Spirobicyclic diamines 1: synthesis of proline-derived spirolactams via thermal intramolecular ester aminolysis

Article abstract of DOI:10.1016/j.tetlet.2006.03.021

Proline-derived [4.4]-spirolactams have been synthesised in good yields by a reductive-amination reaction followed by thermal cyclisation of the resulting amine onto the proline ester group in refluxing toluene. The synthesis of the corresponding [4.5]-spirolactams by the same method gave much reduced yields.

Full text of DOI:10.1016/j.tetlet.2006.03.021

Tetrahedron Letters 47 (2006) 3005–3008
Spirobicyclic diamines 1: synthesis of proline-derived
spirolactams via thermal intramolecular ester aminolysis
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 6 February 2006; revised 22 February 2006; accepted 2 March 2006
Available online 20 March 2006
Abstract—Proline-derived [4.4]-spirolactams have been synthesised in good yields by a reductive-amination reaction followed by
thermal cyclisation of the resulting amine onto the proline ester group in refluxing toluene. The synthesis of the corresponding
[4.5]-spirolactams by the same method gave much reduced yields.
ꢀ 2006 Elsevier Ltd. All rights reserved.
There are currently a large number of methods for the
Couple
(i)
NHR
COOH
N
N
synthesis of spirocyclic compounds and they can also
be easily formed in a stereocontrolled manner.1 Frei-
dinger was the first to incorporate a lactam constraint
into the backbone of a peptide in order to rigidify the
peptide tertiary structure into a more defined conforma-
tion.2 One of the most common methods for the synthe-
sis 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 dependent 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 spon-
taneously at ambient temperature, while others require
heating in a suitable solvent.2b,3
R
R
N
N
Boc
O
O
Boc
Mitsunobu
(ii)
OH
N
N
NHR
Boc
Boc
O
S
S
H
°
C
1. Et N, DMF, 70
3
(iii)
2. CH N
2
2
HN
CO2Me
N
N
N
COOH
CO2Me
Boc
Boc
O
Figure 1. Cyclisation methods for proline-derived spirolactams.3–5
of both enantiomers of proline-derived [4.4]-spirolac-
tams, a racemic synthesis allows both enantiomers to
be accessible, with the possibility of their resolution at
a later stage by, for example, diastereoisomeric salt
formation.6
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. A number of
different strategies have also been used for the critical
final cyclisation step to form the spirobicyclic lactam ring
(Fig. 1).3–5
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. We were interested in having sub-
stituents already in place on the lactam nitrogen, which
would then allow for further manipulation and deriva-
tisation. Of course this would increase the steric
hindrance of the system and might have a detrimental
effect on the yield of the cyclisation reaction. This
As part of a program to synthesise both homochiral and
racemic spirocycles, we were interested in the synthesis
*
Corresponding author. Tel.: +353 1 404 2869; fax: +353 1 404
2700; e-mail addresses: fintan.kelleher@ittdublin.ie; fintan.kelleher@
it-tallaght.ie
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.021

3006
F. Kelleher, S. Kelly / Tetrahedron Letters 47 (2006) 3005–3008
c
a, b
COOMe
COOMe
N
Boc
COOH
N
N
H
Boc
3
2
1
d
H
O
COOMe
4
N
R
e
f
N
R
COOMe
N
N
N
Boc
Boc
O
Boc
5a-c
6a-c
6a, R = -CH2CH=CH2
6b, = -CH2Ph
6c, = -CH2CO2Me
Scheme 1. Reagents and conditions: (a) SOCl2, MeOH, reflux, 94%; (b) (Boc)2O, DMAP, Et3N, DCM, rt, 74%; (c) (i) LiHMDS, THF, À78 ꢁ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, 66–90%.
necessitated the synthesis of secondary amines for subse-
quent cyclisation onto a carboxylic ester (Scheme 1).
and 6b, compared to the reactions performed in the
absence of added base. The reason for this reduction in
yield is as yet unexplained.
Aldehyde 4 was prepared in four steps from L-proline by
methyl ester formation, Boc protection of the nitrogen,
a-allylation using LiHMDS as base with allyl bromide
as alkylating agent and oxidative cleavage of the alkene
using OsO4/NaIO4. We found that it was necessary to
efficiently purify the aldehyde by column chromatogra-
phy to completely free it from any traces of osmium
by-products as failure to do so led to reduced yields in
subsequent steps. Reductive amination of 4 with allyl
amine in ethanol, followed by treatment of the inter-
mediate imine with NaBH4 gave the required secondary
amine spirolactam precursor 5a. Following the method
of Johnson,4e,5 an almost quantitative (99%) yield of
the spirolactam 6a was obtained. Although this cyclisa-
tion was very efficient, we encountered problems in the
workup in removing excess DMF with a large number
of extractions with water being required. As a result
we examined the use of a different solvent and refluxing
toluene was investigated for the cyclisation step. It was
not necessary to purify the secondary amine intermedi-
ate prior to cyclisation, but direct reaction of the crude
product was possible. Although the workup procedure
was now much simpler, the 66% yield obtained was
much reduced. When benzylamine was used in place of
allyl amine, using the same reaction cyclisation condi-
tions (refluxing in toluene), the N-benzyl substituted
spirolactam (6b) was obtained in a higher yield of 75%
(in both cases the cyclisation reactions were performed
in the absence of any acids or bases).
We next examined the use of the thermal ester amino-
lysis method for the synthesis of the homologous [4.5]-
spirolactam analogues. This required the synthesis of
the homologated aldehyde 8 (Scheme 2), for subsequent
reaction to form the spiro d-lactams, under the same
conditions as used to prepare the [4.4]-spirolactams.
The aldehyde was prepared from 3 by hydroboration–
oxidation of the alkene followed by Swern oxidation7
of the resulting alcohol 7. Reductive amination of crude
8 with allyl amine, and cyclisation in refluxing toluene,
gave the required spiro d-lactam 10a in only 20% yield,
the remainder being the uncyclised secondary amine cyc-
lisation precursor 11. Use of benzylamine in the synthe-
sis of N-benzyl spiro d-lactam 10b gave no product after
prolonged heating in refluxing toluene and only a 17%
yield of the product was obtained, after treatment of
the N-benzyl secondary amine analogue of 11, with
sodium hydride in THF at reflux temperature. This was
not unexpected since, in general, the formation of five-
membered rings is thermodynamically more favourable
than the corresponding six-membered ring analogues.
Johnson4e,5 also found a similar outcome when trying
to use the thermal cyclisation method to synthesise the
[4.5.5]-analogue of the compound in Figure 1. In that
case, no cyclisation was observed.
The unsubstituted [4.5]-spirolactam N–H analogue was
synthesised in order to see how effective the thermal cyc-
lisation of a primary amine onto an ester was in prepar-
ing the homologous spirolactam. The primary amine 12
was prepared by alkylation of 2 with the stabase-pro-
tected aminopropyl bromide, followed by deprotection
with potassium carbonate in methanol, and subsequent
stirring at reflux in toluene to induce cyclisation gave
the spiro d-lactam 9 in 30% overall yield from 2. The
N-allyl and N-benzyl derivatives (10a and 10b) were pre-
pared by alkylation with allyl and benzyl bromide,
respectively, using sodium hydride as base in THF.
Attempts to prepare the compound with a –CH2CO2Me
(or the ethyl ester equivalent) side chain by alkylation
In order to investigate the possibility of the use of more
synthetically useful amines in the cyclisation step (e.g.,
amino acids as the amine moiety), the reaction with gly-
cine methyl ester (the free amine was obtained by treat-
ment of the HCl salt with 2 mol equiv of Hunig’s base)
was initially attempted. In this case the bicyclic spirolac-
tam 6c was isolated in 90% yield. Since the syntheses of
6a and 6b were conducted in the absence of added base,
these reactions were then repeated in the presence of
1 mol equiv of Hunig’s base. Surprisingly, this resulted
in reduced yields of 50% and 61%, respectively, for 6a

F. Kelleher, S. Kelly / Tetrahedron Letters 47 (2006) 3005–3008
3007
O
OH
c
a, b
COOMe
N
COOMe
COOMe
N
N
Boc
8
Boc
Boc
7
3
d
h
COOMe
N
N
N
N
Boc
N
Boc
H
Boc
O
O
10a
2
9
e, f
g
i
+
N
NH2
H
COOMe
N
N
COOMe
N
Ph
N
Boc
Boc
Boc
O
11
12
10b
Scheme 2. Reagents and conditions: (a) 1 M borane–THF; (b) 30% H2O2/KOH, 58% from 3; (c) (COCl)2, Et3N, DCM, 94%; (d) (i) allyl amine,
EtOH, (ii) NaBH4, (iii) toluene, 100 ꢁC, 20%; (e) 1 M LiHMDS, THF, 1-(3-bromopropyl)-2,2,5,5-tetramethyl-l-aza-2,5-disilacyclopentane;
(f) K2CO3, MeOH; (g) toluene, reflux, 32% from 2; (h) NaH, THF, allyl bromide, 75%; (i) NaH, THF, benzyl bromide, 73%.
of the lactam nitrogen with methyl bromoacetate or the
more reactive iodoacetate analogue were unsuccessful,
with 9 being recovered unchanged, in each case.
0.5H, J = 17.7 Hz, –CH2–CO2Me), 4.44 (d, 0.5H, J =
17.5 Hz, –CH2–CO2Me), 4.28 (d, 0.5H, J = 15.0 Hz,
–CH2–CO2Me), 3.97 (d, 0.5H, J = 14.5 Hz, –CH2–
CO2Me), 3.75 (s, 3H, –CO2Me), 3.61–3.33 (m, 4H, pyr-
rolidine d-CH2 and lactam c-CH2), 2.78–2.25 (m, 2H,
lactam b-CH2), 2.15–1.83 (m, 4H, pyrrolidine b-CH2
and c-CH2), 1.45 and 1.41 (2 · s, 9H, tert-butyl). 13C
NMR (CDCl3, 75.4 MHz) d 175.3 (lactam carbonyl),
169.3 and 169.0 (ester carbonyl), 153.6 and 153.4 (Boc
carbonyl), 80.0 and 79.6 (spiro-Cq), 66.5 (tert-butyl
Cq), 52.1 (–CO2Me), 47.9 and 47.6 (CH2–CO2Me),
44.7 and 44.5 (lactam d-CH2), 43.9 and 43.7 (lactam
c-CH2), 37.3 and 36.7 (lactam b-CH2), 31.1 and 30.0
(pyrrolidine b-CH2), 28.4 (tert-butyl CH3), 23.3 and
22.7 (pyrrolidine c-CH2). Microanalysis: Found: C, 57.38;
H, 7.86; N, 8.71. Calculated for C15H24N2O5: C,
57.68; H, 7.74; N, 8.97.
In conclusion, the thermal ester aminolysis method
allows the preparation of a series of N-substituted
[4.4]-spirolactams in 60–70% overall yield starting from
a-allyl ester 3. The reactions have been scaled up to 10 g
with no loss in yield. This route also allows the introduc-
tion of the lactam nitrogen substituent at a late stage in
the synthesis and it proceeds from a common intermedi-
ate, namely, aldehyde 4. Currently, we are studying the
extension of this methodology to homochiral a-substi-
tuted amines and a-amino acids. The presence of the
second chiral centre will allow the easy separation of
the diastereoisomeric products. The results of these
studies will be reported in due course.
Typical procedure for spirolactamisation, exemplified by
the synthesis of 6c. To a stirred solution of glycine
methyl ester hydrochloride (1.02 g, 8.10 mmol) in dry
methanol (10 ml) was added dropwise diisopropylethyl-
amine (2.58 ml, 14.80 mmol), followed by a solution of 4
in dry methanol (4 ml). After 3 h, MgSO4 (0.53 g,
4.43 mmol) was added and stirring was continued for
a further 2 h. The reaction was cooled to À4 ꢁC and
sodium borohydride (0.45 g, 11.80 mmol) was added
portionwise, and the solution was stirred for 1 h and then
saturated sodium hydrogen carbonate solution (7 ml)
and water (3 ml) were added. The solution was extracted
with ethyl acetate (3 · 20 ml), dried over MgSO4 and
concentrated in vacuo. The residual oil was stirred at
reflux temperature in toluene (12 ml) for 16 h, allowed to
cool to ambient temperature and concentrated in vacuo.
The residue was chromatographed on silica gel in 10%
ethyl acetate/hexane to give 6c as a pale yellow oil
(1.91 g, 90%). Rf 0.33, 60% ethyl acetate/hexane. IR
Acknowledgements
We thank Dr. Brian Murray for help with NMR spec-
troscopy and useful discussions. We are grateful to
Strand III of the Irish Government’s National Develop-
ment Plan (2000–2006) Technological Sector Research
Program, through the Council of Directors of the Insti-
tutes of Technology, for funding for S.K. (Grant CRS/
01/TA02).
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