Asymmetric synthesis of spiro 2-pyrrolidin-5-ones, 2-piperidin-6-ones and 1-isoindolin-3-ones. Part 2: N-Acyliminium ion cyclisations with an internal alkene nucleophile

Article abstract of DOI:10.1016/j.tet.2003.10.127

Chiral non-racemic bicyclic and tricyclic oxylactams obtained in two steps from N-(2-hydroxy-1(R)-phenylethyl)-succinimide and phthalimide are cyclised diastereoselectively in formic acid to give spiro[cyclohexane-1,2′- pyrrolidin]-5-ones and spiro[cyclohexane-1,1′-isoindolin]-3-ones, respectively.

Full text of DOI:10.1016/j.tet.2003.10.127

Tetrahedron 60 (2004) 1247–1253
Asymmetric synthesis of spiro 2-pyrrolidin-5-ones,
2-piperidin-6-ones and 1-isoindolin-3-ones. Part 2: N-Acyliminium
ion cyclisations with an internal alkene nucleophile
*
Abood A. Bahajaj, John M. Vernon and Giles D. Wilson
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 23 July 2003; revised 20 October 2003; accepted 24 October 2003
Abstract—Chiral non-racemic bicyclic and tricyclic oxylactams obtained in two steps from N-(2-hydroxy-1(R)-phenylethyl)-succinimide
and phthalimide are cyclised diastereoselectively in formic acid to give spiro[cyclohexane-1,20-pyrrolidin]-5-ones and spiro[cyclohexane-
1,10-isoindolin]-3-ones, respectively.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
iminium ion the CvN bond must always be exo.) There are
more recent examples of spiro cyclisations of N-acyl-
iminium ions with an internal alkene nucleophile;6–8 some
are based on the use of oxylactams as precursors for the
cyclisation step,9 although there is no control over the
configuration at the resulting spiro carbon atom.
In the preceding paper,1 we have shown how Meyers’s
chiral bicyclic lactam methodology2 can be used for the
diastereoselective cyclisation of N-acyliminium ion inter-
mediates 1 to form spiro lactams 2 (Scheme 1). In this paper,
we describe similar cyclisations in which the internal
nucleophile is an alkene rather than an arene group.
2. Results and discussion
Bicyclic oxylactams 9 and 10 were prepared in two steps
from the succinimide 6 (Scheme 3). Each of 9 and 10 was
obtained as a single diastereoisomer, which is assigned (S)-
stereochemistry at C-7a from numerous precedents in other
work.2,10 Treatment of 9 with acid under various conditions
failed to give spiro lactam products, and this accords with
previous failures of attempted 5-endo-exo-trig cyclisation
via an N-acyliminium ion intermediate.11 However, experi-
ments with 10 were more successful. Treatment of 10 with
aluminium trichloride in 1,2-dichloroethane afforded 45%
yield of a product oil, which was a ca 3:1 mixture of
diastereoisomeric 6,5-spiro lactams 11a and b, containing
also a small amount of a 5,5-spiro lactam 12. The mass
spectrum showed the correct molecular ion peaks m/z 307
and 309, together with other pairs of peaks indicating the
presence of one chlorine atom and fragment ions (including
loss of 18 and 30 mass units corresponding to H2O and
CH2O, respectively) which indicate that the oxazolidine
ring of 10 has opened to give the HOCH2CHPh side chain in
11a,b. The 13C NMR spectrum showed resonances for the
spiro carbons at d 65.1 and 64.8 for 11a and b and at d 77.2
for 12 (cf. ref. 1). The major diastereoisomer is presumably
11a with (S)-configuration at the spiro carbon to accord with
our previous results for cyclisation to 6,5-spiro lactams.1 In
Scheme 1.
Spiro cyclisations of N-acyliminium ions with an internal
alkene nucleophile were first described by Speckamp and
co-workers (Scheme 2).3 In their spiro lactams 5 the relative
stereochemistry of O- and N-substituents cis-diequatorial in
the cyclohexane ring is a consequence of anti alignment of
bonds made and broken in a chair-like transition state 4 in a
favoured 6-endo-exo-trig cyclisation.4 The less favoured 5-
exo-exo-trig process accounts for the formation of 5,5-spiro
lactam by-products in some related cases3 or as the main
product in one case.5 (Note that for spiro cyclisation of an
Keywords: Diastereoselective; Spiro lactams; N-Acyliminium ions.
*
Corresponding author. Tel.: þ44-1904-432541; fax: þ44-1904-432516;
e-mail address: jmv2@york.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.127

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A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1247–1253
Scheme 2.
Scheme 3. Reagents: (i) CH2¼CH(CH2)nMgBr; (ii) TFA/DCM.
the 1H NMR spectrum the signal assigned to CHCl appeared
as a triplet of triplets, J¼4.3 and 11.4 Hz; the larger
coupling constant is consistent with trans-diaxial coupling
of CHCl to adjacent ring hydrogens and hence with chlorine
being in an equatorial position (cf. ref. 3). Unfortunately,
this mixture of 11a,b and 12 was inseparable by
chromatography, so we next examined alternative con-
ditions for cyclisation of 10 with a view to obtaining
crystalline spiro products.
fragment ion at m/z 240 corresponds to the loss of
CH2OCHO, suggesting that the formate group is in the
side chain. Hence structure 13 is assigned. Although the
position of the ring double bond is uncertain, a comparison
of 13C chemical shifts for the spiro carbon in 13 with the
values for 14a,b suggests that 13 is a cyclohex-3-ene rather
than a cyclohex-2-ene. The more polar fraction was the
main product (78% yield), which was shown to be a 4:1
mixture of spiro lactams 14a and b (13C NMR spectrum).
The mass spectrum showed the correct molecular ion m/z
345, the fragment ion at m/z 286 (loss of CH2OCHO), and
the base peak at m/z 106 (the same as for 11a,b). Also, as for
Treatment of the bicyclic lactam 10 with formic acid at
room temperature gave a product mixture which was
separated chromatographically into two fractions. The less
polar material (7% yield) appeared to be a mixture of
diastereoisomeric spiro lactams (13C NMR signals for the
spiro carbon at d 64.8 and 65.4) containing one rather than
two formate ester groups. In the mass spectrum a strong
1
11a,b the H NMR signal for CHOCHO (d 4.9) in the
Figure 1. ORTEP drawing of the crystal structure of spiro lactam 15a with
crystallographic numbering scheme (hydrogen atoms omitted).

A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1247–1253
1249
Scheme 4. Reagents: (i) CH2¼CH(CH2)nMgBr; (ii) TFA/DCM.
cyclohexane ring was a triplet of triplets, J¼4.6 and
11.0 Hz, with the larger coupling constant consistent with
trans-diaxial couplings and hence with the formate group
equatorial. Hydrolysis of this mixture of diformates gave the
corresponding diols 15a,b, from which the major diastereo-
isomer was separated by fractional crystallisation. It was
shown by X-ray diffraction to have the structure 15a (Fig. 1)
with (S)-configuration at the spiro centre. Therefore, the
major diformate diastereoisomer is 14a, and the selectivity
of spiro cyclisation from 10 with an alkene nucleophile is
the same as that already established for similar cyclisations
to 6,5-spiro lactams with an arene nucleophile.1
chromatography, with the major diastereoisomer being the
more polar component (eluted second) in each case. The
structure 17a for the major isomer was established by X-ray
crystal structure determination (Fig. 2).
Treatment of 17a with TFA in DCM afforded the tricyclic
lactam 19 as the major product (78% yield) as a single
diastereoisomer, which has aR,9bS stereochemistry as in
2412 and other related examples.1 By-products, which were
incompletely separated from one another, included probably
the enelactam 21. The same mixture of products was
obtained from 17b with TFA in DCM, consistent with
cyclisation via a N-acyliminium ion intermediate in which
C-3 of 17a,b becomes planar. Consequently, separation of
diastereoisomeric hydroxy lactams is unnecessary (where
this is possible), and a mixture of 18a and b was treated with
TFA in DCM to give the corresponding bicyclic lactam 20
(71% yield), again as a single diastereoisomer, alongside a
very small amount of a by-product, probably the enelactam
22 (Scheme 4).
The scope of this approach to spiro lactams was extended to
include compounds derived from phthalimide 16. Addition
of v-alkenyl Grignard reagents to 16 gave, as expected,
hydroxy lactams 17 and 18, in each case as a mixture of
diastereoisomers (Scheme 4). These were separable by
Figure 2. ORTEP drawing of the crystal structure of compound 17a with
crystallographic numbering scheme (hydrogen atoms omitted).

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A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1247–1253
From 19 in formic acid we were unable to obtain a 5,5-spiro
lactam, but only very small amounts of unidentified
products (cf. 9). However, from 20 in formic acid we
obtained a 4:1 mixture of spiro lactams 26a and b (47%
yield), in which 26a must be the major diastereoisomer. In
addition, less polar material eluted in an earlier column
fraction was a mixture of at least two by-products, in which
the major component was tentatively identified as the
enelactam 23 and the minor component as the spirocyclo-
hexene 25 (13C NMR spectra and other evidence).
123.5 (CH), 127.6 (CH), 127.9 (2£CH), 128.5 (2£CH),
129.6 (CH), 130.7 (C), 132.7 (CH), 136.7 (C), 138.9 (C),
146.5 (C) and 168.8 (CvO); MS m/z 324 (MHþ, 2%), 305
(M2H2O, 4), 292 (M2CH2OH, 46), 250 (24), 187 (61), 106
(100), 91 (60) and 78 (92).
(aR,3R)-Hydroxy lactam 17a: yield 420 mg (76%), mp
126–129 8C (from ethyl acetate/hexane) (HREIMS found
M
þ 323.1516. C20H21NO3 requires M 323.1521); 1H NMR
(270 MHz) d 1.16 (2H, dd, J¼7.6, 15.7 Hz, CH2), 1.77–
1.88 (1H, m), 2.00–2.19 (1H, m), 3.75–3.84 (1H, m), 4.42
(1H, dd, J¼1.7, 17.1 Hz), 4.63–4.68 (3H, m), 4.77–4.89
(1H, m), 5.11–5.26 (1H, m), 5.40 (1H, s) and 7.30–7.65
(9H, m, aryl H); 13C NMR (67.5 MHz) d 28.0 (CH2), 36.0
(CH2), 59.0 (CH), 62.9 (CH2), 92.2 (C-3), 114.9 (CH2),
122.1 (CH), 123.3 (CH), 128.1 (CH), 128.7 (2£CH), 128.9
(2£CH), 129.8 (C), 131.7 (CH), 132.8 (CH), 136.8 (CH),
138.9 (C), 146.7 (C) and 169.1 (CvO); MS m/z 324 (MHþ,
2%), 305 (M2H2O, 2), 292 (M2CH2OH, 46), 250 (18), 187
(65), 106 (100), 91 (59) and 78 (89).
In conclusion, we have demonstrated several examples of
diastereoselective cyclisation of N-acyliminium0 ion inter-
mediates to spirocyclohexane[1,20]-pyrrolidin-5 -ones and
spirocyclohexane[1,10]isoindolin-30-ones. The stereo-
chemical preference for formation of the new quaternary
carboncentrefollowsthe samepatternasthatfoundfor similar
N-acyliminium ion cyclisations with an internal arene
nucleophile.1 The same approach was not successful for the
preparation of corresponding spirocyclopentane derivatives
by cyclisations with an internal alkene nucleophile.
3.1.2. (aR,3R)- and (aR,3S)-3-Hydroxy-2-(2-hydroxy-1-
phenylethyl)-3-(pent-4-enyl)-2,3-dihydroisoindol-1(1H)-
ones 18a,b. The Grignard reagent was prepared from
magnesium (165 mg, 6.8 mmol) and 5-bromo-1-pentene
(1.02 g, 6.8 mmol) in THF (30 mL). This was added to the
phthalimide 21 (454 mg, 1.7 mmol) in THF (20 mL) at 0 8C
with stirring. After aqueous work up, the crude product was
chromatographed on silica, from which two fractions were
eluted with EtOAc/CHCl3 (1:1 v/v).
3. Experimental
1
NMR spectra were recorded at 90 MHz for H (22.5 MHz
for 13C) on JEOL 90Q or at 270 MHz for 1H (67.5 MHz for
13C) on JEOL FX270 spectrometers for solutions in
deuteriochloroform (unless otherwise stated) with tetra-
methylsilane as internal standard. Assignments of 13C NMR
signals were assisted by use of DEPT spectra. In 13C NMR
spectra lines enclosed in l l are assigned to the minor
diastereoisomer of a pair. Mass spectra were obtained by
electron impact at 70 eV on a VG Autospec spectrometer;
high resolution spectra were obtained in EI mode or in CI
mode using ammonia. Chromatographic separations were
performed on MN-silica (230–400 mesh). THF and diethyl
ether were dried before use. Light petroleum refers to the
fraction bp 40–60 8C (unless otherwise stated). DCM refers
to dichloromethane.
(aR,3S)-Hydroxy lactam 18b: 166 mg (29%), mp 90–93 8C
(from toluene/light petroleum) (HREIMS found Mþ
337.1667. C21H23NO3 requires M 337.1678); 1H NMR
(270 MHz) d 0.68 and 0.95 (each 1H, m, HA and HB of CH2
at C-3), 1.54–2.09 (4H, m, 2£CH2), 4.09 (1H, m), 4.36 (3H,
m), 4.85–5.07 (3H, m), 5.54 (1H, m) and 7.21–7.67 (9H, m,
aryl H); 13C NMR (67.5 MHz) d 22.6 (CH2), 33.0 (CH2),
35.8 (CH2), 57.6 (CH2), 63.5 (CH2), 92.9 (C-3), 115.0
(CH2), 121.5 (CH), 123.4 (CH), 127.5 (CH), 128.0 (2£CH),
128.3 (2£CH), 129.4 (CH), 130.6 (C), 132.5 (CH), 137.7
(CH), 138.7 (C), 146.7 (C) and 168.9 (CvO); MS m/z 337
(Mþ, 1%), 307 (31), 306 (M2CH2OH, 49), 250 (34), 183
(34), 159 (47), 106 (100) and 77 (30).
3.1. Hydroxy lactams 17a,b and 18a,b
3.1.1. (aR,3R)- and (aR,3S)-3-(But-3-enyl)-3-hydroxy-2-
(2-hydroxy-1-phenylethyl)-2,3-dihydroisoindol-1(1H)-
ones 17a,b. The Grignard reagent was prepared from
magnesium (0.13 g) and 4-bromo-1-butene (0.73 g,
5.4 mmol) in THF (30 mL) and added rapidly to (R)-N-(2-
(aR,3R)-Hydroxy lactam 18a: 409 mg (71%), viscous oil
(HREIMS found Mþ 337.1667. C21H23NO3 requires M
337.1678); 1H NMR (270 MHz) d 0.41 (2H, quint,
J¼7.0 Hz, CH2), 1.39–1.47 (1H, m), 1.55–1.66 (1H, m),
1.81–1.94 (1H, m), 3.69 (1H, br d, J¼10.8 Hz), 4.53–4.70
(5H, m), 5.06–5.21 (1H, m), 5.35 (1H, s) and 7.23–7.55
(9H, m, aryl H); 13C NMR (67.5 MHz) d 22.8 (CH2), 33.0
(CH2), 35.9 (CH2), 58.9 (CH), 62.9 (CH2), 92.2 (C), 114.7
(CH2), 121.8 (CH), 123.2 (CH), 127.9 (CH), 128.3 (2£CH),
128.5 (2£CH), 129.5 (CH), 131.5 (C), 132.5 (CH), 137.9
(CH), 138.9 (C), 146.7 (C) and 168.9 (CvO); MS m/z 337
(Mþ, 1%), 307 (31), 306 (M2CH2OH, 53), 250 (32), 183
(34), 159 (49), 106 (100), 91 (25) and 77 (32).
hydroxy-1-phenylethyl)phthalimide
161
(0.46 g,
1.72 mmol) in THF (20 mL) with stirring at 0 8C. The
crude product isolated after aqueous work up was then
chromatographed on silica and two products eluted with
ethyl acetate/chloroform (1:1 v/v).
(aR,3S)-Hydroxy lactam 17b: yield 105 mg (19%), viscous
oil (HREIMS found Mþ 323.1516. C20H21NO3 requires M
323.1521); H NMR (270 MHz) d 1.30 and 1.60 (each 1H,
m, HA and HB of CH2 at C-3), 2.07 (2H, m, CH2), 3.57 (1H,
s br, OH), 4.02 (2H, m, CH2OH), 4.33 (1H, m, CHPh), 4.67
(1H, s, OH), 4.73 and 4.83 (each 1H, m, HA and HB of
CHvCH2), 5.41 (1H, m, CHvCH2) and 7.08–7.72 (9H, m,
aryl H); 13C NMR (67.5 MHz) d 27.6 (CH2), 35.6 (CH2),
58.1 (CH), 63.8 (CH2), 92.7 (C-3), 114.9 (CH2), 121.6 (CH),
1
3.2. General procedure for bicyclic/tricyclic oxylactams
9, 10, 19 and 20
A two to threefold excess of the Grignard reagent was

A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1247–1253
1251
freshly prepared from the appropriate v-alkenyl bromide
and magnesium in THF and added rapidly with stirring to
the imide 6 or 16 dissolved in THF at 0 8C. This solution
was stirred during 1 h and allowed to warm to room
temperature before aqueous work up and extraction with
ether to give the crude hydroxy lactam. This was redissolved
in DCM, cooled in ice, and treated with TFA. After stirring
for 1 h at 0 8C, the solution was allowed to warm to room
temperature, saturated ammonium chloride solution was
added, the organic layer was separated, washed with water,
dried (MgSO4), and the solvent evaporated. The crude
product was chromatographed on silica using ethyl acetate/
chloroform (1:4 v/v) as eluent.
(1H, dd, J¼8.7, 6.8 Hz), 4.78–4.88 (3H, m), 5.33 (1H, dd,
J¼7.7, 7.3 Hz), 5.54–5.69 (1H, m)7.28–7.42 (5H, m, aryl
H) and 7.52–7.67 (3H, m, aryl H) and 7.81–7.85 (1H, m,
aryl H); 13C NMR (67.5 MHz) d 28.4 (CH2), 33.4 (CH2),
58.2 (CH), 75.7 (CH2), 101.6 (C-9b), 114.9 (CH2), 122.3
(CH), 124.5 (CH), 125.6 (2£CH), 127.5 (CH), 128.7
(2£CH), 130.3 (CH), 132.3 (C), 133.3 (CH), 136.8 (CH),
140.1 (C), 145.4 (C) and 174.6 (CvO); MS m/z 305 (Mþ,
8%), 250 (M2C4H7, 100), 232 (31), 214 (26), 130 (11), 103
(22) and 49 (13). The same product 19 with identical spectra
was obtained in similar yield starting from hydroxy lactam
17a or from a mixture of 17a and b. A later fraction from the
column afforded an impure sample of the isomeric
enelactam 21 (16 mg).
3.2.1. (3R,7aS)-7a-(But-3-enyl)-3-phenyl-2,3,7,7a-tetra-
hydropyrrolo[2,1-b]oxazol-5(6H)-one 9. From 4-bromo-
1-butene (0.93 g, 6.9 mmol) and (R)-N-(2-hydroxy-1-
phenylethyl) succinimide 6 (0.50 g, 2.28 mmol); the
hydroxy lactam 7 treated with TFA (2.60 g, 22.8 mmol).
Bicyclic oxylactam 9 was obtained (183 mg, 31%) as a
viscous oil (HREIMS found Mþ 257.1419. C16H19NO2
3.2.4. (3R,9bS)-9b-(Pent-4-enyl)-3-phenyl-2,3,5,9b-tetra-
hydrooxazolo[2,3-a]isoindol-5-one 20. The mixture of
hydroxy lactams 18a,b (523 mg, 1.55 mmol) in DCM
(30 mL) was treated with TFA (265 mg, 2.33 mmol) at
0 8C. After aqueous work up and chromatography, as above,
tricyclic lactam 20 was obtained (350 mg, 71%) as a viscous
oil (HREIMS found Mþ 319.1578. C21H21NO2 requires M
319.1572); 1H NMR (270 MHz) d 0.92–1.08 (1H, m),
1.21–1.42 (1H, m),1.86–2.15 (4H, m, 2£CH2), 4.41 (1H,
dd, J¼8.7, 6.7 Hz), 4.79 (1H, t, J¼8.5 Hz), 4.83–4.91 (2H,
m, CHvCH2), 5.59 (1H, ddt, J¼17.7, 9.6, 6.7 Hz,
CHvCH2), 7.25–7.39 (5H, m, aryl H), 7.50–7.57 (2H,
m, aryl H), 7.59–7.66 (1H, m, aryl H) and 7.80–7.84 (1H,
m, aryl H); 13C NMR (67.5 MHz) d 23.3 (CH2), 33.2 (CH2),
33.5 (CH2), 58.2 (CH), 75.6 (CH2), 101.8 (C-9b), 115.1
(CH2), 122.3 (CH), 124.4 (CH), 125.6 (2£CH), 127.4 (CH),
128.6 (2£CH), 130.2 (CH), 132.2 (C), 133.2 (CH), 137.7
(CH), 140.1 (C), 145.6 (C), and 174.6 (CvO); MS m/z 319
(Mþ, 5%), 250 (M2C5H9, 100), 232 (22), 130 (12), 103
(23) and 77 (12). A later fraction from the column
afforded an impure sample of the isomeric enelactam 22
(7 mg); 13C NMR (67.5 MHz) d 27.2 (CH2), 34.3 (CH2),
61.6 (CH), 64.7 (CH2), 115.2 (CH), 116.5 (CH2), 123.9
(CH), 124.3 (CH), 127.4 (2£CH), 128.3 (CH), 129.1 (CH),
129.4 (2£CH), 130.7 (C), 132.9 (CH), 137.6 (CH), 138.4
(C) and 168.8 (CvO); MS m/z 319 (Mþ, 22%), 288 (11),
278 (30), 246 (8), 200 (10), 158 (100), 103 (14), 91 (23) and
77 (10).
1
requires M 257.1416); H NMR (270 MHz) d 1.71–1.95
(2H, m, CH2), 2.21–2.33 (3H, m), 2.42–2.51 (1H, m), 2.68
(1H, ddd, J¼17.3, 10.2, 2.7 Hz), 2.93 (1H, dt, J¼17.3,
9.9 Hz), 4.16 (1H, td, J¼8.5, 1.1 Hz), 4.73 (1H, t, J¼
8.5 Hz), 5.00–5.10 (2H, m, vCH2), 5.28 (1H, t, J¼7.8 Hz),
5.83 (1H, ddt, J¼17.0, 10.2, 6.6 Hz, vCH) and 7.31–7.45
(5H, m, aryl H); 13C NMR (67.5 MHz) d 28.3 (CH2), 30.8
(CH2), 33.1 (CH2), 35.4 (CH2), 57.5 (CH), 72.8 (CH2),
102.3 (C-7a), 115.0 (CH2), 125.4 (2£CH), 127.4 (CH),
128.6 (2£CH), 137.2 (CH), 140.0 (C) and 179.3 (CvO);
MS m/z 257 (Mþ, 4%), 202 (M2C4H7, 100), 120 (18), 103
(13), 91 (11) and 55 (12).
3.2.2. (3R,7aS)-7a-(Pent-4-enyl)-3-phenyl-2,3,7,7a-tetra-
hydropyrrolo[2,1-b]oxazol-5(6H)-one 10. From 5-bromo-
1-pentene (1.09 g, 7.3 mmol) and (R)-N-(2-hydroxy-1-
phenylethyl)succinimide 6 (0.40 g, 1.8 mmol); the hydroxy
lactam 8 treated with TFA (2.08 g, 18.3 mmol). Bicyclic
oxylactam 10 was obtained (278 mg, 56%) as a viscous oil
(HREIMS found Mþ 271.1575. C17H21NO2 requires M
271.1572); 1H NMR (270 MHz) d 1.41–1.75 (4H, m,
2£CH2), 1.90–2.07 (2H, m, CH2), 2.17 (1H, dt, J¼13.5,
10.2 Hz), 2.36 (1H, ddd, J¼13.2, 9.9, 2.6 Hz), 2.59 (1H,
ddd, J¼17.2, 10.2, 2.6 Hz), 2.83 (1H, dt, J¼17.2, 10.2 Hz),
4.08 (1H, dd, J¼8.6, 7.3 Hz), 4.62 (1H, t, J¼8.6 Hz), 4.90–
4.99 (2H, m, CHvCH2), 5.18 (1H, t, J¼7.6 Hz), 5.71 (1H,
ddt, J¼17.2, 13.2, 6.6 Hz, CHvCH2) and 7.21–7.38 (5H,
m, aryl H); 13C NMR (67.5 MHz) d 23.6 (CH2), 31.3 (CH2),
33.6 (CH2), 33.8 (CH2), 36.0 (CH2), 57.8 (CH), 73.1 (CH2),
102.9 (C-7a), 115.4 (CH2), 115.4 (CH), 125.8 (2£CH),
127.7 (CH), 129.0 (2£CH), 138.2 (CH), 140.4 (C) and 179.6
(CvO); MS m/z 271 (Mþ, 2%), 102 (M2C5H9, 100), 120
(14) and 55 (10).
3.3. Spiro lactams 11a,b, 14a,b, 15a,b and 26a,b. General
procedure for cyclisation in formic acid
The hydroxy lactam in freshly distilled formic acid was
allowed to stand at room temperature or heated under reflux
until reaction was complete (tlc). The solvent was
evaporated in vacuo and the residue redissolved in chloro-
form, which was washed with aqueous sodium bicarbonate
solution, then with water, dried (MgSO4), and evaporated to
dryness. The crude product was chromatographed on silica
with ethyl acetate/chloroform (1:4 v/v) as eluent.
3.2.3. (3R,9bS)-9b-(But-3-enyl)-3-phenyl-2,3,5,9b-tetra-
hydrooxazolo[2,3-a]isoindol-5-one 19. TFA (195 mg,
1.7 mmol) was added to hydroxy lactam 17a (275 mg,
0.85 mmol) in DCM (25 mL) at 0 8C. After the usual work
up and chromatography, as above, tricyclic lactam 19 was
obtained (200 mg, 74%) as a viscous oil (HREIMS found
3.3.1. (aR,3S,spiroS)- and (aR,3R,spiroR)-3-Hydroxy-10-
(2-hydroxy-1-phenylethyl) spiro[cyclohexane-1,20-pyr-
rolidin]-50-ones 15a,b and diformates 14a,b; (aR,
spiroS)- and (aR,spiroR)-10-(2-formyloxy-1-phenyl-
ethyl)spiro[cyclohex-3-ene-1,20-pyrrolidin]-50-ones 13.
From bicyclic lactam 10 (223 mg, 0.82 mmol) in formic
acid (10 mL) 10 h at room temperature. First material eluted
M
þ 305.1419. C20H19NO2 requires M 305.1416); 1H NMR
(270 MHz) d 1.61–1.74 (1H, m), 1.99–2.24 (3H, m), 4.42

1252
A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1247–1253
from the column was a mixture of spirocyclohexene
diastereoisomers 13 (17 mg, 7%) as a viscous oil (HREIMS
found Mþ 299.1527. C18H21NO3 requires M 299.1521); 1H
NMR (270 MHz) d 1.24–2.62 (10H, m), 4.33–4.43 (3H,
m), 5.65 (2H, m), 7.23–7.48 (5H, m, aryl H), 8.01 (1H, s,
CHO) and l8.09 (1H, s, CHO)l; 13C NMR (67.5 MHz) d
23.1 (CH2), l23.2 (CH2)l, 29.6 (CH2), l29.7 (CH2)l, 29.8
(CH2), l30.1 (CH2)l, l31.2 (CH2)l, 32.8 (CH2), 32.9 (CH2),
l33.0 (CH2)l, l56.6 (CH)l, 60.5 (CH), l64.0 (CH2)l, l64.8
(spiro C)l, 65.0 (CH2), 65.4 (spiro C), 124.5 (CH), 124.6
(CH), 126.6 (CH), 126.7 (CH), 127.2 (CH), 127.5 (CH),
127.9 (CH), 128.0 (CH), 128.6 (CH), 128.8 (CH), l138.5
(C)l, 138.9 (C), l160.9 (CHO)l, 163.0 (CHO), l176.7 (lactam
CvO)l and 177.7 (lactam CvO); MS m/z 299 (Mþ, 36%),
253 (M2HCO2H, 10), 245 (64), 240 (M2CH2OCHO, 47),
200 (60), 186 (30), 148 (25), 121 (58), 106 (74), 98 (100), 91
(73) and 77 (60). Later column fractions afforded a mixture
of spiro lactams 14a,b (220 mg, 78%, 4:1 ratio) as a viscous
oil (HREIMS found Mþ 345.1579. C19H23NO5 requires M
signals d 20.0 (CH2), 29.7 (CH2), 31.7 (CH2), 45.5 (CH2),
59.5 (CH), 64.0 (CH2), 66.6 (CH), 126.9 (CH), 138.3 (C)
and 178.0 (CvO).
3.3.2. (aR,3S,spiroR)- and (aR,3R,spiroS)-3-Formyloxy-
20-(2-formyloxy-1-phenylethyl)-20,30-dihydrospiro[cyclo-
hexane-1,10-isoindol]-30-ones 26a,b. Tricyclic oxylactam
20 (287 mg, 0.90 mmol) was dissolved in formic acid
(10 mL) and stirred at room temperature for 32 h. After
work up and chromatography, as above, a first fraction was
obtained (93 mg, 32%) of viscous oil which was the 3-(pent-
4-enylidene)isoindolin-1-one 23 admixed with other com-
ponent(s) (HREIMS found Mþ 347.1516. C22H21NO3
1
requires M 347.1521); H NMR (270 MHz) d 1.81–2.69
(4H, m, 2£CH2), 4.77–5.45 (5H, m, 2£CvCH and
PhCHCH2O), 5.64–5.90 (2H, m, CHvCH2), 7.28–7.94
(9H, m, aryl H) and 8.03 (1H, s, CHO); 13C NMR
(67.5 MHz) d 26.5 (CH2), 33.7 (CH2), 53.5 (CH), 62.5
(CH2), 113.4 (CH), 115.8 (CH2), 123.4 (CH), 123.6 (CH),
126.9 (2£CH), 127.9 (CH), 128.7 (CH), 128.8 (2£CH),
132.2 (CH), 137.0 (C), 138.2 (C), 160.6 (CHO) and 167.2
(lactam CvO); MS m/z 347 (Mþ, 47%), 306 (M2C3H5,
54), 293 (30), 288 (30), 249 (40), 236 (100), 234 (28),158
(82), 149 (32), 130 (33), 121 (66), 103 (66), 91 (42) and 77
(50). Additional weaker 13C NMR signals attributable to the
isomeric spiro enelactam 25: d 24.0 (CH2), 30.6 (CH2), 32.8
(CH2), l53.4 (CH)l, 56.4 (CH), l61.7 (CH2)l, 64.1 (CH2),
64.7 (C), 122.6 (CH), 123.5 (CH), 125.2 (CH), 127.0 (CH),
127.6 (CH), 128.1 (CH), 128.2 (CH), 128.6 (CH), 129.7
(CH), 131.8 (CH), 133.9 (C), 134.2 (CH), 135.5 (C), 136.5
(C), 137.0 (CH), 138.0 (C), l138.4 (C)l, 150.3 (C), 160.3
(CHO), l160.9 (CHO)l, l168.1 (lactam CvO)l and 168.9
(lactam CvO).
1
345.1576); H NMR (270 MHz) d 1.22–2.19 (10H, m),
2.35–2.60 (2H, m), 4.44 (1H, dd, J¼9.3, 6.0 Hz), 4.71 (1H,
dd, J¼11.0, 5.8 Hz), 4.92 (1H, tt, J¼11.0, 4.6 Hz), 5.18 (1H,
apparent td, J¼9.7, 2.8 Hz), 7.28–7.37 (3H, m, aryl H), 7.48
(2H, d J¼7.7 Hz, aryl H), l7.90 (s, CHOl, 8.03 and 8.07
(each 1H, s, CHO); 13C NMR (67.5 MHz) d 19.9 (CH2),
l20.5 (CH2)l, 30.3 (CH2), l30.5 (CH2)l, 31.1 (CH2), l32.9
(CH2)l, 36.5 (CH2), 39.5 (CH2), l42.9 (CH2)l, l56.7 (CH)l,
56.8 (CH), 64.1 (CH2), l64.2 (CH2)l, 65.9 (spiro C), l70.1
(CH)l, 70.7 (CH), 128.3 (2£CH), 128.5 (CH), 129.2
(2£CH), l129.3 (CH)l, l138.5 (C)l, 138.7 (C), l160.8
(CHO)l, 160.9 (CHO), 161.3 (CHO), l161.4 (CH)l, l176.0
(lactam CvO)l and 176.1 (lactam CvO); MS m/z 345 (Mþ,
7%), 300 (48), 299 (M2HCO2H, 57), 286 (M2CH2OCHO,
73), 198 (28), 152 (40), 121 (62), 106 (100), 103 (51), 91
(47) and 77 (34).
Further elution afforded the spiro lactams 26a,b (165 mg,
47%, 4:1 ratio) as a viscous oil (HREIMS found Mþ
393.1573. C23H23NO5 requires M 393.1576); 1H NMR
(270 MHz) d 1.35–2.33 (8H, m), 4.81–4.91 (2H, m), 5.40–
5.56 (2H, m), 7.28–8.09 (9H, m, aryl H), 8.02, 8.05 land
8.09l (each 1H, s, CHO); 13C NMR (67.5 MHz) dl18.5
(CH2)l, 19.9 (CH2)l, 30.2 (CH2), l32.7 (CH2)l, 32.8 (CH2),
l38.6 (CH2)l, 38.7 (CH2), l55.9 (CH)l, 56.0 (CH), 63.8
(CH2), l64.0 (CH2)l, l66.2 (spiro C)l, 67.0 (spiro C), l69.1
(CH)l, 69.2 (CH), 122.9 (CH), 124.1 (CH), 127.5 (CH),
127.6 (2£CH), 127.9 (CH), 128.4 (CH), 128.6 (2£CH),
l130.9 (C)l, 131.1 (C), l131.5 (CH)l,131.7 (CH), l137.4 (C)l,
137.6 (C), 149.1 (C), l150.1 (C)l, l160.0 (CHO)l, 160.1
(CHO), 160.8 (CHO), l160.9 (CHO)l, 168.3 (lactam CvO)
and l168.6 (lactam CvO)l; MS m/z 393 (Mþ, 1%),
347 (M2HCO2H, 36), 334 (M2CH2OCHO, 100), 246
(22), 200 (12), 183 (42), 165 (21), 103 (25), 91 (27) and 77
(18).
The mixture of diformates 14a,b (178 mg) was added to
potassium hydroxide (0.33 g) dissolved in water (3 mL) and
ethanol (3 mL) and stirred at room temperature for 8 h. The
solution was acidified by addition of dilute hydrochloric
acid and extracted several times with chloroform. The
combined organic extract was washed, dried (MgSO4), and
the solvent evaporated in vacuo. The crude product was a
mixture of the spiro lactam diols 15a,b (4:1 ratio from 13C
NMR spectrum). The first crop obtained after fractional
crystallisation was diol 15a (85 mg), mp 226–228 8C (from
ethanol) (HREIMS found Mþ 289.1672. C17H23NO3
requires M 289.1678. Found M2CH2O 259.1570.
C16H21NO2 requires 259.1572); 1H NMR (270 MHz)
(CHCl3-d/MeOH-d4) d 1.06–1.96 (9H, m), 2.10 (1H, ddd,
J¼12.9, 8.9, 4.5 Hz), 2.40–2.60 (2H, m), 3.61–3.71 (1H,
m), 3.91–4.00 (1H, m), 4.08 (2H, s, OH, exchanged with
MeOH-d4), 4.34–4.45 (2H, m) and 7.23–7.40 (5H, m, aryl
H); 13C NMR (67.5 MHz) d 19.4 (CH2), 29.6 (CH2), 29.9
(CH2), 33.7 (CH2), 35.5 (CH2), 42.0 (CH2), 59.6 (CH), 63.8
(CH2), 66.6 (spiro C), 67.2 (CH), 127.0 (2£CH), 127.1
(CH), 128.2 (2£CH), 138.5 (C) and 176.9 (CvO); MS m/z
289 (Mþ, ,1%), 259 (M2CH2O, 75), 258
(M2CH2OH,73), 216 (13), 170 (36), 106 (100) and 91
(32). The sample of diol 15a submitted to X-ray analysis
was further recrystallised from hexane/ethyl acetate. The
second crop of crystals (27 mg) from ethanol was relatively
enriched in diol 15b, which showed additional 13C NMR
3.3.3. (aR,3S,spiroS)- and (aR,3R,spiroR)-3-Chloro-10-
(2-hydroxy-1-phenylethyl)spiro [cyclohexane-1,20-pyr-
rolidin]-50-ones 11a,b. Bicyclic oxylactam 10 (0.19 g,
0.70 mmol) in 1,2-dichloroethane (10 mL) was added with
stirring to a cold (25 8C) solution of aluminium trichloride
(0.28 g) in 1,2-dichloroethane (10 mL). Cooling and stirring
were maintained for 4 h, after which the mixture was poured
onto ice, acidified with dilute sulfuric acid, and extracted
with chloroform. The extract was washed with saturated
sodium bicarbonate solution and with water, dried

A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1247–1253
1253
(MgSO4), and the solvent evaporated in vacuo. The residue
Acknowledgements
was chromatographed on silica, and products eluted with
ethyl acetate/chloroform (1:1 v/v). The 6,5-spiro lactam
11a,b was obtained as an oil (97 mg, 45%, ca 3:1 ratio),
Grateful acknowledgement is made of an ORS award to
A. A. B.
1
containing a small amount of the 5,5-spiro lactam 12; H
NMR (270 MHz) d 1.06–2.31 (10H, m), 2.48–2.57 (2H,
m), 3.74 (1H, tt, J¼11.4, 4.3 Hz, CHCl), 3.92–4.03 (1H, m,
PhCH), 4.29–4.46 (2H, m, CH2OH) overlapping 4.54 (1H,
br s, OH), and 7.25–7.36 (5H, m, aryl H); 13C NMR
(67.5 MHz) d 26.9 (CH2), 29.3 (CH2), l29.4 (CH2)l, 29.7
(CH2), 30.2 (CH2), 31.0 (CH2), l32.8 (CH2)l, l33.1 (CH2)l,
33.7 (CH2), l57.1 (CHCl)l, 57.3 (CHCl), l60.0 (CH)l, 60.1
(CH), l64.8 (C)l, 65.1 (CH2), l65.4 (C)l, 65.5 (CH2), 127.1
(CH), 127.2 (2£CH), l127.3 (CH)l, 128.4 (2£CH), l128.5
(CH)l, l138.7 (C)l, 139.0 (C), 176.6 CvO) and l176.7
(CvO)l; MS m/z 307 (Mþ, ,1%), 279, 277 (M2CH2O, 14,
43), 278, 276 (M2CH2OH, 24, 56), 242 (33), 200 (18), 188
(29), 120 (16), 106 (100) and 91 (29). Additional, weaker
13C NMR signals attributed to 12 d 32.3, 32.5, 33.0, 35.8,
42.3, 43.2, 47.2, 55.1, 65.3, 77.2 (spiro C), 126.9, 127.4,
138.6 and 171.2 (CvO).
References and notes
1. Bahajaj, A. A.; Moore, M. H.; Vernon, J. M. Tetrahedron
2004, 60, 1235–1246.
2. (a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47,
9503–9569, and references therein. (b) Meyers, A. I. In
Stereocontrolled organic synthesis; Trost, B. M., Ed.;
Blackwell Scientific: Oxford, 1994; pp 145–161. (c) Meyers,
A. I.; Brengel, G. P. J. Chem. Soc., Chem. Commun. 1997,
1–8.
3. (a) Schoemaker, H. E.; Speckamp, W. N. Tetrahedron Lett.
1978, 1515. (b) Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron 1980, 36, 951.
4. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
5. Schoemaker, H. E.; Kruk, C.; Speckamp, W. N. Tetrahedron
Lett. 1979, 2437.
3.4. Crystallographic structure determinations
6. Inoue, Y.; Tazawa, N.; Watanabe, A.; Aoki, Y.; Kakisawa, H.
Bull. Chem. Soc. Jpn 1992, 65, 2866–2868.
X-ray analysis of 15a and 17a was carried out on a Rigaku
AFC6S four-circle diffractometer with graphite-mono-
chromated Mo Ka radiation, l¼0.710.70 at 20 8C. The
structures were solved by direct methods using SHELX-76
and refined on F 2 using SHELXL.
7. Sun, P.; Sun, C.; Weinreb, S. M. Org. Lett. 2001, 3,
3507–3510.
8. Abe, H.; Aoyagi, S.; Kibayashi, C. Angew. Chem. Intl Ed.
2002, 41, 3017–3020.
9. Ito, T.; Yamazaki, N.; Kibayashi, C. Synlett 2001, 1506–1509.
10. (a) Meyers, A. I.; Burgess, L. E. J. Org. Chem. 1991, 56,
2294–2296. (b) Burgess, L. E.; Meyers, A. I. J. Am. Chem.
Soc. 1991, 113, 9858–9859. (c) Burgess, L. E.; Meyers, A. I.
J. Org. Chem. 1992, 57, 1656–1662.
3.4.1. Crystal data for 15a.13 C17H23NO3, M¼289.36 The
crystal size was 0.50£0.50£0.40 mm; monoclinic, space
group C2, with unit cell a¼16.402(3), b¼8.955(7),
3
˚
˚
c¼10.899 4(1) A, b¼103.518, V¼1556.7(12) A , Z¼4,
Dc¼1.269 g cm21 1521 reflections were collected in the
range 5,2u,508, of which 1465 were independent
(Rint¼0.0170). Full matrix least squares refinement on F 2
with 192 parameters for 1465 reflections with I.2sI gave
final values of R1¼0.0349 and wR2¼0.0892.
11. Lochead, A. W.; Proctor, G. R.; Caton, M. P. L. J. Chem. Soc.,
Perkin Trans. 1 1984, 2477.
12. Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z.
Tetrahedron Lett. 1997, 38, 3627–3630.
13. Crystallographic data for compounds 15a and 17a have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 213792 and
213791, respectively. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (Fax: þ44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
3.4.2. Crystal data for 17a.13 C20H21NO3, M¼323.38 The
crystal size was 0.30£0.10£0.05 mm; orthorhombic, space
group P212121, with unit cell a¼25.502(6), b¼8.1085(1),
3
21
˚
˚
c¼8.708(2) A, V¼1800.6(6) A , Z¼4, Dc¼1.193 g cm
2769 reflections were collected in the range 5,2u,558, of
which 2343 were independent (Rint¼0.0081). Full matrix
least squares refinement on F 2 with 220 parameters for
2337 reflections with I.2sI gave final values of R1¼0.0318
and wR2¼0.0820.