Spirobicyclic diamines. Part 2: Synthesis of homochiral diastereoisomeric proline derived [4.4]-spirolactams

Article abstract of DOI:10.1016/j.tetlet.2006.05.154

l-Proline derived diastereoisomeric [4.4]-spirolactams have been prepared by a reductive-amination reaction of (R)- or (S)-alanine methyl ester, followed by thermal cyclisation of the resulting amine onto the proline ester group in refluxing toluene. Unde

Full text of DOI:10.1016/j.tetlet.2006.05.154

Tetrahedron Letters 47 (2006) 5247–5250
Spirobicyclic diamines. Part 2: Synthesis of homochiral
diastereoisomeric proline derived [4.4]-spirolactamsI
a
Fintan Kellehera,b, and Sinead Kelly
*
aDepartment of Science and Advanced Smart Materials Centre, Institute of Technology Tallaght, Dublin 24, Ireland
bNational Institute for Cellular Biotechnology, Institute of Technology Tallaght, Dublin 24, Ireland
Received 26 April 2006; revised 15 May 2006; accepted 24 May 2006
Available online 13 June 2006
Abstract—L-Proline derived diastereoisomeric [4.4]-spirolactams have been prepared by a reductive-amination reaction of (R)- or
(S)-alanine methyl ester, followed by thermal cyclisation of the resulting amine onto the proline ester group in refluxing toluene.
Under similar conditions (R)- or (S)-phenylalanine methyl ester gave no cyclisation products, while R- or S-a-methylbenzylamine
required treatment with NaNH2 in refluxing toluene to induce cyclisation giving diastereoisomeric [4.4]-spirolactams.
Ó 2006 Elsevier Ltd. All rights reserved.
There are currently a large number of methods for the
synthesis of spirocyclic compounds and they can also
be easily formed in
proline derived [4.4]-spirolactams, we recently reported
on our studies on the preparation of racemic spiro-
lactams by a thermal intramolecular ester aminolysis
method.4 The route we employed is shown in Figure 1,
where N-Boc L-proline methyl ester was a-alkylated
with allyl bromide, using LiHMDS as base. The alkene
of the allyl group was oxidatively cleaved by the OsO4/
NaIO4 system to give the aldehyde 4. Reductive amina-
tion of the aldehyde with allyl amine, benzylamine or
glycine methyl ester gave the desired secondary amines
5 as suitable cyclisation precursors. Heating solutions
of the amino esters 5 in refluxing toluene gave [4.4]-spi-
rolactams 6 in yields of 66–90%. Since the amines used
in this study were achiral, the resulting spirolactams
were obtained as racemic mixtures. It was of interest
to us to examine the extension of the scope of the
a
stereocontrolled manner.1
Although Freidinger was the first to incorporate a lac-
tam constraint into the backbone of a peptide in order
to rigidify the peptide tertiary structure into a more
defined conformation,2 this is now a widely used method
to constrain the secondary structures of peptides. Of the
range of methods available for lactam synthesis, one of
the most common is the cyclisation of an amino group
(primary or secondary) onto a carboxylic ester, with
concomitant loss of an alcohol. Many of the reactions
take place spontaneously at ambient temperature, while
others require heating in a suitable solvent.2b,3 The over-
all efficiency of the cyclisation is dependent on a number
of factors, including the size of the ring being formed,
the nature of the amino substituent in the case of a
secondary amine, any substituents on the resulting ring
and the structure of the alkyl moiety of the ester
group.
COOMe
COOMe
N
Boc
COOH
N
N
H
Boc
L-Proline derived spirolactams have, in particular, been
studied for their use in constraining peptides with L-pro-
line residues to mimic a b-turn, a very important compo-
nent of peptide secondary structures.3 As part of a
program to synthesise both homochiral and racemic
3
2
1
H
O
COOMe
4
N
R
N
R
COOMe
N
N
N
q For part 1, see Ref. 4.
Boc
6
Boc
O
Boc
5
*
Corresponding author. Tel.: +353 1 404 2869; fax: +353 1 404 2700;
e-mail addresses: fintan.kelleher@ittdublin.ie; fintan.kelleher@
it-tallaght.ie
Figure 1. Synthesis of racemic [4.4]-spirolactams.4
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.154

5248
F. Kelleher, S. Kelly / Tetrahedron Letters 47 (2006) 5247–5250
reaction by employing chiral amines, for example, R- or
S-a-methylbenzylamine. This would result in diastereo-
isomeric amino esters which would, in each case, give
a mixture of two spirolactams after cyclisation. It was
expected that these diastereoisomeric compounds would
be separable by column chromatography, giving us a
route to all four homochiral [4.4]-spirolactams from a
common racemic precursor, namely, aldehyde 4.
stereochemistry of the spiro centre in each of the four
isolated diastereoisomers. We were unable to obtain
crystals of sufficient quality for X-ray analysis of the
structure. Molecular modelling5 was used to give mini-
mised energy conformations of the RR and SR diaste-
reoisomeric pair 6a and 6b. It was immediately evident
from the minimised structures (Fig. 2) that in the SR
diastereoisomer the hydrogens of the Boc protecting
group and the meta hydrogens of the phenyl group were
˚
Reductive amination of 4 with either R- or S-a-methyl-
benzylamine cleanly gave 5a and 5b, the desired precur-
sors to the spirolactams. Using the conditions employed
in our previous studies, i.e. stirring in toluene at reflux,
did not give any of the desired [4.4]-spirolactam cyclisa-
tion products, with only the starting material being iso-
lated in each case, even after prolonged heating. It was
therefore apparent that the extra steric hindrance in
the system, with the addition of an extra methyl group
in the position a to the nitrogen of the amine compared
to benzylamine, was sufficient to stop cyclisation from
occurring. We surmised that converting the secondary
amine cyclisation precursor to a secondary lithium or
sodium amide ion, by deprotonation with a sufficiently
strong base, would give a stronger nucleophile which
might be able to overcome the inherent steric hindrance
of the system. Since we had performed all our cycli-
sations in refluxing toluene and sodium amide is
commercially available as a 50% solution in toluene, this
was the strong base that we employed. Treating
solutions of the secondary amines 5a or 5b, dissolved
in toluene, with NaNH2 in toluene, gave no indication
of cyclisation after stirring at ambient temperature,
but when the solutions were stirred at reflux, cyclisation
proceeded with the desired spirolactams 6a–d (as pairs
of diastereoisomers which were separable by column
chromatography) being isolated in yields of 30% and
51% from aldehyde 4 (Scheme 1). In both cases, the ratio
of diastereoisomers isolated was approximately 1:1.
close in space (closest distance of 2.67 A), whereas in the
RR isomer the Boc and phenyl groups were a large
distance apart. As a result of this it was expected that
NOE NMR experiments would be able to distinguish
between the two diastereoisomers. We were pleased to
find that irradiation of the signal for the hydrogens of
the Boc group of the diastereoisomer assigned as SR
did indeed show an NOE to the phenyl hydrogens,
whilst no similar NOE was observed in the case of the
RR diastereoisomer. Although this is not conclusive
proof of the absolute stereochemistry of the spiro centre
we have now tentatively assigned the stereochemistry,
based on the molecular modelling and NOE studies, of
all four diastereoisomers.
We next examined the synthesis of diastereoisomeric spiro-
lactams with carboxylic ester side-chains on the lactam
nitrogen. Previously we had found that when glycine
methyl ester was used, cyclisation was very efficient.
The use of (R)-alanine methyl ester, with the incorpora-
tion of a methyl group in the position a to the nitrogen,
was expected to reduce considerably, or possibly com-
pletely stop, cyclisation from taking place under the
thermal ester aminolysis protocol. We found that by
using the thermal cyclisation method the two diastereo-
isomeric spirolactams 6e and 6f were obtained in a much
reduced yield of 40% even after stirring for 3 days in
refluxing toluene, compared to the 90% for glycine
methyl ester after stirring for 24 h in refluxing toluene
(Scheme 2). The diastereoisomeric ratio in this case
was 6:1. Repeating the synthesis, but this time using
(S)-alanine methyl ester again for 3 days in refluxing
toluene, gave the two diastereoisomeric spirolactams
Although the stereochemistry of the a-methyl benzyl
substituent was known from our choice of the starting
homochiral amine, we were unaware of the absolute
H
N
6a
b
N
N
N
Boc
O
O
CO2Me
N
Boc
+
a
O
COOMe
4
5a
6b
6c
N
Boc
N
Boc
c
H
N
N
N
N
Boc
d
CO2Me
O
O
N
Boc
+
5b
6d
N
Boc
Scheme 1. Reagents and conditions: (a) (i) (R)-a-methylbenzylamine, MgSO4, MeOH, (ii) NaBH4, rt; (b) NaNH2 in toluene, reflux, 30% from 4; (c)
(i) (S)-a-methylbenzylamine, MgSO4, MeOH, (ii) NaBH4, rt; (d) NaNH2 in toluene, reflux, 51% from 4.

F. Kelleher, S. Kelly / Tetrahedron Letters 47 (2006) 5247–5250
5249
Figure 2. Energy minimised conformations of 6b (S,R) and 6a (R,R).5
H
N
6e
6f
CO2Me
CO2Me
CO2Me
b
N
N
N
Boc
O
O
CO2Me
N
+
a
Boc
O
CO2Me
4
5c
N
N
Boc
Boc
c
H
6g
6h
CO2Me
CO2Me
CO2Me
N
N
N
N
Boc
d
CO2Me
O
O
N
Boc
+
5d
N
Boc
Scheme 2. Reagents and conditions: (a) (i) (R)-alanine, MgSO4, MeOH, (ii) NaBH4, rt; (b) toluene, reflux, 40% from 4; (c) (i) (S)-alanine, MgSO4,
MeOH, (ii) NaBH4, rt; (d) toluene, reflux, 54% from 4.
6g and 6h in a slightly improved yield of 54%. The
diastereoisomeric ratio in this case was 1.75:1. As
before, we were unable to obtain crystals of sufficient
quality for X-ray analysis from any of the four
diastereoisomeric compounds. For both sets of reac-
tions, the remaining material was the unreacted amino
cyclisation precursors 5c and 5d.
lactams, with a group larger than methyl causing
the complete absence of any products arising from
cyclisation. It would be our recommendation that
for the synthesis of homochiral proline derived
H
CO2Me
N
We expected that increasing the steric bulk of the amino
acid component would cause a further reduction in the
isolated yield of the diastereoisomeric spirolactams.
When (S)-phenylalanine methyl ester was used no spiro-
lactam products were isolated, with the secondary amine
5f being isolated as an inseparable mixture of diastereo-
isomers (one spot by TLC) in 72% yield, while the use of
(R)-phenylalanine methyl ester gave a similar result with
the uncyclised diastereoisomeric amine 5e being ob-
tained in a yield of 80% (Scheme 3).
CO2Me
N
Boc
a
O
CO2Me
4
5e
N
Boc
b
H
CO2Me
N
CO2Me
N
Boc
5f
In conclusion, it is apparent that the size of the a-sub-
stituents on the primary amine component is critical
to the overall success of the thermal ester aminolysis
method for the synthesis of proline derived [4.4]-spiro-
Scheme 3. Reagents and conditions: (a) (i) (R)-phenylalanine, MgSO4,
MeOH, (ii) NaBH4, rt, 80%; (b) (i) (S)-phenylalanine, MgSO4, MeOH,
(ii) NaBH4, rt, 72%.

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F. Kelleher, S. Kelly / Tetrahedron Letters 47 (2006) 5247–5250
[4.4]-spirolactams with larger groups on the lactam
nitrogen, the thermal ester aminolysis is not the method
of choice. It is more appropriate to synthesise the cycli-
sation precursor, hydrolyse the proline ester, and then to
use peptide coupling methods to induce lactamisation.3
Currently, we are attempting to obtain crystals suitable
for X-ray analysis of a number of derivatives of these
spirolactams and we are also examining their chemical
properties. The results of these studies will be reported
in due course.
References and notes
1. Sannigrahi, M. Tetrahedron 1999, 55, 9007.
2. (a) Freidinger, R.; Veber, D.; Perlow, D.; Brooks, J.;
Saperstein, R. Science 1980, 210, 656; (b) Freidinger, R.;
Perlow, D.; Veber, D. J. Org. Chem. 1982, 47, 104.
3. A number of examples are given and the list is far from
exhaustive, but they are included to exemplify the methods
used: (a) Mueller, R.; Revesz, L. Tetrahedron Lett. 1994, 35,
4091; (b) Reddy, P.; Hsiang, B.; Latifi, T.; Hill, M.;
Woodward, K.; Rothman, S.; Ferrendelli, J.; Covey, D.
J. Med. Chem. 1996, 39, 1898; (c) Batey, R.; Mackay, D.
Tetrahedron Lett. 2000, 41, 9935; (d) Vitry, C.; Vasse, J.-L.;
Dupas, G.; Levacher, V.; Queguiner, G.; Bourguignon, J.
Tetrahedron 2001, 57, 3087; (e) Nagata, T.; Nishida, A.;
Nakagawa, M. Tetrahedron Lett. 2001, 42, 8345; (f)
Herrero, S.; Garcia-Lopez, M.; Latorre, M.; Cenarruzabei-
tia, E.; Del Rio, J.; Herranz, R. J. Org. Chem. 2002, 67,
3866.
Acknowledgements
We thank Dr. Brian Murray for help with NMR spectro-
scopy and useful discussions. We are grateful to Strand
III of the Irish Government’s National Development
Plan (2000–2006) Technological Sector Research
Program, through the Council of Directors of the
Institutes of Technology, for funding for S.K. (Grant
CRS/01/TA02).
4. Part 1: Kelleher, F.; Kelly, S. Tetrahedron Lett. 2006, 47,
3005.
5. HYPERCHEM Release 7.5, Hypercube Inc., Gainesville,
Florida, USA.