7088
J . Org. Chem. 1997, 62, 7088-7089
Sch em e 1. Retr osyn th esis for SP S of Hyd r oxa m ic
Acid s
A New a n d Efficien t Solid P h a se Syn th esis
of Hyd r oxa m ic Acid s
Khehyong Ngu and Dinesh V. Patel*
Versicor Inc., 34790 Ardentech Court,
Fremont, California 94555
Received J uly 14, 1997
The hydroxamic acid functionality is a key structural
constituent of a wide spectrum of bioactive agents includ-
ing various antibacterial, antifungal, and anticancer
agents.1,2 Hydroxamates are very effective metal-ion
chelators and have led to the rational design and
discovery of novel and potent inhibitors of metalloen-
zymes such as thermolysin,3 angiotensin-converting en-
zyme (ACE),4 and the matrix metalloprotease (MMP)
family of enzymes.5 The growing importance of combi-
natorial chemistry as a modern drug discovery tool has
created a need for developing new solid phase synthesis
(SPS) methods for important classes of bioactive com-
pounds.6 Our interest in novel metalloenzyme inhibitors
prompted us to explore the possibility of combinatorial,
SPS of hydroxamic acids.
Since a hydroxamate moiety would be a common
feature of all library members, a convergent and versatile
strategy calls for immobilizing the hydroxylamine
[HONH2] group first, and then subjecting it to various
synthetic transformations to prepare diverse sets of
hydroxamate pharmacophore inhibitor libraries. Unlike
solution phase synthesis, it then becomes necessary to
have fully (both N- and O-) protected alkoxyamine 4 and
hydroxamate intermediates 2 on solid support, to avoid
undesired potential side reactions with synthetic reagents
or intermediates encountered during subsequent trans-
formations leading to the final products.7 On the basis
of these considerations, we decided to investigate the
synthesis and potential applications of O-protected, N-
immobilized hydroxamates 2, wherein the linker group,
besides being a cleavable site of attachment for the
molecule to a solid support, also serves as a nitrogen
protecting group for the hydroxamate functionality.
The two critical aspects of this approach are the
selection of a suitable O-protecting group and the N-
linker group. After examining several alkoxyamines, we
selected two complementary O-protecting groupssthe
acid stable allyl group and an acid labile tetrahydropyran
(THP) group. Initial experimentation with our recently
described bromo resin8 derived from commercially avail-
able alcohol resins resulted only in modest recovery of
desired hydroxamic acids.9 These results suggested the
need for a more acid labile linker to permit smooth
cleavage of the desired hydroxamate products. The
hypersensitive acid-labile (HAL) tris(alkoxy)benzyl ester
linker 5 was thus chosen for our study.10
Since early stage synthetic steps involving the attach-
ment of an alkoxyamine group on the linker do not
contribute to chemical diversity, these reactions were
conducted in solution to benefit from the convenience of
scale-up, purification, and analytical characterization of
intermediates (Scheme 2).11 Thus, reductive amination
of aldehyde 510 with NH2OCH2CH)CH2 6 (Aldrich) or
H2N-OTHP 712 gave the alkoxy-amine acids 8 (70%) and
9 (63%), respectively. The intermediate oximes are stable
and require prolonged treatment for effective reduction
(NaBH3CN, AcOH, 18 h).13 Compounds 8 and 9 are Fmoc
protected14 to give the fully protected alkoxyamines 10
(89%) and 11 (87%), respectively, suitable for immobiliza-
tion on a wide variety of amine resins. In our case, we
proceeded with acylation of Tentagel S NH2 resin (RAPP
Polymere) with acids 10 and 11 followed by Fmoc removal
to obtain resins 12 and 13, respectively.
N-Tethered, O-protected alkoxyamine resins 12 and 13
proved to be ideal starting materials for general SPS of
various types of hydroxamic acids. Thus, allyloxy resin
12 was acylated with 3-phenylpropionyl chloride and
treated with 50% TFA for 1 h followed by treatment with
Pd(PPh3)4/PPh3 in solution to furnish the desired hydrox-
amic acid 14 (84%). Cleavage of hydroxamate ether from
this linker was cleaner and faster in comparison to the
relatively less acid-labile linkers.9 Analogous synthesis
of 14 was also carried out with O-THP alkoxyamine resin
13 (Scheme 3). In this instance, the acylated intermedi-
ate was first treated with 2.5% aqueous TFA in CH2Cl2
for 1 h to remove the THP group, followed by treatment
with 50% aqueous TFA in CH2Cl2 for 1 h to cleave 14
from the resin (88%). The convenience of simultaneously
(1) (a) Miller, M. J . Acc. Chem. Res. 1986, 19, 49. (b) B. Stearn,
Losee, K. A.; Bernstein, J . J . Med. Chem. 1963, 6, 201. (c) Young, C.
W.; Schachetman, C. S.; Hodas, S.; Bolis, M. C. Cancer Res. 1967, 27,
535.
(2) Miller, M. J . Chem. Rev. 1989, 89, 1563.
(3) (a) Nishino, N.; Powers, J . C. Biochemistry 1978, 17, 2846. (b)
Nishino, N.; Powers, J . C. Biochemistry 1979, 18, 4340.
(4) Petrillo, E. W., J r.; Ondetti, M. A. Med. Res. Rev. 1982, 2, 1.
(5) (a) Gowravaram, M. R.; Tomczuk, B. E.; J ohnson, J . S.; Delecki,
D.; Cook, E. R.; Ghose, A. K.; Mathiowetz, A. M.; Spurlino, J . C.; Rubin,
B.; Smith, D. L.; Pulvino, T.; Wahl, R. C. J . Med. Chem. 1995, 38, 2570.
(b) Rockwell, A.; Melden, M.; Copeland, R. A.; Hardman, K.; Decicco,
C. P.; Degrado, W. F. J . Am. Chem. Soc. 1996, 118, 10337. (c)
Hagmann, W. K.; Lark, M. W.; Becker, J . W. Ann. Rep. Med. Chem.,
Ed. Bristol, J . A. Academic Press Inc. 1996, 31, 231.
(6) (a) Patel, D. V. Annual Reports in Combinatorial Chemistry and
Molecular Diversity; Moos, W. H., Pavia, M. R., Ellington, A. D., Kay,
B. K., Eds.; ESCOM: Leiden, 1997; Vol. 1, p 78. (b) Patel, D. V.;
Gordon, E. M. Drug Discovery Today, 1996, 1, 134. (c) Gordon, E. M.;
Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144. (d) Thompson,
L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555.
(8) Ngu, K.; Patel, D. V. Tetrahedron Lett. 1997, 38, 973.
(9) Attempted cleavage of the product from the Wang resin gave
the p-hydroxybenzyl-derived adduct derived from partial O-cleavage
of the linker group.
(7) We and others have recently independently published the SPS
of hydroxamic acids commencing from O-linked hydroxylamine resins
(Support-O-NH2). While this method works well for simple examples,
the acidic NH group (app pKa ) 10) of such hydroxamate intermediates
is vulnerable to side reactions such as alkylations and cyclizations
under basic and Mitsunobu type conditions, thus limiting the potential
for further synthetic manipulations typically required for synthesizing
nonpeptidic metalloenzyme inhibitors. For SPS of O-linked hydrox-
amic acids, see (a) Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker,
M. Tetrahedron Lett. 1996, 37, 8045. (b) Richter, L. S.; Desai, M. C.
Tetrahedron Lett. 1997, 38, 321. (c) Gordeev, M. F.; Hui, H. C.; Gordon,
E. M.; Patel, D. V. Tetrahedron Lett. 1997, 38, 1729. (d) Miller, S. L.;
McGuire, C.; Chan, W. C. Tetrahedron Lett. 1997, 38, 3311.
(10) Aldehyde 5 was purchased from Perseptive Biosystems Inc.,
MA. For synthesis and early applications of HAL linker, see Albericio,
F.; Kneib-Cordonier, N.; Biancalana, S.; Gera, L.; Maseda, I.; Hudson,
D.; Barany, G. J . Org. Chem. 1990, 55, 3730.
(11) Direct attachment of linker
5 to resin followed by oxime
formation with alkoxyamines 6 and 7 and reduction on solid support
to arrive at alkoxyamines 13 and 12, respectively, was attempted but
found to be less satisfactory compared to the current approach.
(12) Patel, D. V.; Young, M. G.; Robinson, S. P.; Hunihan, L.; Dean,
B. J .; Gordon, E. M. J . Med. Chem. 1996, 39, 4197.
(13) (a) Lane, C. F. Synthesis, 1975, 135. (b) Borch, R. F.; Bernstein,
M. D.; Durst, H. D. J . Am. Chem. Soc. 1971, 93, 2897.
(14) Carpino, L. A. Acc. Chem. Res. 1987, 20, 401.
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