TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 683–685
An enantioselective synthesis of sulphonamide hydroxamic acids
as matrix metalloproteinase inhibitors
Robert J. Watson,* D. Batty, A. D. Baxter, D. R. Hannah, D. A. Owen and J. G. Montana
Celltech R & D Ltd, Granta Park, Abington, Cambridge CB1 6GS, UK
Received 12 September 2001; accepted 8 November 2001
Abstract—A high yielding and enantioselective synthesis of a-substituted hydroxamic acids as inhibitors of matrix metallo-
proteinases is described. © 2002 Published by Elsevier Science Ltd.
Excess proteolytic activity of matrix metalloproteinase
enzymes (MMPs) has been implicated in a wide range
of disease states including cancer,1 arthritis2 and inflam-
matory bowel disease.3 In spite of the intense efforts
within the pharmaceutical industry over the past
decade, clinical development of MMP inhibitors has so
far been disappointing, with problems of poor efficacy
Compound 4 was prepared as shown in Scheme 1. The
acrylate 5 was converted via the bromo ester 6 to the
thioacetate 7 in excellent overall yield and this was
efficiently converted into the key sulphonyl chloride 8
which was readily obtained in multigram quantities.
Coupling with the commercially available amine and
cleavage of the tert-butyl ester gave the acid 9. Conver-
sion to the desired hydroxamic acid 4 was achieved
either by EDC mediated coupling with TBS-protected
hydroxylamine, followed by deprotection with HCl in
ether, or by formation of the acid chloride and reaction
with aqueous hydroxylamine. Both methods gave excel-
lent yields of the desired product.
and unacceptable side effects.4 Compounds such as
Marimastat 1 have been shown to cause dose limiting
joint pain in patients even at low doses, limiting the
achievable efficacy of the drug.5 However, the thiol
BMS275291 2 shows no such effects in man, even at
high doses, indicating that MMP inhibitors with accept-
able side effect profiles are achievable.6
In order to progress compounds such as 4 we required
a scaleable route by which to prepare this and related
products in optically pure form. Optically active b-
sulphonamido acids have previously been prepared by
enzymic resolution of the analogous sulphonamido
esters8 but our objective was the preparation of an
optically enriched sulphonyl chloride with which to
prepare a range of sulphonamide products. Although
Evans oxazolidinone chemistry is often the method of
choice for the preparation of chiral a-substituted acids,
its application to b-sulphonamido acids has not previ-
ously been described. Our development of an efficient
route to such compounds is described in Scheme 2.
As part of our ongoing research, we recently disclosed
a series of arylsulphonyl hydroxamic acids such as 37
with good potency against the MMP enzymes and have
developed from this, compound 4, where the sulphone
group has been replaced by a sulphonamide.
The titanium enolate of 10 was quenched with trioxane9
to give the hydroxymethyl compound 11 in excellent
Keywords: MMP; hydroxamic acid; sulphonamide; oxazolidinone.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
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