Synthesis of enantiopure 2-azabicyclo[3.3.1]nonanes by a radical ring closure

Article abstract of DOI:10.1016/S0957-4166(99)00221-9

The first synthesis of enantiomerically pure 2-azabicyclo[3.3.1]nonanes by an intramolecular radical reaction of the trichloroacetamido group bearing an (S)-N-1-phenylethyl substituent with the silyl enol ether moiety in compounds 7 is described. The procedure allows the two enantiomers of the 2- azabicyclo[3.3.1]nonane-3,6-dione, 3 and ent-3, to be prepared separately. β-Lactam 8 and normorphan 9 are also formed from 7 through an initial radical translocation process in the cyclization step.

Full text of DOI:10.1016/S0957-4166(99)00221-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2399–2410
Synthesis of enantiopure 2-azabicyclo[3.3.1]nonanes by a radical
ring closure
Josefina Quirante, Mercè Torra, Faïza Diaba, Carmen Escolano and Josep Bonjoch ∗
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Received 20 May 1999; accepted 2 June 1999
Abstract
The first synthesis of enantiomerically pure 2-azabicyclo[3.3.1]nonanes by an intramolecular radical reaction
of the trichloroacetamido group bearing an (S)-N-1-phenylethyl substituent with the silyl enol ether moiety in
compounds 7 is described. The procedure allows the two enantiomers of the 2-azabicyclo[3.3.1]nonane-3,6-dione,
3 and ent-3, to be prepared separately. β-Lactam 8 and normorphan 9 are also formed from 7 through an initial
radical translocation process in the cyclization step. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
We have recently reported the synthesis of 2-azabicyclo[3.3.1]nonanes by radical cyclization of 1-
(carbamoyl)dichloromethyl radicals with simple,1 as well as electron poor2 or electron rich alkenes.3 As
part of our continuing interest in radical cyclizations leading to morphan compounds,4–8 we have initiated
a study of the synthesis of enantiopure 2-azabicyclo[3.3.1]nonanes, for which there is no precedent in the
literature.9
In this paper we describe the application of our procedure for the cyclization of trichloroacetamides
with silyl enol ethers, reported in the racemic series (I -→ rac-II),3 using a trichloroacetamide carrying
the N-[(S)-1-phenylethyl] substituent to obtain a diastereomeric mixture of morphans 1 and 2 (Scheme 1).
The aim of this work was the preparation of two enantiomers of 2-azabicyclo[3.3.1]nonane-3,6-dione (3
and ent-3) by a synthetic route involving diastereomeric precursors that could be easily separated and
thus allow the determination of their absolute configuration by NMR techniques, taking advantage of the
chiral substituent with a known configuration upon the nitrogen atom. These two enantiomers, 3 and ent-
3, could be useful as models in polarimetry determination in other asymmetric synthesis of morphans.
Unexpectedly, studying the course of radical cyclization became a second goal because it diverges from
that observed in the racemic series, as commented on below.
∗
Corresponding author. E-mail: bonjoch@farmacia.far.ub.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00221-9

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Scheme 1.
2. Results and discussion
2.1. Radical cyclization of trichloroacetamides 7 by the hydride method
The preparation of enantiopure trimethylsilylenol ethers 7 was carried out following the same reaction
sequence we had previously performed for the preparation of the racemic N-benzyl analogue I.3
Reductive amination of 1,4-cyclohexanedione monoethylene acetal with (S)-1-phenylethylamine (i,
molecular sieves; ii, NaBH4) gave 4 in excellent yield. Formation of the trichloroacetamide 5 requires
more vigorous conditions (CH2Cl2, reflux) than those used in the benzyl series. Hydrolysis of the acetal
in 5 (3N HCl, reflux), followed by treatment of the resulting ketone 6 with HMDS and TMSI afforded a
non-separated mixture of the two diastereomers 7a and 7b in almost quantitative yield (Scheme 2).
Scheme 2.
Trimethylsilylenol ethers 7a and 7b were obtained in an equimolecular ratio (determined by 1H NMR)
as the chiral inductor was too far from the two diastereotopic methylene groups to the carbonyl group
to promote an enantioselective discrimination. The NMR analysis of trichloroacetamides 7 showed that
each diastereomer appears with a different preferred conformation around the amide bond.10 We assigned
the structure 7a to the compound with an E preferred conformation and the structure 7b to the compound
with a Z preferred conformation, taking into account their behaviour in the following cyclization step.
Surprisingly, when we submitted the trimethylsilylenol ether mixture 7a and 7b to the same reaction
conditions described for cyclization of the N-benzyl analogue I (TTMSS 3.5 equiv., AIBN 1 equiv.
in benzene, reflux 3 h), four compounds were isolated after careful chromatographic separation of the
reaction mixture. Together with the expected diastereomers 1 and 2 in 10% and 21% yield, respectively,
the β-lactam 8 (7%) and normorphan 9 (18%) were also isolated (Scheme 3).
One possible explanation for the observed different course in the radical cyclization of 7a and 7b is
based on the consideration of the Felkin–Anh model for the radical intermediates (Scheme 4). The two
Felkin–Anh conformers A and B, where the N–C bond of the amide is regarded as a double bond, can
be considered for the radical intermediates generated from 7a and 7b. In conformer A steric repulsion
between the phenyl group and the cyclohexane backbone becomes evident. We assumed, therefore, that
the cyclization might proceed more quickly by way of the sterically favoured radical intermediate B.

J. Quirante et al. / Tetrahedron: Asymmetry 10 (1999) 2399–2410
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Scheme 3.
Intermediate A, meanwhile, suffers preferentially competitive pathways leading to 8 and 9. Additionally,
as we have noted, 7a (the precursor of A) has an E conformation around the amide bond which is
unfavourable for the cyclization purpose.11
Scheme 4. Reaction pathway of radicals derived from 7a and 7b
Isolation of β-lactam 8 and normorphan 9 could be explained on the basis of a radical translocation
from the initially formed 1-(carbamoyl)dichloromethyl radical to a 1-amido-1-phenylethyl radical, which
directly or indirectly gives rise to these two products. The mechanism of the reaction is currently under
study in our laboratory. Interestingly, normorphan 9 is an enantioenriched product (see below) even
though the stereogenic centre at the benzylic position had been converted into a radical intermediate
during its formation. This fact implies that 9 arises preferentially from one of the silyl enol ethers, in fact
from 7a. The formation of 9 could be derived from an oxidation12 of the translocated amidoyl radical
to an acyliminium ion which can undergo the cyclization upon the silyl enol ether group. We suggest
that 7a evolves preferentially by this pathway, not only because the transition state reflected in Scheme 4
leading to 1 is sterically demanding but also because its E rotamer evolves easier by an initial hydrogen
transfer. On the other hand, β-lactam 8 is a quasi-racemic compound considering the NMR analysis of its
acetal with a chiral diol (see below). A review of processes involving N-(1-phenylethyl)carbamoylmethyl
radicals,13,14 which lacks two additional chloro atoms present in our initial radical species from 7, did
not show any by-product related to those isolated by us.
When we used experimental conditions for the radical cyclization different to those described above,
the results did not improve. The cyclization of trichloroacetamides 7a and 7b at higher temperatures
(TTMSS 3.5 equiv., AIBN 1 equiv. in refluxing toluene) gave, along with normorphan 9 (8%), a separable
1:2 mixture of the monochlorinated bicyclo ketones 10a and 10b in 33% yield (Fig. 1).
These two compounds, upon reduction with Zn/NH4Cl afforded the previously obtained ketones 1 and
2. On the other hand, when the reaction was carried out with 4.5 equiv. of TTMSS (AIBN 1 equiv. in
refluxing benzene) the bicyclic alcohols 11a and 11b were obtained in addition to compounds 1, 2, 8 and

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Figure 1.
9. Using Bu3SnH instead of TTMSS the resulting crude material showed even more complexity. After
laborious column chromatography, monochloro bicyclo alcohols 12a and 12b in a 2:3 ratio and 26%
combined yield were isolated. These compounds were converted into the bicyclic alcohols 11a and 11b
by reduction with Zn/NH4Cl.
We noted that in all cases, compounds of series a (configuration 1S) were formed in lower yield than
those of series b (configuration 1R) as was observed for compound 1 with respect to 2 (Scheme 5).
Scheme 5.
Treatment of 1 and 2 separately with sodium in liquid ammonia gave the corresponding two enan-
tiomers of the 2-azabicyclo[3.3.1]nonane-3,6-dione, 3 and ent-3, in 45 and 54% yield, respectively. No
reduction of the ketone carbonyl group was observed in any case. The specific rotation for the (1S,5R)
enantiomer 3 was [α]22 +33 (c 1.0, MeOH), whereas for the (1R,5S) enantiomer ent-3 was [α]22 −36 (c
D
D
1.0, MeOH).
2.2. Spectroscopic analysis of azabicyclic compounds isolated
The structural assignment for the target compounds 1, 2 and 3, the unexpected compounds 8 and 9,
and morphans 10–12 (a,b) were carried out by 2D NMR analysis (COSY, HMQC, NOESY and HMBC).
Positive diagnostic evidence for the (1S,5R) configuration for 1 and (1R,5S) configuration for 2 came
from NOESY experiments on these compounds (Fig. 2). The resulting 2D spectrum for 1 showed
off-diagonal cross-peaks connecting H-1 and H-8eq with methyl protons, thus indicating their spacial
proximity. Strong correlations were also observed between aromatic protons and H-1 and H-9, whereas
the methine proton of the side chain did not show any signal. On the other hand, for compound 2 a
good correlation between the methyl group and the H-1 proton was observed. Moreover, in its 1H NMR
spectrum, the signal for H-8eq appears shielded (δ 0.84) with regard to that of isomer 1 (δ 2.26). The
high-field shift of H-8eq in 2 indicates that this proton is held directly below the benzene ring.
NMR spectra of compound 8 indicate a 4-substituted cyclohexanone pattern and the IR spectrum
shows a diagnostic absorption for the β-lactam carbonyl group (1741 cm−1). In the 13C NMR spectrum
there are signals for a quaternary aliphatic carbon (δ 59.0) and a single aliphatic methine carbon (δ 51.2).
The methyl group appears as a singlet (δ 1.83) and the enantiotopic protons at the 3-position appear as
two doublets (J=15 Hz) in the 1H NMR spectrum.

J. Quirante et al. / Tetrahedron: Asymmetry 10 (1999) 2399–2410
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Figure 2.
Figure 3.
For compound 9, most of the signals in the 1H and 13C NMR spectra are duplicated due to the presence
of two rotamers in a 1:1 ratio. In the 13C NMR spectrum the acetamide methyl group appears at δ 23.8
and 24.1 for each rotamer. On the other hand, the methyl group bonded to the quaternary carbon resonates
at δ 23.0 and 24.9 for each rotamer.
The enantiomeric purity of 8 and 9, both containing a ketone group, was determined by analysis
of the NMR spectra of their enantiomeric pure cyclic acetals, which were obtained by condensation
(benzene reflux, TsOH) with (−)-(2R,3R)-butane-2,3-diol.15 The resulting acetal 13 showed to be a quasi-
equimolecular mixture of two compounds reflecting the quasi-racemic character of 8 (Fig. 3). NMR
spectra of 14 were complex due to the presence of rotamers and we decided to reduce the amide carbonyl
group (LiAlH4, THF) to give the amino derivative 15, whose 13C NMR spectrum showed two sets of
signals that correspond to a mixture of diastereomers in a 5:1 ratio (determined by the singlet of the
1
methyl groups in the H NMR spectrum). As a consequence, compound 9 is a scalemic mixture, in
which the enantiomer depicted in Scheme 3 is the predominant one.
The absolute configuration for 9 at C-1, which in turn implies the configuration at C-5, was deduced
from the 13C NMR16 of compound 15.17 The configuration at the quaternary centre at C-7 was established
by analysis of NOESY spectra of 15. In this compound a contact between H-8 and CH3 at C-7 was
observed implying that CH3 has a cis location with respect to the bridgehead protons and thus allowing
the 7S configuration to be established.
The spectroscopic data of morphans 10 are very similar to those of the dechlorinated ones 1 and 2.
Hence, the isomer which shows a shielded H-8eq was assigned to the absolute configuration depicted
for compound 10b. The same diagnostic criteria were applied for alcohols 11 and 12. When the H-8eq
was shielded, for example 11b shows this proton at δ 0.54, the compound was considered to belong to
the 1R,5S series. The stereochemistry at C-4 in compounds 10a and 12a (R) and 10b and 12b (S) was
deduced from the coupling constant of H-4ax, J∼7 Hz, which indicates an equatorial disposition for the
chlorine atom at C-4. The preferred formation of these stereoisomers indicates that the hydrogen atom
transfer from the hydride reagent to the monochlorinated radical intermediate centred at C-4 occurs in an

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J. Quirante et al. / Tetrahedron: Asymmetry 10 (1999) 2399–2410
axial fashion.18 The equatorial disposition of the hydroxyl group at C-6 for compounds 11 and 12 was
deduced from the multiplicity of H-6ax.
3. Conclusions
The first synthesis of enantiomerically pure 2-azabicyclo[3.3.1]nonanes is described. Although the
yield in the radical cyclization of N-(α-methylbenzyl) substituted trichloroacetamides 7 was low, dia-
stereomers 1 and 2 have allowed the preparation of enantiopure 2-azabicyclo[3.3.1]nonane-3,6-diones 3
and ent-3, which can be used as pattern compounds in other asymmetric approaches to the synthesis of
morphans. Furthermore, the radical process from 7 has followed an unexpected course, resulting in the
formation, by a radical translocation, of interesting structures, such as β-lactam 8 and normorphan 9.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in CDCl3 solution at 300 MHz, or at 500 MHz when noted,
and 75.4 MHz, respectively. In addition, 2D NMR COSY and HMQC experiments were performed on
a Varian XL-500 instrument. Chemical shifts are reported as δ values (ppm) relative to internal Me4Si.
Infrared spectra were recorded on a Nicolet 205 FT-IR spectrophotometer. HRMS were determined on
an Autospec-VG apparatus. Optical rotations were taken on a Perkin–Elmer 241 polarimeter with a 1 ml
(L=1 dm) cell. TLC was performed on SiO2 (silica gel 60 F254, Merck). The spots were located by UV
light, a 1% KMnO4 solution or hexachloroplatinate or anisaldehyde reagents. Chromatography refers
to flash column chromatography and was carried out on SiO2 (silica gel 60, SDS, 230–400 mesh). All
reactions were carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous
conditions. Drying of organic extracts during the work-up of reactions was performed over anhydrous
Na2SO4. Melting points were determined in a capillary tube on a Büchi apparatus. Microanalyses were
performed by the ‘Centro de Investigación y Desarrollo’ (CSIC), Barcelona. As a chiral starting material
(S)-α-methylbenzylamine (98% ee) was used.
4.2. 4-[(S)-1-Phenylethylamino]cyclohexan-1-one ethylene acetal 4
A mixture of (S)-(−)-α-methylbenzylamine (2.76 ml, 21.5 mmol) and 1,4-cyclohexanedione mono-
ethylene acetal (3 g, 19.2 mmol) was stirred for 4 h with activated 4 Å molecular sieves. The resulting
suspension was filtered through a short pad of Celite and the filtrate concentrated. To the residue dissolved
in MeOH (40 ml) and cooled at 0°C was added NaBH4 (1.3 g, 34.4 mmol) and the mixture stirred for an
additional 4 h. Water (10 ml) was added to the reaction mixture and MeOH was evaporated. The residue
was dissolved in CH2Cl2 and washed with brine. Concentration of the dried organic extracts afforded 4
(4.8 g, 96%) as an orange oil, which was used in the next step without further purification. An analytical
sample was obtained by chromatography (EtOAc:CH2Cl2, 1:1): [α]22 −50.5 (c 1.6, MeOH); IR (NaCl):
D
3450; 1H NMR: 1.32 (d, J=7 Hz, 3H, CH3), 1.37–1.99 (m, 8H), 2.38 (m, 1H, H-4ax), 3.91 (s, 4H, OCH2),
3.88–3.96 (m, 1H, CH), 7.20–7.35 (m, 5H, ArH); 13C NMR: 25.0 (CH3), 29.6 and 31.1 (C-3 and C-5),
32.7 and 32.9 (C-2 and C-6), 51.9 (C-4), 54.7 (CH), 64.0 and 64.1 (CH2O), 108.6 (C-1), 126.3, 126.6
and 128.3 (Ar), 146.1 (C-ipso); HRMS calcd for C16H23NO2: 261.1728; found: 261.1723.

J. Quirante et al. / Tetrahedron: Asymmetry 10 (1999) 2399–2410
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4.3. 2,2,2-Trichloro-N-[(S)-1-phenylethyl]-N-(4-ethylenedioxycyclohex-1-yl)acetamide 5
To a solution of 4 (5 g, 19.1 mmol) in CH2Cl2 (54 ml) containing triethylamine (5.5 ml, 38.4 mmol)
trichloroacetyl chloride (4.3 ml, 38.3 mmol) in CH2Cl2 (10 ml) was added dropwise. The mixture was
heated at reflux for 24 h, concentrated and the resulting residue was dissolved in CH2Cl2, washed with
1N aqueous HCl, saturated aqueous K2CO3, and brine. The organic layer was dried and concentrated to
leave a solid which was triturated with ether to give, as a brown crystalline material, trichloroacetamide
5 (5.75 g, 80%) as a 1:3 mixture (estimated by 1H NMR) of rotamers Z and E: mp 147–148°C (CH2Cl2);
[α]22 −49.5 (c 1, MeOH); IR (NaCl): 1681; H NMR: 1.50–2.20 (m, 8H), 1.83 (d, J=7 Hz, 3H, CH3),
1
D
3.81–4.00 (m, 4H, CH2O and 0.25H, rotamer Z, H-1ax), 4.52–4.65 (m, 1.6H, rotamer E, H-1ax and CH),
5.84 (q, J=6.5 Hz, 0.2H, rotamer Z, CH), 7.18–7.55 (m, 5H, ArH); 13C NMR: 64.3 and 64.5 (CH2O),
94.2 (CCl3), 125.7, 126.5, 127.4, 127.9, 128.1 and 128.3 (Ar); rotamer Z: 17.0 (CH3), 25.3 and 25.9 (C-2
and C-6), 33.9 and 34.0 (C-3 and C-5), 56.7 (CH), 58.4 (C-1), 107.3 (C-4), 140.5 (C-ipso), 158.2 (CO);
rotamer E: 17.8 (CH3), 27.2 and 27.7 (C-2 and C-6), 33.6 and 33.9 (C-3 and C-5), 54.7 (C-1), 58.2 (CH),
107.0 (C-4), 138.0 (C-ipso), 159.5 (CO). Anal. calcd for C18H22Cl3NO3: C, 53.15; H, 5.45; N, 3.44; Cl,
26.15; found: C, 52.96; H, 5.34; N, 3.66; Cl, 26.28.
4.4. 2,2,2-Trichloro-N-[(S)-1-phenylethyl]-N-(4-oxocyclohex-1-yl)acetamide 6
A solution of 5 (2.5 g, 6.15 mmol) in THF (10 ml) and 3N aqueous HCl (10 ml) was heated at reflux
for 10 h. The THF was evaporated and the mixture was basified with 2.5N aqueous NaOH, and extracted
with CH2Cl2. Concentration of the dried extracts gave a residue which was chromatographed (CH2Cl2)
to give, as a white solid, ketone 6 (2 g, 90%) as a 7:3 mixture (estimated by 1H NMR) of rotamers Z and
E: mp 127–128°C (CH2Cl2); [α]22 −54.0 (c 1, MeOH); IR (NaCl): 1717, 1689; 1H NMR: 2.17–2.59 (m,
D
6H), 2.69 and 2.83 (2 qd, J=12 and 5 Hz, 2H, H-3ax and H-5ax), 7.30–7.57 (m, 5H, ArH); rotamer Z: 1.81
(d, J=7 Hz, 2.1H, CH3), 3.20 (tt, J=11 and 5 Hz, 0.7H, H-1ax), 5.91 (q, J=7 Hz, 0.7H, CH); rotamer E:
1.85 (d, J=7 Hz, 0.9H, CH3), 4.55 (q, J=7 Hz, 0.3H, CH), 5.07 (tm, J=11 Hz, 0.3H, H-1ax); 13C NMR:
94.1 (CCl3), 125.6, 126.8, 127.3, 128.2, 128.3 and 128.5 (Ar); rotamer Z: 17.1 (CH3), 26.2 and 26.7 (C-2
and C-6), 39.1 and 39.2 (C-3 and C-5), 56.2 (C-1), 56.9 (CH), 138.0 (C-ipso), 159.1 (CON), 209.9 (CO);
rotamer E: 18.0 (CH3), 29.1 and 29.7 (C-2 and C-6), 39.4 and 39.7 (C-3 and C-5), 55.0 (C-1), 57.3 (CH),
140.0 (C-ipso), 158.2 (CON), 207.7 (CO). Anal. calcd for C16H17Cl3NO2: C, 53.14; H, 4.74; N, 3.87;
Cl, 29.41; found: C, 53.27; H, 4.72; N, 3.83; Cl, 29.31.
4.5. 2,2,2-Trichloro-N-[(S)-1-phenylethyl]-N-(4-trimethylsilyloxycyclohex-3-en-1-yl)acetamides 7a and
7b
To a cooled (−20°C) solution of ketone 6 (2 g, 5.54 mmol) in 1:1 pentane:CH2Cl2 (140 ml) were added
hexamethyldisilazane (3.1 ml, 14.7 mmol) and trimethylsilyl iodide (1.6 ml, 11.1 mmol). The resulting
solution was stirred at −20°C for 2 h and quenched by the addition of saturated aqueous NaHCO3 (70
ml). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined
organic extracts were washed with 10% aqueous sodium thiosulfate, dried, and concentrated to give a
nearly 1:1 mixture of diastereomeric silyl enol ethers 7 (2.38 g, quantitative) as a yellow oil, which
was used without further purification in the next step. An analytical sample of 7 was obtained after
chromatography (CH2Cl2) as a colourless oil; IR (NaCl): 1685; 1H NMR: 0.11 and 0.20 (2 s, 9H, CH3Si),
1.75 and 1.84 (2 d, J=7 Hz, 3H, CH3), 1.84–2.70 (m, 6H), 2.90–3.11 and 4.78 (2 m, 1H, H-1ax), 4.53
and 5.85 (2 q, J=6.5 Hz, 1H, CH), 4.73 and 4.83 (2 m, W1/2=11 Hz, 1H, H-3), 7.20–7.60 (m, 5H, ArH);

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J. Quirante et al. / Tetrahedron: Asymmetry 10 (1999) 2399–2410
13C NMR: 7a (E conformer): 0.2 (CH3Si), 18.2 (CH3), 25.6, 26.9 and 30.0 (C-2, C-5 and C-6), 55.0
(C-4), 56.2 (CH), 94.5 (CCl3), 102.2 (C-3), 125.3, 125.9, 126.7, 127.4, 127.9, 128.2, 128.3 and 128.4
(Ar), 140.5 (C-ipso), 149.6 (C-4), 158.7 (CO); 7b (Z conformer): 0.2 (CH3Si), 17.1 (CH3), 25.8, 27.3
and 29.6 (C-2, C-5 and C-6), 56.2 (CH), 56.9 (C-4), 94.3 (CCl3), 101.2 (C-3), 126.7, 128.0 and 128.4
(Ar), 138.5 (C-ipso), 149.7 (C-4), 158.9 (CO). Minor signals for other rotamers were observed. HRMS
calcd for C19H26Cl3NO2Si: 433.0798; found: 433.0790.
4.6. Radical cyclization of trichloroacetamides 7. General procedure. With 3.5 equiv. of TTMSS in
benzene
A suspension of 7 (500 mg, 1.15 mmol) and AIBN (200 mg, 1.22 mmol) in benzene (10 ml) was
heated to reflux. Then, TTMSS (1.24 ml, 4.02 mmol) was added dropwise and the reaction mixture was
stirred at this temperature for 3 h. After evaporation of the solvent the residue was chromatographed
(cyclohexane to EtOAc). TLC (2% MeOH in EtOAc, anisaldehyde reagent).
The first eluate gave 4-methyl-4-phenyl-1-(4-oxo-1-cyclohexyl)-2-azetidinone (8, 20 mg, 7%): [α]22
D
1
−4.4 (c 1.0, MeOH); Rf 0.34 (purple); IR (NaCl): 1741, 1721; H NMR (500 MHz, COSY, NOESY):
1.83 (s, 3H, CH3), 1.95–2.01 (m, 2H, H-2 and H-6), 2.08–2.22 (m, 4H), 2.30–2.38 (m, 2H, H-3 and
H-5), 2.93 (2 d, J=15 Hz, 2H, CH2), 3.54 (m, 1H, H-1ax), 7.20–7.40 (m, 5H, ArH); 13C NMR (HMQC,
HMBC): 23.7 (CH3), 30.2 and 30.3 (C-2 and C-6), 39.2 and 39.4 (C-3 and C-5), 51.2 (C-1), 53.8 (CH2),
59.0 (C), 125.5, 127.8, 128.0, 128.6 and 128.8 (Ar), 141.9 (C-ipso), 167.2 (CON), 209.1 (CO). HRMS
calcd for C16H19NO2: 257.1415; found: 257.1414.
The second eluate gave (1S,5R)-N-[(S)-1-phenylethyl]-2-azabicyclo[3.3.1]nonane-3,6-dione (1, 30
mg, 10%): mp 138–139°C; [α]22 −7.8 (c 1.0, MeOH); Rf 0.26 (dark green); IR (NaCl): 1715, 1635;
D
1H NMR (500 MHz, COSY, NOESY): 1.64 (d, J=7 Hz, 3H, CH3), 1.82 (tdd, J=14.5, 5 and 2.5 Hz, 1H,
H-8ax), 1.85–1.93 (m, 2H, H-9), 2.26 (dm, J=14 Hz, 1H, H-8eq), 2.36 (dd, J=15.5 and 5 Hz, 1H, H-7eq),
2.52 (dd, J=18 and 2 Hz, 1H, H-4eq), 2.58 (td, J=15.5 and 6.5 Hz, 1H, H-7ax), 2.77 (m, 1H, H-5eq), 2.80
(dd, J=18 and 8 Hz, 1H, H-4ax), 3.43 (m, 1H, H-1eq), 6.17 (q, J=7.5 Hz, 1H, CH), 7.20–7.40 (m, 5H,
ArH); 13C NMR (HMQC): 17.2 (CH3), 33.3 (C-8), 33.5 (C-9), 33.9 (C-7), 35.0 (C-4), 43.9 (C-5), 46.6
(C-1), 51.7 (CH), 127.3, 127.7 and 128.6 (Ar), 140.0 (C-ipso), 168.3 (C-3), 211.0 (C-6). Anal. calcd for
C16H19NO2.1/3 H2O: C, 72.99; H, 7.53; N, 5.32; found: C, 72.78; H, 7.60; N, 5.30.
The third eluate gave (1R,5S)-N-[(S)-1-phenylethyl]-2-azabicyclo[3.3.1]nonane-3,6-dione (2, 61 mg,
21%): [α]22 −196 (c 1.0, MeOH); Rf 0.25 (dark green); IR (NaCl): 1714, 1631; H NMR (500 MHz,
1
D
COSY, NOESY): 0.84 (dm, J=14 Hz, 1H, H-8eq), 1.36 (tdd, J=14.5, 5 and 2.5 Hz, 1H, H-8ax), 1.58 (d,
J=7 Hz, 3H, CH3), 2.01 (dd, J=15.5 and 5 Hz, 1H, H-7eq), 2.04–2.07 (m, 2H, H-9), 2.29 (td, J=15.5 and
6.5 Hz, 1H, H-7ax), 2.49 (ddd, J=21.5, 3.5 and 1 Hz, 1H, H-4eq), 2.75 (dd, J=22 and 8 Hz, 1H, H-4ax),
2.75 (m, 1H, H-5eq), 3.79 (m, 1H, H-1eq), 6.17 (q, J=7 Hz, 1H, CH), 7.20–7.43 (m, 5H, ArH); 13C NMR
(HMQC): 15.7 (CH3), 31.8 (C-8), 33.7 (C-7 and C-9), 35.0 (C-4), 43.8 (C-5), 46.5 (C-1), 51.0 (CH),
127.8, 128.0 and 128.6 (Ar), 140.2 (C-ipso), 167.9 (C-3), 211.3 (C-6). Anal. calcd for C16H19NO2: C,
74.68; H, 7.44; N, 5.44; found: C, 74.86; H, 7.52; N, 5.39.
The fourth eluate gave (1R,5S,7S)-6-acetyl-7-methyl-7-phenyl-6-azabicyclo[3.2.1]octan-2-one (9, 53
mg, 18%). The following data correspond to a scalemic mixture of 9 and its enantiomer in a 5:1 ratio:18
[α]22 −66.4 (c 1.0, MeOH); Rf 0.22 (orange); IR (NaCl): 1708, 1649; 1H NMR (500 MHz, COSY): 1.58
D
(d, J=12.5 Hz, 0.5H, rotamer E, H-8syn), 1.64 (d, J=12.5 Hz, 0.5H, rotamer Z, H-8syn), 1.75 (dtd, J=13.5,
10 and 2.5 Hz, 0.5H, H-4), 1.85 (s, 1.5H, rotamer E, CH3), 1.87 (s, 1.5H, rotamer E, CH3CON), 1.89
(s, 1.5H, rotamer Z, CH3), 1.85–1.90 (m masked, 0.5H, H-4), 1.90–2.10 (m, 0.5H, H-3), 2.10–2.16 (m,
0.5H, rotamer E, H-8anti), 2.17–2.23 (m, 0.5H, rotamer Z, H-8anti), 2.29 (s, 1.5H, rotamer Z CH3CON),

J. Quirante et al. / Tetrahedron: Asymmetry 10 (1999) 2399–2410
2407
2.28–2.35 (m, 0.5H, H-3 and 0.5H, H-4), 2.42–2.60 (m, 0.5H, H-3 and 0.5H, H-4), 2.70–2.74 (m, 1H, H-
1), 4.39 (m, W1/2=13 Hz, 0.5H, rotamer Z, H-5), 4.89 (m, W1/2=13 Hz, 0.5H, rotamer E, H-5), 7.15–7.40
(m, 5H, ArH); 13C NMR (HMQC, HMBC): 27.5 and 29.7 (C-4), 34.8 and 35.1 (C-3), 125.0, 125.7,
126.8, 127.5, 128.2 and 128.6 (Ar); rotamer Z: 23.0 (CH3), 23.8 (CH3CON), 30.8 (C-8), 56.6 (C-5), 63.6
(C-1), 69.2 (C-7), 142.8 (C-ipso), 168.6 (CON), 208.9 (C-2); rotamer E: 24.1 (CH3CON), 24.9 (CH3),
29.4 (C-8), 56.1 (C-5), 65.7 (C-1), 67.1 (C-7), 143.8 (C-ipso), 170.5 (CON), 209.8 (C-2). HRMS calcd
for C16H19NO2: 257.1416; found: 257.1415.
4.7. Radical cyclization of trichloroacetamides 7. With 3.5 equiv. of TTMSS in toluene
Following the general procedure trimethylsilyl enol ethers 7 (350 mg, 0.8 mmol) in toluene (7 ml)
were treated with AIBN (139 mg, 0.85 mmol) and 3.5 equiv. of TTMSS (0.86 ml, 2.8 mmol) and the
crude material was chromatographed (1% MeOH in CH2Cl2). The first eluate gave the monochloro
bicyclo ketones 10a and 10b (77 mg, 33% combined yield) as a mixture of diastereomers in a 1:2
ratio. The second eluate gave normorphan 9 (16 mg, 8%). Separation of the diastereomeric mixture
was accomplished by a second column chromatography (EtOAc in hexane from 50% to 70%). The
first eluate gave (1S,4R,5S)-4-chloro-[(S)-1-phenylethyl]-2-azabicyclo[3.3.1]nonane-3,6-dione 10a: IR
(NaCl): 1717, 1652; 1H NMR (500 MHz, COSY): 1.66 (d, J=7.5 Hz, 3H, CH3), 1.82 (tdd, J=15, 5 and
2.5 Hz, 1H, H-8ax), 1.99 (m, 2H, H-9), 2.25 (dm, J=14 Hz, 1H, H-8eq), 2.46 (dm, J=14 Hz, 1H, H-7eq),
2.66 (td, J=15 and 7 Hz, 1H, H-7ax), 3.11 (m, W1/2=14 Hz, 1H, H-5eq), 3.46 (br s, 1H, H-1eq), 4.70
(d, J=7 Hz, 1H, H-4ax), 6.10 (q, J=7 Hz, 1H, CH), 7.28–7.50 (m, 5H, ArH); 13C NMR (HMQC): 17.1
(CH3), 33.1 (C-8), 34.2 (C-9), 34.8 (C-7), 47.2 (C-5), 52.0 (C-1), 53.2 (CH), 55.5 (C-4), 127.4, 128.1 and
128.9 (Ar), 139.4 (C-ipso), 165.7 (C-3), 206.9 (C-6). Anal. calcd for C16H18NO2Cl.1/4 H2O: C, 64.86;
H, 6.29; N, 4.73; found: C, 64.55; H, 6.29; N, 4.97. The second eluate gave (1R,4S,5R)-4-chloro-2-[(S)-
1
1-phenylethyl]-2-azabicyclo[3.3.1]nonane-3,6-dione 10b: IR (NaCl): 1721, 1650; H NMR (500 MHz,
COSY): 0.85–0.95 (m, 1H, H-8eq), 1.41 (tdd, J=14, 4.5 and 2.5 Hz, 1H, H-8ax), 1.63 (d, J=7 Hz, 3H,
CH3), 2.16 (dm, J=14 Hz, 2H, H-7eq and H-9anti), 2.26 (ddd, J=14, 6.5 and 2.5 Hz, 1H, H-9syn), 2.40 (td,
J=14.5 and 7 Hz, 1H, H-7ax), 3.15 (m, W1/2=14 Hz, 1H, H-5eq), 3.81 (br s, 1H, H-1eq), 4.67 (d, J=7.5
Hz, 1H, H-4ax), 6.16 (q, J=7 Hz, 1H, CH), 7.25–7.50 (m, 5H, ArH); 13C NMR (HMQC): 15.8 (CH3),
31.4 (C-8), 34.5 (C-9), 34.6 (C-7), 47.2 (C-5), 51.6 (C-1), 52.3 (CH), 55.2 (C-4), 127.7, 128.3 and 128.8
(Ar), 139.5 (C-ipso), 165.3 (C-3), 207.0 (C-6).
4.8. Radical cyclization of trichloroacetamides 7. With 4.5 equiv. of TTMSS in benzene
Following the general procedure, trichloroacetamides 7 (1 g, 2.3 mmol) in benzene (20 ml) were
treated with AIBN (377 mg, 2.3 mmol) and 4.5 equiv. of TTMSS (3.2 ml, 10.35 mmol), and the crude
material was chromatographed (EtOAc in hexane from 50% to 70%). The first fraction gave the β-
lactam 8 (34 mg, 6%), the second fraction gave the ketone 1 (42 mg, 7%), the third fraction afforded
the ketone 2 (70 mg, 12%), the fourth fraction gave the normorphan 9 (110 mg, 19%), and the last
fraction gave a diastereomeric mixture of alcohols 11a and 11b (80 mg, 13% combined yield) in a
1:3 ratio. (1S,5R,6R)-6-Hydroxy-2-[(S)-1-phenylethyl]-2-azabicyclo[3.3.1]nonan-3-one 11a: IR (NaCl):
3600, 1608; 1H NMR: 1.56 (d, J=7.5 Hz, CH3), 2.13 (m, H-5), 2.48 (dd, J=19 and 7.5 Hz, H-4ax), 2.83
(d, J=19 Hz, H-4eq), 3.59 (m, W1/2=9 Hz, H-1), 3.72 (m, H-6ax), 6.07 (q, J=7.5 Hz, CH), 7.20–7.40 (m,
ArH); 13C NMR: 17.2 (CH3), 25.8 (C-7), 29.7 (C-8), 31.2 (C-9), 31.7 (C-4), 33.9 (C-5), 46.5 (C-1), 51.2
(CH), 71.4 (C-6), 127.8, 128.4 and 128.5 (Ar), 140.7 (C-ipso), 171.1 (C-3). (1R,5S,6S)-6-Hydroxy-2-
1
[(S)-1-phenylethyl]-2-azabicyclo[3.3.1]nonan-3-one 11b: IR (NaCl): 3600, 1608; H NMR: 0.54 (dm,

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J. Quirante et al. / Tetrahedron: Asymmetry 10 (1999) 2399–2410
J=13.7 Hz, 1H, H-8eq), 0.99 (tdd, J=13.5, 4 and 2.5 Hz, 1H, H-8ax), 1.21 (qd, J=13.5 and 4 Hz, 1H, H-
7ax), 1.35 (dm, J=14 Hz, 1H, H-7eq), 1.52 (d, J=7 Hz, 3H, CH3), 1.82–1.94 (m, 2H, H-9), 2.22 (m, 1H,
H-5), 2.43 (dd, J=19 and 7.5 Hz, 1H, H-4ax), 2.80 (dd, J=19 and 0.75 Hz, 1H, H-4eq), 3.52 (m, W1/2=9
Hz, 1H, H-1), 3.65 (dt, J=11 and 4.5 Hz, 1H, H-6ax), 6.05 (q, J=7.5 Hz, 1H, CH), 7.20–7.40 (m, 5H,
ArH); 13C NMR: 15.7 (CH3), 25.6 (C-7), 29.3 (C-8), 31.0 (C-9), 32.1 (C-4), 33.7 (C-5), 46.5 (C-1), 50.9
(CH), 71.3 (C-6), 127.2, 127.3 and 127.6 (Ar), 140.6 (C-ipso), 170.6 (C-3). HRMS calcd for C16H21NO2
259.1572; found: 259.1579.
4.9. Radical cyclization of trichloroacetamides 7. With 3.5 equiv. of Bu3SnH in benzene
Following the general procedure, trichloroacetamides 7 (200 mg, 0.46 mmol) in benzene (4 ml) were
treated with AIBN (80 mg, 0.49 mmol) and 3.5 equiv. of Bu3SnH (0.43 ml, 1.61 mmol), and the crude
material was chromatographed (1% MeOH in CH2Cl2) to give a diastereomeric mixture of monochloro
bicyclo alcohols 12a and 12b (36 mg, 27% combined yield) in a 1:2 ratio. (1S,4R,5S,6R)-4-Chloro-6-
1
hydroxy-2-[(S)-1-phenylethyl]-2-azabicyclo[3.3.1]nonan-3-one 12a: IR (NaCl): 3450, 1648; H NMR:
1.20–2.10 (m, 6H), 1.62 (d, J=7 Hz, 3H, CH3), 3.23 (m, 1H, H-5eq), 3.70 (m, 1H, H-6ax), 3.91 (m,
1H, H-1eq), 4.88 (d, J=6.5 Hz, 1H, H-4), 5.99 (q, J=7.5 Hz, 1H, CH), 7.20–7.50 (m, 5H, ArH); 13C
NMR: 15.9 (CH3), 26.6 (C-7), 31.1 (C-8), 34.2 (C-9), 40.1 (C-5), 47.1 (C-1), 53.1 (CH), 59.5 (C-4), 74.7
(C-6), 127.3 and 127.9 (ArH), 139.8 (C-ipso), 166.2 (C-3). (1R,4S,5R,6S)-4-Chloro-6-hydroxy-2-[(S)-
1
1-phenylethyl]-2-azabicyclo[3.3.1]nonan-3-one 12b: IR (NaCl): 3450, 1648; H NMR: 0.71 (dm, J=13
Hz, 1H, H-8eq), 1.10 (tm, J=13 Hz, 1H, H-8ax), 1.57 (d, J=7 Hz, 3H, CH3), 1.25–2.10 (m, 4H), 2.82 (m,
W
1/2=12 Hz, 1H, H-5eq), 3.57 (m, 1H, H-1eq), 3.70 (m, 1H, H-6ax), 4.82 (d, J=6.5 Hz, 1H, H-4), 5.94 (q,
J=7.5 Hz, 1H, CH), 7.20–7.50 (m, 5H, ArH); 13C NMR: 17.1 (CH3), 26.8 (C-7), 29.3 (C-8), 34.4 (C-9),
39.8 (C-5), 47.5 (C-1), 52.7 (CH), 59.4 (C-4), 74.7 (C-6), 127.7 and 128.5 (ArH), 139.8 (C-ipso), 166.2
(C-3).
4.10. Reduction of monochloro ketones 10a and 10b
To a solution of monochlorinated bicyclo ketones 10a and 10b (55 mg, 0.19 mmol) in MeOH (4 ml)
were added ammonium chloride (61 mg, 1.14 mmol) and, after cooling to 0°C, powdered zinc (120 mg,
1.9 mmol). Stirring was continued at room temperature for 24 h and the reaction mixture was filtered
through Celite and the filtrate concentrated to give ketones 1 and 2 (43 mg, 89% combined yield).
4.11. Reduction of monochloro alcohols 12a and 12b
Operating as above, 12a and 12b (35 mg, 0.12 mmol) in CH3OH (4 ml) were treated with powdered
zinc (76 mg, 1.2 mmol) and ammonium chloride (38 mg, 0.12 mmol) to give alcohols 11a and 11b (26
mg, 85% combined yield).
4.12. (1S,5R)-2-Azabicyclo[3.3.1]nonane-3,6-dione 3
To a solution of amide 1 (30 mg, 0.12 mmol) in THF (6 ml) at −78°C was added liquid ammonia (25
ml) and sodium (22 mg, 0.95 mmol) in small portions, and the mixture was stirred at this temperature for
1 h. The reaction was quenched by the addition of ammonium chloride, and the mixture was allowed
to warm to room temperature to remove any excess ammonia. To the reaction mixture was added
successively saturated ammonium chloride solution (3 ml), EtOAc (100 ml) and, after stirring for 2

J. Quirante et al. / Tetrahedron: Asymmetry 10 (1999) 2399–2410
2409
h, Na2SO4, and the dried organic extracts concentrated. Purification by chromatography (EtOAc:MeOH,
90:10) of the residue afforded morphan 3 (8 mg, 45%) as a white solid: mp 107–108°C; [α]22 +33 (c
D
1.0, MeOH); IR (NaCl): 3200, 1706, 1648; 1H NMR (500 MHz, COSY, HMQC): 1.97 (tdd, J=13.5, 5.5
and 2.5, 1H, H-8ax), 2.09 (dm, J=13.5 Hz, 1H, H-9), 2.15 (m, 1H, H-8eq), 2.21 (ddd, J=13.5, 6.5 and
3 Hz, 1H, H-9), 2.45 (m, 2H, H-4eq and H-7eq), 2.60 (ddd, J=16.5, 13 and 7 Hz, 1H, H-7ax), 2.70 (dd,
J=18.5, 7 Hz, 1H, H-4ax), 2.84 (m, W1/2=13 Hz, 1H, H-5eq), 3.84 (m, W1/2=11 Hz, 1H, H-1eq), 6.20 (br
s, 1H, H-1eq); 13C NMR (HMQC): 31.1 (C-9), 33.4 (C-8), 33.7 (C-7), 34.5 (C-4), 43.5 (C-1), 46.2 (C-5),
170.5 (C-3), 210.7 (C-6). Anal. calcd for C8H11NO2.H2O: C, 56.13; H, 7.65; N, 8.18; found: C, 56.39;
H, 7.68; N, 8.14.
4.13. (1R,5S)-2-Azabicyclo[3.3.1]nonane-3,6-dione ent-3
Operating as above, from amide 2 (40 mg, 0.12 mmol), liquid ammonia (25 ml) and sodium (30 mg,
1.3 mmol) in THF (6 ml), after chromatography (EtOAc:MeOH, 90:10), ent-3 (13 mg, 54%) was isolated
as a white solid; [α]22 −36 (c 1.0, MeOH). The mp, IR, 1H and 13C NMR spectra were coincident with
D
those of 3. MS (CI) m/z 154 ([M+H]+, 100), 149 (6), 85 (10), 83 (15).
Acknowledgements
Support for this research was provided by DGES (Spain) through Grant PB97-0877. Thanks are
also due to the Comissionat per a Universitats i Recerca (Catalonia) for Grant 1997SGR-00166 and
fellowships to C.E. and F.D. The laboratory work by undergraduate student Xavier Vila is gratefully
acknowledged.
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compound 5: Z:E rotamers 1:3 ratio; compound 6: Z:E rotamers 7:3 ratio.

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17. (1R,5S,7S)-6-Ethyl-2-[40R,50R-40,50-dimethyl-spiro-1030-dioxolane]-7-methyl-7-phenyl-6-azabicyclo[3.2.1]octane (15):
13C NMR: 15.5 (CH3), 17.3 and 18.1 (CH3 acetal), 21.8 (7-CH3), 25.9 (C-4), 32.0 and 32.7 (C-3 and C-8), 38.4 (NCH2),
54.2 (C-5), 55.9 (C-1), 67.1 (C-7), 77.6 and 78.9 (CH acetal), 110.6 (C-2), 125.3, 126.1, 127.4, 152.8 (Ar). The minor
signals corresponding to the (1S,5R,7R) isomer are the following: 14.0, 16.8, 17.0, 21.7, 26.2, 29.7, 31.4, 38.4, 53.9, 55.3,
68.1, 77.2, 77.9, 110.2, 124.9, 126.0, 127.4 and 152.8.
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