One-pot direct conversion of 2,3-epoxy alcohols into enantiomerically pure 4-hydroxy-4,5-dihydroisoxazole 2-oxides

Article abstract of DOI:10.1021/ol0070379

Equation presented A new methodology for the one-pot direct conversion of 2,3-epoxy alcohols into enantiomerically pure 4-hydroxy-4,5-dihydroisoxazole 2-oxides 1 has been found. The reaction works at room temperature and can be run at the 5-10 g scale. Th

Full text of DOI:10.1021/ol0070379

ORGANIC
LETTERS
2001
Vol. 3, No. 5
727-729
One-Pot Direct Conversion of 2,3-Epoxy
Alcohols into Enantiomerically Pure
4-Hydroxy-4,5-dihydroisoxazole 2-Oxides
Emanuela Marotta, Laure Marie Micheloni, Noemi Scardovi, and Paolo Righi*
Dipartimento di Chimica Organica “A. Mangini”, UniVersita` di Bologna,
Viale del Risorgimento, 4 - I-40136 Bologna, Italy
righi@ms.fci.unibo.it
Received December 21, 2000
ABSTRACT
A new methodology for the one-pot direct conversion of 2,3-epoxy alcohols into enantiomerically pure 4-hydroxy-4,5-dihydroisoxazole 2-oxides
1 has been found. The reaction works at room temperature and can be run at the 5−10 g scale. The mixture of 4,5-cis and 4,5-trans isomers
obtained can be separated as such or as the bis-TDS ethers. A preliminary example of reductive cleavage of 1 to the corresponding amino
polyol is also reported.
4-Hydroxy-4,5-dihydroisoxazoles (Figure 1) represent a very
interesting subclass of the dihydroisoxazole family,1 since
Unfortunately, the usual method for the preparation of 4,5-
dihydroisoxazoles, nitrile oxide cycloaddition to alkenes,
cannot be applied to the synthesis of 4-hydroxy derivatives.
In fact, when vinyl ethers are employed, 5-oxygenated rather
than 4-oxygenated heterocycles are obtained with cyclo-
addition to furans being an exception.2b,e
An even more difficult problem is represented by the
preparation of enantiomerically pure products. Some ap-
proaches to this problem have been devised,2,4,5 but each one
of these methodologies suffers from one or more of the
following disadvantages: lack of generality, chiral auxiliries
that require several steps to prepare and are not readily
available in both enantiomerically pure forms, and low ee
values of the products.
For the past 10 years we have been investigating a new
approach for the synthesis of 2-oxide derivatives of these
heterocycles based on the tandem nitroaldol-intramolecular
cyclization reaction between an activated primary nitroalkane
and an aldehyde bearing a leaving group on the R-position
(Scheme 1).6,7
Figure 1. General structure of 4-hydroxy-4,5-dihydroisoxazoles.
the several manipulations possible at the heterocyclic ring
can lead to expeditious preparations of biologically interest-
ing compounds.2,3
(1) Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p 1069.
(2) For examples, see: (a) Vogel, P.; Schaller, C. Synlett 1999, 1219.
(b) Schaller, C.; Vogel, P.; Ja¨ger, V. Carbohyr. Res. 1998, 314, 25. (c)
Wade, P. A.; Shah, S. S.; Govindarajan, L. J. Org. Chem. 1994, 59, 7199.
(d) Panek, J. S.; Beresis, R. T. J. Am. Chem. Soc. 1993, 115, 7898. (e) Yin,
H.; Franck, R. W.; Chen, S.-L.; Quigley, G. J.; Todaro, L. J. Org. Chem.
1992, 57, 644. (f) Ja¨ger, V.; Schro¨ter, D. Synthesis 1990, 556. (g) Schwab,
W.; Ja¨ger, V. Angew. Chem., Int. Ed. Engl. 1981, 20, 603.
(4) Davis, F. A.; Kumar, A.; Reddy, R. E.; Chen, B.-C.; Wade, P. A.;
Shah, S. W. J. Org. Chem. 1993, 58, 7591.
(3) Recently, it has also been found that a 4-oxygenated-4,5-dihydroisox-
azole derivative is itself biologically active as a galactosidase inhibitor.
Schaller, C.; Demange, R.; Picasso, S.; Vogel, P. Bioorg. Chem. Med. Lett.
1999, 277.
(5) Zhang, A.; Kan, Y.; Zhao, G.-L.; Jiang, B. Tetrahedron 2000, 56,
965. (b) Wallace, R. H.; Liu, J.; Zong, K. K.; Eddings, A. Tetrahedron
Lett. 1997, 38, 6791. (c) Liu, J.; Eddings, A.; Wallace, R. H. Tetrahedron
Lett. 1997, 38, 6795.
10.1021/ol0070379 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/03/2001

Scheme 1. Tandem Nitroaldol-Intramolecular Cyclization
Preparation of 4-Hydroxy-4,5-dihydroisoxazole 2-Oxides
Table 1. Results of the One-Pot Reactions Depicted in Scheme
2
In our continuing efforts to perform the “chiral switch”
of the tandem procedure depicted in Scheme 1,8 we turned
our attention to 2,3-epoxy aldehydes. These substrates, which
can be obtained by oxidation of the corresponding glycidols,
are very interesting starting materials for this process. During
the intramolecular cyclization they undergo a stereospecific
epoxide ring opening, affording 4,5-dihydroisoxazoles of type
1, possessing an additional acyclic and stereochemically
defined chiral center bearing a hydroxy group.6a A drawback
of this procedure is that, in many cases, these aldehydes are
difficult to isolate from the oxidation medium, if at all, as is
the case for simple glycidols, such as 3a and 3b. The overall
yields for the glycidol oxidation-tandem sequence is usually
in the range 0-40%.
a 4,5-Cis/4,5-trans ratio. b Prepared according to ref 11.
procedure are much better than those obtained for the two-
step sequence, and especially for 4,5-dihydroisoxazoles 1a
and 1b which could not be obtained with the previous
methodology.
In this Letter we describe a new one-pot consecutive9
conversion of enantiomerically pure 2,3-epoxy alcohols into
4-hydroxy-4,5-dihydroisoxazole 2-oxides 1 that requires no
isolation of the intermediate aldehyde. For this purpose we
screened several oxidation methodologies to find one that is
compatible with the rest of the new one-pot procedure and
found the Piancatelli oxidation10 to be the one of choice.
Under these conditionssbisacetoxyiodobenzene (BAIB) as
the stoichiometric oxidant and tetramethylpiperidinyloxy
radical (TEMPO) as the catalysts2,3-epoxy alcohols 3 were
smoothly converted at room temperature to the corresponding
aldehydes in 4-5 h. Addition of ethyl nitroacetate and
imidazole at this stage completed the one-pot consecutive
process and afforded, after another 18-24 h stirring at room
temperature, the corresponding 4-hydroxy-4,5-dihydroisox-
azole 2-oxides 1 as a mixture of 4,5-cis and 4,5-trans isomers
(Scheme 2 and Table 1), where the former slightly predomi-
nates.
The 4,5-cis or 4,5-trans stereochemical configuration of
the dihydroisoxazoles obtained has been assigned by means
of the coupling constant between the protons on C4 and C5
and through NOE experiments. The low selectivity of this
process is of course a drawback, but it can also be considered
an advantage since both diastereoisomers are easily available
in gram quantities. Moreover, considering that starting 2,3-
epoxy alcohols can be obtained in every stereochemical
configuration through Sharpless asymmetric epoxidation, this
procedure makes available 4,5-dihydroisoxazole of type 1
in every absolute stereochemical configuration at C4 and C5
of the heterocyclic ring.
The mixture of diastereoisomeric products could be
separated directly by flash column chromatography in the
case of 4,5-dihydroisoxazoles 1c and 1d, while products 1a
and 1b required preliminary derivatization as the bis-tert-
butyldimethylsilyl (TDS) ethers 4a and 4b. If needed, the
stereoisomerically pure 4,5-cis- and 4,5-trans-4a,b can be
deprotected to the corresponding free diols 1a,b, under the
usual conditions (anhydrous tetrabutylammonium fluoride in
THF) in yields ranging from 78% to 90%.12
These reactions could usually be carried out on a 5-10 g
scale, and Table 1 reports the isolated yields and diastereo-
isomer ratios of the products for the reactions with four
different 2,3-epoxy alcohols, chosen to demonstrate the
generality of this approach. Yields of this new one-pot
(6) (a) Rosini, G.; Marotta, E.; Righi, P.; Seerden, J.-P. J. Org. Chem.
1991, 56, 6258. (a) Rosini, G.; Galarini, R.; Marotta, E.; Righi, P. J. Org.
Chem. 1990, 55, 781. For a review on the nitroaldol reaction, see: Rosini,
G. The Henry (Nitroaldol) Reaction. In ComprehensiVe Organic Synthesis;
Trost, B. M., Heathcock, C. H., Eds; Pergamon Press: Oxford, 1991; Vol.
2, p 321.
(7) (a) Righi, P.; Marotta, E.; Rosini, G. Chem. Eur. J. 1998, 4, 2501.
(b) Righi, P.; Marotta, E.; Landuzzi, A.; Rosini, G. J. Am. Chem. Soc. 1996,
118, 9446.
Scheme 2. One-Pot Consecutive Transformation of 2,3-Epoxy
Alcohols 3 into 4-Hydroxy-4,5-dihydroisoxazole 2-Oxides 1
(8) Marotta, E.; Baravelli, M.; Maini, L.; Righi, P.; Rosini, G. J. Org.
Chem. 1998, 63, 8235.
(9) For a clear explanation of the terms tandem, consecutive, and domino
process, see: Tietze, L. Chem. ReV. 1996, 96, 115.
(10) Piancatelli, G.; Margherita, R.; De Mico, A.; Parlanti, L.; Vescovi,
A. J. Org. Chem. 1997, 62, 6974.
(11) Kim, Y. J.; Ichikawa, M.; Ichikawa, Y. J. Org. Chem. 2000, 65,
2599.
(12) See Supporting Information for full details.
728
Org. Lett., Vol. 3, No. 5, 2001

Each of the bis-TDS ethers, 4,5-cis- and 4,5-trans-4a-c,
could be deoxygenated in very good yields,6a,8 by exposure
to hot trimethyl phosphite, to obtain the corresponding 4,5-
dihydroisoxazoles 5a-c (Table 2). Again, if needed, depro-
tection of these compounds can afford the stereoisomerically
pure free diols.12
Scheme 3. Linearization of a 4,5-Dihydroisoxazole Derivative
Table 2. Deoxygenation of 4,5-Dihydroisoxazole 2-Oxides
configuration of the newly formed chiral center was assigned
on the basis of known steric considerations,2e,f,g assuming
that the reducing agent attacks from the opposite side of the
two bulky silyloxy groups on C4 and C5.
substrate
yield (%)
To summarize, in this Letter we reported a new gram-
scale one-pot preparation of enantiomerically pure 5-hy-
droxylakyl-4-hydroxy-4,5-dihydroisoxazole 2-oxides 1. The
advantage of this new approach is the establishment of a
direct link between one of the more easily available enan-
tiomerically pure substrates, 2,3-epoxy alcohols, and 4-hy-
droxy-4,5-dihydroisoxazoles, intermediates of great synthetic
potentiality for the preparation of biologically interesting
substrates. Further work is now underway to expand this one-
pot methodology to other starting materials and to the
synthesis of linear amino polyols.
4,5-cis-4a
4,5-trans-4a
4,5-cis-4b
4,5-trans-4b
4,5-cis-4c
4,5-trans-4c
quant
quant
quant
95
94
93
One the most important transformations that a 4,5-
dihydroisoxazole can undergo is the lithium aluminum
hydride reductive ring cleavage of the heterocycle.2f This
reaction results in the stereoselective reduction of the C,N
double bond with concomitant N,O bond cleavage.
To demonstrate the viability of this new approach to the
synthesis of amino polyhydroxylated compounds, we per-
formed the conversion of compound 4,5-cis-5b to the
corresponding amino polyol (Scheme 3).
Thus, the ester functionality of dihydroisoxazole 4,5-cis-
5b was preliminarily reduced13 with sodium borohydride and
the crude alcohol protected to afford 6 in a 86% overall yield.
Lithium aluminum hydride reduction in diethyl ether fol-
lowed by an acid workup resulted in ring cleavage and
deprotection to give the corresponding amino polyol 7 as
the predominating isomer (de > 9/1), which was fully
characterized as the tetraacetate 8. The stereochemical
Acknowledgment. This work was supported by the
Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica (MURST), Italy, the Consiglio Nazionale delle
Ricerche (CNR), Italy, and by the University of Bologna,
Italy (Progetto d’Ateneo: Biomodulatori Organici and
National Project Stereoselezione in Sintesi Organica. Metod-
ologie ed Applicazioni).
Supporting Information Available: (1) Detailed de-
scriptions of experimental procedures for the preparation of
compounds 4,5-trans- and 4,5-cis-1a-d, 4,5-trans- and 4,5-
cis-4a,b, 4,5-trans- and 4,5-cis-5a,b, 6, and 8; (2) actual 1H
and 13C NMR spectra of compounds 4,5-trans- and 4,5-cis-
1a-d, 4,5-trans- and 4,5-cis-4a,b, 4,5-trans- and 4,5-cis-
5a,b, 6 and 8. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) When compound 4,5-cis-5b was directly subjected to the LiAlH4
ring cleavage, a reduction-elimination of the ester function with concomi-
tant ring opening afforded the corresponding 3-hydroxy nitrile in moderate
yields.
OL0070379
Org. Lett., Vol. 3, No. 5, 2001
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