Solution- and solid-phase synthesis of 4-hydroxy-4,5-dihydroisoxazole serivatives from enantiomerically pure N-tosyl-2,3-aziridine alcohols

Article abstract of DOI:10.1021/ol0170152

(formula presented) Enantiomerically pure N-tosyl-2,3-aziridine alcohols are directly converted into 4-hydroxy-4,5-dihydroisoxazole 2-oxides through oxidation to the corresponding aldehydes followed by in situ tandem nitroaldol-intramolecular cyclization.

Full text of DOI:10.1021/ol0170152

ORGANIC
LETTERS
2002
Vol. 4, No. 4
497-500
Solution- and Solid-Phase Synthesis of
4-Hydroxy-4,5-dihydroisoxazole
Derivatives from Enantiomerically Pure
N-Tosyl-2,3-aziridine Alcohols
,†
Paolo Righi,* Noemi Scardovi,† Emanuela Marotta,† Peter ten Holte,‡ and
,‡
Binne Zwanenburg*
Dipartimento di Chimica Organica “A. Mangini”, UniVersita` di Bologna, Viale del
Risorgimento, 4, I-40136 Bologna, Italy, and Department of Organic Chemistry,
UniVersity of Nijmegen, ToernooiVeld 1, 6525 ED Nijmegen, The Netherlands
righi@ms.fci.unibo.it
Received November 8, 2001
ABSTRACT
Enantiomerically pure N-tosyl-2,3-aziridine alcohols are directly converted into 4-hydroxy-4,5-dihydroisoxazole 2-oxides through oxidation to
the corresponding aldehydes followed by in situ tandem nitroaldol-intramolecular cyclization. This study was concerned with (i) the selection
of a suitable aziridine activation, (ii) the preparation of the target 4-hydroxy-4,5-dihydroisoxazole derivatives in solution, and (iii) the elaboration
of a solid-phase process using hydroxy Merrifield-supported nitroacetic acid ester.
In recent years we have been investigating new methodolo-
gies for the preparation of 4-hydroxy-4,5-dihydroisoxazoles.1
This is an interesting class of substrates that can lead to
expeditious preparations of aminopolyhydroxylated com-
pounds, which often exhibit therapeutical properties.1,2
However, these heterocycles cannot be prepared directly by
nitrile oxide cycloaddition to alkenes,3 and, to the best of
our knowledge, no solid-phase synthesis of 4-hydroxy-4,5-
dihydroisoxazoles has yet been reported.4
We developed a new approach to the synthesis of
4-hydroxy-4,5-dihydroisoxazole 2-oxides5,6 based on the
tandem7,8 nitroaldol-intramolecular cyclization reaction be-
tween an activated primary nitroalkane and an aldehyde
bearing a leaving group on the R-position. When enantio-
merically pure starting materials are employed, this process
affords enantiopure 4,5-dihydroisoxazoles.9 We recently
(3) When vinyl ethers are employed, 5-oxygenated rather than 4-oxygen-
ated heterocycles are obtained, with cycloaddition to furans being an
exception.
(4) Solid-supported 4-unoxygenated derivatives are routinely obtained
via the cycloaddition route; see, for example: Zou, N.; Jiang, B. J. Comb.
Chem. 2001, 2, 6 and refs cited therein.
(5) Rosini, G.; Marotta, E.; Righi, P.; Seerden, J.-P. J. Org. Chem. 1991,
56, 6258. Rosini, G.; Galarini, R.; Marotta, E.; Righi, P. J. Org. Chem.
1990, 55, 781.
(6) Righi, P.; Marotta, E.; Rosini, G. Chem. Eur. J. 1998, 4, 2501. Righi,
P.; Marotta, E.; Landuzzi, A.; Rosini, G. J. Am. Chem. Soc. 1996, 118,
9446.
† Universita` di Bologna.
‡ University of Nijmegen.
(1) Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p 1069. Vogel,
P.; Schaller, C. Synlett 1999, 1219. Schaller, C.; Vogel, P.; Ja¨ger, V.
Carbohydr. Res. 1998, 314, 25. Wade, P. A.; Shah, S. S.; Govindarajan, L.
J. Org. Chem. 1994, 59, 7199. Ja¨ger, V.; Schro¨ter, D. Synthesis 1990, 556.
Schwab, W.; Ja¨ger, V. Angew. Chem., Int. Ed. Engl. 1981, 20, 603.
(2) It has been found that a 4-oxygenated-4,5-dihydroisoxazole derivative
is itself biologically active: Schaller, C.; Demange, R.; Picasso, S.; Vogel,
P. Bioorg. Chem. Med. Lett. 1999, 277.
(7) Tietze, L. Chem. ReV. 1996, 96, 115.
(8) Hudlicky, T. Chem. ReV. 1996, 96, 3-30.
10.1021/ol0170152 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/24/2002

disclosed that enantiopure 2,3-epoxy alcohols can be directly
converted to the corresponding 4,5-dihydroisoxazoles of type
1,10 without the need to isolate or even manipulate the
intermediate aldehyde (Scheme 1, X ) O).
Scheme 2. Direct Conversion of N-Tosyl Aziridine Alcohol
3a to the Corresponding 4,5-Dihydroisoxazole 4aa
Scheme 1. One-Pot Conversion of 2,3-Epoxy Alcohols into
4,5-Dihydroisoxazoles 1
a (a) TFA, -78 °C, then TsCl, Et3N -40 to 0 °C; (b) BAIB,
catalytic TEMPO, rt, 5 h, then ethyl nitroacetate, ImH, 20 h, rt.
When alcohol 2 was subjected to the same one-pot reaction
conditions depicted in Scheme 1 (X ) NTrt), the monitoring
of the reaction by TLC revealed the formation of the
corresponding aldehyde and its subsequent consumption upon
addition of the base and ethyl nitroacetate. However, no 4,5-
dihydroisoxazole was detected in the reaction mixture. This
is probably due to the failure of the final ring-closure step,
indicating that a nonactivated aziridine nitrogen atom cannot
act as a leaving group. Therefore, we decided to try the
N-tosyl group as a more activating N-substitution, performing
the direct switch from the N-trityl to the N-tosyl group.15
Application of the reaction conditions depicted in Scheme 1
to N-tosyl aziridine alcohol 3a furnished the desired 4,5-
dihydroisoxazole 4a in a 94% yield as an 88:12 mixture of
4,5-trans:4,5-cis isomers (Scheme 2). This observation thus
demonstrates that activation of the heteroatom of the aziridine
ring is needed for it to serve as a leaving group in the final
4,5-dihydroisoxazole ring closure.
In this paper, we wish to report the extension of this one-
pot multibond-forming process to the use of enantiomerically
pure aziridine alcohols as the starting materials. A solid-
phase version of this reaction will also be discussed.
2,3-Aziridine alcohols are valuable building blocks for
diastereoselective reactions and can be obtained in either
enantiomeric configuration from a variety of convenient
sources, including 2,3-epoxy alcohols.11 Moreover, the 4,5-
dihydroisoxazole derivatives that would arise from 2,3-
aziridine alcohols will give, after N-deoxygenation9,10 and
reductive ring cleavage,1 linear polyhydroxylated 2,5-di-
aminoalkanes, some of which are known to be selective
inhibitors of the HIV-1 protease.12
i. Selection of a Suitable N-Substitution. The use of
aziridines, instead of epoxides, poses the question of how
to fill the additional valence on nitrogen.13 By studying this,
we will also have a better understanding of the driving force
involved in the final step of the one-pot procedure, the 4,5-
dihydroisoxazole ring closure with concomitant opening of
the three-membered ring (Scheme 1).
We also investigated whether N-activation alone (without
aziridine ring strain) is sufficient for 4,5-dihydroisoxazole
ring formation. In fact, we knew that the intramolecular
cyclization step does take place with the oxygenated
equivalent when linear R-tosyloxyaldehydes are employed
as the starting materials.9 For this purpose, we prepared the
(S)-phenylalaninol derivatives 5a-c16 (Figure 1) with in-
Initially, we focused on nonactivated N-trityl-2,3-aziridine
alcohols. Following a known methodology,14 (S)-threonine
methyl ester hydrochloride was converted into aziridine
alcohol 2 (Scheme 2).
Figure 1.
(9) Marotta, E.; Baravelli, M.; Maini, L.; Righi, P.; Rosini G. J. Org.
Chem. 1998, 63, 8235.
(10) Marotta, E.; Micheloni, L. M.; Scardovi, N.; Righi, P. Org. Lett.
2001, 3, 727.
(11) (a) Nayak, S. K.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1999,
40, 981. (b) Andres, J. M.; de Elena, N.; Pedrosa, R.; Perez-Encabo, A.
Tetrahedron 1999, 55, 14137. (c) Nayak, S. K.; Thijs, L.; Zwanenburg, B.
Synlett 1998, 1187. (d) Hwang, G. I.; Chung, J. H.; Lee, W. K. J. Org.
Chem. 1996, 6183.
creasing electron-withdrawing substitutions on the nitrogen
atom. However, under the same conditions, all of these
substrates failed to give the corresponding 4,5-dihydroisoxa-
zoles.
Thus, contrary to what we found for oxygen, in the case
of nitrogen, both the three-membered ring strain and het-
(12) Kohl, N. E.; Emini, E. A.; Schleif, W. A.; Davis, L. J.; Heimbach,
J. C.; Dixon, R. A: F.; Scolnick, W. M.; Sigal, I. S. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 4686. Schreiner, E. P.; Gstach, H. Synlett 1996, 1131.
Ettmayer, P.; Hu¨bner, M.; Gstach, H. Tetrahedron Lett. 1994, 35, 3901.
(13) Unprotected aziridine alcohols or aldehydes are rather unstable.
(14) Okawa, K.; Nakajima, K. Biopolymers 1981, 20, 1811. cf.: Willems,
J. G. H.; Hersmis, M. C.; de Gelder, R.; Smits, J. M. M.; Hammink, J. B.;
Dommerholt, J.; Thijs, L.; Zwanenburg, B. J. Chem. Soc., Perkin Trans. 1
1997, 963.
(15) Fujii, N.; Nakai, K.; Habashita, H.; Hotta, Y.; Tamamura, H.; Otaka,
A.; Ibuka T. Chem. Pharm. Bull. 1994, 42, 2241.
(16) Compounds 5a-c were prepared by adapting the procedures found
in the following references. 5a: Backer, Y.; Eisenstadt, A.; Stille, J. K. J.
Org. Chem. 1980, 45, 2145. 5b: Jurczak, J.; Gryko, D.; Kobrycka, E.;
Gruza, H.; Prokopowicz, P. Tetrahedron 1998, 54, 6051. 5c: DeChristopher,
P. J.; Adamek, J. P.; Lyon, G. D.; Klein, S. O.; Baumgarten, R. J. J. Org.
Chem. 1974, 39, 3525.
498
Org. Lett., Vol. 4, No. 4, 2002

eroatom activation are necessary for the final step of the
process to occur.
ii. Solution-Phase Process. After these preliminary results,
we prepared three more aziridine alcohols 3b-d (see Table
1) from commercially available (S)-serine methyl ester
a 5-exo nucleophilic attack on the 2-position of the aziridine
ring. The process is increasingly trans selective as the steric
hindrance of the C3-substituent of the aziridine alcohol
increases, becoming stereospecific for substrates 3c and 3d.18
In the case of the pair of products 4a, the diastereoisomers
could be separated directly by flash column chromatography.
However, products 4b could not be separated as such or as
their corresponding tert-butyldimethylsilyl ether.9
Table 1. One-Pot Formation of 4,5-Dihydroisoxazoles 4
iii. Solid-Phase Process. A solid-phase version of the
above methodology requires the immobilization of one of
the two starting materials. Because product variation in the
target compounds results from the different aziridine alcohols
employed, the logical starting material to immobilize is the
nitroacetic ester. The polymer-bound nitroacetate 6 was
prepared in high yield by reacting nitroacetic acid19,20 with
hydroxymethyl polystyrene21 in the presence of diisopropyl-
carbodiimide (DIC)22 (Scheme 3).
Scheme 3. Solid-Phase Approach to the One-Pot
Nitroaldol-Cyclization Procedure
a Conditions: BAIB, catalytic TEMPO, rt, 5 h, then ethyl nitroacetate,
ImH, 20 h, rt.
hydrochloride, (1S,2S)-2-amino-1-phenyl-1,3-propanediol,
and (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (the
free base of choramphenicol), respectively. The one-pot
conditions applied for the reaction shown in Scheme 1 for
the epoxy alcohols were used for the aziridine alcohols.
According to this methodology, oxidation17 of the alcohol
moiety, employing bisacetoxyiodobenzene (BAIB) as the
stoichiometric oxidant and tetramethylpiperidinyloxy radical
(TEMPO) as the catalyst, smoothly converted 2,3-aziridine
alcohols 3 to the corresponding aldehydes in 4-5 h at room
temperature. Upon in situ addition of imidazole and ethyl
nitroacetate, the corresponding 4-hydroxy-4,5-dihydroisoxa-
zole 2-oxides 4 were obtained after stirring for 20 h at room
temperature. The results of this one-pot three-bond-forming
process are reported in Table 1. The overall yields of this
one-pot direct conversion of 2,3-aziridine alcohols into
enantiomerically pure 4,5-dihydroisoxazole derivatives are
more than satisfactory, except for that of the product 4d.
This lower yield is probably due to the extremely low
solubility of 4d in all the common organic solvents. The only
way we found to isolate it was by direct crystallization from
the crude reaction mixture. The final 4,5-dihydroisoxazole
ring closure is completely regiospecific and proceeds through
The formation of the polymer-bound nitroacetate was
monitored by the infrared absorptions at 1565 cm-1 (nitro
group) and 1755 cm-1 (ester). Moreover, completion of the
coupling reaction could be observed by the disappearance
of hydroxyl absorption (3572 cm-1, free; 3446 cm-1,
hydrogen bonded).
N-Tosyl aziridine alcohols 3a-c were selected for the
parallel solid-phase approach. According to the solution-
phase approach, the aziridine alcohols were converted into
the corresponding aldehydes by TEMPO/BAIB oxidation.
Subsequent treatment of the aziridine aldehyde with polymer-
bound nitroacetate in the presence of imidazole resulted in
the formation of the polymer-supported nitroaldol-cyclization
reaction (Scheme 3). The course of this reaction was followed
(18) The assignment of relative stereochemical configuration 4,5-trans
or 4,5-cis is based on the value of the coupling constant between C4H and
C5H in the 1H NMR spectrum (Jcis ) 6.5-6.6 Hz, Jtrans ) 1.9-3.0 Hz).
The evaluation of the relative amount of the two isomers is based on the
integration of the C5H signal and on HPLC analysis of the mixtures.5
(19) Zen, S.; Koyama, M.; Koto, S. Org. Synth. 1976, 55, 77.
(20) Armarego, W. L. F. J. Chem. Soc. C 1969, 986.
(21) Hydroxymethyl polystyrene (100-200 mesh, 1% DVB, loading 0.68
mequiv/g) was purchased from Novabiochem and used as received.
(22) A similar procedure was recently reported for Wang resin: Kuster,
G. J.; Scheeren, H. W. Tetrahedron Lett. 2000, 41, 515. See also: Sylvam,
C.; Wagner, A.; Mioskowski, C. Tetrahedron Lett. 1999, 40, 875.
(17) Piancatelli, G.; Margherita, R.; De Mico, A.; Parlanti, L.; Vescovi,
A. J. Org. Chem. 1997, 62, 6974.
Org. Lett., Vol. 4, No. 4, 2002
499

by the disappearance of the infrared nitro absorption at 1565
cm-1. The presence of a typical band at 1625 cm-1 (CdN)
in the final product confirmed the successful formation of
the five-membered heterocyclic target compound on the solid
support (7). Fortunately, no large excess of the solution
component (the aldehyde) is necessary to drive the process
to completion since only a 0.1 equiv excess is needed to
observe complete disappearance of the IR nitro group
absorption in a reasonable reaction time.
Table 2. Solid-Phase One-Pot Formation of Isoxazoles 8
starting material
yield (%)
trans:cis ratio
3a
3b
3c
Quant.
72
82
92:8
66:34
100:0
2-oxides in solution. The starting aziridine alcohols can be
obtained in a few steps from natural amino acids or readily
available chiral amino alcohols. The overall yields of the
sequence from the commercially available starting chiral
building blocks are in the range of 33-63%. Moreover, we
have shown that this procedure can also be used in a solid-
phase approach, with no modification even in the stoichi-
ometry of the reactants. This solid-phase procedure is a
convenient way to rapidly prepare solid-supported 4,5-
dihydroisoxazole derivatives and offers an attractive starting
point for further on-resin elaboration of the enantiopure
5-aminoalkyl-4-hydroxy-4,5-dihydroisoxazole 2-oxides.
Detachment of the 4,5-dihydroisoxazole derivatives from
the resin was achieved by means of base-induced transes-
terification with methanol to give the free methyl esters 8.
In all cases, triethylamine was used as the base. Fine-tuning
of the conditions for cleavage demonstrated that the most
efficient transesterification was achieved in a 20/10/1 toluene/
methanol/triethylamine mixture. In this solvent system,
complete detachment took place at 50 °C within 48 h
(Scheme 3). It is worth noting that the same reaction using
ethanol, instead of methanol, did not go to completion under
these optimized conditions, even after a reaction time of 6
days. Complete removal of the target compound from the
resin was ascertained by infrared spectroscopy. No absorption
at 1625 and 1737 cm-1 could be detected in the resulting
polymer. The overall yields of this solid-phase nitroaldol-
cyclization reaction and cleavage steps range from good
(72%, R ) H) to very good (quantitative yield, R ) Me).
The trans:cis ratios are, to some extent, different from those
observed for the solution-phase counterparts. For R ) H,
the trans:cis ratio amounts to 66:34, as opposed to the 42:
58 trans:cis ratio found in solution. For R ) Me or Ph, the
resulting trans:cis ratios are practically the same as those
found in solution (see Table 2).
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, the University of Bologna, Italy
(Progetto d’Ateneo: Biomodulatori Organici and National
Project “Stereoselezione in Sintesi Organica. Metodologie
ed Applicazioni”), and the Faculty of Science, University
of Nijmegen, The Netherlands.
Supporting Information Available: Experimental pro-
cedures for the preparation of compounds 2, 3a-d, 4a-d,
6, 7a-c, and 8a-c; actual 1H and 13C NMR spectra of 4,5-
dihydroisoxazoles 4a-d; and actual IR spectra of solid-
supported 4,5-dihydroisoxazoles 7a-c. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have shown that our one-pot tandem
procedure reported in Scheme 1 can be further extended to
enatiomerically pure N-tosyl 2,3-aziridine alcohols, leading
to a new class of enantiopure 4-hydroxy-4,5-dihydroisoxazole
OL0170152
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