N-linked hydroxylamine resin: Solid-phase synthesis of hydroxamic acids

Article abstract of DOI:10.1080/00397910500278115

A novel hydroxylamine resin for solid-phase synthesis of hydroxamic acids is described. Its facile application is illustrated by the solid-phase synthesis of various hydroxamic acids. Cleavage is induced under acidic conditions by treatment with trifluoroacetic acid, providing hydroxamic acids in high purity and good yields. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500278115

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Synthetic Communications: An
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N‐Linked Hydroxylamine
Resin: Solid‐Phase Synthesis of
Hydroxamic Acids
a
a
a
Zheng Yin , KaySiang Low & PekLing Lye
a
S*BIO Pte Ltd , Singapore
Published online: 21 Aug 2006.
To cite this article: Zheng Yin , KaySiang Low & PekLing Lye (2005) N‐Linked
Hydroxylamine Resin: Solid‐Phase Synthesis of Hydroxamic Acids, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:23, 2945-2950
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Synthetic Communications , 35: 2945–2950, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500278115
N-Linked Hydroxylamine Resin:
Solid-Phase Synthesis of Hydroxamic Acids
Zheng Yin, KaySiang Low, and PekLing Lye
S*BIO Pte Ltd., Singapore
Abstract: A novel hydroxylamine resin for solid-phase synthesis of hydroxamic
acids is described. Its facile application is illustrated by the solid-phase synthesis of
various hydroxamic acids. Cleavage is induced under acidic conditions by treatment
with trifluoroacetic acid, providing hydroxamic acids in high purity and good yields.
Keywords: Hydroxamic acids, hydroxylamine resin, solid-phase synthesis
Hydroxamic acids, as effective ion chelators, are key structural components in
[
1]
the design of a wide spectrum of bioactive agents, especially in the field of
zinc metalloenzyme inhibitors such as MMP (matrix metalloprotease) inhibi-
[2]
tors. Recently, solid-phase synthesis has emerged as an important tool for
[3]
the high-throughput synthesis of hydroxamic acids. A variety of methods
for the preparation of hydroxylamine resin via O-linkage have been
[4]
reported. However, the use of O-linked hydroxylamine resins for the
multistep synthesis of hydroxamic acids may result in undesired by-
products derived from side reactions of the NH group of the hydroxamate.
Therefore, we were interested in the development of N-linked hydroxylamine
resins in which the linker group serves not only as a cleavage site of attach-
ment for the molecule to a solid support but also as a nitrogen-protecting
group for the hydroxamate functionality. Here we present the preparation of
a novel N-linked hydroxylamine resin derived from Merrifield resin and its
application to the synthesis of various hydroxamic acids.
Received in Japan March 27, 2005
Address correspondence to Zheng Yin, Novartis Institute for Tropical Diseases,
1
0 Biopolis Road, #05-01 Chromos, Singapore 138670. Tel.: þ 65-6777 7281;
Fax: þ 65-6777 7218; E-mail: zheng.yin@novartis.com
2
945

2946
Z. Yin, K. Low, and P. Lye
The synthesis of hydroxylamine resin 4 is summarized in Scheme 1.
Merrifield resin was first converted to PS-MB-CHO resin 1 by loading with
an acid labile aldehyde linker. The acid labile O-2,4-dimethoxylbenzyl
[
DMB) protected hydroxylamine 3 was easily attached to resin 1 using
5]
(
amino functionality via simple reductive amination in the presence of
sodium cyanoborohydride to obtain N-linked hydroxylamine resin 4. DMB
was chosen as the protecting group for convenient simultaneous deprotection
and cleavage of final hydroxamic acids from the solid support. In addition, the
cation generated from DMB during deprotecion by TFA was reported to poly-
[5]
merize, which can be potentially removed by filtration to afford the hydro-
xamic acids with high purity.
The formation of resin 4 was confirmed by the product of acylation with
benzoyl chloride. Resin 4 was treated by benzoyl chloride in the presence of
diisopropylethylamine. Cleavage of the product from the resin was readily
achieved by 95% v/v TFA in dichloromethane for half an hour, providing
the desired phenyl hydroxamic acid 5 in high purity (95%) and quantitative
yield (Scheme 2).
To establish the utility of hydroxylamine resin 4, the synthesis of hydro-
xamic acids via coupling with carboxylic acids was performed. Hydroxyla-
mine resin 4 was coupled with carboxylic acids under standard
carbodiimide coupling condition, followed by acidolysis cleavage, which
provided the desired hydroxamic acids. Representative results are summarized
in Table 1. Both coupling and cleavage reactions proceeded well to afford the
hydroxamic acids in good to high purities.
In summary, we have developed a novel N-linked hydroxylamine resin for
the generation of hydroxamic acids on solid support. Its simple and efficient
production, effective acylation using standard solid-phase methodology, and
compound cleavage (accomplished by acidolysis) make it invaluable for the
solid-phase synthesis of hydroxamic acid based molecules by multiple and
combinatorial approaches. Efforts to synthesize heterocyclic hydroxamic
Scheme 1.

N-Linked Hydroxylamine Resin
2947
Scheme 2.
acids and apply of this resin to the production of a variety of combinatorial
libraries for biological screening are underway.
EXPERIMENTAL
Synthesis of PS-MB-CHO Resin 1 (SASRIN Resin)
Into a 5-L dry three-neck round-bottom flask, K CO anhydrous (69 g,
2
3
5
00 mmol) and 4-hydroxy-2-methoxybenzaldehyde (76 g, 500 mmol)
followed by N-methyl-2-pyrrolidone (2 L) were added under N gas. Then,
2
Merrifield resin (250 g, 1 mmol/g, 250 mmol) was added, and the reaction
was allowed to shake at 1208C for 20 h. The resin was then washed through
reverse filtration using the following washing cycle at 10-min intervals
unless otherwise indicated: DMF (1 ꢀ 1 L), H O (2 ꢀ 1 L), DMF (2 ꢀ 1 L),
2
H O (2 ꢀ 1 L), DMF (1 ꢀ 1 L), DMF (1 ꢀ 1 L, 16 h), CH Cl (1 ꢀ 1 L),
2
2
2
2
AcOH (1 ꢀ 1 L), H O (1 ꢀ 1 L), DMF (8 ꢀ 1 L), MeOH (1 ꢀ 1 L), CH Cl
2
2
(
1 ꢀ 1 L), and lastly dried in vacuo. The resin loading is estimated by
analysis of the cleavage product of derivative: Sasrin resin 1 (500 mg) was
added into a 20-mL scintillation vial followed by benzylamine (546 mL,
5
erature for 18 h and the resin was then washed using CH Cl . Subsequently,
mmol) in TMOF. The reaction mixture was allowed to shake at room temp-
2
2
BH –pyridine complex in THF (8 M, 125 mL, 1 mmol) and MeOH:CH Cl :
3
2
2
AcOH (2 : 2 : 1) (5 mL) was added to the washed resin, and the reaction
mixture was shaken at room temperature for 18 h. The resin was then
washed with the following cycle at 10-min intervals: DMF (2 ꢀ 50 mL),
MeOH (2 ꢀ 50 mL), and CH Cl (2 ꢀ 50 mL). The resin was dried in
2
2
vacuo. The dried resin was added to a solution of benzoyl chloride (500 mL,
0.43 mmol) and DIEA (1 mL, 5.75 mmol) in CH Cl (5 mL) and shaken at
2 2
room temperature for 18 h. The resin was then washed using the following

2948
Z. Yin, K. Low, and P. Lye
Table 1. Representative hydroxamic acids starting from resin 4
a
b
Compound
R
Purity
98.8
Yield
81
6
7
8
9
95.5
85.7
69
90
62.5
93.0
95
80
1
0
1
1
1
2
91.3
98.0
90
83
1
1
3
4
98.2
89.5
80
76
a
Purity determined from relative peak areas of reverse-phase HPLC chromatograms
monitoring at 254 nm.
b
Product yields determined using the loading level of the starting resin.

N-Linked Hydroxylamine Resin
2949
cycle at 10-min intervals: DMF (1 ꢀ 3 mL), H O (1 ꢀ 3 mL), DMF
2
(
(
1 ꢀ 3 mL), H O (1 ꢀ 3 mL), DMF (3 ꢀ 3 mL), MeOH (1 ꢀ 3 mL), CH Cl
2 2
2
2
2
1 ꢀ 3 mL), MeOH (1 ꢀ 3 mL), and CH Cl (1 ꢀ 3 mL). The dried resin
was subjected to cleavage by treating with 95% TFA in CH Cl (3 mL) for
2
2
3
h. Subsequently, the cleaved solution was filtered and dried to obtain
N-benzyl benzamide. The loading of the SASRIN resin 1 was then calculated
as 0.59 mmol/g.
Synthesis of the Hydroxylamine Resin 4
To a pot of SASRIN resin (5 g, 0.59 mmol/g, 2.95 mmol) was added DMB
(
NaBH CN was added (2.8 g, 45 mmol). The reaction mixture was allowed
5.5 g, 30 mmol) followed by DCM:EtOH:AcoH (2 : 2 : 1) (37.5 mL). Then,
3
to shake at room temperature for 24 h. Resin was then washed via reverse
filtration using the following cycle at 10-min intervals: DMF (2 ꢀ 50 mL),
MeOH (2 ꢀ 50 mL), CH Cl (2 ꢀ 50 mL). The cycle was repeated twice,
2
2
and the resin was dried in vacuo.
General Procedure for the Solid-Phase Synthesis of Hydroxamic
Acid (Compound 11)
To a pot of resin 4 (25 mg, 0.025 mmol) was added trans-4-chloro-3-nitrocin-
namic acid (34 mg, 0.15 mmol) and DMAP (catalytic) followed by N-methyl-
2-pyrrolidone (500 mL) and DIC (19.3 mL, 0.125 mmol). The reaction mixture
was shaken at room temperature for 16 h. The resin was then washed using the
following cycle at 5-min intervals: DMF (1 ꢀ 3 mL), H O (1 ꢀ 3 mL), DMF
2
(
(
1 ꢀ 3 mL), H O (1 ꢀ 3 mL), DMF (3 ꢀ 3 mL), MeOH (1 ꢀ 3 mL), CH Cl
2 2
2
2
2
1 ꢀ 3 mL), MeOH (1 ꢀ 3 mL), and CH Cl (1 ꢀ 3 mL). The resin was
dried in vacuo and subsequently subject to acidolysis cleavage using 95%
TFA in DCM (300 mL).
Characterization of Novel Compounds
1
Compound (10): H NMR (400 MHz, MeOD): d 7.92 (dd, 1H, J ¼ 9 Hz, 2 Hz),
1
3
8
.13 (d, 1H, J ¼ 9 Hz), 8.49 (s, 1H), 9.38 (s, 1H); C NMR (400 MHz,
MeOD): d 122.8, 124.0, 126.2, 131.2, 135.3, 156.1, 159.7, 167.4; IR (neat):
þ
433, 3201, 1672 cm ; HRMS (EI): calcd. for C H N O S (M ):
8 6 2 2
2
1
3
1
94.0150; found: 194.0145.
1
Compound (11): H NMR (400MHz, DMSO): d 6.61 (d, 1H, J ¼ 16Hz), 7.52
(
d, 1H, J ¼ 16Hz), 7.80 (d, 1H, J ¼ 8 Hz), 7.89 (dd, 1H, J ¼ 8 Hz, 2 Hz), 8.29
1
d, 1H); C NMR (400MHz, DMSO):d 122.7, 124.0, 125.0, 132.0, 132.2,
3
(

2950
Z. Yin, K. Low, and P. Lye
21
;
1
HRMS (EI): calcd. for C H ClN O (M ): 242.0094; found: 242.0086.
35.0, 135.6, 150.0, 161.9; IR (neat): 3442, 3178, 1618, 1537, 1353, 1048cm
þ
9
7
2 4
1
Compound (13): H NMR (400 MHz, MeOD): d 7.08 (d, 1H, J ¼ 4 Hz), 7.20
1
3
(
d, 1H, J ¼ 3 Hz), 7.63–7.64 (m, 2H), 8.05–8.09 (m, 1H), 8.20 (s, 1H);
C
NMR (400 MHz, MeOD): d 107.4, 115.4, 120.2, 124.0, 127.0, 128.9, 129.9,
2
1
1
HRMS (EI): calcd. for C H F NO (M ); 271.0456, found: 271.0448.
30.4, 130.7, 145.0, 153.7, 157.0; IR (neat): 3238, 1614, 1334 cm
þ
;
1
2
8
3
3
1
Compound(14): HNMR(400MHz, MeOD):d4.84(s, 3H),7.40–7.60(m, 5H),
1
.89 (s, 1H); C NMR (400MHz, MeOD): d 9.8, 112.2, 125.0, 128.1, 128.5,
3
7
21
1
37.5, 138.0, 141.8, 162.6; IR (neat): 3311, 3067, 2829, 1644 cm ; HRMS
þ
(
EI): calcd. for C H N O (M ): 217.0851; found: 217.0857.
1
1 11 3 2
REFERENCES
1
. For a review, see Muri, E. M. F.; Nieto, M. J.; Sindelar, R. D.; Williamson, J. S.
Hydroxamic acids as pharmacological agents. Curr. Medicinal Chem. 2002,
, 1631.
9
2. For a review, see Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J. H. Design
and therapeutic application of matrix metalloproteinase inhibitors. Chem. Rev.
1999, 99, 2735.
3
4
. Yang, K.; Lou, B. Molecular diversity of hydroxamic acids: Part I. Solution- and
solid-phase synthesis. Mini. Rev. Med. Chem. 2003, 3, 249.
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hydroxamic acids. Tetrahedron Lett. 1997, 38, 321; (b) Floyd, C. D.; Lewis, C. N.;
Patel, S. R.; Whittaker, M. A method for the synthesis of hydroxamic acids on solid
phase. Tetrahedron Lett. 1996, 37, 8045; (c) Bauer, U.; Ho, W.-B.; Koslcinen, M. P.
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Lett. 1997, 38, 7233; (d) Mellor, S. L.; McGuire, C.; Chan, W. C. Tetrahedron
Lett. 1997, 38, 3311; (e) Mellor, S. L.; Chan, W. B. 4-[2,4-dimethoxyphenyl
(
N-fluoren-9-ylmethoxycarbonyl-N-alkylaminooxy)-methyl]phenoxymethyl poly-
styrene: A multiple solid-phase approach to N-alkylhydroxamic acids. Chem.
Commun. 1997, 20, 2005.
. Barlaam, B.; Hamon, A.; Maudet, M. New hydroxylamines for the synthesis of
5
hydroxamic acids. Tetrahedron Lett. 1998, 39, 7865.