Synthesis of homochiral dihydroxy-4-nitroisoxazolines via one-pot asymmetric dihydroxylation-reduction

Article abstract of DOI:10.1021/ol800397z

Herein we report a one-pot procedure to prepare a family of homochiral dihydroxy-4-nitroisoxazolines 3. This new methodology affords the title compounds in good yields, excellent enantiopurity, and without the use of chromatography.

Full text of DOI:10.1021/ol800397z

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1807-1810
Synthesis of Homochiral
Dihydroxy-4-nitroisoxazolines via
One-Pot Asymmetric
Dihydroxylation-Reduction
Mauro F. A. Adamo* and Murali Nagabelli
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical
and Medicinal Chemistry, The Royal College of Surgeons in Ireland, 123 St. Stephen’s
Green, Dublin 2, Ireland
madamo@rcsi.ie
Received February 20, 2008
ABSTRACT
Herein we report a one-pot procedure to prepare a family of homochiral dihydroxy-4-nitroisoxazolines 3. This new methodology affords the
title compounds in good yields, excellent enantiopurity, and without the use of chromatography.
4-Nitro-5-styrylisoxazoles 1 (Scheme 1) have emerged as
useful building blocks for the synthesis of medicinally
Scheme 1. Retrosynthetic Analysis of Targets 6
relevant compounds including propionic acids1–4 and novel
heterocycles.5–7 As a part of our ongoing efforts in develop-
ing one-pot procedures to access families of small bioactive
molecules, we envisaged that styrylisoxazoles of general
structure 1 could serve as starting materials for the prepara-
tion of ∆2 isoxazolines 3 and polyaminoalcohols 6. Com-
pounds 6 have shown a rich medicinal chemistry8 and have
(1) Adamo, M. F. A.; Duffy, E. F. Org. Lett. 2006, 8, 5157–5159
(2) Adamo, M. F. A.; Konda, V. R. Org. Lett. 2007, 9, 303–305
(3) Adamo, M. F. A.; Donati, D.; Duffy, E. F.; Sarti-Fantoni, P.
Tetrahedron 2007, 63, 2047
(4) Adamo, M. F. A.; Donati, D.; Duffy, E. F.; Sarti-Fantoni, P.
Tetrahedron 2007, 63, 2684
(5) (a) Adamo, M. F. A.; Chimichi, S.; De Sio, F.; Donati, D.; Sarti-
Fantoni, P. Tetrahedron Lett. 2002, 43, 4157–4160. (b) Adamo, M. F. A.;
Donati, D.; Duffy, E. F.; Sarti-Fantoni, P. J. Org. Chem. 2005, 70, 8395–
.
.
.
been used as precursors for the preparation of pyrrolidines,9
piperidines,10 aminosugars,11 or complex natural products.12
In our plan, compounds 1 would be submitted to a prelimi-
.
8399
.
(6) Adamo, M. F. A.; Nagabelli, M. Tetrahedron Lett. 2007, 48, 4703–
4706
.
(9) (a) Setoi, H.; Kayakiri, H.; Takeno, H.; Hashimoto, M. Chem. Pharm.
Bull. 1987, 35, 3995–3999. (b) Fleet, G. W. J.; Son, J. C.; Green, D. C.;
Bello, I. C.; Winchester, B. Tetrahedron 1988, 44, 2649–2655. (c) Ikota,
N.; Hanaki, A. Chem. Pharm. Bull. 1989, 37, 1087–1089.
(10) Marwenna, S. M. P.; Monique, M. A.; Valerie, F.; Jacques, L. Eur.
J. Org. Chem. 2005, 11, 2159–2191.
(7) Adamo, M. F. A.; Konda, V. R.; Donati, D.; Sarti-Fantoni, P.;
Torroba, T. Tetrahedron 2007, 63, 9741–9745
.
(8) (a) Umezawa, H.; Aoyagi, T.; Morishima, H.; Matsuzaki, M.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1970, 23, 259. (b) Aoyagi, T.; Tobe,
H.; Kojima, F.; Hamada, M.; Takeuchi, T. J. Antibiot. 1978, 31, 636. (c)
Umezawa, H.; Aoyagi, T.; Suda, H.; Hamada, M.; Takeuchi, T. J. Antibiot.
(11) Golebiowski, A.; Jurczak, J. Synlett 1993, 241–248.
(12) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
1976, 29, 97
.
10.1021/ol800397z CCC: $40.75
Published on Web 04/02/2008
2008 American Chemical Society

Table 1. Synthesis of Compounds 2a-j
Table 2. Isolated Yields of 3a-j and 4a-j
entry
product
Ar
yield %a
ee %
% yield % yield % yield
entry reactant
Ar
of 3a
of 3b
of 4b
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5
95
96
98
93
96
96
95
97
97
90
75d
92c
88c
1
2
3
4
5
2a
2b
2c
2d
2e
2f
C6H5
61
63
62
61
63
61
65
62
62
58
15
18
14
15
15
16
14
14
11
13
20
16
16
20
15
14
18
10
12
18
4-F-C6H4
4-Cl-C6H4
4-F-C6H4
4-Cl-C6H4
3,4-(OCH3)-C6H3
3-CH3-C6H4
4-(OCH3)-C6H4
4-NO2-C6H4
2-Cl-C6H4
4-CN-C6H4
2-naphthyl
3-indolyl
94c
94b
92c
94b
3,4-(OCH3)-C6H3
3-CH3-C6H4
4-(OCH3)-C6H4
4-NO2-C6H4
2-Cl-C6H4
6
7
8
9
2g
2h
2i
9
80c
4-CN-C6H4
2-naphthyl
10
11
12
2j
2k
2l
10
2j
a Yields obtained after filtration. b Yields obtained from the mother liquor
2-furyl
a Isolated yields. b Determined using Chiral HPLC analysis using a
Chiralcel-AD column, 10% isopropanol in n-heptane as an eluent.
c Determined using Chiral HPLC analysis using a Chiralcel-OJ column,
10% isopropanol in n-heptane as an eluent. d Obtained using 1 equiv of
OsO4 in pyridine.
using column chromatography.
alkenes were used.21 For this reason, the development of
alternative and practical methods for the preparation of
functionalized ∆2 isoxazolines continues to be an attractive
subject of research.22,23 In this context, we decided to develop
a one-pot procedure to convert isoxazoles 1 to ∆2 isoxazo-
lines 3 that involved sequential dihydroxylation–reduction.
Considering that compounds 1 could be easily prepared from
commercially available 3,5-dimethyl-4-nitroisoxazole and an
aromatic aldehyde,24 this procedure would furnish a rapid
and practical entry to potentially bioactive compounds. It
was recognized that dihydroxylation and reduction could be
run in one pot provided that (a) conversion of 2 to 3 does
not require protection of the hydroxyls; (b) the reducing agent
is compatible with the presence of small quantities of OsO4.
In order to find an optimal set of conditions, the conversions
of 1 to 2 (Table 1) and of 2 to 3 (Table 2) were independently
studied.
nary Sharpless asymmetric dihydroxylation13 and the result-
ing dihydroxyisoxazoles 2 converted to dihydroxyisoxazo-
lines 3 by partial reduction of the 4-nitroisoxazole core. In
this context, the Sharpless dihydroxylation reaction would
serve as a means to functionalize the exocyclic alkene in 1
and to set the absolute stereochemistry in the final compounds
6. We have extensively studied the reactivity of 4-nitro-5-
styrylisoxazoles toward nucleophiles.1–7 On the basis of these
studies, we anticipated the 4-nitroisoxazole moiety in 2 would
undergo reaction to give ∆2 isoxazolines 3 when reacted with
a suitable metal hydride. ∆2 Isoxazolines are medicinally
relevant compounds that possess a plethora of biological
activities including antibacterial,14 antiplatelet,15 antiviral,16
anticonvulsant,17 immunostimulatory,18 and antihyperten-
sive.19 ∆2 Isoxazolines are also valuable building blocks for
the preparation of ꢀ-hydroxy carbonyls or ꢀ-aminoalcohols.20
The conventional method of preparation of ∆2 isoxazolines
involves a 1,3-dipolar cycloaddition of nitrile oxides to
alkenes. This reaction is highly regioselective. However, high
asymmetric induction could be observed only when chiral
In a test experiment, we reacted 5-styryl-4-nitroisoxazole
1a (Table 1) with a catalytic amount of OsO4 (0.05 equiv),
DHQD2Phal (0.1 equiv), and an excess (2.2 equiv) of
N-methylmorpholine (NMO).
Under these conditions, dihydroxyisoxazole 2a was ob-
tained in high yield and enantioselectivity (Table 1, entry
1). The conversion of 1a to 2a was studied in various solvents
including pyridine and mixtures of tBuOH/H2O, EtOH/H2O,
MeOH/H2O, (CH3)2CO/H2O, and THF/H2O. This study
identified mixtures of THF/H2O (10:1 or 20:1) as the optimal
medium. Similarly, 4-nitro-5-styrylisoxazoles 1b-j contain-
ing a substituted phenyl ring were converted to the corre-
(13) Hartmuth, C.; Kolb, M.; VanNieuwenhze, S.; Sharpless, K. B.
Chem. ReV. 1994, 94, 2483–2547.
(14) Kang, Y. K.; Shin, K. J.; Yoo, K. H.; Seo, K. J.; Hong, C. Y.; Lee,
C.; Park, S. Y.; Kim, D. J.; Park, S. W. Bioorg. Med. Chem. Lett. 2000,
10, 95–103.
(15) Xue, C.; Roderick, J.; Mousa, S.; Olson, R. E.; DeGrado, W. F.
Bioorg. Med. Chem. Lett. 1998, 8, 3499–3509.
(16) Diana, G. D.; McKinlay, M. A.; Brisson, C. J.; Zalay, E. S.;
Miralles, J. V.; Salvador, U. J. J. Med. Chem. 1985, 28, 748–759.
(17) Lepage, F.; Tombert, F.; Cuvier, G.; Marivain, A.; Gillardin, J. M.
Eur. J. Med. Chem. 1992, 27, 581–588.
(21) Lee, C. K. Y.; Herlt, A. J.; Simpson, G. W.; Willis, A. C.; Easton,
C. J. J. Org. Chem. 2006, 71, 3221–3231
(22) Kumar, R. R.; Perumal, S. Tetrahedron 2007, 63, 12220–12231
(23) Kaffy, J.; Pontikis, R.; Carrez, D.; Croisy, A.; Monneret, C.; Florent,
.
(18) Ryng, S.; Machon, Z.; Wieczorek, Z.; Zimecki, M.; Mokrosz, M.
Eur. J. Med. Chem. 1998, 33, 831–835.
.
(19) Dallanoce, C.; Meroni, G.; De Amici, M.; Hoffman, C.; Klotz, K.-
N.; De Micheli, C. Bioorg. Med. Chem. 2006, 14, 4393–4401.
(20) Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587–1590.
J.-C. Bioorg. Med. Chem. 2006, 14, 4067–4077.
(24) Adamo, M. F. A.; Duffy, E. F.; Konda, V. R.; Murphy, F.
Heterocycles 2007, 71, 1173–1181.
1808
Org. Lett., Vol. 10, No. 9, 2008

Scheme 2
.
Reduction of Compounds 2a
Table 3. One-Pot Synthesis of 3a-j and 4a-j
% yield % yield % yield
entry reactant
Ar
of 3a
of 3b
of 4b
sponding diols 2b-j (Table 1). 4-Nitro-5-styrylisoxazoles
1k-l bearing an aromatic heterocycle failed to give the
desired diols 2k-l. In particular, the indolyl-substituted
4-nitro-5-styrylisoxazole 1k was dihydroxylated only in the
presence of a stoichiometric amount of OsO4. The dihy-
droxylation of 1l gave a complex reaction mixture.
Having determined a set of conditions to prepare 2a-k,
we turned our attention to the synthesis of isoxazolines 3.
NaBH4 was selected as the reducing agent since (a) this
hydride is compatible with the presence of free alcohols and
does not require alcohol protection, (b) the 4-nitroisoxazolyl
core is prone to react with mild nucleophiles; less reactive
4-carbethoxyisoxazoles also underwent reduction when
treated with NaBH4.21 In a preliminary test, compound 2a
was reacted with NaBH4 (3.0 equiv) in MeOH. Under these
conditions, a complete conversion of 2a occurred and
isoxazolines 3a and 4a were obtained in 75 and 20% yields,
respectively (Scheme 2).
1
2
3
4
5
1a
1b
1c
1d
1e
1f
C6H5
63
61
58
63
65
62
65
64
61
57
11
14
12
13
12
13
11
15
12
10
15
13
12
15
14
12
16
5
4-F-C6H4
4-Cl-C6H4
3,4-(OCH3)-C6H3
3-CH3-C6H4
4-(OCH3)-C6H4
4-NO2-C6H4
2-Cl-C6H4
6
7
8
9
1g
1h
1i
4-CN-C6H4
2-naphthyl
11
15
10
1j
a Yields obtained after filtration. b Yields obtained from the mother liquor
using column chromatography.
Importantly, it was confirmed that the dihydroxylation of
1a-j to obtain 2a-j and the subsequent reduction to ∆2
isoxazolines 3a-j could be performed in one pot (Table 3).
Compounds 1a-j were first submitted to dihydroxylation
and then, upon disappearance of starting material, treated
with a solution of NaBH4 in methanol. This procedure
furnished compounds 3a-j and 4a-j in high yields and in
a diastereoisomeric ratio similar to that of the stepwise
process (Table 3).
Isoxazolines 3a-j and 4a-j constitute two classes of versatile
synthons that could be employed for the preparation of other
compounds.25 In order to evaluate their potential in synthesis,
we have submitted compound 3c to reaction with several
reducing agents. Isoxazoline 3c was therefore reacted with Pd/C
and H2,26 Zn0/HCl,27 Mo(CO)6,28 NaBH4, and LiAlH4 under
several reaction conditions. These experiments furnished a
complex reaction mixture in which imine 5c (Table 4) was
obtained contaminated by several side products. The reaction
of 3c with excess Zn0/CH3COOH29 furnished iminoalcohol 5c
in high isolated yield and as a single diastereoisomer (Table
4). The identity of compounds 5 was confirmed by 13C NMR
and by 2D NMR studies carried out on compound 5f. In
particular, one signal is present in the 13C NMR of compounds
5f at ca. 159 ppm that is a quaternary carbon. Additionally, in
the HMBC-NMR spectrum, a resonance occurred between the
protons of the methyl group (1.87 ppm) and the carbon of the
imine (159 ppm).30
The structure of the major product 3a was elucidated by
X-ray analysis. The structure of 4a was identified by
1
comparison of its H NMR, 13C NMR, and NOE data with
those of 4a. In particular, in compound 3a, NOE enhance-
ment was noted between Hb and Hd, while in compound 4a,
NOE enhancements were noted between Ha and Hb and
between Hb and Hc; this latter one being determinant for the
stereochemical assignment.
The preferential formation of compound 3a over 4a could
be explained by a chelation control exerted by the alcohol
functionalities present in 2a. Hence, formation of compound
3a occurred by delivery of hydride to the more hindered face
of the isoxazole. We have briefly investigated the effect of
temperature and rate of addition of NaBH4 on the ratio 3a:
4a, but we have noted only small variations. The relative
stereochemistry of the two stereogenic centers formed on
the ∆2 isoxazoline ring was exclusively trans.
Diols 2b-j were submitted to reaction with NaBH4, and
the correspondent ∆2 isoxazolines 3b-j and 4b-j were
obtained in high isolated yields (Table 2).
Notably, compounds 3a-j were obtained pure without the
use of chromatography. It was noted that compound 3a
precipitated at the end of the reaction by means of an aqueous
acidic workup (Table 2). A sample of 3a was analyzed by
chiral HPLC, and its enantiomeric purity was determined as
97% ee. Compounds 3b-j behaved similarly and were
isolated in good yields (Table 2). The ease of purification
of 3a-j rendered their preparation operationally simple and
practical. The isomeric 4a-j were purified by flash chro-
matography together with an additional amount of 3a-j
present in the mother liquor.
(25) Patrick, A.; Lisbet, K.; Roger, W. G.; Florian, K.; Carreira, E. M.
Org. Lett. 2005, 7, 5741–5742.
(26) Caplan, J. F.; Zheng, R.; Blanchard, J. S.; Vedeiras, J. C. Org.
Lett. 2000, 2, 3857–3860.
(27) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262–1269.
(28) (a) Nitta, M.; Kobayashi, T. J. Chem. Soc., Chem. Commun. 1982,
877–878. (b) Baraldi, P. G.; Barco, A.; Benetti, S.; Guarneri, M.; Manfredini,
S.; Pillini, G. P.; Simoni, D. Tetrahedron Lett. 1985, 26, 5319–5322.
(29) (a) Watanabe, Y.; Iida, H.; Kibayashi, C. J. Org. Chem. 1989, 54,
4088–4097. (b) Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki, K. Org.
Lett. 2003, 5, 391–394. (c) Lepore, S. D.; Schacht, A. L.; Wiley, M. R.
Tetrahedron Lett. 2002, 43, 8777–8779.
Org. Lett., Vol. 10, No. 9, 2008
1809

Table 4. Yields of Iminoalcohols 5c-h
Scheme 3. Synthesis of Compound 10
entry reactant
Ar
product % yield of 5a
1
2
3
4
5
3c
3d
3e
3f
4-Cl-C6H4
3,4-(OCH3)-C6H3 5d
3-CH3-C6H4
4-(OCH3)-C6H4
2-Cl-C6H4
5c
76
62
54
68
80
5e
5f
5h
3h
a Isolated yield after chromatography.
In conclusion, we have developed a practical one-pot
dihydroxylation-reduction procedure that afforded homo-
chiral ∆2-isoxazolines 3a-j in good yields and without the
use of column chromatography. The synthetic potential of
compounds 3 was then explored, identifying an efficient
methodology to generate enantiopure iminoalcohols 5c-h.
A strategy to obtain protected polyaminoalcohols 10 was also
described. Applications of this synthetic strategy to the
preparation of natural bioactive compounds are in progress.
This latter proved unequivocally that in 5f the CH3 is
bound to an sp2 quaternary carbon. Isoxazolines 3c-h reacted
similarly to afford iminoalcohols 5c-h in high yields (Table
4).
Compounds 5c-h showed a remarkable resistance to
reduction and were recovered unreacted after treatment with
NaCNBH3, Zn/NaOH, or Zn/Zn(TfO)2. Reaction of 5c with
LiAlH4 or hydrogenolysis in the presence of Pd/C gave a
complex mixture of compounds. It is possible that in
compounds 5 a hydrogen bond is formed between the imine
and the vicinal hydroxyls that is responsible for their
exceptional stability.
Acknowledgment. We would like to acknowledge PTRLI
cycle III for a grant to M.F.A.A. and the Health Research
Board (HRB) for financial support to M.N.
Supporting Information Available: General procedures
for the preparation of compounds 2a-j (Table 1), 3a-j, and
4a-j (Table 2) and for compounds 5c-h (Table 4);
procedure for the one-pot preparation of compounds 3a-j
Imine 9 (Scheme 3), in which two hydroxyls and the amine
were protected, underwent fast and efficient reduction when
treated with NaBH4 in the presence of NiCl2·H2O. The
identity of compound 10 was confirmed by 13C NMR and
by 2D NMR. In particular, in the 1H NMR, a doublet at 0.92
ppm integrating for 3H (CH3) and a multiplet at 3.16 ppm
integrating for 1H (2HNCHCH3) are present. The doublet at
0.92 ppm and the multiplet at 3.16 ppm resonate in the H-H
COSY. We have attempted to elucidate the stereochemistry
of the newly formed chiral center in 10 by running NOE
studies, but results collected were inconclusive.
1
and 4a-j (Table 3). Spectroscopic data and copies of H
NMR and 13C NMR for compounds 2a-j, 3a-j, 4a-j, 5c-f
and 5h, 7, 8, 9, and 10; chiral HPLC chromatograms of
compounds 2a-j; chiral HPLC chromatogram of 3a ac-
etonide; X-ray diagram of compound 3a; 2D NMR, HMBC-
NMR, and HMQC-NMR of compound 5f and 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(30) The 1D and 2D NMR spectra and a full assignment of 1H and 13
NMR are included in the Supporting Information.
C
OL800397Z
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Org. Lett., Vol. 10, No. 9, 2008