An efficient method for synthesis of succinate-based MMP inhibitors

Article abstract of DOI:10.1021/ol026331t

(matrix presented) A differentially protected fumarate undergoes radical addition followed by allylstannane trapping to provide disubstituted succinates in good yields and high anti diastereoselectivity. The conversion of the succinate to a known MMP inhi

Full text of DOI:10.1021/ol026331t

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3347-3349
An Efficient Method for Synthesis of
Succinate-Based MMP Inhibitors
Mukund P. Sibi* and Hikaru Hasegawa
Department of Chemistry and Center for Protease Research, North Dakota State
UniVersity, Fargo, North Dakota 58105
mukund.sibi@ndsu.nodak.edu
Received June 8, 2002
ABSTRACT
A differentially protected fumarate undergoes radical addition followed by allylstannane trapping to provide disubstituted succinates in good
yields and high anti diastereoselectivity. The conversion of the succinate to a known MMP inhibitor has been accomplished.
Matrix metalloproteinases, a family of zinc-containing pro-
teases, play a key role in tissue degradation and have been
implicated in diseases such as arthritis and cancer.1 In the
past several years, succinates with substituents on the carbon
backbone have received attention because of their potential
use in the development of potent matrix metalloproteinase
(MMP) inhibitors.2 In this regard, a differentially protected
succinate is an extremely useful synthon for ready function-
alization of the carbon backbone. We have recently shown
that the intermediate radical formed from conjugate radical
addition to simple enoates can be efficiently trapped with
allyl stannane.3 These reactions proceed with high diastereo-
and enantioselectivity. In an effort to expand the utility of
this chemistry to the synthesis of MMP inhibitors, we have
undertaken the regio- and stereocontrolled radical additions
to differentially protected fumarate 1 and trapped the
intermediate radical with a variety of allylstannanes to
provide products 3 or 4 (Scheme 1). Furthermore, the
application of the radical methodology to the synthesis of
BB-1101, a compound of some promise in the MMP inhibitor
arena, is illustrated.4
Our experiments began with finding optimal reaction
conditions for the addition/trapping process using fumarate
1 (eq 1) as the substrate. We5e and others5 have previously
shown that the regioselectivity in radical addition to desym-
metrized fumarates can be controlled either by Lewis acids
or other factors. Initial experiments were designed to evaluate
different Lewis acids for the addition of i-BuI to 16 followed
by trapping with allylstannane using triethylborane/oxygen
as a radical initiator (Table 1). Reaction even in the absence
of a Lewis acid was possible, suggesting that the fumarate
is a highly reactive substrate (entry 1). Magnesium Lewis
acids were only marginally effective, and the chemical
efficiency was dependent on the counterion, with magnesium
perchlorate performing the best (compare entry 2 and 4 with
Scheme 1
(1) (a) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000,
43, 305. (b) Michaelides, M. R.; Curtin, M. L. Curr. Pharm. Des. 1999, 5,
787. (c) Foda, H. D.; Zucker, S. Drug DiscoVery Today 2001, 6, 478.
(2) For a recent review article, see: Whittaker, M.; Floyd, C. D.; Brown,
P.; Geraing, A. J. H. Chem. ReV. 1999, 99, 2735 and references therein.
(3) Sibi, M. P.; Chen, J. J. Am. Chem. Soc. 2001, 123, 9472.
(4) Crimmin, M. J.; Beckett, P. R.; Davis, M. H. British Bio-Technology
Ltd.; WO 94 21,625; Chem. Abstr. 1995, 122, 188173y.
10.1021/ol026331t CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002

Table 1. Effect of Lewis Acid on Radical Addition/Trapping
Table 2. Addition/Trapping Experiments with Different
Radicals
Y(OTf)3
yield
Sm(OTf)3
entry
Lewis acid
time (h)
yield (%)b
drc
yield
(%)a
1
2
3
4
5
6
7
8
4
6
4
2
4
4
4
2
2
4
44
26
70
58
41
43
56
91
85
67
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
entry
product
7 R ) Et
8 R ) (CH2)3CHdCH2
9 R ) (CH2)3Ph
6 R ) i-Bu
10 R ) i-Pr
11 R ) t-Bu
12 R ) adamantyl
(%)a
drb
drb
MgI2
Mg(ClO4)2
Mg(OTf)2
Al(OTf)3
In(OTf)3
Sc(OTf)3
Y(OTf)3
Sm(OTf)3
Yb(OTf)3
1
2
3
4
5
6
7
85
66
72
91
80
62
15
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
87
63
74
85
82
64
22
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
g99:1
9
10
a Isolated yield. b Diastereomer ratio determined by 1H NMR (500 MHz).
a For reaction conditions, see Supporting Information. b Isolated yield.
c Diastereomer ratio determined by H NMR (500 MHz).
1
diastereoselectivity (entries 1-4).11 Of the two Lewis acids
examined, yttrium triflate gave slightly better results. Ad-
dition of a secondary radical was also very effective,
providing 10 (entry 5). Even the bulky tertiary radical derived
from t-BuI gave the addition/trapping product 11 with good
chemical yield as a single diastereomer (entry 6). However,
addition of adamantyl radical was not efficient (entry 7). A
large amount of 7 (33%), the ethyl addition byproduct, was
obtained in this reaction. These results show that a variety
of disubstituted succinates can be prepared in moderate to
high chemical yield with very high anti diastereoselectivity.
Three different allyl stannanes were investigated as trap-
ping agents in the tandem reaction (eq 3). The addition of
isobutyl radical to 1 using yttrium triflate as the Lewis acid
was used to evaluate the trapping reagents (Table 3). The
reaction with parent allyl stannane is shown in entry 1 for
comparison. Trapping experiments with the more reactive
methallylstannane 13 was also very efficient, and the product
(15) was produced as a single isomer (entry 2).12 In contrast,
reaction with 2-acetoxymethylallylstannae (14) gave only a
modest yield of the product (16) but as a single isomer (entry
3). Thus different allyl stannanes can be employed as
trapping reagents to produce functionalized succinates.
A variety of methodologies have been developed to
prepare disubstituted succinates to access MMP inhibitors.13
Generally, the establishment of the required anti stereochem-
istry for the substituents in these approaches has been
problematic. To demonstrate the utility of our stereoselective
methodology we undertook the synthesis of BB-1101, a
representative succinate-based MMP inhibitor (Scheme 2).4
Selective cleavage of the tert-butyl ester in 6 using TFA gave
the mono functionalized succinate 17 in high yield. The
3).7 Aluminum and indium Lewis acids were less effective
(entries 5 and 6). In contrast, prelanthanide and lanthanide
triflates gave better yields (entries 7-10). Of these, yttrium
and samarium triflates showed the best reaction character-
istics (entry 8 and 9).8 The selectivity in all of these reactions
was very high. The stereochemistry of the major diastereomer
was established as anti9 by converting 6 to a known
compound.10 The high anti selectivity is noteworthy since
this stereochemistry is required for the preparation of MMP
inhibitors with high bioactivity (vide infra).
Having established the feasibility of the addition/trapping
reactions, we then examined the efficacy of different
nucleophilic radicals using both yttrium and samarium
triflates as the Lewis acid (eq 2). Results from these studies
are tabulated in Table 2. Addition of a variety of primary
radicals proceeded in moderate to good yields but with high
(5) For work on radical addition to fumarates using imides derived from
Kemps triacid, see: (a) Stack, J. G.; Curran, D. P.; Geib, S. V.; Rebek, J.,
Jr.; Ballester, P. J. Am. Chem. Soc. 1992, 114, 7007. For examination of
selectivity in radical addition to fumarates and related systems, see: (b)
Porter, N. A.; Bruhnke, J. D.; Wu, W.-X.; Rosenstein, I. J.; Breyer, R. A.;
McPhail, A. T. J. Am. Chem. Soc. 1992, 114, 7664. (c) Giese, B.; Zehnder,
M.; Roth, M.; Zeitz, H.-G. J. Am. Chem. Soc. 1990, 112, 6741. (d) Porter,
N. A.; Scott, D. M.; Lacher, B.; Giese, B.; Zeitz, H. G.; Lindner, H. J. J.
Am. Chem. Soc. 1989, 111, 8311. (e) Sibi, M. P.; Liu, P.; Ji, J.; Chen. J. J.
Org. Chem. 2002, 67, 1738.
(6) See Supporting Information for the synthesis of 1.
(7) For an excellent recent review, see: Renaud, P.; Gerster, M. Angew.
Chem., Int. Ed. 1998, 37, 2562. Also see: Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vols. 1 and
2. (c) Sibi, M. P.; Ji, J.; Sausker J. B.; Jasperse, C. P. J. Am. Chem. Soc.
1999, 121, 7517. (d) Sibi, M. P.; Ji, J.; Wu, J. H.; Gu¨rtler, S.; Porter, N. A.
J. Am. Chem. Soc. 1996, 118, 9200.
(8) Varying amounts (1-20%) of the ethyl radical addition/trapping
product was also observed depending on the Lewis acid.
(9) For a discussion on the origins of the high anti selectivity observed
in the addition/trapping experiments, see ref 3.
(10) The oxazolidinone functionality in compound 6 was selectively
hydrolyzed to a known acid. Pratt, L. M.; Bowles, S. A.; Courtney, S. F.;
Hidden, C.; Lewis, C. N.; Martin, F. M.; Todd, R. S. Synlett 1998, 531.
See Supporting Information for details.
(11) The amount of ethyl addition byproduct in entries 2-6, Table 2,
varied from 1% to 10%. This is an indirect reflection of radical chain length.
(12) The anti stereochemistry for the product was assigned on the basis
of analogy.
3348
Org. Lett., Vol. 4, No. 20, 2002

Scheme 2a
Table 3. Addition/Trapping Experiments with Different
Allylstannanes
entry allyl stannane
product
6 R ) H
15 R ) CH3
16 R ) CH2OAc
yield (%)a
drb
1
2
3
5
13
14
91
77
28
g99:1
g99:1
g99:1
a Isolated yield. b Diastereomer ratio determined by 1H NMR (500 MHz).
racemic acid 17 was coupled with enantiomerically pure
phenylalanine-N-methylamide using EDCI as a coupling
agent to produce a diastereomeric mixture of amides 18 and
19 in 63% yield. The diastereomers were cleanly separated
using column chromatography. We have recently developed
a very convenient methodology for the conversion of
oxazolidinones to hydroxamic acids.14 A variety of nucleo-
philes were evaluated for the conversion of 18 to BB-1101
using the previously established conditions with little success
(Sm(OTf)3/amine/rt or heat).15 Reaction with THP-protected
hydroxylamine proved to be very efficient. Thus, treatment
of 18 with THPONH2 and Sm(OTf)3 gave the protected
hydroxamic acid product, which was treated with acid
a Key: (a) TFA, CH2Cl2, 98%. (b) EDCI/HOBT/amino acid/
DMF 63% yield (36% of 18 and 27% of 19). (c) (i) THPONH2/
Sm(OTf)3/THF, (ii) dilute HCl workup, 75% over two steps.
without purification to produce BB-1101 (20) in excellent
yield in four steps starting from 1. Thus the methodology
developed in this work is a convenient way to prepare
biologically active targets efficiently.
In conclusion, we have developed an efficient protocol
for the preparation of a variety of disubstituted succinates
with excellent control of relative stereochemistry. The
application of the methodology in an efficient synthesis of
a MMP inhibitor was also accomplished. Experiments are
underway to carry out the addition/trapping sequence enan-
tioselectively.
(13) For some selected examples of the synthesis of succinate-based
MMP inhibitors, see: (a) Hilpert, H. Tetrahedron 2001, 57, 7675. (b)
Yamamoto, M.; Tsujishita, H.; Hori, N.; Ohishi, Y.; Inoue, S.; Ikeda, S.;
Okada, Y. J. Med. Chem. 1998, 41, 1209. (c) 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. (d) Fray, M. J.; Burslem, M. F.; Dickinson, R. P. Bioorg. Med.
Chem. Lett. 2001, 11, 567. (e) Fray, M. J.; Dickinson, R. P. Bioorg. Med.
Chem. Lett. 2001, 11, 571. (f) McClure, K. F.; Axt, M. Z. Bioorg. Med.
Chem. Lett. 1998, 8, 143. (g) 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. (h) Pratt, L. M.;
Beckett, P.; Bellamy, C. L.; Corkill, D. J.; Cosins, J.; Courtney, P. F.; Davies,
S. J.; Davidson, A. H.; Drummond, A. H.; Helfrich, K.; Lewis, C. N.
Mangan, M.; Martin, F. M.; Miller, K.; Nayee, P.; Ricketts, M. L.; Thomas,
W.; Todd, R. S.; Whittaker, M. Bioorg. Med. Chem. Lett. 1998, 8, 1359.
(14) Sibi, M. P.; Hasegawa, H.; Ghorpade, S. Org. Lett. 2002, 4, 3343.
(15) Reaction with BnONH2 was effective (68%). However, the benzyl
group could not be cleaved selectively without affecting the alkene. Reaction
with NH2OH, TMSONH2, or TMSONHTMS gave low yields of BB-1101.
Acknowledgment. This work was supported by a grant
from the National Institutes of Health-National Center for
Research Resources 1 P20 RR15566-01. We thank Drs.
Sandeep Ghorpade and Mona Aasmul for experimental
assistance.
Supporting Information Available: Characterization
data for compounds 1-20 and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026331T
Org. Lett., Vol. 4, No. 20, 2002
3349