July 1998
SYNLETT
761
Solid Phase Synthesis of Hydroxamic Acids
Sharon M. Dankwardt
Roche Bioscience, Inflammatory Disease Unit, Parallel Synthesis Group, 3401 Hillview Ave, Palo Alto, California 94304
Received 11 December 1997
Abstract: The solid phase synthesis of hydroxamic acids is presented.
Carboxylic acid ester linked, polymer-supported CBZ-protected amino
acids were displaced from the resin with aqueous hydroxylamine to
provide the corresponding hydroxamic acids.
Hydroxamic acids have become an increasingly important structural
class of compounds. They serve as efficient zinc ligands and are
1
especially useful as inhibitors of matrix metalloproteinases. This paper
presents a useful way of preparing hydroxamic acids using solid phase
techniques which allows for the rapid preparation of a large number of
pure compounds for screening. Recently, there have been several
published routes for the preparation of hydroxamic acids on solid
2
phase. These generally involve the preparation of a special linker to
which hydroxylamine is attached to the resin or formation of a protected
hydroxamic acid on solid support. Our approach obviates the need for
special linkers or protecting groups, by displacing the desired
hydroxamic acid from the resin directly using hydroxylamine, as
3
illustrated below.
The preparation of the substrates is straightforward. Commercially
available Cbz-protected amino acids are coupled to ArgoGel-OH using
3 equivalents of 1,3-diisopropylcarbodiimide (DIC) with a catalytic
amount of 4-dimethylaminopyridine (DMAP) in CH Cl . The amino
2
2
acid derivatives were then treated with 25 eq. of 50% aq. NH OH in
2
THF for 2 days. The resin is filtered away and washed with CH Cl and
2
2
Acknowledgments. We would like to thank Johnson Jiang and Ken
Straub from Roche Bioscience for analytical support.
MeOH and the desired hydroxamic acid is obtained after evaporation of
the volatiles under vacuum. Table 1 illustrates the range of substituents
in the alpha position that are amenable to this novel method of preparing
hydroxamic acids.
REFERENCES AND NOTES
(1) Davidson, A. H.; Drummond, A. H.; Galloway, W. A.; Whittaker,
M. Chem. Ind. (London) 1997, 7, 258-261. MacPherson, L. J.;
Parker, D. T. Eur. Pat. Appl., EP 606046 A1 940713, 1993.
(2) Recent papers on solid phase synthesis of hydroxamic acids:
(a) Floyd, C. D.; Lewis, C. N. PCT Int. Appl. WO 9626223 A1
960829, 1996. (b) Floyd, C. D.; Lewis, C. N.; Patel, S. R.;
Whittaker, M. Tetrahedron Lett. 1996, 37, 8045-8048. (c) Chen, J.
J.; Spatola, A. F. Tetrahedron Lett. 1997, 38, 1511-1514.
(d) Richter, L. S.; Desai, M. C. Tetrahedron Lett. 1997, 38, 321-
322. (e) Floyd, C. D.; Whittaker, M. PCT Int.Appl., WO 9626918
A1 960906, 1996. (f) Ngu, K.; Patel, D. V. J. Org. Chem. 1997, 62,
7088-7089. (g) Mellor, S. L.; McGuire, C.; Chan, W. C.
Tetrahedron Lett. 1997, 38, 3311-3314.
Limitations of this method are seen with the more sterically hindered
amino acids (entries #9, 10, 16, 19 and 20) which give low overall
yields. Some yields may be low due to incomplete coupling of amino
acid to the resin. All yields are based on the given loading of the
ArgoGel-OH. Most amino acids gave >70% pure products with the
(3) Floyd et al. in ref 2b, indicate they have attempted this
transformation with irreproducible yields, but this is not observed
under our conditions. We have however encountered difficulties
(low yields, carboxylic acid byproducts) with polystyrene resins
5
exception of valine, lysine and Glu(OBn). Glutamine, asparagine and
and with different sources of hydroxylamine (i.e. NH OH•HCl) or
2
unprotected threonine do not give the desired hydroxamic acid as
evidenced by mass spectroscopy. The benzyl esters of protected aspartic
or glutamic acid give the dihydroxamic acid product.
other solvents on different substrates.
(4) Percent purity is determined by reversed phase HPLC at 235 nM.
All products show the desired parent ion by MS with the exception
noted in the text. Yields are isolated weight and are based on a
loading of 0.45 mmole/gr of ArgoGel-OH. NMR was obtained on
#1 in order to authenticate the method.
In conclusion, this method provides a viable route to the preparation of
hydroxamic acids on solid support with good yields and high purities.
The experimental ease and the large variety of amino acids that can be
successfully applied, illustrate the advantage of this technique for
preparing large number of hydroxamic acids.
(5) Note added in proof - The use of HL Tentagel gave >70% purity of
the sterically hindered amino acid, Val with comparable yields and
purities as ArgoGel with Ser, Tyr, Tyr(OBn) and Pro in a side by
side comparison.
Dankwardt, Sharon M.
