The diastereoselective synthesis of functionalised spirocyclic lactams and lactones using a Cope elimination/intramolecular nitrone cycloaddition strategy

Article abstract of DOI:10.1016/j.tetlet.2007.01.046

Functionalised hydroxylamine derivatives of (S)-proline and pipecolic acid have been prepared using a Cope elimination. These hydroxylamines have been found to undergo oxidation to the nitrone either in the presence of air or a catalytic quantity of TPAP. An intramolecular 1,3-dipolar cycloaddition then occurs between the nitrone and pendant double bond to give tricyclic lactams and lactones with high diastereoselectivity.

Full text of DOI:10.1016/j.tetlet.2007.01.046

Tetrahedron Letters 48 (2007) 1687–1690
The diastereoselective synthesis of functionalised spirocyclic
lactams and lactones using a Cope elimination/intramolecular
nitrone cycloaddition strategy
Gemma L. Ellis,a Ian A. O’Neil,a,* V. Elena Ramos,a S. Barret Kalindjian,b
Alan P. Chorltonc and David J. Tapolczayc
aRobert Robinson Laboratories, Department of Chemistry, University of Liverpool, Crown Street, 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 18 December 2006; accepted 10 January 2007
Available online 14 January 2007
Abstract—Functionalised hydroxylamine derivatives of (S)-proline and pipecolic acid have been prepared using a Cope elimination.
These hydroxylamines have been found to undergo oxidation to the nitrone either in the presence of air or a catalytic quantity of
TPAP. An intramolecular 1,3-dipolar cycloaddition then occurs between the nitrone and pendant double bond to give tricyclic lac-
tams and lactones with high diastereoselectivity.
Ó 2007 Published by Elsevier Ltd.
Previously there have been few general methodologies for
the construction of azaspirocyclic ring systems.1–7 The
azaspirocyclic substructure is seen in numerous biologi-
cally active alkaloids such as (+)-lactacystin,8 histrio-
nicotoxin,9 sibirine,10 nitramine,11 amanthaspiramide F12
and cylindricine C.13 The spirolactam substructure is also
present in several different conformationally constrained
peptidomimetics, for example, those developed by Hinds
et al. and Casamitijana and co-workers.14,15
paper.17 Treatment of 1 with m-CPBA gave the N-oxide 2.
This then underwent Cope elimination in situ to gener-
ate the hydroxylamine 3 in 81% yield. Oxidation of
hydroxylamine 3 with 5 mol % TPAP and 1.5 equiv of
N-methyl morpholine N-oxide (NMNO) in MeCN18,19
at room temperature gave the stable nitrone 4 in 98%
yield. Previously related nitrones have not been stable
and have rapidly undergone 1,3-dipolar cycloaddition.17
The explanation for the stability of 4 lies in the hydrogen
bonding between the N-oxide and NH. This was con-
1
Recently, we reported the preparation of functionalised
isoxazolidines using a Cope elimination/intramolecular
nitrone cycloaddition strategy.16 Incorporation of the
lactam and lactone functionalities into our spirocyclic
compounds was imperative in expanding the scope and
applicability of our synthetic strategy. We now wish to
report the synthesis of tricyclic lactams and lactones
derived from (S)-proline and pipecolic acid. In addition
the use of 4(R)-hydroxy-2-(S)-proline allows us to report
the synthesis of a homochiral spirocyclic lactone.
firmed by H NMR analysis which shows the NH shift-
ing from 7.0 ppm in 3 to 10.1 ppm in 4. The 1,3-dipolar
cycloaddition was achieved by heating 4 in acetonitrile
at reflux for 5 days to give 5 as a single diastereoisomer
in 91% yield (Scheme 1).20–22 Spirocyclic lactam 5 was
also formed by refluxing 3 in methanol open to the air
for 5 days in a 58% yield, the oxidant in this case was
oxygen in the air. The stereochemistry of 5 was assigned
unambiguously by NOE studies. Irradiation of the sig-
nal for the H-3a0 proton gave an enhancement with
one of the hydrogens at C-8, so fixing the relative config-
uration. We have also recently reported that the hydr-
oxylamines generated by Cope elimination will undergo
reverse Cope elimination under different reaction condi-
tions.23 Examples of the incorporation of the lactam and
lactone functionalities into the reverse Cope elimination
protocol can be found in the accompanying paper.17
The synthesis of the tricyclic lactams began with the (S)-
proline derived amide 1. The synthesis of all precursor
amides and esters are described in the accompanying
*
Corresponding author. Tel.: +44 151 794 3485; fax: +44 151 794
3588; e-mail: ion@liv.ac.uk
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.01.046

1688
G. L. Ellis et al. / Tetrahedron Letters 48 (2007) 1687–1690
O
Cope
elimination
TPAP (cat.)
NMO, 98%
m-CPBA, K2CO3
NH
3a
O
O
MeCN, heat
91%
O
O
1
8
N
O
N
O
N
N
DCM, -78 oC,
81%
N
N
HN
HN
HN
OH
H
O
NC
NC
Scheme 1.
3
4
5
1
2
In order to investigate the effect of ring size on the cyclo-
addition, racemic pipecolic acid was used as a substrate.
Amide 6 was selectively oxidised using m-CPBA to give
the N-oxide 7, which then underwent spontaneous Cope
elimination to give 8 in 79% yield. Oxidation of the
hydroxylamine 8 with catalytic TPAP and NMNO gave
in this case the tricyclic lactam 10 in 74% yield (Scheme
2). In this case none of the nitrone 9 was isolated indicat-
ing that the pipecolic derivatives are more reactive.
None of the nitrone 14 was isolated from the reaction
as it spontaneously underwent 1,3-dipolar cycloaddi-
tion. In this case the stereochemistry could not be deter-
mined by NOE spectroscopy as the key protons to be
irradiated overlapped on the H NMR spectrum. How-
ever, by analogy with the tricyclic lactam 5 the stereo-
chemistry for 15 which is shown below was assigned.
1
A similar synthetic route was used in the preparation of
the analogous pipecolic acid derivative. Formation of
hydroxylamine 18 was achieved using m-CPBA to give
selectively the N-oxide 17, which then underwent spon-
taneous Cope elimination to give 18 in 89% yield. Oxi-
dation of the hydroxylamine 18 as before gave the
tricyclic spiro lactone 20 in an 83% yield via the unisol-
able nitrone 19 (Scheme 4).
As the lactam functionality had been successfully incor-
porated into the synthetic strategy, our attention turned
to the incorporation of a lactone moiety. Formation of
hydroxylamine 13 was achieved using m-CPBA to give
selectively the N-oxide 12, which then underwent spon-
taneous Cope elimination to give 13 in 77% yield. Oxi-
dation of the hydroxylamine 13 using a catalytic
quantity of TPAP and 1.5 equiv of NMNO gave the tri-
cyclic spiro lactone 15 in 79% yield (Scheme 3). Spiro
lactone 15 was also formed in a 28% yield by heating
13 at reflux, open to the air in chloroform for 5 days.
With the lactone functionality easily incorporated into
our tricyclic systems it seemed logical to see if these tri-
cyclic compounds could be made with a fixed chiral cen-
tre, as any previously incorporated chirality had been
O
Cope
TPAP (cat.)
m-CPBA, K2CO3
DCM, -78 oC
elimination
74%
NMO
NH
O
O
N
O
N
O
N
N
79%
N
NH
N
NC
NH
OH NH
H
O
NC
10
8
9
7
6
Scheme 2.
O
Cope
TPAP (cat.)
NMO
m-CPBA, K2CO3
DCM, -78 oC
O
O
O
elimination
O
79%
O
1
8
N
N
O
N
N
O
N
O
77%
O
O
3a
O
OH
O
NC
NC
15
14
13
11
12
Scheme 3.
O
Cope
TPAP (cat.)
NMO
m-CPBA, K2CO3
DCM, -78 oC
elimination
83%
O
O
O
N
O
N
N
N
89%
N
O
O
O
NC
O
OH NH
O
NC
20
18
19
17
16
Scheme 4.

G. L. Ellis et al. / Tetrahedron Letters 48 (2007) 1687–1690
TBDMSO
O TBDMS-OTf
1689
HO
HO
TBDMSO
allyl alcohol
TBDMSO
m-CPBA, K2CO3
acrylonitrile
O
O
O
O
N
N
N
N
N
O
DCM, -78 oC
24
H
2,6-lutidine
86%
OMe
NaH (cat.),
Δ, 48 h
58%
OMe NEt3, MeOH
83%
OMe
O
O
HCl
NC
NC
NC
NC
23
22
21
25
Cope
elimination
91%
TBDMSO
TBDMSO
O
O
TBDMSO
TBDMSO
TPAP (cat.)
NMO
O
O
O
O
N
OH
N
O
+
N
N
O
O
O
O
28a 71%
28b 28%
27
26
Scheme 5.
lost during formation of the nitrone, with subsequent
1,3-dipolar cycloaddition leading to racemic material.
It was therefore reasonable to presume that inclusion
of a fixed chiral centre in the pyrrolidine ring would lead
to the desired chiral cycloadduct (Scheme 5). The
4-hydroxyproline derivative 21 is commercially available
and was converted to the cyanoethylated product 22 in
83% yield by reaction with acrylonitrile. The 4-hydroxy
group was then protected using 2,6-lutidine and TBDM-
SOTf to give 23 in 86% yield. Ester exchange with allyl
alcohol was achieved using a catalytic quantity of NaH
to give 24 in a 58% yield. Oxidation of 24 using m-CPBA
gave the N-oxide 25, this then underwent spontaneous
Cope elimination of acrylonitrile, and gave hydroxyl-
amine 26 in a 91% yield. Oxidation to the nitrone 27 fol-
lowed by spontaneous 1,3-dipolar cycloaddition gave,
interestingly, two diastereomers that were separable by
flash column chromatography. The major diastereomer
28a was isolated in 71% yield and the minor diastereo-
mer 28b was isolated in 28% yield. Diastereoisomer
28a was also formed by heating 26 at reflux in methanol,
open to the air for 4 days in a 36% yield.
attempted, including reductive cleavage using H2 Pd/C,
Zn/AcOH and Zn/AcOH/Cu(OAc)2. Oxidative cleavage
using m-CPBA was also tried. However, all these meth-
ods failed. An adaptation of the Zn/AcOH method devel-
oped by Chiacchio et al. proved more successful, leading
to bicyclic compound 29 in a 77% yield (Scheme 6).24
To conclude, we have demonstrated that the Cope elim-
ination/intramolecular nitrone cycloaddition strategy
can be applied to incorporate the lactam and lactone
structural motifs into complex tricyclic spiro adducts.
Incorporation of a fixed chiral centre has also been
achieved.
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
measurements.
Supplementary data
The stereochemistry of the major diastereomer was con-
firmed by NOE measurements. The formation of the
minor diastereomer had never been seen in any of our
previous systems.
The following supplementary data is available: (1)
detailed descriptions of experimental procedures, (2)
1H NMR spectra. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.01.046.
Conversion of these tricyclic compounds into their bicy-
clic derivatives by cleavage of the N–O bond was of con-
siderable interest, with the bicyclic spiro structure being
seen more commonly in several natural products and
peptidomimetics. This cleavage proved to be more diffi-
cult than initially anticipated. Several methods were
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