The synthesis of functionalised chiral bicyclic lactam and lactone N-oxides using a tandem Cope elimination/reverse Cope elimination protocol

Article abstract of DOI:10.1016/j.tetlet.2007.01.045

Functionalised hydroxylamine derivatives of (S)-proline and (R)-pipecolic acid have been prepared using a Cope elimination. These undergo reverse Cope elimination onto a pendant double bond to give bicyclic lactam and lactone N-oxides containing three contiguous chiral centres, this extends the scope and applicability of the reverse Cope elimination in the synthesis of heterocyclic systems by incorporation of the lactone and lactam structural motifs.

Full text of DOI:10.1016/j.tetlet.2007.01.045

Tetrahedron Letters 48 (2007) 1683–1686
The synthesis of functionalised chiral bicyclic lactam and lactone
N-oxides using a tandem Cope elimination/reverse Cope
elimination protocol
Gemma L. Ellis,a Ian A. O’Neil,a,* V. Elena Ramos,a Ed Cleator,a S. Barret Kalindjian,b
Alan P. Chorltonc and David J. Tapolczayc
aRobert Robinson Laboratories, Department of Chemistry, University of Liverpool, Crown St, Liverpool L69 7ZD, UK
bJames Black Foundation, 68, Half Moon Lane, Dulwich, London SE24 9JE, UK
cPharmorphix Ltd, Cambridge Science Park, 250 Milton Road, Cambridge, CB4 0WE, UK
Received 11 July 2006; revised 2 January 2007; accepted 11 January 2007
Available online 14 January 2007
Abstract—Functionalised hydroxylamine derivatives of (S)-proline and (R)-pipecolic acid have been prepared using a Cope elimi-
nation. These undergo reverse Cope elimination onto a pendant double bond to give bicyclic lactam and lactone N-oxides contain-
ing three contiguous chiral centres, this extends the scope and applicability of the reverse Cope elimination in the synthesis of
heterocyclic systems by incorporation of the lactone and lactam structural motifs.
Ó 2007 Published by Elsevier Ltd.
The reverse Cope elimination is rapidly becoming a
valuable and powerful method for the synthesis of a
wide variety of heterocyclic systems.1–19 Recently we re-
ported the synthesis of functionalised chiral morphol-
ines derived from (S)-prolinol.20 These compounds
were prepared using a tandem Cope elimination/reverse
Cope elimination protocol. We now report the develop-
ment of this protocol to the first reported synthesis
of chiral bicyclic lactam and lactone N-oxides using
the reverse Cope elimination.
then spontaneously underwent Cope elimination under
the reaction conditions to generate hydroxylamine 4 in
an 81% yield. This could be purified by flash column
1
chromatography, but H NMR analysis indicated that
it had started to undergo reverse Cope elimination to
the bicyclic lactam N-oxide 5 at room temperature. This
reaction was accelerated by heating 4 in methanol under
a nitrogen atmosphere to give a 52% yield of N-oxide 5
containing three contiguous chiral centres and the lac-
tam functionality. The reaction was also performed in
chloroform and resulted in a 48% yield of 5 (Scheme
1). The configuration of the two newly formed contigu-
ous chiral centres was confirmed by NOE experiments.
Irradiation of H-9a gave a strong enhancement with
the methyl group at C-4, which confirmed the (4S,5S)
configuration.
Our initial investigations started with (S)-proline. Treat-
ment of this with acrylonitrile and potassium hydroxide
in water, followed by Soxhlet extraction with acetone
gave 1 in an 84% yield.21 The coupling of allylamine
to 1 proved more problematic with several methods
being tried. These included the use of DCC with DMAP,
EDCI with DIEA and the use of oxalyl chloride. The
most successful method by far was the use of triethyl-
amine and methyl chloroformate to form the mixed
anhydride. Allylamine was then added in a one-pot pro-
cedure, to give 2 in a 62% yield. Treatment of tertiary
amine 2 with m-CPBA gave selectively N-oxide 3. This
In addition to the reverse Cope product 5 the unsatu-
rated amide 6 was also isolated. Using methanol as the
reaction solvent, 6 was formed in a 23% yield. In chloro-
form this increased to 41%. This compound is possibly
formed from the minor diastereomer of the reverse Cope
elimination 5a, which is set up stereochemically to elim-
inate water with the proton and N-oxide being anti to
one another. Amide 6 was a yellow crystalline solid
and its structure was confirmed by X-ray crystallogra-
phy (Fig. 1).22
*
Corresponding author. Tel.: +44 (0) 151 794 3485; fax: +44 (0) 151
794 3588; e-mail: ion@liv.ac.uk
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.01.045

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G. L. Ellis et al. / Tetrahedron Letters 48 (2007) 1683–1686
1. ClCO2Me, NEt3
m-CPBA, K2CO3
THF, 0 oC.
O
CN
KOH
O
N
N
DCM, -78 oC, 81%
CO2H
CO2H
N
N
H
HN
O
HN
2. allylamine, 62%
Soxhlet
extraction, 84%
NC
NC
NC
2
3
1
Cope
elimination
solvent, heat,
5 days, N2
reverse-Cope
elimination
H
H
O
O
O
O
N
N
N
+
N
HN
O
O
OH
NH
NH
NH
5
4
6
5a
Scheme 1.
Figure 1. X-ray structure of bicyclic lactam 6.
In order to investigate the effect of ring size on the reac-
tion we studied the derivatives of pipecolic acid. Race-
mic pipecolic acid was resolved using L-tartaric acid to
give amine 7.23 Addition of acrylonitrile to 7 using
KOH gave 8 in a quantitative yield. The mixed anhy-
dride methodology was applied to the coupling of allyl-
amine to 8 as this had been successful in the previous
system, giving amide 9 in a 59% yield. Treatment of 9
with m-CPBA gave selectively N-oxide 10. This then
spontaneously underwent Cope elimination under the
reaction conditions to generate hydroxylamine 11 in a
79% yield. This could be purified by flash column chro-
the irradiation of H-4ax gave enhancements with H-7ax
and H-9ax. These NOEs not only settled the stereo-
chemistry of this isomer as (4R,5R), but also suggest a
distorted trans-decalin conformation for the system.
As incorporation of the lactam functionality had been
successful, incorporation of the lactone functionality
was investigated. In this case it was envisaged that allyl
alcohol could be prepared by using an ester exchange
reaction. Therefore, the methyl ester hydrochloride salt
of (S)-proline was used as the starting material. This
was treated with acrylonitrile in methanol to give 13 in
a 93% yield. Addition of allyl alcohol was achieved by
treating 13 with 6 equiv of allyl alcohol and a catalytic
quantity of NaH, this gave 14 in a 61% yield. Treatment
of 14 with m-CPBA selectively gave N-oxide 15, which
spontaneously underwent Cope elimination to generate
hydroxylamine 16 in a 77% yield. Heating hydroxyl-
amine 16 in chloroform, under nitrogen for 5 days
unfortunately gave an inseparable mixture of hydroxyl-
1
matography, but again H NMR measurements indi-
cated that it had started to undergo reverse Cope
elimination to give bicyclic lactam N-oxide 12 at room
temperature. This reaction was accelerated by heating
11 in chloroform under nitrogen to give an 87% yield
of N-oxide 12 as a single diastereoisomer (Scheme 2).
The configuration of the two newly created chiral cen-
tres was again confirmed by NOE measurements. Thus,
1. ClCO2Me, NEt3
m-CPBA, K2CO3
CN
THF, 0 oC.
O
O
N
N
N
CO2H
DCM, -78 oC, 79%
KOH, r.t.,
MeOH, 84%
N
H
CO2H
2. allylamine, 59%
O
HN
HN
NC
CN
NC
10
9
7
8
Cope
elimination
CHCl3, heat,
O
O
2 days, N2, 87%
reverse-Cope
elimination
H
N
N
CH3
O
O
9
N
4
N
H
O
H
H
H
NH
OH HN
7
H
12
11
12: nOe enhancements
Scheme 2.

G. L. Ellis et al. / Tetrahedron Letters 48 (2007) 1683–1686
1685
m-CPBA, K2CO3
allyl alcohol,
CN
O
O
N
O
N
CO2Me
DCM, -78 oC, 77%
NaH (cat.),
heat, 48 h,
61%
CO2Me
N
N
MeOH, r.t.
93%
O
O
H
HCl
NC
15
NC
NC
13
14
solvent, heat,
5 days, N2
reverse-Cope
elimination
Cope
elimination
H
O
O
N
N
O
O
OH
O
17
16
Scheme 3.
1. SOCl2
2. NEt3
m-CPBA, K2CO3
allyl alcohol,
O
O
N
N
N
CO2Me
DCM, -78 oC, 79%
N
H
CO2H
3.
NaH (cat.),
heat,
48 h, 71%
CN
O
O
O
NC
MeOH
61%
CN
NC
20
7
18
19
CHCl3, heat,
5 days, N2
reverse-Cope
elimination
Cope
elimination
O
+
O
O
N
N
22/23 = 5:1
N
O
O
O
OH
O
O
23
22
21
Scheme 4.
amine 16 and the reverse Cope product 17 as a single
diastereomer, with the equilibrium lying in favour of
the hydroxylamine in a ratio of 9:1. The ratio was deter-
mined from the alkene protons of 16 and the distinctive
methyl protons of 17 appearing as a doublet at 1.2 ppm.
Attempts to carry out this reaction in alternative sol-
vents failed to improve this ratio (Scheme 3).
nation. The lactone bicyclic compounds have been
observed by 1H NMR but are inseparable from
the hydroxylamine starting material in both cases.
Acknowledgements
We would like to thank the James Black Foundation
and Pharmorphix Ltd. for their continued support of
this work. Manuel Perez is thanked for the NOE mea-
surements and Jamie Bickley is thanked for the X-ray
crystallography.
As the pipecolic lactam had been higher yielding than
the proline derivative it was hoped that the same trend
would be seen with the lactone leading to the isolation
of a pure bicyclic lactone N-oxide. In this case the pre-
viously resolved (R)-pipecolic acid 7 was treated with
thionyl chloride, triethylamine and then acrylonitrile in
methanol to give 18 in a 60% yield. Treatment of 18 with
a catalytic quantity of NaH, using allyl alcohol as the
solvent gave 19 in a 71% yield. Oxidation of 19 gave
N-oxide 20, which spontaneously underwent Cope elim-
ination to give hydroxylamine 21 in an 89% yield. Heat-
ing hydroxylamine 21 in chloroform under nitrogen at
reflux for 5 days gave again an inseparable mixture of
hydroxylamine 21 and N-oxide 22 in a more favourable
ratio of 6:1, but as two diastereomers in a ratio of 5:1
(Scheme 4).
Supplementary data
The following supplementary data is available: (1) de-
tailed descriptions of experimental procedures, (2) X-
ray data for compound 6, (3) 1H NMR spectra. Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2007.01.045.
References and notes
In conclusion, we have demonstrated that the novel tan-
dem Cope elimination/reverse Cope elimination proto-
col can be applied to more complex systems using
derivatives of (S)-proline and (R)-pipecolic acid. This
has led to the first reported synthesis of chiral bicyclic
lactam and lactone N-oxides by the reverse Cope elimi-
1. Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243–
269.
2. Knight, D. W.; Staples, E. R. Tetrahedron Lett. 2002, 43,
6771–6773.
3. Knight, D. W.; Salter, R. Tetrahedron Lett. 1999, 40,
5915–5918.

1686
G. L. Ellis et al. / Tetrahedron Letters 48 (2007) 1683–1686
14. O’Neil, I. A.; Southern, J. M. Tetrahedron Lett. 1998, 39,
4. Holmes, A. B.; Adams, J. P.; Davies, I. E.; Roughley,
S. D.; Williams, G. M. J. Am. Chem. Soc. 1999, 121, 4900–
9089–9092.
4901.
15. O’Neil, I. A.; Wooley, J. C.; Southern, M. J.; Hobbs, H.
Tetrahedron Lett. 2001, 42, 8243–8245.
16. O’Neil, I. A.; Cleator, E.; Southern, J. M.; Bickley, J.;
Tapolczay, D. J. Tetrahedron Lett. 2001, 42, 8251–8254.
17. O’Neil, I. A.; Cleator, E.; Tapolczay, D. J. Tetrahedron
Lett. 2001, 42, 8247–8249.
5. Knight, D. W.; Bell, K. E.; Coogan, M. P.; Gravestock,
M. B.; Thornton, S. R. Tetrahedron Lett. 1997, 38, 8545–
8548.
6. Knight, D. W.; Coogan, M. P.; Gravestock, M. B.;
Thornton, S. R. Tetrahedron Lett. 1997, 38, 8549–8552.
7. Knight, D. W.; Leese, M. P.; Wheildon, A. R. Tetrahedron
Lett. 1997, 38, 8553–8556.
18. O’Neil, I. A.; Cleator, E.; Southern, J. M.; Hone, N.;
Tapolczay, D. J. Synlett 2000, 1408–1410.
8. Ciganek, E.; Read, J. M., Jr.; Calabrese, J. C. J. Org.
Chem. 1995, 60, 5795–5802, and 5803–5807.
9. Oppolzer, W.; Bochet, C. G.; Spivey, A. C. J. Am. Chem.
Soc. 1994, 116, 3139–3140.
19. Palmer, A.; Ja¨ger, V. Synlett 2000, 1405–1407.
20. O’Neil, I. A.; Cleator, E.; Ramos, V. E.; Chorlton, A. P.;
Tapolczay, D. J. Tetrahedron Lett. 2004, 45, 3655–
3658.
10. Holmes, A. B.; Forbes, I. T.; Fox, M. E.; Thompson, M.
J. Chem. Soc., Perkin Trans. 1 1994, 3379–3395.
11. Gravestock, M. B.; Knight, D. W.; Thornton, S. R. J.
Chem. Soc., Chem. Commun. 1993, 169–171.
12. Ciganek, E. J. Org. Chem. 1990, 55, 3007–3009.
13. O’Neil, I. A.; Cleator, E.; Southern, J. M.; Hone, N.;
Tapolczay, D. J. Synlett 2000, 695–697.
21. Nagasawa, H. T.; Kohlhoff, J. G.; Fraser, P. S.; Mikhail,
A. A. J. Med. Chem. 1972, 15, 483–486.
22. The crystal structure has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition
number CCDC 629516.
23. Shiraiwa, T.; Shinjo, K.; Kurokawa, H. Bull. Chem. Soc.
Jpn. 1991, 64, 3251–3255.