Convenient synthesis of a library of discrete hydroxamic acids using the hydroxythiophenol (Marshall) resin

Article abstract of DOI:10.1016/j.tetlet.2007.12.073

Several resins have reportedly been used to synthesize hydroxamic acids except for the hydroxythiophenol (Marshall) resin. Herein, we report the use of the Marshall resin to synthesize hydroxamic acids from carboxylic acids and its application to convert a library of 14 discrete aliphatic and aromatic carboxylic acids including N-protected amino acids to their corresponding hydroxamic acids in good yields.

Full text of DOI:10.1016/j.tetlet.2007.12.073

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1103–1106
Convenient synthesis of a library of discrete hydroxamic acids
using the hydroxythiophenol (Marshall) resin q
Jinil Choi, Jewn Giew Park, Yuan-Ping Pang *
Computer-Aided Molecular Design Laboratory, Mayo Clinic, Rochester, MN, USA
Received 21 November 2007; revised 11 December 2007; accepted 13 December 2007
Available online 23 December 2007
Abstract
Several resins have reportedly been used to synthesize hydroxamic acids except for the hydroxythiophenol (Marshall) resin. Herein,
we report the use of the Marshall resin to synthesize hydroxamic acids from carboxylic acids and its application to convert a library of 14
discrete aliphatic and aromatic carboxylic acids including N-protected amino acids to their corresponding hydroxamic acids in good
yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Hydroxamic acids are known as zinc coordinators that
have been widely used as zinc protease inhibitors.1–11 In
the course of developing small-molecule inhibitors of the
zinc endopeptidase of botulinum neurotoxin serotype A
(BoNTA),12,13 we needed a method to convert a library
of discrete carboxylates immobilized on the hydroxythio-
phenol (Marshall) resin to hydroxamates to derivatize
our hydroxamate-containing BoNTA inhibitors using
split-and-pool combinatorial synthesis.14,15 Several resins
have reportedly been used for the syntheses of hydroxamic
acids and these include (1) the thioester-attached resin,16
(2) the O-immobilized-hydroxylamine-containing Wang
resin,17–22 (3) the oxime (Kaiser) resin,23 (4) the N-hydroxy-
benzenesulfonamide-attached resin,24 (5) the trityl
resin,25,26 (6) the chlorotrityl resin,27 and (7) the HMBA-
AM resin.28 However, the Marshall resin has not been
reported for its use in synthesizing hydroxamic acids.
The reports of facile cleavage of amides from the Mar-
shall resin by primary or secondary amines using pyridine
as a swelling solvent29–38 prompted us to investigate the
feasibility of obtaining hydroxamic acids from carboxyl-
ates immobilized on the Marshall resin using hydroxyl-
amine as a cleavage agent (Scheme 1). On converting
2-(thiophen-3-yl)acetate immobilized on the Marshall resin
to N-hydroxy-2-(thiophen-3-yl)acetamide (Scheme 1), we
obtained the desired pure product when cleaving the ace-
tate from the Marshall resin using 50% hydroxylamine
aqueous solution in pyridine and using high-performance
O
O
HNR'R''
R
RCO2H
R
S
OH
S
O
R''R'N
pyridine
r.t., 18-36h
the Marshall resin
R' = alkyl; R'' = H or alkyl
HOHNOC
50% NH2OH aq soln
pyridine, r.t., 24 h
S
~1: 1
+
O
HO2C
S
S
S
O
S
50% NH2OH aq soln
DCM, r.t., 24 h
HOHNOC
q
96% yield for the
crude product
74% purity
Author contributions: Conceived and designed the experiments: J.G.P.
Performed the experiments: J.C. and J.G.P. Analyzed the data: J.C.,
J.G.P., and Y.P.P. Wrote the Letter: J.G.P., and Y.P.P.
*
Scheme 1. Syntheses of amides and hydroxamic acids using the Marshall
resin.
Corresponding author. Tel.: +1 507 284 7868; fax: +1 507 266 6518.
E-mail address: pang@mayo.edu (Y.-P. Pang).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.073

1104
J. Choi et al. / Tetrahedron Letters 49 (2008) 1103–1106
O
O
ous solution in dichloromethane (DCM) or toluene and
O
50% NH2OH aq soln
CH2Cl2, r.t., 17-24 h
R
R
readily obtained the desired hydroxamic acid without con-
tamination by the carboxylic acid according to the proton
NMR spectrum of the crude hydroxamic acid.
S
HOHN
Scheme 2. Syntheses of hydroxamic acids using the Marshall resin.
Further studies showed that the new method of convert-
ing carboxylates to hydroxamates shown in Scheme 239 is
applicable to both aromatic and aliphatic acids including
N-protected amino acids. This method can be used for
the synthesis of a library of discrete hydroxamic acids
(Table 1). For the synthesis of a library of 14 discrete,
representative hydroxamic acids listed in Table 1, only
1H-indole-5-carboxylic acid (entry 13) had a low yield of
liquid chromatography (HPLC) purification. However, the
crude product was in a mixture (nearly 1:1 ratio) with the
corresponding carboxylic acid that was generated presum-
ably by water in the presence of pyridine during the cleav-
age. To avoid the formation of the carboxylic acid, we
performed the cleavage by using 50% hydroxylamine aque-
Table 1
Syntheses of a library of discrete hydroxamic acids using the Marshall resin
Entry
Starting material
Product
Yielda (%)
Purityb (%)
CO2H
CONHOH
1
2
3
96
74
97
94
S
S
63c
80
CO2H
Ph
CONHOH
Ph
MeO
MeO
CO2H
CONHOH
CO2H
CONHOH
4
5
71
82
88
91
CO2H
NHCbz
CONHOH
NHCbz
6
7
50
79
95
CO2H
CONHOH
100
Br
CO2H
Br
CONHOH
CbzHN
CbzHN
CO2H
8
9
100
92
94
91
CbzHN
CbzHN
CONHOH
CONHOH
CO2H
NHCbz
CO2H
NHCbz
CONHOH
10
11
87
85
81
CO2H
NHAc
CONHOH
NHAc
100
HN
HN
CO2H
CONHOH
12
13
86
85d
N
N
HO2C
HOHNOC
33
67
92
93
N
H
N
H
CO2H
CONHOH
14
N
H
N
H
a
The yield for the crude product was calculated according to the capacity of the resin.
Purity was estimated according to the integration (area %) of the HPLC chromatogram at 254 nm with correction of the methanol peak. The HPLC
b
analysis condition: Zorbax SB C-18 4.6 ꢀ 250 mm, 1.0 mL/min, and linear gradient [the concentration of B in A was changed from 20% to 100% over
20 min, A = H2O (0.1% TFA), B = CH3CN/H2O 9:1 (0.1% TFA)].
c
The same amount of the product was obtained when toluene was used as a swelling solvent.
Linear gradient: the concentration of B in A was changed from 0% to 2% over 20 min.
d

J. Choi et al. / Tetrahedron Letters 49 (2008) 1103–1106
1105
16. Zhang, W.; Zhang, L.; Li, X.; Weigel, J. A.; Hall, S. E.; Mayer, J. P.
J. Comb. Chem. 2001, 2001, 151–153.
17. Ngu, K.; Patel, D. V. J. Org. Chem. 1997, 62, 7088–7089.
18. Grigg, R.; Major, J. P.; Martin, F. M.; Whittaker, M. Tetrahedron
Lett. 1999, 40, 7709–7711.
33% while others had yields of 50–100%. Purities of the
products cleaved from the Marshall resin were 74–97%
according to HPLC analysis. Liquid-chromatography–
mass-spectrometry analyses of the 14 crude products listed
in Table 1 showed that all products were free of starting
materials except that hydroxamic acids of entries 8 and
12 were contaminated, respectively, by 2% and 15% of cor-
responding carboxylic acids that can be readily separated
from the hydroxamic acids by HPLC.
The above results show that the Marshall resin is a use-
ful solid-phase support for converting a wide range of car-
boxylic acids to hydroxamic acids by using split-and-pool
combinatorial method.14,15 The Marshall resin can yield
directly a hydroxamic acid, unlike the thioester-attached
resin that requires the use of NH2OTMS and needs an
extra step of deprotection after obtaining the O-protected
hydroxamic acid. The convenient synthesis of a library of
discrete hydroxamic acids using the Marshall resin demon-
strated herein is useful to the syntheses of hydroxamate-
containing inhibitors of metalloproteins involved in many
diseases such as cancers,5 cardiovascular diseases,6–8
AIDS,9,10 and Alzheimer’s disease.11
19. Gu, X.; Wang, Y.; Kumar, A.; Ye, G.; Parang, K.; Sun, G. J. Med.
Chem. 2006, 49, 7532–7539.
20. Robinson, D. E.; Holladay, M. W. Org. Lett. 2000, 2, 2777–2779.
21. Stanger, K. J.; Krchnak, V. J. Comb. Chem. 2006, 8, 435–439.
22. Richter, L. S.; Desai, M. C. Tetrahedron Lett. 1997, 38, 321–322.
23. Thouin, E.; Lubell, W. D. Tetrahedron Lett. 2000, 41, 457–460.
24. Porcheddu, A.; Giacomelli, G. J. Org. Chem. 2006, 71, 7057–
7059.
25. Bauer, U.; Ho, W.-B.; Koskinen, A. M. P. Tetrahedron Lett. 1997, 41,
7233–7236.
26. Boldt, G. E.; Kennedy, J. P.; Janda, K. D. Org. Lett. 2006, 8, 1729–
1732.
27. Mellor, S. L.; McGuire, C.; Chan, W. C. Tetrahedron Lett. 1997, 38,
3311–3314.
28. Ho, C. Y.; Strobel, E.; Ralbovsky, J.; Galemmo, R. A. J. J. Org.
Chem. 2005, 70, 4873–4875.
29. Marshall, D. L.; Liener, I. E. J. Org. Chem. 1970, 35, 867–868.
30. Fantauzzi, P. P.; Yager, K. M. Tetrahedron Lett. 1998, 39, 1291–1294.
31. Breitenbucher, J. G.; Hui, H. C. Tetrahedron Lett. 1998, 39, 8207–
8210.
32. Dressman, B. A.; Singh, U.; Kaldor, S. W. Tetrahedron Lett. 1998, 39,
3631–3634.
33. Breitenbucher, J. G.; Johnson, C. R.; Haight, M.; Phelan, J. C.
Tetrahedron Lett. 1998, 39, 1295–1298.
Acknowledgments
34. Irving, M. M.; Kshirsagar, T.; Figliozzi, G. M.; Yan, B. J. Comb.
Chem. 2001, 3, 407–409.
35. Boldi, A. M.; Dener, J. M.; Hopkins, T. P. J. Comb. Chem. 2001, 3,
367–373.
36. Fang, L.; Demee, M.; Sierra, T.; Kshirsagar, T.; Celebi, A. A.; Yan,
B. J. Comb. Chem. 2002, 4, 362–368.
37. Bunin, B. A.; Dener, J. M.; Kelly, D. E.; Paras, N. A.; Tario, J. D.;
Tushup, S. P. J. Comb. Chem. 2004, 6, 487–496.
This work was supported by the US Army Medical
Research Acquisition Activity (W81XWH-04-2-0001) and
the National Institutes of Health/National Institute of
Allergy and Infectious Diseases (5R01AI054574-03).
The opinions or assertions contained herein belong to the
authors and are not necessarily the official views of the
US Army or the US National Institutes of Health.
38. Kamal, A.; Devaiah, V.; Reddy, K. L.; Rajendar; Shetti, R. V. C. R.
N. C.; Shankaraiah, N. J. Comb. Chem. 2007, 9, 267–274.
39. Procedure: the Marshall resin (1.6 mmol/g obtained from Aldrich
Chem. Co., Milwaukee, WI, catalog number 554804-5G) was loaded
into porous polypropylene containers, termed MicroKans (IRORI,
San Diego, CA), using the dry resin filler from IRORI (ꢁ0.05 mmol,
ꢁ30 mg of the resin per MicroKan). The resin-containing MicroKans
were shaken in DCM on an orbital shaker at room temperature for
10 min. Each member of a library of discrete carboxylic acids
(3.0 equiv), N,N0-diisopropylcarbodiimide (26 lL, 3.2 equiv), and 4-
di(methylamino)pyridine (6 mg, 0.9 equiv) were added to a labeled
resin-containing MicroKan. [Note: addition of 1 mL of dimethylform-
amide (DMF) was necessary to dissolve carboxylic acids of entries 3, 4,
11, and 13.] The resulting MicroKans were shaken on an orbital shaker
at room temperature for 20–30 h. The MicroKans were washed with
DMF (2 ꢀ 3 mL/MicroKan), methanol (3 mL/MicroKan), and DCM
(3 mL/MicroKan). The sequential washing with methanol and DCM
was repeated two more times. The MicroKans were dried under high
vacuum, and 100 lL of 50% hydroxylamine aqueous solution was then
added to each MicroKan soaked separatedly in 3 mL of DCM. The
resulting MicroKans were shaken on an orbital shaker at room
temperature for 17–24 h. Afterwards the organic layer was separated
from the aqueous layer by using a disposable pipette and concentrated
under N2 stream then further dried under high vaccum overnight to give
the desired hydroxamic acid. 1H NMR (400 MHz, DMSO-d6) spectra
of the products (purity: 74–97%) are as follows.
References and notes
1. El Yazal, J.; Pang, Y.-P. J. Phys. Chem. A 1999, 103, 8346–8350.
2. El Yazal, J.; Pang, Y.-P. J. Phys. Chem. B 2000, 104, 6499–6504.
3. Brown, S.; Meroueh, S. O.; Fridman, R.; Mobashery, S. Curr. Top.
Med. Chem. 2004, 4, 1227–1238.
4. Kelly, W. K.; Marks, P. A. Nat. Clin. Pract. Oncol. 2005, 2, 150–157.
5. Price, S.; Dyke, H. J. Expert Opin. Ther. Patents 2007, 17, 745–765.
6. Kehl, H. J. Am. Osteopath. Assoc. 1973, 72, 498–501.
7. Subissi, A.; Criscuoli, M.; Sardelli, G.; Guelfi, M.; Giachetti, A.
J. Cardiovasc. Pharmacol. 1992, 20, 139–146.
8. MacPherson, L. J.; Bayburt, E. K.; Capparelli, M. P.; Bohacek, R. S.;
Clarke, F. H.; Ghai, R. D.; Sakane, Y.; Berry, C. J.; Peppard, J. V.;
Trapani, A. J. J. Med. Chem. 1993, 36, 3821–3828.
9. Dhawan, S.; Wahl, L. M.; Heredia, A.; Zhang, Y.; Epstein, J. S.;
Meltzer, M. S.; Hewlett, I. K. J. Leukoc. Biol. 1995, 58, 713–716.
10. Tournaire, R.; Arnaud, S.; Hamedi-Sangsari, F.; Malley, S.; Grange,
J.; Blanchet, J. P.; Dore, J. F.; Vila, J. Leukemia 1994, 8, 1703–1707.
11. Parvathy, S.; Hussain, I.; Karran, E. H.; Turner, A. J.; Hooper, N. M.
Biochem. Soc. Trans. 1998, 26, S 242.
12. Park, J. G.; Sill, P. C.; Makiyi, E. F.; Garcia-Sosa, A. T.; Millard, C.
B.; Schmidt, J. J.; Pang, Y.-P. Bioorg. Med. Chem. 2006, 14, 395–408.
13. Tang, J.; Park, J. G.; Millard, C. B.; Schmidt, J. J.; Pang, Y.-P. PLoS
ONE 2007, 2, e761.
14. Nicolaou, K. C.; Xiao, X.-Y.; Parandoosh, Z.; Senyei, A.; Nova, M.
P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2289.
N-Hydroxy-2-(thiophen-3-yl)acetamide (entry 1): d 10.61 (s, 1H), 8.81
(s, 1H), 7.44 (dd, J = 4.9, 2.9 Hz, 1H), 7.22 (m, 1H), 7.00 (d, J = 4.9 Hz,
1H), and 3.28 (s, 2H).
15. Park, J. G.; Langenwalter, K. J.; Weinbaum, C. A.; Casey, P. J.;
Pang, Y.-P. J. Comb. Chem. 2004, 6, 407–413.
N-Hydroxy-2-phenylacetamide (entry 2): d 10.64 (s, 1H), 8.81 (s, 1H),
7.22 (m, 5H), and 3.25 (s, 2H).

1106
J. Choi et al. / Tetrahedron Letters 49 (2008) 1103–1106
N-Hydroxy-3-methoxybenzamide (entry 3): d 11.0 (br s, 1H), 9.1 (br s,
1H), 7.48–7.27 (m, 3H), 7.06 (m, 1H), and 3.77 (s, 3H).
N-Hydroxybenzamide (entry 4): d 11.20 (s, 1H), 9.02 (s, 1H), 7.74–7.71
(m, 2H), and 7.52–7.41 (m, 3H).
Benzyl 1-(hydroxyamino)-4-methyl-1-oxopentan-2-ylcarbamate (entry
10): d 10.66 (s, 1H), 8.80 (br s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.37–7.27
(m, 5H), 4.99 (s, 2H), 3.90 (m, 1H), 1.56–1.31 (m, 3H), 0.85 (d,
J = 6.6 Hz, 3H), and 0.81 (d, J = 6.6 Hz, 3H).
Benzyl 1-(hydroxyamino)-1-oxo-3-phenylpropan-2-ylcarbamate (entry
5): d 10.71 (s, 1H), 8.87 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.34–7.13 (m,
10H), 4.95 (s, 2H), 4.09 (m, 1H), 2.87 (dd, J = 13.6, 4.9 Hz, 1H), and
2.76 (dd, J = 13.6, 3.5 Hz, 1H).
2-Acetamido-N-hydroxy-3-(1H-indol-3-yl)propanamide (entry 11): d
10.78 (s, 1H), 8.8 (br s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.57 (d,
J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 7.03
(m, 1H), 6.95 (m, 1H), 6.44 (br s, 1H), 4.40 (m, 1H), 3.02 (dd, J = 14.4,
5.9 Hz, 1H), 2.85 (dd, J = 14.4, 8.8 Hz, 1H), and 1.75 (s, 3H).
N-Hydroxyisonicotinamide (entry 12): d 11.40 (s, 1H), 9.22 (br s, 1H),
8.90 (s, 1H), 8.69 (d, J = 4.3 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), and 7.49
(dd, J = 8.0, 3.1 Hz, 1H).
N-Hydroxy-1H-indole-5-carboxamide (entry 13): d 11.31 (s, 1H), 11.2
(s, 1H), 8.82 (br s, 1H), 7.99 (s, 1H), 7.50 (dd, J = 8.6, 1.6 Hz, 1H), 7.40
(m, 2H), and 6.49 (m, 1H).
N-Hydroxy-1H-indole-2-carboxamide (entry 14): d 11.63 (s, 1H), 11.25
(br s, 1H), 9.1 (br s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.2 Hz,
1H), 7.15 (m, 1H), 7.01 (m, 1H), and 6.96 (s, 1H).
4-tert-Butyl-N-hydroxybenzamide (entry 6): d 11.1 (br s, 1H), 8.9 (br s,
1H), 7.66 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), and 1.27 (s, 9H).
4-Bromo-N-hydroxybenzamide (entry 7): d 11.6 (br s, 1H), 9.32 (br s,
1H), 8.29 (d, J = 8.8 Hz, 2H), and 7.97 (d, J = 8.8 Hz, 2H).
Benzyl 6-(hydroxyamino)-6-oxohexylcarbamate (entry 8):d 10.32 (s,
1H), 8.65 (s, 1H), 7.34 (m, 6H), 4.98 (s, 2H), 2.94 (m, 2H), 1.90 (t,
J = 7.2 Hz, 2H), 1.45 (m, 2H), 1.36 (m, 2H), and 1.20 (m, 2H).
Benzyl 4-(hydroxyamino)-4-oxobutylcarbamate (entry 9): d 10.34 (s,
1H), 8.75 (br s, 1H), 7.37–7.25 (m, 6H), 4.98 (s, 2H), 2.96 (m, 2H), 1.93
(t, J = 7.5 2H), and 1.60 (m, 2H).