Regiochemical aspects of intramolecular cycloadditions of nitrones derived from N-(2-alkenyl)-2-pyrrolecarbaldehydes. Competitive entries to pyrrolizidine and indolizidine derivatives

Article abstract of DOI:10.1016/S0040-4020(01)00785-2

Intramolecular cycloadditions of unsaturated nitrones derived from a series of N-(2-alkenyl)-2-pyrrolecarbaldehydes (2) have been systematically studied. A pronounced substituent effect has been observed as far as the competitive formation of fused- and bridged-ring regioisomers are concerned. Further elaboration of the two kinds of cycloadducts has given pyrrolizidine and indolizidine derivatives, respectively.

Full text of DOI:10.1016/S0040-4020(01)00785-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 8323±8332
Regiochemical aspects of intramolecular cycloadditions of
nitrones derived from N-ꢀ2-alkenyl)-2-pyrrolecarbaldehydes.
Competitive entries to pyrrolizidine and indolizidine derivatives
Gianluigi Broggini,a Concetta La Rosa,b Tullio Pilati,c Alberto Terraneod and Gaetano Zecchia,p
a
Á
Dipartimento di Scienze Chimiche, Fisiche e Matematiche dell'Universita dell'Insubria, via Lucini 3, 22100 Como, Italy
b
Á Á
Istituto di Chimica Organica della Facolta di Farmacia dell'Universita di Milano, via Venezian 21, 20133 Milano, Italy
c
Á
Centro CNR per le Relazioni tra Struttura e Reattivita Chimica, via Golgi 19, 20133 Milano, Italy
Á
Dipartimento di Chimica Organica e Industriale dell'Universita di Milano, via Golgi 19, 20133 Milano, Italy
d
Received 8 May 2001; accepted 2 August 2001
AbstractÐIntramolecular cycloadditions of unsaturated nitrones derived from a series of N-(2-alkenyl)-2-pyrrolecarbaldehydes (2) have
been systematically studied. A pronounced substituent effect has been observed as far as the competitive formation of fused- and bridged-ring
regioisomers are concerned. Further elaboration of the two kinds of cycloadducts has given pyrrolizidine and indolizidine derivatives,
respectively. q 2001Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2.1. Intramolecular nitrone cycloadditions
Intramolecular cycloaddition of a nitrone functionality to
the ethylenic bond1,2 constitutes a ¯exible and powerful
methodology which has resulted in the synthesis of an
impressive array of bioactive compounds, both natural and
unnatural, such as alkaloids,2,3 terpenes,4 sugar analogues,5
modi®ed nucleosides,6 and b-lactam antibiotics.7 Novel and
fruitful applications of this methodology, where new stereo-
genic centres are often formed under relative and/or
absolute stereocontrol, are continually appearing in the
chemical literature.8
In light of the above purpose, we synthesized the substituted
2-pyrrolecarbaldehydes 2a±d and treated them with benzyl-
hydroxylamine in order to generate the unsaturated nitrones
3a±d (Scheme 1). Heat treatment of the latter gave two
kinds of intramolecular cycloadducts, namely the fused-
ring compounds 4 and the bridged-ring compounds 5. In
both instances, however, the relative con®guration of the
newly-created stereogenic centres was unique as a conse-
quence of the following concomitant features: (i) the
concerted, i.e. stereoconservative, mechanism of the
cycloaddition and (ii) the forced cis-junction of the two
formed rings. The latter constriction would not have been
operative in intermolecular nitrone cycloadditions, which
usually exhibit lower degrees of diastereoselection unless
stringent steric demands or attractive secondary interactions
are involved.2a,12
Our previous contribution to this area was concerned with
the synthesis of enantiopure 3-hydroxymethylchromanes of
potential interest as a-adrenergic blocking agents.9 Later,
we turned our attention towards pyrrolizidines and indo-
lizidines structurally related to alkaloids endowed with
cytostatic activities.10 Having in mind these targets, nitrones
derived from N-(2-alkenyl)substituted 2-pyrrolecarbalde-
hydes were conceived as appropriate intermediates. The
®rst, albeit promising, results were limited to the simple
N-allyl-2-pyrrolecarbaldehyde (2e).11 In the present paper,
with the aim of better de®ning the scope and limitations of
our synthetic approach, we describe a systematic study
involving a number of related substrates.
As far as the regiochemical outcome of the cycloaddition is
concerned, the isolation yields reported in Scheme 1reveal
a marked substituent effect, which is possibly steric more
than electronic in origin. Molecular models show that the
formation of the bridged-ring product requires the dis-
position of the pendent dipolarophile to be towards the
inside of the molecule (Fig. 1).
Keywords: regioselection; nitrones; pyrrolizidines; indolizidines; intra-
molecular cycloaddition.
Corresponding author. Tel.: 139-031-326-219; fax: 139-031-326-230;
e-mail: mabuck@icil64.cilea.it
Therefore, encumbering substituents at the dipolarophilic
site should work against such a disposition. In line with
this view, the bridged-ring product is formed to the greatest
p
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00785-2

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G. Broggini et al. / Tetrahedron 57 22001) 8323±8332
b
Scheme 1. Intramolecular cycloaddition reactions of nitrones 3. aIsolation yield of pure product after column chromatography. From Ref. [11].
A similar regiochemical trend was observed when we
reacted the same aldehydes 2a±d with (R)-a-methylbenzyl-
hydroxylamine in order to synthesize optically active
compounds. Actually, the intramolecular cycloaddition of
the ®rst-formed nitrones 6a±d resulted in two diastereo-
isomeric pairs of regioisomers (Scheme 2). The regio-
chemical proportions roughly re¯ect those observed for
the corresponding nitrones 3a±d, although the formation
of bridged-ring structures was generally depressed owing
Figure 1. Regioisomeric approaches for the intramolecular cycloaddition
to the increase of the steric hindrance exerted by the
of nitrones 3 to give fused-ring (A) and bridged-ring (B) adducts.
N-pendant of the dipole.
extent in the case of the most simple substrate 3e, while it is
not formed at all in the case of 3c having two methyl groups
on the dipolarophilic double bond. Recent papers13 have
pointed out that a complex interplay of factors intervenes
to dictate the regiochemistry of intramolecular nitrone
cycloadditions, such that prediction of product outcomes
may well be a complex matter.
Absolute con®gurations were assigned to the cycloadducts
on the basis of the NMR evidence, corroborated by the
X-ray diffractometric analysis of 7d (Fig. 2). The latter
demonstrated that, due to the spatial location of the phenyl
ring, the pyrrolic hydrogen in the 3-position (dHˆ5.37 ppm)
suffers from a shielding effect. On the other hand, a confor-
mational analysis by molecular models indicated that such
Scheme 2. Intramolecular cycloaddition reactions of nitrones 6.

G. Broggini et al. / Tetrahedron 57 22001) 8323±8332
8325
Figure 2. Structure of 7d determined by X-ray analysis. Thermal ellipsoids
at 50% probability level.
Table 1. Observed chemical shifts of the pyrrolic 3-hydrogens
Entry
7
8
9
10
A
B
C
D
4.70
4.78
5.28
5.37
3
5.816.1 5.60
5.83
5.85
6.08
±
5.915.54
5.53
±
5.83
an effect is possible only for one isomer of each diastereo-
isomeric pair. Consequently, the observed differences
between the chemical shifts of the pyrrolic 3-hydrogens
became fully diagnostic (Table 1).
Scheme 3. Hydrogenation reactions of cycloadducts 4a±d and 5d.
2.2. Elaboration of the cycloadducts
The second part of our study was focused on the elaboration
of the above described cycloadducts, particularly with the
idea of bringing to light the latent functionalities of the
isoxazolidine ring. Furthermore, we perceived that
saturation of the pyrrole nucleus would give pyrrolizidine
or indolizidine derivatives more strictly related to natural
alkaloids. In order to gain these targets, catalytic hydro-
genation was chosen as the most appropriate procedure.
Experimental results concerning racemic cycloadducts are
outlined in Scheme 3.
Scheme 4. Hydrogenation reactions of optically active cycloadducts:
MeOH±HCl with Pd(OH)2/C as catalyst.
by steric demands due to the cis-fusion of the pyrrolizidine
skeleton.
The requisite saturation of the pyrrole nucleus took place
only when operating in the presence of HCl. These strongly
protic conditions, on the other hand, induced concurrent
pathways: (i) the complete loss of the pseudobenzylic
amino group in the case of 4d and 5d, which afforded 12
and 14, respectively; (ii) the partial removal of the alcoholic
function, if tertiary or benzylic, so determining the forma-
tion of 13a,c. Stereochemical assignments to the products,
which contain newly created stereocentre(s), were based
upon the following NMR considerations: (i) the electron
pair of the bridge-head nitrogen exerts a pronounced
deshielding effect on the a-hydrogens only if they are cis
disposed; (ii) the axial disposition of the hydroxyl group in
14 is proven by the NMR signal of the adjacent hydrogen
which does not exhibit any large, i.e. diaxial, coupling
constant. The total diastereoselection observed in the satura-
tion of the pyrrole nucleus must be stressed as a noteworthy
feature. Literature data14 indicate that cis-2,5-disubstituted
pyrrolidines are preferred products in the catalytic hydro-
genation of pyrroles. Therefore, the formation of 12 is
somewhat surprising and may be tentatively accounted for
The hydrogenolytic treatment of optically active cyclo-
adducts, summarized in Scheme 4, allowed the isolation
of pyrrolizidine aminoalcohol 11a, alcohol 12, amines
13a,c and indolizidine alcohol 14 in enantiopure form.
The enantiomeric purity was veri®ed in the case of (1)-14
and (2)-14 by recording the 1H NMR spectra at 300 MHz in
the presence of (R)-(1)-O-acetylmandelic acid.
3. Conclusion
In light of the results here reported, one can conclude that
intramolecular cycloadditions of nitrones available from
N-(2-alkenyl)-2-pyrrolecarbaldehydes constitute an ef®cient
and stereoselective route to pyrrolizidine derivatives. The
same sequence may serve to achieve indolizidine deriva-
tives with dependence on the regiochemical outcome of
the intramolecular cycloaddition, namely provided that no
structural factors, steric in nature, work against the forma-
tion of bridged-ring cycloadducts.

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G. Broggini et al. / Tetrahedron 57 22001) 8323±8332
4. Experimental
Jˆ7.5 Hz), 4.74 (1H, dd, Jˆ1.2, 17.1 Hz), 4.91±5.04 (2H,
m), 5.08 (1H, dd, Jˆ1.2, 10.3 Hz), 5.93 (1H, tdd, Jˆ4.6,
10.3, 17.1 Hz), 6.06 (1H, d, Jˆ3.9 Hz), 6.88 (1H, d,
Jˆ3.9 Hz), 9.40 (1H, s). MS: m/z 191 (M1). IR: n
4.1. General
1672 cm21
.
Preparative column chromatography was carried out on
silica gel 60 (Merck) (mesh size 63±200 mm). NMR spectra
were recorded on an AC 300 Bruker. Chemical shifts are
reported in ppm relative to CHCl3 (1Hˆ7.26) and CDCl3
(13Cˆ77.0) as internal standard. Optical rotations were
measured on a Perkin±Elmer 241polarimeter. Mass spectra
were determined on a WG-70EQ instrument. IR spectra
were taken on a FT-IR Perkin±Elmer 1725X spectro-
photometer. Melting points were measured on a BuÈchi
B-540 heating unit and are not corrected.
4.2. General procedure for the synthesis of nitrones 3a±d
A suspension of N-benzylhydroxylamine hydrochloride
(7.0 mmol), MgSO4 (85 mmol) and NaHCO3 (12 mmol) in
dry diethyl ether (100 mL) was stirred for 1 h, then a
solution of 2 (5.6 mmol) in diethyl ether was added. The
mixture was stirred for the time given below, ®ltered and
evaporated. The crude oil so obtained was crystallized with
diisopropyl ether (entries b and c) or chromatographed on a
silica gel column (entries a and d) to give 3a±d.
4.1.1. 5-Butyl-2-pyrrolecarbaldehyde ꢀ1). Phosphorus
oxychloride (8.9 g, 58 mmol) in dry toluene (8 mL) was
added, at 5±108C, to a stirred solution of dimethylforma-
mide (5 mL) in dry toluene (6 mL). After 30 min, 2-butyl-
pyrrole15 (6.4 g, 52 mmol) in dimethylformamide (6 mL)
was added at 5±108C. The solution was stirred for 1h at
208C, then poured in ice±water (60 mL). Until a basic
solution was obtained, 10% aqueous NaOH was added
and the product was extracted into chloroform. The organic
layer was dried over Na2SO4 and evaporated under reduced
pressure to give 5.49 g (70%) of 1.16
4.2.1. Nitrone 3a. 48 h. Eluent: ethyl acetate. Yield: 60%.
1
Mp 141±1438C. H NMR (300 MHz, CDCl3): dˆ4.60±
4.63 (2H, overlapping), 4.97 (2H, s), 6.13±6.15 (2H, over-
lapping), 6.29 (1H, dd, Jˆ2.9, 3.7 Hz), 6.82 (1H, dd, Jˆ1.6,
2.9 Hz), 7.26±7.46 (11H, overlapping), 7.85 (1H, dd,
Jˆ1.6, 3.7 Hz). 13C NMR (75 MHz, CDCl3): dˆ50.0 (t),
74.6 (t), 109.3 (d), 117.8 (d), 124.1 (d), 125.0 (s), 125.2
(d), 125.9 (d), 126.1 (d), 128.1 (d), 128.5 (d), 128.8 (d),
129.0 (d), 129.2 (d), 132.5 (d), 136.0 (s), 138.8 (s). MS:
m/z 316 (M1). C21H20N2O (316.4): calcd C 79.72, H 6.37,
N 8.85; found C 79.57, H 6.49, N 8.66.
4.1.2. 1-Cinnamyl-2-pyrrolecarbaldehyde ꢀ2a). Cinnamyl
bromide (3.2 g, 16 mmol), triethylbenzyl ammonium
bromide (170 mg, 0.5 mmol) and 50% aqueous NaOH
(6 mL) were added to a solution of 2-pyrrolecarbaldehyde
(1.0 g, 10 mmol) in benzene (32 mL). The mixture was
vigorously stirred at room temperature for 1h. The organic
layer was separated, washed with water and dried over
Na2SO4. The solvent was evaporated under reduced
pressure to give 1.98 g (57%) of 2a. Oil. 1H NMR
(300 MHz, CDCl3): dˆ5.15 (2H, d, Jˆ5.9 Hz), 6.29 (1H,
dd, Jˆ2.5, 4.0 Hz), 6.36 (1H, dt, Jˆ5.9, 15.8 Hz), 6.49 (1H,
d, Jˆ15.8 Hz), 6.99 (1H, dd, Jˆ1.7, 4.0 Hz), 7.05 (1H, br s),
7.22±7.39 (5H, overlapping), 9.60 (1H, s). MS: m/z 211
4.2.2. Nitrone 3b. 72 h. Yield: 84%. Mp 111±1138C (from
1
diisopropyl ether). H NMR (300 MHz, CDCl3): dˆ0.86
(3H, t, Jˆ7.4 Hz), 1.33 (2H, tq, Jˆ7.4, 7.4 Hz), 1.93 (2H,
dt, Jˆ7.4, 7.4 Hz), 4.37 (2H, d, Jˆ5.2 Hz), 4.99 (2H, s),
5.28±5.41(2H, m), 6.24 (H1 , dd,
(1H, dd, Jˆ1.7, 3.0 Hz), 7.30±7.43 (6H, overlapping),
Jˆ3.0, 3.5 Hz), 6.77
7.81(H1, dd,
Jˆ1.7, 3.5 Hz). 13C NMR (75 MHz,
CDCl3): dˆ13.6 (q), 22.0 (t), 34.0 (t), 49.3 (t), 69.5 (t),
109.0 (d), 116.6 (d), 124.0 (s), 124.5 (d), 125.2 (d), 125.4
(d), 128.8 (d), 128.9 (d), 129.2 (d), 132.3 (s), 133.9 (d). MS:
m/z 282 (M1). C18H22N2O (282.4): calcd C 76.56, H 7.85, N
9.92; found C 76.39, H 7.99, N 10.05.
(M1). IR: n 1673 cm21
.
4.1.3. 1-ꢀ2-Hexenyl)-2-pyrrolecarbaldehyde ꢀ2b).
A
4.2.3. Nitrone 3c. 168 h. Yield: 59%. Mp 123±1248C (from
1
solution of 2-pyrrolecarbaldehyde (0.95 g, 10 mmol) in
dioxane (20 mL) was treated with K2CO3 (4.8 g, 35 mmol)
and 2-hexenyl bromide (4.9 g, 30 mmol). The suspension
was re¯uxed for 24 h, then diluted with toluene (60 mL)
and ®ltered through celite. The solvent was removed
under reduced pressure to give 1.63 g (92%) of 2b. Oil.
1H NMR (300 MHz, CDCl3): dˆ0.86 (3H, t, Jˆ7.4 Hz),
1.37 (2H, tq, Jˆ7.4, 7.4 Hz), 1.94±2.04 (2H, m), 4.89
(2H, d, Jˆ4.2 Hz), 5.54±5.67 (2H, m), 6.22 (1H, dd,
Jˆ3.9, 2.6 Hz), 6.92 (1H, dd, Jˆ3.9, 1.5 Hz), 6.96 (1H, br
diisopropyl ether). H NMR (300 MHz, CDCl3): dˆ1.59
(3H, s), 1.69 (3H, s), 4.40 (2H, d, Jˆ6.6 Hz), 5.00 (2H s),
5.14 (1H, br t, Jˆ6.6 Hz), 6.22 (1H, dd, Jˆ3.0, 3.7 Hz), 6.76
(1H, dd, Jˆ1.7, 3.0 Hz), 7.22 (1H, s), 7.36±7.43 (5H, over-
lapping), 7.82 (1H, dd, Jˆ1.7, 3.7 Hz). 13C NMR (75 MHz,
CDCl3): dˆ18.3 (q), 25.9 (q), 46.0 (t), 70.0 (t), 109.3 (d),
117.0 (d), 120.5 (d), 124.4 (s),124.9 (d), 125.8 (d), 128.8 (d),
129.2 (d), 129.8 (d), 133.9 (s), 136.4 (s). MS: m/z 268 (M1).
C17H20N2O (268.4): calcd C 76.09, H 7.51, N 10.44; found
C 76.18, H 7.33, N 10.38.
s), 9.53 (1H, s). MS: m/z 177 (M1). IR: n 1666 cm21
.
4.2.4. Nitrone 3d. 96 h. Eluent: hexane/ethyl acetate 1:1.
Yield: 41%. Mp 75±788C (from diisopropyl ether). 1H
NMR (300 MHz, CDCl3): dˆ0.91(3H, t, Jˆ7.3 Hz), 1.36
(2H, tq, Jˆ7.3, 7.5 Hz), 1.53±1.61 (2H, m), 2.49 (2H, t,
Jˆ7.5 Hz), 4.33±4.39 (2H, m), 4.63 (1H, d, Jˆ17.1 Hz),
4.97 (2H, s), 5.06 (1H, d, Jˆ10.5 Hz), 5.75 (1H, ddt,
Jˆ4.5, 10.5, 17.1 Hz), 6.05 (1H, d, Jˆ3.9 Hz), 7.14 (1H,
s), 7.33±7.42 (5H, overlapping), 7.80 (1H, d, Jˆ3.9 Hz).
13C NMR (75 MHz, CDCl3): dˆ13.8 (q), 22.4 (t), 26.2 (t),
4.1.4. 1-Prenyl-2-pyrrolecarbaldehyde ꢀ2c). The com-
pound was prepared as described in the literature.17
4.1.5. 1-Allyl-5-butyl-2-pyrrolecarbaldehyde ꢀ2d). Accord-
ing to the preceding procedure, 5-butyl-2-pyrrolcarbalde-
hyde and allyl bromide gave 2d (62%). Oil. 1H NMR
(300 MHz, CDCl3): dˆ0.94 (3H, t, Jˆ7.4 Hz), 1.40 (2H,
tq, Jˆ7.4, 7.4 Hz), 1.56±1.70 (2H, m), 2.54 (2H, t,

G. Broggini et al. / Tetrahedron 57 22001) 8323±8332
8327
30.6 (t), 45.5 (t), 69.3 (t), 107.8 (d), 115.9 (d), 116.5 (t),
123.7 (s), 124.7 (d), 128.6 (d), 128.8 (d), 129.3 (d), 133.3
(d), 133.6 (s), 138.4 (s). MS: m/z 296 (M1). C19H24N2O
(296.4): calcd C 76.99, H 8.16, N 9.45; found C 77.04, H
8.02, N 9.61.
CDCl3): dˆ0.96 (3H, t, Jˆ7.3 Hz), 1.43 (2H, tq, Jˆ7.3,
7.5 Hz), 1.66±1.89 (2H, m), 2.44 (1H, dd, Jˆ7.3, 7.4 Hz),
3.57 (2H, s), 4.02 (1H, dd, Jˆ1.7, 12.3 Hz), 4.05 (1H, br s),
4.16 (1H, dd, Jˆ2.1, 12.3 Hz), 4.43 (1H, br s), 5.91 (1H, dd,
Jˆ1.5, 3.3 Hz), 6.14 (1H, dd, Jˆ3.1, 3.3 Hz), 6.65 (1H, dd,
Jˆ1.5, 3.1 Hz), 7.19±7.37 (5H, overlapping). 13C NMR
(75 MHz, CDCl3): dˆ13.9 (q), 20.6 (t), 32.1 (t), 49.2 (d),
53.8 (t), 58.5 (t), 59.5 (d), 76.6 (d), 106.4 (d), 108.1 (d),
119.7 (d), 127.1 (d), 128.6 (d), 128.9 (d), 129.9 (s), 137.98
(s). MS: m/z 282 (M1). C18H22N2O (282.4): calcd C 76.56,
H 7.85, N 9.92; found C 76.65, H 7.66, N 9.86.
4.3. General procedure for the cycloaddition reaction of
nitrones 3a±d
A solution of 3 (4.8 mmol) in toluene (90 mL) was re¯uxed
for 24 h. After evaporation of the solvent, the residue was
chromatographed on a silica gel column.
Entry cÐElution with light petroleum/diethyl ether 3:1
gave 4c (83%).
Entry aÐElution with toluene/ethyl acetate 15:1 gave 5a
(15%) and 4a (80%).
4.3.5. ꢀ3aRp,8bRp)-1-Benzyl-3,3-dimethyl-1,3a,4,8b-tetra-
hydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ4c). Oil. H NMR
1
4.3.1. ꢀ3Rp,3aRp,8bRp)-1-Benzyl-3-phenyl-1,3a,4,8b-tetra-
hydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ4a). Oil. H NMR
1
(300 MHz, CDCl3): dˆ1.29 (3H, s), 1.41 (3H, s), 3.51 (1H,
dt, Jˆ3.9, 8.2 Hz), 3.93 (1H, dd, Jˆ8.2, 11.2 Hz), 4.09 (1H,
dd, Jˆ3.9, 11.2 Hz), 4.11, 4.17 (2H, AB, Jˆ13.2 Hz), 4.51
(1H, br s), 5.57 (1H, br s), 6.19 (1H, t, Jˆ3.0 Hz), 6.56 (1H,
br d, Jˆ3.0 Hz), 7.23±7.34 (3H, overlapping), 7.36±7.44
(2H, overlapping). 13C NMR (75 MHz, CDCl3): dˆ22.8
(q), 28.2 (q), 46.3 (t), 59.8 (d), 67.9 (d), 80.11 (t), 94.5
(s), 101.4 (d), 112.8 (d), 114.0 (d), 126.9 (d), 128.3 (d),
130.2 (d), 137.5 (s), 154.3 (s). MS: m/z 268 (M1).
C17H20N2O (268.4): calcd C 76.09, H 7.51, N 10.44;
found C 75.89, H 7.38, N 10.61.Entry dÐElution with
(300 MHz, CDCl3): dˆ3.78±3.86 (1H, m), 4.06±4.17 (3H,
overlapping), 4.32 (1H, d, Jˆ12.9 Hz), 4.50 (1H, br s), 4.94
(1H, d, Jˆ7.2 Hz), 5.35 (1H, br s), 6.18 (1H, br s), 6.55 (1H,
br s), 7.26±7.46 (10H, overlapping). 13C NMR (75 MHz,
CDCl3): dˆ49.5 (t), 59.9 (d), 61.2 (t) 69.6 (d), 86.0 (d),
102.1 (d), 104.1 (s), 114.1 (d), 115.0 (d), 127.3 (d), 128.2
(d), 128.7 (d), 128.9 (d), 129.2 (d), 130.4 (d), 137.2 (s),
139.3 (s). MS: m/z 316 (M1). C21H20N2O (316.4): calcd C
79.72, H 6.37, N 8.85; found C 79.75, H 6.24, N 8.98.
4.3.2. ꢀ1Rp,4Rp,10Rp)-2-Benzyl-10-phenyl-1,2,4,5-tetra-
hydro-1,4-methanopyrrolo[2,1-d][1,2,5]oxadiazepine ꢀ5a).
Mp 102±1048C (from diisopropyl ether). 1H NMR
(300 MHz, CDCl3): dˆ3.62, 3.66 (2H, AB, Jˆ14.0 Hz),
3.70 (1H, br s), 4.19, 4.27 (2H, AB, Jˆ12.3 Hz), 4.27
(1H, br s), 4.77 (1H, br s), 5.98 (1H, dd, Jˆ1.5, 3.3 Hz),
6.23 (1H, dd, Jˆ3.0, 3.3 Hz), 6.72 (1H, dd, Jˆ1.5, 3.0 Hz),
7.20±7.40 (8H, overlapping), 7.55±7.58 (2H, overlapping).
13C NMR (75 MHz, CDCl3): dˆ54.0 (t), 54.2 (d), 58.4 (t),
61.5 (d), 77.1 (d), 106.6 (d), 108.3 (d), 120.0 (d), 126.8 (d),
127.0 (d), 128.1 (d), 128.2 (d), 128.3 (d), 128.4 (d), 129.6
(s), 137.8 (s), 139.7 (s). MS: m/z 316 (M1). C21H20N2O
(316.4): calcd C 79.72, H 6.37, N 8.85; found C 79.61, H
6.44, N 9.02.
hexane/dichloromethane/diethyl ether 5:4:1gave
(25%) and 5d (44%).
4d
4.3.6. ꢀ3aRp,8bRp)-1-Benzyl-6-butyl-1,3a,4,8b-tetrahydro-
3H-isoxazolo[3,4-a]pyrrolizine ꢀ4d). Mp 65±678C (from
1
diisopropyl ether). H NMR (300 MHz, CDCl3): dˆ0.91
(3H, t, Jˆ7.3 Hz), 1.36 (2H, qt, Jˆ7.3, 7.5 Hz), 1.49±1.61
(2H, m), 2.47 (2H, t, Jˆ7.5 Hz), 3.82 (1H, dd, Jˆ3.3,
3.6 Hz), 3.84±3.96 (2H, overlapping), 4.01, 4.12 (2H, AB,
Jˆ13.4 Hz), 4.04 (1H, dd, Jˆ2.0, 7.9 Hz), 4.24 (1H, br s),
4.43 (1H, br s), 5.66 (1H, br s), 5.90 (1H, d, Jˆ3.0 Hz),
7.22±7.36 (3H, overlapping), 7.38±7.43 (2H, overlapping).
13C NMR (75 MHz, CDCl3): dˆ13.9 (q), 22.5 (t), 26.3 (t),
31.1 (t), 49.1 (t), 51.0 (d), 68.6 (d), 72.4 (t), 100.9 (d), 109.7
(d), 110.3 (s), 127.4 (d), 128.1 (d), 129.1 (d), 133.7 (s),
137.4 (s). MS: m/z 296 (M1). C19H24N2O (296.4): calcd C
76.99, H 8.16, N 9.45; found C 77.08, H 8.27, N 9.64.
Entry bÐElution with light petroleum/dichloromethane/
diethyl ether 10:4:1 gave 5b (10%) and 4b (58%).
4.3.7. ꢀ1Rp,4Sp)-2-Benzyl-7-butyl-1,2,4,5-tetrahydro-1,4-
methanopyrrolo[2,1-d][1,2,5]oxadiazepine ꢀ5d). Mp 61±
63 8C (from diisopropyl ether). Major conformer: 1H NMR
(300 MHz, CDCl3): dˆ0.97 (3H, t, Jˆ7.3 Hz), 1.43 (2H, qt,
Jˆ7.3, 7.5 Hz), 1.56 (2H, tt, Jˆ7.3, 7.5 Hz), 2.26 (1H, d,
Jˆ10.9 Hz), 2.52 (2H, dt, Jˆ7.3, 7.3 Hz), 2.80 (1H, ddd,
Jˆ4.6, 6.7, 10.9 Hz), 3.51, 3.62 (2H, AB, Jˆ13.4 Hz), 3.79
(1H, d, Jˆ12.2 Hz), 3.99 (1H, d, Jˆ12.2 Hz), 4.26 (1H, d,
Jˆ4.4 Hz), 4.77 (1H, br d, Jˆ4.5 Hz), 5.87±5.96 (2H,
overlapping), 7.20±7.42 (5H, overlapping). 13C NMR
(75 MHz, CDCl3): dˆ13.9 (q), 22.6 (t), 25.9 (t), 30.7 (t),
35.9 (t), 51.3 (t), 56.7 (d), 59.1 (t), 72.5 (d), 104.3 (d), 106.3
(d), 115.3 (s), 127.1 (d), 128.3 (d), 129.2 (d), 135.5 (s),
4.3.3. ꢀ3Rp,3aSp,8bSp)-1-Benzyl-3-propyl-1,3a,4,8b-tetra-
hydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ4b). Mp 79±818C
(from hexane/benzene). 1H NMR (300 MHz, CDCl3):
dˆ0.96 (3H, t, Jˆ7.2 Hz), 1.32±1.79 (4H, overlapping),
3.36±3.48 (1H, m), 3.92±4.09 (3H, overlapping), 4.03,
4.18 (2H, AB, Jˆ12.9 Hz), 4.29 (1H, br d, Jˆ7.2 Hz),
5.31 (1H, br s), 6.14 (1H, dd, Jˆ3.0, 3.1Hz), 6.51 (1H,
dd, Jˆ1.5, 3.1 Hz), 7.28±7.42 (5H, overlapping). 13C
NMR (75 MHz, CDCl3): dˆ14.6 (q), 19.8 (t), 35.9 (t),
49.6 (t), 57.8 (d), 68.6 (t), 69.3 (d), 84.0 (d), 101.7 (d),
113.7 (d), 114.6 (d), 127.8 (d), 128.7 (d), 130.0 (d), 133.9
(s), 137.31 (s). MS: m/z 282 (M1). C18H22N2O (282.4): calcd
C 76.56, H 7.85, N 9.92; found C 76.71, H 7.70, N 10.07.
1
137.7 (s). Minor conformer: H NMR (300 MHz, CDCl3):
4.3.4. ꢀ1Rp,4Sp,10Rp)-2-Benzyl-10-propyl-1,2,4,5-tetra-
hydro-1,4-methanopyrrolo[2,1-d][1,2,5]oxadiazepine ꢀ5b).
Mp 76±788C (from diisopropyl ether). 1H NMR (300 MHz,
dˆ0.97 (3H, t, Jˆ7.3 Hz), 1.43 (2H, qt, Jˆ7.3, 7.5 Hz),
1.56 (2H, tt, Jˆ7.3, 7.5 Hz), 2.16±2.23 (1H, m),
2.37±2.50 (2H, m), 2.62±2.73 (1H, m), 3.52±4.18 (5H,

8328
G. Broggini et al. / Tetrahedron 57 22001) 8323±8332
overlapping), 4.91±5.00 (1H, m), 5.76±5.85 (2H, over-
lapping), 7.20±7.42 (5H, overlapping). 13C NMR
(75 MHz, CDCl3): dˆ13.9 (q), 22.6 (t), 25.9 (t), 31.6 (t),
35.9 (t), 50.5 (t), 56.7 (d), 63.0 (t), 73.6 (d), 104.3 (d),
106.3 (d), 115.3 (s), 127.1 (d), 128.3 (d), 129.1 (d),
135.6 (s), 137.7 (s). MS: m/z 296 (M1). C19H24N2O
(296.4): calcd C 76.99, H 8.16, N 9.45; found C 76.83, H
8.09, N 9.43.
4.5. General procedure for the cycloaddition reaction of
nitrones 6a±c
A solution of 6a±c (1.9 mmol) in toluene (40 mL) was
re¯uxed for 24 h. After evaporation of the solvent, the
residue was chromatographed on a silica gel column.
Entry aÐElution with toluene gave 10a (4%), 9a (12%) and
a third fraction, which was chromatographed with light
petroleum/diethyl ether 3:1as eluent to give 8a (21%) and
7a (36%).
4.4. General procedure for the synthesis of nitrones 6a±c
A suspension of (R)-N-(a-methylbenzyl)hydroxylamine
(5.5 mmol), 2a±d (4.8 mmol) and MgSO4 (70 mmol) in
dry diethyl ether (100 mL) was stirred for the time given
below, ®ltered and evaporated. The crude oil so obtained
was treated with diisopropyl ether (entry c) or chromato-
graphed on a silica gel column (entries a, b and d) to give
6a±d.
4.5.1. ꢀaR,3S,3aS,8bS)-3-Phenyl-1-ꢀa-phenylethyl)-1,3a,
ꢀ7a).
4,8b-tetrahydro-3H-isoxazolo[3,4-a]pyrrolizine
1
Mp 98±998C (from hexane/benzene). H NMR (300 MHz,
CDCl3): dˆ1.63 (3H, d, Jˆ6.5 Hz), 3.60±3.74 (1H, m),
3.93±4.12 (3H, overlapping), 4.62±4.78 (2H, overlapping),
4.86 (1H, d, Jˆ7.9 Hz), 6.05 (1H, br s), 6.46 (1H, br s),
7.34±7.49 (10H, overlapping). 13C NMR (75 MHz,
CDCl3): dˆ22.4 (q), 48.1(t), 59.3 (d), 69.1(d), 84.7 (d),
85.4 (d), 102.5 (d), 113.2 (s), 114.2 (d), 114.8 (d), 127.4 (d),
128.7 (d), 128.9 (d), 129.3 (d), 129.4 (d), 129.7 (d), 138.8
4.4.1. Nitrone 6a. 48 h. Eluent: ethyl acetate. Yield: 49%.
Mp 100±1028C (from diisopropyl ether). 1H NMR
(300 MHz, CDCl3): d 1.86 (3H, d, Jˆ6.9 Hz), 4.65 (2H,
d, Jˆ4.0 Hz), 5.08 (1H, q, Jˆ6.9 Hz), 6.17 (1H, dt,
Jˆ4.0, 16.2 Hz), 6.21 (1H, d, Jˆ16.2 Hz), 6.30 (1H,dd,
Jˆ2.8, 3.8 Hz), 6.83 (1H, dd, Jˆ1.7, 2.8 Hz), 7.24±7.42
(11H, overlapping), 7.86 (1H, dd, Jˆ1.7, 3.8 Hz). 13C
NMR (75 MHz, CDCl3): dˆ19.4 (q), 49.8 (t), 74.0 (d),
109.7 (d), 117.0 (d), 123.6 (d), 124.8 (s), 125.2 (d), 126.0
(d), 126.9 (d), 127.8 (d), 128.5 (d), 128.9 (d), 129.1 (d),
129.2 (d), 132.5 (d), 136.3 (s), 139.1 (s). MS: m/z 330
(s), 142.8 (s). MS: m/z 330 (M1). [a]D ˆ146.0 (cˆ0.10,
22
CHCl3). C22H22N2O (330.4): calcd C 79.97, H 6.71, N 8.48;
found C 79.99, H 6.66, N 8.64.
4.5.2. ꢀaR,3R,3aR,8bR)-3-Phenyl-1-ꢀa-phenylethyl)-1,
3a,4,8b-tetrahydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ8a).
Mp 57±588C (from hexane/benzene). H NMR (300 MHz,
1
CDCl3): dˆ1.57 (3H, d, Jˆ6.8 Hz), 3.49±3.63 (1H, m),
3.99 (1H, dd, Jˆ8.0, 10.8 Hz), 4.08 (1H, dd, Jˆ3.8,
10.8 Hz), 4.14 (1H, q, Jˆ6.8 Hz), 4.43 (1H, d, Jˆ8.8 Hz),
4.79 (1H, d, Jˆ7.2 Hz), 5.81(1H, d, Jˆ3.5 Hz), 6.21(1H,
dd, Jˆ3.0, 3.5 Hz), 6.53 (1H, d, Jˆ3.0 Hz), 7.19±7.38 (8H,
overlapping), 7.42 (2H, d, Jˆ8.5 Hz). 13C NMR (75 MHz,
CDCl3): dˆ21.9 (q), 49.1 (t), 59.9 (d), 65.0 (d), 66.3 (d),
84.2 (s), 85.3 (d), 102.4 (d), 113.9 (d), 115.0 (d), 127.0 (d),
127.6 (d), 128.6 (d), 128.7 (d), 128.9 (d), 129.0 (d), 134.9
22
(M1). [a]D ˆ138.0 (cˆ0.10, CHCl3). C22H22N2O
(330.4): calcd C 79.97, H 6.71, N 8.48; found C 79.91, H
6.56, N 8.33.
4.4.2. Nitrone 6b. 120 h. Eluent: hexane/ethyl acetate 1:1.
Yield: 45%. Mp 93±958C (from diisopropyl ether). 1H
NMR (300 MHz, CDCl3): d 0.85 (3H, t, Jˆ7.2 Hz), 1.32
(2H, qt, Jˆ7.2, 7.4 Hz), 1.87 (3H, d, Jˆ6.9 Hz), 1.83±1.97
(2H, m), 4.39 (2H, d, Jˆ5.1Hz), 5.09 (1H, q, Jˆ6.9 Hz),
5.27±5.46 (2H, overlapping), 6.23 (1H, dd, Jˆ2.8, 3.7 Hz),
6.75 (1H, dd, Jˆ1.6, 2.8 Hz), 7.30±7.48 (5H, overlapping),
7.00±7.64 (1H, m), 7.80 (1H, dd, Jˆ1.6, 3.7 Hz). 13C NMR
(75 MHz, CDCl3): dˆ13.6 (q), 19.1 (q), 22.0 (t), 34.0 (t),
49.3 (t), 73.4 (d), 109.0 (d), 116.7 (d), 123.9 (d), 123.9 (s),
125.3 (d), 125.6 (d), 127.3 (d), 128.4 (d), 128.5 (d), 133.9
(s), 142.6 (s). MS: m/z 330 (M1). [a]D ˆ131.8 (cˆ0.10,
22
CHCl3). C22H22N2O (330.4): calcd C 79.97, H 6.71, N 8.48;
found C 79.89, H 6.89, N 8.30.
4.5.3. ꢀaR,1S,4S,10S)-10-Phenyl-2-ꢀa-phenylethyl)-1,2,4,
5-tetrahydro-1,4-methanopyrrolo[2,1-d][1,2,5]oxadiaze-
pine ꢀ9a). Mp 150±1528C (from hexane/benzene). 1H NMR
(300 MHz, CDCl3): dˆ1.22 (3H, d, Jˆ6.5 Hz), 3.31(1H, q,
Jˆ6.5 Hz), 3.69 (1H, s), 4.11 (1H, dd, Jˆ1.7, 12.3 Hz), 4.23
(1H, dd, Jˆ2.2, 12.3 Hz), 4.46 (1H, s), 4.69 (1H, br s), 6.13
(1H, br s), 6.26 (1H, t, Jˆ3.2 Hz), 6.72 (1H, br s), 7.13±7.43
(8H, overlapping), 7.57±7.60 (2H, overlapping). 13C NMR
(75 MHz, CDCl3): dˆ22.8 (q), 54.6 (t), 54.7 (d), 60.6 (d),
63.5 (d), 77.1 (d), 106.9 (d), 108.8 (d), 120.5 (d), 127.2 (d),
127.4 (d), 127.6 (d), 128.8 (d), 128.9 (d), 129.3 (d), 130.0
(d), 138.8 (d). MS: m/z 296 (M1). [a]D ˆ113.9 (cˆ0.14,
22
CHCl3). C19H24N2O (296.4): calcd C 76.99, H 8.16, N 9.45;
found C 77.12, H 8.01, N 9.64.
4.4.3. Nitrone 6c. 144 h. Yield: 36%. Mp 89±908C (from
diisopropyl ether). 1H NMR (300 MHz, CDCl3): d 1.62 (3H,
s), 1.66 (3H, s), 1.88 (3H, d, Jˆ6.9 Hz), 4.42 (2H, d,
Jˆ6.6 Hz), 5.09 (1H, q, Jˆ6.9 Hz), 5.15 (1H, br t,
Jˆ6.6 Hz), 6.21(1H, dd, Jˆ2.1, 3.9 Hz), 6.76 (1H, dd,
Jˆ1.6, 2.1 Hz), 7.30±7.40 (4H, overlapping), 7.44±7.48
22
(s), 140.5 (s), 145.5 (s). MS: m/z 330 (M1). [a]D ˆ180.0
(cˆ0.10, CHCl3). C22H22N2O (330.4): calcd C 79.97, H
6.71, N 8.48; found C 79.94, H 6.80, N 8.59.
(2H, overlapping), 7.81(H1, dd,
Jˆ1.6, 3.9 Hz). 13C
NMR (75 MHz, CDCl3): dˆ18.4 (q), 19.6 (q), 25.9 (q),
45.9 (t), 74.0 (d), 109.2 (d), 116.8 (d), 120.6 (d), 123.6
(d), 124.5 (s), 125.6 (d), 112.7 (d), 128.9 (d), 129.1 (d),
4.5.4. ꢀaR,1R,4R,10R)-10-Phenyl-2-ꢀa-phenylethyl)-1,2,
4,5-tetrahydro-1,4-methanopyrrolo[2,1-d][1,2,5]oxa-
diazepine ꢀ10a). Mp 52±538C (from diisopropyl ether). 1H
NMR (300 MHz, CDCl3): dˆ1.42 (3H, d, Jˆ6.3 Hz), 3.36
(1H, q, Jˆ6.3 Hz), 3.56 (1H, s), 4.06 (1H, s), 4.16 (1H, dd,
Jˆ1.8, 12.2 Hz), 4.30 (1H, dd, Jˆ2.2, 12.2 Hz), 4.77 (1H,
22
136.4 (s), 139.4 (s). MS: m/z 282 (M1). [a]D ˆ132.0
(cˆ0.10, CHCl3). C18H22N2O (282.4): calcd C 76.56, H
7.85, N 9.92; found C 76.75, H 7.68, N 10.08.

G. Broggini et al. / Tetrahedron 57 22001) 8323±8332
8329
dd, Jˆ1.8, 2.2 Hz), 5.60 (1H, dd, Jˆ1.6, 3.5 Hz), 6.16 (1H,
dd, Jˆ3.0, 3.5 Hz), 6.70 (1H, dd, Jˆ1.6, 3.0 Hz), 7.14±7.41
(8H, overlapping), 7.57±7.61(2H, overlapping). 13C NMR
(75 MHz, CDCl3): dˆ23.6 (q), 54.2 (d), 54.3 (t), 59.7 (d),
63.3 (d), 77.3 (d), 107.1 (d), 108.0 (d), 119.6 (d), 126.9 (d),
127.6 (d), 127.8 (d), 128.1 (d), 128.2 (d), 128.3 (d), 129.9
4.5.8. ꢀaR,1R,4S,10R)-2-ꢀa-Phenylethyl)-10-propyl-1,2,
4,5-tetrahydro-1,4-methanopyrrolo[2,1-d][1,2,5]oxa-
diazepine ꢀ10b). Oil. 1H NMR (300 MHz, CDCl3): dˆ0.95
(3H, t, Jˆ7.3 Hz), 1.37 (3H, d, Jˆ6.3 Hz), 1.28±1.46 (2H,
overlapping), 1.74±1.85 (2H, m), 2.31 (1H, t, Jˆ7.3 Hz),
3.26 (1H, t, Jˆ6.3 Hz), 3.84 (1H, s), 3.99 (1H, dd, Jˆ1.7,
12.2 Hz), 4.16 (1H, dd, Jˆ2.2, 12.2 Hz), 4.46 (1H, s), 5.53
(1H, dd, Jˆ1.4, 3.4 Hz), 6.11 (1H, dd, Jˆ3.4, 3.4 Hz), 6.62
(1H, dd, Jˆ1.4, 3.4 Hz), 7.24±7.33 (5H, overlapping). 13C
NMR (75 MHz, CDCl3): dˆ14.0 (q), 20.6 (t), 23.5 (q), 32.1
(t), 48.9 (d), 53.8 (t), 57.9 (d), 63.1(d), 76.7 (d), 106.9 (d),
107.8 (d), 119.3 (d), 127.0 (d), 127.4 (s), 127.9 (d), 128.1
(s), 140.0 (s), 143.5 (s). MS: m/z 330 (M1). [a]D ˆ1111.0
22
(cˆ0.16, CHCl3). C22H22N2O (330.4): calcd C 79.97, H
6.71, N 8.48; found C 80.11, H 6.65, N 8.37.
Entry bÐElution with light petroleum/diethyl ether 8:1
gave 8b (22%), 7b (36%) and a third fraction which was
re-chromatographed with light petroleum/dichloromethane/
diethyl ether 20:4:1as eluant to give 10b (2%) and 9b (3%).
(d), 136.9 (s). MS: m/z 296 (M1). [a]D ˆ215.0 (cˆ0.08,
22
CHCl3). C19H24N2O (296.4): calcd C 76.99, H 8.16, N 9.45;
found C 77.13, H 7.98, N 9.51.
4.5.5. ꢀaR,3R,3aS,8bS)-1-ꢀa-Phenylethyl)-3-propyl-1,3a,
4,8b-tetrahydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ7b). Mp
73±758C (from diisopropyl ether). 1H NMR (300 MHz,
CDCl3, 558C): dˆ0.98 (3H, t, Jˆ7.3 Hz), 1.47 (2H, qt,
Jˆ7.3, 7.5 Hz), 1.58 (3H, d, Jˆ6.4 Hz), 1.59±1.82 (2H,
m), 3.32 (1H, dddd, Jˆ3.2, 8.1, 8.3, 8.5 Hz), 3.84±3.99
(4H, overlapping), 4.45 (1H, d, Jˆ8.5 Hz), 4.78 (1H, br s),
6.04 (1H, dd, Jˆ3.0, 3.1Hz), 6.42 (1H, dd, Jˆ1.5, 3.0 Hz),
7.27±7.44 (5H, overlapping). 13C NMR (75 MHz, CDCl3):
dˆ14.2 (q), 19.6 (t), 21.6 (q), 35.7 (t), 48.1 (t), 56.7 (d), 66.0
(d), 69.5 (d), 83.0 (d), 101.6 (d), 113.2 (d), 113.8 (d), 127.8
(d), 128.5 (d), 128.8 (d), 128.9 (s), 192.0 (s). MS: m/z 296
Entry cÐElution with light petroleum/diethyl ether 7:1
gave 8c (8%) and 7c (56%).
4.5.9. ꢀaR,3aS,8bS)-3,3-Dimethyl-1-ꢀa-phenylethyl)-1,
3a,4,8b-tetrahydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ7c).
Mp 58±598C (from diisopropyl ether). 1H NMR
(300 MHz, CDCl3): dˆ1.16 (3H, s), 1.42 (3H, s), 1.53
(3H, d, Jˆ6.5 Hz), 3.41(1H, dt, Jˆ2.6, 7.7 Hz), 3.88 (1H,
dd, Jˆ7.7, 11.2 Hz), 3.99±4.08 (2H, overlapping), 4.70
(1H, br s), 5.28 (1H, br s), 6.13 (1H, br s), 6.50 (1H, br s),
7.23±7.35 (3H, overlapping), 7.40±7.44 (2H, overlapping).
13C NMR (75 MHz, CDCl3): dˆ22.7 (q), 22.9 (q), 29.2 (q),
46.9 (d), 59.7 (d), 65.9 (d), 66.2 (d), 80.9 (s), 102.2 (d),108.3
(s), 113.5 (d), 114.3 (d), 127.7 (d), 128.4 (d), 128.8 (d),
22
(M1). [a]D ˆ110.4 (cˆ0.07, CHCl3). C19H24N2O (296.4):
calcd C 76.99, H 8.16, N 9.45; found C 76.98, H 8.27, N 9.29.
22
138.0 (s). MS: m/z 282 (M1). [a]D ˆ142.4 (cˆ0.10,
4.5.6. ꢀaR,3S,3aR,8bR)-1-ꢀa-Phenylethyl)-3-propyl-1,3a,
4,8b-tetrahydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ8b). Mp
71±738C (from diisopropyl ether). H NMR (300 MHz,
CHCl3). C18H22N2O (282.4): calcd C 76.56, H 7.85, N
9.92; found C 76.64, H 7.99, N 10.02.
1
CDCl3): dˆ0.91(3H, t, Jˆ7.2 Hz), 1.25±1.52 (3H, over-
lapping), 1.54 (3H, d, Jˆ6.9 Hz), 1.62±1.70 (1H, m), 3.25
(1H, dddd, Jˆ3.9, 8.0, 8.2, 8.7 Hz), 3.85 (1H, q, Jˆ6.9 Hz),
3.93 (1H, dd, Jˆ3.9, 10.7 Hz), 4.02 (1H, dd, Jˆ8.2,
10.7 Hz), 4.04 (1H, ddd, Jˆ7.4, 7.9, 8.0 Hz), 4.32 (1H, br
d, Jˆ8.7 Hz), 5.83 (1H, d, Jˆ3.0 Hz), 6.24 (1H, dd, Jˆ3.0,
3.0 Hz), 6.54 (1H, br d, Jˆ3.0 Hz), 7.21±7.33 (3H, over-
lapping), 7.40±7.43 (2H, overlapping). 13C NMR (75 MHz,
CDCl3): dˆ14.1 (q), 19.3 (t), 21.6 (q), 35.3 (t), 48.9 (t), 57.1
(d), 64.7 (d), 65.9 (d), 83.0 (d), 102.0 (d), 113.3 (d), 114.3
(d), 127.1 (d), 127.9 (d), 128.1 (d), 135.1 (s), 142.8 (s). MS:
4.5.10. ꢀaR,3aR,8bR)-3,3-Dimethyl-1-ꢀa-phenylethyl)-1,
3a,4,8b-tetrahydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ8c).
Mp 55±568C (from diisopropyl ether). 1H NMR
(300 MHz, CDCl3): dˆ1.24 (3H, s), 1.35 (3H, s), 1.48
(3H, d, Jˆ6.6 Hz), 3.38 (1H, dt, Jˆ2.9, 8.2 Hz), 3.86 (1H,
dd, Jˆ8.2, 11.2 Hz), 4.00±4.11 (2H, overlapping), 4.49
(1H, d, Jˆ8.2 Hz), 5.85 (1H, d, Jˆ3.1Hz), 6.23 (1H, t,
Jˆ3.1Hz), 6.56 (1H, d, Jˆ3.1Hz), 7.20±7.33 (3H, over-
lapping), 7.43 ±7.46 (2H, overlapping). MS: m/z 282 (M1).
C18H22N2O (282.4): calcd C 76.56, H 7.85, N 9.92; found C
76.49, H 7.78, N 9.77.
22
m/z 296 (M1). [a]D ˆ148.0 (cˆ0.4, CHCl3). C19H24N2O
(296.4): calcd C 76.99, H 8.16, N 9.45; found C 77.07, H
8.01, N 9.53.
4.6. Cycloaddition reaction between 2d and ꢀR)-N-
ꢀa-phenylethyl)hydroxylamine via nitrone 6d
4.5.7. ꢀaR,1S,4R,10S)-2-ꢀa-Phenylethyl)-10-propyl-1,2,4,
5-tetrahydro-1,4-methanopyrrolo[2,1-d][1,2,5]oxadiaze-
pine ꢀ9b). Oil. 1H NMR (300 MHz, CDCl3): dˆ1.00 (3H, t,
Jˆ7.3 Hz), 1.28 (3H, d, Jˆ6.5 Hz), 1.44±1.50 (2H, m),
1.70±1.94 (2H, overlapping), 2.42 (1H, t, Jˆ7.2 Hz), 3.19
(1H, br q, Jˆ6.5 Hz), 3.95 (1H, dd, Jˆ2.4, 12.3 Hz), 4.09
(1H, dd, Jˆ1.8, 12.3 Hz), 4.30 (1H, s), 4.34 (1H, br s), 6.08
(1H, br s), 6.22 (1H, br t, Jˆ2.1 Hz), 6.65 (1H, br s), 7.17±
7.34 (5H, overlapping). 13C NMR (75 MHz, CDCl3):
dˆ14.0 (q), 20.6 (t), 22.2 (q), 32.2 (t), 49.0 (d), 53.8 (t),
57.9 (d), 62.8 (d), 76.1 (d), 106.0 (d), 107.9 (d), 119.7 (d),
126.6 (d), 126.9 (d), 128.2 (d), 130.0 (s), 145.0 (s). MS: m/z
A
suspension of (R)-N-(a-phenylethyl)hydroxylamine
(10.1 mmol), 2d (5.7 mmol) and MgSO4 (86.4 mmol) in
dry toluene (110 mL) was re¯uxed under stirring for 48 h.
After ®ltration and evaporation of the solvent, the residue
was chromatographed on a silica gel column with hexane/
ethyl acetate 3:1as eluent to give 8d (20%), 7d (15%), 9d
(17%) and 10d (6%).
4.6.1. ꢀaR,3aS,8bS)-1-ꢀa-Phenylethyl)-6-butyl-1,3a,4,8b-
tetrahydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ7d). Mp
116±1178C (from diisopropyl ether). H NMR (300 MHz,
CDCl3, 558C): dˆ0.84 (3H, t, Jˆ7.3 Hz), 1.29 (2H, qt,
Jˆ7.3, 7.5 Hz), 1.44 (3H, d, Jˆ6.4 Hz), 1.42±1.49 (2H,
m), 2.38 (2H, t, Jˆ7.3 Hz), 3.68±3.77 (3H, overlapping),
1
22
296 (M1). [a]D ˆ1108.0 (cˆ0.23, CHCl3). C19H24N2O
(296.4): calcd C 76.99, H 8.16, N 9.45; found C 76.83, H
8.36, N 9.28.

8330
G. Broggini et al. / Tetrahedron 57 22001) 8323±8332
3.84±3.94 (2H, overlapping), 4.14 (1H, dd, Jˆ7.5, 9.3 Hz),
4.51(1H, br d, Jˆ7.1Hz), 5.37 (1H, br d, Jˆ3.0 Hz), 5.78
(1H, d, Jˆ3.0 Hz), 7.16±7.29 (3H, overlapping), 7.33±7.37
(2H, overlapping). 13C NMR (75 MHz, CDCl3, 258C):
dˆ13.8 (q), 22.1 (q), 22.4 (t), 26.2 (t), 31.2 (t), 49.3 (t),
50.4 (d), 63.5 (d), 67.0 (d), 72.1 (t), 109.8 (d), 109.8 (d),
110.0 (s), 127.5 (d), 127.9 (d), 128.1 (s), 128.5 (d), 143.6 (s).
(d), 106.8 (d), 127.0 (d), 128.1 (d), 128.3 (d), 128.5 (s),
22
130.1 (s), 143.4 (s). MS: m/z 310 (M1). [a]D ˆ160.4
(cˆ0.27, CHCl3). C20H26N2O (310.4): calcd C 77.38, H
8.44, N 9.02; found C 77.38, H 8.27, N 9.15.
4.7. General procedure for the hydrogenation reaction of
cycloadducts
22
MS: m/z 310 (M1). [a]D ˆ26.9 (cˆ0.10, CHCl3).
C20H26N2O (310.4): calcd C 77.38, H 8.44, N 9.02; found
C 77.29, H 8.42, N 9.09.
A mixture of 10% Pd(OH)2/C (100 mg, 0.095 mmol) and
isoxazolidinic compound (0.31mmol) in a 0.06N solution
of HCl in MeOH (15 mL) was stirred under H2 for 24 h.
After ®ltration through celite, the solvent was removed
under reduced pressure and the residue was treated with a
solution of NaOH in methanol. The solvent was evaporated
under reduced pressure and the residue was taken up into
dichloromethane. The organic solution was separated and
evaporated, and the crude product was chromatographed on
silica gel column.
4.6.2. ꢀaR,3aR,8bR)-1-ꢀa-Phenylethyl)-6-butyl-1,3a,4,
8b-tetrahydro-3H-isoxazolo[3,4-a]pyrrolizine ꢀ8d). Oil.
1H NMR (300 MHz, CDCl3): dˆ0.91(3H, t, Jˆ7.2 Hz),
1.36 (2H, qt, Jˆ7.5, 7.6 Hz), 1.51 (3H, d, Jˆ6.6 Hz),
1.48±1.60 (2H, overlapping), 2.47 (2H, t, Jˆ7.5 Hz),
3.68±3.84 (3H, overlapping), 3.92±4.04 (2H, overlapping),
4.14 (1H, dd, Jˆ7.3, 8.1Hz), 4.48 (1H, br d, Jˆ7.5 Hz),
5.83 (1H, br s), 5.93 (1H, d, Jˆ3.4 Hz), 7.21±7.43 (5H,
overlapping). 13C NMR (75 MHz, CDCl3, 258C): dˆ12.4
(q), 13.9 (q), 22.5 (t), 26.3 (t), 31.2 (t), 48.6 (t), 51.2 (d),
62.0 (d), 66.7 (d), 72.2 (t), 101.7 (d), 109.9 (d), 127.1 (d),
128.3 (d), 129.2 (d), 136.6 (s), 143.1 (s), 155.9 (s). MS: m/z
Compound 4aÐElution with chloroform/methanol/32%
aqueous ammonia 7:1:1 gave 13a (34%) and 11a (10%).
310 (M1). [a]D ˆ154.0 (cˆ0.05, CHCl3). C20H26N2O
4.7.1.
ꢀaRp,1Rp,2Rp,7aRp)-1-Amino-2,3,5,6,7,7a-hexa-
22
(310.4): calcd C 77.38, H 8.44, N 9.02; found C 77.51, H
8.30, N 8.88.
hydro-a-phenyl-1H-2-pyrrolizinemethanol ꢀ11a). Oil.
1H NMR (300 MHz, CDCl3): dˆ1.24 (3H, br s, missing
after deuteriation), 1.68±1.75 (2H, overlapping), 1.85±
2.00 (2H, overlapping), 2.44±2.69 (3H, overlapping), 2.82
(1H, dd, Jˆ6.0, 8.4 Hz), 3.02 (1H, ddd, Jˆ4.6, 6.4,
10.4 Hz), 3.40 (1H, dd, Jˆ4.9, 5.0 Hz), 3.62 (1H, dt,
Jˆ5.0, 7.3 Hz), 4.78 (1H, d, Jˆ7.2 Hz), 7.21±7.37 (5H,
overlapping). 13C NMR (75 MHz, CDCl3): dˆ24.6 (t),
28.1(t), 53.2 (d), 53.8 (d), 54.7 (t), 55.6 (t), 69.9 (d), 73.7
(d), 126.8 (d), 127.9 (d), 128.6 (d), 144.3 (s). MS: m/z 232
(M1). IR: n 3435 cm21. C14H20N2O (232.3): calcd C 72.38,
H 8.68, N 12.06; found C 72.26, H 8.81, N 11.89.
4.6.3. ꢀaR,1S,4R)-2-ꢀa-Phenylethyl)-7-butyl-1,2,4,5-tetra-
hydro-1,4-methanopyrrolo[2,1-d][1,2,5]oxadiazepine
ꢀ9d). Compound present as a 3:2 mixture of two conformers.
Oil. Major conformer: 1H NMR (300 MHz, CDCl3):
dˆ0.94 (3H, br s), 1.31 (3H, br d, Jˆ5.7 Hz), 1.42±1.65
(4H, overlapping), 2.25 (1H, br d, Jˆ10.9 Hz), 2.43±2.61
(2H, m), 2.80 (1H, br s), 3.18 (1H, br d, Jˆ5.5 Hz), 3.73
(1H, br s), 3.90 (1H, br s), 4.50 (1H, br s), 4.66 (1H, br s),
5.91 (1H, br s), 6.05 (1H, br s), 7.20±7.35 (5H, over-
lapping). 13C NMR (75 MHz, CDCl3): dˆ4.1(q), 2.16
(q), 22.5 (t), 25.9 (t), 31.4 (t), 35.8 (t), 51.3 (t), 55.1 (d),
63.3 (d), 72.0 (d), 104.1 (d), 104.3 (d), 127.0 (d), 127.3 (d),
128.2 (d), 129.5 (s), 133.4 (s), 144.6 (s). Minor conformer:
1H NMR (300 MHz, CDCl3): dˆ0.94 (3H, br s), 1.41 (3H,
br d, Jˆ7.3 Hz), 1.42±1.65 (4H, overlapping), 2.08 (1H, br
d, Jˆ10.6 Hz), 2.43±2.61 (2H, m), 3.72±3.76 (2H, over-
lapping), 3.88±4.02 (2H, overlapping), 4.13 (1H, br s),
4.96 (1H, br s), 5.61 (1H, br s), 5.75 (1H, br s), 7.20±7.35
(5H, overlapping). 13C NMR (75 MHz, CDCl3): dˆ14.0 (q),
22.5 (q), 22.6 (t), 25.9 (t), 31.5 (t), 35.8 (t), 50.4 (t), 55.5 (d),
66.7 (d), 73.8 (d), 102.3 (d), 105.9 (d), 127.0 (d), 127.5 (d),
128.7 (d), 129.4 (s), 133.3 (s), 143.7 (s). MS: m/z 310 (M1).
4.7.2. ꢀ1Rp,2Rp,7aRp)-1-Amino-2-benzyl-2,3,5,6,7,7a-hexa-
hydro-1H-pyrrolizine ꢀ13a). Oil. 1H NMR (300 MHz,
CDCl3): dˆ1.70±2.00 (4H, overlapping), 2.28 (2H, br s,
missing after deuteriation), 2.40±2.51(2H, overlapping),
2.61±2.81 (3H, overlapping), 3.04±3.15 (3H, overlapping),
3.71(1H, dt, Jˆ5.0, 7.4 Hz), 7.13±7.32 (5H, overlapping).
13C NMR (75 MHz, CDCl3): dˆ24.0 (t), 27.4 (t), 32.8 (t),
47.7 (d), 52.1 (d), 54.3 (t), 55.4 (t), 69.7 (d), 126.5 (d), 128.3
(d), 128.7 (d), 154.0 (s). MS: m/z 216 (M1). IR: n
3420 cm21. C14H20N2 (216.3): calcd C 77.73, H 9.32, N
12.95; found C 77.74, H 9.19, N 13.07.
22
[a]D ˆ225.0 (cˆ0.12, CHCl3). C20H26N2O (310.4): calcd
Compound 4bÐEvaporation of the solvent gave 11b
(77%).
C 77.38, H 8.44, N 9.02; found C 77.26, H 8.59, N 8.84.
4.6.4. ꢀaR,1R,4S)-2-ꢀa-Phenylethyl)-7-butyl-1,2,4,5-tetra-
hydro-1,4-methanopyrrolo[2,1-d][1,2,5]oxadiazepine
4.7.3.
ꢀaRp,1Sp,2Rp,7aSp)-1-Amino-2,3,5,6,7,7a-hexa-
hydro-a-propyl-1H-2-pyrrolizinemethanol ꢀ11b). Oil.
1H NMR (300 MHz, CDCl3): dˆ0.82±0.96 (4H, over-
lapping), 1.23±1.58 (6H, overlapping, 3H after deuteria-
tion), 1.66±1.76 (2H, overlapping), 1.86±1.98 (2H,
overlapping), 2.29±2.54 (3H, overlapping), 3.01±3.10
(2H, overlapping), 3.40 (1H, dd, Jˆ5.1, 5.4 Hz), 3.60 (1H,
ddd, Jˆ5.4, 7.5, 7.8 Hz), 3.70 (1H, ddd, Jˆ3.3, 7.6, 7.9 Hz).
13C NMR (75 MHz, CDCl3): dˆ14.1 (q), 18.8 (t), 24.2 (t),
27.8 (t), 39.0 (t), 52.4 (d), 52.9 (d), 54.3 (t), 55.2 (t), 69.4 (d),
1
ꢀ10d). Oil. H NMR (300 MHz, CDCl3): dˆ0.96 (3H, t,
Jˆ7.2 Hz), 1.41 (3H, d, Jˆ6.4 Hz), 1.34±1.48 (2H, m),
1.50±1.67 (2H, m), 2.13 (1H, d, Jˆ11.0 Hz), 2.49 (2H, t,
Jˆ7.1 Hz), 2.74 (1H, br s), 3.34 (1H, br s), 3.75 (1H, d,
Jˆ11.0 Hz), 3.97 (1H, d, Jˆ11.0 Hz), 4.04 (1H, br s),
4.82 (1H, d, Jˆ6.3 Hz), 5.54 (1H, br s), 5.81 (1H, d,
Jˆ3.4 Hz), 7.26±7.33 (5H, overlapping). 13C NMR
(75 MHz, CDCl3): dˆ14.0 (q), 22.6 (t), 23.1 (q), 25.9 (t),
30.6 (t), 35.8 (t), 51.3 (t), 55.1 (d), 63.4 (d), 72.4 (d), 103.9
69.9 (d). MS: m/z 198 (M1). IR: n 2908, 2957, 3367 cm21
.

G. Broggini et al. / Tetrahedron 57 22001) 8323±8332
8331
C11H22N2O (198.3): calcd C 66.62, H 11.18, N 14.31; found
C 66.89, H 11.40, N 14.43.
(t), 64.3 (d), 64.9 (d), 65.1(d). MS: m/z 197 (M1). IR: n
3436 cm21. C12H23NO (197.3): calcd C 73.04, H 11.75, N
7.10; found C 73.08, H 11.64, N 7.00.
Compound 4cÐElution with chloroform/methanol/32%
aqueous ammonia 7:1:1 gave 11c (13%) and 13c (32%).
Compound 7aÐElution with chloroform/methanol/32%
aqueous ammonia 7:1:1 gave (2)-13a (60%) and (2)-11a
(22%).
4.7.4. ꢀ1Rp,2Rp,7aRp)-1-Amino-2,3,5,6,7,7a-hexahydro-
a,a-dimethyl-1H-2-pyrrolizinemethanol ꢀ11c). Oil. 1H
NMR (300 MHz, CDCl3): dˆ1.15 (3H, s), 1.36 (3H, s),
1.59±1.86 (2H, overlapping), 1.90±2.03 (2H, overlapping),
2.21(1H, ddd, Jˆ4.5, 6.7, 12.5 Hz), 2.32 (3H, br s, missing
after deuteriation), 2.45 (1H, dt, Jˆ7.1, 9.4 Hz), 2.70 (1H,
dd, Jˆ9.4, 12.5 Hz), 3.12 (1H, ddd, Jˆ3.8, 5.8, 9.4 Hz),
3.25 (1H, dd, Jˆ6.7, 9.4 Hz), 3.34 (1H, dd, Jˆ4.5,
4.5 Hz), 3.65 (1H, dt, Jˆ4.5, 7.5 Hz). 13C NMR (75 MHz,
CDCl3): dˆ28.7 (t), 29.9 (q), 30.1(t), 30.8 (q), 52.1(t), 54.3
(d), 55.2 (d), 56.0 (t), 69.7 (d), 70.8 (s). MS: m/z 184 (M1).
IR: n 3435 cm21. C10H20N2O (184.3): calcd C 65.18, H
10.94, N 15.20; found C 65.31, H 10.95, N 15.07.
4.7.8. ꢀaS,1S,2S,7aS)-1-Amino-2,3,5,6,7,7a-hexahydro-
ˆ
22
a-phenyl-1H-2-pyrrolizinemethanol ꢀ2)-ꢀ11a). [a]D
217.3 (cˆ0.11, CHCl3).
4.7.9. ꢀ1S,2S,7aS)-1-Amino-2-benzyl-2,3,5,6,7,7a-hexa-
22
hydro-1H-pyrrolizine ꢀ2)-ꢀ13a). [a]D ˆ25.2 (cˆ0.14,
CHCl3).
Compound 7cÐElution with chloroform/methanol/32%
aqueous ammonia 7:1:1 gave (1)-13c (66%).
4.7.10. ꢀ1S,2S,7aS)-1-Amino-2,3,5,6,7,7a-hexahydro-2-
22
4.7.5. ꢀ1Rp,2Rp,7aRp)-1-Amino-2,3,5,6,7,7a-hexahydro-2-
ꢀ1-methylethyl)-1H-pyrrolizine ꢀ13c). Oil. 1H NMR
(300 MHz, CDCl3): dˆ1.04±1.28 (7H, overlapping),
1.28±1.49 (1H, m), 1.59±1.70 (1H, m), 1.74±1.95 (3H,
overlapping), 2.08 (2H, br s, missing after deuteriation),
2.14±2.34 (2H, overlapping), 2.52 (1H, dt, Jˆ6.1,
10.5 Hz), 2.86 (1H, dt, Jˆ6.2, 10.4 Hz), 3.07 (1H, dd,
Jˆ6.3, 6.6 Hz), 3.48 (1H, dt, Jˆ6.3, 7.7, 14.5 Hz). 13C
NMR (75 MHz, CDCl3): dˆ29.1(q), 29.5 (q), 29.9 (d),
30.5 (t), 33.4 (t), 48.5 (d), 52.2 (d), 54.8 (t), 55.8 (t),
ꢀ1-methylethyl)-1H-pyrrolizine ꢀ1)-ꢀ13c). [a]D ˆ18.3
(cˆ0.42, CHCl3).
Compound 7dÐElution with dichloromethane/methanol/
32% aqueous ammonia 6:1:1 gave (2)-12 (35%).
4.7.11. ꢀ2R,5R,7aS)-5-Butyl-2,3,5,6,7,7a-hexahydro-1H-
22
2-pyrrolizinemethanol ꢀ2)-ꢀ12). [a]D ˆ22.5 (cˆ0.18,
CHCl3).
65.9(d). MS: m/z 168 (M1). IR: n 3384, 3335 cm21
.
Compound 8dÐElution with dichloromethane/methanol/
32% aqueous ammonia 6:1:1 gave (1)-12 (33%).
C10H20N2 (168.3): calcd C 71.37, H 11.98, N 16.65; found
C 71.31, H 12.10, N 16.61.
4.7.12. ꢀ2S,5S,7aR)-5-Butyl-2,3,5,6,7,7a-hexahydro-1H-
22
2-pyrrolizinemethanol ꢀ1)-ꢀ12). [a]D ˆ12.1( cˆ0.18,
Compound 4dÐElution with dichloromethane/methanol/
32% aqueous ammonia 6:1:1 gave 12 (26%).
CHCl3).
4.7.6. ꢀ2Rp,5Rp,7aSp)-5-Butyl-2,3,5,6,7,7a-hexahydro-1H-
2-pyrrolizinemethanol ꢀ12). Oil. 1H NMR (300 MHz,
CDCl3): dˆ0.88 (3H, t, Jˆ6.8 Hz), 1.15 (1H, ddd, Jˆ9.4,
9.4, 11.7 Hz), 1.21±1.37 (4H, overlapping), 1.38±1.94 (5H,
overlapping, 4H after deuteriation), 1.95±2.12 (3H, over-
lapping), 2.29 (1H, dd, Jˆ9.8, 9.9 Hz), 2.53±2.68 (2H,
overlapping), 3.29 (1H, dd, Jˆ6.7, 9.4 Hz), 3.58±3.63
(1H, m), 3.65 (2H, d, Jˆ6.3 Hz). 13C NMR (75 MHz,
CDCl3): dˆ14.0 (q), 22.9 (t), 29.6 (t), 31.9 (t), 34.7 (t),
36.0 (t), 36.1(t), 45.8 (d), 57.9 (t), 65.3 (t), 65.7 (d), 68.3
(d). MS: m/z 197 (M1). IR: n 3391cm 21. C12H23NO
(197.3): calcd C 73.04, H 11.75, N 7.10; found C 72.98,
H 11.91, N 7.01.
Compound 9dÐElution with dichloromethane/methanol/
light petroleum 7:2:1gave ( 1)-14 (43%).
4.7.13. ꢀ3S,6R,8aS)-3-Butyl-1,2,3,5,6,7,8,8a-octahydro-
22
indolizin-6-ol ꢀ1)-ꢀ14). [a]D ˆ148.9 (cˆ0.18, CHCl3).
Compound 10dÐElution with dichloromethane/methanol/
light petroleum 7:2:1gave ( 2)-14 (31%).
4.7.14. ꢀ3R,6S,8aR)-3-Butyl-1,2,3,5,6,7,8,8a-octahydro-
22
indolizin-6-ol ꢀ2)-ꢀ14). [a]D ˆ247.1( cˆ0.04, CHCl3).
4.8. X-Ray crystallographic study
Compound 5dÐElution with dichloromethane/methanol/
light petroleum 7:2:1gave 14 (39%).
Single-crystal X-ray diffraction measurement was
performed on a Bruker SMART-APEX diffractometer,
graphite monochromator, MoKa radiation
Ê
0.71073 A). The crystal data are as follows: C20H26N2O,
(lˆ
4.7.7. ꢀ3Rp,6Sp,8aRp)-3-Butyl-1,2,3,5,6,7,8,8a-octahydro-
indolizin-6-ol ꢀ14). Oil. 1H NMR (300 MHz, CDCl3):
dˆ0.88 (3H, t, Jˆ6.9 Hz), 1.14±1.47 (8H, overlapping),
1.48±1.74 (3H, overlapping), 1.75±1.89 (3H, overlapping),
1.98±2.03 (1H, m), 2.05 (1H, dd, Jˆ1.3, 11.2 Hz), 2.17±
2.23 (1H, m), 2.96 (1H, br s, missing after deuteriation),
3.16 (1H, ddd, Jˆ2.3, 2.5, 11.3 Hz), 3.88 (1H, br quintet,
Jˆ2.3 Hz). 13C NMR (75 MHz, CDCl3): dˆ14.0 (q), 23.0
(t), 26.1(t), 28.0 (t), 28.1(t), 29.7 (t), 31.9 (t), 32.8 (t), 56.9
Mrˆ310.43, orthorhombic, space group P212121, aˆ
Ê
Ê 3
5.2871(7), bˆ14.8271(12), cˆ22.724(2) A, Vˆ1781.4(3) A ,
Zˆ4, Dcˆ1.157 g cm23, m(MoKa)ˆ0.071mm 21; 17,714
collected data, Raveˆ0.0260; ®nal values for 2393[1317 with
Io . 2sꢀIo†] re¯ections, Rw(F2)ˆ0.1032(0.0980) and Rˆ
0.0765(0.0408). The absolute con®guration was assigned
on the knowledge of the stereochemistry at C12. All crystal-
lographic data (excluding structure factors) were deposited

8332
G. Broggini et al. / Tetrahedron 57 22001) 8323±8332
7. (a) Ihara, M.; Takahashi, M.; Fukumoto, K.; Kametani, T.
J. Chem. Soc., Chem. Commun. 1988, 9. (b) Kang, S. H.;
Lee, H. S. Tetrahedron Lett. 1995, 36, 6713±6716.
to the Cambridge Crystallographic Data Center as
supplementary publication no CCDC-157419. Copies of
the data can be obtained free of charge on application to
CCDC, 2 Union Road, Cambridge CB2 1EZ, UK, e-mail:
deposit@ccdc.cam.ac.uk.
8. (a) Uddin, Md. J.; Kikuchi, M.; Takedatsu, K.; Arai, K.-I.;
Fujimoto, T.; Motoyoshiya, J.; Kakehi, A.; Iriye, R.; Shirai,
H.; Yamamoto, I. Synthesis 2000, 365±374. (b) Cordero,
F. M.; Gensini, M.; Goti, A.; Brandi, A. Org. Lett. 2000, 2,
2475±2477. (c) Ishikawa, T.; Kudo, T.; Shigemori, K.; Saito,
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Singh, G.; Batsanov, A. Tetrahedron: Asymmetry 2000, 11,
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Acknowledgements
We are grateful to MURST and CNR for ®nancial support.
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