Synthesis of hydroxamic acids by using the acid labile O-2-methylprenyl protecting group

Article abstract of DOI:10.1055/s-0032-1317687

Coupling of carboxylic acids with O-2-methylprenyl hydroxylamine provided O-protected hydroxamic acids, which could be deprotected by treatment with trifluoroacetic acid (TFA) in dichloromethane giving volatile by-products. Protected hydroxamic acids could be N-arylated or alkylated followed by deprotection to give N-substituted hydroxamic acids. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317687

2972▌
LETTER
lSetyternthesis of Hydroxamic Acids by Using the Acid Labile O-2-Methylprenyl
Protecting Group
Synthesis of Hydroxamic Acids
Anna Nikitjuka, Aigars Jirgensons*
Latvian Institute of Organic Synthesis, Riga, 1006, Latvia
Fax +371(754)1408; E-mail: aigars@osi.lv
Received: 01.10.2012; Accepted after revision: 02.11.2012
peared to be stable under relatively mild acid conditions
Abstract: Coupling of carboxylic acids with O-2-methylprenyl hy-
compatible with the hydroxamic acid functionality. Next,
droxylamine provided O-protected hydroxamic acids, which could
we turned our attention to the 2-methylprenyl group,
which could be more labile under acidic conditions due to
be deprotected by treatment with trifluoroacetic acid (TFA) in di-
chloromethane giving volatile by-products. Protected hydroxamic
acids could be N-arylated or alkylated followed by deprotection to the additional carbenium ion stabilizing effect of the 2-
methyl group.10
give N-substituted hydroxamic acids.
Key words: protecting groups, cleavage, carboxylic acids,
hydroxamic acids, hydroxylamine
O-Methylprenyl hydroxylamine was prepared according
to Scheme 1. Radical bromination of 2,3-dimethyl-2-
butene (1) gave the allylic bromide,11 which, without pu-
rification, was transformed into N-hydroxyphthalimide
Hydroxamic acids have received particular attention as
metalloproteinase inhibitors due to their ability to coordi-
nate with metal ions in the active site of an enzyme.1 One
of the commonly used methods to install the hydroxamic
acid functionality involves coupling of a carboxylic acid
with an O-protected hydroxylamine followed by deprot-
ection of the resulting intermediate. Such an approach
avoids diacylation and, in addition, the less polar protect-
ed intermediates can be purified prior to deprotection.
Nevertheless, currently used protecting groups for hy-
droxamic acids are often unsuitable due to chemoselectiv-
ity problems and formation of by-products in the
deprotection step that are difficult to remove. For exam-
ple, benzyl protection can be used if no other functional
group sensitive to hydrogenolysis is present in the
molecule2 and this method may lead to competitive N–O
bond cleavage.3 By-product removal after deprotection
requires chromatography or crystallization of the product
if DMB,4 PMB,5 Tr6 or TBS2b,7 protecting groups are
used. THP is a very convenient protection group that gives
a water-soluble by-product during acidic deprotection.8
However, work-up typically involves aqueous extraction,
which is not suitable for water-soluble products. Recently,
a similar O-(1-isobutoxyethyl) protection has been intro-
duced that gives volatile by-products under acidic cleav-
age conditions.9 A minor disadvantage of O-THP and O-
(1-isobutoxyethyl) protection is that these groups posses a
stereogenic center, which can complicate the NMR spec-
tra.
derivative 2. Intermediate 2 was treated with hydrazine
hydrate to give the volatile hydroxylamine, which was
isolated by precipitation as the hydrochloride salt 3.
1. NBS, BPO, CCl4
110 °C, 4 h
O
PhthN
2. N-hydroxyphthalimide
K2CO3, DMSO, r.t., 12 h
2
1
40% over two steps
1. H2N–NH2⋅H2O
Et2O, 4 Å MS,
76%
r.t., 12 h
2. HCl, Et2O
O
H2N
⋅HCl
3
Scheme 1 Synthesis of O-2-methylprenyl hydroxylamine hydro-
chloride (3)
Carboxylic acids 4a–j (Figure 1) were coupled with hy-
droxylamine derivative 3 using EDCI (method A) or
HATU (method B) to give O-2-methylprenyl-protected
hydroxamic acids 5a–j in good yields (Table 1). Screen-
ing of cleavage conditions at several TFA concentrations
in CH2Cl2 revealed that 10 vol% TFA (method C) gave
clean conversion of the protected intermediate 5a into hy-
droxamic acid 6a in a reasonable reaction time (Table 1,
entry 1). These conditions were applied to other protected
hydroxamic acids 5b–j to give pure products 6b–h, with-
out additional purification, according to HPLC and NMR
analysis (Table 1, entries 2–8). The only exceptions were
protected hydroxamic acids 5i and 5j, which gave prod-
ucts 6i and 6j, respectively, with lower purity (Table 1,
entries 9 and 11). In these cases, addition of TESH
(method D) as a cation scavenger improved the purity of
the products (Table 1, entries 10 and 12).12
Our research efforts have focused on developing an alter-
native O-protecting group for hydroxamic acids that could
be cleaved to generate volatile by-products. Initially the
prenyl group was investigated as a potential acid-labile O-
protection for hydroxamic acids. However, this group ap-
SYNLETT 2012, 23, 2972–2974
Advanced online publication: 28.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317687; Art ID: ST-2012-D0839-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Hydroxamic Acids
2973
Table 1 Synthesis of Hydroxamic Acids 6a–j from Coupling of Carboxylic Acids 4a–j with Hydroxylamine Derivative 3 and Deprotection
O
TFA (10 vol%)
(+ TESH), CH2Cl2
O
3, base,
condensing agent
O
OH
O
R
N
R
N
R
OH
H
see Table 1
H
see Table 1
6
4
5
Entry
Substrate
Protection methoda Yield of 5 (%)
Deprotection methodb Time (h)
Purity of 6 (%)c
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
A
A
B
B
A
B
A
A
A
99
95
90
98
93
92
83
96
88
C
C
C
C
C
C
C
C
1.5
3
99
97
92
96
88d
97d
94
99
2
2.5
1.5
2
4g
4h
4i
2
2
9
10
C
D
1.5
1.5
38
91
11
12
4j
A
83
C
D
1.5
3
88
91
a Method A: EDCI, HOBT, DIPEA, DMFA, r.t., 12 h; Method B: HATU, DIPEA, CH2Cl2, r.t., 0.5 h;
b Method C: TFA (10 vol%)/CH2Cl2; Method D: TFA (10 vol%)/TESH (10 vol%)/CH2Cl2.
c HPLC purity at 254 and 210 nm (the least pure given) if not stated otherwise; quantitative yield by NMR with methylsulfone as internal stan-
dard.
various reaction conditions (Table 2). Conditions given in
O
O
O
O
entries 1–5 were selected as potential alternative deprot-
ection conditions. However, none of them provided hy-
droxamic acid 6a in appreciable yields. The 2-methyl-
prenyl group appeared to be stable to Pd(0) deprotection,
fluoride ions and strongly basic aqueous media.
OH
OH
HO
OH
4a
4c
HO
4b
O
O
O
OH
Finally, we demonstrated that N-substituted hydroxamic
acids can be obtained from their O-2-methylprenyl-pro-
tected precursors (Scheme 2). Substrate 5a was alkylated
with benzylbromide13 to give intermediate 7 or arylated
with iodobenzene14 to give intermediate 8.
O
O
OH
OH
NHFmoc
O
4g
4d
4f
4e
Deprotection of compounds 7 and 8 gave hydroxamic ac-
ids 9 and 10. For O-protected N-phenyl substituted hy-
droxamic acid 8, a higher concentration of TFA in CH2Cl2
(20 vol%) was necessary to achieve the cleavage in a rea-
sonable reaction time. This was attributed to lower elec-
tron density on the oxygen, which prevented protonation
of the hydroxamic acid.
O
O
OH
OH
O
O
OH
NHCbz
O
4h
4j
4i
Figure 1 Structure of carboxylic acids 4
The stability of the O-2-methylprenyl-protected
hydroxamic acids was also investigated with 5a under
In summary, we have demonstrated that coupling of car-
boxylic acids with O-2-methylprenyl hydroxylamine fol-
for 9 TFA (20 vol%)
O
for 7 BnBr, NaH
O
O
CH2Cl2, 1.5 h, r.t.
toluene, 12 h, 115 °C
O
O
OH
N
H
N
R
N
R
for 8 Cu2O, PhI, DMEDA
toluene, 20 h, 80 °C
for 10 TFA (20 vol%)
CH2Cl2, 7 h, r.t.
5a
7, R = Bn, 56%
8, R = Ph, 62%
9, R = Bn, HPLC purity 90%..
10, R = Ph, HPLC purity 82%
Scheme 2 Synthesis and deprotection of N-substituted hydroxamic acids
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2972–2974

2974
A. Nikitjuka, A. Jirgensons
LETTER
Table 2 Deprotection Conditions Investigated for 5a
Entry
Reaction conditions
LC/MS result
1
2
3
4
5
6
7
8
DDQ (1.2 equiv), CH2Cl2/H2O, r.t., 12 h
AcCl, MeOH, r.t., 12 h
mixture
mixture
I2, Zn, MeOH, r.t., 12 h
mixture (14% 6a)
mixture (20% 6a)
mixture
TMSOTf (5 vol%) CH2Cl2, r.t., 12 h
FeCl3 (100 mol%), CH2Cl2, r.t., 12 h
[Pd(PPh3)4] (5 mol%), MeOH, r.t., 48 h or reflux 4 h
TBAF (2 equiv), THF, r.t., 24 h
NaOH (1 M), THF, r.t., 12 h
stable
stable
stable
(6) For selected references, see: (a) Yang, S.-M.; Lagu, B.;
Wilson, L. J. J. Org. Chem. 2007, 72, 8123. (b) Zhu, Z.;
Mazzola, R.; Sinning, L.; McKittrick, B.; Niu, X.; Lundell,
D.; Sun, J.; Orth, P.; Madison, V.; Guo, Z.; Ingram, R.;
Beyer, B. M. J. Med. Chem. 2008, 51, 725. (c) Mwakwari, S.
C.; Guerrant, W.; Patil, V.; Khan, S. I.; Tekwani, B. L.;
Gurard-Levin, Z. A.; Mrksich, M.; Oyelere, A. K. J. Med.
Chem. 2010, 53, 6100.
lowed by deprotection under acidic conditions is an
efficient method for the synthesis of hydroxamic acids. O-
2-Methylprenyl protection may also be useful for the syn-
thesis of other N-hydroxy compounds such as N-hydroxy-
amidines and N-hydroxyguanidines. This is a topic of
further investigation in our group.
(7) (a) Holms, J.; Mast, K.; Marcotte, P.; Elmore, I.; Li, J.;
Pease, L.; Glaser, K.; Morgan, D.; Michaelides, M.;
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Tron, G. C.; Sorba, G.; Pirali, T. J. Med. Chem. 2009, 52,
2776.
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(b) Lai, M.-J.; Huang, H.-L.; Pan, S.-L.; Liu, Y.-M.; Peng,
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Acknowledgment
Funding from European Social Fund (No. 2009/0203/1DP/
1.1.1.2.0/09/APIA/VIAA/023) is gratefully acknowledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
synthetic procedures for compounds 2–10, their spectroscopic cha-
racterization as well as NMR spectra of compounds 2, 3, 5a–j, 6a–j
and 7–10.SnoIuifopg
r
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ioSrantnugIifonp
r
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otmart
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Synlett 2012, 23, 2972–2974
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