hz, 1 H), 1.76 (dd,
J ) 8.3, 14.5 Hz, 1 H), 1.37-1.29 (m, 1 H), 0.94 (d, J ) 6.6
Hz, 3 H), 0.92 (d, J ) 6.6 Hz, 3 H), 0.54-0.45 (m, 1 H), 0.36
(ddd, J ) 5.6, 7.5, 9.9 Hz, 1 H); 13C NMR (CD3OD) δ 177.6,
172.3, 139.4, 130.3, 129.3, 127.5, 65.5, 41.3, 40.6, 36.9, 35.7,
28.0, 26.0, 23.1, 23.0; IR ν 3358, 3230, 2958, 1658, 1540, 1464,
1087 cm-1; MS m/z 334.2130 [C18H27N3O3 + H requires
334.2131], 318, 301, 273 (base), 259, 179, 120.
(3R)-3-H yd r oxym et h yl-5-m et h ylh exa n oic Acid ter t-
Bu tyl Ester (25). A solution of 2230 (4.59 g, 11.8 mmol) and
LiBH4 (257 mg, 11.8 mmol) in Et2O (60 mL) containing MeOH
(478 µL, 11.8 mmol) was stirred at 0 °C for 1.5 h. Saturated

Matrix Metalloprotease Inhibitors
J . Org. Chem., Vol. 67, No. 12, 2002 4071
aqueous Na2CO3 (60 mL) was added, and the biphasic mixture
was stirred at room temperature for 0.5 h to ensure complete
hydrolysis of the boranes. The layers were separated, and the
aqueous layer was extracted with Et2O (2 × 60 mL). The
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure. The resulting yellow oil was purified
by flash chromatography eluting with pentane/Et2O (1:1) to
yield 2.15 g (84%) of 25 as a colorless liquid: 1H NMR δ 3.63
(dd, J ) 11.0, 4.4 Hz, 1 H), 3.46 (dd, J ) 11.0, 7.0 Hz, 1 H),
2.29 (dd, J ) 15.1, 7.4 Hz, 1 H), 2.24 (dd, J ) 15.1, 5.4 Hz, 1
H), 2.08-2.00 (m, 1 H), 1.67-1.59 (m, 1 H), 1.44 (s, 9 H), 1.23-
1.17 (m, 1 H), 1.13-1.07 (m, 1 H), 0.89 (d, J ) 6.6 Hz, 3 H),
0.88 (d, J ) 6.6 Hz, 3 H); 13C NMR δ 173.3, 80.6, 66.0, 40.4,
38.4, 35.7, 28.1, 25.2, 22.8, 22.6; IR ν 3442, 1713, 1369, 1155
cm-1; MS m/z 217.1804 [C12H24O5 + H requires 217.1804], 161
(base), 143.
(3R)-3-Br om om eth yl-5-m eth ylh exa n oic Acid ter t-Bu tyl
Ester (26). Solid Ph3P (3.80 g, 14.5 mmol) was added to a
mixture of 25 (2.09 g, 9.66 mmol) and CBr4 (4.81 g, 14.5 mmol)
in CH2Cl2 (100 mL). The mixture was stirred at room tem-
perature for 2 h, and the solvent was removed under reduced
pressure to give a yellow oil that was purified by flash
chromatography eluting with pentane/Et2O (20:1) to yield 2.41
g (89%) of 26 as a colorless liquid: 1H NMR δ 3.53 (dd, J )
10.0, 3.8 Hz, 1 H), 3.44 (dd, J ) 10.0, 5.4 Hz, 1 H), 2.37 (dd, J
) 15.3, 6.8 Hz, 1 H), 2.24-2.15 (comp, 2 H), 1.65-1.56 (m, 1
H), 1.43 (s, 9 H), 1.35-1.27 (m, 1 H), 1.18-1.13 (m, 1 H), 0.89
(d, J ) 6.6 Hz, 3 H), 0.88 (d, J ) 6.6 Hz, 3 H); 13C NMR δ
171.7, 80.5, 41.8, 39.0, 39.0, 34.3, 28.1, 25.0, 22.9, 22.3; IR ν
1717, 1368, 1257, 1156 cm-1; MS m/z 279.0954 [C12H23BrO2 +
H requires 279.0960], 255, 223 (base), 143.
(3R)-5-Met h yl-3-[(1S)-(1-m et h ylca rb a m oyl-2-p h en yl-
eth yla m in o)m eth yl]h exa n oic Acid ter t-Bu tyl Ester (27).
A mixture of 26 (1.26 g, 4.50 mmol), phenylalanine N-methyl
amide (1.60 g, 9.00 mmol), solid K2CO3 (1.24 g, 9.00 mmol),
and Bu4NI (166 mg, 0.450 mmol) in DMF (23 mL) was stirred
at 60 °C for 6 days. The solvent was removed under reduced
pressure, and the residue was dissolved in EtOAc (20 mL).
The organic solution was washed with saturated aqueous
NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL) and dried
(MgSO4). The solvent was removed under reduced pressure,
and the resulting yellow oil was purified by flash chromatog-
raphy eluting with hexane/EtOAc (1:1) to yield 705 mg (42%)
of 27 as a yellow oil: 1H NMR δ 7.34-7.18 (comp, 6 H), 3.27-
3.20 (comp, 2 H), 2.81 (d, J ) 5.0 Hz, 3 H), 2.63 (app t, J )
11.3 Hz, 1 H), 2.40 (dd, J ) 11.8, 4.6 Hz, 1 H), 2.31 (dd, J )
11.8, 5.0 Hz, 1 H), 2.15-2.07 (m, 2 H), 1.90-1.87 (m, 1 H),
1.39 (s, 9 H), 1.30-1.22 (comp, 2 H), 0.94-0.85 (m, 2 H), 0.76
(d, J ) 6.6 Hz, 3 H), 0.69 (d, J ) 6.4 Hz, 3 H); 13C NMR δ
174.2, 172.6, 137.8, 129.0, 128.8, 126.9, 80.3, 64.3, 51.4, 41.2,
39.3, 39.2, 33.2, 28.1, 25.8, 24.9, 22.8, 22.4; IR ν 3443, 3375,
2400, 1716, 1662, 1526, 1475, 1423, 1223, 728, 670 cm-1; MS
m/z 377.2809 [C22H36N2O5 + H requires 377.2804] (base), 318.
(3R)-3-{[Ben zyloxyca r bon yl-(1S)-(1-m eth ylca r ba m oyl-
2-ph en yleth yl)am in o]m eth yl}-5-m eth ylh exan oic Acid ter t-
Bu tyl Ester (28). A solution of 27 (598 mg, 1.59 mmol) in
THF/H2O (3:1, 13 mL) was adjusted to pH ) 10 by adding
saturated aqueous Na2CO3. Benzyl chloroformate (453 µL, 3.18
mmol) was added, and the solution was stirred at room
temperature for 0.5 h while maintaining a pH of 10 by adding
saturated aqueous Na2CO3. The THF was evaporated under
reduced pressure. A solution of 10% aqueous citric acid was
added to adjust the pH to 4, and the mixture was then
extracted with EtOAc (3 × 15 mL). The combined organic
layers were dried (MgSO4) and concentrated under reduced
pressure. The resulting yellow oil was purified by flash
chromatography eluting with hexane/EtOAc (2:1) to yield 743
mg (92%) of 28 as a yellow oil: 1H NMR (DMSO-d6, 90 °C) δ
7.48-7.43 (m, 1 H), 7.37-7.29 (comp, 5 H), 7.23-7.14 (comp,
5 H), 5.08 (d, J ) 12.5 Hz, 1 H), 5.04 (d, J ) 12.5 Hz, 1 H),
4.44 (app t, J ) 7.5 Hz, 1 H), 3.24 (dd, J ) 13.8, 7.0 Hz, 1 H),
3.13 (dd, J ) 14.3, 8.3 Hz, 1 H), 3.05-2.97 (comp, 2 H), 2.58
(d, J ) 4.6 Hz, 3 H), 2.17-2.10 (comp, 2 H), 1.87 (dd, J ) 14.3,
6.9 Hz, 1 H), 1.53-1.47 (m, 1 H), 1.38 (s, 9 H), 1.07-0.96 (m,
2 H), 0.79 (d, J ) 6.6 Hz, 3 H), 0.75 (d, J ) 6.6 Hz, 3 H); 13C
NMR (DMSO-d6, 90 °C) δ 171.1, 169.2, 155.6, 137.8, 136.2,
128.4, 127.7, 127.6, 127.2, 127.2, 125.7, 78.9, 66.1, 61.7, 50.1,
41.1, 37.6, 35.1, 32.1, 27.3, 25.2, 24.2, 22.2, 22.0; IR ν 3442,
3350, 1708, 1682, 1368, 1235, 1154 cm-1; MS m/z 511.3170
[C30H42N2O5+H requires 511.3172], 455 (base), 377.
(3R)-3-{[Ben zyloxyca r bon yl-(1S)-(1-m eth ylca r ba m oyl-
2-p h en yleth yl)a m in o]m eth yl}-5-m eth ylh exa n oic Acid . A
solution of 28 (670 mg, 1.31 mmol) in a mixture of CF3CO2H
(13 mL) and CH2Cl2 (13 mL) was stirred at room temperature
for 0.5 h. Toluene (10 mL) was added, and the solution was
concentrated under reduced pressure. The residual CF3CO2H
was removed by azeotropic distillation under reduced pressure
with toluene (2 × 10 mL). The resulting yellow oil was purified
by flash chromatography eluting with CH2Cl2/MeOH (19:1) to
yield 591 mg (99%) of a white foam: 1H NMR (DMSO-d6, 90
°C) δ 11.53 (br s, 1 H), 7.47-7.42 (m, 1 H), 7.37-7.29 (comp,
5 H), 7.23-7.14 (comp, 5 H), 5.09 (d, J ) 12.6 Hz, 1 H), 5.04
(d, J ) 12.6 Hz, 1 H), 4.43 (app t, J ) 7.5 Hz, 1 H), 3.24 (dd,
J ) 13.8, 6.9 Hz, 1 H), 3.16 (dd, J ) 14.2, 6.4 Hz, 1 H), 3.02-
2.96 (comp, 2 H), 2.58 (d, J ) 4.6 Hz, 3 H), 2.20 (dd, J ) 15.1,
5.1 Hz, 1 H), 2.18-2.13 (m, 1 H), 1.95 (dd, J ) 15.1, 7.2 Hz, 1
H), 1.53-1.48 (m, 1 H), 1.08-0.99 (m, 2 H), 0.78 (d, J ) 6.6
Hz, 3 H), 0.75 (d, J ) 6.6 Hz, 3 H); 13C NMR (DMSO-d6, 90
°C) δ 173.2, 169.3, 155.6, 137.8, 136.3, 128.4, 127.7, 127.6,
127.2, 127.2, 125.6, 66.1, 61.7, 50.2, 41.2, 36.4, 35.0, 31.9, 25.2,
24.2, 22.2, 22.0; IR ν 3448, 2400, 1683, 1523, 1423, 1475, 1210,
768, 671 cm-1; MS m/z 455.2528 [C26H34N2O5 + H requires
455.2546] (base), 411, 321, 303, 244.
(2R)-(2-Hydr oxycar bam oylm eth yl-4-m eth ylpen tyl)-(1S)-
(1-m eth ylca r ba m oyl-2-p h en yleth yl)ca r ba m ic Acid Ben -
zyl Ester (29). Isobutyl chloroformate (197 µL, 1.52 mmol)
was added to a solution of the acid from the preceding reaction
(575 mg, 1.26 mmol) and N-methylmorpholine (195 µL, 1.77
mmol) in THF (6.5 mL) at -10 °C. The mixture was stirred at
-10 °C for 0.5 h, and O-(trimethylsilyl)hydroxylamine (201
µL, 1.64 mmol) was added. The cooling bath was removed, and
the mixture was stirred for 4 h at room temperature. The THF
was removed under reduced pressure, and the resulting yellow
oil was purified by flash chromatography eluting with CH2Cl2/
MeOH (19:1) to yield 501 mg (85%) of 29 as a white solid: mp
75-77 °C; 1H NMR (DMSO-d6, 90 °C) δ 10.00 (br s, 1 H), 8.31
(br d, J ) 14.4 Hz, 1 H), 7.48-7.43 (m, J ) 4.6 Hz, 1 H), 7.37-
7.29 (comp, 5 H), 7.23-7.14 (comp, 5 H), 5.10 (d, J ) 12.6 Hz,
1 H), 5.04 (d, J ) 12.6 Hz, 1 H), 4.36 (app t, J ) 7.5 Hz, 1 H),
3.26 (dd, J ) 13.8, 6.8 Hz, 1 H), 3.16 (dd, J ) 14.3, 8.5 Hz, 1
H), 3.00 (dd, J ) 13.8, 8.2 Hz, 1 H), 2.87 (dd, J ) 14.3, 5.7 Hz,
1 H), 2.59 (d, J ) 4.6 Hz, 3 H), 2.15-2.08 (m, 1 H), 2.02 (br d,
J ) 14.1 Hz, 1 H), 1.75-1.87 (m, 1 H), 1.52-1.44 (m, 1 H),
1.07-1.02 (m, 1 H), 0.97-0.92 (m, 1 H), 0.76 (d, J ) 6.6 Hz, 3
H), 0.74 (d, J ) 6.6 Hz, 3 H); 13C NMR (DMSO-d6, 90 °C) δ
169.4, 169.4, 155.6, 137.9, 136.3, 128.5, 127.7, 127.6, 127.1,
127.1, 125.6, 66.1, 61.8, 50.7, 41.3, 35.0, 34.8, 31.9, 25.3, 24.2,
22.2, 22.0; IR ν 3320, 2400, 1676, 1526, 1473, 1427, 1214, 728,
671 cm-1; MS m/z 470.2636 [C26H35N3O5 + H requires 470.2655]
(base), 454, 426, 320, 303.
5-Met h yl-(3R)-3-[(1S)-(1-m et h ylca r b a m oyl-2-p h en yl-
eth yla m in o)m eth yl]h exa n oic Acid Hyd r oxyl Am id e (9).
A mixture of 29 (165 mg, 0.351 mmol) in MeOH (3.5 mL)
containing 5% Pd-BaSO4 (75 mg) was stirred under a H2
atmosphere (1 atm) at room temperature for 0.5 h. The catalyst
was removed by filtration through a Celite pad, which was
washed with MeOH (2 × 5 mL). The combined filtrates were
concentrated under reduced pressure, and the resulting light
yellow solid was purified by flash chromatography eluting with
CH2Cl2/MeOH (9:1) to yield 111 mg (94%) of 9 as a white
solid: mp 119 °C dec; 1H NMR (CD3OD) δ 7.30-7.19 (comp, 5
H), 3.20 (dd, J ) 8.2, 5.9 Hz, 1 H), 2.98 (dd, J ) 13.5, 5.9 Hz,
1 H), 2.75 (dd, J ) 13.5, 8.2 Hz, 1 H), 2.70 (s, 3 H), 2.43 (dd,
J ) 11.8, 4.6 Hz, 1 H), 2.31 (dd, J ) 11.8, 5.6 Hz, 1 H), 2.08
(dd, J ) 15.7, 9.6 Hz, 1 H), 2.00-1.94 (comp, 2 H), 1.46-1.38
(m, 1 H), 1.07-0.95 (m, 2 H), 0.81 (d, J ) 6.6 Hz, 3 H), 0.77
(d, J ) 6.4 Hz, 3 H); 13C NMR (CD3OD) δ 177.1, 172.3, 139.1,
130.2, 129.6, 127.8, 65.9, 52.3, 42.7, 40.5, 37.4, 34.6, 26.2, 26.0,
23.3, 22.9; IR (Nujol) ν 3321, 3165, 2473, 2309, 1650, 1633,

4072 J . Org. Chem., Vol. 67, No. 12, 2002
Reichelt et al.
1556, 1407, 1329, 700 cm-1; MS m/z 336.2271 [C18H29N3O5 +
H requires 336.2287] (base), 320, 303, 179.
MS m/z 266.1407 [C14H19NO4 + H requires 266.1392], 250
(base), 232, 144.
[1R-(1r,2r,3r)]-2-(4-Meth oxyp h en yl)-3-tr iisop r op ylsi-
lyloxym eth yl-1-N-m eth yl-N-m eth oxy Cyclop r op yl Am id e
(34). A solution of the alcohol from the preceding experiment
(268 mg, 1.0 mmol), 2,6-lutidine (180 µL, 2.5 mmol), and
TIPSOTf (350 µL, 1.3 mmol) in CH2Cl2 (10 mL) was stirred at
0 °C for 2 h, whereupon H2O (10 mL) was added. The layers
were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed
with H2O (10 mL) and brine (10 mL), dried (Na2SO4), and
concentrated under reduced pressure. The resulting clear oil
was purified by flash chromatography eluting with hexanes/
EtOAc (10:1) to give 360 mg (85%) of 34 as a clear oil: 1H
NMR δ 7.25 (d, J ) 8.7 Hz, 2 H), 6.81 (d, J ) 8.7, 2 H), 4.17
(dd, J ) 8.7, 11.2 Hz, 1 H), 4.07 (dd, J ) 4.8, 11.2 Hz, 1 H),
3.82 (s, 3 H), 3.78 (s, 3 H), 3.12 (s, 3 H), 2.73 (app t, J ) 8.9
Hz, 1 H), 2.55 (app t, J ) 8.9 Hz, 1 H), 1.90-1.81 (m, 1 H),
1.18-1.03 (comp, 21 H); 13C NMR δ 172.2, 158.7, 132.0, 127.6,
114.1, 62.1, 59.6, 55.7, 55.7, 27.9, 27.5, 20.3, 18.7, 12.6; IR ν
2943, 2866, 1658, 1612, 1514, 1464 cm-1; MS m/z 422.2716
[C23H39NO4Si + H requires 422.2727], 378 (base), 248.
[1R-(1r,2â,3â)]-2-(4-Meth oxyph en yl)-3-tr iisopr opylsilyl-
oxym eth yl Cyclop r op a n e-1-ca r boxylic Acid (35). Freshly
sublimed t-BuOK (823 mg, 7.3 mmol) was added in one portion
to a solution of 34 (387 mg, 0.92 mmol) in Et2O (12 mL) at 0
°C. The suspension was allowed to warm to room temperature
and stirred for 90 min, whereupon H2O (16.5 µL, 0.92 mmol)
was added dropwise. The reaction was stirred for another 15
min at room temperature, and 10% aqueous citric acid (15 mL)
was added. The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 12 mL). The combined organic
layers were dried (Na2SO4) and concentrated under reduced
pressure. The resulting yellow oil was purified by flash
chromatography eluting with hexanes/EtOAc (3:1) to give 310
mg (89%) of 35 as a clear oil: 1H NMR δ 7.23 (d, J ) 8.7 Hz,
2 H), 6.83 (d, J ) 8.7 Hz, 2 H), 3.80 (s, 3 H), 3.62 (dd, J ) 5.9,
10.7 Hz, 1 H), 3.42 (dd, J ) 8.9, 10.7 Hz, 1 H), 2.90 (dd, J )
4.8, 9.3 Hz, 1 H), 2.12-2.16 (m, 1 H), 1.94 (app t, J ) 4.8 Hz,
1 H), 1.03-0.94 (comp, 21 H); 13C NMR δ 180.6, 159, 130.9,
128.0, 114.2, 61.8, 55.9, 31.7, 24.1, 18.5, 18.5, 12.5; IR ν 3148,
2944, 2866, 1896, 1612, 1515, 1463 cm-1; MS m/z 379.2296
[C21H34O4Si + H requires 379.2304], 361, 335, 233, 205 (base).
[1R-(1r,2â,3â)]-(2-(4-Meth oxyp h en yl)-3-tr iisop r op ylsi-
lyloxym eth yl) Cyclop r op a n e-1-N-a lloxyca r bon yla m in o-
cyclop r op a n e (36). Et3N (100 µL, 0.72 mmol) was added
dropwise to a solution of 35 (193 mg, 0.51 mmol) in acetone (3
mL) and H2O (90 µL) at 0 °C. Ethyl chloroformate (70 µL, 0.73
mmol) was added; the solution was stirred at 0 °C for 30 min,
and 4.3 N aqueous NaN3 (180 µL, 0.77 mmol) was added. The
mixture was stirred at 0 °C for an additional 2 h and then
partitioned between Et2O (3 mL) and H2O (2 mL). The aqueous
layer was extracted with Et2O (3 × 3 mL). The combined
organic layers were dried (MgSO4), and toluene (2 mL) was
added. The Et2O was removed under reduced pressure, and
freshly distilled allyl alcohol (3 mL) was added. The mixture
was heated at reflux for 3 h and then concentrated under
reduced pressure. The resulting yellow oil was purified by flash
chromatography eluting with hexanes/EtOAc (8:1) to give 177
mg (80%) of 36 as a clear oil: 1H NMR δ 7.35 (br s, 2 H), 6.80
(d, J ) 8.7 Hz, 2 H), 5.94 (ddt, J ) 15.9, 10.6, 5.5 Hz, 1H),
5.33 (d, J ) 15.9 Hz, 1 H), 5.23 (d, J ) 10.6 Hz, 1 H), 5.12 (br
s, 1 H), 4.59-4.63 (m, 2 H), 3.79 (s, 3 H), 3.60-3.66 (m, 1 H),
3.40 (dd, J ) 10.7, 7.7 Hz, 1 H), 2.82 (dd, J ) 6.1, 3.9 Hz, 1
H), 2.35 (dd, J ) 10.0, 3.9 Hz, 1 H), 1.62-1.52 (m, 1 H), 1.08-
0.93 (comp, 21 H); 13C NMR δ 158.3, 156.7 132.8, 130.7, 128.4,
117.7, 113.6, 65.6, 61.5, 55.3, 33.3, 29.7, 29.0, 17.9, 11.9; IR ν
3444, 2944, 2866, 1723, 1612, 1514 cm-1; MS m/z 434.2723
[C20H39NO4Si + H requires 434.2727] (base), 390, 260, 246.
2-(R)-Isobu tyl-4-ter t-bu tylbu ta n oa te P en ta flu or op h en -
yl Ester (38). A solution of pentafluorophenol (249 mg, 1.35
mmol) and DCC (91 mg, 0.44 mmol) in EtOAc (1.8 mL) was
stirred at 0 °C for 30 min, and a solution of 3730 (0.44 mmol)
in EtOAc (0.9 mL) was added. The mixture was stirred at 0
°C for 1 h and then overnight at room temperature. The
3-(4-Meth oxyp h en yl)-(2Z)-p r op en -1-ol (31). A solution
of NaBH4 (171 mg, 4.5 mmol) in 0.1 N ethanolic NaOH (4.6
mL) was added dropwise to a stirred suspension of Ni(OAc)2‚
4H2O (1.15 g, 4.6 mmol) in EtOH (14 mL), and the mixture
was stirred under argon at room temperature for 1 h. The
mixture was stirred under H2 (1 atm), and ethylenediamine
(0.60 mL, 9.0 mmol) was added dropwise. A solution of 3-(4-
methoxyphenyl)-2-propyn-1-ol36 (5.02 g, 31.0 mmol) in EtOH
(25 mL) was added, and the reaction was stirred under H2 (1
atm) until 695 mL (31.0 mmol) of H2 was absorbed (3 days). A
mixture of pentane/Et2O (1:1, 100 mL) was added, and the
solids were removed by filtration through a pad of Florisil,
which was rinsed with pentane/Et2O (1:1, 5 × 100 mL). The
combined filtrates and washings were concentrated under
reduced pressure, and the resulting yellow solid was purified
by recrystallization (CH2Cl2/pentane) to give 31 as pale yellow
plates (first crop, 2.78 g; second crop, 1.49 g; 84% total yield):
1
mp 45-50 °C; H NMR δ 7.10 (d, J ) 8.7 Hz, 2 H), 6.39 (d, J
) 8.7 Hz, 2 H), 6.39 (d, J ) 11.8 Hz, 1 H), 5.76 (dt, J ) 6.1,
11.8 Hz, 1 H), 4.40 (dd, J ) 6.1, 1.8 Hz, 2 H), 3.71 (s, 3 H); 13
C
NMR δ 158.8, 130.6, 130.1, 129.4, 129.2, 113.7, 59.7, 55.3; IR
ν 3612, 2955, 1602, 1572, 1508, 1467 cm-1; MS m/z 164.0834
[C10H12O2 requires 164.0837], 254, 147 (base).
3-(4-Meth oxyp h en yl)-(2Z)-p r op en yl Dia zoa ceta te (32).
A solution of the tosylhydrazone of glyoxylic acid chloride (9.3
g, 36 mmol), 31 (3.25 g, 19.8 mmol); N,N-dimethylaniline (4.8
mL, 38 mmol) in CH2Cl2 (50 mL) was stirred at 0 °C for 10
min, whereupon Et3N (15 mL, 108 mmol) was added. The
solution was stirred for 15 min at 0 °C and then overnight at
room temperature. The solvent was removed under reduced
pressure, and the residue was purified by flash chromatogra-
phy eluting with hexanes/EtOAc (15:1) to give 3.00 g (65%) of
32 as a bright yellow oil: 1H NMR δ 7.15 (d, J ) 8.7 Hz, 2 H),
6.88 (d, J ) 8.7 Hz, 2 H), 6.59 (d, J ) 11.8 Hz, 1 H), 5.71 (dt,
J ) 6.6, 11.8 Hz, 1 H), 4.92 (dd, J ) 1.4, 6.6 Hz, 2 H), 4.77 (br
s, 1 H), 3.79 (s, 3 H); 13C NMR δ 158.9, 133.3, 129.9, 128.5,
123.8, 113.7, 61.7, 55.1, 46.1; IR ν 3022, 2959, 2114, 1690, 1608
cm-1; MS m/z 232.0850 [C12H12N2O3 requires 232.0848], 155
(base).
[1S-(1r,5r,6r)]-6-(4-Meth oxyph en yl)-3-oxabicyclo[3.1.0]-
h exa n -2-on e (33). A solution of 32 (1.32 g, 5.68 mmol) in
CH2Cl2 (20 mL) was added via a syringe pump over 18 h to a
solution of Rh2[5(S)-MEPY]4 (52.8 mg, 0.057 mmol) in CH2Cl2
(350 mL) under reflux. The reaction was concentrated under
reduced pressure, and the crude product was purified by flash
chromatography eluting with hexanes/EtOAc (3:1) to give 720
mg (62%) of 33 as a white crystalline solid: mp 102-103 °C;
1H NMR δ 7.23 (d, J ) 8.7 Hz, 2 H), 6.87 (d, J ) 8.7 Hz, 2 H),
4.35 (dd, J ) 5.1, 4.5 Hz, 1 H), 4.04 (d, J ) 9.6 Hz, 1 H), 3.78
(s, 3 H), 2.70 (app t, J ) 8.4 Hz, 1 H), 2.58-2.50 (comp, 2 H);
13C NMR δ 174.9, 159.1, 130.5, 124.1, 114.3, 65.8, 55.2, 25.5,
24.0, 23.6; IR ν 2967, 1760, 1613, 1580, 1515, 1474 cm-1; MS
m/z 205.0864 [C12H12O3 + H requires 205.0865], 160 (base).
[1S-(1r,2r,3r)]-2-Hyd r oxym eth yl-3-(4-m eth oxyph en yl)-
1-N-m eth oxy-N-m eth yl Cyclop r op yl Am id e. A solution of
Me3Al (2 N in hexanes) (1 mL, 2 mmol) was slowly added
dropwise to a stirred suspension of N,O-dimethylhydroxyl-
amine hydrochloride (149 mg, 1.52 mmol) in CH2Cl2 (2.8 mL),
and the mixture was stirred at room temperature for 45 min.
A solution of 33 (77 mg, 0.38 mmol) in CH2Cl2 (1.9 mL) was
added dropwise, and the reaction was stirred overnight at room
temperature. The mixture was then cooled to 0 °C; 1 N aqueous
HCl (10 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give 96
mg (94%) of a pale yellow oil that was used without further
purification: 1H NMR δ 7.03 (d, J ) 8.8 Hz, 2 H), 6.75 (d, J )
8.8 Hz, 2 H), 3.92 (dd, J ) 6.2, 5.5 Hz, 1 H), 3.80 (dd, J ) 11.7
Hz, 1 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 3.21 (s, 3 H), 2.71 (app t,
J ) 8.5 Hz, 1 H), 2.47-2.34 (m, 1 H), 1.86 (m, 1 H); 13C NMR
δ 158.1, 130.4, 127.0, 113.6, 61.1, 59.0, 55.0, 32.7, 27.5, 27.5,
25.2, 21.3; IR ν 3506, 2943, 1655, 1608, 1514, 1461, 1038 cm-1
;

Matrix Metalloprotease Inhibitors
J . Org. Chem., Vol. 67, No. 12, 2002 4073
mixture was filtered through a Celite pad that was rinsed with
EtOAc (2 × 3 mL), and the combined filtrate and washings
were concentrated under reduced pressure. The resulting pale
yellow oil was purified by flash chromatography eluting with
hexanes/EtOAc (10:1) to give 159 mg (91%) of 38 as a clear
oil: 1H NMR δ 3.26-3.15 (m, 1 H), 2.75 (dd, J ) 9.3, 16.8 Hz,
1 H), 2.53 (dd, J ) 5.2, 16.8, 1 H), 1.81-1.66 (m, 2 H), 1.49-
1.38 (m, 1 H), 1.46 (s, 9 H), 1.00 (d, J ) 6.4 Hz, 3 H), 0.97 (d,
J ) 6.4 Hz, 3 H); 13C NMR δ 171.3, 170.2, 40.9, 39.5, 37.6,
27.9, 25.8, 22.6, 22.0; IR ν 2954, 1778, 1519, 1155, 1096, 1002
cm-1; MS m/z 397.1434 [C18H21F5O4 + H requires 397.1438],
341, 323.
(m, 1 H), 0.96 (d, J ) 6.6 Hz, 3 H), 0.90 (d, J ) 6.6 Hz, 3 H);
13C NMR δ 197.6, 179.8, 176.0, 160.0, 130.4, 125.4, 114.0, 55.2,
40.5, 38.0, 34.7, 34.0, 30.9, 26.0, 22.9, 21.5; IR ν 2960, 2839,
1712, 1613, 1516 cm-1; MS m/z 330.1708 [C19H23NO4 + H
requires 330.1705], 175 (base), 156.
[1S-(1r,2â,2â)]-2-(3-(R)-Isobu tylsu ccin im ido)-3-(4-m eth -
oxyp h en yl) Cyclop r op a n e Ca r boxylic Acid (43). A solu-
tion of 0.1 M aqueous NaClO2 (13 mL, 1.3 mmol) was added
dropwise over 1.5 h to a solution of aldehyde from the
preceding experiment (299 mg, 0.91 mmol) in MeCN (9 mL)
containing 0.65 M aqueous NaH2PO4 (3.6 mL) and 30%
aqueous H2O2 (0.23 mL, 2.2 mmol) at 0 °C. The reaction was
stirred at 0 °C for 2 h, and sodium sulfite (50 mg, 0.40 mmol)
was added. The mixture was acidified to pH ) 4 by adding 1
N aqueous HCl and then extracted with EtOAc (3 × 10 mL).
The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The resulting pale yellow
oil was purified by flash chromatography eluting with hexanes/
EtOAc (1:1) to give 301 mg (96%) of 43 as a pale yellow foam:
[1R-(1r,2â,3â)]-1-[(2-(R)-Isobu tyl-4-ter t-bu toxycar boxyl)-
bu tan oyl] Am in o-3-(4-m eth oxyph en yl)-2-tr iisopr opylsilyl-
oxym eth yl Cyclop r op a n e (39). A solution of 36 (515 mg,
1.2 mmol), 38 (566 mg, 1.4 mmol), (Ph3P)4Pd (28 mg, 0.024
mmol), and freshly distilled Bu3SnH (380 mg, 1.3 mmol) in
CH2Cl2 (2.4 mL) was heated under reflux overnight. The
mixture was concentrated under reduced pressure, and the
residue was purified by flash chromatography eluting with
hexanes/EtOAc (15:1) to give 560 mg (84%) of 39 as a pale
yellow syrup that crystallized upon prolonged standing under
1
mp 128-131 °C; H NMR δ 9.43 (br s, 1 H), 7.26 (d, J ) 8.7
Hz, 2 H), 6.82 (d, J ) 8.7 Hz, 2 H), 3.78 (s, 3 H), 3.69 (dd, J )
4.5, 5.9 Hz, 1 H), 3.16 (dd, J ) 5.9, 10.3 Hz, 1 H), 2.88-2.80
(comp, 2 H), 2.71 (app dt, J ) 10.3, 4.5 Hz, 1 H), 2.35 (dd, J )
13.4, 8.0 Hz, 1 H), 1.84-1.70 (comp, 2 H), 1.40-1.32 (m, 1 H),
0.97 (d, J ) 6.4 Hz, 3 H), 0.93 (d, J ) 6.4 Hz, 3 H); 13C NMR
δ 108.7, 176.9, 174.8, 159.4, 130.8, 126.2, 114.3, 55.8, 41.1, 38.5,
35.4, 35.3, 31.1, 26.9, 26.6, 23.6, 22.1; IR ν 3092, 2961, 2872,
2839, 1712, 1614, 1517 cm-1; MS m/z 346.1652 [C19H23NO5 +
H requires 346.1654], 328 (base), 173.
1
vacuum: mp 80-83 °C; H NMR δ 7.32 (d, J ) 8.8 Hz, 2 H),
6.76 (d, J ) 8.8 Hz, 2 H), 6.01 (br s, 1 H), 3.74 (s, 3 H), 3.67
(dd, J ) 5.8, 10.8 Hz, 1 H), 3.33 (dd, J ) 8.4, 10.8 Hz, 1 H),
2.88 (dd, J ) 4.0, 7.6 Hz, 1 H), 2.60-2.53 (comp, 2 H), 2.27
(dd, H ) 12.4, 2.8 Hz, 1 H), 2.21 (dd, J ) 4.0, 9.8 Hz, 1 H),
1.65 (ddd, J ) 5.8, 9.0, 13.4 Hz, 1 H), 1.59-1.42 (m, 1 H), 1.55-
1.49 (m, 1 H), 1.40 (s, 9 H), 1.16 (ddd, J ) 5.2, 8.2, 13.4 Hz, 1
H), 0.97-0.93 (comp, 21 H), 0.90 (d, J ) 6.62 Hz, 3 H), 0.88
(d, J ) 6.62 Hz, 3 H); 13C NMR δ 176.2, 172.0, 158.2, 130.8,
128.4, 113.5, 80.9, 61.6, 55.2, 41.4, 40.7, 38.5, 32.7, 29.5, 28.9,
28.0, 25.8, 23.0, 22.2, 17.9; IR ν 3438, 3014, 2958, 2867, 1718,
1673, 1514 cm-1; MS m/z 562.3952 [C32H55NO5Si + H requires
562.3928], 521, 430, 391 (base), 176.
[1S-(1r,2â,3â)]-2-Allyloxycar bon ylam in o-1-(3-(R)-isobu -
tylsu ccin im id o)-3-(4-m eth oxyp h en yl) Cyclop r op a n e (44).
Et3N (37 µL, 0.26 mmol) was added dropwise to a solution of
43 (65 mg, 0.19 mmol) in acetone (1 mL) containing H2O (35
µL) at 0 °C. Ethyl chloroformate (20 µL, 0.26 mmol) was added,
and the mixture was stirred at 0 °C for 30 min. A solution of
4.3 M aqueous sodium azide (66 µL, 0.28 mmol) was added,
and stirring was continued at 0 °C for 2 h. The reaction
mixture was partitioned between H2O (1 mL) and CH2Cl2 (2
mL), and the aqueous layer was extracted with CH2Cl2 (3 × 2
mL). The combined organic layers were dried (MgSO4); toluene
(1 mL) was added, and the CH2Cl2 was removed under reduced
pressure. Allyl alcohol (2 mL) was added, and the mixture was
heated at reflux for 4 h. The mixture was concentrated under
reduced pressure, and the resulting amber oil was purified by
flash chromatography eluting with hexanes/EtOAc (2:1) to
afford 62 mg (81%) of 44 as a white solid: mp 113-117 °C; 1H
NMR δ 7.22 (br d, J ) 8.7 Hz, 2 H), 6.83 (d, J ) 8.7 Hz, 2 H),
5.93-5.79 (m, 1 H), 5.23 (d, J ) 18.4 Hz, 1 H), 5.18 (d, J )
10.9 Hz, 1 H), 4.56-4.05 (comp, 3 H), 3.76 (s, 3 H), 3.76-3.73
(m, 1 H), 3.32-3.25 (m, 1 H), 3.01 (dd, J ) 5.6, 8.6 Hz, 1 H),
2.83-2.76 (comp, 2 H), 2.32 (dd, J ) 7.7, 13.3 Hz, 1 H), 1.82-
1.77 (m, 1 H), 1.73-1.68 (m, 1 H), 1.33 (ddd, J ) 5.5, 8.0, 10.2
Hz, 1 H), 0.95 (d, J ) 6.6 Hz, 3 H), 0.89 (d, J ) 6.6 Hz, 3 H);
13C NMR δ 180.1, 176.3, 158.9, 156.2, 132.6, 130.2, 125.3,
117.8, 114.1, 65.7, 55.2, 40.5, 38.0, 35.6, 34.8, 33.6, 27.2, 26.1,
[1S -(1r,2â,3â)]-1-(3-(R )-Isob u t ylsu ccin im id o)-2-h y-
d r oxym eth yl-3-(4-m eth oxyp h en yl) Cyclop r op a n e (42). A
solution of 39 (717 mg, 1.3 mmol) in formic acid (13 mL) was
stirred at room temperature for 1 h, and the reaction was
concentrated under reduced pressure. The resulting oil was
dissolved in AcCl (5.2 mL), and the solution was heated under
reflux for 1 h. The mixture was concentrated under reduced
pressure; the residual oil was dissolved in MeOH (50 mL), and
the solution was heated under reflux for 1 h. The mixture was
again concentrated under reduced pressure, and the resulting
brown oil was purified by flash chromatography eluting with
hexanes/EtOAc (2:1) to give 286 mg (66%) of 42 as an off-white
1
solid: mp 107-110 °C; H NMR δ 7.25 (d, J ) 8.7 Hz, 2 H),
6.80 (d, J ) 8.7 Hz, 2 H), 3.77-3.75 (m, 1 H), 3.75 (s, 3 H),
3.20 (dd, J ) 9.2, 11.3 Hz, 1 H), 2.84-2.74 (comp, 3 H), 2.69
(app t, J ) 4.3 Hz, 1 H), 2.34 (dd, J ) 13.8, 3.2 Hz, 1 H), 1.83-
1.69 (comp, 3 H), 1.33 (ddd, J ) 5.6, 10.1, 15.5 Hz, 1 H), 0.95
(d, J ) 5.6 Hz, 3 H), 0.89 (d, J ) 5.6 Hz, 3 H); 13C NMR δ
180.7, 176.9, 158.6, 130.3, 127.6, 113.9, 61.3, 55.2, 40.5, 38.0,
34.8, 32.5, 27.4, 27.3, 26.1, 22.9, 21.5; IR ν 3508, 3002, 2959,
2874, 1775, 1705, 1612, 1515 cm-1; MS m/z 332.1856 [C19H25NO4
+ H requires 332.1862], 314 (base), 300, 156.
26.1, 23.0, 21.5; IR ν 3686, 3021, 2962, 1710, 1602, 1516 cm-1
;
MS m/z 401.2072 [C22H28N2O5 + H requires 401.2076], 343,
[1S-(1r,2â,2â)]-2-(3-(R)-Isobu tylsu ccin im ido)-3-(4-m eth -
oxyp h en yl) Cyclop r op a n e Ca r boxa ld eh yd e. A solution of
42 (96 mg, 0.29 mmol) in CH2Cl2 (1.5 mL) was added dropwise
to a stirred suspension of Dess-Martin periodinane (209 mg,
0.58 mmol) in CH2Cl2 (1.5 mL), and stirring was continued at
room temperature for 30 min. A solution of 5% aqueous
NaHCO3 (3 mL) containing Na2S2O3 (50 mg, 0.32 mmol) was
added in one portion. Stirring was continued for 15 min, and
the layers were separated. The aqueous layer was extracted
with CH2Cl2 (3 × 5 mL), and the combined organic layers were
dried (Na2SO4) and concentrated under reduced pressure. The
resulting crude yellow oil was purified by flash chromatogra-
phy eluting with hexanes/EtOAc (4:1) to give 92 mg (96%) of
a white solid: mp 88-90 °C; 1H NMR δ 9.12 (dd, J ) 2.2, 5.0
Hz, 1 H), 7.26 (d, J ) 8.8 Hz, 2 H), 6.80 (d, J ) 8.8 Hz, 2 H),
3.91 (dd, J ) 5.0, 10.2 Hz, 1 H), 3.75 (s, 3 H), 3.39 (dd, J )
5.8, 10.2 Hz, 1 H), 2.88-2.76 (comp, 3 H), 2.34 (d, J ) 13.5
Hz, 1 H), 1.82-1.77 (m, 1 H), 1.75-1.67 (m, 1 H), 1.37-1.31
300, 184, 156 (base).
[1S-(1r,2â,3â)]-2-Aceta m id o-1-(3-(R)-isobu tylsu ccin im -
id o)-3-(4-m eth oxyp h en yl) Cyclop r op a n e (45). (Ph3P)4Pd
(8 mg, 0.0069 mmol) and Bu3SnH (100 µL, 0.37 mmol) were
added to a solution of 44 (131 mg, 0.33 mmol) in CH2Cl2 (3.3
mL) containing Ac2O (65 µL, 0.69 mmol) at room temperature.
The mixture was stirred at room temperature for 15 min and
then concentrated under reduced pressure. The residue was
purified by flash chromatography eluting with hexanes/EtOAc
(1:1) to give a white solid that was recrystallized from benzene
to give 99 mg (84%) of 45 as a white solid: mp 135-139 °C;
1H NMR (C5D5N) δ 9.07 (br s, 1 H), 7.59 (d, J ) 8.7 Hz, 2 H),
6.92 (d, J ) 8.7 Hz, 2 H), 4.31 (m, 1 H), 3.62 (s, 3 H), 3.51 (dd,
J ) 3.5, 5.0 Hz, 1 H), 3.11 (dd, J ) 5.0, 7.7 Hz, 1 H), 2.90-
2.76 (comp, 2 H), 2.40 (d, J ) 13.4 Hz, 1 H), 1.90 (s, 3 H), 1.80
(ddd, J ) 4.5, 8.6, 13.3 Hz, 1 H), 1.61 (m, 1 H), 1.27 (m, 1 H),
0.82 (d, J ) 6.6 Hz, 3 H), 0.76 (d, J ) 6.6 Hz, 3 H); 13C NMR
δ 180.7, 177.0, 171.4, 159.1, 131.2, 127.9, 114.2, 55.2, 40.4, 38.4,

4074 J . Org. Chem., Vol. 67, No. 12, 2002
Reichelt et al.
35.2, 35.1, 34.1, 29.3, 26.2, 23.1, 22.7, 21.6; IR ν 3428, 3026,
2974, 1709, 1516, 1402 cm-1; MS m/z 359.1966 [C20H26N2O4
+ H requires 359.1971], 291, 279, 206.
Hz, 1 H), 1.93 (s, 3H), 1.39 (s, 9 H); 13C NMR δ 170.7, 158.4,
156.5, 130.2, 129.1, 114.1, 79.7, 55.3, 52.1, 44.1, 38.3, 28.3, 23.2;
IR ν 1596, 1511, 1368, 1245, 1169, 1037 cm-1; MS m/z 323.1978
[C17H26N2O4 + H requires 323.1971], 295, 267, 223 (base).
N -[(2S)-2-Am in o-3-(4-m e t h oxyp h e n yl)p r op yl]a ce t a -
m id e Hyd r och lor id e (49). A solution of the carbamate from
the preceding experiment (1.02 g, 3.16 mmol) in 1 M metha-
nolic HCl (50 mL) was stirred at room temperature for 45 min,
whereupon the solvent was removed under reduced pressure.
The resulting solid was recrystallized from i-PrOH/heptanes
to give 659 mg (81%) of the hydrochloride salt of 49 as a white
solid (mp 191-195 °C) that contained a minor impurity (<3%
by 1H NMR). An analytical sample of the free base was
obtained by dissolving a small sample (30 mg) of 49 in
saturated aqueous NaHCO3 (2 mL) and extracting the solution
with CH2Cl2 (4 × 4 mL). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure. The
resulting yellow oil was purified by flash chromatography
eluting with hexanes/EtOAc (1:4) to yield 21 mg (80%) of the
free amine as a white solid: mp 95-97 °C; 1H NMR δ 7.06 (d,
J ) 8.6 Hz, 2 H), 6.82 (d, J ) 8.6 Hz, 2 H), 6.10-6.04 (m, 1
H), 3.77 (s, 3 H), 3.43 (ddd, J ) 12.9, 6.1, 3.6 Hz, 1 H), 3.07-
2.97 (comp, 2 H), 2.73 (dd, J ) 13.7, 4.6 Hz, 1 H), 2.41 (dd, J
) 13.7, 8.2 Hz, 1 H), 1.97 (s, 3 H); 13C NMR δ 170.2, 158.3,
130.3, 130.1, 114.0, 55.2, 52.4, 45.2, 41.8, 23.3; IR ν 3436, 3370,
1663, 1612, 1513, 1248, 1178, 1036, 809 cm-1; MS m/z 223.1447
[C12H18N2O2 + H requires 223.1447] (base), 206.
[1S-(1â,2r,3r)]-2-Acetam ido-1-[(2-(R)-isobu tyl-4-h ydr oxy-
ca r boxa m id o)bu ta n oyl]a m in o-3-(4-m eth oxyp h en yl) Cy-
clop r op a n e (10). A solution of 2 M methanolic KOH (0.5 mL)
was added with stirring to a solution of 1 M methanolic
HONH2‚HCl (0.75 mL), which was prepared from freshly
recrystallized HONH2‚HCl (MeOH). The mixture was allowed
to stand until the precipitated KCl settled. A portion (0.42 mL)
of the resulting solution was added dropwise to a solution of
45 (30 mg, 0.084 mmol) in MeOH (0.42 mL) at room temper-
ature. After 20 min, H2O (1.5 mL), saturated aqueous Na2CO3
(0.2 mL), and EtOAc (2 mL) were added. The layers were
separated, and the organic layer was extracted with H2O (2 ×
2 mL). The combined aqueous layers were acidified with 6 N
aqueous HCl, saturated with solid NaCl, and extracted with
EtOAc (3 × 5 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give 25
mg (76%) of a mixture of the isomeric hydroxamic acids 10
and 46 as a clear glass. The desired hydroxamic acid 10 was
isolated by preparative TLC, eluting three times with EtOAc/
MeOH/AcOH (42:2:1), as the less polar isomer (7.5 mg, 30%
of crude mixture): 1H NMR (DMSO-d6) δ 10.39 (br s, 1 H),
8.76 (br s, 1 H), 8.30 (d, J ) 3.8 Hz, 1 H), 7.95 (d, J ) 4.8 Hz,
1 H), 7.09 (d, J ) 8.6 Hz, 2 H), 6.80 (d, J ) 8.6 Hz, 2 H), 3.70
(s, 3 H), 3.11 (dd, J ) 4.4, 8.4 Hz, 1 H), 3.02 (app dt, J ) 8.4,
4.4 Hz, 1 H), 2.68-2.60 (m, 1 H), 2.16-2.08 (comp, 2 H), 1.96
(dd, J ) 7.4, 14.2 Hz, 1 H), 1.62 (s, 3 H), 1.48-1.39 (comp, 2
H), 1.07-1.02 (m, 1 H), 0.86 (d, J ) 6.2 Hz, 3 H), 0.80 (d, J )
6.2 Hz, 3 H); 13C NMR δ 175.0, 170.1, 167.2, 157.6, 129.5,
127.9, 113.3, 54.9, 41.0, 35.6, 33.6, 30.3, 25.5, 22.2, 21.8, 20.9;
IR ν 3684, 3617, 3421, 3282, 3019, 2796, 2899, 1713, 1666,
1613, 1515 cm-1; MS m/z 392.2183 [C20H29N3O5 + H requires
392.2185], 359, 343, 279, 221, 204, 172 (base).
N-[(1S)-2-Azido-1-(4-m eth oxyph en ylm eth yl)eth yl](ter t-
bu toxy)ca r boxa m id e (48). Freshly distilled methanesulfonyl
chloride (865 µL, 11.2 mmol) was added dropwise to a stirred
solution of 4744 (2.10 g, 7.45 mmol) and Et3N (1.31 mL, 11.9
mmol) in CH2Cl2 (250 mL) at 0 °C, and the resulting mixture
was stirred at 0 °C for 20 min. The mixture was washed with
H2O (100 mL) and brine (100 mL), and the layers were
separated. The organic layer was dried (MgSO4) and concen-
trated under reduced pressure. The crude mesylate was
dissolved in DMF (75 mL); solid NaN3 (2.44 g, 37.3 mmol) was
added, and the mixture was stirred at 60 °C for 4 h. The DMF
was removed under reduced pressure, and the residue was
partitioned between H2O (100 mL) and EtOAc (100 mL). The
aqueous layer was extracted with EtOAc (2 × 100 mL). The
combined organic layers were washed with brine (100 mL),
dried (MgSO4), and concentrated under reduced pressure. The
resulting yellow oil was purified by flash chromatography
eluting with hexanes/EtOAc (6:1) to yield 1.64 g (72%) of 48
as a white solid: mp 59-60 °C; 1H NMR δ 7.08 (d, J ) 8.6 Hz,
2 H), 6.82 (d, J ) 8.6 Hz, 2 H), 4.69-4.58 (m, 1 H), 3.94-3.85
(m, 1 H), 3.76 (s, 3 H), 3.38 (br dd, J ) 12.2, 3.7 Hz, 1 H), 3.27
(dd, J ) 12.2, 4.5 Hz, 1 H), 2.79 (br dd, J ) 13.8, 5.8 Hz, 1 H),
2.69 (dd, J ) 13.8, 8.0 Hz, 1 H), 1.40 (s, 9 H); 13C NMR δ 158.4,
155.1, 130.2, 129.0, 114.1, 79.7, 55.2, 53.0, 51.4, 37.2, 28.3; IR
ν 3438, 2104, 1706, 1504, 1245, 1168 cm-1; MS m/z 307.1773
[C15H22N4O3 + H requires 307.1770], 251 (base), 207.
(3R)-3-[2-Acetyla m in o-(1S)-1-(4-m eth oxyben zyl)eth yl-
ca r ba m oyl]-5-m eth ylh exa n oic Acid ter t-Bu tyl Ester (51).
A solution of isobutyl chloroformate (206 µL, 1.59 mmol), 3730
(305 mg, 1.32 mmol), and N-methylmorpholine (204 µL, 1.85
mmol) in THF (6.6 mL) at -10 °C was stirred for 1 h at -10
°C. The amine hydrochloride 49 (411 mg, 1.59 mmol) was then
added, and the mixture was stirred at room temperature
overnight. The THF was removed under reduced pressure, and
the residue was dissolved in EtOAc (15 mL). The organic
solution was washed with 10% aqueous citric acid (10 mL),
saturated aqueous NaHCO3 (10 mL), and brine (10 mL), dried
(MgSO4), and concentrated under reduced pressure. The
resulting yellow oil was purified by flash chromatography
eluting with hexanes/EtOAc (3:2) to yield 462 mg (81%) of 51
1
as a white solid: mp 133-134 °C; H NMR δ 7.10 (d, J ) 8.6
Hz, 2 H), 6.80 (d, J ) 8.6 Hz, 2 H), 6.37-6.31 (m, 1 H), 6.09
(d, J ) 7.1 Hz, 1 H), 4.01-3.97 (m, 1 H), 3.76 (s, 3 H), 3.40-
3.32 (m, 2 H), 2.91 (dd, J ) 13.9, 6.8 Hz, 1 H), 2.66 (dd, J )
13.9, 7.3 Hz, 1 H), 2.53-2.47 (comp, 2 H), 2.27 (dd, J ) 20.5,
8.5 Hz, 1 H), 1.93 (s, 3 H), 1.53-1.37 (comp, 2 H), 1.41 (s, 9
H), 1.15-1.09 (m, 1 H), 0.83 (d, J ) 5.2 Hz, 3 H), 0.82 (d, J )
5.3 Hz, 3 H); 13C NMR δ 175.8, 172.0, 171.0, 158.4, 130.1,
129.5, 114.0, 80.9, 55.2, 52.3, 43.0, 41.4, 41.3, 38.3, 37.5, 28.1,
25.7, 23.1, 22.9, 22.2; IR ν 1717, 1663, 1514, 1246, 1216, 1156
cm-1; MS m/z 435.2858 [C24H38N2O5 + H requires 435.2859]
(base), 379.
(3R)-3-[2-Acetyla m in o-(1S)-1-(4-m eth oxyben zyl)eth yl-
ca r ba m oyl]-5-m eth ylh exa n oic Acid . A solution of 51 (245
mg, 0.563 mmol) in a mixture of CF3CO2H (5.6 mL) and CH2Cl2
(5.6 mL) was stirred at room temperature for 2 h. Toluene (5
mL) was added, and the solution was concentrated under
reduced pressure. The residual CF3CO2H was removed by
azeotropic distillation with toluene (2 × 5 mL) to give a yellow
oil that was purified by flash chromatography eluting with
CH2Cl2/MeOH (19:1) to yield 188 mg (88%) of a white solid:
N-(2S)-2-[(tert-Butoxycarbonylamino)-3-(4-methoxyphen-
yl)p r op yl]a ceta m id e. A solution of 48 (1.57 g, 5.12 mmol)
in Ac2O (100 mL) containing 10% Pd-C (545 mg) was stirred
under H2 (1 atm) at room temperature for 5 h. The excess Ac2O
was removed under reduced pressure, and the residue was
dissolved in MeOH (50 mL). The catalyst was removed by
vacuum filtration through a Celite pad that was washed with
MeOH (2 × 25 mL). The combined filtrate and washings were
concentrated under reduced pressure, and the resulting solid
was recrystallized from i-PrOH/heptanes to yield 1.22 g (74%)
1
mp 92-94 °C; H NMR (CD3OD) δ 7.13 (d, J ) 8.7 Hz, 2 H),
6.81 (d, J ) 8.7 Hz, 2 H), 4.12-4.08 (m, 1 H), 3.74 (s, 3 H),
3.29 (dd, J ) 13.7, 9.0 Hz, 1 H), 3.23 (dd, J ) 13.7, 4.9 Hz, 1
H), 2.72 (d, J ) 7.2 Hz, 2 H), 2.67-2.63 (m, 1 H), 2.37 (dd, J
) 16.4, 8.1 Hz, 1 H), 2.25 (dd, J ) 16.4, 6.2 Hz, 1 H), 1.90 (s,
3 H), 1.49-1.37 (comp, 2 H), 1.17-1.11 (m, 1 H), 0.87 (d, J )
6.5 Hz, 3 H), 0.84 (d, J ) 6.5 Hz, 3 H); 13C NMR (CD3OD) δ
177.6, 175.5, 173.6, 159.8, 131.4, 131.3, 114.8, 55.6, 52.5, 43.5,
42.7, 42.4, 38.5, 38.1, 26.9, 23.5, 22.7, 22.4; IR ν 1714, 1661,
1513, 1248 cm-1; MS m/z 379.2247 [C20H30N2O5 + H requires
379.2233), 361 (base), 223.
1
of a white solid: mp 130-131 °C; H NMR δ 7.08 (d, J ) 8.6
Hz, 2 H), 6.81 (d, J ) 8.6 Hz, 2 H), 6.13-6.05 (m, 1 H), 4.78-
4.68 (m, 1 H), 3.85-3.80 (m, 1H), 3.76 (s, 3 H), 3.33-3.19 (m,
2 H), 2.78 (br dd, J ) 7.5, 5.6 Hz, 1 H), 2.66 (dd, J ) 14.0, 7.5
N-1-[2-Acetyla m in o-(1S)-1-(4-m eth oxyben zyl)eth yl]-N-
4-h yd r oxy-(2S)-2-isobu tylsu ccin a m id e (11). A solution of

Matrix Metalloprotease Inhibitors
J . Org. Chem., Vol. 67, No. 12, 2002 4075
acid from the preceding experiment (169 mg, 0.447 mmol),
isobutyl chloroformate (70 µL, 0.536 mmol), and N-methyl-
morpholine (69 µL, 0.625 mmol) in THF (2.2 mL) was stirred
at -10 °C for 0.5 h, whereupon O-(trimethylsilyl)hydroxyl-
amine (66 µL, 0.536 mmol) was added. The cooling bath was
removed, and the mixture was stirred at room temperature
for 3 h. The reaction mixture was filtered through a Celite
pad that was washed with MeOH (2 × 5 mL). The combined
filtrate and washings were concentrated under reduced pres-
sure, and the resulting light yellow solid was recrystallized
from THF to yield 160 mg (91%) of 11 as a white solid: mp
134 °C dec; 1H NMR (CD3OD) δ 7.12 (d, J ) 8.7 Hz, 2 H), 6.81
(d, J ) 8.7 Hz, 2 H), 4.13-4.08 (m, 1 H), 3.73 (s, 3 H), 3.28-
3.26 (m, 2 H), 2.75 (dd, J ) 14.1, 6.6 Hz, 1 H), 2.70 (dd, J )
14.1, 8.5 Hz, 1 H), 2.68-2.63 (m, 1 H), 2.07 (dd, J ) 14.4, 7.1
Hz, 1 H), 1.99 (dd, J ) 14.4, 7.5 Hz, 1 H), 1.91 (s, 3 H), 1.50-
1.44 (m, 1 H), 1.40-1.35 (m, 1 H), 1.09-1.03 (m, 1 H), 0.85 (d,
J ) 6.9 Hz, 3 H), 0.83 (d, J ) 6.8 Hz, 3 H); 13C NMR (CD3OD)
δ 177.2, 173.6, 170.6, 159.8, 131.4, 131.3, 114.8, 55.7, 52.4, 43.6,
42.7, 42.1, 38.5, 37.1, 26.9, 23.8, 22.7, 22.2; IR (Nujol) ν 3216,
1660, 1614, 1556, 1514, 1302, 1242, 1183, 1030, 818 cm-1; MS
m/z 394.2348 [C20H31N3O5 + H requires 394.2342], 362 (base),
352, 225, 172.
Ack n ow led gm en t. We wish to thank the National
Institutes of Health, the Robert A. Welch Foundation,
and the Texas Advanced Research Program for their
generous support of this work. We are thankful to Dr.
Steven K. Davidsen, Dr. Patrick A. Marcotte, and Ms.
Ildiko Elmore of Abbott Laboratories (Abbott Park, IL)
for performing the enzyme assays.
Su p p or tin g In for m a tion Ava ila ble: NMR data for all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O0110698