An enantioselective synthesis of sulphonamide hydroxamic acids as matrix metalloproteinase inhibitors

Article abstract of DOI:10.1016/S0040-4039(01)02151-7

A high yielding and enantioselective synthesis of α-substituted hydroxamic acids as inhibitors of matrix metalloproteinases is described.

Full text of DOI:10.1016/S0040-4039(01)02151-7

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.
PII: S0040-4039(01)02151-7

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R. J. Watson et al. / Tetrahedron Letters 43 (2002) 683–685
Scheme 1. Reagents and conditions: (a) HBr, AcOH, 90%; (b) isobutylene, H2SO4, 85%; (c) KSAc, DMF, 90%; (d) Cl2, water,
DCM, 90%; (e) 4-ClC6H4O(CH2)2N(Me)H, Et3N, DCM, 95%; (f) TFA, DCM, 90%; (g) (i) H2NOTBS, EDC, DCM, (ii) HCl,
ether, DCM, 85%; (h) (COCl)2, cat. DMF, DCM, then H2NOH, aq. THF, 90%.
Scheme 2. Reagents and conditions: (a) TiCl4, trioxane, Hunig’s base, DCM, 0°C, 95%; (b) I2, PPh3, imidazole, toluene, reflux 1
h, 95%; (c) KSAc, DMF, rt, 3 h, 96%; (d) Cl2, DCM, water, 0°C, 90%; (e) 4-ClC6H4O(CH2)2N(Me)H, Et3N, DCM, 90%; (f)
LiOH, H2O2, THF or EtOH, water, 85%; (g) H2NOTBS, EDC, DCM, then HCl, ether 80%; (h) (COCl2), cat. DMF, DCM, then
aq. H2NOH, THF, water, 95%.
yield with no evidence of the other diastereomer. Sev-
eral approaches to the preparation of the thioacetate 12
were investigated. Conversion of 11 to its methane-
sulphonate was efficient and gave crystalline material,
however, reaction with potassium thioacetate in DMF
proceeded slowly and gave by-products arising from
attack of the nucleophile on the oxazolidinone ring.
The analogous triflate reacted rapidly to give 12 along
with several unidentified by-products. We were pleased
to find that reaction of 11 with triphenylphosphine and
iodine, while slow at room temperature, was rapid,
clean and gave no racemisation in boiling toluene.
Iodide 13 was easily obtained in sufficiently pure form
by silica plug filtration, removing triphenylphosphine
oxide and reacted smoothly to give the thioacetate 12 in
excellent yield and optical purity.
Reaction of 12 with chlorine in a mixture of DCM and
water at 0°C gave the sulphonyl chloride 14 in quanti-
ties up to 30 g as a viscous oil. This was then coupled
with the required amine and cleaved under standard
conditions to give the acid 15. As we were concerned
about racemisation in the conversion to the hydroxamic
acid 16, we initially employed EDC mediated coupling
at low temperature with silyl protected hydroxylamine,
followed by mild acidic cleavage of the silyl group. This

R. J. Watson et al. / Tetrahedron Letters 43 (2002) 683–685
685
procedure gave 16 in 80% yield and >99.8% enan-
tiomeric excess. Alternative conversion of 15 to the acid
chloride followed by quenching with aqueous hydroxyl-
amine gave a significantly improved yield of 16 with the
e.e. still excellent at 99.5%.
4. Heath, E. I.; Grochow, L. B. Drugs 2000, 59, 1043–
1055.
5. Montana, J. G.; Baxter, A. D. Curr. Opin. Drug Discov.
Res. 2000, 3, 353–361.
6. Baxter, A. D.; Bird, J.; Bannister, R.; Bhogal, R.; Manal-
lack, D. T.; Watson, R. J.; Owen, D. A.; Montana, J. G.;
Henshilwood, J.; Jackson, R. C. In Cancer Drug Discovery
and Development: Matrix Metalloproteinase Inhibitors in
Cancer Therapy; Clandennin, N. J.; Appelt, K., Eds.;
Humana Press: Totowa, NJ, USA, 2000; Vol. 8, pp.
193–221.
In conclusion, we have developed a high yielding route
to matrix metalloproteinase inhibitors with excellent
optical purity. Further development of our series of
chiral sulphonamide hydroxamic acids will be reported
separately.
7. Baxter, A. D.; Bhogal, R.; Bird, J.; Keily, J. F.; Hannah,
D. R.; Manallack, D. T.; Montana, J. G.; Nicholson, E. J.;
Owen, D. A.; Pitt, W. R.; Watson, R. J.; Wills, R. E.
Bioorg. Med. Chem. Lett. 2001, in press.
8. Rosenberg, S. H.; Spina, K. P.; Condon, S. L.;
Polakoswski, J.; Yao, Z. J. Med. Chem. 1993, 36, 460.
9. Saksena, A. K.; Girijavallabhan, V. M.; Wang, H.; Liu,
Y.-T.; Pike, R. E.; Ganguly, A. K. Tetrahedron Lett. 1996,
37, 5657.
References
1. McCawley, L. J.; Matrisian, L. M. Mol. Med. Today 2000,
6, 149–156.
2. Elliott, S.; Cawston, T. Drugs Aging 2001, 18, 87–99.
3. Vaalamo, M.; Karjalainen-Lindsberg, M. L.; Puolak-
kainen, P.; Kere, J.; Saarialho-Kere, U. Am. J. Pathol.
1998, 152, 1005–1014.