Improved solution- and solid-phase preparation of hydroxamic acids from esters

Article abstract of DOI:10.1021/jo050036f

The addition of small amounts of solid KCN to solution and solid-phase esters in THF/MeOH/50% aqueous NH₂OH increases the efficiency of their transformation to the corresponding hydroxamic acids.

Full text of DOI:10.1021/jo050036f

TABLE 1. Solution-Phase Hydroxamic Acid Formation
from Esters with and without KCN Additive
Improved Solution- and Solid-Phase
Preparation of Hydroxamic Acids from
Esters
Chih Y. Ho,* Eric Strobel, Janet Ralbovsky, and
Robert A. Galemmo, Jr.
Oncology Team, Drug Discovery, Johnson & Johnson
Pharmaceutical Research and Development,
Spring House, Pennsylvania 19446-0776
cho@prius.jnj.com
Received January 6, 2005
The addition of small amounts of solid KCN to solution and
solid-phase esters in THF/MeOH/50% aqueous NH2OH
increases the efficiency of their transformation to the cor-
responding hydroxamic acids.
Hydroxamic acid analogues are important targets for
the medicinal chemist because of the bidentate chelating
interaction of this functional group with the Zn2+ in the
active site of metalloproteinases.1,2 We required an ef-
ficient conversion of esters to hydroxamic acids suitable
for the preparation of multigram quantities of compound
and a solid-phase method versatile enough to support a
variety of syntheses directed toward hydroxamic acid
targets. The direct solution-phase hydroxyamination of
esters is generally achieved by a two-step preparation of
the potassium salt of hydroxylamine followed by the
addition of the ester in alcohol solvent3 or by the stepwise
saponification of the ester to the acid followed by activa-
tion of the acid as the acyl chloride or mixed anhydride
and then quenching with an O-protected hydroxylamine
analogue.4 In special cases, the hydroxyamination of ester
substrates has been achieved via enzymatic methods5 or,
for more reactive esters, by treatment with excess hy-
droxylamine in alcohol solvent.6 The solid-phase synthe-
sis of hydroxamic acids via the direct transhydrox-
amination of an ester-linked substrate has been re-
ported.7 However, this method required exposure of the
a Ratios were calculated from the integrated area for the ester
or hydroxamic acid HPLC peaks divided by the total area for the
ester and hydroxamic acid multiplied by 100. b Final product
contains about 15% carboxylic acid. c Final product contains trace
(<2%) carboxylic acid. d Final product contains about 8% carboxylic
acid.
(1) Jung, M. Curr. Med. Chem. 2001, 8, 15065-1511.
(2) Brown, P. D.; Davidson, A. H.; Gearing, A.; Whittaker, M.
Hydroxamic acid matrix metalloproteinase inhibitors. In Matrix Met-
alloproteinase Inhibitors In Cancer Chemotherapy; Clendeninn, N. J.,
Appelt, K., Eds.; Humana Press: Totowa, NJ, 2001; pp 113-142.
(3) Hauser, C. R.; Renfrow, W. B. Organic Syntheses; Wiley: New
York, 1943; Collect. Vol. II, pp 67-68.
(4) (a) Burns, C. J.; Groneberg, R. D.; Salvino, J. M.; McGeehan,
G.; Condon, S. M.; Morris, R.; Morrissette, M.; Mathew, R.; Darn-
brough, S.; Neuenschwander, K.; Scotese, A.; Djuric, S.; Ullrich, J.;
Labaudiniere, R. Angew. Chem., Int. Ed. 1998, 37, 2848-2850. (b) Mori,
K.; Koseki, K. Tetrahedron 1988, 44, 6013-6020.
esterified resin to concentrated aqueous hydroxylamine
in THF over 2 days and was regarded as being of limited
scope because it often fails to give reproducible results.8a
Several activated resins have been designed to facilitate
the direct transhydroxamination process but have the
(5) Chen, S.-T.; Lin, S.-L.; Hsiao, S.-C.; Wang, K.-T. Bioorg. Med.
Chem. Lett. 1992, 2, 1685-1690.
(6) Spengler, J.; Burger, K. Synthesis 1998, 1, 67-70.
(7) (a) Dankwardt, S. M. Synlett 1998, 7, 761. (b) Dankwardt, S.
M.; Billedeau, R. J.; Lawley, L. K.; Abbot, S. C.; Martin, R. L.; Chan,
C. S.; Van Wart, H. E.; Walker, K. E. Bioorg. Med. Chem. Lett. 2000,
10, 2513-2516.
(8) (a) Zhang, W.; Zhang, L.; Li, X.; Weigel, J. A.; Hall, S. E.; Mayer,
J. P. J. Comb. Chem. 2001, 3, 151-153. (b) Thouin, E.; Lubell, W. D.
Tetrahedron Lett. 2000 457-460.
10.1021/jo050036f CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/10/2005
J. Org. Chem. 2005, 70, 4873-4875
4873

TABLE 2. Solid-Phase Reaction of Hydroxylamine with
Esters of HMBA-AM Resin 5a-c with and without KCN
Additive
potential to be substantially more reactive than the
simple ester linkage.8 Another approach has been a
stepwise method where the ester library was cleaved
from the resin to give carboxylic acid intermediates that
are subsequently reattached to a hydroxylamine resin by
a peptide coupling agent then cleaved to the hydroxamic
acids.9 Alternatively, a variety of specialized hydroxyl-
amine resins can be used.10 The pitfall of this strategy is
the limitation imposed upon subsequent chemistry. Im-
portant synthetic transformations such as the Mitsunobu
reaction and reactions requiring basic conditions, such
as alkylations, become problematic because of the acidic
NH group (pKa ∼ 10) and are only compatible in the
presence of the hydroxylamine-linking group when fully
protected.11
We believed we could improve upon the existing
methods by finding a way of transiently activating an
ester toward the N-acylation of hydroxylamine. Hogberg
et al.12 have reported that the conversion of esters with
ammonia and simple amines to amides is enhanced by
the addition of small amounts of cyanide ion. The authors
suggested that this reaction proceeds through an acyl-
cyanide intermediate followed by nucleophilic substitu-
tion by the amine. To the best of our knowledge, there is
no literature report of a cyanide-mediated N-hydroxy-
amination of esters to hydroxamic acids. This paper
describes our study of the utility of KCN for the synthesis
of hydroxamic acids from esters in solution and solid-
phase chemistry.
We followed the time-dependence of the solution-phase
N-hydroxyamination of a series of esters 1 with and
without catalytic amounts (∼0.2 equiv) of KCN additive
in THF/MeOH with 50% aqueous hydroxylamine at room
temperature (Table 1). In all cases, addition of the KCN
accelerates the formation of the desired N-acylhydrox-
amic acid product 2a-e. For methyl benzoate (1a, entry
1) with KCN added the reaction is essentially complete
after 24 h, while little of the corresponding hydroxamic
acid 2a is formed in that same time without KCN. For
entries 2-4, almost all of the ester 1b-d is converted to
the corresponding hydroxamic acid 2b-d within 6 h with
added KCN, while considerable amounts of 1b-d remain
for the controls. In the case of the dihydroindole 1e (entry
5), reaction is complete after 2 h with KCN while 60% of
1e is unchanged after 24 h without KCN. Trace amounts
of the corresponding carboxylic acid are formed as a
byproduct in entries 2 and 3 (e2%) with more substantial
amounts of carboxylic acid formed for methyl benzoate
(entry 1, 15%) and methyl mandelate (entry 4, 8%). No
carboxylic acid was detected for the dihydroindole in
entry 5. To apply this methodology to synthetic-scale
a Determination of % conversion: The HPLC peak areas of
products 6a-c were normalized to the peak area of an internal
standard (1-indanol). Complete cleavage of the product was
apparent when the normalized peak areas for 6a-c were observed
to increase no further at subsequent time points. Percentages of
conversion were all calculated relative to time point at which
complete cleavage was observed. b In these experiments, 5 mg of
KCN was used for 100 mg of resin.
reactions, we prepared the hydroxamic acids of methyl
phenylacetate 1b and methyl 3-phenylpropionate 1c on
a 2 mmol scale. Using a mixture of THF/MeOH/50%
aqueous NH2OH (1:1:0.5, 2.5 mL) with KCN (5 mg), a
77% yield of the N-acylhydroxamic acid 2b was obtained
from 1b after 2 h at ambient temperature and a 67%
yield of the hydroxamic acid 2c from 1c after 3 h at
ambient temperature.
To explore the effectiveness of cyanide in the assistance
of hydroxylamine mediated cleavage for solid-phase
library synthesis, we selected the hydroxymethylbenz-
amide (HMBA-AM) resin because of the well-established
compatibility of the ester linkage with Fmoc and Boc
chemistry as well as stability toward Mitsunobu and
reductive amination conditions.13 A solid-phase library
of DL-phenylalanine and several constrained analogues
(3a-c, Scheme 1) was prepared on the HMBA resin by
the esterification of the Fmoc-protected DL-amino acids
using standard DCC coupling conditions at room tem-
perature overnight. The resin-bound Fmoc amino acids
4a-c were deprotected with piperidine/DMF (1:4) and
(9) Salvino, J. M.; Mathew, R.; Kiesow, T.; Narensingh, R.; Mason,
H. J.; Dodd, A.; Groneberg, R.; Burns, C. J.; McGeehan, G.; Kline, J.;
Orton, E.; Tamg, S.-H.; Morrisette, M.; Labaudininiere, R. Bioorg. Med.
Chem. Lett. 2000, 10, 1637-1640.
(10) (a) Barlaam, B.; Koza, P.; Berriot, J. Tetrahedron 1999, 55,
7221-7232. (b) Mellor, S. L.; McGuire, C.; Chan, W. C. Tetrahedron
Lett. 1997, 38, 3311-3314. (c) Floyd, C. D.; Lewis, C. N.; Patel, S. R.;
Whittaker, M. Tetrahedron Lett. 1996, 37, 8045-8048. (d) Ede, N. J.;
James, I. W.; Krywuth, B. M.; Griffiths, R. M.; Eagle, S. N.; Gubbins,
B.; Leitch, J. A.; Sampson, W. R.; Bray, A. M. Lett. Pep. Sci. 1999, 6,
157-163. (e) Bauer, U.; Ho, W.-B.; Koskinen, A. M. P. Tetrahedron
Lett. 1997, 7233-7236.
(11) Ngu, K.; Patel, D. V. J. Org. Chem. 1997, 62, 7088-7089.
(12) Hogberg, T.; Strom, P.; Ebner, M.; Ramsby, S. J. Org. Chem.
1987, 52, 2033-2036.
4874 J. Org. Chem., Vol. 70, No. 12, 2005

SCHEME 1. Preparation of Solid-Phase Librarya
a Reagents and conditions: (a) 3a-c (3 equiv), HMBA-AM resin, DCC (3 equiv), DMAP (3 equiv) DMF, rt, 15 h; (b) piperidine-DMF
1:4; (c) 4-MeOPhSO2Cl (3 equiv), Et3N (3 equiv), DCM, rt, 3 h.
sulfonated with 4-methoxybenzenesulfonyl chloride to
give 5a-c. After several attempts, we found that the
sulfonamide esters are efficiently cleaved from the resin
as the free hydroxamic acids (6a-c, Table 2) with a
mixture of 5:5:2 THF/MeOH/50% aqueous NH2OH and
5 mg of KCN for 100-200 mg of loaded resin. The
importance of KCN additive using these conditions was
assessed with this series of analogues by following the
time-dependent cleavage of the substrates from the solid
support by hydroxylamine in parallel experiments with
and without KCN (Table 2). In the case of entries 1 and
2, KCN-assisted cleavage to the hydroxamic acid is
complete after 2 h, while in the unassisted parallel
experiments, up to 20 h or more for entries 1 and 2 is
required. For entry 3, the KCN assisted experiment is
complete after 2 h while the unassisted cleavage from
the resin to the hydroxamic acid is complete in 4 h. It
was important to follow these reactions carefully and
work them up upon completion. Extended exposure to
the hydroxylamine solution appeared to result in decom-
position of the product.
Experimental Section
Standard Procedure for Solution-Phase Time Course
Experiments. Entry 3, Methyl 3-Phenylpropionate (1c) to
N-Hydroxy-3-phenylpropionamide (2c). Two batches of
methyl 3-phenylpropionoate (0.10 g, 0.38 mmol) in 1:1 THF/
MeOH (1 mL) were prepared. Then 50% aqueous NH2OH (0.25
mL) was added to each batch followed by the immediate addition
of KCN (5 mg) to one reaction while the other was maintained
as a control. The parallel reactions were stirred at ambient
temperature, and 0.025 mL aliquots of each reaction mixture
were withdrawn and diluted with 0.2 mL of MeOH at time points
of 1, 2, 4, 6, and 24 h. The aliquots were analyzed by reversed-
phase HPLC within 10 min of being diluted. For details on
product peak identification and the data used to estimate of the
ratio of starting ester 1c to product hydroxamic acid 2c formed
see the Supporting Information.
Standard Procedure for Solid-Phase Resin Cleavage
Time Course Experiments. Entry 1, Cleavage of N-(4-
Methoxyphenylsulfonyl)-DL-phenylalanine-Modified HM-
BA-AM Resin (5a) to the Hydroxamic Acid (6a).
To demonstrate the utility of this procedure on a
synthetic scale, 200 mg of the resin 5a (0.2 mmol of
compound based on a loading capacity of 1 mmol of
compound per 1 g of HMBA-AM resin) was treated with
a mixture of THF/MeOH/50% aqueous NH2OH (1:1:0.4,
2.4 mL) and KCN (5 mg) to give a 57% yield of hydrox-
amic acid 6a, based upon the presumed resin loading.
In this work, we have shown that the addition of small
amounts of solid KCN can effectively accelerate the
formation of hydroxamic acids from simple esters of alkyl,
aryl, and amino acids. The use and advantage of this
methodology has been demonstrated for both solution-
phase and solid-phase applications.
Stock Solution Preparation. Indan-1-ol (33 mg) was dis-
solved with a mixture of THF (5 mL)/MeOH (5 mL)/NH4OH
(1 mL, 50% aqueous solution).
Resin Cleavage. THF (0.3 mL) and the stock solution (1 mL)
prepared above were added to resin 5a (100 mg), and the
reaction was shaken. For the reaction with KCN, 5 mg of KCN
was added immediately while, for the control, no KCN was
added. At time points of 0.5, 1, 2, 4, 6, and 24 h an aliquot (0.05
mL) of the reaction was removed by syringe and immediately
diluted with MeOH (0.20 mL). These samples were analyzed by
HPLC within 10 min of sampling. The absorbance of the
1-indanol peak and the product 6a was recorded for each time
point. For details on product peak identification and the data
used to estimate the percent conversion to product, see the
Supporting Information.
(13) The resin used in these experiments was the 4-hydroxymeth-
ylbenzoic acid AM (HMBA-AM) resin supplied by Calbiochem-Nova-
biochem Corp., product no. 01-64-0122.
(14) (a) Reddy, A.; Kumar, M.; Reddy, G.; Tetrahedron Lett. 2000,
41, 6285-6288. (b) Giacomelli, G.; Porcgddu, A.; Salris, M. Organic
Lett. 2003, 5, 2715-2717. (c) Liguori, A.; Sindona, G.; Romeo, G.;
Uccella, N. Synthesis 1987, (2), 168. (d) Couturier, M.; Tucker, J.;
Proulx, C.; Boucher, G.; Dube, P.; Andersen, B.; Ghosh, A. J. Org.
Chem. 2002, 67, 4833-4838. (e) Ebbers, E.; Ariaans, G.; Bruggink,
A.; Zwanenburg, B. Teteahedron Asymmetry 1999, 10, 3701-3718. (f)
Matter, H.; Schudok, M.; Schwab, W.; Thorwart, W.; Barbier, D.; Billen,
G.; Haase, B.; Neises, B.; Weithmann, K.-U.; Wollmann, T. Bioorg.
Med. Chem. 2002, 10, 3529-3544.
Supporting Information Available: Typical experimen-
tal procedures, analytical data, and time course experimental
data for all products not listed in the text. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO050036F
J. Org. Chem, Vol. 70, No. 12, 2005 4875