A concise cross-metathesis route to enantiopure 1-azaspirocycle S

Article abstract of DOI:10.1055/s-0033-1338527

A concise synthesis of spiropyrrolidines and spiropiperidines has been developed. The approach employs a ruthenium-alkylidene-catalysed cross-metathesis reaction of enantiopure N-protected allylglycine with methylenecycloalkanes. The resultant alkene intermediates can then undergo a tandem acid-catalysed cyclisation to form spiropyrrolidines. Ring expansion of the spiropyrrolidine system, via an aziridinium intermediate, grants access to the homologous spiropiperidine ring system with excellent stereoretention. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338527

3118▌
PAPER
paper
A Concise Cross-Metathesis Route to Enantiopure 1-Azaspirocycles
Concise Synthesis of Enantiopure 1-Azaspirocycles
Zhen James Wang, Nicolas Daniel Spiccia, Christopher James Gartshore, Jayamini Illesinghe, William Roy Jackson,
Andrea Jane Robinson*
School of Chemistry, Monash University, Clayton 3800, Australia
Fax +61(3)99054597; E-mail: andrea.robinson@monash.edu
Received: 06.07.2013; Accepted after revision: 20.08.2013
We dedicate this manuscript to Adrian Blackman (University of Tasmania) and wish him well in his retirement.
with isobutylene.14 In this study, we extended this strategy
Abstract: A concise synthesis of spiropyrrolidines and spiropiper-
to the CM of the N-benzoylallylglycine 9 with the meth-
idines has been developed. The approach employs a ruthenium–
ylenecycloalkanes 10–12 to rapidly generate alkene inter-
alkylidene-catalysed cross-metathesis reaction of enantiopure N-
protected allylglycine with methylenecycloalkanes. The resultant
mediates 13–15 for subsequent cationic cyclisation.15
alkene intermediates can then undergo a tandem acid-catalysed cy- Unfortunately, this ruthenium–alkylidene-catalysed
clisation to form spiropyrrolidines. Ring expansion of the spiropyr-
rolidine system, via an aziridinium intermediate, grants access to
the homologous spiropiperidine ring system with excellent stereo-
the CM of 9 with methylenecyclohexane (11) (Table 1).
retention.
transformation was initially found to be capricious and
optimum conditions were therefore firstly developed for
Under conventional heating in a Fischer–Porter tube, the
reaction suffered from poor conversion despite a long re-
action time (Table 1, entry 1). When conventional heating
Key words: spiro compounds, metathesis, ring expansion, cataly-
sis, piperidines, pyrrolidines
was replaced by microwave (MW) irradiation, an en-
hancement in conversion was achieved in a shorter reac-
tion time (Table 1, entry 2).
The 1-azaspirocyclic ring system 1 (Figure 1) can be
found in a number of bioactive natural product families.1
Lepadiformine (2),2 cephalotaxine (3)3 and cylindricine A
(4)4 all share a common spirocyclic pyrrolidine core
(n = 1), and fasicularin (5),2e,5 halichlorine (6),6 histrioni-
cotoxin (7)7 and cylindricine B (8)8 possess a homologous
spirocyclic piperidine centre (n = 2). Many different strat-
egies have been developed to construct the azaspirocyclic
motif within these alkaloids and these include the use of
Diels–Alder cycloaddition,9 semipinacol rearrangement10
and acid-catalysed diene–iminium cyclisation.11 Nitrone–
alkene cycloaddition of acyclic diene intermediates, gen-
erated via olefin cross-metathesis (CM),12 has also been
used to generate the spiropiperidine core of histrionico-
toxin (7).13 To the best of our knowledge, with the excep-
tion of this single communication, the use of CM
chemistry to efficiently construct 1-azaspirocyclic struc-
tures 1 has not yet been explored. Herein, we report the
development of a generic, catalysis-driven approach to 1-
azaspiranes exploiting an alkene CM reaction and subse-
quent Brønsted acid induced cyclisation (Scheme 1). Ad-
vantages of this strategy include high functional group
tolerance, modular design and telescopic processing to
form the target spirocyclic pyrrolidine architecture. In ad-
dition, a commercially available α-amino acid is used to
provide requisite alkaloid stereochemistry and ring ex-
pansion into chiral spirocyclic piperidines.
H
N
N
O
NCS
C6H13
C6H13
N
HO
O
fasicularin
lepadiformine
Me
OH
5
2
Cl
OCH3
HO
n
O
R
m
N
H
halichlorine
O
6
H
N
1
m = 0, 1, 2
n = 1, 2
cephalotaxine
3
HN
OH
O
O
N
N
Cl
C6H13
C6H13
Cl
cylindricine A
cylindricine B
histrionicotoxin
7
4
8
Figure 1 Marine alkaloids bearing the 1-azaspirocyclic core
m
m
m
acid-catalysed
cyclisation
Our synthetic approach is based on previous work which
employed a catalytic two-step synthesis of 5,5-dimethyl-
proline derivatives via the CM of allylglycine derivatives
n
CM
NBz
n
MeO
n
NHBz
m = 0, 1, 2
n = 1, 2
MeO
O
O
NHBz
MeO
O
SYNTHESIS 2013, 45, 3118–3124
Advanced online publication: 27.09.2013
DOI: 10.1055/s-0033-1338527; Art ID: SS-2013-N0463-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Tandem CM/acid-catalysed cyclisation route to 1-azaspi-
rocycles
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

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Concise Synthesis of Enantiopure 1-Azaspirocycles
3119
Table 1 Optimisation of the CM Reaction between 9 and 11
Table 2 Preparation of Enantiopure 1-Azaspirocycles 16–18
m
catalyst (5 mol%)
CH2Cl2
MeO
NHBz
MeO
m
m
TfOH
(20 mol%)
CHCl3
10–12 (10 equiv)
HGII (5 mol%)
NBz
O
O
NHBz
O
MW (100 W)
100 °C, 4 h
MeO
MeO
NHBz
9
11 (10 equiv)
14
NHBz
MeO
O
O
9
13–15
16–18
N
N
Mes
Mes
N
N
Mes
Mes
Ph
Cl
Entry Cross partnera Yield (%) of 13–15 Yieldb (%) of 16–18
Cl
Ru
O
Ru
catalyst:
Cl
1
2
3
10 (m = 0)
11 (m = 1)
12 (m = 2)
13, 95
14, 96
15, 79
16, 85 (87)
17, 79 (80)
18, 80 (67)
Cl
PCy3
GII
HGII
Entry Catalyst Conditions
Conversiona (%)
a Volatiles purged at 2 h.
b Yield in parentheses obtained via the telescopic method.
1
2
3
4
5
GII
heat, 48 h
40
60
76
79
96
GII
MW (100 W), 100 °C, 2 h
MW (100 W), 100 °C, 2 h
MW (100 W), 100 °C, 4 h
MW (100 W), 100 °C, 4 hb
halides,16c,d quenching of a zirconocene complex with ke-
tenes,16e and aldol condensation16f or nickel(0)-catalysed
addition of isocyanates to vinylcyclohexane.16g We be-
lieve that CM represents a facile and synthetically viable
approach to trisubstituted alkenes such as 13–15.
HGII
HGII
HGII
a Determined by 1H NMR spectroscopy.
b Volatiles purged after 2 h.
Next, the key acid-catalysed cationic cyclisation was in-
vestigated. Trifluoromethanesulfonic acid induced (20
mol%) cyclisation of olefin intermediates 13–15 gave the
corresponding spiropyrrolidines 16–18 in 85%, 79% and
80% yield, respectively. Chiral HPLC analysis showed no
loss of enantiopurity over the two catalytic steps. Further-
more, comparable yields were obtained when telescopic
processing was employed to generate the target spiropyr-
rolidines 16–18 (Table 2, yields in parentheses). This con-
veniently eliminates the need for intermediate isolation
and purification.
Further improvement in conversion was achieved when
second-generation Grubbs catalyst (GII) was replaced
with second-generation Hoveyda–Grubbs catalyst
(HGII) (Table 1, entries 3 and 4). Optimal CM conditions
were obtained when the reaction was microwave-irradiat-
ed (100 W) at 100 °C for four hours with a purge of the
volatile ethylene byproduct after two hours (Table 1, entry
5). Attempts were made to lower the equivalents of alkene
11, however this resulted in reduced conversion into 14 in
all cases; the given stoichiometry (10 equiv) was deemed
necessary to achieve quantitative conversion into 14. Nev-
ertheless, excess, unreacted 11 could be readily recovered
by distillation and recycled in subsequent reactions.
Unfortunately, extension of this chemistry towards the
construction of homologous spiropiperidines was unsuc-
cessful. Cross-metathesis of the N-protected homoallylg-
lycine 19 with methylenecyclohexane (11) under the
previously optimised reaction conditions led to partial
isomerisation of 19 to the crotylglycine derivative 20
which upon sequential CM reaction with 11 gave the trun-
cated alkene byproduct 21 (Scheme 2). This byproduct
was chromatographically inseparable from the desired
cross product 22. Additives such as benzoquinone and
acetic acid have been used previously to suppress such
isomerisation;17 however, the addition of benzoquinone to
these CM reactions merely suppressed the overall yields
without eliminating the isomerisation process. In addi-
tion, attempts to cyclise the mixture of 21 and 22 only re-
sulted in the spiropyrrolidine analogue 23 (generated from
21) and endo-isomerised alkene 24 (generated from 22).
Our attempts to prepare spiropiperidine compounds via
acid-catalysed cyclisation were unsuccessful, as per the
observations made by Haskins and Knight.15
With the optimised reaction conditions in hand, CM of 9
with homologous methylenecycloalkanes 10 and 12 were
explored. Gratifyingly, the corresponding alkenes 13 and
15 were also obtained in good to excellent yields from 10
and 12, respectively (Table 2).
It should be noted that access to trisubstituted alkenes
bearing pendent amide functionality (general structure of
13–15) via traditional olefination chemistry has been re-
ported. In comparison, these other methods16 require a
higher number of synthetic steps and/or do not yield an
enantiopure product. More specifically, access to the gen-
eral trisubstituted alkenyl amide structure has been
achieved via Wittig olefination of cyclohexanone fol-
lowed by functional group interconversion,16a,b nucleo-
philic substitution of prefunctionalised alkenyl
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3118–3124

3120
Z. J. Wang et al.
PAPER
CX4, Ph3P
LiAlH4
THF
0 °C→r.t.
CHCl3
0 °C→r.t.
OH
isomerisation
secondary CM
CO2Me
N
N
71%
MeO
NHAc
Ph
Ph
O
Ph
O
17
25
20
X
X
N
N
11 (10 equiv)
HGII (5 mol%)
Ph
26 X = Cl
MeO
MeO
MeO
NHAc
NHAc
NHAc
X
O
O
O
27 X = Cl
28 X = Br
19
21
22
N
inseparable mixture
KSCN
29 X = SCN
72% (88% ee)
22/21 = 4:1
Ph
TfOH (20 mol%)
CHCl3
Scheme 4 Ring expansion of a spiropyrrolidine to access spiropiper-
idines
NAc
NAc
OMe
MeO
OMe
O
NHAc
HPLC analysis of the thiocyanate analogue 29 showed
high retention of enantiomeric excess.
O
not
observed
O
24
23
In conclusion, a facile and generic route to enantiopure
spiropyrrolidine and spiropiperidine frameworks has been
achieved through a common trisubstituted alkene. Ruthe-
nium-catalysed CM of commercially available allylgly-
cine and methylenecycloalkanes followed by acid-
catalysed cyclisation facilitates expedient access to syn-
thetically useful, chiral spiropyrrolidine analogues. These
spiropyrrolidines can then be ring expanded to generate
spiropiperidine analogues. In order to complete the syn-
thesis of tricyclic marine alkaloids (Figure 1) via this
strategy, the methylenecycloalkane CM partner needs to
bear reactive functionality in the α-position. We have re-
cently described chemistry for the cross-metathesis of this
olefin subtype19 which should provide facile entry into 1-
azaspirocyclic alkaloid natural products in the future.
Scheme 2 Attempted preparation of spiropiperidines
Fortunately, nature provides the key to a viable synthesis
of the elusive spiropiperidine framework. Interconversion
between the spirocyclic marine alkaloids cylindricine A
and B is postulated to involve a stereospecific ring expan-
sion of the pyrrolidine via an aziridinium intermediate
(Scheme 3).4a–c,18 Hence, we postulated that access to spi-
ropyrrolidine and spiropiperidine systems could be re-
alised through a common and readily prepared CM-
generated precursor.
O
O
O
N
N
N
Cl
H
Cl
Melting points were determined using a Reichert hot-stage melting
point apparatus. IR spectra were recorded on a Perkin-Elmer 1600
H
Cl
C6H13
C6H13
H
C6H13
1
series Fourier transform infrared spectrophotometer. H and 13C
cylindricine A
cylindricine B
4
8
NMR spectra were recorded on a Bruker DPX300 spectrometer
1
(300 MHz for H NMR, 75 MHz for 13C NMR) or a Bruker
Scheme 3 Interconversion between cylindricine A and B
1
DRX400 spectrometer (400 MHz for H NMR, 100 MHz for 13C
NMR). Low-resolution electrospray ionisation (ESI) mass spectra
were recorded on a Micromass Platform Electrospray mass spec-
trometer (quadrupole mass electrometry) as solutions in the speci-
fied solvents. High-resolution electrospray mass spectra (HRMS)
were recorded on a Bruker BioApex 47e Fourier transform mass
spectrometer (4.7 tesla magnet). Optical rotations [α]D25 were mea-
sured on a Perkin-Elmer model 141 polarimeter. Gas chromato-
grams were recorded on an Agilent 6850 GC system equipped with
an SGE capillary column HP1-(PN190912-413) (30 m × 0.32
mm × 0.25 μm). The capillary column was operated with standard
parameters, which involved holding the system at a constant 80 °C
for 1 min, a ramp of 10 °C/min until 280 °C was reached, and a sec-
ond hold period at this temperature for 9 min. Chiral GC was per-
formed on a [50CP2/XE60.SVALSAPEA] column (50 cm × 0.25
mm), using helium as the carrier gas (5 mL/min). Chiral HPLC was
performed on an Agilent 1200 LC binary system with an Agilent
variable UV–vis detector. Analysis was performed on a Daicel Chi-
ralcel OD column using a flow rate of 1.0 mL/min at 254 nm with a
solvent mixture of i-PrOH–hexane (1:9). Microwave reactions were
carried out using a CEM Discover® system fitted with a benchmate
Towards this end, the previously prepared spiropyrro-
lidine 17 was globally reduced with lithium aluminum hy-
dride to give amino alcohol 25 in good yield (Scheme 4).
Interestingly, when 25 was subjected to Appel conditions
using carbon tetrachloride, a 1:1 mixture of regioisomers
26 and 27 (X = Cl) was obtained. The equilibrium that ex-
ists between chlorides 26 and 27 mirrors that found in the
cylindricine family, notably cylindricine A and B. In con-
trast, when carbon tetrabromide was used in the Appel re-
action, only the spiropiperidine analogue 28 was
observed. Due to its instability on silica gel during chro-
matography, isolation of 28 proved to be difficult; howev-
er, it was conveniently converted in situ into the
thiocyanate analogue 29 (Scheme 4), a motif found in the
ascidian alkaloids cylindricine J and fasicularin (5). Chiral
Synthesis 2013, 45, 3118–3124
© Georg Thieme Verlag Stuttgart · New York

PAPER
Concise Synthesis of Enantiopure 1-Azaspirocycles
3121
option. CH2Cl2 was supplied by Merck and distilled over CaH2 prior
to use. CHCl3, EtOAc, hexane and MeOH were used as supplied by
Merck. Et2O and THF were stored over Na wire and distilled prior
to use. [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]di-
chloro(o-isopropoxyphenylmethylene)ruthenium (HGII) and
benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyli-
dene]dichloro(tricyclohexylphosphine)ruthenium (GII) were used
as supplied by Aldrich.
HGII (6.27 mg, 5 mol%), 10 (227 μL, 2.15 mmol), CH2Cl2 (2.0
mL), 100 °C, 100 W, 4 h (evacuate and purge with argon at time = 2
h). Purification by silica gel column chromatography (hexane–
EtOAc, 3:1) gave (S)-13 as a colourless crystalline solid; yield: 58.7
mg (95%); mp 74.0–76.2 °C.
Chiral GC (run isothermally at 200 °C for 40 min): tR = 24.9 min
(>99% ee).
IR (KBr): 3323 (s), 2944 (s), 1744 (s), 1641 (s), 1580 (w), 1533 (s),
1487 (s), 1435 (m), 1354 (w), 1277 (w), 1221 (m), 1200 (m), 1097
(w) cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.85–7.75 (m, 2 H), 7.52–7.39 (m,
3 H), 6.70 (br d, J = 7.5 Hz, 1 H), 5.23–5.16 (m, 1 H), 4.83 (dt,
J = 7.5, 5.5 Hz, 1 H), 3.76 (s, 3 H), 2.67–2.54 (m, 2 H), 2.28–2.12
(m, 4 H), 1.64–1.55 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 172.9, 167.0, 148.6, 134.3, 131.8,
128.8, 127.1, 113.1, 52.5(3), 52.5(0), 33.9, 32.6, 29.1, 26.3(7),
26.3(6).
(S)-Methyl 2-Benzamidopent-4-enoate (9)
(S)-2-Benzamidopent-4-enoic acid (1.00 g, 4.57 mmol) was dis-
solved in a solution of methanolic HCl (50 mL, pH 2). After being
stirred at r.t. for 18 h, the reaction mixture was diluted with H2O (10
mL) and sat. aq NaHCO3 (10 mL), and the MeOH was removed un-
der reduced pressure. The aqueous phase was then extracted with
CH2Cl2 (3 × 25 mL), and the combined organic extract was washed
with H2O (25 mL) and brine (25 mL), dried (Na2SO4), filtered and
concentrated under reduced pressure to give 9 as a colourless solid;
yield: 1.05 g (99%); mp 44–47 °C.
HRMS (ESI+, MeOH): m/z [M + Na]+ calcd for C17H21NNaO3:
310.1414; found: 310.1399.
Chiral GC (run isothermally at 200 °C for 40 min): tR = 16.8 min
(>99% ee).
[α]D25 +50.7 (c 1.09, CHCl3).
(S)-Methyl 2-Benzamido-4-cyclohexylidenebutanoate (14)
IR (KBr): 3325 (br, w), 3062 (w), 2955 (w), 2360 (w), 1743 (s),
1644 (s), 1603 (w), 1580 (w), 1538 (m), 1489 (m), 1438 (w), 1360
(w), 1268 (w), 1225 (w), 1159 (w), 1075 (w), 1028 (w), 925 (m),
802 (w), 714 (w), 668 (w) cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.79–7.76 (m, 2 H), 7.52–7.39 (m,
3 H), 6.71 (br d, J = 6.5 Hz, 1 H), 5.81–5.67 (m, 1 H), 5.18–5.12 (m,
2 H), 4.91–4.85 (m, 1 H), 3.76 (s, 3 H), 2.74–2.56 (m, 2 H).
Table 1, Entry 1
The cross-metathesis of (S)-methyl 2-benzamidopent-4-enoate (9)
and methylenecyclohexane (11) was carried out according to the
conventional cross-metathesis procedure under the following con-
ditions: (S)-9 (50 mg, 0.21 mmol), GII (9.0 mg, 5 mol%), 11 (240
1
μL, 2.14 mmol), CH2Cl2 (2.0 mL), 50 °C, 48 h. H NMR analysis
showed 40% conversion into compound 14.
13C NMR (75 MHz, CDCl3): δ = 172.5, 167.3, 134.1, 132.7, 131.9,
128.7, 127.3, 119.2, 52.5, 52.3, 36.6.
Table 1, Entry 2
The cross-metathesis of (S)-methyl 2-benzamidopent-4-enoate (9)
and methylenecyclohexane (11) was carried out according to the
microwave cross-metathesis procedure under the following condi-
tions: (S)-9 (50 mg, 0.21 mmol), GII (9.0 mg, 5 mol%), 11 (240 μL,
2.14 mmol), CH2Cl2 (2.0 mL), 100 °C, 100 W, 2 h. 1H NMR analy-
sis showed 60% conversion into compound 14.
MS (ESI+, MeOH): m/z [M + Na]+ calcd for C13H15NNaO3: 256.1;
found: 256.2.
Conventional Cross-Metathesis; General Procedure
In a nitrogen-filled drybox, a Fischer–Porter tube was loaded with
substrate (50 mg), deoxygenated solvent, reacting olefin and cata-
lyst (5 mol%). The system was sealed, removed from the drybox,
immersed in a water bath and heated at a specified temperature for
a specified period of time. The reaction mixture was then exposed
to air and the solvent was removed under reduced pressure. Metath-
esis experiments are described using the following format: substrate
(mg), catalyst (mg), reacting olefin (10 equiv), solvent (mL), reac-
tion temperature (°C), reaction time (h). Reaction conversion into
the desired cross product was determined by 1H NMR spectroscopy.
The crude product was purified by column chromatography. Chro-
matographic purification conditions and isolated yields (%) are list-
ed where applicable.
Table 1, Entry 3
The cross-metathesis of (S)-methyl 2-benzamidopent-4-enoate (9)
and methylenecyclohexane (11) was carried out according to the
microwave cross-metathesis procedure under the following condi-
tions: (S)-9 (50 mg, 0.21 mmol), HGII (7.0 mg, 5 mol%), 11 (240
1
μL, 2.14 mmol), CH2Cl2 (2.0 mL), 100 °C, 100 W, 2 h. H NMR
analysis showed 76% conversion into compound 14.
Table 1, Entry 4
The cross-metathesis of (S)-methyl 2-benzamidopent-4-enoate (9)
and methylenecyclohexane (11) was carried out according to the
microwave cross-metathesis procedure under the following condi-
tions: (S)-9 (50 mg, 0.21 mmol), HGII (7.0 mg, 5 mol%), 11 (240
Microwave Cross-Metathesis; General Procedure
1
In a nitrogen-filled drybox, a microwave reactor vessel was loaded
with substrate (50–100 mg), deoxygenated solvent, reacting olefin
and catalyst (5 mol%). The system was sealed, removed from the
drybox, and microwave-irradiated and stirred at 100 °C. After 2–4
h, the reaction mixture was cooled to r.t. and exposed to air. The sol-
vent was then removed under reduced pressure. Metathesis experi-
ments are described using the following format: substrate (mg),
catalyst (mg), reacting olefin (10 equiv), solvent (mL), reaction
temperature (°C), microwave power (W), reaction time (h). Reac-
tion conversion into the desired cross product was determined by 1H
NMR analysis. The crude product was purified by column chroma-
tography. Chromatographic purification conditions and isolated
yields (%) are listed where applicable.
μL, 2.14 mmol), CH2Cl2 (2.0 mL), 100 °C, 100 W, 4 h. H NMR
analysis showed 79% conversion into compound 14.
Table 1, Entry 5
The cross-metathesis of (S)-methyl 2-benzamidopent-4-enoate (9)
and methylenecyclohexane (11) was carried out according to the
microwave cross-metathesis procedure under the following condi-
tions: (S)-9 (50 mg, 0.21 mmol), HGII (7.0 mg, 5 mol%), 11 (240
μL, 2.14 mmol), CH2Cl2 (2.0 mL), 100 °C, 100 W, 4 h (evacuate
and purge with argon at time = 2 h). 1H NMR analysis showed 99%
conversion into compound 14. The crude product was purified via
silica gel column chromatography (hexane–EtOAc, 1:4) to give (S)-
14 as a colourless solid; yield: 60.5 mg (96%); mp 72.6–73.5 °C.
IR (KBr): 3344 (br, s), 3060 (w), 3026 (w), 2926 (s), 2852 (s), 1751
(s), 1641 (s), 1527 (s), 1489 (m), 1432 (m), 1218 (m), 1175 (m),
1101 (w), 818 (w), 721 (w), 693 (m) cm–1.
(S)-Methyl 2-Benzamido-4-cyclopentylidenebutanoate (13)
(S)-Methyl 2-benzamidopent-4-enoate (9) was subjected to the mi-
crowave cross-metathesis procedure with methylenecyclopentane
(10) under the following conditions: (S)-9 (50 mg, 0.22 mmol),
© Georg Thieme Verlag Stuttgart · New York
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3122
Z. J. Wang et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.75–7.68 (m, 2 H), 7.48–7.32 (m,
3 H), 6.62 (br d, J = 5.5 Hz, 1 H), 4.95 (t, J = 7.5 Hz, 1 H), 4.77 (dt,
J = 7.5, 5.5 Hz, 1 H), 3.71 (s, 3 H), 2.75–2.43 (m, 2 H), 2.05–1.95
(m, 4 H), 1.50–1.25 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 172.8, 167.2, 145.1, 134.3, 131.9,
128.8, 127.3, 114.2, 52.8, 52.6, 37.5, 30.0, 29.0, 28.9, 28.1, 26.9.
[α]D25 –101.2 (c 1.00, CHCl3).
IR (neat): 2944 (s), 2867 (s), 1744 (s), 1644 (s), 1577 (w), 1444 (m),
1394 (s), 1272 (m), 1200 (s), 1177 (s), 1106 (w), 1017 (w) cm–1.
1H NMR (400 MHz, CDCl3, 55 °C): δ = 7.34–7.31 (m, 3 H), 7.30–
7.27 (m, 2 H), 4.34 (dd, J = 8.0, 2.0 Hz, 1 H), 3.53 (s, 3 H), 2.79–
2.57 (m, 2 H), 2.21–2.11 (m, 1 H), 2.03–1.88 (m, 5 H), 1.63–1.46
(m, 4 H).
HRMS (ESI+, MeOH): m/z [M + H]+ calcd for C18H24NO3:
302.1756; found: 302.1751.
13C NMR (100 MHz, C2D2Cl4, 100 °C): δ = 172.6, 169.7, 138.6,
128.8, 128.0, 126.1, 73.0, 63.0, 51.6, 40.7, 36.6, 36.4, 28.3, 25.0(7),
25.0(6).
(S)-Methyl 2-Benzamido-4-cycloheptylidenebutanoate (15)
The cross-metathesis of (S)-methyl 2-benzamidopent-4-enoate (9)
and methylenecycloheptane (12) was carried out according to the
microwave cross-metathesis procedure under the following condi-
tions: (S)-9 (50 mg, 0.21 mmol), HGII (7.0 mg, 5 mol%), 12 (236
mg, 2.14 mmol), CH2Cl2 (2.0 mL), 100 °C, 100 W, 4 h (evacuate
and purge with argon at time = 2 h). Purification by silica gel col-
umn chromatography (hexane–EtOAc, 4:1) gave (S)-15 as a colour-
less solid; yield: 53.3 mg (79%); mp 71.8–72.4 °C.
1
The H and 13C NMR spectra were recorded at elevated tempera-
tures, due to the presence of rotamers.
HRMS (ESI+, MeOH): m/z [M + Na]+ calcd for C17H21NNaO3:
310.1414; found: 310.1409.
(S)-Methyl 1-Benzoyl-1-azaspiro[4.5]decane-2-carboxylate (17)
In a microwave vessel under argon atmosphere, TfOH (2.9 μL,
0.033 mmol) was added to a stirred solution of (S)-methyl 2-benz-
amido-4-cyclohexylidenebutanoate (14; 50 mg, 0.17 mmol) in
CHCl3 (5.0 mL). The system was sealed and microwave-irradiated
(40 W) whilst being stirred at 50 °C for 1 h. The reaction mixture
was then cooled to r.t. and quenched with sat. aq NaHCO3 (10 mL).
The phases were separated and the aqueous phase was extracted
with Et2O (2 × 15 mL). The combined organic extract was washed
with H2O (20 mL) and brine (20 mL), dried (MgSO4), filtered and
concentrated in vacuo to give a pale yellow oil. Purification via sil-
ica gel column chromatography (hexane–EtOAc, 4:1) gave 17 as a
colourless solid; yield: 40.5 mg (79%); mp 116–118 °C.
IR (KBr): 3317 (m), 2921 (s), 2850 (m), 1743 (m), 1643 (m), 1603
(w), 1580 (w), 1532 (m), 1489 (w), 1439 (w), 1213 (w), 695 (w),
632 (w), 579 (w) cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.79–7.76 (m, 2 H), 7.51–7.46 (m,
1 H), 7.43–7.39 (m, 2 H), 6.71 (br d, J = 7.5 Hz, 1 H), 5.08 (t, J = 7.5
Hz, 1 H), 4.84 (dt, J = 7.5, 5.5 Hz, 1 H), 3.76 (s, 3 H), 2.73–2.51 (m,
2 H), 2.23–2.18 (m, 4 H), 1.53–1.45 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 172.8, 167.0, 146.2, 134.1, 131.7,
128.7, 127.1, 117.8, 52.4(9), 52.4(7), 38.0, 30.5, 30.1, 29.8, 29.3,
29.1, 27.0.
HRMS (ESI+, MeOH): m/z [M + Na]+ calcd for C19H25NNaO3:
Yield from telescopic method: 80%.
338.1727; found: 338.1728.
IR (KBr): 2935 (s), 2857 (s), 1741 (s), 1715 (w), 1642 (s), 1396 (s),
1364 (s), 1235 (w), 1212 (s), 1103 (s) cm–1.
1H NMR (400 MHz, CDCl3, 55 °C): δ = 7.32–7.30 (m, 3 H), 7.25–
7.23 (m, 2 H), 4.33 (m, 1 H), 3.54 (s, 3 H), 2.95–2.65 (m, 2 H), 2.16–
2.06 (m, 2 H), 1.94–1.86 (m, 2 H), 1.81–1.74 (m, 3 H), 1.61–1.56
(m, 1 H), 1.45–1.27 (m, 4 H).
13C NMR (100 MHz, C2D2Cl4, 100 °C): δ = 172.7, 170.3, 139.0,
128.6, 127.7, 125.9, 67.9, 63.1, 51.6, 34.5, 34.3, 32.7, 27.4, 25.0,
24.5, 24.0.
1-Azaspirocycles 16–18 by the Telescopic Method; General Pro-
cedure
A microwave vessel was charged with (S)-methyl 2-benzamido-
pent-4-enoate (9; 50 mg, 0.21 mmol), HGII (7.0 mg, 5 mol%),
methylenecycloalkane 10, 11 or 12 (2.14 mmol, 10 equiv) and
CH2Cl2 (2.0 mL). The reaction vessel was sealed and microwave-
irradiated (100 W) whilst being stirred at 100 °C for 4 h (evacuate
and purge with argon at time = 2 h). Then, the reaction mixture was
cooled to r.t. and the solvent was removed in vacuo to afford the
crude cross product as a brown oil. To the crude reaction mixture
was then added a solution of TfOH (3.8 μL, 0.04 mmol) in CHCl3
(4.0 mL). The system was sealed and microwave-irradiated (40 W)
whilst being stirred at 50 °C. After 60 min, the reaction mixture was
cooled to r.t. and quenched with sat. aq NaHCO3 (10 mL). The phas-
es were then separated and the aqueous phase was extracted with
Et2O (2 × 15 mL). The combined organic extract was washed with
H2O (20 mL) and brine (20 mL), dried (MgSO4), filtered and con-
centrated in vacuo to give a pale yellow oil. Purification via column
chromatography yielded the desired spirocyclic product 16–18.
1
The H and 13C NMR spectra were recorded at elevated tempera-
tures, due to the presence of rotamers.
HRMS (ESI+, MeOH): m/z [M + H]+ calcd for C18H24NO3:
302.1756; found: 302.1752.
(S)-Methyl 1-Benzoyl-1-azaspiro[4.6]undecane-2-carboxylate
(18)
In a microwave vessel under argon atmosphere, TfOH (2.8 μL,
0.032 mmol) was added to a stirred solution of (S)-methyl 2-benz-
amido-4-cycloheptylidenebutanoate (15; 50 mg, 0.16 mmol) in
CHCl3 (5.0 mL). The system was sealed and microwave-irradiated
(40 W) whilst being stirred at 50 °C for 1 h. The reaction mixture
was then cooled to r.t. and quenched with sat. aq NaHCO3 (10 mL).
The phases were separated and the aqueous phase was extracted
with Et2O (2 × 15 mL). The combined organic extract was washed
with H2O (20 mL) and brine (20 mL), dried (MgSO4), filtered and
concentrated in vacuo to give a pale yellow oil. Purification via sil-
ica gel column chromatography (hexane–EtOAc, 4:1) gave 18 as a
colourless oil; yield: 40 mg (80%).
(S)-Methyl 1-Benzoyl-1-azaspiro[4.4]nonane-2-carboxylate
(16)
In a microwave vessel under argon atmosphere, TfOH (7.4 μL,
0.083 mmol) was added to a stirred solution of (S)-methyl 2-benz-
amido-4-cyclopentylidenebutanoate (13; 120 mg, 0.42 mmol) in
CHCl3 (5.0 mL). The system was sealed and microwave-irradiated
(40 W) whilst being stirred at 50 °C for 30 min. The reaction mix-
ture was then cooled to r.t. and quenched with sat. aq NaHCO3 (10
mL). The phases were separated and the aqueous phase was extract-
ed with Et2O (2 × 15 mL). The combined organic extract was
washed with H2O (20 mL) and brine (20 mL), dried (MgSO4), fil-
tered and concentrated in vacuo to give a pale yellow oil. Purifica-
tion via silica gel column chromatography (hexane–EtOAc, 4:1)
gave 16 as a colourless oil; yield: 102 mg (85%).
Yield from telescopic method: 67%.
IR (neat): 2920 (m), 2857 (m), 1748 (s), 1639 (s), 1447 (m), 1391
(s), 1356 (m), 1195 (m), 1173 (s), 1028 (m) cm–1.
1H NMR (400 MHz, C2D2Cl4, 100 °C): δ = 7.34–7.33 (m, 3 H),
7.28–7.26 (m, 2 H), 4.35 (dd, J = 8.0, 3.0 Hz, 1 H), 3.54 (s, 3 H),
2.83–2.61 (m, 2 H), 2.23–2.14 (m, 1 H), 2.03–1.99 (m, 2 H), 1.96–
1.80 (m, 4 H), 1.75–1.52 (m, 5 H), 1.47–1.40 (m, 2 H).
Yield from telescopic method: 87%.
Chiral GC: tR = 19.8 min (>99% ee).
Synthesis 2013, 45, 3118–3124
© Georg Thieme Verlag Stuttgart · New York

PAPER
Concise Synthesis of Enantiopure 1-Azaspirocycles
3123
13C NMR (100 MHz, C2D2Cl4, 100 °C): δ = 172.7, 169.9, 139.0,
128.6, 127.9, 126.0, 70.9, 63.0, 51.5, 37.9, 37.7, 37.1, 28.5, 28.2,
27.3, 24.2, 23.6.
oil. Purification by silica gel flash chromatography (EtOAc–
hexane, 1:3) gave 25 as a colourless oil; yield: 105 mg (71%).
IR (neat): 3441 (br, s), 3085 (m), 3062 (m), 3028 (s), 2921 (s), 1603
(w), 1493 (s), 1453 (s), 1394 (m), 1356 (m), 1322 (m), 1255 (m),
1209 (m), 1184 (m), 1132 (m), 1078 (m), 1029 (m), 963 (w), 942
(w), 904 (m), 880 (w), 847 (w), 825 (w), 737 (m), 700 (m) cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.11 (m, 5 H), 4.02 (d,
J = 14.5 Hz, 1 H), 3.22 (d, J = 14.5 Hz, 1 H), 3.02 (dd, J = 11.0, 1.5
Hz, 1 H), 2.94–2.90 (m, 1 H), 2.83 (dd, J = 11.0, 3.0 Hz, 1 H), 2.00
(br s, 1 H), 1.94–0.98 (m, 14 H).
13C NMR (100 MHz, CDCl3): δ = 142.5, 128.5, 127.8, 126.9, 66.0,
65.5, 63.5, 52.2, 38.6, 33.8, 28.3, 26.5, 26.2, 24.8, 24.1.
HRMS (ESI+, MeOH): m/z [M + H]+ calcd for C17H26NO:
260.2009; found: 260.2012.
1
The H and 13C NMR spectra were recorded at elevated tempera-
tures, due to the presence of rotamers.
HRMS (ESI+, MeOH): m/z [M + H]+ calcd for C19H26NO3:
316.1907; found: 316.1912.
(±)-Methyl 2-Acetamidohex-5-enoate (19)
(±)-2-Acetamidohex-5-enoic acid (2.00 g, 11.7 mmol) was added to
a stirred solution of methanolic HCl (50 mL, pH 2). After being
stirred at r.t. for 18 h, the reaction mixture was diluted with sat. aq
NaHCO3 (50 mL), and the MeOH was removed under reduced pres-
sure. The aqueous phase was then extracted with CH2Cl2 (3 × 25
mL), and the combined organic extract was washed with H2O (25
mL) and brine (25 mL), dried (MgSO4), filtered and concentrated
under reduced pressure to give 19 as a colourless solid; yield: 2.16
g (99%); mp 57.0–58.5 °C.
(S)-1-Benzyl-2-(chloromethyl)-1-azaspiro[4.5]decane (26) and
(S)-1-Benzyl-3-chloro-1-azaspiro[5.5]undecane (27)
Carbon tetrachloride (48.0 μL, 0.49 mmol) was added to a stirred
solution of [(S)-1-benzyl-1-azaspiro[4.5]decan-2-yl]methanol (25;
115 mg, 0.44 mmol) in CHCl3 (4.0 mL). The reaction mixture was
cooled to 0 °C before a solution of Ph3P (128 mg, 0.49 mmol) in
CHCl3 (2 mL) was added dropwise via syringe. The reaction mix-
ture was stirred at r.t. for 72 h and then concentrated in vacuo to give
a yellow oil. Purification by silica gel flash chromatography (EtO-
Ac–hexane, 1:10) gave compound 26, and the isomeric piperidine
isomer 27, as an inseparable 1:1 mixture; yield: 79 mg (64%).
1H NMR (300 MHz, CDCl3): δ (compound 26) = 7.38–7.19 (m, 5
H), 4.11 (d, J = 15.0 Hz, 1 H), 3.45 (d, J = 15.0 Hz, 1 H), 3.18–3.10
(m, 1 H), 2.96 (dd, J = 12.0, 3.0 Hz, 1 H), 2.87 (dd, J = 12.0, 1.0 Hz,
1 H), 2.09–1.28 (m, 14 H); δ (compound 27) = 7.38–7.19 (m, 5 H),
4.03–3.93 (m, 1 H), 3.96 (d, J = 15 Hz, 1 H), 3.43 (d, J = 15.0 Hz,
1 H), 2.85–2.81 (m, 1 H), 2.73 (dd, J = 12.0, 9.0 Hz, 1 H), 2.09–1.28
(m, 14 H).
IR (KBr): 3362 (br, s), 3080 (m), 2979 (s), 2929 (m), 1740 (s), 1663
(s), 1506 (s), 1466 (m), 1450 (m), 1390 (w), 1370 (w), 1313 (m),
1270 (m), 1202 (m), 1143 (m), 1097 (m), 1079 (m), 1032 (w), 915
(m), 858 (m), 813 (w), 785 (w), 759 (w), 684 (w), 640 (w) cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.07 (br s, 1 H), 5.81–5.72 (m, 1
H), 5.06–4.96 (m, 2 H), 4.66–4.58 (m, 1 H), 3.73 (s, 3 H), 2.09–2.06
(m, 2 H), 1.99 (s, 3 H), 2.01–1.73 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 173.1, 170.1, 136.9, 115.6, 53.4,
51.8, 31.5, 29.5, 22.3.
MS (ESI+, MeOH): m/z [M + Na]+ calcd for C9H15NNaO3: 208.1;
found: 208.0.
Attempted Synthesis of Methyl 2-Acetamido-5-cyclohexyli-
denepentanoate (22)
The cross-metathesis of (±)-methyl 2-acetamidohex-5-enoate (19)
and methylenecyclohexane (11) was carried out according to the
microwave cross-metathesis procedure under the following condi-
tions: (±)-19 (38.9 mg, 0.21 mmol), HGII (7.0 mg, 5 mol%), 11
(240 μL, 2.14 mmol), CH2Cl2 (2.0 mL), 100 °C, 100 W, 4 h (evac-
uate and purge with argon at time = 2 h). The reaction mixture was
concentrated in vacuo and gave a chromatographically inseparable
mixture of alkenes 21 and 22 in ca. 1:4 ratio. Further attempts to iso-
late compound 22 were unsuccessful.
HRMS (ESI+, MeOH): m/z [M + H]+ calcd for C17H2535ClN:
278.1676; found: 278.1669; m/z [M + H]+ calcd for C17H2537ClN:
280.1646; found: 280.1641.
(R)-1-Benzyl-1-azaspiro[5.5]undecan-3-yl Thiocyanate (29)
Carbon tetrabromide (194 mg, 0.586 mmol) was added to a stirred
solution of [(S)-1-benzyl-1-azaspiro[4.5]decan-2-yl]methanol (25;
75.9 mg, 0.293 mmol) in CHCl3 (2.0 mL). The reaction mixture was
cooled to 0 °C before a solution of Ph3P (84.5 mg, 0.322 mmol) in
CHCl3 (2.0 mL) was added dropwise via syringe. The reaction mix-
ture was stirred at r.t. for 24 h and then concentrated in vacuo to give
a yellow oil. The residue, containing crude bromide 28, was dis-
solved in acetone (5.0 mL) and potassium thiocyanate (287 mg,
2.93 mmol) was added. The reaction mixture was stirred for a fur-
ther 12 h and then concentrated in vacuo to give a white solid. Puri-
fication by silica gel flash chromatography (EtOAc–hexane, 1:10)
gave 29 as an off-white solid; yield: 63.0 mg (72%); mp 89.4–
90.2 °C.
Attempted Synthesis of Methyl 1-Acetyl-1-azaspiro[5.5]undec-
ane-2-carboxylate
In a microwave vessel under argon atmosphere, TfOH (2.9 μL,
0.033 mmol) was added to a stirred solution of a mixture of alkenes
21 and 22 (1:4) in CHCl3 (5.0 mL). The system was sealed and mi-
crowave-irradiated (40 W) whilst being stirred at 50 °C for 1 h. The
reaction mixture was then cooled to r.t. and quenched with sat. aq
NaHCO3 (10 mL). The phases were separated and the aqueous
phase was extracted with Et2O (2 × 15 mL). The combined organic
extract was washed with H2O (20 mL) and brine (20 mL), dried
(MgSO4), filtered and concentrated in vacuo. Analysis of the resi-
due by 1H NMR spectroscopy showed a mixture of compounds 23
and 24.
Chiral HPLC: tR = 11.0 min (minor enantiomer) and 13.0 min (ma-
jor enantiomer), 88% ee.
[α]D25 –49.2 (c 1.00, CH2Cl2).
IR (KBr): 3021 (w), 2929 (s), 2853 (s), 2150 (s), 1493 (w), 1455 (s),
1447 (s), 1419 (w), 1368 (w), 1316 (w), 1224 (m), 1208 (m), 1194
(m), 1127 (m), 1074 (m), 1009 (w), 888 (w), 754 (m), 728 (s), 698
(s) cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.15 (m, 5 H), 4.00 (d,
J = 14.0 Hz, 1 H), 3.26 (d, J = 14.0 Hz, 1 H), 3.24–3.19 (m, 1 H),
2.56 (dd, J = 12.5, 2.0 Hz, 1 H), 2.43 (dd, J = 12.5, 5.0 Hz, 1 H),
2.11–0.92 (m, 14 H).
[(S)-1-Benzyl-1-azaspiro[4.5]decan-2-yl]methanol (25)
Freshly distilled THF (3.0 mL) was added to LiAlH4 (65.0 mg, 1.71
mmol) under an inert atmosphere. The resultant grey suspension
was cooled to 0 °C before a solution of (S)-methyl 1-benzoyl-1-aza-
spiro[4.5]decane-2-carboxylate (17; 172 mg, 0.571 mmol) in THF
(2.0 mL) was added dropwise via syringe. The reaction mixture was
stirred for a further 16 h at r.t. Upon complete conversion of the
starting material 17, the reaction mixture was quenched by sequen-
tial addition of H2O (0.4 mL), 20% NaOH solution (0.4 mL) and
H2O (0.8 mL). Vigorous gas formation was observed and further
stirring resulted in a white suspension. The reaction mixture was
dried (MgSO4), filtered and concentrated in vacuo to give a clear
13C NMR (100 MHz, CDCl3): δ = 141.4, 128.4, 128.3, 127.1, 114.2,
66.4, 63.2, 52.2, 41.7, 38.1, 33.1, 28.8, 27.9, 26.1, 24.8, 24.1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3118–3124

3124
Z. J. Wang et al.
PAPER
HRMS (ESI+, MeOH): m/z [M + H]+ calcd for C18H25N2S:
301.1733; found: 301.1735.
3542. (e) Liu, D.; Acharya, H. P.; Yu, M.; Wang, J.; Yeh, V.
S. C.; Kang, S.; Chiruta, C.; Jachak, S. M.; Clive, D. L. J.
J. Org. Chem. 2009, 74, 7417.
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Acknowledgment
Financial support from the Australian Research Council (for Z.J.W.
and N.D.S.) is gratefully acknowledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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