Stereoselective synthesis of novel β,γ-epoxyhydroxylamines and 4-hydroxyalkyl-1,2-oxazetidines

Article abstract of DOI:10.1021/ol061256y

A simple and efficient stereoselective synthesis of polysubstituted β,γ-epoxyhydroxylamines and 4-hydroxyalkyl-1,2-oxazetidines, based on the addition of α-lithiated aryloxiranes to nitrones and subsequent cyclization of the corresponding intermediates in

Full text of DOI:10.1021/ol061256y

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3923-3926
Stereoselective Synthesis of Novel
-Epoxyhydroxylamines and
â,γ
4-Hydroxyalkyl-1,2-oxazetidines
Vito Capriati,† Saverio Florio,*,† Renzo Luisi,† Antonio Salomone,† and
Corrado Cuocci‡
Dipartimento Farmaco-Chimico, UniVersita` di Bari, C.N.R.,
Istituto di Chimica dei Composti OrganoMetallici “ICCOM”, Sezione di Bari,
Via E. Orabona 4, I-70125-Bari, Italy, Dipartimento Geomineralogico,
UniVersita` di Bari, Via E. Orabona 4, I-70126-Bari, Italy, and
Istituto di Cristallografia (IC-CNR), Via Amendola 122/o, I-70125-Bari, Italy
florio@farmchim.uniba.it
Received May 23, 2006
ABSTRACT
A simple and efficient stereoselective synthesis of polysubstituted
â
,
γ
-epoxyhydroxylamines and 4-hydroxyalkyl-1,2-oxazetidines, based on
the addition of
described.
r-lithiated aryloxiranes to nitrones and subsequent cyclization of the corresponding intermediates in a 4-exo-tet mode, is
Nitrones are compounds extremely important in synthetic
organic chemistry. They mainly undergo two fundamental
reactions: 1,3-dipolar cycloadditions1 and nucleophilic addi-
tions.2 Nucleophilic addition reactions have been thoroughly
investigated, including alkylation, arylation, alkenylation,
cyanation, acylalkylation,2,3 allylation,4 allenylation,5 and
alkynylation6-8 for the preparation of a large variety of
substances.
optically active 5-isoxazolidinones and â-amino acids,9a
optically active oxazolinyl[1,2]oxazetidines,9b R-epoxy-â-
amino acids,9c alkenyloxazolines,9d carbon-linked glyco-
glycines,9e lipoxygenase inhibitors,9f and imino-C-nucleosides.9g
By way of contrast, the addition of R-lithiated aryloxiranes,
successfully used for the synthesis of structurally complex
(2) (a) Lombardo, M.; Trombini, C. Synthesis 2000, 759-774. (b)
Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Synlett 2000, 442-454.
(3) (a) Lombardo, M.; Trombini, C. Curr. Org. Chem. 2002, 6, 695-
713. (b) Murga, J.; Portoles, R.; Falomir, E.; Carda, M.; Alberto Marco, J.
Tetrahedron: Asymmetry 2005, 16, 1807-1816. (c) Kazuta, Y.; Abe, H.;
Matsuda, A.; Shuto, S. J. Org. Chem. 2004, 69, 9143-9150. (d) Bonanni,
M.; Marradi, M.; Cicchi, S.; Faggi, C.; Goti, A. Org. Lett. 2005, 7, 319-
322. (e) Dondoni, A.; Perrone, D.; Rinaldi, M. J. Org. Chem. 1998, 63,
9252-9264. (f) Chang, Z. Y.; Coates, R. M. J. Org. Chem. 1990, 55, 3464-
3474. (g) Pennings, M. L. M.; Reinhoudt, D. N.; Harkema, S.; van Hummel,
G. J. J. Org. Chem. 1982, 47, 4419-4425. (h) Okino, T.; Hoashi, Y.;
Takemoto, Y. Tetrahedron Lett. 2003, 44, 2817-2821. (i) Murahashi, S.;
Imada, Y.; Kawakami, T.; Harada, K.; Yonemushi, Y.; Tomita, N. J. Am.
Chem. Soc. 2002, 124, 2888-2889. (j) Kawakami, T.; Ohtake, H.; Arakawa,
H.; Okachi, T.; Imada, Y.; Murahashi, S. Org. Lett. 1999, 1, 107-110. (k)
Camiletti, C.; Dhavale, D. D.; Gentilucci, L.; Trombini, C. J. Chem. Soc.,
Perkin Trans. 1 1993, 3157-3165.
The addition reaction of heterosubstituted organolithiums
to nitrones has been successfully used for the preparation of
† Dipartimento Farmaco-Chimico, Universita` di Bari.
‡ Dipartimento Geomineralogico, Universita` di Bari and Istituto di
Cristallografia.
(1) (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A.,
Ed.; Wiley: New York, 1984; Vol. 1, p 1. (b) Tufariello, J. J. In 1,3-Dipolar
Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol.
1, p 83. (c) Torssell, K. B. G. In Nitrile Oxides, Nitrones and Nitronates in
Organic Synthesis; VCH: New York, 1988; Chapter 3, pp 75-93. (d) The
Chemistry of Heterocyclic Compounds: Synthetic Applications of 1,3-
Dipolar Cycloaddition Reactions towards Heterocycles and Natural Product;
Padwa, A., Pearson, W., Eds.; Wiley: New York, 2002; Chapter 59, pp
1-81. (e) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-
910. (f) Gothelf, K. V.; Jorgensen, K. A. Chem. Commun. 2000, 4, 1449-
1458. (g) Frederickson, M. Tetrahedron 1997, 53, 403. (h) Karlsson, S.;
Hogberg, H.-E. Org. Prep. Proc. Int. 2001, 33, 102.
(4) (a) Merino, P.; Mannucci, V.; Tejero, T. Tetrahedron 2005, 61, 3335-
3347. (b) Dhavale, D. D.; Jachak, S. M.; Karche, N. P.; Trombini, C.
Tetrahedron 2004, 60, 3009-3016.
10.1021/ol061256y CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/02/2006

Table 1. Preparation of â,γ-Epoxyhydroxylamines 5a-k and 1,2-Oxazetidines 6a-k
nitrone
hydroxylamine
5 (yield, %)a
1,2-oxazetidine
6 (yield, %)a
oxirane
R1
R2
R3
Ar
4
drb
1
1
1
1
1
1
2
3c
1
1
1
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
cumyl
cumyl
cumyl
cumyl
cumyl
cumyl
cumyl
cumyl
t-Bu
Ph
4a
4b
4c
4d
4e
4f
4c
4c
4g
4h
4i
5a (60)
5b (42)
5c (50)
5d (82)
5e (54)
5f (82)
5g (60)
5h (65)
5i (60)
5j (63)
5k (78)
6a (50)
6b (70)
6c (70)
6d (62)
6e (40)
6f (65)
6g (80)
6h (75)
6i (50)d
6j (85)d
6k (95)d
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
90/10e
>98/2
>98/2
4-MeC6H4
4-ClC6H4
2-furyl
4-MeOC6H4
5-(3-CF3C6H4)-2-furyl
4-ClC6H4
4-ClC6H4
4-CF3C6H4
Ph
t-Bu
t-Bu
4-ClC6H4
a Isolated yields after column chromatography on silica gel. b Diastereomeric ratio (dr) calculated by 1H NMR analysis of the crude reaction mixture.
c Lithiation reaction performed with n-BuLi (see the Supporting Information). d Cyclization reaction performed at room temperature. e Separable mixture of
diastereoisomers (see the Supporting Information).
epoxides and derivatives,10 has never been investigated. In
the present paper, we report the stereoselective preparation
of novel â,γ-epoxyhydroxylamines and 4-hydroxyalkyl-1,2-
oxazetidines based on the addition of R-lithiated aryloxiranes
to nitrones.
subsequently oxazetidines 6i-k. In contrast, an acid-base
reaction occurred when N-benzylnitrone 4l was added to 1-Li
leading to styrene oxide, N-phenylethyl nitrone 4m and
compound 7 upon quenching first with MeI and then with
aqueous NH4Cl (Figure 1).
R-Lithiated styrene oxide 1-Li was prepared by treating
commercially available styrene oxide 1 with s-BuLi in THF
and TMEDA at -98 °C, as reported.11 Addition of N-cumyl-
phenyl nitrone 4a to the dark red solution of 1-Li furnished
the epoxyhydroxylamine 5a, after quenching with aqueous
NH4Cl, with an excellent diastereoselectivity (Table 1).
Subsequent treatment of 5a with NaOH/i-PrOH led to the
diastereoselective formation of 4-hydroxymethyl-1,2-oxaze-
tidine 6a (dr > 98/2), which is the result of an oxirane ring-
opening-promoted intramolecular cyclization taking place in
4-exo-tet mode. In a comparable manner 1-Li reacted with
aryl and heteroaryl cumyl nitrones 4b-f to give epoxyhy-
droxylamines 5b-f and then hydroxyalkyl-1,2-oxazetidines
6b-f (Table 1).
The substitution effect in the starting oxirane was briefly
investigated. Lithiated trans-phenylpropylene oxide 2-Li and
cis-stilbene oxide 3-Li reacted with nitrone 4c giving the
expected hydroxylamines 5g and 5h and then oxazetidines
6g and 6h in comparable chemical yields and diastereose-
lectivity after treatment with NaOH. In contrast, no addition
occurred when lithiated trans-stilbene oxide was treated with
nitrone 4c, likely because of steric reasons (see ahead).
Concerning the nitrone N-substitution we found that the
reaction of 1-Li with N-tert-butyl nitrones 4g-i afforded,
as expected, the N-tert-butyl hydroxylamines 5i-k and
Figure 1.
The configurational assignment of the above epoxyhy-
droxylamines and oxazetidines gave insights into the reaction
(5) Pulz, R.; Cicchi, S.; Brandi, A.; Reiâig, H. U. Eur. J. Org. Chem.
2003, 1153-1156 and references therein.
3924
Org. Lett., Vol. 8, No. 18, 2006

Figure 2. Addition of 1-3-Li to the re or si face of the nitrone 4h.
mechanism as well as the observed stereochemistry. The
configuration of the epoxyhydroxylamines was assigned by
1H and 13C NMR spectroscopy and, in some cases, the
assignment was also confirmed by an X-ray analysis.
The relative configuration of the two stereocenters (3R*,4S*)
of 1,2-oxazetidines 6d,g-k was established by detecting
positive NOE effects, diagnostic of the spatially close
omer (not observed, except in the case of the reaction of
1-Li with nitrone 4g, Figure 2).13
Supporting such a mechanistic hypothesis is the experi-
mental evidence that lithiated trans-stilbene oxide does not
add to nitrone 4c, probably because of the unfavorable
additional steric interaction between the aryl groups belong-
ing to the nitrone and the oxirane (R1 ) Ph) in a transition
state of the TS-A type. It is worth noting that the ring closure
of hydroxylamines 5 to isoxazolidines 8 (Figure 1) does not
occur probably because it is less thermodynamically favored
under these conditions.
1
hydrogen relationship, after applying selective H preirra-
diations within a double pulsed field gradient spin-echo
NOE (DPFGSE-NOE) sequence.12 In the case of the major
isomers of 6d,g-k, a preirradiation of HA enhanced either
of the methyl protons of the cumyl and tert-butyl group
linked at the oxazetidine nitrogen or the carbinol proton HB,
as depicted in Figure 1.
The possibility of making optically active hydroxylamines
and oxazetidines of the type of 5 and 6 was next evaluated.
Indeed, we found that (R)-1-Li adds to nitrones 4c and 4h
Only in the case of the reaction of 1-Li with 4g was it
possible to isolate the minor diastereomeric oxazetidine
(3R*,4R*)-6i: for this isomer, the NOE enhancement of HD
was observed after selective preirradiation of HC. This type
of assignment was unambiguously confirmed by the X-ray
analysis in the case of 1,2-oxazetidine 6j. The relative
configuration of oxazetidine 6c was confirmed by the X-ray
analysis of its precursor 5c considering that, in the oxaze-
tidine cyclization reaction, there is inversion of configuration
at the benzylic carbon attacked by the sodium alkoxide and
retention at the other oxirane ring carbon atom. The relative
configuration of the other 4-hydroxyalkyl-3-aryl-substituted
1,2-oxazetidines 6a,b,e,f could be determined by analogy.
Indeed, the chemical shift of the proton at the C-3 ring carbon
atom for all the major isomers was always found to fall into
the range 5.4-5.7 ppm, whereas that for (3R*,4R*)-1,2-
oxazetidine 6i was 5.22 ppm.
To explain the observed diastereoselectivity we envisage
a preliminary coordination of the lithiated oxirane on the
nitrone oxygen followed by the addition to the nitrone going
through two different five-membered cyclic transition
states: the one leading to the observed (1R*,2R*) diastere-
oisomer (TS-A), after the addition of 1-Li to the re face of
the nitrone, would not experience the steric interaction
between the two aryl groups, which instead is important in
the transition state TS-B leading to the (1R*,2S*) diastere-
(6) (a) Patel, S. K.; Py, S.; Pandya, S. U.; Chavant, P. Y.; Valle`e, Y.
Tetrahedron: Asymmetry 2003, 14, 525-528. (b) Fassler, R.; Frantz, D.
E.; Oetiker, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 3054-
3056. (c) Pinet, S.; Pandya, S. U.; Chavant, P. Y.; Ayling, A.; Valle`e, Y.
Org. Lett. 2002, 4, 1463-1466. (d) Topic, D.; Aschwanden, P.; Fassler,
R.; Carreira, E. M. Org. Lett. 2005, 7, 5329-5330. (e) Patel, S. K.; Murat,
K.; Py, S.; Valle`e, Y. Org. Lett. 2003, 5, 4081-4084.
(7) Dagoneau, C.; Tomassini, A.; Denis, J. N.; Valle`e, Y. Synthesis 2001,
150-154 and references therein.
(8) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995,
60, 4999-5004.
(9) (a) Luisi, R.; Capriati, V.; Florio, S.; Vista, T, J. Org. Chem. 2003,
68, 9861-9864. (b) Luisi, R.; Capriati, V.; Florio, S.; Piccolo, E. J. Org.
Chem. 2003, 68, 10187-10190. (c) Luisi, R.; Capriati, V.; Degennaro, L.;
Florio, S. Org. Lett. 2003, 5, 2723-2726. (d) Capriati, V.; Degennaro, L.;
Florio, S.; Luisi, L. Eur. J. Org. Chem. 2002, 2961-2969. (e) Dondoni,
A.; Junquera, F.; Merchan, F. L.; Merino, P.; Scherrmann, M. C.; Tejero,
T. J. Org. Chem. 1997, 62, 5484-5496. (f) Basha, A.; Henry, R.;
McLaughlin, M. A.; Ratajczyk, J. D.; Wittenberger, S. J. J. Org. Chem.
1994, 59, 6103-6106. (g) Evans, G. B.; Furneaux, R. H.; Hausler, H.;
Larsen, J. S.; Tyler, P. C. J. Org. Chem. 2004, 69, 2217-2220.
(10) For recent reviews on oxiranyl anions, see: (a) Hodgson, D. M.;
Bray, C. D. In Aziridines and Epoxides in Organic Synthesis; Yudin, A.
K., Ed.; Wiley-VCH: Weinheim, Germany, 2006; pp 145-184. (b)
Hodgson, D. M.; Bray, C. D.; Humphreys, P. G. Synlett 2006, 1-22. (c)
Capriati V.; Florio S.; Luisi, R. Synlett 2005, 1359-1369. (d) Chemla`, F.;
Vrancken, E. In The Chemistry of Organolithium Reagents; Rappoport, Z.,
Marek, I., Eds.; Wiley & Sons: New York, 2004; pp 1165-1242.
(11) Capriati, V.; Florio, S.; Luisi, R.; Salomone, A. Org. Lett. 2002, 4,
2445-2448.
(12) Neuhaus, D.; Williamson, M. In The Nuclear OVerhauser Effect in
Structural and Conformational Analysis; VCH: New York, 1989; p 264.
(13) The two competitive mechanistic pathways depicted in Figure 2
refer, in particular, to the addition of 1-3-Li to the re or si face of the
nitrone 4h.
Org. Lett., Vol. 8, No. 18, 2006
3925

with an excellent diastereo- and enantioselectivity leading
to the formation of hydroxylamines (1S,2S)-5c and (1S,2S)-
5j and then to oxazetidines (3S,4R)-6c and (3S,4R)-6j upon
treatment with NaOH/i-PrOH (Table 2). Similarly, (S)-1-Li
aryloxiranes have been reported to couple with carbonyl
compounds with no or poor diastereoselectivity.10c,11,14,15
Moreover, considering that the cyclization reaction of 5 to
6 occurs with inversion of configuration at the oxirane ring
carbon that is attacked by the oxygen of the hydroxylamino
functionality, the above transformation of (R)- or (S)-1 to 5
and then to 6 represents a useful stereospecific synthesis of
so far undescribed optically active 1,2-oxazetidines 6.
In conclusion, with this work we have developed a simple
and efficient stereoselective method for synthesizing polysub-
stituted â,γ-epoxyhydroxylamines 5 and hydroxyalkyl-1,2-
oxazetidines 6, simply by adding lithiated aryloxiranes to
nitrones. These novel scaffolds, that are accessible in two
steps, and which are perfectly stable, seem to be promising
for synthetic elaboration to other substances.
Table 2. Preparation of Optically Active
â,γ-Epoxyhydroxylamines 5c,d,j and 1,2-Oxazetidines 6c,d,j
Acknowledgment. This work was carried out under the
framework of the National Project “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” and the FIRB
Project “Progettazione, preparazione e valutazione biologica
e farmacologica di nuove molecole organiche quali potenziali
farmaci innovativi” supported by the MIUR (Rome), by the
University of Bari, and by the Interuniversities Consortium
CINMPIS.
hydroxylamine 1,2-oxazetidine
1-Li
nitrone 4
5 (yield, %)a
6 (yield, %)a
erb
(R)-1-Li
(S)-1-Li
(R)-1-Li
(S)-1-Li
4c
4d
4h
4h
(1S,2S)-5c (78)
(3S,4R)-6c (78) 98/2
(1R,2R)-5d (60) (3R,4S)-6d (62) 98/2
(1S,2S)-5j (63)
(1R,2R)-5j (60)
(3S,4R)-6j (80)
(3R,4S)-6j (75)
98/2
98/2
Supporting Information Available: Full experimental
1
details and copies of H NMR and 13C NMR spectra for
a Isolated yields after column chromatography on silica gel. b Enantio-
meric ratio (er) calculated by HPLC (see the Supporting Information).
compounds 5a-k and 6a-k. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL061256Y
reacted with nitrones 4d and 4h to give (1R,2R)-5d and
(1R,2R)-5j and subsequently (3R,4S)-6d and (3R,4S)-6j.
The highly diastereoselective formation of hydroxylamines
5 described above is quite intriguing considering that lithiated
(14) Capriati, V.; Florio, S.; Luisi, R.; Nuzzo, I. J. Org. Chem. 2004,
69, 3330-3335.
(15) Florio, S.; Aggarwal, V.; Salomone, A. Org. Lett. 2004, 6, 4191-
4194.
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Org. Lett., Vol. 8, No. 18, 2006