Effective synthesis of enantiopure hydroxamates by displacement of resin-bound esters with hydroxylamine

Article abstract of DOI:10.1016/S0040-4039(99)02092-4

Enantiopure hydroxamic acids have been synthesized by nucleophilic displacement of carboxylates linked to oxime resin using hydroxylamine in a MeOH:CHCl₃ solution.

Full text of DOI:10.1016/S0040-4039(99)02092-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 457–460
Effective synthesis of enantiopure hydroxamates by displacement
of resin-bound esters with hydroxylamine
∗
Eryk Thouin and William D. Lubell
Département de chimie, Université de Montréal, C. P. 6182, Succursale Centre Ville, Montréal, H3C 3J7, Canada
Received 7 October 1999; accepted 16 October 1999
Abstract
Enantiopure hydroxamic acids have been synthesized by nucleophilic displacement of carboxylates linked to
oxime resin using hydroxylamine in a MeOH:CHCl3 solution. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: solid phase synthesis; hydroxamic acids; amino acids; amino acid derivatives.
The hydroxamic acid functional group is an important constituent of many biologically relevant
1
–3
4–6
compounds,
such as specific matrix metalloprotease enzyme inhibitors.
Several strategies have
thus emerged that employ solid-phase chemistry to synthesize hydroxamic acid libraries. For example,
7
8
hydroxylamine, O-protected and N-tethered to MBHA and Tentagel™ resin, as well as O-tethered
9
,10
11,12
13,14
to Wang,
Sasrin
and trityl
resins, has served as the starting point for syntheses of various
hydroxamates. Alternatively, direct nucleophilic displacement of support-bound carboxylates has been
employed to synthesize hydroxamates with some limitations. For example, O-tert-butyldimethylsilyl-
protected hydroxylamine displaced ordinary acids and N-(toluenesulfonyl)proline from oxime resin;
however, an additional treatment with trifluoroacetic acid (TFA) was necessary to remove the silyl group
to afford the hydroxamic acids in 27–89% yields.15 Although 50% aqueous hydroxylamine in THF
cleaved N-(Cbz)amino esters from ArgoGel-OH™ resin, 25 equivalents of hydroxylamine and a reaction
time of 2 days were required to effect this transformation which gave N-(Cbz)proline hydroxamate in
only 33% yield.1
6
We have effectively synthesized azacycloalkane amino acids that serve as conformationally rigid
1
7–19
scaffolds.
Because proline-derived hydroxamates may act in constrained analogs of metalloprotease
we have sought a convenient technique for using related proline analogs to generate hy-
1
5,16
inhibitors,
droxamate libraries by parallel synthesis. Perceiving that nucleophilic displacement with hydroxylamine
could furnish hydroxamate of high purity without the need of protection nor resin alteration, we modified
the original procedure for cleaving N-(acyl)amino acids from oxime resin20–23 and have found that
∗
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02092-4
tetl 16020

4
58
anhydrous hydroxylamine in a MeOH:CHCl solution provides enantiopure hydroxamates possessing
3
a variety of functional groups.
Three N-(BOC)amino acids, proline, phenylalanine and alanine, were anchored onto oxime resin using
dicyclohexylcarbodiimide (DCC) and ethyl-2-(hydroxyimino)-2-cyanoacetate (EACNOx) in dichloro-
methane at room temperature (rt, Scheme 1),24 and the loading of N-(BOC)amino esters 1a–d was
determined by weighing displaced amide from treatment of resin samples with iso-butylamine. The BOC
group was then removed with TFA and the amines were free based with diisopropylethylamine (DIEA).
Scheme 1. Synthesis and modification of resin-bound esters 1–5
Resin-bound L-proline was, respectively, acylated with 4-toluenesulfonyl chloride, 4-
methoxyphenylsulfonyl chloride and benzyl chloroformate in the presence of DIEA in dichloromethane
to furnish support-bound prolines 2b–4b. Under similar conditions L-phenylalanine was reacted with
benzyl chloroformate until a negative ninhydrin test25 was observed and provided support-bound
N-(Cbz)phenylalanine 4c. Resin-linked L- and D-phenylalanine were also coupled to N-(BOC)-L-
phenylalanine using benzotriazolyl-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) with DIEA in
DMF to yield dipeptides 5c and 5d, that were converted to their respective hydroxamates by cleavage
under the standard conditions in order to examine if treatment with hydroxylamine would cause
epimerization at the α-center of the active ester.
Nine different hydroxamates 6–14 were synthesized by exposing oxime resin-bound substrates 1–5 to
solutions of hydroxylamine in 1:6 MeOH:CHCl (Scheme 2, Table 1). Evaporation of the filtrate gave
3
1
crude hydroxamates 6–14 of good purity as determined by H NMR spectroscopy and reverse-phase
HPLC analysis. Thin layer chromatography of the crude material and staining with a solution of FeCl3
in aqueous HCl detected only a single hydroxamate spot in each case. Certain cases were further purified
by column chromatography. Furthermore, analysis of L,D- and L,L-N-(BOC)phenylalanyl-phenylalanine
hydroxamates 13 and 14 by HPLC and incremental additions of the minor isomer showed that the
dipeptide hydroxamic acids were of a >99% diastereomeric ratio; hence, no epimerization at the α-center
of the active ester occurred during the hydroxamate syntheses.

4
59
Scheme 2. Synthesis of hydroxamic acids 6–14
Table 1
Recovery and purity of hydroxamic acid
General protocol for displacements with HONH : A stock hydroxylamine solution was prepared
2
by dissolving HONH Cl (0.695 g, 10 mmol) in dry MeOH (5 mL), cooling to 0°C, and adding 2 mL
3
of MeONa in MeOH (25% wt/wt, 8.75 mmol). The precipitated NaCl was removed by filtration and the
filtrate was diluted up to a volume of 50 mL with CHCl . Resino ester 1–5 (100 mg, 0.059–0.065 mmol)
3
was suspended in CHCl (0.5 mL) in a 10 mL borosilicate test tube, treated with 1.0 mL of the stock
3
solution (0.175 mmol of HONH ), shaken on a vortex-evaporator (Labconco™) for 12 h, filtered and
2
washed with CHCl (2×1 mL) and 1:1 CHCl :MeOH (2×1 mL). The combined filtrates were evaporated
3
3
1
to crude hydroxamate 6–14 that was analyzed directly by H NMR spectroscopy in CDCl or by reverse-
3
phase HPLC on a C-18 column using a flow rate of 1.5 mL/min and the detector centered at 254 nm. The
majority of the compounds were analyzed with a gradient of 10–100% CH CN in H O containing 0.1%
3
2
TFA over 30 min; 8 was analyzed with 15% CH CN and 12 was analyzed with 30% CH CN in H O
3
3
2
2
6
containing 0.1% TFA.

4
60
Acknowledgements
This research was supported in part by the Natural Sciences and Engineering Research Council
(NSERC) of Canada, and the Ministère de l’Éducation du Québec.
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6. (S)-N-(BOC)Alanine hydroxamate (6) was purified by column chromatography on silica gel using 0.5% AcOH in EtOAc:
20
1
R
f
=0.60 (3% AcOH in EtOAc); [α]
D
−35 (c 0.8, MeOH), H NMR: (CD
3
OD, 400 MHz) δ 1.28 (d, 3H, J=7.1), 1.43
(s, 9H), 4.01 (q, 1H, J=7.0). (S)-N-(BOC)Proline hydroxamate (7) chromatographed on silica gel with 0.5% AcOH/EtOAc:
20
1
R
f
=0.45 (3% AcOH/EtOAc); [α]
D
−57 (c 1.0, MeOH); H NMR: (CD
3
OD, 400 MHz) δ 1.4–1.47 (m, 9H), 1.80–2.00 (m,
3
H), 2.10–2.25 (m, 1H), 3.35–3.51 (m, 2H), 4.00–4.13 (m, 1H). (S)-N-(Cbz)Proline hydroxamate (8) was purified on silica
2
0
1
gel with 0.5% AcOH/EtOAc: R
δ 1.83–2.05 (m, 3H), 2.10–2.27 (m, 1H), 3.43–3.60 (m, 2H), 4.20 (m, 1H), 5.10 (m, 2H), 7.25–7.40 (m, 5H). (S)-N-(p-
Toluenesulfonyl)proline hydroxamate (9): R
f
=0.43 (3% AcOH/EtOAc); [α]
D
−45 (c 0.5, MeOH); H NMR: (CD
3
OD, 400 MHz)
1
f 3
=0.53 (3% AcOH in EtOAc); H NMR: (CD OD, 400 MHz) δ 1.50–1.62 (m,
1
H), 1.70–1.97 (m, 3H), 2.44 (s, 3H), 3.20 (m, 1H), 3.50 (m, 1H), 4.00 (m, 1H), 7.43 (d, 2H, J=8.0), 7.75 (d, 2H, J=8.3). (S)-
1
N-(p-Methoxybenzenesulfonyl)proline hydroxamate (10): R
f 3
=0.43 (3% AcOH in EtOAc); H NMR: (CD OD, 400 MHz)
δ 1.53–1.63 (m, 1H), 1.70–1.97 (m, 3H), 3.20 (m, 1H), 3.50 (m, 1H), 3.88 (s, 3H), 4.00 (m, 1H), 7.12 (d, 2H, J=9.0),
1
7
.81 (d, 2H, J=9.0). (S)-N-(BOC)Phenylalanine hydroxamate (11): R
f 3
=0.76 (3% AcOH in EtOAc); H NMR: (CD OD, 400
MHz) δ 1.36 (s, 9H), 2.83 (dd, 1H, J=6.6, 13.6), 3.03 (dd, 1H, J=8.4, 13.6), 4.17 (t, 1H, J=7.4), 7.15–7.30 (m, 5H). (S)-N-
1
(
(
Cbz)Phenylalanine hydroxamate (12) R
f 3
=0.56 (EtOAc); H NMR: (CD OD, 400 MHz) δ 2.87 (dd, 1H, J=8.7, 13.6), 3.06
dd, 1H, J=6.3, 13.7), 4.25 (t, 1H, J=7.5), 5.00 (m, 2H), 7.15–7.35 (m, 10H). (S,S)-N-(BOC)Phenylalanyl-phenylalanine
1
hydroxamate (14): R
9
f 3
=0.56 (EtOAc); H NMR: (CD OD, 400 MHz) δ 1.34 (s, 9H), 2.60–3.10 (m, 4H), 4.23 (dd, 1H, J=5.2,
.2), 4.50 (t, 1H, J=7.3), 7.10–7.30 (m, 10H).