Spirobicyclic diamines. Part 3: Synthesis and metal complexation of proline-derived [4.4]-spirodiamines

Article abstract of DOI:10.1016/j.tet.2007.06.050

The syntheses of racemic and homochiral [4.4]-spirolactams, starting from l-proline, in good yields are described. Reduction of the lactam carbonyl group of spirolactams, containing chiral substituents on the lactam nitrogen, with lithium aluminium hydride, gives?a series of homochiral [4.4]-spirodiamines. The crystal structure of one of these spirodiamines on complexation with zinc chloride was obtained. Interestingly it showed a hydrogen-bonded dimeric structure, where the monomers are diastereoisomeric diamines.

Full text of DOI:10.1016/j.tet.2007.06.050

Tetrahedron 63 (2007) 9235–9242
Spirobicyclic diamines. Part 3: Synthesis and metal
complexation of proline-derived [4.4]-spirodiamines
a
c
Fintan Kelleher,a,b, Sinead Kelly and Vickie McKee
*
aDepartment of Science and Advanced Smart Materials Centre, Institute of Technology Tallaght, Tallaght, Dublin 24, Ireland
bNational Institute for Cellular Biotechnology, Institute of Technology Tallaght, Tallaght, Dublin 24, Ireland
cChemistry Department, Loughborough University, Loughborough, Leics, LE11 3TU, UK
Received 28 March 2007; revised 29 May 2007; accepted 14 June 2007
Available online 21 June 2007
Abstract—The syntheses of racemic and homochiral [4.4]-spirolactams, starting from L-proline, in good yields are described. Reduction of
the lactam carbonyl group of spirolactams, containing chiral substituents on the lactam nitrogen, with lithium aluminium hydride, gives a
series of homochiral [4.4]-spirodiamines. The crystal structure of one of these spirodiamines on complexation with zinc chloride was
obtained. Interestingly it showed a hydrogen-bonded dimeric structure, where the monomers are diastereoisomeric diamines.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of applications in asymmetric synthesis.5 Another method of
constraint, which has been used is to introduce a spirofusion
of two rings, which forces the nitrogen atoms into a mutually
orthogonal relationship (4, Fig. 1).
Diamines, especially vicinal diamines, are of interest be-
cause of their ability to strongly bind metal ions leading to
Lewis acid complexes, which have found use as catalysts
in a wide range of organic syntheses.1 Many of the well
known diamines, such as ethylenediamine (1, Fig. 1), are
acyclic and are very flexible in nature. The introduction of
constraints into such structures is a well studied method
for reducing this conformational flexibility giving molecules
with a more defined 3D structure [e.g., trans-1,2-diaminocy-
clohexane (2)2 is a constrained version of ethylenediamine].
In some cases this has been used in biologically active mole-
cules to either increase the affinity of the molecule for its
target (cyclic versus acyclic peptides),3 or to make the mole-
cules more metabolically stable, which can lead to improved
bioavailability.4 The naturally occurring polycyclic diamine
(ꢀ)-sparteine (3) has found use as a chiral ligand in a number
There are currently a large number of methods for the syn-
thesis of spirocyclic compounds and they can also be easily
formed in a stereocontrolled manner.6 Freidinger was the
first to incorporate a lactam constraint in the backbone of
a peptide in order to rigidify the peptide tertiary structure
into a more defined conformation.7 One of the most common
methods for the synthesis of lactams is the cyclisation of an
amino group (primary or secondary) onto a carboxylic ester,
with concomitant loss of an alcohol. The overall efficiency
of the cyclisation is dependant on 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. Many of
the reactions take place spontaneously at ambient tempera-
ture, while others require heating in a suitable solvent.8
H2N
NH2
1
H2N
NH2
2
L-Proline-derived spirolactams have, in particular, been
studied for their use in constraining peptides with L-proline
residues to mimic the b-turn, a very important component
of peptide secondary structure. Depending on their final
use spirolactams are synthesised either as racemic mixtures
or as single enantiomers. In most cases these syntheses start
from L-proline, which must then be alkylated in the a-posi-
tion. Full control of the stereochemistry can easily be
achieved using Seebach’s ‘self-reproduction of chirality’
methodology,9 whereas the racemic compounds simply re-
quire alkylation of the enolate of a suitably protected proline
molecule, which, after a series of further functional group
manipulations, gives cyclisation precursors.
H
H
N
N
H
N
N
H
H
H
4
3
Figure 1. Structure of ethylenediamine 1; trans-1,2-diaminocyclohexane 2;
(ꢀ)-sparteine 3 and 1,7-diazaspiro[4.5]decane 4.
Keywords: Spirolactam; Spirodiamines; Synthesis; X-ray crystal structure;
Dimer.
* Corresponding author. Department of Science and Advanced Smart
Materials Centre, Institute of Technology Tallaght, Tallaght, Dublin 24,
Ireland. Tel.: +353 1 404 2869; fax: +353 1 404 2700; e-mail: fintan.
kelleher@ittdublin.ie
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.050

9236
F. Kelleher et al. / Tetrahedron 63 (2007) 9235–9242
(i)
The required secondary amines (9a–c) would be obtained by
NHR
COOH
Couple
reductive amination of the racemic aldehyde 8, so the effi-
cient synthesis of this aldehyde was critical to the overall
success of this method, as a generalised route to spirolac-
tams. Compound 8 was prepared in four steps from L-proline
by Boc protection of the nitrogen of the methyl ester of
L-proline, which was obtained quantitatively from L-proline
by treatment with SOCl2 in methanol. The a-allyl group was
efficiently introduced in 80% yield.14 Oxidative cleavage of
the alkene using OsO4/NaIO4 gave the aldehyde 8 in a 74%
yield.10e It was necessary to efficiently purify the aldehyde
by column chromatography to free it from any traces of
osmium by-products, as failure to do so led to major reduc-
tions in the yield of the subsequent reductive amination and
cyclisation reactions, with a large amount of decomposition
occurring. Reductive amination of 8 with allylamine, gave
the required secondary amine spirolactam precursor 9a. Fol-
lowing the method of Johnson,11a thermal cyclisation of 9a
in DMF at 70 ꢁC gave the spirolactam 10a in a 99% yield,
though the work-up was lengthy. Cyclisation in refluxing
toluene gave 10a in a 66% yield, with a simpler work-up pro-
cedure. When benzylamine was used in place of allylamine,
using the same reaction cyclisation conditions, the N-benzyl
substituted spirolactam (10a) was obtained in a higher yield
of 75%.
N
N
R
N
N
Boc
Boc
O
O
(ii)
OH
NHR
Mitsunobu
N
R
S
N
Boc
O
Boc
S
H
1. Et3N, DMF, 70 °C
2. CH2N2
(iii)
HN
CO2Me
N
N
N
COOH
CO2Me
Boc
Boc
O
Figure 2. Cyclisation methods for proline-derived spirolactams.8,10,11
A number of different strategies have also been used for the
critical final cyclisation step to form the spirobicyclic lactam
ring. These include (i) intramolecular amide coupling, with
a coupling agent (e.g., DCC or EDC), of tethered secondary
amines with the deprotected proline carboxylic acid group;10
(ii) cyclisation of proline carboxylic amides onto a primary
alcohol under Mitsunobu conditions11 and (iii) thermal
cyclisation of a tethered secondary amine onto a proline
carboxylic ester in DMF at 70 ꢁC, although the yield of
the latter reaction was very low (27%), with only one diaste-
reoisomer cyclising and the side chain carboxylic acid sub-
sequently being converted to the methyl ester by treatment
with diazomethane (Fig. 2).12
Extension of this methodology using chiral a-substituted
amines would give pairs of diastereoisomeric spirolac-
tams.15 Reductive amination of aldehyde 8 with either
(R)- or (S)-a-methylbenzylamine gave spirolactams 11a
and 11b (Scheme 2). Prolonged stirring of solutions of these
compounds in refluxing toluene gave no indication of any
cyclisation. In a similar cyclisation reaction of a secondary
amine, where alanine methyl ester was used in the reductive
amination step, Auberson et al. were able to successfully
achieve cyclisation in yields of >90%, by stirring at reflux
temperature in xylenes for 2 h.16 Stirring solutions of amino
ester 11a or 11b in refluxing xylenes, even for extended
periods of time, gave no indication of any cyclisation reac-
tion occurring.
2. Results and discussion
As part of a programme of research to synthesise both race-
mic and homochiral spirocycles, the synthesis of proline-
derived [4.4]-spirolactams13,15 and their conversion to
spirodiamines were of interest.
The variety of different cyclisation methods used, along with
their wide ranging yields, prompted us to study one of the
methods, the thermal cyclisation reaction, in more detail in
order to investigate whether it was a viable method for the
synthesis of a range of proline-derived [4.4]-spirolactams.
This necessitated the synthesis of secondary amines for sub-
sequent cyclisation onto a carboxylic ester (Scheme 1).13
Treatment of toluene solutions of 11a or 11b with sodium
amide (50% solution in toluene) at reflux temperature gave
the desired spirolactams 12a–d (as pairs of diastereoisomers
in 1:1 ratios), isolated in yields of 30 and 51%, from alde-
hyde 8. HPLC analysis of each diastereoisomer showed a
high degree of purity (all greater than 98.8% pure). The
only impurity identified, in each case, was the diastereoiso-
meric product produced in the reaction.
c
a, b
COOMe
COOMe
N
Boc
COOH
N
N
H
Boc
7
6
5
It was not possible to obtain crystals suitable for X-ray analy-
sis of any of the four diastereoisomers 12a–d. Although the
stereochemistry of the a-methyl benzyl substituent was
known from the choice of the starting homochiral amine
the absolute stereochemistry of the spirocentre in each
case was not known. Molecular modelling17 was used to
give minimised energy conformations of the SR and RR
diastereoisomeric pair (12a and 12b). It was immediately
evident from the minimised structures (Fig. 3) that in the
SR diastereoisomer the hydrogens of the Boc protecting
group and the meta hydrogens of the phenyl group were
d
H
O
COOMe
8
N
R
e
f
N
R
O
10a-b
COOMe
N
Boc
N
Boc
N
Boc
9a-b
10a, R = -CH2CH=CH2
10b, = -CH2Ph
Scheme 1. Reagents and conditions: (a) SOCl2, MeOH, reflux, 94%; (b)
(Boc)2O, DMAP, Et3N, DCM, rt, 74%; (c) (i) LiHMDS, THF, ꢀ78 ꢁC,
(ii) allyl bromide, rt, 80%; (d) OsO4/NaIO4, THF/H2O (4:1), rt, 74%; (e)
(i) RNH2, EtOH, (ii) NaBH4, rt; (f) toluene, reflux, 60–88%.
˚
close in space (closest distance of 2.67 A), whereas in the
RR isomer the Boc and phenyl groups were a large distance

F. Kelleher et al. / Tetrahedron 63 (2007) 9235–9242
9237
H
12a
b
N
N
N
N
Boc
O
O
CO2Me
N
Boc
+
a
O
COOMe
8
11a
12b
N
Boc
N
Boc
c
H
12c
N
N
N
N
Boc
d
CO2Me
O
O
N
Boc
+
11b
12d
N
Boc
Scheme 2. Reagents and conditions: (a) (i) (R)-1-phenylethylamine, MgSO4, MeOH, (ii) NaBH4, rt; (b) NaNH2 in toluene, reflux, 30% from 8;
(c) (i) (S)-1-phenylethylamine, MgSO4, MeOH, (ii) NaBH4, rt; (d) NaNH2 in toluene, reflux, 51% from 8.
The homochiral diamines derived from the spirolactams
12a–d were obtained when the N-Boc protecting group
was cleanly removed from each spirolactam to give the
free amino spirolactams 13a–d, and the reduction of the
lactams was then examined. The optimal condition found
for successful reduction was the use of 20 M equiv of lithium
aluminium hydride in THF (Scheme 3), which gave the
diamines 14a–d in acceptable isolated yields (43–56%).
One of our interests is in the use of these diamines as ligands
for metal ions, thus giving chiral complexes, which may
have potential as novel chiral catalysts in asymmetric trans-
formations. The first step was to examine whether the amines
bound to a metal ion. No complexation was observed when
Figure 3. Energy minimised conformations of 12a (S,R) and 12b (R,R).17
apart. It was therefore expected that NOE NMR experiments
would be able to distinguish between the two diastereoiso-
mers. Irradiation of the signal for the hydrogens of the Boc
group of the diastereoisomer assigned as SR showed an
NOE to the phenyl hydrogens, whilst no similar NOE was
observed in the case of the RR diastereoisomer, though this
is not conclusive proof of the absolute stereochemistry of
the spirocentre.
ethanolic solutions of the amines were treated with cop-
per(II) acetate. Zinc(II) was then chosen as it is diamagnetic,
making studies of complexation also possible by NMR spec-
troscopy. When ethanolic solutions of amines 14a–d were
refluxed with 1.5 M equiv of ZnCl2 and the solutions were
left standing at room temperature, the solutions containing
amines 14a and 14b each gave one small single crystal
(15a and 15b) suitable for X-ray analysis. The surprise result
N
N
N
b
N
H
a
N
Boc
N
H
O
O
14a
12a
13a
N
N
N
b
a
N
H
N
Boc
N
H
O
O
O
O
14b
12b
13b
N
N
N
b
a
N
H
N
Boc
N
H
14c
12c
13c
N
N
N
b
N
H
a
N
Boc
N
H
O
O
14d
12d
13d
Scheme 3. Reagents and conditions: (a) (i) 50% TFA in DCM, (ii) 3 M KOH; (b) LiAlH4, THF, rt.

9238
F. Kelleher et al. / Tetrahedron 63 (2007) 9235–9242
ꢁ
˚
Table 1. Selected bond lengths (A) and angles ( ) for 15a
Bond
Bond lengths
Angle
Bond angles
Zn(1A)–N(1A)
Zn(1A)–N(2A)
Zn(1A)–Cl(1A)
Zn(1A)–Cl(2A)
Zn(1B)–N(1B)
Zn(1B)–N(2B)
Zn(1B)–Cl(2B)
Zn(1B)–Cl(1B)
2.067(5)
2.104(6)
2.213(2)
2.2191(18)
2.049(5)
2.117(5)
2.2118(19)
2.213(2)
N(1A)–Zn(1A)–N(2A)
N(1A)–Zn(1A)–Cl(1A)
N(2A)–Zn(1A)–Cl(1A)
N(1A)–Zn(1A)–Cl(2A)
N(2A)–Zn(1A)–Cl(2A)
Cl(1A)–Zn(1A)–Cl(2A)
N(1B)–Zn(1B)–N(2B)
N(1B)–Zn(1B)–Cl(2B)
N(2B)–Zn(1B)–Cl(2B)
N(1B)–Zn(1B)–Cl(1B)
N(2B)–Zn(1B)–Cl(1B)
Cl(2B)–Zn(1B)–Cl(1B)
84.4(2)
113.11(16)
117.00(16)
108.42(17)
107.20(16)
120.71(7)
84.4(2)
109.46(16)
111.39(17)
110.69(17)
116.31(17)
119.11(7)
from these studies was that the X-ray crystal structures of the
zinc complexes 15a and 15b were identical (Fig. 3).
complexed diamine 14a remained in solution with only
a small amount crystallising out with the opposite diastereo-
isomeric diamine ‘impurity’ 14b. Also by HPLC analysis
amine 14b was found to be 99.3% pure, contaminated
with only 0.7% of the diasteresoisomer 14a. Again on com-
plexation with zinc chloride the same result was obtained as
before.
Close examination of the X-ray structures shows that a 1:1
dimeric complex had formed where each spirodiamine
accommodates one zinc metal. The asymmetric unit of
the crystal contains two independent molecules linked to a
hydrogen-bonded dimer. Each zinc atom occupies a pseudo-
tetrahedral geometry, where it is complexed to the two
nitrogens of the spirocycle and to two chlorine atoms. The
N–Zn–N angle is 84.4(2)ꢁ in both molecules of the dimer,
and the Cl–Zn–Cl angle is 120.71(7) ꢁ in one molecule while
it is 119.11(7)ꢁ in the other. The dimer is then formed by two
intermolecular hydrogen bonds via one of the chlorine atoms
and an amine N–H. The nitrogen to chlorine distances for
Thus the ability of the chiral spirodiamines to complex a
selected metal ion has been demonstrated. Mukaiyama has
studied the asymmetric catalysis of the aldol reaction
(Mukaiyama aldol) using diamines derived from L-proline,
which are complexed to tin(II) triflate, as asymmetric-
catalysts (Fig. 4).18 Using molecular modelling,17 when
the proline-derived diamine 16 was bound to zinc chloride
and was minimised, the N–N distance was calculated to be
˚
the two hydrogen bonds are 3.355(6) and 3.372(6) A. The
˚
important bond lengths and angles are shown in Table 1.
The formation of a dimer may not be in itself unusual, but
the most intriguing aspect of the crystal structure is that
the two spirodiamines that make up the dimer are diastereo-
isomeric. This result was certainly not anticipated as purifi-
cation of each precursor amine (14a–d) was carried out very
carefully. HPLC analysis showed that there was only a very
small amount of the corresponding diastereoisomer present
in the ‘purified’ amines. In the case of 14a it was shown to
be 98.7% pure with 1.2% of 14b being present. Therefore
on complexation with zinc chloride the vast majority of
2.77 A. From the crystal structure of complex 15a it is ob-
˚
served that the N–N distances are 2.797 and 2.798 A. Thus
these distances compare very favourably with the calculated
value for the Mukaiyama ligand 16, above (Fig. 5).17,18 This
leads us to believe that the spirodiamines 14a–d have the po-
tential to be used as ligands for Sn2+, with the resulting com-
plexes being used as catalysts in the asymmetric Mukaiyama
aldol reaction. It is also envisaged that the spirodiamines will
complex other metal ions, and thus have applications in
metal catalysed asymmetric synthetic reactions. It is also en-
visaged that the homochiral spirolactams 13a–d will have
Figure 4. X-ray crystal structure of spirodiamine–ZnCl2 complex 15a.

F. Kelleher et al. / Tetrahedron 63 (2007) 9235–9242
9239
Microanalysis: Found C, 57.51; H, 8.60; N, 5.88. Calculated
for C11H19NO4: C, 57.60; H, 8.34; N, 6.10.
R2
R3
R2
R3
N
N
R3
N
N
N
N
Sn
Zn
R1
R
R2
R
1
16
4.1.2. ( )-a-Allyl N-Boc-proline methyl ester (7).14 Com-
pound 7 was prepared from 6 by the method of Confalone,14
except a 1 M solution of LiHMDS in tetrahydrofuran, in-
stead of hexane, was used as the base. Microanalysis: Found
C, 62.29; H, 8.80; N, 4.95. Calculated for C14H23NO4: C,
62.43; H, 8.61; N, 5.20.
1Cl
TfO
OTf
Cl
Figure 5. Mukaiyama’s diamines 16, complexed to Sn(OTf)217 and ZnCl2.
applications as novel organocatalysts. All of these studies
are currently being undertaken.
4.1.3. ( )-a-Formylmethyl N-Boc-proline methyl ester
(8).10e Compound 8 was prepared from 7 by the method of
Johnson.10e Microanalysis: Found C, 53.59; H, 7.60; N,
4.22. Calculated for C14H23NO4 (0.33 CHCl3): C, 53.43;
H, 7.40; N, 4.67.
3. Conclusions
In conclusion, a series of homochiral spirolactams derived
from L-proline have been prepared. These spirolactams
were reduced to spirodiamines using lithium aluminium
hydride as reductant, and the diamines formed complexes
with zinc chloride. The X-ray crystal structure of one of
these complexes showed an unusual dimeric form where
the two spirodiamines present were diastereoisomeric. The
properties of these spirodiamines are currently being further
elucidated and their potential as ligands for metals to act as
catalysts in asymmetric synthesis is currently being under-
taken. The results of these studies will be reported in due
course.
4.1.4. ( )-7-Allyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-
carboxylic acid tert-butyl ester (10a). Method A: to a stirred
solution of 8 (0.10 g, 0.35 mmol) in ethanol (3 ml) under
nitrogen was added dropwise allylamine (0.030 ml,
0.35 mmol) over 10 min at ambient temperature, and the
solution was stirred for 2 h. Sodium borohydride (0.020 g,
0.42 mmol) was added in small portions over 5 min and
the resulting solution was stirred at ambient temperature
for 48 h. Water (30 ml) was added and the mixture was
extracted with ethyl acetate (3ꢂ15 ml), and the combined
organic layers were washed with brine (2ꢂ15 ml), dried
over MgSO4 and concentrated in vacuo. The residue was dis-
solved in DMF (5 ml) under nitrogen, to which triethylamine
(0.050 ml, 0.35 mmol) was added. The solution was stirred
at 70 ꢁC for 24 h, poured into water (50 ml) and extracted
with ethyl acetate (3ꢂ20 ml). The combined organic layers
were washed with 10% citric acid solution (2ꢂ20 ml), water
(4ꢂ20 ml) and brine (2ꢂ20 ml), dried over MgSO4 and con-
centrated in vacuo giving 10a as an oil (0.092 g, 99%). Rf
0.21, 40% ethyl acetate/hexane. IR (thin film)/cmꢀ1 2986,
4. Experimental
4.1. General
Allylbromide was purified by passing it through a plug of ac-
tivity III basic alumina. TLC was performed on Merck silica
gel 60F254 plates and column chromatography was per-
1
˚
formed on Aldrich silica gel, 70–230 mesh, 60 A. H and
13C NMR (d ppm; J Hz) spectra were recorded on a Jeol
JNM-LA300 FTNMR spectrometer using CDCl3 solutions
with Me4Si as internal reference, unless otherwise indicated,
with resolutions of 0.18 Hz and 0.01 ppm, respectively.
CHCl3 was used to remove last traces of ethyl acetate
from some samples. The last trace of CHCl3 persisted even
after prolonged heating in vacuo and in these cases was vis-
ible in NMR spectra and microanalysis. Infrared spectra
(cmꢀ1) were recorded as KBr discs or liquid films between
NaCl plates using a Nicolet Impact 410 FTIR. Melting
points were obtained on a Bibby Stuart Scientific SMP1
melting point apparatus and are uncorrected. Microanalyses
were carried out at the Microanalytical Laboratory of Uni-
versity College Dublin. Mass spectra were obtained in the
Centre for Synthesis and Chemical Biology, School of
Chemistry and Chemical Biology, University College Dub-
lin. X-ray crystal structures were obtained in the Chemistry
Department, Loughborough University, Loughborough, UK.
HPLC analysis were carried out using methods on a Shi-
madzu HPLC system Class-VP, incorporating a LC-10AD
pump, SPD-M10AVP Diode Array Detector, Auto-injector
SIJ-10A with a system controller SCL-10A VP. Polarimetry
was carried out at Dublin City University (DCU), using
a Perkin–Elmer 343 with cell path-length of 100 mm at
20 ꢁC.
1
1682, 1388, 901. H NMR (two rotamers present) d 5.81–
5.66 (m, 1H, olefin CH), 5.26–5.16 (m, 2H, olefin CH2),
4.13–4.01 (m, 1H, allyl CH2), 3.85–3.67 (m, 1H, allyl
CH2), 3.57–3.47 (m, 2H, pyrrolidine a-CH2), 3.41–3.14
(m, 2H, lactam g-CH2), 2.70–2.41 (m, 2H, lactam b-CH2),
2.12–1.80 (m, 4H, pyrrolidine b- and g-CH2), 1.44 and
1.42 (2ꢂs, 9H, tert-butyl). 13C NMR d 174.24 and 174.20
(lactam carbonyl), 154.0 and 153.6 (Boc carbonyl), 136.6
and 136.2 (olefin CH), 118.6, 117.9 (olefin CH2), 80.0 and
79.5 (tert-butyl Cq), 67.0 and 66.7 (spiro Cq), 48.0 and
47.7 (allyl CH2), 46.1 (pyrrolidine d-CH2), 43.1 and 42.7
(lactam g-CH2), 37.6 and 37.1 (lactam b-CH2), 31.0 and
30.2 (pyrrolidine b-CH2), 28.6 (tert-butyl CH3), 23.4 and
22.7 (pyrrolidine g-CH2). Microanalysis: Found C, 57.81;
H, 7.98; N, 8.60. Calculated for C15H24N2O3 (0.5 CHCl3):
C, 57.76; H, 7.66; N, 8.69.
Method B: to a stirred solution of allylamine (0.37 ml,
4.9 mmol) in dry methanol (7 ml) was added a solution of
8 (1.20 g, 4.4 mmol) in dry methanol (1.5 ml). Magnesium
sulfate (0.316 g, 2.6 mmol) was added to the solution after
3 h and the solution was then stirred for a further 2 h. The re-
action was cooled to ꢀ4 ꢁC and NaBH4 (0.294 g, 7.8 mmol)
was added portionwise. The reaction was quenched after 1 h
with a saturated solution of NaHCO3 (5 ml) and water (5 ml).
The mixture was extracted with ethyl acetate (3ꢂ30 ml) then
dried over MgSO4 and concentrated in vacuo. The resulting
4.1.1. N-Boc-L-proline methyl ester (6).14 Compound 6
was prepared from L-proline by the method of Confalone.14

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F. Kelleher et al. / Tetrahedron 63 (2007) 9235–9242
oil was stirred at reflux temperature in toluene (15 ml) for
16 h. After cooling to ambient temperature the solution
was concentrated in vacuo giving an oil, which was purified
on silica gel in 10% ethyl acetate/hexane to give a pale
yellow oil (0.685 g, 60%). For analysis see method A.
(m, 1H, lactam g-CH2), 2.79–2.67 (m, 1H, lactam g-CH2),
2.61–2.37 (m, 1H, lactam b-CH2), 2.13–1.66 (m, 5H, pyrro-
lidine b- and g-CH2, and lactam b-CH2), 1.58 and 1.56
(2ꢂd, 3H, J¼9.87 Hz, a-CH3), 1.48 and 1.46 (2ꢂs, 9H,
tert-butyl CH3). 13C NMR d (two rotamers present) 174.1
(C]O, lactam), 153.5 (C]O, Boc), 140.4 (ipso aromatic),
128.4 (meta), 127.6 (ortho), 127.1 (para), 80.0 and 79.4
(tert-butyl Cq), 67.3 (spiro Cq), 49.6 and 49.2 (a-CH), 48.1
and 47.8 (pyrrolidine a-CH2), 38.6 and 37.9 (CH2, lactam
g-CH2), 36.9 and 36.6 (CH2, pyrrolidine g-CH2), 30.4
and 29.9 (lactam b-CH2), 28.5 and 28.4 (tert-butyl CH3),
23.3 and 22.4 (CH2, pyrrolidine b-CH2), 15.6 and 15.5
(a-CH3). Microanalysis: Found C, 69.87; H, 8.49; N, 7.86.
Calculated for C20H28N2O3: C, 69.74; H, 8.16; N, 8.13.
4.1.5. ( )-7-Benzyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-
carboxylic acid tert-butyl ester (10b). Method A: com-
pound 10b was prepared by a similar method to that used
for 10a (method A) using benzylamine giving a pale yellow
oil (88% yield). Rf 0.12, 40% ethyl acetate/hexane. IR (thin
film)/cmꢀ1: 3000, 2950, 1700, 1680. 1H NMR (two rotamers
present) d 7.35–7.22 (m, 5H, aromatic), 4.90 (d, 1H, J¼
14.7 Hz, benzyl CH2), 4.72 (d, 1H, J¼14.4 Hz, benzyl
CH2), 4.28 (d, 1H, J¼15 Hz, benzyl CH2), 3.97 (d, 1H,
J¼14.5 Hz, benzyl CH2), 3.62–3.42 (m, 2H, pyrrolidine
a-CH2), 3.34–3.03 (m, 2H, lactam g-CH2), 2.66–2.39 (m,
1H, lactam b-CH2), 2.21–2.08 (m, 1H, lactam b-CH2),
2.06–1.95 (m, 2H, pyrrolidine b-CH2), 1.89–1.76 (m, 2H,
pyrrolidine g-CH2), 1.46 and 1.39 (2ꢂs, 9H, tert-butyl).
13C NMR (two rotamers present) d 174.5 and 174.4 (lactam
carbonyl), 153.5 and 153.4 (Boc carbonyl), 136.6 (ipso aro-
matic), 128.7, 128.4 and 128.3 (aromatic CH), 80.0 and 79.5
(tert-butyl Cq), 67.0 and 66.9 (spiro Cq), 48.0 and 47.8 (ben-
zyl CH2), 47.5 and 47.4 (lactam g-CH2), 42.9 and 42.7 (pyr-
rolidine d-CH2), 37.8 and 37.1 (lactam b-CH2), 30.9 and
30.8 (pyrrolidine b-CH2), 28.5 (tert-butyl CH3), 23.4 and
22.8 (pyrrolidine g-CH2). Microanalysis: Found C, 62.55;
H, 7.39; N, 7.14. Calculated for C15H24N2O3 (0.5 CHCl3):
C, 62.73; H, 7.42; N, 7.50.
Compound 12b was obtained as a white solid. Rf 0.68 (60%
ethyl acetate/hexane). Mp 128–132 ꢁC. IR (KBr)/cmꢀ1
3032, 2975, 1700, 1685, 1360. 1H NMR (two rotamers
present) d 7.45–7.22 (m, 5H, aromatic), 5.48 (q, 0.5H, J¼
7.14 Hz, a-CH), 5.38 (q, 0.5H, J¼7.14 Hz, a-CH), 3.61–
3.48 (m, 2H, pyrrolidine a-CH2), 3.19–3.03 (m, 2H, lactam
g-CH2), 2.58–2.37 (2ꢂm, 1H, lactam b-CH2), 2.17–1.76 (m,
5H, pyrrolidine b- and g-CH2, and lactam b-CH2), 1.50 and
1.48 (2ꢂd, 3H, J¼14.28 Hz, a-CH3), 1.46 and 1.26 (2ꢂs,
9H, tert-butyl CH3). 13C NMR (two rotamers present) d
174.4 and 174.2 (C]O, lactam), 153.5 (C]O, Boc), 140.1
(ipso aromatic), 127.64 (meta), 127.61 (ortho), 127.5
(para), 80.3 and 79.5 (spiro Cq), 67.5 and 67.4 (tert-butyl
Cq), 50.9 and 49.5 (a-CH), 48.6 and 48.2 (CH2, pyrrolidine
a-CH2), 38.9 and 38.7 (CH2, lactam g-CH2), 37.5 and 37.1
(CH2, pyrrolidine g-CH2), 30.4 and 30.1 (CH2, lactam
b-CH2), 28.8 and 28.5 (CH3, tert-butyl CH3), 23.6 and
22.6 (CH2, pyrrolidine b-CH2), 16.6 and 16.4 (CH3,
a-CH3). Microanalysis: Found C, 70.38; H, 8.65; N, 7.53.
Calculated for C20H28N2O3: C, 69.74; H, 8.16; N, 8.13.
Method B: compound 10b was prepared by a similar method
to that used for 10a (method B) giving a pale yellow oil
(1.46 g, 75%) after purification on silica gel in 15% ethyl
acetate/hexane. For analysis see method A.
4.1.6. (5S)- and (5R)-6-Oxo-7-((10R)-phenylethyl)-1,7-di-
azaspiro[4.4]nonane-1-carboxylic acid tert-butyl esters
(12a and 12b). To a stirred solution of (R)-(+)-1-phenylethyl
amine (1.29 ml, 10.1 mmol) in dry methanol (6 ml) was
added a solution of aldehyde 8 (2.5 g, 9.22 mmol) in dry
methanol (2 ml). After 1 h of stirring at ambient tempera-
ture, magnesium sulfate (0.66 g, 5.5 mmol) was added to
the solution and stirring was continued for 4 h. The reaction
was cooled to ꢀ4 ꢁC and NaBH4 (0.56 g, 15 mmol) was
added portionwise over 10 min. The reaction was quenched
after 1 h at ambient temperature with a saturated solution of
NaHCO3 (7 ml) and water (3 ml). The aqueous layer was ex-
tracted with ethyl acetate (3ꢂ30 ml), dried over MgSO4 and
concentrated in vacuo to give a yellow oil (2.10 g). The
resulting oil was stirred at reflux temperature for 24 h in
toluene (20 ml) in the presence of 50% sodium amide (sus-
pension) in toluene (0.20 ml, 5.2 mmol). After cooling to
ambient temperature the solution was quenched with H2O
(4 ml) and extracted with ethyl acetate (3ꢂ20 ml). The com-
bined organics were then concentrated in vacuo to give a
colourless oil (0.909 g, 30%), which was purified by flash
column chromatography on silica gel in 10% ethyl acetate/
hexane resulting in 12a (0.491 g, 54%) as a white solid. Rf
0.78 (60% ethyl acetate/hexane). Mp 92–96 ꢁC. IR (KBr)/
cmꢀ1 3031, 2976, 1702, 1682, 1361. 1H NMR (two rotamers
present) d 7.35–7.25 (m, 5H, aromatic), 5.77–5.49 (m, 1H,
a-CH), 3.58–3.44 (m, 2H, pyrrolidine a-CH2), 3.42–3.23
4.1.7. (5R)- and (5S)-6-Oxo-7-((10S)-phenylethyl)-1,7-di-
azaspiro[4.4]nonane-1-carboxylic acid tert-butyl esters
(12c and 12d). Compound 12c was prepared by a similar
method to the preparation of 12a and 12b using (S)-(ꢀ)-1-
phenylethyl amine in 51% yield. Compound 12c was
obtained as a white solid. Analytical data were the same
as 12b. Microanalysis: Found C, 69.68; H, 8.14; N, 8.05.
Calculated for C20H28N2O3: C, 69.74; H, 8.16; N, 8.13.
Compound 12d was obtained as a white solid. Analytical
data were the same as 12a. Microanalysis: Found C, 69.49;
H, 8.14; N, 7.89. Calculated for C20H28N2O3: C, 69.74; H,
8.16; N, 8.13.
4.1.8. (5S)-6-Oxo-7-((10R)-phenylethyl)-1,7-diazaspiro-
[4.4]nonane (13a). To a stirred solution of 12a (0.270 g,
0.78 mmol) in DCM (2.7 ml) was added TFA (2.7 ml) and
the resulting solution was stirred for 2 h at ambient temper-
ature. The solution was basified to pH 10 with aqueous 3 M
KOH solution, and extracted with chloroform (2ꢂ30 ml).
The combined organic layers were washed with brine
(2ꢂ20 ml), dried over MgSO4 and concentrated in vacuo
giving a yellow oil (0.169 g, 89%). Rf 0.24 (10% metha-
nol/ethyl acetate). [a]2D0 +9616.6 (c 0.0180, methanol). IR
(thin film)/cmꢀ1 3329, 2972, 2876, 1682. 1H NMR d 7.36–
7.26 (m, 5H, aromatic), 5.50–5.46 (q, 1H, J¼6.93 Hz,
a-CH), 3.29–3.20 (m, 2H, pyrrolidine a-CH2), 2.98–2.90

F. Kelleher et al. / Tetrahedron 63 (2007) 9235–9242
9241
and 2.84–2.76 (2ꢂm, 2H, lactam g-CH2), 2.06 (br s, 1H, N–
H), 2.01–1.74 (m, 6H, pyrrolidine b- and g-CH2, and lactam
b-CH2), 1.55 (d, 3H, J¼7.14 Hz, a-CH3). 13C NMR d 176.74
(C]O, lactam), 140.0 (ipso aromatic), 128.5 (meta), 127.5
(ortho), 126.9 (para), 67.9 (spiro Cq), 49.4 (a-CH), 47.5
(lactam g-CH2), 39.0 (pyrrolidine a-CH2), 35.2 (CH2, pyrro-
lidine g-CH2), 34.8 (lactam b-CH2), 26.1 (pyrrolidine
g-CH2), 16.0 (a-CH3).
(pyrrolidine B a-CH2), 52.0 (pyrrolidine B d-CH2),
45.2 (pyrrolidine A a-CH2), 38.2 (pyrrolidine A g-CH2),
37.8 (pyrrolidine B g-CH2), 24.7 (pyrrolidine A b-CH2),
23.6 (CH3, a-CH3). Mass spectrum m/z [M+H] 231.1857
(calculated for C15H23N2 231.1861).
4.1.13. (5R)-7-((10R)-Phenylethyl)-1,7-diazaspiro[4.4]-
nonane (14b). Compound 14b was prepared from 13b, by
the method used for 14a. Yield 46%, as a pale yellow oil.
Rf 0.12 (40% methanol/chloroform). [a]2D0 +3928.5 (c
0.021, methanol). IR (thin film)/cmꢀ1 3359, 2970, 2776.
1H NMR d 7.35–7.21 (m, 5H, aromatic), 3.27 (q, 1H, J¼
6.6 Hz, a-CH), 3.03–2.84 (m, 3H, pyrrolidine B d-CH2
and pyrrolidine A a-CH2), 2.52 (d, 1H, J¼9.5 Hz, pyrroli-
dine B a-CH2), 2.40 (d, 1H, J¼9.5 Hz, pyrrolidine B
a-CH2), 2.4–2.36 (m, 1H, pyrrolidine B d-CH2), 1.94–1.74
(m, 6H, pyrrolidine B g-CH2, pyrrolidine A b-CH2 and
4.1.9. (5R)-6-Oxo-7-((10R)-phenylethyl)-1,7-diazaspiro-
[4.4]nonane (13b). Compound 13b was prepared from
12b, by the method used for 12a. Yield 73%, as a light yellow
oil. Rf 0.26 (10% methanol/ethyl acetate). [a]2D0 +13211.3 (c
0.0246, methanol). IR (thin film)/cmꢀ1 3484, 2970, 2876,
1
1682. H NMR d 7.36–7.26 (m, 5H, aromatic), 5.46–5.39
(q, 1H, J¼7.14 Hz, a-CH), 3.34–3.15 (m, 2H, pyrrolidine
a-CH2), 3.08–2.94 (2ꢂm, 2H, lactam g-CH2), 2.77 (br s,
1H, N–H), 2.04–1.73 (m, 6H, pyrrolidine b- and g-CH2,
and lactam b-CH2), 1.55 (d, 3H, J¼7.14 Hz, a-CH3). 13C
NMR d 175.9 (C]O, lactam), 139.0 (ipso aromatic), 128.6
(meta), 127.5 (ortho), 126.9 (para), 68.1 (spiro Cq), 49.6
(CH, a-CH), 47.2 (lactam g-CH2), 39.1 (pyrrolidine
a-CH2), 35.1 (pyrrolidine g-CH2), 34.2 (lactam b-CH2),
25.7 (CH2, pyrrolidine g-CH2), 16.3 (CH3, a-CH3).
pyrrolidine A g-CH2), 1.35 (d, 3H, J¼6.6 Hz, a-CH3). 13
C
NMR d 145.35 (ipso aromatic), 128.2 (meta), 127.1 (ortho),
126.7 (para), 68.4 (spiro Cq), 65.3 (a-CH), 64.3 (pyrrolidine
B a-CH2), 51.7 (pyrrolidine B d-CH2), 45.0 (pyrrolidine A
a-CH2), 37.9 (pyrrolidine A g-CH2), 37.1 (pyrrolidine B
g-CH2), 24.3 (pyrrolidine A b-CH2), 22.8 (a-CH3). Mass
spectrum m/z [M+H] 231.1858 (calculated for C15H23N2
231.1861).
4.1.10. (5R)-6-Oxo-7-((10S)-phenylethyl)-1,7-diazaspiro-
[4.4]nonane (13c). Compound 13c was prepared from 12c,
by the method used for 12a. Yield 76%, as a light yellow
oil. Analytical data were the same as 13a.
4.1.14. (5R)-7-((10S)-Phenylethyl)-1,7-diazaspiro[4.4]-
nonane (14c). Compound 14c was prepared from 13c, by
the method used for 14a. Yield 48%, as a pale yellow oil.
Analytical data were the same as 14a. Mass spectrum m/z
[M+H] 231.1864 (calculated for C15H23N2 231.1861).
4.1.11. (5S)-6-Oxo-7-((10S)-phenylethyl)-1,7-diazaspiro-
[4.4]nonane (13d). Compound 13d was prepared from 12d,
by the method used for 13a. Yield 80%, as a light yellow
oil. Analytical data were the same as 13b.
4.1.15. (5S)-7-((10S)-Phenylethyl)-1,7-diazaspiro[4.4]-
nonane (14d). Compound 14d was prepared from 13d, by
the method used for 14a. Yield 43%, as a pale yellow oil.
Analytical data were the same as 14b. Mass spectrum m/z
[M+H] 231.1871 (calculated for C15H23N2 231.1861).
4.1.12. (5S)-7-((10R)-Phenylethyl)-1,7-diazaspiro[4.4]-
nonane (14a). To a stirring solution of lithium aluminium
hydride 1 M solution in THF (14.8 ml, 14.8 mmol) in dry
THF (5 ml) at ꢀ20 ꢁC under nitrogen, was added a 13a
(0.179 g, 0.74 mmol) in dry THF (1 ml) and the solution
was allowed to warm to ambient temperature and stirred
for 48 h. To the reaction mixture, saturated sodium chloride
solution and 50% sodium hydroxide solution were added
alternately (each time adding three drops), until no hydride
was left (i.e., until the solution did not vigorously react).
The solution was then filtered, and the precipitate was
washed thoroughly with chloroform (3ꢂ20 ml). The com-
bined washings were dried over K2CO3 and concentrated
in vacuo giving a yellow oil, which was purified on prepar-
ative TLC on silica gel in 40% methanol/chloroform to
give a pale yellow oil (0.090 g, 53%). Rf 0.12 (40% metha-
nol/chloroform). [a]2D0 +4736.8 (c 0.019, methanol). IR
(thin film)/cmꢀ1 3354, 2970, 2776. [Note: pyrrolidine ring
derived from lactam is labelled pyrrolidine B and other is
4.2. X-ray crystallography
Suitable crystals of 15a and 15b for X-ray study were ob-
tained from ethanol solutions. The data were collected at
150(2) K on a Bruker APEX CCD diffractometer. The struc-
ture was solved by direct methods and refined on F2 using all
the reflections.19 All the non-hydrogen atoms were refined
using anisotropic atomic displacement parameters and
hydrogen atoms were inserted at calculated positions using
a riding model.
Compound 15a. Crystal data: C15H22Cl2N2Zn, M¼366.62,
˚
triclinic, a¼7.288(3), b¼10.862(5), c¼11.169(5) A,
a¼90.304(6)ꢁ, b¼103.671(5)ꢁ, g¼95.005(6)ꢁ, U¼
3
˚
855.5(7) A , space group P1, Z¼2, m(Mo Ka)¼
1.740 mmꢀ1; 6662 data (5905 unique, Rint¼0.0261) were
measured in the range 1.88<q<25.99ꢁ. R1(I>2s(I))¼
0.0376 and wR2 (all data)¼0.0986. Goodness of fit on
F2¼1.004. CCDC No. 641381.
1
pyrrolidine A.] H NMR d 7.34–7.21 (m, 5H, aromatic),
3.24 (q, 1H, J¼6.6 Hz, a-CH), 3.01–2.88 (m, 3H, pyrroli-
dine B d-CH2 and pyrrolidine A a-CH2), 2.62–2.54 (m,
2H, pyrrolidine B d-CH2 and pyrrolidine B a-CH2), 2.37
(d, 1H, J¼9.33 Hz, pyrrolidine B a-CH2), 1.89–1.68 (m,
6H, pyrrolidine B g-CH2, pyrrolidine A b-CH2 and pyrroli-
dine A g-CH2), 1.35 (d, 3H, J¼6.6 Hz, a-CH3). 13C NMR
d 145.43 (ipso aromatic), 128.2 (meta), 127.0 (ortho),
126.7 (para), 68.21 (spiro Cq), 65.5 (a-CH), 64.8
4.3. Molecular modelling
The energy of the conformations of 12a and 12b were
minimised using the MM+ molecular mechanics force field
in HYPERCHEM 7.5.

9242
F. Kelleher et al. / Tetrahedron 63 (2007) 9235–9242
Bourguignon, J. Tetrahedron 2001, 57, 3087–3098; (f)
4.4. Supplementary data
Nagata, T.; Nishida, A.; Nakagawa, M. Tetrahedron Lett.
2001, 42, 8345–8349; (g) Herrero, S.; Garcia-Lopez, M.;
Latorre, M.; Cenarruzabeitia, E.; Del Rio, J.; Herranz, R.
J. Org. Chem. 2002, 67, 3866–3873.
Crystallographic data for 15a has been deposited with the
Cambridge Crystallographic Data Centre. Copies of this
information may be obtained free of charge from deposit@
ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk.
9. Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. J. Am. Chem.
Soc. 1983, 105, 5390–5398.
10. (a) Castelhano, A.; Witter, D. Patent No. US 6638941B1, 2003;
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Acknowledgements
We thank Dr. Brian Murray for the help with NMR spectros-
copy and useful discussions. We are grateful to Kuldip Singh
for access to the Apex diffractometer at the University of
Leicester, UK. We are grateful to Strand III of the Irish
Government0s National Development Plan (2000–2006)
Technological Sector Research Program, through the Coun-
cil of Directors of the Institutes of Technology, for funding
for S.K. (Grant CRS/01/TA02).
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