The diastereoselective synthesis of functionalised isoxazolidines using a Cope elimination/intramolecular nitrone cycloaddition strategy

Article abstract of DOI:10.1016/j.tetlet.2004.03.041

Functionalised hydroxylamine derivatives of (S)-prolinol prepared by a Cope elimination have been found to undergo oxidation to the nitrone either in the presence of air or a catalytic quantity of TPAP. These undergo intramolecular cycloaddition to give t

Full text of DOI:10.1016/j.tetlet.2004.03.041

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3659–3661
The diastereoselective synthesis of functionalised isoxazolidines
using a Cope elimination/intramolecular nitrone cycloaddition
strategy
Ian A. O’Neil,a,* V. Elena Ramos,a Gemma L. Ellis,a Ed Cleator,a Alan P. Chorlton,b
David J. Tapolczayb and S. Barret Kalindjianc
aRobert Robinson Laboratories, Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK
bMillennium Pharmaceuticals, 75, Sidney Street, Cambridge, MA, USA
cJames Black Foundation, 68, Half Moon Lane, Dulwich, London SE24 9JE, UK
Received 26 January 2004; revised 27 February 2004; accepted 5 March 2004
Abstract—Functionalised hydroxylamine derivatives of (S)-prolinol prepared by a Cope elimination have been found to undergo
oxidation to the nitrone either in the presence of air or a catalytic quantity of TPAP. These undergo intramolecular cycloaddition to
give tricyclic isoxazolidines with high diastereoselectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
In the accompanying paper we describe the synthesis of
a functionalised morpholine N-oxide derivative 4 util-
ising a tandem Cope elimination/reverse-Cope elimina-
tion protocol1 (Scheme 1).
to give an intermediate nitrone 6, which underwent an
intramolecular cyclisation to give the racemic spirocyclic
ether. Hydroxylamine 3 was found to undergo both the
reverse Cope elimination and the oxidation/nitrone
cycloaddition slowly at room temperature, particularly
if they were in solution (MeOH or CHCl3). However, 3
could be stored indefinitely at )20 °C under nitrogen.
This type of oxidation of secondary hydroxylamines has
been observed previously by Holmes and co-workers.2
The intramolecular cycloaddition was rapid as we could
not isolate any of the intermediate nitrone 6. We then
examined the use of an oxidant to accelerate the oxi-
dation reaction. Thus, treatment of the hydroxylamine 3
with 5 mol % of TPAP and 1.5 equiv of N-methyl
We observed that if the reverse-Cope elimination was
carried out in the presence of air then a minor product 5
was formed in addition to the N-oxide 4 (Scheme 2).
Spectroscopic analysis indicated that it had the structure
shown in Scheme 2 and it was formed as a single dia-
stereoisomer.
This result could rationally be accounted for by the in
situ oxidation of the secondary hydroxylamine 3 by air
Reverse-Cope
Elimination
MeOH, N2,∆, 95%
mCPBA
CH2Cl2
Cope
Elimination
N
N
N
N
O
O
O
O
O
OH
O
CN
H3C
CN
92%
4
CN
3
2
1
Scheme 1.
Keywords: Cope elimination; Nitrones; Cycloaddition.
* Corresponding author. Tel.: +44-151-794-3485; fax: +44-151-794-3588; e-mail: ion@liv.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.041

3660
I. A. O’Neil et al. / Tetrahedron Letters 45 (2004) 3659–3661
Reverse-Cope
Elimination
O
MeOH, ∆, 95%
N
N
N
O
O
5
O
4
OH
O
H3C
3
12%
84%
air
N
O
O
6
Scheme 2.
Figure 1.
morpholine N-oxide (NMNO) in MeCN3 at room
temperature resulted in quantitative formation of the
spiro compound 5 in 1 h; again the product 5 was
formed as a single diastereoisomer, containing a
quaternary centre4 (Scheme 3). The structure of 5 was
established through NOE measurements.
product of the reaction was characterised by X-ray
crystallography (Fig. 1).
Substitution at the other end of the alkene was achieved
by a similar protocol. Thus, allylation of the alcohol 7
with methallyl bromide gave the ether 21. Oxidation and
subsequent in situ Cope elimination gave the hydroxyl-
amine 22 in excellent yield. Treatment of the hydroxyl-
amine 22 with catalytic TPAP and NMNO gave the
cycloaddition product 23 bearing two adjacent quater-
nary centres, along with the nitrone 24 in a 4:1.5 ratio
(Scheme 5).
In order to explore the scope and generality of the
reaction we decided to prepare a number of derivatives
in which there were additional substituents on the ter-
minus of the alkene. Such substituents generally retard
reverse-Cope eliminations.5 The methods used are out-
lined in Scheme 4. Thus, the alcohol 7 was allylated by
treatment with NaH and the functionalised allyl bro-
mides 8–10 to give the ethers 11–13. N-Oxidation fol-
lowed by an in situ Cope elimination gave the
hydroxylamines 14–16 in excellent yields. These could be
isolated and purified by chromatography.
We also briefly examined the corresponding chemistry
on the piperidinol system. Thus, the allyl ether 25 was
prepared using methods described previously. Oxidation
with mCPBA followed by an in situ Cope elimination
gave the hydroxylamine 26. Treatment of 26 with cata-
lytic TPAP and NMNO gave the tricyclic product 27 in
92% yield as a single diastereoisomer. The stereochem-
istry was again determined by NOE measurements
Scheme 6.
Treatment of the hydroxylamines 14–16 with catalytic
TPAP (5 mol %) in the presence of NMNO (1.5 equiv)
gave excellent yields of the cycloaddition products as
single diastereoisomers. In the case of R ¼ Ph the
The N–O bond in the product spiro hydroxylamines
could be cleaved using zinc in AcOH6 yielding the novel
hydroxy amines as shown in Scheme 7.
O
TPAP (5 mol%)
NMNO (1.5 eqs)
N
N
MeCN, 1h, 100%
In summary, we have demonstrated that hydroxylam-
ines generated from prolinol derivatives via a Cope
elimination, undergo oxidation in the presence of cata-
lytic TPAP/NMNO to generate the more substituted
nitrones, which undergo intramolecular cycloaddition to
O
OH
3
O
5
Scheme 3.
mCPBA
CH2Cl2
O
R
TPAP (5 mol%)
NaH, THF, Bu4NI
N
N
N
N
NMNO (1.5 eqs)
MeCN
O
OH
O
O
OH
R
Br
CN
CN
7
R = Me
R = Ph
8
9
R
R
R = p-BrPh 10
R = Me
R = Ph
17 (66%)
R = Me
R = Ph
R = p-BrPh 16 (71%)
14 (97%)
R = Me
R = Ph
11 (83%)
12 (78%)
18 (100%)
15 (75%)
R = p-BrPh 19 (100%)
R = p-BrPh 13 (73%)
Scheme 4.

I. A. O’Neil et al. / Tetrahedron Letters 45 (2004) 3659–3661
3661
mCPBA
NaH, THF, Bu4NI, 86%
CH2Cl2
N
OH
N
N
100%
Me
O
O
OH
Br
22
CN
21
CN
Me
7
20
Me
O
TPAP (5 mol%)
NMNO (1.5 eqs)
MeCN, 36h
N
O
N
Me
O
O
23
24
Me
Scheme 5.
TPAP (5 mol%)
mCPBA, CH2Cl2
63%
N
N
NMNO (1.5 eqs)
MeCN, 92%
O
N
O
OH
O
NC
O
H
27
26
25
Scheme 6.
surements. Jamie Bickley is thanked for the X-ray
crystallography.
O
R
O
R
Zn/AcOH
N
N
H
O
HO
References and notes
R = H
= Me
= Ph
= p-BrPh
R = H (80%)
= Me (72%)
= Ph (80%)
1. O’Neil, I. A.; Cleator, E.; Ramos, V. E.; Chorlton, A. P.;
Tapolczay, D. J. Tetrahedron Lett. 2004, 45, see previous
paper. doi:10.1016/j.tetlet.2004.03.040.
= p-BrPh (92%)
Scheme 7.
2. Davison, E. C.; Forbes, I. T.; Holmes, A. B.; Warner, J. A.
ꢀ
Tetrahedron 1996, 52, 11601; Alcaide, B.; Saez, E. Tetra-
hedron Lett. 2000, 41, 1647.
3. Goti, A.; De Sarlo, F.; Romani, M. Tetrahedron Lett. 1994,
35, 6571.
give tricyclic products bearing a quaternary centre with
high diastereoselectivity.
4. For a overview on related nitrone cycloadditions see: Grigg,
R.; Markandu, J.; Perrior, T.; Surendrakumar, S.; War-
nock, W. J. Tetrahedron 1992, 48, 6929; Grigg, R.;
Hadjisoteriou, M.; Kennewell, P.; Markandu, J.; Thornton-
Pett, M. J. Chem. Soc. 1992, 1340.
5. Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243.
6. Thibonnet, J.; Knochel, P. Tetrahedron Lett. 2000, 41,
3319.
Acknowledgements
I.O.N. would like to thank Millennium Pharmaceuticals
and James Black Foundation for their continued sup-
port of this work and Manuel Perez for the NOE mea-