Enantiomerically enriched bicyclic hydroxamic acids in one step from α-aminohydroxamic acids and keto acids via cyclocondensation

Article abstract of DOI:10.1080/00397911.2012.717162

New enantiomerically enriched bicyclic hydroxamic acids, 1-hydroxy-dihydro-1Hpyrrolo[ 1,2-a]imidazole-2,5(3H,6H)-diones, have been synthesized by the cyclocondensation of L-α-aminohydroxamic acids with keto acids in a highly chemo- and stereoselective manner. The cis configuration between the amino acid side chain and the methyl group at C7a in 1H-pyrrolo[1,2-a]imidazole-2,5-dione was unambiguously established by X-ray crystallographic analysis. This method could also be applied to the cyclocondensation with o-formylbenzoic acid, giving a tricyclic hydroxamic acid in a good yield. Copyright

Full text of DOI:10.1080/00397911.2012.717162

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Enantiomerically Enriched Bicyclic
Hydroxamic Acids in One Step from α-
Aminohydroxamic Acids and Keto Acids
via Cyclocondensation
Yujiro Hoshino a , Masanori Oyaizu a , Yoko Koyanagi a & Kiyoshi
Honda a
a Graduate School of Environment and Information Sciences,
Yokohama National University , Yokohama , Japan
Accepted author version posted online: 26 Mar 2013.Published
online: 03 Jun 2013.
To cite this article: Yujiro Hoshino , Masanori Oyaizu , Yoko Koyanagi & Kiyoshi Honda (2013):
Enantiomerically Enriched Bicyclic Hydroxamic Acids in One Step from α-Aminohydroxamic Acids
and Keto Acids via Cyclocondensation, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:18, 2484-2492
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Synthetic Communications1, 43: 2484–2492, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.717162
ENANTIOMERICALLY ENRICHED BICYCLIC
HYDROXAMIC ACIDS IN ONE STEP FROM
a-AMINOHYDROXAMIC ACIDS AND KETO
ACIDS VIA CYCLOCONDENSATION
Yujiro Hoshino, Masanori Oyaizu, Yoko Koyanagi, and
Kiyoshi Honda
Graduate School of Environment and Information Sciences,
Yokohama National University, Yokohama, Japan
GRAPHICAL ABSTRACT
Abstract New enantiomerically enriched bicyclic hydroxamic acids, 1-hydroxy-dihydro-1H-
pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones, have been synthesized by the cyclocondensa-
tion of L-a-aminohydroxamic acids with keto acids in a highly chemo- and stereoselective
manner. The cis configuration between the amino acid side chain and the methyl group at
C7a in 1H-pyrrolo[1,2-a]imidazole-2,5-dione was unambiguously established by X-ray
crystallographic analysis. This method could also be applied to the cyclocondensation with
o-formylbenzoic acid, giving a tricyclic hydroxamic acid in a good yield.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Chiral compounds; cyclocondensation; hydroxamic acids; N-hydroxyimida-
zolidinones; keto acids
INTRODUCTION
Cyclic hydroxamic acids are widely distributed in nature, such as in sidero-
phores, antibiotics, and microbial pigments, and exhibit several biological activities,
including inhibitory activities of matrix metalloproteinases, human hypoxia-inducible
factor (HIF) prolyl hydroxylase, phosphatase, interleukin IL-1b converting enzyme
(ICE), and HIV-1 integrase; antagonistic activity of N-methyl-D-aspartate (NMDA)
Received July 3, 2012.
Address correspondence to Yujiro Hoshino, Graduate School of Environment and Information
Sciences, Yokohama National University, Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan.
E-mail: yhoshino@ynu.ac.jp
2484

ENANTIOMERICALLY ENRICHED BICYCLIC HYDROXAMIC ACIDS
2485
receptor; immunosuppressive activity; and antimalarial activity.[1–9] The synthesis of
cyclic hydroxamic acids has attracted the attention of many research groups. One
interesting area of research is the cyclocondensation reaction of a-aminohydroxamic
acids with carbonyl compounds, giving monocyclic hydroxamic acids,
3-hydroxyimidazolidin-4-ones.[10] This cyclocondensation reaction provides a poten-
tially attractive method to stereoselectively prepare the 2,5-disubstituted
3-hydroxyimidazolidin-4-ones, which allows diverse elements to be incorporated at
the C2 and C5 positions.
Chiral acyclic hydroxamic acids have recently received increasing attention as
chiral ligands in the field of asymmetric transition-metal catalysis such as epoxida-
tion of alkenols,[11] alkenylsulfonamides,[12] or simple olefins,[13] oxidation of sul-
fides;[14] and reduction of ketones.[15] On the other hand, chiral cyclic hydroxamic
acids, to the best of our knowledge, have never been examined as a chiral ligand
candidate in asymmetric metal catalysis. The structural diversity of 2,5-disubstituted
3-hydroxyimidazolidin-4-ones makes this compound class convenient for explo-
ration and optimization of chiral cyclic hydroxamic acid ligands and necessitates
the development of stereoselective synthesis of such molecules. Although the
reaction of glycine hydroxamic acid or some racemic a-aminohydroxamic acids with
aldehydes or symmetric ketones have been reported,[10] the examples of diastereose-
lective cyclocondensation of a-aminohydroxamic acids to 2,5-disubstituted
3-hydroxyimidazolidin-4-ones have been fairly limited and have not indicated the
selectivities.[10a-c,h] In addition, the competitive O-alkylation of hydroxamic acids
may result in the unfavorable formation of 1,2,5-oxadiazinan-3-ones,[10a,16] though
N-alkylation of amide N-H preferentially occurred in the condensation of a-amino
acid phenylhydrazides with levulinic acids and carbonyl compounds.[17] Herein we
report the first synthesis of enantiomerically enriched 1-hydroxy-dihydro-
1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones,
a
kind
of
2,5-substituted
3-hydroxyimidazolidin-4-one derivatives, by means of the cyclocondensation of
L-a-aminohydroxamic acids 1a–e with levulinic acid (2) or 5-oxohexanoic acid (5),
which has a feature that enables the facile combinatorial synthesis of the libraries
of chiral cyclic hydroxamic acids from commercially available or easily prepared
a-aminohydroxamic acids and carbonyl compounds. The stereochemistry of
(3S,7aR)-1H-pyrrolo[1,2-a]imidazole-2,5-dione 3a was unambiguously confirmed
by X-ray crystallographic analysis. This method also could be applied to the
cyclocondensation of a-aminohydroxamic acids with o-formylbenzoic acid (6).
RESULTS AND DISCUSSION
L-a-Aminohydroxamic acids 1a–e were prepared in good yields from their
respective methyl esters in a manner similar to the literature procedure.[18] When
L-phenylalanine hydroxamic acid (1a) was treated with levulinic acid (2) in refluxing
toluene, the sparingly soluble compound 3a, which gave a positive (purple) color test
with ferric chloride suggesting the presence of a hydroxamic acid function, was
1
obtained in a good yield (Table 1, entry 1). The H NMR analysis of the solid 3a
suggested a 1:1 condensation product of 1a with 2 but elucidation of the structure
remained ambiguous. The irradiation of CH3 group of 3a caused a positive nuclear
Overhause effect (NOE) for the Ar-H and had no effect on the hydrogen atom of CH

2486
Y. HOSHINO ET AL.
Table 1. Cyclocondensation of a-aminohydroxamic acids (1) with levulinic acid (2)
Entry
1
R1
Conditions
3
Yield (%)
1
2
3
4
5
6
1a
1a
1b
1c
1d
1e
PhCH2
Toluene, reflux, 2 h
3a
3a
3b
3c
3d
3e
84
82
49
59
95
96
Toluene, reflux, 18 h (Dean-Stark app.)
Toluene, 80 ꢀC, 5 h
Toluene, reflux, 4 h
Me
i-Pr
indol-3-ylmethyl
imidazol-4-ylmethyl
2-Propanol, reflux, 2 h; toluene, reflux, 7 h
2-Propanol, reflux, 2 h; toluene, reflux, 7 h
a to the hydroxamic acid moiety (Fig. 1). Similarly, irradiation of the benzylic CH2
led to a positive NOE for the CH3. These 1H NMR data provide evidence for the cis
stereochemistry of the CH3 group to the benzyl group. Finally, the structure of cyclic
hydroxamic acid 3a was established by X-ray diffraction analysis (Fig. 2). It is
important to note that the reaction proceeded in a highly chemo- and stereoselective
manner to give exclusively the cis isomer. This stereochemical outcome is compara-
ble to the related cyclization reactions.[17,19] The procedure using a Dean–Stark
apparatus is also applicable to the condensation, giving the same results (entry 2).
Figure 1. NOE experiment of 3a.
Figure 2. ORTEP diagram of 3a.

ENANTIOMERICALLY ENRICHED BICYCLIC HYDROXAMIC ACIDS
2487
Scheme 1. Cyclocondensation of L-a-aminohydroxamic acids 1 with levulinic acid (2).
Some representative aminohydroxamic acids were evaluated for cycloconden-
sation with levulinic acid (Table 1, entries 3–6). Aliphatic aminohydroxamic acids
1b and 1c gave the cyclic hydroxamic acids 3b and 3c in moderate yields (49–
59%). On the other hand, aromatic aminohydroxamic acids 1d and 1e were sparingly
soluble in toluene and the unknown brown gum substance appeared in the refluxing
reaction mixture. Consequently, the condensations of 1d and 1e with 2 were carried
out in refluxing 2-propanol for 2 h. Then, toluene was added to the reaction mixture,
which was heated to 135 ꢀC while 2-propanol and water were distilled off azeotropi-
cally with toluene. This method gave the desired cyclic hydroxamic acids 3d and 3e in
good yields (95–96%). It is noted that all the products obtained show the cis con-
figuration of methyl group and side chain of aminoacyl moiety.
Next, the possibility of varying the structure of keto acids was examined
(Table 2). Phenyl substituted keto acid 4 was conducted in either toluene or
2-propanol, but the desired phenyl-substituted bicyclic hydroxamic acid was not
obtained at all, presumably because the first ring closure or the second cyclization
might be suppressed by sterically demanded phenyl group. 5-Oxohexanoic acid (5)
was condensed with 1a, affording the corresponding 5-6 bicyclic hydroxamic acid
8 in a good yield.
To expand this method, benzoic acid derivatives were next examined. While the
reaction of formylbenzoic acid 6 with aminohydroxamic acid 1a in the reaction con-
ditions gave poor results (Table 2, entry 2), addition of p-toluenesulphonic acid (0.1
equiv) as an acid catalyst improved the yield of 9 (40%). Because the white solid
intermediate appeared during the reaction, o-xylene (140 ꢀC) was used as solvent
to dissolve the solid, but the yield was not improved. After some trials, use of ben-
zene as solvent and Dean–Stark apparatus for azeotropic distillation resulted in a
good yield (72%). The absolute configuration of the newly generated chiral center
in 9 was determined by NOE experiments. A similar trans-orientation of H3 and
H9b was reported in the related condensations by Katritzky et al.[20] For the reaction
with o-acetylbenzoic acid (7), the starting material aminohydroxamic acid was
Table 2. Cyclocondensation of L-phenylalanine hydroxamic acid (1a) with oxo acids
Entry
Oxo acid
Conditions
Cyclic hydroxamic acid
Yield (%)
1
2
3
4
5
5
6
6
6
6
Toluene, reflux, 7 h
Toluene, reflux, 20 h
8
9
9
9
9
67
15
40
27
72
p-TsOH (0.1 equiv), toluene, reflux, 20 h
p-TsOH (0.1 equiv), xylene, reflux, 20 h
p-TsOH (0.1 equiv), benzene, reflux, 20 h

2488
Y. HOSHINO ET AL.
Scheme 2. Cyclocondensation of L-phenylalanine hydroxamic acid (1a) with oxo acids.
consumed quantitatively, but complex mixtures were obtained. No desired product
was observed in spectroscopic analysis.
In summary, we have demonstrated that the cyclocondensation of L-a-amino-
hydroxamic acids with c- and d-keto acids afforded optically active, sterically rigid
bi- or tricyclic hydroxamic acids in a highly chemo- and stereoselective manner.
The simple experimental procedure along with ready accessibility of reactants is also
an attractive feature. Application of these cyclic hydroxamic acids to catalytic
asymmetric reactions using metal complexes is in progress.
EXPERIMENTAL
Typical Experimental Procedure for the Cyclocondensation
of L-a-Aminohydroxamic Acids (1) with Levulinic Acid
Levulinic acid (0.241 mL, 2.35 mmol) was slowly added to a stirred suspension
of L-phenylalanine hydroxamic acid (1a) (0.326 g, 1.81 mmol) in toluene (30 mL) at
120 ꢀC. After the reaction mixture was stirred for 2 h at the same temperature, it
was carefully concentrated to about 10 mL by evaporation and stood at room tem-
perature overnight. The precipitated white solid was filtrated and washed with
diethyl ether to afford bicyclic hydroxamic acid 3a (0.397 g, 84%). The stereochem-
istry of 3a was determined by NOE experiments and X-ray diffraction analysis.
(3S,7aR)-3-Benzyl-1-hydroxy-7a-methyl-dihydro-1H-pyrrolo
[1,2-a]imidazole-2,5(3H,6H)-dione (3a)
25
Colorless crystal; mp 205 ꢀC; Rf 0.35 (ethyl acetate); [a]D þ 118 (c ¼ 1.0,
CHCl3); IR (KBr) 3127, 2928, 2867, 1727, 1700, 1666, 1458, 1332, 702, 574 cmꢁ1
;
1H NMR (270 MHz, CDCl3) d 0.99 (s, 3H), 2.17–2.45 (m, 3H), 2.61–2.76 (m, 1H),
3.07 (dd, J ¼ 5.9, 13.9 Hz, 1H), 3.16 (dd, J ¼ 5.3, 13.9 Hz, 1H), 4.60 (t, J ¼ 5.9 Hz,
1H), 7.17–7.32 (m, 5H); 13C NMR (68 MHz, CDCl3) d 24.0, 30.9, 34.7, 36.9, 58.3,
82.3, 127.1, 128.5, 129.9, 135.9, 168.4, 178.6. Anal. calcd for C14H16N2O3: C,
64.60; H, 6.20; N, 10.76. Found: C, 64.34; H, 6.17; N, 10.66.
Crystal Data for 3a
C14H16N2O3; M ¼ 260.29, colorless block crystals, 0.30 ꢂ 0.30 ꢂ 0.10 mm,
orthorhombic, space group P212121 (no. 19), a ¼ 11.327(7), b ¼ 13.653(6),

ENANTIOMERICALLY ENRICHED BICYCLIC HYDROXAMIC ACIDS
2489
3
c ¼ 8.520(3) A, V ¼ 1317.(1) A , Z ¼ 4, Dc ¼ 1.31 g cmꢁ3. F(000) ¼ 552, m(CuKa) ¼
˚
˚
0.769 mmꢁ1
.
Typical Experimental Procedure for the Cyclocondensation of
Aromatic L-a-Aminohydroxamic Acids (1) with Levulinic Acid
Levulinic acid (1d) (0.241 mL, 2.35 mmol) was slowly added to a stirred suspen-
sion of L-tryptophan hydroxamic acid (0.397 g, 1.81 mmol) in 2-propanol (30 mL) at
80 ꢀC. The mixture was stirred at the same temperature and monitored by thin-layer
chromatography (TLC). After stirring for 2 h at 80 ꢀC, the temperature was raised to
120 ꢀC, and toluene (35 mL) was added in small portions to remove 2-propanol by
azeotropic distillation. After an additional stirring for 7 h, the volatile compounds
were evaporated under reduced pressure. Dichloromethane and Na2CO3 were added
to the mixture and stirred vigorously for 1 h. The precipitated crystal was filtrated
and washed with diethyl ether to give bicyclic hydroxamic acid 3d (0.516 g, 95%).
(3S,7aR)-1-Hydroxy-3-(1H-indol-3-ylmethyl)-7a-methyl-dihydro-1H-
pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione (3d)
25
Colorless crystal; mp 219–220 ꢀC; Rf 0.34 (ethyl acetate); [a]D þ 74.7 (c ¼ 1.0,
methanol); IR (KBr) 3311, 2658, 1698, 1509, 1459, 1427, 1354, 1136, 751, 595 cmꢁ1
;
1H NMR (400 MHz, CD3OD) d 0.65 (s, 3H), 2.07–2.34 (m, 3H), 2.61–2.70 (m, 1H),
3.21–3.37 (m, 2H), 4.52 (t, J ¼ 4.9 Hz, 1H), 6.95–7.08 (m, 3H), 7.30 (d, J ¼ 8.1 Hz,
1H), 7.50 (d, J ¼ 8.1 Hz, 1H); 13C NMR (68 MHz, CD3OD) d 23.5, 27.3, 31.9,
36.0, 59.7, 83.6, 110.8, 112.2, 119.6, 119.8, 122.4, 124.9, 129.6, 137.8, 170.1, 180.8.
Anal. calcd for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04. Found: C, 63.79; H,
5.73; N, 13.95.
Cyclocondensation of L-Phenylalanine Hydroxamic Acid (1a) with
o-Formylbenzoic Acid
L-Phenylalanine hydroxamic acid (1a) (0.360 g, 1.81 mmol), o-formylbenzoic
acid (0.300 g, 2.00 mmol), p-toluenesulfonic acid monohydrate (0.038 g, 0.20 mmol),
and benzene (20 mL) were refluxed in a 50-mL, two-necked flask equipped with
Dean–Stark apparatus for 20 h, after which no more water appeared to be evolved
from the reaction. The mixture was concentrated by evaporation until a white solid
appeared. The solid was filtered off, and the filtrate stood at room temperature. The
precipitated white solid was filtered and washed with ether to afford tricyclic hydro-
xamic acid 9 (0.421 g, 72%). The stereochemistry of 9 was determined by NOE
experiments.[20]
(3S,9bR)-3-Benzyl-1-hydroxy-1,9b-dihydro-imidazo[2,1-a]isoindole-
2(3H),5-dione (9)
25
Colorless crystal; mp 189–190 ꢀC; Rf 0.51 (ethyl acetate); [a]D þ 153 (c ¼ 1.0,
CHCl3); IR (KBr) 3063, 2924, 2831, 1716, 1695, 1374, 1215, 742, 706, 695, 507 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 3.15 (dd, J ¼ 5.1, 13.9 Hz, 1H), 3.21 (dd, J ¼ 4.1,

2490
Y. HOSHINO ET AL.
13.9 Hz, 1H), 4.59 (t, J ¼ 4.4 Hz, 1H), 4.79 (s, 3H), 7.22–7.35 (m, 5H), 7.53–7.63 (m,
3H), 7.81 (d, J ¼ 7.2 Hz, 1H), 9.67 (br s, 1H); 13C NMR (68 MHz, CDCl3) d 37.1,
58.8, 74.7, 124.3, 124.8, 127.4, 128.6, 129.9, 130.7, 131.8, 133.2, 135.1, 142.1,
172.5, 173.5. Anal. calcd for C17H14N2O3: C, 69.38; H, 4.79; N, 9.52. Found: C,
69.22; H, 4.79; N, 9.48.
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra can be found via the
Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
We are grateful to Nobuto Minowa (Meiji Seika Kaisha, Ltd.) for X-ray
diffraction analysis of 3a. We also thank Seiichi Inoue (Yokohama National Univer-
sity, Japan) for his suggestions and valuable discussions. We are grateful to Nissan
Chemical Industries, Ltd., for financial support.
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