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.
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Org. Lett., Vol. 3, No. 5, 2001