Intramolecular O-arylation of phenols with phenylboronic acids: Application to the synthesis of macrocyclic metalloproteinase inhibitors

Article abstract of DOI:10.1021/ol015572i

(matrix presented) The copper acetate mediated intramolecular O-arylation of phenols with phenylboronic acid pseudopeptides is the key step in the preparation of macrocyclic biphenyl ether hydroxamic acid inhibitors of collagenase 1 and gelatinases A and

Full text of DOI:10.1021/ol015572i

ORGANIC
LETTERS
2001
Vol. 3, No. 7
1029-1032
Intramolecular O-Arylation of Phenols
with Phenylboronic Acids: Application
to the Synthesis of Macrocyclic
Metalloproteinase Inhibitors
Carl P. Decicco,* Ying Song, and David A. Evans
Chemical and Physical Sciences, The DuPont Pharmaceuticals Company,
Experimental Station, Wilmington, Delaware 19880-E500-1604B, and
The Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
carl.p.decicco@dupontpharma.com
Received January 17, 2001
ABSTRACT
The copper acetate mediated intramolecular O-arylation of phenols with phenylboronic acid pseudopeptides is the key step in the preparation
of macrocyclic biphenyl ether hydroxamic acid inhibitors of collagenase 1 and gelatinases A and B. The intramolecular macrocyclization was
found to be mild and tolerant of common chemical functionality. This methodology should provide a general route to macrocyclic biphenyl
ethers.
The macrocyclization of biologically active peptides (or
pseudopeptides) often leads to compounds with chemical and
physical properties distinct from those of their acyclic
analogues. The macrocyclic structure disfavors peptide
aggregation through intermolecular hydrogen bonding (â-
sheet formation) and functions to sterically shield H-bonding
atoms, resulting in lower desolvation energy.1 This has led
to the use of macrocylcization as a strategy for producing
peptide derivatives that have acceptable pharmaceutical
properties.2 As a result of their unique structure and
physicochemical properties, macrocycles are not generally
recognized by peptidases, making them less prone to standard
routes of in vivo degradation. In addition, they have been
found to be more permeable to cell membranes, which has
led to the development of orally bioavailable macrocycles.
This approach has been exemplified and applied in the design
of cyclic enzyme inhibitors of HIV protease,3 renin,4 ACE
(3) (a) Janetka, J. W.; Raman, P.; Satyshur, K.; Flentke, G. R.; Rich, D.
H. J. Am. Chem. Soc. 1997, 119, 441. (b) Janetka, J. W.; Rich, D. H. J.
Am. Chem. Soc. 1995, 117, 10585. (c) March, D. R.; Abbenante, G.;
Bergman, D. A.; Brinkworth, R. I.; Wickramasinghe, W.; Begun, J.; Martin,
J. L.; Fairlie, D. P. J. Am. Chem. Soc. 1996, 118, 3375. (d) Ettmayer, P.;
Billich, A.; Hecht, P.; Rosenwirth, B.; Gasach, H. J. Med. Chem. 1996, 39,
3291. (e) Chen, J. J.; Coles, P. J.; Annold, L. D.; Smith, R. A.; MacDonald,
I. D.; Carriere, J.; Drantz, A. Biorg. Med. Chem. Lett. 1996, 6, 435. (f)
Tyndall, J. D. A.; Reid, R. C.; Tyssen, D. P.; Jardine, D. K.; Todd, B.;
Passmore, M.; March, D. R.; Pattenden, L. K.; Bergman, D. A.; Alewood,
D.; Hu, S.-H.; Alewood, P. F.; Birch, C. J.; Martin, J. L.; Fairlie, D. P. J.
Med. Chem. 2000, 43, 3495.
(1) (a) Bai, Y.; Englander, S. W. Genetics 1994, 18, 262. (b) Conradi,
R. A.; Hilgers, A. R.; Ho, N. F. H.; Burton, P. S. Pharm. Res. 1992, 9,
435. (c) Karls, M. S.; Rush B. D.; Wilkinson, K. F.; Vidmar, T. J.; Burton,
P, S.; Ruwart, M. J. Pharm. Res. 1991, 8, 1477. (d) Augustijns, P. F.; Brown,
S. C.; Willard, D. H.; Consler, T. G.; Annaert, P. P.; Hendren, R. W.;
Bradshaw, T. P. Biochemistry 2000, 39, 7621-7630.
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1, 208.
10.1021/ol015572i CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/09/2001

and NEP,5 and, relevant to this communication, matrix
metalloproteinases (MMP).6 One of the best examples of an
important orally bioavailable macrocyclic peptide is cy-
closporine, which is a major drug in use for organ trans-
plantation and immune suppression.7
A biologically active macrocyclic template that has been
observed repeatedly in nature is the diaryl ether linker.
Important examples in this class include the vancomycin
family of antibiotics,8 the chloropeptins,9 and protease
inhibitors K-13 and OF4949I-IV.10 The medicinal signifi-
cance of these molecules has resulted in intensive efforts
toward their synthesis, and a number of interesting ap-
proaches to these complex natural products have been
published.11
In drug design, the use of a diarly ether macrocyle has
recently proven effective in the preparation of HIV protease
inhibitors.3 In addition our group has previously shown that
succinyl peptide inhibitors of MMPs can be cyclized to
produce biologically active cyclophanes as exemplified by
SE205,6a a highly water soluble MMP inhibitor that is
bioavailable in rats and dogs (Figure 1). MMPs are a class
ether linked macrocycle and report herein the application of
the Cu(II)-assisted intramolecular O-arylation of a phenol
with an aryl boronic acid as the key reaction. This mild
procedure complements the intermolecular version of this
reaction recently reported by Chan, Evans, and Lam.13
The rational design of cyclic MMP inhibitors has been
facilitated through the examination of X-ray crystal structures
of enzyme inhibitor complexes. The key inhibitor binding
interactions with the enzyme involves a bidentate ligation
of the hydroxamic acid to the active-site zinc and a series
of four hydrogen bonds formed between the two amides of
the inhibitor and subsite residues of the enzyme. The
macrocyclic linker does not interact directly with the enzyme
and is projected toward solvent.6 This observation allows
one to manipulate the physical properties of the molecule
through changing the linker without having a deleterious
effect on binding, provided the above key binding interac-
tions are maintained. Computer modeling of our proposed
diaryl ether macrocyclic targets suggested that the com-
pounds could adopt an appropriate conformation suitable for
binding to the enzymes in the MMP class.
A representative synthetic example is presented in Scheme
1. The desired anti-succinate 2 was prepared from the chiral
succinyl half ester 1.14 Treatment of 1 with 2.1 equiv of
lithium diisopropylamide (LDA), followed by monoalkyla-
tion of the dianion with 3-(4-benzyloxy)phenyliodopropane,
gave a 1:1 mixture of anti/syn products. Equilibration of this
mixture resulted in a 2:1 anti/syn mixture and could be
subsequently improved to about 3:1 with successive depro-
tonation and acid quenching steps as described in the
procedure of Becket et al.14 We investigated the use of
counterions other than Li in this equilibration process. It was
found that deprotonation with LDA at -78 °C, warming to
0 °C and cooling to -78 °C, followed by the addition of 2
equiv of diethyl-aluminum chloride at -78 °C, subsequent
warming to 0 °C and cooling to -78 °C, and rapid quenching
with acidic methanol resulted in a 10:1 separable mixture
of anti/syn products. The generality of this result is currently
under investigation and will be fully disclosed in a future
publication.
Figure 1. Structure of SE205.
of matrix degrading enzymes that have been implicated in
cancer and arthritis.12 In the further exploration of macro-
cyclic MMP inhibitors, we set out to examine the biphenyl
(5) (a) Ksander, G. M.; de Jesus, R.; Yuan, A.; Ghai, R. D.; McMartin,
C.; Bohacek, R. J. Med. Chem. 1997, 36, 506. (b) MacPherson, L. J.;
Bayburt, E. K.; Capparelli, M. P.; Bohacek, R. S.; Clarke, F. H.; Ghai, R.
D.; Sakane, U.; Berry, C. J.; Peppard, J. V.; Trapani, A. J. J. Med. Chem.
1993, 36, 3821. (c) Stanton, J. L.; Sperbeck, D. M.; Trapani, A. J.; Cote,
D.; Sakane, Y.; Berry, C. J.; Ghai, R. D. J. Med. Chem. 1993, 36, 3829.
(6) (a) Xue, C.-B.; He, X.; Roderick, J.; DeGrado, W. F.; Cherney, R.
J.; Hardman, K. D.; Nelson, D. J.; Copeland, R. A.; Jafee, B. D.; Decicco,
C. P. J. Med. Chem. 1998, 41, 1745. (b) Cherney, R. J.; Wang, L.; Meyer,
D.; 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. (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.
(7) (a) In Cyclosporine; Prog. Allergy; Borel, J. F.; Ed.; Karer: Basel,
1986; p 38. (b) Borel, J. F. In Cyclosporine; White, D. J. G., Ed.; Elsevier
Biomedical: Amsterdam, 1982; p 5. (c) Kahan, B. D.; Borel, J. F.
Transplant. Proc. 1983, 15, Suppl. 1. (d) Stiller, C. R.; Keown, P. A. In
Progress in Transplantation; Morris, P. J., Tilney, N. L., Eds.; 1984; pp 1,
11.
Purified anti product 2 was then coupled to a functional-
ized and appropriately protected phenethylamine derivative
to obtain the succinyl peptides 3a-c in good yield. Aryl
boronic esters 4 were prepared using the Pd(0)-catalyzed
(10) (a) Kase, H.; Kaneko, M.; Yamada, K. J. Antibiot. 1987, 40, 450.
(b) Yasuzawa, T.; Shirahata, K.; Sano, H. J. Antibiot. 1987, 40, 455. (c)
Sano, S.; Ikai, K.; Kuroda, H.; Nakamura, T.; Obayashi, A.; Ezure, Y.;
Enomotom H. J. Antibiot. 1986, 39, 1674. (d) Sano, S.; Ueno, M.; Katayama,
K.; Nakamura, T.; Obayashi, A. J. Antibiot. 1986, 39, 1697. (e) Sano, S.;
Kuroda, H.; Ueno, M.; Yoshikawa, Y.; Nakamura, T.; Obayashi, A. J.
Antibiot. 1987, 40, 519.
(11) Nicalaou, K. C.; Brase, S.; Winssinger, N. Angew. Chem., Int. Ed.
1999, 38, 2097.
(12) ) (a) Cawston, T. E. Pharm. Ther. 1996, 70, 163. (b) Johnson, L.
L.; Dyer, R.; Hupe, D. J. Curr. Opin. Chem. Biol. 1998, 2, 466, (c) Massova,
I.; Kotra, L. P.; Fridman, R.; Mobashery, S. FASEB J. 1998, 12, 1075.
(13) ) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters M. P.
Tetrahedron Lett. 1998, 39, 2933. (b) Evans, D. A.; Katz, J. L.; West T. R.
Tetrahedron Lett. 1998, 39, 2937. (c) Lam, P. Y. S.; Clark, C. G.; Saubern,
S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 39, 2941.
(8) (a) Evans, D. A.; DeVries, K. M. In Glycopeptide Antibiotics;
Nagarajan, R., Ed.; Marcel Dekker: New York, 1994; pp 63-104. (b) Rama
Rao, A.; Garjar, M.; Reddy, K.; Rao, A. Chem ReV. 1995, 95, 2135.
(9) (a) Mtsuzaki, K.; Ikeda, H.; Ogino, T.; Matsumoto, A.; Woodruff,
H. B.; Tanaka, H.; Omura, S. J. Antibiot. 1994, 47, 1173. (b) Matsuzaki,
K.; Ogino, T.; Sunazuka, T.; Tanaka, H.; Omura, S. J. Antibiot. 1997, 50,
66. (c) Kaneko, I.; Kamoshida, K.; Takahashi, S. J. Antibiot. 1989, 42,
236.
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1993, 137.
1030
Org. Lett., Vol. 3, No. 7, 2001

Scheme 1a
Table 1. Cu(OAc)2-Assisted Macrocyclization of Phenyl
Boronic Acid and Phenol
entry
R
product
yield (%)
1
2
3
CO2Me
CONHMe
H
6a
6d
6c
54
52
43
is general for para-substituted phenols. The cyclization
conditions are sufficiently mild to tolerate common chemical
functionalities such as amides and esters. Intramolecular
cross-coupling of the 4-hydroxy-3-boronic acid 5b produced
only a trace amount of product under these conditions;
however, the methyl ether derivative 5e did couple effectively
to give desired product 6e (Table 2).
Table 2. Cu(OAc)2-Assisted Macrocyclization
a Reagents and conditions: (a) 2.1 equiv LDA, 3-(4-benzyloxy)-
phenyliodopropane; (b) (i) LDA; (ii) 2.2 equiv Et2AlCl; (iii) MeOH;
(c) phenylethylamine, TBTU, NMM; (d) pinacol diboron, KOAc,
PdCl2(pddf), DMSO; (e) H2/Pd-C; (f) HCl (aq), PhB(OH)2.
entry
R′
product
% yield
4
5
OH
OMe
6b
6e
<5
52
cross-coupling reaction of pinacol diboron to the aryl halide
(bromide or iodide).15 We next removed the benzyl protecting
group under catalytic hydrogenation conditions. Initial at-
tempts to effect the intramolecular coupling of the phenol
to the pinacol boronate by treatment of 4 with cupric acetate
and Et3N in methylene chloride led to only a trace amount
of desired cyclized product. Removal of the pinacol group
through trans-boro-esterification with phenyl boronic acid
and 2 N HCl provided the free boronic acid phenol 5 in high
yield. The intramolecular arylation proceeded effectively with
these substrates using stoichiometric copper(II), under dilute
concentrations, to provide useful yields of the diaryl ether
macrocycles 6.
Subsequent modification of the cyclized products to the
corresponding hydroxamic acids provided the molecules of
interest for in vitro analysis16 against a panel of MMPs (Table
3). With the exception of compound 7a, the targets were
found to have broad activity against the gelatinases (MMP-2
and 9) and collagenase-1 (MMP-1). Compound 7c, which
lacks the P3′ amide, was suprisingly the most active
compound in this class. This result suggests that the diaryl
ether macrocyles may bind differently to the enzyme than
the previously prepared cyclophanes.6a
The inhibition of matrix metalloproteinases are the subject
of intensive investigation as a clinical approach to human
pathological conditions involving the breakdown of tissue
Tables 1 and 2 summarize the results obtained with this
key reaction for a set of analogues of interest within our
drug discovey program. Entries 1-3 show that the reaction
(15) ) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508.
(16) ) Copeland, R. A.; Lombardo, D.; Giannaras, J.; Decicco, C. P.
Bioorg. Med. Chem. Lett. 1995, 5, 1947.
Org. Lett., Vol. 3, No. 7, 2001
1031

In summary, we have developed an intramolecular version
of the Cu(II)-assisted boronic acid O-arylation reaction and
applied it to the synthesis of medicinally important com-
pounds. The reaction was found to proceed under sufficiently
mild conditions to accommodate chemical functionality
commonly employed in the synthesis of peptidomimetics.
Table 3. MMP Activities of Macrocyclic Biphenyl Ethers
Acknowledgment. The authors would like to acknowl-
edge Dr. Richard Liu for determining the MMP Ki values
and Dr. Patrick Lam for helpful discussions.
Ki, nM
product
R
MMP-1
MMP-2
MMP-9
7a
7d
7c
7f
CO2Me
CONHMe
H
>4949
4338
748
>3333
1938
91
>2128
1428
207
Supporting Information Available: Experimental pro-
cedures with spectroscopic data for compounds 3a-c, 4a,
4d, 4b, 4e, 5a, 5d, 5e, 6a, 6b, 6d, 6e, 7a, 7b, 7d, and 7f.
This material is available free of charge via the Internet at
http://pubs.acs.org.
CONHMe
2547
1418
293
extracellular matrix. The in vitro results described here
indicate that the diaryl ether macrocycles represent a new
active chemical scaffold against MMPs.
OL015572I
1032
Org. Lett., Vol. 3, No. 7, 2001