Synthesis of 2-azaspiro[4.4]nonan-1-ones via phosphine-catalysed [3+2]-cycloadditions

Article abstract of DOI:10.1016/j.tet.2005.06.050

The phosphine-catalyzed [3+2]-cycloaddition of the 2-methylene γ-lactams 4 and 5 and the acrylate 6 with the ylides derived from the ethyl ester, the amide or the chiral camphor sultam derivative of 2-butynoic acid (7a-c) give directly, or indirectly after reductive cyclization, spiro-heterocyclic products. The acid 32 underwent Curtius rearrangement and then acid hydrolysis to give two novel spiro-cyclic ketones, 41 and 42.

Full text of DOI:10.1016/j.tet.2005.06.050

Tetrahedron 61 (2005) 8120–8129
Synthesis of 2-azaspiro[4.4]nonan-1-ones via phosphine-catalysed
[3C2]-cycloadditions
a,
Sarah R. Yong,a Morwenna C. Williams,a Stephen G. Pyne,a, Alison T. Ung,
*
*
Brian W. Skelton,b Allan H. Whiteb and Peter Turnerc
aDepartment of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
bDepartment of Chemistry, University of Western Australia, Crawley, WA 6009, Australia
cSchool of Chemistry, University of Sydney, NSW 2006, Australia
Received 14 April 2005; revised 31 May 2005; accepted 16 June 2005
Available online 11 July 2005
Abstract—The phosphine-catalyzed [3C2]-cycloaddition of the 2-methylene g-lactams 4 and 5 and the acrylate 6 with the ylides derived
from the ethyl ester, the amide or the chiral camphor sultam derivative of 2-butynoic acid (7a–c) give directly, or indirectly after reductive
cyclization, spiro-heterocyclic products. The acid 32 underwent Curtius rearrangement and then acid hydrolysis to give two novel spiro-
cyclic ketones, 41 and 42.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The 2-azaspiro[4.4]nonan-1-one structure (1) is found in
several bioactive natural products, including alkaloids,
where it forms part of a spiro[cyclopentane-1,10-[1H]iso-
indol]-30(20H)-one (2) or spiro[3H-indole-3,30-pyrrolidin]-
2(1H)-one (3) ring system.1,2
We report here, a new strategy for the synthesis of both
racemic and enantio-enriched versions of the 2-azaspiro-
[4.4]nonan0-1-one and spiro[cyclopentane-1,10-[1H]iso-
indol]-30(2 H)-one ring systems using the phosphine-
catalyzed [3C2]-cycloaddition of the ethyl ester (7a), the
chiral camphor sultam (7b) or the amide (7c) derivative of
2-butynoic acid with either 2-methylene g-lactams 4 or 5 or
the acrylate 6, followed by reductive cyclization with zinc
(Scheme 1). Enantiomerically enriched versions of 2 can be
obtained using or the chiral (1S)-camphor sultam analogue
Keywords: Phosphine-catalyzed; [3C2]-Cycloaddition; 2-Methylene
g-lactams; Spiro-heterocyclics; Curtius rearrangement.
*
Corresponding authors. Tel.: C612 4221 3511; fax: C612 4221 4287;
e-mail addresses: spyne@uow.edu.au; aung@uow.edu.au
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.050

S. R. Yong et al. / Tetrahedron 61 (2005) 8120–8129
8121
7b to generate the key spiro-heterocyclic system of these
target molecules (Scheme 1). The phosphine-catalyzed
cycloaddition of ethyl buta-2,3-dienoate or ethyl
2-butynoate with electron-deficient alkenes has been
established as a useful method for preparing substituted
cyclopentenes3–13 both in racemic and enantio-enriched
forms.14 However, only a few examples of preparing spiro-
heterocyclic derivatives using this method have been
reported.7,11–13 During the initial phase of our study, Lu et
al. reported the triphenylphosphine-catalyzed cycloaddition
reaction of 4 and 7a.13
2. Results and discussion
The results of the phosphine-catalyzed [3C2]-cycloaddi-
tion reactions of the 2-methylene g-lactams 4 and 5 with the
ylide 8a (XZOEt), that was generated in situ from the
reaction of ethyl 2-butynoate 7a and tributylphosphine
(TBP) are shown in Scheme 2. The reaction of 413 with ethyl
2-butynoate (2 equiv) and TBP (1 equiv) in benzene
solution at rt for 15 h gave a mixture (ca. 80:20) of two
racemic regio-isomeric cycloadducts, 9 and 10, that were
isolated in yields of 51 and 21%, respectively, after column
chromatography. We found that the use of a stoichiometric
amount of TBP was required to obtain a good conversion to
9 and 10. The structures of 9 and 10 were confirmed by
extensive 2D NMR experiments and the structure of 10 was
established by single-crystal X-ray structural analysis
(Fig. 1).15 The spectroscopic data of these compounds
agreed well with that reported by Lu et al.13 who reported a
combined yield for 9 and 10 (drZ62:38) of only 33% when
the more hindered and less nucleophilic catalyst, triphenyl-
Figure 1. Molecular projection of 10.
phosphine (0.1 equiv), was employed. Based on steric
considerations alone, the regiochemical outcome of this
reaction can be rationalised as occurring via the transition
state A (RZH, XZOEt), which would be expected to be
favoured over the more sterically demanding transition state
B (RZH, XZOEt, Scheme 3).12,13
Scheme 3.
Under similar conditions the chiral 2-methylene g-lactam
516 reacted with the ylide 8a (XZOEt) to produce three
cycloadducts, 11, 12 and 13, in a ratio of 63:17:30,
1
respectively, from H NMR analysis of the crude reaction
mixture (Scheme 2). Diastereomerically pure samples of
11 (28% yield) and 13 (13% yield) could be obtained
after extensive purification, however, a pure sample of 12
could not be obtained due to difficulties in separating 12
from 11 and 13. Although the absolute stereochemistries
of 11 and 13 could not be unequivocally proven from 2D
NMR experiments we assume that the major cycloadduct
Scheme 2. Compounds 9 and 10 are racemic.

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S. R. Yong et al. / Tetrahedron 61 (2005) 8120–8129
11 arises from attack of the ylide onto the face of the
2-methylene group of 5 that is anti to the ethyl ester
substituent (via transition state A, RZCO2Et, XZOEt,
Scheme 3).
Treatment of ethyl 2-(2-nitrophenyl)propenoate 617 with
ethyl 2-butynoate 7a and TBP (0.2 equiv) gave the racemic
cycloadduct 14 as a single regio-isomer in 93% yield
(Scheme 4). Upon exposure to zinc/aqueous HCl, 14
underwent reductive cyclization to give the spiro[cyclo-
pentane-1,10-[1H]isoindol]-30(20H)-one derivative 15 in
98% yield (Scheme 4).
In order to prepare enantiomerically enriched versions of
15, the corresponding cycloaddition reaction of 6 with the
chiral alkyne 7b, derived from Oppolzer’s (1S)-chiral
sultam,18 was examined (Scheme 5). This reaction produced
a 3.3:1 mixture of the diasteromeric cycloadducts 16 and 17
from, which pure samples could be obtained after column
chromatography, along with mixed fractions in a combined
yield of 66% (Scheme 5). The absolute (1S)-configuration of
the cyclopentane ring of 16 ([a]2D6 K22.0 (c 0.3, CHCl3))
was established by a single-crystal X-ray structural analysis,
(Fig. 2)15 which then allowed assignment of the 1R-
configuration to this ring of the minor diastereomer 17
([a]2D4 C19.0 (c 0.6, CHCl3)). The chiral auxiliary was then
removed by methanolysis of (S)-16 and (R)-17 in the
presence of samarium(III) triflate19 to give the methyl
esters, (K)-(S)-18 and (C)-(R)-19 in yields of 67 and 68%,
Scheme 4. Compounds 14 and 15 are racemic.
Scheme 5. Reagents and conditions: (a) Sm(OTf)3 (1 equiv), MeOH, 50 8C,
18 h, 67% ((S)-18), 68% ((R)-19); (b) Zn dust (24 equiv), 8.9 M HCl,
MeOH/H2O, reflux, 2 h, 69% ((S)-20), 56% ((R)-21).
Figure 2. Molecular projection of 16.

S. R. Yong et al. / Tetrahedron 61 (2005) 8120–8129
8123
respectively. Reductive cyclization of (K)-(S)-18 or (C)-(R)-
19 by treatment with zinc/aqueous HCl gave the tricyclic
lactams, (K)-(S)-20 or (C)-(R)-21, respectively (Scheme 5).
basic conditions and the resulting compounds 23 and 29,
respectively, were converted to the N-aryl amide derivatives
25a,b15 and 31a, respectively, through amide bond
formation between their respective carboxylic acids, 24
and 3015 and aniline and 4-N,N-dimethylaminoaniline
(Scheme 6). Amide 2715 was obtained from the coupling
reaction of aniline and the carboxylic acid 26 obtained from
base catalyzed hydrolysis of ester 22.
The spiro-cyclic compounds 9, 10 and 15 have three
functional groups that can be further derivatised to provide
compounds with increased structural diversity. For
example, the N-Boc protecting group in racemic 9 and
10 was readily removed upon exposure to trifluoroacetic
acid (TFA) to give compounds 22 and 28, respectively
(Scheme 6). Both compounds gave single crystals for X-ray
structural analysis (not shown).15 The nitrogen atom of 22
and 28 was readily N-benzylated with benzyl bromide under
Using related chemistry, the ester 15 was converted to the
N-aryl amides 33a,b via the carboxylic acid 32 (Scheme 7).
To explore a more direct method to these N-aryl amide
derivatives, the phosphine-catalyzed [3C2]-cycloaddition
reactions of the 2-methylene g-lactam 4 and acrylate 6 with
the ylide 8 (XZNHPh), that was generated in situ from the
reaction of N-phenyl 2-butynamide 34, was examined
(Schemes 8 and 9). These reactions were unsuccessful,
presumably due to internal quenching of the ylide 8 (XZ
NHPh) by the relatively acidic secondary amide NH. In
accordance with this hypothesis was the fact that the
Scheme 8. All compounds are racemic. Reagents and conditions:
(a) anisole (10 equiv), TFA (125 equiv), DCM, 15 h, 57%.
Scheme 6. All compounds are racemic. Reagents and conditions: (a) TFA,
DCM, 2.5 h, 91% (22), 86% (28); (b) NaH (1.3 equiv), Bu4NI (0.1 equiv),
BnBr (1.5 equiv), dry THF, rt, 1–5 h, 74% (23), 47% (29); (c) K2CO3
(2 equiv), MeOH/H2O, high pressure tube, 60 8C, 1 day, 93% (24), 53%
(26), 80% (30); (d) aniline or 4-N,N-dimethylaminoaniline (1.2 equiv),
HOBT (1 equiv), EDCI (1 equiv), dry MeCN, 0–60 8C, 1–2 days, 54%
(25a), 64% (25b), 91% (27), 91% (31a).
Scheme 7. All compounds are racemic. Reagents and conditions:
(a) K2CO3 (2 equiv), MeOH/H2O, high pressure tube, 60 8C, 5 h, 94%;
(b) aniline or 4-N,N-dimethylaminoaniline (1.7 equiv), HOBT (1 equiv),
EDCI (1 equiv), MeCN, 0 8C/rt, 15 h, 92% (33a), 44% (33b).
Scheme 9. All compounds are racemic. Reagents and conditions:
(a) activated Zn dust (3.4 equiv), acetic acid, 1.5 h, 16%; (b) anisole
(10 equiv), TFA (125 equiv), DCM, 15 h, 52%.

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S. R. Yong et al. / Tetrahedron 61 (2005) 8120–8129
corresponding N-PMB protected ylide 8c (XZN(PMB)Ph),
generated in situ from the tertiary amide 7c, gave the
racemic cycloadducts 35 and 36, in yields of 14 and 55%,
respectively (Schemes 8 and 9). These reactions, while poor to
modest in yields, were completely regioselective, presumably
due to the increased steric bulk of the ylide, 8c, which would
further destabilize transition state B over transition state A
(Scheme 3). Treatment of the cycloladdition product 35 with
TFA, gaveN-phenylamide27(Scheme 8)thatwasidenticalto
the compound 27 prepared according to Scheme 6. Similarly,
reductive cyclization of 36 followed by deprotection of the
product37withTFAgave33a(Scheme9)thatwasidenticalto
the compound 33a prepared according to Scheme 7. To the
best of our knowledge the phosphine-catalyzed [3C2]-
cycloaddition reactions of alkenes and 2-butynamides has
not been previously reported.
spiro-cyclic ketones 41 and 42 (Scheme 10). These
compounds were readily separated by column chromato-
graphy and were isolated in yields of 54 and 35%,
1
respectively. The H NMR spectrum of 42 showed two
distinct N–H resonances (dH (C6D6) 7.96 (br s), 4.84 (br s))
and a deshielded aromatic proton (dH (C6D6) 8.64 (d, JZ
8 Hz), consistent with the presence of the N-aminocarbonyl
group with internal H-bonding to the lactam carbonyl group.
The structures of 41 and 42 were confirmed by a single
crystal X-ray structural analysis (42: Fig. 3).15 We assume
that the unexpected product 42 arises from self-conden-
sation of the intermediate vinyl isocyanate 38 to give the
carbamate derivative 39. Acid hydrolysis of 39 then gives,
via 40, the spiro-cyclic ketones 41 and 42 (Scheme 10).
We have not, however, attempted to isolate or characterize
the intermediates involved.
With the aim of preparing the novel spiro-cyclic ketone 41,
the racemic carboxylic acid 32 was converted to the
corresponding acyl azide by treatment with diphenylphos-
phoryl azide (DPPA),20 which was then heated under
Curtius rearrangement conditions. Acid hydrolysis of the
resulting product mixture gave ca. a 1:1 mixture of the
Figure 3. Molecular projection of 42.
Catalytic hydrogenation of the alkene moiety of racemic 15
gave a 1.8:1 mixture of the diastereomers 43 and 44,
respectively, that were readily separated by column
chromatography (Scheme 11). The relative stereochemistry
of 43 was determined by 1D NOE experiments that showed
a significant enhancement of the signal for the methine
proton Ha upon radiation of the aromatic proton Hb and vice
versa.
Scheme 11. All compounds are racemic.
2.1. Cytotoxicity studies
Compounds 15, 25a,b, 27, 31, 33a,b, 41, 42, 43 and 44 were
all tested for their cytotoxic activity against the cancer cell
lines H460 (human non small cell lung), MCF-7 (human
breast) and SF-268 (human CNS) at the Peter MacCallum
Cancer Centre, St Andrew’s Place, East Melbourne, Vic,
3002, Australia. Biological testing was performed using
Scheme 10. All compounds are racemic.

S. R. Yong et al. / Tetrahedron 61 (2005) 8120–8129
8125
standard NCI procedures at a drug concentration of 25 mM
(5 mM drug stocks were prepared in DMSO. Cells were
then exposed to 25 mM of each drug for 72 h. The cells were
then fixed, stained with SRB and the percentage cell growth
relative to the solvent control determined). Percent cell
growth calculated from this testing showed little or no
cytotoxic activity. The best activity was 50% cell growth at
25 mM for 33b against H460.
([MHC -C(CH3)3], 100%), 210.1 ([MHCKBoc], 85%);
HRMS (CI) Calcd for C16H24NO5 [MHC] 310.1654. Found:
310.1664. NMR data for 9 agreed well with literature when
performed under the literature conditions.13 Compound 10:
a white crystalline solid (44.3 mg, 0.14 mmol, 21%), mp
100–102 8C (lit.13 107–110.5 8C), Rf 0.58 (30% EtOAc:PS).
1H NMR (500 MHz) d 6.99 (t, JZ2.5 Hz, 1H, CH]), 4.17
(ddd, JZ14.5, 7, 0.5 Hz, 2H, CH2CH3), 3.90 (ddd, JZ10.5,
9.5, 3.5 Hz, 1H, NCHACHB), 3.63 (ddd, JZ10.5, 8.5,
8.5 Hz, 1H, NCHBCHA), 2.62–2.69 (m, 1H, CHACHB-8),
2.51–2.58 (m, 1H, CHBCHA-8), 2.38–2.46 (om, 2H,
CHACHB-9 and CHACHB-4), 1.98 (ddd, JZ13, 8.5,
4.5 Hz, 1H, CHBCHA-9), 1.92 (ddd, JZ12.5, 8.5, 4 Hz,
1H, CHBCHA-4), 1.54 (s, 9H, (C(CH3)3), 1.26 (dt, JZ7.5,
2.5 Hz, 3H, CH3CH2). 13C NMR d 176.8 (C-1), 163.6
(CO2Et), 150.6 (NCO2), 147.5 (CH]), 138.0 (C-6), 83.0
(C(CH3)3), 60.8 (CH2CH3), 59.7 (C-5), 44.2 (NCH2), 37.4
(CH2-9), 31.7 (CH2-8), 29.8 (CH2-4), 28.4 (C(CH3)3), 14.5
(CH3CH2). MS (ES) m/z 310.2 ([MHC], 53%), 332.1
([MCCNaC], 29%), 348.1 ([MCCKC], 23%), 254.1
([MHC-C(CH3)3], 100%), 209.8 ([MHCKBoc], 95%);
HRMS (ES) Calcd for C16H24NO5 [MHC] 310.1654.
Found: 310.1654. The NMR data collected for 10 agreed
well with those found in literature.13
In conclusion, we have developed a new strategy for the
synthesis of both racemic and enantio-enriched versions of
the 2-azaspiro[4.40]nonan-1-one and spiro[cyclopentane-1,
10-[1H]isoindol]-3 (20H)-one ring systems using the phos-
phine-catalyzed [3C2]-cycloaddition of both ester (7a) and
amide derivatives (7c) of 2-butynoic acid. Enantiomerically
enriched versions of 2 can be obtained using a chiral (1S)-
camphor sultam derivative 7b of 2-butynoic acid. We have
also demonstrated the potential of these compounds as
scaffolds for developing libraries of novel spiro-hetero-
cyclic compounds.
3. Experimental
3.1. General
3.1.2. 2-tert-Butyl 3,7-diethyl (3S,5S)-1-oxo-2-azaspiro[4.
4]non-7-ene-2,3,7-tricarboxylate (11) and 2-tert-butyl
3,7-diethyl (3S,5R)-1-oxo-2-azaspiro[4.4]non-7-ene-
2,3,7-tricarboxylate (13). To a solution of 5 (125.8 mg,
0.47 mmol) in dry benzene (3 mL) was added ethyl-2-
butynoate (0.06 mL, 1.12 mmol) and tributylphosphine
(0.25 mL, 1.01 mmol). The reaction was allowed to stir at
rt for 15 h, under an atmosphere of N2. The solvent was
evaporated in vacuo and 1H NMR analysis showed a
mixture of the two diastereomers, 11 and 12, and one
regioisomer 13 (11/12/13Z63:17:30). Compounds 11 and
13 were purified by column chromatography using 20–90%
EtOAc:PS as eluent and further by PTLC (30% EtOAc:PS).
A pure sample of 12 was unable to be isolated. Compound
11: a yellow oil (50.5 mg, 0.13 mmol, 28%), [a]2D2 K17.5 (c
4.6, CHCl3), Rf 0.57 (30% EtOAc:PS). 1H NMR (500 MHz)
d 6.57 (s, 1H, CH]), 4.54 (dd, JZ9.5, 4.5 Hz, 1H, CH-5),
4.21 (dq, JZ6.5, 1.5 Hz, 2H, NCHCO2CH2), 4.16 (q, JZ
6.7 Hz, 2H, CCO2CH2), 3.15 (dd, JZ16.5, 2 Hz, 1H,
CH-6b), 3.04 (dd, JZ18.5, 1.5 Hz, 1H, CH-9b), 2.55 (d, JZ
16.5 Hz, 1H, CH-6a), 2.39 (d, JZ17.5 Hz, 1H, CH-9a),
2.33–2.55 (m, 1H, CHACHB-4), 2.09 (dd, JZ13, 4 Hz, 1H,
CHBCHA-4), 1.49 (s, 9H, C(CH3)3), 1.23–1.29 (m, 6H,
CH2CH3). 13C NMR d 176.9 (C-1), 171.5 (NCHCO2Et),
164.3 (CCO2Et), 149.6 (NCO2) 139.8 (CH]), 134.4 (C-7),
84.0 (C(CH3)3), 61.9 (NCHCO2CH2), 60.7 (CCO2CH2),
56.7 (CH-5), 51.0 (C-3), 45.2 (CH2-9), 43.5 (CH2-6), 37.9
(CH2-4), 28.1 (C(CH3)3), 14.4 (CH3CH2), 14.3 (CH3CH2).
MS (ES) m/z 382.2 ([MHC], 5%); HRMS (ES) Calcd for
C19H28NO7 [MHC] 382.1866. Found: 382.1892. 13: a
yellow oil (24 mg, 63 mmol, 13%), [a]2D3 K1.88 (c 0.14,
For X-ray structure determinations see Supplementary data.
All H NMR spectra were performed at 300 MHz and all
1
13C NMR (DEPT) spectra at 75 MHz in CDCl3 solution,
unless otherwise noted.
Abbreviations: PS (petroleum spirit, bp 40–60 8C) and DCM
(dichloromethane).
3.1.1. Ethyl (5S*) 2-(tert-butoxycarbonyl)-1-oxo-2-aza-
spiro[4.4]non-7-ene-7-carboxylate (9) and ethyl (5R*)
2-(tert-butoxycarbonyl)-1-oxo-2-azaspiro[4.4]non-6-ene-
6-carboxylate (10). To a solution of 4 (200.7 mg,
1.02 mmol) in dry benzene (3 mL) was added ethyl
2-butynoate (0.13 mL, 1.12 mmol) and tributylphosphine
(0.25 mL, 1.01 mmol). The reaction mixture was allowed to
stir at rt for 15 h, under an atmosphere of N2. The solvent
was then evaporated in vacuo. An 82:18 mixture of the two
regioisomers, 9 and 10 respectively, resulted (determined
from analysis of the 1H NMR spectrum of the crude reaction
product). Compounds 9 and 10 were purified by column
chromatography using 10–30% EtOAc:PS as the eluent.
These compounds were further purified by PTLC (30%
EtOAc:PS). Compound 9: a yellow oil (161.7 mg,
0.52 mmol, 51%), Rf 0.78 (30% EtOAc:PS). 1H NMR
(C6D6, 500 MHz) d 6.37 (t, JZ2 Hz, 1H, CH]), 3.98 (dd,
JZ14, 7.5 Hz, 2H, CH2CH3), 3.20 (ddd, JZ13, 6, 6 Hz, 2H,
NCH2), 3.04 (dq, JZ16.5, 2.5 Hz, 1H, CH-6b), 2.71 (dq,
JZ18.5, 2.5 Hz, 1H, CH-9b), 2.13 (d, JZ16.5 Hz, 1H, CH-
6a), 1.73 (d, JZ18 Hz, 1H, CH-9a), 1.48 (s, 9H, C(CH3)3),
1.12 (ddd, JZ13, 6, 6 Hz, 1H, CHACHB-4), 1.04 (ddd, JZ
13, 6, 6 Hz, 1H, CHACHB-4), 0.97 (t, JZ7.5 Hz, 3H,
CH3CH2). 13C NMR (C6D6, 75 MHz) d 175.4 (C-1), 163.7
(CO2Et), 151.0 (NCO2), 139.8 (CH]), 134.3 (C-7),
82.1 (C(CH3)3), 60.1 (CH2CH3), 51.6 (C-5), 43.3 (CH2-9),
42.9 (NCH2), 42.3 (CH2-6), 33.2 (CH2-4), 28.1 (C(CH3)3),
14.3 (CH3CH2). MS (ES) m/z 348 ([MC CK], 15%),
332.1 ([MC CNa], 60%), 310.0 ([MHC], 32%), 254.1
1
CHCl3), Rf 0.36 (30% EtOAc:PS). H NMR (500 MHz) d
6.65 (s, 1H, CH]), 4.57 (dd, JZ9.5, 3.5 Hz, 1H, CH-5),
4.21–4.29 (m, 2H, NCHCO2CH2), 4.18 (q, JZ7.5 Hz, 2H,
CCO2CH2), 3.12–3.17 (m, 1H, CH-6b), 3.08–3.12 (m, 1H,
CH-9b), 2.51 (d, JZ16.5 Hz, 1H, CH-6a), 2.45 (d, JZ
18.5 Hz, 1H, CH-9a), 2.33 (dd, JZ13.5, 9.5 Hz, 1H,
CHACHB-4), 2.20 (dd, JZ13.5, 4 Hz, 1H, CHBCHA-4),

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S. R. Yong et al. / Tetrahedron 61 (2005) 8120–8129
1.51 (s, 9H, C(CH3)3), 1.31 (t, JZ7 Hz, 3H, CCO2CH2-
CH3), 1.27 (t, JZ7 Hz, 3H, NCHCO2CH2CH3). 13C NMR d
177.0 (C-1), 171.1 (NCHCO2Et), 164.3 (CCO2Et), 149.4
(NCO2), 139.9 (C-8), 133.8 (C-7), 83.8 (C(CH3)3), 61.8
(NCHCO2CH2), 60.4 (CCO2CH2), 56.4 (CH-5), 50.7 (C-3),
44.8 (CH2-9), 43.6 (CH2-6), 37.8 (CH2-4), 27.8 (C(CH3)3),
14.2 (CH3CH2), 14.1 (CH3CH2). MS (ES) m/z 382.2
([MHC], 5%); HRMS (ES) Calcd for C19H28NO7 [MHC]
382.1866. Found: 382.1914.
3.1.5. (3aS,6R,7aR,40S)-Hexahydro-40-methoxycarbonyl-
40-(200-nitrophenyl)-1 ((S)-16)-(cyclopenten-10-ylcarbo-
nyl)-8,8-dimethyl-2,2-dioxide-3H-3a,6-methano-2,1-
benzisothiazole) and (3aS,6R,7aR,40R)-hexahydro-40-
methoxycarbonyl-40-(200-nitrophenyl)-10-(cyclopenten-
10-ylcarbonyl)-8,8-dimethyl-2,2-dioxide-3H-3a,6-
methano-2,1-benzisothiazole ((R)-17). To a solution of 6
(147 mg, 0.709 mmol) and 7b (198 mg, 0.706 mmol) in dry
benzene (1.5 mL) under a N2 atmosphere was added
tributylphosphine (0.02 mL, 71 mmol). The reaction was
stirred at rt for 18 h and then the solvent was removed in
vacuo. The diastereomeric products were obtained in a ratio
3.1.3. 3-Ethyl, 1-methyl 1-(2-nitrophenyl)-cyclopent-3-
ene-1,3-dicarboxylate (14). To a solution of alkene 6
(1.013 g, 4.9 mmol) and ethyl 2-butynoate (0.63 mL,
5.4 mmol) in dry benzene (35 mL) was slowly added
tributylphosphine (0.24 mL, 0.98 mmol). The reaction was
left to stir for 6 h. Upon evaporation in vacuo of volatiles,
the resulting crude product was purified by column
chromatography using 20–50% EtOAc:PS as eluent to
yield a peach coloured oil (1.45 g, 4.5 mmol, 93%), Rf 0.81
(50% EtOAc:PS). 1H NMR d 7.93 (dd, JZ8.1, 1.5 Hz, 1H,
ArH-3), 7.58 (dt, JZ7.8, 1.8 Hz, 1H, ArH-5), 7.42 (dt, JZ
7.6, 1.5 Hz, 1H, ArH-4), 7.40 (d, JZ7.8 Hz, 1H, ArH-6),
6.74 (t, JZ1.8 Hz, 1H, CH]), 4.20 (q, JZ6.9 Hz, 2H,
CH2CH3), 3.64 (s, 3H, CO2CH3), 3.62 (dq, JZ19.2, 2.7 Hz,
1H, CH-50a), 3.52 (dq, JZ17.4, 2.5 Hz, 1H, CH-20a), 3.21
(dm, JZ17.1 Hz, 1H, CH-20b), 2.99 (dt, JZ19.2, 2.4 Hz,
1H, CH-50b),1.29 (t, JZ6.9 Hz, 3H, CH3CH2). 13C NMR d
174.0 (CO2Me), 164.0 (CO2Et), 148.1 (ArC-2), 140.1
(CH]), 138.1 (ArC-1), 133.8 (C-30), 133.2 (ArCH-5),
128.3 (ArCH-6), 128.0 (ArCH-4), 125.3 (ArCH-3), 60.6
(CH2CH3), 55.6 (C-10), 52.4 (CO2CH3), 45.8 (CH2-50), 44.2
(CH2-20), 14.2 (CH2CH3). MS (CI) m/z C16H18NO6 320
([MHC], 100%), 288 ([MHCKEt], 41%), 206 (68%), 246
(22%), 188 (21%); HRMS (CI) Calcd for C16H18NO6
[MHC] 320.1134. Found: 320.1132.
1
of 3.3:1 (S)-16/(R)-17 from H NMR analysis of the crude
reaction mixture. The crude mixture was purified by column
chromatography using 15% EtOAc:PS as eluent, yielding
pure diastereomeric products (S)-16 (140.6 mg, 0.29 mmol,
13%) and (R)-17 (154 mg, 0.32 mmol, 15%) and a mixture
(400 mg, 0.82 mmol, 38%) containing both diastereomeric
products in a ratio of 4.3:1 (S)-16/(R)-17. Further
purification by PTLC (20% EtOAc:PS) could yield the
pure diastereomeric products. (S)-16: a colourless crystal,
mp 196–200 8C, [a]D26 K22.0 (c 0.3, CHCl3), Rf 0.53 (30%
EtOAc:PS). 1H NMR (500 MHz) d 7.94 0(0d, JZ7.5 Hz, 1H,
00
ArH-3 7.56 (br s, 2H, ArH-500, ArH-6 ), 7.41 (br s, 1H,
00
ArH-4 ), 6.74 (br s, 1H, CH]), 4.07 (t, JZ5.5 Hz, 1H,
CH-7a), 3.74 (d, JZ19.5 Hz, 1H, CH-30a), 3.66 (s, 3H,
CO2CH3), 3.64 (d, JZ19.0 Hz, 1H, CH-50a), 3.45 (ABq,
JZ13.5 Hz, 2H, CH2-3), 3.19 (d, JZ19.0 Hz, 1H, CH-50b),
3.06 (d, JZ19.5 Hz, 1H, CH-30b), 2.09–1.99 (m, 2H, H-7a,
CH-7b), 1.97–1.91 (m, 3H, CH-4b, CH-5b, CH-6), 1.44–
1.37 (m, 2H, CH-4a, CH-5a), 1.24 (s, 3H, CH3-9), 1.00 (s,
3H, CH3-10). 13C NMR (125 MHz) d 174.8 (CO2Me), 171.3
(]CCO), 148.5 (ArC-200), 141.6 (CH]), 138.4 (ArC-100)
134.7 (C-10), 133.4 (ArCH0-0500), 129.2 (ArCH-600), 1280.0
(ArCH-400), 125.1 (ArCH-3 ), 65.6 (CH-7a), 54.6 (C-4 ),
53.7 (CH2-3), 52.4 (CO2CH3), 48.1 (C-3a), 47.7 (C-8), 47.0
(CH2-30), 45.5 (CH2-50), 45.2 (CH-6), 38.3 (CH2-7), 33.3
(CH2-4), 26.5 (CH2-5), 21.3 (CH3-9), 19.9 (CH3-10). LRMS
(EI) m/z 488 ([MC], 5%); HRMS (CI) Calcd for
C24H29N2O7S [MHC] 489.1695. Found: 489.1690. (R)-17:
a colourless crystal, mp 198–202 8C, [a]2D4 C19.0 (c 0.6,
3.1.4. Ethyl 2-oxo-spiro[30-cyclopentene-10,3-[3H]
indole]-30-carboxylate (15). To a solution of 14 (29.5 mg,
0.092 mmol) in EtOH (0.7 mL) and H2O (0.18 mL) was
added activated Zn dust (96 mg, 1.5 mmol) and 8.9 M HCl
(0.14 mL). The reaction was heated at reflux for 2 h.
Another portion of activated Zn dust (96 mg, 1.5 mmol) was
added and the reaction was left at reflux for an additional
4 h. The mixture was then filtered through Celite and diluted
with H2O. The filtrate was then extracted with EtOAc and
the organic extracts were combined and dried over MgSO4
to yield a creamy brown oil (23.4 mg, 0.091 mmol, 98%), Rf
0.5 (50% EtOAc:PS). 1H NMR (500 MHz) d 9.15 (br s, 1H,
NH), 7.21 (d, JZ7.5 Hz, 1H, ArH-4), 7.20 (t, JZ8 Hz, 1H,
ArH-6), 7.01 (t, JZ7.7 Hz, 1H, ArH-5), 6.93 (d, JZ8 Hz,
1H, ArH-7), 6.86 (br s, 1H, CH]), 4.23 (q, J0Z7 Hz, 2H,
CH2CH3), 3.27 (dd, JZ16.5, 2.5 Hz, 1H, CH-2 a), 3.19 (dd,
JZ18.7, 2.25 Hz, 1H, CH-50a), 2.90 (d, JZ16.5 Hz, 1H,
CH-20b), 2.80 (d, JZ18.5 Hz, 1H, CH-50b), 1.31 (t, JZ
7.25 Hz, 3H, CH3CH2). 13C NMR d 183.2 (C-2), 164.2
(CO2Et), 140.6 (CH]), 139.7 (C-7a), 136.6 (C-3a), 134.8
(C-30), 128.1 (ArCH-6), 123.0 (ArCH-5), 122.1 (ArCH-4),
109.9 (ArCH-7), 60.5 (CH2CH3), 52.5 (C-3), 44.9 (CH2-50),
43.4 (CH2-20), 14.2 (CH3CH2). MS (CI) m/z 258 ([MHC],
100%), 212 ([MCKOEt], 12%), 184 ([MCKCO2Et],
12%); HRMS (EI) Calcd for C15H15NO3 [MC] 257.1052.
Found: 257.1048.
1
CHCl3), Rf 0.43 (30% EtOAc:PS). H NMR (500 MHz) d
7.95 (d, JZ8.0 Hz, 1H, ArH-300), 7.60 (t,00JZ7.5 Hz, 1H,
ArH-500), 7.54 (d, JZ8.0 Hz, 1H, ArH-6 ), 7.43 (t, JZ
7.5 Hz, 1H, ArH40), 6.66 (s, 1H, CH]), 4.07 (m, 1H,
CH-7a), 3.80 (d, JZ19.0 Hz, 1H, CH-30b), 3.68 (s, 3H,
CO2CH3), 3.50 (d, JZ13.5 Hz, 1H, CH-3A), 3.46–3.42 (m,
3H, CH-50b, CH-50a, CH-3B), 2.97 (d, JZ19.0 Hz, 1H, CH-
30a), 2.06–2.00 (m, 2H, CH-7a, CH-7b), 1.98–1.90 (m, 3H,
CH-4b, CH-5b, CH-6), 1.42 (m, 2H, CH-4a, CH-5a), 1.23 (s,
3H, CH3-9), 1.00 (s, 3H, CH3-10). 13C NMR (125 MHz) d
173.9 (CO2Me), 165.7 (]CCO), 148.2 (ArC-200), 139.9
(CH]), 138.1 00(ArC-100), 134.7 (C-10), 133.3 (ArCH-500),
128.6 (ArCH-6 ), 128.0 (ArCH-400), 125.4 (ArCH-300), 65.5
(CH-7a), 55.9 (C-400), 53.6 (CH2-3), 52.5 (CO2CH3), 48.1
(C-3a), 47.7 (C-8), 46.3 (CH2-30), 44.8 (CH2-50), 45.2 (CH-
6), 38.4 (CH2-7), 33.2 (CH2-4), 26.5 (CH2-5), 21.3 (CH3-9),
19.9 (CH3-10). MS (EI) m/z 488 ([MC], 2.6%); HRMS (CI)
Calcd for C24H29N2O7S [MHC] 489.1695. Found:
489.1713.
3.1.6. Dimethyl (1S)-1-(20-nitrophenyl)-3-cyclopentene-
1,3-dicarboxylate ((S)-18). To a solution of (S)-16

S. R. Yong et al. / Tetrahedron 61 (2005) 8120–8129
8127
(199 mg, 0.4 mmol) in dry MeOH (10.2 mL) was added
Sm(OTf)3 (258 mg, 0.43 mmol). The reaction was heated at
50 8C for 15 h. The mixture was then cooled and the solvent
was removed in vacuo. The residue was then diluted with
DCM. The mixture was then washed with brine and
saturated NaHCO3, dried and solvent removed in vacuo.
The crude mixture was purified by column chromatography
using 8:11:1 (DCM:PS:EtOAc) as eluent to afford (S)-18 as
a peach oil (82.4 mg, 0.27 mmol, 67%) and the recovered
chiral auxiliary as white crystals. (S)-18: [a]2D4 K42.5 (c 0.1,
CHCl3), Rf 0.42 (20% EtOAc:PS). 1H NMR d 7.95 (dd, JZ
7.8, 1.5 Hz, 1H, ArH-30), 7.59 (dt, JZ7.5, 1.5 Hz, 1H, ArH-
50), 7.44 (dt, JZ7.5, 1.5 Hz, 1H, ArH-40), 7.42 (dd, JZ7.8,
1.5 Hz, 1H, ArH-60), 6.76 (m, 1H, CH]), 3.77 (s, 3H,
]CCO2CH3), 3.67 (s, 3H, PhCCO2CH3), 3.62 (dddd, JZ
19.5, 5.1, 5.1, 2.7 Hz, 1H, CH-5a), 3.51 (dddd, JZ17.4, 5.1,
5.1, 2.4 Hz 1H, CH-2a), 3.22 (dt, JZ17.1, 1.5 Hz, 1H,
CH-2b), 2.98 (dddd, JZ19.1, 2.4, 2.4, 0.9 Hz, 1H, CH-5b).
13C NMR (125 MHz) d 174.0 (PhCCO2Me), 164.4
(]CCO2Me), 148.2 (ArC-20), 140.4 (CH]), 138.0 (ArC-
10), 133.6 (C-3), 133.2 (ArCH-50), 128.3 (ArCH-60), 128.1
(ArCH-40), 125.3 (ArCH-30), 55.7 (C-1), 52.4 (PhCCO2-
CH3), 51.7 (]CCO2CH3), 45.8 (CH2-5), 44.2 (CH2-2). MS
(ES) m/z 306 ([MHC], 13%); HRMS (ES) Calcd for
C15H16NO6 [MHC] 306.0978. Found: 306.0966.
MS (EI) m/z 243 ([MC], 11%); HRMS (ES) Calcd for
C14H14NO3 [MHC] 244.0974. Found: 244.0966.
3.1.9. Methyl (10R)-2-oxo-spiro[30-cyclopentene-10,3-
[3H]indole]-30-carboxylate ((R)-21). The title compound
was prepared using a similar method to that described above
for the synthesis of (S)-20 using (R)-19 (14.6 mg,
0.048 mmol). Compound (R)-21 was obtained as a peach
oil (6.5 mg, 0.027 mmol, 56%), [a]2D3 C57.4 (c 1.0, CHCl3),
Rf 0.52 (30% EtOAc:PS). The 1H NMR spectrum of (R)-21
was identical to that of (S)-20. MS (EI) m/z 243 ([MC],
50%); HRMS (ES) Calcd for C14H14NO3 [MHC] 244.0974.
Found: 244.0963.
3.1.10. Ethyl (5S*)-1-oxo-2-azaspiro[4.4]non-7-ene-7-
carboxylate (22). To a solution of 9 (852.4 mg,
2.76 mmol) in dry DCM (2.5 mL), was added TFA
(2.5 mL). The solution was left to stir for 2.5 h under an
atmosphere of N2. The solvent was removed in vacuo, and
the oily residue was then treated with saturated NaHCO3
solution (2!10 mL) and extracted with DCM (2!20 mL).
The organic portions were dried, and evaporated in vacuo to
yield 22 as brown needle-like crystals (524.2 mg, 2.5 mmol,
1
91%), mp 70–78 8C, Rf 0.26 (70% EtOAc:PS). H NMR d
7.50 (br s, 1H, NH), 6.69 (t, JZ2.7 Hz, 1H, CH]), 4.19 (q,
JZ7.2 Hz, 2H, CH2CH3), 3.35 (t, JZ7.1 Hz, 2H, NCH2),
3.02 (od, JZ16.5, Hz, 2H, CH-6b, CH-9b), 2.59 (d, JZ
15.9 Hz, 1H, CH-6a), 2.46 (d, JZ18.9 Hz, 1H, CH-9a),
2.14–2.16 (m, 2H, CH2-4), 1.32 (t, JZ7.0 Hz, 3H,
CH2CH3). 13C NMR d 182.35 (C-1), 164.65 (CO2Et),
140.9 (CH]), 134.5 (C-7), 60.4 (CH2CH3), 49.4 (C-5),
43.5 (CH2-9), 42.0 (CH2-6), 39.5 (NCH2), 37.8 (CH2-4),
14.4 (CH2CH3). MS (CI) m/z 210 ([MHC], 100%); HRMS
(CI) Calcd for C11H16NO3 [MHC] 210.1130. Found:
210.1132.
3.1.7. Dimethyl (1R)-1-(20-nitrophenyl)-3-cyclopentene-
1,3-dicarboxylate ((R)-19). The title compound was
prepared using a similar method to that described above
for the synthesis of (S)-18 using (R)-17 (81.9 mg,
0.17 mmol). Purification by column chromatography in
solvent system 8:11:1 (DCM:PS:EtOAc) gave (R)-19 as a
brown oil (34.7 mg, 0.1 mmol, 68%) and recovered chiral
auxiliary as white crystals. (R)-19: [a]2D6 C50.0 (c 0.7,
CHCl3), RfZ0.26 in 20% EtOAc:PS). MS (ESCve) m/z
306 (26%) [MHC]; HRMS (ESCve) Calcd for C15H16NO6
[MHC] 306.0978. Found: 306.0984. The 1H NMR spectrum
of (R)-19 was identical to that of its enantiomer (S)-18.
3.1.11. Ethyl (5S*)-2-benzyl-1-oxo-2-azaspiro[4.4]non-7-
ene-7-carboxylate (23). To a stirred solution of 22
(255.7 mg, 1.22 mmol) in dry THF (15 mL), under an
atmosphere of N2, was added in quick succession, NaH
(76 mg, 1.6 mmol, 50% dispersion in paraffin oil), tetra-
butylammonium iodide (45 mg, 0.12 mmol) and benzyl
bromide (0.22 mL, 1.85 mmol). The reaction mixture was
left stirring for 1 h. The reaction mixture was then quenched
with H2O (50 mL) and extracted with DCM (3!40 mL).
The combined organic extracts were then dried and
evaporated in vacuo. The crude product was purified by
column chromatography using 40–60% EtOAc:PS as the
eluent to give 23 as a brown oil (271.5 mg, 0.91 mmol,
3.1.8. Methyl (10S)-2-oxo-spiro[30-cyclopentene-10,3-
[3H]indole]-30-carboxylate (S)-20). To a solution of (S)-
18 (21.7 mg, 0.07 mmol) in MeOH (0.5 mL) and H2O
(0.17 mL) was added activated Zn dust (112 mg, 1.7 mmol)
and 8.9 M HCl (0.1 mL). The reaction was heated at reflux
for 2 h. The mixture was then cooled and filtered through
Celite, and the precipitate was washed with H2O and
MeOH. The filtrate was evaporated in vacuo. The crude
product was purified by column chromatography using 30%
EtOAc:PS as eluent and further purified by PTLC (30%
EtOAc:PS). Compound (S)-20 was obtained as a yellow oil
(11.9 mg, 0.049 mmol, 69%), [a]2D4 K40.8 (c 1.2, CHCl3),
1
74%), Rf 0.56 (50% EtOAc:PS). H NMR d 7.21–7.34 (m,
5H, ArH), 6.69 (s, 1H, CH]), 4.46 (ABq, JZ14.5 Hz, 2H,
NCHACHBPh), 4.19 (dq, JZ6.9, 2.4 Hz, 2H, CH2CH3),
3.16–3.21 (m, 2H, CH2-3), 3.05 (od, JZ16.2 Hz, 2H,
CH-6b, CH-9b), 2.56 (d, JZ15.3 Hz, 1H, CH-6a), 2.43 (d,
JZ18.9 Hz, 1H, CH-9a), 1.91–2.04 (m, 2H, CH2-4), 1.28
(dt, JZ2.4, 7.2 Hz, 3H, CH2CH3). 13C NMR d 178.0 (C-1),
164.6 (CO2Et), 141.0 (CH]), 136.6 (C-7), 134.4 (ArC-i),
128.9 (ArCH-m), 128.2 (ArCH-o), 127.8 (ArC-p), 60.5
(CH2CH3), 50.3 (C-5), 47.1 (NCH2Ph), 43.81 (CH2-9),
43.78 (CH2-3), 42.2 (CH2-6), 35.5 (CH2-4), 14.5 (CH2CH3).
MS (CI) m/z 300 ([MHC], 8%); HRMS (EI) Calcd for
C18H21NO3 [MC] 299.1521. Found: 299.1508.
1
Rf 0.23 (30% EtOAc:PS). H NMR d 8.73 (br s, 1H, NH),
7.21 (dd, JZ7.5, 1.2 Hz, 1H, ArH-4), 7.20 (td, JZ7.8,
1.2 Hz, 1H, ArH-6), 7.01 (td, JZ7.8, 0.9 Hz, 1H, ArH-5),
6.92 (d, JZ7.8 Hz, 1H, ArH-7), 6.88–6.84 (m, 1H, CH-40),
3.79 (s, 3H, CH3), 3.26 (ddd, JZ18.3, 5.1, 2.7, 2.4 Hz, 1H,
CH-20a), 3.20 (ddd, JZ20.3, 5.1, 2.7, 2.4 Hz, 1H, CH-50a),
2.90 (ddd, JZ18.3, 2.4, 1.5 Hz, 1H, CH-20b), 2.80 (m, 1H,
CH-50b). 13C NMR d 182.9 (C-2), 164.6 (CO2Me), 140.9
(CH]), 139.7 (C-7a), 136.5 (C-3a), 134.5 (C-30), 128.1
(ArCH-6), 123.0 (ArCH-5), 122.2 (ArCH-4), 109.8 (ArCH-
7), 52.5 (C-3), 51.7 (CH3), 45.0 (CH2-50), 43.4 (CH2-20).

8128
S. R. Yong et al. / Tetrahedron 61 (2005) 8120–8129
3.1.12. (5S*)-2-Benzyl-1-oxo-2-azaspiro[4.4]non-7-ene-
7-carboxylic acid (24). A solution of a 23 (271.5 mg,
0.91 mmol) in MeOH (2 mL) contained within a sealed tube
was added a solution of K2CO3 (251 mg, 1.82 mmol) in
water (2.5 mL). The mixture was left stirring at 40 8C for
4 days, another equivalent of K2CO3 was added and
temperature was raised to 60 8C for 1 day. The solvent
was removed in vacuo and the oily residue was dissolved in
H2O (15 mL) and washed with Et2O (2!25 mL). The
aqueous fraction was acidified (pHw1) with 10% HCl and
extracted with EtOAc (3!25 mL). The organic portions
were combined, dried and evaporated in vacuo to yield a
white solid (229.7 mg, 0.85 mmol, 93%), Rf 0.06 (50%
EtOAc:PS). 1H NMR d 9.16 (br s, 1H, OH); 7.24–7.35 (m,
3H, ArH), 7.22 (d, JZ6.3 Hz, 2H, ArH-o), 6.81 (s, 1H,
CH]), 4.49 (ABq, JZ14.7 Hz, 2H, NCHACHBPh), 3.17–
3.23 (m, 2H, CH2-3), 3.11 (ddd, JZ18.3, 4.9, 2.2 Hz, 1H,
CH-9b), 3.05 (d, JZ16.5, 4.9, 2.2, Hz, 1H, CH-6b), 2.56 (d,
JZ17.1 Hz, 1H, CH-6a), 2.45 (d, JZ18.6 Hz, 1H, CH-9a),
1.92–2.08 (m, 2H, CH2-4). 13C NMR d 178.1 (C-1), 168.8
(CO2H), 143.5 (CH]), 136.4 (C-7), 133.9 (ArC-i), 128.9
(ArCH-m), 128.2 (ArCH-o), 127.8 (ArCH-p), 50.7 (C-5),
47.4 (NCH2Ph), 44.1 (CH2-9), 44.0 (CH2-3), 42.0 (CH2-6),
35.6 (CH2-4). MS (CI) m/z 272 ([MHC], 100%); HRMS
(CI) Calcd for C16H17NO3 [MC] 271.1208. Found:
271.1123.
30 min then 8.9 M HCl (0.05 mL) was cautiously added.
The mixture was then heated at reflux for another 1 h before
allowing to cool to rt with stirring for 15 h. The solvent was
removed in vacuo. NMR analysis of the crude mixture
revealed a 1:1 mixture of 41/42, respectively. The crude
mixture was purified by column chromatography in 30–50%
EtOAc:PS and then a second time with 2:1:1 (DCM:PS:
EtOAc). 41: a semi-crystalline yellow oil (26.5 mg,
0.13 mmol, 54%), Rf 0.28 (50% EtOAc:PS). 1H NMR
(C6D6, 500 MHz) d 8.81 (br s, 1H, NH), 6.96 (t, JZ7.8 Hz,
1H, ArH-6), 6.79 (t, JZ7.8 Hz, 1H, ArH-5), 6.66 (d, JZ
7.5 Hz, 1H, ArH-4), 6.55 (d, JZ7.5 Hz, 1H, ArH-7), 2.53–
2.62 (m, 1H, CH-40a), 2.51 (d, JZ17.5 Hz, 1H, CH-20a),
2.06–2.15 (m, 1H, CH-40b), 2.05 (d, JZ18 Hz, 1H, CH-20b),
2.01–2.06 (m, 1H, CH-50a), 1.60 (dt, JZ13, 8.5 Hz, 1H,
CH-50b). 13C NMR (C6D6, 125 MHz) d 214.0 (C-30), 182.7
(C-2), 141.0 (C-7a), 133.4 (C-3a), 128.4 (ArCH-6), 122.7
(ArCH-5), 1022.5 (ArCH-4), 110.3 (ArCH-7), 51.1 (C-3),
46.7 (CH2-2 ), 36.5 (CH2-40), 33.4 (CH2-50). MS (EI) m/z
201 ([MC], 67%), 145 ([MC-(CH2)2CO], 100%); HRMS
(EI) Calcd for C12H12NO2 [MHC] 202.0868. Found:
202.0874. 42: white crystals (21.1 mg, 0.086 mmol, 35%),
mp 139–143 8C, Rf 0.73 (50% EtOAc:PS). 1H NMR (C6D6,
500 MHz) d 8.64 (d, JZ8 Hz, 1H, ArH-7), 7.96 (br s, 1H,
NHAHB), 7.08 (t, JZ8 Hz, 1H, ArH-6), 6.85 (t, JZ7.5 Hz,
1H, ArH-5), 6.55 (d, JZ7.5 Hz, 1H, ArH-4), 4.84 (br s, 1H,
NHAHB), 2.37 (ddd, JZ18, 9, 9 Hz, 1H, CH-40a), 2.22
(d, JZ18.5 Hz, 1H, CH-20a), 2.01 (ddd, JZ18.5, 9, 6 Hz,
1H, CH-40b), 1.87 (d, JZ18.5 Hz, 1H, CH-20b), 1.68–1.74
(m, 1H, 1H, CH-50a), 1.37–1.43 (m, 1H, 1H, CH-50b). 13C
NMR (C6D6, 125 MHz) d 212.5 (C-30), 182.0 (C-2), 152.1
(CONH2), 139.9 (C-7a), 131.5 (C-3a), 128.8 (ArCH-6),
125.0 (ArCH-5), 121.6 (ArCH-4), 117.0 (ArCH-7), 51.3
(C-3), 47.0 (CH2-20), 36.1 (CH2-40), 34.0 (CH2-50). LRMS
(EI) m/z 244 ([MC], 2%), 201 ([MC -CONH2], 36%);
HRMS (EI) Calcd for C13H12N2O3 [MC] 244.0848. Found:
244.0823.
3.1.13. (5S*)-2-Benzyl-1-oxo-N-phenyl-2-azaspiro[4.4]
non-7-ene-7-carboxamide (25a). To a solution of 24
(52.2 mg, 0.21 mmol) and HOBT (26 mg, 0.2 mmol) in
dry MeCN (2 mL) at 0 8C, was added aniline (0.02 mL,
0.25 mmol). The solution was stirred for 10 min at 0 8C
before the addition of EDCI (38.2 mg, 0.2 mmol) and left to
stir at rt for 15 h and then at 60 8C for 2 h. The solvent was
then removed, and the residue was extracted with DCM and
washed successively with H2O and brine. The organic
portions was then dried and evaporated in vacuo.
Purification of the crude product was achieved through
column chromatography using 70% EtOAc:PS as the eluent
to yield 25a as white crystals (36.2 mg, 0.11 mmol, 54%),
mp 148–150 8C, Rf 0.32 (60% EtOAc:PS). 1H NMR
(500 MHz) ( 7.55 (d, JZ8 Hz, 2H, ArH-o), 7.29–7.34 (m,
5H, ArH), 7.23 (d, JZ7.5 Hz, 2H, ArH-m), 7.11 (t, JZ
7.25 Hz, 1H, ArH-p), 6.50 (s, 1H, CH]), 4.49 (ABq, JZ
14.5 Hz, 2H, NCH2), 3.21 (q, JZ7 Hz, 2H, CH2-3), 3.15 (d,
JZ16 Hz, 1H, CH-6(), 3.08 (d, JZ18 Hz, 1H, CH-9(), 2.68
(d, JZ15 Hz, 1H, CH-6(), 2.49 (d, JZ18 Hz, 1H, CH-9(),
2.00–2.11 (m, 2H, CH2-4). 13C NMR (125 MHz) ( 177.6
(C-1), 162.7 (CONHPh), 137.8 (ArC-i), 137.7 (C-7), 136.2
(ArC-i0), 135.0 (CH]), 128.8 (ArCH), 128.6 (ArCH-m),
127.9 (ArCH), 127.5 (ArCH), 124.2 (ArCH-p), 119.9
(ArCH-o), 50.3 (C-5), 47.1 (NCH2), 43.7 (CH2-3 and
CH2-9), 42.4 (CH2-6), 35.3 (CH2-4). MS (CI) m/z 347
([MHC], 80%); HRMS (CI) Calcd for C22H22N2O2 [MC]
346.1681. Found: 346.1632.
3.1.15. Ethyl (S*)-2-oxo-spiro[30-cyclopentane-10,3-[3H]
indole]-(30S*)-carboxylate (43) and ethyl (R*)-2-oxo-
spiro[30-cyclopentane-10,3-[3H]indole]-(30R*)-carb-
oxylate (44). To a mixture of spiroalkene 15 (34.9 mg,
0.136 mmol) in EtOAc (2.2 mL) was added 10 wt%
palladium on activated carbon (9.4 mg). The system was
then flushed with H2 gas and left stirring under a H2
atmosphere for 15 h. The crude reaction mixture was filtered
on Celite and washed multiple times with EtOAc. These
organic extracts were evaporated in vacuo. NMR analysis of
crude mixture revealed a 1.75:1 (43/44). The crude product
was purified by column chromatography in 20–30%
EtOAc:PS and then further by PTLC in 30% EtOAc:PS.
43: a creamy white oil (20.1 mg, 0.78 mmol, 57%), Rf 0.28
1
(30% EtOAc:PS). H NMR (500 MHz) d 8.91 (br s, 1H,
NH), 7.20 (t, JZ7.7 Hz, 1H, ArH-6), 7.18 (d, JZ7 Hz, 1H,
ArH-4), 7.02 (t, JZ7.7 Hz, 1H, ArH-5), 6.93 (d, JZ7.5 Hz,
1H, ArH-7), 4.18 (q, JZ7.3 Hz, 2H, CH2CH3), 3.25 (m, 1H,
CH-30b), 2.51 (dd, JZ13, 10 Hz, 1H, CH-20a), 2.28–2.40
(m, 3H, CH2-40 and CH-50a), 2.14 (dd, JZ13, 8 Hz, 1H,
CH-20b), 1.84–1.95 (m, 1H, CH-50b), 1.28 (t, JZ7.3 Hz, 3H,
CH3CH2). 13C NMR (125 MHz) d 183.1 (C-2), 174.4
(CO2Et), 140.1 (C-7a), 136.1 (C-3a), 127.7 (ArCH-6),
122.53 (ArCH-4), 122.49 (ArCH-5), 109.8 (ArCH-7), 60.6
(CH2CH3), 54.3 (C-3), 44.8 (CH-30b), 40.8 (CH2-20), 37.3
3.1.14. Spiro[cyclopentane-10,3-[3H]indole]-2,30(1H)-
dione (41) and spiro[cyclopentane-10,3-[3H]indole]-
2,30(1H)-dione-1-carboxamide (42). A solution of racemic
acid 32 (55.6 mg, 0.24 mmol), diphenylphosphoryl azide
(DPPA) (0.11 mL, 4.8!10-4 mol) and NEt3 (0.07 mL,
0.48 mmol) in anhydrous toluene (3 mL) was heated at
85 8C for 3 h. The mixture was then heated at reflux for

S. R. Yong et al. / Tetrahedron 61 (2005) 8120–8129
8129
(CH2-50), 29.6 (CH2-40), 14.2 (CH3CH2). MS (EI) m/z 259
References and notes
([MC], 72%), 260 ([MHC], 12%); HRMS (EI) Calcd for
C15H17NO3 [MC] 259.1208. Found: 259.1219. 44: a yellow
oil (6.9 mg, 0.26 mmol, 20%), Rf 0.38 (30% EtOAc:PS). 1H
NMR (C6D6, 500 MHz) d 8.14 (br s, 1H, NH), 7.22 (d, 1H,
JZ7.5 Hz, ArH-4) 6.96 (dt, JZ7.5, 1 Hz, 1H, ArH-6),
6.86 (dt, JZ7.5, 1 Hz, 1H, ArH-5), 6.48 (d, JZ8 Hz, 1H,
ArH-7), 3.99 (q, JZ7 Hz, 2H, CH2CH3), 3.38 (ddd, JZ16,
16, 8 Hz, 1H, CH-30a), 2.43 (dd, JZ13.5, 8.5 Hz, 1H,
CH-20a), 2.33–2.38 (m, 1H, CH-40a), 2.31 (dd, JZ14, 8 Hz,
1H, CH-20b), 2.19–2.25 (m, 1H, CH-40b), 2.10 (dt, JZ13,
7.5 Hz, 1H, CH-50a) 1.87 (dt, JZ12.5, 7.5 Hz, 1H, CH-50b),
0.96 (t, JZ7 Hz, 3H, CH3CH2). 13C NMR (C6D6, 125 MHz)
d 183.6 (C-2), 175.2 (CO2Et), 140.9 (C-7a), 135.6 (C-3a),
123.4 (ArCH-4), 127.7 (ArCH-6), 122.7 (ArCH-50), 109.5
(ArCH-7), 60.3 (CH2CH3), 54.3 (C-3), 44.5 (CH-3 a), 40.6
(CH2-20), 38.1 (CH2-50), 30.8 (CH2-40), 14.2 (CH3CH2).
LRMS (EI) m/z 259 ([MC], 64%), 260 ([MHC], 12%);
HRMS (EI) Calcd for C15H17NO3 [MC] 259.1208. Found:
259.1220.
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Acknowledgements
We thank the University of Wollongong for financial
support and the Australian Research Council for a Ph.D.
scholarship to S.R.Y. Use of the ChemMatCARS Sector 15
at the Advanced Photon Source, was supported by the
Australian Synchrotron Research Program, which is funded
by the Commonwealth of Australia under the Major
National Research Facilities Program. ChemMatCARS
Sector 15 is also supported by the National Science
Foundation/Department of Energy under grant numbers
CHE9522232 and CHE0087817 and by the Illinois Board of
Higher Education. The Advanced Photon Source is
supported by the US. Department of Energy, Basic Energy
Sciences, Office of Science, under Contract No. W-31-109-
Eng-38.
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this compound.
Supplementary data
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Supplementary data associated with this article can be
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050
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Details of the X-ray crystal/refinement data and
experimental procedures for the synthesis of compounds
25b-37.