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

Article abstract of DOI:10.1016/j.tet.2003.10.128

A series of chiral non-racemic 5,5- and 5,6-bicyclic lactams is prepared from (R)-phenylglycinol. These are isomerised on treatment with aluminium trichloride in 1,2-dichloroethane to give spiro lactams in high yield and >3:1 diastereoselectivity. From four structures determined by X-ray crystallography, it follows that spiro indenes are formed preferentially with retention of configuration at the spiro carbon atom and spiro naphthalenes with inversion.

Full text of DOI:10.1016/j.tet.2003.10.128

Tetrahedron 60 (2004) 1235–1246
Asymmetric synthesis of spiro 2-pyrrolidin-5-ones,
2-piperidin-6-ones and 1-isoindolin-3-ones. Part 1:
N-Acyliminium ion cyclisations with an internal arene nucleophile
*
Abood A. Bahajaj, Madeleine H. Moore and John M. Vernon
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 23 July 2003; revised 20 October 2003; accepted 24 October 2003
Abstract—A series of chiral non-racemic 5,5- and 5,6-bicyclic lactams is prepared from (R)-phenylglycinol. These are isomerised on
treatment with aluminium trichloride in 1,2-dichloroethane to give spiro lactams in high yield and .3:1 diastereoselectivity. From four
structures determined by X-ray crystallography, it follows that spiro indenes are formed preferentially with retention of configuration at the
spiro carbon atom and spiro naphthalenes with inversion.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2.1. Bicyclic lactam precursors
Spiro lactam structures result from the intramolecular
reaction of cyclic N-acyliminium ion intermediates with
an alkene nucleophile tethered to the iminium carbon
atom.1 – 6 We have reported similar cyclisations, for
example 1!4, involving an arene nucleophile.7 Two other
examples are known in the context of a thiolium/
N-acyliminium ion tandem cyclisation sequence.8 Our
first attempts to achieve diastereoselective cyclisation
by the same route were unsuccessful, because the
chiral N-1-phenylethyl group was too easily lost under
the acidic conditions required for formation of the
iminium ion 2, and most of the cyclised product was
racemic debenzylated spiro lactam 5.7 We describe
herein9 how this problem was overcome and
diastereoselective spiro cyclisation of 3 achieved by the
use of a chiral N-substituent derived from (R)-phenyl-
glycinol.
Bicyclic oxylactams based on structures 6 and 7 have been
widely employed in asymmetric synthesis of tertiary and
quaternary carbon centres;10 in particular, the synthesis of
pyrrolidines from 6 and piperidines from 7,11,12 and
similarly of 3-substituted isoindolinones from 8.13 Similar
bicyclic lactams incorporating the requisite v-arylalkyl
substituent at the ring junction position are appropriate
precursors for generation of N-acyliminium ions 3 and
cyclisation to spiro lactams.14 Indeed, the same method-
ology has been employed before with alkene nucleophiles
(as in Scheme 1),5 but without any diastereoselection
for configuration at the resulting spiro carbon atom.
Accordingly, we prepared a series of bicyclic lactams
starting from ketoacids 9–12 by condensation with
(R)-phenylglycinol or, for 17, with (S)-valinol.
Keywords: Diastereoselective; N-Acyliminium ions; Spiro lactams.
*
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.2003.10.128

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A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
Scheme 1. Reagents: (i) TiCl4, DCM, 20 8C (ii) H2/Pd-C, EtOH; (iii) Bu3SnH, AIBN; (iv) Na, NH3, EtOH, 278 8C.
in ca. 84:16 ratio (from 13C NMR spectra), in accordance
with literature precedents.10,12 The major diastereoisomer is
19a or 20a, although the greater conformational flexibility
of the 6-membered lactam ring (in comparison with that in
15 and 16) can accommodate a 3-substituent on the endo
face of the bicyclic system in the minor isomer 19b or 20b.
The mixed stereochemistry at the 8a-position is of no
consequence because the N-acyliminium ion intermediate in
the ensuing cyclisation step is planar at this position and the
diastereoselectivity of formation of the ultimate spiro lactam
products does not depend upon the stereochemistry of the
precursor bicyclic lactams.
The corresponding ketoacids 13 and 14 required for the
preparation of tricyclic lactams 25 and 26 were made by
Grignard addition to phthalic anhydride, but they were
imperfectly purified by column chromatography, so the
alternative route via the phthalimide 22 was preferable.
Grignard addition to 22 afforded the 3-hydroxyisoindolin-
ones 23 and 24 as single diastereoisomers after chroma-
tography (Scheme 3). Our assignment of (R)-configuration
to C-3 in these products is based on X-ray crystallographic
results for the related adduct of 3-butenyl Grignard reagent
and 22 described in the accompanying paper.15 However,
the C-3 stereochemistry in 23 and 24 is unimportant,
because subsequent acid-catalysed steps involve inter-
mediates in which this position becomes planar and give
rise to end-products with either (R)- or (S)-configuration at
this centre.
Bicyclic lactams 15–17 were obtained in 52–75% yields, in
each case as a single diastereoisomer with the substituent at
the ring junction 7a-position cis to phenyl (or isopropyl) at
the 3-position. This assignment of stereochemistry follows
numerous precedents in Meyers’s work,10,11 and the folded
shape of the 5,5-fused bicyclic system would be severely
strained by a 3-substituent on the inside (endo) face.
Bicyclic lactams 15 and 16 were also obtained by the
alternative route via imide 21 shown in Scheme 2, but in
only ca. 21% overall yield from (R)-phenylglycinol. The
first route from ketoacids represents more efficient use of
phenylglycinol.
Treatment of 23 with trifluoroacetic acid (TFA) in
dichloromethane (DCM) at 0 8C afforded a mixture of
tricyclic lactam 25 and isomeric enamide 27. Similarly, 24
afforded a mixture of 26 and 28, which were separated by
chromatography. It was noted that decreasing the quantity
of TFA resulted in a higher ratio of 26:28, although the
highest yield (of both products) was obtained from 24 using
a 10-fold excess of TFA (Table 1). Also, partial inter-
conversion of 26 and 28, and similarly of 25 and 27,
occurred in the presence of TFA in DCM. Tricyclic lactams
25 and 26 were obtained as single diastereoisomers, in
which C-9b must have the (S)-configuration shown for the
The 5,6-fused bicyclic lactams 19 and 20 were obtained in
72% yield as inseparable mixtures of two diastereoisomers
Scheme 2. Reagents: (i) (R)-HOCH2CH(Ph)NH2, PhMe, reflux; then Et3N, reflux; (ii) Ph(CH2)nMgBr, THF, 0 8C; (iii) TFA, DCM, 0 8C.

A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
1237
Scheme 3. Reagents: (i) Ph(CH2)nMgBr, THF, 0 8C; (ii) TFA, DCM, 0 8C.
Table 1. Effect of TFA on product distribution, 26 and 28
products 29a and b, which were cleanly separated by
column chromatography. The optimum conditions were
found to be a 1:3 mole ratio of 15 to aluminium trichloride
in DCE at 25 8C, from which 29a and b were isolated in
93% yield and 78:22 ratio. This ratio appears to be the result
of kinetic control, because the minor isomer survived
treatment again with AlCl3 in DCE and no interconversion
to 29a occurred. Both spiro products showed IR absorption
for OH (absent in 15) and 13C NMR absorptions for the
spiro carbon and for an additional unprotonated aromatic
carbon in comparison with the spectra of 15. The major
isomer was more polar, eluting second in chromatography.
Its structure was confirmed as 29a by single crystal X-ray
analysis.9 The minor isomer is therefore 29b.
Mole ratio 24:TFA
Yield 26
(%)
Yield 28
(%)
Total yield
(%)
Ratio 26:28
1:30
1:20
1:10
1:2
18.1
38.4
48.5
77.5
78.5
53.5
45.2
40.7
3.5
71.6
83.6
89.2
81.0
82.7
25:75
46:54
53:47
96:4
1:1
4.2
95:5
same reasons discussed previously and following the
precedent of 8.13 Subsequent conversion into spiro lactams
was pursued only with the lactams 25 and 26, although in
principle the enamides could also have been used as
precursors for the same N-acyliminium ion intermediates
and for spiro cyclisation.
Bicyclic lactam 19 (in this case a mixture of 19a and b) was
unreactive under the same reaction conditions used for
cyclisation of 15. 6-Membered lactams such as 7 are also
less reactive than 5-membered lactams 6 in metalation and
alkylation reactions.10 However, by using a 1:4 mole ratio of
19 and AlCl3 in DCE at room temperature, cyclisation to the
spiro lactams 30a and b was achieved in 88% yield. The
major isomer was again the slower running component in
chromatography. Single crystal X-ray analysis confirmed
the spiro structure with the relative configuration shown in
Figure 1. As the side chain chiral centre is derived from
(R)-phenylglycinol, the spiro carbon is (S)-configuration
and the structure is as drawn in 30a. This is entirely
consistent with the formation of 29a as the major product
2.2. Cyclisation to spiro lactams
In our previous work, involving the synthesis of spiro
lactams,16 we have used TFA or polyphosphoric acid to
achieve the spiro cyclisation step. However, when bicyclic
lactam 15 was heated in TFA under reflux for 3 h, it was
incompletely converted into a new product, subsequently
identified as the spiro lactam 29a, which was isolated in
only 11% yield. On the other hand, treatment of 15 with
aluminium trichloride in either dichloromethane or
1,2-dichloroethane (DCE) at room temperature or below
resulted in high conversion into two diastereoisomeric spiro

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A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
from 15; in both 29a and 30a the new bond to the spiro
centre is formed by phenyl from the Ph(CH2)n group
replacing oxygen of the oxazolidine ring with retention of
configuration.
and 30a are characterised by intermolecular hydrogen
bonding. The chemical shift of the spiro carbon atom varied
with the size of rings, in line with previous observations,2
but the differences between the chemical shift values for
diastereoisomeric pairs were always small and did not
correlate reliably with the stereochemistry as deduced from
comparisons of chromatographic behaviour (Table 2). On
the other hand, comparisons of 1H NMR spectra were
informative in two respects. The position of the OH
resonance differed in most cases by almost 1 ppm between
diastereoisomeric pairs, with the resonance for the less polar
(intramolecularly hydrogen bonded) compound being
always at lower field. In the spectrum of one compound in
each pair, which was always the less polar component and
the one to which we have assigned stereochemistry
involving retention of configuration in forming the spiro
centre, signals for two aromatic hydrogens are deshielded,
with a complex splitting pattern. These signals are assigned
to (one each) ortho and meta hydrogens of the side chain
phenyl group, which is consistent with the absence of
corresponding signals in the spectra of either isomeric spiro
lactam 35a and b derived from (S)-valinol (vide infra).
For the corresponding spiro lactam products 31a and b and
32a and b obtained in the same way from bicyclic lactams
16 and 20, respectively, the diastereoisomer ratio was about
the same as before, between 3:1 and 4:1, but the major
isomer was now the less polar component in each case.
X-Ray diffraction by a single crystal of the major isomer
from 20 proved the structure is 32b.9 The minor isomer is
therefore 32a, and the minor and major products from 16 are
assigned the structures 31a and b, respectively. Formation
of the 6-membered carbocyclic ring in 31 and 32 has
occurred prefentially with inversion of configuration at the
spiro carbon in relation to that in the precursor bicyclic
lactams 16 and 20.
Although conformations in solution are not necessarily the
same as those seen in the solid state, it is noteworthy that
crystal structures of the less polar products 32b and 35b
(vide infra) both show intramolecular hydrogen bonding,
whereas crystal structures of the more polar products 29a
For spiro cyclisation of the phthalimide-derived tricyclic
lactams 24 and 25, the diastereoselectivity was low.
Nevertheless, using comparisons of chromatographic beha-
viour between diastereoisomeric products, we are able to
determine which product has which structure. The major
product of the pair 33a and b (with the 5,5-spiro ring
system) was the more polar component and its structure is
therefore 33a (formed with retention of configuration at the
spiro centre). Conversely, the major product of the pair 34a
and b (with the 6,5-spiro ring system) was the less polar
component and its structure is therefore, 34b (formed with
inversion of configuration at the spiro carbon). These
assignments are also consistent with differences between 1H
NMR spectra of diastereoisomeric product pairs in respect
of both criteria (OH resonance and deshielded aromatic
hydrogen resonances, see Table 2) discussed above.
Bicyclic lactams 6 react with nucleophiles at the
7a-position, with opening of the oxazolidine ring. The
stereoselectivity of these reactions depends on several
factors. Reduction of 6 (R¼Pr, Bu, Ph, PhCH2) by alane or
by triethylsilane catalysed by TiCl4 gives pyrrolidines 36
or pyrrolidinones 37 with high diastereoselectivity, the
result of retention of configuration.11 On the other hand,
reaction of 6 (R¼H) with allyltrimethylsilane in the
presence of TiCl4 gives predominantly 37 (R¼allyl) by
inversion of configuration; allylation of 6 (R¼Me) gives a
similar result, with inversion preferred over retention by a
Figure 1. ORTEP drawing of the crystal structure of spiro lactam 30a with
crystallographic numbering scheme (hydrogen atoms omitted).

A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
Table 2. Comparisons between spiro lactam products
1239
Compound
Ring sizea
Relative polarity
Yield (%)
d spiro C
d OH
d aryl H
29a
29b
30a
30b
31a
31b
32a
32b
33a
33b
34a
34b
35a
35b
5,5
5,5
6,5
6,5
5,6
5,6
6,6
6,6
5,5
5,5
5,6
5,6
5,5
5,5
More
Less
More
Less
More
Less
More
Less
More
Less
More
Less
More
Less
72.6
19.9
67.3
21.2
18.3c
72.1c
24.9
74.3
43.0
32.0
33.5
41.5
64.2
22.4
77.5
77.3
74.7
74.3
69.5
69.6
66.2
66.4
78.4
78.4
68.3
70.1
76.2
76.2
4.3
4.9
4.1b
5.1
4.3b
5.2
4.2b
5.1
4.4
5.0
4.1
5.3
4.5
5.0
6.5–7.2
7.1–7.5
6.5–7.3
7.1–7.3
6.4–7.3
7.1–7.4
6.4–7.3
7.0–7.5
6.1–7.8
6.8–8.0
6.1–7.9
6.8–8.0
7.3 (s)
7.3 (s)
a
Lactam, carbocycle.
OH signal overlapped by signals for CHCH2OH between d 3.9–4.4.
Yields 19.8 and 78.4%, respectively, corrected for recovery of 8% unreacted 16.
b
c
factor of 10.11 However, this stereoselectivity is reversed
by a bulkier 3-substituent; for example, for allylation of
18 the diastereoisomer ratio is 1:2 for pyrrolidinones formed
by inversion or retention, respectively.
restricted. We have modelled the cyclisation step, assuming
that the oxazolidine ring is opened to give an N-acyliminium
ion intermediate 38, in which the conformation of the
N-substituent is ordered through the CvO group coordinat-
ing to aluminium. This confirms that cyclisation with
retention of configuration to form a 5-membered ring is
preferred, in agreement with our experimental findings,
but the model does not indicate a clear preference for
inversion vs. retention of configuration for formation of a
6-membered ring.
In the light of Meyers’s results, we changed the 3-phenyl
group in 15 for isopropyl in 17 to see what effect, if any, this
might have on the diastereoselectivity of cyclisation to spiro
lactams. Rearrangement of 17 catalysed by AlCl3 afforded a
3:1 mixture of diastereoisomeric spiro lactams 35a and b, in
which the more polar (slower running) component was the
major isomer 35a. The crystal structure of the minor isomer
35b was determined by X-ray analysis (Fig. 2), which shows
the same intramolecular hydrogen bond and inversion of
configuration at the spiro centre as in 32b. In this system,
in contrast to that studied by Meyers,11 the change of
3-substituent has almost no effect on the diastereo-
selectivity. This may be attributable to the fact that, for
the internal nucleophile involved in spiro cyclisation, the
freedom of movement to approach the reaction centre is
A further variation in the substitution pattern of the
oxazolidine ring of the bicyclic lactam precursors led to
an unexpected result. The bicyclic lactam 39 was prepared
from (1R,2S)-norephedrine and keto acid 9. (1H and 13C
Figure 2. ORTEP drawing of the crystal structure of spiro lactam 35b with
crystallographic numbering scheme (hydrogen atoms omitted).

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A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
NMR spectra of 39 indicated the presence of 3% of the
7a-epimer.) We expected 39 to be cyclised to spiro lactam
40, the major product being the result of retention of
configuration as for all the other spiro indenes. However, the
product obtained in 44% yield from treatment of 39 with
was continued for 3 h. The mixture was poured into dilute
sulfuric acid and extracted with ether. The ether extract was
extracted with saturated aqueous NaHCO3. The aqueous
layer was reacidifed with dilute sulfuric acid and extracted
with chloroform. The chloroform extract was dried with
MgSO4, filtered, and the solvent evaporated. The residue
was purified by chromatography on silica. 6-Phenyl-4-
oxohexanoic acid 9 thereby obtained from 2-phenylethyl
magnesium bromide and succinic anhydride; mp 88–89 8C
(from toluene–light petroleum) (lit.18 89 8C). 7-Phenyl-4-
oxoheptanoic acid 10 from 3-phenylpropyl magnesium
bromide and succinic anhydride, 7-phenyl-5-oxoheptanoic
acid 11 from 2-phenylethyl magnesium bromide and
glutaric anhydride, and 8-phenyl-5-oxooctanoic acid 12
from 3-phenylpropyl magnesium bromide and glutaric
anhydride were all oils, with IR, 1H NMR and mass spectra
consistent with the structures assigned.
1
AlCl3 showed no IR or H NMR absorption for an OH
group, and the 13C NMR spectrum included signals for four
(instead of three) substituted aromatic carbons as well as
for the quaternary spiro carbon. The tetracyclic structure 41
for this product is compatible with all the spectroscopic
evidence. The spiro carbon must have the (S)-configuration
(from 40) and C-5 must have the (S)-configuration (from
norephedrine), but the configuration at the benzylic position
(C-6) is apparently inverted in the process of intramolecular
Friedel–Crafts substitution in 40 catalysed by AlCl3. A
Dreiding model of structure 41 shows a conformationally
rigid piperidine ring with the methyl group in a pseudo-axial
position. With the phenyl group also pseudo-axial, the
dihedral angle between bonds to H-5 and H-6 is ca. 608 and
the bonds to H-6 and H-7 are nearly coplanar. This accounts
for the small coupling constant (J¼1.7 Hz) between H-5 and
H-6 and for the strong NOE interactions observed between
H-5 and H-6 and between H-6 and H-7.
3.2. General procedure for bicyclic lactams obtained via
keto acids
Equimolar quantities of the appropriate keto acid and
(R)-(2)-phenylglycinol were dissolved in toluene and
heated under reflux for 22–24 h in a Dean–Stark apparatus
for azeotropic removal of water. The solution was cooled
and toluene removed by evaporation in vacuo. The residue
was chromatographed on silica, from which the bicyclic
lactam product was eluted with ethyl acetate–chloroform
(1:4 v/v).
In conclusion, our results demonstrate the efficient forma-
tion of a range of spiro lactams by intramolecular reaction of
N-acyliminium ion intermediates with a tethered arene
nucleophile. Stereochemistry, established by X-ray analysis
of four spiro lactams, has been correlated with comparisons
of chromatographic behaviour and spectroscopic properties
between pairs of diastereoisomeric products. Although the
diastereoselectivity is only ca. 3:1, diastereoisomeric
products are cleanly separable. This paves the way towards
the preparation of enantio-pure spiro lactams by removal of
the side chain from nitrogen.17
3.2.1. (3R,7aS)-3-Phenyl-7a-(2-phenylethyl)-2,3,7,7a-tet-
rahydropyrrolo[2,1-b]oxazol-5-one 15. The title com-
pound was obtained from keto acid 9 (0.38 g) and
(R)-phenylglycinol (0.25 g), yield 0.433 g (76.5%), mp
113–114 8C (from toluene–light petroleum); HREIMS
found Mþ 307.1574. C20H21NO2 requires M 307.1572; IR
1
n
max/cm21 (CHCl3) 1710 (CvO); H NMR (270 MHz) d
1.83–2.07 (2H, m, CH2), 2.22 (1H, dt, J¼13.5, 10.1 Hz),
2.35–2.47 (1H, m), 2.57–2.73 (3H, m, CH2 and H-3), 2.87
(1H, dt, J¼17.3, 9.9 Hz), 4.12 (1H, dd, J¼7.1, 8.7 Hz), 4.66
(1H, t, J¼8.5 Hz), 5.22 (1H, t, J¼7.6 Hz) and 7.03–7.37
(10H, m, aryl H); 13C NMR (67.5 MHz) d 30.4 (CH2), 31.0
(CH2), 33.2 (CH2), 38.2 (CH2), 57.6 (CH), 72.7 (CH2),
102.3 (C-7a), 125.5 (2£CH), 126.1 (CH), 127.4 (CH), 128.2
(2£CH), 128.5 (2£CH), 128.7 (2£CH), 139.9 (C), 140.9 (C)
and 179.2 (CvO); MS m/z 307 (Mþ, 2%), 277, (1), 248 (1)
and 202 (M2(CH2)2Ph, 100).
3. Experimental
IR Spectra were recorded on Pye-Unicam SP3-200 or
Perkin Elmer 1420 spectrophotometers; only those absorp-
tions appropriate to recognise functional groups are
reported. NMR Spectra were recorded at 90 MHz for H
(22.5 MHz for 13C) on JEOL FX90Q or at 270 MHz
for H (67.5 MHz for 13C) on JEOL FX270 or at 300 MHz
for 1H (75 MHz for 13C) on Bruker MSL300 spectrometers
for solutions in deuteriochloroform (unless otherwise stated)
with tetramethylsilane 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 spectro-
meter; 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 and DCE to 1,2-dichloroethane.
1
1
3.2.2. (3R,7aS)-3-Phenyl-7a-(3-phenylpropyl)-2,3,7,7a-
tetrahydropyrrolo[2,1-b]oxazol-5-one 16. The title com-
pound was obtained from keto acid 10 (0.50 g) and
(R)-phenylglycinol (0.25 g), yield 0.312 g (54%), viscous
oil; HREIMS found Mþ 321.1729. C21H23NO2 requires M
1
321.1729; IR nmax/cm21 (CHCl3) 1710 (CvO); H NMR
(90 MHz) d 1.66–1.85 (4H, m, 2£CH2), 2.00–2.88 (6H, m,
3£CH2), 3.99 (1H, dd, J¼7.1, 8.6 Hz, H-3), 4.55 (1H, t,
J¼8.4 Hz), 5.15 (1H, apparent t, J¼7.7 Hz) and 7.02–7.35
(10H, m aryl H); 13C NMR (22.5 MHz) d 25.7 (CH2), 30.8
(CH2), 33.2 (CH2), 35.6 (CH2), 35.8 (CH2), 57.5 (CH), 72.6
(CH2), 102.4 (C-7a), 125.5 (2£CH), 125.9 (CH), 127.3
(CH), 128.3 (3£CH), 128.6 (2£CH), 140.0 (C), 141.6 (C)
and 179.8 (CvO); MS m/z 321 (Mþ, ,1%), 264 (1), 230
(1), 217 (7), 202 (M2(CH2)3Ph, 100) and 91 (47).
3.1. General procedure for keto acids 9–12
The Grignard reagent freshly prepared in THF was added
slowly to the acid anhydride in THF with stirring, which

A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
1241
3.2.3. (3R,7aS)-3-(1-Methylethyl)-7a-(2-phenylethyl)-
2,3,7,7a-tetrahydropyrrolo[2,1-b]oxazol-5-one 17. The
title compound was obtained from keto acid 9 (0.51 g)
and (S)-valinol (0.255 g), yield 0.377 g (56%), viscous oil;
HREIMS found Mþ 273.1730. C17H23NO2 requires M
33.2 (CH2), 40.8 (CH2), 55.2 (CH), 82.0 (CH), 100.6 (C-7a),
126.1 (2£CH), 127.8 (CH), 128.3 (2£CH), 128.4 (2£CH),
128.6 (CH), 136.5 (C), 141.3 (C) and 178.6 (CvO); MS m/z
321 (Mþ, ,1%), 303 (,1), 232 (,1), 215 (100), 186 (10),
1
124 (65), 117 (15) and 91 (30). Additional lines in the H
1
273.1729; IR nmax/cm21 (CHCl3) 1710 (CvO); H NMR
NMR spectrum due to ca 4% of the 7a-epimer d 1.02 (3H, d,
J¼6.9 Hz, CHCH3), 4.10 (1H, m, CHCH3) and 5.46 (1H, d,
J¼7.6 Hz, CHPh).
(270 MHz) d 0.88 (3H, d, J¼6.6 Hz, CH3), 1.08 (3H, d,
J¼6.6 Hz, CH3), 1.63 (1H, m), 1.90–2.81 (8H, m, 4£CH2),
3.63 (1H, dt, J¼7.1, 10.6 Hz, H-3), 3.81 (1H, dd, J¼6.6,
8.9 Hz), 4.22 (1H, apparent t, J¼8.6 Hz) and 6.88–7.46
(5H, m, aryl H); 13C NMR (67.5 MHz) d 18.9 (CH3), 20.8
(CH3), 30.6 (CH2), 30.7 (CH2), 33.0 (CH2), 34.0 (CH), 39.0
(CH2), 61.7 (CH), 70.9 (CH2), 101.8 (C-7a), 126.1 (CH),
128.1 (2£CH), 128.5 (2£CH), 141.0 (C) and 179.4 (CvO);
MS m/z 273 (Mþ, 1%), 230 (1), 217 (1), 188 (2), 174 (24),
168 (M2(CH2)2Ph 100), 100 (16) and 91 (24).
3.3. (R)-N-(2-Hydroxy-1-phenylethyl)-succinimide 21
and -phthalimide 22
The succinimide 21 was prepared following the literature
procedure for the (S)-enantiomer,19 but using (R)-phenyl-
1
glycinol; yield 59% of a viscous oil, H NMR spectrum in
agreement with lit.19 The phthalimide 22 was prepared from
phthalic anhydride (0.27 g) and (R)-phenylglycinol (0.25 g),
which were mixed and heated at 140–150 8C for 4 h. The
mixture was cooled and dissolved in chloroform (40 mL),
then extracted successively with dilute sulfuric acid (1 M,
2£20 mL), aqueous sodium bicarbonate (2£20 mL) and
water (2£20 mL), dried (MgSO4), and the solvent evapor-
ated in vacuo. The residue was chromatographed on silica
from which ethyl acetate–chloroform (1:4 v/v) eluted the
phthalimide 22 (0.49 g, 100%), mp 64–66 8C (toluene–
light petroleum); HREIMS found MHþ 268.0980.
C16H14NO3 requires 268.0974; 1H and 13C NMR and
mass spectra in agreement with those reported for 22, which
was obtained previously as an oil.20
3.2.4. (3R,7aS)- and (3R,7aR)-3-Phenyl-8a-(2-phenyl-
ethyl)-2,3,6,7,8,8a-hexahydrooxazolo[3,2-a]pyridin-
5(5H)-one 19a and b. The title compounds were obtained
from keto acid 11 (0.82 g) and (R)-phenylglycinol (0.50 g),
yield 0.84 g (71.5%), viscous oil; diastereoisomer ratio
80:20 of 19a:19b from 13C NMR spectrum; 1H NMR
(90 MHz) d 1.50–2.80 (10H, m, 5£CH2), 3.90 (1H,
apparent t, J¼8.4 Hz, H-3), 4.52 (1H, apparent t, J¼
8.6 Hz), 5.37 (1H, apparent t, J¼8.4 Hz) and 7.09–7.42
(10H, m, aryl H); 13C NMR (22.5 MHz) d 16.8 (CH2), l17.0
(CH2)l, l30.0 (CH2)l, 30.5 (CH2), 30.7 (CH2), 31.1 (CH2),
l36.3 (CH2)l, 36.5 (CH2), 58.8 (CH), l59.1 (CH)l, 69.5
(CH2), l71.4 (CH2)l, l95.0 (C-8a)l, 95.8 (C-8a), 125.5
(2£CH), 126.1 (CH), 126.3 (CH), 127.2 (CH), 127.4 (CH),
128.2 (2£CH), 128.6 (3£CH), 139.8 (C), 141.1 (C), l141.7
(C)l, l167.5 (CvO)l and 170.0 (CvO); MS m/z 321 (Mþ,
,1%), 251 (8), 216 (M2(CH2)2Ph, 100) and 120 (24).
3.4. Bicyclic/tricyclic lactams obtained via imides
An excess of the Grignard reagent freshly prepared from
2-phenylethyl bromide (1.1 g) and magnesium (0.15 g) in
THF was added to the succinimide 21 (0.44 g) in THF with
stirring. After aqueous work up and extraction of the
product into ether, which was dried (MgSO4) and
evaporated, the crude hydroxy lactam was redissolved in
DCM (10 mL) and added dropwise to TFA (1.6 mL) in
DCM (25 mL) cooled at 0 8C. The mixture was allowed to
warm to room temperature and stirred for a further 1 h
before addition of saturated aqueous ammonium chloride
(100 mL) and extraction with chloroform (2£20 mL). The
extract was dried (MgSO4) and the chloroform evaporated
in vacuo. The residue was chromatographed on silica,
eluting with ethyl acetate–chloroform (1:4 v/v) to afford the
bicyclic lactam 15 (0.24 g, 21% based on (R)-phenylglyci-
nol), identical with the sample obtained above. In the same
way starting from 3-phenylpropyl bromide and succinimide
21, the bicyclic lactam 16 was obtained (20% based on
(R)-phenylglycinol), identical with the sample obtained via
keto acid 10.
3.2.5. (3R,7aS)- and (3R,7aR)-3-Phenyl-8a-(3-phenylpro-
pyl)-2,3,6,7,8,8a-hexahydrooxazolo[3,2-a]pyridin-5(5H)-
one 20a and b. The title compounds were obtained from
keto acid 12 (0.80 g) and (R)-phenylglycinol (0.47 g), yield
0.82 g (71.5%), viscous oil; diastereoisomer ratio 83:17 of
1
20a:20b from 13C NMR spectrum; H NMR (90 MHz) d
1.36–1.90 (6H, m, 3£CH2), 2.05–2.73 (6H, m, 3£CH2),
3.67 (1H, dd, J¼8.0, 8.9 Hz, H-3), 4.39 (1H, apparent t,
J¼8.6 Hz), 5.30 (1H, apparent t, J¼7.7 Hz) and 7.10–7.35
(10H, m, aryl H); 13C NMR (22.5 MHz) d l14.2 (CH2)l, 16.5
(CH2), 25.5 (CH2), l29.7 (CH2)l, l30.2 (CH2)l, 30.6 (CH2),
30.7 (CH2), l33.4 (CH2)l, 33.8 (CH2), 35.3 (CH2), 58.2
(CH), l58.7 (CH)l, 69.0 (CH2), l70.9 (CH2)l, l94.9 (C-8a)l,
95.6 (C-8a), 125.4 (2£CH), 125.6 (CH), l125.8 (CH)l, 126.1
(2£CH), l127.1 (CH)l, 127.9 (CH), 128.1 (3£CH), 128.3
(2£CH), 139.8 (C), 141.4 (C), l167.1 (CvO)l and 169.5
(CvO); MS m/z 335 (Mþ, 1%), 264 (1), 216
(M2(CH2)3Ph, 100) and 120 (20).
3.4.1. 2-(2-Hydroxy-1(R)-phenylethyl)-3(R)-hydroxy-3-
(2-phenylethyl)-2,3-dihydroisoindol-1(1H)-one 23. The
Grignard reagent was prepared from 2-phenylethyl bromide
(1.50 g) and magnesium (0.20 g) in THF and added rapidly
with stirring to phthalimide 22 (0.49 g) in THF (20 mL) at
0 8C. After evaporation of the solvent, the crude product was
chromatographed on silica, eluting with ethyl acetate–
chloroform (1:4 v/v) to give the lactam 23 (0.40, 59%) as a
viscous oil; HREIMS found Mþ 373.1678. C24H23NO3
requires M 373.1678; 1H NMR (270 MHz) d 1.57 (2H,
3.2.6. (2R,3S,7aR)-3-Methyl-2-phenyl-7a-(2-phenyl-
ethyl)-2,3,7,7a-tetrahydropyrrolo[2,1-b]oxazol-5(6H)-
one 39. The title compound was obtained from keto acid 9
(0.53 g) and (1R,2S)-norephedrine (0.39 g), yield 0.42 g
(50%), viscous oil; IR nmax/cm21 (CHCl3) 1715 (CvO); 1H
NMR (270 MHz) d 0.85 (3H, d, J¼7.3 Hz, CHCH3), 2.04–
3.03 (8H, m, 4£CH2), 4.50 (1H, m, CHCH3), 5.03 (1H, d,
J¼5.6 Hz, CHPh) and 7.20–7.44 (10H, m, aryl H); 13C
NMR (67.5 MHz) d 15.6 (CH3), 30.4 (CH2), 32.6 (CH2),

1242
A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
apparent quint, J¼12.6, 5.1 Hz, CH2), 1.94 (1H, td, J¼13.8,
4.8 Hz), 2.14 (1H, td, J¼12.6, 7.6 Hz), 3.69 (1H, dd,
J¼10.5, 3.8 Hz, CHPh), 4.59–4.80 (2H, m, CH2OH), 5.42
(1H, s, OH), 6.31 (2H, m, aryl H), 7.01 (2H, m, aryl H) and
7.30–7.60 (10H, m, aryl H); 13C NMR (67.5 MHz) d 29.8
(CH2), 38.5 (CH2), 58.8 (CH), 62.8 (CH2), 91.9 (C-3), 121.7
(CH), 123.2 (CH), 125.7 (CH), 128.0 (5£CH), 128.6
(2£CH), 128.8 (2£ CH), 129.5 (CH), 131.5 (C), 132.7
(CH), 138.9 (C), 140.5 (C), 146.4 (C) and 168.9 (CvO);
MS m/z 373 (Mþ, 10%), 355 (13), 342 (21), 250 (16), 237
(18), 130 (10), 106 (36), 91 (100) and 77 (14).
(from toluene–light petroleum); HREIMS found Mþ
355.1581. C24H21NO2 requires M 355.1572; 1H NMR
(270 MHz) d 3.86 and 3.94 (each 1H, overlapping dd,
J¼17.0, 7.8 Hz, CH2OH), 4.18–4.32 (2H, m, CH2Ph),
4.48–4.59 (1H, br, OH), 5.25 (1H, dd, J¼3.7, 7.8 Hz,
alkene CHCH2), 5.60 (t, J¼7.8 Hz, alkane CHCH2), 6.99
(1H, dd, J¼7.3, 1.6 Hz, aryl H), 7.15–7.35 (7H, m, aryl H),
7.48 (2H, m, aryl H), 7.79 (1H, d, J¼7.3 Hz, aryl H) and
7.94 (1H, dd, J¼6.6, 1.5 Hz, aryl H); 13C NMR (67.5 MHz)
d 33.2 (CH2), 61.0 (CH), 64.0 (CH2), 113.2 (CH), 123.2
(CH), 123.7 (CH), 126.5 (CH), 126.7 (2£CH), 127.6 (CH),
128.0 (2£CH), 128.6 (2£CH), 128.8 (2£CH), 129.0 (CH),
130.1 (C), 132.4 (CH), 135.3 (C), 135.9 (C), 137.7 (C),
139.2 (C) and 168.2 (CvO); MS m/z 355 (Mþ, 4%), 324
(M2CH2OH, 27), 264 (15), 246 (14), 236 (19), 234 (22),
232 (27), 189 (12), 165 (12), 130 (30), 103 (30), 91 (100)
and 77 (30).
3.4.2. 2-(2-Hydroxy-1(R)-phenylethyl)-3(R)-hydroxy-3-
(3-phenylpropyl)-2,3-dihydroisoindol-1(1H)-one 24. The
title compound was obtained in the same way starting from
3-phenylpropyl bromide (1.48 g), magnesium (0.18 g) and
phthalimide 22 (0.52 g); yield 0.45 g (65%) of a viscous oil;
HREIMS found MHþ 388.1915. C25H26NO3 requires
388.1913; 1H NMR (270 MHz) d 0.55–0.72 (2H, m,
CH2), 1.22–2.05 (4H, m, 2£CH2), 3.75 (1H, dd, J¼10.6,
4.0 Hz, CHPh), 4.22 br (1H, s, OH), 4.61 (1H, dd, J¼10.2,
4.3 Hz), 4.75 Br (1H, apparent t, J¼10.6 Hz) overlapping
4.80 (1H, s, OH), 6.64 (2H, dd, J¼5.6, 2.0 Hz, H-4 and H-
7), 7.02–7.14 (3H, m, aryl H), 7.27–7.41 (5H, m, aryl H)
and 7.46–7.55 (4H, m, aryl H); 13C NMR (67.5 MHz) d
25.7 (CH2), 35.4 (CH2), 36.3 (CH2), 59.0 (CH), 63.2 (CH2),
92.3 (C-3), 122.0 (CH), 123.4 (CH), 125.9 (CH), 128.2
(CH), 128.3 (2£CH), 128.4 (2£CH), 128.7 (2£CH), 129.0
(2£CH), 129.7 (CH), 131.6 (C), 132.8 (CH), 139.0 (C),
141.7 (C), 146.7 (C) and 169.1 (CvO); MS m/z 388 (MHþ,
75%), 370 (9), 340 (100), 278 (10), 250 (25), 106 (27) and
91 (13).
3.4.4. (R)-3-Phenyl-(S)-9b-(3-phenylpropyl)-2,3,5,9b-
tetrahydrooxazolo[2,3-a]isoindol-5-one 26 and 2-[(R)-
(2-hydroxy-1-phenylethyl)]-3-(3-phenylpropylidene)-
2,3-dihydroisoindol-1(1H)-one 28. These were prepared in
the same way starting from hydroxy lactam 24 (0.36 g)
treated with TFA (0.21 g) in DCM, followed by work up and
chromatography. Lactam 26 (266 mg, 77%); white solid,
mp 107–108 8C (toluene–light petroleum); HREIMS found
1
MHþ 388.1915. C25H26NO3 requires 388.1913; H NMR
(270 MHz) d 0.58–0.75 (2H, m, CH2), 1.65–2.05 (4H, m,
2£CH2), 3.75 and 4.61 (each 1H, dd, J¼10.6, 4.0 Hz,
CH2OH), 4.22 br (1H, s, OH), 4.75 br (1H, t, J¼10.6 Hz,
CHPh) overlapping 4.80 (1H, s, OH), 6.63 (2H, dd, J¼7.5,
1.8 Hz, H-4 and H-7), 7.02–7.14 (2H, m, aryl H), 7.27–7.40
(5H, m, aryl H) and 7.46–7.54 (5H, m, aryl H); 13C NMR
(67.5 MHz) d 25.7 (CH2), 35.4 (CH2), 36.3 (CH2), 59.0
(CH), 63.2 (CH2), 92.3 (C-3), 122.0 (CH), 123.4 (CH),
125.9 (CH), 128.2 (CH), 128.3 (2£CH), 128.4 (2£CH),
128.7 (2£CH), 129.0 (2£CH), 129.7 (CH), 131.6 (C), 132.8
(CH), 139.0 (C), 141.7 (C), 146.7 (C) and 169.1 (CvO);
MS m/z 388 (MHþ, 75%), 370 (M2OH, 100), 340 (10), 278
(10), 250 (M2(CH2)3Ph, 25), 106 (27) and 91 (13).
Enamide 28 (12 mg, 7%) obtained from later fractions;
white solid, mp 117–121 8C (toluene–light petroleum);
HREIMS found Mþ 369.1730. C25H23NO2 requires M
3.4.3. (R)-3-Phenyl-(S)-9b-(2-phenylethyl)-2,3,5,9b-
tetrahydrooxazolo[2,3-a]isoindol-5-one 25 and 2-[(R)-
(2-hydroxy-1-phenylethyl)]-3-(2-phenylethylidene)-2,3-
dihydroisoindol-1(1H)-one 27. Hydroxy lactam 23
(0.18 g) in dry DCM (5 mL) was added slowly with stirring
to TFA (0.11 g) in DCM cooled to 0 8C. The solution was
stirred for 1 h as it warmed to room temperature, then
poured into saturated aqueous sodium bicarbonate. The
organic phase was separated and the aqueous layer
reextracted with chloroform (2£10 mL). The extracts were
combined, dried (MgSO4), and the solvent evaporated. The
residue was chromatographed on silica, eluting with ethyl
acetate–chloroform (1:4 v/v). Lactam 25 (135 mg, 74%)
was obtained as a viscous oil; HREIMS found Mþ
373.1682. C24H23NO3 requires M 373.1678; 1H NMR
(270 MHz) d 1.53 and 1.62 (each 1H, overlapping dt,
J¼12.4, 5.3 Hz, CH2), 1.94 and 2.14 (each 1H, distorted dt,
J¼12.4, 5.3 Hz, CH2), 2.53 br (1H, s, OH), 3.69 and 4.62
(each 1H, dd, J¼9.0, 4.0 Hz, CH2OH) overlapping 4.75 br
(1H, t, J¼9.0 Hz, CHPh), 5.43 (1H, s, OH), 6.28–6.32 (2H,
m, aryl H), 7.00–7.03 (3H, m, aryl H), 7.31–7.39 (4H, m,
aryl H) and 7.47–7.60 (5H, m, aryl H); 13C NMR
(67.5 MHz) d 29.8 (CH2), 38.5 (CH2), 58.8 (CH), 62.8
(CH2), 91.9 (C-3), 121.0 (CH), 123.2 (CH), 125.7 (CH),
128.0 (5£CH), 128.6 (2£CH), 128.8 (2£CH), 129.5 (CH),
131.5 (C), 132.7 (CH), 138.9 (C), 140.5 (C), 146.4 (C) and
168.9 (CvO); MS m/z 373 (Mþ, ,1%), 342 (M2CH2OH,
21), 250 (16), 237 (18), 130 (10), 106 (36), 91 (100) and 77
(13). Later fractions eluted from the column afforded the
enamide 27 (9 mg, 5%) as a white solid, mp 158–159 8C
1
369.1729; H NMR (270 MHz) d 1.25 (1H, m), 1.60 (1H,
m), 2.01 (1H, m), 2.79 (2H, m), 4.19–4.48 (2H, m), 5.12–
5.48 (2H, m) and 6.65–7.92 (14H, m, aryl H); 13C NMR
(67.5 MHz) d 29.1 (CH2), 35.7 (CH2), 61.0 (CH), 64.1
(CH2), 114.1 (CH), 123.2 (CH), 123.6 (CH), 126.2 (CH),
126.7 (2£CH), 127.6 (CH), 128.4 (CH), 128.5 (CH), 128.7
(3£CH), 130.0 (C), 132.3 (CH), 135.3 (C), 137.7 (C), 140.6
(C) and 168.1 (CvO); MS m/z 369 (Mþ, 5%), 338 (7), 278
(6), 250 (10), 158 (100), 103 (12) and 91 (32).
3.5. General procedure for cyclisation to spiro lactams
with aluminium trichloride
The hydroxy lactam precursor dissolved in DCE was added
dropwise with stirring to aluminium trichloride (typically
3–4 mol eq) in DCE at the temperature stated. An orange–
brown colour developed. The mixture was stirred for 3–4 h
or until analysis by tlc showed disappearance of the starting
material; it was then poured onto ice, acidified by addition
of dilute sulfuric acid (1 M) and extracted twice with

A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
1243
chloroform. The combined extracts were dried (MgSO4)
and the solvent evaporated in vacuo. The residue was
chromatographed on silica and the products eluted with
ethyl acetate–chloroform (1:4 v/v).
(C), 123.2 (CH), 125.6 (CH), 126.6 (CH), 126.9 (2£CH),
127.3 (CH), 128.2 (2£CH), 128.5 (CH), 137.9 (C), 141.8
(C), 145.6 (C) and 173.4 (CvO); MS m/z 321 (Mþ, ,1%),
303 (M2H2O, 2), 291 (M2CH2O, 45), 202 (32), 185 (50),
143 (36) and 106 (100).
3.5.1. (R,R)- and (R,S)-10-(2-Hydroxy-1-phenylethyl)-2,3-
dihydrospiro[indene-1,20-pyrrolidin]-50-ones 29a and b.
The title compound were obtained from bicyclic lactam 15
(0.31 g) and aluminium trichloride (0.40 g) in DCE at
25 8C. Elution of the column gave first unreacted 15 (3 mg,
1%), followed by the(R,S)-spiro lactam 29b (61 mg, 20%),
mp 172–173 8C (from toluene–light petroleum); found: C,
77.68; H, 6.64; N, 4.29. C20H21NO2 requires C, 78.14; H,
6.88; N, 4.56%; IR nmax/cm21 (CHCl3) 3340 (O–H) and
3.5.3. (R,R)- and (R,S)-10-(2-Hydroxy-1-phenylethyl)-
1,2,3,4-tetrahydrospiro[naphthalene-1,20-pyrrolidin]-50-
ones 31a and b. The title compound were obtained from the
bicyclic lactam 16 (325 mg) and aluminium trichloride
(0.40 g) in DCE at 25 8C. Elution of the column gave first
unreacted starting material 16 (26 mg, 8%), then the (R,S)-
spiro lactam 31b (234 mg, 72%), mp 176–177 8C (toluene–
light petroleum); found: C, 77.93; H, 7.12; N, 4.20.
C21H23NO2 requires C, 78.47; H, 7.21; N, 4.36%; HREIMS
1
1655 (CvO); H NMR (90 MHz) d 1.86–2.04 (2H, m,
CH2), 2.09–2.37 (2H, m, CH2), 2.62–2.85 (4H, m, 2£CH2),
4.04 (3H, m, CH2CH), 4.88 (1H, br s, OH) and 7.10–7.52
(9H, m, aryl H); 13C NMR (22.5 MHz) d 29.2 (CH2), 30.6
(CH2), 35.0 (CH2), 36.7 (CH2), 61.1 (CH), 65.8 (CH2), 77.3
(C), 122.9 (CH), 125.4 (CH), 127.3 (2£CH), 127.6 (CH),
128.5 (2£CH), 128.7 (CH), 139.0 (C), 142.9 (C), 144.4 (C)
and 177.5 (CvO); MS m/z Mþ absent, 289 (M2H2O, 1),
277 (M2CH2O, 100), 276 (61), 188 (19), 143 (34) and 106
(67). Further elution of the column afforded the (R,R)-spiro
lactam 29a (223 mg, 73%), mp 195–196 8C (toluene–light
petroleum); IR nmax/cm21 (CHCl3) 3350 br (O–H) and
found Mþ 321.1733. C21H23NO2 requires M 321.1729; IR
1
n
max/cm21 (CHCl3) 3320 br (O–H) and 1655 (CvO); H
NMR (90 MHz) d 1.50–1.87 (4H, m, 2£CH2), 2.13–2.34
(2H, m, CH2), 2.58–2.80 (4H, m, 2£CH2), 3.79–4.25 (3H,
m, CH2CH), 5.12–5.27 (1H, m, exchangeable, OH) and
7.10–7.35 (9H, m, aryl H); 13C NMR (22.5 MHz) d 20.1
(CH2), 29.3 (CH2), 29.9 (CH2), 35.0 (CH2), 36.6 (CH2), 61.7
(CH), 65.8 (CH2), 69.6 (C), 126.1 (CH), 126.8 (CH), 127.2
(CH), 127.3 (2£CH), 127.6 (CH), 128.4 (2£CH), 129.7
(CH), 138.2 (C), 139.2 (C), 139.6 (C) and 177.9 (CvO);
MS m/z 321 (Mþ, ,1%), 291 (M2CH2O, 67), 202 (18), 185
(22), 143 (20), 129 (22) and 106 (100). Later fractions
afforded the (R,R)-spiro lactam 31a (59 mg, 18%), mp 235–
236 8C (toluene–light petroleum); IR nmax/cm21 (CHCl3)
3360 br (O–H) and 1655 (CvO); 1H NMR (90 MHz)
(CHCl3-dþMeOH-d4) d 1.72–2.92 (10H, m, 5£CH2),
3.77–3.99 (2H, m, CH2CH), 4.28 (1H, br, OH) overlapping
4.30 (1H, dd, J¼8.2, 12.6 Hz, CH2CH), 6.44–6.72 (2H, m,
aryl H) and 6.87–7.29 (7H, m, aryl H); 13C NMR
(22.5 MHz) (CHCl3-dþMeOH-d4) d 20.9 (CH2), 29.8
(CH2), 30.5 (CH2), 32.7 (CH2), 36.6 (CH2), 62.5 (CH),
65.0 (CH2), 69.6 (C), 125.6 (CH), 127.3 (2£CH), 128.0
(2£CH), 128.6 (3£CH), 129.2 (CH), 137.3 (C), 138.5 (C),
139.1 (C) and 177.7 (CvO); MS m/z 321 (Mþ, ,1%), 303
(M2H2O, 1), 291 (M2CH2O, 41), 202 (16), 185 (20) and
106 (100).
1
1652 (CvO); H NMR (90 MHz) d 2.06–2.46 (4H, m,
2£CH2), 2.53–2.78 (2H, m, CH2), 2.87–3.12 (2H, m, CH2),
3.74–4.10 (3H, m, CH2CH), 4.33 (1H, br t, OH), 6.45 (1H,
d, J¼7.9 Hz, o-ArH), 6.71–6.89 (1H, m, m-ArH) and 7.02–
7.16 (7H, m, aryl H); 13C NMR (22.5 MHz) d 29.4 (CH2),
31.0 (CH2), 35.0 (CH2), 35.7 (CH2), 61.8 (CH), 65.3 (CH2),
77.5 (C), 124.6 (CH), 124.7 (CH), 126.4 (CH), 127.2 (CH),
127.9 (2£CH), 128.1 (2£CH), 128.5 (CH), 139.1 (C), 142.9
(C), 143.1 (C) and 177.1 (CvO); MS m/z Mþabsent, 289
(M2H2O, 1), 277 (M2CH2O, 100), 276 (86), 188 (30), 143
(43), 128 (33) and 106 (97).
3.5.2. (R,R)- and (R,S)-10-(2-Hydroxy-1-phenylethyl)-2,3-
dihydrospiro[indene-1,20-piperidin]-60-ones 30a and b.
The title compound were obtained from the bicyclic lactam
19 (0.33 g) and aluminium trichloride (0.54 g) in DCE at
room temperature. Elution of the column gave first the
(R,R)-spiro lactam 30b (70 mg, 21%), semi-solid; HREIMS
3.5.4. (R,R)- and (R,S)-10-(2-Hydroxy-1-phenylethyl)-
1,2,3,4-tetrahydrospiro[naphthalene-1,20-piperidin]-60-
ones 32a and b. The title compound were obtained from the
bicyclic lactam 20 (0.35 g) and aluminium trichloride
(0.52 g) in DCE at room temperature. Elution of the column
afforded first the (R,S)-spiro lactam 32b (260 mg, 74%), mp
113–115 8C (toluene–light petroleum); HREIMS found
1
found Mþ 321.1721. C21H23NO2 requires M 321.1729; H
NMR (90 MHz) d 1.78–2.37 (6H, m, 3£CH2), 2.62–2.90
(4H, m, 2£CH2), 3.95–4.30 (3H, m, CH2CH), 5.11 (1H, br s,
OH) and 7.08–7.33 (9H, m, aryl H); 13C NMR (22.5 MHz)
d 17.8 (CH2), 29.0 (CH2), 33.9 (CH2), 35.8 (CH2), 36.8
(CH2), 63.7 (CH), 65.8 (CH2), 74.8 (C), 123.3 (CH), 125.6
(CH), 126.7 (CH), 126.9 (2£CH), 127.3 (CH), 128.2
(2£CH), 128.6 (CH), 137.9 (C), 141.9 (C), 145.7 (C) and
173.4 (CvO). This was followed by the (R,S)-spiro lactam
30a (220 mg, 67%), mp 173–174 8C (toluene–light petro-
leum); found: C, 78.16; H, 7.14; N, 4.19. C21H23NO2
requires C, 78.47; H, 7.21; N, 4.36%; IR nmax/cm21
(CHCl3) 3360 br (O–H) and 1710 (CvO); 1H NMR
(270 MHz) d 1.23–3.06 (10H, m, 5£CH2), 3.67 (1H, dd,
J¼7.4, 12.6 Hz, CHCH2), 3.82–3.97 (1H, m,) and 4.06–
4.23 (1H, m, CHCH2), 6.48 (1H, d, J¼7.2 Hz, o-ArH), 6.62
(1H, t, J¼7.2 Hz, m-ArH) and 6.90–7.33 (7H, m, aryl H);
13C NMR (22.5 MHz) d 17.7 (CH2), 29.0 (CH2), 33.9
(CH2), 35.8 (CH2), 36.8 (CH2), 63.7 (CH), 65.8 (CH2), 74.8
Mþ 335.1873. C22H25NO2 requires M 335.1885; IR nmax
/
cm21 (CHCl3) 3380 br (O–H) and 1720 (CvO); 1H NMR
(270 MHz) d 1.67–2.06 (7H, m) and 2.19–2.29 (1H, m,
4£ring CH2), 2.66–2.82 (4H, m, 2£ring CH2), 3.80–3.95
(2H, m, CHCH2OH), 4.17 br (1H, d, J¼5.1 Hz, CHCH2),
5.08 (1H, dd, J¼9.8, 2.8 Hz, CH2OH) and 7.09–7.37 (9H,
m, aryl H); after shaking the sample with D2O the OH signal
at d 5.08 disappeared, the signal at d 4.17 was unchanged,
and the signal for CH2OH simplified to d 3.84 (1H, dd, J¼
19.0, 5.1 Hz) and 3.91 (1H, dd, J¼19.0, 1.9 Hz); 13C NMR
(22.5 MHz) d 17.1 (CH2), 20.5 (CH2), 29.4 (CH2), 33.3
(CH2), 33.8 (CH2), 38.3 (CH2), 64.6 (CH), 65.4 (CH2), 66.4
(C), 126.4 (CH), 126.9 (2£CH), 127.4 (CH), 127.6 (CH),
128.1 (2£CH), 129.4 (CH), 138.1 (C), 138.5 (C), 139.9 (C)

1244
A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
and 173.6 (CvO); MS m/z 335 (Mþ, ,1%), 317 (M2H2O,
5), 305 (M2CH2O, 37), 216 (16), 199 (16), 157 (18), 129
(26), 106 (100) and 91 (18). This was followed by the
(R,R)-spiro lactam 32a (87 mg, 25%), mp 98–100 8C
(toluene–light petroleum). Anal. found C, 78.47; H, 7.63;
N, 3.84. C22H25NO2 requires C, 78.77; H, 7.51; N, 4.18%;
IR nmax/cm21 (CHCl3) 3360 br (O–H) and 1680 (CvO);
1H NMR (90 MHz) d 1.62–2.38 (8H, m, 4£CH2), 2.54–
2.98 (4H, m, 2£CH2), 3.86–4.41 (4H, m, CH2CH and OH)
and 6.35–7.30 (8H, m, aryl H); 13C NMR (22.5 MHz) d
17.4 (CH2), 20.9 (CH2), 29.9 (CH2), 33.3 (CH2), 33.6 (CH2),
37.7 (CH2), 66.1 (C), 66.8 (CH), 125.2 (CH), 126.4 (CH),
126.9 (CH), 127.5 (2£CH), 128.5 (3£CH), 129.2 (CH),
137.5 (C), 138.2 (C), 139.1 (C) and 173.5 (CvO); MS m/z
335 (Mþ, ,1%), 305 (M2CH2O, 32), 216 (17), 199 (19),
129 (20) and 106 (100).
(270 MHz) d 1.68–2.35 (4H, m, 2£CH2), 2.84?2.89 (2H,
m, CH2), 4.03–4.12 (2H, m, CH2CH), 4.29 (1H, dd, J¼5.5,
2.2 Hz, CHPh), 5.30 br (1H, s, OH), 6.77 (1H, d, J¼7.9 Hz,
aryl H), 6.99–7.10 (1H, m, aryl H), 7.18–7.33 (2H, m, aryl
H), 7.43–7.50 (8H, m, aryl H) and 7.94–7.97 (1H, m, aryl
H); 13C NMR (67.5 MHz) d 20.4 (CH2), 29.3 (CH2), 34.6
(CH2), 61.6 (CH), 66.2 (CH2), 70.1 (C), 122.8 (CH), 123.9
(CH), 126.1 (CH), 127.2 (CH), 127.3 (2£CH), 127.4 (CH),
128.1 (CH), 128.2 (CH), 128.5 (2£CH), 129.8 (CH and C),
132.4 (CH), 133.7 (C), 139.0 (C), 139.2 (C), 153.3 (C) and
170.8 (CvO); MS m/z 369 (Mþ, ,1%), 339 (M2CH2O,
100), 338 (M2CH2OH, 42), 250 (11), 234 (38), 233 (76),
215 (35), 106 (17) and 91 (16). Further elution gave the
(R,S)-spiro lactam 34a (55 mg, 33.5%) as a viscous oil;
HREIMS found MHþ 370.1804. C25H24NO2 requires
1
370.1807; H NMR (270 MHz) d 1.95–2.02 (1H, m) and
2.50–2.62 (1H, ddd, J¼13.5, 10.6, 5.6 Hz, CH2-2), 2.12–
2.28 (2H, m, CH2), 2.91–3.07 (2H, m, CH2), 4.06 br (1H, s,
OH) overlapping 4.12 (1H, dd, J¼11.6, 4.6 Hz) and 4.31
(1H, dd, J¼7.6, 4.6 Hz, CH2OH), 4.55–4.62 (1H, m,
CHPh), 6.11 (1H, dd, J¼7.9, 1.0 Hz, o-ArH), 6.37 (1H, t,
J¼6.9 Hz, m-ArH) and 6.92 (1H, dd, J¼7.6, 1.3 Hz, aryl H),
7.05–7.17 (7H, m, aryl H), 7.35–7.41 (2H, m, aryl H) and
7.81–7.85 (1H, m, aryl H); 13C NMR (67.5 MHz) d 20.0
(CH2), 28.6 (CH2), 33.9 (CH2), 61.0 (CH), 63.8 (CH2), 68.3
(C), 121.2 (CH), 122.5 (CH), 124.6 (CH), 126.2 (CH), 126.5
(CH), 126.8 (2£CH), 126.9 (CH), 127.7 (2£CH), 128.6
(CH), 129.3 (C), 131.0 (CH), 131.3 (C), 137.7 (C), 152.6 (C)
and 169.0 (CvO); MS m/z 369 (Mþ, ,1%), 351 (M2H2O,
2), 339 (M2CH2O, 100), 338 (M2CH2OH, 72), 250 (8),
233 (77), 215 (55), 202 (34), 178 (16), 106 (25), 91 (37) and
77 (21).
3.5.5. (R,R)- and (R,S)-20-(2-Hydroxy-1-phenylethyl)-
2,3,20,30-tetrahydrospiro[indene-1,10-isoindol]-30-ones
33a and b. The title compound were obtained from the
tricyclic lactam 25 (0.17 g) and aluminium trichloride
(0.19 g) in DCE at 0 8C. Elution of the column afforded
first the (R,R)-spiro lactam 33b (55 mg, 32%) as a viscous
oil; HRCIMS found MHþ 356.1651. C24H22NO2 requires
1
356.1651; H NMR (90 MHz) d 2.27 (2H, t, J¼7.2 Hz,
CH2), 2.97–3.18 (2H, m, CH2), 3.95–4.25 (3H, m,
CHCH2OH), 4.98 br (1H, t, OH), 6.82 (1H, d, J¼6.8 Hz,
o-ArH), 7.02–7.13 (1H, m, m-ArH), 7.19–7.52 (10H, m,
aryl H) and 7.88–7.98 (1H, m, aryl H); 13C NMR
(22.5 MHz) d 30.6 (CH2), 35.4 (CH2), 61.0 (CH), 66.0
(CH2), 78.4 (C), 121.8 (CH), 123.6 (CH), 123.8 (CH), 125.5
(CH), 127.2 (2£CH), 127.4 (CH), 127.8 (CH), 128.4 (CH),
128.6 (2£CH), 129.4 (CH), 130.1 (C), 132.7 (CH), 138.9
(C), 141.4 (C), 144.3 (C), 151.3 (C) and 170.2 (CvO); MS
m/z 356 (MHþ, ,1%), 325 (M2CH2O, 46), 234 (26), 219
(100), 189 (16), 165 (12) and 106 (13). This was followed
by the (R,S)-spiro lactam 33a (74 mg, 43%); white solid, mp
143–145 8C (toluene–light petroleum); HRCIMS found
3.5.7. (S,S)- and (S,R)-10-(1-Hydroxy-3-methylbut-2-yl)-
2,3-dihydrospiro[indene-1,20-pyrrolidin]-50-ones 35a and
b. The title compound were obtained from the bicyclic
lactam 17 (0.33 g) and aluminium trichloride (0.50 g) in
DCE at 25 8C. Chromatography of the crude product
afforded first the (S,R)-spiro lactam 35b (74 mg, 22.4%);
white solid, mp 142–143 8C; HREIMS found Mþ 273.1731.
1
MHþ 356.1653. C24H22NO2 requires 356.1651; H NMR
(270 MHz) d 2.67 (1H, ddd, J¼14.7, 9.4. 6.6 Hz) and 2.87
(1H, ddd, J¼14.7, 8.9, 4.3 Hz, CH2-2), 3.20–3.45 (2H, m,
CH2-3), 4.00 (1H, dd, J¼11.5, 4.3 Hz) and 4.22 (1H, dd,
J¼8.3, 4.3 Hz, CH2OH), 4.35 br (1H, s, OH), 4.68 br (1H, t,
J¼10.6 Hz, CHPh), 6.12 (1H, d, J¼7.6 Hz, o-ArH), 6.63
(1H, t, J¼7.6 Hz, m-ArH), 7.01–7.13 (3H, m, aryl H),
7.25–7.44 (7H, m, aryl H) and 7.77 (1H, d, J¼7.6 Hz, aryl
H); 13C NMR (67.5 MHz) d 31.4 (CH2), 36.9 (CH2), 62.4
(CH), 64.7 (CH2), 78.4 (C), 122.2 (CH), 123.5 (CH), 125.1
(CH), 125.7 (CH), 127.1 (CH), 127.5 (CH), 128.2 (2£CH),
128.3 (2£CH), 128.5 (CH), 129.2 (CH), 131.4 (C), 132.7
(CH), 139.2 (C), 140.9 (C), 144.5 (C), 151.7 (C) and
169.6 (CvO); MS m/z 356 (Mþ, ,1%), 325 (M2CH2O,
41), 324 (37), 219 (100), 191 (14), 189 (16), 165 (11) and
106 (14).
1
C17H23NO2 requires M 273.1729; H NMR (90 MHz) d
0.98 (6H, d, J¼6.6 Hz, 2£CH3), 1.98–3.08 (9H, m, 4£CH2
and CH), 3.60–3.70 br (2H, m, CH2OH), 4.98 br (1H, s,
OH) and 7.29 (4H, s, aryl H); 13C NMR (22.5 MHz) d 20.2
(CH3), 20.9 (CH3), 24.9 (CH), 29.5 (CH2), 29.9 (CH2), 35.1
(CH), 37.8 (CH2), 62.4 (CH), 65.1 (CH2), 76.2 (C), 123.0
(CH), 125.3 (CH), 127.2 (CH), 128.7 (CH), 142.2 (C), 144.8
(C) and 177.9 (CvO); MS m/z 273 (Mþ, 7%), 255
(M2H2O, 3), 242 (M2CH2OH, 68), 188 (23), 171 (47),
143 (55), 128 (100), 115 (41) and 72 (72). Further elution
gave the (S,S)-spiro lactam 35a (212 mg, 64%); white solid,
mp 125–126 8C (toluene–light petroleum). Anal. found C,
74.63; H, 8.62; N, 4.99. C17H23NO2 requires C, 74.69; H,
1
8.48; N, 5.13%; H NMR (90 MHz) d 0.59 (3H, d, J¼
6.6 Hz, CH3), 0.81 (3H, d, J¼6.6 Hz, CH3), 2.05–3.02 (9H,
m, 4£CH2 and CH), 3.78–4.10 br (2H, m, CH2OH), 4.53 br
(1H, s, OH) and 7.30 (4H, s, aryl H); 13C NMR (22.5 MHz)
d 20.1 (CH3), 20.9 (CH3), 25.7 (CH), 30.0 (CH2), 30.7
(CH2), 35.0 (CH), 38.6 (CH2), 62.6 (CH), 76.2 (C), 125.0
(CH), 125.2 (CH), 126.8 (CH), 129.2 (CH), 142.5 (C), 144.5
(C) and 176.9 (CvO); MS m/z 273 (Mþ, 6), 255 (M2H2O,
6), 242 (M2CH2OH, 86), 230 (5), 188 (40), 171 (49), 143
(68), 128 (53), 115 (28), 72 (100) and 60 (27).
3.5.6. (R,R)- and (R,S)-20-(2-Hydroxy-1-phenylethyl)-
1,2,3,4,20,30-hexahydrospiro[naphthalene-1,10-isoindol]-
30-ones 34a and b. The title compound were obtained from
the tricyclic lactam 26 (164 mg) and aluminium trichloride
(0.18 g) in DCE at 0 8C for 5 h. Elution of the column
afforded first the (R,R)-spiro lactam 34b (68 mg, 41.5%);
white solid, mp 155–157 8C; HRCIMS found MHþ
370.1802. C25H24NO2 requires 370.1807; 1H NMR

A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
1245
4367–4416. (b) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817–3856, and references therein.
2. (a) Schoemaker, H. E.; Speckamp, W. N. Tetrahedron Lett.
1978, 1515–1518. (b) Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron 1980, 36, 951–958.
3.5.8. 5-Methyl-6-phenyl-1,2,5,6,10,11-hexahydrocyclo-
penta[kl]pyrrolo[2,1-a]isoquinolin-3(3H)-one 41. The
title compound was obtained from the bicyclic lactam 39
(0.30 g) and aluminium trichloride (0.40 g) in DCE at 0 8C.
Chromatography afforded the tetracyclic lactam 41
(125 mg, 44%) as a viscous oil; HREIMS found Mþ
303.1631. C21H21NO requires M 303.1623; IR nmax/cm21
3. (a) Evans, D. A.; Thomas, E. W. Tetrahedron Lett. 1979,
411–414. (b) Evans, D. A.; Thomas, E. W.; Cherpeck, R. E.
J. Am. Chem. Soc. 1982, 104, 3695–3700.
1
(CHCl3) 1720 (CvO); H NMR (270 MHz) d 0.97 (3H,
d, J¼7.0 Hz, CH3), 1.46–1.59 (1H, m), 1.89 (1H, dd)
overlapping 1.92–2.00 (1H, m), 2.17 (1H, dd, J¼11.5,
7.0 Hz), 2.36 (1H, dd, J¼11.2, 5.6 Hz), 2.49 (1H, ddd,
J¼16.5, 12.8, 7.0 Hz), 2.75 (1H, dd, J¼15.5, 7.3 Hz), 3.11
(1H, ddd, J¼15.5, 11.4, 5.6 Hz), 4.02 (1H, s, H-6), 5.20
(1H, dq, J¼7.0, 1.7 Hz, CH3CH), 7.04 (1H, d, J¼6.6 Hz,
H-7 or H-9) and 7.16–7.31 (7H, m, aryl H); 13C NMR
(67.5 MHz) d 19.5 (CH3), 30.0 (CH2), 31.5 (CH2), 32.9
(CH2), 42.3 (CH2), 50.5 (CH), 51.8 (CH), 68.4 (C-11a),
123.7 (CH), 126.6 (CH), 127.8 (CH), 128.0 (2£CH), 128.2
(CH), 128.5 (2£CH), 132.9 (C), 140.8 (C), 142.3 (C),
142.6 (C) and 177.6 (CvO); MS m/z 303 (Mþ, 100%),
288 (M2CH3, 7), 260 (13), 232 (11), 203 (18), 128 (16)
and 91 (14).
4. Inoue, Y.; Tazawa, N.; Watanabe, A.; Aoki, Y.; Kakisawa, H.
Bull. Chem. Soc. Jpn 1992, 65, 2866–2868.
5. Ito, T.; Yamazaki, N.; Kibayashi, C. Synlett 2001,
1506–1509.
6. (a) Sun, P.; Sun, C.; Weinreb, S. M. Org. Lett. 2001, 3,
3507–3510. (b) Abe, H.; Aoyagi, S.; Kibayashi, C. Angew.
Chem., Int. Ed. 2002, 41, 3017–3020.
7. (a) Bailey, P. D.; Morgan, K. M.; Smith, D. I.; Vernon, J. M.
Tetrahedron Lett. 1994, 35, 7115–7118. (b) Bailey, P. D.;
Morgan, K. M.; Smith, D. I.; Vernon, J. M. Tetrahedron 2003,
59, 3369–3378.
8. Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T.; McClure, M. S.
J. Org. Chem. 1998, 63, 6778–6779.
9. Preliminary publication of some of these results: Bahajaj,
A. A.; Bailey, P. D.; Moore, M. H.; Morgan, K. M.;
Vernon, J. M. J. Chem. Soc., Chem. Commun. 1994, 1994,
2511–2512.
3.6. Crystallographic structure determinations
X-Ray analysis of 30a and 35b were 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. Crystal structures of 29a
and 32b have been reported previously.9
10. (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.
11. (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.
3.6.1. Crystal data for 30a.21 C21H23NO2, M¼321.40. The
crystal size was 0.50£0.50£0.40 mm; orthorhombic, space
group P212121, with unit cell a¼10.969(3), b¼15.196(3),
3
21
˚
˚
c¼10.266(2) A, V¼1711.2(7) A , Z¼4, Dc¼1.248 g cm
.
12. (a) Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett. 1994, 35,
2223–2226. (b) Munchhof, M. J.; Meyers, A. I. J. Org. Chem.
1995, 60, 7084–7085. (c) Micouin, L.; Quirion, J.-C.; Husson,
H.-P. Tetrahedron Lett. 1996, 37, 849–852. (d) Amat, M.;
2672 reflections were collected in the range 5,2u,508, of
which 2378 were independent (Rint 0.0161). Full matrix
least squares refinement on F 2 with 219 parameters for
2378 reflections with I.2sI gave final values of R1¼0.0301
and wR2¼0.0721.
´
Llor, N.; Hidalgo, J.; Hernandez, A.; Bosch, J. Tetrahedron:
Asymmetry 1996, 7, 977–980.
3.6.2. Crystal data for 35b.21 C17H23NO2, M¼273.36. The
crystal size was 0.50£0.30£0.20 mm; orthorhombic, space
group P212121, with unit cell a¼11.915(1), b¼18.256(4),
13. (a) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z.
Tetrahedron Lett. 1997, 38, 3627–3630. (b) Allin, S. M.;
Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. J. Chem. Soc.,
Perkin Trans. 1 2000, 1715–1721.
3
21
˚
˚
c¼6.915(3) A, V¼1504.1(7) A , Z¼4, Dc¼1.207 g cm
.
14. Some other syntheses of spiro lactams via alkylation of the
5-cyano derivative of 7 are unrelated to our present work: cf.
(a) Zhu, J.; Quirion, J.-C.; Husson, H.-P. J. Org. Chem. 1993,
58, 6451–6456. (b) Ribeiro, C. M. R.; de Melo, S. J.; Bonin,
M.; Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett. 1994, 35,
7227–7230.
3103 reflections were collected in the range 5,2u,508, of
which 2651 were independent (Rint 0.0152). Full matrix
least squares refinement on F 2 with 182 parameters for
2650 reflections with I.2sI gave final values of R1¼0.0425
and wR2¼0.1041.
15. Bahajaj, A. A.; Vernon, J. M.; Wilson, G. D. Tetrahedron,
2004, 60, 1247–1253.
Acknowledgements
16. (a) Bahajaj, A. A.; Hitchings, G. J.; Moore, M. H.; Vernon,
J. M. J. Chem. Soc., Perkin Trans. 1 1994, 1211–1214.
(b) Bahajaj, A. A.; Vernon, J. M. J. Chem. Soc., Perkin Trans.
1 1996, 1041–1046.
Grateful acknowledgement is made of an ORS award to
A. A. B.
17. Fains, O.; Vernon, J. M. Tetrahedron Lett. 1997, 38,
8265–8266.
18. Staudinger, H.; Schneider, H. Ber. 1923, 56, 699.
19. Meyers, A. I.; Lefker, B. A.; Sowin, T. J.; Westrum, L. J.
J. Org. Chem. 1989, 4243, 4246. The (R)-enantiomer 21
References and notes
1. (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,

1246
A. A. Bahajaj et al. / Tetrahedron 60 (2004) 1235–1246
has also been reported: Groaning, M. D.; Meyers, A. I.
Tetrahedron Lett. 1999, 40, 4639–4642.
as supplementary publication numbers CCDC 213789 and
213790, 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).
`
20. Aguilar, N.; Moyano, A.; Pericas, M. A.; Riera, A. Synthesis
1998, 313–316.
21. Crystallographic data for compounds 30a and 35b have been
deposited with the Cambridge Crystallographic Data Centre