A facile synthesis of a spironitrone and a study of its cycloaddition and nuoleophilic addition reactions

Article abstract of DOI:10.1055/s-0028-1083151

The synthesis of spironitrone 5 via microwave-assisted intramolecular alkylation of bromo oxime 10 is reported. The bromo oxime is prepared by alkylation of methyl cyclohexanecarboxylate with 1,4-dibromobutane followed by conversion of the methyl ester to an oxime. Spironitrone 5 undergoes facile 1,3-dipolar cycloaddition to a range of olefins to form a range of spirocyclic isoxazolidines. Nucleophilic addition of several Grignard reagents to spironitrone 5 provided access to a series of alkyl-substituted spirohydroxylamines.

Full text of DOI:10.1055/s-0028-1083151

PAPER
3319
A Facile Synthesis of a Spironitrone and a Study of Its Cycloaddition and
Nucleophilic Addition Reactions
S
ynthesis and Stud
a
ies of
a
Spi
r
ronitron
y
e
l Crimmins, Ivaylo Dimitrov, Patrick D. O’Connor, Vittorio Caprio, Margaret A. Brimble*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 4 June 2008
Abstract: The synthesis of spironitrone 5 via microwave-assisted
intramolecular alkylation of bromo oxime 10 is reported. The bro-
mo oxime is prepared by alkylation of methyl cyclohexanecarbox-
ylate with 1,4-dibromobutane followed by conversion of the methyl
ester to an oxime. Spironitrone 5 undergoes facile 1,3-dipolar cy-
cloaddition to a range of olefins to form a range of spirocyclic isox-
azolidines. Nucleophilic addition of several Grignard reagents to
spironitrone 5 provided access to a series of alkyl-substituted spiro-
hydroxylamines.
R1
O
N
H
R1
N+
O–
OH
N
5
R2 MgBr
R2
Key words: 1,3-dipolar cycloaddition, spironitrones, microwave,
Grignard reagents
Scheme 1
1 has been investigated, providing a range of spirocyclic
hydroxylamines for pharmacological evaluation. Closely
related spironitrones have provided key intermediates for
construction of the core structures of the bicyclic alkaloid
pinnaic acid4 and the ABC ring system of the alkaloid
upenamide5 lends itself well to the application of spironi-
trone cycloaddition chemistry.
The 1,3-dipolar cycloaddition of nitrones to dipolaro-
philes is a reaction of much utility in alkaloid synthesis,
yielding isoxazolidines with up to three new defined car-
bon stereocentres in a single step. A variety of compounds
can then accessed by synthetic manipulation of the isox-
azolidine cycloadducts.1Specifically, reduction of the
isoxazolidine ring proceeds with retention of configura-
tion affording b-amino alcohols of defined stereochemis-
try,2 while oxidation yields nitrones that may be further
functionalised. As part of a programme aimed at the syn-
thesis of a variety of spirocyclic scaffolds related to the
core heterocyclic framework of the 7,6-spiroimine unit of
the spirolide family of shellfish toxins3 (Figure 1), we
herein report the facile synthesis of 7,6-spironitrone 1 to-
gether with a study of its 1,3-cycloaddition to a range of
dipolarophiles (Scheme 1). Additionally, nucleophilic ad-
dition of a series of organometallic agents to spironitrone
Spironitrone 5 was easily accessed in five steps
(Scheme 2) via monoalkylation of methyl cyclohexane-
carboxylate 6 with lithium diisopropylamide (LDA) and
quenching with 1,4-dibromobutane to afford bromide 7 in
88% yield. Conversion of the methyl ester to an aldehyde
in one step proved problematic. However, conversion of
the methyl ester to an alcohol 8 using diisobutylaluminum
hydride (DIBAL-H) in toluene and thence to aldehyde 9
Br
CO2Me
LDA, THF, –78 °C
1,4-dibromobutane
88%
CO2Me
7
6
DIBAL-H, toluene,
–78 °C, 3 h
Me
R1
80%
N
Br
Br
PCC, CH2Cl2, 2 h
84%
O
O
O
OH
H
O
O
2
3
Me
H
8
Me
HO
9
O
Me
Me
HO
NH2OH⋅HCl, NaOAc,
MeOH, 16 h
82%
R2
spirolide A (1) ∆2,3, R1 = H, R2 = Me; spirolide B (2) R1 = H, R2 = Me
spirolide C (3) ∆2,3, R1 = Me, R2 = Me; spirolide D (4) R1 = Me, R2 = Me
Br
K2CO3, aq acetone,
N+
O–
Figure 1 Structure of the spirolides
N
microwave (110 W),
90 °C, 100 psi, 4 h
OH
H
10
SYNTHESIS 2008, No. 20, pp 3319–3325
Advanced online publication: 25.09.2008
x
x.
x
x
.
2
0
0
8
46%
5
DOI: 10.1055/s-0028-1083151; Art ID: P06108SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthesis of spironitrone 5

3320
D. Crimmins et al.
PAPER
using pyridinium chlorochromate (PCC), allowed prepa- nitrones as 1,3-dipoles. Spironitrone 5 failed to undergo
ration of bromo oxime 10. Formation of spironitrone 5 cycloaddition with 1,3-dipolarophiles bearing electron-
from oxime 10 under thermal conditions was plagued by withdrawing groups such as maleic anhydride, maleim-
a slow cyclisation rate and the decomposition of the ide, dimethyl maleate, and cyclohexenone. Gratifyingly,
spironitrone product during the long reaction time. After heating spironitrone 5 with an electron-rich dipolarophile,
considerable experimentation, the key intramolecular cy- styrene 11 (3 equiv), in toluene for 12 hours, afforded a
clisation to spironitrone 5 was effected in acetone–water 7:1 mixture of the major exo-cycloadduct 16 together with
(4:1) in the presence of potassium carbonate using a CEM the minor endo-cycloadduct (epimeric at C14). An X-ray
Discovery microwave reactor (100 W, 90 °C and 100 psi crystal structure7 of the major exo-adduct 16 (Figure 2)
for 4 h).
confirmed both the regiochemical outcome of the cy-
cloaddition reaction and the relative stereochemistry of
the major product. Thus, the X-ray crystal structure of cy-
cloadduct clearly established that the bridgehead proton
was syn to the phenyl group.7
Spironitrone 5 was used immediately as a 1,3-dipole for
cycloaddition reactions as it was unstable at room temper-
ature and underwent decomposition upon storage in the
fridge for a few days. The synthetic utility of spironitrone
5 was investigated by examining its 1,3-dipolar cycload- Reaction of CBz-protected allylamine 12 with spironitro-
dition with several diverse dipolarophiles (Table 1).
ne 5 under similar conditions afforded exo-cycloadduct 17
in 88% yield. Breuer et al.8 concluded that most cycload-
ditions between a nitrone and a monosubstituted ethylene
The 1,3-dipolar additions under investigation were based
on work reported by Ishibashi et al.6 using simple cyclic
Table 1 1,3-Dipolar Cycloadditions of Spironitrone 5 with Dipolarophiles 11–15 To Give Cycloadducts 16–20
10
R1
11
9
N8
O13
14
toluene
12
6
N+
O
O–
N
1
4
+
or
or
2
3
reflux, 12 h
7
H
R1
R2
R1
H
R1
15
5
5
R2
Entry
1
1,3-Dipolarophilea
Cycloadduct
Yield (%)b
O
N
72
Ph
14
7:1 exo/endo
H
11
Ph
16
H
O
N
88
2
3
N
1.3:1 exo/endo
NHCbz
Cbz
H
12
17
O
N
EtO2C
CO2Et
15
56
H
CO2Et
CO2Et
13
18
O
N
Ph
Ph
4
5
55
33
H
H
14
15
Ph
Ph
Ph
19
O
N
H
Ph
20
a Unless stated otherwise, cycloadditions were carried out using at least 3 equiv of dipolarophile.
b Isolated yields.
Synthesis 2008, No. 20, 3319–3325 © Thieme Stuttgart · New York

PAPER
Synthesis and Studies of a Spironitrone
3321
Table 2 Nucleophilic Addition of Organometallic Reagents to
Spironitrone 5 to Give Hydroxylamines 21–25
derivative lead to formation of 5-substituted isoxazo-
lidines rather than the corresponding 4-isoxazolidines, re-
gardless of the presence of electron-withdrawing or
electron-donating groups. Surprisingly, however, heating
spironitrone 5 in toluene under reflux with symmetrically
substituted diene 13 (3 equiv) resulted in formation of a
1.3:1 mixture of C-15 epimers of cycloadduct 18 in 56%
yield. The regiochemical outcome of the reaction was pre-
sumably dictated by steric effects in this case.1
10
11
9
8
12
6
N+
1
4
O–
N
OH
R1 MgBr
+
2
3
7
R1
5
5
Entry Reagenta
Hydroxylamine
Yield (%)c
86
N
OH
1
2
3
4
5
MeMgBr
EtMgBr
PhMgBr
Me
21
22
23
24
N
OH
OH
OH
OH
72
38
57
30
Et
Figure 2 X-ray crystal structure of cycloadduct 16 (note different
numbering system to that used in Table 1).
N
Ph
Individual reaction of spironitrone 5 with diphenylacety-
lene 14 (3 equiv) and phenylacetylene 15 (3 equiv) in tol-
uene for 12 hours under reflux, afforded cycloadducts 19
and 20 in 55% and 33% yield respectively.
N
CH2=CHMgBr
Addition of carbon nucleophiles to nitrones is a highly
efficient method with which to prepare secondary hy-
droxylamines.9 We therefore next focused on the reaction
of several Grignard reagents with spironitrone 5 in order
to generate a novel series of substituted spirocyclic hy-
droxylamines (Table 2).
N
CH2=CHCH2ZnBrb
In a typical procedure, spironitrone 5 was dissolved in tet-
rahydrofuran at 0 °C then treated with the organometallic
reagent for one hour. Use of commercially available Grig-
nard reagents (MeMgBr, EtMgBr, PhMgBr and
CH2=CHMgBr) afforded the corresponding hydroxyl-
amines 21, 22, 23 and 24 in variable yields. Addition of
allylmagnesium bromide to spironitrone 5 proved prob-
lematic, whilst addition of an allylzinc reagent did afford
allyl substituted hydroxylamine 25 albeit in 30% yield.
The latter proved to be highly sensitive, which may have
contributed to the low yield of the product isolated from
the reaction.
25
a Unless stated otherwise, additions were carried out in THF at 0 °C
for 1 h, using at least 3 equiv of organometallic reagent.
b THF, 0 °C to r.t., 0.5 h.
c Isolated yield.
All reactions were carried out under an N2 atmosphere using oven-
dried glassware and standard syringe and septum techniques, unless
otherwise stated. THF was distilled from Na/benzophenone under
N2. CH2Cl2 was distilled from CaH2 under N2. Flash chromatogra-
phy was performed using Riedel-de Häen or Merck 0.032–0.063
mm silica gel. Analytical TLC was performed with 0.20 mm silica
gel 60 aluminium-backed plates and analysed using 365 nm ultra-
violet irradiation, followed by staining with either alkaline perman-
ganate or vanillin/H2SO4 solution. High-resolution mass spectra
were obtained using EI, CI and FAB techniques on a VG70-SE
spectrometer operating at a nominal accelerating voltage of 70 eV
and a nominal resolution of 5000 to 10000 as appropriate. NMR
spectra were recorded on either a Bruker DRX300 spectrometer op-
erating at 300 MHz for 1H nuclei and 75 MHz for 13C nuclei or on
a Bruker DRX400 spectrometer operating at 400 MHz for 1H nuclei
and 100 MHz for 13C nuclei or on a Bruker DRX600 operating at
600 MHz for 1H nuclei and 150 MHz for 13C nuclei. 1H NMR data
is reported as chemical shift in d ppm from TMS as an internal stan-
In conclusion, a concise synthesis of spironitrone 5 has
been developed. Furthermore, the use of this spironitrone
in 1,3-dipolar cycloadditions to a range of dipolarophiles
has been demonstrated. Nucleophilic addition of several
Grignard reagents to spironitrone 5 has facilitated access
to a range of substituted spirocyclic secondary hydroxyl-
amines. The heterocyclic motifs reported herein comprise
the core 7,6-ring system of the spiroimine unit of the
spirolide family of shellfish toxins, which is thought to be
the key pharmacophore in these intrinsically bioactive
molecules.
Synthesis 2008, No. 20, 3319–3325 © Thieme Stuttgart · New York

3322
D. Crimmins et al.
PAPER
dard; multiplicity as follows: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet or overlap of non-equivalent resonances,
br = broadening. 13C NMR data is reported as follows: chemical
shift in d ppm from TMS with the solvent as an internal indicator
(CDCl3, d = 77.0 ppm), multiplicity with respect to proton (deduced
from DEPT experiments) is also reported.
1-(4¢-Bromobutyl)cyclohexanecarboxaldehyde (9)
PCC (15.8 g, 74.0 mmol) was added to a slurry of [1-(4¢-bromobu-
tyl)cyclohexyl]methanol (8; 6.13 g, 25.0 mmol) and Celite® (20 g)
in anhydrous CH2Cl2 (100 mL). After 2 h at r.t., Et2O (100 mL) was
added and the mixture was filtered through a pad of Celite®. The fil-
trate was dried over anhydrous MgSO4, concentrated in vacuo and
the residue was purified by flash chromatography (hexane–EtOAc,
19:1) to give the title compound 9.
Methyl 1-(4¢-Bromobutyl)cyclohexanecarboxylate (7)
A solution of LDA was prepared by adding n-BuLi (1.6 M in hex-
ane, 17.5 mL, 28.0 mmol) slowly over 30 min to a stirred suspen-
sion of diisopropylamine (4.35 mL, 30.8 mmol) in anhydrous THF
(17 mL) at –78 °C under argon. After 30 min at –78 °C, methyl cy-
clohexanecarboxylate (6; 4.0 mL, 28 mmol) was added slowly to
the stirring reaction mixture. After 30 min at –78 °C, 1,4-dibromo-
butane (10.3 mL, 84 mmol) was added slowly to the stirring reac-
tion mixture. After 10 min at –78 °C, the reaction mixture was then
allowed to warm to r.t. and the mixture was quenched with H2O (15
mL), acidified with aq HCl (1 M, 10 mL) and extracted with Et2O
(3 × 10 mL). The combined extracts were dried over anhydrous
MgSO4, concentrated in vacuo and the residue was purified by flash
chromatography (hexane–Et2O, 19:1) to give the title compound 7.
Yield: 5.1 g (84%); pale-yellow oil; Rf = 0.30 (hexane–EtOAc,
19:1).
IR (NaCl): 2933, 2690, 1724, 1453, 1373, 1263, 1241, 1196, 1169,
953, 830, 744, 647 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33–1.50 (m, 12 H, 6 × CH2),
1.53–1.76 (m, 4 H, 2 × CH2), 3.38 (t, J = 6.8 Hz, 2 H, H-4¢), 9.40 (s,
1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 21.6, 23.1, 25.7, 33.1, 33.2, 33.9,
34.6, 35.3 (all CH2), 49.5 (q, C-1), 206.9 (CHO).
MS (EI): m/z (%) = 247 (2) [M]+, 217 (32), 149 (100), 128 (90), 95
(40).
HRMS (EI): m/z [M]+ calcd for C11H1879BrO: 245.0541; found:
Yield: 6.25 g (88%); pale-yellow oil; Rf = 0.25 (hexane–Et2O,
245.0539.
19:1).
HRMS (EI): m/z [M]+ calcd for C11H1881BrO: 247.0521; found:
247.0520.
IR (NaCl): 2937, 2854, 1728, 1452, 1432, 1222, 1209, 1160, 1136
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.13–1.70 (m, 4 H, 2 × CH2),
1.33–1.55 (m, 8 H, 4 × CH2), 1.75 (quin, J = 6.8 Hz, 2 H, H-3¢),
2.01 (br d, J = 12.7 Hz, 2 H, CH2), 3.32 (t, J = 6.7 Hz, 2 H, H-4¢),
3.63 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): d = 22.6, 23.1, 25.8, 32.9, 33.2, 33.9,
34.1, 39.3 (all CH2), 46.8 (q, C-1), 51.3 (CH3, OCH3), 176.9 (q,
C=O).
MS (EI): m/z (%) = 276 (5) [M]+, 217 (59), 142 (100), 93 (43), 70
(12).
HRMS (EI): m/z [M]+ calcd for C12H2179BrO2: 276.0725; found:
276.0721.
1-(4¢-Bromobutyl)cyclohexanecarbaldehyde Oxime (10)
A mixture of 1-(4¢-bromobutyl)cyclohexanecarboxyaldehyde (9;
1.61 g, 6.50 mmol), hydroxylamine hydrochloride (450 mg, 6.50
mmol) and NaOAc (1.1 g, 13.4 mmol) in MeOH (20 mL) was
stirred at r.t. overnight. The solvent was then removed in vacuo and
the residue was quenched by the addition of sat. NaHCO3 (10 mL).
The mixture was extracted with EtOAc (3 × 10 mL) and the organic
phase was washed with H2O (10 mL). The combined organic ex-
tracts were dried over anhydrous MgSO4 and the solvent was re-
moved in vacuo. The resultant residue was purified by flash
chromatography (hexane–EtOAc, 9:1) to give the title compound
10.
HRMS (EI): m/z [M]+ calcd for C12H2181BrO2: 278.0704; found:
278.0706.
Yield: 1.4 g (82%); colourless crystalline solid; mp 44.8–45 °C;
Rf = 0.30 (hexane–EtOAc, 9:1).
IR (NaCl): 3325, 2931, 2853, 1738, 1449, 1299, 1242, 950, 930
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25–1.66 (m, 12 H, 6 × CH2),
1.69–1.74 (m, 2 H, CH2), 1.76–1.85 (quin, J = 6.8 Hz, 2 H, H-3¢),
3.38 (t, J = 6.7 Hz, 2 H, H-4¢), 7.21 (s, 1 H, HC=N), 9.14 (s, 1 H, N-
OH).
13C NMR (100 MHz, CDCl3): d = 21.9, 22.0, 25.9, 33.1, 33.3, 34.1,
38.7 (all CH2), 39.8 (q, C-1), 157.4 (CH2, C-1¢¢).
MS (EI): m/z (%) = 261 (5) [M]+, 183 (100), 81 (60), 73 (45).
HRMS (EI): m/z [M]+ calcd for C11H2079BrNO: 261.0728; found:
[1-(4¢-Bromobutyl)cyclohexyl]methanol (8)
DIBAL-H (1.4 M in toluene, 12.5 mL, 17.4 mmol) was added slow-
ly at –78 °C to a solution of methyl 1-(4¢-bromobutyl)cyclohexane-
carboxylate (7; 4.2 g, 15.3 mmol) in anhydrous toluene (50 mL)
under argon. After 3 h at –78 °C, the reaction mixture was quenched
with MeOH (40 mL), warmed to r.t. and filtered through a pad of
Celite®. After removal of the solvents in vacuo, the residue was pu-
rified by flash chromatography (hexane–Et2O, 2:1) to give the title
compound 8.
Yield: 3.0 g (80%); pale-yellow oil; Rf = 0.13 (hexane–Et2O, 2:1).
IR (NaCl): 3376, 2827, 2859, 1453, 1264, 1242, 1037 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24–1.30 (m, 4 H, 2 × CH2),
1.33–1.50 (m, 10 H, 5 × CH2), 1.83 (quin, J = 6.9 Hz, 2 H, H-3¢),
3.41 (s, 2 H, H-1¢¢), 3.42 (t, J = 6.7 Hz, 2 H, H-4¢).
261.0726.
HRMS (EI): m/z [M]+ calcd for C11H2081BrNO: 263.0707; found:
263.0721.
13C NMR (75 MHz, CDCl3): d = 21.4, 21.5, 26.3, 32.3, 33.4, 33.6
8-Azoniaspiro[5.6]dodec-7-en-8-olate (5)
(all CH2), 33.9 (CH2 C-4¢), 36.9 (q, C-1), 68.2 (CH2, OCH2).
A mixture of 1-(4¢-bromobutyl)cyclohexanecarbaldehyde oxime
(10; 50.0 mg, 0.19 mmol) and K2CO3 (80 mg, 0.57 mmol) in ace-
tone–H2O (4:1, 3 mL) was put in a microwave reactor at 110 W,
90 °C, 100 psi for 4 h. The mixture was cooled to r.t., diluted with
H2O (3 mL) and extracted with CH2Cl2 (3 × 5 mL). The combined
extracts were dried over anhydrous MgSO4 and the solvent was re-
moved in vacuo. The residue was purified by flash chromatography
(CH2Cl2–MeOH, 19:1) to give the title compound 5.
MS (CI): m/z (%) = 266 (100) [M + NH4]+, 216 (50), 137 (129), 109
(20).
HRMS (CI): m/z [M + NH4]+ calcd for C11H2579BrNO: 266.1119;
found: 266.1121.
HRMS (CI): m/z [M + NH4]+ calcd for C11H2581BrNO: 268.1099;
found: 268.1100.
Synthesis 2008, No. 20, 3319–3325 © Thieme Stuttgart · New York

PAPER
Synthesis and Studies of a Spironitrone
3323
Yield: 16 mg (46%); unstable colourless oil; Rf = 0.13 (CH2Cl2–
MeOH, 19:1).
(m, 1 H, Hb-9), 3.54 (m, 1 H, Hb-1¢), 3.88–3.96 (m, 1 H, H-7), 5.05
(br s, 1 H, NH), 5.09 (s, 2 H, OCH2), 7.26–7.38 (m, 5 H, ArH).
IR (NaCl): 2930, 2854, 2210, 1580, 1448, 1242, 1179, 1150, 1104,
924, 909 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.27–1.31 (m, 3 H, Ha-1, Ha-3 and
Ha-5), 1.37–1.42 (m, 2 H, H-4), 1.52–1.58 (m, 5 H, 2 × CH2 and
Hb-3), 1.74–1.85 (m, 6 H, 2 × CH2, Hb-1 and Hb-5), 4.12 (m, 2 H,
H-9), 7.04 (s, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 20.7, 20.9, 21.5, 26.4, 27.8, 31.3,
33.6, 34.2, 34.3 (all CH2), 36.1 (q, C-6), 42.9 (CH2, C-1¢), 59.3
(CH2, C-9), 66.7 (CH2, CBz), 75.4 (CH, C-7), 76.5 (CH, C-14),
128.0 (CH, ArH), 128.0 (CH, ArH), 128.5 (CH, ArH), 136.5 (q, Ar),
156.5 (q, C=O).
MS (EI): m/z (%) = 372 (18) [M]+.
13C NMR (150 MHz, CDCl3): d = 21.8, 22.7, 25.3, 25.6, 35.6, 36.5
(all CH2), 37.5 (q, C-6), 64.8 (CH2, C-9), 146.0 (CH, HC=N).
HRMS (EI): m/z [M]+ calcd for C22H32N2O3: 372.2412; found:
372.2409.
MS (EI): m/z (%) = 181 (99) [M]+, 122 (59), 84 (100).
HRMS (EI): m/z [M]+ calcd for C11H19NO: 181.1466; found:
8-Aza-15-[1¢-(2¢,2¢-diethyloxycarbonylpent-4¢-enyl)]isoxazo-
lo[2,3-g]spiro[5.6]dodecane (18)
181.1464.
Spironitrone 5 (143 mg, 790 mmol) and diethyl 2,2-diallylmalonate
(564 mg, 2.37 mmol) was dissolved in toluene (10 mL) under an ar-
gon atmosphere and the solution was heated under reflux for 12 h.
The reaction mixture was cooled to r.t., the solvent was concentrat-
ed in vacuo and the residue was purified by flash chromatography
(hexane–EtOAc, 5:1) to give an inseparable mixture (1.3:1) of the
title compound 18 and the C-15 epimer. Chemical shifts for the
C-15 epimer are indicated by an asterisk (*).
8-Aza-14-phenylisoxazolo[2,3-g]spiro[5.6]dodecane (16)
Spironitrone 5 (550 mg, 1.96 mmol) and styrene (905 mL, 7.9
mmol) were dissolved in toluene (10 mL) under an argon atmo-
sphere and the solution was heated under reflux for 12 h. After cool-
ing to r.t., the reaction mixture was concentrated in vacuo and the
residue was purified by flash chromatography (hexane–EtOAc,
10:1) to give an inseparable mixture (7:1) of the title compound 16
and the C-14 epimer. Recrystallization from Et2O gave white
prisms, which were subjected to single crystal X-ray analysis, con-
firming the structure of the major component. Chemical shifts for
the minor C-14 epimer are indicated by an asterisk (*).
Yield: 186 mg (56%); yellow oil.
IR (NaCl): 2980, 2930, 2862, 1733, 1463, 1446, 1286, 1218, 1198,
1143, 1097 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20–1.24 (2 × t, J = 7.4 Hz, 6 H,
2 × OCH2CH3), 1.16–1.91 (m, 16 H, 8 × CH2), 2.13–2.25 (m, 2 H,
CH2), 2.17–2.19 (m, 2 H, CH2), 2.50–2.65 (m, 1 H, Ha-9), 2.64–
2.81 (m, 1 H, H-7), 3.37–3.42 (m, 1 H, Hb-9), 3.73–3.81 (m, 1 H, H-
15), 4.10–4.19 (m, 2 H, H-14), 4.17* (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.18 (q, J = 7.1 Hz, 2 H, OCH2CH3), 5.07 (br d, J = 9.9
Hz, 1 H, Ha-5¢), 5.12 (m, 1 H, Hb-5¢), 5.70 (m, 1 H, H-4¢).
13C NMR (100 MHz, CDCl3): d = 14.0 (CH3, OCH2CH3), 14.07*
(CH3, OCH2CH3), 14.1 (CH3, OCH2CH3), 20.7, 20.9, 21.6, 22.1,
26.4, 28.1, 31.3, 33.5, 34.4 (all CH2), 36.0 (q, C-6), 36.1, 36.7, 36.8*
(all CH2), 56.2, 57.2 (q, C-2¢), 59.6 (CH2, C-9), 61.2 (CH2,
OCH2CH3), 61.3 (CH2, C-14), 72.4 (CH, C-15), 76.1 (CH, C-7),
119.0* (CH2, C-5¢), 119.1 (CH2, C-5¢), 132.3 (CH, C-4¢), 132.7*
(CH, C-4¢), 170.7 (q, C=O), 171.0 (q, C=O).
Yield: 403 mg (72%); white solid.
IR (NaCl): 3031, 2927, 2861, 2246, 1947, 1874, 1806, 1738, 1605,
1496, 1452, 1371, 1243, 1048 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.02–1.15 (m, 2 H, CH2), 1.17–
1.25 (m, 1 H, CHa), 1.27–1.85 (m, 12 H, 6 × CH2), 1.95 (dd,
J = 12.9, 8.1 Hz, 1 H, CHb), 2.22 (dt, J = 12.4, 10.4 Hz, 1 H, Ha-15),
2.32* (q, J = 11.1 Hz, 1 H, Ha-15), 2.41–2.47* (m, 1 H, Hb-15),
2.52–2.58 (m, 1 H, Hb-15), 2.72 (dt, J = 11.5, 4.4 Hz, 1 H, Ha-9),
2.84 (dd, J = 10.6, 4.0 Hz, 1 H, H-7), 2.95–3.06* (m, 1 H, Ha-9),
3.47–3.53* (m, 1 H, Hb-9), 3.54–3.62 (m, 1 H, Hb-9), 4.79 (dd,
J = 10.0, 5.8 Hz, 1 H, H-14), 5.19* (dd, J = 10.5, 4.4 Hz, 1 H, H-
14), 7.25–7.35 (m, 3 H, ArH), 7.37–7.39 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 20.7, 20.9, 21.0*, 21.5, 21.6*,
26.4, 28.0*, 31.3*, 31.5, 33.5, 34.3*, 34.4 (all CH2), 36.3 (q, C-6),
39.4 (CH2, C-15), 41.6* (CH2, C-15), 59.5 (CH2, C-9), 60.2* (CH2,
C-9), 76.8 (CH, C-7), 77.8* (CH, C-7), 78.2 (CH, C-14), 78.3* (CH,
C-14), 126.3* (CH, ArH), 126.7 (CH, ArH), 127.7* (CH, ArH),
127.8 (CH, ArH), 128.2* (CH, ArH), 128.3 (CH, ArH), 139.1 (q,
Ar).
MS (EI): m/z (%) = 421 (42) [M]+, 69 (100).
HRMS (EI): m/z [M]+ calcd for C24H39NO5: 421.2828; found:
421.2832.
8-Aza-14,15-diphenylisoxazolino[2,3-g]spiro[5.6]dodecane (19)
Spironitrone 5 (50 mg, 276 mmol) and diphenylacetylene (147 mg,
828 mmol) were dissolved in toluene (10 mL) under an argon atmo-
sphere and the mixture was heated under reflux for 12 h. The reac-
tion mixture was cooled to r.t. and the solvent was concentrated in
vacuo. The residue was purified by preparative layer chromatogra-
phy (hexane) on a 20 cm × 20 cm plate to give the title compound
19.
MS (EI): m/z (%) = 285 (32) [M]+, 69 (100).
HRMS (EI): m/z [M]+ calcd for C19H27NO: 285.2092; found:
285.2091.
8-Aza-14-[1¢-benzyl-N-methylcarbamate]isoxazolo[2,3-g]spi-
ro[5.6]dodecane (17)
Yield: 54 mg (55%); pale-yellow oil.
Spironitrone 5 (50.0 mg, 276 mmol) and benzyl N-allylcarbamate
(158 mg, 828 mmol) was dissolved in toluene (10 mL) under an ar-
gon atmosphere and the solution was heated under reflux for 12 h.
The reaction mixture was cooled to r.t. and the solvent was concen-
trated in vacuo. The residue was purified by flash chromatography
(hexane–Et2O, 2:1) to give the title compound 17.
IR (NaCl): 3056, 3025, 2925, 2858, 2247, 1949, 1884, 1806, 1661,
1601, 1497, 1446, 1245, 1129 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.78–0.95 (m, 1 H, CHa), 0.98–
1.12 (m, 1 H, CHb), 1.16–1.53 (m, 8 H, 4 × CH2), 1.54–1.65 (m,
2 H, CH2), 1.69–1.84 (m, 3 H, CH2 and CHa), 2.08 (dd, J = 13.8, 8.3
Hz, 1 H, CHb), 3.06 (dt, J = 10.9, 5.4 Hz, 1 H, Ha-9), 3.72–3.78 (m,
1 H, m, Hb-9), 4.46 (s, 1 H, 7-H), 7.10–7.18 (m, 5 H, ArH), 7.20–
7.33 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 21.0, 21.2, 21.8, 26.1, 28.7, 30.7,
33.9, 34.4 (all CH2), 38.7 (q, C-6), 61.7 (CH2, C-9), 86.4 (CH, C-7),
108.0 (q, C-15), 126.7, 127.4 (CH, ArH), 127.8 (CH, ArH), 128.2
Yield: 90 mg (88%); colourless oil.
IR (NaCl): 2929, 2862, 2248, 1717, 1517, 1453, 1251, 909 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93–1.13 (m, 2 H, CH2), 1.16–
1.79 (m, 13 H, 6 × CH2 and CHa), 1.82–1.93 (m, 2 H, CH2), 2.17–
2.26 (m, 1 H, CHb), 2.58 (dt, J = 11.1, 4.7 Hz, 1 H, Ha-9), 2.66 (dd,
J = 10.3, 4.7 Hz, 1 H, H-14), 3.16–3.25 (m, 1 H, Ha-1¢), 3.40–3.45
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3324
D. Crimmins et al.
PAPER
(CH, ArH), 128.5 (CH, ArH), 129.2 (q, Ar), 130.3 (CH, ArH), 135
(q, Ar), 146.7 (q, C-14).
MS (EI): m/z (%) = 359 (55) [M]+, 105 (100).
mL). The combined extracts were dried over anhydrous MgSO4,
concentrated in vacuo and the residue was purified by flash chroma-
tography (hexane–Et2O, 4:1) to give the title compound 22.
Yield: 59 mg (72%); pale-yellow oil.
IR (NaCl): 3216, 2929, 2857, 2221, 1597, 1461, 1149, 1124 cm–1.
HRMS (EI): m/z [M]+ calcd for C25H29NO: 359.2249; found:
359.2239.
1H NMR (400 MHz, CDCl3): d = 1.03 (t, J = 7.4 Hz, 3 H, H-2¢),
1.27–1.77 (m, 18 H, 9 × CH2), 2.62–2.67 (m, 1 H, H-7), 2.91–2.98
(m, 1 H, Ha-9), 3.21–3.27 (dt, J = 10.3, 5.1 Hz, 1 H, Hb-9), 7.09 (br
s, 1 H, N-OH).
13C NMR (100 MHz, CDCl3): d = 15.9 (CH3, C-2¢), 18.3 (CH2,
C-1¢), 21.5, 22.1, 22.2, 26.4, 26.8, 34.1, 34.4, 36.4 (all CH2), 39.8
(q, C-6), 57.2 (CH2, C-9), 77.6 (CH, C-7).
8-Aza-14-phenylisoxazolino[2,3-g]spiro[5.6]dodecane (20)
Spironitrone 5 (50 mg, 276 mmol) and ethynylbenzene (90 mL, 828
mmol) were dissolved in toluene (10 mL) under an argon atmo-
sphere and the mixture was heated under reflux for 12 h. The reac-
tion mixture was cooled to r.t. and the solvent was concentrated in
vacuo. The residue was purified by preparative layer chromatogra-
phy (hexane–EtOAc, 20:1) on a 20 × 20 cm plate to give the title
compound 20.
MS (EI): m/z (%) = 211 (3) [M]+, 41 (100).
HRMS (EI): m/z [M]+ calcd for C13H25NO: 211.1936; found:
Yield: 26 mg (33%); pale-yellow oil.
211.1938.
IR (NaCl): 2925, 2857, 1947, 1879, 1804, 1726, 1655, 1494, 1448,
1326, 1280, 1061 cm–1.
7-Phenyl-8-azaspiro[5.6]dodecan-8-ol (23)
1H NMR (300 MHz, CDCl3): d = 1.05–1.22 (m, 2 H, CH2), 1.23–
1.84 (m, 13 H, 6 × CH2), 2.01 (dd, J = 13.1, 8.0 Hz, 1 H, CHb), 3.00
(dt, J = 10.9, 4.8 Hz, 1 H, Ha-9), 3.75–3.80 (m, 1 H, Hb-9), 4.02 (d,
J = 2.0 Hz, 1 H, H-7), 5.14 (d, J = 2.1 Hz, 1 H, H-15), 7.25–7.35
(m, 3 H, ArH), 7.49–7.54 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 21.1, 21.2, 21.8, 26.5, 28.6, 32.9,
34.5, 34.7 (all CH2), 36.7 (q, C-6), 61.0 (CH2, C-9), 83.8 (CH, C-7),
93.5 (CH, C-15), 125.2 (CH, ArH), 128.2 (CH, ArH), 128.4 (CH,
ArH), 151.4 (q, Ar).
A solution of PhMgBr (3.0 M in Et2O, 167 mL, 502 mol) was added
dropwise to a solution of spironitrone 5 (26 mg, 143 mmol) in anhy-
drous THF (5 mL) at 0 °C under an argon atmosphere. The mixture
was stirred for 1 h at 0 °C then quenched with sat. NH4Cl (10 mL).
The mixture was extracted with Et2O (3 × 15 mL) and the organic
phase washed with H2O (2 × 10 mL) and brine (2 × 10 mL). The
combined extracts were dried over anhydrous MgSO4, concentrated
in vacuo and the residue was purified by flash chromatography
(hexane–Et2O, 4:1) to give the title compound 23.
MS (FAB): m/z (%) = 284 (100) [M + H]+.
Yield: 14 mg (38%); colourless oil.
HRMS (FAB): m/z [M + H]+ calcd for C19H26NO: 284.2014; found:
284.2012.
IR (NaCl): 2936, 2863, 1793, 1731, 1600, 1466, 1377, 1251, 1096
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.82–0.89 (m, 1 H, CHa), 0.97 (dt,
J = 12.7, 4.7 Hz, 1 H, CHb), 1.18–1.32 (m, 4 H, 2 × CH2), 1.32–
1.52 (m, 4 H, 2 × CH2), 1.53–1.67 (m, 4 H, 2 × CH2), 1.80–2.04 (m,
2 H, CH2), 3.12–3.23 (m, 1 H, Ha-9), 3.34 (ddd, J = 13.3, 6.9, 3.0
Hz, 1 H, Hb-9), 3.52 (s, 1 H, H-7), 4.64 (s, 1 H, N-OH), 7.23–7.35
(m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): d = 20.8, 21.6, 21.8, 23.7, 25.7, 30.2,
31.9, 36.4 (all CH2), 38.5 (q, C-6), 58.1 (CH2, C-9), 85.5 (CH, C-7),
126.7 (CH, ArH), 127.6 (CH, ArH), 129.8 (CH, ArH), 141.6 (q, Ar).
7-Methyl-8-azaspiro[5.6]dodecan-8-ol (21)
A solution of MeMgBr (3.0 M in Et2O, 193 mL, 579 mmol) was add-
ed dropwise to a solution of spironitrone 5 (30.0 mg, 165 mmol) in
anhydrous THF (5 mL) at 0 °C under an argon atmosphere. The
mixture was stirred for 1 h at 0 °C then quenched with sat NH4Cl
(10 mL). The mixture was extracted with Et2O (3 × 15 mL) and the
organic phase was washed with H2O (2 × 10 mL) and brine (2 × 10
mL). The combined extracts were dried over anhydrous MgSO4,
concentrated in vacuo and the residue was purified by flash chroma-
tography (hexane–Et2O, 2:1) to give the title compound 21.
MS (EI): m/z (%) = 259 (6) [M]+, 242 (100) [M – OH]+.
HRMS (EI): m/z [M]+ calcd for C17H25NO: 259.1936; found:
Yield: 28 mg (86%); colourless oil.
259.1932.
IR (NaCl): 3232, 2927, 2855, 1597, 1449, 1373, 1150, 909, 733
cm–1.
7-Vinyl-8-azaspiro[5.6]dodecan-8-ol (24)
1H NMR (300 MHz, CDCl3): d = 1.09 (d, J = 6.8 Hz, 3 H, H-1¢),
1.15–1.70 (m, 15 H, Ha-10 and 7 × CH2), 1.74–1.87 (m, 1 H,
Hb-10), 2.99–3.15 (m, 2 H, H-9), 3.23 (q, J = 6.8 Hz, 1 H, H-7),
7.81 (br s, 1 H, N-OH).
13C NMR (75 MHz, CDCl3): d = 7.2 (CH3, C-1¢), 20.4, 21.7, 25.5,
26.3, 34.2, 34.5, 36.8 (all CH2), 37.7 (q, C-6), 54.2 (CH2, C-9), 69.8
(CH, C-7).
A solution of vinylmagnesium bromide (1.0 M in THF, 828 mL, 828
mmol) was added dropwise to a solution of spironitrone 5 (50.0 mg,
276 mmol) in anhydrous THF (5 mL) at 0 °C under an argon atmo-
sphere. The mixture was stirred for 1 h at 0 °C then quenched with
sat. NH4Cl (10 mL). The mixture was extracted with Et2O (3 × 15
mL) and the organic phase washed with H2O (2 × 10 mL) and brine
(2 × 10 mL). The combined extracts were dried over anhydrous
MgSO4, concentrated in vacuo and the residue was purified by flash
chromatography (hexane–EtOAc, 4:1) to give the title compound
24.
MS (EI): m/z (%) = 197 (16) [M]+, 180 (100) [M – OH]+.
HRMS (EI): m/z [M]+ calcd for C12H23NO: 197.1779; found:
197.1779.
Yield: 33 mg (57%); colourless oil.
7-Ethyl-8-azaspiro[5.6]dodecan-8-ol (22)
IR (NaCl): 3232, 2927, 2858, 1738, 1595, 1455, 1240, 1106 cm–1.
A solution of EtMgBr (3.0 M in Et2O, 383 mL, 1.10 mmol) was add-
ed dropwise to a solution of spironitrone 5 (70.0 mg, 386 mmol) in
anhydrous THF (5 mL) at 0 °C under an argon atmosphere. The
mixture is stirred for 1 h at 0 °C then quenched with sat. NH4Cl (10
mL). The mixture was extracted with Et2O (3 × 15 mL) and the or-
ganic phase was washed with H2O (2 × 10 mL) and brine (2 × 10
1H NMR (400 MHz, CDCl3): d = 1.13–1.69 (m, 14 H, 7 × CH2),
1.72–1.93 (m, 2 H, CH2), 2.86–2.96 (m, 1 H, Ha-9), 3.05–3.18 (m,
1 H, Hb-9), 3.49 (d, J = 9.8 Hz, 1 H, H-7), 4.96 (br s, 1 H, N-OH),
5.27 (dd, J = 16.4, 1.4 Hz, 1 H, Ha-2¢), 5.39 (dd, J = 10.2, 2.1 Hz,
1 H, Hb-2¢), 5.91 (dt, J = 16.8, 6.5 Hz, 1 H, H-1¢).
Synthesis 2008, No. 20, 3319–3325 © Thieme Stuttgart · New York

PAPER
Synthesis and Studies of a Spironitrone
3325
13C NMR (75 MHz, CDCl3): d = 20.4, 21.4, 21.5, 25.6, 26.3, 34.1,
36.6, 36.7 (all CH2), 36.9 (q, C-6), 55.6 (CH2, C-9), 78.5 (CH, C-7),
121.3 (CH2, C-2¢), 132.2 (CH, C-1¢).
HRMS (CI): m/z [M – H]+ calcd for C14H24NO: 222.1858; found:
222.1853.
MS (FAB): m/z (%) = 211 (52) [M – H]+, 192 (17), 164 (45).
HRMS (FAB): m/z [M – H]+ calcd for C13H22NO:208.1701; found:
Acknowledgment
We thank the University of Auckland and the Royal Society of New
Zealand Marsden Fund for financial support.
208.1693.
7-Allyl-8-azaspiro[5.6]dodecan-8-ol (25)
A solution of allylzinc bromide (0.6 M in THF, 2.2 mL, 1.3 mmol)
was added dropwise to a solution of spironitrone 5 (80 mg, 441
mmol) in anhydrous THF (5 mL) at 0 °C under an argon atmosphere.
The mixture was stirred for 30 min at r.t. then quenched with sat.
NaHCO3 (10 mL). The mixture was filtered through a pad of
Celite®, extracted with Et2O (3 × 15 mL), and the organic phase was
washed with H2O (2 × 10 mL) and brine (2 × 10 mL). The com-
bined extracts were dried over anhydrous Na2SO4, concentrated in
vacuo and the residue was purified by flash chromatography (hex-
ane–Et2O, 3:1) to give the title compound 25.
References
(1) For reviews on the cycloadditions of nitrones, see:
(a) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396.
(b) Confalone, P. N.; Huie, E. M. Org. React. (N.Y.) 1998,
36, 1. (c) Fredickson, M. Tetrahedron 1997, 53, 403.
(d) De March, P.; Figueredo, M.; Font, J. Heterocycles 1999,
50, 1213. (e) Koumbis, A. E.; Gallos, J. E. Curr. Org. Chem.
2003, 7, 585.
(2) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
(3) For a review on the synthesis of spiroimine-containing
shellfish toxins, see: O’Connor, P. D.; Brimble, M. A. Nat.
Prod. Rep. 2007, 24, 869.
Yield: 30 mg (30%); colourless oil.
IR (NaCl): 3233, 2927, 2858, 1740, 1637, 1452, 1241, 1047 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25–1.80 (m, 17 H, N-OH,
8 × CH2), 2.20–2.26 (m, 1 H, Ha-1¢), 2.49–2.56 (m, 1 H, Hb-1¢),
3.00–3.07 (m, 2 H, m, Ha-9 and H-7), 3.21–3.27 (m, 1 H, Ha-9),
4.97–5.01 (m, 1 H, Ha-3¢), 5.07 (ddd, J = 17.0, 3.2, 1.5 Hz, 1 H,
Hb-3¢), 5.97–6.07 (m, 1 H, H-2¢).
13C NMR (100 MHz, CDCl3): d = 20.9, 21.6, 21.7, 24.9, 26.3, 30.4,
34.1, 34.7, 36.4 (all CH2), 39.3 (q, C-6), 56.1 (CH2, C-9), 74.4 (CH,
C-7), 114.6 (CH2, C-3¢), 140.3 (CH, C-2¢).
(4) Yang, S.-H.; Caprio, V. Synlett 2007, 1219; and references
cited therein.
(5) Schmidt, J. P.; Beltran-Rodil, S.; Cox, R. J.; McAllister,
G. D.; Reid, M.; Taylor, R. J. K. Org. Lett. 2007, 9, 4041.
(6) Tamura, O.; Toyao, A.; Ishibashi, H. Synlett 2002, 8, 1344.
(7) Crimmins, D.; Choi, K. W.; Boyd, P. D. W.; Brimble, M. A.
Acta Crystallogr., Sect. E: Struct. Rep. Online 2008, 64,
1535.
(8) Breuer, E.; Aurich, H.; Nielsen, A. Nitrones, Nitronates,
Nitroxides; John Wiley and Sons: New York, 1989.
(9) Merino, P.; Franco, S.; Gascon, J. M.; Merchan, F. L.;
Tejero, T. Tetrahedron: Asymmetry 1999, 10, 1867.
MS (CI): m/z (%) = 221 (61) [M + H]+, 220 (100), 206 (68), 98 (69).
Synthesis 2008, No. 20, 3319–3325 © Thieme Stuttgart · New York